Steven-Huy Han

The evolution of liver transplantation during 3 decades: analysis of 5347 consecutive liver transplants at a single center.

Objective:To analyze a 28-year single-center experience with orthotopic liver transplantation (OLT) for patients with irreversible liver failure. Background:The implementation of the model for end-stage liver disease (MELD) in 2002 represented a fundamental shift in liver donor allocation to recipients with the highest acuity, raising concerns about posttransplant outcome and morbidity. Methods:Outcomes and factors affecting survival were analyzed in 5347 consecutive OLTs performed in 3752 adults and 822 children between 1984 and 2012, including comparisons of recipient and donor characteristics, graft and patient outcomes, and postoperative morbidity before (n = 3218) and after (n = 2129) implementation of the MELD allocation system. Independent predictors of survival were identified. Results:Overall, 1-, 5-, 10-, and 20-year patient and graft survival estimates were 82%, 70%, 63%, 52%, and 73%, 61%, 54%, 43%, respectively. Recipient survival was best in children with biliary atresia and worst in adults with malignancy. Post-MELD era recipients were older (54 vs 49, P < 0.001), more likely to be hospitalized (50% vs 47%, P = 0.026) and receiving pretransplant renal replacement therapy (34% vs 12%, P < 0.001), and had significantly greater laboratory MELD scores (28 vs 19, P < 0.001), longer wait-list times (270 days vs 186 days, P < 0.001), and pretransplant hospital stays (10 days vs 8 days, P < 0.001). Despite increased acuity, post-MELD era recipients achieved superior 1-, 5-, and 10-year patient survival (82%, 70%, and 65% vs 77%, 66%, and 58%, P < 0.001) and graft survival (78%, 66%, and 61% vs 69%, 58%, and 51%, P < 0.001) compared with pre-MELD recipients. Of 17 recipient and donor variables, era of transplantation, etiology of liver disease, recipient and donor age, prior transplantation, MELD score, hospitalization at time of OLT, and cold and warm ischemia time were independent predictors of survival. Conclusions:We present the worlds largest reported single-institution experience with OLT. Despite increasing acuity in post-MELD era recipients, patient and graft survival continues to improve, justifying the “sickest first” allocation approach.

Posttransplantation Hepatitis B Prophylaxis with Combination Oral Nucleoside and Nucleotide Analog Therapy

Liver transplant recipients are at risk of developing recurrent hepatitis B after liver transplantation for hepatitis B virus (HBV)‐related liver disease. We evaluated the efficacy of a new hepatitis B prophylaxis regimen involving conversion from at least 12 months of HBIg with lamivudine to combination therapy with an oral nucleoside and nucleotide analog. Between June 2008 and May 2010, a total of 61 liver transplant recipients were converted to a combination of a nucleoside and nucleotide analog. The mean (±standard deviation) follow‐up time after conversion was 15.0 (±6.1) months. Recurrent HBV occurred in two (3.3%) patients at 3.1 and 16.6 months after HBIg cessation. The overall person time incidence rate for HBV recurrence after HBIg cessation was 2.7 cases per 100 person‐years. The estimate of HBV recurrence was 1.7% at 1 year after HBIg cessation. HBIg cessation a minimum of 12 months after liver transplantation with subsequent combination therapy with a nucleoside and nucleotide analog provides effective prophylaxis against recurrent HBV infection. The clinical implications of HBsAg detection without clinical, biochemical or molecular manifestations of recurrent hepatitis B require further study.

Predictive Index for Tumor Recurrence after Liver Transplantation for Locally Advanced Intrahepatic and Hilar Cholangiocarcinoma

BACKGROUND Current criteria for orthotopic liver transplantation (OLT) for cholangiocarcinoma (CCA) remain restricted to early stage and small hilar tumors, excluding patients with locally advanced intrahepatic and hilar CCA for potential cure. The present study was undertaken to define a prognostic scoring system for risk stratification of patients with intrahepatic and hilar CCA who might benefit from OLT and to allow expansion of current OLT criteria. STUDY DESIGN We conducted a retrospective review of 40 patients who underwent OLT for locally advanced intrahepatic and hilar CCA at our center between February 1985 and June 2010. Median follow-up was 3 years. Independent risk factors for tumor recurrence after OLT were identified using the Cox model and were assigned risk score points. Points were summed and assigned to predictive index categories: 0 to 3 for low risk, 4 to 7 for intermediate risk, and 8 to 15 for high risk. RESULTS Seven multivariate factors predictive for tumor recurrence included multifocal tumor, perineural invasion, infiltrative growth pattern, lack of neoadjuvant and adjuvant therapy, history of primary sclerosing cholangitis, hilar tumors, and lymphovascular invasion. The 5-year tumor recurrence-free patient survival was significantly higher in low-risk (78%) compared with intermediate- (19%) and high-risk (0%) groups (p < 0.001); survival benefit was also seen in intermediate- compared with high-risk groups. CONCLUSIONS This model was highly predictive of long-term outcomes after OLT for locally advanced intrahepatic and hilar CCA and can be applied clinically for risk stratification of patients considered for OLT. Long-term disease recurrence-free survival was excellent in low-risk and acceptable in intermediate-risk groups, justifying the expansion of liver transplant criteria for treatment of this challenging malignancy.

Prevalence and Risk Factors for Diabetes Mellitus in Moderate Term Survivors of Liver Transplantation

The prevalence and risk factors for diabetes mellitus after liver transplantation are not well understood. Thus, we sought to identify independent risk factors for the development of diabetes after liver transplantation using currently accepted medical criteria.

Duplex Doppler ultrasound of the hepatic artery in patients with acute alcoholic hepatitis

Background Acute alcoholic hepatitis (AAH) is a clinical diagnosis associated with increased hepatic artery diameter and flow. Duplex Doppler ultrasound (DDU) has been shown to accurately measure arterial flow in both liver and kidney transplant patients. The authors conducted a blinded, controlled study to evaluate the accuracy of measuring hepatic artery parameters with DDU in diagnosing AAH. Study Duplex Doppler ultrasound was performed by an investigator, blinded to group makeup, on 22 consecutive hospital inpatients with the clinical diagnosis of AAH. The diagnosis of AAH was based on specific criteria, including the following: recent alcohol abuse, hyperbilirubinemia, prolonged prothrombin time, leukocytosis, hepatomegaly, hepatic bruit, and marked redistribution of isotope on 99mTc-sulfur colloid liver–spleen scan. Controls were 12 cirrhotic patients without AAH and 17 healthy volunteers. Duplex Doppler ultrasound measurements were obtained most consistently from the proximal right hepatic artery. Measured parameters included the following: peak systolic velocity (PSV); resistive index = (PSV − end diastolic velocity [EDV])/PSV; pulsatility index = (PSV − EDV)/mean velocity; and hepatic artery diameter. Results The mean hepatic artery diameter was significantly larger in patients with AAH (3.55 ± 0.72 mm) than in patients with cirrhosis (2.75 ± 0.69 mm;p = 0.003) and healthy controls (2.68 ± 0.69 mm;p = 0.001). The mean PSV was significantly higher in patients with AAH (187 ± 52 cm/s) compared with cirrhotic (67 ± 51 cm/s) and healthy (66 ± 51 cm/s) controls (p = 0.0001). The mean resistive index was lower in AAH patients (0.60 ± 0.11) compared with cirrhotic (0.69 ± 0.10;p value was not significant) and healthy controls (0.72 ± 0.11;p = 0.004). The mean pulsatility index was lower in AAH patients (1.04 ± 0.47) compared with cirrhotic (1.36 ± 0.45;p value was not significant) and healthy controls (1.53 ± 0.45;p = 0.01). Conclusions In the appropriate clinical setting, an elevated hepatic artery diameter or PSV measurement is suggestive of AAH. Duplex Doppler ultrasound offers a noninvasive test to assist in the diagnosis of AAH.

Hepatitis B Virus–Specific and Global T-Cell Dysfunction in Chronic Hepatitis B

BACKGROUND & AIMS T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Coil-Assisted Retrograde Transvenous Obliteration (CARTO) for the Treatment of Portal Hypertensive Variceal Bleeding: Preliminary Results

OBJECTIVES:To describe the technical feasibility, safety, and clinical outcomes of coil-assisted retrograde transvenous obliteration (CARTO) in treating portal hypertensive non-esophageal variceal hemorrhage.METHODS:From October 2012 to December 2013, 20 patients who received CARTO for the treatment of portal hypertensive non-esophageal variceal bleeding were retrospectively evaluated. All 20 patients had at least 6-month follow-up. All patients had detachable coils placed to occlude the efferent shunt and retrograde gelfoam embolization to achieve complete thrombosis/obliteration of varices. Technical success, clinical success, rebleeding, and complications were evaluated at follow-up.RESULTS:A 100% technical success rate (defined as achieving complete occlusion of efferent shunt with complete thrombosis/obliteration of bleeding varices and/or stopping variceal bleeding) was demonstrated in all 20 patients. Clinical success rate (defined as no variceal rebleeding) was 100%. Follow-up computed tomography after CARTO demonstrated decrease in size with complete thrombosis and disappearance of the varices in all 20 patients. Thirteen out of the 20 had endoscopic confirmation of resolution of varices. Minor post-CARTO complications, including worsening of esophageal varices (not bleeding) and worsening of ascites/hydrothorax, were noted in 5 patients (25%). One patient passed away at 24 days after the CARTO due to systemic and portal venous thrombosis and multi-organ failure. Otherwise, no major complication was noted. No variceal rebleeding was noted in all 20 patients during mean follow-up of 384±154 days.CONCLUSIONS:CARTO appears to be a technically feasible and safe alternative to traditional balloon-occluded retrograde transvenous obliteration or transjugular intrahepatic portosystemic shunt, with excellent clinical outcomes in treating portal hypertensive non-esophageal variceal bleeding.

Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy‐proven histological damage

Current guidelines for management of chronic hepatitis B recommend treatment for patients presenting with elevated hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) or histological evidence of liver disease. Retrospective analyses have demonstrated that significant hepatic necroinflammation and fibrosis were present in a substantial proportion of patients with ALT 1 to 2 × ULN. To assess therapeutic efficacy in this clinical setting, we retrospectively examined treatment endpoints among the subset of nucleoside‐naïve chronic hepatitis B (CHB) patients treated in phase 3 clinical trials of entecavir who had both screening and baseline serum ALT 1.3 to 2 × ULN. A total of 1347 patients were randomized to treatment with entecavir or lamivudine. Three hundred thirty‐six patients, constituting 25% of the total study population, had screening and baseline ALT 1.3 to 2 × ULN. Clinically significant necroinflammation (Knodell necroinflammation score ≥7) was observed in 60% and 72% of hepatitis B e antigen (HBeAg)‐positive and HBeAg‐negative patients, respectively, whereas marked fibrosis (Ishak fibrosis score ≥4) was observed in 8% and 15% of HBeAg‐positive and HBeAg‐negative patients, respectively. Among entecavir‐treated HBeAg‐negative patients, the proportions of patients achieving histological improvement, HBV DNA <300 copies/mL, and ALT normalization were similar between patients with mildly elevated ALT and those with ALT >2 × ULN. However, entecavir‐treated HBeAg‐positive patients with mildly elevated ALT had lower response rates for histological improvement, HBV DNA less than 300 copies/mL, ALT normalization, and HBeAg seroconversion than those with ALT greater than 2 × ULN. Conclusion: This retrospective analysis demonstrated that HBeAg‐negative CHB patients treated with entecavir responded similarly irrespective of baseline ALT level. However, HBeAg‐positive patients with mildly elevated ALT responded less well to treatment with entecavir than did those with ALT greater than 2 × ULN. (HEPATOLOGY 2010.)

Comparison of clinical outcomes in chronic hepatitis B liver transplant candidates with and without hepatocellular carcinoma

Patients with hepatocellular carcinoma (HCC) receive a higher MELD score and may undergo liver transplantation (OLT) earlier compared to patients with cirrhosis, potentially decreasing waiting list mortality. However, post‐OLT survival may be reduced by recurrence of HCC. We compared clinical outcomes between patients with HBV‐cirrhosis and no HCC and patients with HBV‐HCC. A total of 279 patients (HBV‐cirrhosis = 183; HBV‐HCC = 96) in the US HBV‐OLT study were followed for a median of 30.2 months from listing. Patients with HCC were older, more likely to be Asian, and had less severe liver impairment than patients with HBV‐cirrhosis. Despite a higher rate of OLT in patients with HCC (78.1% vs. 51.4%; P < 0.001), intention‐to‐treat (ITT) survival (73% vs. 78%) and survival without OLT (82% vs. 79%) at 5 years were similar for patients with and without HCC. Cox regression analysis identified higher albumin, lower MELD, no HCC at listing, and being transplanted to be associated with better ITT survival. Ninety‐four patients with HCC (including 19 new HCC) and 75 with HBV‐cirrhosis underwent OLT. Post‐OLT survival (83% vs. 90%) and HBV recurrence (11% vs. 10%) at 3 years were similar, while disease (HBV and/or HCC) recurrence (19% vs. 10%; P = 0.043) was higher in patients with HBV‐HCC vs. HBV‐cirrhosis. Disease recurrence was the only independent predictor of post‐OLT survival. In conclusion, despite more advanced liver disease and a lower rate of transplantation, ITT survival of patients listed for HBV‐cirrhosis was comparable to those with HBV‐HCC, possibly related to beneficial effects of antiviral therapy. Liver Transpl 13:334‐342, 2007.

Two-dimensional MR spectroscopy of minimal hepatic encephalopathy and neuropsychological correlates in vivo.

To evaluate regional cerebral metabolic and structural changes in patients with minimal hepatic encephalopathy (MHE) using two‐dimensional (2D) MR spectroscopy (MRS) and T   1 ‐weighted MRI, to correlate the observed MR changes with neuropsychological (NP) test scores, and to compare the diagnostic accuracy of MRI, 2D MRS, and NP tests in discriminating between patients and healthy subjects.