Nikolaos Pyrsopoulos

Lipid-Lowering Agents and Hepatotoxicity

Lipid-lowering therapy is increasingly being used in patients for a variety of diseases, the most important being secondary prevention of cardiovascular disease. Many lipid-lowering drugs carry side effects that include elevations in hepatic function tests and liver toxicity. In many cases, these drugs are not prescribed or they are underprescribed because of fears of injury to the liver. This article attempts to review key trials with respect to the hepatotoxicity of these drugs. Recommendations are also provided with respect to the selection of low-risk patients and strategies to lower the risk of hepatotoxicity when prescribing these medications.

Immunobiology of hepatocarcinogenesis: Ways to go or almost there?

Hepatocellular carcinoma is on the rise and occurs in the setting of chronic liver disease and cirrhosis. Though treatment modalities are available, mortality from this cancer remains high. Medical therapy with the utilization of biologic compounds such as the Food and Drug Administration approved sorafenib might be the only option that can increase survival. Immunotherapy, with modern pharmacologic developments, is a new frontier in cancer therapy and therefore the immunobiology of hepatocarcinogenesis is under investigation. This review will discuss current concepts of immunobiology in hepatocarcinogenesis along with current treatment modalities employing immunotherapy. The tumor microenvironment along with a variety of immune cells coexists and interplays to lead to tumorigenesis. Tumor infiltrating lymphocytes including CD8(+) T cells, CD4(+) T cells along with regulatory T cells, tumor associated macrophages, tumor associated neutrophils, myeloid derived suppressor cells, and natural killer cells interact to actively provide anti-tumor or pro-tumor effects. Furthermore, oncogenic pathways such as Raf/mitogen-activated protein kinase/extracellular-signal-regulated kinase pathway, phosphatidyl-3-kinase/AKT/mammalian target or rapamycin, Wnt/β-catenin, nuclear factor-κB and signal transducers and activators of transcription 3 may lead to activation and proliferation of tumor cells and are also considered cornerstones in tumorigenesis. Immunotherapy directed at this complex milieu of cells has been showned to be successful in cancer treatment. The use of vaccines, adoptive cell therapy and immune checkpoint inhibitor modulation are current options for therapy. Further translational research will shed light to concepts such as anti-tumor immunity which can add another alternative in the therapeutic armamentarium.

Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States and carries a very poor prognosis, with a median survival time of <50% at 1 year for advanced disease. To date, sorafenib is the only therapy approved by the Food and Drug Administration for the treatment of advanced HCC. Tivantinib (ARQ-197), a non-ATP competitive inhibitor of cellular mesenchymal–epithelial transcription factor (c-MET), has shown a survival benefit in patients with advanced HCC who have failed or are intolerant to sorafenib in Phase I and II trials. Those patients who have tumors with high concentrations of MET (MET-high) appear to derive the greatest benefit from tivantinib therapy. Currently, two large randomized double-blind placebo-controlled Phase III trials (METIV-HCC [NCT01755767] and JET-HCC [NCT02029157]) are evaluating tivantinib in patients with MET-high advanced HCC, with the primary end points of overall survival and progression-free survival, respectively. This study reviews the evidence for the use of tivantinib in advanced HCC. Specific topics addressed include the pharmacology, dosing, toxicity, and biomarkers associated with tivantinib use.

New Methods of Testing and Brain Imaging in Hepatic Encephalopathy: A Review

The diagnosis of hepatic encephalopathy is predominantly clinical, and the tests available assist in the diagnosis only by excluding other causes. Covert hepatic encephalopathy, which is defined as abnormal performance on psychometric tests when standard neurologic examination is completely normal, has gained widespread attention in recent years due to its effect on quality of life. This review focuses on the tests available to aid in the diagnosis of this significant complication of liver disease, and discusses the complex pathophysiologic mechanisms identified through new imaging techniques and their significance toward development of new therapeutic targets for this condition.

Acute Liver Failure: Mechanisms of Disease and Multisystemic Involvement

Acute liver failure is accompanied by a pathologic syndrome common to numerous different etiologies of liver injury. This acute liver failure syndrome leads to potentially widespread devastating end-organ consequences. Systemic dysregulation and dysfunction is likely propagated via inflammation as well as underlying hepatic failure itself. Decoding the mechanisms of the disease process and multisystemic involvement of acute liver failure offers potential for targeted treatment opportunities and improved clinical outcomes in this sick population.

Emricasan (IDN‐6556) Lowers Portal Pressure in Patients with Compensated Cirrhosis and Severe Portal Hypertension

Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan‐caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open‐label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49‐80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End‐Stage Liver Disease score of 8 (range 6‐15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] –1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] –3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase‐3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti‐inflammatory effect.

Liver Transplantation for Acute Liver Failure

With the advent of liver transplant for acute liver failure (ALF), survival rate has improved drastically. Liver transplant for ALF accounts for 8% of all transplant cases. The 1-year survival rates are 79% in Europe and 84% in the United States. Some patients with ALF may recover spontaneously, and approximately half will undergo liver transplant. It is imperative to identify patients with ALF as soon as possible to transfer them to a liver transplant center for a thorough evaluation. Emergent liver transplant in a patient with ALF may place the patient at risk for severe complications in the postoperative period.

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo

Background & Aims: Caspase‐mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan‐caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non‐alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child‐Pugh class A or B; mean score, 6.9; 38% with alcohol‐associated cirrhosis, 29% with HCV‐associated cirrhosis, and 23% with NASH) and model for end‐stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open‐label Emricasan (25 mg) twice‐daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK‐18) at month 3. Results: Seventy‐four patients completed the 3‐month study period (40 given Emricasan and 34 given placebo); 69 patients received open‐label Emricasan for 3 months afterward. At the 3‐month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child‐Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, –0.2882 to –0.0866) and total bilirubin (95% CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child‐Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full‐length CK‐18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK‐18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasans effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child‐Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

LEFT VENTRICULAR DIASTOLIC DYSFUNCTION IS AN INDEPENDENT PREDICTOR OF LONG-TERM MORTALITY IN PATIENTS WHO UNDERWENT LIVER TRANSPLANT FOR END STAGE LIVER DISEASE

Patients with end-stage liver disease (ESLD) may develop left ventricular diastolic dysfunction in the absence of coronary artery disease or hypertension. Prognostic value of the presence of diastolic dysfunction on post orthotopic liver transplant (OLT) survival is unknown. We report on the

An Uncommon Cause of Gastrointestinal Bleeding in Patients With Portal Hypertension

40-year-old man with a history of Laennec cirrhosis was transferred to our tertiary care facility for the management of massive hematemesis and low hemoglobin. Patient was treated with multiple blood transfusions, and an esophagogastroduodenoscopy failed to reveal the bleeding source. Subsequently, a singleballoon push enteroscopy was performed, revealing large varices in the fourth portion of the duodenum with stigmata of active bleeding (Figures A–C). The patient was immediately referred for transjugular intrahepatic portosystemic shunt. Variceal bleeding is a common complication of portal hypertension. The most common locations for varices are the esophagus and the stomach. Duodenal varices are uncommon and can be seen in up to 0.4% of patients with portal hypertension. 1 The most common sites are the duodenal bulb, followed by the second portion of the duodenum. 2 When present, they can cause massive upper gastrointestinal bleeding associated with associated mortality of up to 40%. 3 Multiple strategies have been described in the literature regarding management. Endoscopically, sclerotherapy has been used as a first-line therapeutic measure, although there is a risk of perforation, embolism, and tissue injury associated with its use. 4 In addition, banding and the use of hemoclips have been reported, although in the presence of portal hypertension this is merely a temporary solution. As such, transjugular intrahepatic portosystemic shunt is a much safer and effective approach to the management of ectopic varices in patients with portal hypertension. 5