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Arie Regev M.D. Chair, Liver and GI Safety Committee Global Patient Safety Eli Lilly & Company Global Patient roduct Safety Drug Induced Steatosis and Steatohepatitis Arie Regev, M.D. Global Patient Safety Eli Lilly and Company Hepatic Steatosis Definitions and Nomenclature (I) Hepatic steatosis is defined as fat deposition within hepatocytes. It is seen microscopically as vacuoles of fat in a microvesicular or macrovesicular distribution. Stetohepatitis is defined as fat deposition WITH inflammation/ liver cell damage (i.e. ballooning) or hepatic fibrosis Liver Disorders Associated with Steatosis Hepatic steatosis is associated with various liver disorders: alcoholic liver disease nonalcoholic fatty liver disease (NAFLD) nonalcoholic steatohepatitis (NASH) hepatitis C Wilson’s disease acute fatty liver of pregnancy drug induced steatosis NAFLD/NASH Versus Drug Induced Steatosis/Steatohepatitis (I) NAFLD/NASH ≠ drug induced steatosis/steatohepatitis!! Nonalcoholic liver disease (NAFLD) is defined by the presence of hepatic steatosis in people who do not consume alcohol in high quantities and do not take drugs that may cause steatosis. Nonalcoholic steatohepatitis (NASH) is a subgroup of NAFLD patients that show features of steatohepatitis (inflammation/ ballooning/ fibrosis) Studies on NAFLD and NASH exclude patients who drink high quantities of alcohol or take drugs that are known to cause steatosis. Based on abundant evidence, clinical manifestations and prognosis of NAFLD/NASH is generally different from drug induced steatosis/steatohepatitis Pathogenesis of NAFLD/NASH Pathogenesis “The dogma of sequential progression from NAFL to NASH has grown out of favor”1 1. Paredes AH, et al. Clin Liver Dis 2012;16:397-419 NAFLD Pathogenesis The vast majority of NAFLD cases occur in the setting of insulin resistance1 The pathogenesis of NAFLD involves multiple interactions between the liver and peripheral adipose tissue1,2 Insulin resistance promotes hepatic triglyceride accumulation by causing imbalance between factors that favor hepatic lipid accumulation AND factors that decrease lipid build-up 1. Feldstein A, et al. Seminars in Liver Disease 2012;30:391 2. Smith BW, et al. Nat Rev Endocrinol 2011;7:456-465 NASH Pathogenesis In a subgroup of patients an adipose tissue inflammatory response results in secretion of proinflammatory cytokines1 Suspected mechanism: inability to appropriately expand adipose tissue in the setting of obesity leads to local hypoxia2 activation of adipocyte cell death signaling and apoptosis leads to accumulation of adipose tissue macrophages 3 Adipose tissue secretes inflammatory cytokines (e.g. IL-6, TNF) and reduced amounts of adiponecting Inflammatory cytokines together with steatosis induce oxidative stress and activate fibrogenic hepatic stellate cells to cause NASH 1. Feldstein A, et al. Seminars in Liver Disease 2012;30:391 2. Ye J, et al. Am J Physiol Endocrinol Metab 2007;293:E1118–1128 3. Alkhouri N, et al. J Biol Chem 2010;285(5):3428–3438 Drug Induced Steatosis Drugs associated with hepatic steatosis: aspirin methotrexate amiodarone glucocorticoids tamoxifen 5-fluorouracil valproate NRTIs* (zidovudine and didanosine) *NRTIs, nucleoside reverse transcriptase inhibitors Patel and Sanyal. Clin Liver Dis 2013:17;533–546 Mechanisms of Drug Induced Steatosis The mechanisms leading to DIS and steatohepatitis are not well understood and often extrapolated from NASH literature. In some cases the pathogenesis of liver damage is thought to include: mitochondrial dysfunction increased reactive oxygen species (ROS) formation Endoplasmic Reticulum (ER) stress that induces Inflammation liver cell death hepatic fibrosis Patel and Sanyal. Clin Liver Dis 2013:17;533–546 Stravitz and Sanyal .Clin Liver Dis 2003;7:435–51. Farrell GC. Semin Liver Dis 2002;22:185–94. Suspected Mechanisms of Drug Induced Steatosis/steatohepatitis • • • • • Inhibition of entry of long chain fatty acids (FFA) via the carnitine palmitoyl shuttle (CPT) Inhibition of ß-oxidation leading to increased free fatty acids which are esterified to TG Blocked transport of TG as very low density lipoprotein (VLDL) Blocked flow of electrons through the electron transport chain (ETC) Accumulation of electrons can lead to direct interaction with oxygen to produce reactive oxygen species (ROS). • Damage to mtDNA can induce mitochondrial permeability transition (MTP) pore formation Patel and Sanyal. Clin Liver Dis 2013:17;533–546 Clinical Manifestations and Suspected Mechanisms Drug Clinical Manifestations Pathologic Findings Suspected Mechanisms Aspirin Reye syndrome: lactic acidosis and hepatic dysfunction with encephalopathy, hypoglycemia, but mild increase in TBL. In children with viral infection. Develops within a few days. Often rapidly fatal. Microvesicular steatosis Arrests ß oxidation by consuming CoA. Increases mitochondrial permeability by MPT pore formation. Methotrexate Asymptomatic steatosis after a long term treatment. May lead to fibrosis and cirrhosis. Increased risk with higher cumulative doses. Macrovesicular steatosis, steatohepatitis, fibrosis and cirrhosis Inhibits mitochondrial electron transport chain Amiodarone Macrovesicular steatosis, steatohepatitis, hepatic necrosis, phospholipidosis Decreases ß oxidation; increases lipid peroxidation, ROS generation and lipogenesis Hepatocellular or cholestatic injury. More common with prolonged administration and higher dose. May resemble alcoholic liver disease Patel and Sanyal. Clin Liver Dis 2013:17;533–546 NIDDK LiverTox. Clinical Manifestations and Suspected Mechanisms Drug Clinical Manifestations Pathologic Findings Suspected Mechanisms Corticosteroids Hepatomegaly and steatosis, with long term administration. Usually due to worsening of underlying NAFLD. Steatosis is rapidly reversed with discontinuation. Progressive liver disease is rare. Macrovesicular steatosis. Can also cause hepatic glycogen accumulation. Promote weight gain, glucose intolerance; inhibit mitochondrial ß oxidation, decrease hepatic triglyceride secretion, and induce lipid peroxidation 5-fluorouracil Usually limited to transient asymptomatic increases in ALT. Clinically significant liver injury is rare. Rare cases of hyperammonemia and coma with normal liver tests were described with high IV doses. Macrovesicular Unknown steatosis. Typically isolated with no steatohepatitis. Tamoxifen Steatosis after long term therapy (years.) Typically improves on withdrawal. Mild or no ALT/AST changes. Macrovesicular steatosis and steatohepatitis. Rare cirrhosis Patel and Sanyal. Clin Liver Dis 2013:17;533–546. NIDDK LiverTox. Promotes de novo fatty acid synthesis. Inhibits ß oxidation. Worsens NAFLD. Clinical Manifestations and Suspected Mechanisms (III) Drug Clinical Manifestations Pathologic Findings Suspected Mechanisms Valproate May cause acute hepatocellular injury or Reye’s like syndrome. May cause steatosis in a high percentage of patients. May worsen NAFLD through weight gain and worsening of insulin resistance. Microvesicular steatosis and cirrhosis Inhibits CPT-1 activity, sequestering CoA; arresting ETC and ATP synthesis; promotes weight gain NRTIs (zidovudine and didanosine) May cause acute liver injury Microvesicular steatosis and which may lead to hepatic steatohepatitis failure and metabolic acidosis. Serum enzymes are only modestly elevated and may initially be normal. May worsen preexisting NAFLD. Mitochondrial dysfunction by mtDNA depletion and stimulation of autophagy NRTIs, nucleoside reverse transcriptase inhibitors Patel and Sanyal. Clin Liver Dis 2013:17;533–546 NIDDK LiverTox. Diagnosis of Drug Induced Steatosis/Steatohepatitis versus Typical Hepatocellular DILI Different ALT/AST/ALP changes may be milder or absent Time to onset typically longer than hepatocellular DILI* Time to resolution often longer (chronic injury)** Other common causes of steatosis difficult to rule out (NAFLD/NASH, alcoholic liver disease) Hepatic imaging may help make the diagnosis * Rare examples of a rapid onset Similar Rechallenge not recommended No specific/diagnostic biomarkers Histopathology generally not specific and not diagnostic (e.g. Reye syndrome) ** Rapid resolution less common but possible (e.g. corticosteroids.) Detecting DIS During Drug Development Currently possible only when DIS is associated with: changes in basic hepatic biochemical tests: ALT/AST/ALP/TBL May be absent signs and symptoms of liver dysfunction Rare and systemic manifestations (e.g. metab. acidosis) too late May be detected only through hepatic imaging (ultrasonography, CT, MRI, MRS) or liver biopsy Not monitored in the majority of clinical trials Asymptomatic DIS that is not associated with changes in hepatic biochemical tests, may not be detected in today’s clinical trials. Summary (I) Drug induced steatosis/steatohepatitis (DIS) is a group of heterogenous disorders which are characterized by fat accumulation in hepatocytes In most known cases of DIS, clinical features, clinical course, biomarkers and prognosis are different from those of NAFLD/NASH In most cases, clinical features, biomarkers and clinical outcome are different for different drugs There are currently no reliable biomarkers to predict the course, severity or prognosis of DIS Although specific biomarkers of fibrosis and necrosis may be useful for certain cases of NAFLD, there is no evidence that the use of such markers can be extrapolated to DIS Summary (II) In contrast with most cases of hepatocellular or cholestatic DILI, DIS may not be associated with significant changes in basic hepatic biochemical tests (ALT/AST/ALP/TBL) There are currently no approved biomarkers which reliably detect or predict DIS during drug development. Liver imaging and liver biopsy are currently the only reliable methods to detect drug induced steatosis There are currently no approved biomarkers that reliably differentiate between drug induced steatosis and steatohepatitis.