Letter to the Editor
Disulfiram hepatotoxicity: Report of three cases
Hepatotoxicidad por disulfiram: a propósito de tres casos
Miriam Celada-Sendino
, Carmen Álvarez-Navascués, Manuel Rodríguez
Corresponding author
Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
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However, it can be difficult to reach a definitive diagnosis, leading to underestimate its potential hepatotoxicity.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case reports</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Case 1</span><p id="par0010" class="elsevierStylePara elsevierViewall">A 48-year-old woman presented in February 2020 with jaundice and malaise. She had been taking disulfiram for the last two months for alcohol addiction. Laboratory tests showed serum aspartate aminotransferase (AST) 2020<span class="elsevierStyleHsp" style=""></span>IU/L, alanine aminotransferase (ALT) 3467<span class="elsevierStyleHsp" style=""></span>IU/L, alkaline phosphatase (ALP) 254<span class="elsevierStyleHsp" style=""></span>IU/L, γ-glutamyltransferase (GGT) 80<span class="elsevierStyleHsp" style=""></span>IU/L and total bilirubin (TB) of 16.4<span class="elsevierStyleHsp" style=""></span>mg/dl. International normalized ratio (INR) was 1.36. Other potential causes of acute hepatitis were ruled out. Liver biopsy showed acute necrotic lesion with numerous eosinophils consistent with acute toxic hepatitis. Causality of disulfiram was probable according to the CIOMS/RUCAM scale (7 points).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> The patient was discharged with no medication and she has evolved satisfactory with liver function tests within normal range in April 2020.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Case 2</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 44-year-old woman was referred to our Unit in March 2020, complaining of fatigue and nausea. She was on treatment with disulfiram for alcohol dependence since August 2019. Blood tests revealed AST 1709<span class="elsevierStyleHsp" style=""></span>IU/L, ALT 1406<span class="elsevierStyleHsp" style=""></span>IU/L, ALP 120<span class="elsevierStyleHsp" style=""></span>IU/L, GGT 111<span class="elsevierStyleHsp" style=""></span>IU/L, TB 15.1<span class="elsevierStyleHsp" style=""></span>mg/dl and INR of 1.49. Notably, an analytical test performed in October 2019 showed similar values in liver tests (AST 1395<span class="elsevierStyleHsp" style=""></span>IU/L, ALT 1134<span class="elsevierStyleHsp" style=""></span>IU/L, ALP 154<span class="elsevierStyleHsp" style=""></span>IU/L, GGT 191<span class="elsevierStyleHsp" style=""></span>IU/L, TB 9.1<span class="elsevierStyleHsp" style=""></span>mg/dl). Nevertheless, she continued with the same treatment. A complete etiological panel was negative and liver biopsy showed necrosis areas with inflammatory infiltration, compatible with acute hepatitis. When CIOMS/RUCAM scale was applied to assess disulfiram role, a score of 7 was obtained (probable). Following disulfiram discontinuation, liver enzymes returned to normal values 6 weeks later.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case 3</span><p id="par0020" class="elsevierStylePara elsevierViewall">A 53-year-old man, who was dentist and with no prior known liver disease, had self-medicated with disulfiram to give up alcohol consumption for ten days before symptom onset. He was admitted to the emergency department of his local hospital in June 2019 with diarrhoea and jaundice. At that time, laboratory tests showed AST 3431<span class="elsevierStyleHsp" style=""></span>IU/L, ALT 2133<span class="elsevierStyleHsp" style=""></span>IU/L, TB 23<span class="elsevierStyleHsp" style=""></span>mg/dl and an INR of 3.48. Disulfiram was stopped promptly and he was transferred to our liver Unit. Etiological studies were negative, except antinuclear antibodies positive 1/160 with nucleolar pattern. Abdominal ultrasound revealed a heterogeneous micronodular liver parenchyma with signs of portal venous hypertension. The calculated CIOMS/RUCAM score for disulfiram causality was 4 (possible). Four days after admission, the patient presented clinical worsening with hepatic encephalopathy, so liver transplant was performed, with satisfactory evolution. The explant showed important liver necrosis and signs of cirrhosis, without findings of steatohepatitis.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Disulfiram has been frequently used as an adjuvant in the treatment of alcohol use disorder (AUD), working as an alcohol deterrent. It is known that chronic therapy with disulfiram is associated with subclinical changes in liver function tests, with a predominantly hepatocellular damage pattern, but marked elevations of transaminases are uncommon.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">2,3</span></a> It is recommended to perform liver function tests before starting disulfiram treatment and periodically during it, being contraindicated in presence of advanced liver disease. Anyhow, if hepatitis is noticed, it is indicated to stop disulfiram as soon as possible.</p><p id="par0030" class="elsevierStylePara elsevierViewall">It could be interesting to debate some issues: firstly, patients with harmful alcohol intake may have already pre-existing liver disease, which can increase the risk of developing hepatotoxicity, so disulfiram prescription should be done with extremely caution. Secondly, alcoholic hepatitis can cause a clinical picture similar to DILI, so liver biopsy can be useful in differential diagnosis. Lastly, although ACLF due to non-alcohol-related cause, such as disulfiram-induced liver injury, is an indication of liver transplant, short term alcohol abstinence and consequently the possibility of relapse in alcohol consumption after transplantation could raise ethical dilemmas.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">We would like to highlight that these three cases described above have been seen in a short period of time, probably related to an increased use of disulfiram in the last months due to the withdrawal from the market in Spain in July 2019 of calcium carbimide, which contrasts with the very small number of cases recorded in the large DILI registries.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> In view of the above, we can hypothesize that this trend will change in the future.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Case reports" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 2" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 3" ] ] ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G. Danan" 1 => "C. Benichou" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0895-4356(93)90101-6" "Revista" => array:6 [ "tituloSerie" => "J Clin Epidemiol" "fecha" => "1993" "volumen" => "46" "paginaInicial" => "1323" "paginaFinal" => "1330" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8229110" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical characteristics and prognostic markers in disulfiram-induced liver injury" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. Björnsson" 1 => "H. Nordlinder" 2 => "R. 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Layden" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00004836-200403000-00018" "Revista" => array:6 [ "tituloSerie" => "J Clin Gastroenterol" "fecha" => "2004" "volumen" => "38" "paginaInicial" => "292" "paginaFinal" => "295" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15128079" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Andrade" 1 => "M.I. Lucena" 2 => "M.C. Fernández" 3 => "G. Pelaez" 4 => "K. Pachkoria" 5 => "E. 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