Non-neoplastic intestinal disease
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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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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

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


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

Normal process of fat digestion and absorption


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


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

17 centuries later...


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

1950: Paulley identified villous abnormality

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


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

Alpha-Gliadin


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

Alpha-GLIADIN PEPTIDES (SYNTHETIC) FOR WHICHTHERE IS IN VIVO EVIDENCE OF ACTIVITY


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

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


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

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


Non neoplastic intestinal disease malabsorption paul l crotty department of pathology

Dermatitis herpetiformis


Chronic pancreatitis

Chronic pancreatitis


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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