APRIL 2006

Common Sense Pathology

A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs

A JOINT INITIATIVE OF

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Australian Government Department of Health and Ageing

The Royal College of Pathologists or Australasia

Malabsorption including coeliac disease and inflammatory bowel disease

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 gastroenterologist with 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 of Australian Doctor and the Royal College of Pathologists of Australasia. It is published by Reed Business Information Tower 2, 475 Victoria Ave, Locked Bag 2999 Chatswood DC NSW 2067. Ph: (02) 9422 2999 Fax: (02) 9422 2800 E-mail: mail@australiandoctor.com.au Web site: www.australiandoctor.com.au (Inc. in NSW) ACN 000 146 921 ABN 47 000 146 921 ISSN 1039-7116 2006 by the Royal College of Pathologists of Australasia www.rcpa.edu.au CEO Dr Debra Graves E-mail: debrag@rcpa.edu.au While the views expressed are those of the authors, modified by expert reviewers, they are not necessarily held by the college. Cover: Professors PM Motta & FM Magliocca/Science Photo Library

Common Sense Pathology editor: Dr Matthew Meerkin E-mail: mmeerkin@ozemail.com.au Chief sub -editor: Kathryn Hogan E-rnail:kathryn.hoqan@reedbusiness.com.au Australian Doctor Editor: Nadine Meehan E-mail: nadine.meehan@reedbusiness.com,au Medical editor : Dr Kerri Parnell E-mail: kerri.parnell@reedbusiness.com.au Commercial director: Suzanne Coutinho E-mail: suzanne.coutinho@reedbusiness.com.au Graphic designer: Edison Bartolome E-mail: edison.bartolome@reedbusiness.com.au Production manager : Marlene Dickinson E-mail: marlene.dickinson@reedbusiness.com.au

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Australian Government Department of Health and Ageing

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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 symptoms Microcytic

anaemia Glossitis Pica

Investigations

Malabsorbed nutrient

Iron studies

Iron

Megaloblastic anaemia Glossitis

Bone pain Osteoporosis

RBC folate, B12 levels

25 -OH vitamin D Serum calcium

B12, folate

Calcium, Vitamin D Vitamin K, Vitamin C

Chvostek sign ALP Bleeding Bruising Petechiae Coags INR

Oedema
Ascites

Total protein
Albumin Lymphocytes Protein

Peripheral neuropathy

Nerve conduction Vitamins B1, studies B6, B12 Vitamin A, Zinc

Australian Government Department of Health and Ageing

Hyperkeratosis Retinol Parakeratosis Zinc

A selected battery of tests is useful in suspected malabsorption because the patient may have no symptoms , or symptoms that mimic those of another condition. Initial testing should include: s FBC s LFTs s B12, red cell folate and iron studies s Thyroid function tests s ESR, CRP s Calcium s Coeliac serology s Stool samples to exclude chronic infection such as giardiasis . Three specimens should be sent if there is a high index of suspicion of protozoan infection s 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 distinguish between small bowel and pancreatic causes of steatorrhoea

Coeliac disease
Coeliac 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 explanation 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 overt coeliac disease

Patients with undiagnosed, silent coeliac disease

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Australian Government Department ofNealth and Ageing

Patients with latent coeliac disease 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 I
Steven, 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: s FBC - Hb 119g/L; MCV elevated at 1.01 fL; Howell-Jolly bodies on the blood film, consistent with hyposplenism. s Normal WCC and platelets. s Stool cultures and examination for ova, cysts and parasites negative.

Test Anti-tTG EMA AGA-A AGA-G

Sensitivity % 91 86 64 84

Specificity % 96 100 92 86

PPV% 97 100 92 89

NPV% 87 83 64 79

Likelihood ratio* Positive Negative 0.04 23 87 0.13 0.39 8 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 AGA-A: Antigliadin antibody (IgA) EMA: Antiendomysial antibody AGA-G: Antigliadin antibody (IgG)

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Australian Government Department of Health and Ageing

s 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.

Case study 2
Danielle, 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.

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Australian Government Department of Health and Ageing

`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.

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.

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.

Inflammatory bowel disease Crohn's disease in particular may cause malabsorption, because it commonly involves the
terminal 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 entities such as tuberculosis, lymphoma, amoebic infection 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

Case study 3
Kerry, 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: s Stool microscopy - red and white cells, no organism cultured or parasites seen. s FBC - WCC 12 x 109/L, Hb 101g/L with a normochromic, normocytic pattern.

s ESR 72, CRP 145, Albumin 31g/L.

s Rheumatoid factor, ANA - negative. s 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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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.
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Australian Government Department of Health and Ageing

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.

Summary Malabsorption can be the result of many different disease processes, leading to a wide variety of signs

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 gratefully acknowledge the funding contribution made by the Department of Health and Ageing to this series.

Australian Government
Department of Health and Ageing