Coeliac disease (CD) can be associated with liver disease.
Coeliac disease (CD) is an immune-mediated intolerance to gluten which affects 1% of the general population and is characterized by small-bowel mucosal damage and subsequent malabsorption. More recently, CD has been recognized as a multisystem disorder which may affect other extraintestinal organs, such as the skin, thyroid, heart, nervous system, pancreas and liver.
CD-related liver dysfunction
The spectrum of liver impairment in CD is particularly wide, including cryptogenic liver disorders, characterized by mild dysfunction or more rarely by severe liver disease, various kinds of autoimmune liver disease (autoimmune hepatitis [AIH], autoimmune overlap syndrome, primary sclerosing cholangitis [PSC], primary biliary cirrhosis), nonalcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and hepatitis C virus (HCV)-related liver disease. Some of these conditions such as NAFLD, NASH, and HCV-related
liver disease are very common in the general population, and their occurrence in patients with CD is likely a coincidence rather than a true correlation. Presently, two different clinical forms of liver damage appear to be strictly related to CD, and they can be distinguished on the basis of their response to a gluten-free diet (GFD):
- Cryptogenic liver disorder (mild or severe), potentially reversible on a GFD
- Autoimmune liver disorder, generally unaffected by a GFD, like: primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, autoimmune cholangitis.
However, until now, it remains unknown whether these two forms of liver disease are really different entities or only different severities of the same disorder, expression of a different genetic predisposition and ⁄ or duration of gluten exposition.
Pathogenesis of liver dysfunction in CD
The wide spectrum of clinical manifestations characterizing liver injury in CD is likely an expression of a unique liver dysfunction where genetic predisposition, immunological factors, and a more or less protracted gluten exposition, in function of an early or delayed CD diagnosis, may influence the response to GFD and the reversibility of the hepatic lesions. In this view, the described cryptogenic and autoimmune injury, generally acknowledged as closely related to CD, would just be a different resultant of the same initial process. Therefore, it is reasonable to think that an early recognition of CD, before the complex interplay between genetic, immunologic, and environmental factors lead to an irreversible liver damage, would allow a
complete recovery from the hepatic lesions.
The pathogenesis of liver damage in CD is still undefined. However, the following mechanisms have been
hypothesized as playing a role in determining the liver injury in CD: (a) malabsorption and long-standing malnutrition, (b) increased intestinal permeability, (c ) small intestine bacterial overgrowth, (d) chronic intestinal inflammation, and (e) common genetic predisposition.
- Malabsorption and long-standing malnutrition. Impaired gut mucosal integrity determines malabsorption and secondary malnutrition. Although, nowadays, malnutrition due to severe malabsorption is rarely observed in CD, it can concur in determining liver dysfunction (mainly steatosis), found in gluten-sensitive enteropathy.
- Intestinal permeability. The hepatic injury seen in CD could depend on an increased intestinal permeability resulting in the arrival of toxins and antigens in the hepatobiliary system through the portal circulation. Intestinal permeability (assessed by oral lactulose/mannitol absorption test) was found to be significantly higher in celiacs with abnormal liver tests than in those with normal liver enzymes. Liver dysfunction occurs not only in patients with CD but also with IBD, cow milk enteropathy, and food allergy, suggesting that it is not gluten by itself but rather the ensuing mucosal damage that leads to the hepatic disorder. In contrast with this hypothesis, patients with tropical sprue who have a similar intestinal damage, including an increased intestinal permeability, did not present liver enzyme abnormalities as frequently as CD patients.
- Bacterial overgrowth. Small intestinal bacterial overgrowth has been postulated as a possible cause of liver dysfunction in CD. The prolonged intestinal transit time in untreated CD patients leads to small bacterial overgrowth with a consequent increase in the bacterial antigen pool available for absorption and enzymatic neoantigen production.
- Intestinal inflammation. A more important role can be attributed to chronic intestinal mucosal inflammation, which leads to the exposure of TG2, which is the main autoantigen of CD, recognized by the specific CD antibodies (anti-tTG and EmA). As is well known, TG2 is ubiquitous in the human body and is present also in the liver. Recently, it has been demonstrated that anti-tTG IgA can reach TG2 in extraintestinal tissues, and their presence has been demonstrated in liver biopsies of two patients with elevated serum transaminases, supporting the hypothesis that these autoantibodies might play a role in extraintestinal manifestations of CD and particularly in liver injury. As generally acknowledged, there is an increased risk of autoimmune disorders after many years of gluten exposition, and it is clearly demonstrated that a GFD, started in early infancy, is protective against the appearance of autoimmune disorders associated with CD, including autoimmune liver disease. A prolonged time of exposure to gluten caused by a delayed diagnosis could thus explain the passage from a reversible cryptogenic liver damage (more or less severe) to an autoimmune liver damage that becomes unresponsive to GFD.
- Genetic predisposition. Genetic predisposition can certainly have an important role in favoring the progression from cryptogenic liver injury to autoimmune hepatic damage. It is well known that CD and some autoimmune liver disorders have a shared inherited predisposition showing the same HLA class II molecules and haplotypes. The main genetic marker of CD is HLA-DQ2, which is found in about 95% of CD patients (the remaining 5% being HLA-DQ8 positive). HLA-DQ2 is in strong linkage disequilibrium with HLA-DR3, which is the major HLA risk factor for AIH.
The diseases that come out are caused, for the majority, by an iron deficiency (that depends on the gut malabsorption). This loss of iron has effects in the entire organism: in particular a first manifestation could be anemia ; from this the oxygen delivery to the cell of the body decreases. The iron deficiency also cause the reduction of cytocromes (some of them belong to the respiratory chain ); so the cell of the organism suffer and, because of the decreased levels of ATP production (caused by a loss of efficiency of the respiratory chain), their productivity isn’t as efficient as before.
There’s a way to make oxygen and iron levels higher: improve tissue perfusion and the permeability of the area that suffer; this process in made by HIF activation and VEGF relising. Hepatocites try also to elevate iron absorption in the gut, by decreasing the hepcidin levels and by increasing the expression of DMT1 (iron transporter).
The iron deficiency, in the liver, is also associated to a decreased productivity and loss of efficiency in the enzymes that are connected in the degradation and elimination of substances that are not necessary to the body, or that could damage it: these substances will be accumulated and will explicate their toxicity in the organism, causing again cell stress.
The increase of the gut permeability and the injury of the mucosal cell (caused by the illness) let the microorganism, which live in the gut, to infect the body. The inflammatory process that is activated by the microorganism infection, cause also high levels of hepcidina in blood (physiological response: hide iron from pathogens): there is a minor absorption of iron from the gut and there is a limitation of the circulating iron. All of this facts cause another decrease of iron levels in blood: this determine more cell stress and worse symptoms.
Hepatocites, because of cell stress, lose their efficiency and their metabolic processes are less controlled: this could cause an accumulation of a lot of substances in these cells and may evolve in some other illnesses, like steatohepatitis.
However, these illnesses of liver correlated to celiac disease have also more different causes; different type of lesions depends also to the patients and to their diet.
Liver Transplantation and Celiac Disease
The testing of CD serological markers seems to be useful in patients considered for liver transplantation: it helps to avoid useless liver transplantation; in fact here are two case reports, where were found CD serological markers and, with a GFD, could avoid the liver transplantation.
- Sonographic diagnosis of coeliac disease in a case with suspected acute liver failure
- Acute cryptogenic liver failure in an untreated coeliac patient: a case report