Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS: We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS: Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION: Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.

High post-transplant virological response in hepatitis C virus infected patients treated with pretransplant protease inhibitor-based triple therapy.

BACKGROUND & AIMS: Prevention of recurrent hepatitis C virus (HCV) following liver transplant (LT) with pre-LT antiviral therapy is limited by poor tolerability and efficacy. We aimed to evaluate the safety and efficacy of NS3/4A protease inhibitor (PI)-based triple therapy in patients awaiting LT. METHODS: Consecutive patients treated with triple therapy pre-LT from two centers were prospectively enrolled in an observational cohort. Overall 12 week sustained virological response (SVR12) was the primary outcome. Pre- and post-LT (pTVR) virological response rates and safety were secondary outcomes. RESULTS: Twenty-nine patients (mean age 57.9, 79% male, 66% prior non-responders) were treated with telaprevir (93%) or boceprevir-based (7%) triple therapy for a median (range) of 27 (3-50) weeks, including a pegylated-interferon and ribavirin lead-in in 18%. Median (range) MELD at treatment was 8 (6-16), 39% had hepatocellular carcinoma and all patients were Child-Turcotte-Pugh class A (62%) or B (38%). Twelve patients underwent LT, 75% with undetectable viral load. The overall SVR12 rate was 52%, including pre-LT SVR12 of 41% in patients who completed treatment and follow-up on the wait list and pTVR12 of 67% among transplanted patients. The pTVR12 rate was 89% among those patients with undetectable viral load at LT. Serious adverse events occurred in nine (31%) patients including one (3%) on-treatment death and eight (28%) hospitalizations. CONCLUSIONS: Overall SVR12 and pTVR12 rates are high among patients treated with PI-based triple therapy while awaiting LT, even in this difficult to treat population. However, caution is needed as early discontinuation and serious adverse events are common.

Bland embolization versus chemoembolization of hepatocellular carcinoma before transplantation.

There is conflicting literature regarding the superiority of transarterial chemoembolization (TACE) versus bland transarterial embolization (TAE), and this has not been well studied before transplantation. Twenty-five TAE patients were matched in a 1:2 ratio with TACE patients by the initial radiographic tumor size and number in a retrospective, case-controlled study. The patients were otherwise treated according to the same protocols. The method of embolization was chosen on the basis of interventionalist practices at 2 sites within the program. Kaplan-Meier survival analyses at 1 and 3 years were the primary endpoints. There were no significant demographic differences between the groups. The mean adjusted Model for End-Stage Liver Disease scores at transplantation and waiting times were not significantly different between the TAE and TACE patients (MELD scores: 26 ± 3 versus 24 ± 3 points, P = 0.12; waiting times: 13 ± 8 versus 11 ± 10 months, P = 0.43). TAE patients (16%) were less likely than TACE patients (40%) to require 2 procedures (P = 0.04). Explant tumors were completely necrotic for 36% of the TAE patients and for 26% of the TACE patients. The 3-year overall survival rates were 78% for the TAE patients and 74% for the TACE patients (P = 0.66), and the 3-year recurrence-free survival rates were 72% for the TAE patients and 68% for the TACE patients (P = 0.67). On an intention-to-treat basis, there was no significant risk of wait-list dropout associated with TAE or TACE (P = 0.83). In conclusion, there were no significant differences in wait-list dropout or in overall or recurrence-free survival between HCC patients undergoing TAE and HCC patients undergoing TACE before transplantation.

Exposure to ionizing radiation during liver transplantation evaluation, waitlist time, and in the postoperative period: a cause for concern.

UNLABELLED: Substantial evidence has linked ionizing radiation exposure (RE) to oncogenesis. Patients evaluated for transplantation undergo extensive diagnostic imaging and have increased baseline cancer risk factors. The objective was to examine exposure in a cohort of patients undergoing evaluation and liver transplantation. Radiation exposure from all diagnostic examinations and procedures were retrospectively recorded. Radiation exposure is reported in mSv, a standardized measure of the detrimental biologic effect of radiation which allows for population-level comparisons. Seventy-four patients (69% male, mean 57 years) were evaluated, of which 13 of 35 subsequently listed patients were transplanted; an additional 18 previously evaluated patients were also transplanted during 2010. The most common indications were hepatitis C (55%) and hepatocellular carcinoma (HCC) (30%). The median observation period was 14 months. In all, 1,826 imaging examinations were performed, of which 408 (22%) involved considerable ionizing radiation and were the focus of investigation. Median annualized effective RE was 51 mSv (interquartile range [IQR]: 19,126), with 10% exposed to almost twice the amount of radiation recommended for a 5-year period. Patients with HCC received significantly (P < 0.00001) higher median annualized effective RE than patients without HCC, 137 mSv (IQR: 87,259) versus 32 mSv (IQR: 13,57), respectively. Computed tomography (CT) abdomen (23%) and chest (16%) accounted for the most common exposures, with CT abdomen accounting for 46% of overall cohort RE. CONCLUSION: Patients undergoing evaluation and liver transplantation at our center are exposed to very high levels of ionizing radiation. Although long-term effects in these patients are yet to be defined, the theoretical increased risk of malignancy must be given its due consideration. Routine use of nonradiation imaging and reconsideration of indications may be preferred and justified in this population.

Prevention of de novo hepatitis B in recipients of core antibody-positive livers with lamivudine and other nucleos(t)ides: a 12-year experience.

BACKGROUND: Lamivudine (LAM) has been shown to prevent de novo hepatitis B virus (HBV) infection in recipients of hepatitis B core antibody (HBcAb)-positive liver transplants (LT) but primarily in small studies with limited follow-up. METHODS: We conducted a retrospective cohort study of HBcAb+ graft recipients at our institution from October 1999 to August 2008. RESULTS: One hundred nineteen recipients without prior HBV were identified (median age, 54 years; 70% male), of which 62 received LAM. The median follow-up was 2.6 years overall and 5.3 years in the LAM group. Among LAM recipients, 44% were HBV naïve (HBsAb-/HBcAb-) at LT, of which 6% developed HBsAb+ and 3% developed HBcAb+ after LT. Eight percent developed de novo HBV: two recipients became hepatitis B surface antigen positive at 70 and 23 months and three experienced breakthrough with HBV DNA more than 2000 IU at 1 to 9 months after LT. Sixty percent (3 of 5) were HBV naïve. Four (6%) other recipients also had transiently detectable HBV less than 2000 IU, which did not require any changes to their prophylaxis regimen. When compared with recipients who received other nucleos(t)ide analogues, there was no difference in de novo rates: LAM 8% (5 of 62), adefovir 15% (5 of 33), tenofovir 0% (0 of 3), entecavir 0% (0 of 1), and 5% (1 of 20) for those not given prophylaxis (P=0.59). CONCLUSIONS: LAM monoprophylaxis was effective in preventing de novo HBV in the vast majority of recipients over long-term follow-up. Adefovir had a higher rate of de novo infections numerically, whereas tenofovir and entecavir had no cases and may be more effective, but this was limited by a small sample size.

Safety of blood group A2-to-O liver transplantation: an analysis of the United Network of Organ Sharing database.

BACKGROUND: ABO-incompatible organ transplantation typically induces hyperacute rejection. A2-to-O liver transplantations have been successful. This study compared overall and graft survival in O recipients of A2 and O grafts based on Organ Procurement and Transplantation Network data. METHODS: Scientific Registry of Transplant Recipients data were used. The first A2-to-O liver transplantation was entered on March 11, 1990; all previous transplantations were excluded. Between March 11, 1990, and September 3, 2010, 43,335 O recipients underwent transplanation, of whom 358 received A2 grafts. RESULTS: There were no significant differences in age, sex, and race between the groups. Recipients of A2 grafts versus O grafts were significantly more likely to be hospitalized at transplantation (45% vs. 38%, P≤0.05) and to have a higher mean (SD) model for end-stage liver disease score (24 [11] vs. 22 [10], P≤0.05). 10% of A2 recipients and 9% of O recipients underwent retransplantation. No significant differences existed in rejection during the transplantation admission and at 12 months: 7% versus 6% and 20% versus 22% for A2 recipients and O recipients, respectively; and there were no significant differences in contributing factors to graft failure or cause of death. At 5 years, overall survival of A2 and O graft recipients was 77% and 74%, respectively (log rank=0.71). At 5 years, graft survival was 66% in both groups (log rank=0.52). Donor blood group was insignificant on Cox regression for overall and graft survival. CONCLUSIONS: Using Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients data, we present the largest series of A2-to-O liver transplantations and conclude this mismatch option to be safe with similar overall and graft survival. This opens possibilities to further meet the demands of a shrinking organ supply, especially with regard to expanding living-donor options.

Prevention of de novo hepatitis B with adefovir dipivoxil in recipients of liver grafts from hepatitis B core antibody-positive donors.

Lamivudine has been shown to prevent de novo hepatitis B virus (HBV) infections in liver transplantation (LT) patients receiving hepatitis B core antibody-positive (HBcAb(+)) grafts, but it may produce long-term resistance. Adefovir dipivoxil (ADV) might be effective in preventing de novo hepatitis and resistance. A single-center, prospective trial was conducted with 16 adults (10 men and 6 women, mean age = 54 ± 11 years) who underwent LT with HBcAb(+) grafts between September 2007 and October 2009. After LT, patients were given ADV [10 mg daily (adjusted for renal function)]. No hepatitis B immune globulin was administered. At LT, all graft recipients were hepatitis B surface antigen-negative (HBsAg(-)), 38% were surface antibody-positive (HBsAb(+)), and 50% were HBcAb(+). The median follow-up after LT was 1.8 years (range = 1.0-2.6 years). All recipients had undetectable HBV DNA (<40 IU/mL) after LT until the end of follow-up. One recipient (6%) who was HBsAb(-) and HBcAb(-) before LT became HBsAg(+) after 52 weeks. One recipient was switched from ADV to entecavir for chronic renal insufficiency, and 19% of the patients had renal dose adjustments. There was a nonsignificant trend of increasing creatinine levels over time (1.2 mg/dL at LT, 1.3 mg/dL 1 year after LT, and 2.0 mg/dL 2 years after LT, P = 0.27). A comparison with a control cohort of LT recipients with hepatitis C virus who did not receive ADV showed no difference in the creatinine levels at LT or 1 year after LT. In conclusion, ADV prophylaxis prevents HBV replication in recipients of HBcAb(+) livers but does not fully protect recipients from de novo HBV. Long-term follow-up is needed to better determine the risk of de novo infection.

Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies.

The treatment of hepatocellular carcinoma (HCC) remains a challenge, with 1- and 3-year survival rates of 20% and 5%, respectively, and a median survival of 8 months. However, a better understanding of the pathogenesis of HCC, and advances in targeted molecular therapies provide physicians treating this disease with new hope. The treatment of HCC is multidisciplinary, requiring surgeons, hepatologists, interventional radiologists and oncologists. Thus, there is enormous potential to combine various treatment modalities to improve survival for patients. This review will describe what is currently known about the molecular pathogenesis of HCC, explore current and future treatments based on these pathways, and describe how these new therapies fit into existing approaches to HCC treatment.

Sorafenib: where do we go from here?

The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.

Live donor liver transplantation: current status.

The inequality between supply of grafts and demand for transplants has forced the transplant community to devise ways to increase the number of available livers for transplant (ie, through use of extended criteria donor grafts and living donation). Since 2002, the number of live donor liver transplantations (LDLT) performed has declined due to concerns of donor safety and lack of clear outcome data establishing success equivalent to that of deceased donor liver transplantation (DDLT). Recent data suggest that LDLT outcomes are comparable with those of DDLT, provided a center has performed more than 20 procedures, both in patients with and without hepatitis C. Further studies are needed to define the optimal donor and the ideal recipient for LDLT. Results from a National Institutes of Health-funded consortium of nine transplant centers are highly anticipated. These data are expected to underscore the viability of LDLT as a life-saving therapy for certain patients with end-stage liver disease.