AGA Technical Review on the Evaluation and Management of ...



Evaluation and Management of Chronic Diarrhea

Definition

• Diarrhea an intestinal disorder characterized by an abnormal frequency and liquidity of fecal evacuations.

• In terms of stool weight fecal weight > 200 g/day.

• Diarrhea should not be defined in terms of fecal weight.

o Some individuals have fecal weight > 300 g/day with normal stool consistency and do not complain of diarrhea.

o Others have normal fecal weight and complain of diarrhea because their stools are loose or watery.

o Dependent on water-holding capacity of insoluble solids/total water

▪ If low stool consistency was loose.

▪ If fecal solids had enough water-holding capacity stools are thick or formed.

• Chronic diarrhoea: Four weeks is the shortest duration of diarrhea that could be considered chronic and 6-8 weeks would provide even more of a distinction.

• Differentiation of chronic diarrhea from irritable bowel syndrome and fecal incontinence

• Irritable bowel syndrome (IBS) is currently defined by consensus as the combination of abdominal pain and abnormal bowel habits (constipation, diarrhea, or variable bowel movements) in the absence of other defined illnesses.

• All patients with diarrhea should be queried about the presence of fecal incontinence.

Prevalence of chronic diarrhea and its causes

• The precise prevalence of chronic diarrhea is unknown.

• According to WHO the prevalence of chronic diarrhea in children worldwide ranges from 3% to 20%.

• Reliable international data for adults are lacking.

|Developed countries |Developing countries |

|IBS |Chronic bacterial |

|Idiopathic inflammatory bowel disease |Mycobacterial |

|Malabsorption syndrome |Parasitic infections |

|Chronic infections |Functional disorders |

|Idiopathic secretory diarrhea |Inflammatory bowel disease |

| |Malabsorption |

• Other categories

|Low volume syndromes |IBS. |

| |Hyperdefecation syndromes. |

| |Fecal incontinence. |

|Microscopic/collagenous colitis |

|After surgery |Postvagotomy |

| |Postgastrectomy |

| |postcholecystectomy |

| |Post-intestinal resection |

|Exocrine pancreatic insufficiency | |

|Small bowel dysfunction |Small bowel bacterial overgrowth |

| |Carbohydrate malabsorption |

| |Diabetes mellitus |

| |Motility disorders |

| |Strongyloides infestation |

| |Sprue, and sprue-like illnesses |

|Radiation enteritis |

|Laxative abuse |

Effect of chronic diarrhea on quality of life

• Patients with chronic diarrhea had significantly worse quality of life scores than similar patients without diarrhea.

Evaluation of diagnostic tests

Medical history

• Indicators of functional etiology (70% specific)

o Long duration of symptoms ([pic]1 year).

o Lack of significant weight loss ( 1 L/day ( significant volume depletion.

• Hypokalemia.

• Other causes excluded.

• Measurement of a few other specific peptides ( other neuroendocrine tumors.

o Calcitonin ( medullary carcinoma of the thyroid.

o Gastrin ( Zollinger Ellison syndrome.

o Glucagon ( glucagonoma.

Serological tests

|Table 2. Serological tests that may be useful in patients with chronic diarrhea |

|Antinuclear antibody |

|Vasculitis, scleroderma, celiac sprue, microscopic colitis, hypothyroidism, autoimmune enteropathy Diagnosis |

|Antigliadin (IgA, IgG), antiendomysial antibodies (IgA) |

|Celiac sprue |Diagnosis; follow-up of condition and compliance with treatment |

|Perinuclear antineutrophil cytoplasmic antibody |

|Ulcerative colitis |Diagnosis; distinguishing from Crohn's colitis |

|Quantitative immunoglobulins |

|Selective IgA deficiency, |Diagnosis; assessment of response to Ig infusions |

|common variable immunodeficiency | |

|HLA-DR, DQ typing |

|Celiac sprue, refractory or unclassified sprue, possibly Crohn's disease and ulcerative colitis |

|Confirmation of a diagnosis of celiac sprue (by finding DR3 or DQ2) when necessary; assessment of refractoriness in a patient with a sprue-like illness; in the |

|future possibly for the diagnosis and/or distinction of Crohn's and ulcerative colitis |

|ESR& CRP |IBD |Diagnosis; response to therapy; DA |

|Antibody titers to E. histolytica |Amebiasis of the colon and/or liver |Diagnosis |

|Antibodies to HIV |AIDS |Diagnosis |

IgA antigliadin antibody

• More specific but less sensitive.

• Serum levels begin decreasing after 1-3 months of a gluten-free diet.

• Disappear by 6-12 months.

IgG antigliadin antibody

• Less specific but more sensitive

• Some reduction over time but never disappear completely.

Antiendomysial antibodies

• Most specific for celiac sprue.

• Specificity 100% & sensitivity range from 74% - 100%.

• Detected by indirect immunofluorescence.

Endoscopic examination and mucosal biopsy

Sigmoidoscopy and colonoscopy

• Sigmoidoscopy can be recommended as the best initial test.

• Biopsy specimens should be obtained from the descending colon, the sigmoid colon, and the rectum (e.g., four biopsy specimens taken every 10-20 cm).

• Chronic disorders diagnosed by inspection of the colonic mucosa include:

|Melanosis coli |Ulceration |Polyps |Tumors |

|Crohn's disease |Ulcerative colitis |Amebiasis | |

• Diseases diagnosed histologically include:

|Lymphocytic and collagenous colitis |Amyloidosis |Whipple's disease |

|Granulomatous infections |Chronic schistosomiasis |

Upper endoscopy

• Standard method for obtaining biopsy specimens from the upper small intestine.

• Duodenal biopsies may be adequate to discover most diffuse mucosal diseases.

• An aspirate of small intestinal contents can be sent for:

o Bacterial culture if bacterial overgrowth is suspected.

o Microscopic examination for parasites.

• Diseases that may be diagnosed by small intestinal biopsy include:

|Crohn's disease |Whipple's disease |Giardiasis |Intestinal lymphoma |

|Celiac sprue |Lymphangiectasia |Mastocytosis | |

|Eosinophilic gastroenteritis |Amyloidosis |Hypogammaglobulinemic sprue |

|Abetalipoproteinemia |Mycobacterial, fungal, protozoal, and parasitic infections |

Radiography

Barium radiography (BMFT & enteroclysis)

• Anatomic changes are best assessed with barium radiography.

• Helpful in diagnosis of:

o Crohn's disease.

o Jejunal diverticulosis.

o Celiac sprue ( malabsorption pattern

▪ Excess luminal fluid.

▪ Dilation.

▪ Irregular mucosal surface.

o Whipple's disease.

o Intestinal lymphoma.

o Carcinoid tumors.

o Scleroderma.

o Detect fistulas and strictures.

o Delineate anatomy after previous surgical resection or bypass.

Mesenteric angiography

• Small intestinal ischemia is a rare cause of chronic diarrhea.

• Mesenteric or celiac angiography may show evidence of intestinal ischemia caused by atherosclerosis or vasculitis.

Computed tomography

• Useful in diagnosis of:

|Pancreatic cancer |Chronic pancreatitis in the presence of malabsorption. |

|Inflammatory bowel disease |Tuberculosis |Neuroendocrine tumors |

|Intestinal lymphoma |Carcinoid syndrome | |

Physiological tests

Mucosal absorption

• Tests of monosaccharide absorption

• Distinguish small intestinal mucosal absorptive defects from pancreatic digestive defects in the setting of malabsorption.

• D-xylose test

• Urinary excretion < 5 g in the 5 hours following ingestion of 25 g of D-xylose is considered abnormal.

• A plasma concentration < 1.3 mmol/L per 1.73 m2 body surface area (20 mg/dL for an average adult) 1 hour after a 25-g oral dose is considered abnormal.

Tests of ileal absorptive function

• The terminal ileum has evolved three specific and unique absorptive functions:

o Absorption of vitamin B12.

o Absorption of sodium chloride against steep electrochemical gradients.

o Absorption of bile acids.

• Schilling test

o Vitamin B12 malabsorption and other interpretations.

• Intestinal perfusion

o Study fluid and electrolyte absorption in the ileum.

o Total gut perfusion is carried out first with a balanced electrolyte solution, and then a solution containing a low concentration of sodium chloride compared with plasma.

o Requires an intact functional ileum for normal active absorption.

• Tests for bile acid malabsorption can be done in two ways:

o Measure the quantity of endogenous bile acids excreted during a quantitative stool collection.

o Measurement of the turnover of radiolabeled bile acid by:

▪ Use of a gamma camera to detect the retained fraction of an orally administered synthetic radiolabeled bile acid.

▪ Measurement of fecal recovery of an oral load of 14C glycocholate during a 48- or 72-hour stool collection and calculation of a retention half-life.

▪ Measurement of serum concentrations of an intermediate of bile acid synthesis.

▪ Therapeutic trial of cholestyramine as an indirect test for the possibility that malabsorbed bile acids are the cause of diarrhea.

Breath tests for physiological testing

• Tests use probe molecules labeled with 14C or 13C or a nonradioactive fermentable sugar.

• Metabolism of these substances produces isotopically labeled CO2 or H2 that can be detected in expired air.

|Breath tests that may be applied to patients with chronic diarrhea |

|Agent administered |Substance measured in breath |Condition assessed |

|Lactose |H2 |Lactase deficiency |

|Sucrose |H2 |Sucrase deficiency |

|Glucose |H2 |Bacterial overgrowth of small intestine |

|Lactulose |H2 |Bacterial overgrowth of small intestine |

|14C-xylose |14C |Bacterial overgrowth of small intestine |

|14C-glycocholate |14C |Bacterial overgrowth of small intestine |

Tests for lactose malabsorption

• Therapeutic trial of a lactose-free diet.

• Oral lactose tolerance test.

o Oral load of lactose is given ( sequential measurement of serum glucose.

▪ ↑ Serum glucose concentration ( lactose has been hydrolyzed and absorbed by the mucosa.

▪ Low sensitivity and specificity due to random fluctuations in endogenous serum glucose concentrations

• Lactose breath hydrogen testing (25-g test dose of lactose is used)

o Requires a 12-hour pretest fasting period to ensure that baseline fasting breath hydrogen levels are low.

o Based on the fact that lactose malabsorbed by the small intestine in lactase-deficient individuals is fermented rapidly in the colon to organic acids and gases, including hydrogen.

o Hydrogen is then absorbed and excreted by the lungs into the breath( collected in a balloon or bag and measured by gas chromatography or other methods.

o ↑ Breath hydrogen of 20 ppm above baseline within 4 hours usually has been set as the cutoff for a positive test result.

Tests for bacterial overgrowth

• Bacterial overgrowth clearly exists, especially when disorders that diminish intestinal motility are present.

• Quantitative culture of an aspirate of luminal fluid

o > 106 organisms/mL in either aerobic or anaerobic conditions is the criterion for a positive culture.

o Fallacies: some asymptomatic individuals have >106 organisms/mL.

o A positive jejunal culture (>106 organisms/mL) can be considered evidence of clinically significant bacterial overgrowth in the upper small intestine.

• Therapeutic trial: patient response to treatment with an appropriate antibiotic.

• Breath tests

o Bacteria in the upper small intestine deconjugate bile acids, making them inadequate for micellar formation and fat absorption.

o 14C glycocholate breath test

o The radiolabeled conjugated bile acid ( deconjugated by the bacteria( 14C ( metabolized to 14CO2( exhaled.

o False positives (in patients with ileal resection or dysfunction).

o 14C xylose breath test

o Nonradioactive glucose breath test

o Measures breath hydrogen excretion

o 50-100 g of glucose is administered in water by mouth, followed by measurement of breath hydrogen concentration at 15-30-minute intervals for 2-4 hours.

o ↑ Breath hydrogen concentration > 12-20 ppm above baseline is considered a positive result.

o Nonradioactive lactulose breath test

o Colonic fermentation would result in a low specificity.

• An elevated concentration of hydrogen in breath after overnight fasting (insensitive but specific marker of small intestinal bacterial overgrowth).

• Abnormal Schilling II test result

o Vitamin B12 absorption normalizes after therapy with broad-spectrum antibiotics has also been considered as a test for small intestinal bacterial overgrowth (the so-called Schilling III test).

o Requires a positive result from parts I or II of the Schilling test.

Tests of pancreatic exocrine function

• Intubation tests (rarely done anymore)

• A tube is placed under fluoroscopic guidance with an aspiration port in the distal duodenum; another port is used to drain gastric juice from the stomach.

• Secretin and/or cholecystokinin are administered intravenously or a test meal is eaten ( duodenal fluid is aspirated ( measurement of bicarbonate concentration and output + pancreatic enzyme levels.

• Bentiromide test

• Relies on the presence of enough chymotrypsin in the duodenal lumen to digest the peptide bond in the bentiromide reagent ( releases para-aminobenzoic acid ( absorbed by the mucosa ( excreted in urine

• Urinary excretion > 85 mg of para-aminobenzoic acid in 6 hours ( positive test.

• Sensitivity 80% & specificity 95%.

• Measurement of pancreatic enzymes in stool

• Simple and accurate.

• Measurements of fecal concentrations of the pancreatic enzymes chymotrypsin, trypsin, lipase, and elastase.

• Fecal chymotrypsin ( sensitivity 80% & specificity 90%.

• Fecal elastase using ELISA (amount rather than the activity of the enzyme).

• Breath tests

o 14C triolein breath test

o Detection of 14CO2 in expired air requires sufficient pancreatic lipase activity to hydrolyze the labeled fatty acid from its glycerol backbone, absorption of the fatty acid by the small intestinal mucosa, metabolism of the labeled fatty acid to 14CO2 in the body, and excretion of 14CO2 in the breath.

o Results affected by abnormalities in any of this stages.

Tests for gastrointestinal food allergy

• Detection of antibodies to food in feces or small intestinal secretions.

• Skin testing.

• Not of proven value in detection of gastrointestinal food allergies.

Medical history

|Implications of some aspects of medical history |

|Line of questioning |Clinical implication |

|Onset |

|   Congenital |Chloridorrhea, Na+ malabsorption |

|   Abrupt |Infections, idiopathic secretory diarrhea |

|   Gradual |Everything else |

|Residence |

|Patients living in rural settings may be exposed to farm animals that can harbor bacterial pathogens (such as Salmonella or Brucella) |

|Family history |

|Congenital absorptive defects, IBD, celiac disease, multiple endocrine neoplasia |

|Dietary history |

|   “Sugar-free” foods |Sorbitol, mannitol ingestion |

|   Raw milk |Brainerd diarrhea |

| Raw seafood or shellfish |Capillariasis |

|Exposure to potentially impure water source |

| Chronic bacterial infections (e.g., Aeromonas), giardiasis, cryptosporidiosis, Brainerd diarrhea |

|Travel history |

| Infectious diarrhea, chronic idiopathic secretory diarrhea |

|Weight loss |

| Malabsorption, pancreatic exocrine insufficiency, neoplasm, anorexia |

|Previous therapeutic interventions (drugs, radiation, surgery, antibiotics) |

| Drug side effects, radiation enteritis, postsurgical status, pseudomembranous colitis |

|Secondary gain from illness |Laxative abuse |

|Systemic illness symptoms |

| Hyperthyroidism, diabetes, vasculitis, tumors, Whipple's disease, IBD, tuberculosis, mastocytosis |

|Intravenous drug abuse, sexual promiscuity |AIDS |

|Immune problems |AIDS, Ig deficiencies |

|Abdominal pain |Mesenteric vascular insufficiency, obstruction, IBS |

| Peri umbilical |Small intestinal cause |

| Lower abdominal |Large bowel |

|Excessive flatus |Carbohydrate malabsorption |

|Leakage of stool |Fecal incontinence |

|Stool characteristics |

|   Blood |Malignancy, IBD |

|   Oil/food particles |Malabsorption, maldigestion |

|   White/tan color |Celiac disease, absence of bile |

|   Nocturnal diarrhea |Organic etiology |

| Malodorous, floating, greasy |Malabsorption |

| Watery and voluminous |Disorder of the small bowel or proximal colon |

| Frequent, small-volume |Disorders of the left colon or rectum |

| Mucus, pus, or blood |IBD, dysenteric infections |

|Tenesmus |Disorders of the rectum |

|Fever or weight loss |

|IBD, amebiasis, intestinal lymphoma, Whipple's disease, tuberculosis, enteric infections, or thyrotoxicosis. |

|Seronegative spondyloarthropathy |Precede the recognition of IBD by many years |

|Magnesium-containing products, and any antibiotics taken within the preceding 6-8-week period |

|Health-care workers may be at risk for nosocomial enteric infections (including Clostridium difficile) and factitious diarrhea. |

|Patient's sexual practices: anal intercourse is a risk factor for proctitis due to gonorrhea, herpes simplex, Chlamydia, syphilis, and amebiasis |

|Promiscuous or unprotected sexual activity |HIV infection |

|Functional disorders IBS |

|Long history - second or third decade - intermittent abdominal pain associated with alteration of bowel habits - classically diarrhea alternating with |

|constipation or passage of pellet-like stools - nonbloody mucus - exacerbated by emotional stress - fecal weight < 400-500 g/day |

Physical examination

• In most cases results of physical examination are normal or nondiagnostic.

• Mouth ulcers, signs of severe atherosclerosis, lymphadenopathy, signs of autonomic failure, and rashes, flushing, or hyperpigmentation of the skin.

|Table 5. Major causes of chronic diarrhea classified by typical stool characteristics |

|Osmotic diarrhea |Secretory diarrhea |

|Mg2+, PO4–3, SO4–2 ingestion |Laxative abuse (nonosmotic laxatives) |

|Carbohydrate malabsorption |Congenital syndromes (chloridorrhea) |

|Fatty diarrhea |Bacterial toxins |

|Malabsorption syndromes |Epidemic secretory (Brainerd) diarrhea |

|      Mucosal diseases |Idiopathic secretory diarrhea |

|      Short bowel syndrome |Neoplasia |

|      Postresection diarrhea |      Colon cancer |

|      Small bowel bacterial overgrowth |      Lymphoma |

|    Ileal bile acid malabsorption |      Villous adenoma |

|      Mesenteric ischemia |   Neuroendocrine tumors |

|Maldigestion |      Gastrinoma |

|      Pancreatic exocrine insufficiency |      VIPoma |

| Inadequate luminal bile acid |      Somatostatinoma |

|Inflammatory diarrhea |      Mastocytosis |

|Inflammatory bowel disease |      Carcinoid syndrome |

|      Ulcerative colitis |      Medullary carcinoma of thyroid |

|      Crohn's disease |   Disordered motility |

|      Diverticulitis |      Postvagotomy diarrhea |

|      Microscopic (lymphocytic) colitis |      Postsympathectomy diarrhea |

| Collagenous colitis |      Diabetic autonomic neuropathy |

|Infectious diseases | IBS |

|      Pseudomembranous colitis | Endocrine |

|      Invasive bacterial infections | Addison's disease |

|         Tuberculosis, yersinosis, others |      Hyperthyroidism |

|      Ulcerating viral infections | Miscellaneous |

|         Cytomegalovirus | Ischemic colitis |

|         Herpes simplex | Radiation colitis |

|      Amebiasis/other invasive parasites | |

Empirical therapy of chronic diarrhea

Indications:

1. As temporizing or initial treatment before diagnostic testing

2. After diagnostic testing has failed to confirm a diagnosis.

3. When a diagnosis has been made, but no specific treatment is available or specific treatment fails to establish a cure.

Empirical therapy include

1. Antibiotic therapy

• Considered as initial therapy if the prevalence of bacterial or protozoal infection is high in a community.

• Chronic diarrhea in a daycare worker ( empiric metronidazole for suspected giardiasis.

• Empiric ciprofloxacin for suspected bacterial pathogen.

• Empiric anti helminthic treatment.

2. Symptomatic therapy

• For undiagnosed or poorly responsive chronic diarrhea.

a. Natural and synthetic opiates ( diphenoxylate and loperamide.

b. Bile acid–binding agents( Cholestyramine.

c. Bismuth subsalicylate.

d. Medicinal fiber.

e. Prodrug loperamide-N-oxide (under development).

f. Enkephalinase inhibitor acetorphan (under development).

g. Somatostatin analogue octreotide has proven effectiveness in carcinoid tumors and other peptide-secreting tumors, dumping syndrome, and chemotherapy-induced diarrhea.

h. Intraluminal agents include adsorbants, such as clays, activated charcoal, and binding resins.

i. Stool modifiers, such as psyllium, may alter stool consistency but do not reduce stool weight.

j. Oral rehydration solutions that include glucose or other nutrients and salt are useful for repletion of body fluids.

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