• Ashwagandha-induced liver injury: A case series from Iceland and the US Drug-Induced Liver Injury Network.

      Björnsson, Helgi K; Björnsson, Einar S; Avula, Bharathi; Khan, Ikhlas A; Jonasson, Jon G; Ghabril, Marwan; Hayashi, Paul H; Navarro, Victor; 1Landspitali University Hospital, Reykjavik, Iceland. 2National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA. 3Indiana University School of Medicine, Indianapolis, IN, USA. 4University of North Carolina, Chapel Hill, NC, USA. 5Einstein Healthcare Network, Sidney Kimmel Medical College, Philadelphia, PA, USA. (Wiley, 2020-01-28)
      Background & aims: Ashwagandha (Withania somnifera) is widely used in Indian Ayurvedic medicine. Several dietary supplements containing ashwagandha are marketed in the US and Europe, but only one case of drug-induced liver injury (DILI) due to ashwagandha has been published. The aim of this case series was to describe the clinical phenotype of suspected ashwagandha-induced liver injury. Methods: Five cases of liver injury attributed to ashwagandha-containing supplements were identified; three were collected in Iceland during 2017-2018 and two from the Drug-Induced Liver Injury Network (DILIN) in 2016. Other causes for liver injury were excluded. Causality was assessed using the DILIN structured expert opinion causality approach. Results: Among the five patients, three were males; mean age was 43 years (range 21-62). All patients developed jaundice and symptoms such as nausea, lethargy, pruritus and abdominal discomfort after a latency of 2-12 weeks. Liver injury was cholestatic or mixed (R ratios 1.4-3.3). Pruritus and hyperbilirubinaemia were prolonged (5-20 weeks). No patient developed hepatic failure. Liver tests normalized within 1-5 months in four patients. One patient was lost to follow-up. One biopsy was performed, showing acute cholestatic hepatitis. Chemical analysis confirmed ashwagandha in available supplements; no other toxic compounds were identified. No patient was taking potentially hepatotoxic prescription medications, although four were consuming additional supplements, and in one case, rhodiola was a possible causative agent along with ashwagandha. Conclusions: These cases illustrate the hepatotoxic potential of ashwagandha. Liver injury is typically cholestatic or mixed with severe jaundice and pruritus, but self-limited with liver tests normalizing in 1-5 months.
    • Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis.

      Efe, Cumali; Lammert, Craig; Taşçılar, Koray; Dhanasekaran, Renumathy; Ebik, Berat; Higuera-de la Tijera, Fatima; Calışkan, Ali R; Peralta, Mirta; Gerussi, Alessio; Massoumi, Hatef; et al. (Wiley, 2021-11-30)
      Background: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods: Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results: We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH. Keywords: SARS-CoV-2; autoimmunity; azathioprine; budesonide; liver transplantation; mercaptopurine.
    • Hepatotoxicity of statins and other lipid-lowering agents.

      Björnsson, Einar S; [ 1 ] Natl Univ Hosp Iceland, Fac Med, Reykjavik, Iceland [ 2 ] Univ Iceland, Fac Med, Reykjavik, Iceland (Wiley-Blackwell, 2017-02)
      Statins are generally well tolerated and adverse effects are relatively rare. Clinical trials are underpowered to detect uncommon adverse effects such as idiosyncratic drug-induced liver injury. This review is aimed at covering the current knowledge on the hepatotoxicity associated with statins and other lipid lowering drugs. Both atorvastatin and simvastatin have been associated with more than 50 case reports of liver injury and other statins have been implicated in this type of liver injury as well. Idiosyncratic liver injury due to statins has been reported to occur 1.9%-5.5% of patients in prospective series of drug-induced liver injury. Atorvastatin and simvastatin have been associated with positive rechallenge and some case reports have described liver injury following dose escalation of the implicated statin. Mortality from liver injury and/or liver transplantation has been documented in a few patients with statin induced liver injury although the vast majority of patients with liver injury have recovered after cessation of therapy.
    • Impact of peri-transplant heart failure & left-ventricular diastolic dysfunction on outcomes following liver transplantation.

      Josefsson, Axel; Fu, Michael; Allayhari, Pari; Björnsson, Einar; Castedal, Maria; Olausson, Michael; Kalaitzakis, Evangelos; Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. axel.josefsson@vgregion.se (Wiley-Blackwell, 2012-09)
      Assess the prevalence of peri-transplant heart failure and its potential relation to post-transplant morbidity and mortality. A retrospective study was performed on 234 consecutive cirrhotic patients undergoing liver transplantation in a single European center from 1999 to 2007 (mean age 52, 30% women, 36% with alcoholic liver disease, 24% with viral hepatitis, 18% cholestatic liver disease). Left ventricular diastolic dysfunction was defined as E/A ratio ≤ 1. We used the Boston classification for heart failure to assess the prevalence of peri-transplant heart failure. Patients were followed up for a mean of 4 years post-transplant (0.5-9 years). Eighteen per cent of patients demonstrated diastolic dysfunction pretransplant. During the peri-transplantation period highly possible heart failure occurred in 27%. In logistic regression analysis, heart failure was independently related to lower mean arterial blood pressure (OR 0.94, 95% CR 0.91-0.98) and prolonged corrected QT time on ECG (OR 9.10, 95% CI 3.77-21.93) pretransplant. Peri-transplant mortality amounted to 5%, and was independently related to heart failure (OR 15.11, 95% CI 1.76-129.62) and the peri-transplant need of dialysis (OR 14.18, 95% CI 1.65-121.89). Heart failure was also associated with longer stay in the intensive care unit and peri-transplant cardiac events (P < 0.05). Long-term transplant-free mortality was independently related to diastolic dysfunction at baseline (Hazard ratio 4.82, 95% CI 1.78-13.06). Heart failure occurs in approximately a quarter of patients with cirrhosis following liver transplantation and it is an independent predictor of mortality and morbidity.
    • Liver injury caused by oral anticoagulants: A population-based retrospective cohort study.

      Björnsson, Helgi K; Gudmundsson, David O; Björnsson, Einar S; 1Department of Internal Medicine, Section of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Wiley, 2020-06-08)
      Background & aims: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse event. DILI caused by direct oral anticoagulants (DOACs) has been reported, however, data on the risk of DILI are limited. The aim of the study was to evaluate the frequency of DILI caused by oral anticoagulants (OACs) in a population-based setting. Methods: A computerized database search in The National Prescription Database was performed identifying all patients in Iceland who were prescribed OACs (rivaroxaban, apixaban, dabigatran, edoxaban or warfarin) in 2008-2017. Personal identification numbers of these patients were linked with a database containing laboratory results for all hospitals and most outpatient clinics in Iceland. A medical chart review was performed in all cases where onset of liver injury followed intake of OACs. Patients with other specific causes of liver injury were excluded. Causality assessment with the RUCAM method was undertaken in cases with suspected DILI. Results: Three cases of suspected DILI were identified. In all cases, rivaroxaban was the implicated agent among patients prescribed this product (n = 3446). All were women with a hepatocellular type of liver injury. One patient developed a suspected drug-induced autoimmune hepatitis and was treated with corticosteroids. No cases of DILI in patients on warfarin (n = 9101), apixaban (n = 1903), dabigatran (n = 1335) and edoxaban (n = 34) were identified. Conclusions: Rivaroxaban was the only OAC associated with DILI during the 10-year study period. Approximately 1 in 1100 patients treated with rivaroxaban developed DILI. Other OACs were not associated with liver injury in this population-based study. Keywords: anticoagulation; drug reactions; hepatotoxicity.
    • Mortality and cancer risk related to primary sclerosing cholangitis in a Swedish population-based cohort.

      de Valle, Maria Benito; Björnsson, Einar; Lindkvist, Björn; Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sweden (2012-03)
      Primary sclerosing cholangitis cases were identified in diagnostic registries. Case validation and follow up was provided through individual review of case files and linkage to the Swedish Cancer and Cause of Death registries. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) for cancer were calculated in relation to the background population. Cox's proportional hazards analysis was used to calculate crude and adjusted relative risks (RRs).
    • Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease.

      Naess, Sigrid; Björnsson, Einar; Anmarkrud, Jarl A; Al Mamari, Said; Juran, Brian D; Lazaridis, Konstantinos N; Chapman, Roger; Bergquist, Annika; Melum, Espen; Marsh, Steven G E; et al. (Wiley-Blackwell, 2014-11)
      Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC.