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
Aretaeus:
The Greek work "koiliakos" used by Aretaeus had originally
meant "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 word
coeliac.
"The Coeliac Diathesis" [by Aretaeus] describes fatty diarrhoea
(steatorrhoea) for the first time and then proceeds to give an
account of several other features of the condition including loss
of weight, pallor, chronic relapsing and the way in which it
affects children as well as adults.
"If the stomach be irretentive of the food and if it pass through
undigested and crude, and nothing ascends into the body, we
call such persons coeliacs".
17 centuries later...
1888: Samuel Gee, using an identical title to Francis
Adams' translation of Aretaeus’ writings , "The
Coeliac Affection", gave the classic description of the
condition.
"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 by
means of diet."
“a child…was fed upon a quart of Dutch mussels
daily, throve wonderfully but relapsed when the
season for mussels was over. Next season, he could
not be prevailed upon to take them.”
1924: Haas: Popularised the banana diet: Essentially
a diet low in carbohydrate except for ripe bananas.
1950: Dicke: In Holland during WW2, severe bread
shortage until Swedish airplanes airdropped bread.
Coeliacs relapsed in parallel with the bread drops:
Dicke systematically showed how coeliac children
benefited dramatically when wheat, rye and oats
flour were excluded from the diet. As soon as these
were excluded, the children's appetite returned and
their absorption of fat improved so that the fatty
diarrhoea disappeared.
1950: Paulley identified villous abnormality
Later shown that the histological abnormality
normalised after gluten withdrawal and recurred
after gluten challenge
Alpha-Gliadin
Alpha-GLIADIN PEPTIDES (SYNTHETIC) FOR WHICH
THERE IS IN VIVO EVIDENCE OF ACTIVITY
31 L-G-Q-Q-Q-P-F-P-P-Q-Q-P-Y-P-Q-P-Q-P-F 49
31 L-G-Q-Q-Q-P-F-P-P-Q-Q-P-Y 43
44 P-Q-P-Q-P-F-P-S-Q-Q-P-Y 55
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
IgA
89%
95%
IgG
99%
86%
EMA
>95%
>95%
tTG (IgA/IgG)
>95%
>95%
AGA
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