A 78-year-old Caucasian female presented to a community hospital in Canada with jaundice, scleral icterus, and mild epigastric discomfort. She reported a 4-day history of progressive fatigue with intermittent nausea and vomiting, diminished appetite, as well as loose, lightly coloured, and foul-smelling stools. She had no evidence of coagulopathy or encephalopathy. Her past medical history included essential hypertension, dyslipidemia, and chronic obstructive pulmonary disease. She had no history of liver disease, intravenous drug use, excessive alcohol consumption, recent travel, infectious symptoms, or constitutional symptoms. She had no exposure to poisonous mushrooms or other common hepatotoxic agents. Her medications were atorvastatin 20 mg daily which she had been taking for many years, a course of clarithromycin for community-acquired pneumonia completed 28 days prior to admission, and nifedipine 10 mg daily for hypertension which was started 14 days prior to admission. She did not take any alternative or complementary therapies.
Physical examination revealed a slightly distended abdomen with diffuse tenderness to palpation, particularly in the epigastric region, and jaundice with scleral icterus. There was no rebound tenderness, guarding, or hepatosplenomegaly. She did not have any other stigmata of liver disease and the rest of her physical examination was unremarkable.
Initial laboratory investigations revealed profound elevations in all liver enzymes, bilirubin, and LDH—all indicative of significant hepatocellular injury:
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ALT 1912 U/L (29× upper limit of normal or “ULN”).
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AST U/L (42× ULN).
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ALP 439 U/L (3× ULN).
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GGT 352 U/L (6× ULN).
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Conjugated bilirubin 119 μmol/L (24× ULN).
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Total bilirubin 134 μmol/L (7× ULN).
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LDH 408 U/L (1.7× ULN).
Her INR was between 1.1 and 1.3 throughout the hospitalization, PTT was 27 s, and albumin was slightly low at 31 g/L (normal > 34 g/L). Lipase was within normal range at 288 U/L, and creatine kinase was normal at 31 U/L.
Her complete blood count was within normal limits. There was a mild monocytosis of 1.4 giga/L. Her electrolytes were within normal range. Creatinine was 65 μmol/L with an estimated glomerular filtration rate (eGFR) of 76 mL/min. Her lactate, anion gap, random blood glucose, and extended electrolytes were all also within normal limits.
Other laboratory investigations ruled out many infectious, metabolic, and autoimmune causes of acute liver injury. Serologies (IgM) for Epstein–Barr virus (EBV) and cytomegalovirus (CMV) were negative. Serologies for the human immunodeficiency virus (HIV) and hepatitis A, B, C, and E viruses (e.g. hepatitis A IgM, HBsAg, Anti-HBs, anti-HBc, anti-HBc IgM, anti-HCV, HBeAg) revealed no sign of current infection. Anti-liver kidney microsome type 1 (anti-LKM1) antibody, anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA), ceruloplasmin, and immunoglobulins were negative. Alpha-1 antitrypsin was also negative. The ANA titre was 1:80, a non-specific finding in the context of the patient’s advanced age.
A computed tomography (CT) scan of the patient’s abdomen revealed that her hepatic parenchyma was unremarkable, with no evidence of hepatic obstruction, biliary duct dilatation, thrombosis, or malignancy (Fig. 1). Incidentally, the patient was discovered to have a prominent Riedel’s lobe of the liver and sigmoid diverticulosis. A follow-up abdominal ultrasound revealed that her liver had a heterogeneous echotexture. The gallbladder was markedly thickened and edematous but decompressed.
The patient was admitted to hospital. Suspicious that her liver injury may be statin-induced, her atorvastatin was held on admission. Nifedipine was also held on admission.
Although her liver enzymes continued to steadily improve during the admission, the patient’s clinical condition deteriorated during the first 14 days of hospitalization with worsening fatigue, jaundice, mild hypotension and development of a generalized, pruritic urticarial eruption that partially responded to antihistamines. The patient then developed an acute COPD exacerbation treated with a 5-day course of prednisone, oral moxifloxacin, nebulized ipratropium and salbutamol, and supplemental oxygen.
Given the ongoing elevation in liver enzymes and jaundice, an ultrasound-guided core liver biopsy was performed. The biopsy demonstrated portal tract and central zone inflammation with necrosis and plasma cell infiltrates, which was consistent with a hypersensitivity-mediated drug-induced hepatitis (see Fig. 2).
Plasma cell infiltration of the liver, seen in our patient’s liver biopsy, can be a sign of autoimmune hepatitis. However, in this case, we felt that the overall histologic pattern of liver damage was not consistent with what would be typically seen in autoimmune hepatitis. This, coupled with the absence of immunological markers associated with autoimmune hepatitis, made the diagnosis of autoimmune hepatitis less likely.
In addition, the patient’s presentation is very consistent with published cases of nifedipine-induced hepatitis, which have suggested that symptoms typically manifest within 2 weeks of initial exposure. This patient’s symptoms began 10 days after she started taking the drug.
During our patient’s third week of hospital stay, her bilirubin and liver enzymes began to normalize. Her jaundice, abdominal pain, and urticaria resolved, and her energy improved. She remained in hospital for 2 additional weeks for supportive care and rehabilitation. She was discharged home after 5 weeks of hospitalization with full resolution of her liver disease and return to baseline functioning.
The limitation of our diagnosis was that it largely relied on the exclusion of other diagnoses. While it remains possible that there was another etiology, we felt the odds were small. One way to confirm the diagnosis would be to re-challenge the patient with nifedipine after she has recovered from the illness, to see if a similar reaction recurred. However, given the severity of the patient’s liver injury, we did not have the option to do this.
The patient’s other medications—in particular atorvastatin and clarithromycin—have also been associated with drug-induced hepatitis. However, for various reasons discussed below, we felt that nifedipine was the most likely cause.
The possibility that the patient’s liver injury was caused by atorvastatin was strongly considered, however ultimately, we believe this to be less likely as the patient had been taking atorvastatin for years with no complications. Twelve weeks after the patient was discharged from hospital, the patient was re-challenged with atorvastatin at gradually increasing doses and experienced no liver injury.
Clarithromycin has been known to cause liver enzyme elevations in 1–3% of patients exposed to the drug, and rarely, it can also cause fulminant hepatitis similar to nifedipine. One key difference is that a number of deaths have been reported in the literature for clarithromycin, whereas none have been reported for nifedipine [13]. The histology of both statin and clarithromycin-induced hepatitis can be similar to the histology of nifedipine-induced hepatitis. All can exhibit signs of cholestasis [14] and infiltration of immune cells [15]. Despite these similarities, the diagnosis of clarithromycin-induced hepatitis was felt to be less likely for our patient as she has been exposed to clarithromycin on multiple occasions for COPD exacerbations over the past several years, and none of her previous exposures to clarithromycin has resulted in drug-induced liver injury. Furthermore, the onset and peak of liver injury in relation to the timing of clarithromycin exposure is not typical of clarithromycin-induced liver injury—at least for the ones that have been reported. A recent review of the literature on this topic demonstrated that the vast majority of fulminant liver injuries caused by clarithromycin occur within days of administration, usually within 1 week [13]. Onset of fulminant liver injury that occurs 3 weeks after discontinuation of clarithromycin has virtually been unreported.
