Marius Braun

Metabolic syndrome in liver transplant recipients: Prevalence, risk factors, and association with cardiovascular events

Features of metabolic syndrome are not uncommon in patients after liver transplantation. To examine the prevalence and risk factors of posttransplantation metabolic syndrome (PTMS), the files of 252 transplant recipients (mean age, 54.5 ± 2.8 years, 57.9% male) were reviewed for pretransplant and posttransplant clinical and laboratory parameters (mean follow‐up, 6.2 ± 4.4 years). Rates of obesity (body mass index >30 kg/m2), hypertriglyceridemia (>150 mg/dL), high‐density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women), hypertension, and diabetes were significantly higher after transplantation than before. Metabolic syndrome was diagnosed in 5.4% of patients before transplantation and 51.9% after. Besides significantly higher rates of the typical metabolic derangements (P < 0.0001), the patients with PTMS were older and heavier than those without PTMS, and they had a higher rate of pretransplant hepatitis C virus infection (P < 0.03) and more posttransplant major vascular and cardiac events (20 events in 15.2% of patients with PTMS versus 6 events in 4.9% of patients without PTMS; P < 0.007). There was no between‐group difference in mortality or causes of death (mainly related to recurrent disease, graft failure, and sepsis). Significant independent predictors of PTMS on logistic regression analysis were age (odds ratio [OR] = 1.04), pretransplant nonalcoholic fatty liver disease (OR = 3.4), body mass index (OR = 1.13), diabetes (OR = 5.95), and triglycerides (OR = 1.01). The rate of metabolic syndrome in liver transplant recipients is more than twice that reported for the general population. PTMS is associated with cardiovascular morbidity but not mortality, and it may be predicted by pretransplantation conditions. Prospective studies are required to determine the significance and management of PTMS. Liver Transpl 17:15–22, 2011.

Predictive value of serum globulin levels for the extent of hepatic fibrosis in patients with chronic hepatitis B infection

Summary.u2002 The mechanism underlying disease progression in hepatitis B virus (HBV) infection is unknown. Immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. A strong association was found between serum immunoglobulin levels and hepatic fibrosis in patients with hepatitis C virus infection. Our objective was to determine if the same index could also be used in patients with chronic HBV infection. The records of 100 patients with biochemical, serological, virological and histological evidence of chronic HBV infection were reviewed for background factors and serum globulin and immunoglobulin levels. Mean (±SD) patient age was 44.0u2003±u200314.7u2003years; 80 (80%) were male. Of the factors found to be significant on univariate analysis, the only significant predictors of severe hepatic fibrosis (stage ≥2) on multivariate analysis were serum globulin level [odds ratio (OR) 5.97, 95% confidence intervals (CI) 1.82–19.53, Pu2003=u20030.0004], platelet count (OR 0.98, CI 0.97–0.99, Pu2003=u20030.001), and immunoglobulin G (IgG) level (OR 1.003, CI 1.000–1.007, Pu2003<u20030.042) but not IgA, alkaline phosphatase, albumin or international normalized ratio. For each increase of 0.33u2003mg/dL in serum globulin, there was a 0.5 point increase in the stage of hepatic fibrosis. There appears to be a strong association between levels of serum globulin and IgG and extent of hepatic fibrosis in patients with chronic HBV infection. They can serve as noninvasive markers of hepatic fibrosis and, if confirmed, have important implications for the management of patients with chronic HBV infection.

Sequential liver and kidney transplantation from a single living donor in two young adults with primary hyperoxaluria type 1

Using living donor organs for sequential liver and kidney transplantation (SeqLKT) in patients with primary hyperoxaluria type 1 (PH1) has emerged as a viable approach. Taking both organs from a single donor, however, is rare. There are 8 reported cases of SeqLKT in the literature, and in all but 1 case, children were the recipients. We present our experience with SeqLKT in 2 young adults with PH1. In the first case, with an interval between procedures of 4.5 months, SeqLKT was performed with a right liver lobe from a 47‐year‐old father for his 19‐year‐old son with PH1 who was on dialysis for 2 years before transplantation. Both the donor and the recipient had an uneventful recovery, although there was re‐exploration for the control of bleeding in the recipient after liver transplantation. Thirty‐three months after transplantation, the patient had normal liver and renal function. In the second case, with an interval between procedures of 22 days, SeqLKT was performed with organs from a 45‐year‐old father for his 19‐year‐old daughter with PH1 who was on dialysis for 8 months. The recipient procedures, including right liver lobe transplantation and kidney transplantation, were uneventful. The donor underwent percutaneous drainage of a subphrenic collection and subsequently fully recovered. Eighteen months after transplantation, the recipients liver and renal allograft function was normal. In conclusion, because of the severe organ shortage, living related SeqLKT using the same donor should be carefully considered for young adults with PH1. Liver Transpl 19:646–648, 2013.

The 13C-caffeine breath test detects significant fibrosis in patients with nonalcoholic steatohepatitis.

Background The 13C-caffeine breath test (CBT) is a noninvasive tool for the evaluation of the cytochrome P450 system, implicated in the development of nonalcoholic steatohepatitis. Goal To apply the CBT to assess the extent of hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Methods Twenty-six consecutive patients (mean age 56.1±6.85u2009y, 69.2% women) with NAFLD underwent the CBT, in addition to the clinical and laboratory evaluations and liver biopsy. Ten healthy individuals matched for age served as controls. Results Mean delta over baseline values differed significantly between patients and controls (1.51±0.9 vs. 2.37±0.8 Δ‰/mg, respectively) (P=0.01) and were significantly higher in patients with fibrosis stage <2 (Brunts system) (2.0±0.77 vs. 1.3±0.9 for stage ≥2, P=0.05). Mean delta over baseline values correlated highly with fibrosis stage (P=0.01), albumin (P=0.007), international normalized ratio (P=0.04), bilirubin (P=0.0008), and platelet count (P=0.0001). On multivariate stepwise logistic regression analysis, CBT was the best predictor of severe fibrosis (stage ≥2) (odds ratio 0.274, 95% confidence interval 0.086-0.872, P=0.028), with an area under the curve of 0.788. Conclusions The CBT is safe and easy to perform. It can reliably predict severe hepatic fibrosis in patients with NAFLD. Further large-scale studies are still needed.

Serum globulin levels in predicting the extent of hepatic fibrosis in patients with recurrent post-transplant hepatitis C infection

Abstract:u2002 The progression of HCV‐related disease is particularly aggressive in the post‐transplantation setting. Recipients with recurrent HCV infection undergo repeated liver biopsies in order to estimate disease progression. A strong association was found between serum immunoglobulins levels and hepatic fibrosis in non‐transplanted patients with chronic HCV infection. The aim of this study was to determine if serum globulin and immunoglobulins levels can predict the extent of fibrosis in patients with recurrent HCV infection. The records of 45 patients (mean age 51.6u2003±u200310.5u2003yr; 53.3% men) with biochemical, serologic, virologic, and histological evidence of recurrent HCV infection were reviewed. Recurrence developed after a median interval of 11.7u2003months (range: 3–106); in 14 patients (31.1%), the recurrent infection was severe. The mean duration of follow‐up was 51.4u2003±u200335.4u2003months. A total of 96 liver biopsies were performed. The mean fibrosis score increased significantly with an increase in the number of biopsies (pu2003<u20030.0001, ru2003=u20030.44). On multivariate analysis, the only predictors of severe fibrosis were serum levels of globulin (OR: 5.97, 95% CI: 1.82–19.53; pu2003=u20030.0004) and IgG (OR: 1.003, 95% CI: 1.001–1.006; pu2003=u20030.018). On linear regression analysis, for each 0.5‐g/dL increase in serum globulin level, there was a 0.22‐point increase in fibrosis stage. In conclusion, serum levels of globulin and IgG can serve as a noninvasive marker of the extent of hepatic fibrosis in patients with post‐transplant recurrent HCV infection, thus avoiding the need for repeated liver biopsies. These findings, if confirmed, have important implications for the prevention and treatment of fibrosis in this patient group.

Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report

The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.

HCV genotype-1 subtypes and resistance-associated substitutions in drug-naive and in direct-acting antiviral treatment failure patients.

BACKGROUNDnDirect-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions.nnnMETHODSnIn a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure.nnnRESULTSnGT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations.nnnCONCLUSIONSnNS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.

Radiotherapy and Sorafenib in the Management of Patients with Hepatocellular Carcinoma Have Led to Improved Survival: A Single Center Experience.

Background & Aims: Hepatocellular Carcinoma (HCC) is the sixth most common malignancy and the third most common cause of cancer mortality worldwide. We aimed to assess the effect of novel treatment options on the survival of HCC patients. Methods: This retrospective study included all HCC patients diagnosed between 2000 and 2013 referred to the Davidoff center and treated by a multidisciplinary team. Results: The analysis included 321 patients (median age, 64 years; 74.8% males; 74.1% viral carriers; 76.0% cirrhosis; 56.7% diagnosis at an early stage). The estimated hazard ratio by multivariate analysis for the effect of the period of diagnosis (2007-2013 vs. 2000-2006) on survival was 0.72 (95% CI: 0.54-0.96; p=0.027). There was no difference in the distribution by CP score, by BCLC stage at diagnosis or in the proportion of patients undergoing surgical procedures (liver transplantation or resection). In the later time frame, there was a significant decrease in the proportion of patients undergoing percutaneous treatments (14.6% vs.4.2%, p=0.004) and embolization (46.9% vs.24.6%, p=0.001), and a significant increase in radiotherapy (1.5% vs. 8.4%, p=0.009) and treatment with sorafenib (6% vs. 18.3%, p=0.002). Conclusion: Technological/pharmaceutical innovations have led to advancement in HCC treatment. Since there was no significant difference in the proportion of patients undergoing surgical procedures during the evaluated timeframe, the improved survival may stem from better management of advanced stage patients by a multidisciplinary team.

The Pattern of Elevated Liver Function Tests in Nonalcoholic Fatty Liver Disease Predicts Fibrosis Stage and Metabolic-Associated Comorbidities

Background: Patients with nonalcoholic fatty liver disease (NAFLD) and with abnormal liver function tests (LFTs) most commonly present with elevated hepatocellular enzymes (H pattern), but a subset of patients is found to have elevated cholestatic enzymes (C pattern) or a mixed (M) pattern. Aims and Methods: To determine whether the epidemiologic background and comorbidities, as well as the degree of liver fibrosis, differ between NAFLD patients with different patterns of elevated LFTs by retrospectively analyzing data of 106 patients with a biopsy-proven diagnosis of NAFLD. The pattern of elevated LFTs was determined by adopting the “R-Ratio” formula commonly used for drug-induced liver injury. Results: Advanced fibrosis (F > 2) was found in 15 out of 48 (31.3%) patients with a C pattern of elevated LFTs as compared to 2 out of 44 (4.5%) in M patients and 2 out of 11 (18.2%) in H patients (p = 0.004). Group C patients are older and also had a higher prevalence of diabetes, a higher mean hemoglobin A1c, and a higher prevalence of hypertension, as well as a trend for a higher prevalence of hypertriglyceridemia. Conclusions: Using a simple formula incorporating routine LFTs can help to categorize NAFLD patients as low or high risk for advanced fibrosis stage and metabolic-associated comorbidities.

Characterization of hepatitis B and delta coinfection in Israel

BackgroundCharacteristics of hepatitis B (HBV) and delta (HDV) coinfection in various geographical regions, including Israel, remain unclear. Here we studied HDV seroprevalence in Israel, assessed HDV/HBV viral loads, circulating genotypes and hepatitis delta antigen (HDAg) conservation.MethodsSerological anti HDV IgG results from 8969 HBsAg positive individuals tested in 2010-2015 were retrospectively analyzed to determine HDV seroprevalence. In a cohort of HBV/HDV coinfected (n=58) and HBV monoinfected (n=27) patients, quantitative real-time PCR (qRT-PCR) and sequencing were performed to determine viral loads, genotypes and hepatitis delta antigen (HDAg) protein sequence.Results6.5% (587/8969) of the HBsAg positive patients were positive for anti HDV antibodies. HDV viral load was >2 log copies/ml higher than HBV viral load in most of the coinfected patients with detectable HDV RNA (86%, 50/58). HDV genotype 1 was identified in all patients, most of whom did not express HBV. While 66.6% (4/6) of the HBV/HDV co-expressing patients carried HBV-D2 only 18.5% (5/27) of the HBV monoinfections had HBV-D2 (p=0.03). Higher genetic variability in the HDAg protein sequence was associated with higher HDV viral load.ConclusionsThe overall significant prevalence of HDV (6.5%) mandates HDV RNA testing for all coinfected patients. Patients positive for HDV RNA (characterized by low HBV DNA blood levels) carried HDV genotype 1. Taken together, the significant HDV seroprevalence and the lack of effective anti-HDV therapy, necessitates strict clinical surveillance especially in patients with higher HDV viral loads and increased viral evolution.