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Liver abnormalities in rheumatic diseases
Clin Liver Dis 6 (2002) 933 – 946
Liver abnormalities in rheumatic diseases Nancy J. Walker, MD*, Robert B. Zurier, MD Division of Rheumatology, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01655, USA
Historically, the first observation of a possible association between liver disease and arthritis was made by Still in 1897, who studied the beneficial effects of jaundice in patients with rheumatoid arthritis (RA) [1]. Hench at the Mayo Clinic later observed that of 45 patients with rheumatic conditions, 22 obtained total remission, and 9 (29%) exhibited remission of joint symptoms for a mean duration of 19.5 weeks after the spontaneous onset of jaundice [2]. Interest in the therapeutic relationship between jaundice and joint disease precipitated a number of attempts to reproduce artificially the therapeutic benefits of jaundice. Infusions of bilirubin, dehydrochloic acid, and chenodeoxycholic acid produced transient relief of joint symptoms [2– 6]. Deliberate induction of viral hepatitis also provided symptom relief before the onset of jaundice in patients with RA [7]. Attempts to isolate the beneficial properties of jaundice continued: In 1949, Pinals demonstrated that hepatotoxin-induced liver injury, which resulted in severe but temporary necrotising hepatitis without jaundice, suppressed joint inflammation in rats with adjuvant induced arthritis [80]. This finding suggested that an anti-inflammatory substance was released from the damaged liver. The effect of acute liver injury on joint tissue largely is unexplained but provides a fascinating connection between the liver and joint symptoms. Because abnormalities in liver function do not always result in relief of arthritis, the use of liver injury as a therapeutic intervention is limited. Although initial liver injury transiently improves arthritis, many chronic metabolic and infectious causes of liver malfunction produce associated joint symptoms. Many severe rheumatic diseases are associated with hepatic injury by virtue of multisystem immune and inflammatory involvement. A review of the literature to determine the association between primary rheumatologic disease and associated hepatic abnormalities and the pharmaceutical interventions that are related to liver damage are presented.
This article was supported by NIH Grant T32 AR07572. * Corresponding author. E-mail address: [email protected] (N.J. Walker). 1089-3261/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 8 9 - 3 2 6 1 ( 0 2 ) 0 0 0 5 2 - 1
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Rhematologic diseases with liver abnormalities RA Rheumatoid arthritis is a chronic polyarthritis that is associated with many extra-articular features. Elevated levels of serum aminotransferases have been reported in patients with RA who are not taking systemic therapy and who do not have an alternate diagnosis that explains the increased levels of liver enzymes [8,9]. The term rheumatoid liver was coined by Kendall and colleagues in 1970 based on the finding that 26% of patients with RA had elevated levels of alkaline phosphatase that were confirmed to be of hepatic origin by correlation with serum 5-nucleotidase concentrations [10]. In 1979, a similar trend was reported by Fernandes, who observed that 35 of 100 patients with RA had elevated levels of serum alkaline phosphatase [8]. In patients who had features of sicca syndrome, 47% had elevated serum alkaline phosphatase levels, whereas only 19% of patients with normally functioning lacrimal glands had elevated levels. Additional markers of liver function, including levels of serum bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), were all within normal limits. A review of liver biopsy findings in patients with RA does not suggest a consistent structural abnormality. Most biopsy reports suggest only minor nonspecific changes. In 117 patients with RA and without extra-articular complications 35% of liver biopsy specimens were normal, 43% showed nonspecific hepatitis, and 22% were associated with fatty change [11]. In another group of 31 patients with more severe RA and biochemical evidence of liver dysfunction, 23 (74%) liver biopsy specimens had nonspecific reactive changes, 4 (13%) suggested chronic liver disease, and only 4 were normal [12]. Of the 13 patients with chronic liver disease, diagnoses of one of each of the following was made: primary biliary cirrhosis (PBC), chronic active hepatitis, alcoholic cirrhosis, and amyloidosis [12]. Because primary liver disease was found in 30% of cases, the changes that were attributed to RA may have been overestimated. Although liver biopsies are not done routinely in the management of RA, the results of most liver biopsies are consistent with chronic inflammation. These findings suggest that, except for mild elevation in levels of serum aminotransferases, liver abnormalities are not common in RA. Patients with unexplained liver abnormalities require further testing to exclude chronic active hepatitis, alcoholic cirrhosis, amyloidosis, and PBC. Felty’s syndrome Felty’s Syndrome (FS) is a rare but severe complication of RA that develops in 1% of patients and is characterized by neutropenia and splenomegaly [13]. The cause of FS is unknown. More than 90% of patients with FS are HLA-DR4 – positive, compared with 70% of patients with RA, suggesting a genetic basis [14]. It has been suggested that two mechanisms for liver involvement in patients with FS exist: (1) nodular regenerative hyperplasia (NRH) and (2) splenomegaly [15].
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NRH occurs more frequently in patients with FS. In one autopsy study, up to 35% of patients with FS and liver function abnormalities exhibited histologic evidence of NRH [16]. The pathogenesis of NRH has not been defined, but vasculitis seems to be important in the initiation and progression of the liver lesion [16,17]. Associated structural abnormalities result from distortion of liver microarchitecture caused by alternating zones of hyperplastic lobules and compressed zones that interfere with blood flow and are presumed to cause associated portal hypertension [18]. A second cause of portal hypertension is related to splenomegaly. Measurements of free and wedged hepatic venous pressure are used to stratify patients by severity and need for medical or surgical management. Hepatic venous pressure gradients (wedged-free hepatic venous pressure) greater than 12 mmHg are associated with significantly more complications, including variceal bleeds, and may be managed with splenectomy or mesocaval shunts [15]. Adult Still’s disease In 1971, it was recognized that, although rare, adults can present with a syndrome that is similar to seronegative juvenile rheumatoid arthritis with systemic manifestations [19]. Adult Still’s disease has the same clinical features as does juvenile chronic arthritis, including intermittent fever, skin rash, seronegative polyarthritis, lymphadenopathy, splenomegaly, pleuritis, and pericarditis [19]. Several liver abnormalities were noted in a 10-year retrospective study of 12 patients who fulfilled diagnostic criteria for adult Still’s disease. Fever was present in 100% of patients, and hepatomegaly was present in 41%. Abnormalities in liver function tests (LFTs) were identified in 92% of patients and included 17% of patients with levels of serum aminotransferases that were five times the normal level and 83% of patients with levels that were between two and five times the normal level. All liver abnormalities resolved spontaneously or with treatment [20]. The authors noted that, although serum aminotransferases were elevated significantly, many patients (75%) were asymptomatic. Fever and abnormal levels of serum aminotransferases suggest a diagnosis of adult Still’s disease, especially when accompanied by negative and complete evaluation for infectious disease and malignancy. Hemochromatosis The differential diagnosis in patients with inflammatory arthritis for more than 12 weeks, especially if involving the metacarpal phalangeal (MCP) joints, includes hemochromatosis. Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism in which the body accumulates excess iron [21]. Deposition of iron in a variety of tissues and organs is the hallmark of this disorder. The liver is vulnerable to iron overload, which can lead to cirrhosis, hepatoma, and liver failure [21,22]. Arthritis is the most common extrahepatic clinical manifestation of hemochromatosis, but the cause is not known [22]. Up to 50% of patients with
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hemochromatosis have arthritis; the main joints that are involved in the disease are the second and third MCP joints and the proximal interphalangeal (PIP) joints (Fig. 1) [23]. Typically, arthritis that is associated with hemochromatosis is polyarticular, involving the MCP and PIP joints; the joints of the knees, wrists, and ankles; vertebral joints; and, less commonly, the hip joints [24]. Although the arthritis is usually symmetric, unilateral presentation may occur. Pain and stiffness usually precede objective evidence of joint enlargement, deformity, restricted range of motion, and nodule formation. Synovial thickening is not typically evident. In some patients, episodes of acute synovitis that are superimposed on the more chronic changes are attributed to precipitation of calcium pyrophosphate crystals, possibly as a result of inhibition of pyrophosphatase by iron deposition in synovial lining cells [25]. Radiographic abnormalities include loss of joint space and presence of osteophytes. Arthritis worsens gradually in 75% of patients, improves in 12.5%, and stabilizes in 12.5% [24]. Joint symptoms may present before the visceral manifestations and may be the sole manifestation of hemochromatosis [26]. Even vigorous and complete iron reduction therapy usually does not lead to improvement in joint symptoms. Systemic sclerosis Systemic sclerosis (SSc) is a rare autoimmune inflammatory abnormality that is characterized by excessive deposition of collagen in several organs and in
Fig. 1. Anterior – posterior view of the hands of a 55-year-old man with hemochromatosis. The typical arthropathy that is associated with hemochromatosis, including hook-like osteophytes at the MCP joints directed proximally and periarticular demineralization, is shown. Images of the wrist (not shown) demonstrate chondrocalcinosis of the triangular fibrocartilage.
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blood vessels. Systemic and limited forms, commonly known as the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerdactyly, and telangiectasia), exist. The presence of liver disease in SSc is rare; in a large series of patients with SSc, the prevalence of liver disease did not exceed that of controls [27]. An association between SSc and the liver has been noted through the coexistence of PBC, which is believed to be an autoimmune-mediated disorder that is characterized by chronic cholestatic liver disease, progressive inflammatory destruction of the interlobular and septal bile ducts with development of periportal inflammation, fibrosis, and cirrhosis [28 – 30]. Coexistent autoimmune diseases are found in many patients with PBC, and it is not uncommon for the patient to have two or more accompanying autoimmune diseases [31,32]. In patients with PBC, the occurrence of SSc is between 3% and 50% [31 – 33]. Cases of the CREST syndrome have been reported but do not occur as frequently as does SSc [31,34]. In patients with PBC, SSc generally is mild, and morbidity is related to the progression of PBC-related liver fibrosis [35]. Studies suggest that PBC may be more frequent in patients with SSc and anticentromere antibodies than in those without them (15.8 versus 0%), but the role of these antibodies in the genesis of liver damage is not clear [12]. An immune abnormality that is common to both conditions has been proposed [12,36]. Ankylosing spondylitis Unlike SSc and RA, ankylosing spondylitis (AS) generally is not considered to be a systemic disorder and is mainly a disorder of bone remodeling in which the axial skeleton is targeted. Increased levels of serum alkaline phosphatase are not unusual and are assumed to be caused by bone in some patients [30,37 – 39]. Robinson [40] and Sheehan [38] demonstrated that a hepatic source for elevations should be considered and may be followed to assess the activity of AS. Robinson [40] followed 35 patients with AS (94% HLA-B27 – positive) for 3 months. All patients had been untreated during the previous 3 months and did not have coexisting disease, significant alcohol intake, hepatosplenomegaly, or other stigmata of chronic liver disease. Liver enzyme abnormalities were detected in 26% of patient ( P < 0.001 versus age-matched controls) and correlated directly with ESR elevations. Elevations in levels of serum alkaline phosphatase and Gamma-glutamyl transpeptidase (GGTP) suggested a hepatobiliary origin [40]. In the second part of the study, patients were allowed to take nonsteroidal antiinflammatory drugs (NSAIDs), and LFTs were performed. Alkaline phosphatase, GGTP, ESR, and immunoglobulin A (IgA) were reduced significantly in patients taking NSAIDs ( P < 0.05– 0.005). These findings suggest that the management of inflammation may improve LFT abnormalities. The authors note that alternate causes of abnormal LFTs, including incidental liver pathology, also may explain these findings. Histologic evidence was not presented. In contrast, Sheehan did not find as strong an association between liver-derived serum alkaline phosphatase and disease activity in a cohort of 11 patients [38]; however, more extra-
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axial – associated conditions were reported and medications were not limited, which may have influenced inflammation [38]. The clinical significance of increased activity of alkaline phosphatase is obscure and may reflect a nonspecific reaction to the inflammatory process. Alkaline phosphatase may be an additional biochemical indicator of disease activity in patients with AS. Vasculitis- and cryoglobulin-related arthralgias Cryoglobulins are immunoglobulins that reversibly can precipitate at reduced temperatures and are present in a variety of autoimmune, neoplastic, and infectious disorders. They can be classified according to the system proposed by Brouet in 1974; two types of cryoglobulins are described. Type I consists of a single monoclonal protein and generally is associated with multiple myeloma and macroglobulinemia. These proteins generally produce no symptoms, and true vasculitis is rare [41]. Type II cryoglobulins, or mixed cryoglobuliemias (MCs), consist of more than one class of immunoglobulins. They are the most frequent type in the Western world and account for two thirds of cryoglobulins that are detected. Type II cryoglobulinemia appears as a primary disorder or as a manifestation of some other underlying disease. One component of MC is IgM, which has antiglobulin activity (rheumatoid factor). Mixed cryoglobulins have all the properties of an immune complex. They activate the complement cascade and, when deposited in small- and medium-sized peripheral blood vessels, cause vasculitis through complement-mediated inflammation [41]. A causative role for hepatitis C virus (HCV) has been demonstrated in a large majority of patients with MC and, to a lesser degree, in patients with hepatitis B virus infection [42]. Patients with HCV often present with arthralgias, which leads to a referral to a rheumatologist. In a cohort of 1614 patients with chronic HCV infection who were followed prospectively to identify extrahepatic manifestations, 74% had rheumatic complaints, including arthralgias and myalgias [43]. A high prevalence of antinuclear antibodies (20%) was noted. Similarly, markers of autoimmunity were observed at increased rates in 224 patients with chronic HCV infection. Fifteen percent of patients had positive antinuclear antibodies versus 6% of controls. Rheumatoid factor was positive in 76%, and antismooth muscle antibodies were found in 66% of patients with HCV infection versus 3% of controls [44]. Treatment with interferon-a usually reduces cryoglobulin levels and clinical symptoms [45].
Rheumatologic disease treatment related to liver and LFT abnormalities Strict monitoring for systemic manifestations of medication intolerance has been recommended by the American College of Rheumatology [46]. The most common toxicities are outlined.
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NSAIDs In addition to widespread over-the-counter use, NSAIDs are among the most frequently prescribed medicines in the world [47,48]. These drugs are a wellknown cause of liver dysfunction, although gastrointestinal toxicities that are associated with dyspepsia and gastric or small-bowel bleeding or ulceration are the most common side effects [49 – 52]. Aspirin is toxic to the liver, whereas most other NSAIDs induce injury to the liver by an idiosyncratic reaction [6,53]. Many reports confirm that NSAIDs cause elevated levels of serum aminotransferases, with convincing episodes after rechallenge [6,47,54 – 58]. An increase in levels of aminotransferases above 1000 U/L occurs in less than 10% of cases [59]. Because NSAIDs may inhibit platelet function and prolong bleeding time, a gastrointestinal bleed can be devastating in patients with baseline liver abnormalities and impaired coagulation. Although hepatic dysfunction is rare, it is a significant concern in patients with diminished coagulation-factor function. Rheumatoid arthritis and systemic lupus erythematosus are believed to increase the risk for liver injury in patients who are treated with ibuprofen. Patients with abnormal LFTs and without clinical symptoms have had serious hepatotoxicity [60]. The value of routine LFTs for most patients receiving NSAIDS is uncertain. It is recommended that LFTs should be performed routinely in patients with intrinsic liver disease or suspected disease. Second-line therapy Hydroxychloroquine Retinal toxicity, which can lead to visual impairment, is the major toxicity associated with hydroxychloroquine (HCQ) [61,62]. Retinal toxicity seems to be more common in patients older than 70 years in whom the cumulative dose is greater than 800 g. The greater risk presumably is caused by the increased prevalence of macular disease in the elderly [62]. A daily HCQ dosage of greater than 6.0 to 6.5 mg/kg also may be associated with an increased risk for retinal toxicity, particularly in patients with abnormal hepatic or renal function [61,63]. Hydroxychloroquine is far less toxic than are other antirheumatic agents [64]. Less serious side effects of HCQ include gastrointestinal symptoms, myopathy, blurred vision, accommodation difficulty, abnormal skin pigmentation, and peripheral neuropathy. Sulfasalazine Sulfasalazine (SSZ) has been used extensively for the treatment of ulcerative colitis and RA. The most serious consequences of SSZ use are hematologic toxicities, which include leukopenia (1% – 3% of patients), thrombocytopenia (rare), hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, agranulocytosis (rare), and aplastic anemia (rare) [65]. More common but less serious toxicities include skin rashes, photosensitivity, headaches, mood alterations, and gastrointestinal symptoms, such as nausea, vomiting, anorexia, abdom-
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inal pain, dyspepsia, and indigestion. These reactions are often dose dependent, and dose reduction can be effective in reducing most of these adverse events. Hepatic failure is rare but has been reported as an adverse drug event with SSZ use. The mechanism is unclear but possibly is related to a hypersensitivity reaction to the sulfapyridine component of the drug [66]. Although the signs of symptoms of a hypersensitivity reaction, including generalized erythematous rash and fever, dissipate a few days after SSZ withdrawal, unpredictable progression of liver injury has been noted [67]. Hepatotoxicity is related to the daily dosage of SSZ, and risk seems to increase when the dosage is greater than 1.5 g/d [68,69]. Potentially dangerous hepatic side effects warrant regular monitoring of LFTs, especially during the first 3 months of therapy, which is when most serious reactions have been noted to occur [69]. Prompt recognition of the reaction and discontinuation of SSZ treatment are of the utmost importance, because degree of hepatic injury cannot be predicted. Glucocorticoids In addition to promoting gluconeogenesis in the liver, glucocorticoids enhance cholesterol synthesis, particularly by increasing levels of low-density lipoprotein cholesterol and decreasing levels of high-density lipoprotein cholesterol [59,70]. This side effect is worrisome for patients with inflammation-mediated atherosclerosis and who are at increased risk for coronary events. It has been recommended that for patients with rheumatic diseases, atherosclerosis risk factors should be modified to the same degree as for patients with diabetes [71]. Gold compounds and D-penicillamine With gold compounds and D-penicillamine, no frequently associated liver abnormalities have been reported. Routine hepatic monitoring with use of these drugs has not been recommended by the American College of Rheumatology [46]. Disease-modifying antirheumatic drugs Collectively, disease-modifying antirheumatic drugs have been shown to alter disease progression through the presence and worsening of radiographic evidence of joint erosions. Methotrexate The most serious liver toxicities caused by methotrexate (MTX) use include fibrosis and cirrhosis, which have been described in 1.1% of 719 patients who used MTX at mean cumulative doses of between 1.3 to 3.0 g [72]. Pneumonitis and myelosuppression are additional serious manifestations. The development of serious liver disease can remain unrecognized until the late clinical findings of hepatic decompensation are present [73]. Independent risk factors for development of serious liver disease include biopsy-proven cirrhosis or clinical evidence of liver disease, such as ascites, esophageal varices, or hepatic encepha-
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lopathy. In patients with RA, age and duration of therapy have been identified as independent risk factors in a case-control study [74,75]. Other potential risk factors for hepatic toxicity include obesity, diabetes, alcohol intake, and previous history of HCV or hepatitis B virus infection [74]. The galactose-elimination capacity (GEC) and aminopyrine breath test (ABT) are quantitative measures of liver function that are superior to conventional liver tests in predicting the severity of disease and survival of patients with chronic liver disease [76]. In a prospective 6-year study of quantitative liver function in 117 patients with RA who received a mean weekly MTX dose of 11.8 mg (range, 5.4 –20 mg), risk factors for impaired liver function were not identified. Although declines in GEC and ABT results were greater in MTX recipients than in agematched controls, these tests were not helpful in detecting early stages of MTXinduced liver toxicity or in identifying the subgroup of patients who will progress to hepatic fibrosis and cirrhosis. Prevention of hepatic fibrosis and cirrhosis includes avoidance of MTX use in patients with liver disease or with another important risk factor. In patients with suspected liver disease, a pretreatment liver biopsy should be obtained. Prevention also includes abstinence from alcohol during treatment with MTX. Once an accepted means to monitor for MTX-associated liver toxicity, routine surveillance liver biopsies are no longer recommended for patients with RA who receive MTX in the recommended doses [77]. Results of liver biopsies examined from a large cohort of patients with RA suggested that routine biopsy is not a cost-effective means of monitoring, at least for the first 10 years of therapy, in patients without abnormal LFTs. Liver biopsy is recommended for patients with LFT abnormalities that persist during MTX treatment or after discontinuation of treatment [74,77]. Lef lunomide Leflunomide (Arava, Aventis Pharmaceuticals Bridgewater, NJ) is a new disease-modifying agent that became available in the United States in April 2000. This medication seems to work by inhibiting pyrimidine metabolism through dihydroorotate dehydrogenase, thereby inhibiting de novo synthesis of uridine, which leads to reduced proliferation of activated lymphocytes. In a 52-week, open-label study in 30 patients with RA whose disease remained active despite therapy with MTX, 10 to 20 mg of leflunomide were added. Of the 23 patients who completed 1 year of therapy, 16 (53%) met American College of Rheumatology (ACR) 20 response criteria, and 2 patients met ACR criteria for remission. The combination generally was well tolerated, although levels of liver enzymes (AST, ALT) were elevated more than 1.2 times the upper limit of normal in nine patients. Three patients discontinued the study because of persistent elevation in serum aminotransferase levels [75]. Leflunomide is not recommended in patients with significant hepatic impairment or evidence of HCV or hepatitis B virus infection because of the risk for increased hepatotoxicity. New guidelines for the monitoring of leflunomide therapy include assessment of liver enzymes every 2 months.
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Other new agents Major advances have been made in the treatment of patients with RA. These new agents collectively are known as biologics, influence the inflammatory cascade at specific sites, and are accepted treatment options in patients who do not respond to the agents described earlier. Agents that block the action of tumor necrosis factor a (TNFa) include etanercept (Enbrel, Wyeth Pharmaceuticals Philadelphia, PA), a soluble TNFa receptor, and infliximab (Remicade, Centocor, Inc, Malvern, PA), an anti-TNFa monoclonal antibody. Although both agents show promise in the management of patients with RA and other rheumatic conditions, precautions regarding systemic infections have emerged [78]. As of July 2001 more than 270,000 patients had been exposed to etanercept or infliximab worldwide [79]. Reports of tuberculosis Mycobacterium tuberculosis (M.Tb) and other opportunistic infections were observed infrequently in patients taking TNF inhibitors. M.Tb has been reported in 82 infliximab-treated and 11 etanercepttreated patients worldwide. Eighty percent of the infliximab cases occurred outside of the United States and predominantly occurred in Europe and Norway. These concerns have led to recommendations for M.Tb screening before treatment with TNFa agents.
Summary Abnormalities of LFTs and liver function occur not infrequently in patients with rheumatic conditions, and many diagnostic possibilities exist. Systemic inflammation that is related to uncontrolled rheumatic disease and periods of disease remission have been described as a cause for fluctuations in levels of serum aminotransferases. Although these benign extra-articular manifestations of rheumatic disease are the most common manifestations, more serious hepatic involvement, including vasculitis, nodular regenerative hyperplasia, and primary biliary cirrhosis, have been observed in specific rheumatic diseases. The cause of rheumatic disease is unclear. Occult HCV infection and associated cryoglobulinemia can mimic rheumatic disease. HCV infection should be suspected routinely in patients with mixed cryoglobulinemia, especially because antiviral therapy may be beneficial. The medical management of rheumatic disease involves medications that are often hepatotoxic. Routine laboratory monitoring, imaging studies, and, if necessary, biopsy examination in situations in which serum aminotransferases remain abnormal, are recommended.
Acknowledgments The authors thank Dr. Richard Waite for his interpretation and Dr. Ralph Schumacher for providing the radiographic image.
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[25] Alexander GM, Dieppe PA, Doherty M, et al. Pyrophosphate arthropathy: a study of metabolic associations and laboratory data. Ann Rheum Dis 1982;41:377 – 81. [26] Hamilton EBD, Bomford AB, Laws JW, et al. The natural history of arthritis in idiopathic hemochromatosis. QJM 1981;50:321 – 9. [27] Medsger Jr. TA, Masi AT. Epidemiology of systemic sclerosis. Ann Inter Med 1971;74:714 – 21. [28] Kaplan MM. Primary biliary cirrhosis. N Engl J Med 1996;335:1570 – 80. [29] Poupom R, Poupon RE. Primary biliary cirrhosis. In: Zakim D, Boyer TD, editors. Hepatology. 3rd edition. Philadelphia: WB Saunders; 1996. p. 1329 – 65. [30] Rose S, Young M, Reynolds J. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin N Am 1998;27:563 – 94. [31] Clark AK, Galbraith RM, Hamilton EBD, et al. Rheumatic disorders in primary biliary cirrhosis. Mayo Clin Proc 1978;37:42 – 7. [32] Culp KS, Fleming CR, Duffy J, et al. Autoimmune associations in primary biliary cirrhosis. Mayo Clinic Proc 1982;57:365 – 70. [33] Reynolds TB, Denison EK, Frankl HD, et al. Primary biliary cirrhosis with scleroderma, Raynaud’s phenomenon, and telangiectasia: a new syndrome. Am J Med 1971;50:302 – 12. [34] Marasini M, Gagetta V, Rossi V, et al. Rheumatologic disorders in primary biliary cirrhosis: an appraisal of 170 patients. Ann Rheum Dis 2001;60:1046 – 9. [35] Katz J, Lichtenstein G. Rhematologic manifestations of gastrointestinal diseases. Gastroenterol Clin North Am 1997;27:533 – 63. [36] Akimoto S, Ishikawa O, Takagi H, et al. Immunological features of patients with primary biliary cirrhosis: a comparison with patients with PBC alone. J Gastroenterol Hepatol 1998;13: 897 – 901. [37] Kendall M, Lawrence D, Shuttleworth G, Whitfield A. Hematology and biochemistry of ankylosing spondylitis. BMJ 1973;ii:235 – 7. [38] Sheehan N, Slavin B, Kind P, et al. Increased serum alkaline phosphatase activity in ankylosing spondylitis. Ann Rheum Dis 1983;42:563 – 5. [39] Smith D, Spencer D, Allam B, et al. Serum alkaline phosphatase in ankylosing spondylitis. J Clin Pathol 1979;32:853 – 4. [40] Robinson AC, Teeling M, Casey E. Hepatic function in ankylosing spondylitis. Ann Rheum Dis 1983;42:550 – 2. [41] Hunder G. Vasculitis. Clinical and laboratory features. In: Primer on the rheumatic diseases. 11th edition. Atlanta: Arthritis Foundation; 1997. p. 294 – 300. [42] Ferri C, Zignego A. Relation between infection and autoimmunity in mixed cryoglobulinemia. Curr Opin Rheumatol 2000;12:53 – 60. [43] Cacoub P, Thierry P, Ghillani P. Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 1999;42:2204 – 12. [44] Clifford B, Donahue D, Smith L, Cable E, et al. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995;21:613 – 9. [45] Akriviadis E, Xanthakis I, Navrozidou C. Prevalence of cryoglobuliniemia in chronic hepatitis C virus infection and response to treatment with interferon a. J Clin Gastroenterol 1997;25: 612 – 8. [46] American College of Rheumatology Ad Hoc Committee. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:723 – 31. [47] Carson JL, Strom BL, Duff A, et al. Safety of nonsteroidal anti-inflammatory drugs with respect to acute liver disease. Arch Intern Med 1993;153:1331 – 6. [48] Carson JL, Willet LR. Toxicity of nonsteroidal anti-inflammatory drugs: an overview of the epidemiological evidence. Drugs 1993;46S:243 – 8. [49] Butt JH, Barthel JS, Moore RA. Clinical spectrum of the upper gastrointestinal effects of nonsteroidal anti-inflammatory drugs: natural history, symptomatology, and significance. Am J Med 1988;84:5 – 14. [50] Corwin HL, Bonventre JV. Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am J Kidney Dis 1984;4:147 – 52.
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[51] Langman MJS. Ulcer complications and nonsteroidal anti-inflammatory drugs. Am J Med 1988; 84:15 – 9. [52] Soll AH, Weinstein WM, Kurata J, et al. Non-steroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med 1991;114:307 – 19. [53] Furst DE. Are there differences among nonsteroidal antiinflammatory drugs? Comparing acetylated salicylates, nonacetylated salicylates, and nonacetylated nonsteroidal antiinflammatory drugs. Arthritis Rheum 1994;37:1 – 9. [54] Banks AT, Zimmerman HJ, Ishak KG, et al. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the food and drug administration as adverse reactions. Hepatology 1995; 22:820 – 7. [55] Benson GD. Hepatotoxicity following the therapeutic use of antipyretic analgesics. Am J Med 1983;85:85 – 93. [56] Freeland GR, Northington RS, Hedrich DA, et al. Hepatic safety of two analgesics used over the counter: ibuprofen and aspirin. Clin Pharmacol Ther 1988;43:473 – 9. [57] Manoukian AV, Carson JL. Nonsteroidal anti-inflammatory drug-induced hepatic disorders. Drug Saf 1996;15:64 – 71. [58] Rodriguez LG, Williams R, Derby L, et al. Acute liver injury associated with nonsteroidal antiinflammatory drugs and the role of risk factors. Arch Intern Med 1994;154:311 – 6. [59] Petri M, Perez-Gutthann S, Spence D, et al. Risk factors for coronary artery disease in patients with sytemic lupus erythematosus. Am J Med 1992;93:513 – 9. [60] Walker AM, Bortnichak EA, Lanza L, et al. The infrequency of liver function testing in patients using nonsteroidal antiinflammatory drugs. Arch Fam Med 1995;4:24 – 9. [61] Bernstein HN. Opthalmologic considerations and testing in patients receiving long-term antimalarial therapy. Am J Med 1983;75:35 – 9. [62] Mills PV, Beck M, Power BJ. Assessment of the retinal toxicity of hydroxychloroquine. Trans Ophthalmol Soc U K 1981;101:109 – 13. [63] MacKenzie AH. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med 1983;75:40 – 5. [64] Brass EP. Hepatic toxicity of antirheumatic drugs. Cleve Clin J Med 1993;60:466 – 72. [65] Day RD. Sulfasalazine. In: Kelley WN, Harris Jr, Ruddy S, Sledge CB, editors. Textbook of rheumatology. 4th edition. Philadelphia: WB Saunders; 1993. [66] Smith MD, Gibson GE, Rowland R. Combined hepatotoxicity and neurotoxicity following sulphasalazine administration. Aust NZ J Med 1982;12:76 – 80. [67] Marinos G, Riley J, Painter D, et al. Sulfasalazine-induced fulminant hepatic failure. J Clin Gastroenterol 1992;14:132 – 5. [68] Hill ME, Gordon C, Situnayake RD, et al. Sulfasalazine induced seizures and dysphagia. J Rheumatol 1994;21:748 – 9. [69] Senturk T, Aydintug A, Duzgun N, et al. Seizures and hepatotoxicity following sulphasalazine administration. Reumatol Int 1997;17:75 – 7. [70] Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: a study of 36 necropsy patients. Am J Med 1997;58:243 – 64. [71] Manzi S, Chester M. Inflammation-mediated rheumatic diseases and atherosclerosis. Ann Rheum Dis 2000;59:321 – 5. [72] Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid arthritis patients receiving longterm methotrexate therapy: a prospective study with baseline and sequential biopsy samples. Arthritis Rheum 1989;32:121 – 7. [73] Beyeler C, Reichen J, Thomann R, et al. Quantitative liver function in patients with rheumatoid arthritis treated with low dose methotrexate: a longitudinal study. Br J Rheum 1997;36:338 – 44. [74] Walker AM, Funch D, Dreyer NA, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993;36:329 – 35. [75] Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999;42:1322 – 8.
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[76] Reichen J. Assessment of hepatic function with xenobiotics. Semin Liver Dis 1995;15:189 – 201. [77] Kremer JM, Alarcon GS, Lightfoot RW, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994;37:316 – 28. [78] Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor a monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932 – 9. [79] American College of Rheumatology. FDA Advisory Committee Reviews Safety of TNF Inhibitors 2001. Available at: http://www.rheumatology.org/research/hotline/0901tnf.html. January 7, 2002. [80] Pinals RS. Effect of hepatic injury on adjuvant arthritis. Ann Rheum Dis 1949;8:97 – 104.
Liver abnormalities in rheumatic diseases Nancy J. Walker, MD*, Robert B. Zurier, MD Division of Rheumatology, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01655, USA
Historically, the first observation of a possible association between liver disease and arthritis was made by Still in 1897, who studied the beneficial effects of jaundice in patients with rheumatoid arthritis (RA) [1]. Hench at the Mayo Clinic later observed that of 45 patients with rheumatic conditions, 22 obtained total remission, and 9 (29%) exhibited remission of joint symptoms for a mean duration of 19.5 weeks after the spontaneous onset of jaundice [2]. Interest in the therapeutic relationship between jaundice and joint disease precipitated a number of attempts to reproduce artificially the therapeutic benefits of jaundice. Infusions of bilirubin, dehydrochloic acid, and chenodeoxycholic acid produced transient relief of joint symptoms [2– 6]. Deliberate induction of viral hepatitis also provided symptom relief before the onset of jaundice in patients with RA [7]. Attempts to isolate the beneficial properties of jaundice continued: In 1949, Pinals demonstrated that hepatotoxin-induced liver injury, which resulted in severe but temporary necrotising hepatitis without jaundice, suppressed joint inflammation in rats with adjuvant induced arthritis [80]. This finding suggested that an anti-inflammatory substance was released from the damaged liver. The effect of acute liver injury on joint tissue largely is unexplained but provides a fascinating connection between the liver and joint symptoms. Because abnormalities in liver function do not always result in relief of arthritis, the use of liver injury as a therapeutic intervention is limited. Although initial liver injury transiently improves arthritis, many chronic metabolic and infectious causes of liver malfunction produce associated joint symptoms. Many severe rheumatic diseases are associated with hepatic injury by virtue of multisystem immune and inflammatory involvement. A review of the literature to determine the association between primary rheumatologic disease and associated hepatic abnormalities and the pharmaceutical interventions that are related to liver damage are presented.
This article was supported by NIH Grant T32 AR07572. * Corresponding author. E-mail address: [email protected] (N.J. Walker). 1089-3261/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 8 9 - 3 2 6 1 ( 0 2 ) 0 0 0 5 2 - 1
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Rhematologic diseases with liver abnormalities RA Rheumatoid arthritis is a chronic polyarthritis that is associated with many extra-articular features. Elevated levels of serum aminotransferases have been reported in patients with RA who are not taking systemic therapy and who do not have an alternate diagnosis that explains the increased levels of liver enzymes [8,9]. The term rheumatoid liver was coined by Kendall and colleagues in 1970 based on the finding that 26% of patients with RA had elevated levels of alkaline phosphatase that were confirmed to be of hepatic origin by correlation with serum 5-nucleotidase concentrations [10]. In 1979, a similar trend was reported by Fernandes, who observed that 35 of 100 patients with RA had elevated levels of serum alkaline phosphatase [8]. In patients who had features of sicca syndrome, 47% had elevated serum alkaline phosphatase levels, whereas only 19% of patients with normally functioning lacrimal glands had elevated levels. Additional markers of liver function, including levels of serum bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), were all within normal limits. A review of liver biopsy findings in patients with RA does not suggest a consistent structural abnormality. Most biopsy reports suggest only minor nonspecific changes. In 117 patients with RA and without extra-articular complications 35% of liver biopsy specimens were normal, 43% showed nonspecific hepatitis, and 22% were associated with fatty change [11]. In another group of 31 patients with more severe RA and biochemical evidence of liver dysfunction, 23 (74%) liver biopsy specimens had nonspecific reactive changes, 4 (13%) suggested chronic liver disease, and only 4 were normal [12]. Of the 13 patients with chronic liver disease, diagnoses of one of each of the following was made: primary biliary cirrhosis (PBC), chronic active hepatitis, alcoholic cirrhosis, and amyloidosis [12]. Because primary liver disease was found in 30% of cases, the changes that were attributed to RA may have been overestimated. Although liver biopsies are not done routinely in the management of RA, the results of most liver biopsies are consistent with chronic inflammation. These findings suggest that, except for mild elevation in levels of serum aminotransferases, liver abnormalities are not common in RA. Patients with unexplained liver abnormalities require further testing to exclude chronic active hepatitis, alcoholic cirrhosis, amyloidosis, and PBC. Felty’s syndrome Felty’s Syndrome (FS) is a rare but severe complication of RA that develops in 1% of patients and is characterized by neutropenia and splenomegaly [13]. The cause of FS is unknown. More than 90% of patients with FS are HLA-DR4 – positive, compared with 70% of patients with RA, suggesting a genetic basis [14]. It has been suggested that two mechanisms for liver involvement in patients with FS exist: (1) nodular regenerative hyperplasia (NRH) and (2) splenomegaly [15].
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NRH occurs more frequently in patients with FS. In one autopsy study, up to 35% of patients with FS and liver function abnormalities exhibited histologic evidence of NRH [16]. The pathogenesis of NRH has not been defined, but vasculitis seems to be important in the initiation and progression of the liver lesion [16,17]. Associated structural abnormalities result from distortion of liver microarchitecture caused by alternating zones of hyperplastic lobules and compressed zones that interfere with blood flow and are presumed to cause associated portal hypertension [18]. A second cause of portal hypertension is related to splenomegaly. Measurements of free and wedged hepatic venous pressure are used to stratify patients by severity and need for medical or surgical management. Hepatic venous pressure gradients (wedged-free hepatic venous pressure) greater than 12 mmHg are associated with significantly more complications, including variceal bleeds, and may be managed with splenectomy or mesocaval shunts [15]. Adult Still’s disease In 1971, it was recognized that, although rare, adults can present with a syndrome that is similar to seronegative juvenile rheumatoid arthritis with systemic manifestations [19]. Adult Still’s disease has the same clinical features as does juvenile chronic arthritis, including intermittent fever, skin rash, seronegative polyarthritis, lymphadenopathy, splenomegaly, pleuritis, and pericarditis [19]. Several liver abnormalities were noted in a 10-year retrospective study of 12 patients who fulfilled diagnostic criteria for adult Still’s disease. Fever was present in 100% of patients, and hepatomegaly was present in 41%. Abnormalities in liver function tests (LFTs) were identified in 92% of patients and included 17% of patients with levels of serum aminotransferases that were five times the normal level and 83% of patients with levels that were between two and five times the normal level. All liver abnormalities resolved spontaneously or with treatment [20]. The authors noted that, although serum aminotransferases were elevated significantly, many patients (75%) were asymptomatic. Fever and abnormal levels of serum aminotransferases suggest a diagnosis of adult Still’s disease, especially when accompanied by negative and complete evaluation for infectious disease and malignancy. Hemochromatosis The differential diagnosis in patients with inflammatory arthritis for more than 12 weeks, especially if involving the metacarpal phalangeal (MCP) joints, includes hemochromatosis. Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism in which the body accumulates excess iron [21]. Deposition of iron in a variety of tissues and organs is the hallmark of this disorder. The liver is vulnerable to iron overload, which can lead to cirrhosis, hepatoma, and liver failure [21,22]. Arthritis is the most common extrahepatic clinical manifestation of hemochromatosis, but the cause is not known [22]. Up to 50% of patients with
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hemochromatosis have arthritis; the main joints that are involved in the disease are the second and third MCP joints and the proximal interphalangeal (PIP) joints (Fig. 1) [23]. Typically, arthritis that is associated with hemochromatosis is polyarticular, involving the MCP and PIP joints; the joints of the knees, wrists, and ankles; vertebral joints; and, less commonly, the hip joints [24]. Although the arthritis is usually symmetric, unilateral presentation may occur. Pain and stiffness usually precede objective evidence of joint enlargement, deformity, restricted range of motion, and nodule formation. Synovial thickening is not typically evident. In some patients, episodes of acute synovitis that are superimposed on the more chronic changes are attributed to precipitation of calcium pyrophosphate crystals, possibly as a result of inhibition of pyrophosphatase by iron deposition in synovial lining cells [25]. Radiographic abnormalities include loss of joint space and presence of osteophytes. Arthritis worsens gradually in 75% of patients, improves in 12.5%, and stabilizes in 12.5% [24]. Joint symptoms may present before the visceral manifestations and may be the sole manifestation of hemochromatosis [26]. Even vigorous and complete iron reduction therapy usually does not lead to improvement in joint symptoms. Systemic sclerosis Systemic sclerosis (SSc) is a rare autoimmune inflammatory abnormality that is characterized by excessive deposition of collagen in several organs and in
Fig. 1. Anterior – posterior view of the hands of a 55-year-old man with hemochromatosis. The typical arthropathy that is associated with hemochromatosis, including hook-like osteophytes at the MCP joints directed proximally and periarticular demineralization, is shown. Images of the wrist (not shown) demonstrate chondrocalcinosis of the triangular fibrocartilage.
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blood vessels. Systemic and limited forms, commonly known as the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerdactyly, and telangiectasia), exist. The presence of liver disease in SSc is rare; in a large series of patients with SSc, the prevalence of liver disease did not exceed that of controls [27]. An association between SSc and the liver has been noted through the coexistence of PBC, which is believed to be an autoimmune-mediated disorder that is characterized by chronic cholestatic liver disease, progressive inflammatory destruction of the interlobular and septal bile ducts with development of periportal inflammation, fibrosis, and cirrhosis [28 – 30]. Coexistent autoimmune diseases are found in many patients with PBC, and it is not uncommon for the patient to have two or more accompanying autoimmune diseases [31,32]. In patients with PBC, the occurrence of SSc is between 3% and 50% [31 – 33]. Cases of the CREST syndrome have been reported but do not occur as frequently as does SSc [31,34]. In patients with PBC, SSc generally is mild, and morbidity is related to the progression of PBC-related liver fibrosis [35]. Studies suggest that PBC may be more frequent in patients with SSc and anticentromere antibodies than in those without them (15.8 versus 0%), but the role of these antibodies in the genesis of liver damage is not clear [12]. An immune abnormality that is common to both conditions has been proposed [12,36]. Ankylosing spondylitis Unlike SSc and RA, ankylosing spondylitis (AS) generally is not considered to be a systemic disorder and is mainly a disorder of bone remodeling in which the axial skeleton is targeted. Increased levels of serum alkaline phosphatase are not unusual and are assumed to be caused by bone in some patients [30,37 – 39]. Robinson [40] and Sheehan [38] demonstrated that a hepatic source for elevations should be considered and may be followed to assess the activity of AS. Robinson [40] followed 35 patients with AS (94% HLA-B27 – positive) for 3 months. All patients had been untreated during the previous 3 months and did not have coexisting disease, significant alcohol intake, hepatosplenomegaly, or other stigmata of chronic liver disease. Liver enzyme abnormalities were detected in 26% of patient ( P < 0.001 versus age-matched controls) and correlated directly with ESR elevations. Elevations in levels of serum alkaline phosphatase and Gamma-glutamyl transpeptidase (GGTP) suggested a hepatobiliary origin [40]. In the second part of the study, patients were allowed to take nonsteroidal antiinflammatory drugs (NSAIDs), and LFTs were performed. Alkaline phosphatase, GGTP, ESR, and immunoglobulin A (IgA) were reduced significantly in patients taking NSAIDs ( P < 0.05– 0.005). These findings suggest that the management of inflammation may improve LFT abnormalities. The authors note that alternate causes of abnormal LFTs, including incidental liver pathology, also may explain these findings. Histologic evidence was not presented. In contrast, Sheehan did not find as strong an association between liver-derived serum alkaline phosphatase and disease activity in a cohort of 11 patients [38]; however, more extra-
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axial – associated conditions were reported and medications were not limited, which may have influenced inflammation [38]. The clinical significance of increased activity of alkaline phosphatase is obscure and may reflect a nonspecific reaction to the inflammatory process. Alkaline phosphatase may be an additional biochemical indicator of disease activity in patients with AS. Vasculitis- and cryoglobulin-related arthralgias Cryoglobulins are immunoglobulins that reversibly can precipitate at reduced temperatures and are present in a variety of autoimmune, neoplastic, and infectious disorders. They can be classified according to the system proposed by Brouet in 1974; two types of cryoglobulins are described. Type I consists of a single monoclonal protein and generally is associated with multiple myeloma and macroglobulinemia. These proteins generally produce no symptoms, and true vasculitis is rare [41]. Type II cryoglobulins, or mixed cryoglobuliemias (MCs), consist of more than one class of immunoglobulins. They are the most frequent type in the Western world and account for two thirds of cryoglobulins that are detected. Type II cryoglobulinemia appears as a primary disorder or as a manifestation of some other underlying disease. One component of MC is IgM, which has antiglobulin activity (rheumatoid factor). Mixed cryoglobulins have all the properties of an immune complex. They activate the complement cascade and, when deposited in small- and medium-sized peripheral blood vessels, cause vasculitis through complement-mediated inflammation [41]. A causative role for hepatitis C virus (HCV) has been demonstrated in a large majority of patients with MC and, to a lesser degree, in patients with hepatitis B virus infection [42]. Patients with HCV often present with arthralgias, which leads to a referral to a rheumatologist. In a cohort of 1614 patients with chronic HCV infection who were followed prospectively to identify extrahepatic manifestations, 74% had rheumatic complaints, including arthralgias and myalgias [43]. A high prevalence of antinuclear antibodies (20%) was noted. Similarly, markers of autoimmunity were observed at increased rates in 224 patients with chronic HCV infection. Fifteen percent of patients had positive antinuclear antibodies versus 6% of controls. Rheumatoid factor was positive in 76%, and antismooth muscle antibodies were found in 66% of patients with HCV infection versus 3% of controls [44]. Treatment with interferon-a usually reduces cryoglobulin levels and clinical symptoms [45].
Rheumatologic disease treatment related to liver and LFT abnormalities Strict monitoring for systemic manifestations of medication intolerance has been recommended by the American College of Rheumatology [46]. The most common toxicities are outlined.
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NSAIDs In addition to widespread over-the-counter use, NSAIDs are among the most frequently prescribed medicines in the world [47,48]. These drugs are a wellknown cause of liver dysfunction, although gastrointestinal toxicities that are associated with dyspepsia and gastric or small-bowel bleeding or ulceration are the most common side effects [49 – 52]. Aspirin is toxic to the liver, whereas most other NSAIDs induce injury to the liver by an idiosyncratic reaction [6,53]. Many reports confirm that NSAIDs cause elevated levels of serum aminotransferases, with convincing episodes after rechallenge [6,47,54 – 58]. An increase in levels of aminotransferases above 1000 U/L occurs in less than 10% of cases [59]. Because NSAIDs may inhibit platelet function and prolong bleeding time, a gastrointestinal bleed can be devastating in patients with baseline liver abnormalities and impaired coagulation. Although hepatic dysfunction is rare, it is a significant concern in patients with diminished coagulation-factor function. Rheumatoid arthritis and systemic lupus erythematosus are believed to increase the risk for liver injury in patients who are treated with ibuprofen. Patients with abnormal LFTs and without clinical symptoms have had serious hepatotoxicity [60]. The value of routine LFTs for most patients receiving NSAIDS is uncertain. It is recommended that LFTs should be performed routinely in patients with intrinsic liver disease or suspected disease. Second-line therapy Hydroxychloroquine Retinal toxicity, which can lead to visual impairment, is the major toxicity associated with hydroxychloroquine (HCQ) [61,62]. Retinal toxicity seems to be more common in patients older than 70 years in whom the cumulative dose is greater than 800 g. The greater risk presumably is caused by the increased prevalence of macular disease in the elderly [62]. A daily HCQ dosage of greater than 6.0 to 6.5 mg/kg also may be associated with an increased risk for retinal toxicity, particularly in patients with abnormal hepatic or renal function [61,63]. Hydroxychloroquine is far less toxic than are other antirheumatic agents [64]. Less serious side effects of HCQ include gastrointestinal symptoms, myopathy, blurred vision, accommodation difficulty, abnormal skin pigmentation, and peripheral neuropathy. Sulfasalazine Sulfasalazine (SSZ) has been used extensively for the treatment of ulcerative colitis and RA. The most serious consequences of SSZ use are hematologic toxicities, which include leukopenia (1% – 3% of patients), thrombocytopenia (rare), hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, agranulocytosis (rare), and aplastic anemia (rare) [65]. More common but less serious toxicities include skin rashes, photosensitivity, headaches, mood alterations, and gastrointestinal symptoms, such as nausea, vomiting, anorexia, abdom-
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inal pain, dyspepsia, and indigestion. These reactions are often dose dependent, and dose reduction can be effective in reducing most of these adverse events. Hepatic failure is rare but has been reported as an adverse drug event with SSZ use. The mechanism is unclear but possibly is related to a hypersensitivity reaction to the sulfapyridine component of the drug [66]. Although the signs of symptoms of a hypersensitivity reaction, including generalized erythematous rash and fever, dissipate a few days after SSZ withdrawal, unpredictable progression of liver injury has been noted [67]. Hepatotoxicity is related to the daily dosage of SSZ, and risk seems to increase when the dosage is greater than 1.5 g/d [68,69]. Potentially dangerous hepatic side effects warrant regular monitoring of LFTs, especially during the first 3 months of therapy, which is when most serious reactions have been noted to occur [69]. Prompt recognition of the reaction and discontinuation of SSZ treatment are of the utmost importance, because degree of hepatic injury cannot be predicted. Glucocorticoids In addition to promoting gluconeogenesis in the liver, glucocorticoids enhance cholesterol synthesis, particularly by increasing levels of low-density lipoprotein cholesterol and decreasing levels of high-density lipoprotein cholesterol [59,70]. This side effect is worrisome for patients with inflammation-mediated atherosclerosis and who are at increased risk for coronary events. It has been recommended that for patients with rheumatic diseases, atherosclerosis risk factors should be modified to the same degree as for patients with diabetes [71]. Gold compounds and D-penicillamine With gold compounds and D-penicillamine, no frequently associated liver abnormalities have been reported. Routine hepatic monitoring with use of these drugs has not been recommended by the American College of Rheumatology [46]. Disease-modifying antirheumatic drugs Collectively, disease-modifying antirheumatic drugs have been shown to alter disease progression through the presence and worsening of radiographic evidence of joint erosions. Methotrexate The most serious liver toxicities caused by methotrexate (MTX) use include fibrosis and cirrhosis, which have been described in 1.1% of 719 patients who used MTX at mean cumulative doses of between 1.3 to 3.0 g [72]. Pneumonitis and myelosuppression are additional serious manifestations. The development of serious liver disease can remain unrecognized until the late clinical findings of hepatic decompensation are present [73]. Independent risk factors for development of serious liver disease include biopsy-proven cirrhosis or clinical evidence of liver disease, such as ascites, esophageal varices, or hepatic encepha-
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lopathy. In patients with RA, age and duration of therapy have been identified as independent risk factors in a case-control study [74,75]. Other potential risk factors for hepatic toxicity include obesity, diabetes, alcohol intake, and previous history of HCV or hepatitis B virus infection [74]. The galactose-elimination capacity (GEC) and aminopyrine breath test (ABT) are quantitative measures of liver function that are superior to conventional liver tests in predicting the severity of disease and survival of patients with chronic liver disease [76]. In a prospective 6-year study of quantitative liver function in 117 patients with RA who received a mean weekly MTX dose of 11.8 mg (range, 5.4 –20 mg), risk factors for impaired liver function were not identified. Although declines in GEC and ABT results were greater in MTX recipients than in agematched controls, these tests were not helpful in detecting early stages of MTXinduced liver toxicity or in identifying the subgroup of patients who will progress to hepatic fibrosis and cirrhosis. Prevention of hepatic fibrosis and cirrhosis includes avoidance of MTX use in patients with liver disease or with another important risk factor. In patients with suspected liver disease, a pretreatment liver biopsy should be obtained. Prevention also includes abstinence from alcohol during treatment with MTX. Once an accepted means to monitor for MTX-associated liver toxicity, routine surveillance liver biopsies are no longer recommended for patients with RA who receive MTX in the recommended doses [77]. Results of liver biopsies examined from a large cohort of patients with RA suggested that routine biopsy is not a cost-effective means of monitoring, at least for the first 10 years of therapy, in patients without abnormal LFTs. Liver biopsy is recommended for patients with LFT abnormalities that persist during MTX treatment or after discontinuation of treatment [74,77]. Lef lunomide Leflunomide (Arava, Aventis Pharmaceuticals Bridgewater, NJ) is a new disease-modifying agent that became available in the United States in April 2000. This medication seems to work by inhibiting pyrimidine metabolism through dihydroorotate dehydrogenase, thereby inhibiting de novo synthesis of uridine, which leads to reduced proliferation of activated lymphocytes. In a 52-week, open-label study in 30 patients with RA whose disease remained active despite therapy with MTX, 10 to 20 mg of leflunomide were added. Of the 23 patients who completed 1 year of therapy, 16 (53%) met American College of Rheumatology (ACR) 20 response criteria, and 2 patients met ACR criteria for remission. The combination generally was well tolerated, although levels of liver enzymes (AST, ALT) were elevated more than 1.2 times the upper limit of normal in nine patients. Three patients discontinued the study because of persistent elevation in serum aminotransferase levels [75]. Leflunomide is not recommended in patients with significant hepatic impairment or evidence of HCV or hepatitis B virus infection because of the risk for increased hepatotoxicity. New guidelines for the monitoring of leflunomide therapy include assessment of liver enzymes every 2 months.
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Other new agents Major advances have been made in the treatment of patients with RA. These new agents collectively are known as biologics, influence the inflammatory cascade at specific sites, and are accepted treatment options in patients who do not respond to the agents described earlier. Agents that block the action of tumor necrosis factor a (TNFa) include etanercept (Enbrel, Wyeth Pharmaceuticals Philadelphia, PA), a soluble TNFa receptor, and infliximab (Remicade, Centocor, Inc, Malvern, PA), an anti-TNFa monoclonal antibody. Although both agents show promise in the management of patients with RA and other rheumatic conditions, precautions regarding systemic infections have emerged [78]. As of July 2001 more than 270,000 patients had been exposed to etanercept or infliximab worldwide [79]. Reports of tuberculosis Mycobacterium tuberculosis (M.Tb) and other opportunistic infections were observed infrequently in patients taking TNF inhibitors. M.Tb has been reported in 82 infliximab-treated and 11 etanercepttreated patients worldwide. Eighty percent of the infliximab cases occurred outside of the United States and predominantly occurred in Europe and Norway. These concerns have led to recommendations for M.Tb screening before treatment with TNFa agents.
Summary Abnormalities of LFTs and liver function occur not infrequently in patients with rheumatic conditions, and many diagnostic possibilities exist. Systemic inflammation that is related to uncontrolled rheumatic disease and periods of disease remission have been described as a cause for fluctuations in levels of serum aminotransferases. Although these benign extra-articular manifestations of rheumatic disease are the most common manifestations, more serious hepatic involvement, including vasculitis, nodular regenerative hyperplasia, and primary biliary cirrhosis, have been observed in specific rheumatic diseases. The cause of rheumatic disease is unclear. Occult HCV infection and associated cryoglobulinemia can mimic rheumatic disease. HCV infection should be suspected routinely in patients with mixed cryoglobulinemia, especially because antiviral therapy may be beneficial. The medical management of rheumatic disease involves medications that are often hepatotoxic. Routine laboratory monitoring, imaging studies, and, if necessary, biopsy examination in situations in which serum aminotransferases remain abnormal, are recommended.
Acknowledgments The authors thank Dr. Richard Waite for his interpretation and Dr. Ralph Schumacher for providing the radiographic image.
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