Hypertransaminasaemia is by far the most common liver abnormality found in untreated coeliac disease and is reversible with a gluten-free diet. The co-existence of chronic autoimmune liver disease and coeliac disease, although well recognized, is rarer and includes primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis [1]. Neuberger [2] noted that the progression of PBC in two newly diagnosed coeliac patients was slowed by a gluten-free diet. The course of other chronic liver disease is similar to the non-coeliac population. However, Kaukinen et al. [3] recently reported that a gluten-free diet may have a beneficial effect on the course of severe hepatic failure in acute and chronic liver disease of various aetiologies. The authors reported a dramatic improvement in liver function in four untreated coeliac patients after the introduction of a gluten-free diet. Before commencing the diet, the severity of the liver disease in three of the patients was such that they had been referred to liver transplant evaluation programmes. After the diagnosis of coeliac disease and the introduction of a gluten-free diet, so great was the improvement in liver function that transplantation was no longer considered necessary. In a separate section of their paper, Kaukinen et al. [3] described finding eight cases of coeliac disease in a prospective study of 185 post-liver transplant cases. The frequency is up to 10 times greater than that found in population screening studies published from the same geographical area. Coeliac disease was diagnosed before liver transplant in six of these individuals; gluten-free diet adherence was poor in two, and was instituted for between 2 and 9 months before surgery in three other individuals. The remaining patient, a 22-year-old woman with congenital hepatic fibrosis, had been on a strict gluten-free diet for 11 years before her transplant. Her coeliac disease was diagnosed at endoscopy for the management of variceal bleeding. Two new cases of coeliac disease were identified post-transplant by this Finnish study, neither had symptoms or signs expected in untreated coeliac disease. The authors pointed out that their post-transplant study may have underestimated the frequency of coeliac disease because these individuals would be on immune suppression, which could theoretically induce false negative serological tests.
In this current edition of the Journal, Ojetti et al. [4] present an additional case report of a 28-year-old woman with acute liver failure of unknown aetiology, in whom coeliac disease was identified during assessment and enrolment into a transplant programme. After the commencement of a gluten-free diet a marked improvement in the liver status ensued. Currently, her liver disease is in remission, with a gluten-free diet being her only therapy. There are thus now 13 individuals with liver failure who have co-existing coeliac disease. The spectrum of liver diseases in these individuals is similar to that usually identified as being associated with coeliac disease: namely PBC, PSC, autoimmune hepatitis and steatosis (non-alcoholic steatohepatitis). The remaining patient had congenital hepatic fibrosis, a condition that is not usually considered to be associated with coeliac disease.
These cases, and especially those in whom dietary gluten exclusion ameliorated their liver disease, raise several important questions. How frequently does undiagnosed coeliac disease occur in populations with severe liver disease undergoing assessment for liver transplant? What is the relationship between coeliac disease, a gluten-free diet and the course of liver disease? Is the improvement in the liver related to enhanced absorption and nutrition secondary to the recovery of small bowel function after gluten withdrawal alone, or is it caused by the suppression of gliadin-driven immune-mediated damage? Are the proline/glutamine-rich residues of dietary gluten/gliadin toxic to the liver in coeliac patients only, or might other non-coeliac liver disease patients benefit from a gluten-free diet? What are the budgetary implications of transplanting patients who might respond to a gluten-free diet alone?
The first question could be best answered by a multi-centred prospective study conducted by liver units and transplant assessment centres. The addition of serological screening with tissue transglutaminase and endomysial antibodies to other routine investigations would identify the majority of cases. In those individuals undergoing upper intestinal endoscopy, the addition of a duodenal biopsy to the protocol would add little to the time or cost of the procedure, but would enable the diagnosis of overt coeliac disease in those patients with negative serological tests. Other patients with less severe liver disease in whom the aetiology is not apparent should be screened for coeliac disease.
As regards the effect of untreated coeliac disease on liver disease, Kaukinen et al. [2] speculated on the reasons for the rapid progression of chronic liver disease. They identified the increased porosity of the small intestine in untreated coeliac disease, which may facilitate the absorption of antigens and peptides of intestinal origin, and suggested that tissue transglutaminase may transform dietary or self-antigens into neoantigens precipitating an immune response in the liver. The intestinal transit time in untreated coeliac disease is prolonged [5]; this leads to small intestinal bacterial overgrowth with a subsequent enlargement of the bacterial antigen pool available for absorption and enzymatic neoantigen production. The hepatic sinusoids are lined by endothelial cells and Kupffer cells. These latter cells are the resident macrophages and play a pivotal role in the regulation of the immune response to bacterial products from the gut. Other tissue macrophages occur in the spleen, where their function includes the removal of elderly erythrocytes and platelets. Splenic hypofunction, characterized by the presence of time-expired erythrocytes (containing ‘pits’ or Howell Jolly bodies) and a high platelet count in the peripheral circulation is a common haematological abnormality found in adults with untreated coeliac disease; splenic function reverts towards normal on a gluten-free diet [6]. There is very little documented information on Kupffer cell function in coeliac disease. Palmer et al. [7] found no evidence of the impaired removal of micro-aggregated albumin from the circulation, and concluded that hypofunction of the tissue macrophages is confined to the spleen. An increase in Kupffer cell numbers has been reported by Jacobsen et al. [8]. Further study of Kupffer cell function in coeliac disease (before and after gluten withdrawal) using newer techniques might be revealing.
Whereas the significant role of gluten/gliadin in coeliac disease and dermatitis herpetiformis is not disputed, the evidence that gluten plays an aetiological role in renal and neurological disease remains contentious. No paediatrician who had witnessed the transformation of a ‘mewling and puking’ infant into a contented baby within days of starting a gluten-free diet doubts that gluten has an adverse effect on brain function in children with untreated coeliac disease. It has been suggested that gliadin peptides may have opioid-like activity, interfering with benzodiazepine receptors in the brain; benzodiazepine receptors are present in cultured liver tumour cell lines. The peptides derived from gluten are uniquely rich in proline and glutamine. Many are particularly immunogenic in coeliac disease, and the resulting cellular and humoral response may lead to the damage of many organs. Is it a gliadin-stimulated immunopathological process or direct toxicity that accelerates the course of chronic hepatic diseases in coeliac disease?
There are enormous resource implications if a patient can be treated efficaciously by a gluten-free diet rather than liver transplantation. According to a recent report from Rotterdam [9], the average cost of a liver transplant, from the pre-transplantation assessment to 3 years post-transplantation, is €141 000 and the inpatient hospital stay is on average 108 days. The expense of coeliac disease diagnosis (serological testing, duodenal biopsy processing and interpretation) is less than that of a day in an intensive care unit after liver transplantation. High costs do not cease at 3 years in the post-transplantation patient, the price of immune-suppressive medication is over €8000 per year. Although a gluten-free diet is more expensive than a normal diet, the additional costs would be less than €1500 per year [10], not to speak of the increased morbidity and mortality associated with a potentially unnecessary liver transplant, or the emotional cost to the patient and their family.
Conflict of interest
None declared.
Authors' contributions
FMS was responsible for the conception, drafting and final approval of this document. RMM contributed to the conception, revising and final approval of this document.
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