Stapled Hemorrhoidectomy

GI POLYPOSIS - Classification

A GI polyp is defined as a mass of the mucosal surface protruding into the lumen of the bowel.
Polyps can be

• neoplastic,
• non-neoplastic, or submucosal.

GI polyposis is characterized by multiple polyps within the GI tract.
A variety of polyposis syndromes can affect the GI tract. These polyposis syndromes may be classified as

• familial inherited (autosomal dominant) or
• nonfamilial.

The inherited polyposis syndromes can be further subdivided into 2 groups depending on whether the polyps are

• adenomas or
• hamartomas.

The adenomatous polyposis syndromes include the classic

• familial adenomatous polyposis (FAP),
• Gardner syndrome,
• Turcot syndrome.

Hamartomatous familial polyposis syndromes include

• Peutz-Jeghers syndrome,
• juvenile polyposis syndrome,
• Cowden disease,
• Ruval-Caba-Myhre-Smith syndrome.

The non-inherited polyposis syndromes include

• Cronkhite-Canada syndrome,
• and a variety of miscellaneous non-familial polyposis.

• From a prognostic viewpoint, these syndromes must be recognized, because the adenomatous polyps are premalignant.
• These syndromes should be considered when
• an intestinal polyp is recognized in the young,
• when 2 or more polyps are seen in any patient,
• when colonic carcinoma is discovered in patients younger than 40 years, and
• when extraintestinal manifestations associated with these syndromes are discovered.
  
  
• GI polyps may be asymptomatic, but may also occur with rectal bleeding and diarrhea.

The urgency of case tracing and genetic counseling is related not so much to the symptoms of the disease but to the potential for the development of a colonic carcinoma. It is probable that patients with familial polyposis, if untreated, will develop a colonic carcinoma.

Gardner's syndrome

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

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 :

1. Family history with concomitant autosomal dominant inheritance
2. Mucocutaneous hyperpigmentation
3. 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

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.

SURGICAL CONSIDERATIONS IN IBD

SURGICAL CONSIDERATIONS IN IBD

• The primary indication for surgical intervention in IBD is the lack of response to medical management.
• In UC, patients are being considered for surgery at an earlier stage of disease, mainly because of restorative procedures that can be offered with successful results.
• In addition, it has been recognized that the complications and side effects of maintaining young patients on high doses of steroids or immunosuppressives, or both, for prolonged periods of time far outweigh the complications of surgical intervention.
• The absolute indications for surgery in UC include
• the development of cancer or severe dysplasia in the colon,
• the presence of growth retardation because of the disease process or its medical treatment,
• and the presence of a stricture or a mass lesion in the colon that precludes complete surveillance or accurate diagnosis.
• In addition, patients who have developed extraintestinal manifestations of the disease may improve when they have undergone surgery.
• This applies to some patients who have developed pyoderma gangrenosum and some patients with musculoskeletal manifestations.
• Some complications, such as sclerosing cholangitis, are unaffected by surgical extirpation of the colon and may continue to be slowly progressive over time.
• The evidence suggests that although medical management is often successful on a temporary basis, it is certainly not curative.
• The majority of patients will require surgery for colon or perianal disease.
• Indications for surgery in Crohn's colitis include failure to respond to medical management or complications of the disease.
• These complications include intestinal obstruction, fistula or abscess formation, and rectal stricture.
• The indications for surgery tend to differ somewhat from those for small bowel disease.
• In a review of patients who underwent surgery at the Cleveland Clinic, bowel obstruction and internal fistula or an abscess tended to be the most common reasons for surgery in patients with small bowel disease.
• The indications for surgery in 127 patients with colonic disease were poor response to medical care (25%), internal fistula and abscess (23%), toxic megacolon (20%), perianal disease (19%), and intestinal obstruction (12%).
• Like all of the operations for CD, recurrence is the major consideration.
• Patients with colon disease alone had a lower recurrence rate than patients with either ileocolonic disease or ileitis.
• The type of operation performed varies depending on the location of the disease.
• Because the rectum and the distal colon are often spared in Crohn's colitis, colectomy with preservation of the rectum is often possible.
• Ileorectal or ileosigmoid anastomosis has the obvious advantage that an ileostomy is not necessary.
• However, to perform an ileorectal anastomosis, the rectum should be spared from disease or be only minimally involved.
• There should be good distensibility of the rectum on air insufflation, sphincter tone should be adequate, there should be no extensive ileal or perianal disease, and patients should not have had a prior significant small bowel resection, because the functional result might be poor.
• None of these criteria are absolute.
• Another option for the patient may be colectomy, ileostomy, and preservation of the rectum in a fashion similar to that described for UC.
• This procedure also allows the option for a future anastomosis if local conditions are favorable.
• During this interval, the patient may be better able to become prepared psychologically for a permanent ileostomy in case removal of the rectum in the future becomes necessary or if reanastomosis appears to be unwise.
• If the rectum is left indefinitely, there is the possibility of the future development of carcinoma.
• Segmental resection for CD is controversial, because disease usually is widespread and occurs both proximally and distally in a patchy distribution.
• Although experience is limited, recurrence after segmental resection appears to be high. Nevertheless, segmental resection may be indicated in patients who have had multiple bowel resections in the past.
• Loop ileostomy may be useful in situations in which the patient may be at some risk with an unprotected anastomosis—for example, after an ileocolic or a sigmoid resection for CD associated with an abscess.
• CD, particularly in the small bowel, may present with obstruction due to stricture formation.
• These strictures are alleviated by a procedure called stricturoplasty.
• To perform a stricturoplasty, the intestine is incised longitudinally and closed horizontally in one layer.
• The results from several institutions, including ours, were reported to be good.
• Stricturoplasty is usually used in CD of the small bowel, and its role in the colon appears to be more limited.
• It has been used in some patients with short colonic strictures and a relatively normal intervening bowel, especially if a significant amount of the intestine has already been removed.
• If a stricture in the colon is present, one must be cautious in offering a stricturoplasty as opposed to a resection because of the risk of carcinoma occurring at the site of the stricturoplasty.

Perianal disease often poses difficult management decisions.

• Treatment will vary in view of the wide spectrum of perianal lesions.
• In making management decisions, one must consider the nutritional status of the patient, the extent and severity of the disease in the remainder of the gastrointestinal tract, and the symptomatology.
• Many patients will have relatively few symptoms from perianal disease, even though it may appear to be quite severe.
• One must understand the limitations of attempting to eradicate the disease, and the aim of treatment, as in other forms of CD, should be to provide symptomatic relief.
• Although treatment may vary according to the specific lesion and the individual patient, certain general measures may be of benefit to most patients, including hospitalization to improve the nutritional status, assessment of the extent and severity of any proximal disease, and treatment of this proximal disease.
• Local skin care includes sitz baths, anesthetic ointments, and frequent dressing changes.
• Skin tags are rarely symptomatic, and their excision should be avoided.
• If they produce symptoms, it is usually because of irritation caused by diarrhea, which results in edema of the tags and generally responds to local care and control of the diarrhea.
• Anal dilatation for anal stenosis is only rarely indicated.
• Dilatation should be performed cautiously and should be limited to one or two fingers only.
• Long strictures, which are also rare occurrences, are a complication of severe rectal disease and, if symptomatic, may require proctectomy.

The typical broad-based fissure seen in CD is often asymptomatic, and no treatment is usually indicated.

• If a fissure is painful, one should suspect associated sepsis, and an examination under anesthesia may be necessary.
• Sphincterotomy should be avoided, because the fissure or ulcer is often a sign of severe rectal or anal involvement.
• Wounds from CD heal poorly, and the disease itself has often damaged the ability of the sphincter to act reliably.
• Treatment with antibiotics, such as metronidazole, or with steroid suppositories may be beneficial in treating the commonly associated rectal disease.

Abscesses and fistulas tend to be the most difficult lesions to treat.

• We do not hesitate to examine the patient under anesthesia to more fully assess the extent and severity of the perianal and rectal disease.
• An abscess should be suspected in patients who complain of severe pain in a previously asymptomatic fissure or fistula.
• Treatment should consist of incision, unroofing, and drainage of the abscess .
• Usually, primary fistulotomy should not be undertaken unless the fistula is of the lowlying variety.
• When cellulitis is associated, broad-spectrum antibiotics such as metronidazole and an aminogly-coside should be prescribed.
• There are several approaches in the treatment of perianal fistulas, depending on various local and general factors.
• low fistula may be managed by fistulotomy with good wound healing.
• For complex fistulas with rectal involvement, treatment should first concentrate on medical management of the rectal disease.
• Antidiarrheal agents may be used judiciously, and nutritional improvement is important.
• Drainage of the abscess with unroofing of the fistula, as well as long-term drains or setons, may be used.
• Metronidazole, azathioprine, 6-mercaptopurine, and cyclosporin have all been used with some success.
• Some patients for whom these treatments fail may require diversion of the intestinal tract as a loop or split ileostomy, and eventually a proctectomy may be necessary.
• After the construction of an ileostomy, initial improvement in the local perianal disease usually occurs; however, it does not usually change the natural history of the disease.
• Relapse is common, and it is not usually possible to restore intestinal continuity.
• Despite these poor long-term results, there may be some merit in the construction of a diverting ileostomy.
• First, the general and nutritional status of the patient often improves, and the perianal sepsis resolves to some extent.
• Therefore, at least theoretically, a subsequent proctectomy or other definitive procedure can be performed with fewer complications.
• Second, some patients may be loath to have definitive surgery in the form of a proctectomy as an initial procedure.
• A loop or split ileostomy allows them to adjust psychologically to a stoma without committing themselves to a permanent ileostomy.

If perianal disease continues and is symptomatic, proctectomy may be necessary, although it is not usually required to treat perianal disease alone.

• Almost always, patients have associated severe rectal or perineal involvement.
• Before a proctectomy is performed, it is important that the patient be in optimal condition, because this operation is associated with relatively high morbidity rates.
• Thus, preoperative measures to decrease local sepsis and improve healing should be undertaken.
• To decrease local sepsis, a staged procedure may be planned.
• As previously discussed, by performing a subtotal colectomy and ileostomy or ileostomy alone, temporary improvement in local perianal sepsis can be expected.
• The general status of the patient is improved, and steroids may be tapered before rectal excision.
• At the time of surgery, measures to decrease the potential for sepsis should be used, including an adequate mechanical bowel preparation and the administration of prophylactic antibiotics.
• An intersphincteric dissection of the anorectum along anatomic planes with meticulous hemostasis is important in preventing the perineal wound problems previously discussed.
• There are some reports that suggest surgical treatment of proximal gastrointestinal disease may result in improvement in the perianal disease.

Laparoscopic Management of Inflammatory Bowel Disease

• The evaluation of the results of these reports reveals that laparoscopy in patients with IBD offers significant advantages compared with laparotomy.
• Reduction in postoperative pain, reduced postoperative ileus, decreased hospitalization time, enhanced cosmesis, less disability, earlier return to work, and a reduction in symptoms attributable to adhesion formation are all advantages of the use of laparoscopy.

Disadvantages of laparoscopic surgery are

• prolonged surgical time,
• difficult instrumentation,
• and demanding expertise.
  

Medical Versus Surgical Approaches in Inflammatory Bowel Disease
Medical as well as surgical efforts in IBD are directed at decreasing and controlling symptoms, thereby improving the patient's quality of life.

• A careful selection of the therapeutic agents is necessary, based on the severity of the disease and of drug side effects.
• Because IBD often is a chronic illness with an unpredictable course and with a significant impact on the patient's quality of life, patient education takes on a very important role in management.
• The medical management of these patients includes systemic, oral, and topical drugs (steroids or 5-ASA derivatives); antibiotics where indicated; immunosuppressives; and the latest cytokines and immunomodulators (see earlier for a detailed discussion).
• Complications, whether chronic or acute, often accompany the course of the disease, necessitating recurrent hospitalizations and surgery when indicated.
• In the United States, the total annual costs (both direct and indirect) incurred by the estimated 380,000 to 480,000 patients affected have been estimated at around $2 billion.
• Drugs were estimated to account for only 10% of total costs, whereas hospitalizations and surgery account for approximately half.
• There are other considerations when weighing medical versus surgical therapy in these patients.
• Side effects of long-term medical treatment (especially steroids and immunosuppressives) and patient compliance are other important concerns with which the physician who treats these patients is faced.
• Although the patient who is compliant, takes his or her medicines regularly, and appears for periodic follow-up on a regular basis can continue on medical treatment, the patient who is noncompliant medically will likely undergo surgery earlier.
• The nature and the extent of the disease are also very important when weighing medical versus surgical treatment.
• An initial medical trial of CD is the usual approach.
• When complications of the disease occur or when patients are noncompliant or do not wish to undergo medical management for fear of the complications involved, then surgery should be undertaken.
• In the case of UC, once operated on, the patient is for all intents and purposes "cured" of the disease, although a different lifestyle is required and follow-up is still necessary.
• Finally, as mentioned, the patient must have an active role in the decisions regarding which kind of therapy should be adopted.
• Patients should be informed about their disease and given all the options of treatment as well as information pertaining to quality of life, and the patient together with the caring physician will then be able to reach the decision of whether to continue the medical therapy or to undergo surgery.
  

QUALITY OF LIFE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
There is increasing recognition that quality of life is an important outcome measure in patients with IBD, whether they are treated medically or surgically.

• Quality of life incorporates not only the physical or functional outcome but also the emotional and social well-being of the patients.
• Sometimes somatic sensation (presence or absence of pain) is also included. Calman proposed a definition for quality of life as "the gap between a person's expectation and achievements," which seems appropriate and incorporates the concept that quality of life is personal and may vary among individuals.
• In the area of surgery, particularly surgery for IBD, morbidity and mortality rates have traditionally been used to assess surgical outcome.

Surgery is rarely performed for a life-saving indication; rather, the most common indication for surgery in patients with IBD is failure of medical therapy or, in effect, poor quality of life.

• In view of the high rate of recurrence of CD after surgical resection, surgical therapy is not curative but palliative.
• Operative therapy is reserved for complications of the disease, and bowel resection in patients with uncomplicated disease is justified only in rare circumstances.
• Surgery is also indicated when medical therapy has failed and the patient is chronically debilitated due to the disease.
• Failure of medical management includes intractability, suggesting that the patient's well-being, life-style, and employment are significantly impaired by unrelenting symptoms, and debilitating side effects of medical therapy.
  
• It is difficult to compare the quality of life of patients treated medically with that of those treated surgically.
• For patients who have undergone surgery, their health status is usually much more stable (except for the early convalescent period).
• Thus, quality of life soon after surgery is probably lower than if it is assessed at a later date.
• Another issue that might result in incorrect conclusions is the reporting of stool frequency. Stool frequency is an important indication of disease activity in UC and, by inference, the quality of life in patients under medical treatment.
• On the other hand, stool frequency seems to have less impact on the quality of life of patients after ileal pouch-anal anastomosis.
• These patients have an excellent quality of life, having five or six bowel movements per day, whereas the same number of bowel movements in a patient treated medically may indicate active disease and an impaired quality of life.
• Reasons for this include urgency and bleeding during the active phase of the disease.
  
• Many studies that compared the quality of life in medical versus surgical therapy have shown that patients who undergo surgery seem to have a better outcome (at least in some domains) than those on medical treatment.
  
• In conclusion, quality of life of most patients after surgery for UC is excellent.
• This is true for most patients, unless there is some associated illness or long-term complication related to the procedure.
• Although the ileal pouch-anal anastomosis procedure has become the procedure of choice for most patients, those who undergo conventional ileostomy also seem to have an excellent quality of life.

THERAPY OF ULCERATIVE COLITIS AND CROHN'S DISEASE

THERAPY OF ULCERATIVE COLITIS AND CROHN'S DISEASE

• Although traditional drugs such as steroids, sulfasalazine, and 5-ASA compounds are the mainstays of the medical management of IBD, many other modalities and drugs are used, including the immunomodulator drugs (azathioprine and 6-mercaptopurine), immunosuppressives (cyclosporine and methotrexate), and the latest cytokine therapy.
  

Sulfasalazine and 5-Aminosalicylic Acid

• Sulfasalazine is composed of sulfapyridine linked to 5-ASA.
• It is poorly absorbed in the upper gastrointestinal tract and is degraded into its two components—sulfapyridine and 5-ASA—by colonic bacteria.
• 5-ASA is the active anti-inflammatory compound of sulfasalazine, whereas sulfapyridine acts only as the carrier for 5-ASA.
• It is the sulfapyridine moiety to which some patients have side effects and allergic reactions.
• Because of this, various 5-ASA compounds have been developed (mesalamine [Asacol, Rowasa]) that have been shown to be as effective as sulfasalazine but with reduced side effects.
• Both sulfasalzine and the various 5-ASA compounds inhibit the various products of the metabolism of arachidonic acid (prostaglandin G2, leukotriene B4, and thromboxane A2)—all known to play a major role in the inflammatory process in the intestinal mucosa.
• They also decrease the synthesis of other inflammatory cytokines (IL-1 and TNF-β) and inhibit the action of interferon.
• Sulfasalazine and 5-ASA enemas may be of benefit in limited colonic distal disease and proctitis.
• Foam preparations and suppositories are more effective than the liquid preparations due to the enhanced retention and absorption, but both can be used for distal disease.
• Mesalamine in the form of suppositories or enemas is the most effective agent in the treatment of distal UC, but its efficacy has not been proved in anorectal CD.
  

Sulfasalazine

• Sulfasalazine is the oldest and the least expensive 5-ASA compound in use.
• In a low dosage (1 to 2 g/day), it is used to maintain remission in patients with UC, whereas in a higher dosage (4 to 6 g/day), it can be used to treat active UC.
• In CD, the efficacy of sulfasalazine is less clear and depends on the site of the disease.
• Because sulfasalazine is cleaved into its active compounds in the colon, its use is limited to CD with ileocolonic or colonic involvement.
• It is of little known benefit in isolated small bowel disease.
• Side effects of sulfasalazine are common and include nausea, headaches, malaise, and vomiting.
• These side effects can be minimized or prevented by initiation of therapy with a relatively low dose and gradual increase in the dosage.
• Hypersensitivity reaction to sulfasalazine can cause rash, fever, hemolytic anemia, hepatic toxicity, and sperm abnormality.
• Should these side effects or hypersensitivity reactions occur, administration of the drug should be discontinued immediately.
  

Olsalazine

• Olsalazine (Dipentum) delivers intact 5-ASA to the terminal ileum, which is then cleaved by the colonic bacteria.
• Olsalazine has been shown to be of benefit in patients with active UC, but no therapeutic benefit has been shown in patients with mild to moderate attacks of CD.
  

Mesalamine

• Pentasa is one brand of mesalamine in which the 5-ASA is coated with ethyl cellulose that is gradually released from the small bowel to the colon.
• Mesalamine at dosages between 3 and 4 g/day has been shown to cause clinical improvement or remission in the mild to moderately active form of CD.
• At a dosage of 2.4 to 4.6 g/day, mesalamine has been beneficial in patients with UC and was found to be as effective as sulfasalazine in maintaining remission in patients with UC.
• In a comparison of medically with postoperatively induced remission in patients with CD, mesalamine has been shown to be more effective in preventing clinical relapse after surgical resection than after medically induced remission.
• In patients with mild to moderate UC, improvement can be achieved with 2 to 4 g/day of a 5-ASA compound.
• Once improvement has been achieved, mesalamine can be continued at the same dose to maintain remission.
• Mesalamine enemas at dosages of 1 to 4 g/day are effective in treating patients with distal UC, whereas patients with limited ulcerative proctitis can benefit from mesalamine suppositories at a dosage of 500 mg twice a day.
  

Steroids

• The benefit of corticosteroid therapy for UC was first reported by Truelove and Witts, and they are the most commonly used agents in the treatment of moderate to severe forms of IBD.
• Their mechanism of action is thought to be via prevention of the liberation of arachidonic acid from the membranes.
• Steroids also decrease neutrophilic phagocytosis and diminish adherence and chemotaxis of neutrophils, eosinophils, and monocytes.
• They inhibit the release of other inflammatory cytokines—mainly IL-1 and IL-2.
• The initial treatment in patients with moderate to severe UC is prednisone at 40 to 60 mg/day.
• In severely ill, hospitalized patients, initial therapy is 100 mg intravenous hydrocortisone three times daily.
• Steroids are also effective in the treatment of moderate to severe CD.
• Prednisone administered at dosages of 0.25 to 0.75 mg/kg/day to 85 patients with active CD resulted in remission in 60% of patients compared with a rate of only 30% in a placebo group.
• The systemic side effects of the traditional steroids in use have led to the development of more potent steroid formulations, which are more rapidly metabolized and offer the promise of being as effective as the traditional steroids with fewer systemic side effects.
• Similar to 5-ASA preparations, different packaging of these agents is available, which offers the possibility of drug delivery to the small bowel and the colon with minimum side effects.
• Budesonide is the most notable of these new steroids used in IBD, and favorable results were demonstrated in distal UC and in active CD.
• Steroids applied topically may be of benefit in patients with either limited distal disease or with rectal involvement along with more proximal disease.
• Steroid enemas or foams can be used for the treatment of active disease, but no role in maintenance therapy has been proved.
  

Antibiotics

• The results of clinical and experimental trials suggest that bacteria may play a role in the pathogenesis of Crohn's disease due to an unusual response of the mucosa to the intestinal flora, a breakdown in the normal mucosal barrier that allows micro-organisms to invade the intestinal mucosa, or even a specific bacteria such as Mycobacterium.
• Metronidazole is the most studied and used of the antibiotics.
• This drug is effective in patients with CD, particularly in those with perianal disease.
• However, when treatment with metronidazole is discontinued, relapse is common.
• Another antibiotic that has also been effective in CD is ciprofloxacin.
• Its maximum benefit is reached within 1 month and continues for at least an additional 5 months.
• Ciprofloxacin can be combined with metronidazole.
• Such combination therapy of metronidazole and ciprofloxacin in fistulous CD produced fistula healing in 3 of 14 patients and improvement in 9 of 14 patients after 3 months of therapy.
• When therapy was discontinued, most patients experienced a relapse, so continuous treatment may be necessary.
• Clarithromycin is another broad-spectrum antibiotic that may be effective in the eradication of micro-organisms at the center of the granulomas in CD.
• A trial with clarithromycin in patients with active CD, of whom many had been resistant to other forms of therapy, demonstrated impressive results.
  

Immunomodulators and Immunosuppressives

• Immunosuppressive agents are of routine use in the treatment of patients with refractory IBD.
• Their use is widely accepted in patients who are not candidates for surgery and in patients in whom steroid treatment has already caused significant adverse reactions.
• These drugs act by blocking the proliferation and activation of the T-helper lymphocytes, which play a major role in the inflammatory cascade through the production of various cytokines, of which the most important in IBD are IL-1, IL-2, IL-6, IL-8, TNF-β, and interferon-γ.
• In the case of Imuran, the therapeutic effects are not seen until after 3 to 4 months of treatment, a period that can sometimes be shortened by initial intravenous loading of the drug.
  

Cyclosporin A

• Cyclosporin A is a potent immunosuppressive drug that is used in organ transplantation as well as in patients with IBD, especially those with more severe or refractory disease.
• It acts via inhibition of the T-helper lymphocytes, thus inhibiting the production and liberation of the above-mentioned cytokines.
• Intravenous cyclosporin A has been shown to be effective in the short term in patients with severe cases of UC as well as CD.
• The major problem with the drug is that although short-term improvement may be achieved, long-term maintenance with the oral form of the drug produces excessive side effects.
• Side effects and toxicity of treatment with cyclosporin A include seizures, nephrotoxicity, hypertension, tremors, and headaches, which can occur in up to 60% of patients treated.[
  

Azathioprine and 6-Mercaptopurine

• Azathioprine (Imuran) and 6-mercaptopurine are purine analogue compounds used in the management of steroid-dependent IBD.
• They act either via inhibition of purine RNA synthesis and cell proliferation or via inhibition of natural killer cells and suppression of cytotoxic T-cell functions.
• These mechanisms of action likely explain the 3- to 4-month delay in the onset of their clinical effectiveness.
• Azathioprine and 6-mercaptopurine are both used in the management of patients with active CD and UC who have not responded to systemic steroids.
• In addition, both drugs have been successfully used as steroid-sparing agents in patients with IBD who are unable to be weaned from steroid therapy.
• Furthermore, as maintenance therapy, both drugs have been shown to be effective in UC as well as in CD.
  
• Among the side effects of azathioprine and 6-mercaptopurine are pancreatitis, which occurs in 3 to 5% of patients, usually presents within the first 6 weeks of therapy, and resolves promptly when the drug is withdrawn.
  

Methotrexate

• Methotrexate acts via impairment of DNA synthesis and reduction in IL-1.
• A multicenter, placebo-controlled trial with 141 patients with active CD confirmed that methotrexate at a dosage of 25 mg administered intramuscularly or subcutaneously once a week, over 16 weeks, allowed steroid tapering and maintenance of remission in 39% of patients treated compared with 19% in those receiving placebo.
• Potential side effects of methotrexate include
• leukopenia and
• hepatic fibrosis, necessitating routine monitoring of blood count and liver function.
  

Cytokine Therapy
In the discussion of the cause and pathogenesis of IBD, the role of cytokines was mentioned. Based on these findings, a rationale for treatment with cytokines was defined, and the number of trials in which the efficacy of cytokine therapy is investigated is rapidly increasing. The effect of cytokine therapy is achieved either through the administration of anti-inflammatory cytokines (IL-4, IL-10, or TGF-β) or through the inhibition of proinflammatory cytokines (IL-1 and TNF).

• Patients with steroid refractory UC who were treated with IL-10 enemas showed clinical improvement.
• When rats with experimental colitis received an expression vector carrying the TGFp cDNA, the colitis was alleviated, suggesting that this therapy for IBD patients merits further investigation.
• IL-1, one of the anti-inflammatory cytokines, may be inhibited in one of three ways:
• with an IL-1 receptor antagonist,
• with soluble IL-1 receptors, or
• with IL-1-specific monoclonal antibodies.
• However, most of the studies were performed on mice, and beneficial effects were not demonstrated.
  

As early as 1995, Van Dullemen et al. showed that the use of anti-TNF antibodies (infliximab [Remicade]) decreased the Crohn's Disease Activity Index score while producing an improvement in the colonoscopic findings in patients with CD.

• A similar randomized, placebo-controlled trial in another population of CD patients showed that a single infusion of infliximab induced a clinical response in 81% of patients and clinical remission in 48%.
• Retreatment of those patients with infliximab every 8 weeks maintained a clinical benefit in nearly all patients throughout the treatment period and 8 weeks after the last infusion.
• In another study of patients with active CD who were treated with infliximab, a response rate was achieved in 82% and closure of fistulas occurred in 68%.
• The consistent benefit of infliximab treatment in patients with moderate to severe active CD and in patients with fistulas was further shown in other studies.
• The treatment with infliximab in another placebo-controlled trial of patients with fistulous CD showed a reduction by more than 50% from baseline in the number of draining fistulas.
• The second stated end point was the closure of all fistulas, and 55% of the patients receiving infliximab had closure of all fistulas.
  

Another cytokine used in the treatment of IBD is interferon.

• Interferon-α has been used in several trials of CD and UC patients.
• Clinical results were impressive in patients with UC but only moderate in patients with CD.

Although the newer agents seem to have great potential, many questions must be answered before cytokines can be considered standard treatment for IBD. Their longer-term efficacy as well as the complications produced must be further assessed.

GRANULOMATOUS COLITIS

GRANULOMATOUS COLITIS

• Granulomatous colitis (Crohn's disease, CD, of the colon) is also an inflammatory disease of the large bowel of unknown cause.
• It is well accepted that CD of the large and small intestine is one disease, but it is separate and distinct from UC.
• CD is more common in Jews, uncommon in blacks, and more frequent in populations of Westernized civilizations than those of Africans and Asians.
• The disease primarily affects young individuals, with 80% of cases occurring in patients younger than 35 years.
• Disease in which the colon is primarily involved affects women slightly more often than men and occurs at a somewhat older age.
• The colon may be involved with granulomatous disease in one of several ways.
• First, the colon alone may be the site of the primary granulomatous disease.
• The large bowel may be involved in its entirety, but more often there is segmental disease with sparing of the rectum and part of the sigmoid.
• In addition to granulomatous disease of the colon, there may be involvement of the small bowel.
• This form of ileocolitis is the most common type of CD.
• The colon may become involved with granulomatous disease only after surgery for regional ileitis, but this is not particularly common, because most recurrences appear at the site of or proximal to the anastomosis.
• Finally, the colon may be involved indirectly via fistula formation from a loop of small bowel that is the site of the primary disease.
• In this case, most commonly there is no primary disease in the colon but only secondary inflammation from the disease in the small intestine.

Pathologic Features

• Granulomatous colitis involves all layers of the bowel wall as a transmural reaction.
• This transmural reaction may be noted grossly but is present in the early phases of the disease when only microscopic changes are noted.

Crohn's disease of the colon.

• Transmural involvement is present with mucosal ulceration (U),
• edema of the entire bowel wall and
• serosal noncaseating granuloma.

Although the gross and microscopic features of CD are well established, there is no pathognomonic feature.

The features of UC and CD are-

• In approximately 10 to 15% of patients, it may be difficult to equivocally differentiate CD from UC.
• The term indeterminate colitis has been used in these cases in which a definitive pathologic diagnosis cannot be made.

Characteristics of Crohn's Colitis and Ulcerative Colitis
Feature
Crohn's Colitis Ulcerative Colitis
Thickened bowel wall + + + +
Narrowing of bowel lumen + + + +
Discontinuous disease + + ○
Rectal involvement ○ + + +
Deep fissures and fistulas + + ○
Confluent linear ulcers + + ○
Perianal disease + + ○
Microscopic
Transmural inflammation + + + +
Submucosal infiltration + + + +
Submucosal thickening, fibrosis + + + ○
Ulceration through mucosa + + + + +
Fissures + + + +
Granulomas + + ○
Features are characterized as being present consistently (+ + +), frequently (+ +), infrequently (+), or rarely (○).

On macroscopic examination

• the bowel wall appears to be thickened, particularly in the submucosal layer.
• Correspondingly, there is narrowing of the lumen.
• Edema, thickening, and overgrowth of the mesenteric fat encroaching on the serosal aspect of the bowel wall are the rule with granulomatous disease of both the small and large intestine.
• The serosa tends to be hyperemic with visible vessel engorgement, and there are chronic subserosal inflammatory changes with exudate production.
• Mesenteric lymph nodes may be enlarged.

The gross appearance of the mucosal surface varies depending on the extent and severity of the disease.

• The mucosa may appear to be normal except for hyperemia and edema, or there may be longitudinal ulcers that cause the mucosal surface to have a cobblestone appearance.
• The ulcers vary in depth but usually extend at least to the submucosa and often to the serosa.
• Because of this, frequently other loops of intestine adhere to the involved segment, and fistulas may occur.

In addition, skip areas may be seen.

Microscopic changes include

• infiltration of inflammatory cells in all layers and
• marked submucosal and subserosal thickening and
• intramural fissures that can extend through to the mesenteric fat.
  

Criteria for the histologic diagnosis of granulomatous colitis have been classified as major and minor.
The major criteria are
(1) giant cells or epithelioid granulomas that occur either intramurally or within regional lymph nodes
(2) intramural fissures or fistulas,
(3) transmural mononuclear inflammation, and
(4) transmural fibrosis.
The minor criteria are
(1) submucosal lymphangiectasia,
(2) chronic serositis when there has been no prior surgery,
(3) muscle wall thickening (more than twice that of normal), and
(4) segmental involvement.

Clinical Features
Symptoms of granulomatous colitis include

• diarrhea,
• mid-abdominal and lower abdominal crampy pain,
• malaise, and
• weight loss.

Other symptoms and clinical findings include

• fever,
• rectal bleeding,
• anemia,
• nausea, and vomiting.

Occasionally, patients may present with symptoms suggestive of an acute abdomen.

It is now recognized that toxic megacolon can complicate Crohn's colitis as well as other forms of colitis.
Extraintestinal manifestations are common, with musculoskeletal manifestations being the most frequent.
Clinically, granulomatous colitis often has an extremely variable onset and course.

• Although diarrhea is a dominant feature of both UC and granulomatous colitis,
• colonic bleeding is less common with granulomatous disease.
• However, massive bleeding from acute granulomatous colitis can occur on occasion.
• Colonic sinuses, fistulas, and strictures are characteristic of granulomatous colitis.
• However, these internal complications do not occur as frequently in colon disease as they do in terminal ileum disease.

Perianal disease is a frequent complication.
· It is an extremely troublesome problem and difficult to treat successfully.
· In the National Cooperative Crohn's Disease Study,

• more than 46% of patients with colon disease had associated perianal lesions,
• whereas the rate was 25% in those with disease localized to the small bowel.
• The perianal lesions can precede the clinical appearance of the colitis by a variable number of years.
• Buchmann and Alexander-Williams classified perianal disease into the following categories: skin lesions, anal canal lesions, fistulas, and hemorrhoids.

Skin lesions include

• maceration,
• erosion,
• ulceration,
• abscess formation,
• and skin tags.

Because of the frequency of diarrhea in this disease, the skin around the anus may become macerated, leading to ulceration and subcutaneous abscess formation.

• Skin tags are frequent manifestations.
• They tend to be edematous and larger, thicker, and harder than those seen in patients without CD.

Anal canal lesions include

• fissures,
• ulcers, and
• stenosis of the anal canal.
  o The fissures tend to be deep and wide, with undermined edges.
  o Particularly important is the fact that they may be eccentrically placed in any position around the anus, in contradistinction to the uncomplicated fissure in patients who do not have CD.
• The fissures in these patients usually lie in the midline; unless there is associated sepsis, they tend to be painless.

Fistulas and abscesses

• are perhaps the most difficult of the perianal lesions.
• They may arise from an infected anal gland, as in patients without CD.
• However, more commonly they result from penetration by anal canal or rectal fissures or ulcers.
• On occasion, these fistulas are low lying and can be treated in a conventional manner.
• The more complex fistulas, however, may have a high internal opening with multiple indirect tracks opening on the buttocks or scrotum.
• Some of these tracks may communicate with each other.
• The fistulas tend to be chronic, indurated, and cyanotic, but despite their appearance, they are often painless.
• If the patient does complain of pain, one should suspect an abscess.

Rectovaginal fistulas can also complicate CD and tend to result from direct penetration of rectal wall fissures into the vagina.

• They are a relatively frequent complication of severe perianal disease, with rates varying from 3.5 to 20%.
• Quite frequently, these fistulas are asymptomatic, and no surgical intervention should be attempted.
• However, if the patient is symptomatic, surgery is indicated.
• Various local procedures have been described, but none are extremely successful.
• Some patients will require proctectomy

Diagnosis of Granulomatous Colitis

• Endoscopic evaluation of the colon and rectum is essential.
• Colonoscopy is particularly important to determine the extent of the disease and,
• in our opinion, is a more sensitive test than radiologic examination.
• For gross features of the disease, endoscopy and radiology might be equivalent.
• However, for the detection of early manifestation of the disease such as superficial ulcers, colonoscopy is superior.
• In addition, the discontinuous nature of the disease can be seen better with the colonoscope than on radiologic examination.
• It is our routine practice for all patients who undergo surgery for CD, including those with CD of the small bowel, to undergo a total colon examination before surgery to fully determine the extent of the disease.

The endoscopic appearance of Crohn's colitis is quite different from that of UC.

• The rectum is spared in approximately 50% of patients with large bowel involvement.
• Depending on the extent and severity of the disease,
• there may be isolated aphthous ulcers with normal intervening mucosa,
• or there may be
• irregular mucosal thickening,
• congestion,
• edema, and
• a cobblestone appearance with
• deep linear ulcerations and fistulas.
• Pathognomonic features of CD (i.e., granulomas) are present in only 20 to 40% of cases.

Radiologic features characteristic of Crohn's colitis are similar to those seen in terminal ileum disease.
The radiologic features that substantiate the diagnosis of Crohn's colitis include

• skip areas,
• longitudinal ulcerations,
• transverse fissures,
• eccentric involvement,
• pseudodiverticula,
• narrowing,
• strictures,
• pseudopolypoid changes,
• a cobblestone pattern,
• internal fistulas,
• sinus tracks,
• and intramural fistulas that extend parallel to the lumen of the thickened bowel.

Any portion of the colon may be involved with Crohn's colitis.

• The segments most frequently involved are the
• transverse colon,
• the cecum, and
• the ascending colon.
• The segment least frequently involved is the rectum.
• The skip areas must be sought carefully,
  o because discontinuous involvement may be limited to one wall,
  o may appear as a nodular filling defect,
  o or may involve straightening and rigidity of a short segment of the colon.

The combination of longitudinal ulcers, edematous mucosa, and transverse linear ulcers produces the cobblestone pattern previously described.

• Transverse linear ulcers may penetrate so deeply into the wall of the colon that they appear in contour as numerous long, thin spicules perpendicular to the long axis of the bowel or as a sinus track.
• They may ultimately lead to small intramural abscesses or fistulas.
• A small bowel enema or enteroclysis should be included as part of the workup in patients with Crohn's colitis to document the total extent of the disease.

Granulomatous Colitis and Carcinoma
Granulomatous ileocolitis has been recognized as a condition predisposing to the development of colorectal carcinoma.
The risk of developing carcinoma in CD is not as well defined as in UC, but some sources quote up to a 20-fold increase in gastrointestinal malignancy in patients with CD.
Carcinoma may also occur in chronic perianal fistulas.
A dilemma arises concerning the association of granulomatous colitis and carcinoma when one considers patient follow-up.
Although the incidence of cancer in Crohn's colitis is increased, it is still unclear how frequently these patients should be followed with either colonoscopy, radiology, or a combination of both.
Our recommendations for patients with Crohn's colitis are similar to those for patients with chronic UC (see earlier).