Distribution of Peripheral Blood Lymphoid Subsets in Alcoholic Liver Cirrhosis: Influence of Ethanol Intake

The aim of the present study was to investigate the effect of chronic ethanol (EtOH) consumption on the immune system in patients with alcoholic liver cirrhosis (ALC), as analyzed by the distribution of peripheral blood (PB-) T, B, and NK lymphoid subsets using multiple stainings with monoclonal antibodies and flow cytometry. For that purpose, we have analyzed a group of patients with ALC and active EtOH intake (ALCET group) which were re-evaluated 3 months after alcohol withdrawal. As controls, both ALC patients with at least 1 year of alcohol withdrawal (ALCAW group) and healthy subjects were used. Regarding the alcohol intake period, the most relevant findings were a significant activation of the PB T-cell compartment, and specifically of the TCR alpha beta+ subset, as reflected by an increased expression of both the HLA DR and CD11c antigens as well as a significant increase of both the PB NK cells (CD3-/CD56+) and the cytotoxic T cells coexpressing the CD3 and CD56 molecules. In addition, a decrease of both the numbers of total B cells and their CD5+/CD19+ subset were observed. After a relatively short withdrawal period (3 months), the abnormalities of T, P, and NK cells disappeared. These findings suggest the existence of a close relationship between EtOH consumption and the abnormalities of the immune system observed during active alcoholism. Nevertheless, ALCAW individuals displayed marked alterations on the immunophenotypic profile, as reflected by a significantly decreased number of total T cells, due to reduced levels of the CD3+/TCR alpha beta+, CD4+, CD8+, and CD4+/CD45RA+ T-cell subsets. In addition, a significantly decreased number of total PB B cells was observed in this group of patients. Our results show that in patients suffering from ALC, the abnormalities of the immune system due to a direct effect of EtOH intake (or its metabolites) should be distinguished from the immunological alterations related to the liver disease itself.     

COVID-19 in Liver Transplant Recipients

Background and AimsCoronavirus disease 2019 (COVID-19) has infected over 93 million people worldwide as of January 14, 2021. Various studies have gathered data on liver transplant patients infected with COVID-19. Here, we discuss the presentation of COVID-19 in immunosuppressed patients with prior liver transplants. We also evaluate patient outcomes after infection.MethodsWe searched the PubMed database for all studies focused on liver transplant patients with COVID-19.ResultsWe identified eight studies that evaluated COVID-19 infection in liver transplant patients (n=494). Hypertension was the most prevalent comorbidity in our cohort. Calcineurin inhibitors were the most common immunosuppressant medications in the entire cohort. The average time from liver transplant to COVID-19 infection in our cohort was 74.1 months. Fever and cough, at 70% and 62% respectively, were the most common symptoms in our review. In total, 50% of the patients received hydroxychloroquine as treatment for COVID-19. The next most prevalent treatment was azithromycin, given to 30% of patients in our cohort. In total, 80% of the patients were admitted to a hospital and 17% required intensive care unit-level care, with 21% having required mechanical ventilation. Overall mortality was 17% in our review.ConclusionsGiven the immunocompromised status of liver transplant patients, more intensive surveillance is necessary for severe cases of COVID-19 infection. As liver transplantations have been restricted during the COVID-19 pandemic, further investigation is warranted for studying the risk of COVID-19 infection in liver transplant patients.     

Diagnosis and Management of Alcoholic Liver Disease

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials.     

Manipulation of Alcohol Drinking by Liver Transplantation

The procedure of liver transplantation in alcoholic liver disease raises the question whether it would be possible to regulate the recipient's future drinking by the choice of donor liver. To address this question, we conducted transplantations with rat lines selected for high (AA) and low (ANA) alcohol preference. AA recipients having alcohol experience before the operation remained heavy drinkers regardless of whether the graft came from an AA or ANA donor. However, in those AA recipients who started drinking only after the operation, differences emerged, with AA grafts creating heavy drinking and ANA donor livers resulting in very low drinking. An overall increase in the acetaldehyde levels was introduced by the ANA livers, thus reflecting the original line differences. Similarly, in subsequent experiments, it was observed that when the aldehyde dehydrogenase inhibitor calcium carbimide was introduced in different amounts to the diet, alcohol drinking was reduced more in animals not used to drinking. The magnitude of this effect, especially in situations with established heavy drinking, is of relevance in future contemplations about liver transplantations between humans with dfferent aldehyde dehydrogenase genotypes.     

Effect of Alcohol Use on Allograft Rejection Rates after Liver Transplantation for Alcoholic Liver Disease

Alcoholic liver disease is a major cause of liver disease and has become an ever-increasing indication for liver transplantation (LTx). Follow-up studies have reported a higher rate of alcohol recidivism in patients transplanted for alcoholic hepatitis, compared with those transplanted for endstage alcohol-associated cirrhosis. It is assumed widely that recurrent alcohol use is associated with reduced compliance with immune suppression and, as a result, an increased risk of graft rejection and loss. To assess this question, 209 alcoholic patients transplanted for either alcoholic hepatitis with cirrhosis or cirrhosis alone between January 1, 1986 and December 31, 1991 were followed, with a mean follow-up of 4.4 ± 0.6 years. There were 175 episodes of acute cellular rejection (ACR) that occurred in 137 patients, for an overall rejection rate of 83.7% or at a rate of 1.25 episodes/patient with rejection. The rate of ACR was three times as great in those who remained alcohol-abstinent (2.24 episodes/patient), compared with those who admitted to continued alcohol use (0.75 episodes/patient) ( p < 0.01). A total of 33 episodes of chronic rejection occurred in 26 patients, for an overall rate of 12.4%. As was the case for ACR, the chronic rejection rate was greater among those who were continuously alcohol-abstinent, compared with those who intermittently used alcohol after successful LTx.
There were no differences in the mean FK 506 or cyclosporin A levels in the groups with and without a rejection episode at the time the rejection episode was documented by liver biopsy. Contrary to generally accepted opinion, these data suggest that continued use of alcohol by liver transplant recipients is associated with a reduction, not an increase, in the rate of rejection.     

Polymorphism of Alcohol-Metabolizing Genes Affects Drinking Behavior and Alcoholic Liver Disease in Japanese Men

Alcohol is known to be mainly metabolized in the liver by alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2), and cytochrome P-45011EI. The purpose of this study was to clarify the role of polymorphism of these ethanol-metabolizing enzymes in drinking behavior and the progression of alcoholic liver disease among Japanese men. Polymorphism of the ADH2, ALDH2, and P-45011EI genes was determined by polymerase chain reaction, followed by restriction fragment-length polymorphism analysis in 189 normal Japanese men and 26 male patients with alcoholic liver disease. Drinking behavior was estimated by self-assessment according to DSM-Ill-R criteria. Facial flushing was reported in 91 subjects heterozygous for ALDH2*1/*2 and in two subjects homozygous for ALDH2*2/*2, but was not found in 96 subjects homozygous for ALDH2*1/*1. In contrast, polymorphism of ADH2 and P-45011EI did not differ between flushers and nonflushers. Although the flushers only drank a small amount of alcohol (<20 g of ethanoVday), the nonflushers were divided into a group of moderate drinkers (20 to 80 glday; n = 54) and a group of heavy drinkers (780 g/day; n = 42). A high preponderance of heterozygosity for the ADH2*1/*2 genes (29/ 42; 69%) and a high frequency of the ADH2*1 allele were found in heavy drinkers, compared with moderate drinkers. However, cytochrome P-45011EI gene polymorphism was similar among the moderate and heavy drinkers. Not only a high frequency of the ALDHPl and ADH2*1 alleles, but also a high frequency of the P-45011EI c2 allele was found in the patients with alcoholic liver disease. From these results, the drinking behavior of Japanese men is strongly influenced by the ALDH2*l allele, and the level of alcohol intake is affected by the ADH2*1 allele, but not by cytochrome P-45011EI. However, progression to alcoholic liver disease among heavy drinkers may be affected by the cytochrome P-45011EI c2 allele.