Background
Primary Sjögren's syndrome (1°SS) is a systemic
autoimmune disorder characterized by dry eyes
(keratoconjunctivitis sicca), dry mouth (xerostomia) as
well as involvement of other exocrine glands. While 1°SS is
typically considered an autoimmune exocrinopathy, the
immune destruction can often extend to affect non-exocrine
organs. Around 25 % of patients with 1°SS can present with
involvement of other organs such as the thyroid, central
nervous system, lungs, kidney and liver. The association of
liver disease and 1°SS was suggested more than 40 years ago
[ 1 ] . While liver involvement in 1°SS has been considered
"rare" [ 2 ] only a few clinical studies specifically
address this complication and evaluate the association of
liver function tests abnormalities with the severity of
1°SS [ 3 4 5 6 ] .
Liver diseases associated with 1°SS include primary
biliary cirrhosis (PBC)-autoimmune cholangitis [ 8 9 10 ] ,
autoimmune hepatitis [ 5 6 ] , viral hepatitis (B and C) [
11 12 13 14 15 16 17 18 19 20 21 ] , sclerosing cholangitis
[ 22 ] , and nodular regenerative hyperplasia [ 23 ] . In
addition, chronic lymphocytic sialadenitis has been found
in patients with different types of liver cirrhosis [ 16 17
18 19 20 21 22 23 24 ] .
We report the results of a review of cases undertaken to
determine the prevalence of abnormal liver function tests
(LFTs) and liver disease in patients with 1°SS referred to
a tertiary care center and the association of abnormal LFTs
with other systemic features and autoimmunity markers of
1°SS.
Methods
Statistical analysis
The statistical analysis included descriptive measures
(means, standard deviations and ranges). Comparison of
results of patients with and without liver disease was
done using t-tests of continuous variables and Fisher's
exact test or x2 for categoric measures.
Results
Of the 115 charts reviewed, 73 cases (55 women and 18
men, median age 53) fulfilled EECC for 1°SS and were
initially included for analysis. Of the 73 patients, a 54%
of them (40 patients) have had a salivary gland biopsy
performed. In all these patients, the biopsy confirmed the
diagnosis of Sjögren's syndrome. All patients studied had
objective evidence of 1°SS, including keratoconjunctivitis
sicca, positive labial salivary gland biopsy,
autoantibodies and/or salivary gland hypofunction. We
excluded those patients without these objective criteria of
1°SS and also those who did not fulfill EECC criteria.
The mean age at time of onset of disease was 45 ± 20.5
years old and disease duration was 4.9 years ± 4.5 years
(mean ± range). Liver function tests had been determined in
59 patients (80.8 %) and abnormal liver function tests were
found in 29 of the 59 patients (49.1 %). Further analysis
was then undertaken in those patients in whom LFTs had been
measured. The clinical and laboratory characteristics of
these patients are shown in Tables 2and 3.
For these SS patients studied, abnormal LFTs were more
common than any other potential non-exocrine features of
SS. Clinical evidence of liver disease, defined in methods
section, was found in 12 patients (20.3%), all of whom had
abnormal liver function tests. Two deaths occurred in the
population studied, both attributed to liver failure. An
additional patient required a liver transplant. In all
cases, the diagnosis of 1°SS antedated the onset of liver
disease or its diagnosis. Markers of viral hepatitis,
sought in 39 patients, were found only in 4. Two patients
carried the surface antigen of hepatitis B virus and one
had antibodies to hepatitis C virus. In a liver biopsy of a
patient who lacked serological markers for hepatitis
viruses, hepatitis B virus was detected by
in situ hybridization.
Risk factors for liver disease were identified in 40% of
the patients with abnormal liver function tests and are
described in Table 4. No association with tobacco use was
found. Only 5 patients had documented evidence of tobacco
consumption. We found no significant differences in risk
factors for abnormal liver function tests among patients
with or without hepatic involvement. Therefore, in 60% of
the patients with sub clinical or clinical evidence of
liver disease, no clear explanation for the abnormal LFTs
was found, except for the association with 1°SS.
The pattern of biochemical liver abnormalities was
mainly hepatocellular (defined as predominant increase of
AST and/or ALT in comparison with AP and/or bilirubins) in
11 cases; cholestatic (defined as predominant increase in
AP and/or bilirubins compared with AST and/or ALT) in 3 and
mixed (evidence of both cholestatic and hepatocellular
damage) in 8 cases. Abnormalities were persistent (present
on every occasion when measured more than once) in 19
patients (65.5% of those with abnormal LFTs), intermittent
(presence of LFT abnormalities was not found in all
determinations) in 9 (31%) and in one case (3.5%) there was
only one determination of liver function tests. The pattern
of liver enzyme abnormalities is shown in Figure 1. None of
the patients with abnormal liver function tests had
clinical evidence of muscle involvement that could explain
the high levels of amino-transferases. Activity of CPK or
aldolase was not elevated when measured in 15 of the 29
patients with abnormal liver function tests.
Anti-mitochondrial antibodies (AMA) and anti-smooth muscle
antibodies (ASMA) were sought in 5 patients, with positive
ASMA in 2.
The association of abnormal liver function tests with
other non-exocrine features of 1°SS is shown in Figure 2.
Patients with abnormal liver function tests were more
likely to have lung, kidney or hematological
manifestations, when compared to Sjögren's patients without
liver disease. Presence of other non-exocrine features of
1°SS was not influenced by prevalence of liver
diseases.
Regarding laboratory test results, patients with liver
disease were more likely to have an elevated sedimentation
rate at some point during the course of their disease. A
positive anti-ENA (anti-Ro, anti-Ro/La, and/or anti-RNP)
was also associated with an increased prevalence of
abnormal liver function tests (Figure 3). The sample was
too small to determine whether a specific ENA was
associated with liver disease. Other markers of systemic
inflammation or autoimmunity did not correlate with the
presence or absence of LFT abnormalities.
Liver biopsies, done in 8 patients, disclosed post-viral
chronic active hepatitis (3), cryptogenic cirrhosis (2),
and one case each of post-viral cirrhosis, alcoholic
hepatitis, and autoimmune hepatitis.
Discussion
In this group of Sjögren's patients seen at a tertiary
care center, abnormal liver function tests were found to be
a common non-exocrine feature of 1°SS. The prevalence of
this association was found to be higher in our study than
in other previous series [ 2 3 4 5 6 7 ] . The true
prevalence could be even higher since liver enzyme profiles
were not done in all patients. The prevalence suggested in
previous reports ranges from 6 to 58 %, but the definition
of hepatic disease varies from the unspecific (e.g.
hepatomegaly) to well proven cases of liver disease [ 1 2 3
4 5 6 7 28 ] . Denko in 1960 reported that 12% of patients
with SS had hepatosplenomegaly [ 29 ] . Other studies done
in the 1960's also confirmed hepatomegaly in 18-20% of
patients with SS [ 30 31 ] . In 1970, Whaley reported liver
disease in 6% of patients with SS and mentioned an
association with anti-mitochondrial antibodies [ 2 ] . In
1986, Tsianos and co-workers described 22 SS patients with
gastrointestinal complications, called from a large cohort;
only two patients had liver disease, each with chronic
active hepatitis [ 4 ] . Other studies have reported
variable prevalence [ 3 28 ] and different
histopathological findings in liver biopsies ranging from
cholestatic liver damage (stage I primary biliary
cirrhosis) to chronic active hepatitis due to hepatitis C
virus.
In our study, liver disease was associated with other
non-exocrine manifestations of 1°SS, specifically those
affecting lung, kidney and blood cells. Those patients with
serological evidence of systemic inflammation, as shown by
an elevated sedimentation rate, were more likely to have
liver test abnormalities. Also, the presence of a positive
anti-ENA correlated positively with hepatic disease. An
association of ENA response with liver disease has been
described in children with autoimmune hepatitis, where
anti-ENA-positive patients demonstrated more severe liver
test abnormalities than those who were anti-ENA-negative [
32 ] . In another study, a 15 % of patients with various
chronic liver diseases were found to be anti-RNP positive [
33 ] .
With etiopathogenesis of 1°SS still an open question [
34 ] , a possible role of hepatitis C virus (HCV) has drawn
attention. Recent studies have mentioned HCV incidence in
patients with 1SS ranging from 14-19% [ 11 12 16 18 21 ] .
Phenotypic characterization of the minor salivary glands
with immunohistochemistry in patients with hepatitis C
virus infection and/or 1°SS has given conflicting results [
14 15 ] Some reports mention that the salivary gland
findings are strikingly similar in patients with liver
disease associated with HCV infection than in those with
1°SS [ 12 ] , while others mention distinctive differences
between both groups regarding focus score, expression of
surface markers in lymphocytes infiltrating the salivary
glands and in epithelial cells, as well as differences in
the degree of inflammation [ 14 15 ] . Transgenic mice
models that carry the HCV envelope genes develop an
exocrinopathy affecting salivary and lachrymal glands [ 19
] . Expression of autoimmunity markers also tends to differ
between HCV-infection and 1°SS. Positive ENAs are rarely
seen in HCV-patients. Also, in most cases sicca symptoms
are not present in individuals with HCV as compared with
the 1°SS population. Although the prevalence of viral
hepatitis markers in our group of patients with liver
disease was very low and did not account for most of the
cases with abnormal liver function tests, these markers
were not sought in a small percentage of these patients. It
is important to note that HCV appears to account for a
subgroup of patients with exocrine complaints in which half
the cases might meet the definition for SS according to
European and Manthorpe criteria. However, this subgroup is
characterized by the absence of clinical manifestations
observed in 1°SS, and the absence of anti-Ro and anti-La [
35 ] .
An aberrant interaction between lymphocytes and
different epithelial tissues has been proposed as a
mechanism for the damage seen in different organs in 1° SS
[ 36 ] . Since it has been suggested that the target tissue
involved in the autoimmune histopathologic lesions of 1°SS
might be the epithelium [ 37 ] , it is interesting that the
findings in our study point to the association of liver
disease with pulmonary and renal abnormalities, all which
are characterized by epithelial damage [ 38 39 ] .
Epithelial cells have been proposed to be active
participants rather than passive targets in the chronic
immune response in 1°SS but further studies are needed to
establish the role of liver epithelial cells in the
pathogenesis of hepatic damage in this disease, including
the analysis of HLA expression and cytokine secretion
pattern in these cells.
The co-existence of liver disease and the presence of
circulating AMAs in Sjögren's patients sera has been
pointed as an indicator that liver pathology might be
autoimmune and similar to that of primary biliary cirrhosis
[ 4 7 8 10 ] . In previous studies, a pericholangial
lymphocytic infiltration similar to that found in stage I
of primary biliary cirrhosis, has been reported in 1°SS
with abnormal liver function tests or positivity for AMA [
4 7 ] . In our review of cases, we found predominance in
hepatocellular liver damage rather than cholestatic
disease, which would argue against a PBC-type of liver
damage. Other authors had proposed that SS associated with
PBC should be considered a form of secondary SS that
resembles more the "sicca complex" with exocrine features
seen in patients with rheumatoid arthritis [ 40 41 ] .
Limitations of the study come primarily from being a
retrospective analysis. Since the patients were studied in
a tertiary care referral center, the severity of the
disease and the prevalence of the manifestations might be
different from the general 1°SS population. Furthermore, in
many cases, Sjögren's syndrome diagnosis had been sought
because of otherwise unexplained non-exocrine features.
While we could not find an association between use of
NSAIDS or other medications and prevalence of liver
function tests abnormalities, the study design did not
allow us to exclude the possibility of over-the-counter
(OTC) medication use that could have affected LFT's
measurement. Drug toxicity is certainly an important factor
to be considered. However, given that most patients had
persistent rather than intermittent abnormalities of LFTs
and that the use of hepatotoxic drugs was not elicited in
the majority of patients with liver abnormalities, a toxic
effect of medications could not be established.
Conclusions
Based on the results of this study, we consider that an
evaluation for clinical and serological evidence of liver
disease should be done in every patient with 1°SS,
particularly if there is evidence of other non-exocrine
complications or serological evidence of systemic
inflammation. Although no other diagnosis explaining liver
disease may be found, the disorders for which treatment
might be beneficial (e.g. immunosuppressants for autoimmune
hepatitis, interferon-alpha for viral hepatitis,
ursodeoxycolic acid for primary biliary cirrhosis) warrant
a diligent search in all cases of 1°SS with abnormal liver
function.
Competing interests
None.
Authors' contributions
Both authors contributed equally to the paper.