39 yr old female pt, unemployed from Bloemfontein Routine follow up at rheumatology Background history of hypertension Diagnosis of ? Mixed connective tissue disease/ Overlap syndrome/ seronegative rheumatoid arthritis Previous serology: ANF, AntiRNP, Scl 70, Anti Jo, elevated CK’s

Severe generalised joint pains No associated swelling reported Morning stiffness Constitutional symptoms Dryness of the eyes No other systemic complaints Sober habits

Medication list: MTX 20 mg /week Nivaquine 200mg daily Prednisone 10mg daily Folate 5mg daily Ridaq 12.5mg daily Pharmapress 20 mg daily po Losec 20 mg daily po Voltaren Dolorol forte

General examination: In discomfort due to pain No pallor/jaundice/adenopathy No vasculitic or skin changes Systemic exam: CVS: haemodynamically stable Resp: clear GIT: no tenderness or organomegaly M/S: bilateral symmetrical tenderness and warmth of joints in upper and lower extremities. No effusions.

Assessment Flare of arthritis Management Depo Medrol 160 mg imi stat Bloods for : Inflammatory markers AST/ALT/Alb Methotrexate increased to 25 mg/week

06/11/200916/04/2010 Total Bili9 AST86669 ALT73760 Albumin4036

Drug induced hepatitis Viral hepatitis Autoimmune hepatitis(AIH)

Patient admitted for evaluation Reports good response to steroids Methotrexate stopped Follow up blood results 16/04/201026/04/2010 Total Bili99 AST ALT Albumin3640

Virological studies Hepatitis A, B and C studies were negative HIV negative Serology ANA, ANCA negative Anti smooth muscle Ab’s unfortunately not done SPEP Normal Abdominal ultrasound Normal

Diagnostic challenge ?

Causes related to: Underlying autoimmune disease Concurrent infections Chronic viral hepatitis Opportunistic infections Drug related toxicity Methotrexate Azathioprine Other causes Alcoholic liver disease Metabolic disorders Malignancy

Cell-mediated immunologic attack against genetically predisposed hepatocytes Progressive necroinflammatory and fibrotic process. Association with other autoimmune diseases Rheumatologic conditions Rheumatoid arthritis and Felty syndrome Sjögren syndrome Systemic sclerosis Mixed connective-tissue disease

Presentation is heterogeneous, and clinical manifestations vary Asymptomatic Debilitating symptoms Fulminant hepatic failure Women are affected more often than men (70-80% of patients are women) Response to steroid and/or immunosuppressive therapy

Risk factors associated with drug induced liver injury Age: elderly at high risk Sex: more common in females Alcohol use Underlying liver disease Co- morbid disease Pregnancy Other drugs Genetic factors

Methotrexate can induce: hepatocyte necrosis Increased ALT Hepatic fibrosis and cirrhosis Common setting in pt treated for psoriasis

Premethotrexate Evaluation Complete blood count with differential count Platelet count Serum creatinine Urea Urinalysis Liver function tests Serum bilirubin Serum albumin Hepatitis A, B, and C serologies HIV risk assessment/testing, if appropriate Chest radiograph Information from Roenigk HH, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol 1998; 38:

Indications for liver biopsy in pt with RA Persistently elevated liver enzymes Abnormal results in five of nine determinations of AST levels within a 12-month period( done 4-8 weekly) Decrease in serum albumin values below the normal range Not cost-effective in the first 10 years in pt’s with normal enzymes Presence of moderate fibrosis/cirrhosis warrants discontinuation

AIH Female gender Underlying autoimmune disorder Previous +ANA ?Response of transaminases to steroids Hepatocellular injury pattern in pt on MTX ?Other possible precipitating factor ?Did pt increase her treatment due to pain MTH hepatotoxicity

Decline in LFT’s to near normal MTX stopped indefinately Prednisone increased to 20 mg For reevaluation in 2/52, ?liver biopsy