Liver involvement in subjects with rheumatic disease

The liver is often overlooked as a target organ, with pathology either secondary to an underlying disease or due to the toxicity of therapies and the medical complications of extrahepatic diseases. It is thus important for the clinical rheumatologist to be aware of the diagnostic procedure to monitor liver injury. Indeed, systemic rheumatologic diseases may be associated with liver abnormalities secondary to the presence of a coexisting autoimmune liver disease (particularly primary biliary cirrhosis or autoimmune hepatitis), the direct involvement of the liver parenchyma, or the impact of medical treatments (particularly methotrexate) on the liver. In addition, the rheumatologist should be aware of the impact of immunosuppressive agents on underlying viral infections, particularly viral hepatitis. We review herein the data on the role of the liver in the clinical management of systemic rheumatic diseases.

abnor malities undergoing liver biopsy or in autoptical studies. Th e common histological features are summarized in Table 1. Chronic active hepatitis, chronic persistent hepa titis, cirrhosis, nodular regenerative hyperplasia, fi brosis, steatosis, and granulomas are the major fi ndings reported in rheumatic diseases, along with less specifi c fi ndings such as mild chronic infl ammatory cell infi ltrate of the portal space [13,14]. Vascular involvement is not uncommon and has been described as intrahepatic small vessel arteritis, Budd-Chiari syndrome, or isolated portal hypertension. Drug-induced liver injury is signifi cantly more frequent than primary disease-related liver involvement and concurrent viral hepatitis or opportunistic infections have to be ruled out in rheumatic patients. Finally, amyloidosis is a rare cause of liver involvement in chronic systemic rheumatic diseases [15].

The liver and connective tissue disease
Liver involvement in connective tissue diseases is not uncommon, but the liver is not the major organ target. In systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and primary Sjögren's syndrome (pSS), serologic liver dysfunction and histological lesions have been described in numerous descriptive studies mostly based on case series.
Abnormal liver function tests are common in patients with SLE -being reported in 3 to 29% of the patients [14], often during disease exacerbations [16]. Numerous histopathological patterns can be found in liver biopsies of SLE patients, including small artery vasculitis reported in up to 21% of the patients [17], nonalcoholic fatty liver diseases in 20 to 73%, nodular regenerative hyperplasia in 5.7%, chronic persistent or active hepatitis in 2.4%, and cirrhosis in 1.1% or fi brosis in 0.8% [17,18]. Moreover, anecdotal cases of giant cell hepatitis, granulomatous hepatitis, massive hepatic necrosis, cholangitis, isolated portal hyper ten sion, Budd-Chiari syndrome, and liver infarc tion have also been described. End-stage liver disease is a very infrequent fi nding [14], while cases of Budd-Chiari syn drome have been reported in asso ciation with anti phos pholipid syndrome. Moreover, antiphospholipid anti bodies have been shown to be involved in small artery intrahepatic damage and in the pathogenesis of nodular regenerative hyperplasia.
Gastrointestinal involvement occurs invariably in SSc. In a large cohort of patients, some minor degree of liver involvement has been reported in 1.1% of the caseswhile at autopsy liver fi brosis was found in 8.8% of patients, slightly more prevalent compared with non-SSc controls [19]. Th e association between SSc and PBC is more signifi cant and a common pathogenetic trait has been suggested [20].
Finally, liver involvement is considered the most common non-exocrine feature in pSS [14,21], presenting as abnormal liver function tests in 27 to 49% of the patients [22]. In two-thirds of the cases cholestasis is found at liver biochemistry, and in up to 50% of cases AIH or PBC is associated with pSS. When presenting as a primary disease-related internal organ involvement, liver disease in pSS is associated with infl ammation markers similar to other systemic manifestations of the diseases [23].

The liver and vasculitis
Vasculitis can aff ect every organ of the digestive system but the liver is not commonly involved. Liver involvement is limited to polymyalgia/Horton's arteritis, polyarteritis nodosa, Wegener's granulomatosis, and Behçet's disease [24]. Abnormal liver function tests commonly manifest a cholestatic pattern with elevated alkaline phosphatase and γ-glutamyl transferase levels that characterize up to 62% of patients with rheumatic polymyalgia [25]. Polymyalgic patients with elevated liver enzymes have an increased risk to develop Horton's arteritis [26]. Liver involvement occurs in a variable proportion (16 to 56%) of patients aff ected by polyarteritis nodosa, although clinical manifestations related to liver disease are quite rare; conversely, necrotizing arteritis of the liver has been found in the vast majority of patients with polyarteritis [27]. Liver injury is rare in Wegener's granulomatosis. Both granulomatous necrotizing hepatic involvement and mild nonspecifi c lobular hepatitis have been described. Liver involvement is rarely observed in patients with Behçet's disease, with a predominance of Budd-Chiari syndrome.

The liver and arthritis
Among patients with arthritis, hepatic involvement has been reported only in cases of rheumatoid arthritis (RA) and its variants. Nevertheless, liver injury is not generally recognized as a signifi cant extra-articular feature of RA. Abnormal liver tests varying with disease activity, mainly elevated alkaline phosphatase, have been reported in 18 to 50% of patients with RA. Similarly, 65% of unselected patients with RA had abnormal liver biopsies -one-half having mild portal chronic infl ammatory infi ltrate of the portal tract and small foci of necrosis, and one in four having fatty liver [28]. As in SLE, drug-induced liver injury is frequent in RA, especially during nonsteroidal anti-infl ammatory drug (NSAID) and methotrexate treatments. Liver involve ment has also been reported in Felty's syndrome as liver enlargement (68%) and a rise in alkaline phosphatase (25%). Liver histology demonstrates diff use lymphocyte infi ltrate, periportal fi brosis with lymphocytic infi ltration, and portal hypertension. Liver enlargement and elevated aminotransferases have also been reported in adult-onset Still's diseases, while liver biopsies have demonstrated aspecifi c mild portal infi ltrate of limited signifi cance [29]. Cases of acute liver failure, however, have also been reported.

The liver and overlap syndromes
Patients with signs and symptoms of two or more immunologic diseases are considered as having overlap syndromes. Overlap syndromes may include AIH and PBC or PSC, as largely reported in the literature (illustrated in Table 2); patients with overlap syndromes manifest both hepatitis and cholestatic biochemical profi les and histological features suggestive of AIH and PBC or PSC. AIH and PBC overlap syndrome has been reported in almost 10% of adults with AIH or PBC, whereas AIH and PSC overlap syndrome has been found in 1.4 to 49% of children, adolescents, and young adults with AIH or PSC. Transition from one to another liver disease is sometimes possible in a time frame of months to years [30]. While cases of anti-mitochondrial antibody-negative PBC and AIH overlap syndromes have been described, there is no clear evidence for the existence of a PBC/PSC overlap syndrome. In addition, AIH and PBC overlap syndrome has been described in patients with SLE, SSc, and pSS [31].
AIH, PBC, and PSC may develop in patients with systemic rheumatic diseases (Table 2). Th e accurate prevalence of overlap diseases is unknown because of a variety of fl aws encountered in the available prevalence studies. Th e majority of data reported only case reports, while in case series the liver histology is derived from autoptical investigations or liver biopsies performed on selected patients frequently with liver enzyme abnormalities.
While in patients with SLE the prevalence of AIH and PBC seems similar among patients with liver abnor malities, in SSc patients PBC has been reported in 51.2% of the cases with liver dysfunction [32] and in more than 50% of patients with a CREST (calcinosis, Raynaud, esophagopathy, sclerodactily, teleangectasia) variant [33], and AIH is rare -only 11 cases have been reported -while only one case of SSc/PSC comorbidity has been described.
A higher frequency of AIH and PBC has been reported in pSS patients with liver dysfunction undergoing hepatic biopsies: these rates ranged between 6 and 47% and between 35 and 57%, respectively [34]. Eleven cases of SS and PSC have been published and all of the patients also had chronic pancreatitis, while in our series SS was a frequent comorbidity condition in PBC cases [35]. A vast number of single case reports are available. As an example, AIH has been described in polymyositis/ dermatomyositis, RA, Still's disease, polymyalgia, and polyarteritis nodosa [36]. On the other hand, PBC has been described in polymyositis/dermatomyositis, RA, Still's disease, polymyalgia, Churg-Strauss's disease, micro scopic polyangiitis, Behcet's disease, and Schonlein-Henoch purpura. Finally, PSC has been exceptionally reported in association with rheumatic diseases.

The liver and medical therapies in rheumatology
Th erapeutic strategies for the treatment of autoimmune liver disease are essentially based on corticosteroids and immunosuppressant drugs such as methotrexate and azathioprine. Th e exception is provided by PBC, for which ursodeoxycholic acid (UDCA) is the only established treatment [37]. Th e combination of UDCA and immunosuppressants, albeit rational, failed to prove eff ective or suffi ciently safe in most cases. Conversely, methotrexate has been shown to be virtually void from consistent adverse eff ects in the treatment of real-life patients with or without concomitant UDCA [38] while being burdened by signifi cant side eff ects in randomized clinical trials [39]. A simpler scenario is provided by AIH, for which corticosteroids represent the cornerstone of currently utilized regimens [40]. Th is treatment should be considered for all patients with AIH regardless of the disease activity at presentation and should be continued until 24 months to achieve normalization of liver tests and, ideally, resolution of liver infl ammatory infi ltrate at histology. In cases of incomplete response or relapse, a long-term maintenance regimen with azathioprine is justifi ed. Salvage therapy includes cyclosporine or mycophenolate mofetil, although more solid data are awaited [40] and new frontier therapeutic approaches may prove benefi cial [41]. Management of overlap syndromes between PBC and AIH is empirical and guided by the predominant manifes tations of the disease. Indeed, patients with AIH and PBC with higher serum alkaline phosphatase and transaminases are candidates for treatment with corticosteroids and UDCA [42].
Of note, potential benefi ts have been proposed for anti-TNFα treatments in autoimmune liver diseases although human data are scanty. In a murine model, anti-TNFα antibodies proved to be eff ective in reducing liver infl ammation, necrosis, and fi brosis. Reports on the impact of anti-TNFα therapy in patients with infl ammatory bowel diseases or other rheumatologic diseases and concomitant liver diseases [43] demonstrated potential benefi ts for nonalcoholic steatohepatitis and PSC; however, AIH and hepatosplenic T-cell lymphoma have also been reported [43].
Several are the implications of concomitant liver disease for the therapeutic intervention in rheumatologic diseases; in fact, the liver is frequently involved in the adverse events of systemic treatments utilized in rheumatology. A complete discussion goes beyond the aims of the present review article, but it is easy to foresee that hepatitis virus reactivation and drug-related liver injuries are rapidly becoming a major cause for liver involvement in rheumatology with the use of more potent immunosuppressants such as biologics [44,45] or hematopoietic stem cell transplantation [46]. Detailed recommendations on the use of immunomodulatory molecules in patients with chronic liver disease were reported by the American College of Rheumatology in 2008 for RA [47] while the American Association for the Study of Liver Diseases also presented practice guidelines in 2009 for the manage ment of patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) chronic infection needing immuno suppres sive therapy [48,49], and clinical guidelines are available for viral hepatitis and infl ammatory bowel disease treat ment [50]. Th ese guidelines support the view that the alanine aminotransferase (ALT) level, anti-HBsAg, anti-HBsAb, anti-HBcAb IgG and, in selected cases, HBV DNA, along with anti-HCV antibodies and HCV RNA, should be tested before an immunosuppressant treatment is initiated [47,50,51]. Currently, a preventive antiviral treatment is recommended in patients with an active chronic HBV infection (HBsAg-positive, elevated ALT and serum HBV DNA levels >2,000 IU/ml) and in patients with chronic HCV infections without extrahepatic contraindications [47,50].
Prophylactic treatment is recommended in patients needing nonbiologic or biologic disease-modifying antirheumatic drugs with inactive HBV (HBsAg-positive, normal ALT and HBV DNA <2,000 IU/ml; or HBsAgnegative and anti-HBcAb-positive with or with out HBsAb, normal ALT and HBV DNA <50 IU/ml), and to be considered in resolved HBV infection (HBsAgnegative, HBsAb-positive and/or anti-HBcAb-positive, normal ALT and HBV DNA <50 IU/ml) together with monitoring of ALT levels and serum HBV DNA in cases of long-term lamivudine use [47,50]. Disease-modifying antirheumatic drugs such as methotrexate and lefl unomide are contraindicated in cirrhosis secondary to chronic HBV and HCV infections, whether treated or untreated, for all Child-Pugh stages [47], while biologics are contraindicated in both chronic HBV and HCV, whether treated or untreated, for those with signifi cant liver injury, defi ned as chronic Child-Pugh classes B or C [47]. Immunosuppressant regimens including gluco corticoids appear to have the highest risk of HBV reactivation and HCV replication, so steroid-sparing treatment should be adopted when possible although low doses appear to be safe [48]. Finally, the use of NSAIDs should be carefully evaluated in patients with liver cirrhosis regardless of the etiology based on the risk of renal injury secondary to tubular ischemia. Referral clinical immunology textbooks report the risk of liver injury related to the use of classical anti-infl ammatory treatments such as acetaminophen, NSAIDs, or methotrexate despite the rarity of such events in clinical trials [52].
Th e American College of Rheumatology guidelines indicate that when the levels of ALT are greater than twofold the upper normal limit, the initiation of diseasemodifying antirheumatic drugs such as metho trexate, lefl unomide, and sulfasalazine is contraindicated, while recommendations on when to discontinue the drug are not provided [47]. Further, recent prospective data put such risk in a more accurate perspective. As an example, the risk of liver injury following acetaminophen intake is now well defi ned and recognizes a dose-dependent increase, with doses as high as 4 g/day proven to be safe in patients with chronic viral hepatitis or recent alcohol abuse as well as in patients with compensated liver cirrhosis [53]. Conversely, the appearance of NSAIDinduced liver injury appears to be dose independent while the new scenarios of biologic-induced autoimmune hepatitis [54] will warrant further studies on the longterm outcomes. A most recent study on the impact of methotrexate on liver function tests demon strated a reasonably safe profi le for this medication if properly used [55], thus suggesting that dedicated studies are necessary to detect the detrimental potential of immunomodulatory treatments. Th e issue of drug-induced liver injury became important with the discovery of the possible implications of occult hepatitis B infection [56] and the subsequent impact on the widespread use of monoclonal antibodies [57] in carriers and cases of chronic infections [58]. Finally, we should expect that the use of hematopoietic stem cell transplantation will also impact liver biology [59,60].

The liver in the present and future of rheumatology
Among patients with systemic rheumatic diseases, those with connective tissue diseases may present a mild liver involvement mainly related to the underlying disease activity that is, subsequently, transient. Progressive liver involvement is generally related to the coexistence of viral hepatitis or autoimmune liver diseases with obviously opposite results of the proposed systemic immunosuppressive treatments. Overlap diseases should be considered once hepatitic and/or cholestatic biochemical profi les, either simultaneously or consecutively, are not clearly explained by liver involvement of a rheumatic disease or by coincidental infection or drug toxicity. Finally, we encourage perspective studies to determine the impact in clinical practice of old and new treatments on the liver biology to overcome ancient beliefs [61] and pave the way for the new exciting developments in the fi eld of biologics [62].