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Liver abnormalities in connective tissue diseases
Best Practice & Research Clinical Gastroenterology 27 (2013) 543–551
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Best Practice & Research Clinical Gastroenterology
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Liver abnormalities in connective tissue diseases Maria De Santis, MD, PhD, Physician Scientist a, b, Chiara Crotti, MD, Physician a, Carlo Selmi, MD, PhD, Assistant Professor of Rheumatology a, b, * a
Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy BIOMETRA Department, University of Milan, Milan, Italy
b
a b s t r a c t Keywords: Systemic lupus erythematosus Autoimmune liver disease Viral hepatitis
The liver is a lymphoid organ involved in the immune response and in the maintenance of tolerance to self molecules, but it is also a target of autoimmune reactions, as observed in primary liver autoimmune diseases (AILD) such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Further, the liver is frequently involved in connective tissue diseases (CTD), most commonly in the form of liver function test biochemical changes with predominant cholestatic or hepatocellular patterns. CTD commonly affecting the liver include systemic lupus erythematosus, antiphospholypid syndrome, primary Sjögren’s syndrome, systemic sclerosis, dermatomyositis, polimyositis, and antisynthetase syndrome, while overlap syndromes between AILD and CTD may also be diagnosed. Although liver cirrhosis and failure are extremely rare in patients with CTD, unusual liver conditions such as nodular regenerative hyperplasia or Budd–Chiari syndrome have been reported with increasing frequency in patients with CTD. Acute or progressing liver involvement is generally related to viral hepatitis reactivation or to a concomitant AILD, so it appears to be fundamental to screen patients for HBV and HCV infection, in order to provide the ideal therapeutic regimen and avoid life-
Abbreviations: CTD, connective tissue disease; AILD, autoimmune liver disease; SLE, systemic lupus erythematosus; pSS, primary Sjogren syndrome; SSc, systemic sclerosis; PM, polymiositis; DM, dermatomyositis; AS, anti-syntehase syndrome; NRH, nodular regenerative hyperplasia.
* Corresponding author. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Suite 6515, Davis, CA 95616, USA. Tel.: þ1 530 752 2884; fax: þ1 530 752 4669. E-mail addresses: [email protected], [email protected] (C. Selmi). 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.016
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threatening reactivations. Finally, it is important to remember that the main cause of biochemical liver abnormalities in patients with CTD is a drug-induced alteration or coexisting viral hepatitis. The present article will provide a general overview of the liver involvement in CTD to allow rheumatologists to discriminate the most common clinical scenarios. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The liver represents the largest lymphoid organ, being involved in the immune response against pathogens and in the maintenance of tolerance to self molecules [1]. Nevertheless, it can also be a target of autoimmune reaction, as observed in primary liver autoimmune diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). From a rheumatologist viewpoint, the liver is frequently affected by connective tissue diseases (CTD), particularly when the affection is mirrored by liver test abnormalities and may produce a biochemical picture with the predominance of cholestatic (with elevated alkaline phosphatase [ALP] and gamma-glutamyl transferase [GGT]) or hepatocellular (with elevated alanine transaminase [ALT] and aspartate transaminase [AST]) damage. We should also note, however, that advanced disease with liver cirrhosis and failure is extremely rare in patients with CTD (Table 1). In systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and primary Sjögren’s syndrome (pSS), serologic liver test alterations and histological lesions have been described in numerous descriptive studies mostly based on case series. The prevalence of autoimmune liver disease (AILD) in CTD is described by Table 2. In the majority of the cases, liver histology will demonstrate only minor changes and the biochemical findings can be ascribed to the primary affection, even though, in a small number of patients an overlap syndrome with a coexisting primary liver disease should not be overlooked. In this setting, the liver damage is usually progressive, frequently complicated by cirrhosis and portal hypertension. Nevertheless, the main cause of biochemical liver abnormalities in patients with CTD is the presence of previous treatments with potentially hepatotoxic drugs or coexisting viral hepatitis. Systemic lupus erythematosus SLE is a multiorgan CTD classically associated to skin rash, glomerulonephritis, serositis, haematological and central nervous system abnormalities. The liver is generally not a major target organ for damage and, as such, abnormalities of liver function are not included in the classification and diagnostic criteria of SLE. Nevertheless, abnormal liver function tests are common in SLE, being found in up to 50% of patients at some point of the disease course [2] and the main causes are disease activity and drug toxicity and only rarely an overlapping primitive autoimmune liver disease. In 20% of cases liver test abnormalities occur during disease flares, while in 23% of SLE cases with abnormalities in liver functions no cause for pathological liver tests can be identified [3]. Elevated liver tests has been shown to correlate with disease activity and to improve with steroid treatment and a chronic active hepatitis – termed ‘lupoid hepatitis’ by some authors – is described in up to 5% of patients with SLE. Antibodies to ribosomal P protein has been shown to strongly correlate with lupus hepatitis, being detected in a significant proportion of patients (69%) [4]. In this setting, histology demonstrates predominantly mild lobular inflammation without piecemeal necrosis. There are no clear recommendations about the opportunity to perform a liver biopsy: we suggest this procedure when there is an increase of Table 1 Prevalence of liver injury in the most common connective tissue diseases. Disease
Enzyme alterations
Biochemical profile
Histologic alterations
Sjogren’s syndrome SLE Systemic sclerosis
50% 30% 1%
cholestatic > hepatocellular cholestatic < hepatocellular cholestatic > hepatocellular
18% 20% 9%
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Table 2 Prevalence of autoimmune liver disease in connective tissue diseases.
SLE aPL pSS SSc PM/DM/AS
PBC
AIH
PSC
References
2.7–15% 1 case 35–57% 51.2% 14.3%
2.7–20% 4 cases 6–47% 11 cases 7.1%
1 case 1 case 11 cases 1 case –
[6,8,65] [66–68] [8,48,69] [8,54] [70]
transaminases in the absence of other causes (no evidence of disease activity or drug induced liver toxicity) or when an overlapping primitive autoimmune liver disease is suspected. Numerous liver histopathological patterns can be found in SLE, including small artery vasculitis reported in up to 21% of the patients [5], nonalcoholic fatty liver diseases in 20–73%, nodular regenerative hyperplasia (NRH) in 5.7%, chronic persistent or active hepatitis in 2.4%, and cirrhosis or fibrosis in 1.1% [5,6]. Moreover, anecdotal cases of giant cell hepatitis, granulomatous hepatitis, massive liver necrosis, cholangitis, isolated portal hypertension, Budd–Chiari syndrome, and liver ischaemia have also been described. End-stage liver disease is an exceptional finding [7], while cases of Budd–Chiari syndrome are mostly associated with anti-phospholipid syndrome (APS), as will be discussed below. In patients with SLE, overlap syndromes with AIH or PBC have been reported with a similar prevalence (2.7%) and a family history for SLE is independently correlated with PBC in a large case control study [8]. In some cases, it may be difficult to discriminate AIH and SLE-associated hepatitis, given the common clinical and serologic presentation and histology may thus be of help [9]. Almost all drugs in the armamentarium against SLE or other rheumatologic diseases may cause liver toxicity, as represented by non-steroidal antiinflammatory drugs (NSAID). NSAID-related liver injury is usually mild, reversing at drug cessation and the diagnosis may be challenging also with the use of probability criteria; in fact, even for experts, the diagnosis of drug-induced liver injury (DILI) can be problematic. Specific instruments such as the Roussel-Uclaf Causality Assessment Method (RUCAM), the Maria and Victorino method and the Naranjo scale have been developed to offer more objective diagnostic strategies. In a head-to-head comparison of these instruments, RUCAM has been found to perform best for diagnosing hepatotoxicity, but it is cumbersome and therefore rarely used in clinical practice [10–13]. The appearance of NSAID-induced liver injury appears to be dose-independent, while the risk of liver-injury following acetaminophen intake is now well defined and recognized as dose-dependent [14]. One exception is the dose-dependent liver damage from salicylate that may also be a factor in producing some of the liver dysfunction associated with SLE and other collagen vascular diseases [15]. Liver injury is not evident at aspirin doses lower than 2.5 g/d or with blood salicylate levels less than 25 mg/dL. Liver AST and ALT levels may sometimes exceed 1000 IU/L and the discontinuation of aspirin usually results in prompt improvement of liver enzyme levels with no chronic sequelae [16]. Other drugs, used to gain or maintain remission in SLE, can have hepatotoxic side effects, as in the case of azathioprine (AZA) which may cause an asymptomatic elevation of AST/ALT, and/or ALP/GGT but hepatotoxicity due to thiopurine analogues generally presents as an increase in serum transaminase levels with toxicity generally not severe, responding to a dose reduction in most patients. NRH is a very rare but potentially severe complication of thiopurine-based therapies; this is often asymptomatic and neither biochemical nor molecular markers are indicative for NRH. The suspicion arises when there are clinical symptoms of portal hypertension, increases in transaminase levels, or thrombocytopenia and a liver biopsy is essential for definitive diagnosis [17]. Only a few anecdotal cases of hepatotoxicity induced by cyclophosphamide are reported [18] while it has been demonstrated that an exposure to a large dosage of glucocorticoids is a significant factor in the aetiology of severe fatty liver. To date, no liver side effects have been reported with rituximab and belimumab, which specifically targets B lymphocyte stimulator protein with variable effectiveness in SLE [19–21]. Anti-phospholipid syndrome Serum anti-phospholipid antibodies (aPL), the serum markers of APS, have been described in a wide range of liver diseases. APS is characterized by venous or arterial thrombosis, fetal
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loss and positivity of serum aPL, namely lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-beta2-glycoprotein I antibodies. APS-related liver manifestations are mainly of vascular origin, including thrombosis of major arterial or venous vessels based on microthrombosis; however, non-thrombotic liver injury has also been reported. Moreover, aPL have been shown to be involved in small artery intrahepatic damage and in the pathogenesis of NRH while cases of Budd Chiari syndrome (BCS) have been reported in association with APS. APS is revealed by BCS in 5% of the cases; the association of aPL positivity with BCS was described for the first time in a report dating back to 1984 [22]; since then, few more cases have been described in literature. BCS is a clinical and pathological entity characterized by structural and functional abnormalities of the liver resulting from obstruction of the outflow of hepatic venous blood [23]. Clinical symptoms may include abdominal pain, hepatomegaly and ascites, and the presentation may range from almost asymptomatic to fulminant liver failure [24]. The pathogenetic role of aPL in BCS is unclear and some authors suggested that the autoantibody production is an epiphenomenon secondary to the liver damage; however, in some cases aPL were detected before the onset of the syndrome and this strongly suggests that the aPL may be primary events [25]. It should be considered that BCS may be the first clinical manifestation of APS: this syndrome should be taken into account in the differential diagnosis of hepatic vein thrombosis. After the first report of a possible association of aPL with hepatic-veno-occlusive disease (HVOD), an unusual hepatic disorder characterized by hepatomegaly and ascites, only sporadic cases have been documented. On the other hand, several cases of histologically proven occlusion of small hepatic veins, which differs from HVOD by the absence of endophlebitis, were reported [26,27]. Hepatic infarction is a rare entity thanks to the dual blood supply to the liver; nevertheless, several cases of hepatic infarction have been reported in association with aPL [28]. aPL positivity has also been linked to hepatic artery thrombosis, a main cause of graft loss and patient mortality after liver transplantation [29,30]. There is not a uniformity of thinking about the necessity of screening for aPL in the pre-transplant workup. Even though some authors claim that aPL positivity does not identify patients at high risk for post-transplant vascular thrombosis, aPL testing in liver pre-transplant patients may be recommended. Idiopathic portal hypertension has also been rarely reported in association with aPL: microthrombi may represent a possible cause for the occurrence of portal hypertension [31]. Among non-thrombotic liver conditions, several reports demonstrated a relationship between aPL and NRH, an uncommon disorder characterized by the transformation of the liver parenchyma into nodules of hyperplastic hepatocytes without fibrosis. In one study, sera from 13 patients with histologically defined NRH were tested for aPL: 77% of the NRH patients had aPL compared with 14% of the patients with autoimmune liver diseases [32]. Although a causal relationship between aPL and NRH is not clearly established, determination of these antibodies may still be advisable in NRH. aPL positivity in patients with liver cirrhosis is reported in sporadic cases but few authors have depicted an association between the severity of alcoholic liver cirrhosis and the presence of aPL [33] and confirmed that aPL positivity is more frequent in patients with alcohol-related liver disease compared to controls and increases with the degree of histological damage, but not with the alcohol intake [33]. However, definite conclusions about this relationship cannot be drawn as in this setting aPL may reflect liver lesions and immunological dysfunction. Serum aPL are also frequently detected in PBC and PSC, being associated with a more severe liver disease. In particular, IgG and/or IgM aCL have been detected in 40% of PBC and PSC patients, compared to 2.25% of healthy controls [34]. In PBC, IgG aCL are associated with cirrhosis, increased Mayo risk score and thrombocytopenia while among PSC patients a relationship with longer disease duration and biochemical activity has been disclosed [26].
Sjogren’s syndrome Primary Sjogren syndrome (pSS) includes keratoconjunctivitis sicca, xerostomia and swelling of the salivary glands, whereas secondary SS (sSS) describes the former in association with RA. Other clinical
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features include Raynaud’s phenomenon, achlorhydria (from atrophic gastritis), alopecia, splenomegaly, and leukopenia [35]. Liver involvement is considered the most common non-exocrine feature in pSS [7,36], presenting as abnormalities of liver function tests in 27–49% of the patients [37] while hepatomegaly is found in 11–21% of patients with pSS at diagnosis. These alterations are usually mild and of little clinical significance, and may be either persistent or intermittent. A cholestatic biochemical profile is detected in 30–60% of cases, but predominantly hepatocellular or mixed patterns may also be observed [37] and in up to 50% of cases AIH or PBC are associated with pSS. When presenting as a primary disease-related internal organ involvement, liver disease in pSS is associated with inflammation markers similar to other systemic manifestations of the diseases [38]. From the hepatologist viewpoint, 47–73% of patients with PBC report sicca symptoms and 26–93% of subjects undergoing a salivary gland biopsy manifest histological changes compatible with pSS. pSS and PBC are characterized by the progressive immune-mediated destruction of the epithelial tissues of the salivary and lacrimal glands and the intra-hepatic bile ducts, respectively. The autoimmune destruction in pSS primarily affects exocrine glands and other organs [39]. Some degree of liver damage is a common finding: studies based on clinical findings and serology estimated that liver abnormalities were found in 18–20% of pSS cases to include autoimmune liver diseases and chronic viral hepatitis [40], while liver enlargement was reported during the examination in 2–20% of patients with pSS [41,42]. Of note, the salivary gland ducts of patients with PBC, independently of the presence of sicca symptoms, manifest a PBC-like immunohistochemical monoclonal AMA staining specific for the self antigen pyruvate dehydrogenase. In PBC the major target is bile duct, salivary gland epithelia and the uroepithelium, on the other hand the main target in pSS are salivary gland, bile duct, bronchial, alveolar and tubular epithelial; therefore, the two diseases are often referred to as ‘generalized autoimmune epithelitis’ [43]. Also the histological setting is similar: a predominance of lymphocytic infiltrate, mainly CD4þ, located around the bile duct in PBC and around the salivary duct in pSS. Although the serum antibodies detected in PBC and pSS are directed against ubiquitous proteins expressed in all nucleated cells, disease manifestations are organ-specific in PBC and – to a minor extent – in pSS, suggesting that the epithelia are active participants in the pathogenesis of both conditions [44]. A cellspecific lack of glutathionylation has been described in the biliary epithelial cells in PBC and in the salivary duct epithelium in pSS, in this way antigens remain intact and retain their immunogenicity during cell apoptosis [45]. Several studies have confirmed a higher prevalence of primary autoimmune liver diseases among patients with pSS [46,47]. In a study on 45 patients, a diagnosis of PBC was established in 9% of cases, while 4% of subjects were found to have AIH [42,48]. More recently, PBC was diagnosed in 7% of 410 subjects with pSS. On the other hand, 92% of pSS patients with a positivity for AMA demonstrated histologic feature consistent with PBC, suggesting the importance of AMA screening. Secondary liver disease in pSS is associated with elevated inflammatory markers, similarly to what is observed in the systemic manifestations of the diseases. In literature there are only occasional reports describing patients with pSS and PSC, suggesting that this association may be sporadic rather than causative [9]. Systemic sclerosis SSc is a chronic fibrotic immuno-mediated systemic disease that targets the skin, lungs, gastrointestinal tract, kidneys and musculoskeletal system. The disorder is characterized by the coexistence of tissue fibrosis, small blood vessel vasculopathy and an autoimmune response associated with specific autoantibodies [49]. In 1% of a large cohort of patients with SSc, a mild degree of liver involvement was observed while liver fibrosis was found in 9% of patients at autopsy, slightly more prevalent compared with non-SSc controls [50]. The association between SSc and PBC is frequent, thus suggesting a possible common pathogenetic trait [51,52]. On the other hand, the overlap syndrome between PBC and SSc warrants discussion; indeed, this is a well characterized association, being first described in 1934. Among PBC cases, 7–12% manifest scleroderma, while PBC has been reported in 2.5% of SSc cases. The prevalence in SSc
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population can be as high as 51.2% when considering patients with only biochemical liver abnormalities [53]. Most subjects with PBC–SSc overlap syndrome have limited cutaneous SSc with AMA and ACA positivity [54]. A recent study aiming to investigate the prevalence of PBC and PBC-associated autoantibodies in Japanese SSc patients detected an even higher prevalence of these two markers in the Japanese SSc population than in the Caucasian SSc population and the authors have suggested that the co-existing presence of AMA and ACA may indicate an increasing risk of PBC in SSc patients [52]. Liver disease in PBC–SSc patients may progress to cirrhosis and results in liver-related morbidity; however, mortality is more commonly ascribed to other scleroderma related complications as PBC appears to be less aggressive in comorbid cases [55]. SSc overlap syndromes with AIH and PSC have been reported only occasionally [56– 58]. Recently, it has been suggested that antibodies against centromeric protein I (CENPI, a protein localized in the inner kinetochore structure) may be a marker of concurrent autoimmune liver disease in SSC patients [59]. Myopathies Idiopathic inflammatory myopathies – polymyositis (PM) and dermatomyositis (DM) – are systemic autoimmune diseases characterized by skeletal muscle inflammation, but other organs are frequently involved such as skin in DM and lungs and heart in both PM and DM [60]. Up to 56% of patients with myositis are positive for serum autoantibodies, which can be classified as associated (present in other rheumatic disorders) or specific (positive predominantly in myositis). Among myositis-specific autoantibodies group, antisynthetase antibodies are the most commonly found and are directed against aminoacyl-transfer-RNA synthetases, a group of cytoplasmic enzymes that catalyse binding of an aminoacid to its cognate tRNA, a necessary step in the formation of polypeptides. These autoantibodies are implicated in the pathogenesis of the muscular and lung injury and directly correlate with disease activity [61,62]. Myositis, interstitial lung disease (ILD), arthritis, fever, Raynaud phenomenon and mechanic’s hands are the main characteristics of a peculiar disease named antisynthetase syndrome. ILD is especially prevalent in this syndrome and is seen in as many as 86% of anti-Jo-1-positive patients [63]. It is commonly accepted that CK, aldolase, ALT, AST and LDH are muscle-derived enzymes in myositis with levels increasing with disease activity [63,64]. Not surprisingly, patients with PM, who typically have more severe muscle disease, have higher levels of these enzymes compared to DM; furthermore, men have higher elevations in enzymes (including CK, CK-MB, CK-MM, aldolase and transaminases) compared to females reflecting their greater average muscle mass. A close correlation of some tests, particularly CK levels and transaminases, lactate dehydrogenase and aldolase, suggest that an increase of transaminases more than CK or a concomitant cholestatic parameter alterations should induce clinicians to detect a possible underlying liver disease, performing further liver evaluation in these patients [63]. Conclusions CTD and liver disease are strictly linked and rheumatologists should have some knowledge of putative liver injury mechanisms and patterns to be expected. While advanced liver disease such as cirrhosis and liver failure are rare in patients with CTD, abnormal liver function tests are quite common and liver histology may reveal a variety of subclinical liver diseases. In particular, unusual liver lesions such as NRH have been reported with increasing frequency in patients with connective tissue diseases. On the other hand, acute or progressing liver involvement is generally related to viral hepatitis reactivation or to a concomitant autoimmune liver disease. Therefore, it is of crucial importance to screen patients for HBV and HCV infection, in order to provide the ideal therapeutic regimen and avoid life-threatening reactivations. Further, patients with unexplained persistent alteration of liver biochemical profile should undergo further investigations and testing for ANA, AMA and SMA should be performed. Further, drug-induced liver injury should be considered as it is significantly more common than primary and secondary diseaserelated liver involvement.
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Practice points - Monitoring liver function tests is strongly recommended in the management of patients with CTD, especially when the patient is taking DMARDs or drugs that are potentially hepatotoxic; - Before initiating any immunomodulatory or antiinflammatory treatment patients should be evaluated for the presence of viral hepatitis or liver cirrhosis; - The presence of chronic hepatitis or liver cirrhosis does not per se increase the risk of idiosynchrasic drug reactions; - When liver function tests are altered in CTD, we recommend to first rule out a drug-induced liver injury, second to evaluate the possibility of a CTD flare or the re-activation of previous HBV or HCV infections, and finally to investigate a coexisting autoimmune liver disease. - Coexisting autoimmune liver diseases must be evaluated with serum AMA, ANA, and liver ultrasonography while a liver biopsy should be performed only in the presence of challenging diagnoses.
Research agenda - We expect that new biomarkers will be soon available to identify patients at risk for liver involvement in CTD and/or liver toxicity from anti-inflammatory drugs and encourage a common effort for clinicians and basic scientists with the available new molecular tools - Searching public and health claim databases may hold promising to identify the risks of serious liver involvement in CTD and DMARD use Conflict of interest statement The authors state that they have no conflict of interest. References [1] Selmi C, Mackay IR, Gershwin ME. The immunological milieu of the liver. Semin Liver Dis 2007;27:129–39. [2] Youssef WI, Tavill AS. Connective tissue diseases and the liver. J Clin Gastroenterol 2002;35:345–9. [3] Runyon BA, LaBrecque DR, Anuras S. The spectrum of liver disease in systemic lupus erythematosus. Report of 33 histologically-proved cases and review of the literature. Am J Med 1980;69:187–94. [4] Ohira H, Takiguchi J, Rai T, Abe K, Yokokawa J, Sato Y, et al. High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis. Hepatol Res. 2004;28:137–9. [5] Matsumoto T, Yoshimine T, Shimouchi K, Shiotu H, Kuwabara N, Fukuda Y, et al. The liver in systemic lupus erythematosus: pathologic analysis of 52 cases and review of Japanese Autopsy Registry Data. Hum Pathol 1992;23:1151–8. [6] Chowdhary VR, Crowson CS, Poterucha JJ, Moder KG. Liver involvement in systemic lupus erythematosus: case review of 40 patients. J Rheumatol 2008;35:2159–64. [7] Abraham S, Begum S, Isenberg D. Hepatic manifestations of autoimmune rheumatic diseases. Ann Rheum Dis 2004;63: 123–9. [8] Efe C, Ozaslan E, Nasiroglu N, Tunca H, Purnak T, Altiparmak E. The development of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome during the course of connective tissue diseases: report of three cases and review of the literature. Dig Dis Sci. 2010;55:2417–21. [9] Schlenker C, Halterman T, Kowdley KV. Rheumatologic disease and the liver. Clin Liver Dis 2011;15:153–64. [10] Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990;11:272–6. [11] Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs–II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993;46:1331–6. [12] Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997;26:664–9. [13] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. [14] Dart RC, Green JL, Kuffner EK, Heard K, Sproule B, Brands B. The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol - a randomized study. Aliment Pharmacol Ther 2010;32:478–86. [15] Seaman WE, Ishak KG, Plotz PH. Aspirin-induced hepatotoxicity in patients with systemic lupus erythematosus. Ann Intern Med 1974;80:1–8. [16] Miller MH, Urowitz MB, Gladman DD, Blendis LM. The liver in systemic lupus erythematosus. Q J Med 1984;53:401–9.
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A study of fiftyeight autopsy cases and fifty-eight matched controls. Am J Med 1969;46:428–40. [51] Hudson M, Rojas-Villarraga A, Coral-Alvarado P, Lopez-Guzman S, Mantilla RD, Chalem P, et al. Polyautoimmunity and familial autoimmunity in systemic sclerosis. J Autoimmun 2008;31:156–9. [52] Imura-Kumada S, Hasegawa M, Matsushita T, Hamaguchi Y, Encabo S, Shums Z, et al. High prevalence of primary biliary cirrhosis and disease-associated autoantibodies in Japanese patients with systemic sclerosis. Mod Rheumatol 2012;22: 892–8.
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Best Practice & Research Clinical Gastroenterology
6
Liver abnormalities in connective tissue diseases Maria De Santis, MD, PhD, Physician Scientist a, b, Chiara Crotti, MD, Physician a, Carlo Selmi, MD, PhD, Assistant Professor of Rheumatology a, b, * a
Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy BIOMETRA Department, University of Milan, Milan, Italy
b
a b s t r a c t Keywords: Systemic lupus erythematosus Autoimmune liver disease Viral hepatitis
The liver is a lymphoid organ involved in the immune response and in the maintenance of tolerance to self molecules, but it is also a target of autoimmune reactions, as observed in primary liver autoimmune diseases (AILD) such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Further, the liver is frequently involved in connective tissue diseases (CTD), most commonly in the form of liver function test biochemical changes with predominant cholestatic or hepatocellular patterns. CTD commonly affecting the liver include systemic lupus erythematosus, antiphospholypid syndrome, primary Sjögren’s syndrome, systemic sclerosis, dermatomyositis, polimyositis, and antisynthetase syndrome, while overlap syndromes between AILD and CTD may also be diagnosed. Although liver cirrhosis and failure are extremely rare in patients with CTD, unusual liver conditions such as nodular regenerative hyperplasia or Budd–Chiari syndrome have been reported with increasing frequency in patients with CTD. Acute or progressing liver involvement is generally related to viral hepatitis reactivation or to a concomitant AILD, so it appears to be fundamental to screen patients for HBV and HCV infection, in order to provide the ideal therapeutic regimen and avoid life-
Abbreviations: CTD, connective tissue disease; AILD, autoimmune liver disease; SLE, systemic lupus erythematosus; pSS, primary Sjogren syndrome; SSc, systemic sclerosis; PM, polymiositis; DM, dermatomyositis; AS, anti-syntehase syndrome; NRH, nodular regenerative hyperplasia.
* Corresponding author. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Suite 6515, Davis, CA 95616, USA. Tel.: þ1 530 752 2884; fax: þ1 530 752 4669. E-mail addresses: [email protected], [email protected] (C. Selmi). 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.016
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threatening reactivations. Finally, it is important to remember that the main cause of biochemical liver abnormalities in patients with CTD is a drug-induced alteration or coexisting viral hepatitis. The present article will provide a general overview of the liver involvement in CTD to allow rheumatologists to discriminate the most common clinical scenarios. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The liver represents the largest lymphoid organ, being involved in the immune response against pathogens and in the maintenance of tolerance to self molecules [1]. Nevertheless, it can also be a target of autoimmune reaction, as observed in primary liver autoimmune diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). From a rheumatologist viewpoint, the liver is frequently affected by connective tissue diseases (CTD), particularly when the affection is mirrored by liver test abnormalities and may produce a biochemical picture with the predominance of cholestatic (with elevated alkaline phosphatase [ALP] and gamma-glutamyl transferase [GGT]) or hepatocellular (with elevated alanine transaminase [ALT] and aspartate transaminase [AST]) damage. We should also note, however, that advanced disease with liver cirrhosis and failure is extremely rare in patients with CTD (Table 1). In systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and primary Sjögren’s syndrome (pSS), serologic liver test alterations and histological lesions have been described in numerous descriptive studies mostly based on case series. The prevalence of autoimmune liver disease (AILD) in CTD is described by Table 2. In the majority of the cases, liver histology will demonstrate only minor changes and the biochemical findings can be ascribed to the primary affection, even though, in a small number of patients an overlap syndrome with a coexisting primary liver disease should not be overlooked. In this setting, the liver damage is usually progressive, frequently complicated by cirrhosis and portal hypertension. Nevertheless, the main cause of biochemical liver abnormalities in patients with CTD is the presence of previous treatments with potentially hepatotoxic drugs or coexisting viral hepatitis. Systemic lupus erythematosus SLE is a multiorgan CTD classically associated to skin rash, glomerulonephritis, serositis, haematological and central nervous system abnormalities. The liver is generally not a major target organ for damage and, as such, abnormalities of liver function are not included in the classification and diagnostic criteria of SLE. Nevertheless, abnormal liver function tests are common in SLE, being found in up to 50% of patients at some point of the disease course [2] and the main causes are disease activity and drug toxicity and only rarely an overlapping primitive autoimmune liver disease. In 20% of cases liver test abnormalities occur during disease flares, while in 23% of SLE cases with abnormalities in liver functions no cause for pathological liver tests can be identified [3]. Elevated liver tests has been shown to correlate with disease activity and to improve with steroid treatment and a chronic active hepatitis – termed ‘lupoid hepatitis’ by some authors – is described in up to 5% of patients with SLE. Antibodies to ribosomal P protein has been shown to strongly correlate with lupus hepatitis, being detected in a significant proportion of patients (69%) [4]. In this setting, histology demonstrates predominantly mild lobular inflammation without piecemeal necrosis. There are no clear recommendations about the opportunity to perform a liver biopsy: we suggest this procedure when there is an increase of Table 1 Prevalence of liver injury in the most common connective tissue diseases. Disease
Enzyme alterations
Biochemical profile
Histologic alterations
Sjogren’s syndrome SLE Systemic sclerosis
50% 30% 1%
cholestatic > hepatocellular cholestatic < hepatocellular cholestatic > hepatocellular
18% 20% 9%
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Table 2 Prevalence of autoimmune liver disease in connective tissue diseases.
SLE aPL pSS SSc PM/DM/AS
PBC
AIH
PSC
References
2.7–15% 1 case 35–57% 51.2% 14.3%
2.7–20% 4 cases 6–47% 11 cases 7.1%
1 case 1 case 11 cases 1 case –
[6,8,65] [66–68] [8,48,69] [8,54] [70]
transaminases in the absence of other causes (no evidence of disease activity or drug induced liver toxicity) or when an overlapping primitive autoimmune liver disease is suspected. Numerous liver histopathological patterns can be found in SLE, including small artery vasculitis reported in up to 21% of the patients [5], nonalcoholic fatty liver diseases in 20–73%, nodular regenerative hyperplasia (NRH) in 5.7%, chronic persistent or active hepatitis in 2.4%, and cirrhosis or fibrosis in 1.1% [5,6]. Moreover, anecdotal cases of giant cell hepatitis, granulomatous hepatitis, massive liver necrosis, cholangitis, isolated portal hypertension, Budd–Chiari syndrome, and liver ischaemia have also been described. End-stage liver disease is an exceptional finding [7], while cases of Budd–Chiari syndrome are mostly associated with anti-phospholipid syndrome (APS), as will be discussed below. In patients with SLE, overlap syndromes with AIH or PBC have been reported with a similar prevalence (2.7%) and a family history for SLE is independently correlated with PBC in a large case control study [8]. In some cases, it may be difficult to discriminate AIH and SLE-associated hepatitis, given the common clinical and serologic presentation and histology may thus be of help [9]. Almost all drugs in the armamentarium against SLE or other rheumatologic diseases may cause liver toxicity, as represented by non-steroidal antiinflammatory drugs (NSAID). NSAID-related liver injury is usually mild, reversing at drug cessation and the diagnosis may be challenging also with the use of probability criteria; in fact, even for experts, the diagnosis of drug-induced liver injury (DILI) can be problematic. Specific instruments such as the Roussel-Uclaf Causality Assessment Method (RUCAM), the Maria and Victorino method and the Naranjo scale have been developed to offer more objective diagnostic strategies. In a head-to-head comparison of these instruments, RUCAM has been found to perform best for diagnosing hepatotoxicity, but it is cumbersome and therefore rarely used in clinical practice [10–13]. The appearance of NSAID-induced liver injury appears to be dose-independent, while the risk of liver-injury following acetaminophen intake is now well defined and recognized as dose-dependent [14]. One exception is the dose-dependent liver damage from salicylate that may also be a factor in producing some of the liver dysfunction associated with SLE and other collagen vascular diseases [15]. Liver injury is not evident at aspirin doses lower than 2.5 g/d or with blood salicylate levels less than 25 mg/dL. Liver AST and ALT levels may sometimes exceed 1000 IU/L and the discontinuation of aspirin usually results in prompt improvement of liver enzyme levels with no chronic sequelae [16]. Other drugs, used to gain or maintain remission in SLE, can have hepatotoxic side effects, as in the case of azathioprine (AZA) which may cause an asymptomatic elevation of AST/ALT, and/or ALP/GGT but hepatotoxicity due to thiopurine analogues generally presents as an increase in serum transaminase levels with toxicity generally not severe, responding to a dose reduction in most patients. NRH is a very rare but potentially severe complication of thiopurine-based therapies; this is often asymptomatic and neither biochemical nor molecular markers are indicative for NRH. The suspicion arises when there are clinical symptoms of portal hypertension, increases in transaminase levels, or thrombocytopenia and a liver biopsy is essential for definitive diagnosis [17]. Only a few anecdotal cases of hepatotoxicity induced by cyclophosphamide are reported [18] while it has been demonstrated that an exposure to a large dosage of glucocorticoids is a significant factor in the aetiology of severe fatty liver. To date, no liver side effects have been reported with rituximab and belimumab, which specifically targets B lymphocyte stimulator protein with variable effectiveness in SLE [19–21]. Anti-phospholipid syndrome Serum anti-phospholipid antibodies (aPL), the serum markers of APS, have been described in a wide range of liver diseases. APS is characterized by venous or arterial thrombosis, fetal
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loss and positivity of serum aPL, namely lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-beta2-glycoprotein I antibodies. APS-related liver manifestations are mainly of vascular origin, including thrombosis of major arterial or venous vessels based on microthrombosis; however, non-thrombotic liver injury has also been reported. Moreover, aPL have been shown to be involved in small artery intrahepatic damage and in the pathogenesis of NRH while cases of Budd Chiari syndrome (BCS) have been reported in association with APS. APS is revealed by BCS in 5% of the cases; the association of aPL positivity with BCS was described for the first time in a report dating back to 1984 [22]; since then, few more cases have been described in literature. BCS is a clinical and pathological entity characterized by structural and functional abnormalities of the liver resulting from obstruction of the outflow of hepatic venous blood [23]. Clinical symptoms may include abdominal pain, hepatomegaly and ascites, and the presentation may range from almost asymptomatic to fulminant liver failure [24]. The pathogenetic role of aPL in BCS is unclear and some authors suggested that the autoantibody production is an epiphenomenon secondary to the liver damage; however, in some cases aPL were detected before the onset of the syndrome and this strongly suggests that the aPL may be primary events [25]. It should be considered that BCS may be the first clinical manifestation of APS: this syndrome should be taken into account in the differential diagnosis of hepatic vein thrombosis. After the first report of a possible association of aPL with hepatic-veno-occlusive disease (HVOD), an unusual hepatic disorder characterized by hepatomegaly and ascites, only sporadic cases have been documented. On the other hand, several cases of histologically proven occlusion of small hepatic veins, which differs from HVOD by the absence of endophlebitis, were reported [26,27]. Hepatic infarction is a rare entity thanks to the dual blood supply to the liver; nevertheless, several cases of hepatic infarction have been reported in association with aPL [28]. aPL positivity has also been linked to hepatic artery thrombosis, a main cause of graft loss and patient mortality after liver transplantation [29,30]. There is not a uniformity of thinking about the necessity of screening for aPL in the pre-transplant workup. Even though some authors claim that aPL positivity does not identify patients at high risk for post-transplant vascular thrombosis, aPL testing in liver pre-transplant patients may be recommended. Idiopathic portal hypertension has also been rarely reported in association with aPL: microthrombi may represent a possible cause for the occurrence of portal hypertension [31]. Among non-thrombotic liver conditions, several reports demonstrated a relationship between aPL and NRH, an uncommon disorder characterized by the transformation of the liver parenchyma into nodules of hyperplastic hepatocytes without fibrosis. In one study, sera from 13 patients with histologically defined NRH were tested for aPL: 77% of the NRH patients had aPL compared with 14% of the patients with autoimmune liver diseases [32]. Although a causal relationship between aPL and NRH is not clearly established, determination of these antibodies may still be advisable in NRH. aPL positivity in patients with liver cirrhosis is reported in sporadic cases but few authors have depicted an association between the severity of alcoholic liver cirrhosis and the presence of aPL [33] and confirmed that aPL positivity is more frequent in patients with alcohol-related liver disease compared to controls and increases with the degree of histological damage, but not with the alcohol intake [33]. However, definite conclusions about this relationship cannot be drawn as in this setting aPL may reflect liver lesions and immunological dysfunction. Serum aPL are also frequently detected in PBC and PSC, being associated with a more severe liver disease. In particular, IgG and/or IgM aCL have been detected in 40% of PBC and PSC patients, compared to 2.25% of healthy controls [34]. In PBC, IgG aCL are associated with cirrhosis, increased Mayo risk score and thrombocytopenia while among PSC patients a relationship with longer disease duration and biochemical activity has been disclosed [26].
Sjogren’s syndrome Primary Sjogren syndrome (pSS) includes keratoconjunctivitis sicca, xerostomia and swelling of the salivary glands, whereas secondary SS (sSS) describes the former in association with RA. Other clinical
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features include Raynaud’s phenomenon, achlorhydria (from atrophic gastritis), alopecia, splenomegaly, and leukopenia [35]. Liver involvement is considered the most common non-exocrine feature in pSS [7,36], presenting as abnormalities of liver function tests in 27–49% of the patients [37] while hepatomegaly is found in 11–21% of patients with pSS at diagnosis. These alterations are usually mild and of little clinical significance, and may be either persistent or intermittent. A cholestatic biochemical profile is detected in 30–60% of cases, but predominantly hepatocellular or mixed patterns may also be observed [37] and in up to 50% of cases AIH or PBC are associated with pSS. When presenting as a primary disease-related internal organ involvement, liver disease in pSS is associated with inflammation markers similar to other systemic manifestations of the diseases [38]. From the hepatologist viewpoint, 47–73% of patients with PBC report sicca symptoms and 26–93% of subjects undergoing a salivary gland biopsy manifest histological changes compatible with pSS. pSS and PBC are characterized by the progressive immune-mediated destruction of the epithelial tissues of the salivary and lacrimal glands and the intra-hepatic bile ducts, respectively. The autoimmune destruction in pSS primarily affects exocrine glands and other organs [39]. Some degree of liver damage is a common finding: studies based on clinical findings and serology estimated that liver abnormalities were found in 18–20% of pSS cases to include autoimmune liver diseases and chronic viral hepatitis [40], while liver enlargement was reported during the examination in 2–20% of patients with pSS [41,42]. Of note, the salivary gland ducts of patients with PBC, independently of the presence of sicca symptoms, manifest a PBC-like immunohistochemical monoclonal AMA staining specific for the self antigen pyruvate dehydrogenase. In PBC the major target is bile duct, salivary gland epithelia and the uroepithelium, on the other hand the main target in pSS are salivary gland, bile duct, bronchial, alveolar and tubular epithelial; therefore, the two diseases are often referred to as ‘generalized autoimmune epithelitis’ [43]. Also the histological setting is similar: a predominance of lymphocytic infiltrate, mainly CD4þ, located around the bile duct in PBC and around the salivary duct in pSS. Although the serum antibodies detected in PBC and pSS are directed against ubiquitous proteins expressed in all nucleated cells, disease manifestations are organ-specific in PBC and – to a minor extent – in pSS, suggesting that the epithelia are active participants in the pathogenesis of both conditions [44]. A cellspecific lack of glutathionylation has been described in the biliary epithelial cells in PBC and in the salivary duct epithelium in pSS, in this way antigens remain intact and retain their immunogenicity during cell apoptosis [45]. Several studies have confirmed a higher prevalence of primary autoimmune liver diseases among patients with pSS [46,47]. In a study on 45 patients, a diagnosis of PBC was established in 9% of cases, while 4% of subjects were found to have AIH [42,48]. More recently, PBC was diagnosed in 7% of 410 subjects with pSS. On the other hand, 92% of pSS patients with a positivity for AMA demonstrated histologic feature consistent with PBC, suggesting the importance of AMA screening. Secondary liver disease in pSS is associated with elevated inflammatory markers, similarly to what is observed in the systemic manifestations of the diseases. In literature there are only occasional reports describing patients with pSS and PSC, suggesting that this association may be sporadic rather than causative [9]. Systemic sclerosis SSc is a chronic fibrotic immuno-mediated systemic disease that targets the skin, lungs, gastrointestinal tract, kidneys and musculoskeletal system. The disorder is characterized by the coexistence of tissue fibrosis, small blood vessel vasculopathy and an autoimmune response associated with specific autoantibodies [49]. In 1% of a large cohort of patients with SSc, a mild degree of liver involvement was observed while liver fibrosis was found in 9% of patients at autopsy, slightly more prevalent compared with non-SSc controls [50]. The association between SSc and PBC is frequent, thus suggesting a possible common pathogenetic trait [51,52]. On the other hand, the overlap syndrome between PBC and SSc warrants discussion; indeed, this is a well characterized association, being first described in 1934. Among PBC cases, 7–12% manifest scleroderma, while PBC has been reported in 2.5% of SSc cases. The prevalence in SSc
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population can be as high as 51.2% when considering patients with only biochemical liver abnormalities [53]. Most subjects with PBC–SSc overlap syndrome have limited cutaneous SSc with AMA and ACA positivity [54]. A recent study aiming to investigate the prevalence of PBC and PBC-associated autoantibodies in Japanese SSc patients detected an even higher prevalence of these two markers in the Japanese SSc population than in the Caucasian SSc population and the authors have suggested that the co-existing presence of AMA and ACA may indicate an increasing risk of PBC in SSc patients [52]. Liver disease in PBC–SSc patients may progress to cirrhosis and results in liver-related morbidity; however, mortality is more commonly ascribed to other scleroderma related complications as PBC appears to be less aggressive in comorbid cases [55]. SSc overlap syndromes with AIH and PSC have been reported only occasionally [56– 58]. Recently, it has been suggested that antibodies against centromeric protein I (CENPI, a protein localized in the inner kinetochore structure) may be a marker of concurrent autoimmune liver disease in SSC patients [59]. Myopathies Idiopathic inflammatory myopathies – polymyositis (PM) and dermatomyositis (DM) – are systemic autoimmune diseases characterized by skeletal muscle inflammation, but other organs are frequently involved such as skin in DM and lungs and heart in both PM and DM [60]. Up to 56% of patients with myositis are positive for serum autoantibodies, which can be classified as associated (present in other rheumatic disorders) or specific (positive predominantly in myositis). Among myositis-specific autoantibodies group, antisynthetase antibodies are the most commonly found and are directed against aminoacyl-transfer-RNA synthetases, a group of cytoplasmic enzymes that catalyse binding of an aminoacid to its cognate tRNA, a necessary step in the formation of polypeptides. These autoantibodies are implicated in the pathogenesis of the muscular and lung injury and directly correlate with disease activity [61,62]. Myositis, interstitial lung disease (ILD), arthritis, fever, Raynaud phenomenon and mechanic’s hands are the main characteristics of a peculiar disease named antisynthetase syndrome. ILD is especially prevalent in this syndrome and is seen in as many as 86% of anti-Jo-1-positive patients [63]. It is commonly accepted that CK, aldolase, ALT, AST and LDH are muscle-derived enzymes in myositis with levels increasing with disease activity [63,64]. Not surprisingly, patients with PM, who typically have more severe muscle disease, have higher levels of these enzymes compared to DM; furthermore, men have higher elevations in enzymes (including CK, CK-MB, CK-MM, aldolase and transaminases) compared to females reflecting their greater average muscle mass. A close correlation of some tests, particularly CK levels and transaminases, lactate dehydrogenase and aldolase, suggest that an increase of transaminases more than CK or a concomitant cholestatic parameter alterations should induce clinicians to detect a possible underlying liver disease, performing further liver evaluation in these patients [63]. Conclusions CTD and liver disease are strictly linked and rheumatologists should have some knowledge of putative liver injury mechanisms and patterns to be expected. While advanced liver disease such as cirrhosis and liver failure are rare in patients with CTD, abnormal liver function tests are quite common and liver histology may reveal a variety of subclinical liver diseases. In particular, unusual liver lesions such as NRH have been reported with increasing frequency in patients with connective tissue diseases. On the other hand, acute or progressing liver involvement is generally related to viral hepatitis reactivation or to a concomitant autoimmune liver disease. Therefore, it is of crucial importance to screen patients for HBV and HCV infection, in order to provide the ideal therapeutic regimen and avoid life-threatening reactivations. Further, patients with unexplained persistent alteration of liver biochemical profile should undergo further investigations and testing for ANA, AMA and SMA should be performed. Further, drug-induced liver injury should be considered as it is significantly more common than primary and secondary diseaserelated liver involvement.
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Practice points - Monitoring liver function tests is strongly recommended in the management of patients with CTD, especially when the patient is taking DMARDs or drugs that are potentially hepatotoxic; - Before initiating any immunomodulatory or antiinflammatory treatment patients should be evaluated for the presence of viral hepatitis or liver cirrhosis; - The presence of chronic hepatitis or liver cirrhosis does not per se increase the risk of idiosynchrasic drug reactions; - When liver function tests are altered in CTD, we recommend to first rule out a drug-induced liver injury, second to evaluate the possibility of a CTD flare or the re-activation of previous HBV or HCV infections, and finally to investigate a coexisting autoimmune liver disease. - Coexisting autoimmune liver diseases must be evaluated with serum AMA, ANA, and liver ultrasonography while a liver biopsy should be performed only in the presence of challenging diagnoses.
Research agenda - We expect that new biomarkers will be soon available to identify patients at risk for liver involvement in CTD and/or liver toxicity from anti-inflammatory drugs and encourage a common effort for clinicians and basic scientists with the available new molecular tools - Searching public and health claim databases may hold promising to identify the risks of serious liver involvement in CTD and DMARD use Conflict of interest statement The authors state that they have no conflict of interest. References [1] Selmi C, Mackay IR, Gershwin ME. The immunological milieu of the liver. Semin Liver Dis 2007;27:129–39. [2] Youssef WI, Tavill AS. Connective tissue diseases and the liver. J Clin Gastroenterol 2002;35:345–9. [3] Runyon BA, LaBrecque DR, Anuras S. The spectrum of liver disease in systemic lupus erythematosus. Report of 33 histologically-proved cases and review of the literature. Am J Med 1980;69:187–94. [4] Ohira H, Takiguchi J, Rai T, Abe K, Yokokawa J, Sato Y, et al. High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis. Hepatol Res. 2004;28:137–9. [5] Matsumoto T, Yoshimine T, Shimouchi K, Shiotu H, Kuwabara N, Fukuda Y, et al. The liver in systemic lupus erythematosus: pathologic analysis of 52 cases and review of Japanese Autopsy Registry Data. Hum Pathol 1992;23:1151–8. [6] Chowdhary VR, Crowson CS, Poterucha JJ, Moder KG. Liver involvement in systemic lupus erythematosus: case review of 40 patients. J Rheumatol 2008;35:2159–64. [7] Abraham S, Begum S, Isenberg D. Hepatic manifestations of autoimmune rheumatic diseases. Ann Rheum Dis 2004;63: 123–9. [8] Efe C, Ozaslan E, Nasiroglu N, Tunca H, Purnak T, Altiparmak E. The development of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome during the course of connective tissue diseases: report of three cases and review of the literature. Dig Dis Sci. 2010;55:2417–21. [9] Schlenker C, Halterman T, Kowdley KV. Rheumatologic disease and the liver. Clin Liver Dis 2011;15:153–64. [10] Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990;11:272–6. [11] Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs–II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993;46:1331–6. [12] Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997;26:664–9. [13] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. [14] Dart RC, Green JL, Kuffner EK, Heard K, Sproule B, Brands B. The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol - a randomized study. Aliment Pharmacol Ther 2010;32:478–86. [15] Seaman WE, Ishak KG, Plotz PH. Aspirin-induced hepatotoxicity in patients with systemic lupus erythematosus. Ann Intern Med 1974;80:1–8. [16] Miller MH, Urowitz MB, Gladman DD, Blendis LM. The liver in systemic lupus erythematosus. Q J Med 1984;53:401–9.
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