COVID-19 in liver transplant patients: Impact and considerations.

The coronavirus disease 2019 pandemic has significantly impacted liver tran splantation worldwide, leading to major effects on the transplant process, including the pretransplant, perioperative, and post-transplant periods. It is believed that patients with chronic liver disease, especially those with cirrhosis, have a higher risk of complications from coronavirus disease 2019 infection compared to the general population. However, evaluation of coronavirus disease 2019 effects on liver transplant patients has not uniformly demonstrated worse outcomes. Nonetheless, the pandemic created significant challenges and restrictions on transplant policies and organ allocation.

Liver transplantation amidst the COVID-19 era: Our center's experience.

Coronavirus disease 2019 significantly impacted the liver transplant process worldwide. Consequently, it brought significant challenges and limitations to transplant policies and organ allocation forcing liver transplant centers to adjust their protocols to ensure maximum benefit and avoid harm to their patients. Our center, like many others, was obliged to adapt to the challenges. This paper provided an overview of the effects of coronavirus disease 2019 on liver transplantations and detailed our center's experience and efforts during this unprecedented pandemic to serve as a guide for future public health crises.

Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy.

BACKGROUND: Persistent inflammation on histology after successful hepatitis C (HCV) treatment has been reported. However, data regarding the long-term impact in liver transplant recipients is limited, particularly after using direct-acting antiviral (DAA) therapies. AIM: To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients. METHODS: We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014. All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy. Only patients with at least one liver biopsy at or after treatment were included. We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA. RESULTS: Persistent inflammation was seen in 12/13 patients on end of treatment biopsy. Inflammation was still seen in the available five follow-up biopsies (range 38-48 wk after the end of treatment). Intrahepatic HCV RNA was undetectable in all biopsies. All patients had preserved graft function for a mean follow-up of 2.5 years, except one that developed chronic rejection. CONCLUSION: After successful HCV treatment with DAAs, liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA. The clinical outcome remained favorable in most patients. Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.

Induction Therapy With Antithymocyte Globulin and Delayed Calcineurin Inhibitor Initiation for Renal Protection in Liver Transplantation: A Multicenter Randomized Controlled Phase II-B Trial.

BACKGROUND: Calcineurin inhibitor (CNI)-based immunosuppression in liver transplantation (LTx) is associated with acute and chronic deterioration of kidney function. Delaying CNI initiation by using induction rabbit antithymocyte globulin (rATG) may provide kidneys with adequate time to recover from a perioperative insult reducing the risk of early post-LTx renal deterioration. METHODS: This was an open-label, multicenter, randomized controlled clinical trial comparing use of induction rATG with delayed CNI initiation (d 10) against upfront CNI commencement (standard of care [SOC]) in those patients deemed at standard risk of postoperative renal dysfunction following LTx. The primary endpoint was change in (delta) creatinine from baseline to month 12. RESULTS: Fifty-five patients were enrolled in each study arm. Mean tacrolimus levels remained comparable in both groups from day 10 throughout the study period. A significant difference in delta creatinine was observed between rATG and SOC groups at 9 mo (P = 0.03) but not at month 12 (P = 0.05). Estimated glomerular filtration rate levels remained comparable between cohorts at all time points. Rates of biopsy-proven acute rejection at 1 y were similar between groups (16.3 versus 12.7%, P = 0.58). rATG showed no significant adverse effects. Survival at 12 mo was comparable between groups (P = 0.48). CONCLUSIONS: Although the use of induction rATG and concurrent CNI deferral in this study did not demonstrate a significant difference in delta creatinine at 1 y, these results indicate a potential role for rATG in preserving early kidney function, especially when considered with CNI deferral beyond 10 d or lower target tacrolimus levels, with acceptable safety and treatment efficacy.

Orthotopic Liver Transplantation in a Cirrhotic Patient With Recent COVID-19 Infection.

The coronavirus disease 2019 (COVID-19) pandemic has led to a decrease in liver transplantation because of concerns regarding safety and healthcare resource utilization. There are scant data regarding the safety, optimal timing, and preferred postsurgical immunosuppression regimens for liver transplantation in patients recovered from COVID-19 infection. We describe our experience with one of the first reported cases of orthotopic liver transplantation in a patient who had recently recovered from COVID-19 infection. Using our experience as an example, orthotopic liver transplantation in patients that have recovered from COVID-19 may be safe.

From hepatitis A to E: A critical review of viral hepatitis.

Viral infections affecting the liver have had an important impact on humanity, as they have led to significant morbidity and mortality in patients with acute and chronic infections. Once an unknown etiology, the discovery of the viral agents triggered interest of the scientific community to establish the pathogenesis and diagnostic modalities to identify the affected population. With the rapid scientific and technological advances in the last centuries, controlling and even curing the infections became a possibility, with a large focus on preventive medicine through vaccination. Hence, a comprehensive understanding of hepatitis A, B, C, D and E is required by primary care physicians and gastroenterologists to provide care to these patients. The review article describes the epidemiology, pathogenesis, clinical presentation, diagnostic tools and current medication regimens, with a focus on upcoming treatment options and the role of liver transplantation.

Pathogenetic mechanisms of nonalcoholic fatty liver disease and inhibition of the inflammasome as a new therapeutic target.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its incidence is increasing. Nonalcoholic steatohepatitis (NASH), the progressive form of the disease, can lead to end-stage liver disease. The pathogenesis of the disease is not fully understood, and there is currently no specific treatment. Therefore, an effective and reliable treatment modality is needed. In recent years, the inflammasome has been shown to play a vital role in many stages of NAFLD pathogenesis. In particular, the detection, by toll-like receptors, of pathogen-associated molecular patterns induced by the gut-liver axis triggers the formation of the NLRP3 (NLR family pyrin domain-containing protein 3) inflammasome. Stimulation of damage-associated molecular patterns also activates the NLRP3 inflammasome. The activated inflammasome has caspase-1 activity, which leads to the release of interleukin (IL)-1 and IL-18 and formation of pores in the cell wall. This process spreads the inflammatory process to the outside of the cell and induces inflammatory cell death (pyroptosis). Subsequent progression of the inflammatory process leads to fibrosis. Recent evidence suggests that the NLRP3 inflammasome may be a potential target for the treatment of NASH. The discovery of specific NLRP3 inflammasome blockers in recent years and evidence of their positive effects in experimental models support this therapeutic approach. In this article, we discuss recent evidence on the pathogenesis of NAFLD, the role of the inflammasome in the pathogenesis of NAFLD, and the potential effects of inhibition of the inflammasome.

Managing liver transplantation during the COVID-19 pandemic: A survey among transplant centers in the Southeast United States.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has had a profound worldwide impact. Indeed, it has led to a vast decrease in organ transplantation, including liver transplants (LT). There is little data regarding adjustments made by LT centers as a response to the COVID-19 pandemic. AIM: To assess the experience of LT centers in the United States during the pandemic. METHODS: We performed an observational survey study from May 11, 2020 to June 5, 2020. We sent out a 13 question survey to 15 LT centers across the southeastern United States. RESULTS: Eleven LT centers responded to the survey. We found that (11/11) 100% of transplant centers made adjustments because of the COVID-19 pandemic. At least 50% of transplant centers had at least one transplant recipient infected with COVID-19. To adjust, greater than 50% of centers performed fewer LT, 100% of patients were tested for COVID-19, and most centers implemented a virtual platform. CONCLUSION: The COVID-19 pandemic greatly affected liver transplantation in the southeastern United States. It was evident that a concerted effort was made by LT centers to protect their patients and employees from COVID-19 but also to continue the life-saving procedure of LT in this sick patient population. Further studies are needed to assess how LT centers around the world managed the pandemic in order to learn strategies to continue life-saving procedures in this patient population.

Early Detection of Hepatocellular Carcinoma Recurrence in the Posttransplant Population: A Comparison of RETREAT and Cleveland Clinic Florida Scoring System.

BACKGROUND: Liver transplantation (LT) for hepatocellular carcinoma (HCC) is curative in most cases; however, recurrence is observed in some patients. The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score is an externally validated scoring system for prediction of post-LT HCC recurrence. The Cleveland Clinic Florida Scoring System (CCFSS) is a potential new scoring system for prediction of HCC recurrence. Our study aimed to compare the RETREAT and CCFSS. METHODS: We conducted a retrospective cohort study of 52 adult patients with HCC who underwent LT at a tertiary care center. Mantel-Haenszel chi-square analyses were conducted to compare the RETREAT and CCFSS classifications for detecting HCC recurrence. RESULTS: A total of 52 patients underwent LT. The median follow-up period was 37 months. Four patients had post-LT HCC recurrence, with all recurrences occurring within 2 years of LT. The RETREAT score was better able to detect low, moderate, and high levels of risk (P < .001), compared to the CCFSS score (P = 0.480). Both risk scores had a sensitivity of 75%; the specificity of the RETREAT score was 95.8%, whereas the specificity of the CCFSS was 60.4%. Alpha-fetoprotein level at the time of LT was associated with HCC recurrence (P = .014). CONCLUSIONS: This is the first study to evaluate the CCFSS as a potential new scoring system to predict HCC recurrence after LT. The RETREAT score is more specific than the CCFSS. The incorporation of alpha-fetoprotein level at the time of LT improves the estimation of HCC recurrence in the post-LT period.

Risk Factors Associated With Postendoscopic Mucosal Resection Bleeding in Patients With Cirrhosis: A Retrospective Multicenter Cohort Study.

BACKGROUND AND AIM: There is limited data regarding the safety of endoscopic mucosal resection (EMR) in the cirrhotic population. Our study aimed to evaluate the safety of colonoscopic EMR in cirrhosis. MATERIALS AND METHODS: This was a retrospective review of cirrhotics who underwent colonic EMR at 8 Cleveland Clinic Centers between January 1, 2006, and December 31, 2018. Patient data including polyp details and complications occurring within 30 days of the procedure were noted. Univariable and multivariable logistic regression analyses were conducted to find risk factors for post-EMR bleeding. RESULTS: A total of 238 patients who underwent EMR were included. There were 145 males (60.9%) and the mean age was 61.9±8.6 years. Immediate and delayed bleeding, and postpolypectomy syndrome rates were 9.2%, 5.8%, and 1.3%, respectively. Significant risk factors for postpolypectomy bleeding were: increased age (P=0.001), procedure duration >37 minutes (P=0.001), antiplatelet use within 5 days (P=0.023), and lesion diameter >15 mm (P=0.004). Multivariable analysis revealed independent predictors of procedure-related bleeding: age above 65 years [odds ratio (OR) 2.14, P=0.044], antiplatelet use within 5 days (OR 2.42, P=0.047), right colon polyp (OR 3.51, P=0.001), and lesion diameter >15 mm (OR 3.22, P=0.003). CONCLUSIONS: EMR in cirrhotics has an acceptable bleeding risk. Age above 65 years, right colon polyp, polyp size >15 mm, and use of antiplatelets within 5 days are independent risk factors for bleeding.

Nasal Bridles for Securing Nasoenteric Feeding Tubes: A Review of Clinical Effectiveness and Potential Complications.

Nasal bridle is a feeding tube retaining device that is now increasingly used worldwide. While common complications tend to be minor, it is important to remain vigilant for newer adverse events. We hereby delineate the case of an elderly female who required nasoenteric feeding tube following simultaneous liver-kidney transplantation. Nasal bridle placement was warranted owing to her significant frailty and poor mentation. Due to her extreme agitation during the procedure, bridle insertion could not be completed. Upon removal of the probe, unprompted detachment of the magnetic tip was noted. Radiological workup revealed the dislodged magnet in the sphenoid sinus. Subsequently, she underwent an uneventful endoscopic sinus surgery, resulting in successful retrieval of the magnet. This paper highlights the spontaneous magnet avulsion from a bridling system and serves the purpose of community awareness regarding this unusual procedural complication. Additionally, we aim to evaluate the efficacy of the nasal bridle, further accentuating its advantages and possible complications.

Hepatitis C Virus NAT-Positive Solid Organ Allografts Transplanted Into Hepatitis C Virus-Negative Recipients: A Real-World Experience.

BACKGROUND AND AIMS: Hepatitis C virus (HCV)-viremic organs are underutilized, and there is limited real-world experience on the transplantation of HCV-viremic solid organs into recipients who are HCV negative. APPROACH AND RESULTS: Patients listed or being evaluated for solid organ transplant after January 26, 2018, were educated and consented by protocol on the transplantation of HCV-viremic organs. All recipients were HCV nucleic acid test and anti-HCV antibody negative at the time of transplant and received an HCV-viremic organ. The primary outcome was sustained virological response (SVR) at 12 weeks after completion of direct-acting antiviral (DAA) therapy (SVR12 ). Seventy-seven patients who were HCV negative underwent solid organ transplantation from a donor who was HCV viremic. No patients had evidence of advanced hepatic fibrosis. Treatment regimen and duration were at the discretion of the hepatologist. Sixty-four patients underwent kidney transplant (KT), and 58 KT recipients had either started or completed DAA therapy. Forty-one achieved SVR12 , 10 had undetectable viral loads but are not eligible for SVR12 , and 7 remain on treatment. One KT recipient was a nonresponder because of nonstructural protein 5A resistance. Four patients underwent liver transplant and 2 underwent liver-kidney transplant. Three patients achieved SVR12 , 1 has completed DAA therapy, and 2 remain on treatment. Six patients underwent heart transplant and 1 underwent heart-kidney transplant. Six patients achieved SVR12 and 1 patient remains on treatment. CONCLUSIONS: Limited data exist on the transplantation of HCV-viremic organs into recipients who are HCV negative. Our study is the largest to describe a real-world experience of the transplantation of HCV-viremic organs into recipients who are aviremic. In carefully selected patients, the use of HCV-viremic grafts in the DAA era appears to be efficacious and well tolerated.

Fibrosing cholestatic hepatitis after kidney transplantation from HCV-viremic donors to HCV-negative recipients: A unique complication in the DAA era.

Fibrosing cholestatic hepatitis (FCH) posttransplantation can lead to graft failure and death. In the era of direct acting antiviral therapy (DAA), several studies have demonstrated the efficacy and safety of transplanting hepatitis C virus (HCV)-positive allografts into HCV-negative recipients. In this case series, we present two cases of HCV-negative recipients who underwent kidney transplantation from viremic donors and developed FCH. Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100 000 000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs. One patient has undetectable HCV 12 weeks after completing treatment and the other patient has undetectable HCV after completing DAA treatment. The introduction of DAAs has changed the landscape of solid organ transplantation with the potential to expand the donor pool and increase access to organs. While HCV viremic organs have tremendous potential to increase access to a scarce resource, FCH is a potentially fatal complication and therefore clinicians must maintain a high index of suspicion for this unique complication.

Transplantation of HCV Viremic Livers into HCV Viremic Recipients Followed by Direct-acting Antiviral Therapy.

Background and Aims: Hepatitis C virus (HCV)-infected organs are underutilized. We aimed to assess the safety and efficacy of direct-acting antiviral agents (DAAs) therapy in HCV viremic patients who are transplanted with a liver from a HCV viremic donor. Methods: We conducted a retrospective study, including patients seen from July 2015 to April 2017. HCV viremic patients transplanted with a liver from a HCV viremic donor and subsequently treated with DAAs were included. Outcomes assessed included undetectable viral load at 12 weeks after completing DAA therapy (sustained virologic response, SVR12), adverse events, and interactions with immunosuppression. Results: Twenty-four HCV viremic recipients received livers from HCV viremic donors. Median age was 63 years, and the majority (79.2%) were genotype 1a. Donors and recipients were viremic at the time of transplant. Median modified model for end-stage liver disease score was 19, and median time on the waitlist was 81 days. Median time from transplant to initiation of DAA therapy was 123 days. Several DAA regimens were used and 15 (62.5%) patients did not receive ribavirin. Treatment duration ranged from 12 to 24 weeks. Twenty-three (95.8%) patients achieved SVR12. Five (20.8%) patients developed adverse events; however, none required DAA discontinuation. Conclusions: DAA therapy was efficacious and well tolerated in HCV viremic recipients who underwent liver transplantation from a HCV viremic donor.

Sofosbuvir/Ledipasvir Without Ribavirin Achieved High Sustained Virologic Response for Hepatitis C Recurrence After Liver Transplantation: Two-Center Experience.

BACKGROUND: Current recommended regimens to treat patients with hepatitis C virus (HCV) infection after liver transplantation include the use of ribavirin (RBV). Limited data are available on the efficacy of RBV-free regimens posttransplant, particularly the use of sofosbuvir (SOF)/ledipasvir (LDV) without RBV in this patient population. We aimed to assess the efficacy and safety of SOF/LDV fixed-dose combination without RBV in patients with HCV recurrence posttransplant. METHODS: This is a retrospective study of 46 patients with HCV recurrence posttransplant. SOF/LDV without RBV was used for 12 weeks in patients with early-stage fibrosis (F0-F2) or for 24 weeks in those with advanced fibrosis (F3-F4) and/or cholestatic hepatitis. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment. Secondary outcomes included relapse after treatment and adverse events. RESULTS: Forty-six patients, with a mean age of 62 ± 8 years, a median duration since time of transplant of 904 days (range, 78-3525 days), an HCV genotype 1, and a mean baseline viral load of 7.79 million IU/mL, were treated. Of these, 32 patients were treated for 12 weeks, and 14 patients were treated for 24 weeks. Twenty-five patients (54%) were treatment experienced (21 with interferon and 4 with SOF). All 46 patients (100%) achieved sustained virological response (SVR) 12. Neither virologic relapses nor serious adverse events were noted. CONCLUSIONS: The combination of SOF/LDV without RBV for 12 or 24 weeks produced 100% SVR 12 in patients with HCV recurrence after liver transplantation. The use of RBV may not be necessary to achieve SVR in this patient population.

Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two-center experience.

BACKGROUND: The interferon-free antiviral regimen, sofosbuvir (SOF) and simeprevir (SIM) without ribavirin has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT). AIM AND METHODS: We aim to report the safety, tolerability and efficacy of SOF + SIM to treat LT recipients with recurrent HCV GT1 in a multicenter cohort study. RESULTS: Eighty-one patients with HCV GT1 met criteria to be considered for treatment. Sixty-seven patients received SOF + SIM following LT to date: 69% male, 39% with HCV RNA >6 000 000 IU/mL, 22% advanced hepatic fibrosis (stage 3-4), 6% cholestatic recurrence. Fifty-eight percent previously failed or did not tolerate interferon-based treatments. Mean time from LT to treatment was 6.1 ± 5.2 yr. All patients had estimated GFR >30 mL/min. Tacrolimus was primary immunosuppression in 84% of patients and minimal immunosuppression dose adjustments were required during treatment. In intention-to-treat analysis, 90% achieved end-of-treatment virologic response and 88% achieved SVR. CONCLUSIONS: Sofosbuvir + SIM combination therapy without ribavirin is well tolerated and results in high virologic response rates in recurrent HCV GT1 infection after liver transplantation.

An Update on Treatment of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) has been linked to more than 1,000 medications and remains the most common cause of acute liver failure in the United States. Here, we review the most current literature regarding treatment and make recommendations for the management of this relatively common disease. Since treatment of DILI remains largely elusive, recent studies have attempted to define new management strategies for these difficult patients. Early diagnosis and withdrawal of the suspected medication is the mainstay of treatment of DILI. For acetaminophen and Amanita mushroom poisoning, there are specific therapies in use. Finally, there are other possible management modalities for DILI, including corticosteroids and ursodeoxycholic acid.

Clinical manifestations and treatment of drug-induced hepatotoxicity.

With an increase of prescription medication and herbal supplement use, drug-induced liver injury (DILI) has become an increasingly important entity. Because DILI is a usually readily treatable condition, it is essential for providers to reach a diagnosis in a timely fashion. Unfortunately, varied clinical presentations, difficulties in establishing causality, and lack of a gold standard diagnostic criterion may make early diagnosis difficult. This article seeks to define commonly used terminology, describe common clinical presentations of DILI, provide an overview of current diagnostic criteria, and provide management guidelines.