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TRANSCRIPT
APRIL 2006
Common Sense Pathology
A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs
A JOINT INITIATIVE OF
RC PAAustralian . Australian Government
f,xr IZov fl (:oiirgr of I'ariloioL isrs of AusCr,ii;4 id Department of Health and Ageing
© The Royal College of Pathologists or Australasia
Malabsorptionincluding coeliac disease andinflammatory bowel disease
Doactor.uRCPA
Australian Government
Department of Health and Ageing
Dr Daniel Stiel (far right) is a gastroenterologist,Royal North Shore Hospital, Sydney, and
clinical associate professor, University of Sydney.
Dr Paul O'Farrell is a gastroenterologistwith an interest in endoscopy and
medical education.
Introduction
Coeliac disease is a common cause of malabsorption in Australia. The prevalence of coeliac disease is
probably much greater than previously estimated, with a recent study suggesting that one in 250 of the
adult population is affected. Inflammatory bowel disease may also cause malabsorption, particularly in
patients with terminal ileal involvement, or indirectly in those with short bowel syndrome following
surgery. This article discusses the investigation of malabsorption, and in particular diagnosis of coeliac
disease and inflammatory bowel disease. A careful and directed history is vital in assessing the likely
process involved. Laboratory testing is best for confirmation or exclusion of different diagnoses. The
various limitations of the available tests must be understood in order for them to be used appropriately.
As a rule of thumb, specific tests are best used not simply to confirm that malabsorption is present, but
to elucidate the underlying cause.
This issue of Common Sense Pathology is a joint initiative ofAustralian Doctor and the Royal College of Pathologists ofAustralasia.
Common Sense Pathology editor: Dr Matthew MeerkinE-mail: [email protected]
Chief sub -editor: Kathryn HoganE-rnail:[email protected]
It is published by Reed Business InformationTower 2, 475 Victoria Ave, Locked Bag 2999Chatswood DC NSW 2067.Ph: (02) 9422 2999 Fax: (02) 9422 2800E-mail: [email protected] site: www.australiandoctor.com.au(Inc. in NSW) ACN 000 146 921ABN 47 000 146 921 ISSN 1039-7116
© 2006 by the Royal College of Pathologists of Australasiawww.rcpa.edu.auCEO Dr Debra GravesE-mail: [email protected] the views expressed are those of the authors, modified byexpert reviewers, they are not necessarily held by the college.
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2
Malabsorption
Maldigestion is defined as the impaired breakdown
of nutrients to absorbable split products.
Malabsorption is the defective uptake and transport
of adequately digested nutrients, including vitamins
and trace elements.
Despite these distinctions, which reflect the
underlying pathophysiology, malabsorption is the
term still widely used to cover all impairment of
digestion and absorption.
Digestion and absorption have been described as
occurring in three phases: the luminal phase, the
mucosal phase and the removal phase. The luminal
phase depends largely on the excretions of the
pancreas and bile; carbohydrates, proteins and fats
are hydrolysed and made soluble. In the mucosal
phase lipids are assimilated and packaged for
transport and peptides and disaccharides undergo
final hydrolysis and are taken up. During the
removal phase the digested nutrients enter the
vascular or lymphatic systems.
Diseases causing malabsorption may interrupt
any of these three phases. An understanding of the
normal processes of digestion and absorption helps
direct laboratory testing strategies and to arrive at a
diagnosis without unnecessary expense or distress
for the patient.
Malabsorption may present in a variety of forms,
from disabling steatorrhoea and rapid loss of
weight, to isolated changes in haematological or
biochemical parameters that are found incidentally
in asymptomatic individuals.
Chronic pancreatitis is suspected when
steatorrhoea occurs with malabsorption. Loss of
about 90% of the exocrine glandular tissue leads
to the classic symptoms of maldigestion of
pancreatic exocrine failure. Because severe chronic
pancreatitis is usually associated with structural
changes, the diagnosis is generally confirmed by
imaging (usually CT) rather than functional testing
of the pancreas.
Non-invasive tests including stool elastase or
chymotrypsin and pancreolauryl testing are rarely
used in practice. Chronic pancreatitis involves the
loss of islets as well as acini, but typically the
endocrine function is preserved until late in the
course of the illness.
Table 1 outlines some of the signs and symptoms
which should be sought specifically. A careful past
history and family history may also give clues to the
aetiology of malabsorption (see table 2, page 4).
It is important not to miss a history of chronic
pancreatitis, chronic cholestasis, or radiotherapy.
Specific enquiries should be made about previous
surgery. Operations, including total or partial
gastrectomy, bowel or pancreatic resection and,
particularly, bariatric surgery, cause malabsorption.
An alcohol history is vital, and it should be
remembered that pancreatic insufficiency typically
takes 10-20 years to develop in alcoholism.
Signs and Investigations Malabsorbedsymptoms nutrient
Microcyticanaemia
Glossitis Iron studies Iron
Pica
Megaloblasticanaemia
RBC folate, B12, folateGlossitis B12 levels
Bone pain 25 -OH vitamin D
Osteoporosis Serum calcium Calcium,
Chvostek sign ALP Vitamin D
Bleeding Coags Vitamin K,
Bruising INR Vitamin C
Petechiae
Oedema Total protein
Ascites Albumin Protein
Lymphocytes
Peripheral Nerve conduction Vitamins B1,neuropathy studies B6, B12
Hyperkeratosis Retinol Vitamin A,
Parakeratosis Zinc ZincAustralian Government
Department of Health and Ageing
3
A selected battery of tests is useful in suspected malabsorption because the patient may have nosymptoms , or symptoms that mimic those of another condition.
Initial testing should include:n FBCn LFTsn B12, red cell folate and iron studiesn Thyroid function testsn ESR, CRPn Calciumn Coeliac serologyn Stool samples to exclude chronic infection such as giardiasis . Three specimens should be sent if
there is a high index of suspicion of protozoan infectionn Sudan III staining of faeces for fat globules is more easily obtainable than three - day faecal fat
quantification for confirmation of suspected steatorrhoea . Tests for faecal fat do not distinguishbetween small bowel and pancreatic causes of steatorrhoea
Doctor.(1'RCPA
Australian Government
Department ofNealth and Ageing
4
Coeliac diseaseCoeliac disease is the most common small intestinal
enteropathy in the developed world. It may present
at any age, and the clinical features are both highly
variable and non-selective for the disease.
Coeliac disease affects mainly Caucasian people,
as well as Arab and Indian people. Japanese,
Chinese and African patients are not generally
affected. Testing for coeliac disease is indicated in
patients with malabsorption, diabetes, autoimmune
thyroid disease, Addison's disease, primary biliary
cirrhosis and in those whose family members are
affected. Patients with Down or Turner syndromes
are at an increased risk. Patients with underlying
coeliac disease may present with neuropsychiatric
disorders including ataxia and epilepsy, depression
and osteoporosis. All osteoporotic patients should
be tested for coeliac disease.
In adults a `classic' presentation is usually the
exception, rather than the rule (see table 3). To
avoid missing the diagnosis in some of the more
unusual manifestations of the disease, a high degree
of suspicion is required. Isolated biochemical
abnormalities such as folate deficiency, low calcium,
iron deficiency and low vitamin D should also
prompt testing for coeliac disease.
Left undiagnosed, coeliac disease leads to
symptoms of malabsorption in some patients.
However; many patients with positive tests for
coeliac disease do not have malabsorption. The
concept of `coeliac iceberg' is an accepted explana-
tion for this finding (see figure 1). Some patients will
have silent coeliac disease, while others will have
latent coeliac disease.
Serological tests for coeliac disease include
antibodies to endomysium, tissue transglutaminase
(TTG) and gliadin.
Gliadin antibodies are moderately sensitive but
not specific for coeliac disease. Tests may be falsely
Common
Fatigue (70%)
Weight loss (70%)
Diarrhoea (70%)
Flatulence (70%)
Irregular menses (25%)
Bloating (50%)
Iron/folate deficiency (70%)
Osteoporosis (60%)
Dermatitis herpetiformis (24%)
Mouth ulcers (20%)
Uncommon
Nausea and vomiting
Abdominal pain
Seizures
Infertility
Recurrent miscarriage
B12 deficiency
Neuropathy
Hyposplenism
Patients with clinically overtcoeliac disease
Patients with undiagnosed,silent coeliac disease
Patients with latent coeliacdisease who have the potential
to develop the disease
positive in any of the conditions that cause
`leakiness' of the membranes of enterocytes,
including Crohn's disease and infectious enteritis.
Endomysial and TTG IgA antibodies are both
highly sensitive and specific for coeliac disease.
Individuals with coeliac disease have IgA deficiency
at a rate of 3.8t%o - far greater than the population
prevalence of one in 500 (0.2%). For this reason
IgA levels should be determined when these
antibodies are requested. IgG antibodies are less
sensitive and specific than IgA (see table 4).
Antigliadin antibodies are not sufficiently
accurate for monitoring compliance with a
gluten-free diet, unless elevated at diagnosis. TTG
antibodies have been used in a quantified manner
to assess progress, because their levels appear to
correlate with the appearance of the small bowel on
biopsy. A rising TTG in the presence of ongoing
diarrhoea suggests poor dietary compliance.
Abnormal serology alone is not sufficient to
make the diagnosis of coeliac disease. A small
bowel biopsy must be performed for confirmation.
Endoscopically, flat mucosa, scalloping of the
duodenal folds (see figure 2, page 6) and abnormal
prominence of the vasculature, if present, give a
clue to the diagnosis. At least four biopsies should
be taken, because the changes may be patchy.
The mucosal injury tends to be most pronounced
in the proximal small intestine and consists of loss
of normal intestinal villi, with crypt hyperplasia and
a mucosal lymphocytic infiltrate. These findings are
not pathognomonic, and if antibodies are negative,
then causes other than coeliac disease should be
considered.
A definitive diagnosis may be made when there is
improvement of the villous architecture after three
months on a gluten-free diet. A trial of gluten
withdrawal is not a substitute for small bowel
biopsy, and can only lead to confusion. However,
sometimes patients will have instigated this diet
before seeing their GP. In such cases, patients
should be advised to eat a gluten-containing diet for
six weeks before antibody testing or biopsy.
Children with coeliac disease present with failure
to thrive, anorexia, weight loss and irritability.
Anaemia and diarrhoea are frequently present.
Confirmation of the diagnosis requires mucosal
biopsy, with some authorities recommending a
repeat biopsy after about six months on a
gluten-free diet to document resolution of villous
atrophy.
Case study ISteven, a 27-year-old barman, presents with lethargy
and mouth ulcers, and several months of bloating
and loose bowel motions three to four times a day.
He has occasional nausea but no abdominal pain,
and describes no haematemesis or melaena. His
weight has dropped from 80kg to 73kg over the
past year, which he attributes to late nights at work.
His appetite is good, and his only recent overseas
travel was to Canada, where he had no change in
his symptoms. On examination there are no signs of
thyroid disease, nor any rash, adenopathy, bruising or
bony tenderness. His family history is unremarkable.
What investigations, if any, would you request?
At this stage, there is a broad differential diagnosis,
and investigation would be directed toward eliciting
a cause for lethargy and confirming your suspicion
of malabsorption as the cause of weight loss.
Investigations
You request the baseline investigations described
previously, with the following results:
n FBC - Hb 119g/L; MCV elevated at 1.01 fL;
Howell-Jolly bodies on the blood film, consistent
with hyposplenism.
n Normal WCC and platelets.
n Stool cultures and examination for ova, cysts and
parasites negative.
Test Sensitivity% Specificity% PPV% NPV% Likelihood ratio*Positive Negative
Anti-tTG 91 96 97 87 23 0.04EMA 86 100 100 83 87 0.13AGA-A 64 92 92 64 8 0.39AGA-G 84 86 89 79 6 0.19
*The likelihood ratio incorporates both the sensitivity and specificity of the test and is an estimate of how much a
test result changes the odds of having a disease. The likelihood ratio for a positive result estimates how much the
odds of the disease increase when a test is positive. The likelihood ratio for a negative result estimates how much
the odds of the disease decrease when a test is negative.
Anti-tTG: Anti-tissue transglutaminase antibody EMA: Antiendomysial antibodyAGA-A: Antigliadin antibody (IgA) AGA-G: Antigliadin antibody (IgG)
Doctor.10)0 RC PA
Australian Government
Department of Health and Ageing
5
Doctor.• RCPA
Australian Government
Department of Health and Ageing
n Sudan III staining reveals an increased quantity of
fat in the stool.
Diagnosis and management
Given Steven's weight loss, with steatorrhoea and
hyposplenism, coeliac disease is the most likely
diagnosis.
Coeliac serology reveals positive antigliadin IgA
and a positive antiendomysial IgA antibody. You
refer Steven for endoscopy, which reveals flattened
mucosa in the second part of duodenum, with
biopsy findings in keeping with coeliac disease.
Steven is referred to a dietician and starts on a
strict gluten-free diet and vitamin and mineral
supplements. He is advised to join the Coeliac
Society of Australia and his family members are
tested for coeliac disease. His weight increases to
78kg over the following year and a repeat biopsy
shows normalisation of his small bowel biopsy.
Steven's anaemia also resolves.
Marked improvement on a gluten-free diet
confirms the diagnosis of coeliac disease.
Investigation of immediate relatives, even if they
are asymptomatic, is important because they have
a risk of about 10% of having coeliac disease. As
such, it is appropriate in adults to perform
endomysial and TTG antibody testing, with IgA
levels. Relatives with symptoms of coeliac disease
should be referred for endoscopy before starting a
gluten-free diet.
Eighteen months after his initial diagnosis Steven
returns. His diarrhoea has flared again and he
weighs 75kg. What is the most likely problem?
The most common cause of diarrhoea in such
cases is the ingestion of food containing gluten.
You take a careful diet history and arrange repeat
referral to the dietician for review.
You repeat Steven's anti-tTG IgA, which is
elevated at similar levels to those seen at diagnosis.
Antigliadin IgA is also elevated as before - this can
be a useful serological test of dietary compliance, but
only works when the levels were elevated at diagnosis.
Steven returns four weeks after seeing the
dietician. His symptoms have again resolved, after
he eliminated instant chicken stock from his diet.
`Occult' gluten in processed foods is a common
difficulty with a gluten-free diet.
In the rare instance that the symptoms fail to
resolve, or flare, on a gluten-free diet, referral to a
gastroenterologist should be considered.
Some patients will require corticosteroids to
achieve remission. Others will be found to have
collagenous sprue or have developed small
intestinal lymphoma.
Case study 2Danielle, 32 , presents with a 14 -year history of
intermittent diarrhoea , bloating, and abdominal
cramps. She has been diagnosed with irritable bowel
syndrome in the past. A friend suggested she see a
naturopath , who recommended a wheat -free diet.
Within two weeks of starting this, Danielle noticed a
great improvement in her bloating and her diarrhoea
had all but resolved.
What are the chances Danielle has coeliac disease?
Intolerance of wheat does not equate with coeliac
disease, and Danielle may have irritable bowel
syndrome exacerbated by the fermentation of starch.
It is not uncommon for patients with irritable
bowel syndrome to improve on a low-starch diet.
Nevertheless, in this case further investigation for
coeliac disease would be necessary. (In a Canadian
study, 24% of patients diagnosed with coeliac
disease in adulthood had previously been diagnosed
with irritable bowel syndrome.)
Danielle's physical examination is unremarkable,
and there is no history of failure to thrive, diarrhoea,
late menses or dermatitis herpetiformis in earlier life.
Investigation findings
Normal haemoglobin, mean cell volume, iron studies
and a normal blood film. Antigliadin antibody levels
IgA 24ufmL (<30ufmL) and IgG 35ufmL (<20u/mL).
What is the significance of mildly positive AGA
levels in this context?
Antigliadin antibody levels lack specificity for the
diagnosis of coeliac disease. Also, the levels may
decrease or normalise in patients with coeliac disease
who are on a gluten-free diet.
6
Diagnosis and management
Because the diagnosis of coeliac disease had still not
been ruled out, endoscopy was performed and blood
tests were repeated after Danielle spent six weeks on
a gluten-containing diet. Repeat antigliadin
antibody levels were essentially unchanged, and
antiendomysial antibodies were negative. Coeliac
disease was excluded on small bowel biopsy. The
final diagnosis was irritable bowel syndrome.
Can Danielle eat gluten?
Danielle was advised to avoid wheat to the point that
she control her symptoms, and was pleased to learn a
strict gluten-free diet was not required in her case.
Inflammatory bowel diseaseCrohn's disease in particular may causemalabsorption, because it commonly involves theterminal ileum. Typically, the symptoms include
abdominal pain, diarrhoea, fever and loss of
weight. Overt rectal bleeding is common. The
small bowel is involved in 80% of cases.
Delay in diagnosis is more common in Crohn's
disease than in ulcerative colitis, perhaps because
rectal bleeding is less pronounced and the symptoms
often less localised. There is broad variation in the
degree and site of involvement. Up to 15% of
patients present with extra-gastrointestinal
manifestations, perianal disease, fistulae or abscesses.
Nutritional deficiencies result not only from loss of
absorptive epithelium, but also from protein losing
enteropathy and poor nutritional intake.
The most important element in making a diagnosis
of inflammatory bowel disease is clinical suspicion.
When the diagnosis is suspected, it can usually be
confirmed after just a few directed investigations.
Stool microscopy and culture should be requested to
examine for infection and confirm inflammation.
Colonoscopy with intuhation of the terminal ileum
and multiple biopsies allows the diagnosis of Crolm's
disease in the majority of instances, with the added
ability to inspect and conduct biopsies for rare enti-
ties such as tuberculosis, lymphoma, amoebic infec-
tion and carcinoid. Patients with suspected Crohn's
disease who have a normal colonoscopy may require
examination of the small intestine by small bowel
series, enteroclysis or capsule endoscopy.
Measurement of inflammatory markers such as
ESR and CRP early in the course allows repeated
measurements to be used as indicators of disease
activity. Initial assessment is directed at determining
the distribution of disease, its activity and the
presence of complications such as iron deficiency.
The antibody tests available for inflammatory
bowel disease have been used to confirm the presence
of the disease, and to differentiate between Crohn's
disease and ulcerative colitis. Anti-Saccharomyces
antibody (ASCA) is more likely to be present in
Crohn's disease and anti-neutrophil cytoplasmic
antibodies (p-ANCA) more likely in ulcerative colitis.
While the specificity of this combination of tests is
high (90%), the sensitivity is low (about 50%),
making it unsuitable for general testing.
Patients with inflammatory bowel disease have an
increased risk of developing colorectal cancer; those
with ulcerative colitis and primary sclerosing
cholangitis have four times the risk of patients with
ulcerative colitis alone. Surveillance of these patients
is usually performed with endoscopy, rather than
serologic tumour markers such as CEA or CA19-9.
Case study 3Kerry, 15, presents with cramping abdominal pain,
joint aches and pains and failure to gain weight. She
had an episode of knee swelling 18 months ago, for
which she took ibuprofen . She gets cramping
abdominal pain after eating, especially fatty meals,
with intermittent diarrhoea . On several occasions
she has noticed streaks of blood mixed in with loose
stool . Her bowel motions tend to float. There is no
history of travel or antibiotic use. Kerry 's mother
says she is concerned her daughter has not yet
experienced menarche, as her own was at age 12.
Kerry's weight has been 42 .5kg for the past year.
She has been profoundly exhausted after playing
netball , still has an appetite for her favourite foods,
is not dieting, and has not made herself vomit.
Examination reveals tenderness of the right lower
quadrant , a small perianal skin tag, no fistula or
discolouration of the anal area, and a small left knee
effusion. No skin rash , adenopathy or iritis is present.
What tests are appropriate at this point?
Kerry's history alerts you to the possibility of
inflammatory bowel disease, with bloody diarrhoea
and primary amenorrhoea of particular concern.
You organise initial blood tests, and referral for
colonoscopy, with the following results:n Stool microscopy - red and white cells, no
organism cultured or parasites seen.
n FBC - WCC 12 x 109/L, Hb 101g/L with a
normochromic, normocytic pattern.
n ESR 72, CRP 145, Albumin 31g/L.n Rheumatoid factor, ANA - negative.
n At colonoscopy the ileocaecal valve is narrowed
but able to be intubated, and patchy ulceration
with contact bleeding is present in the terminal
ileum. Biopsies reveal inflammatory changes with
submucosal inflammation, and several
granulomata (see figure 3, page 8).
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D OCtort
(68RCPA
Australian Government
Department of health and Ageing
7
Doctor.uRGPA
Australian Government
Department of Health and Ageing
Diagnosis and management
The diagnosis of Crohn's disease has been confirmed.
Despite tolerating treatment with corticosteroids,
azathioprine and sulfasalazine , Kerry fails to
improve. Having developed obstructive symptoms,
she requires resection of a segment of her ileum. She
makes an excellent recovery from her operation and
is stabilised on a low dose of prednisolone,
azathioprine and mesalazine.
What absorption problems arise from ileal resection?
Resection of the terminal ileum and ileocaecal valve
is associated with small bowel bacterial overgrowth.
The ileum is also the primary site of absorption of
some nutrients, particularly vitamin B12 and bile
acids. Removing 60cm of the ileum usually results
in B1, deficiency, once body stores are used up.
Resection of more than lm of the ileum usually
results in bile salt malabsorption, with disrupted
enterohepatic circulation and fat soluble vitamin
deficiencies. Unabsorbed bile salts can also cause
secretory diarrhoea when they enter the colon.
SummaryMalabsorption can be the result of many differentdisease processes, leading to a wide variety of signs
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and symptoms and a broad spectrum of severity.
In investigations it is important to identify the
underlying process as well as confirm the presence
of malabsorption.
References available on request.
The RCPA and Australian Doctor gratefullyacknowledge the funding contribution made by the
Department of Health and Ageing to this series.
Australian Government
Department of Health and Ageing
8