Liver transplantation in 2013: challenges and controversies.

Liver transplantation has changed over the past 50 years from an experimental surgery to a life saving intervention that is the treatment of choice for selected patients with end stage liver disease. Since Starzl attempted the first liver transplant in 1963, the procedure has evolved into one that occurs over 12000 times a year worldwide and has one year survival rates approaching 90% and five year survival rates above 70%. With the success of liver transplantation, challenges and controversies have arisen as well. The aim of this review is to discuss the epidemiology of liver transplantation and highlight those challenges and controversies that exist. Current controversies include appropriate selection of recipients and equitable prioritization for allograft distribution. Future challenges include a decrement in donor quality and availability and an ageing medically complex patient and donor population. Addressing these challenges and controversies will dominate transplantation research for the foreseeable future.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network.

BACKGROUND: Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well-described. AIM: To describe the presenting features and outcomes of seven well-characterized patients with suspected duloxetine hepatotoxicity. METHODS: Patients enrolled in the Drug-Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity. RESULTS: Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre-existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury. CONCLUSIONS: Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra-hepatic features were noted at presentation.

Database comparison of the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the SRTR U.S. Transplant Registry.

Data submitted by transplant programs to the Organ Procurement and Transplantation Network (OPTN) are used by the Scientific Registry of Transplant Recipients (SRTR) for policy development, performance evaluation and research. This study compared OPTN/SRTR data with data extracted from medical records by research coordinators from the nine-center A2ALL study. A2ALL data were collected independently of OPTN data submission (48 data elements among 785 liver transplant candidates/recipients; 12 data elements among 386 donors). At least 90% agreement occurred between OPTN/SRTR and A2ALL for 11/29 baseline recipient elements, 4/19 recipient transplant or follow-up elements and 6/12 donor elements. For the remaining recipient and donor elements, >10% of values were missing in OPTN/SRTR but present in A2ALL, confirming that missing data were largely avoidable. Other than variables required for allocation, the percentage missing varied widely by center. These findings support an expanded focus on data quality control by OPTN/SRTR for a broader variable set than those used for allocation. Center-specific monitoring of missing values could substantially improve the data.

Nontransplantation of livers from deceased donors who are able to donate another solid organ: how often and why it happens.

Deceased donor factors associated with poor graft outcome are well known, but how often these factors lead to livers left untransplanted is poorly defined. A nested, case-control study was conducted using the United Network for Organ Sharing (UNOS) database from 1987 to 2005. Only those donating >/=1 solid organ were included. Primary outcome was livers not transplanted (LNT, cases) versus transplanted (LT, controls). Primary variables for multivariate analysis were donor age and obesity. Covariates included donation after cardiac death (DCD), cerebral vascular accident death, viral serologies, cancer, ALT and bilirubin. There were 23 373 (26%) LNT's from 91 362 donors who donated at least one organ. Percent LNT fell over time (1987-1990: 48%; 1991-1995: 29%; 1996-2000: 21%; 2000-2005: 16%; p < 0.01). Increased age (odds ratio: 4.2, 95% confidence interval 3.6-4.9, p < 0.01) and obesity (2.1, 1.9-2.3, p < 0.01) were significantly associated with LNT across all time periods. Other significant factors included DCD and elevated ALT. For 2001-2005, population attributable risk indicate that age >40, abnormal ALT and obesity account for 32.6%, 25.3% and 9.2% of untransplanted livers, respectively. Use of expanded criteria livers has pushed LNT lower in spite of an aging and heavier donor population. Nevertheless, age and obesity still account for a significant portion of untransplanted livers.

A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients.

BACKGROUND: Treatment options for non-alcoholic steatohepatitis (NASH) are limited. Weight loss remains the most recommended therapy. Orlistat is an effective adjunct to dietary weight loss therapy. AIM: To evaluate the efficacy of orlistat, given for 6 months to patients with obesity and biopsy confirmed NASH. METHODS: Ten obese patients with biopsy proven NASH were enrolled. Orlistat was given with meals for 6 months. Body Mass Index (BMI), liver enzymes, haemoglobin A1c, fasting lipids and glucose were assessed at baseline and at completion of the study. Paired liver histology was obtained. RESULTS: Six women and four men were enrolled. The mean weight loss was 22.7 lb and ranged from 0 to 24.3%. The following clinical values significantly improved: mean BMI: 43.4-39.8 (P = 0.007); mean haemoglobin A1c (%): 7.14-5.95 (P = 0.021); mean alanine aminotransferase (ALT) (U/L): 93 -54 (P = 0.009); and mean aspartate aminotransferase (AST) (U/L): 79-48 (P = 0.008). Steatosis improved in six patients, and fibrosis improved in three patients. CONCLUSIONS: Orlistat therapy and dietary counselling were associated with significant decreases in body weight, haemoglobin A1c, ALT and AST. A 10% or greater reduction in weight improved steatosis and fibrosis as well as haemoglobin A1c levels in the majority of patients treated for 6 months. Controlled trials of longer duration are warranted to assess for histopathologic improvement as well as cost-efficacy in comparison to diet and exercise alone.

Review article: adult-to-adult right hepatic lobe living donor liver transplantation.

Spurred on by the critical shortage of cadaveric livers, adult-to-adult right hepatic lobe living donor liver transplantation has grown rapidly as a therapeutic option for selected patients. In the USA alone, the number of living donor liver transplantations has increased six-fold in the last 4 years. The therapy can be complex, bringing together a variety of disciplines, including transplantation medicine and surgery, hepatology, psychiatry and medical ethics. Moreover, living donor liver transplantation is still defining itself in the adult-to-adult application. Uniform standards, guidelines and long-term outcomes are yet to be determined. Nevertheless, initial success has been remarkable, and a basic understanding of this field is essential to any physician contemplating options for their liver failure patients. This review covers a range of topics, including recipient and donor selection and outcomes, donor risk, controversies and future issues.

Influence of ethnicity and gender on cardiovascular responses to active coping and inhibitory-passive coping challenges.

OBJECTIVE: The goal of this study was to evaluate how black and white men and women responded physiologically to specific laboratory challenges. METHODS: Hemodynamic responses to an active coping (evaluated speaking) and two inhibitory-passive coping (mirror tracing, cold pressor) tasks were examined in 138 black and white men and women. RESULTS: Significant ethnicity by gender interactions occurred for the evaluated speaking task. Black men responded with lower blood pressure, cardiac output or heart rate, or both, than black women, white men, and white women, who did not differ from each other. Black men, relative to the other subgroups, also reported more inhibitory-passive coping, hostility, and pessimism, and less social support. Whites also responded with greater increases in systolic blood pressure during mirror tracing than blacks. CONCLUSIONS: These findings indicate that black-white differences in physiological responsivity obtained for men may have limited generalizability for women. The results also suggest that environmental and social factors rather than genetic or constitutional factors may play a role in black-white reactivity differences.

Use of quantitative assays for hepatitis B e antigen and IgM antibody to hepatitis B core antigen to monitor therapy in chronic hepatitis B.

OBJECTIVES: We evaluated the clinical utility of IgM antibody to the hepatitis B (HB) core antigen (anti-HBc) and HB e antigen (HBeAg) serum levels in patients with chronic HB receiving interferon alfa. METHODS: Stored serum from 47 patients with chronic HB participating in a controlled trial of interferon alfa therapy (10 million U three times a week for 16 wk) were analyzed. All were seropositive for HB surface Ag, HBeAg, and HB virus (HBV) DNA before entry. IgM anti-HBc index values and HBeAg standard values were determined by automated microparticle enzyme immunoassay on samples drawn just before therapy and 6 months later. Ten normal subjects were tested as controls. IgM anti-HBc and HBeAg levels were compared to initial serum HBV DNA, DNA polymerase, serum aminotransferase levels, and demographic features. Serial IgM anti-HBc levels were also obtained during and after therapy in 10 responders and five nonresponders, and serial HBeAg levels were also obtained during and after therapy in four responders and four nonresponders. RESULTS: Neither IgM anti-HBc nor HBeAg levels correlated significantly with values for serum HBV DNA, DNA polymerase, aminotransferases, or demographic features. The initial mean IgM anti-HBc level among the 15 responders to therapy (loss of HBeAg and HBV DNA from serum) was no different from that in nonresponders (mean 1.15 vs 1.27, p = not significant). However, the initial mean HBeAg level was significantly lower in responders than in nonresponders (749.4 vs 1356.4, p = 0.019). Among 10 responders, IgM anti-HBc levels decreased progressively over time, so that at latest follow-up (1.5-4 yr later, mean 2.6 yr), the mean had decreased from 1.325 to 0.312 (p = < 0.001). Among five nonresponders, the mean did not change significantly over 1.5-3 yr (mean 2.2 yr) (1.26 vs 1.08, p = not significant). HBeAg values fell in parallel with HBV DNA and DNA polymerase values in four responders tested but remained elevated in four nonresponders. CONCLUSIONS: HBeAg levels, but not IgM anti-HBc levels, are useful in predicting response to interferon alfa, with responders tending to have lower pretreatment HBeAg levels than nonresponders. HBeAg levels may be used to monitor response to interferon alfa in patients with chronic HB.

Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. The Hepatitis C Study Group.

OBJECTIVE: To assess the clinical significance of antibody to hepatitis C virus (anti-HCV) in volunteer blood donors. DESIGN: Prospective cohort study. SETTING: National Institutes of Health Clinical Center, a tertiary referral research hospital. PATIENTS: 60 anti-HCV-positive blood donors, divided into three groups of 20 persons each: Group I had normal alanine aminotransferase levels, group II had levels elevated to values less than twice the normal range, and group III had levels elevated to values greater than twice the normal range. MEASUREMENTS: Medical history, results of laboratory and virologic testing, and percutaneous liver biopsy findings. RESULTS: Participants with normal alanine aminotransferase levels were older and more often female than those with abnormal levels. The source of infection, duration of disease, symptom score, and amount of alcohol consumed were similar in the three groups. Hepatitis C virus RNA was detectable in 85% of participants, more commonly in the groups with elevated alanine aminotransferase levels (95%) than in the group with normal levels (65%); however, titers were similar in all groups. Examination of liver biopsy specimens showed chronic hepatitis in 54 participants (90%) and cirrhosis in 1 participant. The only normal liver biopsy specimens (n = 3) were those from participants who were HCV RNA negative and had normal alanine aminotransferase levels. CONCLUSIONS: Most blood donors with anti-HCV have chronic hepatitis C regardless of their serum alanine aminotransferase levels. Donors with normal alanine aminotransferase levels and no HCV RNA in their serum generally have normal liver histologic findings or minimal changes and have probably recovered from HCV infection.

Peripheral-blood mononuclear cell responses to recombinant hepatitis C virus antigens in patients with chronic hepatitis C.

Peripheral blood mononuclear cell proliferative responses in vitro to recombinant yeast or Escherichia coli hepatitis C virus fusion proteins were evaluated in 20 patients with chronic hepatitis C who were reactive for antibody to hepatitis C virus (on enzyme immunoassay, version 2.0, and a four-antigen recombinant immunoblot assay). Twenty age-matched, healthy individuals negative for antibody to hepatitis C virus were used as a control group. Peripheral-blood mononuclear cells from all chronic hepatitis C patients with antibodies to hepatitis C virus antigens c22 and c100-3 proliferated in vitro in response to the corresponding recombinant hepatitis C virus fusion protein. Peripheral-blood mononuclear cells from 75% of patients infected with hepatitis C virus proliferated in response to cytidine monophosphate-keto-3-deoxyoctulosonic acid-core recombinant antigen but there was no proliferative response to cytidine monophosphate-keto-3-deoxyoctulosonic acid-EF (derived from the NS5 region). All hepatitis C virus-infected patients had 33c antibody, but peripheral-blood mononuclear cells from only 9 of 14 (64%) proliferated in vitro in response to 33c. Ninety-five percent of all hepatitis C virus-infected patients had peripheral-blood mononuclear cells that proliferated in response to at least one recombinant hepatitis C virus fusion protein. The numbers and percentages of CD3 T cells, CD19 B cells and natural killer cells from patients with chronic hepatitis C virus infection did not differ from those in the healthy control group. However, the number of non-major histocompatibility complex-restricted cytotoxic T cells (CD3-positive, CD56-positive, CD16-positive) was increased in patients with chronic hepatitis C virus infection (p < 0.05).

Polymerase chain reaction in gastroenterology.

Polymerase chain reaction (PCR) has had a major impact on molecular biology and is beginning to change our perception of certain disease processes and diagnostic tests. PCR allows the identification and amplification of very rare nucleic acid sequences. This is resulting in our identification of previously elusive infectious agents and of mutations that may affect the course of viral infections or carcinogenesis. PCR can now analyze the expression of genes from single cells or single molecules of nucleic acid from a sample source. Once pitfalls in contamination are overcome and more probes for genes of biological and medical interest become available, PCR technology will become universally employed in the clinical laboratory.

Molecular biology of viral hepatitis and hepatocellular carcinoma.

Five viruses are the major causes of hepatitis. These viruses are totally unrelated to each other in structure and mode of replication despite the similarity in the acute syndrome produced by each virus. HAV is a single-stranded RNA virus that has a very stable capsid and whose proteins are derived from a single polyprotein. HBV is a DNA virus that replicates through an RNA intermediate. HCV is a labile single-stranded RNA virus whose proteins are derived from a polyprotein. HDV is a defective RNA virus related to viroids that encodes a capsid antigen, delta antigen, and requires the envelope protein of HBV (HBsAg) for its propagation. HEV is a labile RNA virus that is unrelated to other known viruses. Hepatitis B, C, and D can cause chronic hepatitis. Both chronic hepatitis B and C virus infections are associated with primary hepatocellular carcinoma. The most likely mechanism for hepatitis B and C promotion of primary hepatocellular carcinoma in that these viruses cause chronic inflammation and increased mitotic activity of the pluripotent oval cells of the liver. Most likely, primary hepatocellular carcinoma arises out of synergy between chronic viral infection and some other carcinogenic stimulus such as exposure to a hepatotoxin.

Hepatitis C virus is detected in a monocyte/macrophage subpopulation of peripheral blood mononuclear cells of infected patients.

Hepatitis C virus (HCV) is the primary agent of posttransfusion non-A, non-B hepatitis. HCV RNA was detected in peripheral blood mononuclear cells (PBMC) by polymerase chain reaction in 17 of 24 HCV-infected patients with chronic hepatitis with or without cirrhosis. One of 5 patients whose PBMC contained HCV RNA also had negative-stranded HCV RNA in the PBMC. In 3 of 11 patients whose PBMC contained HCV RNA, flow cytometry with a murine monoclonal antibody to HCV core epitope revealed cytoplasmic staining of peripheral blood monocytes. The monocyte surface and the peripheral blood lymphocytes did not stain for HCV core epitopes. No correlation could be made between the presence of HCV RNA or antigen in PBMC and any serologic markers of HCV infection. These results indicate that monocyte uptake of HCV by either phagocytosis or infection may be part of the pathophysiology of this chronic disease.

Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination.

In a double-blind, crossover study, five white men with mild-to-moderate hypertension received placebo and fixed doses of atenolol, metoprolol, chlorthalidone, verapamil, and the combination of atenolol and chlorthalidone in a quasi-random order. Daily dosages were: atenolol, 100 mg; metoprolol, 200 mg; chlorthalidone, 50 mg; verapamil, 240 mg; and the same doses of atenolol and chlorthalidone in combination. Standard office and daytime ambulatory blood pressures were assessed at the end of each month-long trial. Atenolol, metoprolol, chlorthalidone, and verapamil controlled office blood pressure with similar reductions. Verapamil did not lower ambulatory blood pressure at this dose (which is lower than is now commonly used), but reductions in ambulatory blood pressure were similar for atenolol, metoprolol, and chlorthalidone. The combination of atenolol and chlorthalidone maintained blood pressure control more effectively than the single drug treatments in both office and ambulatory settings, and the combined hypotensive effects were additive. However, reductions in the office due to the combination appeared to overestimate hypotensive effectiveness in the ambulatory setting. This study suggests that the effectiveness of commonly prescribed antihypertensive regimens varies according to setting as well as drug, and that assessment of treatment effectiveness can be improved by automated ambulatory blood pressure monitoring.

Prevalence of hepatitis C virus antibodies among patients infected with human immunodeficiency virus.

A study was undertaken to determine the prevalence and risk factors for serological evidence of hepatitis C virus (HCV) infection in patients infected with the human immunodeficiency virus (HIV). Tests for anti-HCV antibody were carried out by enzyme-linked immunoassay (EIA) on 101 HIV-infected patients from two university-based outpatient clinics. Anti-HCV antibody reactive samples were tested by using a recombinant immunoblot assay (RIBA) for HCV antibodies. Fourteen of 101 (13.9%) HIV-infected patients were anti-HCV reactive by EIA. Of these 14, only seven were reactive by RIBA: four were intravenous drug users as a sole risk factor for HIV infection; and the remaining three acquired HIV by blood transfusion, contaminated instrument exposure or IV drug use and sexual contact. Acquisition of HIV by sexual activity alone was not associated with HCV infection. It is concluded that HCV infection is found in approximately 7% of a university HIV clinic population. False-positive anti-HCV antibody serology may lead to overestimation of the prevalence of HCV infection. Female sex and intravenous drug use are significantly associated with HCV infection among HIV-infected individuals.