Mirtazapine-Induced Hepatocellular-Type Liver Injury

TO THE EDITOR: The elevation of alanine transaminase (ALT) levels to more than 3 times the upper limit of normal is seen in 2% of mirtazapine-treated patients. However, mirtazapine has rarely been associated with any lethal liver injury. A MEDLINE search yielded only 2 published case reports of mirtazapine-induced liver injury.^1,2 We describe another case of liver injury in a patient taking mirtazapine. To the best of our knowledge, this is the first case report of mirtazapine-induced hepatocellular-type liver injury.

Case Report. A 19-year-old Korean male was admitted to a psychiatric ward due to the onset of a major depressive episode. He had no relevant medical history and no history of substance abuse. Results of baseline laboratory tests were normal: ALT 13 U/L, aspartate aminotransferase (AST) 20 U/L, and total bilirubin 0.5 mg/dL (Table 1). Results of testing for hepatitis A immunoglobulin M antibody, hepatitis C virus antibody, and hepatitis B virus surface antigen were negative. The patient was initially treated with mirtazapine 7.5 mg/day, which was gradually increased to 30 mg/day after 8 days. He also was on lorazepam 0.5 mg/day and alprazolam 0.25 mg/day. After 2 weeks of mirtazapine treatment, the patient reported abdominal discomfort, nausea, and vomiting; the laboratory tests were repeated. His ALT and AST levels had increased to 385 U/L and 189 U/L, respectively, while total bilirubin and alkaline phosphatase (ALP) stayed within normal limits. All medications, including mirtazapine, were discontinued immediately; however, the patient's depressive symptoms rapidly worsened. He was therefore treated with escitalopram 5 mg/day, which was increased to 10 mg/day. His ALT and AST levels decreased to 30 U/L and 19 U/L, respectively, 2 weeks after discontinuing mirtazapine.

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Table 1.

Patient's Liver Function Tests Throughout Hospital Stay

		Day
Test	Reference Range	0 a	16 a	17	18 c	19	20	22	26	29 a
Alanine aminotransferase (U/L)	<40	13	358	385	370	277	207	120	49	30
Aspartate aminotransferase (U/L)	<40	20	150	189	138	76	45	26	18	19
Bilirubin (mg/dL)	0.2-1.3	0.5	0.6		0.7				0.9
Alkaline phosphatase (U/L)	30-120			32	34				38

a

Day 0: presentation to emergency department and baseline laboratory tests. Mirtazapine 7.5 mg/day started on day 1, when the patient was admitted. Days 2-7: mirtazapine increased to 15 mg/day. Day 8: mirtazapine increased to 22.5 mg/day. Days 9-15: mirtazapine increased to 30 mg.

b

Mirtazapine discontinued.

c

Escitalopram 5 mg/day started.

d

Escitalopram increased to 10 mg/day.

Discussion. According to the Roussel Uclaf causality assessment scale ³ and Naranjo probability scale, ⁴ the temporal relationship between elevation of enzyme levels and initiation of mirtazapine makes a causal relationship between mirtazapine treatment and liver injury highly probable in our patient. We believe the effects of alprazolam and lorazepam were minimal in our patient not only because the dosages were quite low (below the therapeutic range), but also because these 2 medications have low potential for causing liver injury.

Drug-induced liver injury is a term that describes abnormalities in liver enzyme levels related to medication intake. The pathology of drug-induced liver injury is divided into cholestatic, hepatocellular, or mixed injury, depending on the particular abnormality detected in the liver function tests. Cholestatic-type injury is characterized by direct damage to the canalicular membranes and bile transporters, resulting in bile duct obstruction and elevation of ALP (as defined by an ALT/ALP ratio of ≤2).^5,6 In contrast to cholestatic injury, hepatocellular injury presents with high ALT levels with little or no change in ALP. ⁵ Furthermore, acute hepatocellular liver injury is defined by ALT levels greater than 2 times the upper limit of normal or an ALT/ALP ratio of 5 or higher. ⁶ Mirtazapine-in-duced liver injury is associated mainly with cholestatic-type injury. Two case reports on 3 patients with mirtazapine-induced liver injury have been published.^1,2 According to the ALT/ALP ratio criteria, ⁶ 2 of these cases were mixed cholestatic-hepatocellular type and the other was cholestatic type.^1,2 In our patient, only his ALT and AST levels were elevated. Thus, our patient's laboratory findings suggested the presence of acute hepatocellular injury. Mirtazapine-induced liver injury can result in a diverse pattern of liver function test results depending on the liver injury type.