The ever –present need for biopsy to diagnose coeliac disease safely

Introduction

We have found cases with significantly high concentration of anti-tTG antibody [>10 × upper limit of normal (ULN)] value but not reflecting CD at mucosal level but demonstrating infestation by giardia. ¹ The widespread practice of recommending a gluten free diet (GFD) based on only high anti- tTG values is therefore erroneous. The purpose of our clinical report is to show that giardiasis, which shares clinical symptoms of CD, may cause a significant false rise in anti-tTG values.^2,3

Case-series

We hereby report a series of eleven children (seven girls) who presented to our Gastro-enterology Clinic in north India with chronic symptoms including chronic abdominal pain, chronic diarrhoea, poor appetite, and chronic constipation. Their mean duration of symptoms was seven months (range 4–12). Their mean age was seven years (range 4–11).Two had short stature and three were underweight.

Systemic examination was unremarkable except that four children had protruding bellies which were soft and non-tender with no organomegaly. Baseline blood investigations including full blood count, serum albumin and liver enzymes were normal in all cases. Routine stool microscopy showed cysts of giardia in two cases. Anti-tTG antibody, performed by recombinant tissue transglutaminase IgA ELISA kit was significantly high (>10 × the upper limit of normal) in all cases. Upper gastro-intestinal endoscopy with properly oriented multiple biopsies including 1–2 from D1 and 4–5 from D2 was performed. There was no evidence of mucosal damage such as crypt hyperplasia, villus atrophy (MARSH 2 or 3) in any case in spite of significant elevation of anti-tTG antibody, but trophozoites of giardia on the luminal aspect was seen in all.

All patients were treated with metronidazole at 30 mg/kg/day for seven days. Counseling of family members were done with regard to proper personal hygiene and the use of boiled water for drinking purposes. All cases responded well clinically to treatment. Anti-tTG antibody levels were repeated after treatment at three months’ follow up in each case and were found to have reverted to normal.

Discussion

The chronic immune-mediated enteropathy caused by exposure to dietary gluten, which is present in wheat, rye and barley, in genetically predisposed individuals (Human leukocyte antigen DQ2/DQ8) primarily affects the small bowel. It affects 1% of the world population. Its prevalence in north India is estimated to be 1.04%.^4,5 Further known symptoms include recurrent nausea and vomiting, abdominal distension, weight loss, failure-to-thrive, stunted growth and recurrent anaemia.

Giardiasis is one of the commonest intestinal protozoal diseases worldwide. Its incidence remains high in low-income countries, affecting up to one third of the population, usually on account of poor sanitary conditions, poor personal hygiene, non-availability of clean drinking water, and lack of education. In India, the prevalence of giardia in patients with diarrhoea ranges from 0.4% to as high as 70%. ⁶ This is a unicellular eukaryotic microscopic enteric protozoon which occurs as a non-motile cyst (responsible for transmission) or a motile trophozoite (associated with clinical symptoms). Children are more severely affected than adults. Giardiasis can vary from an acute self-limiting condition to a chronic entity entirely similar to coeliac disease with identical reduction in brush-border disaccharides accompanied by malabsorption and failure to thrive. ⁷ It may even lead to histopathological changes such as small bowel villous atrophy which is the hallmark of CD. Other changes, such as partial villous atrophy with increased IEL's (more than 30 intraepithelial lymphocytes-IEL per 100 epithelial cells) may also be seen in giardiasis owing to its selective intestinal tropism. Generally, the diagnosis of coeliac disease requires identification of coeliac auto-antibodies as anti-tissue transglutaminase antibody and confirmatory intestinal biopsy in symptomatic children. Current ESPGHAN (European society for paediatric gastroenterology, hepatology and nutrition) guidelines have recommended a biopsy-free approach in cases where high serum anti- tTG antibody (10xULN) values are recorded. The basis of this advice is that such high serum concentrations must predict mucosal changes of coeliac enteropathy (Marsh 2/3), and such high values are rare in children with normal histopathology. ³ Reports have also shown that anti-tTG antibody greater than or equal to hundred units occur almost exclusively in the setting of Marsh III duodenal histopathology in adults and children. ⁸

We likewise suspected CD in view of the suggested clinical picture and significantly high anti-tTG values (≥ 10 × ULN), but performed an intestinal biopsy as our hospital protocol demanded, the rationale being that a gluten free diet is a lifetime restriction. In all our patients, duodenal histopathology did not show changes suggestive of coeliac disease in spite of significantly high anti-tTG values but, instead, we found normal mucosa with trophozoites of giardia in all. Thus the coeliac serology test turned out to be a false positive.

False-positive results in serologic tests are uncommon but have been shown in other inflammatory bowel or connective tissue diseases. ⁹ Serum anti-tTG antibody was originally proposed as a reliable tool to differentiate between giardiasis and coeliac disease but we have shown this to be unsound.