rcpa20 malabsorption er 320 done

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.

Cover: Professors PM Motta & FM Magliocca/Science Photo Library

Australian DoctorEditor: Nadine MeehanE-mail: [email protected],au

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For an electronic version of this and previous articles, you can visit www.australiandoctorcom.au Click on Clinical andLibrary, then Common Sense Pathology. You can also visit the Royal College of Pathologists web site at wwwrcaa.edu.auClick on Publications and Forms, then Common Sense Pathology.

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


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


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



5

Doctor.• RCPA



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


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).

qustr a lian

D OCtort

(68RCPA


Department of health and Ageing

7

Doctor.uRGPA




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.



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rcpa20 malabsorption er 320 done

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