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)