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

Bacterial overgrowth

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

(1) Luminal phase

(2) Mucosal phase

(3) Removal phase

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

Normal process of fat digestion and absorption

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

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

Lymphatic blockage

Primary lymphangiectasia

Obstruction

Major disease entities

Coeliac disease

Chronic pancreatitis

Bacterial overgrowth

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

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

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…

Chronic pancreatitis?

Coeliac disease?

Cholestatic liver disease?

Bacterial overgrowth?

Key role of duodenal biopsyBiopsy 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

Any disease interfering with luminal phase of absorption

chronic pancreatitis

bile salt deficiency

...but also in any primary small bowel disease with focal involvement

Aretaeus:

The Greek work "koiliakos" used by Aretaeus had originallymeant "suffering in the bowels" when used to describe people.Passing through Latin, 'k' became 'c' and 'oi' became 'oe'.Dropping the Greek adjectival ending 'os' gave us the wordcoeliac.

"The Coeliac Diathesis" [by Aretaeus] describes fatty diarrhoea(steatorrhoea) for the first time and then proceeds to give anaccount of several other features of the condition including lossof weight, pallor, chronic relapsing and the way in which itaffects children as well as adults.

"If the stomach be irretentive of the food and if it pass throughundigested and crude, and nothing ascends into the body, wecall such persons coeliacs".

1888: Samuel Gee, using an identical title to FrancisAdams' translation of Aretaeus’ writings , "TheCoeliac Affection", gave the classic description of thecondition.

"to regulate the food is the main part of treatment ...The allowance of farinaceous foods must be small ...but if the patient can be cured at all, it must be bymeans of diet."

“a child…was fed upon a quart of Dutch musselsdaily, throve wonderfully but relapsed when theseason for mussels was over. Next season, he couldnot be prevailed upon to take them.”

17 centuries later...

1924: Haas: Popularised the banana diet: Essentiallya diet low in carbohydrate except for ripe bananas.

1950: Dicke: In Holland during WW2, severe breadshortage until Swedish airplanes airdropped bread.Coeliacs relapsed in parallel with the bread drops:Dicke systematically showed how coeliac childrenbenefited dramatically when wheat, rye and oatsflour were excluded from the diet. As soon as thesewere excluded, the children's appetite returned andtheir absorption of fat improved so that the fattydiarrhoea disappeared.

1950: Paulley identified villous abnormality

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

Alpha-Gliadin

31 L-G-Q-Q-Q-P-F-P-P-Q-Q-P-Y-P-Q-P-Q-P-F 4931 L-G-Q-Q-Q-P-F-P-P-Q-Q-P-Y 4344 P-Q-P-Q-P-F-P-S-Q-Q-P-Y 55

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

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

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

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

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

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 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

Antibodies

Sensitivity Specificity

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

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

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

Dermatitis herpetiformis

Chronic pancreatitis

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?

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

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

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

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

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

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 overgrowth

Factors responsible for overgrowth:

Stasis: strictures, fistulas, blind loops, dysmotility

Achlorhydria

Immune defects

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 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 lecture

Review normal digestion/absorption

How diseases interfere with the process

Tests for malabsorption

Coeliac disease

Chronic pancreatitis

Bacterial overgrowth