Celiac Disease and Primary Biliary Cirrhosis: An Immune Link

Abstract and Introduction

Abstract

The association between celiac disease and primary biliary cirrhosis is well established. The breakdown of gut–liver axis equilibrium plays a central role in the development of immune disorders involving the small bowel and liver. In celiac disease, immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens reach the liver through the portal circulation owing to the increased intestinal permeability. A molecular mimicry between bacterial antigens and the pyruvate dehydrogenase E2 component, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis. An aberrant intestinal T lymphocyte homing to the liver may contribute to trigger immune hepatic damage. Both celiac disease and primary biliary cirrhosis share several features, including a higher prevalence in females, autoimmune comorbidities and specific autoantibodies. Reciprocal screening for both diseases is recommended, as an early diagnosis with the appropriate treatment can improve the outcome of these patients.

Introduction

Growing evidence demonstrates that the gut–liver axis plays a crucial role in the maintenance of biological homeostasis at the gastrointestinal level.^[1] The close anatomical and functional relationship between gut and liver modulates the immune response to bacterial and food antigens in health and disease. The balance of gut microbiome, intestinal permeability, hepatocyte function and Kupffer cell activation is critical for good health, and the breakdown of this equilibrium triggers the development of intestinal and liver disorders.^[2] Many microbiome-associated and immunologically active molecules of intestinal origin enter the portal circulation and reach the liver through this 'busy street'. An aberrant intestinal T lymphocyte homing to the liver is thought to be important for the development of T–cell-mediated hepatic disorders associated with gut inflammation.^[3] In line with this hypothesis, an increased number of T lymphocytes expressing molecules of intestinal origin, that is, integrin α4b7 and chemokine receptor CCR9, have been detected in liver sinusoidal endothelial cells in patients with hepatic involvement. One of the best examples of gut–liver axis failure is the frequent coexistence of celiac disease (CD) and liver abnormalities.^[4]

Liver involvement in CD is well established. In the late 1970s, the first reports demonstrated that transaminases were frequently raised in untreated CD, usually reverting to normal after a few months of a strict gluten-free diet (GFD).^[5,6] In the early 1990s, and even more recently, some original studies carried out after the recognition of CD as an autoimmune disease have highlighted the close association between CD and autoimmune liver disorders.^[7–10] Two clinical forms of liver damage appear to be strictly related to CD: cryptogenic liver disorders (including mild hypertransaminasemia and severe chronic hepatitis or cirrhosis of unknown etiology) and autoimmune liver diseases. Presently, it is difficult to establish whether these two kinds of presentation of liver injury are discrete entities with a different pathogenesis or whether they are expressions of the same disorder, where genetic factors and duration of gluten exposure may have a different impact on the severity and characteristics of liver damage.^[11] The spectrum of autoimmune CD-related liver disorders includes Type 1 and 2 autoimmune hepatitis, overlap syndrome, autoimmune cholangitis, primary sclerosing cholangitis and primary biliary cirrhosis (PBC).^[4] PBC is regarded as the most frequent liver CD-related immune disorder, being considered the most frequent expression of autoimmunity detected in CD after Hashimoto thyroiditis, Type 1 diabetes mellitus and Sjogren syndrome.^[12]

Table 1. Prevalence of celiac disease in patients with primary biliary cirrhosis and *vice versa*.
Study (year)	Patients with PBC (n)	CD in patients with PBC (n)	Patients with CD (n)	PBC in patients with CD (n)	Ref.
Dickey et al. (1997)	57	4 (7%)			[48]
Bardella et al. (1997)	65	0	336	1 (0.29%)	[49]
Kingham et al. (1998)	67	4 (6%)	143	4 (2.8%)	[50]
Niveloni et al. (1998)	10	2 (20%)			[51]
Sorensen et al. (1999)			8631	24 (0.27%)	[52]
Gillett et al. (2000)	378	10 (2.6%)			[53]
Floreani et al. (2002)	87	3 (3.4%)	108	4 (3.7%)	[54]
Volta et al. (2002)	173	7 (4%)			[9]
Chatzicostas et al. (2002)	62	0			[55]
Habior et al. (2003)	115	1 (0.9%)			[56]
Sum of the ten studies considered	1014	31 (3.1%)	9218	33 (0.36%)

CD: Celiac disease; PBC: Primary biliary cirrhosis.

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Key Issues

The breakdown of the gut–liver axis balance plays a crucial role in the development of intestinal and liver disorders.
An aberrant intestinal T lymphocyte homing to the liver and an overload of intestinal microbiome-associated and immunologically active molecules reaching the liver through the portal circulation owing to the increased intestinal permeability are thought to be critical for the development of the T-cell-mediated hepatic disorders associated with gut inflammation, whose best example is the association between celiac disease (CD) and primary biliary cirrhosis (PBC).
CD and PBC are two autoimmune disorders whose association has been widely established (mean prevalence of CD in PBC and PBC in CD is 3.1 and 0.36%, respectively).
PBC is the most frequent CD-related liver disease, being regarded as the most prevalent autoimmune disorder detected in CD after Hashimoto thyroiditis, Type 1 diabetes mellitus and Sjogren syndrome.
CD and PBC share several features, including a large predominance in female patients, a high frequency of the same autoimmune comorbidities (i.e., Hashimoto thyroiditis and Sjogren syndrome), a specific immune response against a well-established autoantigen (tissue transglutaminase [TG2] for CD and E2 component of pyruvate deydrogenase multienzyme complex for PBC).
Environmental infectious factors are thought to contribute to the onset of both the disorders with the demonstration of a molecular mimicry between TG2 and a rotavirus protein (VP7) for CD and between pyruvate deydrogenase multienzyme complex and a Gram–negative bacterium (Novosphingobium aromaticivorans) for PBC.
A genetic susceptibility seems to be present in both the disorders, as CD is found in 3 to 17% of first-degree relatives of celiacs, and PBC is detected in 1–6% of the families with at least another affected component. Moreover, a high concordance rate in monozygotic twins has been observed for both the disorders.
Although only CD displays a close genetic relationship being linked to HLA-DQ2and/or -DQ8, a genome-wide association study undertaken in North American and Italian PBC patients has shown a significant correlation between PBC and polymorphism of HLA–DQB1, IL12A, IL12RB2and STAT4, which have also been observed in CD patients.
When CD is discovered in PBC patients with mild liver damage, the addition of a gluten-free diet to ursodeoxycholic treatment can slow down the progression of the liver disease. On the contrary, in patients with already-established, severe liver damage at the time of CD diagnosis, a gluten-free diet can only improve the intestinal absorption and abnormalities of bone metabolism, but it does not change the natural course of the liver disorder.
Given the evidence of the possible frequent association between CD and PBC and the advantages that an early diagnosis of both the conditions can have for the outcome of these patients, the authors recommend to always perform screening for CD in PBC patients by means of TG2 antibodies, and for PBC in CD patients by means of antimitochondrial antibodies.

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Gut–Liver Axis: An Immune Link Between Celiac Disease and Primary Biliary Cirrhosis

Abstract and Introduction

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