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Non-neoplastic intestinal disease Malabsorption Paul L. Crotty Department of Pathology

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Non-neoplastic intestinal disease Malabsorption Paul L. Crotty Department of Pathology Tallaght Hospital October 2007. Outline of lecture. Review normal digestion/absorption How diseases interfere with the process Tests for malabsorption Coeliac disease Chronic pancreatitis

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slide1

Non-neoplastic intestinal disease

Malabsorption

Paul L. Crotty

Department of Pathology

Tallaght Hospital

October 2007

outline of lecture
Outline of lecture
  • Review normal digestion/absorption
  • How diseases interfere with the process
  • Tests for malabsorption
  • Coeliac disease
  • Chronic pancreatitis
  • Bacterial overgrowth
malabsorption maldigestion
Malabsorption/Maldigestion
  • diverse disease processes
  • final common pathway of interference with normal digestion and absorption of nutrients
  • similar/overlapping clinical presentations
  • understanding normal digestion and absorption is central to understanding diseases that interfere with same
normal digestion and absorption
Normal digestion and absorption
  • (1) Luminal phase
  • (2) Mucosal phase
  • (3) Removal phase
as example triglycerides
As example: Triglycerides
  • Luminal phase: in small intestine
    • Pancreatic lipase: enzymatic hydrolysis into mono-acyl glycerol and free fatty acids
    • Solubilisation: incorporation into micelles with bile salts
  • Mucosal phase: in enterocyte cytoplasm
    • assembly into chylomicra with apoproteins
  • Removal phase: in lymphatics
diseases interfering with luminal phase
Diseases interfering with luminal phase
  • Pancreatic exocrine insufficiency
    • chronic pancreatitis
  • Bile salt deficiency
    • liver disease, especially cholestatic
    • bacterial overgrowth
    • terminal ileal disease
  • Other: post-gastrectomy, Zollinger-Ellison
diseases interfering with mucosal phase
Diseases interfering with mucosal phase
  • Small bowel disease
    • Coeliac disease
    • Tropical sprue
    • Whipple’s disease
    • Crohn’s disease
    • Post-small bowel resection
  • Specific enzyme deficiency,transport protein defects, abetalipoproteinaemia
diseases interfering with removal phase
Diseases interfering with removal phase
  • Lymphatic blockage
  • Primary lymphangiectasia
  • Obstruction
major disease entities
Major disease entities
  • Coeliac disease
  • Chronic pancreatitis
  • Bacterial overgrowth
consequences of malabsorption
Consequences of malabsorption
  • Effects of excess fat in stool
    • Steatorrhoea: bulky, pale, foul-smelling
  • Nutrient deficiencies: global/specific
    • Energy, Protein (failure to thrive, short stature, weight loss)
    • Specific deficiencies esp. fat soluble vitamins A, D, E and K, also iron
quantitation of fat in stool
Quantitation of fat in stool
  • Normal stool fat <6g/day (over range of dietary fat from 60 to 200g)
  • With diarrhoea of any cause: stool fat can rise up to 14g/day
  • With fat malabsorption: stool fat much higher: 50-100g/day range
  • Standard: 3-5 day collection
d xylose test
D-xylose test
  • 5 carbon sugar: absorbed by passive diffusion
  • D-xylose test is a measure of functional surface area of small bowel
  • After overnight fast: 25g D-xylose given p.o
  • Measure serum level at 1h (normal >20mg/dl)
  • 5h urine collection (normal >4g)
  • FP: incomplete collection/dehydration/renal disease
what do you expect the result of a d xylose test will be in
What do you expect the result of a D-xylose test will be in…
  • Chronic pancreatitis?
  • Coeliac disease?
  • Cholestatic liver disease?
  • Bacterial overgrowth?
key role of duodenal biopsy
Key role of duodenal biopsy
  • Biopsy diagnosis of specific diseases
    • Giardia infestation, Whipple’s disease
    • abetalipoproteinaemia, lymphangiectasia
  • Significantly blunted villi or flat mucosa (partial or complete villous atrophy)
    • classically seen in untreated coeliac disease
    • but can also be seen in other food allergies, rarely in viral infection, Crohn’s disease, tropical sprue
  • Normal mucosa
patient with malabsorption with a normal duodenal biopsy
Patient with malabsorption with a normal duodenal biopsy
  • Any disease interfering with luminal phase of absorption
  • chronic pancreatitis
  • bile salt deficiency
  • ...but also in any primary small bowel disease with focal involvement
slide25

1950: Paulley identified villous abnormality

Later shown that the histological abnormality normalised after gluten withdrawal and recurred after gluten challenge

slide29

Ingestion of gluten (or alpha-gliadin or even synthetic peptides) by a patient with coeliac disease causes symptoms in few hours and villous abnormality in 8-12 hours

Why are gliadins toxic in some patients and not in others?

genetic factors
Genetic factors
  • First degree relatives: 10% risk
  • MZ twin concordance: 70-90%
  • HLA-identical sibs: 30-50% concordance
  • In Europe: Coeliac patients >95% HLA-DQ2+ (vs. 25% in non-coeliacs)
  • >99% of DQ2+ individuals do not have coeliac disease
  • But significant component of genetic risk is accounted for by other non-HLA genes
immunological factors
Immunological factors
  • Increased immunoglobulin production in small intestine
  • Most have circulating antibodies to alpha-gliadin
  • ...but is this cause or an effect of the disease ?
  • Antibodies to alpha-gliadin also seen in other intestinal diseases
  • Other circulating antibodies also found in coeliacs
current hypothesis
Current hypothesis
  • T-cell-mediated immunity of primary importance in pathogenesis
  • Increased intraepithelial CD8+ T lymphocytes
  • Increased CD4+ T lymphocytes in lamina propria
  • Evidence of T-cell activation
theory of pathogenesis
Theory of pathogenesis
  • In a patient with a genetic predisposition...
  • Some initial trigger?
  • Adenoviral infection early in life??
  • Immune response including presence of T cells with specific ability to respond to alpha-gliadin peptides
theory of pathogenesis1
Theory of pathogenesis
  • So later when any gluten-containing food is ingested….
  • Rapid T cell activation with Th1 pattern of cytokine release causing enterocyte apoptosis
  • Enterocyte apoptosis leads to villous blunting/flattening
  • Loss of surface area for absorption of nutrients clinically reflected as malabsorption
slide39

Antibodies

SensitivitySpecificity

AGA

IgA 89% 95%

IgG 99% 86%

EMA >95% >95%

tTG (IgA/IgG) >95% >95%

IgA tests negative in the 2-3% of coeliacs with IgA deficiency

presentation
Presentation
  • Any age: failure to thrive/short stature/wt loss
  • Steatorrhoea, fat-soluble vitamin deficiency
  • Diagnosis based on:
  • Clinical suspicion
  • Endoscopy with biopsy
  • Serology: circulating antibodies
  • Response to gluten withdrawal
complications
Complications
  • Long term effects of malabsorption: chronic vitamin deficiencies
  • Refractory sprue, ulcerative jejunoileitis, enteropathy-associated T cell lymphoma: all stages in a monoclonal lymphoid proliferation/lymphoma
  • Controversial whether there is a small increase in risk of carcinoma or not
  • dermatitis herpetiformis
exocrine pancreas
Exocrine pancreas
  • Pancreatic secretions: 2-3 litres/day
  • Secretion co-ordinated with presence of food in duodenum (via intestinal CCK)
  • Proteases (trypsin, chymotrypsin, aminpeptidase)
  • Pancreatic amylase
  • Pancreatic lipases
how does pancreas protect itself from self digestion
How does pancreas protect itself from self-digestion?
  • Secreted as inactive pro-enzymes compartmentalised in granules
  • Activation of pro-enzymes requires presence of activated trypsin
  • Duodenal-derived enterokinase is required to activate trypsin
  • Pancreas also secretes trypsin inhibitors
pancreatitis
Pancreatitis
  • Acute (mild to severe necrotising/haemorrhagic)
  • Chronic (result of repeated episodes of mild acute pancreatitis)
  • Main causes: Alcohol, Gallstone disease
  • Other: medications, trauma, hypercalcaemia, hyperlipidaemia, post-instrumentation, blockage of duct by parasites or tumour
pathogenesis of pancreatitis
Pathogenesis of pancreatitis
  • Gallstone disease: Duct obstruction
  • Alcohol:
  • ? Directly toxic to pancreas
  • ? Altered secretions: leads to plugging of duct
  • ? Sphincter of Oddi: alternate spasm/relaxation
  • In both: pancreatic self-destruction by enzymes
  • If chronic: scarring and loss of exocrine function
tests of pancreatic function
Tests of pancreatic function
  • Direct measure of enzymes in duodenal aspirate
  • Indirect tests:
  • Bentiromide test: NBT-PABA bond cleaved by chymotrypsin: measure urinary PABA metabolites
  • Pancrealauryl test: Fluorescein dilaurate cleaved by pancreatic arylesterase: detect fluorescein in urine
malabsorption due to pancreatic dysfunction
Malabsorption due to pancreatic dysfunction
  • Clinical diagnosis
  • Exclusion of primary small bowel disease
  • Usually don’t need direct tests of pancreatic exocrine function
  • Treatment: Oral enteric-coated pancreatic enzymes
small bowel bacterial overgrowth
Small bowel bacterial overgrowth
  • Normal small bowel: Low bacterial count
  • Factors maintaining low count:
  • Bacterial input from stomach is low due to stomach acidity
  • Continuous peristaltic activity
  • Secreted IgA
  • Intact ileo-caecal sphincter
small bowel bacterial overgrowth1
Small bowel bacterial overgrowth
  • Factors responsible for overgrowth:
  • Stasis: strictures, fistulas, blind loops, dysmotility
  • Achlorhydria
  • Immune defects
small bowel bacterial overgrowth2
Small bowel bacterial overgrowth
  • How does overgrowth causes malabsorption?
  • Main mechanism is by inactivation of bile salts by direct deconjugation, dehydroxylation: interferes with micelle formation
  • ? Also by directly inactivating enzymes
  • ?? Competition for nutrients
small bowel bacterial overgrowth3
Small bowel bacterial overgrowth
  • Tests for bacterial overgrowth:
  • Jejunal aspirate: bacterial count
  • Hydrogen breath tests: basal or after CHO load
  • 14-C D-xylose: Urine xylose low: breath 14-CO2
  • Fairly common: Easily treatable
  • Antibiotics: Tetracycline
outline of lecture1
Outline of lecture
  • Review normal digestion/absorption
  • How diseases interfere with the process
  • Tests for malabsorption
  • Coeliac disease
  • Chronic pancreatitis
  • Bacterial overgrowth
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