Primary Sclerosing Cholangitis; clinical features and diagnosis.

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.

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.

1. Presence of typical cholangiographic abnormalities of PSC (involving bile ducts segmentally or extensively)
2. Compatible clinical, biochemical, and hepatic histologic findings (recognizing that they are nonspecific)
3. 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

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:

1. mechanical ventilation for more than 48 hours (odds ratio 15.6); and
2. 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.

Mirizzi’s syndrome

Introduction

• Mirizzi’s syndrome is caused by an impacted gallstone in the cystic duct or the neck of the gallbladder that compresses the adjacent bile duct and results in complete or partial obstruction of the common hepatic bile duct.
  
• It is often not recognized preoperatively, which can lead to significant morbidity and biliary injury, particularly with laparoscopic surgery.

In 1905, Kehr first reported on external compression of the bile duct following stone impaction in the cystic duct. However, the syndrome was named after the Argentinian surgeon Pablo Mirizzi, who described in 1948 a hepatic duct obstruction due to cholelithiasis and cholecystitis as “syndrome del conducto hepatico”

Incidence

• In the largest series, including 17,000 patients undergoing open surgery for gallstone disease, 219 patients (1.3%) had Mirizzi’s syndrome and/or cholecystobiliary fistula.

• This figure may rise up to 2.7% in high-risk populations such as native American Indians.
  
• The recently published, largest series of 13,023 cases on laparoscopic cholecystectomy found Mirizzi’s syndrome and/or cholecystobiliary fistula in 0.3% of patients.
  
• Approximately 50 to 77% of all patients reported are women, probably reflecting the increased incidence of the gallstone disease in the female population.

A correlation was also noted between the stage of the disease and the mean age of patients.

• In patients with type A disease the mean age was 44 years while the mean age was 62 years in patients with type C compression.

Classification

McSherry et al. initially classified this syndrome into two types.

• Type I involves the external compression of the common hepatic duct due to a stone impacted in the neck of the gallbladder or the cystic duct.
  
• Type II refers to cholecystocholedochal fistula and stone migration into the common hepatic duct.

A further modification of this classification was suggested by Csendes et al., in which

• type II is an obstruction that involves less than one-third of the bile duct,
  
• type III is an obstruction involving up to two-thirds of the duct, and
  
• type IV is complete obstruction of the bile duct.

The third classification expanded the definition of the Mirizzi syndrome :

• Type I referred to a stone impacted in the cystic duct or gallbladder neck.
• Type II was characterized by a fistula of the common duct.
• Type III was defined by hepatic duct stenosis due to a stone at the confluence of the hepatic and cystic ducts.
• Type IV was characterized by hepatic duct stenosis as a complication of cholecystitis in the absence of calculi impacted in the cystic duct or gallbladder neck.

Pathophysiology

• Mirizzi’s syndrome may be caused by either a single large stone or multiple small stones impacted in the Hartmann’s pouch of the gallbladder or in the cystic duct.
• Anatomically, a long cystic duct parallel to the bile duct predisposes to the development of this syndrome.
• Recurrent cystic duct obstruction may lead to recurrent attacks of cholecystitis and may cause gallbladder dilatation, thickening, and inflammation.
  

Impaction of a large gallstone (or multiple small gallstones) in the Hartmann pouch or cystic duct results in the Mirizzi syndrome in 2 ways:

• (1) chronic and/or acute inflammatory changes lead to contraction of the gallbladder,
  • which then fuses with and causes secondary stenosis of the CHD,
    
  • there may present episodes of cholangitis which further increases inflammatory process,
• (2) large impacted stones lead to cholecystocholedochal fistula formation secondary to direct pressure necrosis of the adjacent duct walls.
  
• Increasingly, these phenomena are seen not as distinct and separate steps but as part of a continuum.
• This hypothesis is supported by the observation that in most cases the cholecystocholedochal fistula is occupied by a large impacted gallstone in the fistula tract.

Clinical signs

Mirizzi’s syndrome is typically seen in the setting of longstanding biliary symptoms.

• Obstructive jaundice is the key feature of Mirizzi’s syndrome and is frequently accompanied by pain and fever.
  
• This presentation often suggests acute cholangitis.
  
• Rarely, patients may be anicteric at presentation.

• Patients can also present with cholecystitis or pancreatitis.

Laboratory data are not specific, with hyperbilirubinemia as the most encountered laboratory abnormality. Elevated levels of alkaline phosphatase and transaminases are also common. Leukocytosis is a frequent presence in concomitant acute cholecystitis, pancreatitis, or cholangitis.

Diagnosis

• In clinical practice, the diagnosis is rarely made preoperatively.

The diagnostic approach usually begins with ultrasonography followed by cholangiography via direct cholangiography, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiography.

Endoscopic retrograde cholangiopancreatography (ERCP) is the procedure of choice to establish the diagnosis and to classify the lesion.

• Mirizzi type A presents as an extrinsic compression of the common hepatic duct by a distended gallbladder with dilatation of the intrahepatic biliary tree.
  
• ERCP is also essential in determining the presence of a fistula preoperatively.
  
• Percutaneous transhepatic cholangiography (PTC) can provide similar information.
  
• However, ERCP can identify a low-lying cystic duct that may be missed by PTC.
• In addition, PTC may not visualize the distal common bile duct because of the obstruction in the hepatic duct.
  
• Finally, as discussed below, ERCP offers the opportunity to exercise a variety of therapeutic options including stone retrieval and stenting.

Ultrasonography generally reveals gallstones and a contracted gallbladder. Features suggestive of Mirizzi syndrome include :

• Dilatation of the biliary system above the level of the gallbladder neck.
• The presence of a stone impacted in the gallbladder neck.
• An abrupt change to a normal width of the common duct below the level of the stone.

The literature regarding the use of a CT scan for the diagnosis of Mirizzi’s syndrome is controversial.

• Some authors feel that CT does not provide any additional information beyond what can be obtained with ultrasonography; also, the presence of periductal inflammation can be misinterpreted as carcinoma of the gallbladder.
  
• Overall, CT may be helpful in excluding malignancies in the pancreas, the porta hepatis area, or the liver.

The differential diagnosis includes other causes of obstructive jaundice such as malignancies (e.g., cholangiocarcinoma, carcinoma of the gallbladder, or pancreatic cancer) and sclerosing cholangitis.

Treatment

Surgery remains the treatment of choice for Mirizzi’s syndrome.

• The choice of surgery is determined by whether a fistula into the bile duct is present.
  
• The common surgical approach is usually an incision in the gallbladder fundus and removal of the impacted stone.
  
• A gush of bile indicates a fistula, because the cystic duct is usually occluded.

A standardized surgical approach has been recommended based on the classification of the variants of Mirizzi syndrome:

• Type I — Cholecystectomy plus common bile duct exploration with T-tube placement. Exploration should be performed only if the CBD is easily exposed.

• Type II — Suture of the fistula with absorbable material or choledochoplasty with the remnant gallbladder.
  

• Type III — Choledochoplasty; suture of the fistula is not indicated.

• Type IV — Bilioenteric anastomosis is preferred since the entire wall of the common bile duct has been destroyed.

In any case, excellent drainage should be achieved.

A serious complication of the surgical approach is the ligation of the hepatic duct because a normal caliber hepatic duct may be mistaken for a dilated cystic duct that runs parallel to it.

Laparoscopic surgery —

• The Mirizzi syndrome presents a difficult challenge for laparoscopic surgery because the dense adhesions and edematous inflammatory tissue cause distortion of the normal anatomy and increase the risk for biliary injury.
  
• Thus, the use of laparoscopic surgery as the primary treatment of Mirizzi syndrome is controversial, although it appears to be feasible, especially for type I anatomy.
  
• It has been suggested that a prudent policy is to perform a dissection trial and convert to an open procedure if local conditions are not clear for an experienced laparoscopic surgeon.
• The largest series on Mirizzi’s syndrome identified during laparoscopic cholecystectomy reported a conversion rate of 71% for type A and 100% for type B/C.

Endoscopic therapy —

• The endoscopic treatment is not only for the evaluation, but also for the treatment of Mirizzi’s syndrome.
  
• Whether it is used as primary therapy or in addition to surgical treatment, ERCP is an attractive alternative and may be the only option for high-risk patients.
  
• In general, endoscopic management includes both biliary drainage and stone removal.
  
• Endoscopic sphincterotomy is generally recommended for stone extraction.
  
• Standard stone removal techniques are usually used and include baskets, balloons, and mechanical and electrohydraulic lithotripsy.
  
• The latter may be a valuable modality if standard techniques have failed.
  
• However, multiple treatment sessions may be required and leakage of contrast material from the cystic duct into the peritoneal cavity has been described after the fragmentation of large stones.

Further advances in the design of retrograde cholangioscopes may make this option more attractive in the future.

Association with cancer —

• The Mirizzi syndrome has been associated with a high frequency of gallbladder cancer.
  
• In one series of 1759 cholecystectomies, 18 cases of Mirizzi syndrome were identified; five (28 percent) had coincidental gallbladder carcinoma (versus only 2 percent in the patients without Mirizzi syndrome).
  
• An intraoperative frozen section of the gallbladder wall should be sampled.—in particular in the presence of markedly elevated CA 19-9 levels—to exclude carcinoma.

The patients with gallbladder carcinoma had a longer history of preexistent gallbladder disease (10.4 versus 6.8 years in those without carcinoma).

• The serum concentration of the tumor-associated antigen CA 19-9 was elevated in 12 of the 18 patients with Mirizzi syndrome but was significantly higher in those with malignancy (peaking at 1000 U/mL).

Although gallbladder carcinoma may be common in patients with Mirizzi syndrome, the latter disorder is unusual among patients with gallbladder carcinoma.

Mortality and morbidity

• In the largest series, Csendes reported no operative mortality (within 30 days of operation) in patients with type 1 disease, 2 to 12% with type 2, and 11% with type 3 disease.

Late mortality due to biliary disease was below 5% with any stages of the disease.

• The largest series of Mirizzi’s syndrome, which was found during intended laparosopic cholecystectomy, had no mortality for all types.

Postoperative morbidity includes mainly the development of

• external biliary fistula,
  
• bile peritonitis, and
  
• subphrenic abscess.
  
• The incidence of benign strictures of the bile duct occurs in 4 to 11% of patients.