How will NAFLD change the liver transplant landscape in the 2020s?

Liver steatosis is the hepatic manifestation of the metabolic syndrome, and is now the leading cause of chronic liver disease worldwide. The treatment of metabolic cirrhosis with liver failure and/or hepatocellular carcinoma is liver transplantation (LT). During the past decade, metabolic cirrhosis represented an increasing cause for LT, especially in the United States. At listing, patients with metabolic cirrhosis are older, with numerous cardiovascular (CV) and renal comorbidities, and this requires multidisciplinary pre-transplant assessment. After LT, 5-year survival is similar to other indications. The leading causes of death are infectious, cancers and CV. The recurrence of the initial disease is very frequent, and a significant part of the patients progress towards graft cirrhosis. No specific immunosuppressive regimen is recommended, but the toxicity profiles must probably be taken into account. In these patients, the only etiological treatment is that of obesity, in the absence of specific therapy for non-alcoholic steatohepatitis. The place of bariatric surgery has to be defined, probably sleeve gastrectomy, in a stable patient, 6-12 months after LT.

Non-invasive diagnosis and follow-up in liver transplantation.

The field of liver transplantation directly or indirectly embodies all liver diseases, in addition to specific ones related to organ rejection (cellular and humoral). The recommended non-invasive methods for determining the indication for liver transplantation are the Model for End-stage Liver Disease score, and the alpha-foetoprotein score in case of hepatocellular carcinoma. Radiological methods are the cornerstones for the diagnosis of vascular and biliary complications after liver transplantation. The possible diseases of the liver graft after transplantation are multiple and often intertwined. Non-invasive diagnostic methods have been poorly evaluated in this context, apart from the recurrence of hepatitis C. Liver biopsy remains the gold standard for evaluating graft lesions in the majority of cases, especially graft rejection.

Acute Severe Liver Injury Related to Long-Term Garcinia cambogia Intake.

Herbal and dietary supplements are frequently used as weight loss supplements. However, they account for 20% of drug-induced liver injury. Garcinia cambogia's (GC) active compound, hydroxycitric acid, can be found among those supplements. We report a 26-year-old woman who had been taking GC for 7 months when she presented with subacute liver failure and ultimately required a liver transplantation. This report highlights the risk of liver injury after long-term use of GC and demonstrates the importance of considering a close and prolonged monitoring of patients in a tertiary liver transplant center.

Natural History of Recurrent Alcohol-Related Cirrhosis After Liver Transplantation: Fast and Furious.

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). Severe alcohol relapse can rapidly lead to recurrent alcohol-related cirrhosis (RAC) for the graft. The aim of this study was to describe the natural history of RAC and the overall survival after LT and after an RAC diagnosis. From 1992 to 2012, 812 patients underwent primary LT for ALD in 5 French transplant centers. All patients with severe alcohol relapse and an RAC diagnosis on the graft were included. The diagnosis of cirrhosis was based on the analysis of liver biopsy or on the association of clinical, biological, radiological, and/or endoscopic features of cirrhosis. RAC was diagnosed in 57/162 patients (35.2%) with severe alcohol relapse, and 31 (54.4%) of those patients had at least 1 episode of liver decompensation. The main types of decompensation were ascites (70.9%), jaundice (58.0%), and hepatic encephalopathy (9.6%). The cumulative probability of decompensation was 23.8% at 5 years, 50.1% at 10 years, and 69.9% at 15 years after LT. During the follow-up, 36 (63.2%) patients died, the main cause of death being liver failure (61.1%). After diagnosis of cirrhosis, the survival rate was 66.3% at 1 year, 37.8% at 5 years, and 20.6% at 10 years. In conclusion, RAC is associated with a high risk of liver decompensation and a poor prognosis. Prevention of severe alcohol relapse after LT is a major goal to improve patient survival.

Tacrolimus exposure after liver transplantation for alcohol-related liver disease: Impact on complications.

BACKGROUND: Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects. OBJECTIVE: The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD. METHODS: All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed. RESULTS: The study population consisted in 251 patients, mean age 53.4 ±â€¯7.3 years, and followed during 11.6 ±â€¯4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers. CONCLUSION: Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Pregnancy and donor-specific HLA-antibody-mediated rejection after liver transplantation: "Liaisons dangereuses"?

BACKGROUND: Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection. OBJECTIVE: The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients. METHODS: This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old). RESULTS: The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6-39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1-25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17-18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92-0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died. CONCLUSION: The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.

Portal vein thrombosis and liver cirrhosis: Long-term anticoagulation is effective and safe.

BACKGROUND AND AIMS: Portal vein thrombosis (PVT) is a common complication of liver cirrhosis. Anticoagulation therapy is efficient, but is associated with potentially severe side-effects, especially bleeding episodes. It is therefore still unclear which patients will benefit from anticoagulation, and for what duration. The aim of the present study was to retrospectively analyse our single centre experience on long-term anticoagulation in patients presenting a PVT, complicating cirrhosis. METHODS: Data of 40 cirrhotic patients with PVT treated by anticoagulation therapy from June 2003 to May 2018 were collected. Regular imaging was performed to monitor the outcome of PVT. The hemorrhagic complications and the recurrence of the PVT after anticoagulation withdrawal were also analyzed. RESULTS: The median follow-up under anticoagulation therapy was 33.7 months. Complete (57.5%) or partial (25.0%) recanalization of PVT was observed. Fifteen bleeding episodes (37.5%) occurred in our population, related to portal hypertension in 7 (46.7%). Eleven (73.3%) patients required hospitalization and eight (53.3%) required blood transfusion. No patient died from bleeding complication. Anticoagulation was stopped in 10 patients (25.0%), because of regression of PVT in 5 patients or a haemorrhagic episode in 5 patients. Among those 10 patients, 7 had a recurrence or extension of the initial PVT. CONCLUSIONS: Our results confirm that anticoagulation allows a recanalization of PVT complicating cirrhosis in the majority of the cases, is associated with non-severe bleeding complications, and can be maintained for a long duration in order to avoid recurrence.

De Novo Malignancies Screening After Liver Transplantation for Alcoholic Liver Disease: A Comparative Opportunistic Study.

Patients having received a liver transplantation (LT) for alcoholic liver disease (ALD) have a high risk of de novo malignancies, especially in the upper aerodigestive tract and lungs due to their smoking and alcohol history. The aim of this retrospective study was to compare a group of patients transplanted for ALD who continue to smoke and who were included in an intensive screening program for tobacco-related cancers implemented at the Grenoble University Hospital and a group of similar patients followed according to usual practice (chest computed tomography [CT] scan every 5 years) at the Edouard Herriot Hospital in Lyon. The intensive screening program consisted of an annual checkup, including a clinical examination by an otorhinolaryngologist, a chest CT scan, and an upper digestive endoscopy. A total of 147 patients were included: 71 patients in Grenoble and 76 patients in Lyon. The cumulative incidence of a first tobacco-related cancer was 12.3% at 3 years, 20.6% at 5 years, 42.6% at 10 years, and 64.0% at 15 years. A curative treatment was possible in 80.0% of the patients in Grenoble versus 57.9% in Lyon (P = 0.068). The rates of curative treatment were 63.6% versus 26.3% (P = 0.062) for lung cancers, 100.0% versus 87.5% (P = 0.498) for lip-mouth-pharynx and larynx cancers, and 66.7% versus 100.0% (P = 1) for esophageal cancers, respectively. In addition, for lung cancers, regardless of study group, 68.7% received a curative treatment when the diagnosis was made by CT scan screening versus 14.3% when it was made because of symptoms (P = 0.008). In conclusion, our study strongly confirms the high rate of tobacco-related de novo malignancies in LT patients for ALD and suggests that the screening of lung cancer by annual chest CT scan could significantly increase the rate of curative treatment.

Very late relapse of hepatitis C virus infection immediately after liver transplant.

Late relapse of hepatitis C virus (HCV) infection is very rare in the era of modern direct-acting antiviral therapy. We report here the first case of a late relapse, after direct-acting antiviral therapy, occurring immediately after liver transplant (LT), with 93 weeks of sustained virologic response before LT. HCV RNA in serum and in liver biopsy was negative the day of LT, and relapse was diagnosed 11 days after LT. HCV NS5A sequencing was performed on samples before and after LT, with 99% of homology demonstrating a true late relapse rather than a reinfection. This late relapse could be explained by extrahepatic reservoirs of HCV and the high immunosuppressive therapy, including bolus of steroids, within the first days post LT. In conclusion, our case suggests that monitoring HCV RNA after LT could be recommended to detect and treat early relapse, even after a long virologic response.

Severe alcoholic relapse after liver transplantation: What consequences on the graft? A study based on liver biopsies analysis.

Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT), but up to 20% of patients experience severe alcoholic relapse. The aims of this study were to evaluate the impact of severe alcoholic relapse on the graft (based on histological examination) and to identify predictive factors associated with recurrent alcoholic cirrhosis (RAC). From 1990 to 2010, 369 patients underwent LT for ALD at Edouard Herriot Hospital (Lyon, France) and survived more than 1 year. All patients who presented severe alcoholic relapse and histological follow-up were included. Liver biopsies were performed at 1 and 5 years and at every 5 years after LT, and when clinically indicated. The median follow-up after LT was 11 years (range, 3-18 years). Severe alcoholic relapse was observed in 73 (20%) of the 369 patients, from whom 56 patients with histological evaluation were included. RAC was diagnosed in 18 (32%) of the 56 patients included, which represents 5% of the 369 patients transplanted for ALD. The median delay between LT and RAC was 6 years (range, 3-10 years) and 4.5 years (range, 2-8 years) after severe alcoholic relapse. The median cumulated years of alcohol use before RAC was 3.5 years (range, 2-7 years). The cumulative risk for F4 fibrosis was 15% at 3 years, 32% at 5 years, and 54% at 10 years after severe alcoholic relapse. A young age at LT (≤50 years old) and an early onset of heavy drinking (within the first 3 years after LT) were associated with RAC. In conclusion, severe alcoholic relapse usually occurs in the first years after LT and is responsible for accelerated severe graft injury. Liver Transplantation 22 773-784 2016 AASLD.