malabsorption. case 32 year old man previously well: 3 months loose, soft foul-smelling bowel...
TRANSCRIPT
Malabsorption
Case32 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 8.5-10.2 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 8.5-10.2 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 PhasePancreas
• 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 PancreatitisCalcified 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 OvergrowthSmall Bowel Series
Diverticulosis Scleroderma
Malabsorption – Bacterial OvergrowthBreath Tests
• Hydrogen breath test– Glucose
• Bile acid breath test– C13-glycocholate
breath test
• Xylose breath test– C13-xylose
Malabsorption - Bacterial OvergrowthCulture
• Quantitative culture of an aspirate of luminal fluid– The gold standard– Positive culture > 106 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
Initial blood tests Follow - up tests Complete blood count Serum iron Prothrombin time Serum folate Standard electrolytes Serum vitamin B12 Calcium Serum vitamin A Magnesium Plasma 25 - hydroxy vitamin D Alkaline phosphatase Stool for ova and parasites Cholesterol Total protein and albumin
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
Malabsorption - Investigation
• Xylose Normal
• Suspect pancreatic disease
Malabsorption- Pancreatic FailureTrial 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
Mucosal Postmucosal Celiac sprue Congenital lymphangiectasia Tropical sprue Secondary lymphangiectasia Whipple's disease Eosinophilic enteritis Brush border enzyme deficiency
Lymphoma Short - bowel syndrome Prolonged malnutrition Radiation enteritis Parasitic infection Mesenteric ischemia
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 MalabsorptionBiopsy
• 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
LymphangiectasiaDilated 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 weaknessTrigger• 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
Normal Celiac 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
Normal Celiac 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 AbsorptionGENERAL 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)