GI-L18: Malabsorption and Maldigestion (AIDS and GI Tract)
Malnutrition
*Altered Food Intake Oral Ulcers Esophagitis CNS diseases -Dementia -Toxoplasma Drugs causing anorexia NPO orders Poverty Malabsorption Infectious Diarrhea -CMV -Microsporidia -Cryptosporidia -MAC -Idiopathic diarrhea Metabolic Changes Hypermetabolic State -Chronic infection - HIV -Increased TNF
Celiac Disease, Gluten Sensitive Enteropathy: PREVALENCE
*Common, affects ~1% of the population *All ethnic groups *Evidence from serologic screening studies UK adults (Gut, 2003) 1/100 UK children (BMJ, 2004) 1/100 Finland children (NEJM, 2003) 1/99 Turkey children (J Clin Gastroenterol, 2005)1/115 Turkey adults (J Clin Gastroenterol, 2005) 1/99 North Africa children (Lancet, 1999) 1/18 *USA adults & children (Arch Int Med, 2003) 1/133 *Pediatric disease but can occur in 3rd and 4th decade.
Bacterial Overgrowth: Pathophysiology Consequences - Bacteria will:
*Deconjugate bile salts - remove taurine and glycine --->more lipid soluble, passively reabsorbed in the upper small intestine *Dehydroxylation at 7 alpha position makes bile salts insoluble *Ferment CHO to H2 and CO2 *B12 depletion *Mucosal injury with flattened villi
Malabsorption: Whipple's Disease
*Described by George Hoyt Whipple in 1907. *Present with non-specific symptoms but typically those of malabsorption. *Most common in white men between 40-60 years of age. *Also can see cough, fever, arthritis, dementia and congestive heart failure. *Pathogenesis: -Mucosal invasion with Tropheryma whippleii (Gram + bacteria). -Mesenteric lymphadenopathy leads to lymphatic obstruction. -Routine histology - PAS-positive "foamy" macrophages in lamina propria. *Diagnosis -Needs high clinical suspicion. -Small bowel biopsy -Treatment and Prognosis: -Bactrim for 6 months to 1 year. -Nutrient supplementation/repletion. -Most patients respond within 1 to 3 months. -Relapses common.
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
*Diagnosis -Serum IgA antigliadin antibody (+) - historical -Deaminated gliadin peptide antibody -Serum IgA antiendomysial antibody (+) -Serum IgA anti-tissue transglutaminase antibody (+) -Antiendomysial/tissue transglutamnase - very specific -Best combo - tTg IgA + DGP -False Negatives - IgA deficiency, partial villous atrophy
Maldigestion: Bacterial Overgrowth
*Diagnosis - Difficult to diagnose -Culture of intestinal aspirate is the gold standard and bacterial counts > 105 / ml of jejunal aspirate indicate overgrowth. -C14 D-xylose breath test *Treatment: -Antibiotics -Surgery
Tests for Protein Absorption
*Fecal Nitrogen: -Difficult to measure. -Rarely done clinically. *Fecal a1 - antitrypsin: -False positive in occult blood loss.
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
*First described in 1950. *Malabsorptive disorder characterized by villous flattening.
Malabsorption/Maldigestion: Clinical Investigation
*History - thyroid disease, diabetes, AIDS, Connective tissue diseases (SLE, RA, etc) *Lab tests - CBC, Vit B12 and folate, Iron, Calcium, *Alkaline Phosphatase, Albumin *Diarrhea w/u - see syllabus *Specific tests
Definitions:
*Maldigestion: A defect or impairment of nutrient hydrolysis. *Malabsorption: The defective mucosal absorption of nutrients. *In clinical practice malabsorption is usually used as a global term to encompass all aspects of impaired digestion and absorption.
Maldigestion : Bacterial Overgrowth
*Normal small bowel - no significant amount of bacteria *Causes: -Hypochlorhydria - postgastrectomy, pernicious anemia, PPI's (?) -Altered motility - diabetes, scleroderma -Stasis due to structural problems - strictures, small intestinal diverticula, blind loops
Malnutrition
*Presenting symptoms Weight Loss Change in body habitus Change in Functional Status *Altered Food Intake Anorexia Early Satiety Eating Disorder *Malabsorption Diarrhea Gas Bloating *Metabolic Changes Fever Tachycardia Fatigue
Tests for Fat Absorption
*Quantitative Analysis: -Gold standard to diagnose steatorrhea -72 hour collection from a patient eating 100 grams fat / day. -Normal fecal fat output is < 7 grams / day. -Difficult for both patient and staff to perform. *Qualitative Analysis: -Sudan Stain - done on routine fecal sample. -Correlation between quantitative fecal fat and Sudan staining is poor. -Sensitive only in moderate to severe steatorrhea.
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
*Silent Presentation -Osteoporosis -Iron deficient anemia -Anemia due to B12 or folate deficiency -Neuropathies -Recurrent aphthous somatitis -Infertility -Dermatitis Herpetiformis 1. Usually have no diarrhea. 2. Limited amount of intestine involved. 3. Recognized more frequently, greater % of cases
Malabsorption: Tropical Sprue
*Small intestinal mucosal atrophy occurring in the "tropics": -West Indies -Puerto Rico (endemic) -Haiti, Dominican Republic -India, Southeast Asia *Differs from celiac disease: -in that it involves the entire small intestine -atrophy is less severe.
Malabsorption: Lactase Deficiency
*The most common malabsorption syndrome. *Usually presents as a late onset "acquired" deficiency. *Most of the world's adult population is lactase deficient: -100% Asian Americans -95% American Indian -81% Afro-American -71% Italians *Lactase is a brush border enzyme. *Lactase is more susceptible to mucosal disease than other brush border enzymes. *Therefore lactase deficiency can complicate other diseases of the small intestine: -Acute gastroenteritis -Chronic alcoholism -Sprue -Crohn's disease -AIDS enteropathy *Symptoms: flatulence, diarrhea and abdominal cramping. *Pathophysiology: Undigested lactose reaches the colon where bacteria metabolize lactose to volatile fatty acids, H2 and CO2. *Diagnosis: Lactose Breath Test - give 50 grams lactose and measure breath H2. *Treatment - Avoid dairy products, lactaid.
CELIAC DISEASE: CLINICAL
*Traditionally a malabsorption syndrome *Currently more a multisystem disease NOT PRIMARILY A GI DISEASE *Great spectrum in the clinical presentation
Maldigestion : Pancreatic Insufficiency-Chronic Pancreatitis
*Triad - Chronic pain, steatorrhea, brittle diabetes. -Alcohol is leading cause. Gland usually calcified. -CHO and protein maldigestion occur but not as clinically significant. *Need to lose ~90% of gland. *Diagnosis - tests for steatorrhea, imaging. *Treatment - exogenous pancreatic enzymes which include mainly lipase and some protease and amylase.
Cryptosporidia
*Water Borne agent *Highly infectious *Infects multiple epithelial surfaces *Causes refractory diarrhea in HIV *Disappearing OI *Mechanism of diarrhea -Disrupts intestinal architecture with villous atrophy and crypt hyperplasia -Enterotoxin production -Host response to infection *Therapy -None -rare cases respond to azithromycin/paramomycin -Improve Immune Function -Supportive care
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
*Why Under Diagnosed -Shift to silent form -Failure of doctors and healthcare systems -Lack of pharmaceutical support
Post Surgical Maldigestion
Deficiencies post RYGB: -Iron - 50% -Vitamin B12 - 26-70% -folate - 1-38% -Rare - thiamine, copper -life long MVI & supplements
Causes of Abnormal Liver Tests in Patients with AIDS
Abnormal Liver Tests (ALT, AST, Alkaline Phophatase) are very common in HIV infected patients CAUSES OF ABNORMAL LIVER TESTS Drugs Infectious Diseases Malignancy Biliary Tract Disease
Specific Tests: Imaging
All of the following are clinically useful: -UGIS/SBFT -CT scan -Abdominal ultrasound -Endoscopic ultrasound -ERCP
Management of Malabsorption/Maldigestion
General goals: -Correct the nutritional deficiencies that are present. -Offer specific treatment if possible.
Maldigestion : Causes
Chronic Pancreatitis Bacterial Overgrowth Postgastrectomy - post surgical Bile salt deficiency
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
Classic Presentation Diarrhea, flatulence, weight loss Children → failure to thrive, growth + diarrhea 1. Usually have a significant small bowel involvement. 2. Degree of diarrhea depends on the amount of bowel involved. 3. Diarrhea - usually classified as an osmotic diarrhea 4. Steatorrhea - less than in Chronic Pancreatitis.
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
Clinical Features: *Starts in the duodenum, extends a variable length down the small bowel. *Symptoms/deficiencies depend on how much of the intestine is involved and can vary from minimal to severe. *Prompt improvement - withdrawal of cereal grains from the diet.
Idiopathic Esophageal Ulcers
Diagnosis Pathophysiology -HIV -increased # of apoptotic cells Tx: Steroids, Thalidomide
Candida Esophagitis
Diagnosis Pathophysiology Tx: Fluconazole Natural History: recurrence Prophylaxis: ? Tx of Fluconazole resistance: higher doses, itraconazole, encapsulated oral amphotericin, IV amphotericin
Microsporidiosis
Disappearing Infection Enterocytozoon bieneusi, Enchepalocytozoon intestinalis Dx: Stool examination Tx: E. bieneusi - ? Thalidomide E. intestinalis - albendazole
Malabsorption: Tropical Sprue
Etiology - unclear *Not related to dietary factors *May be related to infectious etiology. EVIDENCE FOR : -GNR found in intestine but no specific organism found -Treated with antibiotics EVIDENCE AGAINST: -No person to person spread -never transmitted to patients outside of tropical areas. *Isolated or combined folate and B12 deficiency are common Diagnosis -Patients from endemic area -folate or B12 deficient -Small intestine villous atrophy Treatment: -Nutrient and vitamin supplementation. -Tetracycline or sulfonamide antibiotics for 6 months to one year. Prognosis: -Excellent. -Recurrences common, unless patients move.
Malabsorption : Causes
Gluten sensitive enteropathy/Sprue/Celiac disease Non-tropical sprue Whipple's Disease Lactase Deficiency Giardiasis/Cryptosporidiosis Intestinal Lymphangectasia Apetolipoproteinemia Crohn's Disease AIDS enteropathy
Malabsorption/Maldigestion: Clinical Presentation
Iron-------> glossitis Folate------->anemia Vitamin B12--->apthous ulcers Vitamin B12--->neurologic sequelae Vitamin A----->hyperkeratosis, night blindness Vitamin D----->rickets, osteomalacia Vitamin K------>bruising, bleeding Calcium-------->Parasthesia Magnesium-----> Tetany Zinc----->poor taste, acrodermatitis
CMV colitis
Late complication of HIV Reactivated infection Multi-system disease Perivasculitis Dx: inclusion bodies Flexible sigmoidoscopy or colonoscopy ? Tx: Ganciclovir, Foscarnet, Cidofivir
Microsporidia
Obligate intracellular parasite Asymptomatic until immune depression Destroys Enterocytes Disappearing OI
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
Pathogenesis: *Immune reaction in the small intestinal mucosa to gluten villous flattening. Mediated by lamina propria T-cells. *Similar protein is found in rye, barley and oats. *Alcohol-soluble protein components of the grains called Prolamins are the toxins. *Gliadins in wheat, Secalins in rye; hordeins in barley. *Unknown how prolamins cause toxicity, but likely immunologic injury in a genetically susceptible host. *100% have either HLA-DQ2 & HLA-DQ8 patients (HLA testing - 100% negative predictive value). DQ2 and DQ8 - 30% of population *Injury is mediated by lamina propria T lymphocytes *Possible previous adenovirus type 12 infection (high amino acid sequence homology of viral E1b protein and gliadin fraction).
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
Pathology: Characterized by: -Villous flattening and crypt hyperplasia. -Marked increase in undifferentiated crypt cells and mitoses. -Significant plasma cell and lymphocyte infiltrate in the lamina propria.
CMV Esophagitis
Pathophysiology: -Ischemia due to endothelial cell involvement Dx: CMV inclusions Obtain at least 10 biopsies Tx: Ganciclovir, Foscarnet, cidofivir Maintenance Therapy: ?
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
Prognosis: *Celiac disease may be fatal if severe and untreated. *Malignant disease higher in celiac disease patients (especially if poorly treated): -Lymphomas -esophageal cancer -Small intestinal adenocarcinomas (80x higher than in normals)
Idiopathic Diarrhea
Proposed etiologies: *Occult Enteric Infections -Abnormal GI Motility -Autonomic Denervation -Bacterial Overgrowth -HIV as an Enteric Pathogen *Most patients do well long term
Tests for Vitamin B12 Absorption: Schilling Test:
STAGE 1 -Small PO dose of radioactive B12 and large IM dose of nonradioactive B12. -If 24 hour urine excretion of radioactivity < 8% of dose, B12 malabsorption confirmed. STAGE 2 -Stage 1 repeated with PO intrinsic factor. -If result now normal, consistent with pernicious anemia. STAGE 3 -Stage 1 and 2 plus pancreatic enzymes STAGE 4 -Stage 1 and 2 plus antibiotics (to check for bacterial overgrowth)
Tests for Carbohydrate Absorption
Stool pH: -acidic secondary to bacterial fermentation of malabsorbed carbohydrates. -Fresh stool sample pH < 5.5 is highly suggestive. D-Xylose Test: *D-xylose: -a pentose sugar that crosses the mucosa by passive diffusion (no active transport mechanisms) -not metabolized. *Test reflects mucosal surface area - abnormal result suggests a decreased absorptive area. *Test differentiates malabsorption from maldigestion. *The patient is fasted overnight. *25 grams of d-xylose is administered orally. *Urine is collected for 5 hours or serum level is checked 1 hour after dose. *Abnormal result - < 4 gm (urine) and 20 mg/dL in the serum indicates abnormality. *Abnormal result means mucosal disease. *If steatorrhea -d-xylose test is normal - then pancreatic or biliary insufficiency is present. -D-xylose abnormal - mucosal disorder *98% Specific. *91% Sensitive.
Malabsorption: Celiac Disease, Gluten Sensitive Enteropathy
Treatment: *Gluten Free diet -Avoid any and all foods that contain cereal grains. -Substitute rice and corn. -Supplement missing nutrients. *Prompt clinical improvement following withdrawal of cereal grains from the diet. *Antibody levels decrease with dietary compliance Future - glutenases
Specific Tests: EGD With Biopsy
Upper Endoscopy: *Can be visually diagnostic for: -Crohn's Disease -Celiac Disease -Lymphangiectasia *Small intestinal mucosal biopsy: -Histology can be pathognomic.
Post Surgical Maldigestion
Weight Loss: -Small Gastric Pouch -Ineffective mixing of digestive juices -Stasis and hypochlorhyria (favor bacterial overgrowth) -Iron and calcium bypass duodenum in RYGB and BII -Fat/acid bypass duodenum in RYGB and BII - decreased secretin & CCK -Vitamin B12 deficiency - decreased IF production