The Liver in Rheumatologic Practice

I wrote this review in 2003. It is useful as a guide for the main subtopics to be discussed under the topic LIVER IN RHEUMATOLOGIC PRACTICE. For a more updated review, you will need to look for another source

A. Generalized disorders affecting both the liver and joints
Connective tissue diseases
Systemic lupus erythematosus
Anti-phospholipid syndrome, mixed connective tissue disease
Polyarteritis nodosa
Temporal arteritis
Behcet’s disease
Cryoglobulinemia
Kawasaki
Infiltrative disorders
Hemochromatosis
Sarcoidosis
Amyloidosis
Mucopolysaccharidosis
Infections
Infectious mononucleosis
Hepatitis B, C
Tuberculosis
Gonorrhea
Lyme disease
Other diseases
Macroglobulinemia
Angioimmunoblastc lymphadenopathy
Weber Christian disease
Common variable immunodeficiency.
POEMS syndrome
B. Rheumatological diseases with recognized hepatic involvement
Rheumatoid arthritis
Juvenile rheumatoid arthritis
Felty’s syndrome
Adult onset still’s disease
C. Hepatic disease with recognized rheumatological involvement
Primary biliary cirrhosis (PBC)
Hepatitis C infection
HCV cryoglobulinemia
Wilson’s disease
Alcoholic cirrhosis
Gaucher’s disease
D. Common disease associations
Primary biliary cirrhosis and CREST
Primary biliary cirrhosis/Chronic active hepatitis and sicca/Sjogren’s
E. Hepatotoxic drugs used in the treatment of rheumatic disorders
Non Steroidal Anti-inflammatory Drugs (NSAIDs)
Sulfasalazine
Steroids
Paracetamol
Methotrexate
Cyclophospahamide
Gold
Penicillamine
Azathioprine
Chlorambucil
Cyclosporine
Allopurinol
Colchicine
F. Rheumatic disorders with abnormal acute phase protein response by the liver
Systemic lupus erythematosus
Systemic sclerosis

A. Generalized Disorders Affecting Both the Liver and Joints

Connective tissue diseases
Systemic lupus erythematosus
Anti-phospholipid syndrome, mixed connective tissue disease
Polyarteritis nodosa
Temporal arteritis
Behcet’s disease
Cryoglobulinemia
Kawasaki
Infiltrative disorders
Hemochromatosis
Sarcoidosis
Amyloidosis
Mucopolysaccharidosis
Infections
Infectious mononucleosis
Hepatitis B, C
Tuberculosis
Gonorrhea
Lyme disease
Other diseases
Macroglobulinemia
Angioimmunoblastc lymphadenopathy
Weber Christian disease
Common variable immunodeficiency.
POEMS syndrome

Connective Tissue Diseases
Systemic lupus erythematosus: Systemic lupus erythematosus is an autoimmune disease that affects many organ systems and is more prevalent in females.
Musculoskeletal manifestations occur in the form of fatigue that can be severe, intermittent nondestructive arthritis, arthralgias (non-deforming, non-erosive symmetric joint affection), avascular necrosis of bone, muscle disease and tenosynovitis (Kelley et al, 1997).
Liver disease:
Hepatomegaly: in 10% of patients.
Abnormal liver function tests: in 30-60% of patients due to hypersensitivity to aspirin and NSAIDs (usually ignored unless they are more than 3 fold elevated), active lupus and infection.
Jaundice: in autoimmune hemolytic anemia, occasionally due to NSIADs and azathioprine.
Ascitis: is due to liver affection (Budd Chiari in APS) or serositis or nephrotic syndrome.
Hepatic vasculitis: inflammation of small and medium sized arteries of the liver is reported in one lupus patient per thousand.
Complications of immunosuppressive therapy: Herpes simplex hepatitis: a case of HSV type 2 hepatitis has been reported in a 26-year old female with focal proliferative lupus nephropathy after having received her first pulse of high dose cyclophosphamide (1 gm / m2). Treatment with parentral acyclovir was successful. HSV hepatitis is a rare complication of HSV infection with a high reported mortality in untreated patients. The early administration of parentral acyclovir is considered to be instrumental in the achievement of a successful outcome. A patient’s serum levels of hepatic transaminases at the time of treatment initiation may predict outcome (Successful acyclovir treatment of herpes simplex 2 hepatitis in a patient with systemic lupus erythematosus: a case report and meta analysis. Chung AB; Fas N. 1998 Am J Med Sci, 316:404-7). Add to cyclophosphamide notes.

Anti-phospholipid syndrome, mixed connective tissue disease: The antiphospholipid syndrome is characterized by venous and arterial thrombosis (often multiple) and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies. Antiphospholipid antibodies are a family of autoantibodies with specificity for the complexes of negatively charged phospholipids and phospholipid binding proteins (Harris EN, Baguley E, Asherson RA, Hughes GRV: Clinical and serological features of the antiphospholipid synndrome (abstr). Br J Rheumatol 26:19, 1987). It may be primary or secondary to a variety of other autoimmune disorders, malignancies, infections or drugs. Articular involvement may occur secondary to vascular occlusion in the form of avascular necrosis of bone (Kelley et al., 1997). Mixed connective tissue disease is an overlap of SLE, polymyositis and systemic sclerosis with a high titer of anti-U1 ribonucleoprotein antibody that commonly presents with Raynaud’s phenomenon or swelling of fingers and hands. (Doria A, Ghirardello A, deZambiasi P et al: Japanese diagnostic criteria for mixed connective tissue disease in Caucasian patients. J Rheumatol 19:259-264, 1992).
Liver disease in APS and MCTD: Budd Chiari syndrome: occlusion of the main hepatic vein leading to massive vascular congestion and painful enlargement of the liver, rapid development of ascitis and portal hypertension and jaundice. Unless, therapeutic portosystemic vascular anastomosis is performed, death results.

Polyarteritis nodosa: is a vasculitic syndrome that mainly affects small and medium-sized arteries. It may affect any organ but the skin, joints and peripheral nerves, gut and kidney are most commonly involved. There is a spectrum of severity from progressive fulminant disease to limited disease. It may be primary or it may be a manifestation or complication of other diseases such rheumatoid arthritis, Sjogren’s syndrome and hepatitis B or C viruses (Kelley et al. 1997). Articular manifestations occur in the form of arthralgias or arthritis that are present in as many as 50% of patients and are attributed to small localized arterial lesions. An asymmetric episodic, non-deforming polyarthritis involving the larger joints of the lower extremity may occur in 20% of cases and is common early in the disease. (Kelley et al., 1997).
Liver disease: Liver involvement, although common in autopsy studies, is rarely detected clinically except in those cases with hepatitis B or C. The only abnormality reflecting liver involvement may be an elevated level of alkaline phosphatase without elevated bilirubin or transaminase levels.
?hepatomegaly +/- jaundice that can proceed to extensive hepatic necrosis?

Temporal arteritis: A vasculitic syndrome involving the cranial branches of the arteries originating from the arch of the aorta most prominently, but may also involve other arteries as well. Nearly all patients are older than 50 years of age when the disease develops. Though common in the United states and Europe, the disease is rare in Egypt and the Middle East (to further confirm). Musculoskeletal involvement occurs in the form of intermittent claudication that may occur in the muscles of mastication (jaw claudication), the extremities and occasionally, the muscles of the tongue or those involved in swallowing. In the jaw muscles, the discomfort is noted especially when chewing meat and may involve the muscles on one side of the mandible more than those on the other. More marked vascular narrowing may, rarely, lead to gangrene of an extremity, the scalp or the tongue.
Polymyalgia rheumatica: is a clinical syndrome characterized by aching and morning stiffness in the proximal portions of the extremities and torso. In addition, other musculoskeletal manifestations include the occurrence of synovitis involving the knees, sternoclaviculars, hips and shoulders in some patients.
Relationship between polymylagia rheumatica and giant cell arteritis: There is a high incidence of a positive association of giant cell arteritis and polymyalgia rheumatica in the same patient. In several reports of giant cell arteritis, polymyalgia rheumatica has been noted in 40 to 60% of patients and was the initial symptom complex in 20 to 40%. Conversely, in series of patients with polymyalgia rheumatica, giant cell arteritis has been found in up to 80% of the patients (Hunder GG, Allen GL: Giant cell arteritis: A review. Bull Rheum 29:980, 1978-79).
Liver disease: Tests of liver functions have been found to be mildly abnormal in approximately one third of patients with giant cell arteritis and slightly less in polymyalgia rheumatica. An increased level of ALP is the most common abnormality in increases in AST and prolonged prothrombin time may also be found (Dickson ER, Maldonado JE, Sheps SG, Cain JA Jr: Systemic giant cell arteritis with polymyalgia rheumatica: Reversible abnormalities of liver function. JAMA 224:1496, 1973). Liver biopsy specimens are generally normal but granulomatous hepatitis has been observed (Calamia KT, Hunder GG: Giant cell arteritis presenting as fever of unknown origin. Arthritis Rheum 24:1414, 1981).

Behcet’s disease: All the events in Behcet’s disease are episodic but sequels can be severe. Articular manifestations include seldom destructive mono or oligoarthrtis of the knees, ankles, wrists and hands that lasts for weeks. Occasionally, sacroiliitis may be present only in patients who are HLA-B27 positive.
Liver disease: Hepatic vein occlusion extending from the IVC resulting in Budd Chiari syndrome that presents with ascitis or frank liver failure.

Cryoglobulinemia: Liver affection is in the form of hepatomegaly.
In mixed cryoglobulinemia, the prevalence and the degree of hepatic involvement does not differ between HBV+ve and HBV-ve patients. Hepatitis is the result of a localized “spillover” of immune complexes from Kuppfer’s cells saturated by cryoglobulins. This is suggested by the demonstration of impaired clearance of immune complexes in these patients and by the beneficial effect of on the clinical manifestations after plasmapharesis and a low antigen content diet.
If HCV is the cause, it is possible that the virus which is both hepatotoxic and lymphotropic may cause hepatic damage through a direct cytotoxic or immune mediated mechanism. That is why alpha interferon which is both an antiviral and an immuno-modifier factor reduces hepatic involvement.

Kawasaki: An acute febrile illness associated with systemic vasculitis that primarily infants and young children that is probably mediated by some as yet unidentified infectious vector. Articular manifestation occur in the form of arthritis or arthralgias.
Liver disease: is relatively uncommon and occurs in the form of hydrops of the gallbladder and jaundice.
Increase in liver enzymes may occur.

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Infiltrative Disorders
Hemochromatosis
Sarcoidosis
Amyloidosis
Mucopolysaccharidosis
Hemochromatosis: Hemochromatosis coexistent with hepatitis C infection has been reported in a patient who was misdiagnosed as rheumatoid arthritis at the onset of his disease. His symptoms began at the age of 44 years with pain of the hand joints, shoulders, hips and knees and positive rheumatoid factor. Four years later her required replacement of both hips due to severe hip disease Abnormalities in liver function were noted early on, but they were attributed to infection with hepatitis C virus, detected serologically and by PCR. The correct diagnosis was delayed until a decision to use methotrexate as treatment for his arthritis led to a liver biopsy, which revealed increased iron deposition consistent with hemochromatosis, confirmed by genetic testing which confirmed that the patient was homozygous for the C282Y mutation of the JHLA-H gene (Diagnostic confusion caused by hepatitis C: hemochromatosis presenting as rheumatoid arthritis. Espinosa-Morales R, Escalante A. J Rheumatolo, 25: 2459-63, Dec 1998)

Sarcoidosis: noncaseating epithelioid granulomas scattered throughout the liver. Confluent granulomas may also be present in cases with more severe hepatic involvement. The characteristic inclusions in giant cells (e.g. Schaumann bodies and asteroid bodies) are not seen in all cases and are not pathognomonic. The granulomas of sarcoidosis may heal without a trace, but confluent granulomas can result in extensive irregular scarring.
Portal hypertension: occlusion of intrahepatic portal vein branches by the granulomatous inflammation probably accounts for the development of portal hypertension in some cases.
Cholestasis: a granulomatous cholangitis leading to ductopenia seems to be the underlying pathogenetic mechanism of the chronic cholestatic syndrome of sarcoidosis. Obstructive jaundice and Budd-Chiari syndrome due to hepatic hilar lymphadenopathy or strictures of the bile ducts may also occur.
A case of hepatic sarcoidosis with a sclerosing cholangitis-like picture but without any pulmonary involvement has been reported in a male patient. The patient was treated with prednisolone and cyclophosphamide. Interestingly, four years later, the patient developed renal adenocarcinoma which was attributed to cyclophosphamide treatment. Although, long-term cyclophosphamide treatment is known to be associated with malignancy, this was the second reported case of its association with renal adenocarcinoma. (Hepatic sarcoidosis and renal carcinoma. Das D, Smith A, Warnes TW. J Clin Gastroenterol 28:61-3, Jan 1999).

Amyloidosis: massive hepatomegaly, intrahepatic cholestasis with severe jaundice is a poor prognostic sign.
Mucopolysaccharidosis: hepatomegaly.

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Infections
Infectious mononucleosis
Hepatitis B, C
Tuberculosis
Gonorrhea: perihepatitis.
Lyme disease: mild recurrent hepatitis.

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Other Diseases
Macroglobulinemia
Angioimmunoblastc lymphadenopathy
Weber Christian disease
Common variable immunodeficiency.
POEMS syndrome: a case of veno-occlusive disease of the liver has been reported in patient with POEMS syndrome: After 3 years of treatment with cyclophosphamide and steroids for POEMS syndrome, a 58 year old man developed hepatalgia, edema, ascitis and jaundice. The diagnosis of hepatic veno-occlusive disease was obtained by hepatic biopsy. Refractory ascitis was treated by transjugular intrahepatic potrosystemic shunt. Gradual improvemetn in clinical status was observed after this therapy. (Veno-occlusive disease of the liver and POEMS syndrome. Andr’es E, Kaltenbach G, Goichot B, Lioure B, Gerget M, Schlienger JL, Imler M. Presse Med, 28:334-6, Feb 20, 1999).

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B. Rheumatological Disease with Recognized Hepatic Involvement

Rheumatoid arthritis
Juvenile rheumatoid arthritis
Felty’s syndrome
Adult onset still’s disease

Rheumatoid arthritis: Rheumatoid arthritis is the most common inflammatory arthritis affecting about 1% of the general population worldwide. Articular involvement occurs in the form of progressive symmetrical erosive polyarthritis involving the proximal interphalangeal joints, metacarpophalangeal joints, wrists, elbows, shoulders, cervical spine, hips, knees, ankles, tarsals and metatarsophalangeal joints. Although mainly considered a disease of the joints, rheumatoid arthritis can also exhibit a variety of extra-articular manifestations (Wolfe AM: The epidemiology of rheumatoid arthritis: A review. Bull Rheum Dis 19:518, 1968).
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Juvenile rheumatoid arthritis: Juvenile rheumatoid arthritis is the most frequent major connective disease in children that, by definition, begins before the age of 16 years. . It is one of the more common chronic diseases of childhood and is a major cause of functional disability and eye disease leading to blindness. There are three major types of JRA, oligoarticular type (60%), polyarticular type (30%) and systemic type (10%). Large joint such as the knees, wrists and ankles are more prominently involved than are small joints and there are less frequent complaints of joint pain than in rheumatoid arthritis. A satisfactory recovery for properly managed children is approximately 85% (Cassidy JT, Pretty RE: Textbook of Pediatric Rheumatology, 3rd edition. Philadelphia, WB Saunders, 1995).
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Felty’s syndrome: Felty’s syndrome is one of the many systemic complications of seropositive rheumatoid arthritis. It was first described by Felty in 1924 and comprises the triad of chronic arthritis, splenomegaly and leucopenia (Felty AR: Chronic arthritis in the adult associated with splenomegaly and leucopenia. Johns Hopkins Hosp Bull 35:16, 1924). It occurs in a group of patients with unusually severe extra-articular disease and immunologic abnormalities (Campion G, Maddison PJ, Goulding N, et al: The Felty syndrome: A case-matched study of clinical manifestations and outcome, serolgogic features and immunogenetic association. Medicine 69:69, 1990).
Liver disease: Regenerative hepatic nodular hyperplasia is an infrequent condition that is generally associated with many diseases the most frequent being Felty’s syndrome. It may cause portal hypertension and variceal bleeding. A histologic study is necessary for diagnosis certain biologic data (persistent elevation of serum transaminases) and the nodular appearance of the hepatic surface (as shown by ultrasonography) may be confused with hepatic cirrhosis from which it may basically be, apart from the histologic features, distinguished by its good prognosis due to the absence of liver failure (Sinusoidal portal hypertension secondary to nodular regenerative hyperplasia of the liver. Gento Pe-na E, Mart’in Lorenta JL, Echevarr’ia Iturbe C, P’erez Alvarez JC, S’aez-Royuela F, L’opez Morante A, Ojeda Gim’enez C. Gastroenterol Hepatol, 22:183-5, Apr 1999).
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Adult onset still’s disease: liver dysfunction, transaminitis
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C. Hepatic Disease with Recognized Rheumatological Involvement

Primary biliary cirrhosis (PBC)
Hepatitis C infection
HCV cryoglobulinemia
Wilson’s disease
Alcoholic cirrhosis
Gaucher’s disease

Primary biliary cirrhosis (PBC):
PBC arthritis: Hypercholestrolemic arthropathy
Metabolic bone disease (osteomalacia and osteoporosis) is a recognized complication of cholsetatic liver diseases as PBC, sclerosing cholangitis, hemochromatosis and alcoholic liver disease.
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Hepatitis C infection: Recent interest has been expressed in the rheumatic manifestations in hepatitis C virus-infected populations. Common manifestations suggesting a rheumatological condition include the presence of arthralgias, myalgia, arthritis, Raynaud’s phenomenon, parasthesias, cryoglobulinemia, sicca symptoms (dry eyes and dry mouth), fibromyalgia, oral ulcers, and abdominal pain. Also, cutaneous vasculitis and antiphospholipid syndrome have been seen in some patients. Although cause and effect remain to be proved, there are reports of HCV infection preceding or co-incident with polyarthritis, rheumatoid arthritis, systemic lupus, polymyositis / dermatomyositis (Mc Murray and Elbourne, 1997). For these reasons, HCV infection should be included in the differential diagnosis of patients with unexplained rheumatological manifestations. Patient’s gender has not been shown to be associated with the occurrence of rheumatic disease (Cryoglobulinemia and rheumatic manifestations in patients with hepatitis C virus infection. Lee YH, Ji JD, Yeon JE, Byun KS, Lee CH, Song GG. Ann Rheum Dis, 57:728-31, Dec 1998). The immune response to HCV includes the development of autoantibodies that have been demonstrated in a large percent of patients. These include RF, ANA, IgM and IgG ACL antibodies, antithyroid antibodies and anti-liver kidney microsomal antibodies (anti-LKM). In addition, HCV/anti-HCV immune complex formation and deposition may occur in HCV patients. Neither the rheumatic complications nor the presence of autoantibodies has been shown to be associated with liver disease severity. (Musculoskeletal manifestations and autoantibody profile in 90 hepatitis C virus infected Israeli patients. Buskila D, Shnaider A, Neumann L, Lorber M, Zilberman D, Hilzenrat N, Kuperman OJ, Sikuler E. Semin Arthritis Rheyum, 28:107-13, Oct 1998).
However, HCV cannot be considered a major causative factor for most autoimmune diseases associated with it. Optimal treatment for HCV-related autoimmune disease remains to be determined. It is true that interferon alpha has successfully reduced viremia / transaminitis, cryoglobulins, proteinuria and nephritis, but still, it may precipitate or exacerbate autoimmune disease symptoms. Moreover, HCV related autoimmune disease also has been treated successfully with corticosteroids, azathioprine and cyclophosphamide although HCV viremia persists and may even worsen (Hepatitis C virus infection and autoimmunity. Mc Murray RW, Elbourne K. Semin Arthritis Rheum, 26:689-701, Feb 1997).

HCV cryoglobulinemia: Viral persistence is considered the greatest problem in the management of HCV infection. It may result from several mechanisms. For example, the high rate of genetic variations during viral replication results in the production of mutants capable of escaping the immune attack. Also, HCV infects cells of the immune system itself, which represent a privileged site that cannot be reached by virus-specific T cell response. Involvement of lymphoid cells in the early stages of HCV infection may provide insight into the pathobiologic patterns of extrahepatic dissemination (lymph nodes, major salivary glands, kidneys, blood vessels). Dissemination of HCV-infected lymphoid cells throughout the organisms is likely to maintain a mobile and extensive reservoir of the virus. In this respect, extrahepatic sites may act a source of continuous reinfection of hepatocytes.
Studies of intrahepatic B lymphocytes indicate that they are infected with HCV, clonally expanded and activated to secrete IgM molecules with rheumatoid factor activity. This strongly suggests that HCV directly stimulates B cell expansion, which may result in an indolent stage of lymphoproliferation (i.e. mixed cryoglobulinemia) or in frank B cell non-Hogkin’s lymphoma. The frequency of NHL, however, is much lower than that of HCV infection, suggesting that HCV alone is not able to induce tumors and that cellular events, in addition to the presence of virus and virus-encoded products, are necessary in order to obtain a malignant B cell phenotype.
The demonstration of HCV productive infection in bone marrow-recruited pluripotent hematopoietic CD34+ stem cells indicates that HCV replication occurs in the early differentiation stages of hematopoietic progenitors. These are stable cell populations and are likely to represent the initial site of infection and a continuous source of virus production. (Hepatitis C virus infection, mixed cryoglobulinemia and non-Hogkin’s lymphoma: an emerging picture. Dammacco F, Gatti P, Sansonno D. Leuk Lymohoma, 31:463-76, Nov 1998).
Cryoglubulinemia in HCV patients can, in turn, be complicated by cryoglobulinemic glomerulonephritis, vasculitis or neuropathy. It can also be associated with membranous and membranoproliferative glomerulonephritis.
can cause In patients with HCV cryoglobulinemia, HCV genotypes did not differ from those in HCV patients without cryoglobulinemia (Lee at al, 1998).
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Wilson’s disease: Osteoporosis, chondrocalcinosis.
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Alcoholic cirrhosis: Dupuytren’s contracture.
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Gaucher’s disease
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D. Common Disease Associations

Primary biliary cirrhosis and CREST
Primary biliary cirrhosis/Chronic active hepatitis and sicca/Sjogren
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E. Hepatotoxic Drugs Used in the Treatment of Rheumatic Diseases

All types of liver pathology may be caused by drugs. Drugs that have recognized hepatic side effects include:
Non Steroidal Anti-inflammatory Drugs (NSAIDs)
Sulfasalazine
Steroids
Paracetamol
Methotrexate
Cyclophospahamide
Gold
Penicillamine
Azathioprine
Chlorambucil
Cyclosporine
Allopurinol
Colchicine

Nonsteroidal antiinflammatory drugs (NSIADs):
a. Hepatitis with scattered necrosis and mononuclear cell infiltration of the portal tracts and, sometimes, biliary stasis. Transient elevations of activity of liver transaminases are seen. Aspirin, diclofenac and sulindac are most commonly associated with this problem (Nonsteroidal antiinflammatory drug-associated toxicity of the liver, lower gastrointestinal tract and esophagus. Bjorkman D. Am J Med, 105:17S-21S, Nov 2 1998). The risk is increased in advanced age, renal impairment, multiple drug use and increase in dose and duration of therapy. Also, marked sensitivity to NSAIDs is especially seen in SLE and JRA. This effect is enhanced by methotrexate and is reduced by hydroxychloroquine.
Management: When starting a patient on an NSAID, it is important to monitor the liver functions during the first 4-6 weeks. If the liver enzymes increase more than 3 folds, stop the medication.
b. Reye’ s syndrome: caused by aspirin.
c. Cholestasis: Case report of cholestatic hepatitis associated with the use of piroxicam: A 22 year old female presented with an acute cholestatic hepatitis after a prolonged period of piroxicam use. Hepatitis was attributed to this drug since all markers for hepaitits viruses (A, B, C, E, Epstein Barr, Cytomegalovirus and Herpes Simplex) were negative, autoimmune markers were negative, serum iron and ceruloplasmin were normal, there was a temporal relationship between the administration of piroxicam and the hepatitis, the histological picture was compatible with this etiology and the patient has a favorable evolution after the discontinuance of the drug. Although this type of hepatotoxicity is not common, yet, it must be born in mind when patients must receive nonsteroidal antiinflammatory drugs for prolonged periods. (Cholestatic hepatitis associated with piroxicam use. Case report. Poniachik J, Guerrero J, Calder’on P, Smok G, Morales A, Mu-noz G, Venegas M. Rev Med Chil, 126:548-52, May 1998).
Three cases of ibuprofen-induced hepatotoxicity have been reported in patients with hepatitis C infection. Hepatotoxicity manifested as a marked rise in hepatic transaminases with one case having repeated rise on rechallenge (Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series. Riley TR 3rd, Smith JP. Am J Gastroenterol, 93:1563-5, Sep 1998).
In an investigation of hepatocyte cytotoxicity of nonsteroidal antiinflammatory drugs, where the extent of hepatotoxicity was assessed by the NSAID-induced leakage of lactate dehydrogenase (LDH), it was shown that the diphenylamine structure, and not the diphenyl, is the cause of LDH leakage as is the case with flufenamic acid, mefenamic acid, tolfenamic acid, diclofenac, indomethacin, acemetacin and flurbiprofen. The cytotoxicity of diflunisal, which has the diphenyl structure was attributed to other substituted group(s) other than the diphenyl structure. All of the cytotoxic NSAIDs and diphenylamine extensively decreased hepatocellular ATP content, whereas the nontoxic NSAIDs did not, indicating that the NSAID-induced decrease in ATP is probably mediated by the their uncoupling effects on mitochondrial oxidative phophorylation. (Structural requirements for hepatotoxicity of nonsteroidal antiinflammatory drugs in isolated rat hepatocytes. Masubuchi Y, Saito H, Horie T. J Pharmacol Exp Ther, 287:208-13, Oct 1998)
Meloxicam has been reported to cause acute cytolytic hepatitis which occurred rapidly after meloxicam admnistration and was associated with the development of antinuclear antibodies suggesting a hypersensitivity mechanism (Meloxicam-induced liver toxicity. Staerkel P, Horsmans Y. Acta Gastoenterol Belg, 62:255-6, Apr-Jun 1999).
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Sulfasalazine: abnormal liver function tests. A case of fulminant hepatic failure, thrombocytopenia and erythroid hypoplasia has been reported in a 12 year old girl with juvenile rheumatoid arthritis 2 weeks after initiation of sulfasalazine therapy. The diagnosis of this syndrome of sulfasalazine hypersensitivity was confirmed by liver histology and bone marrow examination. The patient recovered after the administration of high doses of intravenous immunoglobulin (Successfully treated sulfasalazine-incuded fulminant hepatic failure, thrombocytopenia and reythroid hypoplasia with intravenous immunoglobulin. Huang JL, Hung IJ, Chen LC, Lee WY, Hsueh C, Hsieh KH. Clin Rheumatol, 17:349-52, 1998).
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Steroids: cholestasis, fatty liver (hepatomegaly).
Glucocoticoid therapy in the presence of liver disease: there is no mandate to use prednisolone rather than prednisone for 2 reasons. First, the impaired conversion of prednisone to prednisolone is quantitatively small and is offset by the decrease in the rate of clearance of prednisolone. Second, there is marked variability of the plasma prednisolone levels after administration of either steroid. Whichever agent is used, a somewhat lower dose than would otherwise be used should be employed if serum albumin level is low.
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Paracetamol:
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract.
Fate of therapeutic dose:
1. 90%: metabolized by the liver by glucuroniation and sulfation leading to the production of non-toxic metabolites that are excreted in urine.
2. 5%: metabolized by the liver by mixed function oxidase enzymes P450 leading to the production of highly reactive N-acetyl-P-benzoquinone imine (NAPQI) that is rendered non toxic by preferential conjugation with the intracellular tripeptide glutathione to be excreted as mercapturic acid and cysteine conjugates.
3. 5% excreted unchanged in urine.
Fate of overdose:
Saturation of (1) so that an increasing proportion is metabolized by (2) leading to the production of increasing amounts of NAPQI. At the same time, the liver synthesis of glutathione is directly suppressed in the first few hours following ingestion of a hepatotoxic dose of the drug. Manifestations of hepatotoxicity appear when the glutathione levels fall below 30% of normal.
NAPQI causes:
Inhibition of mitochondrial respiration.
Inhibition of NADH and succinate dehydrogenase.
Oxidation of key Ca-regulating proteins leading to increase in intracellular Ca and activation of catabolic enzymes as proteases.
Hepatic macrophages play a role in toxicity.
Patients at an increased risk for toxicity:
Those who ingest drugs that enhance liver microsomal enzymes as barbiturates, carbamezepine, diphenylhydantoin, alcohol, glucocorticoids, griseovulvin and rifampicin.
Fasting or poor nutritional state that deplete glutathione reserves and enhance the activity of cytochrome P450.
The hepatotoxic dose:
The minimal dose capable of causing hepatotoxic damage is 125 mg/Kg. Actually, the majority of patients ingest less than that dose.
The mean dose capable of causing liver damage is 250 mg/Kg.
Invariable liver damage (severe damage defined as AST that is more than 10,000 IU/lit) occurs with doses above 350 mg/Kg.
Manifestations of hepatotoxicity:
Within few hours: nausea, vomiting, abdominal pain, liver tenderness with increase in prothrombin time.
Within 12-24 hours: increase in AST, hypoglycemia due to impaired gluconeogenesis and may impair the level of consiousness.
Within 24 hours: Jaundice that may deepen rapidly and persist for weeks in cases with severe damage. Hypophosphatemia correlates with the degree of hepatic damage.
Within 24-72 hours: Leucocytosis, thrombocytopenia that correlates with the degree of hepatic damage and is caused by the toxic effect of dose on megakaryocytes, renal failure.
After 72 hours: maximum increase in AST (more than 10,000 IU/L) and PT.
Management of paracetamol toxicity: activated charcoal (50 gm), gastric lavage which are effective if administered within 1 and 4 hours respectively together with the administration of N-acetylcysteine.
Administration of acetylcysteine (Mucomyst): Acetylcysteine is administered if 24 hours or less have passed from the time of acetaminophen ingestion (within 16 hours gives best results).
Steps: (1) Dilute acetylcysteine to a concentration of 5% with cola or other soft drinks (prepare and use within one hour). (2) Empty the stomach by lavage or syrup of ipecac. (3) If activated charcoal has been used, be sure to use lavage before administering acetylcysteine as charcoal adsorbs acetylcysteine. (4) Acetaminophen plasma assay should be started to be done no sooner than 4 hours after acute ingestion. Also baseline liver function tests including enzymes, bilirubin, PT together with serum creatinine, BUN, blood sugar and electrolytes should be done. Continue on monitoring these parameters. (5) Administer a loading dose of acetylcysteine 140 mg / kg. (6) The maintenance dose is 70 mg / kgQ4H, starting 4 hours after the loading dose. Administer 17 doses total unless there is a nontoxic acetaminophen assay. If vomiting occurs within 1 hour of a maintenance dose (acetylcysteine causes nausea and vomiting in large doses), repeat that dose. Duodenal intubation may be considered if the patient is unable to retain doses peroral. (8) Continue lab monitoring daily while acetaminophen level is in the toxic range (The family practice drug handbook. Ellsworth AJ, Bray RF, Bray BS, Geyman JP. Editor: Mosby, 1991.
Estimation of potential for hepatotoxicity can be obtained from Matthew, Rumack Nomogram shown in the figure below.
VIN: If hepatic failure occurs, stop treatment to avoid further exposure to nitrogenous substances.

It has been suggested that the hepatotoxicity of paracetamol can be potentiated if an alpha 1 adrenoreceptor agonist is given 3 hours before the paracetamol. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and paracetamol be coincident. This interaction is of interest because factors or event that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals (Adrenergic modulation of hepatotoxicity. Roberts SM, DeMott RP, James RC, Drug Metab Rev, 29:329-53, Feb-May 1997).
Paracetamol and genotoxicity and carcinogenicity: The publication of several studies reporting genotoxic effects of paracetamol has raised the question of the need for a regulatory action. Studies have, however, shown that the genotoxic effects of paracetamol appear only at dosages that induce pronounced liver and bone marrow toxicity and that the threshold level for genotoxicity is not reached at therapeutic dosages so that paracetamol is not expected to cause heritable damage in man. Studies have also shown that paracetamol is non-carcinogenic when given at non-hepatotoxic doses to rats and mice (Series: Current issues in mutagenesis and carcinogensis, No 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view. Bergman K, M’uller L, Teigen SW. Mutat Res, 349:263-88, Feb 1 1996).

The use of hepatoprotective agents to decrease paracetamol hepatotoxicity (increased serum levels of activity of SGOT, SGPT) has been investigated. Inhibitors of NAD-dependent adenoribosylation reactions (inhibitors of polyADP-ribose metabolism) as nicotinic acid amide, benzamide, caffeine, theophyline and thymidine were injected in mice in addition to 500 mg of oral paracetamol. While PARP activity remained essentially unchanged in liver cell nuclei, the acetaminophen-induced release of SGOT and SGPT from injured liver cells could be inhibited by 90-99% (The influence of antogonists of polyADP-ribose metabolism on acetaminophen hepatotoxicity. Kr’oger H, Ehrlich W, Klewer M, Gr’atz R, Dietrich A, Miesel R. Gen Pharmacol, 27:167-70, Jan 1996).
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Methotrexate hepatotoxicity
Methotrexate has clearly been shown to cause elevations of liver enzymes and has been associated with changes in liver histology (fibrosis) even when used in low dosages for the treatment of nonmalignant conditions. There is, however, considerable controversy over the frequency and severity with which histologic changes occur in patients treated with low dosages. This is because:
1. Histologic liver abnormalities similar to those that have been ascribed to methotrexate have been demonstrated in liver biopsies of patients with psoriasis and, less commonly, RA prior to starting treatment with methotrexate. Several factors related to the specific disease being treated may contribute to the liver pathology.
2. Histologic liver abnormalities are not invariably present in RA patients who had taken methotrexate for at least 3 years.
Risk factors associated with increased risk of methotrexate hepatotoxicity:
Strong association: alcohol abuse (previous or concurrent), pre-existing liver disease, renal insufficiency.
Probable association: duration of MTX treatment >2 years, cumulative MTX dose >1500 mg, obesity and diabetes mellitus, prior treatment with arsenicals.
Possible or potential association: maximum weekly dose >25 mg, obesity alone, diabetes mellitus alone, prior treatment with vitamin A, concurrent use of NSAIDs or treatment with cyclosporine or PUVA, Felty’s syndrome, heterozygous alpha-1 antitrypsin deficiency, pulmonary fibrosis, congestive heart failure.
No association: Gender, HLA phenotype, extent of psoriasis skin lesions, duration of rheumatoid arthritis, corticosteroid therapy.
Negative association: concurrent folate supplementation and concurrent hydroxychloroquine use.
Pathogenesis of MTX-induced hepatic fibrosis:
Methotrexate may activate Ito cells leading to collagen deposition particularly in conjunction with alcohol use.
Another possibility is that, with long-term use, MTX and its polyglutamated metabolites accumulate in hepatic and other tissues producing prolonged inhibition of folate metabolism leading to deficient nucleotide and methionine biosynthesis and resulting in hepatocyte injury. However, there is little evidence to support this hypothesis.
A genetic predisposition to MTX-induced hepatic fibrosis has been hypothesized with little evidence to support this postulation. Finally, many investigators believe that MTX will cause hepatic fibrosis and cirrhosis only in the presence of other contributing factors, such as alcohol use, obesity and previous hepatitis.

Methotrexate toxicity in RA:
Clinically significant hepatic fibrosis is unusual in methotrexate-treated RA patients without other risk factors for liver disease. Reports comparing serial liver biopsies done in RA patients on MTX have shown that although 13% to 52% of liver biopsies will worsen histologically during MTX treatment, up to 46% will improve. Meta-analysis of 15 studies reporting on the progression of liver histology in RA and psoriatic patients receiving MTX predicted that after 3 gms of methotrexate, 1 in 5 (20%) patients will experience progression of at least one histologic grade on liver biopsy, and 1 in 35 (2.9%) will have advanced changes.
A temporary increase in liver enzymes that decreases after temporary discontinuation of the drug may occur. Its significance might be a change in liver pathology grade.
It has been suggested that hypertransaminemia in patients on methotrexate should not always be attributed to the drug as in some cases viral infections as CMV and Epstein-Barr virus have been implicated to be the cause. Such patients are more likely to have a favorable outcome once methotrexate is withdrawn (Hypertransaminemia and methotrexate: not always a toxic effect? Montilla Morales C, L’opez Longo Fj, Moreno Zazo M, Monteagudo S’aez I, Moreno Garc’ia AC, Carre-no P’erez L. Rev Clin Esp, 198:822-4, Dec 1998).

Methotrexate treatment in RA in the presence of liver disease:
Hepatitis B: Severe hepatitis requiring liver transplantation resulting from reactivation of hepatitis B virus infection following discontinuation of methotrexate therapy has been reported.

Methotrexate toxicity in psoriasis:
Earlier studies suggested that there is a greater incidence of hepatotoxicity in MTX-treated psoriasis patients compared to RA patients. However, recent studies, in which other risk factors for methotrexate toxicity have been controlled did not show a higher incidence of methotrexate hepatotoxicity in those patients. Risk factors for methotrexate toxixity include morbid obesity, history of alcohol intake, diabetes, renal insufficiency and cumulative dose.

Methotrexate toxicity in JRA:
Methotrexate may cause reversible elevation of liver enzymes in JRA. Liver fibrosis is rare in JRA patients who have received less than 3000 mg total cumulative dose of MTX.

Noninvasive methods for detection of methotrexate-induced liver fibrosis:
Liver function tests:
Persistently abnormal transaminase level elevations on serial determinations at 4 to 6-week intervals do seem to correlate with liver histology, especially after 2.5 years of methotrexate therapy. Additionally, patients developing hypoalbuminemia while clinically controlled on MTX is a finding also thought to indicate significant liver disease. But it is important to consider that:
1. Concerning the liver enzyme abnormalities: the probability of missing a random elevation of AST is estimated to be 9%, 41% and 68%, depending on whether the patient’s blood is sampled at 30-, 60- or 90-day intervals, respectively. Consequently, a significant number of elevated AST values could be missed if the patient is infrequently monitored, which could potentially lessen the correlation between liver-associated enzymes and liver histology.
2. Concerning the serum albumin levels, it is important to note that patients with active RA may have a low serum albumin level and elevated ALP levels owing to chronic inflammation and activation of the acute phase response prior to starting MTX therapy. Therefore, serum albumin levels should be considered only in patients whose disease is well controlled on MTX.
Serum levels of aminoterminal peptide of type III procollagen (P3NP): are a good marker of ongoing hepatic fibrogenesis. However, it can also increase in the presence of active fibrosis in any other organ and thus, cannot be used as a marker of hepatic fibrosis in RA or psoriasis.

Radiologic and imaging techniques:
Dynamic hepatic scintigraphy: has a sensitivity of 83% and specificity of 82% in detecting fibrosis in MTX-treated psoriasis patients. Additionally, the negative predictive value of a normal scan for fibrosis is 98.5% suggesting that liver biopsy could be avoided in patients with normal scans.

Ultrasound can reliably detect fatty change and fibrosis found on liver biopsy. It cannot, however, differentiate between fatty change and mild fibrosis. Therefore, a normal hepatic ultrasound examination may a good screening tool and spare a patient a liver biopsy. An abnormal liver ultrasound does not reliably predict significant liver histology, however. Furthermore, the diagnostic accuracy of an abnormal ultrasound examination varies with the experience of the operator.

Methotrexate administration and prevention of hepatotoxicity: Theoretically, parentral administration of MTX would be expected to be safer than oral therapy by avoiding the effects of first-pass metabolism in the liver. There have, however, insufficient data to support that claim, particularly because MTX undergoes significant enterohepatic circulation that may lead to high concentrations in bile.
Folic or folinic acid supplementation during MTX therapy can reduce the side effects of the drug without interfering with its efficacy. Frequency of serum transaminase elevation was reduced by 60% with folinic acid supplementation suggesting that transaminase elevations may be related to hepatic folate depletion and that folinic acid therapy may be hepatoprotective. Although the optimal dosing schedule of folate supplementation in relation to MTX is not known, many clinicians use a ration of 1 mg of folic acid per mg of MTX per week (divided into daily doses) or 0.25 to 0.50 mg of folinic acid per mg of MTX given 4 to 24 hours after the weekly MTX dose.

Monitoring for methotrexate hepatotoxicity:
Monitoring for methotrexate hepatotoxicity in rheumatoid arthritis:
American College of Rheumatology recommendations for monitoring hepatic toxicity in patients with rheumatoid arthritis receiving methotrexate:
Baseline: liver functions tests including AST, ALT, ALP, serum albumin and bilirubin in addition to HBV, HCV serologies and CBC and serum creatinine.
A pretreatment liver biopsy is indicated in patients with prior excessive alcohol consumption, persistently abnormal baseline AST values and in chronic hepatitis B or C infection.

Monitor AST, ALT and serum albumin levels at 4-8 weekly intervals.

Perform a liver biopsy if:
Five out of nine determinations of AST within a given 12 months interval (6 of 12 if tests are performed monthly) are abnormal defined as an increase above the upper limit of normal. The ALT was not considered here as the ACR subcommittee reported that their data suggested that ALT values were abnormal whenever AST was elevated into the abnormal range.
There is a decrease in serum albumin level below the normal range in the setting of well-controlled RA.
Continue MTX if the result of the liver biopsy is Roenigk grade I, II or IIIA.
Discontinue MTX if the result of the biopsy is Roenigk grade IIIB or IV, in patients with persistent liver test abnormalities and in patients who refuse a biopsy.
Roenigk classification of liver biopsy findings:
Grade I: normal, mild fatty infiltration, mild portal inflammation.
Grade II: moderate-severe fatty infiltration, moderate-severe portal inflammation.
Grade III: A: mild fibrosis. B: moderate-severe fibrosis.
Grade IV: Cirrhosis.

Recently, a study evaluating the usefulness of the ACR giudelines in predicting liver disease in MTX-treated RA patients has been performed. It showed that the ACR guidelines have resulted in significant cost savings owing to fewer liver biopsies being performed while maintaining a good sensitivity (80%), specificity (82%) but a low positive predictive value. Notably two patients with unsuspected underlying liver disease and normal baseline liver-associated enzymes who did not have a pre-treatment liver biopsy were discovered within the first few months of starting MTX therapy because of subsequent elevations of their AST levels. Another patient with poorly controlled insulin-dependent diabetes mellitus and obesity, however, who had a grade IIIA baseline liver biopsy developed cirrhosis without persistent elevations of serum transaminase levels or a low albumin level and consequently was missed by the ACR guidelines. If obese RA patients with poorly controlled insulin-dependent diabetes mellitus had been considered at risk for MTX hepatotoxicity and undergone surveillance liver biopsies, the ACR guidelines would have had a sensitivity of 100% (Usefulness of the ACR recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients. Erickson AR, Reddy V, Vogelgesang SA, et al. Arthritis Rheum 38(8):115, 1995). Other studies still showed the high specificity and low sensitivity of the ACR guidelines and some editorials have questioned the value of serial AST determinations and whether ALT elevations should also be used to predict MTX liver toxicity.
Finally, it has been proposed that the ACR guidelines may not be applicable to patients receiving greater than 25 mg of MTX weekly or over 10 gm total cumulative dose so that surveillance liver biopsies may be indicated in those patients.
The ACR guidelines may, however, may also be applicable to JRA patients as well although more studies in this patient group are needed. There are insufficient data to recommend applying these guidelines to MTX-treated patients with other diseases.

Liver biopsy: Outpatient liver biopsy using a Menghini-type aspiration needle has an overall risk of complications ot 1.5 to 2 per 1000 procedures and an average mortality rate of 0.03%. These risks may be lessened if the liver biopsy is performed by a skilled physician using a small-bore needle, coagulation tests and platelet counts are normal and aspirin and other NSAIDs have been discontinued prior to the procedure. In addition to risks, uncomplicated liver biopsy also adds to the overall cost of medical care for the patients.
More than 50% of practicing physicians prescribing MTX do not adhere to the guideline recommendations concerning monitoring hepatic enzymes or prescribing liver biopsies.
Moreover, when patients are told the risks and benefits of performing a liver biopsy, Ferraz et al found that 12 of 17 MTX-treated patients preferred to take the risk of developing cirrhosis rather than be subjected to a liver biopsy, showing that properly informed patients can make difficult decisions concerning their health (Patient’s preference regarding the option of performing unselective liver biopsy following methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol 12:621, 1994).
Monitoring for methotrexate hepatotoxicity in psoriasis:
The guidelines for monitoring MTX therapy in psoriasis have included less frequent monitoring of liver enzymes (intervals of 3-4 months) except during initial treatment, when changing dose and during episodes of increased risk of increased blood concentrations of methotrexate as dehydration and impaired renal function in which cases the enzymes are monitored at monthly intervals. Liver biopsy was recommended after a cumulative dose of methotrexate of approximately 1.5 gm and thereafter at 1.0-1.5 gm intervals (Methotrexate in psoriasis: Revised guidelines. Roenigk HH, Auerbach R, Maibach HI, et al. J Am Acad Dermatol 19:145, 1988). However, current available data suggest that significant liver disease occurs less commonly than previously reported in MTX-treated psoriasis patients who do not have risk factors for hepatotoxicity particularly alcohol abuse. Clinicians are beginning to question the necessity of strictly adhering to the above guidelines in low-risk psoriasis patients.

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Cyclophosphamide: effect ranges from a mild increase in liver enzymes to significant liver damage which is rather uncommon. Ascorbic acid supplementation at doses of 25 mg / kg / day have been suggested to reduce the hepatotoxic effects of cyclophosphamide on the liver (Effect of ascorbic acid supplementation on liver and kidney toxicity in cyclophosphamide-treated female albino rats. Ghosh S, Ghosh D, Chattopadhyay S, Debnath J. J Toxicol Sci, 24:141-4, Aug 1999).
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Gold: hypersensitivity cholestasis. It is associated with eosinophilia and recedes rapidly with cessation of gold therapy.
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Penicillamine: hepatitis, cholestasis
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Azathioprine: elevation of liver enzymes, cholestasis, fibrosis, cirrhosis and veno-occlusive disease. A case of azathioprine-induced lymphoma manifesting as fulminant hepatic failure due to massive lymphomatous infiltration of the liver has been reported (Azathioprine-induced lymphoma manifesting as fulminant hepatic failure. Aguilar HI, Burgart LJ, Geller A, Rakela J. Mayo Clin Proc, 72:643-5, Jul 1997).
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Chlorambucil: elevation of liver enzymes.
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Cyclosporine: elevation of liver enzymes. Hepatotoxicity of cyclosporine is attributed only to the inhibition of transport systems.
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Allopurinol: granulomatous hepatitis, jaundice
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Colchicine: overdose may result in hepatocellular failure.
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F. Abnormal Acute Phase Protein Response by the Liver in Some Rheumatic Diseases

SLE: negative CRP
Systemic sclerosis: negative CRP

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