
  
    
      
        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.
      
    
  
