Cholestatic Drug-Induced Liver Injury in a Patient Taking High-Dose Niacin for Hyperlipidemia

Abstract

Niacin, an important component of a balanced diet, is central to lipid metabolism. Occasionally used to treat hyperlipidemia, niacin is widely available without a prescription, making its use often unknown to treating physicians. Severe hepatotoxicity has been reported with niacin use. In the following report, we describe a case of hospitalization for acute decompensated cirrhosis with cholestatic morphology in a patient taking self-initiated large quantities of extended-release niacin. Despite medical management and support, the patient unfortunately expired on day 16 of hospitalization. Given ease of access and unclear long-term benefit in hyperlipidemia, the current case serves to raise awareness of niacin’s potential hepatotoxicity through highlighting a severe outcome. Although mode of liver injury remains unknown, the use of extended-release niacin formulations and prolonged high-dose supplementation is associated with enhanced hepatotoxicity. Careful review and counseling of commonly available supplements remains an important task of both hospital and primary care physicians.

Introduction

Niacin is central to tissue and lipid metabolism, including glycogenolysis. ¹ Supplemental niacin has shown clinical benefit in certain scenarios, including reducing mortality, cardiovascular events, and progression of atherosclerosis in high-risk patients.^2,3 Niacin is naturally present in a variety of alimentary products with recommended daily intake of 14 to 16 mg for adults. ⁴ Prescription strength niacin is available in immediate and sustained release formulations. Niacin is also available without prescription as a dietary supplement with supplementation often unbeknownst to primary care providers.

The use of supplemental niacin is contraindicated in hepatic impairment and unexplained elevation of transaminases due to its hepatotoxic potential.^5-7 Although the mechanism of injury remains unknown, both a hepatocellular and cholestatic pattern of injury has been reported.^5,8,9 We present a case of decompensated cirrhosis with cholestatic morphology in a patient on self-initiated high-dose niacin supplementation.

Case Summary

A 79-year-old man with a past medical history of idiopathic compensated cirrhosis, diabetes, metabolic syndrome, hypertension, dyslipidemia, and coronary artery disease presented to the emergency room with 2 days of jaundice and scleral icterus. The patient also noted darkening of his urine 2 weeks prior and intermittent clay-colored stools for 2 months. The patient had previously undergone extensive evaluation for a 4-year history of slow elevation of aspartate aminotransferase and alkaline phosphatase of unknown cause. During that time, his other symptoms included weight loss, intermittent dark discoloration of urine, intermittent clay-colored stools, abdominal and leg swelling, muscle cramping, tender gynecomastia, and intermittent pruritus. Magnetic resonance imaging performed 2 years earlier revealed cirrhotic liver morphology with confluent bands of enhancing fibrosis, periumbilical and upper abdominal venous collaterals and trace ascites. He was presumed to have cryptogenic cirrhosis with portal hypertension. Prior to the current presentation, his cirrhosis had been compensated with no evidence of jaundice, hepatic encephalopathy, ascites, or variceal bleeding.

Of note, the patient’s diabetes was poorly controlled with HbA1c 9.2% 5 months before presentation. He was also taking icosapent ethyl for hyperlipidemia due to a history of intolerance to multiple statins (atorvastatin, simvastatin, lovastatin), having previously developed severe myalgia and malaise, although no rhabdomyolysis had been documented. Other medications included aspirin 81 mg and carvedilol 3.125 mg for coronary artery disease and hypertension.

On presentation, the patient was hemodynamically stable, with heart rate 91, respiratory rate 18, blood pressure 166/62 mm Hg, and temperature 97.5 °F. Body mass index (BMI) was 26.3 kg/m³. Physical examination showed scleral icterus, generalized jaundice, a distended non-tender abdomen, and bilateral pitting edema up to the knees. Initial laboratory studies were notable for marked direct hyperbilirubinemia with total bilirubin 27.9 and conjugated bilirubin 21.6. The elevation of transaminases was present with alanine aminotransferase 157 and aspartate aminotransferase 409. Calculated MELD-Na score was 30. Lipid panel showed total cholesterol 187, low-density lipoprotein (LDL) 148, high-density lipoprotein (HDL) 19, and triglycerides 108. Given laboratory pattern consistent with obstructive jaundice, we obtained a right upper quadrant ultrasound, which revealed cirrhotic liver morphology and non-specific gallbladder wall thickening. No biliary duct dilatation, cholelithiasis, or biliary sludge was noted. Sonographic Murphy’s sign was negative. We investigated infectious, toxic, and autoimmune etiologies of cholestatic jaundice, including viral hepatitis, anti-mitochondrial antibody, acetaminophen, and ethyl glucuronide, which were all unremarkable.

Subsequent abdominal computed tomography was performed to exclude intra-abdominal infection. This demonstrated liver cirrhosis with sequela of portal hypertension, small volume ascites, portal colopathy, and esophageal varices (Figure 1). No cause of biliary obstruction was identified.

Figure 1.

Computed tomography showing cirrhotic liver morphology with multiple hypodensities.

During hospitalization, direct hyperbilirubinemia continued to worsen with subsequent development of hepatic encephalopathy and somnolence on day 3. We initiated lactulose, rifaximin, and zinc, but there was minimal improvement. We pursued a transjugular liver biopsy given rapidly decompensating cirrhosis. Results demonstrated marked cholestasis with ballooning degeneration and patchy areas of globular accumulation. Mild mixed portal tract infiltrates with focal ductal proliferation were noted without ductopenia. Features of steatohepatitis with Mallory hyaline and sinusoidal fibrosis were also noted (Figure 2). These histological features favored a chronic, toxic metabolic injury. Given the patient’s lack of exposure to common hepatotoxic medications, we performed an extensive review of current and past hepatotoxic substances. This uncovered self-initiated daily use of extended-release 2500 mg niacin for the past 15 years as an adjunct treatment for hyperlipidemia. No other cause of toxic metabolic injury was identified, including lack of alcohol and tobacco exposure. As patient continued to clinically decline, we attempted systemic corticosteroids, and consulted hepatology for possible liver transplant. The patient was considered a poor candidate for transplantation due to his advanced age and comorbidities. Despite the medical team’s effort, the patient developed refractory hypotension and stupor. A family meeting was arranged, after which escalation of care was deemed inconsistent with the patient’s wishes. The patient expired on day 16 of hospitalization.

Figure 2.

Marked cholestasis with ballooning degeneration and patchy areas of globular accumulation (green arrow). The portal tracts show a mixed infiltrate with focal ductal proliferation without ductopenia. Periodic acid-Schiff (PAS)-positive intracellular and extracellular globular accumulation are seen (black arrow: hematoxylin and eosin stain; red arrow: PAS stain).

Discussion

The current report highlights a case of decompensated cirrhosis in an elderly man with an extended history of self-initiated high-dose niacin supplementation. High concentrations of niacin have known risk of hepatotoxicity. ¹⁰ Undergoing first pass metabolism in the liver, resultant niacin metabolites have injurious effects to the liver through an unclear mechanism. ⁸ Immediate release niacin formulations are rapidly absorbed, overwhelming the hepatic amidation pathway and hence metabolized primarily by the conjugation pathway. ⁸ On the contrary, sustained and extended-release formulations are metabolized mainly by the amidation pathway.^8,11 Evidence suggests that sustained and extended-release niacin formulations have a greater hepatotoxic potential, likely due to sustained production of toxic metabolites.^6,11 Literature on niacin-induced liver injury suggests that the mechanism of injury involves mitochondrial injury.^6,8,10,11 In the current case, pathology was consistent with cholestasis and chronic toxic metabolic injury, as represented by the histopathologic features of ballooning degeneration, patchy areas of globular accumulation, mixed portal tract infiltrates, and fibrosis. Hepatic stellate cell hyperplasia ¹² and focal fatty infiltration of the liver have also been reported in cases of niacin-induced liver injury. ¹³ Our case, unlike most others, demonstrated a cholestatic pattern of hepatotoxicity.

The timeline of hepatic injury from niacin is variable, ranging from days to years. ⁷ Reports indicate that both short-term and of low-dose niacin (3000 mg/day or less) may cause acute hepatotoxicity and drug-induced hepatitis. ⁷ Most reported cases of acute liver failure resolved with discontinuation of niacin. In the present case, hepatic injury from long-term use of niacin was irreversible with discontinuation of niacin, evidenced by fibrotic changes and cirrhosis. In our patient, it is likely that the prolonged history of high-dose niacin supplementation resulted in permanent livery injury with subsequent decompensation. In keeping with the patient’s history of uncontrolled diabetes, hypertension, and dyslipidemia, it is important to consider that steatohepatitis, as noted in his liver biopsy, secondary to metabolic syndrome may additionally have contributed to the underlying liver cirrhosis and eventual decompensation. ¹³

The evidence for Niacin use is currently scant to none and its use obsolete in modern practice. Majority of randomized control trials ¹⁴ found that adding extended-release niacin to statin treatment made no difference to the chances of high-risk patients having a heart attack or stroke.

In conclusion, although niacin supplementation may have beneficial effects in hyperlipidemia, severe hepatotoxicity may result from long-term or high-dose supplementation. This case of cirrhosis ultimately resulting in fatality highlights the risks of high-dose niacin use. Given niacin’s ease of availability without physician monitoring, this case serves to raise awareness of potential hepatotoxicity and highlights the importance of in-depth review of non-prescription supplements.