Chiranjeevi Gadiparthi

Use of direct-acting antiviral agents in hepatitis C virus-infected liver transplant candidates

Since the advent of direct acting antiviral (DAA) agents, chronic hepatitis C virus (HCV) treatment has evolved at a rapid pace. In contrast to prior regimen involving ribavirin and pegylated interferon, these newer agents are highly effective, well-tolerated, have shorter course of therapy and safer essentially in all HCV patients including those with advanced liver disease and following liver transplantation. Clinicians caring for HCV-infected patients on the liver transplant (LT) waitlist are often faced with a dilemma whether to treat HCV infection before or after liver transplantation. Sustained virological response (SVR) rates following HCV treatment may improve hepatic function sufficiently enough to negate the need for LT in certain patients. On the other hand, the decrease in MELD without improvement in quality of life in certain patients may lead to delay or dropout from potentially curative LT surgery list. In this context, our review focuses on the approach to and optimal timing of DAA-based treatment of HCV infection in LT candidates in the peri-transplant period.

The Role of Cannabinoids in the Setting of Cirrhosis

Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation. The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids. CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation. CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function. Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects. The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Chronic hepatitis B (CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma (HCC). Liver transplantation (LT) is considered gold standard for treatment of hepatitis B virus (HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival. The combination of lamivudine (LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA (cccDNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.

Mechanistic Potential and Therapeutic Implications of Cannabinoids in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is comprised of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). It is defined by histologic or radiographic evidence of steatosis in the absence of alternative etiologies, including significant alcohol consumption, steatogenic medication use, or hereditary disorders. NAFLD is now the most common liver disease, and when NASH is present it can progress to fibrosis and hepatocellular carcinoma. Different mechanisms have been identified as contributors to the physiology of NAFLD; insulin resistance and related metabolic derangements have been the hallmark of physiology associated with NAFLD. The mainstay of treatment has classically involved lifestyle modifications focused on the reduction of insulin resistance. However, emerging evidence suggests that the endocannabinoid system and its associated cannabinoid receptors and ligands have mechanistic and therapeutic implications in metabolic derangements and specifically in NAFLD. Cannabinoid receptor 1 antagonism has demonstrated promising effects with increased resistance to hepatic steatosis, reversal of hepatic steatosis, and improvements in glycemic control, insulin resistance, and dyslipidemia. Literature regarding the role of cannabinoid receptor 2 in NAFLD is controversial. Exocannabinoids and endocannabinoids have demonstrated some therapeutic impact on metabolic derangements associated with NAFLD, although literature regarding direct therapeutic use in NAFLD is limited. Nonetheless, the properties of the endocannabinoid system, its receptors, substrates, and ligands remain a significant arena warranting further research, with potential for a pharmacologic intervention for a disease with an anticipated increase in economic and clinical burden.

Nonalcoholic Fatty Liver Disease: Epidemiology, Liver Transplantation Trends and Outcomes, and Risk of Recurrent Disease in the Graft

Abstract In parallel with the rising prevalence of metabolic syndrome globally, nonalcoholic fatty liver (NAFL) disease is the most common chronic liver disease in Western countries and nonalcoholic steatohepatitis (NASH) has become increasingly associated with hepatocellular carcinoma. Recent studies have identified NASH as the most rapidly growing indication for liver transplantation (LT). As a hepatic manifestation of the metabolic syndrome, NAFL disease can be histologically divided into NAFL and NASH. NAFL is considered a benign condition, with histological changes of hepatocyte steatosis but without evidence of hepatocellular injury or fibrosis. This is distinct from NASH, which is characterized by hepatocyte ballooning and inflammation, and which can progress to fibrosis and cirrhosis, hepatocellular carcinoma, and liver failure. As for any other end-stage liver disease, LT is a curative option for NASH after the onset of decompensated cirrhosis or hepatocellular carcinoma. Although some studies have suggested increased rates of sepsis and cardiovascular complications in the immediate postoperative period, the long-term posttransplant survival of NASH cases is similar to other indications for LT. Recurrence of NAFL following LT is common and can be challenging, although recurrence rates of NASH are lower. The persistence or progression of metabolic syndrome components after LT are likely responsible for NASH recurrence in transplanted liver. Therefore, while maintaining access to LT is important, concerted effort to address the modifiable risk factors and develop effective screening strategies to identify early stages of disease are paramount to effectively tackle this growing epidemic.

Changing Trends in Etiology- and Ethnicity-Based Annual Mortality Rates of Cirrhosis and Hepatocellular Carcinoma in the United States

With recent improvements in the treatment of end‐stage liver disease (ESLD), a better understanding of the burden of cirrhosis and hepatocellular carcinoma (HCC) is needed in the United States. A population‐based study using the US Census and national mortality database was performed. We identified the age‐standardized etiology‐specific mortality rates for cirrhosis and HCC among US adults ages 20 years or older from 2007 to 2016. We determined temporal mortality rate patterns by joinpoint analysis with estimates of annual percentage change (APC). Age‐standardized cirrhosis‐related mortality rates increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3% (95% confidence interval [CI] 2.0‐2.7). The APC in mortality rates for hepatitis C virus (HCV)‐cirrhosis shifted from a 2.9% increase per year during 2007 to 2014 to a 6.5% decline per year during 2014 to 2016. Meanwhile, mortality for cirrhosis from alcoholic liver disease (ALD, APC 4.5%) and NAFLD (APC 15.4%) increased over the same period, whereas mortality for hepatitis B virus (HBV)‐cirrhosis decreased with an average APC of −1.1%. HCC‐related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at an annual rate of 2.0% (95% CI 1.3‐2.6). Etiology‐specific mortality rates of HCC were largely consistent with cirrhosis‐related mortality. Minority populations had a higher burden of HCC‐related mortality. Conclusion: Cirrhosis‐related and HCC‐related mortality rates increased between 2007 and 2016 in the United States. However, mortality rates in HCV‐cirrhosis demonstrated a significant decline from 2014 to 2016, during the direct‐acting antiviral era. Mortality rates for ALD/NAFLD‐cirrhosis and HCC have continued to increase, whereas HBV‐cirrhosis‐related mortality declined during the 10‐year period. Importantly, minorities had a disproportionately higher burden of ESLD‐related mortality.

Expanding Donor Pool for Liver Transplantation by Utilizing Hepatitis C Virus–Infected Donors for Uninfected Recipients

1. The model is constructed under the assumption that receiving an HCV-positive liver is associated with a higher risk for graft failure as was experienced during the interferon era. However, recent data from the United Network for Organ Sharing (UNOS)(2) registry have suggested that HCV-positive recipients demonstrate comparable, if not marginally improved, short-term graft and patient survival rates during the direct acting antiviral (DAA) era.(2,3) Therefore, improved outcomes may be expected in HCV-negative recipients undergoing liver transplantation (LT) with HCV-positive donors. 2. The article correctly states that the clinical benefit of receiving an HCV-positive donor liver may not be accurately determined by Model for End-Stage Liver Disease (MELD) score alone. Similarly, it may not be prudent to apply the same MELD cut-off score of ≥20 to all UNOS regions with constantly varying donor pool, waitlist additions, MELD at transplant, MELD exception population, etc. As shown in Figure 3, the magnitude of benefit was dependent on the UNOS region and, in fact, a few UNOS regions may have benefitted by a MELD cutoff of ≥18. 3. Furthermore, the attempt to stratify clinical benefit of utilizing HCV-positive donors by UNOS region may not be feasible because of the inconsistencies in the comfort level of LT team from one center to the other, even within the same UNOS region. In addition, some transplant centers may not be comfortable using HCV-positive donors because of relative abundance of HCVnegative donors in that UNOS region, whereas UNOS regions with organ shortage may be more aggressive in using HCV-positive donors. Another real-life issue is the utilization of HCV-positive donors across porous UNOS regional boundaries from a relative donor abundant region to donor shortage region. 4. Finally, the potential addition of HCV-positive donor livers to the “extended criteria donor” (ECD) list may not be suitable. ECD usually refers to donors over the age of 60 years or between 50 and 59 years with two to three comorbidities. Currently, a significant number of HCV-positive liver donors are procured from drug overdose victims who are younger and without comorbid medical conditions. A donor with an increased infection risk may not fulfill the requirements for ECD.(4) This analysis should further adjust for the donor risk profile associated with HCVpositive and HCV-negative donor livers.

Waitlist Outcomes in Liver Transplant Candidates with High MELD and Severe Hepatic Encephalopathy

BackgroundOrgan Procurement and Transplantation Network and United Network for Organ Sharing (OPTN/UNOS) implemented the Share 35 policy in June 2013 to prioritize the sickest patients awaiting liver transplantation (LT). However, Model for End-Stage Liver Disease (MELD) score does not incorporate hepatic encephalopathy (HE), an independent predictor of waitlist mortality.AimTo evaluate the impact of severe HE (grade 3–4) on waitlist outcomes in MELD ≥ 30 patients.MethodsUsing the OPTN/UNOS database, we evaluated LT waitlist registrants from 2005–2014. Demographics, comorbidities, and waitlist survival were compared between four cohorts: MELD 30–34 with severe HE, MELD 30–34 without severe HE, MELD ≥ 35 with severe HE, and MELD ≥ 35 without severe HE.ResultsAmong 10,003 waitlist registrants studied, 41.6% had MELD score 30–34 and 58.4% had MELD ≥ 35. Patients with severe HE had a higher 90-day waitlist mortality in both MELD 30–34 (severe HE 71.1% vs. no HE 56.6%; p < 0.001) and MELD ≥ 35 subgroups (severe HE 85% versus no HE 74.2%; p < 0.001). MELD 30–34 patients with severe HE had similar 90-day waitlist mortality as MELD ≥ 35 patients without severe HE (71.1 vs. 74.2%, respectively; p = 0.35). On multivariate Cox proportional hazards modeling, MELD ≥ 30 patients had 58% greater risk of 90-day waitlist mortality than those without severe HE (HR 1.58, 95% CI 1.53–1.62; p < 0.001).ConclusionPatients awaiting LT with MELD score of 30–34 and severe HE should receive priority status for organ allocation with exception MELD ≥ 35.