Acute liver failure following atorvastatin dose escalation: Is there a threshold dose for idiosyncratic hepatotoxicity?
Authors: Miguel F. Carrascosa, José R. Salcines-Caviedes, M. Isabel Lucena, Raul J. Andrade
Journal: Journal of Hepatology (2014)

The bulk of hepatotoxicity (drug induced liver injury, DILI) cases in clinical practice is idiosyncratic in nature. This assumption is based on the apparent absence of dose dependency and the unpredictability of the reaction, which presents after a relatively long latency period of drug exposure in susceptible individuals. Recent evidence suggests that the administration of high oral daily dose of drugs that undergo extensive hepatic metabolism does influence the risk of developing idiosyncratic DILI (IDILI) [1Lammert C. Einarsson S. Saha C. Niklasson A. Bjornsson E. Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.Hepatology. 2008; 47: 2003-2009Crossref PubMed Scopus (305) Google Scholar, 2Lammert C. Bjornsson E. Niklasson A. Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events.Hepatology. 2010; 51: 615-620Crossref PubMed Scopus (200) Google Scholar]. We report a patient safely treated with atorvastatin at a standard therapeutic dose for more than a year who developed acute liver failure and rhabdomyolysis after doubling the daily dose of the drug (Supplementary Fig. 1). An 85-year-old woman was admitted in February 2014 because of a 4-day history of worsening drowsiness, anorexia, jaundice, dark-yellow-coloured urine, and vomiting. Since early January, she had complained of fatigue, decreasing ability to walk, and sleepiness. Eighteen months prior to the episode six intracoronary stents were placed. Past medical history included diabetes mellitus, hypercholesterolemia, arterial hypertension, and essential tremor. She had been receiving atorvastatin (40 mg daily) since June 2012, along with furosemide, ramipril, omeprazole, aspirin, metformin, and phenobarbital for more than 3 years. She had no toxic habits and denied taking over-the-counter drugs, herbal remedies, dietary supplements, or grapefruit. Five months before admission, the atorvastatin dose was increased to 80 mg daily due to deficient lipaemic control. Liver and renal biochemistry at the time of starting atorvastatin and repeatedly checked thereafter up to September 2013 (prior to atorvastatin dose escalation), had remained within the normal range. On admission, blood pressure was 131/68 mmHg and heart rate 78/min. Physical examination revealed jaundice, confusion, and pronounced asterixis. Her body mass index was 29.5 kg/m2. Diagnostic work-up showed elevated alanine aminotransferase (909 IU/L, n: ⩽31), aspartate aminotransferase (1157 IU/L, n: ⩽31), alkaline phosphatase (415 IU/L, n: ⩽104), total bilirubin (70.1 μmol/L, n: 1.7–20.5), and creatine kinase 4753 IU/L (33–185) levels, and an international normalized ratio of 1.71. Abdominal ultrasonography revealed mild perihepatic ascites. Serology ruled out viral hepatitis and autoimmune disease. There was neither history nor in-hospital evidence of syncope, hypotension or heart failure. In addition, echocardiography displayed normal findings except for mild left ventricular hypertrophy. Atorvastatin induced liver injury was suspected and all drugs were stopped. After 2 days, the patient deteriorated and developed grade IV hepatic encephalopathy (serum ammonia level of 159 μmol/L, n: <48) (Supplementary Table 1) and hypoglycemia. A brain CT scan displayed no relevant abnormalities. Under supportive treatment, however, clinical and laboratory parameters gradually improved and she was discharged on day 12 on her habitual medications except for atorvastatin. A causality for atorvastatin, as assessed using the Roussel Uclaf Causality Assessment Method, was probable (see Supplementary data section). Furthermore, clinically significant pharmacokinetic drug interactions between atorvastatin and the rest of compounds were judged to be highly improbable [3Malhotra H.S. Goa K.L. Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.Drugs. 2001; 61: 1835-1881Crossref PubMed Scopus (134) Google Scholar, 4Björnsson E. Jacobsen E. Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing.J Hepatol. 2012; 56: 374-380Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar]. In April, upon coagulopathy resolution, she underwent a liver biopsy, which revealed portal hepatitis with an inflammatory infiltrate consisting of lymphocytes (mainly T lymphocytes) and eosinophils (Fig. 1A and B, Supplementary Fig. 2). Of note, there was no evidence of chronic liver disease. At a follow-up visit 7 months after discharge, she remained well and serum transaminases, total bilirubin, and creatine kinase had normalized, while alkaline phosphatase remained slightly increased (115 IU/L). The hepatotoxic potential of statins has been controversial and even suggested to be a myth [[5]Bader T. Liver tests are irrelevant when prescribing statins.Lancet. 2010; 376: 1882-1883Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Recent data, however, clearly support that these compounds can cause severe liver damage, occasionally leading to fulminant liver failure [6Russo M.W. Hoofnagle J.H. Gu J. Fontana R.J. Barnhart H. Kleiner D.E. et al.Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.Hepatology. 2014; 60: 679-686Crossref PubMed Scopus (147) Google Scholar, 7Perdices E.V. Medina I. Hernando S. Ortega A. Martín-Ocaña F. Navarro J.M. et al.Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.Rev Esp Enferm Dig. 2014; 106: 246-254PubMed Google Scholar]. Two recent large prospective studies on DILI in the USA and in Spain, respectively included 22 and 47 well vetted hepatotoxicity cases adjudicated to statins. Atorvastatin was the most frequently implicated drug in both cohorts [6Russo M.W. Hoofnagle J.H. Gu J. Fontana R.J. Barnhart H. Kleiner D.E. et al.Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.Hepatology. 2014; 60: 679-686Crossref PubMed Scopus (147) Google Scholar, 7Perdices E.V. Medina I. Hernando S. Ortega A. Martín-Ocaña F. Navarro J.M. et al.Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.Rev Esp Enferm Dig. 2014; 106: 246-254PubMed Google Scholar]. Indeed, among statins, atorvastatin seems to carry a higher risk of DILI with a calculated risk of 1/3693 patients treated in a population-based study [[8]Björnsson E.S. Bergmann O.M. Björnsson H.K. Kvaran R.B. Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar]. Interestingly, the present case highlights the fact that IDILI happened only after increasing the atorvastatin dose. This observation raises the possibility of IDILI occurring after exceeding a threshold dose in each unique susceptible individual. Atorvastatin, a highly lipophilic drug, is extensively metabolized by CYP3A4. Increasing the dose of a drug with these characteristics [[9]Chen M. Borlak J. Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury.Hepatology. 2013; 58: 388-396Crossref PubMed Scopus (216) Google Scholar] can place a patient at a higher risk of developing IDILI. The mechanisms underlying IDILI are complex, multifactorial, and poorly understood but it is generally accepted that an interplay between the drug's pharmacological properties and host factors is needed. We can speculate that enhancing the chemical drug component might have misbalanced this cross-talk, precipitating the event. Existing databases of IDILI patients [6Russo M.W. Hoofnagle J.H. Gu J. Fontana R.J. Barnhart H. Kleiner D.E. et al.Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.Hepatology. 2014; 60: 679-686Crossref PubMed Scopus (147) Google Scholar, 7Perdices E.V. Medina I. Hernando S. Ortega A. Martín-Ocaña F. Navarro J.M. et al.Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.Rev Esp Enferm Dig. 2014; 106: 246-254PubMed Google Scholar], which contain detailed pharmacological information and phenotype description, could enable doctors to establish a risk stratification and determine the safe dose of drugs with presumed hepatic harmful chemical properties. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We thank Dr Inmaculada Medina-Caliz and Dr Ainara Azueta for their invaluable collaboration. Download .pdf (.35 MB) Help with pdf files Supplementary data