Scientific letter
Chronic autoimmune hepatitis triggered by olmesartan
Hepatitis autoinmune crónica desencadenada por olmesartán
Daniel Riado Minguez
, Maria Luisa Gutierrez Garcia, Conrado Fernandez Rodriguez
Corresponding author
Servicio Aparato Digestivo, Hospital Universitario Fundacion Alcorcon, Alcorcón, Madrid, Spain
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Two case reports suggest the association of olmesartan with the development of drug induced liver injury (DILI).<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">1,2</span></a> We present a case of hypertransaminasemia showing temporal association between exposure to olmesartan and onset of clinics, recovery after withdrawal and several episodes of recurrence, the first of them after reexposure to olmesartan. Autoimmunity tests and liver biopsies suggested an autoimmune mechanism to explain this phenomenon. Differencial diagnosis between DILI and autoimmune hepatitis was difficult to carry out, but the second episode of recurrence and the evolution after corticosteroid therapy supported the diagnosis of chronic autoimmune hepatitis triggered by olmesartan.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 61-year old Caucasian male who works as a doctor presented in the Emergency Department of our centre in February 2017 with a 1-month history of vespertine febricula, malaise, fatigue, anorexia, arthromyalgia and weight loss. The patient had no significant medical history except for arterial hypertension and a choledocal cyst operated in 2007 with Roux-en-Y hepaticojejunostomy and cholecystectomy. There was no familial history of chronic liver diseases or significant alcohol intake. He was under treatment with olmesartan 10<span class="elsevierStyleHsp" style=""></span>mg once daily. Laboratory tests revealed 50% of activated lymphocytes, absence of coagulopathy, elevation of liver enzymes [aspartate aminotransferase 504<span class="elsevierStyleHsp" style=""></span>U/L (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>37), alanine aminotransferase 568<span class="elsevierStyleHsp" style=""></span>U/L (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>41), alkaline phosphatase 143<span class="elsevierStyleHsp" style=""></span>U/L (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>129), gamma-glutamyl transpeptidase 135<span class="elsevierStyleHsp" style=""></span>U/L (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>50)] with total bilirubin 0.9<span class="elsevierStyleHsp" style=""></span>mg/dL (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1.0<span class="elsevierStyleHsp" style=""></span>mg/dL) and elevation of lactate dehydrogenase 357<span class="elsevierStyleHsp" style=""></span>U/L (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>235<span class="elsevierStyleHsp" style=""></span>U/L), C-reactive protein 75.6<span class="elsevierStyleHsp" style=""></span>mg/L (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>5.0<span class="elsevierStyleHsp" style=""></span>mg/L) and ferritin 1096<span class="elsevierStyleHsp" style=""></span>ng/mL (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>ng/mL); with no alterations in the rest of iron tests. Initially presumed to be a part of a mononucleosis syndrome, viral serologies (including hepatitis A, B, C, D and E viruses, cytomegalovirus, Ebstein-Barr virus and HIV) resulted negative. Abdominal ultrasonography was unremarkable except for previously known cholecystectomy. In the setting of this clinical presentation the patient had normal levels of blood pressure so he decided to withdraw treatment with olmesartan. Three months later the patient remained asymptomatic, with normal laboratory parameters except for mild elevation of aspartate aminotransferase (48<span class="elsevierStyleHsp" style=""></span>U/L) and lactate dehydrogenase (286<span class="elsevierStyleHsp" style=""></span>U/L). The patient refused to conduct further study and he was later lost to follow-up.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient consulted again in April 2018 because of clinical worsening. He declared having been taking olmesartan during the prior 6 months. Laboratory tests showed elevation of total bilirubin (1.5<span class="elsevierStyleHsp" style=""></span>mg/dL), aspartate aminotransferase (684<span class="elsevierStyleHsp" style=""></span>U/L), alanine aminotransferase (705<span class="elsevierStyleHsp" style=""></span>U/L), alkaline phosphatase (126<span class="elsevierStyleHsp" style=""></span>U/L), gamma-glutamyl transpeptidase (244<span class="elsevierStyleHsp" style=""></span>U/L), lactate dehydrogenase (315<span class="elsevierStyleHsp" style=""></span>U/L), C-reactive protein (22.20<span class="elsevierStyleHsp" style=""></span>mg/L) and ferritin (1320<span class="elsevierStyleHsp" style=""></span>ng/mL). Study of Wilson's disease, hereditary hemochromatosis and alpha-1-antitrypsine deficiency were all negative. Serum immunoglobulin IgA, IgG and IgM were normal. Determination of anti-smooth muscle antibodies was positive (titre 1:80). Antinuclear, anti-mitochondrial and anti-liver kidney microsomal antibodies were negative. Even though our team suggested to perform a liver biopsy, the patient remained reluctant to it.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We decided to discontinue treatment with olmesartan. Symptoms and laboratory parameters improved seven days and one month after withdrawal, respectively. Two months later the patient presented increase of IgG (1620<span class="elsevierStyleHsp" style=""></span>mg/dL [<span class="elsevierStyleItalic">N</span> 690–1400<span class="elsevierStyleHsp" style=""></span>mg/dL]). Liver biopsy was performed this time with the patient's consent, which showed septal fibrosis and periportal hepatitis with the presence of lymphoplasmocytic and eosinophilic infiltration, without significant steatosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). These findings suggested an autoimmune hepatitis although the presence of eosinophils was more characteristic of a drug-induced mechanism. Follow-up 4 months after withdrawal of olmesartan showed no remarkable alterations in laboratory parameters, including liver enzymes and serum immunoglobulins. Due to the improvement in laboratory parameters, the patient refused to receive any treatment. After 12 months of follow-up, he presented an increase of aspartate aminotransferase (221<span class="elsevierStyleHsp" style=""></span>U/L), alanine aminotransferase (190<span class="elsevierStyleHsp" style=""></span>U/L) and IgG (1670<span class="elsevierStyleHsp" style=""></span>mg/dL). We decided then to begin treatment with oral prednisone 40<span class="elsevierStyleHsp" style=""></span>mg daily. 4 weeks after start of corticosteroid therapy liver parameters were normal again, which allowed corticosteroid tapering. After subsequent corticosteroid suspension, the patient remains currently in complete remission.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The diagnostic of DILI was supported by the temporal association between exposure to olmesartan and liver damage, as well as recurrence after reexposure. Casualty assessment was performed using the CIOMS/RUCAM score which was 7 (probable). Other concomitant diseases or potential causes of liver injury were reasonably excluded.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> However, the presence of further episodes of recurrence, serum anti-smooth muscle antibodies, elevated IgG and response to corticosteroid therapy corresponded better to the diagnosis of a chronic autoimmune hepatitis. The histological findings were compatible to both entities: the presence of eosinophils is associated with cases of DILI, but periportal hepatitis and the presence of plasmocytic cells are typical of autoimmune hepatitis. Besides, the presence of septal fibrosis is more consistent to a chronic process, such as autoimmune hepatitis.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> We concluded therefore that a chronic autoimmune hepatitis triggered by olmesartan was the most likely diagnosis.</p><p id="par0030" class="elsevierStylePara elsevierViewall">There are already two cases that have reported an association between olmesartan and DILI. In one of them the appearance of non-alcoholic steatohepatitis might be a consequence of an indirect effect of olmesartan-induced sprue-like enteropathy.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Barge et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> reported the presence of chronic hepatitis with septal fibrosis along with elevation of antinuclear antibodies and IgG that suggested the presence of an autoimmune-like mechanism, regressive after olmesartan withdrawal and with no association with sprue-like enteropathy. Our data seem to be more consistent with an underlying autoimmune mechanism. Many drugs have been associated with drug-induced autoimmune hepatitis. Suspected cases should be evaluated thoroughly to exclude the possibility of idiopatic autoimmune hepatitis, including causality assessment, serology and liver biopsy. In cases who do not show complete remission after drug cessation, it is reasonable to begin corticosteroid therapy in order to alleviate symptoms and speed recovery.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">5,6</span></a> Future follow-up with closely monitoring and determination of HLA could help clarify this case.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 474 "Ancho" => 1255 "Tamanyo" => 157793 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Liver biopsy, which shows septal fibrosis and periportal hepatitis with lymphoplasmocytic and eosinophilic infiltration.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nonalcoholic steatohepatitis heralding olmesartan-induced sprue-like enteropathy" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "The Non-Alcoholic Fatty Liver Disease Study Group" "etal" => true "autores" => array:5 [ 0 => "M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 0 | 10 |
| 2024 October | 59 | 5 | 64 |
| 2024 September | 59 | 6 | 65 |
| 2024 August | 50 | 4 | 54 |
| 2024 July | 90 | 12 | 102 |
| 2024 June | 40 | 3 | 43 |
| 2024 May | 47 | 8 | 55 |
| 2024 April | 45 | 3 | 48 |
| 2024 March | 52 | 3 | 55 |
| 2024 February | 63 | 7 | 70 |
| 2024 January | 65 | 6 | 71 |
| 2023 December | 53 | 3 | 56 |
| 2023 November | 64 | 2 | 66 |
| 2023 October | 65 | 3 | 68 |
| 2023 September | 43 | 1 | 44 |
| 2023 August | 46 | 2 | 48 |
| 2023 July | 62 | 4 | 66 |
| 2023 June | 38 | 3 | 41 |
| 2023 May | 48 | 2 | 50 |
| 2023 April | 25 | 1 | 26 |
| 2023 March | 30 | 1 | 31 |
| 2023 February | 15 | 5 | 20 |
| 2023 January | 13 | 3 | 16 |
| 2022 December | 18 | 8 | 26 |
| 2022 November | 3 | 3 | 6 |
| 2022 October | 5 | 5 | 10 |
| 2022 September | 5 | 4 | 9 |
| 2022 August | 5 | 7 | 12 |
| 2022 July | 1 | 1 | 2 |
| 2022 June | 2 | 2 | 4 |
| 2022 May | 1 | 0 | 1 |
| 2022 March | 1 | 0 | 1 |
| 2022 January | 1 | 0 | 1 |
| 2021 November | 1 | 2 | 3 |
| 2021 September | 1 | 0 | 1 |
| 2021 August | 1 | 0 | 1 |
| 2021 July | 1 | 0 | 1 |
| 2021 May | 1 | 0 | 1 |
| 2021 April | 5 | 0 | 5 |
| 2021 March | 1 | 0 | 1 |
| 2021 February | 4 | 0 | 4 |
| 2021 January | 4 | 0 | 4 |
| 2020 December | 19 | 13 | 32 |
| 2020 November | 1 | 2 | 3 |
| 2020 July | 0 | 2 | 2 |
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