A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis.

BACKGROUND: There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients. METHODS: A search for studies with keywords 'autoimmune hepatitis' and 'tacrolimus' was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected. RESULTS: Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8 mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7 ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis. CONCLUSION: TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function. Key Points There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy. Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined. We report the use and efficacy of tacrolimus (TAC) in patients with AIH. We found that TAC can be safely and effectively used in patients with AIH with minimal side effects. TAC can be a potential treatment option for patients with AIH refractory to standard therapy.

The Effect of Transjugular Intrahepatic Portosystemic Shunt on Platelet Counts in Patients With Liver Cirrhosis.

Thrombocytopenia is a well-known complication of liver cirrhosis. Although the pathogenesis of thrombocytopenia is not well understood, splenic congestion resulting from portal hypertension is considered the most significant underlying mechanism. Therapeutic measures that lower portal hypertension, such as transjugular intrahepatic portosystemic shunt (TIPS), are expected to improve thrombocytopenia associated with liver cirrhosis. At present, there are few studies on the effect of TIPS on platelet counts, and the results are conflicting. This article assesses the effect of TIPS on thrombocytopenia associated with liver cirrhosis. Methods: Seventy-four patients with liver cirrhosis who were referred for TIPS were included in this study. Platelet counts were measured on 3 different occasions over a 3-month period prior to and following placement of TIPS. Thrombocytopenia was defined as a platelet count of 150,000/mm3 or less. Moderate thrombocytopenia was defined as a platelet count of 100,000/mm3 or less. Severe thrombocytopenia was defined as a platelet count of 50,000/mm3 or less. A significant increase in platelet count was defined as a 20% or higher increase from pre-TIPS values. The portosystemic pressure gradient (PSPG) was measured before and after placement of TIPS. The patency of the shunt was checked using Doppler ultrasound 24 hours and 3 months after the procedure. Results: Thirty-four of the 74 patients (46%) who underwent TIPS showed a significant increase in platelet count, with an average increase of 22% (P<.0005). Twenty-five of 40 patients (62%) with moderate thrombocytopenia showed a significant increase in platelet count, with an average increase of 36% (P<.0005). Patients with severe thrombocytopenia showed the greatest response to TIPS; 8 of 11 patients (73%) had a significant increase in platelet count (average increase, 55%; P<.0005). No correlation was found between the response to TIPS and age, sex, etiology of liver disease, pre-TIPS PSPG, or the amount of decrease in PSPG. Conclusion: TIPS may improve thrombocytopenia associated with liver cirrhosis. Patients with severe thrombocytopenia are more likely to benefit from this procedure. No factors other than pre-TIPS platelet count were found to influence the response to TIPS.

Increasing Burden of Chronic Liver Disease Among Adolescents and Young Adults in the USA: A Silent Epidemic.

BACKGROUND AND AIMS: Chronic liver disease (CLD) starts or becomes established in the adolescent and young adult (AYA) age group. This study aimed to estimate trends in CLD prevalence among US AYAs and to assess factors associated with CLD. METHODS: Cross-sectional data from 14,547 AYAs (population-weighted N = 68,274,386) aged 15-39 years enrolled in the National Health and Nutrition Examination Survey from 1988 to 2012 were used. Nonalcoholic fatty liver disease (NAFLD) was defined as elevated alanine aminotransferase (>19 U/L for females and >30 U/L for males) in subjects with BMI ≥ 25 kg/m2; alcoholic liver disease (ALD) as excessive alcohol use (≥3 drinks/day for men and ≥2 drinks/day for women) and elevated aminotransferases after excluding alternative etiologies. Participants were considered hepatitis C virus (HCV) positive if antibody to HCV and HCV-RNA was positive. RESULTS: There was a sharp increase in the prevalence of CLD from 12.9% in 1988-1994 to 28.5% in 1999-2004 that remained stable after that (27.7%). NAFLD was the most common etiology accounting for 22% of all CLD in the later period. The prevalence of ALD has been steadily increasing throughout the years, while HCV has been decreasing. On multivariate analysis, being overweight/obese, Mexican-American ethnicity, later study period, older age, and male gender, were associated with higher odds of having CLD. CONCLUSION: More than one quarter of US AYAs might be affected by CLD. CLD prevalence in this age group has more than doubled over the past three decades mainly due to rise in NAFLD prevalence.

Transjugular Intrahepatic Porto-Systemic Shunt in Patients with Liver Cirrhosis and Model for End-Stage Liver Disease ≥15.

BACKGROUND: It is not known whether transjugular intrahepatic porto-systemic shunt (TIPS) is safe in patients with advanced liver cirrhosis. The aim of our study was to evaluate the impact of TIPS on transplant-free survival in patients with liver cirrhosis and MELD score ≥15. METHODS: All adult patients who underwent TIPS at our institution between 2004 and 2011 were identified (N = 470). A total of 144 patients had MELD ≥15 at the time of TIPS. These patients were matched 1:1 to patients with liver cirrhosis who did not undergo TIPS based on age and MELD score using the greedy algorithm. Patients were followed up until time of death or liver transplantation. Kaplan-Meier curves and log-rank tests were used to test for differences in survival outcome between the two groups. RESULTS: A total of 288 patients with liver cirrhosis were included, of whom 144 underwent TIPS and 144 did not. The two groups were matched based on age and MELD score and were comparable with regard to gender and ethnicity. Mean MELD and Child-Pugh scores in the study population were 20.9 ± 6.5 and 10.5 ± 1.8, respectively. The most common indication for TIPS was varices (49 %), followed by refractory ascites (42 %). In the first 2 months post-TIPS, there was increased mortality or liver transplantation in patients who had TIPS compared to those who did not, but this did not reach statistical significance (p = 0.07). However, after 2 months, TIPS is associated with 56 % lower risk of dying or needing liver transplantation (p < 0.01) than cirrhotic patients who did not undergo TIPS. CONCLUSION: In patients with liver cirrhosis and MELD ≥15, TIPS might improve transplant-free survival for patients who live for at least 2 months after the procedure.

Sofosbuvir/Ledipasvir Without Ribavirin Achieved High Sustained Virologic Response for Hepatitis C Recurrence After Liver Transplantation: Two-Center Experience.

BACKGROUND: Current recommended regimens to treat patients with hepatitis C virus (HCV) infection after liver transplantation include the use of ribavirin (RBV). Limited data are available on the efficacy of RBV-free regimens posttransplant, particularly the use of sofosbuvir (SOF)/ledipasvir (LDV) without RBV in this patient population. We aimed to assess the efficacy and safety of SOF/LDV fixed-dose combination without RBV in patients with HCV recurrence posttransplant. METHODS: This is a retrospective study of 46 patients with HCV recurrence posttransplant. SOF/LDV without RBV was used for 12 weeks in patients with early-stage fibrosis (F0-F2) or for 24 weeks in those with advanced fibrosis (F3-F4) and/or cholestatic hepatitis. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment. Secondary outcomes included relapse after treatment and adverse events. RESULTS: Forty-six patients, with a mean age of 62 ± 8 years, a median duration since time of transplant of 904 days (range, 78-3525 days), an HCV genotype 1, and a mean baseline viral load of 7.79 million IU/mL, were treated. Of these, 32 patients were treated for 12 weeks, and 14 patients were treated for 24 weeks. Twenty-five patients (54%) were treatment experienced (21 with interferon and 4 with SOF). All 46 patients (100%) achieved sustained virological response (SVR) 12. Neither virologic relapses nor serious adverse events were noted. CONCLUSIONS: The combination of SOF/LDV without RBV for 12 or 24 weeks produced 100% SVR 12 in patients with HCV recurrence after liver transplantation. The use of RBV may not be necessary to achieve SVR in this patient population.

Ohio solid organ transplantation consortium criteria for liver transplantation in patients with alcoholic liver disease.

AIM: To evaluate risk of recidivism on a case-by-case basis. METHODS: From our center's liver transplant program, we selected patients with alcoholic liver disease who were listed for transplant based on Ohio Solid Organ Transplantation Consortium (OSOTC) exception criteria. They were considered to have either a low or medium risk of recidivism, and had at least one or three or more months of abstinence, respectively. They were matched based on gender, age, and Model for End-Stage Liver Disease (MELD) score to controls with alcohol-induced cirrhosis from Organ Procurement and Transplant Network data. RESULTS: Thirty six patients with alcoholic liver disease were approved for listing based on OSOTC exception criteria and were matched to 72 controls. Nineteen patients (53%) with a median [Inter-quartile range (IQR)] MELD score of 24 (13) received transplant and were followed for a median of 3.4 years. They were matched to 38 controls with a median (IQR) MELD score of 25 (9). At one and five years, cumulative survival rates (± standard error) were 90% ± 7% and 92% ± 5% and 73% ± 12% and 77% ± 8% in patients and controls, respectively (Log-rank test, P = 0.837). Four (21%) patients resumed drinking by last follow-up visit. CONCLUSION: Compared to traditional criteria for assessment of risk of recidivism, a careful selection process with more flexibility to evaluate eligibility on a case-by-case basis can lead to similar survival rates after transplantation.

Predictors of Successful Downstaging of Hepatocellular Carcinoma Outside Milan Criteria.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) outside Milan criteria (MC) may be candidates for liver transplantation (LT) after successful downstaging. Factors that predict successful downstaging are unclear. We aimed to identify the predictors of successful downstaging of HCC in patients outside MC. METHODS: We performed a retrospective cohort study on consecutive patients with HCC outside MC who received downstaging with locoregional therapy. Clinical and laboratory variables, tumor characteristics including total tumor volume (TTV) and up-to-7 criteria were recorded. We performed univariate and multivariate logistic regression analyses to identify variables associated with successful downstaging. RESULTS: Of 675 patients with HCC, 90 patients outside MC received downstaging. Fifty-three (59%) patients were successfully downstaged, 37 (41%) failed downstaging. University of California at San Francisco criteria, α-fetoprotein, up-to-7 criteria, TTV, and platelet count were predictors of successful downstaging on univariate analysis. Total tumor volume was an independent predictor of successful downstaging on multivariate logistic regression (P = 0.04, area under receiver operating characteristic curve 0.89 (95% confidence interval, 0.82-0.96). Fifty-two (76%) of 68 patients with TTV less than 200 cm were successfully downstaged, whereas only 1 (4.5%) of 22 patients with TTV greater than 200 cm were successfully downstaged. Forty-five (50%) patients underwent LT. Kaplan-Meier survival rates at 1 and 5 years post-LT were 95.3% and 79.4%, respectively. Patients who were successfully downstaged had better survival than patients who failed downstaging (P < 0.01). CONCLUSIONS: Total tumor volume is a good predictor of successful downstaging of HCC. Patients with TTV less than 200 cm may be considered good candidates for downstaging. Further studies with larger cohort of patients are needed to validate this approach in patients with HCC outside Milan.

Three-dimensional printing and pediatric liver disease.

PURPOSE OF REVIEW: Enthusiastic physicians and medical researchers are investigating the role of three-dimensional printing in medicine. The purpose of the current review is to provide a concise summary of the role of three-dimensional printing technology as it relates to the field of pediatric hepatology and liver transplantation. RECENT FINDINGS: Our group and others have recently demonstrated the feasibility of printing three-dimensional livers with identical anatomical and geometrical landmarks to the native liver to facilitate presurgical planning of complex liver surgeries. Medical educators are exploring the use of three-dimensional printed organs in anatomy classes and surgical residencies. Moreover, mini-livers are being developed by regenerative medicine scientist as a way to test new drugs and, eventually, whole livers will be grown in the laboratory to replace organs with end-stage disease solving the organ shortage problem. SUMMARY: From presurgical planning to medical education to ultimately the bioprinting of whole organs for transplantation, three-dimensional printing will change medicine as we know in the next few years.

Metabolomics studies identify novel diagnostic and prognostic indicators in patients with alcoholic hepatitis.

AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis (AH). METHODS: We prospectively recruited patients with cirrhosis from AH (n = 23) and those with cirrhosis with acute decompensation (AD) from etiologies other than alcohol (n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis. Logistic regression analysis was performed to build a predictive model for AH based on clinical characteristics. A survival analysis was used to construct Kaplan Meier curves evaluating transplant-free survival. RESULTS: A comparison of model for end-stage liver disease (MELD)-adjusted metabolomics levels between cirrhosis patients who had AD or AH showed that patients with AH had significantly higher levels of betaine, and lower creatinine, phenylalanine, homocitrulline, citrulline, tyrosine, octenoyl-carnitine, and symmetric dimethylarginine. When considering combined levels, betaine and citrulline were highly accurate predictors for differentiation between AH and AD (area under receiver operating characteristics curve = 0.84). The plasma levels of carnitine [0.54 (0.18, 0.91); P = 0.005], homocitrulline [0.66 (0.34, 0.99); P < 0.001] and pentanoyl-carnitine [0.53 (0.16, 0.90); P = 0.007] correlated with MELD scores in patients diagnosed with AH. Increased levels of many biomarkers (carnitine P = 0.005, butyrobetaine P = 0.32, homocitrulline P = 0.002, leucine P = 0.027, valine P = 0.024, phenylalanine P = 0.037, tyrosine P = 0.012, acetyl-carnitine P = 0.006, propionyl-carnitine P = 0.03, butyryl-carnitine P = 0.03, trimethyl-lisine P = 0.034, pentanoyl-carnitine P = 0.03, hexanoyl-carnitine P = 0.026) were associated with increased mortality in patients with AH. CONCLUSION: Metabolomics plasma analyte levels might be used to diagnose of AH or help predict patient prognoses.

Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two-center experience.

BACKGROUND: The interferon-free antiviral regimen, sofosbuvir (SOF) and simeprevir (SIM) without ribavirin has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT). AIM AND METHODS: We aim to report the safety, tolerability and efficacy of SOF + SIM to treat LT recipients with recurrent HCV GT1 in a multicenter cohort study. RESULTS: Eighty-one patients with HCV GT1 met criteria to be considered for treatment. Sixty-seven patients received SOF + SIM following LT to date: 69% male, 39% with HCV RNA >6 000 000 IU/mL, 22% advanced hepatic fibrosis (stage 3-4), 6% cholestatic recurrence. Fifty-eight percent previously failed or did not tolerate interferon-based treatments. Mean time from LT to treatment was 6.1 ± 5.2 yr. All patients had estimated GFR >30 mL/min. Tacrolimus was primary immunosuppression in 84% of patients and minimal immunosuppression dose adjustments were required during treatment. In intention-to-treat analysis, 90% achieved end-of-treatment virologic response and 88% achieved SVR. CONCLUSIONS: Sofosbuvir + SIM combination therapy without ribavirin is well tolerated and results in high virologic response rates in recurrent HCV GT1 infection after liver transplantation.

Portal Hypertension Complications Are Frequently the First Presentation of NAFLD in Patients Undergoing Liver Transplantation Evaluation.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is likely to replace Hepatitis C as the leading cause of cirrhosis resulting in liver transplantation (LT) within a few years. Unfortunately, due to the lack of established guidelines for the screening of NAFLD in high-risk populations, many patients present with portal hypertension complications as their first manifestation of NAFLD require a LT evaluation. We aimed to investigate what proportion of patients who underwent LT for NAFLD-cirrhosis had knowledge of their liver disease prior to presenting with portal hypertension complications and to identify differences in clinical parameters between those with and without knowledge of preexisting NAFLD. METHODS: Consecutive patients who underwent LT for NAFLD-cirrhosis at a tertiary referral center were included in the study. Demographic and clinical data at the time of the first LT evaluation visit were collected, and patient knowledge of previous NAFLD was documented. Ascites, variceal bleeding, hepatic encephalopathy, and thrombocytopenia leading to diagnosis of underlying cirrhosis were considered as the presenting symptoms of portal hypertension. A p < 0.05 was considered statistically significant. RESULTS: A total of 124 subjects who received LT for NAFLD-cirrhosis were included, 58 % (n = 72) were male. At the time of the first LT evaluation visit, 60 % had diabetes, the mean body mass index was 33.2 [28.6, 37.6] kg/m(2), and the mean Model for End-Stage Liver Disease (MELD) score was 14.0 [11.0, 19.0]. More importantly, 85/124 patients (68.5 %) had no knowledge of preexisting NAFLD prior to presentation with symptoms of portal hypertension. The presenting symptoms were new-onset ascites in 61 %, hepatic encephalopathy in 25 %, variceal bleeding in 18 %, thrombocytopenia in 9 %, and other in 9 % (non-exclusive). Patients with no prior knowledge of NAFLD were less likely to have a diagnosis of hypercholesterolemia (30 vs. 50 %, p = 0.035) and had a trend toward having higher MELD scores at the time of the first LT evaluation visit (15 vs. 13.5, p = 0.05) and presenting with encephalopathy (25 vs. 10 %, p = 0.06) compared to those with previous knowledge of NAFLD diagnosis. CONCLUSION: The majority of patients undergoing liver transplant evaluation for NAFLD-cirrhosis are not aware of underlying NAFLD until they present with features of portal hypertension. New guidelines should consider screening for NAFLD in certain high-risk groups as more effective treatments for NAFLD are emerging.

Liver Transplant in Young Adults with Chronic Hepatitis C Virus: An Argument for Hepatitis C Treatment in Childhood.

OBJECTIVES: We sought to assess the characteristics of hepatitis C virus-positive young adults who received a liver transplant and to evaluate posttransplant outcomes. MATERIALS AND METHODS: United Network for Organ Sharing database was conducted from 1989 to 2012, and retrospective analysis was performed on all hepatitis C virus-positive young adult patients (aged, 8-35 y) who underwent a liver transplant in the United States. RESULTS: A total of 506 hepatitis C virus subjects were included. Average age at time of transplant was 30.1 ± 4.8 years. Median follow-up after first liver transplant was 46.1 months (13, 89.3 mo). During this time, 217 patients (42.8%) died at a mean age at the time of death of 34 ± 6.7 years including 176/ 506 (34.8%) after the first liver transplant, 34/71 (48.6%) after the second liver transplant, and 7/8 (87.5%) after the third liver transplant. The majority (65.7%) of retransplants were performed for hepatitis C virus recurrence. A mean of 1.15 liver transplants were performed per patient. Overall, 262 subjects were transplanted in the pre-Model for End-stage Liver Disease era, and 244 were transplanted post-MELD. Younger age, higher bilirubin, higher creatinine, hepatitis C carcinoma, shorter wait time, shorter cold ischemia time, nonwhite donor race, and the use of mycophenolate mofetil were significantly more common in the post-Model for End-stage Liver Disease era (all with P < .05). Importantly, 5-year patient and graft survival were not different between the pre- and post-Model for End-stage Liver Disease era. CONCLUSIONS: Liver transplant in young adults for hepatitis C virus acquired during childhood has poor outcomes that did not improve in the post-Model for End-stage Liver Disease era. These findings should prompt more aggressive evaluation and treatment for hepatitis C virus in children.

Liver transplantation for nonalcoholic steatohepatitis in young patients.

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and insulin resistance. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival. The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the United States for NASH cirrhosis from the 1987 to 2012 United Network for Organ Sharing (UNOS) database. Kaplan-Meier analysis was used to assess patient and graft survival. A total of 330 patients were included, 68% were Caucasian, and the mean BMI was 33.6 ± 6.3. Age at time of LT ranged between 4 and 40 years (mean 33.9 ± 6.6 years). Fourteen subjects were <18 years of age at time of LT and 20 were between the ages of 18 and 25 years. Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time, 30% of subjects (n = 100) died and 11.5% (n = 38) were retransplanted including 13 for NASH recurrence. In conclusion, NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required retransplantation.

Genetics and hepatitis C: it's good to be 'CC'.

The interleukin-28B (IL28B) gene contains a single-nucleotide polymorphism at location rs12979860 that affects both the natural history of hepatitis C virus infection and the patient's response to treatment, particularly interferon-based regimens with or without protease inhibitors.

Impact of pretransplant rifaximin therapy on early post-liver transplant infections.

Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period.