Sandeep Mukherjee

A Comprehensive Review of Immunosuppression Used for Liver Transplantation

Since liver transplantation was approved for the treatment of end stage liver disease, calcineurin inhibitors (CNIs) have played a critical role in the preservation of allograft function. Unfortunately, these medications cause a variety of Side effects such as diabetes, hypertension and nephrotoxicity which in turn result in significant morbidity and reduced quality of life. A variety of newer immunosuppressants have been evaluated over the last decade in an attempt to either substitute for CNIs or use with reduced dose CNIs while still preserving allograft function However, current data does not recommend complete cessation of CNIs due to unacceptably high rates of allograft rejection. As these medications have their own unique adverse effects, a careful assessment on their risks and benefits is essential, particularly when additive or synergistic effects with CNIs may occur. Furthermore, the impact of these newer medications on the risk of hepatitis C recurrence and progression remains to be elucidated. Controlled trials are urgently required to assist transplant physicians with choosing the optimum immunosuppressive regimen for their patients. This review will discuss commonly used immunosuppressants prescribed in liver transplantation, emerging therapties and where appropriate, the impact of these medications on the recurrence of hepatitis C after liver transplantation.

Impact of pegylated interferon α-2B and ribavirin on hepatic fibrosis in liver transplant patients with recurrent hepatitis C: an open-label series

Abstract: Background: Patients with recurrent hepatitis C virus (HCV) are often treated with interferon‐based therapy in an attempt to eradicate HCV and prevent cirrhosis requiring retransplantation. We describe our experience with pegylated interferon and ribavirin and the impact of this therapy on hepatic fibrosis.

The profile of bile acids and their sulfate metabolites in human urine and serum.

The role of sulfation in ameliorating the hepatotoxicity of bile acids (BAs) in humans remains unknown due to the lack of proper analytical methods to quantify individual BAs and their sulfate metabolites in biological tissues and fluids. To this end, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to characterize the detailed BA profile in human urine and serum. The limit of quantification was 1ng/mL and baseline separation of all analytes was achieved within in a run time of 32min. The method was validated over the dynamic range of 1-1000ng/mL. The LC-MS/MS method was more accurate, precise, and selective than the commercially available kits for the quantification of sulfated and unsulfated BAs, and the indirect quantification of individual sulfated BAs after solvolysis. The LC-MS/MS method was applied to characterize the BA profile in urine and serum of healthy subjects. Thirty three percent of serum BAs were sulfated, whereas 89% of urinary BAs existed in the sulfate form, indicating the role of sulfation in enhancing the urinary excretion of BAs. The percentage of sulfation of individual BAs increased with the decrease in the number of hydroxyl groups indicating the role of sulfation in the detoxification of the more hydrophobic and toxic BA species. Eighty percent of urinary BAs and 55% of serum BAs were present in the glycine-amidated form, whereas 8% of urinary BAs and 13% of serum BAs existed in the taurine-amidated form.

Value of dobutamine stress myocardial contrast perfusion echocardiography in patients with advanced liver disease

Although dobutamine stress echocardiography has been used for the preoperative evaluation of patients with advanced liver disease (ALD), no data exist regarding the value of myocardial perfusion imaging (MPI) with real‐time myocardial contrast echocardiography (RTMCE) in this patient population. We sought to determine the value of MPI during dobutamine stress RTMCE for predicting prognosis in patients with ALD. We examined both wall motion and MPI in 230 patients with ALD who underwent dobutamine stress RTMCE using intravenous commercially available contrast agents (Optison, GE‐Amersham, Princeton, NJ; or Definity, Bristol‐Myers Squibb Medical Imaging, North Billerica, MA). The prognostic value of clinical variables, including the Model for End‐Stage Liver Disease (MELD) score, and echocardiographic data were examined using a Cox Hazard model. The primary endpoint was mortality of all causes. Among the 85 patients who underwent orthotopic liver transplantation, 4 had abnormal MPI and 81 had normal perfusion. The hospital mortality rate was 50% (2/4) in patients with abnormal MPI and 2% (2/81) in patients with normal MPI (P = 0.01). Among patients with abnormal MPI, 1 died from myocardial infarction in the first postoperative day and the second 1 from hemorrhagic shock. During a median follow‐up of 15 months, 53 (23%) patients died. The independent predictors of death were an age of ≥65 yr (RR = 2.2; 95% confidence interval (CI) = 1.1–4.4; P = 0.03), MELD score of ≥25 (RR = 3.2; 95% CI = 1.8–5.5; P < 0.0001), and abnormal MPI (RR = 2.4; 95% CI = 1.1–5.2; P = 0.02). The 2‐yr mortality was 24% for patients with normal MPI and 45% for those with inducible MPI abnormalities (P = 0.003). In conclusion, MPI obtained by RTMCE appears to be a useful tool in predicting mortality in patients with ALD. Further studies are required to verify its independent value. Liver Transpl 12:592–599, 2006.

Pegylated interferon for recurrent hepatitis C in liver transplant recipients with renal failure: A prospective cohort study

Abstract Background Hepatitis C (HCV) universally recurs following orthotopic liver transplantation (OLT), representing an important cause for retransplantation. Although it is often treated with interferon and ribavirin, ribavirin is contraindicated in the presence of renal failure. In this setting of renal failure, pegylated-interferon monotherapy may be useful for recurrent HCV in liver transplant patients. Methods Between June 2001 and November 2002, patients with recurrent HCV were screened to determine if they were eligible for treatment. Renal failure was defined as serum creatinine greater than 1.8 mg/dL. HCVRNA and liver biopsies were performed prior to treatment, end of treatment (EOT) and 6 months after EOT for those who were HCV-RNA negative at EOT. Patients were followed prospectively after starting weekly pegylated-interferon alpha 2b 1.0 μg/kg (Schering-Plough, Kenilworth, NJ, USA). Results Among the 45 patients with recurrent HCV screened, 9 were eligible, including 8 men and 1 woman of average age 55 years. Eight patients were intolerant to the treatment requiring discontinuation within the first 3 months. Two patients developed a sustained response to HCV eradication. One patient who completed treatment has normal liver tests but is still viremic. Conclusion Pegylated-interferon alpha 2b is poorly tolerated in liver transplant recipients with recurrent HCV and chronic renal failure. Larger, prospective studies are required to determine the optimum duration of treatment and the impact of treatment on histology and quality of life.

Urinary bile acids as biomarkers for liver diseases I. stability of the baseline profile in healthy subjects

The role of bile acids (BAs) as biomarkers for liver injury has been proposed for decades. However, the large inter- and intra-individual variability of the BA profile has prevented its clinical application. To this end, we investigated the effect of covariates such as food, gender, age, BMI, and moderate alcohol consumption on the BA profile in healthy human subjects. The BA profile was characterized by the calculation of indices that describe the composition, sulfation, and amidation of total and individual BAs. Both inter- and intra-individual variabilities of BA indices were low in serum and even lower in urine compared with those of absolute concentrations of BAs. Serum BA concentrations increased with consumption of food, whereas urinary BA concentrations were mildly affected by food. Gender differences in the urinary and serum BA profile were minimal. The serum and urinary BA profiles were also not affected by age. BMI showed minimal effect on the urine and serum BA profile. Moderate alcohol consumption did not have a significant effect on the BA profile in both urine and serum. When the effect of the type of alcohol was studied, the results indicate that moderate drinking of beer does not affect BA concentrations and has minimal effect on BA indices, whereas moderate wine consumption slightly increases BA concentrations without affecting the BA indices. In summary, urinary BA indices showed lower variability and higher stability than absolute BA concentrations in serum and showed minimal changes to covariate effects suggesting their utility as biomarkers in clinic.

Interferon alpha 2b and ribavirin for the treatment of recurrent hepatitis C after liver transplantation: Cohort study of 38 patients

Aim: Recurrent hepatitis C virus (HCV) is universal following liver transplantation. Patients are often treated with interferon and ribavirin in an attempt to eradicate the virus. We describe our experience with 38 patients with recurrent HCV from a single liver transplant program.

Mild donor liver steatosis has no impact on hepatitis C virus fibrosis progression following liver transplantation

Background: This study examines the impact of donor liver macrovesicular steatosis on recurrence of hepatitis C virus (HCV) disease after liver transplantation.

Urinary Bile Acids as Biomarkers for Liver Diseases II. Signature Profiles in Patients

Hepatobiliary diseases result in the accumulation of bile acids (BAs) in the liver, systemic blood, and other tissues leading to an unfavorable prognosis. The BA profile was characterized by the calculation of indices that describe the composition, sulfation, and amidation of total and individual BAs. Comparison of the urinary BA profiles between healthy subjects and patients with hepatobiliary diseases demonstrated significantly higher absolute concentrations of individual and total BAs in patients. The percentage sulfation of some individual BAs were different between the two groups. The percentage amidation of overall and most individual BAs was higher in patients than controls. The percentage of primary BAs (CDCA and CA) was higher in patients, whereas the percentage of secondary BAs (DCA and LCA) was lower in patients. BA indices belonging to percentage amidation and percentage composition were better associated with the severity of the liver disease as determined by the model for end-stage liver disease (MELD) score and disease compensation status compared with the absolute concentrations of individual and total BAs. In addition, BA indices corresponding to percentage amidation and percentage composition of certain BAs demonstrated the highest area under the receiver operating characteristic (ROC) curve suggesting their utility as diagnostic biomarkers in clinic. Furthermore, significant increase in the risk of having liver diseases was associated with changes in BA indices.

Immunosuppression in liver transplantation.

Calcineurin inhibitors remain the mainstay of immunosuppression in liver transplantation but are associated with important side effects such as diabetes, hypertension and nephrotoxicity which can influence quality of life and survival rates. A variety of non-calcineurin inhibitors have been used in liver transplantation, either during induction immunosuppression in an attempt to delay the introduction of calcineurin inhibitors or during maintenance immunosuppression with reduced dose calcineurin inhibitors to minimize calcineurin inhibitor toxicity while preserving hepatic allograft function. With few exceptions, single agent immunosuppression with non- calcineurin inhibitors has not been universally practiced outside of clinical trials due to unacceptably high rates of hepatic allograft rejection. Although several single center studies have reported encouraging results with these new agents when used with reduced dose calcineurin inhibitors, large, randomized studies are eagerly awaited. Furthermore, as the impact of these newer agents on the recurrence of hepatitis C continues to evolve, clinicians need to be prudent with their use until data from controlled studies is available. This article will review currently used immunosuppressants in liver transplantation, novel therapies in development and the impact of these medications of the recurrence of hepatitis C after liver transplantation.