Liver involvement in celiac disease

Abstract

Celiac disease may present as a cryptogenic liver disorder being found in 5-10 % of patients with a persistent and cryptogenetic elevation of serum aminotransferase activity. In fact, a wide spectrum of liver injuries in children and adults may be related to CD and in particular: (1) a mild parenchymal damage characterised by absence of any clinical sign or symptom suggesting a chronic liver disease and by non-specific histological changes reversible on a gluten-free diet; (2) a chronic inflammatory liver injury of autoimmune mechanism, including autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis, that may lead to fibrosis and cirrhosis, generally unaffected by gluten withdrawal and necessitating an immunosuppressive treatment; (3) a severe liver failure potentially treatable by a gluten-free diet. Such different types of liver injuries may represent a spectrum of a same disorder where individual factors, such as genetic predisposition, precocity and duration of exposure to gluten may influence the reversibility of liver damage. A rigorous cross-checking for a asymptomatic liver damage in CD individuals and conversely, for CD in any cryptogenic liver disorder including end-stage liver failure is recommended.

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Symposium on Hepatology and Gastroenterology II
Liver Involvement in Celiac Disease
Giuseppe Maggiore and Silvia Caprai
Department of Reproductive Medicine and Child Development University of Pisa, Gastroenterology and Liver Unit
and IsMeTT, University of Pittsburgh Medical Center, Palermo, Italy.
ABSTRACT
Celiac disease may present as a cryptogenic liver disorder being found in 5-10 % of patients with a persistent and cryptogenetic
elevation of serum aminotransferase activity. In fact, a wide spectrum of liver injuries in children and adults may be related to
CD and in particular: (1) a mild parenchymal damage characterised by absence of any clinical sign or symptom suggesting a
chronic liver disease and by non-specific histological changes reversible on a gluten-free diet; (2) a chronic inflammatory liver
injury of autoimmune mechanism, including autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis,
that may lead to fibrosis and cirrhosis, generally unaffected by gluten withdrawal and necessitating an immunosuppressive
treatment; (3) a severe liver failure potentially treatable by a gluten-free diet. Such different types of liver injuries may represent
a spectrum of a same disorder where individual factors, such as genetic predisposition, precocity and duration of exposure to
gluten may influence the reversibility of liver damage. A rigorous cross-checking for a asymptomatic liver damage in CD
individuals and conversely, for CD in any cryptogenic liver disorder including end-stage liver failure is recommended.
[Indian J Pediatr 2006; 73 (9) : 809-811]
E-mail : g.maggiore@clp.med.unipi.it
Key words : Celiac disease; Autoimmune liver disease; Acute liver failure; Cryptogenic liver damage
A possible liver involvement in patients with celiac
disease (CD) was first described in 1977.
1
Even if, due to
the high prevalence of CD in the general population, a
fortuitous association between any type of liver lesion and
CD could not be excluded, however, nowadays, there is
growing evidence that a wide spectrum of liver injuries in
children and adults may be related to CD (table 2)
2
and in
particular:
• a mild type of parenchimal damage reversible on a
gluten-free diet;
• a chronic inflammatory liver injury that may lead to
fibrosis and cirrhosis, generally unaffected by gluten
withdrawal;
• a severe liver failure potentially treatable by a
gluten-free diet.
More rarely, other types of liver lesions including fatty
liver
3
nodular regenerative hyperplasia
4
and
hepatocellular carcinoma, may occur.
1
Persistent elevation of serum aminotransferase activity
is the most common liver abnormality found in untreated
CD.
2
Hagander first in 1977 found that almost 40% of 74
untreated coeliac adult patients showed, at diagnosis, an
hypertransaminasemia, in most cases reversible with a
gluten free diet (GFD).
5
An histological evaluation,
Correspondence and Reprint requests : Prof. Giuseppe Maggiore,
Dipartimento di Medicina della Procreazione e della Età Evolutiva,
Università di Pisa, Via Roma 67 56100 Pisa-Italy. Fax : +39050 888 622
available in 13 patients, demonstrated a mild reactive
hepatitis in 5, and different types of liver lesion ranging
from liver steatosis to pronounced fibrosis and cirrhosis in
the 7 other patients.
5
It was later shown that, also in young
children with CD and gastrointestinal symptoms, mild to
moderate elevation of serum aminotransferase activity,
usually resolving with a GFD, may occur, at diagnosis, in
up to 60% of cases.
6
Liver histology showed, in this case,
a preserved liver architecture with a mild mononuclear
infiltrate of the portal tract and a slight hyperplasia of the
Kupffer cells.
7
On the other hand, celiac disease may
present as a cryptogenic liver disorder. Such an onset was
first described in 1986, in a young girl with persistent and
cryptogenic elevation of serum aminotransferase and a
mild reactive hepatitis. In this case the diagnosis of CD
was suggested by an high titre of antireticulin antibody,
serendipitously found on autoantibody screening.
8
This
TABLE. Liver Diseases Associated with Celiac Disease
Reactive hepatitis ( coeliac hepatitis)
Autoimmune liver disorders
Autoimmune hepatitis
Autoimmune overlap syndrome
Autoimmune (sclerosing) cholangitis
Primary biliary cirrhosis
Non alcoholic fatty liver disease
Acute liver failure
Cryptogenic cirrhosis
Regenerative nodular hyperplasia
Hepatocellular carcinoma
Indian Journal of Pediatrics, Volume 73—September, 2006 809

66
Giuseppe Maggiore and Silvia Caprai
was later confirmed in a series of 6 children without
gastrointestinal or malabsorption symptoms with
hypertransaminasaemia of unknown cause. The liver
biopsy of these patients showed different
histopathological lesions ranging from reactive hepatitis
to a moderately active chronic hepatitis.
9
GFD always led
to normalisation of aminotransferase activity and to an
amelioration of histological lesions in the two children
who were re-biopsied. Gluten challenge after twelve
months of GFD caused again an increase of serum
aminotransferases in three other patients.
Two retrospective studies in adults confirmed these
findings, suggesting that up to 9% of patients with a
persistent and cryptogenetic elevation of serum
aminotransferases activity, may be affected by an
asymptomatic CD.
10,11
This reversible, gluten-related, liver damage today
known as celiac hepatitis
12
is characterised by absence of
any clinical sign or symptom suggesting a chronic liver
disease and by mild, non-specific histological changes
including Kupffer cell hyperplasia, mild lobular and
portal tract inflammation or steatosis.
Response to dietary treatment however, may be
delayed up to 12 months; in such cases, an alternative
diagnosis has to be considered.
2
In fact, less frequently,
hypertransaminasemia may hide a severe chronic liver
injury and even a cirrhosis.
5,13
In these case, the
histological features are consistent with an autoimmune
liver damage including primary biliary cirrhosis (PBC)
primary sclerosing cholangitis with overlap features and
autoimmune hepatitis.
2
Actually, the prevalence of CD in
adults with a chronic liver disease is at least 15-fold
higher than in general population.
14
Moreover, the
prevalence of CD in patients with autoimmune hepatitis
was estimated to be 4% in a large population of adults
15
(a
prevalence eightfold higher than in general population)
and similarly 3.4% among 96 children with autoimmune
hepatitis at King’s College, London, UK.
16
The converse,
in a large multicentre study in children with CD, the
prevalence of autoimmune hepatitis was found to be 1.1
%
17
and another study, recently performed in UK on 4732
adult patients with CD, demonstrated a threefold increase
in risk for autoimmune cholestatic conditions, such as
PBC and PSC, compared with controls.
18
In contrast to
celiac hepatitis, autoimmune inflammatory liver injury do
not seem to benefit from the institution of gluten-free diet
by itself, but need a specific immunosuppressive
therapy.
19
The pathogenetic mechanism of liver damage in celiac
patients is poorly understood. The different types of liver
injuries described may represent a spectrum of a same
disorder where individual factors, such as genetic
predisposition, precocity and duration of exposure to
gluten may influence the reversibility of liver damage.
Autoimmune liver disorders and CD share in fact
common HLA class II haplotypes. In caucasian
population, two haplotypes have been identified as
susceptibility markers of autoimmune hepatitis: the
complex HLA A1 B8 DR3 and the haplotype HLA DR4.
Similarly, specific HLA class II antigens such as HLA-
DR3, particularly the HLA-DQ2 molecule and HLA DR4,
confer susceptibility to CD.
12, 20
Patients with celiac disease have an increased intestinal
permeability which may facilitate the absorption of
antigens from the gut. Increased permeability to
intraluminal antigens could induce, in genetically
predisposed individuals, an immune response both
against antigens sharing common epitopes to self-liver-
proteins and/or against cryptic antigens unmasked by
the reaction with gliadin. It is known that mucosal
damage in CD leads to exposure of tissue transgluta-
minase enzyme, the target antigen recognised by anti-
endomysial antibody. The hypothesis that this
autoantibody may play a role in extraintestinal
manifestations of CD and particularly in liver injury is
supported by the recent finding of extracellular
deposition of IgA class anti-tissue transglutaminase
antibody in liver biopsy of two patients with active celiac
disease.
21
Whether celiac disease is a potentially treatable cause
of liver failure is currently debated.
22
A 4.3% prevalence of
CD was recently found, in Finland, in a group of 185 adult
patients who had undergone liver transplantation. The
nature of the end-stage liver disease leading to liver
transplantation in CD patients was in most cases, of
autoimmune origin.
23
Furthermore, the authors report a
dramatic improvement in liver function on a GFD in four
untreated CD patients listed for liver transplantation,
whom liver failure reversed on GFD, allowing 3 of them
to escape to transplantation.
23
Similarly Ojetti et al.
recently described an additional case of a 28 yr old
woman with acute liver failure of unknown origin, found
to be celiac during the enrolment into a transplant
programme, in whom GFD by itself allowed her to restore
liver function.
24
The occurrence in CD of a cryptogenic
liver failure, requiring liver transplantation, has also been
recently described during childhood.
25
These considerations recommend a rigorous cross-
checking for a asymptomatic liver damage in CD
individuals at diagnosis, and conversely, for CD by
appropriate serology, in any cryptogenic liver disorder
including end-stage liver failure and patients listed for
liver transplantation.
However in patients with chronic liver disease,
attention should be paid, to the risk of false-positive
results of serum anti-tissue transglutaminase, due to the
different degree of specificity of the methods employed,
to the high immunoglobulin concentration
26
and to the
role of tissue transglutaminase in hepatic tissue repair.
27
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