SearchSurgery

Small bowel perforation after blunt injury abdomen and causes of delay in diagnosis

2009-08-28T15:10:00.005+05:30

INTRODUCTION

The diseases of the small bowel are very rare in occurrence. In contrast, there are various kinds of contributory causes to perforation of the small bowel. These are classified as follows, traumatic, foreign body, ulcerative, tumorous, ileus, vessel originated-disease and idiopathic. Needless to say, the death of perforation is closely associated with the time interval from onset to operation.
The small intestine occupies a relatively large surface area within the peritoneal cavity and thus is frequently injured in patients with penetrating abdominal trauma. Because the small bowel is relatively mobile, has a lower bacterial flora, and has fewer anaerobes than the colon, peritoneal contamination secondary to small bowel injuries is better tolerated than that associated with colon injuries.
The Penetrating Abdominal Trauma Index (PATI), which quantitates the severity of abdominal injury based on risk factors associated with specific organs, employs a multiplier of 3 for small bowel injuries (compared with 4 for colon and liver, and 5 for pancreas and duodenum).

The management of penetrating small bowel injuries for these reasons is generally straightforward, with simple repair being the rule.

INCIDENCE

Estimates of the incidence of small bowel rupture associated with blunt abdominal injury range from 3 to 18%.
The death related to perforation of the small bowel 17.1% which is between those of the colon (27.3%) and the stomach and duodenum (1 1.1%), respectively.

DELAY IN DIAGNOSIS

It is generally accepted that delay in diagnosis in common because definite clinical signs is prone to being concealed. It is due to a low incidence of the appearance of free gas in the peritoneal cavity on abdominal X-ray film. To salvage the patients in early stage, surgeons should be alert to a latent interval in this stage.
The diagnosis of SBI is now more frequently made on the basis of clinical signs or an abnormal CT scan, than as an associated injury during a trauma laparotomy. As a result, delays in the diagnosis of SBI may occur and contribute significantly to morbidity and mortality.
Small-bowel perforations are often minute and may seal temporarily before free air is noted." Associated spasm of the circular muscle above and below the level of the perforation, results in a localised ileus which further prevents leakage. After 5 or 6 hours the spasm passes off and contamination of the peritoneal cavity occurs as the isolated segment takes part in the peristaltic activity again.
' Klinger" described 50 patients of all ages, in only 10 of whom he noted free air; in one of them the perforation only became evident on delayed films. Delay in diagnosis may occur as a result of late rupture of an intramural haematoma'" or after serosal and tunica muscularis tears, or after interference with the blood supply, as occurs in avulsion injuries." Delayed diagnosis may also be the result of lack of careful examination in patients with multiple injuries."
In the digestive organ with the lumen, it is necessary that traumatic perforation should be quickly detected and treated. It is without saying that a presence of free gas is a confirmable finding.
In contrast, abdominal free gas is unlikely to appear and often fails to detect in the early stage.

Pathogenesis of perforation of the gut is much different from each other. It is well known that perforation of lower part of the gut more frequently provokes endotoxic shock.

Summary of Amount and Location of Free Air according to Perforation Sites
Perforation ------------Site --------------Amount Location
Stomach/duodenum -----Abundant --------Around liver and stomach
Post-bulbar duodenum ---------------------Right anterior pararenal space
Small bowel -------------Small -------------Mesenteric folds, around liver
Appendix ---------------Small/absent -----Around appendix
Large bowel ------------Variable ----------Pelvis, mesenteric folds, retroperitoneal space

Motor vehicle accidents are the main cause of blunt SBI. The increase in seat belt use has resulted in lower fatality rates and injury severity, but has been accompanied by a concomitant increase in rates of intestinal injuries.
Blunt trauma commonly occurs as a result of motor vehicle crashes, falls from heights, and interpersonal assaults with blunt objects.

Intestinal injuries can occur secondary to blunt trauma by two major mechanisms:

1. Horizontal deceleration or shearing can occur in patients involved in collisions. The regions that are affected most commonly are near junctions between fixed and nonfixed points of bowel (i.e., proximal jejunum, terminal ileum).

2. Direct blow with a linear object (seat belt) across loop of bowel, with a subsequent "blowout" injury, can occur at any point of the intestine or the mesentery.

Serial clinical evaluations of the abdomen are extremely useful in the diagnosis of SBI, particularly in patients with additional associated intra-abdominal injuries.
A bruise across the abdomen inflicted by a seat belt ("seat belt sign") and ongoing abdominal pain are known associated risk factors of SBI.
Fakhry et al. observed that 67.7% of 198 patients with blunt SBI initially presented with signs or symptoms highly suggestive of this lesion, and 84.3% were taken to the operating room without delay. In this study, of the patients involved in motor vehicle crashes, only 30% had the abdominal seat belt sign, which is less than that commonly reported in the literature (nearly 50%). Consistent with prior reports, the most frequent clinical signs were abdominal pain upon admission (75.6%) and abdominal tenderness upon physical examination (46.7%).
Diagnosis of these injuries remains problematic. Early recognition of SBI is important in the prevention of morbidity. DPL is more sensitive than CT imaging for diagnosis of SBI; however, in many cases, it results in nontherapeutic laparotomy. CT imaging is newer than DPL, and it has become popular in recent years. The major advantages of CT include noninvasiveness, capacity to quantify free fluid, the ability to select patients with solid organ injury for non-operative management, and the ability to view retroperitoneal organs.
Saku et al. analyzed the CT findings of 12 patients with SBI perforation due to blunt trauma, all patients underwent radiography and CT, and five underwent presurgical follow-up CT. Radiography demonstrated free air in only 8% (1/12) and 25% (3/12) at the initial and follow-up examinations, respectively. In contrast, the initial and followup CT scans detected extraluminal air in 58% (7/12) and 92% (11/12), respectively, suggesting that the incidence of extraluminal air increases as time elapses, prompting the authors to recommend a repeat CT, particularly after 8 h, in suspect cases to increase sensibility. Mesenteric fat obliteration was seen in 58% (7/12) and 75% (9/12) at initial and follow-up CT, respectively.

Liver haemangioma

2009-04-14T14:22:00.004+05:30

INTRODUCTION
Haemangioma is the most common benign tumour of the liver (prevalence has ranged from 0.4 to 20 percent).

At necropsy, the prevalence of liver haemangioma is 2–5%.
Hepatic hemangiomas are also referred as cavernous hemangiomas because of the cavernous vascular space seen histologically.
Hemangiomas are vary in size from a few millimeters to more than 20 cm.
most of them are of less than 5 cm.
Larger ones ( >5 cm) are referred to as giant hemangiomas.
The size of liver haemangioma is greater in women than in men as well as the occurrence.
In most of the cases they are solitary and many on the surface of roght lobe, but in 40 % of patients, hemangiomas may occur in multiples in bilateral lobes.
Diagnosis is mostly made in the age range between 30 to 50 years.
A symptomatic patient is mostly a young woman.

ETIOLOGY

In incompletely understood etiology, they are considered to be vascular malformation or hamartomas of congenital origin that enlarge by ectasia rather than by hyperplasia or hypertrophy.
Hormonal influence over tumor growth is suggested by enlargement during pregnancy and estrogen and progesterone therapy and regression after withdrawal of therapy.

PATHOLOGY

On macroscopic examination, haemangioma may be located at the surface of the liver or inside the liver, can be found in both lobes of the liver but more oftenly in the right lobe.
Lesions are well circumscribed and often surrounded by a thin capsule.
The larger lesion may be pedunculated and on gross examination appear as cystic lesions with a dark color.
On section it appears round or wedge shaped, dark red in colour and has a honeycomb pattern with spongy consistency and a fibrous capsule which may be calcified.
Large hemangiomas may develop a collagenous scar or fibrous nodule as thrombosis occurs.
On microscopic examination, liver haemangioma are composed of large vascular channels lined by mature, flattened endothelial cells, enclosed in a loose fibroblastic stroma with various amounts of connective tissue.
Occasionally, there is a marked fibrous component.

In a few cases, they are associated with

focal nodular hyperplasia of the liver,
extrahepatic haemangioma or
Rendu–Osler– Weber disease and
bile duct hamartomas.

PRESENTATION

In most cases, liver haemangioma is asymptomatic and is recognized fortuitously by ultrasonography performed for symptoms that are either non specific or unrelated to haemangioma. Hemangiomas are typically discovered incidentally at laparotomy, autopsy, or during an imaging test performed for unrelated conditions.

In a few patients, liver haemangioma is recognized because of abdominal pain which is often due to associated irritable colon.
In one report, for example, abdominal pain was due to other causes in 54 percent of patients .
The most common symptoms are abdominal pain and right upper quadrant discomfort or fullness.
Lesions >4 cm are more likely to cause symptoms .
Acute abdominal pain can result from thrombosis or bleeding within the tumor and associated stretching and inflammation of Glisson's capsule.
Discomfort from an acute thrombosis can last up to three weeks and be associated with fever and abnormal liver function tests.
Giant hemangiomas in children have been associated with high output cardiac failure and hypothyroidism. Hypothyroidism is due to the presence of high levels of 3 iodothyronine deiodinase activity in the hemangioma tissue, which catalyzes the conversion of thyroxine and triiodothyronine to biologically inactive hormones, reverse triiodothyronine, and 3,3'-diiodothyronine.
High output cardiac failure is reported in numerous case reports.
Cutaneous hemangiomas in children may be a marker for hepatic hemangiomas.
The presence of a single large cutaneous hemagioma was generally associated with a single hepatic hemangioma while multiple or milliary cutaneous hemangiomas were associated with the presence of multiple hepatic hemangiomas.
Large haemangiomas can be complicated by thrombocytopenia, consumptive coagulopathy, and microangiopathic anaemia (Kasabach–Merritt syndrome).

Clinical examination is normal in most cases, except in the few patients in whom a large haemangioma results in a palpable tumour. A bruit is seldom heard over the hemangioma.

Liver tests are normal, except in patients in whom haemangioma is associated with an unrelated diffuse liver disease.

DIAGNOSIS

Radiology. A plain X-ray may show a calcified capsule.

Ultrasonography

liver haemangioma appears as a well-defined hyperechoic area.
If the liver is fatty, haemangioma may be as echoic as, or even less echoic, than the rest of the liver parenchyma.
The hemangioma may be hypoechoic in patients with fatty infiltration of the liver due to the bright signal from the surrounding parenchyma.
Blood flow within the hemangioma can be demonstrated by color Doppler in only 10 to 50 percent of hemangiomas, and thus color Doppler does not improve the accuracy of ultrasound.
Sonographic findings also depend upon the size of the hemangioma.

One study characterized 158 hemangiomas as follows:

Lesions <2>
Lesions between 2 and 5 cm were mainly echogenic.
Lesions >5 cm had mixed echogenicity probably because of intratumoral thrombosis and fibrosis.

On a computed tomography (CT) scan without contrast, liver haemangioma appears as a hypodense area.
Calcifications are seen in approximately 10 percent of cases.
On a CT scan after intravenous injection of a contrast bolus, there is an irregular, globular enhancement in the periphery of the lesion; this anomaly is very characteristic; after several minutes, the area of enhancement increases towards the center of the lesion.
Peripheral nodular or globular enhancement representing venous lakes is seen in up to 94 percent of hemangiomas >4 cm in size.
A pattern of globular enhancement isodense to the aorta is seen in 67 percent of hemangiomas, a feature that helps distinguish them from hepatic metastases.
The lesions classically opacify after a delay of three or more minutes and remain isodense or hyperdense on delayed scans.
Possible exceptions are hemangiomas >4 cm, in which the center of the lesion may not opacify completely.
Variations in vascular enhancement among hemangiomas may be due to differences in the size of the vascular spaces, the presence of cystic spaces, and the amount of scar tissue within hemangiomas.
Absence of enhancement is seen in hemangiomas with large cystic areas or scar tissue.

MRI

The most sensitive and specific procedure for diagnosing hepatic haemangioma is magnetic resonance imaging (MRI):

The typical MRI appearance is a smooth, well-demarcated homogeneous mass that has low signal intensity on T1-weighted images and is hyperintense on T2-weighted.
The presence of intratumoral fibrosis results in areas of low intensity on T2-weighted images.
In a few patients, haemangioma appears as an hypervascular area and/or is associated with an arterioportal shunt.
Administration of gadolinium results in early peripheral discontinuous nodular or globular enhancement on arterial phase imaging with progressive centripetal enhancement or "filling-in" on delayed scans similar to that seen on CT scanning.
This enhancement pattern is typical of most hemangiomas >2 cm;
tumors <2>
Small hemangiomas that demonstrate rapid uniform enhancement are sometimes indistinguishable from hypervascular metastases of hepatocellular carcinoma.

Arteriography is no longer used for the diagnosis of haemangioma.

Large arterial branches are displaced.
The hepatic arteries divide to form small vessels before filling the vascular space. Prolonged, up to 18 s, opacification of the lesion may be shown.

SPECT
Scanning with 99Tcm-labelled human red cells is no longer used for the diagnosis of haemangioma (labelled red cells accumulate within the haemangioma).

The diagnosis of haemangioma is reinforced by the absence of changes of the lesion on a second series of imaging procedures (ultrasound or CT scan) six months later.
Single-photon emission CT (SPECT) using 99mTc-RBC increases the spatial resolution of planar scintigraphy, providing sensitivity and accuracy close to that of MRI for lesions >1 cm.
SPECT with 99mTc-labelled red blood cells shows persistent blood pool activity within the lesion.
The best use of 99mTc-RBC SPECT is for lesions >2 cm to confirm a suspected hemangioma seen as a hyperechoic lesion in ultrasound and to clarify the diagnosis when CT findings are unclear.

Imaging in patients with cirrhosis — The diagnosis of a hepatic hemangioma can frequently be made confidently with ultrasound in patients without a prior history of malignancy or chronic liver disease.

In contrast, the hyperechoic metastases and hepatocellular carcinoma (HCC) may have similar sonographic characteristics and are more likely in such patients. As a result, multiple imaging modalities and serum AFP determination may be required to differentiate a benign hemangioma from a malignant lesion in these settings.

This was illustrated in a study that included 1982 patients with cirrhosis of whom 166 (8 percent) had a focal lesion. Of these 166 patients:
Ultrasound showed the presence of a hemangioma-like lesion in 44 patients with a normal AFP.
Contrast-enhanced CT confirmed hemangioma in 12 of the 44 patients.
99mTc-RBC confirmed hemangioma in 10 of the remaining 32 patients.
Fine needle aspiration biopsy (FNAB) confirmed the presence of HCC in the remaining 22 patients.
During follow-up a further 26 hemangioma-like lesions were identified on US, 22 of which were confirmed as HCC and four as dysplastic nodules.

BIOPSY -

It is generally admitted that liver biopsy may be dangerous because of the risk of haemoperitoneum.
However, liver biopsy has been performed in some patients without being complicated by intraperitoneal bleeding.
Because liver haemangioma is soft, the tumour is pushed by the liver biopsy needle and therefore, often no fragment of the tumour is collected.

NATURAL HISTORY

Unchanged - Usually, liver haemangioma does not increase in size with time.
Growth- However, it has been reported that, during pregnancy or during estrogen therapy, the tumour may grow. In a small number of patients, in the absence of pregnancy and oestrogen therapy, the tumour may increase in size.
Spontaneous rupture of liver haemangioma is very rare. It usually occurs in large hemangiomas that are peripherally located, however, follow-up of giant hemangiomas (tumors >5 cm in size) has shown that even these rarely enlarge or rupture.
Traumatic rupture of cavernous hemangioma following blunt trauma to the abdomen is also rare but highlights that traumatic rupture of the liver may be associated with underlying liver pathology.
Iatrogenic rupture or intratumoral bleeding has been described following liver biopsy or fine needle aspiration, which has resulted in a reluctance of most physicians to perform such tests in patients with known or suspected hemangiomas.
Other complication –

Thrombosis, which results in a triad of symptoms consisting of fever, right upper quadrant abdominal pain, and normal white cell count.
thrombocytopenia,
consumptive coagulopathy, and
microangiopathic anaemia (Kasabach–Merritt syndrome).
In the few cases with arterioportal shunt, heart failure can develop. Large haemangiomas can result in abdominal discomfort.

TREATMENT

In most patients, liver haemangioma needs no treatment.
Asymptomatic patients, particularly those with lesions <1.5>
A close radiologic follow-up is required in patients with lesions >5 cm, particularly those in a sub capsular location.
Complicated liver haemangioma must be treated surgically by liver resection, enucleation, hepatic artery ligation, and liver transplantation.
Patients who have pain or symptoms suggestive of extrinsic compression of adjacent structures should be considered for surgical resection.
Orthotopic liver transplantation has also been used successfully to treat symptomatic patients with unresectable giant hemangiomas and hemangiomas associated with Kasabach-Merritt syndrome.
Spontaneous rupture of liver haemangioma can be treated by transcatheter hepatic arterial embolization, which can be followed by surgical resection.

Non-surgical techniques include

hepatic artery embolization,
radiotherapy, and
interferon alpha-2a.

Interferon alpha-2a has been used in infants with life-threatening hemangiomas in extrahepatic sites, although success has not been uniform. Its efficacy for hepatic hemangiomas has not been well studied. Interferon probably works as an antiproliferative/antiangiogenic agent.

Neither oral contraceptives nor pregnancy are contraindicated in women with uncomplicated liver haemangioma.

Hepatic haemangiomatosis
Hepatic haemangiomatosis, i.e. haemangioma involving the liver entirely and diffusely, is very rare. It can be isolated or associated with extrahepatic haemangioma or with Rendu– Osler–Weber disease. A case has been reported in a patient receiving metoclopramide. Heart failure , intraperitoneal bleeding and Kasabach–Merritt syndrome are common.

SUBACUTE THYROIDITIS

2009-02-14T22:49:00.002+05:30

SUBACUTE THYROIDITIS
Synonyms: granulomatous thyroiditis, pseudotuberculous thyroiditis, giant cell thyroiditis
Subacute de Quervain’s thyroiditis is a self-limiting disease accounting for 0.5–3% of all thyroid pathologies and lasts a few weeks to 2 months. Women are 3–6 times more affected than men. The peak incidence is between the second and fifth decade of life.
ETIOLOGY

The etiology of subacute de Quervain’s thyroiditis remains uncertain, but evidence implicates viral infection.
Subacute thyroiditis is an inflammatory disorder of the thyroid gland.
Previously, this condition was termed granulomatous thyroiditis, De Quervain thyroiditis, struma granulomatosa, and pseudotuberculous thyroiditis.
The pathologic hallmarks are granulomas and pseudo giant cells.

Evidence that suggests a viral infection includes the following:

A postviral cytokine-mediated inflammation of
the thyroid is suspected because a seasonal frequency
and an association with upper respiratory tract infection
is noted.
There is no associated polymorphonuclear leukocytosis.
In half of the patients antibodies against mumps, measles, influenza, adenovirus, coxsackievirus, or echovirus are found.
The mumps virus has been cultured from thyroid tissue of patients with subacute thyroiditis.
The process is self-limited.
Furthermore, a genetic predisposition exists with the haplotype HLA-Bw35. Hashimoto disease, have a higher frequency of a certain human leukocyte antigen (HLA) haplotype (HLA-B35)7; it is possible that this HLA association may reflect a genetic susceptibility to subacute thyroiditis after various viral infections

All current evidence suggests that subacute thyroiditis is not an autoimmune disease.

Although low levels of antithyroid antibodies may appear transiently during the course of the disorder, the levels are not of the same magnitude seen in patients with other autoimmune thyroid disorders. Subjects with subacute thyroiditis, but not those with.

CLINICAL FEATURES

These patients characteristically present with a painful, tender goiter that is firm, with pain radiating to the ears, mandible, or occiput.
In some patients, however, these features may be minimal or even absent.
Cervical lymphadenopathy usually is not present, but many patients have prodromal symptoms of an upper respiratory tract infection, fever, myalgia, or arthralgia.
Additionally, patients with subacute thyroiditis often experience a series of changes in thyroid function related to the inflammatory effects in the gland.

Early in the course, symptomatic thyrotoxicosis may arise from the leakage of thyroid hormones from damaged follicular cells.

Subsequently, patients may develop transient hypothyroidism after passing through a euthyroid phase.

The hypothyroidism results from a depletion of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland after the destructive, inflammatory process.

However, patients usually experience a spontaneous recovery of normal thyroid function.

Not all patients with subacute thyroiditis experience all phases of these alterations in thyroid function.

The duration of the illness often is 6 weeks but may be 3 to 6 months.
The inflammatory process may migrate from one area of the thyroid to another and often crosses between the two lobes (“creeping thyroiditis”).

The differential diagnosis encompasses acute suppurative thyroiditis. In contrast to acute suppurative thyroiditis, the gland sonographically reveals irregular hypoperfused areas instead of hyperperfused tissue. On fine-needle biopsy, the differential diagnosis further includes palpation thyroiditis, as well as other granulomatous diseases such as sarcoidosis, tuberculosis,
and rheumatoid diseases.

LABORATORY EVALUATION
Laboratory evaluation usually reveals the following:

elevated erythrocyte sedimentation rate (often >55 mm per hour);
normal or near-normal leukocyte count;
transient elevations of antithyroid antibodies in low titers;
and serum T4 and T3 values that may be high, normal, or low, depending on the phase of the disease.
In the thyrotoxic phase, the serum thyroid-stimulating hormone (TSH) value is suppressed but may be detectable in third-generation assays in nearly 80% of those evaluated.

TSH is normal during the euthyroid phase and elevated during the hypothyroid phase. A thyroid scan during an episode of subacute thyroiditis shows a cold region in the involved section of the thyroid.

Additionally, during the thyrotoxic and euthyroid phases, the radioactive iodine (RAI) uptake is often <1%.>

This finding is of diagnostic importance in the evaluation of patients with suspected thyrotoxicosis, as a low uptake reflects the underlying etiology of destructive thyroiditis—not increased thyroid hormone production and secretion, as in Graves disease or toxic nodular goiter (in which the uptake is normal or high).
Further, the serum thyroglobulin is frequently markedly elevated, a finding that is of value in the differential diagnosis of thyrotoxicosis that is due to surreptitious ingestion of thyroid hormone (thyrotoxicosis factitia).
In the latter disorder, the RAI uptake and the serum thyroglobulin are low.

Although the diagnosis of subacute thyroiditis usually is apparent in patients with typical clinical features, occasionally there is difficulty in establishing the diagnosis—such as with sudden enlargement of the thyroid gland—raising the possibility of anaplastic carcinoma.

In this situation, a thyroid biopsy may be helpful.

The usual microscopic features include degeneration of the follicular epithelium; infiltration of the tissue with leukocytes, lymphocytes, and histiocytes; and formation of granulomas composed of giant cells surrounding colloid. In approximately one-half of patients, microabscesses may be found. In most patients with subacute thyroiditis, the diagnosis can be made clinically.

TREATMENT
The management of patients with subacute thyroiditis is based on relief of symptoms, because no specific therapy is available.

Two aspects of this therapy must be addressed in each patient:

the local symptoms
and the effects of thyroid dysfunction.

Frequently, pain and tenderness in the neck respond to treatment with salicylates, 0.65 g every 4 hours. If no benefit ensues within 48 hours, nonsteroidal antiinflammatory agents may be administered, although it is unclear whether these agents are superior to the salicylates.

Approximately 5% of patients require cortico-steroids for the relief of symptoms.
Prednisone in doses of 30 to 40 mg per day usually results in prompt improvement; however, it may be difficult to reduce the dose without return of pain, so that treatment for 4 to 8 weeks may be necessary before a successful tapering is accomplished.
If the patient does not respond to prednisone within 24 to 48 hours, the diagnosis of subacute thyroiditis should be reevaluated.
Thyroidectomy occasionally is used in patients with severe or recurrent pain that is unresponsive to other therapy, but this approach is required infrequently.
If thyrotoxic symptoms are foremost, the patient should be managed with b-blockade (e.g., propranolol).
The thyrotoxic phase in these patients is transient, and definitive therapy with RAI is neither indicated nor of value because the thyroid uptake is low.
Likewise, the antithyroid drugs propyl-thiouracil or methimazole (Tapazole) should not be given because these medications are also ineffective.
These drugs impair thyroid hormone synthesis, but the excess serum thyroid hormone levels in subacute thyroiditis result from leakage of T3 and T4 from the damaged follicles and not from enhanced synthesis and secretion.
The hypothyroid phase of subacute thyroiditis is usually transient and is often asymptomatic; therefore, thyroid hormone replacement frequently is not necessary.
Additionally, the increased TSH secretion at this time may be important in the recovery of thyroid gland function; consequently, there may be a relative contraindication to thyroid hormone treatment unless the patient is clearly symptomatic.
The long-term prognosis for patients with subacute thyroiditis is excellent.
Recurrent episodes, although uncommon, do occur, in as many as 2% of affected patients yearly, but eventual normal thyroid function is the rule.
Discomfort in the thyroid area can, however, continue for many months.
Rarely, patients with subacute thyroiditis may develop permanent hypothyroidism.
Patients who have had prior thyroid surgery or who have coexistent autoimmune thyroiditis may be especially prone to such an outcome.

Gardner's syndrome

2008-12-05T17:16:00.000+05:30

Gardner's syndrome (GS), a variant of FAP, is distinguished by the presence of prominent extracolonic lesions, such as desmoid tumors, osteomas, and cysts.

In the member familial adenomatous polyposis (FAP) family, when these tumors arise, the family has traditionally been said to have Gardner's syndrome instead of FAP, since all the members of the family have the same mutation in the adenomatous polyposis coli (APC) gene.

In the early 1950s, Gardner described a kindred with intestinal characteristics of familial adenomatous polyposis (FAP), but also with a number of extra-colonic growths, including osteomas, epidermal cysts and fibromas.

The combination of these inherited colonic adenomatosis together with these extracolonic lesions has become known as Gardner's syndrome.

FAP is characterized by 100’s to 1000’s of colonic adenomatous polyps that most often emerge in the second and third decades of life.
The development of Colon cancer is inevitable if the colon is not removed.
The polyposis is also usually observed in the stomach, duodenum, and small bowel, although the cancer risk in these locations is far less than in the colon.
Shortly after discovery of the adenomatous polyposis coli (APC) gene, it became apparent that both FAP and Gardner’s syndrome arose from APC mutations.
It is inherited as autosomal dominant, with near complete penetration of the gastrointestinal phenotype but with variable penetrance of the extraintestinal manifestations of the disease.
Involvement of male and female is equal.
New mutations have been represented by 20 to 30% of newly diagnosed cases.
New cases may also arise from mosaic inheritance, which implies that a mutation occurred in parent's sperm or egg cells, but not in other cells of the body, so the parent did not have clinical disease.
The number of the colonic polyp depends to some degree on where the mutation occurs in the APC gene.
If the mutations occur in the center of the gene (often called the mutation cluster region), it give rise to dense polyposis, with 5000 or more colonic polyps when the disease is fully developed.
If mutations occur proximal or distal to this central gene location, colonic polyps average approximately 1000 with full expression.
Mutations in the extreme proximal or distal locations of the APC gene are associated with many fewer polyps (often less than 100). This clinical variation is referred to as attenuated FAP.
Extraintestinal growths do not correlate with polyp density but have some correlation with mutation location.

The common extraintestinal manifestations associated with Gardner’s syndrome have been described in approximately 20 percent of patients with FAP.

However, many more patients with FAP have these features if they undergo detailed physical and radiologic examinations.
Thus, the difference between FAP and GS is somewhat semantic and GS is usually considered a subset of FAP.
On the other hand, the term GS continues to be commonly applied, particularly in families that exhibit frequent and obvious extraintestinal lesions.

Extraintestinal benign lesions —

Gardner's syndrome is associated with several benign extraintestinal growths including:

Osteomas
Dental abnormalities
Congenital hypertrophy of the retinal pigment epithelium
Cutaneous lesions
Desmoid tumors
Adrenal adenomas
Nasal angiofibromas

Osteomas

Osteomas were originally described in the skull and mandible but more recently have been shown to involve other areas; they may be the only extracolonic manifestations.
The bony tumors may be present for many years before the onset of intestinal symptoms they may appear denovo and continue to grow throughout the rest of life.
Osteomas are found in about 20 percent of families with FAP and are the first described extracolonic lesions of GS.
They are one to dozens in number and are of less than a millimeter to few centimeter in diameter.
Radiologic examination of the mandible is a simple and noninvasive means to screen for young carriers of the FAP gene, but it is crucial to distinguish nonspecific sclerotic lesions in the mandible from true osteomas.
Mandibular osteomas in FAP tend to be multiple, whereas nonspecific sclerotic bony lesions usually are single and located close to a diseased tooth.
Because osteomas have no malignant potential, they are removed only for symptomatic or cosmetic reasons.

Dental abnormalities

Dental abnormalities includ mandibular cysts, impacted teeth, and supernumerary teeths.
They also appear before the development of colonic polyposis.
Panoramic x-ray of jaw in FAP patients they are found in 90% of the cases but clinically their appearance is only 17% whereas 1 to 2 percent in general population.
Again attention is needed only if there is a symptomatic or cosmetic problem.

Congenital hypertrophy of the retinal pigment epithelium

Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) has been reported in some families with FAP or Gardner's syndrome.
More than 90% of patients with Gardner's syndrome have pigmented ocular fundus lesions (vs. 5% of controls), which are likely to be multiple (63% have four or more lesions) and are bilateral in 87% of those affected.
The lesions are discrete, darkly pigmented, round, oval, or kidney shaped, ranging in size from 0.1 to 1.0 times the diameter of the disc.
Pigmented ocular fundus lesions are found in approximately half of the unaffected but at-risk first-degree relatives and have been identified in infants as young as 3 months old, suggesting that they are probably congenital.
The presence of multiple, bilateral lesions appears to be a reliable marker for gene carriage in FAP, and their absence predicts lack of carriage if carrier relatives show CHRPE.
These marker lesions are asymptomatic curiosities that need not be sought in patients with an established diagnosis of FAP.
Slit-lamp examination is usually required for detection.
CHRPE is not known to cause clinical problems. CHRPE is observed with mutations between codons 311 and 1444, although this varies somewhat depending on the study.
CHRPE perhaps reflects the most accurate genotype-phenotype correlation in FAP patients; these lesions occur in patients with APC gene mutations distal to exon 9 up through the proximal portion of exon 15.

Cutaneous lesions

Epidermal cysts:

The association of epidermoid (sebaceous) cysts with FAP has been termed Oldfield's syndrome.
As all other extraintestinal lesions they appear before puberty and also precedes polyposis.
These cysts vary from few millimeters to many centimeters in size.
They may appear any where on the surface of body but most frequently on the legs, face, scalp, and arms, in order of their occurrence.
They are removed surgically if needed for cosmetic reasons.

Fibromas

They appear on the cutaneous surfaces of the scalp, shoulders, arms, and back.
They are few millimeter to few centimeter in size.

Lipomas

There is an increase in the incidence of these lesions in Gardner’s Syndrome in compared to the general population.

Pilomatricomas
Desmoid tumors

A particularly serious complication of the adenoma-tous polyposis syndromes is the development of diffuse mesenteric fibromatosis, also called desmoid tumors
Desmoid tumors are usually benign fibromas that tend to infiltrate locally into adjacent tissue.
They are rare in the general population (5 to 6 per million per year) but in FAP affect from 5 to 25 percent of patients.
Studies have shown that the absolute risk of desmoids in patients with FAP is 2.56/1,000 person-years, with the comparative risk 852 times that of the general population.
Usually, however, desmoid tumors become manifest from 1 to 3 years following surgery for polyposis.
Desmoids can, however, occur in the absence of Gardner's syndrome.
The peak incidence of desmoid occurrence in GS is between 28 and 31 years, although they may occur at any age.
Independent predictors of their occurrence include APC gene mutations 3' of codon 1444, a family history of desmoids, female gender, and the presence of osteomas.
Mutations between codons 1310 and 2011 are associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495).
Although the lesion appears occasionally to emulate fibrosarcoma, metastasis does not occur.
Local recurrence is the rule rather than the exception. The mass tends to develop in abdominal incisions, in the abdominal cavity (particularly the small bowel mesentery), and the retroperitoneum.
Intra-abdominal desmoids may grow to massive sizes, sometimes occupying much of the abdominal cavity and encasing viscera.
The condition may antedate the appearance of the polyposis by developing in an abdominal incision performed for another purpose (e.g., appendectomy).
They may infiltrate adjacent structures, extend along facial planes, attach to and erode bones, and engulf and compress blood vessels, nerves, ureters, small bowel, and other hollow organs of the abdomen.
Severe and sometimes fatal problems can arise especially if the mesenteric vessels or other hollow abdominal organs become obstructed.
Clark and Phillips and others confirmed that intraabdominal desmoids behave unpredictably but are an important source of mortality in those with FAP.
The authors also observed that signal intensity on magnetic resonance imaging reflects tumor cellularity, which may, in part, determine progression; this may aid in management of these individuals.
Surgery (including colectomy) also appears to be an independent risk factor for desmoid disease in FAP, particularly with mutations in certain regions of the APC gene.
Progression is often gradual and survival 10 years after the diagnosis is approximately 63 percent.
Histologically, there may be some differences between fibroblastic growths in GS and sporadic desmoids.
A distinctive fibroblastic growth, called Gardner associated fibroma, may be seen in young patients and appears to be the precursor lesion of desmoids in GS.
o Desmoid tumors in GS are monoclonal growths, implying that they are true neoplasms.
o Desmoids in FAP also arise from APC inactivation and subsequent accumulation of beta-catenin in cells.
o In contrast, APC mutations are uncommon in sporadic desmoids.
Adrenal adenomas
o Adrenal adenomas in FAP harbor a somatic as well as germline APC mutation, indicating these tumors arise as part of FAP.
o Most adrenal adenomas in Gardner’s Syndrome are found incidentally.
o Their prevalence is 7 to 13 percent of patients with Gardner’s Syndrome whereas it is only 3 percent in the general population.
Malignancy of the adrenal is rare in FAP.

Nasal angiofibromas

They are described in some patients of Gardner’s Syndrome.

Extraintestinal malignant lesions
Patients with Gardener’s Syndrome have increased risk for the following malignancies:

Upper Gastrointestinal Tumors (3 to 5 percent)
Thyroid (2 percent)
Pancreatic (2 percent)
Gastric (0.6 percent)
Central nervous system (<1>
Hepatoblastoma (1.6 percent)
Small bowel distal to the duodenum
Possibly adrenal

Upper Gastrointestinal Tumors

Periampullary carcinoma is a well-recognized disease that is associated with Gardner's syndrome.
Twelve percent of patients in the St. Mark's Hospital series who survived for 5 years after colectomy developed carcinoma of the duodenum, ampulla of Vater, or pancreas.
Sugihara and associates reviewed the literature and identified 29 such patients, with a mean age of 45 years.
Eleven patients developed colorectal cancer, all of them having presented with symptoms before the periampullary malignancy.
Gastrointestinal polyps and cancer have been frequently reported with this syndrome. Invasive upper gastrointestinal adenocarcinoma was found in 4.5% of patients with FAP as recorded in ten polyposis registries.
Nederveen Cappel and associates calculated that the lifetime risk of developing duodenal cancer in FAP is 5%.
The most frequent sites for upper gastrointestinal tumors are duodenum, followed by pancreatic ampulla and then stomach. J
apanese studies reveal the incidence of gastric polyps to be as high as 70% with Gardner's syndrome, whereas the incidence of duodenal polyps approaches 100%.
In Korea, where carcinoma of the stomach is the most common neoplasm, one survey identified 72 patients with FAP, three of whom (4.2%) were found to harbor gastric cancer.
This is a much higher risk than would be anticipated from the general population in that country.

Periodic upper gastrointestinal radiologic investigation (optimally with double-contrast technique), or preferably endoscopy at intervals in all patients found to have FAP is recommended in order to diagnose and treat lesions at an earlier stage, before invasive carcinoma supervenes.

This should be accomplished every 6 months to 4 years, depending on the polyp load.
Their kindred should also be studied for the same.

Thyroid cancer

Thyroid carcinoma has been reported to be associated with Gardner's syndrome.
Unique about this observation is that the proliferative abnormalities of the syndrome as listed earlier are of mesenchymal origin, whereas thyroid tumors are not; this suggests a broader potential for the genetic defect.
An association with thyroiditis has also been observed. Risk of thyroid cancer in Gardner’s syndrome is approximately 8 fold in comparison to normal population and occurs in about 12 percent on FAP patients.
Average age of presentation is 33, presents as nodular growth, ultrasound is needed for screening, in addition to palpation.
Histologically they are of papillary type and association of APC mutation in the 5’ end of exon 15 is documented.

Pancreatic cancer

The risk of pancreatic cancer that is adenocarcinoma of pancreas in patients of FAP is 4 times to that of general population.
It may present with any complication of ductal obstruction.

Hepatoblastoma

This malignancy is 800 times more common in boys under age of 5 years in FAP children. But the risk of development remains up to 15 years.
It has some association with mutation of APC at its 5’ end.

Miscellaneous Associations

Other conditions that are believed to represent manifestations of this syndrome include :

carcinoid of the small bowel,
adrenal cancer,
adrenal adenoma,
pheochromcytoma,
skin pigmentation, and
lymphoid polyposis.

There is, however, the possibility that the observations may merely be coincidental.

Peutz-Jeghers Syndrome

2008-10-16T17:30:00.004+05:30

Introduction :

Peutz-Jeghers syndrome (PJS) is a rare entity characterized by hamartomatous polyps, usually less than 100 in number, found throughout the GI tract in association with hypermelanotic macules in the perioral region, buccal mucosa, digits (hands, feet), perianal and genital regions.

In 1921, Peutz reported a familial syndrome of polyps of the gastrointestinal tract with pigmentation of the mouth and other parts of the body. Later, Jeghers and his colleagues established the syndrome by describing a number of cases.

Hamartomas are growths of tissue that can be of endodermal, mesodermal, and/or ectodermal origin, but with an epithelial covering typical of the bowel location where the polyp is found.

Peutz-Jeghers polyps are also hamartomas, arising from smooth muscle in the muscularis mucosa.
These lesions are hemispheric or finger-like protrusions, ranging in size from 0.1 to 10 mm, but they may grow up to 4 cm in diameter.
On microscopy, a core of smooth muscle penetrating into the overlying lamina propria is seen.

Genetic considration :
This familial syndrome appears to be inherited as a single pleiotropic autosomal dominant gene with variable and incomplete penetrance.

Germline mutations of the STK11/LKB1, a serine threonine kinase gene on chromosome 19p, cause this syndrome, but not all families with PJS are linked to this gene locus, suggesting genetic heterogeneity.

Although it has been assumed that these cancers arise from rare foci of adenomatous epithelium that may develop within the Peutz-Jeghers polyps, recent evidence for loss of STK11/LKB1STK11/LKB1 gene itself might be the gatekeeper to carcinogenesis in this syndrome, much like APC gene is the gatekeeper in FAP.

This disorder exhibits autosomal dominant inheritance with variable penetrance.
Significant progress has been made in the identification of a specific genetic defect.
The PJS putative tumor suppressor gene maps to the telomeric region of chromosome 19p at 19p13.3and encodes the serine threonine kinase LKB1/STK11.
Germline mutations in LKB1/STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, result in the phenotypic manifestations of the syndrome.

Clinical features :

Polyposis develops early in life and commonly presents clinically by age 20.

In addition, polyps in the upper respiratory tract, biliary tract, and urinary tract have been reported.
GI bleeding (acute or chronic) and bowel obstruction secondary to intussusception are the most common presentations, but unusual symptoms and signs indicative of biliary obstruction or gastric outlet obstruction are possible.

The polyps are found most frequently in the small bowel, particularly the jejunum, but they also can occur in the stomach, colon, and rectum.

Small intestine — 48 %
Stomach — 24 %
Colon — 24 %
Pancreas — 5 %

Cutaneous pigmentation usually is noted at birth or in infancy, but the skin changes may actually disappear after puberty.

They consist of clusters of black or dark brown spots resembling freckles, 1 to 2 mm in diameter, on and around the lips and buccal mucosa, fingers, and toes.

The most common symptom and the one most difficult to manage is abdominal pain, often caused by intestinal obstruction.

The obstruction is usually the result of a polyp or of an intussusception.
The other frequent complaint is rectal bleeding.
Additional signs and symptoms include prolapse of the polyp, passage of the polyp, hematemesis, and anemia.

Diagnosis :
Diagnosis of the syndrome can usually be made on the basis of family history, skin pigmentation, and gastrointestinal symptoms. Contrast studies in addition to endoscopy confirm the extent of the polypoid disease.
In case of Histopathologically confirmed hemartoma, the diagnostic requirement of PJS is any two findings of the following three :

Family history with concomitant autosomal dominant inheritance
Mucocutaneous hyperpigmentation
Small-bowel polyposis

Complete upper and lower endoscopy in addition to small bowel contrast studies or enteroscopy, if available, are indicated to identify gastrointestinal polyposis.

Modern endoscopic techniques make surveillance and removal of polyps up to 150 cm beyond the ligament of Treitz possible.

Genetic testing is available. Not all mutations associated with PJS have been identified. So in such a case, a negative genetic test does not exclude the diagnosis.

Pathology :

Macroscopically, the polyps vary in size.

They may be as large as several centimeters in diameter, and with increasing size, they tend to become pedunculated.
In visual appearance, they look very much like adenomatous polyps (see Polypoid Adenoma, Adenomatous Polyp, and Tubular Adenoma).

Microscopically, the polyps seem to originate from intestinal glandular epithelium along with a muscular branching framework that arises from the muscularis mucosa.

The tubules of epithelium rest on the branching bands of smooth muscle in a relationship similar to that of the glandular epithelium with the muscularis mucosa of the normal bowel.
Because there is no evidence of hyperplasia, cytologic variation, or loss of differentiation, Morson suggested that the lesion represents a hamartomatous process or malformation, rather than a neoplasm.

Relationship with Cancer :
In a review by Konishi and colleagues, 117 neoplasms were found in 103 patients.There were 50 carcinomas of the gastrointestinal tract, the colon and rectum being the most common site.

It was established that some of these tumors arose within a Peutz-Jegher polyp, but many probably originated in otherwise normal mucosa.

Giardiello and colleagues investigated 31 patients with this syndrome and found that 48% developed a malignancy; this rate was 18 times greater than would be expected.

The increased frequency was noted for cancers of both gastrointestinal and nongastrointestinal origin.

Hizawa and co-workers investigated 75 gastrointestinal polyps resected surgically or endoscopically from seven patients with this syndrome. Nine were accompanied by an adenomatous component, two of which demonstrated malignant transformation with pedicle invasion.

According to one author, that neoplastic transformation was not a rare event and that their results suggested a hamartoma-adenoma-carcinoma sequence in Peutz-Jeghers polyposis.

Linos and colleagues, conversely, reported the considerable Mayo Clinic (Rochester, MN) experience (48 patients) and failed to document one definite instance of cancer; the median follow-up period was 33 years. The authors, furthermore, found that survival was similar to that of the population at large. They recommended that every effort should be made to conserve intestine in the management of this condition. Another reason to be concerned about an aggressive surgical approach is the possibility of misinterpretation of the histologic appearance. Dippolito and colleagues suggested that careful evaluation may reveal most of these lesions to be, in reality, enteritis cystica profunda.

Patients with PJS typically have several potential complications from hamartomatous polyps.
- Not only is malignant transformation a concern, but the polyps can also ulcerate, bleed, infarct, and intussuscept.
- After the age of 30 years, malignant complications become the major concern; by the age of 65 years, over 90% of patients will have a malignancy.
- The most common GI cancers include
  - colon, with a lifetime risk of 39%,
  - pancreatic, with a lifetime risk of 36%,
  - gastric, and SB (Giardiello et al, 2000).
  Non-GI malignancies include
- breast (54% lifetime incidence),
- ovarian (21% lifetime incidence),
- Sertoli cell tumors (9% lifetime incidence with 10 to 20% becoming malignant), and
- lung (15% lifetime incidence).

The high rate of extra-intestinal cancers also deserves attention with regular examination of potentially involved organs. Specific symptoms require special attention and should lead to an aggressive workup to exclude a malignant cause.

Proctalgia Fugax

2008-10-03T14:28:00.000+05:30

Proctalgia fugax is a common cause of pain in the rectum. Symptoms consistent with proctalgia fugax occur in 13 to 19 percent of the general population.
Proctalgia fugax is underrepresented in the medical literature, and many physicians are unaware of its existence. Lack of familiarity on the part of the physician can result in unnecessary diagnostic evaluation. Contributing to the relative lack of familiarity is the fact that most patients with proctalgia fugax do not seek medical attention because the pain is usually brief and often infrequent. Patients may also be reluctant to disclose the symptoms because they fear potentially painful diagnostic procedures or the possibility of a serious condition

Anorectal pain is a relatively common symptom first described by the Romans.
Patients will often delay consulting a healthcare practitioner about this problem due to embarrassment and fear of a sinister diagnosis, tolerating disturbing symptoms for long periods.
There are two functional anorectal pain syndromes:

Proctalgia fugax (PF) (fugax=fugitive/fleeting in Greek) and
Levator ani syndrome (LAS)

They are both characteristic, benign anorectal-pain syndromes of uncertain aetiology.
Despite their benign nature, they can cause severe distress to the sufferer. There is even an account of marital disharmony caused by proctalgia fugax.

Aetiology

They are thought to occur due to spasm of the anal sphincter (PF) or pelvic floor muscles (LAS) but are something of an enigma.
They may be associated with irritable bowel syndrome. The two affected muscles are anatomically contiguous so the two conditions may co-exist, or be different manifestations of the same underlying dysfunction.
The diagnosis of these conditions can usually be made on the basis of the symptoms.
However, more serious diagnoses can present similarly. Thus, it is essential to conduct a thorough clinical assessment to exclude other pathology before offering reassurance.
May be associated with low-fibre diet and irritable bowel syndrome. More than half of affected patients are aged 30–60 years and prevalence declines after age 45.⁶
It has been associated with a variety of other pathologies which may have aetiological significance, for example pudendal nerve neuralgia.

Epidemiology

PF is estimated to affect 8–18% of the population in the developed world, and LAS around 6%.
LAS seems to affect women more than men.
It is thought that only 20–30% of sufferers of these conditions consult a healthcare practitioner.

Differential diagnosis

Irritable bowel syndrome
Haemorrhoids ± thrombosis
Anal fissure (usually causes intense localised pain associated with and following defecation) – should be visible on proctoscopy.
Solitary chronic rectal ulcer
Rectal carcinoma
Perirectal abscess or fistula; hydradentis suppuritiva
Proctitis (especially gonococcal/chlamydial infection)
Crohn's/Ulcerative colitis.
Rectal foreign body
Pruritus ani.
Diverticular disease
Rectal prolapse
Coccygodynia (neuralgic pain around the region of the coccyx)
Retrorectal cysts
Condylomata acuminata (anogenital warts)
Testicular carcinoma
Prostatitis
Cystitis
Psychological cause (some hypothesise that these conditions are psychological rather than physical in origin)
Alcock's canal syndrome (pudendal neuralgia due to entrapment, may present similarly to PF/be aetiologically relevant)
Hereditary anal sphincter myopathy
Bilateral internal iliac artery occlusion

Proctalgia fugax

Presentation

Symptoms:

Recurrent episodes of sudden, severe cramping pain localised to the anus or lower rectum.
Last from seconds to minutes and resolves completely.
The patient is entirely pain free between the episodes.
Symptoms often occur at night and may wake the sufferer. Attacks are infrequent (<5>
Attacks may come in clusters (occurring daily) then abate for long periods.

Signs:

PF has no signs and the diagnosis is made on the basis of characteristic symptoms and the absence of signs of other pathology.
Abdominal and digital rectal examination should constitute the minimum assessment of anal pain.
Ideally, anoscopy/proctoscopy should be carried out.
Consider gynae/scrotal examination if relevant.
Further examination with a sigmoidoscope or colonoscope may be necessary in selected patients where there is suspicion of pathology higher in the colon.
It is worth checking for signs of anaemia if GI bleeding is suspected.

Management

Once the diagnosis is made, reassurance is usually sufficient.
The symptoms are so transient that drug therapy is rarely needed.
In patients who suffer frequent, severe, prolonged attacks, inhaled salbutamol has been shown to reduce their duration.
Clonidine and amylnitrate have also been used but no evidence exists for their efficacy.

Treatment of Cholangiocarcinoma

2008-07-21T22:39:00.001+05:30

Preoperative preparation
Jaundiced patients require vitamin K.
Resective procedures for cholangiocarcinomas are major procedures and, therefore, patients should have good functional status especially if they are elderly.

Preoperative biliary decompression
In general, it is preferable to avoid stents, if possible. Many surgeons find the presence of any biliary stent a hindrance to determining the proximal tumor extent intraoperatively. On the other hand, cholestasis, liver dysfunction, and biliary cirrhosis develop rapidly with unrelieved obstruction. The extent of liver dysfunction is one of the main factors that increase postoperative morbidity and mortality following surgical resection.

The chance of postoperative liver failure may be lessened by preoperative decompression, especially decompression of the side to be retained.

Decompression has the dual purpose of allowing that side to recover function and actually to hypertrophy.
On the other hand, stents may introduce bacteria and cause cholangitis.

Selective percutaneous decompression is an accepted strategy in Japan and multiple stents are often inserted.

A reasonable strategy is to proceed to surgery in younger patients (age less than 70 years) without serious comorbidities who have been jaundiced for less than 4 weeks, whose serum bilirubin is less than 10 mg/dL and whose future remnant liver will be > 40% of total liver mass.

Also, such patients should not have had biliary instrumentation, which always contaminates the obstructed biliary tract.

For the remainder, we routinely decompress the side of the liver to be retained and wait until the serum bilirubin falls to 3 mg/dL.

Preoperative portal vein embolization —

Because the achievement of histologically negative resection margins is so critical to outcome, preoperative portal vein embolization (PVE) has been used in an attempt to increase the limits of safe resection.
The intent of PVE is to induce lobar hypertrophy in patients who have a predicted postoperative liver remnant volume of <25>
By allowing a larger resection volume to be carried out safely, PVE may permit a margin-negative resection in patients who otherwise would be considered unresectable because of concerns about insufficient postoperative residual liver volume.

Treatment
Hilar cholangiocarcinoma

Criteria for resectability — The traditional guidelines for resectability of cholangiocarcinoma in the United States include :

Absence of retropancreatic and paraceliac nodal metastases or distant liver metastases

Absence of invasion of the portal vein or main hepatic artery (although some centers support en bloc resection with vascular reconstruction)

Absence of extrahepatic adjacent organ invasion

Absence of disseminated disease

The goals of surgical resection are to remove the tumour with negative resection margins and to perform a portal and coeliac node dissection.

In order to achieve this, hemihepatectomy with resection of the caudate lobe as well as the suprapancreatic extrahepatic bile duct and the portal and coeliac lymph nodes is required.
Resection of the caudate lobe is needed because, when the tumour is Bismuth 2 or greater, the orifices of the caudate ducts may be involved with tumour.
Hemihepatectomy is required when the tumour involves the sectional ducts (Bismuth 3) on one side of the liver or the artery or portal vein to one side of the liver.
Theoretically, resection of a Bismuth 2 tumour could be accomplished by resection of bile ducts with the caudate lobe but, in practice, negative margins are much more likely to be accomplished by a hemihepatectomy with resection of the caudate lobe.
Therefore, surgical practice has evolved in the past 20 years to the point at which there is a consensus that virtually all hilar cholangiocarcinomas should be resected by hemihepatectomy and caudate resection.
Low-lying Bismuth 1 tumours, in which a negative upper margin can be obtained on the common hepatic duct, i.e. below the level of the orifices of the caudate ducts, may be resected without removing liver tissue, but these instances are uncommon.

Unfortunately, cholangiocarcinomas have a well-known propensity to spread microscopically for long distances along the bile duct.

A positive resection margin occurs in 20–40% of cases even when liver resection has been done.
The resection margin may be extended by dividing through the termination of the sectional ducts, but there is a limit to how far this can be carried.
Mobilizing the portal vein in the umbilical fissure aids this manoeuvre on the left as the bile ducts to the left lateral section pass behind this vein.
The operation can also be extended by taking the left medial section with the right liver (right trisectionectomy) or the right anterior section with the left liver (left trisectionectomy).

The operation may also be extended by vascular resections.
- Involvement of the portal vein may require replacement of the anterior wall of this structure or circumferential resection with anastomosis of the main portal vein to the left portal vein or, less commonly, the right portal vein with or without an interposition graft.
It has been proposed to remove the anterior wall of the portal vein as a routine in order to obtain a higher rate of negative margins.
This recommendation lacks supporting randomized data and is not routinely followed.
Arterial reconstruction of the proper hepatic artery is less commonly performed.
Pancreatoduodenectomy is performed in up to 15% of cases in some series in order to obtain negative lower margins or to remove potentially malignant nodes.
Reconstruction of the biliary tract is by a Roux-en-Y hepaticojejunostomy.
The Roux limb is made at least 60 cm in length to avoid reflux of intestinal contents into the biliary tree.

Results
The important trends are as follows.

Portal vein embolization is becoming more common as a preoperative preparation.
Some 15–50% of patients are found to be unresectable at surgery but, in recent years, the figure has been decreasing towards the lower limit of this range.
More procedures include a major hepatic resection because the chance of achieving an R0 resection is substantially higher when a major resection is performed.
Mortality rates are falling.

Morbidity rates are still high, reflecting the magnitude of the procedure.
R0 resection is necessary for cure; almost no patients who have had R1 resection survive 5 years without recurrence.
Even with R0 resection, the overall 5-year survival is only 20–35%.
Factors affecting survival include

R0 resection,
en bloc hepatectomy,
absence of tumour in lymph nodes,
tumour grade and tumour type with IG type (papillary) having better survival than other types.

The need to perform a vascular resection is associated with a poorer outcome in some series. The value of pancreatoduodenectomy is unclear at this time. Most patients requiring this addition to the procedure have had a relatively short survival.

Lower duct tumours
The rationale and extent of the procedure is the same as that used for pancreatic carcinoma.
Distal lesions are usually treated with pancreaticoduodenectomy (Whipple procedure).

Often, the tissue of origin of the tumour, i.e. whether pancreatic, ampullary or bile duct in origin, is uncertain until after the specimen is examined pathologically and, even then, doubt can remain.
The main complication of this procedure is a fistula from the pancreatic–jejunal anastomosis, which occurs in 5–10% of patients.
Biliary fistulas occur in about 2% of patients.
Patients rarely die from these complications today because of improvements in diagnostic and interventional radiology, intensive care and treatment of infection.

Resection of part of the stomach is no longer required for lower duct cholangiocarcinoma, although there is little or no difference in short-term outcome or quality of life between the pyloruspreserving and standard types of pancreaticoduodenectomy.

Many patients require pancreatic enzyme replacement after this procedure, but few become diabetic.

Five-year overall survival in recent case series varies from 16% to 37%, and results have not improved in the last decade. Overall, the results of pancreatoduodenectomy for lower bile duct cancer are much the same as those for adenocarcinoma of the pancreas and unlike those for ampullary and duodenal cancers, which have a much better prognosis.

Intrahepatic cholangiocarcinomas
The principles of treatment are as for other malignant intrahepatic hepatic lesions.

The tumour must be resected with a margin of normal tissue to obtain microscopically free resection margins (a 1-cm tumour-free resection margin is the goal), yet leave enough normally functioning liver tissue behind for the patient to have adequate liver function in the postoperative period.
The size of the resection may vary from a single segment or less to resection of three of the four hepatic sections.
The role of resection of extrahepatic lymph nodes is unclear, but it is being done with increasing frequency. Lymph node positivity is common in tumours over 4.5 cm in size, but rare in patients with smaller tumours, and lymphadenectomy might reasonably be limited to large tumours.

Four recent series of patients with MF intrahepatic cholangiocarcinoma treated by surgical resection in 60, 35, 52 and 104 patients reported 5-year survival rates of 29%, 33%, 34%
and 10% respectively.
Multivariate analyses of prognostic risk factors identified -

symptomatic patient,
positive surgical margin,
multiple tumours,
vascular invasion,
lymph node metastases
high microvessel counts indicative of angiogenesis as predictors of poor outcome.
Mucin (MUC)4 expression in carcinoma tissues is also associated with poor outcome in MF intrahepatic cholangiocarcinoma.

Fewer data are available for the less common IG and PI types of intrahepatic cholangiocarcinoma.

The IG type has the best prognosis.

Liver transplantation
Liver transplantation has been performed for intrahepatic and upper duct cholangiocarcinoma, but the results have been disappointing until recently.

In one series published in 1993,only 3 of 14 patients (21%) lived more than 28 months after the procedure.
Even in a more recent series, in which transplantation was performed in patients with cholangiocarcinoma in the setting of PSC, the 5-year survival was only 35%.
While these are not poor results for a visceral cancer, they must be evaluated with the knowledge that many patients with endstage chronic liver disease are dying while on a waiting list for liver transplantation, and the comparative survival rate in this group of patients would be expected to be about 90%.
However, two American centres have reported better results for hilar cholangiocarcinoma.

The Mayo Clinic group reported on 56 patients who entered a trial of liver transplantation for unresectable cholangiocarcinoma or cholangiocarcinoma in the setting of PSC.

The patients were staged by EUS and also by staging laparotomy.
All patients received neoadjuvant chemoradiation.
Approximately half the patients were transplanted, with a 5-year actuarial survival of 82% in transplanted patients.
The other group using a similar approach achieved a 5-year survival rate of 50%.

Adjuvant chemotherapy or radiotherapy
One randomized controlled trial of adjuvant therapy using mitomycin C and 5-fluorouracil vs. surgery alone enrolled 139 patients with cholangiocarcinoma at various levels. There was no survival benefit, although there was benefit in a group of patients with gallbladder cancer treated with the same regimen. External beam radiotherapy was associated with improved postoperative survival in patients with hilar cholangiocarcinoma in one non-randomized trial. However, patients in the control group were treated at an earlier time period or tended to be in poor general condition. In an earlier study in which groups of patients with hilar cholangiocarcinoma were more comparable, external beam radiation did not result in
improved survival. Intraluminal brachytherapy does not extend survival and is associated with an increased incidence of complications.

Recurrence of cholangiocarcinoma is often local, suggesting that adjuvant chemotherapy and/or radiation would be beneficial but, currently, there is no evidence to support its use outside clinical trials.

Palliation
The purpose of palliation is to relieve jaundice and pruritus and to extend life.

Jaundice and pruritus are treated by stenting, usually by endoscopic or percutaneous means or, less commonly, by surgery.
Several randomized trials of surgical bypass vs. endoscopic intubation for lower duct tumours have been published.
The three earlier trials favoured endoscopic stenting.
Two of these trials were quite small and, in the third, the surgical procedures were performed by registrars; surgical complication rates were unusually high by current standards.
The reintervention rate was high in the stent group.
There was no difference in survival.
In a more recent trial of patients found to be unresectable by staging laparoscopy, surgical bypass was favoured over stenting with the surgical group achieving a longer survival.

The current surgical consensus is that a surgical bypass should be performed by an experienced HPB surgeon in younger patients without distant metastases or obvious peritoneal disease.

When unresectability is determined at laparotomy, a double bypass is performed to decompress the biliary tree and bypass the duodenum, which may become obstructed.
Surgical decompression of hilar tumours may also be accomplished by bypass to the segment 3 duct, the so-called Bismuth–Corlette procedure.
This provides decompression of the left liver.
It is usually only done when a patient is found to be unresectable at the time of exploration.

Decompression with stents may be achieved by endoscopic or percutaneous means, with the former favoured because it is less invasive.

Metal stents are generally used because of improved stent patency rates.
In the hilum, plastic stents also have the theoretical disadvantage that their solid walls may block smaller side-branches.
For lesions below the bifurcation, a single stent will decompress the entire liver.
Bilateral stents or forked stents have been used to decompress tumours obstructing the confluence.
However, it seems that a unilateral stent is often just as effective provided that it is placed selectively, based upon a preprocedure MRCP, on the side of the liver that will result in decompression of the most functional liver.
It is essential that the side of the liver not to be stented is not cannulated as that often results in cholangitis on that side, and this is associated with much poorer results.
Should inadvertent cannulation of the side of the liver occur on the side that was not intended to be decompressed, then it is best to employ bilateral stents in order to avoid cholangitis.

Intraluminal brachytherapy has not improved results and, as reported in the adjuvant setting, is associated with more complications.

Photodynamic therapy — Photodynamic therapy (PDT) involves the injection of an intravenous porphyrin photosensitizer followed by the endoscopic application of light (of a specific wavelength) to the tumor bed. The interaction between light and the photoagent causes tumor cell death, presumably by the generation of oxygen free radicals.

Initial uncontrolled series suggested that in addition to facilitating biliary decompression in patients with locally advanced disease, that survival might be improved in patients who underwent PDT.
It is thought that the survival benefit is related to prolonged relief of obstruction rather than to any reduction in tumor mass.

PDT is now being studied preoperatively as a means of improving the likelihood of achieving a margin-negative resection. Unfortunately, treatment is not widely available.

Intrahepatic and Lower duct Cholangiocarcinoma

2008-07-19T23:21:00.000+05:30

Lower duct cholangiocarcinomas
Rationale for diagnosis and surgical staging

These tumours are located in the part of the bile duct that lies in the head of the pancreas or at the level of the first part of the duodenum.
They are one of the members of the tetrad of ‘periampullary tumours’, which commonly present with obstructive jaundice.
The group also includes cancers of the ampulla of Vater, duodenum and pancreas, the last being by far the commonest of the four.
Presumably all three subtypes of cholangiocarcinoma can occur in this region but, as the MF (mass-forming) type would be very difficult to differentiate from pancreas cancer and as the IG (Intraductal-growing) type is very uncommon, it is the cicatrizing PI (Periductal-infiltrating) type that is usually recognized.

Diagnosis
In the patient presenting with jaundice, axial imaging may or may not demonstrate a pancreatic mass.

If mass is present, the diagnosis is taken to be other than cholangiocarcinoma, either a malignancy of the head of the pancreas or focal pancreatitis, although, as already stated, some of these may actually be MF cholangiocarcinoma.
When no mass is present, then cholangiocarcinoma is a possibility.

Surgical staging
When the tumours are at the upper border of their range at the level of the duodenum, involvement of the portal vein and hepatic artery is possible.

The extent of the tumour in the bile duct is rarely a staging question as the treatment is a Whipple procedure in which the entire common bile duct is removed along with the gallbladder and cystic duct.

Diagnostic and staging tests
If the initial diagnostic test for painless jaundice is a CT scan, as we recommend, then the findings will be those of obstruction of the bile duct in the intrapancreatic portion with no mass.

Dilation of the bile ducts may terminate anywhere from the upper border of the pancreas to the duodenum depending on the extent of the tumour.
MRI or ERCP are currently both good choices as the second test under these conditions, and there are no evidence-based data to select between them.
The former test is less invasive but also less informative.
ERCP provides an endoscopic view of the duodenum that allows identification and biopsy of ampullary and duodenal tumours, which may block the bile duct and produce jaundice without being seen as a mass on CT scan, and MRI is less informative in this regard.
ERCP may provide a tissue diagnosis and decompress the bile duct when that is desirable. On the other hand, ERCP requires the placement of a stent into the obstructed duct, and complications such as pancreatitis and haemorrhage have occurred.
Both tests will confirm the presence of a bile duct stricture and display its form, although direct cholangiography is still somewhat superior.

The MRI characteristics are those for a PI as described under hilar cholangiocarcinoma.
Focal strictures, especially those with shoulders, suggest malignancy.

Long tapering strictures limited to the intrapancreatic portion of the bile duct suggest chronic pancreatitis.
Concomitant narrowing of the pancreatic duct in the head of the pancreas (double duct sign) suggests the presence of a small pancreatic cancer, not visible on CT scan.
Longer or multiple pancreatic strictures suggest chronic pancreatitis.
A single focal bile duct stricture in the absence of pancreatic duct abnormalities is the hallmark of cancer of the lower bile duct.
Infiltrating cancers of the bile duct may cause more than one stricture along the bile duct but, when more than one stricture is present, other diagnoses such as PSC should be considered.
Patients with the classical double duct sign or single focal shouldered bile duct strictures are likely to have small pancreatic or bile duct tumours.

Further diagnostic support is usually not needed prior to laparotomy, although it is reassuring when the CA19-9 is over 100 U.
When doubt persists after ERCP or MRI, EUS is often quite useful.

EUS may identify a small mass not seen on CT scan and biopsies may be obtained.
Occasionally, enlarged lymph nodes are seen by EUS, and these may also be biopsied. However, negative EUS biopsies in patients who present with painless jaundice do not exclude malignancy and, for such a patient with an identifiable mass on EUS, pancreatoduodenectomy is recommended, even in the presence of negative EUS-guided biopsy.

If a non-operative approach is followed, short-term follow-up at 4–6 weeks with repeat imaging and biopsy is mandatory.

If findings persist, then laparotomy is advisable.
At laparotomy, detection of a mass by palpation or intraoperative ultrasound is reasonable evidence of malignancy, and a pancreatoduodenectomy should be performed.
In the absence of a mass and where clinical or imaging results suggest a benign aetiology for the stricture, ultrasound-guided core biopsies of the bile duct stricture may be helpful in avoiding pancreatoduodenectomy.

Intrahepatic cholangiocarcinoma

Diagnosis
Clinical diagnosis of the common MF type is dependent on the presence of a liver mass that resembles a metastasis on axial imaging, such as MRI or CT scan, in a patient without a history
of liver disease or evidence of an extrahepatic primary.

The presence of an elevated serum CA19-9 level is helpful.
To rule out primary tumours in the intestine, upper and lower endoscopy is usually performed.
FDG-PET scan and mammography are other imaging tests that have been used to search for an extrahepatic primary.
The pathological diagnosis may be made by needle biopsy, but this is required only when diagnostic doubt exists.

Surgical staging
The aim again is subservient to the surgical goals of removal of gross and microscopic tumour, while preserving adequate liver function. The questions to be answered are similar to those
for cholangiocarcinoma, although the vessels in question are the intrahepatic arteries and veins including the hepatic veins.

Atrophy is less of an issue as it is almost always on the side to be resected, as is the case for the extent of bile duct involvement in the PI and IG types.

Diagnostic and staging tests

MRI

The MF type usually appears as an unencapsulated tumour, hypointense on T1-weighted images and hyperintense on T2- weighted images, although the pattern varies depending on the presence of fibrosis, necrosis and mucin in the tumour.
Hypointensity on T2-weighted images may be seen especially in larger tumours.
In these cases, differentiation from the central scar of focal nodular hyperplesia (FNH) is usually possible by the use of gadobenate dimeglumine (Gd BOPTA).
With dynamic imaging, peripheral enhancement with progressive filling towards the centre of the lesion is common.

Satellite lesions are frequent as is capsular retraction.
The PI type appears as a thickened branching spiculated duct with dilation of the ducts peripheral to the tumour, i.e., much like the PI type of hilar tumour but displaced beyond the sectional ducts.
In later stages, the surrounding liver may appear to be invaded.
The IG type is seen as an intraductal enhancing mass with dilation of ducts peripheral to the mass.
The intrahepatic variant otherwise has the characteristics of the hilar type and, indeed, this tumour may exist at any and all levels of the biliary tree.

Computerized tomography
The typical appearance of the MF lesion is of a large hypoattenuating irregular mass, minimally enhancing at the periphery, sometimes with calcifications and often with capsular retraction,
satellite lesions and enlarged malignant-appearing periportal nodes.

Sonography
MF tumours are usually hypoechoic, but may be isoechoic or hypoechoic and homogeneous or heterogeneous. There are no features that differentiate them from metastatic disease, although peripheral ductal dilation is more common in cholangiocarcinoma.

ERCP
ERCP may be helpful in the PI and IG types when the diagnosis is unclear or after MRI when the extent of the tumour in the ducts is incompletely elucidated.

Differential diagnosis
Hilar and lower duct cholangiocarcinomas

Primary sclerosing cholangitis
Eosinophilic cholangitis and lymphoplasmocytic
cholangitis
Benign inflammatory tumours
Cholelithiasis and choledocholithiasis
Adenoma of the bile duct
Carcinoma of the gallbladder
Neuroendocrine cancer of the bile duct
Granular cell tumours
Sarcoma of the bile duct
Lymph nodes

Intrahepatic cholangiocarcinoma

Hepatocellular carcinoma
Secondary tumours
Angiosarcoma
Epithelioid haemangioendothelioma (EHE)
Primary hepatic lymphoma

Cholangiocarcinoma; clinical features and diagnosis.

2008-07-11T23:46:00.003+05:30

Clinical presentation

Cholangiocarcinomas usually become symptomatic when the tumor obstructs the biliary drainage system, causing painless jaundice.

Common symptoms include:

pruritus (66 percent)

abdominal pain (30 to 50 percent)

The pain is generally described as a constant dull ache in the right upper quadrant.

weight loss (30 to 50 percent), and

In later stages of the disease, weight loss and inanition may appear.

fever (up to 20 percent)

fatigue

anorexia and nausea

Rarely, the first manifestation of disease is pancreatitis, which is initiated by pancreatic duct obstruction by tumour emboli that have travelled down the bile duct.

Cholangitis is an unusual presentation.

Patients with primary sclerosing cholangitis and cholangiocarcinoma tend to present with a declining performances status and increasing cholestasis.

Extrahepatic cholangiocarcinomas, whether in the lower duct or in the hilum, present with painless jaundice or jaundice with mild pain in more than 90% of cases.

Intrahepatic cholangiocarcinomas usually present consequent to detection of a mass or abdominal fullness by the patient or as upper abdominal discomfort or pain.

Sometimes, the initial presentation is that of weight loss and inanition.

Jaundice may occur as a result of compression of hilar structures by centrally placed tumours, secondary to tumour embolizing into major bile ducts or due to compromise of overall liver function in endstage disease.

Occasionally, the tumour is detected by imaging done for investigation of an unrelated problem.

Sometimes, the first sign of disease is an abnormality in blood chemistry or an unexpected finding on imaging for another indication in an otherwise healthy individual.

It is not uncommon for newly diagnosed patients to have recently had a cholecystectomy, presumably because it was believed that gallstones were the source of symptoms, or mild abnormalities in liver function tests.

A palpable gallbladder, caused by obstruction distal to the takeoff of the cystic duct (Courvoisier's sign), occurs rarely.

Diagnosis and surgical staging

Surgical staging questions for cholangiocarcinoma.

What is the macroscopic extent of the tumour along the bile ducts?
What is the relationship of the tumour to blood vessels?
What is the extent of hepatic atrophy?
What is the extent of local hepatic invasion by the tumour?
What is the extent of lymph node involvement?
Are there distant intrahepatic metastases?
Are there peritoneal metastases?
Are there extra-abdominal metastases?

Hilar cholangiocarcinoma

Surgical staging of a hilar cholangiocarcinoma is subservient to the goals of surgical resection.

These are to remove all gross and microscopic tumour, while preserving adequate liver function.
To achieve these goals, there must be no evidence of tumour spread outside the confines of the resection, such as lymph node metastases outside the resection zone, peritoneal metastases or extra-abdominal metastases.
The upper extent of the tumour must be limited to the extent that a clear resection margin on the bile ducts can be obtained without the need to remove so much liver tissue that the risk of postoperative liver failure becomes prohibitive.
This will be discussed further under surgical planning and preparation.
If vascular invasion is present, it must be located on the side of a planned resection.
Invasion of the main portal or proper hepatic arteries is a relative contraindication.
If atrophy has affected one hemiliver, it must be on the side chosen for resection.
If there is local invasion of the tumour into the liver, it must be limited to the extent that clear resection margins can be obtained during the planned resection.
Tumour nodules within the liver distant from the hilum are considered to be a contraindication.
These criteria are modified when the resection is part of an orthotopic liver transplant.

Serum and bile markers

The remarks in this section on serum and bile markers pertain to cholangiocarcinoma at all levels of the biliary tree.

When the obstruction is complete, as it usually is at the time of presentation of hilar and lower duct tumours, the bilirubin rises over several weeks to a level of about 30 mg/dL.
- The direct reacting fraction accounts for more than 50% of the total bilirubin.

Marked elevation of serum alkaline phosphatase and γ- glutamyltransferase levels and mild elevation of transaminase levels are also usual.
In intrahepatic cholangiocarcinoma, bile drainage from the unaffected side is usually unimpaired, and bilirubin levels are usually normal, but alkaline phosphatase levels are often elevated.

CA19-9 is the most commonly used tumour marker for diagnosis of cholangiocarcinoma.

In a large study of 322 patients with biliary cancer, the sensitivity and specificity of CA19-9 were 78% and 83%, respectively, at the cutoff value of 37 U/mL in patients without cholangitis or cholestasis.
In patients with cholangitis or cholestasis, the sensitivity and specificity of CA19-9 were 74% and 42%, respectively, whereas the specificity reached 87% at 300 U/mL.
As many patients with cholangiocarcinoma have cholestasis or cholangitis, CA19-9 is most useful when the levels are quite elevated.

In cholangitis, the level may be extremely high; therefore, it is advisable to obtain blood for measurement of CA19-9 in the jaundiced patient prior to instrumentation of the ducts.
CA19-9 is not specific for cholangiocarcinoma and may be elevated in pancreatic cancer and in intestinal and gynaecological malignancies.
In patients with PSC, the specificity of CA19-9 is low if the cutoff value of 37 U/mL is used. A cutoff value of 100 U/mL seems to provide the most satisfactory balance between sensitivity and specificity in PSC.

Serum carcinoembryonic antigen (CEA) levels may also be mildly elevated in cholangiocarcinoma and have been used by Ramage et al. to increase diagnostic accuracy for cholangiocarcinoma in PSC by combining CEA with CA19-9 levels to form an index, although others have found the index to be less useful. CA125 has a low sensitivity for detection of cholangiocarcinoma, but a high specificity as it is rarely elevated in inflammatory conditions.

CA19-9 and CEA in bile Attempts have been made to improve diagnostic sensitivity and specificity for the detection of cholangiocarcinoma by measurement of these markers in bile, but the results have been disappointing.

Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangioscopy (PTC)

ERCP and PTC are considered together as they both involve direct intubation of the bile ducts and the injection of contrast into potentially obstructed ducts.

With both tests, ducts that have been injected with contrast must remain intubated because of the risk of infection.
Often, ERCP is chosen as the first investigation when a patient presents with obstructive jaundice.
In the case of hilar cholangiocarcinoma, the unfortunate result may be insertion of bilateral stents, including a stent into the hemiliver to be resected.
- This is undesirable because the goal in the preoperative period is to encourage hypertrophy of the hemiliver to be retained and atrophy of the hemiliver to be resected.
- Insertion of bilateral stents works against this purpose.
- Also, if the malignant stricture is tight, ERCP may only show the lower limit of the stricture.
- In the past, this problem has been approached by supplementing the ERCP findings with PTC, although PTC is uncommonly used for this particular purpose today.

Beginning the investigation of the jaundiced patient with axial imaging such as computerized tomography (CT) or magnetic resonance imaging (MRI) rather than ERCP has distinct advantages.

If a hilar cholangiocarcinoma is present, it will be suspected by the presence of intrahepatic bile duct dilation in the absence of extrahepatic ductal dilation.
Atrophy of a hemiliver or section may also be seen.
Whether to use stents or not in hilar cholangiocarcinoma is debatable but, if a stent is inserted, only the side to be retained should be intubated.
The side to be surgically removed should be intubated only if there is evidence of cholangitis on that side or if that side is inadvertently injected with contrast.
Another disadvantage of early intubation of the biliary tree is that it interferes with staging by MRI.
Even if the patient is not a surgical candidate, intubation of both sides of the liver by ERCP is disadvantageous because it commits the patient to bilateral rather than unilateral stenting.

One advantage of endoluminal techniques is that biopsies may be obtained by brushings, fine-needle aspiration or forceps biopsy.

However, the individual sensitivity of these test is less than 50% and only 65% when combined.
Attempts to improve the results of routine cytology include digital image analysis (DIA), which uses aneuploidy as a marker for malignancy, and fluorescence in situ hybridization (FISH).
DIA was found to increase sensitivity from 18% to 40% but lower specificity from 98% to 77% in 100 patients.
The FISH assay uses a mixture of fluorescently labelled probes to centromeres of chromosomes to identify cells with chromosomal abnormalities.
In 100 patients, the sensitivity for the detection of malignancy in bile duct brushing specimens was 15% and 34% for routine cytology and FISH, respectively, and the specificity was 91% and 98%.

Percutaneous intubation of the bile ducts has been used to obtain biopsy material and to determine the upper extent of the lesion in the bile ducts.

Cholangioscopy may be useful in determining whether a focal biliary stricture is benign or malignant.

Of particular interest is whether cholangioscopy might be able to determine reliably whether a focal stricture is benign and thus avoid unnecessary surgery or reduce the extent of surgical resection.
However, as benign focal hilar strictures are uncommon and the case series are small, good data on this point are lacking.
MRI and cholangioscopic findings were found to be highly correlated with respect to determining the upper extent of the lesion, a finding which indicates that cholangioscopy may no longer be required for this purpose.
Cholangioscopy may be of most value when the upper limit of the lesion is indefinite on MRI and the tumour is mucin producing.
In this case, percutaneous cholangiography is hampered by the thick mucin.
With cholangioscopy, the mucin may be aspirated and the upper limit of the tumour defined.

Magnetic resonance imaging

MRI has been increasingly favoured for the diagnosis and staging of hilar tumours as this one study can provide a clinical diagnosis.

In terms of bile duct involvement, MRI cholangiography has the same sensitivity (80%) and specificity (100%) as ERCP for the detection of malignancy.
Furthermore, MRI is far superior to ERCP in detecting the upper extent of the lesion, for the reasons noted above.
On MRI, an MF hilar lesion appears as a nodule 1–2 cm in diameter.
- The tumour is usually hypointense on T1-weighted images but hyperintense on T2-weighted images.
In the PI type, the tumour appears as a concentric, sometimes irregular, thickening with gradual or abrupt transition to normal duct.
- The periductal tissue may appear to be invaded, and lymph node metastases are frequently seen.
The IG type is seen as an intraductal enhancing mass confined to the lumen of the bile duct.
- It may have a rounded or bullet shape or appear as a cast of the duct.
- Usually, the bile duct wall can be visualized where it passes around the mass, i.e. as the tumour does not penetrate the duct, the outer bile duct margin is intact.
- Portions of the tumour may break off and be seen in the lower ducts.
- There may be multiple tumours along different segments of the bile ducts.
In all three morphological types, obstruction of the bile duct is usually present so that the bile ducts peripheral to the tumour are dilated, although they usually display normal wall thickness.
When atrophy has been induced in a hemiliver or hepatic section, the dilated bile ducts will make up much of the residual volume of the affected part, giving the appearance of ‘crowding’ of the ducts.
Sometimes, MRI cholangiography may not give the fine detail required for surgical staging.
- This is especially true when the tumour appears to encroach on sectional ducts on the side to be retained.
Direct cholangiography by PTC remains superior to MRI when this level of detail is needed.
MRI also accurately depicts the extent of liver invasion and secondary tumours in the liver.

Computerized tomography

The typical PI cholangiocarcinoma is seen on the portal or delayed phases as an enhancing thickened bile duct and the MF type as a hypoattenuating mass.
While usual spiral CT images have not been able to stage hilar cholangiocarcinomas with the detail provided by MRI, the newer multidetector row CT scanners provide high-quality images of the biliary tree and blood vessels after administration of intravenous contrast agents.
These images provide the same information as MRI images.
A disadvantage of the agents used in CT is that they are nephrotoxic, unlike MRI contrast agents, a feature that may be of importance, particularly in elderly patients.
Thin section CT accurately predicted the upper extent of PG-type hilar tumours in 65% of cases in one study.

Ultrasonography

Sonography may detect all three types of hilar cholangiocarcinoma and is generally more sensitive in the hilum than at lower levels of the biliary tree, where intestinal gas is more likely to interfere with visibility.
It can often display the extent of the tumour in the biliary tree.
Flow Doppler sonography is particularly useful for defining vascular invasion.
The disadvantages of sonography is that it is more operator dependent than axial imaging techniques and its images are somewhat more difficult for the surgeon to use as a guide in the operating room.

Positron emission tomography (PET)
The role of 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET in the diagnosis and staging of cholangiocarcinoma is incompletely investigated. At present, it is not a standard part of preoperative investigation.

Endoscopic ultrasound —

For distal bile duct lesions, endoscopic ultrasound (EUS) can visualize the local extent of the primary tumor, and the status of regional lymph nodes.
EUS-guided fine needle biopsy of tumors and enlarged nodes can also be performed. EUS with fine needle aspiration biopsy has a greater sensitivity for detecting malignancy in distal tumors than does ERCP with brushings.
This technique also avoids contamination of the biliary tree, which can occur with ERCP.

Angiography

Angiography can accurately document vascular encasement or thrombosis of the portal vein and hepatic artery. However, with the advent of multiphasic CT and MRCP, it is rarely necessary before surgery.

Establishing a preoperative tissue diagnosis

The necessity of establishing a tissue diagnosis prior to surgery depends upon the clinical situation.

It is not critical for planning surgery in patients with characteristic findings of malignant hilar biliary obstruction, and may not be necessary for planning palliative therapy, such as biliary drainage, in unresectable cases.

Tissue diagnosis is most important in the following circumstances :

Strictures of clinically indeterminate origin (eg, in patients with a history of biliary tract surgery, bile duct stones, or PSC).

A situation where the physician or patient would be reluctant to proceed with surgery without a tissue diagnosis, or if the patient's or family's acceptance and adjustment to the diagnosis would be facilitated by having a definitive diagnosis.

Prior to chemotherapy or radiation therapy, particularly if the patient will be enrolling on a therapeutic clinical trial.

Staging laparoscopy

Despite the enhanced diagnostic capability of newer radiologic studies such as MRCP and dynamic CT, unless there is clear evidence of metastatic disease, true resectability can be determined only by operative evaluation.

Laparoscopy can identify the majority of patients with unresectable hilar and distal cholangiocarcinoma, thereby reducing the number of unnecessary laparotomies.
However, true resectability can often be determined only after a complete abdominal exploration.

Cholangiocarcinoma; pathogenesis and classification.

2008-07-05T22:13:00.001+05:30

In 1965, the surgeon Gerald Klatskin reported the first series of patients with cholangiocarcinoma of the hepatic hilum, and introduced the concept of radical resection of the diseased bile duct.However, at this time surgery was associated with high morbidity and mortality rates.

Cholangiocarcinoma is an uncommon epithelial malignancy of the biliary tract.
Cholangiocarcinomas may arise at any level of the biliary tree.
They are highly lethal because most are locally advanced at presentation.
More recently, the term cholangiocarcinoma has been used to refer to bile duct cancers arising in the intrahepatic, perihilar, or distal (extrahepatic) biliary tree, exclusive of the gallbladder or ampulla of Vater.
Intrahepatic cholangiocarcinomas usually present as liver masses, and extrahepatic cholangiocarcinomas tend to obstruct bile ducts and present with jaundice.
Sporadic cholangiocarcinomas are relatively uncommon, but the incidence increases significantly in certain inflammatory and infectious conditions.
Surgical resection is the most effective treatment and is currently the only option that provides a chance for cure, but the majority of patients are not eligible for surgical resection.

Incidence and natural history

Cholangiocarcinomas account for approximately 3 percent of all gastrointestinal malignancies, with a prevalence in autopsy studies of 0.01 to 0.46 percent.
As a general rule, the incidence of biliary tract cancers increases with age; the typical patient with cholangiocarcinoma is between 50 and 70 years of age.
However, patients with primary sclerosing cholangitis (PSC) and those with choledochal cysts present nearly two decades earlier.
In contrast to gallbladder cancer, where female gender predominates, the incidence of cholangiocarcinoma is slightly higher in men.
- This probably reflects the higher incidence of PSC in men.
Asians are affected twice as often as whites or black.
Patients with intrahepatic cholangiocarcinoma, the 1-year relative survival increased from 16.4% in the period from 1975 to 1979 to 27.6% in the period from 1995 to 1999, but the 5-year survival rate remains unchanged and below 5%.
Death is often related to infectious complications secondary to biliary obstruction and is rarely a result of tumour burden.

In fact, a number of authors have found that bile duct tumours are relatively slow growing, especially compared with tumours of the gallbladder or pancreas.

Although nodal, peritoneal and haematogenous metastases have been described, local disease is the most common finding at presentation.
Haematogenous metastases are uncommon, and nodal disease is present in about one-third of cases in series of resected patients.
Extended survival depends almost entirely on complete surgical resection.
Survival has traditionally been considered to be worse for lesions at the confluence and better for lesions at the ampulla, but this probably reflects relatively later presentation and more complex operative management as opposed to a difference in biology.
Location within the biliary tree may have little impact on survival provided that complete resection can be achieved.

PATHOGENESIS

Conversion from normal to malignant bile epithelium probably requires a stepwise accumulation of successive genetic abnormalities, similar to the sequence of events that underlies colorectal carcinogenesis.

However, the level of understanding of the molecular pathogenesis of cholangiocarcinoma is significantly less than that of other gastrointestinal cancers.

A variety of molecular defects involving both oncogenes (K-ras, c-myc, c-neu, c-erbB-2, and c-met) and tumor suppressor genes (eg, p53, SMAD4) have been described in specimens of biliary tract tumors.
As an example, between 37 and 80 percent of tumors overexpress p53 (implying the presence of mutations in this tumor suppressor gene), while abnormal expression of K-ras is found in 21 to 100 percent of cases.
These genetic alterations are associated with a more aggressive tumor phenotype.
The detection of these mutations in bile specimens may improve the sensitivity of cytopathology for diagnosing cholangiocarcinoma, although this technique is not widely used.

Some data suggest that p16INK4a promoter point mutations contribute to initiation and progression of cholangiocarcinoma in the setting of PSC. Others propose that intrahepatic cholangiocarcinomas share some common carcinogenic steps with hepatocellular carcinoma such as loss of heterozygosity (LOH) of chromosomes 4q and 6q, and/or inactivation of tumor suppressor genes on chromosome 1p.

RISK FACTORS

Endemic infections

Liver fluke infestations with Opisthorchis species (Thailand) and Clonorchis species (China) are common in countries where raw fish is consumed with frequency.
- In these countries, raw fish is more frequently consumed by men, partially explaining the higher incidence of cholangiocarcinoma in men.
- The larval stage of flukes, as consumed in raw fish, establishes a chronic infection and inflammation in the biliary tree.
- The risk of cancer has been associated with the degree of infestation as measured by the stool egg count.
- In areas where these parasites are endemic, the incidence of cholangiocarcinoma is as high as 87 per 100 000.

Autoimmune diseases

PSC is an autoimmune disease characterized by periductal inflammation, as seen on histological sections, and multifocal strictures of both intrahepatic and extrahepatic bile ducts, as demonstrated by cholangiography.
- The majority of PSC patients (70–80%) have associated ulcerative colitis, but the converse is not true.
- Approximately 10% of patients with ulcerative colitis have PSC.
- The incidence of cholangiocarcinoma remains elevated in patients with PSC even when medical or surgical management appears to control the inflammatory process.
- In other words, treatment of ulcerative colitis by colectomy does not offer protection from development of cholangiocarcinoma in patients with PSC.
- Nearly 30 percent of cholangiocarcinomas are diagnosed in patients with PSC with or without UC.
- The annual incidence of cholangiocarcinoma in patients with PSC has been estimated to be between 0.6 and 1.5 percent per year, with a lifetime risk of 10 to 15 percent.
- However, the incidence is much higher (30 percent or more) in autopsy series.
- Cholangiocarcinoma develops at a significantly younger age (between the ages of 30 and 50) in patients with PSC than in patients without this condition.
- It is also more difficult to diagnose because of the diffusely abnormal biliary tree.
- Over one-third of these cases are diagnosed within two years of the initial diagnosis of PSC, and the risk appears unrelated to the duration of the inflammatory disease.

However, the number of patients who smoked or were former smokers was significantly higher in the cancer group.

Alcohol consumption has been suggested to be a risk factor for the development of cholangiocarcinoma in patients with PSC.

Certain genetic polymorphisms have been implicated as risk factors for cholangiocarcinoma in PSC.

Choledochal cysts and anatomical anomalies
The risk of development of cholangiocarcinoma in congenital biliary cysts may also be related to inflammation.

Many patients with choledochal cysts have an anomalous pancreatobiliary junction (APBJ).
In such patients, the confluence of the pancreatic duct and bile duct occurs at a greater distance from the ampulla than usual, thereby lengthening the common channel.
This predisposes to reflux of pancreatic secretions into the biliary ducts.
Presumably, the pancreatic enzymes become activated by bile and an inflammatory response follows.

Stasis in the ducts might also lead to bacterial contamination and additional inflammation.

In patients who have early surgical intervention for choledochal cysts, the risk of cholangiocarcinoma is greatly reduced.
There is some evidence that the incidence of cholangiocarcinoma increases dramatically in patients not treated until after the age of 20 years or in patients treated with cyst drainage as opposed to cyst resection.

Additional evidence that anatomical anomalies that result in reflux and inflammation may play a role in cholangiocarcinoma is seen in patients who undergo operative sphincteroplasty.

Seven per cent of patients developed a cholangiocarcinoma in a series of 119 patients who had previously received a transduodenal sphincteroplasty for benign disease and who were followed for up to 22 years.
Presumably, bacterial contamination and inflammation may result from surgical sphincteroplasty.
There is currently no evidence to suggest that endoscopic sphincterotomy carries the same degree of risk.

Cholelithiasis and hepatolithiasis
While cholelithiasis is a well-described strong risk factor for gallbladder cancer, the association between gallstones and cholangiocarcinoma is less well established.

Toxic exposures
A clear association exists between exposure to the radiologic contrast agent Thorotrast (a radiologic contrast agent banned in the 1960s for its carcinogenic properties) and subsequent cholangiocarcinoma; malignancy usually develops 30 to 35 years after exposure.

Lynch syndrome and biliary papillomatosis

At least two genetic disorders are associated with an increased risk of cholangiocarcinoma: the inherited "cancer family" syndrome termed Lynch syndrome II, and a rare inherited disorder called multiple biliary papillomatosis.
The latter condition is characterized by multiple adenomatous polyps in the bile ducts, and repeated episodes of abdominal pain, jaundice, and acute cholangitis.
Biliary papillomatosis should be considered a premalignant condition since a high proportion of these lesions (83 percent in one study) undergo malignant transformation.

Chronic liver disease

Hepatitis B virus (HBV) and hepatitis C virus (HCV) as well as liver cirrhosis regardless of etiology, have been examined as risk factors for intrahepatic cholangiocarcinoma.

Viral hepatitis
An association between hepatitis C viral infection (HCV) and cholangiocarcinoma was initially suggested in 1991. Since then, several reports have noted a higher than expected rate of HCV-associated cirrhosis in patients with cholangiocarcinoma, although the risk is much lower than for hepatocellular cancer.

Nonviral chronic liver disease
As with hepatocellular carcinoma, chronic liver disease of nonviral etiology also appears to be associated with intrahepatic cholangiocarcinoma.

Diabetes
An association between diabetes mellitus and cancer of the biliary tract has been suggested in several studies. The risk was increased by approximately two-fold in the population-based case-control study described above.

Obesity and HIV infection are also considered to be the risk factors for cholangiocarcinoma.

Classification

Pathology and classification

The most widely used classifications are that of Weinbren and Mutum, who described the histological features of three subtypes of cholangiocarcinomas,
- nodular,
- sclerosing and
- papillary,
and that of Klatskin, who described three major macroscopic subtypes of hilar cholangiocarcinomas:
- a small hard nodule,
- a segmental stenosis and
- a papillary growth.

The radiological appearance of these lesions has been variably described.
Recently, the Liver Cancer Study Group of Japan has proposed a new macroscopic classification for intrahepatic cholangiocarcinomas pairing the radiographical description with the gross appearance in three subtypes:

mass-forming,
periductal-infiltrating and
intraductalgrowing

Thus, any tumour may have a component that infiltrates along the duct(periductal infiltrating(PI))or a component that projects into( intraductal growth (IG))or away from the lumen of the bile duct( mass-forming (MF)).

Mass-forming (MF) cholangiocarcinoma

MF tumours are less common than the PI type and more common than the IG type.

MF tumours are the most common intrahepatic variant and have frequently been classified as nodular grossly and histologically.
They are characterized by a nodular mass that projects into the lumen of the duct and out into the surrounding tissues.
The tumour is firm and whitish grey on account of the large amount of fibrous stroma.
The margin is often well circumscribed but may be lobulated.
Multicentricity is more common for this subtype and may be the result of the propensity of the tumour to invade adjacent branches of the portal vein.
Multicentricity may also be due to the fact that the MF growth pattern results in late onset of symptoms and thus provides more time for tumour growth compared with the IG or PI subtypes.
Central necrosis is a common feature when the tumours are large.
Bile ducts peripheral to the mass may or may not be dilated.
Regional lymph node metastases are more common with large tumour masses and are therefore more common with this subtype.
Enlarged metastatic lymph nodes are most commonly located in the porta hepatis.

Periductal-infiltrating (PI) cholangiocarcinoma

In contrast to MF tumours, PI cholangiocarcinomas grow along the bile duct and are commonly described as elongated, branchlike or spiculated.
They penetrate the bile duct wall, growing both in the wall and along the exterior of it for extended distances.
Irregular narrowing or obliteration of the involved bile duct commonly occurs, and the proximal biliary tree is almost universally dilated.
PI tumours are the most common variant and are the predominant subtype found at the biliary confluence.
PI lesions are frequently described as sclerosing and fibrotic on histological examination.

The overlying epithelium may appear atypical or may be absent.
PI tumours are characterized by annular thickening with diffuse infiltration and fibrosis of the periductal tissues.
PI lesions may be poorly differentiated and may show signet ring cells.
In pure PI tumours, there is no mass, and differentiation from benign disease is occasionally difficult.

Intraductal-growing (IG) cholangiocarcinoma

IG tumours account for approximately 10% of all cholangiocarcinomas.
IG tumours grow into the lumen.
Although they originate in the wall, they do not usually penetrate it, and the outer margin of the bile duct remains intact.
IG tumours may be polypoid, sessile or can be elongated sheets of tumour spreading along the bile duct lumen, or skip lesions.

These tumours can grow to several centimetres in size and may expand rather than constrict the bile duct, in sharp contrast to the sclerotic process seen in PI tumours.
The majority of IG tumours are of the papillary subtype comprised of numerous frond-like infoldings of proliferated columnar epithelial cells.
Atypical epithelium is easily identified in this variant and may be classified as well differentiated, meaning that much of the normal epithelial architecture is preserved.
These may arise from a stalk or may be broader based, spreading superficially along the surface.
Biliary obstruction may result from a large tumour blocking the duct, from an excessive amount of mucin or pieces of tumour that have broken off and embolized lower levels of the biliary tree.
In some instances, these tumour emboli have even obstructed the common channel, leading to pancreatitis.
There is a variant of this subtype that is very similar to intraductal papillary mucinous tumour (IPMT) of the pancreas, in which mucinous secretions are the predominant feature.
Patients with IG tumours usually have a better outcome than those with other subtypes, in part because they tend to present at an earlier stage.
Patients with the papillary subtype fare better than patients with the nodular sclerosing subtypes (MF, PI) even when compared stage for stage.
This suggests that at least some of the observed difference in patient outcome is derived from the more favourable biological behaviour of the well-differentiated papillary subtype.

Adenocarcinomas account for more than 90% of all cholangiocarcinomas.

Variants of adenocarcinoma of the bile duct include pleomorphic, giant cell, adenosquamous, oat cell and colloid carcinoma.
The microscopic extent of these cancers frequently extends for long distances beyond the palpable tumour.
In a series of 29 cases, the mean distance of microscopic invasion beyond the gross margin was 16.8 mm towards the liver and 6.5 mm towards the duodenum.

Cancers of the upper duct are more frequently well differentiated, whereas tumours of the lower duct are more frequently poorly differentiated.

Well-differentiated cancers with little invasion are difficult to differentiate from inflammatory pseudotumour.
Often, perineural invasion, a prominent feature of cholangiocarcinoma that is not present in PSC or other benign lesions, is the single most useful feature in sorting out the true nature of the disease.

In series of upper duct lesions, benign inflammation accounted for 13–15% of resections. Poorly differentiated tumours of the lower duct may be difficult to distinguish from pancreatic or duodenal cancers.
Biliary tumours of the lower duct, although often poorly differentiated, tend to present early.
- Therefore, lower duct biliary tumours are less likely to have spread to surrounding lymph nodes or to have metastasized distantly than pancreatic cancers, portending a more favourable prognosis following a pancreaticoduodenectomy.

Anatomical classification

Most authorities in this area now classify cholangiocarcinoma into three types depending upon anatomical location.

These are

intrahepatic cholangiocarcinomas,
hilar cholangiocarcinomas and
lower duct cholangiocarcinomas.

These are treated as distinct clinical entities linked by the cell of origin and aetiological factors.

Synonyms for hilar cholangiocarcinoma are upper duct extrahepatic cholangiocarcinomas and Klatskin tumours.
Synonyms for lower duct cholangiocarcinomas are intrapancreatic bile duct tumours (or cholangiocarcinomas)
and distal bile duct tumours (or cholangiocarcinomas).

Hilar cholangiocarcinomas have been estimated to account for between 40% and 60% of all cholangiocarcinomas.

Intrahepatic cholangiocarcinomas account for approximately 10% of cases with distal tumours making up the difference.
Approximately 10% of patients with cholangiocarcinoma have multifocal disease.

Bismuth-Corlette classification

Cancers arising in the perihilar region have been further classified according to their patterns of involvement of the hepatic ducts (the Bismuth-Corlette classification):

Tumors below the confluence of the left and right hepatic ducts (Type I)

Tumors reaching the confluence (Type II)

Tumors occluding the common hepatic duct and either the right or left hepatic duct (Types IIIA and IIIb, respectively)

Tumors that are multicentric, or that involve the confluence and both the right or left hepatic duct (Type IV)

Bile duct tumors that involve the common hepatic duct bifurcation are referred to as Klatskin tumors regardless of whether they arise from the intrahepatic or extrahepatic portion of the biliary tree.

TNM staging classification

Cholangiocarcinomas involving the intrahepatic bile ducts are staged similarly to hepatocellular carcinoma.

TNM staging for hepatocellular cancer and intrahepatic bile duct cancer

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Solitary tumor without vascular invasion
T2	Solitary tumor with vascular invasion, or multiple tumors none more than 5 cm
T3	Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
T4	Tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum
Regional lymph nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis
Distant metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Fibrosis score (F)
F0	Fibrosis score 0-4 (none to moderate fibrosis)
F1	Fibrosis score 5-6 (severe fibrosis or cirrhosis)
Stage grouping
Stage I	T1	N0	M0
Stage II	T2	N0	M0
Stage IIIA	T3	N0	M0
Stage IIIB	T4	N0	M0
Stage IIIC	Any T	N1	M0
Stage IV	Any T	Any N	M1

In contrast, the TNM staging system for hilar and distal tumors differs in the definition of T stage and stage grouping.

TNM classification for extrahepatic bile duct tumors

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor confined to the bile duct histologically
T2	Tumor invades beyond the wall of the bile duct
T3	Tumor invades the liver, gallbladder, pancreas, and/or unilateral branches of the portal vein (right or left) or hepatic artery (right or left)
T4	Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures such as the colon, stomach, duodenum, or abdominal wall.
Regional lymph nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis*
Distant metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Stage Grouping
Stage 0	Tis	N0	M0
Stage IA	T1	N0	M0
Stage IB	T2	N0	M0
Stage IIA	T3	N0	M0
Stage IIB	T1-3	N1	M0
Stage III	T4	Any N	M0
Stage IV	Any T	Any N	M1

It should be emphasized that the current staging classification for cholangiocarcinoma does not predict overall survival or resectability.

Pruritus and cholestasis

2008-07-01T22:14:00.002+05:30

Introduction
Pruritus is a complication of liver disease, in particular when associated with cholestasis, including:

syndromes associated with genetic mutations

progressive familial intrahepatic cholestasis types 1, 2, and 3

conditions of unknown etiology, such as

primary biliary cirrhosis (PBC)

primary sclerosing cholangitis

acquired conditions, such as

drug-induced cholestasis transient or associated with ductopenia

Intra- and extrahepatic obstruction from any cause

(eg, stones, tumors, postsurgical strictures, and nodes)

The magnitude of the problem

It ranges in severity from mild, to moderate in which sleep is disturbed, to extreme in which the lifestyle of the patient is completely disrupted.

The prevalence of pruritus in liver disease in general varies from 5 % in patients with chronic hepatitis C to 70% in patients with PBC.
- Many patients with liver disease and pruritus do not report the symptom to their physicians because they do not make a connection between itch and liver disease.

In one study interesting features found are:

Thirty-five percent of the subjects who described their sensation of itch reported it as ‘‘bugs crawling,’’ and 6 respondents (3.6%) stated they scratched until they bled.
- Indeed, bloody sheets are often reported by the parents of children with cholestasis and pruritus, a distressing situation.
Sixty-five percent of the subjects reported that the itch was worse at night, consistent with what is reported by patients who suffer from any type of pruritus.
- This worsening at night may be due to the decrease of external stimuli at night with sensory input taking over cognition.
Twenty-five percent of respondents addressing the question reported that the itch increased in the premenstrual state.
- This observation may relate to the hormonal milieu associated with menstruation. In this context, intrahepatic cholestasis of pregnancy, which is characterized by pruritus usually in the last trimester, may be triggered by increased availability of estrogens and by alterations in progesterone metabolites.
Fourteen percent of 112 respondents reported that their itch was worse after meal.
- This report may support the idea that the pruritogen or pruritogens are excreted in bile, poured into the duodenum, and subsequently reabsorbed into the systemic circulation.
Sixty-four percent of 88 respondents reported that something cool relieved their itch.
Forty-six percent of 52 respondents reported that they itched more in the summer than in the winter

Pathogenesis

The pathogenesis of pruritus in cholestasis is unknown but several hypotheses have been proposed, including bile acid accumulation and increased opiodergic tone.

It is inferred that the pruritus of cholestasis results in part from substances normally excreted in bile that, as a result of cholestasis, accumulate in plasma and other tissues. The liver is considered to be the source of the pruritogen or pruritogens. The fact that pruritus disappears after liver transplantation and after the resolution of extrahepatic obstruction seems to support this idea.

Bile acids — One theory proposed that elevated levels of bile acid in the skin of patients with cholestatic diseases act as pruritogens. Observations in favor of this theory include the recovery of bile acids from the skin surface of affected patients in relation to the intensity of pruritus , although the reliability of the methods used is uncertain.

However, a strong line of evidence suggests that bile acids are not the pruritogens in cholestasis.

In patients with cholestasis and pruritus, the pruritus tends to cease as the liver fails.
At this stage, bile acids tend to be very high in plasma and other tissues. This observation suggests that some mechanism other than bile acids alone mediates the pruritus of cholestasis.
In addition, it suggests that some degree of synthetic function is necessary for pruritus to be experienced, and that the pruritogen, pruritogens, or cofactors to pruritogens are made in the liver.
It is conceivable that a certain proportion of bile acids in the bile acid pool of cholestatic patients is required for the pruritus to be experienced, but this is highly speculative at present.

Increased central neurotransmission via the endogenous opioid system can result in pruritus.

This situation is best exemplified by the pruritus that results from the central (eg, intrathecal) administration of morphine.
Morphine is an alkaloid that exerts its effect by stimulating opioid receptors, in particular, the mu opioid receptor.
Naloxone and other opiate antagonists can effectively relieve and prevent morphine-induced pruritus, which supports the hypothesis that the pruritus is mediated by the opioid receptor.

Pproposal that serotonin neurotransmission may mediate pruritus is plausible. Serotonin can cause itch in experimental conditions.

For example, the intracutaneous administration of serotonin can cause pruritus in humans; however, this is not a model of pruritus in cholestasis.
It has not been documented that central serotoninergic neurotransmission is altered in cholestasis is altered.

Treatment of the pruritus of cholestasis

The lack of understanding of the pathogenesis of the pruritus of cholestasis has led to a large body of literature on therapeutic interventions based on empiricism.

On the other hand, clinical observations are the pillars for understanding pathophysiology and have provided some insight into the pathogenesis of the pruritus of cholestasis. Therefore, it seems reasonable that relevant observations be followed by controlled studies that apply behavioral methodology.

The treatment of choice for pruritus associated with cholestasis is correction of the underlying hepatobiliary disease.

o In cases of extrahepatic biliary obstruction in which definitive therapy is not possible, biliary drainage is usually effective in eliminating pruritus.

o In cases of intrahepatic cholestasis in which definitive therapy is not possible, several measures can be attempted to relieve bothersome pruritus.

It has been difficult to evaluate the efficacy of medical therapy for pruritus in controlled trials since pruritus is a subjective symptom that can wax and wane spontaneously.

In mild cases, pruritus can often be controlled by nonspecific measures such as warm baths and emollients. However, these measures often fail when the pruritus is moderate to severe and often accompanied by excoriations. In such cases, the following options are available.

Bile acid resins — The bile acid resins cholestyramine and colestipol are effective first-line agents in the management of moderate or severe cholestatic pruritus based upon their favorable safety profile and clinical experience.

These drugs are nonabsorbable, basic polystyrenes which bind anions in the gut lumen, including bile acids.
They lower bile acid levels by inhibiting the reabsorption of bile acids by approximately 90 percent.
They also decrease pruritus in noncholestatic disorders, such as uremia and polycythemia vera. Hence, these resins bind other pruritogens.

The effective dose of cholestyramine ranges from 4 to 16 grams per day. Efficacy may be increased by administering a dose before and after breakfast in patients with an intact gallbladder to enhance the excretion of the pruritogens, which presumably accumulate in the gallbladder during the overnight fast. However, compliance is a major problem with the use of bile acid resins. These drugs are relatively unpalatable, induce constipation, and can interfere with the absorption of a number of medications including digoxin, warfarin, propranolol, and thiazide diuretics.

The administration of metronidazole, another antibiotic, at doses of 250 mg orally three times a day for one week has been reported to control refractory pruritus in patients with PBC.

In patients with primary sclerosing cholangitis and pruritus, which can be triggered by infection in the biliary tree, metronidazole has been associated with relief of pruritus; however, long-term use of this drug is discouraged because of side effects (eg, neuropathy).

A report of relief of pruritus after smoking marihuana in a patient with pruritus and liver disease refractory to other therapies was followed by the experience on the use of dronabinol, an agonist at the cannabinoid B1 receptor, which was reported to be associated with relief of intractable pruritus and improvement in sleep. The experience on the use of dronabinol has not been followed by controlled studies.

The original reports on ligocaine, propofol, and lidocaine as providing amelioration of pruritus in cholestasis have not been followed by controlled studies since the initial reported experience.

Pruritus secondary to histamine release is associated with erythema and edema, which are absent in the skin of patients with the pruritus of cholestasis.

In contrast, the skin of patients with cholestasis may reveal excoriations, thickening, and prurigo nodularis from chronic scratching.
Antihistamine drugs do not appear to have a specific antipruritic effect in patients with cholestasis.
However, they are associated with sedation and, in this context, may help patients sleep, which is often a major problem in patients with chronic pruritus.

UDCA, a choleretic agent, may decrease the degree of cholestasis in many instances. However, UDCA is not consistently associated with relief in pruritus. Furthermore, UDCA has not been studied specifically as an antipruritic agent in cholestasis.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, usually in the third trimester.

Serum levels of bile acids of 40 micromoles/L or more have been was associated with a four-fold increase in spontaneous premature births and meconium passage into the amniotic fluid; however, a diagnosis of ICP cannot be excluded if the serum concentration of bile acids is normal.
UDCA is reported to be associated with relief of pruritus and decreased intrauterine fetal death, although recommendations for the systematic use of UDCA in ICP are not available because the data to support this treatment have not been considered robust.
The use of cholestyramine in ICP can contribute to vitamin K deficiency and to increased risk of hemorrhagic consequences in the peripartum period. Therefore, everyone involved in the care of these mothers must be made aware of potential hemorrhagic complications.

Treatments aimed at removing pruritogens from the body

Plasma separation, anion adsorption, and two recently developed extracorporeal liver support systems (Molecular Adsorbent Recirculating System [MARS] and Prometheus) have been used to treat patients with intractable pruritus and have been reported to be associated with relief. Some investigators have commented on the need for clinical trials on the use of this intervention.

Antibiotics

In a study of the effect of rifampicin as an enzyme inducer in patients with cholestasis, it was reported that the drug ‘‘strikingly improved’’ their pruritus.

In reports of two meta-analyses, rifampicin was found to relieve pruritus.
However, the hepatotoxicity of this drug is well documented, indicating that the liver profile has to be followed when this medication is prescribed.
Rifampicin is a ligand of the pregnane X receptor, whose stimulation induces drug-metabolizing enzymes and transporters.
Rifampin may induce microsomal enzymes that promote 6- alpha-hydroxylation and subsequent glucuronidation of toxic bile salts.

Changes in neurotransmission

Opiate antagonists

The publication of a meta-analysis that explored the efficacy and safety of opiate antagonists in the treatment of the pruritus of cholestasis reported that this type of drug significantly reduced the pruritus of cholestasis.

The opioid-withdrawal–like reaction seems to be the limiting factor to accepting this type of drug to treat the pruritus of cholestasis. Not all patients experience this reaction and most of those who do experience a mild reaction. However, because those who will experience the reaction or will have a severe reaction cannot be identified a priori, treatment with opiate antagonists can be started at a dose lower than what is provided in the naltrexone tablet, the opiate antagonist available for oral use.
The naltrexone tablet can be divided in four to provide 12.5 mg per dose, instead of the 50 mg provided by the whole preparation. Alternatively, patients can be admitted for intravenous naloxone infusions to be followed by oral naltrexone.
If admission to the hospital is not an alternative, infusions in a well equipped outpatient unit can be considered.
The point of intravenous infusions of naloxone is to introduce an opiate antagonist slowly to prevent the withdrawal reaction.
As done in two controlled studies, an intravenous bolus of naloxone (0.4 mg) can be given slowly, immediately followed by an infusion of naloxone at doses of 0.2 mg/kg/min in 250 or 500 mL of a suitable intravenous solution.
Ultra-low doses of naloxone (0.002 mg/kg/min) have also been used at the start of the infusion to prevent an opiate-withdrawal–like syndrome.
The rate can be increased gradually every 2 to 4 hours, if tolerated, until approximately 0.8 mg/kg/min or until the patient reports relief. After 24 or 48 hours of infusion, naltrexone at a dose of 12.5 mg/d can be introduced and the infusion stopped.
The dose of naltrexone can be increased by 12.5 mg every week or two until the patient’s pruritus decreases. The dose should not be increased if signs of an opiate withdrawal–like syndrome arise.
In general, the drug can be held or maintained at the same dose, as the reaction tends to subside spontaneously. One hundred milligrams of naltrexone per day can be required. There are cases in which 250 mg of naltrexone per day have been prescribed. This dose is high and is not required by the majority of patients. When such high doses are required, alternative treatments should be considered. The treatment with naltrexone should be followed with a comprehensive panel to detect any toxicity, which is not common, but which has been reported. Thus, following up the liver profile and a complete blood count after starting patients seems prudent. In decompensated liver disease, naltrexone metabolites can accumulate, which requires dose reduction. However, it is not common for patients with liver failure to experience pruritus. Thus, the need to use this drug in advanced disease does not often arise.

Serotonin antagonists

Nociception is mediated in part by serotonin neurotransmission. Ondansetron was reported to decrease the pruritus associated with cholestasis in studies that applied subjective methodology, including a case of cholestasis of pregnancy. Intravenous ondansetron (4 and 8 mg) and not placebo was reported to be associated with a decrease in pruritus in a small number of patients. Studies that have incorporated behavioral methodology (ie, measurement of scratching activity) have not confirmed an antipruritic effect of ondansetron in cholestasis.

Changes in threshold to experience nociception

The drug gabapentin has been studied as a therapeutic alternative in the treatment of pruritus.
The rationale for the research is that such a drug might raise the nociception threshold. In this context, a double-blind randomized placebo-controlled study was conducted to observe the effect of gabapentin on the perception of pruritus and on its behavioral manifestation, scratching activity. In this study, the administration of gabapentin was associated with an increase in hourly scratching activity, in contrast to the placebo administration, which was associated with a decrease in this behavior.

Gabapentin was used at doses of 300 mg/d in divided doses, to a maximum of 2400 mg/d. This study underscores the importance of behavioral studies in pruritus and the antipruritic effect of a placebo intervention.
Furthermore, these results confirm existing doubts on the reliability of data in studies of pruritus that apply subjective methodology only.
In addition, provocative ideas on the neurotransmission of the placebo effect as potentially antipruritic have emerged from this study.

Antidepressants

Data from a retrospective analysis of subjective reports on pruritus in patients with PBC who participated in a clinical study of UDCA and methotrexate and who were on sertraline suggested that this drug was associated with relief in pruritus.
It was reported from a randomized, placebo controlled crossover study of sertraline, at doses associated with relief of pruritus (75 to 100 mg) in the dose-finding open-label phase of the study, that this medication was associated with relief of pruritus, as assessed by the visual analog scale, and its cutaneous consequences (ie, scratch marks), as evaluated by physical examination.
Eight of 21 subjects associated the use of sertraline with mood stability, and the subjects who met criteria for depression at baseline improved on sertraline. However, it was reported that the decrease in the visual analog score for pruritus was independent from the improvement in depression.

Selective serotonin reuptake inhibitors have been reported to decrease pruritus in polycythaemia vera and in patients with malignancy whose pruritus was multifactorial.
Mirtazapine, a noradrenergic and serotonergic antidepressant, has also been reported to relieve pruritus in a small heterogeneous group of patients with malignancy and uremia, and in patients with nocturnal itch from skin diseases.
Taken together, these data may suggest that not only the serotonin system, but also other neurotransmitters, including noradrenaline, may contribute to the pruritus of cholestasis and other forms of pruritus.

Approach to the patient with liver disease and pruritus

A thorough medical history should provide information about the presence of pruritus in patients with liver disease.
Other causes of pruritus (eg, skin lesions) need to be excluded because the treatment in those cases may be completely different.
As cholestyramine tends to be well tolerated by most patients, treatment can be started with this resin. Doses of more than 16 g/d are not recommended. The method for taking cholestyramine takes into account the presumed storage of pruritogenic substance (or substances) in the gallbladder during the overnight fast. Thus, one dose (ie, 4 g) immediately before and after breakfast can be prescribed to start the treatment. This method allows for the resin to decrease the absorption of the pruritogen or pruritogens presumably excreted in bile as this substance is poured into the duodenum after breaking the overnight fast.
If this dose does not suffice, increasing to 4 g at lunch and/or dinnertime can follow.
If the treatment with resins is not associated with relief of pruritus, naltrexone or rifampicin can be prescribed.
The American Association for the Study of Liver Disease practice guidelines for the management of pruritus in PBC suggest to proceed to rifampicin. If that recommendation is followed, hepatic panel has to be followed carefully over time to detect any early signs of hepatotoxicity. The drug should be stopped immediately if alterations from the baseline are noted in the liver panel. Naltrexone can also be started if cholestyramine fails or is not sufficient.
A combination of cholestyramine and naltrexone can be used, provided that the naltrexone (and other drugs) is taken at least 2 hours before or after the cholestyramine.
If the patient does not experience relief of the pruritus, sertraline can be prescribed at doses of 75 to 100 mg, as reported in the controlled study. Prudence suggests starting at low doses, as would be done for depression (eg, 25 mg/d).
For care of the skin, which is important, moisturizers can be useful.
Patients should avoid as much as possible environmental factors that worsen pruritus (eg, extreme temperatures).
Medications known to cause pruritus should be discontinued or replaced with substitutes.

Patients who fail the regimen described above pose a problem.

In those patients, such interventions as dronabinol, ondansetron, and short-term metronidazole can be tried.
Butorphanol, available in spray form, can be used. However, this drug has addiction potential and caution must be exercised when prescribing it. Doses of up to 2 mg per day (1 mg per puff) have been used in a patient with chronic hepatitis C and intractable pruritus and in patients who have primary biliary cirrhosis.
Filtration procedures, including those provided by extracorporeal liver support systems (MARS and Prometheus) can be explored.
- These procedures tend to be available, sometimes for research purposes, at institutions where liver transplantations are performed.
Surgical procedures that divert the flow of bile are reported to relieve pruritus. These procedures cannot be recommended at this point because specific expertise is necessary and insufficient information on the long-term effect on the pruritus in adult subjects is not available.
Intractable pruritus can be an indication for liver transplantation.

Cancer gallbladder; treatment of advance and unresectable disease.

2008-06-22T22:06:00.002+05:30

Patients with locally advanced, unresectable gallbladder carcinoma may present with symptoms of jaundice, pain, and bowel obstruction. These patients have a limited life expectancy, on the order of months, especially in the setting of liver and/or peritoneal dissemination.

The treatment of locally advanced, unresectable gallbladder carcinoma is palliation aimed at relief of pain, jaundice, and bowel obstruction, along with prolongation of life.

Patients who have pain from local growth may benefit from radiation therapy with or without concomitant chemotherapy.
Although biliary or intestinal bypass can be considered, a percutaneous or endoscopic approach may be preferred, given the limited median survival in patients with advanced disease (generally, less than six months).

Recurrence
In a recent retrospective review of the patterns of initial disease recurrence after potentially curative surgical resection, Jarnagin et al. followed 80 patients with gallbladder carcinoma and compared them to 76 patients with hilar cholangiocarcinoma.

The median time to disease recurrence was shorter for gallbladder carcinoma patients (11.5 months) compared to patients with hilar cholangiocarcinoma (20.3 months).
At a median follow-up of 24 months, 68% of patients with hilar cholangiocarcinoma and 66% of patients with gallbladder carcinoma suffered disease recurrence.
The site of initial disease recurrence was locoregional in only 15% of patients with gallbladder carcinoma compared to 59% of patients with hilar cholangiocarcinoma.
In contrast, 85% of patients with gallbladder carcinoma had a distant (+/−locoregional) site as their initial site of failure compared to 41% of patients with hilar cholangiocarcinoma.
This study provides considerable insight into the clinical behavior of these malignancies and suggests that in the case of gallbladder carcinoma, improvements in survival are most likely to be achieved with more effective systemic therapies as opposed to adjuvant treatment such as radiation therapy designed to achieve better locoregional control.

Radiation therapy

External beam radiation(EBRT) may be considered for palliative management of patients with locally advanced disease, particularly if there is no evidence of metastatic disease, and patients are symptomatic. At the time of exploration, the margins of unresectable and/or residual disease are often marked with radiopaque clips to facilitate treatment planning.

Hanna and Rider reported on 51 patients with gallbladder carcinoma from the Princess Margaret Hospital, 35 of whom underwent a potentially curative surgical resection and EBRT.

There was a survival advantage for those patients who received adjuvant EBRT in addition to surgery compared with those who had surgery alone.

Several other small, retrospective series consisting of heterogeneous groups of patients with diverse treatment schema and follow up criteria have been published, making definitive conclusions about the potential benefits of adjuvant EBRT difficult.
Most recently, Kresl et al. published their retrospective analysis of adjuvant EBRT with concurrent 5-FU after curative surgical resection in 21 patients with gallbladder cancer treated at the Mayo Clinic from 1985 through 1997. Patients with a margin-negative (R0) resection followed by adjuvant EBRT plus 5-FU had a favorable 5-year survival rate of 64%.
However, similar to the findings of Jarnagin et al. [58], 67% of the patients suffered distant failure, emphasizing the need for more effective adjuvant chemotherapy for this disease.

Intraoperative radiation therapy (IORT) has been advocated as a means to deliver high-dose, small-field therapy directly to the tumor bed without the dose limitations associated with EBRT. Todoroki et al. have reported the most substantial experience with IORT in 85 patients with AJCC stage IV gallbladder cancer who underwent aggressive surgical resection with or without IORT at a mean dose of 21 Gy.

Fortyseven patients in total received some form of radiation therapy (EBRT and/or IORT).
The local control rate was significantly higher after adjuvant radiotherapy (59%) than after resection alone (36%).
Moreover, the 5-year survival rate was significantly higher after adjuvant radiotherapy (9%) than after resection alone (3%), with the most pronounced improvement in 5-year survival rate (17%) in patients with only microscopic residual disease (R1 resection).

The role of radiation therapy for the palliation of symptoms such as jaundice, pain, and pruritus in patients with unresectable disease is difficult to ascertain as published studies consist of small numbers of patients with the significant confounding variable that most patients also underwent a biliary drainage procedure.

Chemotherapy

Most published studies concerning the role of chemotherapy in patients with locally advanced or metastatic gallbladder carcinoma are limited by the small numbers of patients and by the inclusion of patients with biliary tract cancers.

Unfortunately, no single chemotherapeutic agent or combination of agents has been identified to be effective in the treatment of this disease .
Though overall response rates range as high as 64%, complete responses are rare and median overall survival rates range from only 20 weeks to 15 months.
5-fluoruracil (5-FU), administered either alone or in combination, is the most extensively studied chemotherapeutic agent for this disease.
In a prospective, randomized study of 53 patients with advanced gallbladder cancer treated with oral 5-FU alone or in combinationwith either streptozocin or methyl-CCNU, objective response rates ranged from 5 to 12% in the three treatment arms.
5-FU administered in combination with doxorubicin and mitomycin C (FAM) or in combination with cisplatin and epirubicin (CEF) has yielded response rates of 8% and 33%, respectively.
Better response rates have been published in patients treated with combinations of 5-FU with hydroxyurea (30%) or interferon alpha-2b (34%).

Other chemotherapeutic agents have exhibited variable success in the treatment of advanced gallbladder cancer. Cisplatin, mitomycin C, paclitaxel, and CPT-11 have produced response rates of 10% or less as single agents.

In contrast, four of eight patients with gallbladder carcinoma treated with single-agent oral capecitabine had either a complete (n =2) or partial (n =2) response.
Several case reports have shown that gemcitabine is active in the treatment of patients with gallbladder carcinoma.
Accordingly, several phase II studies of gemcitabine in combination with other agents have subsequently been reported.
Gemcitabine in combination with cisplatin has yielded response rates of 36 to 64%; in combination with docetaxel yielded a response rate of only 9%; and in combination with 5-FU has produced response rates of 9 to 33%.
Based on these studies, it appears that gemcitabine is an important component of the systemic therapy of gallbladder carcinoma, but additional studies of gemcitabine in combination with other agents are warranted, as the survival benefit with existing regimens is modest at best.

Hepatic arterial infusion chemotherapy has been studied in a few patients with locally unresectable gallbladder cancer.

Partial response rates of up to 60% have been reported, but the median duration of response was only 3 months and all patients developed progressive disease.
The median overall survival rates of 12 to 14 months in these studies is comparable to that achieved with intravenous chemotherapy, providing little impetus to recommend this more complicated mode of drug delivery.

Targeted therapy —

Early data suggest possible benefit from blockade of the epidermal growth factor receptor (EGFR) by the oral tyrosine kinase inhibitor erlotinib.

In one study, 42 patients with advanced biliary cancer (not stratified according to primary site), 57 percent of whom had received prior chemotherapy, received erlotinib (150 mg daily).
There were three partial responses (two with documented expression of EGFR) and seven additional patients remained progression-free at six months.
All responding patients had mile (grade 1 or 2) skin toxicity.

Further experience with this drug is needed, particularly combined with cytotoxic chemotherapy.

Palliative surgery

For patients with unresectable disease detected radiographically or laparoscopically, biliary drainage is best achieved by endoscopic or percutaneous means.

If unresectable disease is discovered at the time of laparotomy, a biliary bypass (hepaticojejunostomy or segment III bypass) can be performed.
However, in a prospective study of 21 consecutive patients with unresectable gallbladder cancer who underwent a segment III bypass, six (29%) suffered complications; three (14.3%) patients had bile leaks, and three patients died as a result of the procedure.
The median survival of these 21 patients was only 20 weeks, and all but three patients died within 32 weeks of the surgery.
Given this limited life expectancy, patients with unresectable gallbladder cancer and biliary obstruction are best palliated by percutaneous or endoscopic stenting.

Intestinal bypass offers durable relief of intestinal obstruction, though there are reports of excellent palliation of malignant duodenal obstruction by the endoscopic placement of expandable metal Wallstents.

Carcinoma Gallbladder; curative surgery

2008-06-17T17:56:00.000+05:30

The poor prognosis associated with Ca Gallbladder is thought related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder, and the vagueness and nonspecificity of symptoms.

Complete surgical resection offers the only chance for cure of gallbladder cancer.
Unfortunately, only 10 to 30% of patients have surgically resectable disease.
The extent of surgery is largely dictated by the T stage of the tumor, which in turn is proportional to the likelihood of lymph node metastases (N stage) and peritoneal and distant dissemination (M stage).

The most significant change in sixth edition of The American Joint Committee on Cancer (AJCC) TNM staging system for gallbladder carcinoma, is that there is no longer a distinction between T3 and T4 tumors based on the depth of liver invasion.

The management of patients with gallbladder carcinoma is dependent on the stage of disease at presentation. Patients present in one of three ways:

(1) an incidental finding after cholecystectomy for suspected benign disease;
(2) a suspected or confirmed lesion that appears resectable after preoperative studies;
(3) advanced, unresectable disease.

Each of these presentations demands a unique treatment strategy, with surgical resection as the only curative option.

Though high-quality cross-sectional imaging studies are increasingly capable of detecting metastatic disease that would preclude curative resection, all patients with potentially resectable gallbladder carcinoma should undergo staging laparoscopy prior to an attempt at curative resection.
- Approximately 50% of patients with gallbladder carcinoma have metastatic disease detected at the time of laparoscopy and thus can be spared a laparotomy.
- Should the staging laparoscopy prove negative, definitive curative resection should then be entertained.

Contraindications

Among the absolute contraindications to surgery are liver or peritoneal metastases, ascites, extensive involvement of the hepatoduodenal ligament, and encasement or occlusion of major vessels. Direct involvement of colon, duodenum, or liver is not an absolute contraindication.

Five-year survival rates are 5 to 12 percent in many large series. In data derived from the National Cancer Data Base, five-year survival rates stratified according to stage were:

Tis disease — 60 percent

T1 N0 — 39 percent

T2 N0 — 15 percent

T3 N0 or node-positive disease — 5 percent

Better outcomes have been noted in the last decade, and attributed to more aggressive surgery and the use of postoperative adjuvant therapy.
The impact of radical surgery can be illustrated by results of one Japanese series.

The five-year survival rates following simple cholecystectomy among all patients with T2 tumors was 40 percent, but in a small group who underwent radical reoperation (resection of the gallbladder fossa, 2 cm of adjacent liver, extrahepatic bile duct, and regional lymph nodes), 90 percent survived five years.
Unfortunately, T1 or T2 disease is an uncommon finding in incidentally diagnosed Ca Gallbladder, accounting only for 5 to 10 percent of cases.

Even for patients with more locally advanced but potentially resectable disease, radical surgery that achieves negative margins can result in long-term survival in a minority of patients.

Spread of the Disease

Lymphatic metastases can be found in 35 to 80 percent of patients with ≥T2 disease at diagnosis.

The gallbladder lymphatics drain first to the cystic node and the common duct (pericholedochal) nodes (previously called N1 nodes in the 1997 TNM classification, now classified only as regional nodes) and
then into the pancreaticoduodenal, celiac axis, and paraaortic nodes (previously referred to as N2 nodes in the 1997 classification; currently considered regional nodes,
with the exception of peripancreatic nodes along the body and tail of the pancreas, which denote metastatic disease).
However, the lymphatic drainage pattern does not always follow a predictable pattern.
In some cases, lymph nodes posterior to the pancreas or portal vein are involved initially.

Direct spread.

GBC frequently extends directly to adjacent structures such as liver, stomach, duodenum, pancreas, colon, omentum, or the abdominal wall.

Hematogenous spread.

Fewer than 10 percent of cases present with hematogenous metastases.

Peritoneal carcinomatosis involving the upper abdomen may complicate the disease in patients with transmural or serosal penetration.

For patients undergoing cholecystectomy for gallstone-related disease, the surgeon should maintain a high index of suspicion for cancer gallbladder, particularly in an older patient with a longstanding history of gallstones or a thick-walled or calcified (porcelain) gallbladder, both major risk factors for Ca gallbladder.

If cancer is suspected during an open procedure, a small biopsy should be obtained before dissection of the gallbladder.
Although intraoperative frozen section analysis can reliably indicate whether a lesion is benign or malignant, it cannot reliably predict the depth of tumor invasion.

Current consensus is that patients should undergo a second curative procedure if an unexpected cancer gallbladder is diagnosed postoperatively after cholecystectomy, except for those who are found to have T1a disease.

The likelihood of finding an unsuspected GBC during a laparoscopic cholecystectomy is similar to that with open procedures.

In two large series combined, incidental GBC was found in 14 of 2616 patients undergoing laparoscopic cholecystectomy (0.5 percent).
If GBC is strongly suspected, an open rather than laparoscopic procedure is recommended
If an obviously malignant lesion is encountered laparoscopically, it is best not to sample it laparoscopically to reduce the hazard of seeding, and the procedure should be converted to an open resection if surgical expertise with resection of gallbladder cancer is available.
Otherwise, patients should be referred to a tertiary center for further exploration.
Although available data suggests that laparoscopic manipulation does not diminish the survival of patients with incidentally found GBC, port site recurrences have been described.
- Because of this, laparoscopic port sites should be removed at the time of reexploration.

Surgical options

Simple cholecystectomy

Radical or extended cholecystectomy, which includes removal of the gallbladder plus at least 2 cm of the gallbladder bed, and dissection of the regional lymph nodes from the hepatoduodenal ligament behind the second portion of the duodenum, head of the pancreas and the celiac axis

Radical cholecystectomy with resection of liver (segmental or lobar), or bile duct/pancreaticoduodenectomy

When it is deemed necessary, the extent of liver dissection is controversial, with recommendations ranging from nonanatomical wedge resection to removal of segments IV and V, segments IV, V, and VIII, right hepatic lobectomy, and right trisegmentectomy (segments IV, V, VI, VII, VIII). Right hepatic lobectomy alone is generally not recommended, since up to one-third of tumors invade the left lobe (segment IV), which remains untreated with this approach. A right hepatic lobectomy may make sense in selected patients because of clinical or anatomic considerations (eg, tumor of the gallbladder neck involving the right portal triad). For T3/T4 tumors, a formal segmental hepatic resection (segment IVb and V) is generally required.

For patients with gallbladder carcinoma in situ (Tis) or invasive carcinoma limited to the mucosa (T1a),

most surgeons agree that simple cholecystectomy is adequate treatment provided that the cystic duct margin is negative.
The incidence of lymph node metastases in patients with T1a tumors is only 2.5% and so an extended resection to include the regional lymph nodes, with its attendant increased morbidity and mortality, is not justified for the small potential survival benefit.

There is justification for an extended resection in patients with T1b (invasive of muscle) tumors, however, given a 15% incidence of nodal metastases with these lesions [36].

Several investigators have shown an improvement in 5-year survival after extended cholecystectomy for T1b tumors.

As T2 (invasive of perimuscular connective tissue) tumors are associated with a 56% incidence of regional lymph node metastases, an extended cholecystectomy with regional lymphadenectomy is warranted.

In addition, since a routine cholecystectomy employs a subserosal plane of dissection on the liver side that will result in a positive margin, an extended cholecystectomy including at least a wedge resection of the gallbladder fossa of the liver (segments IVb and V) must be performed.
The benefit of extended resection in these patients is supported by data demonstrating improved survival. Shirai et al. reported a 5-year survival rate of 40% for T2 tumors after simple cholecystectomy compared with a rate of 90% after extended cholecystectomy. Chijiiwa et al. reviewed 28 patients with T2 gallbladder carcinomas who underwent surgical resection and found a significantly better 5-year survival rate in patients who underwent an extended cholecystectomy (59%) compared to those who had a simple cholecystectomy (17%).
Radical second operations for T2 tumors are also associated with improved 5-year survival rates of 61 to 75%.
Even patients with involved cystic, portal and portacaval lymph nodes may be curable by extended lymphadenectomy.
In contrast, few if any patients with peripancreatic, celiac, and/or superior mesenteric nodal involvement are long-term survivors, and resection cannot be generally recommended.

In the medically high-risk patient for whom reresection is not feasible, observation could be considered for cancer limited to the mucosa or submucosa, while radiation therapy (RT) with concomitant chemotherapy should be strongly considered for more advanced lesions, if the patient can tolerate this treatment.

Locally advanced (T3/4) resectable disease

In the past, surgeons were reluctant to operate on patients with locally advanced (T3/4) disease because of their overall poor prognosis.

Some Japanese groups advocate even more extensive surgery involving hepatectomy, pancreaticoduodenectomy, colectomy, and even nephrectomy for patients with locally advanced but potentially resectable disease.
Although long-term survivors are reported, morbidity and mortality rates are high (48 to 54, and 15 to 18 percent, respectively).

For patients with regional nodal (N1) disease (ie, limited to cystic, portal, and portocaval nodes), five-year survival rates from 28 to 60 percent are reported with radical resection.
Results with radical lymphadenectomy are less favorable with N2 disease, particularly if the extent of nodal disease is beyond the hepatoduodenal ligament, posteriosuperior pancreaticoduodenal area, and along the common hepatic artery.

Locally advanced, unresectable disease

Patients who are locally unresectable (eg, because of major encasement of vascular structures) should be referred for chemotherapy alone or chemoradiotherapy.
There is no indication for radical surgery for the purpose of debulking, and attempted resection should only be undertaken if it is possible to achieve a complete resection.

Although the value of a debulking simple cholecystectomy has not been definitely proven in this situation, this approach is recommended by some to prevent future episodes of cholecystitis in patients with locally unresectable disease.
The optimal way to manage these patients has not been established and treatment must be individualized based on extent and resectability of the disease and experience of the management team.

Gallbladder carcinoma

2008-06-15T17:53:00.000+05:30

In the United States, Gallbladder Carcinoma (GBC) is the fifth most common gastrointestinal (GI) cancer, and the most common involving the biliary tract; fewer than 5000 new cases are diagnosed each year in the United States.

The majority are found incidentally in patients undergoing exploration for cholelithiasis; a tumor will be found in 1 to 2 percent of such cases.
The poor prognosis associated with GBC is thought related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder, and the vagueness and nonspecificity of symptoms.

EPIDEMIOLOGY

High rates of GBC are seen in South American countries, particularly Chile, Bolivia, and Ecuador, as well as some areas of India, Pakistan, Japan and Korea.
- In Chile, mortality rates from GBC are the highest in the world.
- These populations all share a high prevalence of gallstones and/or salmonella infection, both recognized risk factors for GBC.

Worldwide, there is a prominent geographic variability in GBC incidence that correlates with the prevalence of cholelithiasis.

Gallbladder carcinoma affects women three times more often than men and its incidence increases steadily with age, with a steep rise beyond the age of sixty.

The incidence of gallbladder cancer is higher in certain ethnic groups, mirroring the incidence of cholelithiasis in these groups.
Alaskan and American Indian natives have a frequency of gallbladder cancer that is six times that of the rest of the country.
GBC is more common in Caucasians than in blacks

In the United States, however, the incidence and mortality rates of gallbladder cancer have been decreasing since 1970, related at least in part to increasing numbers of cholecystectomies performed annually for gallbladder disease in the United States.

RISK FACTORS
Gallstone disease

Gallstones are present in 70 to 90 percent of patients with GBC, and a history of gallstones appears to be one of the strongest risk factors for the development of GBC.
Despite the increased risk of GBC in patients with gallstones, the overall incidence of GBC in patients with cholelithiasis is only 0.5 to 3 percent.
The risk is higher with larger gallstones (in one study, patients with stones larger than 3 cm had a 10-fold higher risk of GBC compared to those with stones <1>

Cholecystoenteric fistula

There is a 15% incidence of gallbladder cancer in patients with a history of a cholecystoenteric fistula and the presence of Mirizzi’s syndrome.

Porcelain gallbladder

Porcelain gallbladder is an uncommon manifestation of chronic cholecystitis that is characterized by intramural calcification of the gallbladder wall.
It is associated with cholelithiasis in more than 95 percent of cases.
As with other gallstone-related conditions, these patients are at increased risk of GBC.
The reported incidence of GBC in patients with a porcelain gallbladder ranges from 12.5 to 60 percent.

Gallbladder polyps

Gallbladder polyps are outgrowths of the gallbladder mucosal wall that can be benign or malignant, and benign lesions are further classified as nonneoplastic (eg, cholesterol and inflammatory polyps, adenomyomas) or neoplastic (eg, adenomas, leiomyomas).

The most common benign neoplastic lesion is an adenoma, a glandular tumor composed of cells resembling biliary tract epithelium.
It is unclear whether adenomatous polyps represent a premalignant lesion, and if so, the frequency with which they progress to carcinoma.
Unlike GBC, gallbladder polyps tend not to occur in patients with cholelithiasis, chronic inflammation is generally absent, and cancer-related molecular changes that are seen in GBCs have not been identified in adenomas.
Nevertheless, larger polyps are more likely to contain foci of invasive cancer, and some studies suggest a correlation between the presence of gallbladder polyps and the risk of GBC.

Chronic infection

Salmonella
- In endemic settings, approximately 1 to 4 percent of acutely infected individuals become chronic asymptomatic carriers of salmonella typhi (S. typhi).
- Several reports suggest an association between chronic S. typhi carriage and elevated risk of GBC.
- A prospective case control study of patients with carcinoma of the gallbladder and gallstones (cases) or gallstones alone (controls) identified the S. typhi carrier state as an independent risk factor for carcinoma of the gallbladder (OR=14).
- Because chronic carriage occurs more often in individuals with cholelithiasis, gallstones are thought to represent a potential nidus for ongoing infection.

Helicobacter
- Helicobacter colonization of the biliary epithelium (particularly H. bilis) has been implicated in the pathogenesis of gallbladder disease including gallbladder cancer based upon detection of Helicobacter-derived cytotoxins and surface proteins using sensitive molecular and immunohistochemical techniques.
- The strength of this association requires further clarification.

Congenital biliary cysts

Biliary cysts are associated with an increased risk of cancer, particularly cholangiocarcinoma.
The incidence of malignancy varies with age.
In a 1983 review of all published series of biliary cysts, the incidence of cancer was 0.7 percent in patients under 10 years of age, 6.8 percent in patients 11 to 20 years of age, and 14.3 percent in patients over 20 years of age.
An incidence as high as 50 percent has been reported in older patients.
At least one study suggests that the increased incidence of carcinoma in biliary cysts is confined to patients with an anomalous pancreaticobiliary duct junction.

Abnormal pancreaticobiliary duct junction

Anomalous pancreaticobiliary duct junction is a rare anatomic variation in which the pancreatic duct drains into the common bile duct, resulting in a long common channel (usually over 2 cm in length).
This condition may represent failure of the embryological ducts to migrate fully into the duodenum.
This condition is most prevalent in Asians populations, mostly Japanese.

The long common channel may predispose to reflux of pancreatic juice into the biliary tree, since the ductal junction lies outside of the sphincter of Oddi.

Elevated sphincter of Oddi pressures have been documented in anomalous pancreaticobiliary duct junction, and could also promote pancreaticobiliary reflux.
The result is increased amylase levels in bile, intraductal activation of proteolytic enzymes, alterations in bile composition, and presumed biliary epithelial damage, inflammation, ductal distension, and cyst formation.

Anomalous pancreaticobiliary duct junction appears to increase the risk of biliary and pancreatic malignancy even in patients without a biliary cyst or ductal dilation.
Gallbladder cancer is the most common malignancy seen in patients with anomalous pancreaticobiliary duct junction and no bile duct cyst.
As a result, prophylactic cholecystectomy is recommended in affected patients.

The molecular pathogenesis of GBC arising in patients with an anomalous pancreaticobiliary duct junction appears to be different from that underlying the development of GBC in the setting of gallstone disease.

Medications

Some drugs have also been implicated in biliary carcinogenesis, including

methyledopa,
oral contraceptives, and
isoniazid.

Others have found no convincing evidence for an association between oral contraceptive use and GBC.

Carcinogen exposure

Evidence is accumulating that carcinogen exposure may also be involved in the etiology of GBC. An increased risk of GBC has been described in workers in the oil, paper, chemical, shoe, textile, and cellulose acetate fiber manufacturing industries, and in miners exposed to radon.

MOLECULAR PATHOGENESIS

Differences in the demographics, clinical presentation, and gender distribution suggest that there are two key pathways to developing GBC in patients with cholelithiasis and anomalous pancreaticobiliary duct junction.

The main mechanism involves cholelithiasis and resultant cholecystitis, and seems to be the driving force in most regions of the world where GBC is strongly associated with gallstone disease, female gender bias, and age over 65.

It is hypothesized that chronic irritation of the gallbladder mucosa over a period of years may predispose to malignant transformation, or act as a promoter for carcinogenic exposure or genetic predisposition.
In keeping with this hypothesis, bile samples from patients in endemic areas are more mutagenic than those from patients from low incidence areas.
Despite these data, there is no conclusive evidence linking bile composition to GBC.

A second mechanism involves anomalous pancreaticobiliary duct junction, which is associated with a relatively high proportion of cases of GBC in Japan.

Cancers associated with this condition occur at a younger age, show less female gender bias, and have a lower incidence of associated cholelithiasis.

There are also histologic and molecular differences in GBCs associated with an anomalous pancreaticobiliary duct junction and those associated with gallstones, providing further evidence that two distinct pathogenetic pathways are involved.
- GBCs arising in Japan in the setting of an anomalous pancreaticobiliary duct junction are characterized by K-ras mutations and relatively late onset of p53 mutations.
- By contrast, in Chilean patients with cholelithiasis and chronic cholecystitis, K-ras mutations are rare, while p53 mutations arise early during multistage pathogenesis.

Multistage pathogenesis

Most epithelial cancers are preceded by a series of histologic and molecular changers that evolve over a period of several years or decades.

Similar to other GI tract adenocarcinomas, adenocarcinomas involving the gallbladder progress from dysplasia, to carcinoma in situ (CIS), and then to invasive cancer.
The molecular changes that characterize these sequential changes are less well characterized than those in colorectal cancer.

Preneoplastic changes can be found in the mucosa adjacent to over 90 percent of GBCs, and they are relatively frequent in routine cholecystectomy specimens.
The entire sequence appears to take approximately 15 years.
metaplasia is a rare premalignant lesion found in association with invasive squamous cell GBC.

By contrast, in both adults and children with an anomalous pancreaticobiliary duct junction, epithelial hyperplasia with a papillary or villous appearance is present in 39 to 61 percent of cases, and is thought to represent a premalignant histologic change in the gallbladder mucosa. Hyperplasia then progresses to dysplasia, similar to the usual form of GBC.

CLINICAL FEATURES

The symptoms of gallbladder cancer are typically those of benign gallbladder disease. Common symptoms include right upper quadrant abdominal pain, nausea, and fatty food intolerance.
More advanced symptoms include jaundice, anorexia, and weight loss.

Rarely, patients present with extraabdominal metastases, hepatomegaly, a palpable mass, ascites, or paraneoplastic syndromes (eg, ectopic hormone secretion or acanthosis nigricans).

DIAGNOSTIC MODALITIES

Given the nonspecific presentation of patients with gallbladder carcinoma, the disease is difficult to diagnose preoperatively.
Accordingly, the disease is usually diagnosed either incidentally after cholecystectomy or at a very advanced stage.
If a gallbladder cancer is suspected preoperatively, usually as a result of an abnormally thickened gallbladder wall or the presence of a gallbladder mass on ultrasound, then further investigation with contrast-enhanced computed tomography scan or magnetic resonance imaging is warranted.
These imaging modalities are critical in the determination of resectability, providing information about the local extent of disease, including portal vascular invasion, as well as the presence of lymphadenopathy and liver metastases.
At The University of Texas M. D. Anderson Cancer Center, we perform percutaneous fine needle aspiration preoperatively to confirmthe diagnosis of gallbladder carcinoma in order to determine the extent of the planned surgical resection and any associated treatment, including portal vein embolization and neoadjuvant chemoradiation.

Ultrasound

Findings that are suggestive but not diagnostic of GBC include mural thickening or calcification, a mass protruding into the lumen, a fixed mass in the gallbladder, loss of the interface between the gallbladder and liver, or direct liver infiltration.

Small polypoid lesions within the gallbladder may represent adenomas, papillomas, cholesterolosis, or carcinomas.
- Polyps over 1 cm in diameter are more likely to contain an invasive cancer than smaller ones.

Endoscopic ultrasound

Endoscopic ultrasonography (EUS) is more accurate for imaging the gallbladder than is extracorporeal US. It is useful both in the differential diagnosis of gallbladder polyps, and in staging tumor extent.

CT and MRI

On CT, GBC can appear as a polypoid mass protruding into the lumen or completely filling it, a focal or diffuse thickening of the gallbladder wall, or a mass in the gallbladder fossa with the gallbladder itself being indiscernible; liver invasion, suspected nodal involvement, or distant metastases may be shown.

CT is less helpful in distinguishing benign from malignant polyps.
In contrast, dynamic MRI and MR cholangiopancreatography (MRCP) can help to differentiate benign from malignant gallbladder lesions in equivocal cases, and provide information as to disease extent.
MRI is particularly useful for visualizing invasion into the hepatoduodenal ligament, portal vein encasement, and lymph node involvement.

Cholangiography

These procedures may be helpful in planning the surgical procedure as they may indicate tumor growth in intrahepatic biliary ducts or in the common bile duct.

Laboratory studies

Laboratory studies are typically unremarkable unless the patient has developed obstructive jaundice an elevated alkaline phosphatase or serum bilirubin may be related to bile duct obstruction.
Unfortunately, there are no reliable tumor markers, including CEA and CA 19-9 levels which are often elevated, but not diagnostically useful because they lack specificity and sensitivity.

HISTOLOGY

The majority are adenocarcinomas, although other histologic types are occasionally found, including small cell cancer, squamous cell carcinoma, lymphoma, and sarcoma.
Grossly, GBC can appear infiltrative, nodular, papillary, or a combination of these morphologies.
Papillary carcinomas, which can sometimes fill the entire gallbladder, have the most favorable prognosis.

Adenocarcinomas originate as mucosal lesions, invading the gallbladder wall as they grow.
The lack of a well-defined muscularis layer permits early vascular, lymphatic, and neural invasion.
Tumors frequently extend outside of the gallbladder, invading adjacent organs, particularly the liver, as they grow.

STAGING

Nevin staging system — Originally described in 1976, the Nevin staging system for GBC includes five stages that are defined as follows :

Stage I — Intramucosal only

Stage II — Involvement of mucosa and muscularis

Stage III — Involvement of all three layers

Stage IV — Involvement of all three layers and the cystic lymph node

Stage V — Involvement of liver by direct extension or metastases to any other organ.

TNM Staging

Primary tumor (T)

TX -Primary tumor cannot be assessed

T0 -No evidence of primary tumor

Tis -Carcinoma in situ

T1 -Tumor invades lamina propria or muscle layer

T1a -Tumor invades lamina propria

T1b -Tumor invades muscle layer

T2 -Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

T3 -Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, or pancreas, omentum or extrahepatic bile ducts

T4 -Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

Regional lymph nodes (N)

NX -Regional lymph nodes cannot be assessed

N0 -No regional lymph node metastasis

N1 -Regional lymph node metastasis

Distant metastasis (M)

MX -Distant metastasis cannot be assessed

M0 -No distant metastasis

M1 -Distant metastasis

Stage grouping

Stage 0 -Tis N0 M0

Stage IA -T1 N0 M0

Stage IB -T2 N0 M0

Stage IIA -T3 N0 M0

Stage IIB -T1 N1 M0, T2 N1 M0, T3 N1 M0

Stage III -T4 Any N M0

Stage IV -Any T Any N M1

Gallbladder Tumors; clinical features, diagnosis and management.

2008-06-12T00:52:00.000+05:30

CHOLESTEROLOSIS AND CHOLESTEROL POLYPS

Cholesterolosis has been recognized since 1857, when Virchow described it in a report on the role of the gallbladder in fat metabolism.
It is a benign condition that is usually diagnosed incidentally during cholecystectomy or on ultrasonography

Cholesterolosis or ‘strawberry’ gallbladder is a disordercharacterized by deposits of cholesterol esters and otherlipids in the macrophages of lamina propria.
The same lipids are deposited to a lesser degree in the epithelium andstroma of the gallblader wall.
The planar variety of cholesterolosisis diffuse, creating a carpet of fine yellow papulesover the mucosa surface.
In more than one third of cases, these surface masses are less than 1 mm in diameter.
The polypoid form of cholesterolosis are single or multiple, discrete cholesterol polypoid lesions (‘polyps’)

Cholesterol polyps are the most common pseudotumors of the gallbladder.

The polyps can be single or multiple, usually less than 10 mm in size.
They have no predilection for any particular gallbladder site, and usually are attached to the gallbladder wall by a delicate, narrow pedicle.
Cholesterol polyps and cholesterolosis may occasionally occur in association.
No malignant potential has been identified for this type of pseudotumor.

Epidemiology

Cholesterolosis is common; its prevalence in surgical studies varies from 9 to 26 percent.
A large autopsy series of 1300 cases found the prevalence to be 12 percent.
Cholesterolosis in association with gallstones is by far the most common pathologic finding in the gallbladder.
Most surgical series suggest risk factors that are similar to those for gallstone formation.
However, as mentioned above, an ultrasound study showed no association with any of the known risk factors for gallstones.
Similarly, while gallstone disease is known to be more common in women, an autopsy series found the prevalence of cholesterolosis to be equal between men and women.
These contradictory observations may be explained by the observation that surgical series generally focus on gallbladders from patients who were symptomatic, which is not necessarily the case in autopsy or ultrasonographic studies.

Pathology —

Cholesterolosis results from abnormal deposits of triglycerides, cholesterol precursors, and cholesterol esters into the gallbladder mucosa.
The lipid accumulation creates yellow deposits that are generally visible to the naked eye.
The appearance of the yellow deposits on a background of hyperemic mucosa led to the description of this finding as a "strawberry gallbladder".

The main microscopic feature is the presence of fat laden macrophages within elongated villi.

Most of the lipid in the cytoplasm of the macrophages is in the form of liquid crystals, which leads to birefringence under polarized light and gives a characteristic foamy appearance under microscopy.
The hyperplastic villus is filled and distended with these cells, creating the small yellow nodules under the epithelium.
In about two-thirds of cases, these nodules are less than 1 mm in diameter, which gives the mucosa the coarse and granular appearance that is characteristic of the diffuse or planar type of cholesterolosis.
The remaining one-third of cases are referred to as the polypoid form in which the nodules are larger and polypoid in appearance.
In the polypoid form the deposits give rise to solitary or multiple cholesterol polyps that are attached to the underlying mucosa with a fragile epithelial pedicle, the core of which is composed of lipid filled macrophages.
These polyps can break off, leading to complications similar to those caused by small gallstones, such as biliary pain, pancreatitis, or obstructive jaundice.

CLINICAL FEATURES —

Polyps of the gallbladder are typically incidental findings detected during radiologic imaging of the abdomen.
Their significance usually surrounds uncertainty regarding their potential for malignancy.
In addition, regardless of their type or etiology, gallbladder polyps can be associated with biliary pain.
Proposed mechanisms of pain include prolapse of the polyp into Hartman's pouch, which, if occurring during gallbladder ejection, can lead to biliary type pain that subsides upon spontaneous reduction.
- Another possible mechanism is that a detached portion of a polyp, when lying free in the gallbladder lumen, can obstruct the cystic duct in much the same way a gallstone would, leading to biliary colic or cholecystitis.
The detached portion can also obstruct the common bile duct, leading to obstructive jaundice and pancreatitis.
In a review of 3,797 cholecystectomies, 55 cases of gallbladder cholesterolosis without cholelithiasis were identified.
Twenty-seven of these patients presented with recurrent attacks of acute pancreatitis, which disappeared after cholecystectomy.
The gallbladders had frank cholesterolosis with a polypoid appearance.
The authors postulated that the detached cholesterol polyps temporarily impact at the sphincter of Oddi, leading to pancreatitis.

Chronic dyspeptic abdominal pain.
- In a study of 269 patients who underwent cholecystectomy and were found to have cholesterolosis, 96 percent had abdominal pain that was described as severe and had persisted for more than two years in most patients.
Other symptoms reported in the same study were nausea and vomiting (61 percent) and dyspepsia (60 percent).
Most of these symptoms resolved after cholecystectomy.
In another study, 35 of 55 patients with chronic abdominal pain underwent cholecystectomy; cholesterolosis was found in 20 patients, 19 of whom had improvement in symptoms.
It has been suggested that these lesions can lead to poor gallbladder emptying and compartmentalization that may be responsible for these symptoms.
However, the mechanism of these dyspeptic symptoms remains unclear since these observations have not been confirmed in other studies and the results of surgery are variable.
Thus, it remains debatable whether polyps, cholesterolosis, or adenomyomatosis can lead to chronic dyspeptic pain.

DIAGNOSIS —

Although none of the available modalities can reliably and unequivocally predict the type, histology, or the presence of malignancy, a combination of features seen on ultrasound, CT scan, and endoscopic ultrasonography (EUS) can provide valuable information.

Ultrasonography —

Polyps are easily identified on ultrasonography as single or multiple echogenic foci that can be easily differentiated from gallstones because they are fixed.
They do not move when the patient is rolled from one side to another and they do not cast a shadow.
As noted above, the most useful predictive feature for malignancy is the size of the polyp.
Polyps larger than 2 cm are almost always malignant and in many cases the cancer is advanced.
Polyps of 1 to 2 cm in size should be regarded as possibly malignant.
As mentioned above, several pathologic studies support this with the incidence of carcinoma being 43 to 77 percent in polyps larger than 1 cm and 100 percent in polyps larger than 2 cm.
Cholesterol polyps are usually smaller than 1 cm.

In addition to size and number, ultrasonography can delineate other useful distinguishing characteristics in the appearance of polyps. These may include

echogenicity,
surface architecture, and the
presence of a pedicle.

Cholesterol polyps are usually

multiple,
homogeneous, and
pedunculated polypoid lesions
that are more echogenic than the liver parenchyma.
They may or may not contain hyperechoic spots and have a mulberry-like surface.

Adenomas are also

homogeneous, but are
isoechogenic with the liver parenchyma, and
have a smooth surface and no pedicle.

Adenocarcinomas are

homogeneous, heterogeneous sessile, or mass-like polypoid structures that are usually
isoechogenic with the liver parenchyma and
exhibit a mulberry-like surface.

When located in the fundus, adenomyomatosis can produce a mucosal projection that can give the appearance of a polyp on ultrasonography.

These polypoid lesions are about 10 to 20 mm in diameter.

In contrast to cholesterol polyps, diffuse cholesterolosis has no specific ultrasonographic finding. As a result, the diagnosis is usually made during surgery.

In patients with adenomyomatosis, ultrasonography shows

non-specific focal thickening (>4 mm) of the gallbladder wall.
Careful examination may predict the presence of adenomyomatosis by revealing diffuse or segmental thickening with round anechoic foci that represent the intramural diverticula.

Oral cholecystography —

Oral cholecystography (OCG) has fallen out of favor since ultrasonography is much more sensitive and specific.
The OCG requires a functioning gallbladder and a patent cystic duct to visualize the gallbladder.
Polyps would appear as immobile filling defects which are usually difficult to differentiate from gallstones.
Adenomyomatosis has a characteristic appearance of an invagination in the wall that may occasionally show Rokitansky-Aschoff sinuses.

Computed tomography —

Computed tomography is generally most useful in patients with gallbladder cancer since it can stage the disease by revealing liver invasion or metastasis.
There are only limited data regarding the use of the CT scan in the differential diagnosis of gallbladder polyps.
One study noted a 100 percent sensitivity of contrast enhanced CT for detecting gallbladder polyps in 20 patients who underwent CT scans with and without contrast and subsequently had cholecystectomy.
As in other studies, the size of the polyp was a useful predictor for malignancy.
None of the six polyps less than 10 mm in diameter were neoplastic, while 5 of 14 polyps more than 10 mm in diameter were malignant and two were adenomas.
Unenhanced CT missed all cholesterol and hyperplastic polyps, while all adenomas and carcinomas (except for one) were seen before and after administration of contrast. Furthermore, all cholesterol polyps were pedunculated while most of the carcinomas were sessile.

Endoscopic ultrasonography —

Endoscopic ultrasonography has the advantage of being able to image the gallbladder through the gastric wall without the deleterious attenuation by subcutaneous fat and interference from intestinal gas, which limit the usefulness of conventional extracorporeal ultrasonography.
These benefits potentially make endoscopic ultrasonography a much more accurate imaging modality for the gallbladder compared to extracorporeal ultrasonography.
However, EUS is not widely available and the data for its use in the differential diagnosis of gallbladder polyps are sparse.

One retrospective study defined certain criteria for diagnosing cholesterol polyps, adenomyomatosis, and adenocarcinoma on EUS.

The presence of internal echo patterns characterized as tiny echogenic spots or an aggregation of multiple highly echogenic 1 to 3 mm spots with or without echogenic areas was considered diagnostic for cholesterol polyps.
Adenomyomatosis (localized type) was diagnosed when there was a sessile echogenic mass containing multiple microcysts (corresponding to the dilated Rokitansky-Aschoff sinuses) or a comet tail artifact.
In the absence of echogenic spots, multiple microcysts or a comet tail artifact, the lesion was diagnosed as neoplastic (adenoma or adenocarcinoma).

In a more recent follow-up study by the same group using the same EUS criteria, a total of 194 patients with small (<20>

Fifty-eight of these patients underwent surgery either because of symptoms or a suspicion of a neoplastic lesion on EUS.
Using these criteria, EUS correctly predicted the histology in 97 percent of the cases compared to 76 percent for transabdominal ultrasonography.

MANAGEMENT —

The only effective treatment for gallbladder polyps or cholesterolosis is cholecystectomy, which should be considered in symptomatic patients or as prophylaxis to prevent malignant transformation. Optimal follow-up of patients who do not undergo cholecystectomy is unclear.

Although most gallbladder polyps are benign, the main objective is to exclude the presence of malignancy because advanced gallbladder cancer carries a poor prognosis and resection at an early stage offers the only hope for cure.
What complicates matters is that none of the available imaging modalities can unequivocally distinguish neoplastic from non-neoplastic polyps.
This can be achieved only by microscopic examination after surgery.
Nevertheless, as discussed above, extracorporeal ultrasonography and endoscopic ultrasonography can give valuable information in the differential diagnosis of gallbladder polyps.

Patients who have gallbladder polyps and concomitant gallstones should undergo cholecystectomy regardless of the polyp size or the presence of symptoms since gallstones are a risk factor for gallbladder cancer in patients with gallbladder polyp.

Gallbladder polyps arising in the setting of primary sclerosing cholangitis are frequently malignant and thus warrant cholecystectomy.
Cholecystectomy should also be recommended for patients who have biliary colic or pancreatitis since an appreciable proportion of such patients who have cholesterolosis or adenomyomatosis improve after cholecystectomy.
On the other hand, patients with non-specific dyspeptic symptoms but without symptoms consistent with biliary colic should be managed conservatively (unless they have gallstones) since the pathogenesis of these symptoms is unclear and cholecystectomy may not relieve the symptoms. Such patients should be treated symptomatically as in other patients with chronic functional dyspepsia.

Recommendations for patients who do not fit in these categories can be made based upon the size of the polyps.

Lesions larger than 18 to 20 mm —

Lesions larger than 18 to 20 mm are usually malignant and should be resected.
Because these lesions may represent advanced cancer, patients should undergo preoperative staging with a CT scan and EUS.
An extended cholecystectomy with lymph node dissection and partial hepatic resection in the gallbladder bed is required when performing cholecystectomy for malignancy.

Lesions from 10 to 20 mm —

Polyps 10 to 20 mm in diameter should be regarded as possibly malignant (incidence of gallbladder cancer of 25 to 77 percent).
Cancer of this size is usually an early stage cancer and laparoscopic cholecystectomy with full thickness dissection (removal of the entire connective tissue layers of the gallbladder bed to expose the liver surface) is recommended.

Lesions from 5 to 10 mm —

Lesions 5 to 10 mm in diameter may represent cholesterol polyps, adenomas, or carcinomas.
Multiple polyps, pedunculated polyps, and those that are hyperechoic as compared to the liver are usually cholesterol polyps, while solitary and sessile polyps that are isoechogenic with the liver are more likely to be neoplastic.
However, the most reassuring finding is the stability of a polyp on repeated follow-up examinations.
There is no consensus regarding the frequency of ultrasonographic examinations that need to be performed for these lesions.
One group recommends that polyps of 5 to 10 mm in diameter should be followed in three months, six months, and then yearly.
An increase in polyp size is an absolute indication for surgery.

Lesions smaller than 5 mm —

Polyps smaller than 5 mm are usually benign and most frequently represent cholesterolosis.
Asymptomatic patients with cholesterol polyps do not need treatment.
However, a repeat ultrasound examination in 6 and 12 months may be appropriate.
Follow-up examination are not necessary if the polyp is stable.
Medical management aimed at increasing the solubility of cholesterol in bile by administering UDCA is without benefit in patients with cholesterolosis.

Tumors of the Gallbladder

2008-06-09T23:58:00.000+05:30

Benign and pseudotumors of the gallbladder

Most benign tumors of the gallbladder are detected as polypoid lesions.
In 1970, Christensen and Ishak proposed a simplified classification scheme of benign gallbladder lesions, which are classified as either tumors or pseudotumors.
Benign tumors are further classified into
- epithelial (adenoma) and
- mesenchymal (hemangioma, lipoma, etc.) variants.
Pseudotumors include such lesions as
- cholesterol and inflammatory polyps,
- adenomatous hyperplasia, and
- heterotopic tissues.

The prevalence of polypoid lesions of the gallbladder (PLG) in healthy subjects varies from 3 to 7% on ultrasound in up to 10% in cholecystectomy specimens.

The most common type of PLG is the cholesterol polyp, comprising 63% of 172 cases in the largest series of PLG reported in the literature.

Cholesterol polyps are characteristically small (10 mm), multiple, and appear as yellow spots on the surface of the gallbladder mucosa, giving rise to the term “strawberry gallbladder.”
They are formed by the proliferation of lipid-laden macrophages in the lamina propria and have no malignant potential.

Inflammatory polyps of the gallbladder are reactive lesions without malignant potential that are usually discovered at the time of cholecystectomy performed for chronic cholecystitis.

Microscopically, there is evidence of focal epithelial hyperplasia associated with a marked infiltration of chronic inflammatory cells.

Adenomyomatous hyperplasia of the gallbladder is characterized by extensions of the mucosa into and through a thickened muscular wall, typically in the fundus of the gallbladder.

These lesions have long been thought to have no malignant potential, though there are case reports of gallbladder carcinoma developing in areas of adenomyomatosis.

Simplified classification of benign tumors and pseudotumors of the gallbladder.

Benign tumors

Epithelial
- Adenoma, papillary
- Adenoma, nonpapillary

Supporting tissue
- Hemangioma
- Lipoma
- Leiomyoma
- Granular cell tumor

Benign pseudotumors

Hyperplasia
- Adenomatous
- Adenomyomatous (adenomyoma)

Heterotopia
- Gastric mucosa
- Intestinal mucosa
- Pancreas
- Liver
Polyp
- Inflammatory
- Cholesterol

Miscellaneous
- Fibroxanthogranulomatous inflammation
- Parasitic infection
- Other

The incidence of adenoma of the gallbladder is approximately 1% in cholecystectomy specimens, and these lesions can be papillary or sessile.

It is unclear whether a gallbladder adenoma represents a premalignant lesion.
Evidence in support of the adenoma to adenocarcinoma sequence comes from a study by Kozuka et al., in which the histology of 1605 gallbladders was reviewed.
Adenomatous components were identified in all of the in situ carcinomas and in 19% of the invasive carcinomas.
There was a distinct correlation between the size of the lesion and malignant change, with all benign adenomas measuring less than 12 mm in diameter, all adenomas with malignant change measuring greater than 12 mm in diameter, and most of the invasive cancers measuring greater than 30 mm in diameter.
Similarly, Koga et al. performed a comparative analysis between benign and malignant gallbladder lesions and found that 94% of benign lesions were smaller than 10 mm, whereas 88% of malignant lesions were greater than 10 mm.
Yang et al. provided further evidence in support of the malignant potential of large PLG in a clinicopathologic review of 182 patients with PLG. All 138 PLG less than 10 mm in diameter were benign, whereas all 13 malignant PLG measured greater than 10 mm in diameter, and most of these (11/13) were greater than 15 mm.

Others refute the polyp-to-cancer sequence and believe that gallbladder carcinomas arise in situ from flat, dysplastic epithelium.

Wistuba et al. extracted DNA from gallbladder adenomas and screened for mutations in the p53, Kras, and N-ras genes and five different chromosomal regions that had previously been shown to be frequently deleted in dysplasia, carcinoma in situ, and gallbladder carcinoma.

They found no mutations of the p53 gene in 16 gallbladder adenomas but did identify K-ras mutations in 25% of the adenomas.
K-ras mutations are rare in gallbladder carcinomas.
They concluded that gallbladder adenomas lack the molecular changes frequently seen in gallbladder cancers, arguing against a proposed adenoma–carcinoma pathway.
Other investigators have followed the natural history of PLG.

Moriguchi et al. followed 109 asymptomatic patients with PLG (94% <1>

Only one gallbladder carcinoma was identified, at a site distinct from that of the pre-existing polyp, and 88% of the PLG were unchanged in size.
The authors concluded that most PLG detected by ultrasound are benign.

Csendes et al. followed 111 patients with PLG smaller than 10 mm by clinical examination and ultrasound for a mean time of 71 months.

No patient developed symptoms of biliary disease, gallstones, or gallbladder carcinoma.

Collectively, these studies confirm that the most significant risk factor for malignancy in a PLG is a diameter greater than 10 mm.

Other risk factors include solitary PLG, symptomatic PLG, concurrent gallstones, and patient age greater than 50 years.

These factors then allow for the proper selection of patients with PLG who would most likely benefit from cholecystectomy.

Primary Sclerosing Cholangitis; treatment.

2008-06-03T16:26:00.000+05:30

Treatment of primary sclerosing cholangitis

Of critical importance is understanding a fundamental difference between sclerotic biliary tract disorders and disorders of a hepatocellular nature. Hepatocytes have a remarkable ability to regenerate, and, when the inciting agent (i.e. fulminant viral hepatitis) is removed, treated, or spontaneously disappears, patients can fully recover despite a major insult.

On the other hand, when patients with PSC (or other sclerotic biliary disorders) scar their biliary tree, this results in a permanent loss of function with limited ability for regeneration.
Once the serum bilirubin starts to rise, a seemingly irreversible, medically untreatable disorder is present and liver transplantation is the only viable, long-term alternative.

Ideally, medical therapy should be directed at the underlying cause of PSC (but this is unknown) and administered early in the course of the disease when the patient is asymptomatic, which is not always possible.

Although a variety of antifibrotic, anti-inflammatory, and immunosuppressive medications have been used to treat PSC, none of them has shone effectiveness in altering the natural history of the disease.

Treatment of the disorder is therefore divided into

medical therapy for PSC,
symptom control,
complication therapy, and
monitoring for malignancy

MEDICAL THERAPY

Medical treatments evaluated in primary sclerosing cholangitis.

Ursodeoxycholic acid (UDCA)
Methotrexate
Azathioprine
Cyclosporine
Corticosteroids
Colchicine
Cholestyramine
Antibiotics

Ursodeoxycholic acid (UDCA)

(UDCA), a hydrophilic bile acid, is the most extensively studied of all medical treatments for PSC.
UDCA, at a dose up to 15 mg/kg/d is thought to exert its effects in cholestatic conditions via

protection of cholangiocytes against cytotoxic hydrophobic bile acids,
stimulation of hepatobiliary secretion,
protection of hepatocytes against bile-acid induced apoptosis, and induction of antioxidants.

Although the standard dosages of UDCA (10 to 15 mg/kg) have been used in most studies, if biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22 to 25 mg/kg may be more effective than lower doses.
UDCA may have an immunologic effect by decreasing the expression of Class 1 antigens, and a choleretic effect by increasing bile flow.
Numerous uncontrolled trials demonstrated a beneficial effect (primarily biochemically with improvement of alkaline phosphatase).
Symptom improvement was variable and liver histology usually not available.

In one study UDCA was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin concentrations at one and two years, but there was no significant difference between the groups in time to treatment failure or liver transplantation.
Similarly, UDCA is not able to prevent the development of biliary strictures.
A derivative of UDCA (24-norursodeoxycholic acid) has shown promise in an animal model of PSC.
In a more recently presented abstract, the combination of UDCA with metronidazole in a randomized sample of 80 patients resulted in improved histology and New Mayo Risk Scores in patients in the combined group over a period of 3 years. The theory in this study is that the antibiotic may have activity against anaerobes and thereby decrease anaerobic bacteria within the biliary tree.

From these studies, it can be concluded that there is a beneficial effect of UDCA on serum transaminases and alkaline phosphatase; unfortunately, it does not appear to improve hepatic histology or symptoms or prolong survival, evolution of cirrhosis, or time to transplantation.

Recently, a study of 52 PSC/UC patients were assigned to UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06–0.92; P 0.034) versus a control group. UDCA therefore, significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.

Corticosteroids —

No studies to date have demonstrated a long-term benefit from corticosteroid therapy, either alone or in combination with agents such as colchicines.

As an example, a trial in which hydrocortisone was applied topically to the biliary tree via lavage with a nasobiliary tube resulted in worsening of liver function tests and also led to cholangitis and septicemia in some patients.
Systemic corticosteroid have also been associated with enhanced loss of trabecular bone, which leads to an increased risk of osteoporosis and spinal compression fractures.
This has been confirmed in a randomized trial from Sweden where colchicine (1 mg/day) was compared with placebo in 84 patients with PSC. At 3-year follow-up there were no differences in clinical symptoms, serum biochemistry, liver histology, or survival between the two groups.

METHOTREXATE

Methotrexate yielded promising results in an uncontrolled trial of 10 PSC patients.

Unfortunately, when the authors performed a prospective double-blind randomized control trial (methotrexate 15 mg/week versus placebo) in 24 patients with PSC, the only significant change was a fall (31%) in the serum alkaline phosphatase in those receiving methotrexate.
There was no improvement in symptoms, histology, serum albumin, bilirubin, or transaminases.
Complications of methotrexate were minimal, with only a single episode reported of Campylobacter enterocolitis and one leukopenic episode related to bacterial cholangitis.
Since many patients in this study had advanced disease (7/12 receiving methotrexate had cirrhosis), it is possible that a positive effect in early-stage PSC could have been missed.

A larger trial in early stage PSC is required to definitively determine the role of methotrexate in this disease.

Unfortunately, given its toxicity such as pulmonary fibrosis and hair loss, and the lack of benefit of methotrexate added to ursodeoxycholic acid (UDCA) in 19 patients with PSC by Lindor et al., it is unlikely that a larger trial can be justified.

D-PENICILLAMINE

Since hepatic copper levels are increased in all patients with cholestatic liver disorders, penicillamine was tested in a well-designed, randomized, placebo-controlled trial of 70 patients at the Mayo Clinic.

As expected, urinary excretion of copper increased with concomitant reduction in hepatic copper concentrations; however, after 3 years there were no beneficial effects on symptoms, biochemical results, liver histology, disease progression, or survival.
In addition, significant toxicity, such as proteinuria and pancytopenia, leading to permanent discontinuation of penicillamine, was noted in 21% of patients, thereby discouraging any further use of this agent in PSC.

IMMUNOSUPPRESSIVE THERAPY

Other immunosuppressive drugs have been tried in a number of studies. No controlled trials are available for azathioprine but in one uncontrolled study two patients improved, while in the other case report the patient deteriorated.

Cyclosporine —

A single controlled clinical trial has assessed the efficacy of cyclosporine in the treatment of PSC.

Aside from a decrease in serum alkaline phosphatase in treated patients, there was no effect upon symptoms or disease progression.
A case report noted radiologic and biochemical improvement after treatment with cyclosporine followed by prednisolone; however, the patient was also given ursodeoxycholic acid concomitantly, and follow-up was unavailable after eight months.

In another study Cyclosporine has been used in a randomized clinical trial involving 34 patients with PSC, most with coexisting ulcerative colitis. After 2 years of therapy, the ulcerative colitis had improved but there was no beneficial effect demonstrated on serum hepatic biochemistry.

Tacrolimus (FK-506) has been used in one open study in10 patients with PSC.

After 360 days, there was evidence of biochemical improvement in all patients. A randomized controlled clinical trial is required to confirm these results.

Etanercept (25 mg subcutaneously twice weekly) has also been used in a pilot study of 10 patients with symptomatic PSC.

Although there was some improvement in pruritis, there was no improvement in biochemical parameters.

Mycophenolate mofetil (MMF) is a new immunosuppressive medication that inhibits proliferation of B and T lymphocytes.

Recently, 30 patients underwent a 1-year trial with mycophenolate mofetil with no significant clinical or biochemical improvements.

MANAGEMENT OF COMPLICATIONS OF PSC

Associated complications of PSC include fatigue, pruritus, steatorrhea, fat soluble vitamin deficiency and its complications, including osteoporosis.

Fatigue often parallels progression of disease and can be disabling; however, no medical treatment has been demonstrated to be effective in ameliorating this symptom.

Pruritus can be intense, leading to a diminished quality of life as well as skin and systemic infections arising from excoriations.

The pathogenesis of itching may be related to the increased availability of endogenous opiate ligands at central receptors.
Although therapy for pruritus associated with cholestatic liver diseases typically is initiated with cholestyramine, other medical therapies include activated charcoal, rifampicin, phenobarbitol, plasmapheresis, and opiate antagonists (naloxone, nalmefene).
Cholestyramine is a nonabsorbable resin that binds bile acids and therefore results in increased fecal excretion of bile by inhibiting enterohepatic circulation.
- The dose is typically 12 to 24 g/day, but since over 50% of patients receiving the drug are troubled by constipation and nausea, compliance is often poor.
In primary biliary cirrhosis, rifampicin has been demonstrated to be more effective in reducing pruritus than phenobarbital.
- Unfortunately, up to 10% of patients develop drug-induced hepatitis from rifampicin, necessitating discontinuation of this medication.
Opiate antagonists such as naloxone are occasionally useful in ameliorating pruritus but they are awkward to use and can be expensive.
A more recent attempt at extracorporeal albumin dialysis in a single case was met with some improvement in biochemical parameters as well as pruritis.

Cholestasis eventually results in significant changes in fat malabsorption.

Although chronic pancreatitis and celiac disease have been associated with PSC and can contribute to fat malabsorption, most patients with PSC have steatorrhea secondary to decreased bile acid concentrations within the small intestine.
Fat-soluble vitamins (A, D, E, and K) are typically malabsorbed and patients can occasionally develop night blindness, osteomalacia, and coagulopathy.
Patients should be screened for these deficiencies and supplemental therapy supplied as required.

Osteoporosis is a common problem in cholestatic liver disease.

In 50% of PSC patients undergoing transplantation, the bone density levels are below the fracture threshold.
One third of liver transplant patients with PSC will develop vertebral compression fractures.
Bone mineral densities do not correlate with serum bilirubin (or the severity of liver disease) or 25-hydroxyvitamin D, fecal fat, or the presence or absence of ulcerative colitis.
As in primary biliary cirrhosis (PBC), the etiology of the osteoporosis is unknown and therapy has not been fully evaluated.
Dual-energy Xray absorptiometry and dual-photon absorptiometry are noninvasive techniques that provide an excellent quantification of the bone mass.
Antiresorptive agents such as the biphosphonates (etidronate, pamidronate, alendronate) may avoid the osteopenic complications but further clinical trials in this area are necessary.

The end stages of PSC are often associated with portal hypertension resulting in esophageal varices, ascites, and encephalopathy.

These complications can be managed in the usual fashion for patients with end-stage liver disease, with a few exceptions.

It has been demonstrated that 36% of patients with PSC will have esophageal varices and that a suppressed platelet count, advanced histological stage, and low albumin levels are all predictors of the presence of esophageal varices.
These patients should be targeted for endoscopic variceal screening protocols.
Particular caution should be maintained in patients being considered for systemic surgical shunting for difficult to control esophageal or gastric varices.

A troublesome complication of portal hypertension that occurs in those patients who have undergone proctocolectomy is bleeding from peristomal varices.

This bleeding can be severe with therapy of sclerosants only providing temporary relief.
TIPS or surgical portosystemic shunts can control bleeding, but since most of these patients have severe portal hypertension, liver transplantation should always be considered.

A recently recognized complication of PSC patients with a history of colitis is a substantially increased risk of colon cancer.

This risk appears to start relatively early in their course and continues even after liver transplantation (risk of colorectal cancer 10 to 14% at 5 years post-transplant).
Aggressive endoscopic surveillance is recommended.

ENDOSCOPIC MANAGEMENT OF PSC

Although bacterial cholangitis is an unusual presentation of PSC, once the biliary tree has been manipulated (either percutaneously, endoscopically, or surgically) it becomes colonized, typically with Gram-negative organisms, and recurrent biliary sepsis is common.

If “dominant” strictures are present, several major endoscopy centers have demonstrated that endoscopic therapy is successful in relieving sepsis and improving biochemical tests.
In 1987, the Milwaukee group reported on 10 patients with PSC in whom a total of 19 Gruentzig-type balloon dilations were performed.
- In those with high-grade strictures, endoprostheses were inserted.
- Strictures treated endoscopically were typically at the level of the hilum or common bile or hepatic duct.
- The number of hospitalizations decreased from 2.5 to 0.2 per year and over a follow-up period of 19 months both the serum bilirubin and alkaline phosphatase decreased significantly from 6.9 to 2.7 mg/dL and 959 to 385 IU/L respectively.
- Three patients died; one from a cholangiocarcinoma, one from bleeding peristomal varices, and the last from an unknown cause.
- Only one complication of endoscopic therapy was noted in this series: a single case of mild pancreatitis.

Subsequently, Cotton et al. reported a 32% reduction in bilirubin levels and 29% reduction in alkaline phosphatase after a mean follow-up of 6 months in 17 PSC patients treated with a combination of endoscopic dilation, endoprosthesis, and biliary sphincterotomy.

In 1991, the Milwaukee group expanded their previous cohort to 35 patients with a mean follow-up of 24 months.

They used a combination of dilating catheters and hydrostatic balloon dilators to dilate perceived dominant strictures.
In addition, biliary stents were inserted in 11 patients who could not be adequately dilated.
Typically, the stents were removed in 2 to 3 months and dilation performed during a second ERC.
They demonstrated that the number of hospitalizations, total serum bilirubin, and average radiological stricture score all decreased significantly in patients treated endoscopically.

Lee et al. subsequently reviewed the Duke experience by evaluating the results of 85 ERCPs in 53 patients with PSC.

Overall, 77% of patients had improvement in their clinical symptoms, liver function tests, or cholangiograms.
From the patients’ point of view, of 50 patients available for evaluation, 28 felt better, 21 the same, and one felt worse following the therapeutic ERCP.
These procedures are done with broad spectrum antibiotics before the ERC and for a minimum of 24 hours after the procedure.
Dilating balloons are typically held in position for 30 to 60 seconds until the constricted “waist” is obliterated.

Predicting which patients may benefit from a therapeutic ERC is always difficult. A single large study to evaluate these predictors was performed and reviewed all patients at Duke University undergoing ERC at PSC.

It demonstrated that those patients who underwent therapeutic procedures, had a dominant stricture (could be assessed pre-ERC with MRC to localize diseased segments), or were jaundiced had an increased rate of clinical/laboratory improvement following the procedure.

There are several problems with ERC in patients with PSC.

First, as noted by Gaing et al. in 1993, approximately 50% of patients will have disease that is primarily intrahepatic in nature, thereby making it more difficult to treat endoscopically.
With advancing radiological techniques such as magnetic resonance cholangiograms (MRC), it might be reasonable to consider screening patients with PSC with MRC to determine if there is disease that is amenable to endoscopic therapy.
Providing that MRC is sensitive and specific for the location of endoscopically amenable strictures, it could avoid diagnostic ERCs in selected patients.
Conceivably, even if, in theory, the lesions were amenable to endoscopic therapy the site and complexity of the procedure could be predicted (i.e. hilar strictures) and referral to a center with specialized ERCP expertise considered.
Second, the complication rate following an ERC in a patient with PSC may be as high as 15%.
- This is primarily accounted for by ascending cholangitis. Pre- and postoperative antibiotic should be administered in all patients with known and suspected PSC to avoid this complication.
Third, strictures in PSC must always be evaluated for the presence of malignancy.
- Even with aggressive brushing sampling, only a 50 to 60% sensitivity is obtained.
- A combination of serological tumor markers (e.g. CEA, CA19-9) with repeated brushings may increase the diagnostic yield of cholangiocarcinoma in this disease.
Finally, although there are reports of possible prolongation of survival with endoscopic therapy, convincing evidence of this, or increased survival or delaying transplantation, has not been demonstrated in most patients with PSC treated endoscopically.
Additionally, more recently some authors have challenged the results of endoscopic series suggesting that at follow-up after endoscopic treatment of dominant strictures there is actually very little, if any, alteration in biliary biochemical parameters.
Randomized trials have been suggested but are unlikely to be performed as, given that this is a relatively uncommon condition, a multicenter approach would be required and patients would be difficult to randomize to a “sham” arm of the study.

Recent investigators have looked at the use of nasobiliary lavage following endoscopic therapy.

Wagner et al. followed 12 patients with dominant strictures from PSC treated with hydrostatic balloon dilation and nasobiliary drainage for up to 50 months.
Eight patients demonstrated biochemical improvement with only three requiring liver transplantation.
No major complications were reported.

Present methods of endoscopic therapy have not been controlled or randomized and clearly have significant bias. However, the results demonstrated by multiple authors have proven a major role for ERC in the therapy of PSC by demonstrating significant biochemical and radiological improvement in selected patients.
Although the diagnostic potential of MRC may be great, the therapeutic role of ERC in PSC is unlikely to be replaced in the near future.

It must be remembered, however, that published results have been produced by experts at experienced biliary centers and these results may not be generalizable to smaller centers.

CHOLANGIOCARCINOMA

Up to 15% of patients with PSC may eventually develop cholangiocarcinoma.

The patients at highest risk have traditionally been reported to be those with longstanding cirrhosis and ulcerative colitis.
However, in a single study by Burak et al. the only clinical risk factor for cholangiocarcinoma in this patient population was a history of variceal bleeding (RR 24.2; 95%CI: 3.3–67.1).
It would be logical to theorize that cholangiocarcinoma may be more common in those patients with dominant biliary strictures and one recent abstract has demonstrated a 20% malignancy rate over the 2 years following diagnosis of a dominant biliary stricture in a large series of PSC patients.

Bile duct carcinomas have been difficult to diagnose since no single test has proven both sensitive and specific for the disorder.

Ultrasound and computed tomography (CT) have a low sensitivity for the diagnosis of primary bile duct tumors.
The advent of duplex ultrasonography and bolus-enhanced CT scans may increase sensitivity up to 80%.
Biliary brushings of the stricture have a variable yield of between 50 and 80%.
In addition to technical factors regarding tissue sampling, the yield may be increased by careful attention to cytological classification systems.
Tumor markers, such as serum CEA, have not been shown to be sensitive, with a sensitivity of only 53% being reported in one group of 15 patients with cholangiocarcinoma (11 occult tumors).
Serum levels of Ca 19-9 appear to be slightly more sensitive and specific, although it has not been found to be predictive of cholangiocarcinoma in patients with advanced disease (the group thought most likely to develop this tumor).
Ramage et al. have shown that the calculation of a serum tumor index (CEA . 40 + carbohydrate antigen (CA) 19-9) was 86% accurate in diagnosing cholangiocarcinoma in PSC patients and probably is the best laboratory-based method to raise suspicion of a malignant lesion.
Biliary CEA, which can be detected through bile aspirates, also has been suggested as a possible marker for cholangiocarcinoma.
- Unfortunately, it is also elevated in patients with intrahepatic cholelithiasis, which is relatively common in PSC.
- Biliary CEA is also mildly elevated in PSC itself making its accuracy in assessing cholangiocarcinoma in PSC questionable.
Biliary Mac-2BP levels were elevated by a factor of approximately three in the biliary carcinoma group compared with the group of patients who had PSC or another type of non-neoplastic biliary disease.
Serum levels of Mac-2BP levels were not elevated in those patients with biliary tract cancers.
- According to the immunohistochemical analysis, Mac-2BP was expressed in 34 of 36 patients (94.4%) with biliary tract carcinoma.
- As a diagnostic marker for biliary carcinoma, Mac-2BP levels were as accurate as biliary CA19-9 levels; however, the use of both of these bile markers in combination led to significantly better diagnostic accuracy compared with the accuracy achieved using CA19-9 alone (area under the curre, 0.75; P < 0.001).
- It appears from this study that biliary Mac-2BP levels show promise as a novel diagnostic marker for biliary tract carcinoma.

The prognosis for cholangiocarcinoma in the setting of PSC is poor, with a reported survival of less than 12 months.

However, in patients with the incidental finding of cholangiocarcinoma in the explanted liver (with regional lymph nodes clear of disease), long-term survival similar to those undergoing transplant without cholangiocarcinoma has been reported.
Therefore, those patients who are diagnosed with cholangiocarcinoma preoperatively may be expected to have a poor prognosis; however, it has been reported that those with cholangiocarcinoma discovered incidentally may have a long survival.
In other studies, however, even those with cholangiocarcinoma discovered incidentally have been demonstrated to do poorly with liver transplantation, typically dying of metastatic disease, leading most transplant centers to “steer clear” of suspected malignant biliary trees.
Some authors have suggested that early transplantation (pre-emptive transplant) to decrease the risk of cholangiocarcinoma may be considered.
- One argument against this approach is that retransplantation rates appear to be higher with graft survival slightly shorter than other commonly transplanted disorders (i.e. PBC) and therefore PSC would not be an ideal setting to initiate early transplantation.

Liver transplantation

Despite limitations, the treatment of choice for end-stage PSC is liver transplantation.

The reported 1- and 3-year survival rates are 85 and 75% respectively.
Patients with PSC undergoing liver transplantation have significantly improved survival when compared to patients undergoing liver transplantation for most other indications.
One of the challenges facing today’s hepatologists is not only the timing of the transplant, but determining when patients should be referred to transplant centers to optimize the results and minimize resource utilization.
Although results with liver transplantation are improved, there is a shortage of donor livers for transplant and actual survival from the time of listing to transplant is much shorter than the results demonstrated after transplantation.
In a recent Nordic study the 5- and 10-year survival from the time of listing for transplant was evaluated and demonstrated to be 68% and 58% respectively.
Additionally, resource utilization is a clear concern and overall expenditures for PSC patients in liver transplantation have been demonstrated to be more favorable than those patients with alcoholic liver disease, which clearly is more common.
Additionally, in the same study the cost per quality-adjusted life-year from time of listing for PBC was greater (29,000 pounds) than PSC (21,000 pounds).

In conclusion, liver transplantation increases the survival and health-related quality of life of patients with each of three end-stage liver diseases; however, when evaluating cost issues, PSC is very favorable.
Anther disease-specific complication that occurs in PSC transplantation is a recurrence of the underlying disease, which does occur pathologically in up to 30% of patients.

Clearly, transplantation may be required for the usual complications of cirrhosis, such as recurrent variceal bleeding, diuretic-resistant ascites, and hepatic encephalopathy.
Unlike other causes of cirrhosis, however, symptoms particular to PSC such as wasting, fatigue, pruritus, recurrent bacterial cholangitis, and jaundice without evidence of cholangiocarcinoma often prompt referral to transplant centers.
In an era where organs such as livers are in short supply, it is often difficult to accommodate potential recipients (even if they are excellent candidates) and various strategies for transplant assessment are used.
Rarely, other types of surgical procedures, such as hepaticojejunostomy or partial hepatectomy, can be considered.
These types of procedures need to be performed with consultation of transplant orientated surgeons to ensure that they don’t preclude the patient from subsequent liver transplantation.
In rare, selective cases long-term symptom relief may be obtained with selective surgical intervention.

A number of complications particular to PSC patients do occur post-transplant.

PSC patients seem to have a higher incidence of chronic ductopenic rejection post-liver transplant compared with PBC.
In addition, colon cancer in patients with PSC and ulcerative colitis represents a significant cause of late mortality after liver transplantation; therefore, surveillance every 6 to 12 months by colonoscopy is recommended.
Nonanastomotic biliary strictures, not associated with recurrent PSC, post-liver transplantation have been reported with increasing frequency and can be difficult to manage.
Although definitive criteria for the diagnosis of PSC recurrence have not been established post-liver transplantation, some patients appear to develop a similar syndrome postoperatively.
Males and an intact colon prior to transplant have been shown to have a higher risk of recurrent PSC in one pathological study of 152 transplanted PSC patients of whom 52 had recurrent PSC.
Other conditions such as ischemia, cytomegalovirus infection, and chronic ductopenic rejection must also be considered in the differential diagnosis of post-transplant PSC.

Primary Sclerosing Cholangitis; clinical features and diagnosis.

2008-05-27T18:35:00.000+05:30

Continued destruction of bile ducts in PSC leads to end-stage liver disease and portal hypertension. Patients with PSC also may develop a number of other complications, including:

Cholestasis-associated problems
Biliary stricture
Cholangitis and cholelithiasis
Cholangiocarcinoma
Colon cancer

Clinical manifestations

PSC predominantly affects males, with a median onset of 40 years of age but a wide range of 1 to 90 years. Pediatric cases show an increased association with immunodeficiency states (10%) and histiocytosis X (15%), and a lesser association with inflammatory bowel disease (47%). The male predominance occurs primarily in patients with both PSC and ulcerative colitis.

Clinical presentation of primary sclerosing cholangitis.
Source: Ludwig et al.
Symptom Percent of presentation
Jaundice 75–80
Right upper quadrant pain 50–55
Pruritus 30–35
Fever 20–25
Weight loss 15–20
Fatigue 10–15
Asymptomatic 5–10

PSC has been reported in all races.
The disorder tends to develop insidiously, with symptoms present in one study for a mean of 52 months (range 0– 451 months) prior to diagnosis.
Symptoms of PSC are often nonspecific initially, but jaundice, right upper quadrant pain, pruritis, fever, weight loss, and fatigue subsequently develop.
Atypical presentations of fever of unknown origin or acute supportive cholangitis have been reported.
Periodic exacerbations and remissions are typical of the disorder.
- Exacerbations may be precipitated by gallstones, which form in a strictured biliary tree where normal flow is impeded.
Depending on the location of the stones and the strictures, endoscopic or percutaneous treatment can be useful in removing a nidus of recurrent infection.
Unfortunately, many strictures and stones develop in the proximal biliary tree, which may be less amenable to mechanical intervention.
An association with other autoimmune disorders has been noted in patients with PSC.
More recently, an association with celiac disease has also been documented.

With the increased awareness of PSC, availability of ERCP, and use of laboratory screening, more patients who have asymptomatic elevations in liver enzymes are being diagnosed with this disorder, particularly if they have underlying ulcerative colitis.

In particular, asymptomatic elevations of alkaline phosphatase in the setting of chronic ulcerative colitis should raise the suspicion of sclerosing cholangitis and trigger further investigation.

Early in the course of PSC, the physical examination is normal.

As the disease progresses, physical stigmata of chronic liver disease (spider angioma, jaundice, palmar erythema) and hepatosplenomegaly may become apparent, as well as the development of portal hypertension, resulting in ascites and varices.

Laboratory evaluations

Elevation of cholestatic liver enzymes is typical of this disease.

Up to 98% of patients will have an increase in the alkaline phosphatase level, although normal alkaline phosphatase levels have occasionally been recorded, even in symptomatic patients.
Most often, the serum alkaline phosphatase is at least twice the upper limit of normal, out of proportion to that of the serum bilirubin.
Serum bilirubin levels are also variable (especially early in the course of the disease) but inevitably, as the disease progresses, elevations occur in conjunction with a gradual decline in serum albumin.
Caution must be used in interpreting isolated findings of low albumin as a negative prognostic factor in PSC, as it may also be decreased by active inflammatory bowel disease in many patients.
Transient worsening of serum transaminases and bilirubin often occurs during exacerbations of the disease.
These will often return to near normal when the episode of fever, chills, or right upper quadrant pain has resolved.

Additional serologic findings in patients with PSC include:

Hypergammaglobulinemia — 30 percent
Increased serum IgM levels — 40 to 50 percent
Atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) — 30 to 80 percent
Human leukocyte antigen DRw52a — 0 to 100 percent in various reports.

Antimitochondrial antibodies, which are characteristic of primary biliary cirrhosis, are usually absent in PSC

The presence of autoantibodies did not correlate with disease severity, with the exception of anticardiolipin antibodies, which correlated with the Mayo risk score.
Interestingly, elevated serum IgG4 (a marker of autoimmune pancreatitis) has been described in up to 9 percent of patients with PSC.
Hepatic and urinary copper levels are increased and serum ceruloplasmin is reduced in most patients with PSC.
- However, these findings are not specific, being commonly found in patients who have other forms of chronic cholestatic liver disease.
- Copper accumulation worsens as the disease progresses.

DIAGNOSIS

The diagnosis of PSC is established by the demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography.
Abnormal bile ducts may also be suggested on ultrasound, although findings are usually not diagnostic.
Magnetic resonance cholangiography may be an alternative to endoscopic cholangiography, particularly if the image quality continues to improve.

The biliary strictures may be focal, with normal intervening areas, or diffuse and involve a long segment. Strictures can occur in any part of the biliary tree. In one report of 100 patients, strictures were present in the following distribution:

Intrahepatic and extrahepatic bile ducts — 87 percent
Intrahepatic bile ducts alone — 11 percent
Extrahepatic bile ducts alone — 2 percent

The gallbladder and cystic duct may also be involved.

An ERC in patients with PSC is not without risk; a complication rate of up to 14% has been documented.

In particular, cholangitis can occur, presumably because focal areas of the biliary tree are poorly drained, resulting in biliary stasis.
Since an ERC catheter is not sterile, infection of the biliary tree following an ERC is not uncommon.
To decrease this risk, all patients with suspected PSC should receive broad-spectrum antibiotics prior to the procedure.
Those who have been demonstrated at ERC to have PSC should receive several days of antibiotics postprocedure.
Since most ERCs are done as daycare procedures, an oral antibiotic is preferable, although parenteral antibiotics can easily be administered prior to the procedure.
Ciprofloxacin is effective against most of the typical biliary pathogens.

In contrast to the characteristic strictures, shallow ulcerations of the bile ducts may be the only cholangiographic finding in patients with early stage disease.

In addition, cholangiography is normal in a small percentage of patients who have a variant of PSC known as "small-duct primary sclerosing cholangitis."
This variant (sometimes referred to as "pericholangitis") is probably a form of PSC involving small caliber bile ducts.
It has similar biochemical and histologic features to classic PSC. It appears to have a significantly better prognosis than classic PSC, although it may evolve into classic PSC.
Classic PSC developed in only 4 of 27 patients in one series that focused on 27 of 32 patients with small-duct PSC who had undergone repeated cholangiographic examinations after a median of 72 month.
Pancreatograms have been noted to be abnormal in up to 10% of PSC patients. Stricturing or tapering of the pancreatic duct was noted in 3/40 patients with PSC in the Mayo series.
An unusual amount of pancreatic duct reflux was noted in 43% of patients and overall pancreatic duct abnormalities in up to 50% of patients.

Differential diagnosis —

Secondary causes of the cholangiographic findings described above should be considered. These include

chronic bacterial cholangitis,
infectious or ischemic cholangiopathy, and
malignancy.

A rare, steroid-responsive disorder involving stricturing of the pancreaticobiliary tract and elevated serum levels of IgG4 has been described that shares clinical and radiographic features with PSC.

This disorder has been referred to as sclerosing pancreatocholangitis, autoimmune pancreatitis, and immunoglobulin G4 associated cholangitis.
Some authorities suggest that serum IgG4 be measured in all newly diagnosed patients with PSC.
Corticosteroids can given to those with clinical, biochemical and imaging features of immunoglobulin G4 associated cholangitis provided that a response can be assessed on imaging and liver biochemistries.

Liver biopsy —

A percutaneous liver biopsy may support the diagnosis of PSC, but is rarely diagnostic.

The most specific histologic finding in PSC is fibrous obliteration of small bile ducts, with concentric replacement by connective tissue in an "onion skin" pattern.
More often, histologic abnormalities in PSC are nonspecific and are similar to those in primary biliary cirrhosis.

The histologic findings initially involve the portal triads, but expand into the hepatic parenchyma as the disease progresses.
As a result, liver biopsy is helpful for staging the disease and determining prognosis.

The staging system used most commonly in PSC is similar to that used in primary biliary cirrhosis:

Stage I — Enlargement, edema, and scarring of the portal triads, and mononuclear cell infiltration with some piecemeal necrosis and damage to isolated bile ducts. Proliferation of interlobular bile ducts with mononuclear and polymorphonuclear cells may also be present, although the inflammation is usually less dense than in primary biliary cirrhosis.

Stage II — Expansion of portal triads with fibrosis extending into the surrounding parenchyma

Stage III — Bridging fibrosis

Stage IV — Cirrhosis

Liver biopsies are not routinely recommended following a diagnostic cholangiogram.

PROGNOSIS —

PSC is usually a progressive disorder that ultimately leads to complications of cholestasis and hepatic failure.
Median survival without liver transplantation after diagnosis is 10 to 12 years.
Survival is significantly worse for patients who are symptomatic at the time of diagnosis.

Several groups have studied variables that appear to predict prognosis in PSC. These include age, histological stage, hepatomegaly, splenomegaly, serum alkaline phosphatase, and serum bilirubin.

One study, for example, found that approximately 90 percent of those with stage II disease would be expected to progress to bridging fibrosis or cirrhosis while approximately one-half of those who had already developed bridging fibrosis were expected to develop cirrhosis within five years. This was a predicted progression based on their model.

Variables associated with prognosis have been incorporated in a well-validated statistical model (the Mayo risk score.

The components of the Mayo risk score include age, serum bilirubin, serum albumin, serum AST, and history of variceal bleeding.
The calculation of this risk score correlates well with observed survival and is useful in assessing prognosis and determining timing for liver transplantation.

CHOLESTASIS —

The complications common to all of the chronic cholestatic liver diseases such as PSC include fatigue, pruritus, steatorrhea, fat-soluble vitamin deficiencies (A, D, E, and K), and metabolic bone disease. Little is known about the pathogenesis of fatigue; nevertheless, it may become quite debilitating, and is one of the prime indications for liver transplantation.

Pruritus —

Pruritus is a common symptom of PSC which can be extremely disabling, leading to severe excoriations and a decreased quality of life.

The pathogenesis of pruritus in PSC, as in other disorders which cause cholestasis, is not clear. Several hypotheses have been proposed, including bile acid accumulation and endogenous opioids.
Treatment should be based upon the severity of the pruritus.

Steatorrhea and vitamin deficiency —

Steatorrhea with concomitant fat soluble vitamin deficiency in patients with PSC is generally thought to be due to decreased secretion of conjugated bile acids into the small intestine.
However, associated conditions that may coexist with PSC, such as chronic pancreatitis and celiac disease, may also contribute to the genesis of steatorrhea; these disorders should be considered in the differential diagnosis of steatorrhea in a patient with PSC who has no jaundice or evidence of cirrhosis by histology.

Vitamin A deficiency has been reported in up to 82 percent of patients with advanced PSC, occasionally accompanied by night blindness.
In addition, vitamin D and vitamin E deficiencies occur in approximately one-half of those with advanced disease.
Thus, patients with PSC should be screened for fat soluble vitamin deficiencies by determination of the prothrombin time (vitamin K) and serum levels of vitamins A, D, and E.
Supplemental therapy should be administered as necessary.

Metabolic bone disease —

Metabolic bone disease, in particular osteoporosis, is a complication of advanced PSC, with radiologic and histologic evidence of osteopenia in the lumbar spine, iliac crest, and femur.
An illustrative study found that 38 percent of patients with PSC had a bone density more than three standard deviations below the mean in the lower lumbar spine and the femoral neck on dual photon absorptiometry.
In a second report, bone density was measured in 30 patients with advanced PSC (group1) and 18 patients with newly diagnosed disease (group 2).
- Mean bone mineral density was significantly reduced in group 1 compared with age-matched and sex-matched controls (0.97 versus 1.25 gm/cm2); in 15 of the 30 patients, bone density was below the fracture threshold.
- In contrast, bone mineral density in group 2 was not significantly different from controls, and no patient was below the fracture threshold.

Patients with PSC are also prone to develop fractures after liver transplantation, even in the absence of metabolic bone disease, due to immobilization and concomitant therapy with Corticosteroids.

The pathogenesis of bone disease in PSC and other chronic cholestatic liver diseases (eg, primary biliary cirrhosis) is unknown.
Bone disease in patients with PSC is due to osteopenia/osteoporosis rather than osteomalacia, and thus, malabsorption of vitamin D,
slow serum vitamin D concentration is not the cause in most cases.
Furthermore, vitamin repletion in the minority of cases with low serum levels does not reduce either the presence or severity of osteoporosis.

Radiologic techniques such as dual photon absorptiometry are superior to traditional serum and urinary markers of bone loss for diagnosing osteopenia in patients with PSC. The axial skeleton (eg, trabecular bone of the lumbar spine) is affected more commonly than the appendicular skeleton (cortical bone).

Although few studies have specifically addressed the treatment of bone disease in PSC, management principles are similar to those in primary biliary cirrhosis. Calcium supplementation and measurement of vitamin D levels are generally recommended.

For patients with more significant loss of bone density, bisphosphonate therapy may also be beneficial.

DOMINANT BILIARY STRICTURES —

Approximately 20 percent of patients with PSC develop a dominant stricture in the intrahepatic or extrahepatic biliary tree.
Strictures can occur at the biliary hilum or anywhere along the common hepatic or common bile ducts.
Patients typically present with evidence of mechanical biliary obstruction manifested by jaundice, pruritus, ascending cholangitis, and malabsorption.
This presentation is difficult to distinguish from that of cholangiocarcinoma.
Thus, if a dominant stricture is identified, cytologic brushings of the stricture should be performed to exclude malignancy.

Medical therapy to treat biliary strictures has been ineffective. Nonsurgical modalities to relieve biliary obstruction, such as endoscopically or radiologically guided balloon dilation of strictures or placement of prosthetic stents across strictures, should be attempted initially.

CHOLANGITIS AND CHOLELITHIASIS —

Choledocholithiasis and cholelithiasis, due to cholesterol and/or pigment stones, may be present in up to one-third of patients with PSC.
Ultrasonography can identify biliary obstruction but has a low sensitivity for determining its cause (eg, stricture, stone, or neoplasm).
Thus, cholangiography should be used to detect reversible causes of biliary obstruction.

Gallstones in patients with PSC are treated the same way as in other patients.

are made to remove gallstones only if they are causing obstruction of the major bile ducts; incidental gallstones in the gallbladder are not treated unless the clinical scenario dictates that they need to be removed.

Bacterial cholangitis can occur in patients with PSC.

The risk is greatest after endoscopic or surgical manipulation (including liver biopsy), but cholangitis can also develop spontaneously, particularly in patients with bile duct stones or obstructing strictures. Biliary candida infections have also been described.

CHOLANGIOCARCINOMA —

Patients with PSC have a 10 to 15 percent lifetime risk of developing cholangiocarcinoma; those with inflammatory bowel disease and cirrhosis may be at highest risk.
In one series, the only independent risk factor for development of cholangiocarcinoma in patients with PSC was variceal bleeding.

The annual incidence of cholangiocarcinoma developing in the setting of PSC has been estimated to be 1.5 percent.
In a series of 161 patients seen at the Mayo clinic, 7 percent developed cholangiocarcinoma during a mean follow-up of 11.5 years.
The development of cholangiocarcinoma is often heralded by rapid clinical deterioration with jaundice, weight loss, and abdominal discomfort.
The presence of progressive biliary dilatation in the setting of a dominant stricture should also raise a strong suspicion of cholangiocarcinoma.

Why patients with PSC develop cholangiocarcinoma is not well understood.

A case-control study compared 20 patients with PSC and hepatobiliary carcinoma (17 cholangiocarcinoma, 2 hepatocellular carcinoma, 1 gallbladder carcinoma) to 20 age- and sex-matched patients with PSC without cancer.
No clinical or biochemical risk factors for the development of cancer could be identified in the year before cancer diagnosis.
In another case-control trial, the risk was increased by regular alcohol consumption.

Diagnosis and screening —

The diagnosis of cholangiocarcinoma can be extremely difficult in patients with PSC.
In an illustrative study, 10 percent of patients with PSC undergoing liver transplantation had an unsuspected cholangiocarcinoma.
Delayed diagnosis often results in the discovery of tumors at an advanced stage when they cannot be resected for cure.
As previously mentioned, it is also difficult to distinguish a dominant stricture from a cholangiocarcinoma, even with imaging, endoscopic biopsy, and cytology.

The tests used to make the diagnosis include biliary brush cytology, endobiliary biopsy, CT or MRI scanning, and serum tumor markers such as CEA or CA 19-9.

However, all of these studies have limitations while none has proven to be beneficial for screening.
It is not recommended to do routine screening for cholangiocarcinoma in patients with PSC.
No studies have been performed that demonstrate a benefit in patient outcomes with screening using serum tumor markers, imaging studies, or cholangiographic brush cytology.

Prognosis — The presence of cholangiocarcinoma portends a poor prognosis in patients with advanced PSC; only 10 percent of patients survived two years in one report.

Liver transplantation has been a disappointment in the treatment of cholangiocarcinoma, with significantly lower patient survival due to recurrent disease.
Thus, most transplant centers are not transplanting these patients outside of study protocols.
The poor prognosis has led to the suggestion for earlier liver transplantation in patients with PSC before cholangiocarcinoma has a chance to develop.

COLON CANCER —

Patients with both PSC and ulcerative colitis have an increased risk of colon cancer and progression of neoplastic transformation.

Based upon these data, it would seem appropriate to perform frequent colonoscopic surveillance with multiple biopsies every 10 cm in the colon to screen for dysplasia in patients with PSC and ulcerative colitis. Surveillance colonoscopy should begin once a diagnosis of ulcerative colitis is established in a patient with PSC.

Primary sclerosing cholangitis (PSC); epidemiology, classification and etiology.

2008-05-22T16:54:00.000+05:30

INTRODUCTION

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease of unknown etiology, characterized by inflammation, destruction, and eventual fibrosis of intrahepatic and extrahepatic bile ducts which can lead to end-stage liver disease.

Focal strictures of the biliary tree lead to cholestasis and a characteristic beaded appearance on cholangiography.
The disease may progress silently, or with recurrent episodes of cholangitis characterized by right upper quadrant pain, fever, and jaundice.
Insidious, but continuous, progression to cirrhosis with concomitant portal hypertension and liver failure is typical.
PSC is much less common than alcoholic liver disease; nonetheless, because it often affects otherwise healthy young people, it is the fourth most common indication for liver transplantation in the US
Delbet first described the syndrome of PSC in 1924, the disease was considered a rare medical curiosity with fewer than 100 cases reported up until 1970
With the advent improved imaging techniques, particularly endoscopic retrograde cholangiography (ERC) in 1974, the numbers of cases diagnosed in most major centers increased.
Mayo Clinic and Royal Free Hospital in London increased interest in the disease as it was quickly realized that the disorder had an association with inflammatory bowel disease (IBD), more often affecting young males with ulcerative colitis.

EPIDEMIOLOGY

In one study it was found that between the years 1976 and 2000 the incidence of PSC in men (1.25/100,000 person-years) was twice that of women (0.54/100,000 person-years).
The prevalence of PSC, during the same time period, was three times greater in men (20.9/100,000 versus 6.3/100,000) than women. The same study confirmed the findings that 73% of cases have IBD, most of them ulcerative colitis.

One of the reasons why the prevalence of this disease appears to be increasing is that the availability of diagnostic tests has increased.
Many patients may simply have mildly increased liver enzymes and through thorough investigations be found to have PSC.
The widespread implementation of ERCP and MRCP has likely led to a greater number of patients being diagnosed at an earlier stage of the disease, which has also contributed to an improved understanding of the disorder.

PSC and inflammatory bowel disease —

UC has been reported in 25 to 90 percent of patients with PSC.
A survey of 23 hospitals in Spain, for example, examined the reported cases of PSC from 1984 to 1988; UC was present in 44 percent.
It is likely that this figure is an underestimate, since the colonic mucosa may be grossly normal in appearance despite the presence of histologic colitis.
The true prevalence of UC in PSC is probably closer to 90 percent when rectal and sigmoid biopsies are routinely obtained.

There are varying reports of the prevalence of PSC in UC.

A survey of 1500 patients with UC in Sweden, for example, found that 72 (5 percent) had an elevated serum alkaline phosphatase; endoscopic retrograde cholangiopancreatography (ERCP) was performed in 65, of whom 55 (85 percent) had evidence of PSC.
PSC was more prevalent in patients with pancolitis than in those with distal colitis (5.5 versus 0.5 percent).
It was also more common in men than women.
Another report found that more than 7 percent of patients with UC may have PSC.

PSC also occurs in patients with Crohn's disease.

In one report of 262 patients with Crohn's disease, 38 (15 percent) had long-standing abnormal liver biochemical tests and underwent endoscopic cholangiography and liver biopsy.
Nine of these patients (3.4 percent) were diagnosed with PSC.

Gender —

Approximately 70 percent of patients with PSC are men, with a mean age at diagnosis of 40 years, even though the sex distribution is equal between men and women in the overall UC population.
However, in the small subset of patients without UC, the male:female ratio is lower (0.8:1) and patients are diagnosed at an older age.
Women with PSC are generally diagnosed at an older age.

CLASSIFICATION

The early classifications of PSC were very rigid and excluded patients with gallstones, previous biliary tract surgery, inflammatory bowel disease, and retroperitoneal fibrosis.

Additionally, progression of disease over a 2-year time period was mandatory prior to the diagnosis.
These strict criteria seem unjustified and present classification schemes divide sclerosing cholangitis into
- primary (of unknown etiology) and
- secondary (with a known or suspected underlying cause).

Criteria for the diagnosis of primary sclerosing cholangitis.
Source: Porayko et al.

Presence of typical cholangiographic abnormalities of PSC (involving bile ducts segmentally or extensively)
Compatible clinical, biochemical, and hepatic histologic findings (recognizing that they are nonspecific)
Exclude the following in most instances.
- Biliary calculi (unless related to stasis)
- Biliary tract surgery (other than simple cholecystectomy)
- Congenital abnormalities of the biliary tract
- AIDS-associated cholangiopathy
- Ischemic strictures
- Bile duct neoplasms (unless PSC previously established)
- Exposure to irritant chemicals (fl oxuridine, formalin)
- Evidence of another type of liver disease, such as primary biliary cirrhosis or chonic active hepatitis.

Since the majority of patients with PSC have IBD, patients can be further classified as those with associated inflammatory bowel disease and those without

The most common secondary causes of sclerosing cholangitis include

ischemia (arising from operative trauma, hepatic arterial infusion of floxuridine, allograft rejection),
recurrent biliary sepsis,
multifocal cholangiocarcinoma,
AIDS, and
toxic agents (formaldehyde, absolute alcohol).

Radiographically, secondary causes of sclerosing cholangitis simulate PSC but the clinical course and therapeutic options may differ considerably.

Caroli and Rosner developed an anatomical classification in which the condition is divided according to whether involvement of the biliary tree is diffuse or segmental.

Segmental involvement could further be divided into disease that affects the hepatic duct junction, the common hepatic duct, or the common bile duct.

Longmire’s classification of primary sclerosing cholangitis.
Source: Longmire.

Type Frequency Clinical/radiological features (%)

Type -1 5–10% Affecting primarily distal common bile duct

Type -2 5–10% Occurring soon after attack of acute necrotizing cholangitis

Type -3 40–50% Chronic diffuse

Type -4 40–50% Chronic diffuse associated with inflammatory bowel disease

Type of duct/ Cholangiographic appearance classification
Intrahepatic
Type I Multiple strictures, normal caliber of bile ducts
Type II Multiple strictures, saccular dilations, decreased arborization
Type III Only central branches filled, severe pruning

Extrahepatic
Type I Slight irregularity of duct contour, no stricture
Type II Segmental stricture
Type III Stricture of almost the entire length of the duct
Type IV Extremely irregular margin, diverticulum outpouchings.

The classic onion-skin lesions are rarely seen on percutaneous biopsy of the liver; therefore, the diagnosis has usually been made through cholangiography.

Histologically, PSC tends to gradually progress through four reasonably well-characterized stages.

Stage 1 is the earliest, characterized by degeneration of epithelial cells in the bile duct and an inflammatory infiltrate localized to the portal triads.
In stage 2, fibrosis and inflammation infiltrate the hepatic parenchyma with subsequent destruction of periportal hepatocytes resulting in piecemeal necrosis and loss of bile ducts.
In stage 3, cholestasis becomes more prominent and portal-to-portal fibrotic septa are characteristic.
In stage 4, frank cirrhosis develops, with histological features similar to other causes of cirrhosis.

Associated disorders

The most common association is with inflammatory bowel disease, which affects up to 75% of patients with PSC.

Of these patients, over 80% have ulcerative colitis (UC) and less than 20% have Crohn’s disease.
Conversely, only 2.5 to 7.5% of patients with UC have or will develop PSC.
The true prevalence is likely much higher, but because many patients with UC are asymptomatic and show only minimal elevation in liver enzymes, cholangiography is not performed and they may remain undiagnosed.

Many other disorders, particularly inflammatory disorders, show an association with PSC. These include

hypereosinophilic syndrome,
Sjögren’s syndrome,
systemic sclerosis,
celiac disease,
pancreatitis,
Behçet’s syndrome,
histiocytosis X,
sarcoidosis,
sicca complex,
rheumatoid arthritis,
systemic mastocytosis,
histiocytosis X, and
Reidel’s thyroiditis.

PATHOGENESIS —
The cause of PSC is unknown, and multiple mechanisms are likely to play a role.

The tight association between PSC and UC (a known autoimmune disease) suggests an autoimmune process. However, other mechanisms are likely to be important since only a minority of patients with UC have PSC.

An inflammatory reaction in the liver and bile ducts may be induced by chronic or recurrent entry of bacteria into the portal circulation. Liver damage may also result from the accumulation of toxic bile acids that are abnormally produced by colonic bacteria or chronic viral infection.

Ischemic damage to the bile ducts may occur.

Although the relationship between PSC and UC suggests a possible common pathogenesis, the two disorders may occur at different times. PSC may develop years after colectomy for UC, and UC may first present after liver transplantation has been performed for PSC.

Given the close association of PSC with ulcerative colitis, early investigators postulated that recurrent portal bacteremia might be an important factor in the development of the disorder.

Recurrent portal infection could lead to chronic biliary tract infection, inflammation, and subsequent fibrosis and classical stricture formation.
One study even found that portal bacteremia was present in patients who had colonic surgery.
Subsequent studies, however, could not confirm the findings of portal vein phlebitis.
Furthermore, if recurrent colitis leads to portal vein phlebitis, colectomy (or at least controlled colonic disease) should have a protective effect.
- This has not been demonstrated to be true.
Additionally, hepatic histology does not support portal venous infection since the hallmark of this disorder, portal phlebitis, is mild or absent in most patients with PSC.
Thus, there is little evidence to support the colonic-bacterial infection hypothesis.

If portal bacteremia from a colonic source is not a critical factor, then toxins that might be released from a diseased colon could be suspect.

Theoretically, toxic bile acids such as lithocholic acid, which arise from bacterial activity within the colon, can be absorbed through a diseased colon with its increased mucosal permeability.
Lithocholic acid is formed from chenodeoxycholic acid by bacterial 7-α- dehydroxylation in the colon, and it has even been shown to be hepatotoxic in animals.
- Unfortunately, abnormalities in bile acid metabolism in PSC or UC patients have not been demonstrated.
- Furthermore, in human tissue, lithocholic acid is rapidly sulfated and rendered nontoxic, a process which does not occur in animal models.

Other toxic substances that have been considered more recently are N-formylated chemotactic peptides,
- produced by enteric flora,
- which have been shown in animal studies to induce fibrosis and damage to major bile ducts through colonic absorption and enterohepatic circulation.
- Increased biliary excretion of these peptides has been shown in experimentally induced colitis in animal models.
- Further investigation to delineate the role of these peptides in the etiology of PSC is required.

The major criticism of the theories of colonic toxins causing PSC comes from studies looking at the natural history of the disorder.

It has been demonstrated that the severity of the colitis bears little relation to the development or severity of PSC.
Furthermore, patients who have a colectomy show no change in their PSC natural history.
Some patients develop PSC years after a colectomy or even prior to the onset of their colitis.
Some patients who develop PSC never even have inflammatory bowel disease.

Antibiotics (which could, theoretically, alter the colonic flora) appear to have little effect on the natural history of PSC. Because of these findings, colonic toxins are likely to play only a minor role, if any, in the overall etiology of PSC.

The association of appendectomy with IBD is an interesting one.

Appendectomy has been demonstrated to have some interesting associations with UC and UC-associated PSC.
In a case–control study in Australia, patients with PSC/UC, PSC alone, and UC were matched to controls in regards to the effects of appendectomy and smoking, and PSC in regards to disease onset, severity, and extent.
Appendectomy rates in PSC patients were no different from controls; however, the appendectomy rates in those with UC were four times less than controls, suggesting a protective effect of appendectomy in this patient population.
Additionally, those patients with appendectomy in both PSC and UC groups resulted in a 5- year delay in onset of either intestinal or biliary symptoms.

Abnormalities of copper metabolism have also been implicated in the pathogenesis of PSC.

Several authors have noted that liver samples from patients with PSC show an excess of hepatic copper, which is known to be hepatotoxic.
However,unlike other disorders with excessive copper deposition, treatment with chelating agents (penicillamine), has not been shown to have any benefit.
Likely, as with many cholestatic disorders, copper accumulation is the result of poor biliary excretion, rather than a primary inciting event critical to the pathogenesis of the disorder.

Chronic infection of the biliary tree has been implicated in the pathogenesis of PSC through several observations.

Longmire,who noted that some patients appear to develop PSC after an initial episode of acute necrotizing cholangitis, classified this group as a separate category (type 2) of PSC.

Patients with acquired immunodeficiency syndrome (AIDS) have been noted to have a sclerosing cholangitis that is felt to be caused by opportunistic infection (i.e. cytomegalovirus, cryptosporidium).

Unfortunately,an extensive investigation of 37 PSC patients showed evidence of cytomegalovirus (polymerase chain reaction (PCR) testing of liver tissue) in only one patient.
Although reversibility of sclerosing disease in an infectious environment has been demonstrated in immunocompromised patients who have the underlying infection treated, this has not been demonstrated in normal hosts who have a fully functional immune system.

Experimental cholangitis and biliary atresia can be induced in animal models through infection with Reovirus type 3.

Early reports suggested that patients with PSC had a significant increase in antibody titers to this virus compared to controls.
More recent data, however, show no difference in prevalence or titers of Reovirus between controls and PSC patients.

Rubella can also cause an obliterative cholangitis of the intrahepatic ducts in the fetus, although the histological picture differs from that of PSC. Despite these negative studies, an infectious etiological agent that alters antigenic determinants has yet to be excluded in PSC.

Immune activation —

There are multiple lines of evidence supporting an immunopathogenic cause for PSC. A number of abnormalities in humoral immunity have been described in these patients:

Up to 50 percent have an elevated IgM level, and some may also have an increased IgG fraction.
Autoantibodies are frequently present in patients with PSC, with titers in the range associated with autoimmune hepatitis. The most common are antismooth muscle antibodies and antinuclear antibodies, which are found in approximately 75 percent of patients
Antibodies directed against cytoplasmic and nuclear antigens of neutrophils with a characteristic perinuclear staining pattern (P-ANCA) are found in up to 80 percent of adults with PSC.
The antibodies appear to be directed against a myeloid 50 kilodalton nuclear envelope protein, not myeloperoxidase as in typical P-ANCA antibodies. In one report, P-ANCA had a 100 percent specificity for PSC compared to controls with other liver diseases; P-ANCA is also found in 25 to 30 percent of unaffected first degree family members of patients with PSC. P-ANCA has also been identified in children with PSC but not in those with UC alone.
These antibodies are not related to the presence or absence of UC.

Abnormalities of the cellular immune response have also been described in patients with PSC:

There are conflicting data reporting either an increase or decrease in the total number of circulating T cells; however, the number of CD4 positive T-cells in the liver is increased.
Bile duct epithelial cells in PSC may be targets for immune-mediated attack by T cells.
The bile duct cells in PSC express antigens which cross-react with colonic epithelial cells.
Bile duct cells aberrantly express HLA class II antigens, and ICAM (intercellular adhesion molecule)-1 is expressed by ductular epithelial cells.

Genetic factors —

There may be a genetic predisposition to PSC since these patients have an increased prevalence of HLA-B8, -DR3, and -DRw52a .
One study, for example found that HLA DRw52a was present in 100 percent of patients with PSC.
Subsequent reports, however, have only found a 50 percent prevalence of this haplotype.
Both HLA-DRw52a and -DR4, which occurs less frequently, appear to increase the risk for severe or progressive disease.

Ischemic ductal injury —

Ischemic injury to the bile ducts results in a clinical, biochemical, and cholangiographic picture similar to PSC.
Intraarterial infusion of floxuridine also results in a comparable appearance.
Thus, it is possible that ischemic injury to peribiliary arterioles and capillaries may be involved in the pathogenesis of PSC.
However, there are no data to support this hypothesis, or to demonstrate that hepatic or biliary blood flow is deficient in patients with this disorder.

Cystic fibrosis transmembrane conductance regulator mutations —

Because of the radiologic and histologic similarities between PSC and cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been sought in patients with PSC.
One preliminary study suggested that a subset of patients with PSC had evidence of CFTR-mediated ion transport dysfunction; affected patients had a chloride secretory response intermediate between patients with cystic fibrosis and controls.

Stress ulcer prophylaxis in the ICU patients

2008-05-11T18:31:00.000+05:30

INTRODUCTION —

Stress ulcerations are mucosal erosions that generally occur in the fundus and body of the stomach, but sometimes develop in the antrum, duodenum, or distal esophagus.
They tend to be shallow and cause oozing of blood from superficial capillary beds, but deeper lesions can erode into the submucosa, causing massive hemorrhage and/or perforation.

The risk of stress ulceration depends upon the severity and type of a patient's underlying illness.

Studies of various intensive care unit populations have estimated the risk of stress ulceration complicated by clinically significant bleeding at 1.5 to 15 percent.
Stress ulcerations are the most common cause of gastrointestinal (GI) bleeding in intensive care unit (ICU) patients, and the presence of GI bleeding due to these lesions is associated with a five-fold increase in mortality compared to ICU patients without bleeding.

Considerable effort and expense are devoted to the prevention of stress ulcerations in pati
ents in the ICU because the consequences of GI bleeding can be severe.

However, continued use of stress ulcer prophylaxis in hospitalized patients who have been discharged from the ICU is generally unwarranted and alarmingly common.

PATHOPHYSIOLOGY —

Erosions begin to develop in the proximal regions of the stomach within hours of major trauma or serious illness.
In one study, endoscopy performed within 72 hours of a major burn or cranial trauma revealed evidence of acute mucosal disease in 75 to 100 percent of patients.
Up to 50 percent of these early mucosal lesions have endoscopic evidence of recent or ongoing bleeding,

but only a small percentage of these patients experience hemodynamic compromise due to acute blood loss.

Stress ulcerations that evolve after the first several days of hospitalization tend to be deeper and occur more distally within the GI tract.

As an example, one study of 67 patients with GI bleeding which occurred a mean of 14 days after admission found that duodenal ulceration was the most common source of bleeding.
It is uncertain if early and late ulcerations have the same pathophysiology, but both types are thought to result from derangements in the balance between gastric acid production and mucosal protective mechanisms.

One or more of the following processes may be involved:

Hypersecretion of acid —

Hypersecretion of acid due to excessive gastrin stimulation of parietal cells is seen primarily in patients with head trauma.
Acid secretion tends to be normal or subnormal in most other patients, in whom stress ulceration results from a breakdown of mechanisms normally protecting the gastric mucosa from the effects of acid.

Defects in gastric glycoprotein mucus —

The stomach normally is protected by a glycoprotein mucous layer, which both forms a physical barrier to hydrogen ion diffusion and traps bicarbonate, allowing neutralization of gastric acid in the area adjacent to the stomach wall.
In critically ill patients, increased concentrations of refluxed bile salts or the presence of uremic toxins can denude the glycoprotein mucous barrier and permit gastric injury.

Ischemia —

Shock, sepsis, and trauma can lead to impaired perfusion of the gut.
Experimental models of shock suggest a relationship between gastric mucosal ischemia and diminished secretion of protective mucus and bicarbonate.

H pylori —

The influence of infection with H. pylori on the development of stress ulcers in the intensive care unit has not been well studied.
One multicenter case-control study identified 29 patients with acute upper GI bleeding following admission to an intensive care unit, and found that these patients were more likely than nonbleeding ICU patients to have evidence of H. pylori infection (36 versus 16 percent).
In a separate report, a statistically nonsignificant trend toward an increased risk of macroscopic gastrointestinal bleeding was observed among 67 H. pylori positive patients compared to 33 H. pylori negative controls.
Furthermore, nurses in the intensive care unit were more likely to be infected with H. pylori than age-matched controls (40 versus 19 percent), suggesting the possibility of nosocomial transmission.

RISK FACTORS —

A prospective multicenter cohort study of 2252 ICU patients identified two major risk factors for clinically significant bleeding due to stress ulcers:

mechanical ventilation for more than 48 hours (odds ratio 15.6); and
coagulopathy (odds ratio 4.3).

The risk of clinically important bleeding in patients without either of these risk factors was only 0.1 percent.

A number of smaller studies have reported additional risk factors for stress ulcerations, including :

Shock
Sepsis
Hepatic failure
Renal failure
Multiple trauma
Burns over 35 percent of total body surface area
Organ transplant recipients
Head or spinal trauma
Prior history of peptic ulcer disease or upper GI bleeding

PROPHYLACTIC AGENTS — A variety of medications may be used to reduce the incidence of stress ulceration, including antacids, H2 blockers, sucralfate, proton pump inhibitors, and prostaglandin analogs.

Antacids —

The action of antacids are to decrease gastric acidity by direct neutralization of stomach acid.
Antacids are generally considered effective in the prevention of stress ulceration because numerous studies have shown roughly equivalent outcomes with these agents and H2 blockers.
However, one meta-analysis found only a nonsignificant trend toward efficacy with antacids compared to placebo.

Drug costs are low, but these agents require administration of 30 to 60 mL orally or via nasogastric tube every one to two hours.

The increase in nursing costs necessary for such administration negates some of the potential cost savings.
Side effects of antacids can include hypermagnesemia, hypophosphatemia, constipation, diarrhea, nasogastric tube obstruction, and an increased risk of nosocomial pneumonia.

H2 blockers —

H2 blockers raise gastric pH by decreasing the stimulatory effects of histamine on parietal cell acid secretion.
Their effectiveness in preventing stress ulceration has been documented in most (but not all) trials.
One meta-analysis, for example, reported a significantly lower risk of clinically significant GI hemorrhage with cimetidine versus placebo (3 versus 15 percent).

Administration of H2 blockers by continuous infusion provides better control of gastric pH than bolus infusion, but is not more effective in preventing clinically significant bleeding.

H2 blockers are also effective if given orally or via nasogastric tube.

H2 blockers are generally well tolerated, but occasionally the drugs may produce interstitial nephritis, confusion, or thrombocytopenia.
Furthermore, the pharmacokinetics of drugs such as theophyline and warfarin may be significantly affected by cimetidine but not other H2 blockers.
The costs of H2 blockers can be substantial, and dosing via continuous infusion may increase the number of intravenous catheters required by the patient.

Sucralfate —

Sucralfate is a complex polyaluminum hydroxide salt of sucrose sulfate which exerts its effects via coating and protection of the gastric mucosa rather than through neutralization or inhibition of gastric acid.
Sucralfate becomes highly polar at acid pH and binds preferentially to the granulation tissue of exposed ulcer beds, protecting them from further damage from acid, bile salts, or pepsin.

The most rigorous randomized trial to date studied 1200 mechanically ventilated patients and found a significantly higher risk of clinically important GI bleeding with sucralfate versus H2 blocker (ranitidine) (3.8 versus 1.7 percent).
This trial was important because of its large sample size, the fact that care givers, research personnel, and analysts were blinded to treatment assignments, its high rates of compliance, and the fact that clinical bleeding and pneumonia were strictly defined.
One meta-analysis described similar findings, but reported a reduced mortality rate with sucralfate versus antacids and H2 blockers, possibly due to the less frequent development of nosocomial pneumonia (see below).
Other, less rigorous trials have been done and in general reported that sucralfate and H2 blockers have similar efficacy.

Sucralpate is generally well tolerated.

Elevations of plasma aluminum concentration have not been observed in intubated patients receiving 6 grams/day of sucralfate for 14 days, even in the presence of renal impairment.
Costs may differ substantially between institutions, but the use of sucralfate generally is less expensive than the use of parenteral H2 blockers.

Proton pump inhibitors —

Proton pump inhibitors, such as, omeprazole and others, contain a reactive sulfhydryl group that forms a disulfide bond with a cysteine residue on the H-K-ATPase pump, thereby inactivating the enzyme.
Data regarding the efficacy and potential adverse effects of these drugs in the prevention of stress ulceration are less extensive than the sucrafate, H2 blockers, and antacids.
Short-term use of proton pump inhibitors is rarely associated with significant side effects.
Hypotheses regarding an increased incidence of nosocomial pneumonia due to elevations in gastric pH have not been adequately tested.

The ability of omeprazole oral suspension to decrease stress-induced GI bleeding was assessed in two prospective, open-label trials of mechanically ventilated with at least one additional risk factor for stress-related mucosal damage.

In the first study, 75 patients received two doses of omeprazole oral suspension 40 mg six to eight hours apart, followed by 20 mg/day delivered via nasogastric tube.

There were no episodes of bleeding and no evidence of toxicity.
Similar results were noted in a subsequent study of 60 patients treated with omeprazole administered using the dosing regimen described above.

The relative efficacy of intravenous omeprazole, intravenous H2 blocker, and sucralfate in preventing bleeding associated with stress ulcers was evaluated in a prospective, randomized, three-arm trial published in abstract form.

Omeprazole (40 mg every 12 hours) and ranitidine (150 mg/day) were administered intravenously; sucralfate 1 g every six hours was administered by nasogastric tube.
The frequency of upper gastrointestinal bleeding was similar in patients treated with ranitidine and sucralfate (10.5 percent and 9.3 percent, respectively).

One study randomized 67 high-risk patients to prophylaxis with either intravenous H2 blocker or oral omeprazole.

A significantly larger proportion of patients in the ranitidine group developed clinically important bleeding (31 versus 6 percent); however the ranitidine group had more risk factors for GI bleeding despite randomization, potentially confounding the results of the study.
A subsequent larger trial compared oral omeprazole and intravenous the cimetidine in 359 ICU patients, and noted similar rates of GI bleeding in both groups (4.5 versus 6.8 percent, respectively;) .
It has been suggested that oral PPI therapy may be more cost-effective than intravenous cimetidine for the prevention of stress ulcer-related gastrointestinal bleeding.

Prostaglandin analogs —

Prostaglandin analogs such as the mesoprostol have both antisecretory and cytoprotective effects.
The latter may result from capillary bed vasodilation, which protects against local ischemia.
Several small trials and animal experiments suggest that misoprostol may be as effective as H2 blockers or antacids, in preventing stress ulceration, but the paucity of data and the propensity to cause diarrhea limit its clinical use in this setting.

Nutrition —

Several studies have reported that enteral nutrition may reduce the risk of bleeding due to stress ulcerations.
As an example, one study of 526 seriously burned patients compared treatment with antacids and cimetidine, versus enteral nutrition in the absence of prophylactic medications.
The rate of overt GI hemorrhage was significantly lower in the group that received enteral nutrition as the sole form of GI prophylaxis (3.3 versus 8.3 percent).

A separate study analyzed data from 1077 critically ill Canadian patients who required mechanical ventilation for more than 48 hours.

Patients who received enteral nutrition were significantly less likely to develop an upper gastrointestinal hemorrhage (risk ratio 0.30; 95% CI 0.13-0.67).
However, treatment was not randomized, so it is possible that patients with a lower intrinsic risk of bleeding were better able to tolerate enteral feeding.

The effect of enteral nutrition is not mediated by an increase in gastric pH.

Nutrition may prevent exhaustion of gastric epithelial energy stores and thereby prevent necrosis and ulcer formation; this mechanism may explain the protective effect against stress ulceration that has been reported with total parenteral nutrition (TPN).

NOSOCOMIAL PNEUMONIA —

The major concern about prophylactic therapy for stress ulceration has been the potential increased risk of nosocomial pneumonia.
Agents that raise gastric pH may promote the growth of bacteria in the stomach, particularly gram-negative bacilli that originate in the duodenum.
Esophageal reflux and aspiration of gastric contents along the endotracheal tube may lead to endobronchial colonization and to pneumonia.

A number of studies have documented an increased frequency of nosocomial pneumonia in patients treated with H2 blockers or antacids as compared with the sucralfate.

As an example, one study randomized 258 intubated patients to treatment with one of the following regimens: ranitidine at a rate of 6.25 mg/hour,; antacid 20 mL of antacid via nasogastric tube every two hours; or 1 gram of sucralfate via nasogastric tube every four hours.
Nosocomial pneumonia occurring four or more days after intubation was significantly less frequent in patients receiving sucralfate (five versus 16 percent with antacids and 21 percent with ranitidine).
No significant differences in macroscopic gastric bleeding were noted among the three treatment groups.

A subsequent study of 1200 mechanically ventilated patients randomized to prophylaxis with either 1 gram every 6 hours of sucralfate or 50 mg every 8 hours of intravenous H2 blocker found only a nonsignificant trend toward a lower incidence of ventilator-associated pneumonia among sucralfate-treated patients.

SUMMARY

Stress ulcers are mucosal erosions which primarily occur in the stomach, but can also be found in the distal esophagus or duodenum. They can develop within hours of a trauma or the onset of a critical illness. Critically ill patients who bleed from these lesions have a five-fold increase in mortality compared with patients who do not bleed.

Stress ulcers are believed to be caused by an imbalance between gastric acid production and mucosal protection mechanisms. Mucosal ischemia may be an important cause in patients with underlying shock, sepsis, and trauma.

Definite risk factors for the development of stress ulcers include mechanical ventilation for more than 48 hours and coagulopathy.

In addition, possible risk factors include shock, sepsis, hepatic and renal failure, multiple trauma, burns (>35 percent total body surface area), organ transplantation, head and/or spinal trauma, and a prior history of upper GI bleeding or peptic ulcer disease.

Pharmacologic agents available for stress ulcer prophylaxis include H2-antagonists, antacids, sucralfate, prostaglandin analogs, and proton pump inhibitors (PPIs).

It is widely suggested that oral PPIs are for patients who are able to receive enteral medications, rather than intravenous H2 blockers, because they are superior at maintaining gastric pH >4, are not limited by tolerance, and may be more cost-effective.
In contrast, intravenous H2 blockers in for patients who cannot receive enteral medications, rather than intravenous PPIs.
This is based on the opinion that the far greater cost of intravenous PPIs outweighs the nominally greater efficacy that may exist.

Stress ulcer prophylaxis should be discontinued after discharge from the ICU.

The role of enteral nutrition in stress ulcer prophylaxis is uncertain.

Early enteral nutrition contributes to stress ulcer prophylaxis;
however, it alone cannot be recommended as sole stress ulcer prophylaxis in high risk patients.

Whether acid suppression therapy confers an increased risk of nosocomial pneumonia is uncertain due to conflicting published data.