Rolland C. Dickson

Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C

Background. The use of liver allografts from an older donor (OD) (age >50 years) is a widespread strategy to manage the disparity between supply and demand of organs for liver transplantation. This study determines the effect of OD allografts on fibrosis progression and graft survival after liver transplantation in patients with and without infection caused by hepatitis C virus (HCV). Methods. All patients undergoing liver transplantation at our center from March 1998 to December 2001 were analyzed. Protocol liver biopsies were performed at 1, 16, and 52 weeks after transplantation and yearly thereafter. One liver pathologist scored all biopsy specimens for modified hepatic activity index (0–18) and fibrosis (0–6). Results. A total of 402 patients (167 with HCV and 235 without HCV) underwent liver transplantation during the study period. Among patients with HCV, baseline characteristics of OD recipients were similar to younger donor (YD) (age <50 years) recipients. In patients with HCV, graft survival was shorter in OD graft recipients than in YD recipients (P <0.001). In patients without HCV, graft survival was independent of donor age. In patients with HCV, a fibrosis score of 3 or greater was present in 17% of OD recipients at 4 months and in 26% at 12 months after transplantation, compared with 8% of YD recipients at 4 months and 13% at 12 months (P <0.001). Conclusions. Liver transplantation with OD grafts is associated with rapid progression of fibrosis and decreased graft survival in patients with HCV, but not in patients without HCV. OD grafts should be considered preferentially for patients without HCV.

Liver Transplantation Using Controlled Donation After Cardiac Death Donors: An Analysis of a Large Single-Center Experience

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow‐up was 48 months. The 1‐, 3‐, and 5‐year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1‐, 3‐, and 5‐year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long‐term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts. Liver Transpl 15: 1028–1035, 2009.

Effectiveness of Simeprevir Plus Sofosbuvir, with or Without Ribavirin, in Real-World Patients with HCV Genotype 1 Infection

BACKGROUND & AIMS The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis.

Background Autoimmune hepatitis (AIH) is an immune mediated chronic liver disease with a prevalence of 17 cases/100,000. Resistance to the standard treatment of AIH (prednisone and azathioprine) occurs in 15% to 20%. There is currently no standard treatment of patients with steroid refractory AIH. Goals Determine the efficacy of tacrolimus in the treatment of steroid refractory AIH. Methods This is a retrospective study evaluating the efficacy of Tacrolimus in the treatment of steroid refractory AIH. Results Between October 1998 and February 2002, 11 patients with steroid refractory AIH were treated with tacrolimus. Mean age was 63 years. Median duration of steroid treatment before starting tacrolimus was 9 months. Median duration of tacrolimus treatment was 25 months. Median follow-up period was 16 months. Median baseline ALT, AST were 77 U/L and 68 U/L and became 21 U/L and 32 U/L respectively at end of follow-up (P = 0.005 and 0.01 respectively). Significant weight reduction was seen in all patients (P = 0.02). Tacrolimus treatment was safe and well tolerated. Conclusion Use of low dose tacrolimus led to successful biochemical and histologic remission and weaning off prednisone in patients with steroid refractory AIH. This data supports further studies in evaluating the use of tacrolimus in the treatment of AIH.

Improving outcomes of liver retransplantation: an analysis of trends and the impact of Hepatitis C infection.

Retransplantation (RT) in Hepatitis C (HCV) patients remains controversial. Aims: To study trends in RT and evaluate the impact of HCV status in the context of a comprehensive recipient and donor risk assessment. The UNOS database between 1994 and October 2005 was utilized to analyze 46  982 LT and RT. Graft and patient survival along with patient and donor characteristics were compared for 2283 RT performed in HCV and non‐HCV patients during 1994–1997, 1998–2001 and 2002–October 2005. Overall HCV prevalence at RT increased from 36% in the initial period to 40.6% after 2002. In our study group, 1‐year patient and graft survival post‐RT improved over the same time intervals from 65.0% to 70.7% and 54.87% to 65.8%, respectively. HCV was only associated with decreased patient and graft survival with a retransplant (LT‐RT) interval (RI) >90 days. Independent predictors of mortality for RT with RI >90 days were patient age, MELD score >25, RI <1 year, warm ischemia time ≥75 min and donor age ≥60 (significant for HCV patients only). Outcomes of RT are improving, but can be optimized by weighing recipient factors, anticipation of operative factors and donor selection.

Early and late onset Clostridium difficile-associated colitis following liver transplantation.

Clostridium difficile colitis (CDC) remains a serious and common complication after liver transplantation (LT). Four hundred and sixty‐seven consecutive LTs in 402 individuals were performed between 1998 and 2001 at our center. Standard immunosuppression consisted of tacrolimus, mycophenolate, and steroids. CD toxins A and B were detected by using a rapid immunoassay or enzyme immunoassay. CDC was diagnosed in 32 patients (5–1999 days post‐LT), with 93.8% (30/32) of patients developing CDC during the first year post‐LT; three individuals had CDC more than 3 years post‐LT, one of which also had early CDC. All patients presented with abdominal pain and watery diarrhea. Patients who developed CDC within 1‐year post‐LT were significantly more likely to have a hemorrhagic, biliary, or infectious complication. Patients who developed CDC within 28 days post‐LT had a significantly higher model end‐stage liver disease score. Treatment consisted of fluid and electrolyte replacement and metronidazole and no patients developed toxic megacolon, required colonic resection, or died from CDC. CDC represents a potentially severe complication following LT. Most cases occur early post‐LT. Development of a hemorrhagic, biliary, or infectious complication is associated with the development of CDC.

Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C

Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL‐40, could be used to predict rapid fibrosis progression (RFP) post‐LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha‐smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 ± 2 (biopsy 1) and 39 ± 6 (biopsy 2) months post‐LT, respectively. RFP was defined as an increase in the fibrosis score ≥ 2 from biopsy 1 to biopsy 2 (a mean interval of 33 ± 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL‐40 performed significantly better than conventional parameters and HSCA in predicting RFP post‐LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA ≥ 90 μg/L and YKL‐40 ≥ 200 μg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL‐40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL‐40 in post‐LT management are warranted. Liver Transpl 14:1294–1302, 2008.

Risk stratification and targeted antifungal prophylaxis for prevention of aspergillosis and other invasive mold infections after liver transplantation

Antifungal prophylaxis has been proposed for liver transplant recipients at increased risk for invasive mold infection. Risk factors for invasive mold infection after liver transplantation were selected to divide recipients into 3 groups: (1) high risk—transplantation on hemodialysis or delay of hospital discharge beyond day 7 after transplantation because of allograft or renal insufficiency; (2) intermediate risk—retransplantation or transplantation for fulminant hepatic failure; (3) low risk—absence of conditions in groups 1 and 2. During an intervention period (February 1999–April 2001), prophylactic administration of a lipid complex of amphotericin (Abelcet) at 5 mg/kg intravenously every 24 to 48 hours was recommended for high‐risk recipients. The frequency of mold infection was compared to that of a preintervention period (February 1998–January 1999) when antifungal prophylaxis was not provided. During the intervention period, invasive mold infection developed in 2 (6%) of 35 high‐risk recipients, 0 of 28 intermediate‐risk recipients, and 1 (0.5%) of 187 low‐risk recipients. Overall, of 58 liver transplant recipients, 3 (5%) developed an invasive mold infection during the preintervention period, compared with 3 (1%) of 250 during the intervention period (P = 0.08). The only death from invasive mold infection occurred during the preintervention period. Rates of pulse corticosteroid treatment of rejection and cytomegalovirus infection were lower during the intervention period. In conclusion, readily identifiable patient characteristics can be used to stratify liver transplant recipients for risk of invasive mold infection. Antifungal prophylaxis given to high‐risk recipients may provide cost‐effective prevention of these infections. (Liver Transpl 2005;11:656–662.)

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Abstract:  Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Contribution of Ascites to Impaired Gastric Function and Nutritional Intake in Patients With Cirrhosis and Ascites

BACKGROUND & AIMS Protein calorie malnutrition and weight loss are common among patients with cirrhosis and ascites. The cause of these symptoms is unclear, with several putative mechanisms proposed. The primary aims of this study were to compare gastric volumes and accommodation between patients with cirrhosis complicated by ascites and healthy controls, and to evaluate the effect of large-volume paracentesis in the patient group. METHODS Patients with cirrhosis and ascites underwent assessment of gastric volumes as measured by single-photon emission computed tomography, gastric sensation assessed by a validated nutrient drink test, and a 3-day assessment of caloric intake before and after large-volume paracentesis. Age- and sex-adjusted linear regression models were used to compare gastric volumes and accommodation ratios between patients and healthy volunteers. Paired Wilcoxon rank-sum tests were used to compare gastric measures before and after paracentesis among the patient group. RESULTS Fifteen patients (median age, 54 y) were compared with 112 healthy (age- and sex-matched) controls. Median postprandial gastric volumes (627 mL patients vs 721 healthy controls) and gastric accommodation were reduced significantly in patients compared with healthy controls (P = .02 and .006, respectively). After paracentesis: (1) fasting gastric volumes were increased (median 312 mL post- vs 241 mL pre-, P = .04), (2) patients tolerated ingestion of larger maximum volumes (median 964 mL post- vs 738 mL pre-, P = .04), and (3) caloric intake was increased (median 34% kcal post- vs 3110 kcal pre-, P = .005). CONCLUSIONS Postprandial gastric volumes and accommodation ratios are reduced in patients with cirrhosis and ascites compared with healthy controls. In addition, large-volume paracentesis increases fasting gastric volumes, volumes ingested until maximal satiation, and caloric intake.