Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations.

OBJECTIVE: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. METHODS: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. RESULTS: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. CONCLUSION: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial.

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.

Benefit of Early Palliative Care Intervention in End-Stage Liver Disease Patients Awaiting Liver Transplantation.

BACKGROUND: Patients with end-stage liver disease have a predictable and progressive decline in their quality of life because of physical symptoms and psychological distress. Early palliative care intervention (EPCI) correlates with better symptom control and mood. We aimed to improve symptomatology and mood in liver transplant candidates by implementing a longitudinal multidisciplinary EPCI. MEASURES: Depression level and symptom burden were assessed with Center for Epidemiological Studies Depression Scale and a modified liver-specific Edmonton Symptom Assessment System scale. INTERVENTION: All patients referred for liver transplant evaluation between July 2013 and May 2014 were scheduled for EPCI. OUTCOMES: After EPCI, 50% of moderate-to-severe symptoms improved (P < 0.05), and 43% of patients showed improvement in clinically significant depressive symptoms (P = 0.003). Notably, patients with more symptoms showed a greater improvement in Center for Epidemiological Studies Depression Scale scores (P = 0.001). CONCLUSIONS/LESSONS LEARNED: Implementation of EPCI improved symptom burden and mood in end-stage liver disease patients awaiting transplant.

Limited sampling estimates of epigallocatechin gallate exposures in cirrhotic and noncirrhotic patients with hepatitis C after single oral doses of green tea extract.

BACKGROUND: Epigallocatechin-3-gallate (EGCG) has antiangiogenic, antioxidant, and antifibrotic properties that may have therapeutic potential for the treatment of cirrhosis induced by hepatitis C virus (HCV). However, cirrhosis might affect EGCG disposition and augment its reported dose-dependent hepatotoxic potential. OBJECTIVE: The safety, tolerability, and disposition of a single oral dose of EGCG in cirrhotic patients with HCV were examined in an exploratory fashion. METHODS: Eleven patients with hepatitis C and detectable viremia were enrolled. Four had Child-Pugh (CP) class A cirrhosis, 4 had Child-Pugh class B cirrhosis, and 3 were noncirrhotic. After a single oral dose of green tea extract 400 mg containing 94% pure EGCG, blood for EGCG levels and safety parameters was ascertained at 2, 4, and 10 hours. RESULTS: C(max) and AUC to EGCG overlapped among the 3 groups, which suggests that the disposition of EGCG was not significantly altered in these patients with cirrhosis. CONCLUSIONS: A single 400-mg oral dose of EGCG was safe and well tolerated by all of the patients in the study. These results provide guidance for the continued investigation of the long-term safety and antitumor potential of EGCG in cirrhotic patients with HCV.

Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C.

BACKGROUND: Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C. PURPOSE: We describe our strategy for a phased approach for studying the impact of silymarin in hepatitis C, in the context of the unique challenges of botanical product clinical trials and the development of specific and curative antiviral therapy. METHODS: This multicenter, randomized, double-masked, placebo-controlled trial was conducted with four clinical centers and a data-coordinating center in the United States, to assess the impact of silymarin therapy in patients with chronic hepatitis C who failed conventional antiviral therapy. RESULTS: Key aspects relevant to performing clinical trials of botanical products include early identification of an appropriate product with standard product chemistry, acquisition of pharmacokinetic and dosing information, selection of the appropriate study group, and choosing rigorous outcome variables. POTENTIAL LIMITATIONS: Trial participants were chronic hepatitis C patients who were nonsustained virologic responders to IFN-based therapy; therefore, the findings are not generalizable to all hepatitis C populations. Further, alanine aminotransferase, a biochemical liver test, rather than hepatitis viral RNA or liver histology was the primary end point. CONCLUSIONS: The challenges identified and addressed during development of this United States multicenter Phase II trial to evaluate silymarin for treatment of patients with chronic hepatitis C infection who had failed to respond successfully to previous IFN-based therapy are common and must be addressed to conduct rigorous trials of botanical products.

Human drug hepatotoxicity: a contemporary clinical perspective.

BACKGROUND: Drug-induced liver injury (DILI) constitutes a significant medical challenge. The rising number of marketed drugs, aging population and polypharmacy make it imperative to understand the clinical presentation of DILI and the processes used in the assessment of causality and early detection. OBJECTIVE: This article reviews the current clinical understanding of DILI including presentation patterns, causality assessment, risk factor ascertainment and early detection strategies including liver test monitoring. Significant initiatives such as the Drug-Induced Liver Injury Network (DILIN) are also discussed. METHODS: A narrative review of clinical studies of DILI, with emphasis on clinical features, causality and surveillance. CONCLUSION: DILI remains a serious challenge in contemporary clinical practice. Further research and collaboration in the areas of epidemiology, causality and early detection are required to enhance the diagnosis and management of DILI.

The mortality burden of chronic liver disease may be substantially underestimated in the United States.

PURPOSE: The United States National Center for Health Statistics (NCHS) uses death certificate data to estimate the burden of serious disease. This study aimed to determine the accuracy of the NCHS method for estimating the burden of chronic liver disease (CLD). METHOD: The authors identified death certificates of New Haven County residents who died from October 1999-September 2000 that were assigned one of 115 ICD-10 codes that might indicate CLD. They reviewed medical charts, medical examiner records and a certifier questionnaire to determine whether CLD was the cause of death. RESULT: Using the authors' determination of CLD status as the gold standard, the specificity of the NCHS classification was high (86%), but the sensitivity was low (36%). The authors found that adding selected ICD-10 codes to those considered by the NCHS to be CLD (certain CLD malignancies and viral hepatitis) could improve sensitivity. Ensuring that deaths attributed by certifiers to "End Stage Liver Disease" were coded as CLD could also improve completeness. These modifications could increase sensitivity substantially with little effect on specificity. CONCLUSION: The NCHS method may understate the CLD burden substantially which could have a detrimental effect on planning for and evaluating prevention and treatment. Modifications could improve completeness.

Compensated hepatitis C: unenhanced MR imaging correlated with pathologic grading and staging.

BACKGROUND: We prospectively examined unenhanced MR imaging findings in relation to pathologic fibrosis, inflammation and steatosis in patients with compensated chronic hepatitis C viral infection (HCV). METHODS: Unenhanced MRI at 1.5 T was obtained within one month of core liver biopsy in 64 consecutive candidates for antiviral therapy for compensated HCV. Two pathologists independently graded inflammatory activity index (HAI) and steatosis, and staged fibrosis (grades 0-6). Morphologic MRI findings of cirrhosis, periportal lymph nodes, and MR fat signal ratio from dual gradient echo images were assessed independently by two radiologists blinded to clinical data. MRI and laboratory liver function results were correlated with pathologic results, using Spearman correlation coefficient and stepwise multiple regression. RESULTS: MR fat signal ratio correlation coefficient with pathologic steatosis was 0.71 (p < 0.0001). Coefficients with fibrosis stage were highest for surface nodularity (r (s) = 47, p < 0.0001) and expanded gallbladder fossa (r (s) = 0.42, p = 0.0006). Coefficients with HAI were highest for lymph node size (r (s) = 0.355, p = 0.0040), surface nodularity (r = 0.47, p < 0.0001), expanded gallbladder fossa (r = 0.332, p = 0.0073), and caudate/right lobe ratio (r = 0.326, p = 0.0110). Combined lab and MRI variables provided the best prediction of fibrosis stage (r (2) = 0.656) and HAI (r (2) = 0.597). CONCLUSIONS: A combination of MRI and laboratory findings was most predictive of fibrosis and inflammation.

Hepatocellular carcinoma with indeterminate or false-negative findings at initial MR imaging: effect on eligibility for curative treatment initial observations.

PURPOSE: To retrospectively evaluate the effect of indeterminate or false-negative findings at magnetic resonance (MR) imaging on eligibility for curative treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by the institutional review board; the need for informed consent was waived. Of 166 patients with cirrhosis in whom HCC was detected with MR imaging, 21 (13 men, eight women; mean age, 60 years) had 33 proved HCCs that were not detected on previous MR images obtained 6-24 months earlier. MR imaging included T1-weighted, T2-weighted, and dynamic contrast material-enhanced T1-weighted imaging. Serial MR images and treatment records were reviewed to evaluate nodule growth and the effect of delayed diagnosis on treatment eligibility. RESULTS: Of 33 HCCs in 21 patients, 24 corresponding nodules (73%) were described on previous MR images as benign or indeterminate. Five additional nodules were visible at retrospective evaluation, but only on arterial phase images. The diameters of these 29 visible but indeterminate nodules were initially 0.6-1.9 cm (mean, 1.1 cm) and increased to 0.9-4.5 cm (mean, 1.9 cm) at HCC diagnosis (mean follow-up, 378 days). The mean doubling time was 856 days for diameter and 285 days for volume. All nine HCCs with a delayed diagnosis of less than 1 year were smaller than 3 cm at diagnosis, and the patients had undergone liver transplantation (n=3) or technically successful ablation or embolization (n=6). All 10 subcentimeter indeterminate nodules were smaller than 2 cm at HCC diagnosis, and none progressed to untreatable HCC. CONCLUSION: Indeterminate nodules smaller than 2 cm did not become untreatable HCC with delayed HCC diagnosis of 6-12 months.

Hepatitis C risk assessment, testing and referral for treatment in urban primary care: role of race and ethnicity.

AIM: To determine rates of hepatitis C (HCV) risk factor ascertainment, testing, and referral in urban primary care practices, with particular attention to the effect of race and ethnicity. METHODS: Retrospective chart review from four primary care sites in Philadelphia; two academic primary care practices and two community clinics was performed. Demographics, HCV risk factors, and other risk exposure information were collected. RESULTS: Four thousand four hundred and seven charts were reviewed. Providers documented histories of injection drug use (IDU) and transfusion for less than 20% and 5% of patients, respectively. Only 55% of patients who admitted IDU were tested for HCV. Overall, minorities were more likely to have information regarding a risk factor documented than their white counterparts (79% vs 68%, P < 0.0001). Hispanics were less likely to have a risk factor history documented, compared to blacks and whites (P < 0.0001). Overall, minorities were less likely to be tested for HCV than whites in the presence of a known risk factor (23% vs 35%, P = 0.004). Among patients without documentation of risk factors, blacks and Hispanics were more likely to be tested than whites (20% and 24%, vs 13%, P < 0.005, respectively). CONCLUSION: (1) Documentation of an HCV risk factor history in urban primary care is uncommon, (2) Racial differences exist with respect to HCV risk factor ascertainment and testing, (3) Minority patients, positive for HCV, are less likely to be referred for subspecialty care and treatment. Overall, minorities are less likely to be tested for HCV than whites in the presence of a known risk factor.

Antiviral therapy of HCV in the cirrhotic and transplant candidate.

Despite the improved efficacy of peginterferons, the rate of sustained virologic response is suboptimal in cirrhotic patients, relative to non-cirrhotic patients. However, the treatment of patients with compensated cirrhosis has recently been encouraged by expert panels. Interferon-based therapy may provide additional benefit by reducing the risk of hepatocellular carcinoma in cirrhotic patients as suggested in preliminary studies. Results of two ongoing prospective studies are awaited to answer the important question of the effectiveness of suppressive interferon therapy, even in the absence of sustained virologic response. Given the importance of recurrent HCV following liver transplantation, attention has been directed toward the antiviral treatment of patients with advanced liver disease. This approach needs to be pursued with caution given the potential morbidity of the therapy. Recently, a low accelerating dosage regimen has provided excellent results and is the subject of additional inquiry.

Cystinosis as a cause of noncirrhotic portal hypertension.

Cystinosis is a rare autosomal recessive storage disorder, characterized by the abnormal accumulation of cystine in cellular lysosomes. This accumulation, which can occur in any organ system, leads to crystallization of trapped cystine and ultimately cellular death. Hepatic manifestations of Cystinosis although rare, have been described in the literature. However, to our knowledge, only one other case of non-cirrhotic portal hypertension secondary to cystine accumulation in Kupffer cells has been reported. In this case and ours, portal hypertension was found in the absence of bridging fibrosis. Furthermore, in our case, for the majority of the patient's course, hepatic synthetic function remained normal. Cysteamine is therapeutic in this disorder, and can lead to significant removal of cystine, and thus to reversibility of disease, however, it requires high doses and must be taken regularly. Porto-systemic shunting in combination with aggressive medical therapy could potentially benefit patients who develop non-cirrhotic portal hypertension in this clinical setting.