Severe acute hepatic failure secondary to amiodarone overdose

Balint Ilie, Celina; Montón Dito, José María; Esteban Molina, Ana

doi:10.1016/j.medcle.2022.09.007

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Its long-term side effects, such as impaired thyroid and liver function, development of peripheral neuropathy, and pulmonary fibrosis, are widely known. However, there are few case reports of acute amiodarone toxicity, including fulminant hepatitis, a potentially fatal entity.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>We report the case of a 66-year-old male patient, with a history of hypertension, type II diabetes mellitus, and dyslipidaemia, receiving treatment with telmisartan-hydrochlorothiazide, metformin-vildagliptin, fenofibrate, and ezetimibe. He came to the Emergency Department for a 5-day history of asthenia, myalgia and dyspnoea. On initial assessment he was conscious, oriented, with a systolic blood pressure (SBP) of 100 mmHg, atrial flutter at 150 bpm. Eupnoeic, bilateral normal ventilation, baseline oxygen saturation of 97%, and adequate distal perfusion. Soft abdomen, not painful on deep palpation. Blood analysis: renal function and ions in normal range. Ultrasensitive troponin T 12 ng/l, total bilirubin (TB) 0.7 mg/dl, GOT 24 IU/l, GPT 17 IU/l, white blood cells 8000/l. Procalcitonin < 0.1 ng/ml. Haemoglobin 15 g/dl.Platelets 265,000/l. Prothrombin activity (PA) 87%. Positive COVID-19 nasal swab PCR. Chest X-ray without pathological findings. Treatment was started with bisoprolol 5 mg, diltiazem 60 mg and continuous amiodarone infusion (1200 mg/24 h).The patient was admitted to the hospital ward for heart rate monitoring.Atrial flutter persisted in the following hours with ventricular response around 120−140 bpm without haemodynamic instability or symptoms. Treatment was intensified, with 2400 mg of IV amiodarone administered within 48 h of admission. The total cumulative dose was 2600 mg amiodarone over 56 h. After that time, he began to experience general malaise and epigastric pain accompanied by vomiting. Clinical worsening with obtundation, tachypnoea, slow atrial flutter, maintaining a 90−100 mmHg SBP. Emergency laboratory tests showed severe metabolic acidosis (pH 6.8, pO2 138 mmHg, pCO2 13 mmHg, bicarbonate 2 mmHg, base excess — 31 mmol/l), lactate > 17 mmol/l, acute renal failure with creatinine 5 mg/dl, hyperbilirubinaemia (2.32 mg/dl) at the expense of direct bilirubin (1.42 mg/dl), hyperphosphataemia (10.8 mg/dl), with elevation of hepatic cytolysis enzymes: GOT 21,256 IU/l and GPT 6.327 IU/l, GGT 79 IU/l, coagulopathy with PA 33%. Haemodynamic resuscitation was started, antiarrhythmic treatment was discontinued, and orotracheal intubation, connection to mechanical ventilation and admission to the Intensive Care Unit (ICU) ensued.Transthoracic echocardiography showed adequate biventricular function, and abdominal ultrasound ruled out filling defects, chronic liver disease, and infiltrative disease. The study was completed with IV contrast abdominal computed tomography, showing free fluid in the peritoneal recesses with no other findings. Blood cultures, urine culture, bronchial aspirate, hepatotropic virus serologies (HAV, HBV, HCV, HDV and E, EBV, Herpes Virus, CMV, Parvovirus, HIV), complete autoimmunity study, and cupremia were normal.Based on the diagnostic hypothesis of severe acute toxic liver failure secondary to amiodarone, supported by the use of supratherapeutic doses of the drug (>1200 mg in 24 h), IV N-acetylcysteine, respiratory and haemodynamic support were administered. A significant laboratory improvement was observed 24 h after drug discontinuation, with a decrease in lactate, cytolysis enzymes and improved coagulation times.Applying Karch and Lasagna's algorithm<a class="elsevierStyleCrossRef" href="#bib0015">3</a> (time sequence + 1, prior knowledge + 2, withdrawal effect + 2, re-exposure 0, alternative causes + 1, contributing factors + 1, supplementary evidence 0), with a score of 8 out of 12, confirmed the relationship between IV amiodarone administration and fulminant hepatitis as an adverse reaction. No notification was made to the National Pharmacovigilance Service.The remaining treatments that were administered prior to his admission to ICU (dexamethasone 4 mg every 24 h, metoclopramide 10 mg every 8 h, omeprazole 40 mg every 24 h, bisoprolol 2, 5 mg every 12 h, ezetimibe 10 mg every 24 h, fenofibrate 160 mg every 24 h) had no evident relationship with the doses used in the development of fulminant hepatitis, as described in the literature.In conclusion, it should be emphasised that acute toxic hepatitis secondary to intravenous amiodarone is an uncommon condition with rare occurrences in the medical literature, but with a high mortality rate in the reported cases<a class="elsevierStyleCrossRef" href="#bib0020">4</a>; therefore, it should be known and assessed when using this drug, remembering that the maximum dose of intravenous amiodarone is 1200 mg per day.Transient transaminase elevation occurs in 15–40% of patients receiving amiodarone. Although the mechanism of hepatotoxicity is not yet well known, the toxicity of one of its excipients has been described, polysorbate 80, which produces a massive increase in oxygen radicals in the liver, inducing mitochondrial toxicity, oxidative stress and centrilobular necrosis.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The short half-life of the excipient in plasma would explain the rapid recovery after drug withdrawal.It is important to monitor liver enzymes during treatment; discontinuation of the drug would halt progression and lead to resolution of the condition.FundingNo funding was received for the preparation of this manuscript.Conflict of interestsCelina Balint Ilie: I declare that I have no financial or personal relationship that may involve a conflict of interest.Jose Maria Montón Dito: I declare that I have no financial or personal relationship that may involve a conflict of interest.Ana Esteban Molina: I declare that I have no financial or personal relationship that may involve a conflict of interest." 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Available from: <a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/28417882/">https://pubmed.ncbi.nlm.nih.gov/28417882/</a>." ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "N-Acetylcysteine for non-paracetamol (acetaminophen)-related acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.T.P. Siu" 1 => "T. Nguyen" 2 => "R.D. Turgeon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/14651858.CD012123.pub2" "Revista" => array:3 [ "tituloSerie" => "Cochrane Libr [Internet]" "fecha" => "2020" "volumen" => "12" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Gob.pe. Instructivo para evaluación de la causalidad usando el algoritmo Karch y Lasagna modificado [Accessed 30 May 2022]. Available from: <a target="_blank" href="http://www.essalud.gob.pe/ietsi/pdfs/farmacoytecno/4_Formato_Evaluac_deCausalidad_Algoritmo.pdf">http://www.essalud.gob.pe/ietsi/pdfs/farmacoytecno/4_Formato_Evaluac_deCausalidad_Algoritmo.pdf</a>." ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "LiverTox: Clinical and research information on drug-induced liver injury [internet]" ] ] "host" => array:2 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2012" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "https://pubmed.ncbi.nlm.nih.gov/31643176/" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute hepatotoxicity of intravenous amiodarone: case report and review of the literature" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.-C. 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Vol. 160. Issue 2.