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Short answers

1 This patient is an atypical presentation of coeliac disease. Patients presenting with gastrointestinal symptoms are thought to have "classic" or typical coeliac disease, but those presenting with no gastrointestinal symptoms are described as atypical. A substantial proportion of patients with coeliac disease have no gastrointestinal symptoms and present with extraintestinal manifestations or associated conditions such as weight loss, arthralgia, arthritis, aphthous ulcers, or skin rash. Osteoporosis and neurological symptoms can also be presenting features of coeliac disease. This patient presented atypically with a raised concentration of alkaline phosphatase.

2 Possible causes of a raised concentration of alkaline phosphatase include: vitamin D deficiency; coeliac disease; and autoimmune liver disease. Untreated coeliac disease is the most likely cause and adherence to a gluten free diet should normalise serum alkaline phosphatase. Autoimmune hepatitis, autoimmune cholangitis, and primary biliary cirrhosis are unlikely in the absence of anti-nuclear and anti-mitochondrial antibodies.

3 Repeat endoscopy and duodenal biopsy are the most effective methods of monitoring patient adherence to a gluten free diet and assessing recovery of intestinal lesions. Serological tests are not sensitive enough to monitor recovery of the intestinal mucosa.

Long answers
1 Atypical presentation
Coeliac disease was originally thought to be a disease of childhood, but now is more commonly diagnosed in adults than in children. Unlike children, adult patients rarely present with symptoms suggestive of malabsorption. Non-specific abdominal pain, diarrhoea, bloating, steatorrhoea, or symptoms indicative of irritable bowel syndrome are the presenting features in some adults. Non-abdominal symptoms such as fatigue, arthralgia, arthritis, myositis, recurrent aphthous ulcers, skin rash, and iron deficiency anaemia are more common presentations.¹

Coeliac disease is an immune mediated enteropathy triggered by the ingestion of gluten—a protein in wheat, rye, and barley—in genetically susceptible individuals. The disease is associated with HLA-DQ2 in 90-95% of cases and with HLA-DQ8 in 5-10% of people.² These HLA genotypes are necessary but not sufficient to predispose an individual to coeliac disease, hence the absence of these molecules has a negative predictive value for coeliac disease close to 100%. Thanks to the availability of highly sensitive and specific serological tests, many patients with an atypical presentation of coeliac disease are now being diagnosed. The prevalence of coeliac disease is estimated to be 0.5-1%, and patients most commonly present in their fourth decade.³ Nevertheless, estimates indicate that for every confirmed case of coeliac disease, there are eight undiagnosed patients.⁴

2 Raised alkaline phosphatase
Liver and bone diseases are the most common causes of pathological elevation of alkaline phosphatase levels, although alkaline phosphatase can originate from other tissues such as the placenta, kidneys, intestines, or leucocytes.⁵ Cholestatic liver disease in the absence of ductal obstruction on ultrasound (as in our patient) can occur in patients with intermittent obstruction, in the acute phase of obstruction, and in primary sclerosing cholangitis. Intrinsic diseases of the liver—such as alcoholic liver disease, primary biliary cirrhosis, and autoimmune cholangitis—can also cause cholestatic symptoms in patients with no evidence of ductal obstruction. Hepatitis C and cytomegaloviruses are the two viruses that most often present with cholestatic component. Other causes of cholestatic signs in individuals without ductal dilatation are infiltrative disorders of the liver caused by sarcoidosis and haematological malignancies.⁶ Both fluphenazine and olanzapine may cause cholestatic jaundice; however, bilirubin concentration is also abnormal in patients with drug related jaundice.

Liver abnormalities are common in coeliac disease. The most common hepatic presentation of coeliac disease is isolated hypertransaminasaemia with histological evidence of non-specific changes in a liver biopsy sample. In one study, alkaline phosphatase was the only enzyme elevated in 9% of patients with coeliac disease, whereas aspartate aminotransferase and/or alanine aminotransferase was elevated in 13% of patients with a normal alkaline phosphatase concentration.⁷ In another study, alkaline phosphatase was elevated in as many as 22% of patients with coeliac disease.⁸ A raised concentration of alkaline phosphatase in coeliac disease can be caused by associated liver abnormalities or osteomalacia secondary to the malabsorption of vitamin D. A third, less common cause of raised alkaline phosphatase is the "spill over" of intestinal alkaline phosphatase into the circulation as a result of damage to the intestinal mucosa.⁹ Moreover, coeliac disease can coexist with autoimmune liver disorders such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.¹⁰ A gluten free diet normalises levels of liver enzymes and any histological abnormalities in most patients with coeliac disease.

Ultraviolet B light from the sun converts 7-dehydrocholesterol in the skin to previtamin D₃, which is immediately converted to vitamin D₃. Vitamin D₂ and vitamin D₃ from dietary sources are transported by the lymphatic system into the venous circulation via chylomicrons. Vitamin D₂ and vitamin D₃ made in the skin or ingested in the diet are bound in the circulation to the vitamin D binding protein, which transports vitamins to the liver where they are converted by vitamin D 25-hydroxylase to calcidiol. Calcidiol is then converted in the kidneys by 25-hydroxyvitamin D 1-hydroxylase to the biologically active form of vitamin D—calcitriol. Parathyroid hormone stimulates 1-hydroxylase enzyme activity to enhance calcitriol synthesis, whereas calcitriol decreases the synthesis and secretion of parathyroid hormone by the parathyroid glands. Calcitriol also decreases its own synthesis through negative feedback.¹¹ In coeliac disease, reduced calcitriol owing to malabsorption of vitamin D diminishes calcium absorption in the small intestine, which can lead to hypersecretion of parathyroid hormone. This chain of events ultimately leads to impaired bone mass and osteomalacia.¹² Vitamin D replacement in the form of calcitriol, in conjunction with a gluten free diet, results in healing of bones and correction of metabolic abnormalities.

3 Adherence to gluten free diet and recovery of intestinal mucosa
Adherence to a gluten free diet can be assessed subjectively by the patient or a dietitian, as well as using serology or by performing a duodenal biopsy. The sensitivity of the IgA endomysial antibody test is 85-100% and the specificity close to 100% in patients with untreated coeliac disease. IgA deficiency causes false negative coeliac serology results in patients with coeliac disease and must, therefore, be excluded if serological tests are negative despite high clinical suspicion of coeliac disease. Management with a gluten free diet causes a rapid decrease in titres of IgA endomysial antibody. Although such a drop might be of value in monitoring dietary adherence, it is not sensitive enough to detect villous recovery.¹³ The test for tissue transglutaminase antibody has sensitivity of 91-95% and a negative predictive value of 100%. False positive results can occur in chronic liver disease, monoclonal gammopathy, and type 1 diabetes. Moreover, seronegative coeliac disease occurs in 6.4-9.1% of patients.¹⁴ Duodenal biopsy is, therefore, required in order to diagnose coeliac disease. Biopsy samples must be taken before a gluten free diet is commenced. Tissue transglutaminase antibodies should disappear with strict adherence to a gluten free diet. However, a substantial number of coeliac patients who have negative findings on tests for tissue transglutaminase antibodies have mucosal villous atrophy. These tests are, therefore, not reliable in monitoring adherence to a gluten free diet.¹⁵ Small bowel biopsy is still necessary to ensure patient adherence and recovery of the duodenal mucosa.

Cite this as: BMJ 2009;338:b1874