Malabsorption

Case 32 year old man previously well: 3 months loose, soft foul-smelling bowel movement 6 kg weight loss Tired, weak Abdominal distension Bleeding tendency Back pain

Case Thin, pale, bruises on skin Ankle edema Hemoglobin 11.2 g/dL, MCV 105 Albumin 3.1 g/dL (N >3.4) PT-INR 1.9 (N <1.2) Serum calcium 6.9 (N mg/dL) Stool fecal fat excretion 19 g/day

Malabsorption Clinical syndrome: Due to defects occurring during the digestion and absorption of food nutrients by the gastrointestinal tract Result of many different disease processes: –Luminal –Absorptive –Post-abortive phases

Symptoms 3 months loose, soft foul-smelling bowel movement Diarrhea –Most common symptomatic complaint –Frequently watery –Cause Osmotic load received by the intestine Bacteria produce hydroxy fatty acids from undigested fat increases net fluid secretion from the intestine

Symptoms 3 months loose, soft foul-smelling bowel movement - Stool fecal fat excretion 19 g/day Steatorrhea >7g fat/day –Steatorrhea - fat malabsorption –Pale, bulky, and malodorous stools Float on top of the toilet water Difficult to flush Oil droplets in the toilet following defecation

Symptoms 6 kg weight loss Tired Weight loss and fatigue –Weight loss is common –Compensate by increasing caloric consumption, –Most noticeable in diffuse diseases Celiac disease and Whipple disease

Symptoms Abdominal distension Flatulence and abdominal distention –Bacterial fermentation of unabsorbed food hydrogen and methane Causes abdominal distention and cramps

Symptoms Bleeding tendency, bruises on skin, PT-INR 1.9 (N <1.2) Bleeding disorders –Vitamin K malabsorption and subsequent hypoprothrombinemia. –Easy bruising –Rarely melena and hematuria

Symptoms Ankle edema, albumin 3.1 g/dL (N >3.4) Edema (also ascites) Hypoalbuminemia –Protein malabsorption –Loss of protein into lumen Intestinal lymphangiectasia –Obstruction of the lymphatic system, Lymphoma

Symptoms Back pain, serum calcium 6.9 (N mg/dL) Metabolic defects of bones –Vitamin D deficiency Osteopenia or osteomalacia. –Bone pain and pathological fractures Malabsorption of calcium can lead to secondary hyperparathyroidism.

Symptoms Weakness Neurological manifestations –Vitamin malabsorption Generalized motor weakness Peripheral neuropathy

Digestion and Absorption Carbohydrate (CHO) Protein Fat Vitamins and minerals Water and electrolytes

Malabsoption - Mechanisms Luminal phase –Impaired nutrient hydrolysis –Impaired micelle formation –Luminal processing Mucosal phase –Impaired brush-border hydrolase activity –Impaired nutrient absorption Post absorptive phase

Malabsorption Luminal Phase

Luminal Phase Pancreas Exocrine –Enzymes (acini) –Bicarbonate (ducts)

Luminal Malabsortion or Maldigestion Impaired Nutrient Hydrolysis Pancreatic insufficiency –Chronic pancreatitis, pancreatic resection, pancreatic cancer, or cystic fibrosis –Lipase, protease, carbhydrase deficiency leads to lipid,protein, carbohydrate malabsorption, respectively

Malabsorption - Pancreas Methods to assess dysfunction 1.Anatomic - damage 2.Physiology - assessement of function

Anatomical – Chronic Pancreatitis Calcified Pancreas

Anatomical – ERCP Chronic Pancreatitis and Carcinoma Carcinoma

Anatomical – Chronic Pancreatitis - EUS

Malabsorption – Pancreatic Function Secretory Function Non-invasive –Low fecal Chymotrypsin and Elastase 1 –Bentiromide Test Invasive –Collect pancreatic juice –Before and after hormonal stimulation Secretin, CCK –Analyze volume, enzyme activity and bicarbonate

Function - Bentiromide Test PABA is cleaved off by pancreatic chymotrypsin Free PABA is absorbed, conjugated by the liver, and excreted in urine and measured Decreased PABA excretion pancreatic insufficiency Highly sensitive and specific for advanced pancreatic failure Not very sensitive in mild pancreatic insufficiency

Luminal Malabsortion or Maldigestion Impaired Micelle Formation – Bacterial Overgrowth Bile salt deconjugation: Stasis of intestinal content caused by a motor abnormality (eg, scleroderma, diabetic neuropathy, intestinal obstruction), Anatomic abnormality (eg, small bowel diverticula, stricture, blind loops Small bowel contamination from enterocolonic fistulas

Malabsorption - Bacterial Overgrowth Small Bowel Series DiverticulosisScleroderma

Malabsorption – Bacterial Overgrowth Breath Tests Hydrogen breath test –Glucose Bile acid breath test –C 13 -glycocholate breath test Xylose breath test –C 13 -xylose

Malabsorption - Bacterial Overgrowth Culture Quantitative culture of an aspirate of luminal fluid –The gold standard –Positive culture > 10 6 organisms/mL –Aerobic or anaerobic culture

Luminal Malabsortion or Maldigestion Impaired Micelle Formation Impaired fat solubilization – Decreased bile salt synthesis from severe parenchymal liver disease –impaired bile secretion from biliary obstruction or cholestatic jaundice X

Luminal Malabsortion or Maldigestion Impaired Micelle Formation –Impaired enterohepatic bile circulation small bowel resection or regional enteritis X

Luminal Malabsortion or Maldigestion Impaired Nutrient Hydrolysis Inadequate mixing of nutrients, bile, and pancreatic enzymes –Rapid transit –Gastrojejunostomy

Malabsorption Mucosal phase

Malabsorption Mucosal phase Reduced brush-border hydrolase Primary lactase deficiency –Genetic factors Secondary lactase deficiency –Acute gastroenteritis, chronic alcoholism, celiac sprue, radiation enteritis, regional enteritis, or AIDS enteropathy.

Malabsorption - Mucosal phase Impaired nutrient absorption Acquired disorders Damaged absorbing surface: –Celiac sprue, tropical sprue, giardiasis, Crohn disease, AIDS enteropathy, chemotherapy, or radiation therapy Decreased absorptive surface area: –intestinal resection or intestinal bypass –Infiltrating disease of the intestinal wall: lymphoma and amyloidosis.

Malabsorption Postabsorptive Phase

Malabsorption Postabsorptive Phase Obstruction of the lymphatic system Congenital : –Intestinal lymphangiectasia Acquired –Whipple disease, neoplasm [ie.g. lymphoma], tuberculosis –Impaired absorption of chylomicrons and lipoproteins –fat malabsorption and/or protein-losing enteropathy

Investigation of Malabsorption Confusion Jungle

Malabsorption - Investigation Does the patient have malabsorption? –History –Physical –Initial blood tests Deficiencies of vitamins and minerals –Stool examination 3-Day Fecal Fat >6g/day or > 7% of fat intake

Suspected malabsorption

Malabsorption Major Categories and Causes Intraluminal - maldigestion –Pancreatic insufficiency –Bacterial overgrowth –Defective bile secretion Mucosal - malabsorption –Celiac disease –Tropical sprue –Infection – bacteria, parasites –Whipple’s disease –Intestinal resection –short gut –Abetalipoproteinemia –Crohn’s disease

Malabsorption Luminal, Mucosal or Postabsorptive? D-Xylose test –Oral dose 25 g D-xylose in 250 – 500 mL water over 10 min to fasting subject –D-xylose measurement in blood hourly upto 5 h and in 5 h-urine –Normal blood D-xylose rises upto 30 – 35 mg/dL –at least 25 % of the dose should be excreted in 5 h-urine Diabetes mellitus Liver disease (20% of cirrhosis patients, chronical hepatitis, fat liver) Hypoglycemia Malnutrition Overdose antidiabetic drug Pancreas cancer Chronical alcohol abuse Hyperglycemia Reference range for OGTT: Fasting 60 min 120 min normal <100 mg/dL 160 mg/dL 120 mg/dL impaired mg/dL mg/dL mg/dL Assessment of Malabsorption Carbohydrate I – oral dose 25 g D-xylose in 250 – 500 mL water over 10 min to fasting subject – D-xylose measurement in blood hourly upto 5 h – Normal blood D-xylose rises upto 30 – 35 mg/dL at least 25 % of the dose should be excreated in 5 h-urine D-Xylose test in patient with bowel resection after treatment with TPN and EN

Malabsorption - Investigation Xylose Normal Suspect pancreatic disease

Malabsorption- Pancreatic Failure Trial of Treatment Pancreatic enzyme replacement –Provides sufficient lipase, trypsin, and amylase to abolish maldigestion of fat, protein, and carbohydrate – Arrives intact in appropriate amounts in the duodenum –Liberates active enzyme in the duodenum –Has a long shelf life. –Palatable, cheap and reliable.

Malabsorption - Bacterial Overgrowth Trial of treatment –Antibiotics

Malabsorption Mucosal/Postmucosal Disease

Mucosal Malabsorption – Small Bowel Series Small bowel barium studies –An abnormal small bowel pattern –The mucosa pattern associated with celiac disease often becomes obliterated or coarsened –Flocculation of the barium occurs in the gut lumen –Regional enteritis of the small intestine can lead to stricture, ulceration, and fistula formation

Mucosal Malabsorption Biopsy Endoscopically obtained Definitive diagnosis of malabsorption of the mucosal/post absorptive phase Examples –Celiac sprue, giardiasis, Crohn disease, Whipple disease, amyloidosis, abetalipoproteinemia, and lymphoma.

Jejunal biopsy-Whipple's disease

Eosinophilic Gastroenteritis

Lymphangiectasia Dilated Submucosal Lacteals

Celiac disease

Celiac Disease Genetically-determined Chronic inflammatory intestinal disease Environmental precipitant- gluten. Mainly non-gastrointestinal symptoms Patients present to various medical practitioners

Celiac Disease - Genetics Multigenic disorder Associated with HLA-DQ2 (DQA1*05/DQB1*02) or HLA-DQ8 (DQA1*0301/DQB1*0302). HLA-DQ2 >90% of people with coeliac disease. HLA-DQ2 or HLA-DQ8 necessary, but not sufficient, to develop the disease. Identical twins 70% concordance

Epidemiological studies 1/100 people Any age Mortality excess - 1·9–3·8 Reduction in excess mortality after 1–5 years on gluten free diet

Celiac Disease – The Old Picture

Celiac disease – The Usual Picture

What we see is the tip of the iceberg

Celiac Disease Most cases undiagnosed

Celiac Disease - Clinical Classification Symptomatic, active, or classic celiac disease –diarrhoea, with or without malabsorption; Asymptomatic –Gastrointestinal symptoms are absent or not prominent Latent celiac disease –May develop celiac disease in the future –At time of investigation has normal mucosa while ingesting gluten

Celiac – Spectrum of Disease

Celiac Disease – Toxic Proteins Gliadin - most studied All gluten containing proteins Barley - hordeins Rye - secalins Dose-dependent response

Celiac Disease - Clinical Symptomatic –weight loss, metabolic bone disease, anaemia, and general weakness Trigger Pregnancy Traveler's diarrhea Gastroenteritis Gastrointestinal surgery

Celiac Disease – Atypical Presentations Osteoporosis Infertility Autoimmune diseases Malignant disease, especially lymphomas

Celiac Disease – Atypical Presentations Aphthous stomatitis Arthritis Dental enamel defects Abnormal liver transminases

Celiac Disease – Atypical Presentations Villous atrophy in patients undergoing endoscopy Assessment of iron concentrations and bone density Dermatitis herpetiformis Neurological symptoms –peripheral neuropathy –ataxia –epilepsy

Celiac Disease - Screening First-degree relatives Type 1 diabetes Down's syndrome Chronic liver disease –primary biliary cirrhosis

Celiac Disease - Diagnosis Small intestinal biopsy – gold standard Improvements in clinical symptoms or histological tests on a gluten-free diet Positive serological tests

Celiac Disease - Endoscopy NormalCeliac Disease

Celiac Disease - Biopsies Loss of crypts Increased mitotic activity Loss of brush border Infiltration with lymphocytes and plasma cells (B-cells sensitized to gliaden) Lesion more severe in proximal small intestine than distal NormalCeliac Disease

Celiac Disease - Serological Testing Anti-gliadin antibodies Anti-endomysium almost 100% Anti- tissue transglutaminase (Anti-tTG)

Celiac Disease – Pitfalls in Diagnosis Serological tests Selective IgA deficiency 1·7%–2·6% 10 to 16-fold higher - general population Check total serum IgA Test for IgG endomysial antibodies, IgG anti-tTG

Celiac Disease – Serological Testing Titres of anti-endomysial antibodies correlate with: –Degree of villous atrophy –Presentation with symptoms Patients with partial villous atrophy –May not have antibodies against endomysium or tTG –Usually have antibodies against gliadin Anti endomysium only – miss 20% Up to 33% - one antibody absent Titres of endomysial antibodies are usually undetectable after 6–12 months on diet

Celic Disease – Role of Serological Testing Screening patients or populations at risk Confirming diagnosis when biopsy questionable Follow-up for compliance Diagnosis? – biopsy still required

Celiac Disease - Treatment Dietician - gluten-free diet for life Avoid trial of gluten restriction without a biopsy Avoid wheat, barley, and rye Oats are not toxic Support groups Correct deficiencies Active follow-up - compliance

Celiac Disease - Response Rapid – most patients Extremely ill – admission –repletion of fluids and electrolytes, –intravenous alimentation – steroids. Iron or folate supplements if deficiency documented

Celiac Disease Before treatment 3 months treatment

Poorly or Non-responsive Celiac Disease Review original biopsy, Continued gluten ingestion Lactose or fructose intolerance Intolerance to other foods is rare Microscopic colitis Collagenous colitis Inflammatory bowel disease Lymphoma, Ulcerative jejunitis, Collagenous sprue

Refractory Sprue. Intractable diarrhoea Severe villous atrophy Failure to respond to a gluten-free diet. Response to steroids, azathioprine or cyclosporin

Celiac Disease – Special Considerations Malignant disease – increased –Small bowel adenocarcinoma, –Esophageal and oropharyngeal squamous carcinoma –non-Hodgkin lymphoma A gluten-free diet is protective

Celiac Disease - Autoimmune Disorders Autoimmune disorders RR x10arise –Insulin dependent diabetes –Thyroid disease –Sjögren's syndrome –Addison's disease –Autoimmune liver disease –Cardiomyopathy –Neurological disorders. Can improve on diet

Celiac Disease – Other Complications Osteoporosis –Measurement of bone mineral density Fertility –Delayed menarche, –Premature menopause, –Amenorrhoea, –Recurrent abortions Postnatal –Low birthweight –Increased perinatal mortality –shorter duration of breast feeding Gluten-free diet improves

Digestion and Absorption GENERAL PRINCIPLES Breakdown of complex molecules – Enzymes (pH) Absorption into gut cells – Intestinal epithelium – Lymphatics

SECRETIONS OF THE GUT

Bulk flow of liquid in gut Input –Ingestion ~ 2 litres per day –Secretion (gut) ~ 7 litres/day Output –Faeces ~100 ml/day Conclude ~ 9 litres/day absorbed

Carbohydrate Digestion

Carbohydrate Absorption

Protein Digestion Proteins to peptides –Gastric pepsinogen –Activated by HCl AND pepsin –Pancreatic proteases (trypsin, chymotrypsin etc.)

Protein Absorption Peptides to amino acids (brush border) Absorbed by secondary active transport –Depends on Na + transport

Fat Digestion Fat to triglycerides (pancreatic lipase) Bile salts emulsify (surface area) Bile salts — micelles containing monoglycerides and free fatty acids (FFA) Enter passively Triglyceride synthesis — chylomicrons Exocytosis and thence to lacteals

Fat Absorption Monoglycerides and FFA enter cells by diffusion Triglyceride synthesis Add protein Chylomicrons To lacteal (lymph)