An Approach to Drug-Induced Liver Injury from the Geriatric Perspective.

PURPOSE OF REVIEW: With its high variability in both presentation and severity, drug-induced liver injury (DILI) is a complex condition increasingly confronting all providers. DILI has an even more muddled presentation among the geriatric population due to age-related changes in liver physiology and biochemistry as well as polypharmacy common in the geriatric population. RECENT FINDINGS: Most cases of DILI are idiosyncratic and unpredictable. DILI, especially related to herbal and dietary supplement (HDS) use, is increasingly recognized as a leading cause of acute liver failure and need for liver transplantation. Unfortunately, liver transplantation is a limited option for the elderly, a population that exhibits significant HDS use. One recent study suggests that early use of N-acetylcysteine may be useful in preventing progression to acute liver failure in non-acetaminophen DILI. In the future, a personalized medicine approach using genomic signatures may be feasible to prevent DILI. This review serves to raise recognition of the unique aspects of DILI in the geriatric population to promote rapid diagnosis and early intervention to prevent progression to liver failure and death. For now, DILI remains a diagnosis of exclusion, and care providers for the elderly must focus on obtaining a thorough history that includes HDS use and intervening early in suspected DILI cases.

Hypo-vascular hepatocellular carcinoma and liver transplantation: Morphological characteristics and implications on outcomes.

BACKGROUND: The clinical importance of hypovascular liver lesions in cirrhotic patients awaiting liver transplantation (LT) has not been fully investigated. The objective of this study was to characterize the clinicopathologic features and management of these tumors and to assess their impact on post-LT outcomes. METHODS: We performed a retrospective review of cirrhotic patients with lesions suspicious for hypovascular hepatocellular carcinoma (HCC) who underwent LT at a single institution from 2011- 2017. RESULTS: We identified 22 pre-LT patients with radiologic diagnosis of a lesion(s) suspicious for hypovascular HCC. There were 28 hypovascular lesions within the 22 patient cohort; 9 lesions (32%) converted to hypervascular HCC before LT and 19 lesions remained hypovascular at LT. 88% of hypovascular lesions were HCC on explant pathology. Compared to patients with hyper-vascular HCC lesions, hypovascular HCC lesions underwent less preoperative tumor ablation (58% vs 89%; P < .01). Hypovascular HCC were more likely to be well-differentiated (67% vs 11%; P < .01), but there were no differences in the microvascular invasion, tumor recurrence, or survival post-LT. CONCLUSIONS: Hypovascular HCC has similar clinical outcomes and needs for transplantation as hypervascular HCC. The high prevalence of HCC within suspicious hypovascular lesions supports a similar monitoring and locoregional therapy strategy as for hypervascular HCC.

Bile Duct Injury due to Drug Induced Liver Injury.

PURPOSE OF REVIEW-: Drug-induced liver injury (DILI) can present with a variable clinical and pathological phenotype and can be classified using liver enzymes as hepatocellular, cholestatic or a mixed pattern. The cholestatic pattern has been considered amongst the spectrum of direct liver damage at the microscopic level, but recently bile duct injury as a manifestation of DILI has emerged as a distinct entity and this review examines several examples of biliary tract abnormalities due to DILI from a clinical, radiologic and pathologic perspective. RECENT FINDINGS-: Case series and reports have emerged over the last few years of drugs causing cholangiographic changes or direct injury to the intra-and extra-hepatic biliary tree, such as ketamine and several chemotherapy agents. The DILI Network (DILIN) in the United States has published their experience of cases with vanishing bile duct syndrome on histology and sclerosing cholangitis like changes seen on cholangiography. The pathogenesis of these changes is unclear but it appears that this type of injury is more severe and more likely to lead to a chronic injury with increased mortality than other cases of DILI. SUMMARY-: Bile duct injury due to DILI is an increasingly recognized entity and imaging of the biliary tree in conjunction with liver biopsy should be considered in patients with severe cholestatic DILI.

Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation.

Ipilimumab is a first-in-class immunological checkpoint blockade agent and monoclonal antibody against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) that has demonstrated survival benefit and durable responses in patients with metastatic melanoma. To date, solid organ transplant recipients have been excluded from clinical trials with cancer immunotherapies on the basis of their concurrent treatment with immunosuppressive agents. We present the first case to our knowledge of a patient with advanced cutaneous melanoma receiving ipilimumab status post orthotopic liver transplantation with a partial response. Transaminitis was observed 4 months after administration of ipilimumab that resolved with close observation. No evidence of graft rejection has been observed to date. This case advocates for further investigation of the safety and efficacy of cancer immunotherapies in solid organ transplant recipients.

Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus.

AIM: To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS: From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS: The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION: LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.

Case report of successful treatment of fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin after liver transplantation.

Fibrosing cholestatic hepatitis is an unusual complication of hepatitis C virus (HCV) recurrence after liver transplant. Fibrosing cholestatic hepatitis is marked by aggressive progression of cholestasis and fibrosis, leading to accelerated graft loss and/or death. Sofosbuvir (GS-7977) is an oral nucleotide analogue inhibitor of HCV polymerase activity. It is a second-generation, direct-acting, antiviral for the treatment of HCV infection. This case illustrates a patient with recurrent HCV with fibrosing cholestatic hepatitis, who was successfully treated with a combination of sofosbuvir and ribavirin with normalization of liver enzyme activities and resolution of HCV-related symptoms. The favorable side effect profile and the lack of drug-drug interaction with immunosuppressive medications make the combination of sofosbuvir and ribavirin a promising regimen for severe HCV recurrence.

Steatohepatitis secondary to long-term glucocorticoid treatment for congenital adrenal hyperplasia: a potential diagnostic pitfall.

A 24-year-old woman with congenital adrenal hyperplasia (CAH) was referred for evaluation of elevated liver enzyme activities over the preceding 6 months. The patient was diagnosed with CAH at the age 12 when she presented with irregular menses and hirsutism. Since then, she had been on dexamethasone to maintain a normal menstrual cycle and prevent hirsutism and acne. She had no history of chronic liver disease and drank alcohol socially. An extensive workup for other treatable causes of liver disease was unrevealing. Therefore, a liver biopsy was performed, which revealed extensive ballooned degenerative hepatocytes containing Mallory-Denk hyalines. The ballooned hepatocytes were located predominantly in centrilobular areas and without any accompanying steatosis. Even though the histopathologic features are most compatible with alcoholic and/or nonalcoholic steatohepatitis, it was not supported by the patient's medical history and clinical presentation. The patient had a normal body mass index and only occasional alcohol use. Based on the biopsy finding and clinical presentation, we postulated that the abnormal liver enzyme and pathological features seen on the liver biopsy were secondary to CAH and long-term use of glucocorticoid. A few studies have shown that patients with CAH often develop metabolic abnormalities and insulin resistance, particularly women treated with glucocorticoid for several years. To our knowledge, this is the first report describing steatohepatitis secondary to CAH and prolonged glucocorticoid treatment. It is important to be aware that steatohepatitis can develop in these patients due to long-term glucocorticoid use and potentially lead to progressive liver damage. Furthermore, in patients with CAH who develop abnormal liver enzyme activities a liver biopsy is warranted to assess for steatohepatitis and any associated fibrosis. If indeed fibrosis is already present, a consultation with the endocrinologist should be undertaken in an effort to lower the dose of the glucocorticoids as much as possible while still controlling the symptoms of the disease.

Liver cancer and alcohol.

Annually, hepatocellular carcinoma is diagnosed in approximately a half-million people worldwide. Based on the association of alcohol with cancer, a International Agency for Research on Cancer working group recently deemed alcoholic beverages "carcinogenic to humans," causally related to occurrence of malignant tumors of the oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast. Alcohol metabolism in the liver leads to reactive oxygen species production, induction of activity of cytochrome P450s, and reduction of antioxidants. This review analyzes the epidemiology and pathogenesis of alcohol in hepatocellular cancer.

Care of the cirrhotic patient.

Timely surveillance for varices and hepatocellular carcinoma, prophylaxis against spontaneous bacterial peritonitis (SBP) improve survival in patients awaiting transplantation. Early diagnosis of minimal or overt hepatic encephalopathy can delay life threatening complications, reduce need for hospitalization, and potentially improve survival pending liver transplantation.