Case №2

Interpretation of data Complaints: medium yellowish of skin and icterus of sclera , choluria Anamnesis morbi: Patient had a viral hepatitis A in the past year. Since then, these symptoms have appeared. He was treated by hepatoprotectors (without positive dinamics). Paraclinical data: hyperfermentemia and hyperbilirubinemia (mixed) during the year; ultrasound - diffuse changes of the liver parenchyma, hepatomegaly; Total blood assay – relative lymphocytosis, levels of RBC and Hb at the upper limit of normal. Anamnesis vitae: Systemic sclerosis since childhood, he was treated with «Metoject», i.m., 1 time per week, until March of 2014. Cumulative dose of metotrexate – about 2 grams (or more) TOXIC HEPATITIS ?

Additional laboratory tests To exclude other causes of liver damage: 1. Markers of viral hepatitis В and С (ELISA for anti-НСV and HBsAg); 2. ELISA for AMA, ANA; 3. ELISA for anti-Opisthorhis felineus antibody (IgG /IgM) ; 4. Evaluation of Fe and Cu metabolism (levels of serum Fe, serum total iron-binding capacity, transferrin, ferritin, ceruloplasmin); 5. Split-lamp examination (by ophthalmologist) - search Kayser-Fleischer rings. NEGATIVE To exclude other causes of liver damage: 1. Markers of viral hepatitis В and С (ELISA for anti-НСV and HBsAg); 2. ELISA for AMA, ANA; 3. ELISA for anti-Opisthorhis felineus antibody (IgG /IgM) ; 4. Evaluation of Fe and Cu metabolism (levels of serum Fe, serum total iron-binding capacity, transferrin, ferritin, ceruloplasmin); 5. Split-lamp examination (by ophthalmologist) - search Kayser-Fleischer rings. NEGATIVE Confirmation of proposal diagnosis: 1. Biochemical blood assay (levels of glucose, bilirubin, transaminases, GGT, LDG, AChE-activity, bile acids, creatinine, urea); 2. Evaluation of hemostasis (protrombin, protrombin time, fibrinogen); 3. FibroTest; 4. Total and biochemical urine assays; 5. Coprogram, fecal stercobilin level. SINGS OF PARENCHYMATOUS JAUNDICE, indirect fibrotic signs

Additional instrumental examination Pulmonary system examination: 1. Assessment of respiratory function (spirography, impulse oscillometry, diffusion capacity, bronchodilatation response); 2. Chest CT; 3. EchoCG (pulmonary pressure assessment). NORMAL VALUES Pulmonary system examination: 1. Assessment of respiratory function (spirography, impulse oscillometry, diffusion capacity, bronchodilation response); 2. Chest CT; 3. EchoKG (pulmonary pressure assessment). NORMAL VALUES Liver examination: Elastography (FibroScan); Liver biopsy. STEATOHEPATITIS with the initial signs of fibrosis

Liver biopsy Liver biopsy from a patient on long-term methotrexate therapy. The biopsy shows evidence of macrovesicular steatosis (fat vacuoles pushing the nuclei to the periphery of hepatocytes signet ring appearance), ballooning (empty arrow), and bands of fibrosis (solid arrow). (From Aithal G.P., 2013)

Final diagnosis can be made only after histological verification. Toxic liver disease (methotrexate-induced) with non-alcoholic steatohepatitis and fibrosis. On the basis of anamnestic data, complaints, physical, laboratory and instrumental examination. Final diagnosis can be made only after histological verification.

Pathogenesis Hepatotoxicity may be mediated through the effect of methotrexate and its metabolites on methylation processes and methionine biosynthesis (From Aithal G.P., 2013).

Pathogenesis D E C O M P N S A T I VGА Methotrexate and its metabolites Hepatocyte: oxidative stress, fatty infiltration Stellate cells: excessive synthesis of collagen, fibrosis METHOTREXATE-ASSOCIATED CHRONIC LIVER DISEASE

Differential diagnosis Viral hepatitis A (the convalescence period); Viral hepatitis B and C; Primary biliary cirrhosis; Autoimmune hepatitis; Parasitic invasion; Hereditary metabolic disorders (hemochromatosis, Wilson disease). ?

Treatment Regimen. Alcohol and drugs with potential hepatotoxicity should be excluded. A diet with a high content of polyunsaturated fatty acids (antioxidant effect) is recommended. Folic acid, 1mg/day, for a long time. Folate supplementation therapy will reduce the risk of progression toxic liver damage. Vitamin Е (alpha-tocopherol), 800 МЕ/day, for a long time. Ursodeoxycholic acid, 13-15 mg/kg/day, for 2-3 months. Prednisolone, 30 mg/day, until signs of clinical and laboratory improvement, followed by gradual dose reduction (5 mg/week).