Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice.

Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain-containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte-specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol-fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P < 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients. CONCLUSION: Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (Hepatology 2018;67:1109-1126).

Fibrin deposition following bile duct injury limits fibrosis through an αMß2-dependent mechanism.

Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor αMß2, we tested the hypothesis that disruption of the fibrin(ogen)-αMß2 interaction in Fibγ(390-396A) mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, α-naphthylisothiocyanate (ANIT)-induced liver fibrosis increased in Fibγ(390-396A) mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fibγ(390-396A) mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fibγ(390-396A) mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)γ induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fibγ(390-396A) mice. Fibrin(ogen)-αMß2 interaction inhibited iNOS induction in macrophages stimulated with IFNγ in vitro and ANIT-challenged IFNγ-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances αMß2-dependent cell adhesion to fibrin. These studies characterize a novel mechanism whereby the fibrin(ogen)-integrin-αMß2 interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease.

Functional coupling of ATP-binding cassette transporter Abcb6 to cytochrome P450 expression and activity in liver.

Although endogenous mechanisms that negatively regulate cytochrome P450 (P450) monooxygenases in response to physiological and pathophysiological signals are not well understood, they are thought to result from alterations in the level of endogenous metabolites, involved in maintaining homeostasis. Here we show that homeostatic changes in hepatic metabolite profile in Abcb6 (mitochondrial ATP-binding cassette transporter B6) deficiency results in suppression of a specific subset of hepatic P450 activity. Abcb6 null mice are more susceptible to pentobarbital-induced sleep and zoxazolamine-induced paralysis, secondary to decreased expression and activity of Cyp3a11 and Cyp2b10. The knock-out mice also show decrease in both basal and xeno-inducible expression and activity of a subset of hepatic P450s that appear to be related to changes in hepatic metabolite profile. These data, together with the observation that liver extracts from Abcb6-deficient mice suppress P450 expression in human primary hepatocytes, suggest that this mouse model may provide an opportunity to understand the physiological signals and the mechanisms involved in negative regulation of P450s.

Pre-transplant portal vein thrombosis is an independent risk factor for graft loss due to hepatic artery thrombosis in liver transplant recipients.

BACKGROUND: Hepatic artery thrombosis is an uncommon but catastrophic complication following liver transplantation. We hypothesize that recipients with portal vein thrombosis are at increased risk. METHODS: Data on all liver transplants in the U.S. during the MELD era through September 2014 were obtained from UNOS. Status one, multivisceral, living donor, re-transplants, pediatric recipients and donation after cardiac death were excluded. Logistic regression models were constructed for hepatic artery thrombosis with resultant graft loss within 90 days of transplantation. RESULTS: 63,182 recipients underwent transplantation; 662 (1.1%) recipients had early hepatic artery thrombosis; of those, 91 (13.8%) had pre-transplant portal vein thrombosis, versus 7.5% with portal vein thrombosis but no hepatic artery thrombosis (p < 0.0001). Portal vein thrombosis was associated with an increased independent risk of hepatic artery thrombosis (OR 2.17, 95% CI 1.71-2.76, p < 0.001) as was donor risk index (OR 2.02, 95% CI 1.65-2.48, p < 0.001). Heparin use at cross clamp, INR, and male donors were all significantly associated with lower risk. DISCUSSION: Pre-transplant portal vein thrombosis is associated with post-transplant hepatic artery thrombosis independent of other factors. Recipients with portal vein thrombosis might benefit from aggressive coagulation management and careful donor selection. More research is needed to determine causal mechanism.

Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C.

UNLABELLED: The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25-5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11-3.53). CONCLUSIONS: The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment.

Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes.

3'-Hydroxyacetanilide orN-acetyl-meta-aminophenol (AMAP) is generally regarded as a non-hepatotoxic analog of acetaminophen (APAP). Previous studies demonstrated the absence of toxicity after AMAP in mice, hamsters, primary mouse hepatocytes and several cell lines. In contrast, experiments with liver slices suggested that it may be toxic to human hepatocytes; however, the mechanism of toxicity is unclear. To explore this,we treated primary human hepatocytes (PHH) with AMAP or APAP for up to 48 h and measured several parameters to assess metabolism and injury. Although less toxic than APAP, AMAP dose-dependently triggered cell death in PHH as indicated by alanine aminotransferase (ALT) release and propidium iodide (PI) staining. Similar to APAP, AMAP also significantly depleted glutathione (GSH) in PHH and caused mitochondrial damage as indicated by glutamate dehydrogenase (GDH) release and the JC-1 assay. However, unlike APAP, AMAP treatment did not cause relevant c-jun-N-terminal kinase (JNK) activation in the cytosol or phospho-JNK translocation to mitochondria. To compare, AMAP toxicity was assessed in primary mouse hepatocytes (PMH). No cytotoxicity was observed as indicated by the lack of lactate dehydrogenase release and no PI staining. Furthermore, there was no GSH depletion or mitochondrial dysfunction after AMAP treatment in PMH. Immunoblotting for arylated proteins suggested that AMAP treatment caused extensive mitochondrial protein adduct formation in PHH but not in PMH. In conclusion, AMAP is hepatotoxic in PHH and the mechanism involves the formation of mitochondrial protein adducts and mitochondrial dysfunction.

Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis.

Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models.

Mechanisms of acetaminophen-induced cell death in primary human hepatocytes.

UNLABELLED: Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5mM, 10mM or 20mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24h and 48h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6h after APAP and a partial protection when given at 15 h. CONCLUSION: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic.

Combined transmesenteric and transhepatic recanalization of chronic portal and mesenteric vein occlusion to treat bleeding duodenal varices.

Two patients presented with bleeding duodenal varices secondary to mesenteric and portal vein chronic occlusion. After a failed transhepatic recanalization, a combined transmesenteric and transhepatic approach was used to recanalize the chronic portal and mesenteric venous obstruction. The occluded segment was treated with transmesenteric stent placement in one patient and stent placement and coil embolization of varices in the second patient. Follow-up imaging and endoscopy showed decompression of the duodenal varices in both patients and absence of further bleeding episodes.

Identification and Functional Characterization of Alternative Transcripts of LncRNA HNF1A-AS1 and Their Impacts on Cell Growth, Differentiation, Liver Diseases, and in Response to Drug Induction.

The long non-coding RNA (lncRNA) hepatocyte nuclear factor-1 alpha (HNF1A) antisense RNA 1 (HNF1A-AS1) is an important lncRNA for liver growth, development, cell differentiation, and drug metabolism. Like many lncRNAs, HNF1A-AS1 has multiple annotated alternative transcripts in the human genome. Several fundamental biological questions are still not solved: (1) How many transcripts really exist in biological samples, such as liver samples and liver cell lines? (2) What are the expression patterns of different alternative HNF1A-AS1 transcripts at different conditions, including during cell growth and development, after exposure to xenobiotics (such as drugs), and in disease conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD) cirrhosis, and obesity? (3) Does the siRNA used in previous studies knock down one or multiple transcripts? (4) Do different transcripts have the same or different functions for gene regulation? The presented data confirm the existence of several annotated HNF1A-AS1 transcripts in liver samples and cell lines, but also identify some new transcripts, which are not annotated in the Ensembl genome database. Expression patterns of the identified HNF1A-AS1 transcripts are highly correlated with the cell differentiation of matured hepatocyte-like cells from human embryonic stem cells (hESC), growth and differentiation of HepaRG cells, in response to rifampicin induction, and in various liver disease conditions. The expression levels of the HNF1A-AS1 transcripts are also highly correlated to the expression of cytochrome P450 enzymes, such as CYP3A4, during HepaRG growth, differentiation, and in response to rifampicin induction.

Transjugular intrahepatic portosystemic shunts in liver transplant recipients: technical analysis and clinical outcome.

OBJECTIVE: The purpose of this study is to compare the technical success of transjugular intrahepatic portosystemic shunt (TIPS) in transplanted versus nontransplanted livers and to assess the clinical outcome of TIPS in liver transplant recipients. MATERIALS AND METHODS: A retrospective audit of patients receiving a TIPS was performed in two institutions during 1996-2009. The technical success of the TIPS was compared for transplanted versus nontransplanted livers. Clinical success was defined as graft survival longer than 1 month with improvement in symptoms. The cohort was divided into grafts that survived less than 3 months versus 3 months or more. The model for end-stage liver disease (MELD) scores and portosystemic gradients before and after TIPS creation were evaluated for predictive value for graft survival. The TIPS stent type, MELD scores and portosystemic gradients before and after TIPS creation, and causes of liver disease were evaluated for their predictive value for ascites response after TIPS creation. RESULTS: Thirty-nine TIPS in transplanted livers were found, representing 5.5% (39/715) of all TIPS procedures performed and 2.0% (39/1992) of all liver transplant recipients. Ninety percent of TIPS in transplanted livers had ascites. The median time from transplant to creation of the TIPS was 29 months (2-127 months). The median MELD score was 16 before and 22 after the TIPS procedure. The technical success rates for TIPS were 97% (38/39) in transplanted livers versus 97% (657/676) in nontransplanted livers (p = 1.00). Intent-to-treat clinical success rates were 36% for all indications versus 31% for ascites only. There were no predictors for ascites response. Six-, 12-, and 24-month graft survival rates were 43%, 32%, and 22%, respectively. One-year graft survival for a MELD score less than 17 versus a score of 17 or higher was 54% versus 8%, respectively (p < 0.05). CONCLUSION: Transplantation does not pose a technical challenge to TIPS creation. One third of patients have a favorable outcome. MELD score is the only predictor of graft survival.

Self expandable metal stents for anastomotic stricture following liver transplant.

BACKGROUND: Endoscopic treatment for biliary strictures with plastic stent placement has been used widely. The use of covered self-expandable metal stents (CSEMS) has been reported in anastomotic strictures post liver transplant. The aim of this study was to evaluate the efficacy of different CSEMS in these subjects. METHODS: A total of 55 patients with anastomotic stricture received CSEMS, which were removed after 3-4 months. There were 19 patients in group A (partially covered SEMS), 21 patients in group B (fully covered SEMS with fins) and 15 patients in group C (fully covered SEMS with flared ends). Technical success, stricture resolution, follows up, and complications were documented. RESULTS: CSEMS were successfully deployed in all 55 cases. There was no evidence of significant difference with regards to stricture resolution (14 [74%] vs. 15 [71%] vs. 9 [60%] p=0.6630, df=2) or complications between groups. Stent-related complications were as follows: three in group A (2 migration, 1 occlusion), five in group B (4 occlusions, 1 migration), and one proximal migration in group C (p=0.3894, df=2). Three cases required surgery (hepatico-jejunostomy) due to refractory strictures. CONCLUSIONS: The observed clinical success rate of CSEMS (70.4%) proved to be below the reported one for multiple plastic stents, while no significant differences between CSEMS types were observed.

Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation.

BACKGROUND: Liver transplantation is the most effective therapy for cirrhosis-associated hepatocellular carcinoma (HCC) but its utility is limited by post-transplant tumor recurrence. Use of the Milan, size-based criteria, has reduced recurrence rate to less than 10% but many patients remain ineligible. Reduction of tumor size with local therapies has been used to "downstage" patients to allow them to qualify for transplantation, but the optimal criteria to predict tumor recurrence in these latter patients has not been established. The existence of a progenitor cell population, sometimes called cancer stem cells (CSCs), has been proposed to be one mechanism accounting for the chemotherapy resistance and recurrence of hepatocellular carcinoma. The aim of this study was to determine if transcatheter arterial chemoemolization (TACE) treated tumors have increased CSC marker expression and whether these markers could be used to predict tumor recurrence. METHODS: Formalin fixed specimens were obtained from 39 HCC liver explants (23 with no treatment and 16 after TACE). Immunohistochemical staining was performed for EpCAM, CD44, CD90, and CD133. Staining for each marker was scored 0-3 by evaluating the number and intensity of positive tumor cells in 5 hpf of tumor in each specimen. RESULTS: TACE treated tumors displayed greater necrosis and fibrosis than non-TACE treated samples but there were no differences in morphology between the viable tumor cells of both groups. In TACE treated specimens, the staining of both EpCAM and CD133 was greater than in non-TACE specimens but CD44 and CD90 were the same. In the TACE group, the presence of high EpCAM staining was associated with tumor recurrence. Four of ten EpCAM high patients recurred while 0 of 6 EpCAM low patients recurred (P = 0.040). None of the other markers predicted recurrence. CONCLUSION: High pre-transplant EpCAM staining predicted HCC recurrence. This suggests that the abundance of tumor cells with a CSC phenotype may be a critical factor in the likelihood of tumor recurrence in patients receiving liver transplantation after TACE.

Elderly recipients of hepatitis C positive renal allografts can quickly develop liver disease.

Our institution explored using allografts from donors with Hepatitis C virus (HCV) for elderly renal transplantation (RT). Thirteen HCV- elderly recipients were transplanted with HCV+ allografts (eD+/R-) between January 2003 and April 2009. Ninety HCV- elderly recipients of HCV- allografts (eD-/R-), eight HCV+ recipients of HCV+ allografts (D+/R+) and thirteen HCV+ recipients of HCV- allografts (D-/R+) were also transplanted. Median follow-up was 1.5 (range 0.8-5) years. Seven eD+/R- developed a positive HCV viral load and six had elevated liver transaminases with evidence of hepatitis on biopsy. Overall, eD+/R- survival was 46% while the eD-/R- survival was 85% (P = 0.003). Seven eD+/R- died during follow-up. Causes included multi-organ failure and sepsis (n = 4), cancer (n = 1), failure-to-thrive (n = 1) and surgical complications (n = 1). One eD+/R- died from causes directly related to HCV infection. In conclusion, multiple eD+/R- quickly developed HCV-related liver disease and infections were a frequent cause of morbidity and mortality.

Prevalence, presentation, and endovascular management of hemodynamically or clinically significant arterio-portal fistulae in living and cadaveric donor liver transplant recipients.

PURPOSE: To compare the prevalence (cadaveric vs. living donor transplants), clinical features, and the effectiveness of endovascular management of significant arterio-portal fistulae (APF) in liver transplant recipients. METHODS: A retrospective audit of liver transplant recipients in two institutions was performed (1996-2009). Significant APF were included and were defined as symptomatic and/or hemodynamically significant (causing graft dysfunction and/or having abnormal Doppler findings in the portal vein). Patients with significant APF were evaluated for presenting symptoms, imaging features, size/branch order portal vein involvement, and effectiveness of the endovascular management (coil embolization). RESULTS: Four significant APF were found in 1992 (0.2%) liver transplants. Two were symptomatic and two were asymptomatic but were hemodynamically significant with liver function test abnormalities. All four APF were found in cadaveric donor graft recipients (0.23%, N = 4/1753) and none in 239 living donor graft recipients. However, there was no statistical difference between cadaveric and living donor graft recipients (p = 1.0, odds ratio = 1.23). Coil embolization was technically and clinically successful in all 4 without complications and causing normalization of the abnormal Doppler findings. CONCLUSION: Significant APF are a rare diagnosis (0.2% of transplants). Coil embolization is a safe and effective treatment option for APF in transplants.

Fully covered self-expanding metal stents placed temporarily in the bile duct: safety profile and histologic classification in a porcine model.

BACKGROUND: Fully covered Self-Expanding metal stents (FCSEMS) have been shown efficacious in palliating malignant biliary obstructions. There is little data analyzing mucosal response to their temporary placement in the bile duct. METHODS: Ten mini pigs underwent endoscopic placement of a FCSEMS (Wallflex, Boston Scientific). FCSEMS were kept in place for three months. At the end of the 3 months, FCSEMS were removed endoscopically. Five pigs were euthanized and their bile ducts harvested. The other five were kept alive for another month post removal. A single pathologist, created a scoring system (to determine degree of inflammation, fibrosis, and epithelial injury), examined all specimens in a blinded fashion. RESULTS: Four FCSEMS spontaneously migrated in the duodenum. On post mortem examination, mild mucosal thickness was noted in three bile duct specimens while superficial inflammation of the bile duct was noted in five animals. Histologic examination of the bile duct revealed focal acute inflammation in both groups. For the 5 animals euthanized immediately after stent removal, there was a tendency to have superficial mucosal erosion and fibrosis. In contrast, increased chronic inflammation was more commonly seen in the animals 1 month post stent removal, with all animals in this group showing moderate degrees of mononuclear inflammatory cell mucosal infiltrates. No severe inflammatory or fibrotic duct injury was observed in any of the study animals, with degree of injury graded as mild to moderate. CONCLUSION: FCSEMS appear to induce minimal tissue overgrowth or fibrosis post placement. Ease of removability and no significant histologic injury are advantages noted with FCSEMS., however, further studies are needed to evaluate treating benign biliary strictures with FCSEMS in humans.

Sorafenib therapy for hepatocellular carcinoma prior to liver transplant is associated with increased complications after transplant.

This study compared post-transplant outcomes of patients with hepatocellular carcinoma (HCC) who took sorafenib prior to orthotopic liver transplantation (OLT) with those patients who were not treated with sorafenib. Thirty-three patients with HCC who were listed for liver transplantation were studied: 10 patients were treated with sorafenib prior to transplantation in an attempt to prevent progression of HCC while awaiting transplant. The remaining 23 patients were considered controls. The mean duration of sorafenib use was 19.2 (SD 25.2) weeks. Overall death rates were similar between the sorafenib group and control group (20% vs. 8.7%, respectively, P = 0.56). However, the patients in the sorafenib group had a higher incidence of acute cellular rejection following transplantation (67% vs. 22%, OR = 7.2, 95% CI 1.3-39.6, P = 0.04). The sorafenib group also had a higher rate of early biliary complications (67% vs. 17%, OR = 9.5, 1.6-55.0, P = 0.01). The use of sorafenib was found to be an independent predictor of post-transplant biliary complications (OR 12.6, 1.4-116.2, P = 0.03). Sorafenib administration prior to OLT appears to be associated with an increase in biliary complications and possibly in acute rejection following liver transplantation. Caution should be taken in this setting until larger studies are completed.

Innovation for reducing blood culture contamination: initial specimen diversion technique.

We hypothesized that diversion of the first milliliter of venipuncture blood-the initial specimen diversion technique (ISDT)-would eliminate incompletely sterilized fragments of skin from the culture specimen and significantly reduce our blood culture contamination rate (R). We studied our hypothesis prospectively beginning with our control culture (C) definition: one venipuncture with two sequentially obtained specimens, 10 ml each, the first specimen (M1) for aerobic and the second (M2) for anaerobic media. The test ISDT culture (D) was identical, with the exception that each was preceded by diverting a 1-ml sample (DS) from the same venipuncture. During the first of two sequential 9-month periods, we captured D versus C data (n=3,733), where DMXR and CMXR are R for D and C specimens. Our hypothesis predicted DS would divert soiled skin fragments from DM1, and therefore, CM1R would be significantly greater than DM1R. This was confirmed by CM1R (30/1,061 [2.8%]) less DM1R (37/2,672 [1.4%]; P=0.005), which equals 1.4%. For the second 9-month follow-up period, data were compiled for all cultures (n=4,143), where ADMXR is R for all (A) diversion specimens, enabling comparison to test ISDT. Our hypothesis predicted no significant differences for test ISDT versus all ISDT. This was confirmed by DM1R (37/2,672 [1.4%]) versus ADM1R (42/4,143 [1.0%]; P=0.17) and DM2R (21/2,672 [0.80%]) versus ADM2R (39/4,143 [0.94%]; P=0.50). We conclude that our hypothesis is valid: venipuncture needles soil blood culture specimens with unsterilized skin fragments and increase R, and ISDT significantly reduces R from venipuncture-obtained blood culture specimens.

Pretransplant predictors of recovery of renal function after liver transplantation.

The Model for End-Stage Liver Disease system has given priority on the liver transplant waiting list to candidates with renal failure. This study determined the predictors of spontaneous recovery of renal function after transplantation in 1041 liver transplant recipients on renal replacement therapy (RRT) at the time of transplant (from February 2002 to January 2007). Data from these patients were obtained from the US Organ Procurement and Transplantation Network and US Renal Data System databases. Univariate and multivariate survival models were constructed along with multivariate logistic regression models to find independent predictors of spontaneous renal recovery. Seven hundred seven recipients (67.9%) had spontaneous recovery of renal function after liver transplantation. Those recovering spontaneously had a significantly shorter course of RRT in the pretransplant time period (15.6 versus 36.6 days, P < 0.001). Recovery of renal function was observed in 70.8% and 11.5% of recipients on RRT for less than 30 days and more than 90 days, respectively. Other statistically significant pretransplant variables independently associated with recovery of renal function included recipient age, recipient pretransplant diabetes, and donor age. In conclusion, the duration of pretransplant RRT is highly predictive of spontaneous renal recovery post-transplant. Liver transplant candidates requiring less than 30 days of pretransplant RRT are likely to spontaneously recover renal function after liver transplantation, whereas those on RRT for more than 90 days are not.

Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis.

Organ donors are screened for the hepatitis C antibody (anti-HCV) and those with positive tests can be used under extended criteria donation. However, there is still a question of long-term organ viability. The aim of this study was to assess the long-term outcomes of anti-HCV positive (HCV+) liver grafts. The US Organ Procurement and Transplantation Network Scientific Registry was reviewed for the period from April 1994 to February 6, 2008 and 56,275 liver transplantations were analyzed. In total, there were 19,496 HCV+ recipients and 934 HCV+ donors. Patient and graft survival were assessed accounting for both donor and recipient anti-HCV status. Multivariable proportional hazards survival models were developed to adjust for factors known to affect post-transplant survival. With anti-HCV negative (HCV-) recipient/HCV- donor as the reference, the adjusted hazard ratio for death was similar for HCV+ recipient/HCV- donor compared with HCV+ recipient/HCV+ donor (1.176 vs. 1.165, P = 0.91). Our results suggest that HCV+ liver donors do not subject the HCV+ recipient to an increased risk for death over the HCV- donor, keeping in mind that careful donor and recipient selection is critical for the proper use of these extended criteria donors.