diseases of the small bowel. malabsorption syndrome. crohn ... · malabsorption syndrome. crohn´s...

Diseases of the Small Bowel.

Malabsorption syndrome.

Crohn´s Disease.

Celiac Sprue

• Celiac sprue is a T-cell–mediated gluten intolerance in genetically predisposed individuals in whom exposure to wheat, barley, or rye induces a characteristic mucosal lesion that responds to dietary gluten withdrawal.

• It occurs in 0.3–1.0% of Caucasians of European extraction.

• Symptoms may initially present at virtually any age, ranging from infancy (upon addition of gluten-containing cereal to feedings) to late adulthood.

• Pathogenesis

• Genetic factors and altered immune function both play a major role in the pathogenesis of celiac sprue.

• The disease has a prevalence of 8–12% in first-order relatives.

• Ninety to 95% of affected individuals carry the HLA-DQ2 heterodimer, the vast majority of the remaining 5–10% carries the HLA-DQ8 heterodimer.

• Clinical Findings• In those with a mild lesion involving only the proximal

small intestine, the disease may be completely silent with no evident clinical manifestations.

• In others with a lesion limited to the proximal intestine selected nutrient deficiencies, which may include iron, folate, or calcium, may be present with resultant anemia or osteopenia but with no significant gastrointestinal symptoms.

• If a more severe lesion extends to the more distal intestine, panmalabsorption with gastrointestinal symptoms, including weight loss, diarrhea, excess flatus, and abdominal discomfort, may all be present in concert with evidence of involvement of other systems.

• B. Laboratory Findings• Laboratory findings, like the clinical manifestations, may vary

enormously depending on extent of disease, ranging from no abnormalities or only isolated iron or folate deficiency to multiple abnormalities including steatorrhea, hypoalbuminemia, hypoprothrombinemia, hypocalcemia.

• Serologic tests are useful screening tests for celiac sprue. Either the IgA anti-tissue transglutaminase test (tTGA) or the IgA antiendomysial antibody test (EMA) are useful and have reported sensitivities of 80–95% and specificities of 95–99%.

• Both conventional tTGA and EMA measure IgA class antibodies; therefore, some false-negative tests are inevitable as the prevalence of selective IgA deficiency among celiac sprue patients is 2–4%.

• IgG-tTGA and IgG-EMA can be determined.

• Mucosal intestinal biopsy of the distal duodenum or proximal jejunum, coupled with a clinical response to the dietary withdrawal of gluten, remains the gold standard for the diagnosis of celiac sprue.

• Villi may be blunted or the mucosal surface may appear to be flat with complete absence of villi.

• Crypts are hyperplastic, with increased numbers of mitotic figures.

• Surface absorptive cells are damaged and infiltrated by increased numbers of IELs.

Celiac sprue

Celiac sprue

• Other diseases that may have similar clinical manifestations and may have similar mucosal histology include refractory sprue, tropical sprue, viral gastroenteritis (especially when caused by rotavirus in children), intraluminal bacterial overgrowth, and eosinophilic gastroenteritis.

• Clinical response to gluten withdrawal is a crucial step in establishing the diagnosis.

• Treatment

• The cornerstone of treatment of celiac sprue is the elimination of products containing wheat, barley, and rye from the diet.

• Many other dietary carbohydrates including rice, corn, potatoes, and soybeans are well tolerated by celiac patients.

• Micronutrient deficiencies including iron and folate deficiencies should be treated.

• • Initial treatment of celiac sprue.

• Avoid all wheat, barley, rye, and oat gluten

• • Rice, corn, millet, potato, buckwheat, and soybeans are safe

• • Read all labels of processed foods, be suspicious of all additives such as hydrolyzed vegetable protein

• • Limit intake of dairy products until diarrhea disappears

• • Replace all deficient micronutrients with specific supplements as needed (calcium, iron, folate, vitamins)

• • Join a local celiac lay support group

• If diarrhea and steatorrhea are present, lactose restriction may be needed initially as clinically significant secondary lactase deficiency is often present.

• A repeat serologic test (IgA-tTGA or IgAEMA) is helpful 6–10 months after initiation of gluten withdrawal as the antibodies disappear in fully compliant celiac patients.

• Course & Prognosis

• The prognosis of patients with celiac sprue is excellent.

• There is a higher incidence of lymphoma, especially of the T-cell type, among celiac patients.

• There is increasing evidence that strict adherence to a gluten-free diet substantially reduces the risk of subsequent lymphoma development.

• All immediate family members should be screened for celiac sprue.

• The prevalence of celiac sprue also is high in several other conditions, many of which are associated with autoimmunity.

• Prevalence of celiac sprue in selected diseases.• Dermatitis herpetiformis > 90%• Diabetes mellitus type 1 2–8%• Autoimmune thyroid disease ~3%• Down syndrome 3–12%• Turner syndrome 2–10%• Unexplained infertility 2–4%• Unexplained osteopenia 2–3%• Unexplained anemia 2–8%• Irritable bowel syndrome Up to 10%• ↑ Liver function tests 1.5–9.0%• Selective IgA deficiency Up to 8%

Dermatitis herpetiformis Duhring

Tropical Sprue

• Tropical sprue occurs among natives of, visitors to, and expatriots from selected countries located, by and large, between the Tropic of Cancer and the Tropic of Capricorn.

• The cause of tropical sprue remains obscure, but its epidemiology and its response to antibiotic therapy strongly suggest that colonization of the intestine by an infectious agent or alterations in the intestinal bacterial flora induced by the exposure to another environmental agent is important.

• Clinical symptoms and signs are nonspecific and include diarrhea, steatorrhea, weight loss, nausea, and anorexia.

• Anemia is common and most often megaloblastic, reflecting vitamin B12 or folate deficiency, or both.

• Mucosal biopsy of the small intestine reveals a nonspecific lesion of variable severity.

• Architectural changes range from minimal villous blunting to complete absence of villi.

• The histologic lesion cannot be distinguished with certainty from that observed in celiac sprue, viral gastroenteritis, or intraluminal bacterial overgrowth.

• The diagnoses relies on excluding celiac sprue and other diseases such as protozoal infections,

• Recommended treatment includes an antibiotic such as tetracycline and high-dose folic acid.

• 1 month of treatment appears to be sufficient for most travelers and expatriates.

• Specific nutritional deficiencies such as vitamin B12 and calcium deficiencies should also be corrected.

Whipple Disease

• Whipple disease is an unusual and uncommon systemic infectious disease with protean clinical manifestations.

• The small intestine is almost always involved, producing malabsorption in the majority of patients.

• The cause is infection by the actinobacter Tropheryma whipplei.

• Clinical Findings• In the classic presentation, gastrointestinal symptoms are usually striking

and resemble those seen in other diseases with generalized malabsorption.

• Weight loss, diarrhea, steatorrhea, and abdominal distention are present in 80–90% of patients, and both peripheral edema reflecting hypoproteinemia from protein-losing enteropathy and poor nutrition are common.

• Fever is present in 30–50% of patients.• Arthralgia and arthritis occur in 60–75%.• Cardiac manifestations, including pericarditis and culture-negative

endocarditis, or pleuropulmonary involvement, including pleural effusions, cough, and sarcoid-like pulmonary infiltrates, may be the initial manifestations.

• In addition to the physical findings characteristic of malabsorption, skin hyperpigmentation, peripheral lymphadenopathy, cardiac murmurs, signs of arthritis, and neurologic abnormalities may be present.

• Anemia with or without occult gastrointestinal bleeding, hypoalbuminemia, and hypocalcemia are relatively common.

• The diagnosis is established by demonstration of T whipplei in involved tissues by microscopy together with the characteristic infiltration of periodic acid–Schiff (PAS)-positive macrophages.

• Electron microscopy reveals the characteristic bacteria in the mucosa.

• Biopsy of the mucosa of the proximal intestine is the procedure of choice because the small intestinal mucosa is involved in the vast majority of patients.

Whipple Disease

• Treatment

• Empiric treatment with antibiotics results in prompt improvement in most patients and in permanent cure in many.

• Because of the danger of central nervous system involvement even in the absence of symptoms, use of antibiotics that penetrate the blood-brain barrier is desirable.

• Recommended regimen is ceftriaxone,

2 g/day for 2 weeks followed by twice daily trimethoprim, 160 mg, and sulfamethoxazole, 800 mg, for 1–3 years, but trimethoprim–sulfamethoxazole alone has been successful in most patients.

• The overall prognosis in the absence of central nervous system involvement is excellent.

• Patients should be carefully monitored indefinitely for signs of relapse.

Small Intestinal BacterialOvergrowth (SIBO)

• Under normal circumstances the proximal small intestinal lumen harbors less than 105 bacteria per milliliter of intestinal contents, most of which are derived from the oropharyngeal flora.

• The major mechanisms limiting excessive bacterial growth in the proximal intestine are normal intestinal motor function and normal gastric acid secretion.

• The presence of any condition that interferes with these protective mechanisms, notably impaired intestinal motility, structural lesions predisposing to intestinal stasis, profound reduction or absence of gastric acid secretion, and immunodeficiency syndromes may precipitate SIBO.

• Causes of bacterial overgrowth in the proximal intestine.• 1. Motility disorders• a. Scleroderma• b. Amyloidosis• c. Pseudo-obstruction• d. Vagotomy• e. Diabetes with visceral neuropathy• 2. Structural abnormalities• a. Diverticula• b. Strictures• • Crohn disease• • Vascular disease• • Radiation enteritis• c. Adhesions causing partial obstruction• d. Afferent loop stasis after Billroth II gastrectomy• e. Fistulas• • Gastrocolic• • Jejunocolic• • Jejunoileal• 3. Hypochlorhydria or achlorhydria• a. Gastric atrophy with or without pernicious anemia• b. Vagotomy or gastric resection• 4. Hypogammablobulinemia or agammaglobulinemia

• Clinical Findings• The clinical features of SIBO that are caused by the

bacterial overgrowth are typical of those seen in other malabsorptive states, with weight loss, diarrhea, steatorrhea, flatulence, and abdominal distention being common.

• Quantitative culture of the duodenal fluid is the diagnostic gold standard.

• Tissue retrieved by small intestinal mucosal biopsy may range from normal histology to a severe but nonspecific lesion with villus blunting, crypt hyperplasia, damaged absorptive cells, and substantial mucosal inflammation.

• Treatment

• If a correctable lesion such as a gastrocolic fistula or a discrete intestinal stricture is the cause of SIBO, surgical repair is the treatment of choice.

• If SIBO is associated with chronic motor abnormalities, achlorhydria, or noncorrectable anatomic abnormalities such as multiple jejunal diverticula, antibiotics are the treatment of choice.

• Some patients respond to amoxicillin–clavulanate alone; others require broader coverage with the addition of metronidazole.

• Promising responses have been obtained with rifaximin.

Crohn’s disease

• Crohn’s disease is a relapsing systemic inflammatory disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations and associated immune disorders.

• Any level of the gastrointestinal tract may be affected from the mouth to the anus, with the ileum, colon and perineum most frequently involved.

• Extraintestinal manifestations (EIMs) may occur and can affect the skin, joints, liver/biliary tree, and eyes.

EPIDEMIOLOGY • Crohn’s disease is more common in the West than developing

countries. • Incidence 7 per 100,000/year• Ethnicity also has an effect on presentation of Crohn’s

disease; in the USA, African Americans are more likely to have colonic and perianal disease and less likely to have ileal disease than their white counterparts.

• Rates in the East are increasing, especially in China and India.• Jews, in particular Ashkenazi Jews, have a high prevalence.• There is a bimodal distribution of age at presentation, with

the main peak at 10-40 years of age, with a smaller peak in the 60s.

AETIOLOGY

• The aetiology of Crohn’s disease is incompletely understood.

• It is known that immunological, microbiological, lifestyle, and genetic factors are implicated.

• Current opinion is that in genetically susceptible individuals, there is an immune dysregulation to an environmental factor, and the intestinal microbiota plays a central role.

GENETICS

• Family history is a major risk factor for Crohn’s disease.

• Having a first degree relative with the disease increases the risk 10-fold.

• The highest risk is with monozygotic twins, where disease concordance is between 35-50%.

• The first Crohn’s disease gene identified was Nucleotide-binding oligomerisation domain-containing protein 2 (NOD2).

IMMUNOLOGY

• Defects in both the innate and adaptive immune systems are present in Crohn’s disease.

• Barrier function, the first line of innate defence, is impaired by both an inadequate mucous layer, and by abnormally low levels of protective antimicrobial peptides (such as the human α-defensin produced in health by Paneth cells), which admit greater antigenic and microbial exposure to the epithelium.

•

ENVIRONMENTAL FACTORS

Smoking

• Smoking is an independent risk factor for developing Crohn’s disease.

• Smoking increases progression to more advanced disease (stricturing and/or penetrating).

• Cessation of smoking is associated with a reduction in progression.

Diet

• No food component has yet been proven to be clearly implicated in the pathogenesis.

• Elemental and polymeric diets, both with lower antigenic load than a normal diet, are successful treatments for Crohn’s disease in children.

• Microbiome

• Reduced firmicute (especially Faecalibacterium prausnitzii) and bacteroides spp. organism ratios are associated with disease.

PATHOPHYSIOLOGY• Crohn’s disease is characterised by transmural inflammation

of any part of the gastrointestinal (GI) tract.• The most common disease locations are the distal ileum, the

colon, and the perineum.• Multiple sites may be diseased, and the pattern of healthy

mucosa between diseased segments is termed ‘skip lesions’ and is typical of Crohn’s disease.

• The deep inflammation allows penetrating (fistulising) and stricturing disease.

• Histologically the disease is recognised by transmural inflammation, with lymphocyte and plasma cell infiltration, crypt disruption and the presence of non-caseating granulomas.

CLINICAL PRESENTATION

• The most common presenting symptoms are diarrhoea, weight loss, abdominal pain, and fatigue.

• EIMs predominantly affect the skin (erythema nodosum, pyoderma gangrenosum), the joints (small joint polyarthropathy, large joint arthropathy, ankylosing spondylitis), the eyes (episcleritis, scleritis and uveitis), and the biliary tree (primary sclerosing cholangitis [PSC]).

• Patients with Crohn’s disease also have an increased risk of venous thromboembolic disease, colorectal cancer (CRC), gallstones, renal stones, and osteoporosis.

DIAGNOSIS

• Laboratory Tests

• C-reactive protein and erythrocyte sedimentation rate.

• Anaemia and thrombocytosis are common findings.

• Stool tests should include microscopy and culture; Clostridium difficile toxin assay and faecal granulocyte proteins (calprotectin or lactoferrin).

•

Endoscopy

• Ileocolonoscopy with biopsies is the gold standard investigation for diagnosing Crohn’s disease.

• Typical endoscopic features include isolated aphthous ulcers, cobblestoning, and deep ulceration.

• Capsule endoscopy is well validated for small bowel Crohn’s disease.

• Double balloon enteroscopy is sensitive for small bowel lesions.

Crohn´s disease

Crohn´s disease, capsule endoscopy

Imaging

• Fluoroscopy has been superceded by CT and MR enterography.

• Ultrasonography has the advantage of avoiding ionising radiation, but is highly operator dependent.

• Standard abdominal radiography is useful for emergency presentations as a quick, cheap, and easy test to assess small bowel dilatation and colonic inflammation.

CT enterography

MANAGEMENT

• Smoking

• Cessation of smoking is an effective intervention in the treatment of Crohn’s disease. Smoking predisposes to a more aggressive disease course, with stricturing and fistulising disease.

• Diet

• Polymeric and elemental diets are effective at inducing remission in children, but less so in adults.

• A low residue diet helps prevent sub-acute bowel obstruction in patients with stricturing disease.

Aminosalicylates

• European guidelines are that 5-ASAs are not recommended for maintenance of medically-induced remission of Crohn’s disease.

• Sulphasalazine may be used for mild colonic disease and may be used in patients with joint symptoms.

• There may be a role for mesalazine in prevention of recurrence of post-operative Crohn’s.

Corticosteroids

• Budesonide is first-line therapy for inducing remission of mild exacerbations of ileocaecal Crohn’s disease.

• Systemic steroids can be used for inducing remission during severe flares of ileocolonic Crohn’s disease.

• Steroids are not safe or efficacious for maintenance therapy.

Antibiotics, Probiotics, Prebiotics, and Faecal Transplantation

• Ciprofloxacin and metronidazole are effective for treating septic complications of Crohn’s disease and for perianal disease.

• There are no data that probiotics, prebiotics or faecal transplantation provide any benefit in the treatment of Crohn’s disease.

Immunomodulators• The thiopurines azathioprine and 6-mercaptopurine

(6-MP) are widely used to maintain medically induced remission of moderate-to-severe Crohn’s disease.

• Common adverse effects include nausea, vomiting, pancytopaenia, and pancreatitis.

• Methotrexate, • an anti-metabolite, is used in Crohn’s disease. It is

also effective at treating inflammatory bowel disease (IBD)-related arthropathy.

Anti-TNF Therapy

• Monoclonal antibody therapy, including infliximab, adalimumab and certolizumab, is effective for induction and maintenance of remission of moderate-to-severe Crohn’s disease.

Surgery

• Distal ileal resection can be considered for short segment moderate-to-severe disease.

• Extensive small bowel resection can lead to short bowel syndrome.

• Surgery is also performed for perianal complications and includes laying open fistulae and seton insertion as well as drainage of abscesses.