Subfulminant Liver Failure and Severe Hepatotoxicity Caused by Loratadine Use

Case Reports

Patient 1

A 42-year-old woman presented with a 2-month history of abdominal pain on the right side and jaundice after cholecystectomy had been done for these symptoms at another hospital 1 month earlier. She had been receiving loratadine, 10 mg, for allergic arthritis for 14 months after having been switched from terfenadine. Loratadine therapy was discontinued at the time of surgery, and the patient was receiving no other medications. The patient drank alcohol socially and was not taking any over-the-counter medications. She had no family history of liver disease or other significant medical disorders. Physical examination was remarkable for scleral icterus, ascites, and mild abdominal tenderness of the right upper quadrant with hepatosplenomegaly. No cutaneous stigmata of chronic liver disease were evident.

Laboratory findings were as follows: serum bilirubin level, 177.8 µmol/L; aspartate aminotransferase level, 10.74 µkat/L; alanine aminotransferase level, 10.15 µkat/L; alkaline phosphatase level, 3.45 µkat/L; albumin level, 21 g/L; and prothrombin time, 16.9 seconds. Complete blood count, electrolyte levels, and ceruloplasmin levels were normal. The results of serologic tests for hepatitis A, B, and C and human immunodeficiency virus (HIV) were negative. Antinuclear, antimitochondrial, and anti-smooth-muscle antibodies were not present.

Examination of a transjugular liver biopsy specimen showed submassive hepatic necrosis. The patient's condition continued to deteriorate, and she received an orthotopic liver transplant 3 weeks later because of progressive liver failure and worsening encephalopathy.

The explanted liver weighed 1059 g and had a diffusely nodular appearance. Histologic microscopic examination showed massive hepatic necrosis with collapse of the reticulin network that was more prominent in zone 3. The necrotic zones contained an inflammatory infiltrate, proliferating bile ductules, and hemorrhage. Prominent canalicular and intracytoplasmic cholestasis was also present (Figure 1). No definite evidence indicated chronic liver disease.

The patient had a complicated course after the transplantation, but she eventually recovered and continued to do well 12 months later.

Patient 2

A previously healthy man, 33 years of age, presented with a 1-week history of increasing jaundice, fatigue, pruritus, fever, nausea, and abdominal pain on the right side. Three weeks earlier, he had begun receiving loratadine, 10 mg/d, for allergic rhinitis. Two weeks after that time, the patient discontinued loratadine therapy and therapy with bisoprolol fumarate, 2.5 mg, and hydrochlorothiazide, 6.25 mg (Ziac, Lederle Laboratories, Wayne, New Jersey), after the appearance of jaundice. He had been treated with Ziac for hypertension for the preceding 5 months with no adverse effects. The patient had no history of hepatitis, receipt of transfusions, or use of intravenous drugs. He was not taking other prescription or over-the-counter medications, vitamin supplements, or herbal preparations.

Physical examination showed scleral icterus and tender hepatomegaly. No cutaneous stigmata indicative of chronic liver disease were evident. The results of serologic tests for hepatitis A and B viruses, Epstein-Barr virus, cytomegalovirus, and HIV were negative. The results of enzyme immunoassay for hepatitis C virus (HCV) antibody were positive, but the results of polymerase chain reaction assay for HCV RNA were negative [4].

The serum bilirubin level was 273.6 µmol/L, the alanine aminotransferase level was 26.8 µkat/L, the aspartate aminotransferase level was 16.1 µkat/L, the alkaline phosphatase level was 2.2 µkat/L, the prothrombin time was 11.5 seconds, and the albumin level was 48 g/L. Complete blood count and serum protein electrophoresis were normal; no antimitochondrial, antinuclear, or anti-smooth-muscle antibodies were seen.

The patient's symptoms subsided and serum aminotransferase levels improved during the next 3 weeks. Liver biopsy was done 2 weeks after the patient's initial presentation. Microscopic examination showed hepatocellular and focal cholestatic injury. Foci of lobular necrosis were present, and the portal areas contained a mixed inflammatory infiltrate that included eosinophils. Microgranulomas and regenerative activity of hepatocytes were also present; mild canalicular and intracytoplasmic cholestasis was evident (Figure 2). No evidence indicated alcohol-induced or other chronic liver disease.

Three weeks later, the patient's serum bilirubin level was 44.5 µmol/L, his aspartate aminotransferase level was 1.3 µkat/L, his alanine aminotransferase level was 3.2 µkat/L, and his alkaline phosphatase level was 2.0 µkat/L. Two months later, the results of all liver enzyme tests were normal, the results of enzyme immunoassay for HCV antibody remained positive, and the results of polymerase chain reaction for HCV RNA remained negative.

Discussion

According to Physicians' Desk Reference, “abnormal hepatic function, jaundice, hepatitis and hepatic necrosis” occurred rarely during the early clinical testing of loratadine (Claritin, Schering Corp., Kenilworth, New Jersey) [5]. However, no reports of such occurrences have been published. A case of possible loratadine hepatotoxicity resulting in fulminant hepatitis that necessitated orthotopic liver transplantation has been seen, but that patient was also receiving ketoconazole, a well-documented hepatotoxin (Iezzoni DG. Personal communication).

Patient 1 had a comprehensive work-up for causes of subfulminant liver failure, with negative results on viral serologic tests and tests for markers of autoimmune liver disease and normal values for ceruloplasmin and α-1-antitrypsin. The patient had taken loratadine for 14 months before developing jaundice, and the disease progressed after surgery despite discontinuation of therapy with the drug. Whether this patient had other underlying liver disease that predisposed her to loratadine hepatotoxicity is not known.

Patient 2 had a self-limited bout of acute necroinflammatory liver injury with spontaneous resolution. The positive results of testing for antibody to HCV in the absence of HCV RNA suggests either false-positive results or a remote infection with no active viral replication. Examination of the liver biopsy specimen did not suggest HCV infection. Although the patient had been a heavy drinker, the biochemical and histopathologic features did not suggest alcohol-induced liver injury. Without histologic evidence of other causes of liver disease, the evidence of necroinflammatory and cholestatic injury is consistent with drug-related disease. It is extremely unlikely that bisoprolol fumarate was responsible for the acute hepatitis, although mildly elevated aminotransferase levels have been reported with its use [5].

These two cases clearly show that loratadine may cause acute necroinflammatory liver disease that rarely results in the need for liver transplantation. This complication may occur soon after therapy is initiated or as late as 14 months after. Clinicians should be aware of the risk for hepatotoxicity in patients treated with this drug.

Dr. Bellary: 224 Washington Street, Cumberland, MD 21502.

Dr. Cassidy: Suite 13, 1723 Woodbourne Road, Levittown, PA 19057.

Dr. Thomas: Pathology Department, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140.

Dr. Black: Gastroenterology Section, Temple University Hospital, 8th Floor, Parkinson Pavilion, 3401 North Broad Street, Philadelphia, PA 19140.