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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 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

Any disease interfering with luminal phase


of absorption
chronic pancreatitis
bile salt deficiency
...but also in any primary small bowel
disease with focal involvement
CELIAC DISEASE
1950: Paulley identified villous abnormality

Later shown that the histological abnormality


normalised after gluten withdrawal and recurred
after gluten challenge
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
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

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