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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 - PowerPoint PPT Presentation
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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
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
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