Victor I. Machicao

Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation.

Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti‐viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus‐based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine‐based immunosuppression (n = 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus‐based therapy (n=59, P = 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose‐dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon‐based therapy and should be studied in a prospective randomized trial. Liver Transpl 12:51–57, 2006.

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.

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.

The natural history of hepatitis C cirrhosis after liver transplantation

Hepatitis C after liver transplantation leads to graft cirrhosis in up to 30% of patients within 5 years, but limited data exist regarding the clinical course of cirrhosis after transplantation. The aims of this study were to report the natural history of hepatitis C cirrhosis after liver transplantation and to identify risk factors for decompensation and survival. Hepatitis C patients underwent protocol liver biopsies yearly after liver transplantation. After cirrhosis was identified by biopsy, the outcomes of interest were the development of decompensation, death, or retransplantation for hepatitis C. Kaplan‐Meier and Cox regression analysis was used to determine survival and risk factors for decompensation and mortality. Out of 502 liver transplants performed for hepatitis C, 88 patients (18%) had cirrhosis within 3.7 years. Seventy‐one patients were compensated at diagnosis. The cumulative probability of decompensation 1 year after cirrhosis was 30%. A Model for End‐Stage Liver disease score ≥ 16 was predictive of decompensation and poor survival, whereas successful interferon treatment was found to reduce this risk (relative risk = 0.05). Once decompensation occurred, 1‐year survival was 46%. In conclusion, the results confirm an accelerated natural history of hepatitis C cirrhosis after liver transplantation and demonstrate poor survival after decompensation. The Model for End‐Stage Liver Disease can stratify risk for decompensation and survival, whereas successful antiviral therapy may be protective. Liver Transpl 15:1063–1071, 2009.

Colonoscopy in octogenarians: a prospective outpatient study

OBJECTIVES: The number of octogenarians (age ≥80 yr) referred for colonoscopy is increasing. Reported success rates regarding colonoscopy completion and adequacy of colonic preparation are poor overall in this group. This may be the result of age-related differences or biases due to retrospective data. The aims of this study were to prospectively determine differences between octogenarians and nonoctogenarians in adequacy of colonic preparation, success in completing colonoscopy, and complications of conscious sedation. METHODS: Prospective cohort study of 250 consecutive outpatients (150 nonoctogenarians and 100 octogenarians) referred for colonoscopy. Colonic preparation tolerance was assessed before colonoscopy, and the success rate and preparation were evaluated after the procedure. Conscious sedation complications were compared. RESULTS: In octogenarians and nonoctogenarians preparation tolerance (86% and 90%, respectively) was similar. Endoscopic success rate was slightly lower in octogenarians (90% vs 99%, p = 0.002). Preparation was poor in 16% of octogenarians compared with 4% of nonoctogenarians (p = 0.001). This was independent of the type of preparation used. Oxygen desaturation was more common in octogenarians (27% vs 19%, p = 0.0007) and associated with a higher meperidine dose (1.05 vs 0.75 mg/kg). No adverse outcomes occurred in either study group. CONCLUSIONS: Colonic preparations were well tolerated and colonoscopic success rates were high in octogenarians and nonoctogenarians. However, poor colonic preparation was four times as likely in octogenarians and was the most important impediment to adequate colonoscopy.

Pulmonary complications in chronic liver disease.

The association of chronic liver disease with respiratory symptoms and hypoxia is well recognized. Over the last century, three pulmonary complications specific to chronic liver disease have been characterized: hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH). The development of portal hypertension is fundamental in the pathogenesis of each of these disorders. HPS is the most common condition, found in 5%‐30% of cirrhosis patients, manifested by abnormal oxygenation due to the development of intrapulmonary vascular dilatations. The presence of HPS increases mortality and impairs quality of life, but is reversible with liver transplantation (LT). POPH is characterized by development of pulmonary arterial hypertension in the setting of portal hypertension, and is present in 5%‐10% of cirrhosis patients evaluated for LT. Screening for POPH in cirrhosis patients eligible for LT is critical since severe POPH is a relative contraindication for LT. Patients with moderate POPH, who respond adequately to medical therapy, may benefit from LT, although sufficient controlled data are lacking. HH is a transudative pleural effusion seen in 5%‐10% of cirrhosis patients, in the absence of cardiopulmonary disease. Diagnosis of HH should prompt consideration for LT, which is the ultimate treatment for HH. Conservative management includes salt restriction and diuretics, with thoracentesis and transjugular intrahepatic portosystemic shunt (TIPS) as second‐line therapeutic options. (Hepatology 2014;59:1627‐1637)

Using an immune functional assay to differentiate acute cellular rejection from recurrent hepatitis C in liver transplant patients.

In transplant recipients transplanted for hepatitis C, presentation of abnormal transaminases can herald the presentation of recurrent hepatitis C, cellular rejection, or both. Given the sometimes ambiguous histology with these 2 entities, the ability to distinguish them is of great importance because misinterpretation can potentially affect graft survival. We used an immune functional assay to help assess the etiology of abnormal liver function test results in liver transplant recipients. Blood samples for the immune functional assay were taken from 42 recipients prospectively at various times post‐transplant and compared with clinical and histologic findings. In patients whose liver biopsy showed evidence of cellular rejection, the immune response was noted to be very high, whereas in those with active recurrence of hepatitis C, the immune response was found to be very low. This finding was found to be statistically significant (P < 0.0001). In those patients in whom there was no predominant histologic features suggesting 1 entity over the other, the immune response was higher than in those with aggressive hepatitis C but lower than in those with cellular rejection. In conclusion, these data show the potential utility of the ImmuKnow assay as a means of distinguishing hepatitis C from cellular rejection and its potential usefulness as a marker for outlining the progression of hepatitis C. Liver Transpl 15:216–222, 2009.

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.

Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial

Objective. To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc). Methods. Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests. Results. Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003). Conclusion. Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.

Impact of implementation of the MELD scoring system on the prevalence and incidence of chronic renal disease following liver transplantation

The implementation of the model for end‐stage liver disease (MELD) score decreased mortality of those awaiting liver transplantation (LT); however, the impact of the MELD allocation system on the risk of chronic renal disease after LT remains unknown. We conducted a non‐concurrent single‐center cohort study of 174 patients undergoing LT at our center. We compared patients who underwent LT one year prior to MELD implementation (pre‐MELD cohort) to those patients who underwent LT 1 year following MELD implementation (MELD cohort). All patients were followed for at least 2 years after LT. Stage 3 chronic renal disease (CRD‐3) was defined by an estimated creatinine clearance (CLCr) below 60 ml/min/1.73 m 2 , and stage 4 chronic renal disease (CRD‐4) was defined by an estimated CLCr below 30 mL/min/1.73 m 2 according to the validated Modification of Diet and Renal Disease (MDRD) formula. Requirement of kidney transplantation and need for hemodialysis were also evaluated following LT. The pre‐MELD cohort (n=97) and the MELD cohort (n=77) were comparable in baseline characteristics, prevalence of diabetes and hypertension, and immunosuppression. Mean calculated MELD score in the pre‐MELD cohort was significantly lower than in the MELD cohort (16 vs. 19, P < 0.05). The estimated CLCr at time of LT was lower in the MELD cohort compared with the pre‐MELD cohort (75 vs. 95, P < 0.01). However, the incidence and prevalence of CRD‐3 and CRD‐4 at 6, 12, and 24 months after LT were comparable between the two cohorts. Need for kidney transplantation or hemodialysis after LT was comparable between the groups. In multivariate analysis, serum creatinine at LT was the only variable associated with the development of CRD‐3 in the first 2 years after LT. In conclusion, the implementation of the MELD allocation system is not associated with increased mortality or occurrence of CRD‐3 or CRD‐4 in the first 2 years after LT. Liver Transpl 12:754–761, 2006.