Disulfiram hepatotoxicity: Report of three cases

Celada-Sendino, Miriam; Álvarez-Navascués, Carmen; Rodríguez, Manuel

doi:10.1016/j.medcle.2021.04.019

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However, it can be difficult to reach a definitive diagnosis, leading to underestimate its potential hepatotoxicity.Case reportsCase 1A 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) 2020IU/L, alanine aminotransferase (ALT) 3467IU/L, alkaline phosphatase (ALP) 254IU/L, γ-glutamyltransferase (GGT) 80IU/L and total bilirubin (TB) of 16.4mg/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">1</a> The patient was discharged with no medication and she has evolved satisfactory with liver function tests within normal range in April 2020.Case 2A 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 1709IU/L, ALT 1406IU/L, ALP 120IU/L, GGT 111IU/L, TB 15.1mg/dl and INR of 1.49. Notably, an analytical test performed in October 2019 showed similar values in liver tests (AST 1395IU/L, ALT 1134IU/L, ALP 154IU/L, GGT 191IU/L, TB 9.1mg/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.Case 3A 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 3431IU/L, ALT 2133IU/L, TB 23mg/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.DiscussionDisulfiram 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">2,3</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.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">4</a>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">5</a> In view of the above, we can hypothesize that this trend will change in the future." 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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. Olsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2005.12.016" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2006" "volumen" => "44" "paginaInicial" => "791" "paginaFinal" => "797" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16487618" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disulfiram-induced hepatitis. Report of four cases and review of the literature" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X. Forns" 1 => "J. Caballería" 2 => "M. Bruguera" 3 => "J. Salmerón" 4 => "A. Vilella" 5 => "A. Mas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0168-8278(94)80249-1" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "1994" "volumen" => "21" "paginaInicial" => "853" "paginaFinal" => "857" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7890903" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver transplantation for disulfiram-induced fulminant hepatic failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.R. Mohanty" 1 => "D.R. LaBrecque" 2 => "F.A. Mitros" 3 => "T.J. 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. García-Ruiz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.gastro.2005.05.006" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2005" "volumen" => "129" "paginaInicial" => "512" "paginaFinal" => "521" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16083708" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015800000003/v1_202202040749/S2387020622000183/v1_202202040749/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015800000003/v1_202202040749/S2387020622000183/v1_202202040749/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622000183?idApp=UINPBA00004N"]

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Vol. 158. Issue 3.

Pages 145-146 (February 2022)

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