Hepatocellular necrosis associated with labetalol

Abstract

A 51-year-old African American woman was referred to our tertiary care center with stage 2 hypertension. She was asymptomatic and presented on diltiazem therapy with a blood pressure of 210/110 mm Hg. Evaluation for secondary causes of hypertension was negative and her baseline alanine transaminase (ALT) (normal 9-52 IU/L), aspartate transaminase (AST) (normal 8-39 IU/L), and total bilirubin (0.1-1.3 mg/dL) levels were within normal limits. She was started on labetalol 200 mg by mouth twice daily and diltiazem was discontinued. Eight weeks into labetalol therapy, the patient's blood pressure remained elevated at 200/100 mm Hg and she remained asymptomatic. Hydrochlorothiazide (HCTZ) 25 mg once daily was added, and the labetalol was increased to 300 mg 3 times a day. After failing to keep her scheduled follow-up appointment and approximately 3 months after initiation of labetalol and 4 weeks after beginning HCTZ, she called the clinic complaining of "yellow eyes." She denied fever but further assessment revealed a history of nausea, abdominal pain, fatigue, and dark urine 1 to 2 weeks earlier. On examination, her blood pressure was >300/130 mm Hg, liver enzymes were elevated (ALT, 1102 IU/L; AST, 757 IU/L), and total bilirubin was 7.0 mg/dL. She was admitted to the hospital with a diagnosis of acute hepatitis and hypertensive emergency.The patient's differential diagnosis of hepatitis included viral, drug-induced, and autoimmune hepatitis. She reported no history of intravenous drug use, recent travel, or ethanol abuse or recent use. She also denied recent acetaminophen use or the use of any other prescription or over-thecounter medications or herbal remedies. Viral hepatitis serologies were negative for hepatitis A, B, and C. In consultation with the gastroenterology department, extensive testing for autoimmune and infectious causes of hepatitis (including antinuclear antibodies, antimitochondrial antibodies, anti-smooth muscle antibodies, cytomegalovirus, and Epstein-Barr virus) were negative (Table). Serum iron, total iron-binding capacity, copper, and ceruloplasmin were within normal limits. An ultrasound of the liver and gallbladder showed no evidence of obstruction in the portal or hepatic veins and no focal abnormalities.HCTZ was initially suspected as a cause of druginduced hepatitis due to the temporal relationship of its appearance with her symptoms. HCTZ was discontinued and trandolapril and spironolactone were added for blood pressure management. Her blood pressure improved to 150/90 mm Hg and liver enzymes, although not returning to baseline values, initially showed a downward trend after the HCTZ was discontinued. Her jaundice clinically improved. She was discharged and scheduled for follow-up with gastroenterology and the hypertension clinic.At her clinic visit, 1 week after hospital discharge, she had complaints of continued weakness, malaise, and decreased appetite. Her blood pressure was 220/110 mm Hg, and on physical examination

Labetalol-Induced Hepatotoxicity during Pregnancy: A Case Report

“…6 Labetalol can cause transaminitis and in rare occasions may lead to significant hepatotoxicity, hepatocellular injury, hepatocellular necrosis, liver failure, and death. [1][2][3]7,8 The hepatotoxicity is most often considered an idiosyncratic response due to a presentation at therapeutic doses along with an indolent and variable latency period which can range from 5 to 90 days. 2 Idiosyncratic drug reactions account for approximately 20% of cases with liver injury severe enough for hospitalization and occur more commonly in women than men.…”

“…7 Since case reports emerged in the 1980s, the hepatotoxicity of labetalol has been documented in multiple reports. 2,3,7,8 This is significant, as rarely this can progress to hepatic failure in pregnancy. 8 The pathogenesis of labetalol hepatotoxicity is not completely known but is attributed to several intracellular pathways, of which one is the mitochondrial cytochrome P450 enzymatic pathway.…”

“…2,3,7,8 This is significant, as rarely this can progress to hepatic failure in pregnancy. 8 The pathogenesis of labetalol hepatotoxicity is not completely known but is attributed to several intracellular pathways, of which one is the mitochondrial cytochrome P450 enzymatic pathway. Patients with isoenzyme differences or mutations in this enzyme gene may be more susceptible to its hepatotoxic effects.…”

“…Other mechanisms may include an autoimmune and inflammatory response. 3,7,8 Liver biopsies in patients diagnosed with labetalol hepatoxicity typically show scant amounts of lymphocytes and diffuse findings of variable degrees of necrosis and apoptosis. In contrast, specimens from patients with autoimmune or infectious hepatitis show lymphocytic infiltration.…”

“…5 But since the 1980s, there have been few reports underlining serious hepatic injury in patients taking labetalol. 1,[6][7][8] Due to its rarity, physicians may be unaware of this possible cause of hepatotoxicity.…”