Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI). METHODS: We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type. RESULTS: Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P < .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77). CONCLUSIONS: More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.

Malignant Peritoneal Mesothelioma Presenting as Mucinous Ascites.

We present a rare case of a 46-year-old man presenting with mucinous ascites secondary to malignant peritoneal mesothelioma (MPM) that was diagnosed via colonoscopy with biopsies. Both our findings and the clinical presentation were unique. While it is widely known that asbestos exposure is commonly associated with pleural mesothelioma, 6-10% of malignant mesotheliomas arise from the peritoneum. To date, only 4 cases of MPM with the primary tumor site in the colon have been described in the literature.

Hepatitis C: Treatment of difficult to treat patients.

Over the past several years, more so recently, treatment options for hepatitis C virus (HCV) have seemed to exponentially grow. Up until recently, the regimen of pegylated interferon (peg-IFN) and ribavirin (RBV) stood as the standard of care. Direct acting antivirals, which target nonstructural proteins involved in replication and infection of HCV were first approved in 2011 as an addition to the peg-IFN and RBV regimen and with them have come increased sustained virological response rates (SVR). The previously reported 50%-70% SVR rates using the combination of peg-IFN and RBV are no longer the standard of care with direct acting antiviral (DAA) based regimens now achieving SVR of 70%-90%. Peg-IFN free as well as "all oral" regimens are also available. The current randomized controlled trials available show favorable SVRs in patients who are naive to treatment, non-cirrhotic, and not human immunodeficiency virus (HIV)-co-infected. What about patients who do not fit into these categories? In this review, we aim to discuss the currently approved and soon to be approved DAAs while focusing on their roles in patients that are treatment experienced, cirrhotic, or co-infected with HIV. In this discussion, review of the clinical trials leading to recent consensus guidelines as well as discussion of barriers to treatment will occur. A case will attempt will be made that social services, including financial support and drug/alcohol treatment, should be provided to all HCV infected patients to improve chances of cure and thus prevention of late stage sequela.

Hepatitis C cirrhosis: New perspectives for diagnosis and treatment.

Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.

Pre-and-post transplant considerations in patients with nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression.

Challenges of recurrent hepatitis C in the liver transplant patient.

Cirrhosis secondary to hepatitis C virus (HCV) is a very common indication for liver transplant. Unfortunately recurrence of HCV is almost universal in patients who are viremic at the time of transplant. The progression of fibrosis has been shown to be more rapid in the post-transplant patients than in the transplant naïve, hence treatment of recurrent HCV needs to be considered for all patients with documented recurrent HCV. Management of recurrent HCV is a challenging situation both for patients and physicians due to multiple reasons as discussed in this review. The standard HCV treatment with pegylated interferon and Ribavarin can be considered in these patients but it leads to a lower rate of sustained virologic clearance than in the non-transplanted population. Some of the main challenges associated with treating recurrent HCV in post-transplant patients include the presence of cytopenias; need to monitor drug-drug interactions and the increased incidence of renal compromise. In spite of these obstacles all patients with recurrent HCV should be considered for treatment since it is associated with improvement in survival and a delay in fibrosis progression. With the arrival of direct acting antiviral drugs there is renewed hope for better outcomes in the treatment of post-transplant HCV recurrence. This review evaluates current literature on this topic and identifies challenges associated with the management of post-transplant HCV recurrence.

Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma.

The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1­19.2) for the entire cohort, 27.6 months (17.7-37.6) for curative resection, 12.9 months (6.5-19.2) for palliative chemoradiotherapy and 4.9 months (0.4-9.6) for best supportive care (p<0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

Hepatic preservation injury: severity of hepatitis C recurrence and survival after liver transplantation.

BACKGROUND: Preservation injury in the HCV liver transplant population has been reported to correlate with poorer survival outcomes compared to preservation injury in the non-HCV liver transplant population. However, determinants of progression to cirrhosis in HCV infection remain poorly defined in this population. AIM: This study aimed to determine if the presence and severity of preservation injury impact the acceleration of HCV recurrence and survival after liver transplant. METHODS: We retrospectively reviewed liver transplant HCV patients over a 10-year period. Biopsies from postoperative day 7 were assessed for preservation injury and 4- and 12-month biopsies were assessed for fibrosis. Patients with Ishak fibrosis >0.8 Units/year were considered rapid fibrosers. RESULTS: Our study group consisted of 255 patients. The mean age was 49.3 years old, 180 (70.6 %) were male, and 221 (86.7 %) were Caucasian. The incidence of preservation injury on the 7-day biopsy was 69.0 %. A strong correlation between postoperative peak AST within the first week and preservation injury was found. The overall prevalence of rapid fibrosers at 4 months, 1 and 2 years was 47.4, 75.2, and 58.9 %, respectively. The prevalence of rapid fibrosers at 4 months, 1 and 2 years between patients with or without preservation injury was not statistically significant (p = 0.39, p = 0.46, and p = 0.53, respectively). No differences were seen between patients with and without PI in terms of patient and graft survival. CONCLUSION: In this study, the presence and severity of preservation injury were not associated with development of rapid HCV recurrence or worsening in survival.

CC genotype donors for the interleukin-28B single nucleotide polymorphism are associated with better outcomes in hepatitis C after liver transplant.

BACKGROUND/AIMS: Interleukin-28B (IL-28B) polymorphism is the strongest pretreatment predictor of viral clearance in the hepatitis C (HCV) population. Donor and recipient IL-28B genomic background may play an important role in post-transplant HCV recurrence. We sought to examine the role of IL-28B polymorphisms of donor and recipients in liver transplant patients with recurrent HCV and its impact on the response to interferon-based therapy. METHODS: The cohort study consisted of 135 adult liver transplant patients who received interferon-based therapy for recurrent HCV between 1996 and 2005 at the University of Florida. IL-28B single nucleotide polymorphism (rs. 12979860) was characterized using liver tissue from all donors and recipients. RESULTS: The CC genotype was observed in approximately 30% of donors and recipients. Sustained viral response (SVR) to HCV therapy was 100% if both recipient and donor were CC genotype, while the SVR was only 25% if neither donor nor recipient had a CC genotype. (Recipient, P = 0.025, Donor, P < 0.001). Recipients and donors with CC genotype had less fibrosis than recipients with genotypes CT and TT, but the difference was not statistically significant. IL-28B genotype did not seem to play a role in the overall survival in these patients. CONCLUSION: In conclusion, recipient and donor CC genotype is associated with a better treatment response to interferon-based therapy after liver transplant. Our study suggests that using CC genotype donor livers for HCV patients may improve the overall clinical outcome after liver transplantation.

Management of recurrent hepatitis C infection after liver transplantation.

Recurrence of hepatitis C virus remains a near-universal phenomenon after liver transplantation (LT) and is responsible for the high morbidity and low survival seen in these patients. The severity of recurrent disease varies depending on multiple factors, only some of which are modifiable. Antiviral therapy is associated with improved outcomes, but viral clearance is only attainable in a small percentage of this patient population. This patient population is in need of new therapeutic options, and it remains to be seen whether direct-acting antiviral agents will be the answer to this ongoing therapeutic question.

The use of cyclosporine for recurrent hepatitis C after liver transplant: a randomized pilot study.

BACKGROUND: Cyclosporine has antiviral activity in vitro against hepatitis C (HCV). We performed a pilot study to prospectively determine the antiviral effect of cyclosporine during therapy with PEGalfa-2a and ribavirin in liver transplant recipients with recurrent HCV infection. METHODS: Patients with HCV recurrence (Ishak Fibrosis Stage > or = 2) were enrolled for 2 years at the University of Florida. Thirty-eight patients were randomized to continued tacrolimus or switched to cyclosporine. Both groups received PEGalfa-2a and ribavirin. RESULTS: Twenty patients received tacrolimus and 18 cyclosporine, with a mean age of 53. Eighty-two percent were men, 84% Caucasian, and 90% genotype 1. In patients switched from tacrolimus to cyclosporine, HCVRNA levels decreased by a mean of 0.39 million IU/ml during the 1 month prior to initiating PEG/RBV. Sustained viral response for cyclosporine was higher than in patients on tacrolimus receiving PEG/RBV therapy. CONCLUSIONS: This randomized controlled pilot study is the first in vivo study evaluating cyclosporine versus tacrolimus in liver transplant recipients undergoing antiviral therapy. Change from tacrolimus to cyclosporine led to a modest HCV RNA drop and appeared to enhance the antiviral response of PEG/RBV. A larger randomized study is necessary to see if cyclosporine offers any advantage over tacrolimus.

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 >or= 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.

Management of viral hepatitis in hematologic malignancies.

Viral hepatitis is the third major cause of liver dysfunction in allogeneic transplant recipients and has become a significant concern in patients with hematological malignancies receiving chemotherapy. Thus, identification of patients at risk for viral hepatitis is very important when evaluating and treating hematological malignancies. Serologic screening for all patients should include anti-HCV, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) testing. Current therapies for hepatitis B (HBV) virus infection are aimed at viral suppression, while treatment for hepatitis C (HCV) virus can eradicate infection in many treated patients. To prevent HBV viral reactivation, prophylaxis with nucleoside analogues should be initiated for all HBsAg-positive patients. HCV infection appears to have little impact on short-term survival after bone marrow transplantation (BMT), but eventually can impact long-term survival due to progression of liver disease. In this review we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.

Listeria monocytogenes following orthotopic liver transplantation: central nervous system involvement and review of the literature.

Listeria monocytogene is a well-recognized cause of bacteremia in immunocompromised individuals, including solid organ transplant recipients, but has been rarely reported following orthotopic liver transplantation. We describe a case of listeria meningitis that occurred within a week after liver transplantation. The patient developed a severe headache that mimicked tacrolimus encephalopathy, and was subsequently diagnosed with listeria meningitis by cerebrospinal fluid culture. The infection was successfully treated with three-week course of intravenous ampicillin. Recurrent hepatitis C followed and was successfully treated with interferon alfa and ribavirin. Fourteen cases of listeriosis after orthotopic liver transplantation have been reported in the English literature. Most reported cases were successfully treated with intravenous ampicillin. There were four cases of listeria meningitis, and the mortality of them was 50%. Early detection and treatment of listeria meningitis are the key to obtaining a better prognosis.

Current and future hepatitis C therapies.

Treatment of chronic hepatitis C patients has evolved significantly in the past 15 years. With a better knowledge of viral kinetics and molecular virology of the hepatitis C virus, we have gone from a low chance of viral eradication to a chance as high as 50%. Despite this, current therapies are not ideal and are associated with side effects, complications, and poor patient tolerability. Therefore, an urgent need to look for better strategies to treat this disease is imperative. Thanks to the current knowledge and ongoing research, we know the way we treat hepatitis C today will change dramatically in the next 5-10 years. This review will focus on current therapies for hepatitis C and the most recent advances in the search for new therapies.

Is early recurrence of hepatitis C associated with biliary anastomotic stricture after liver transplantation?

BACKGROUND: While the main effect of hepatitis C virus (HCV) is hepatitis, HCV is also known to cause a variety of systemic immunologic inflammatory abnormalities. The effect of HCV infection on the biliary tract after liver transplantation (LT) is not well understood. The aim of the current study is to determine if recurrence of hepatitis C affects biliary complications after LT, with special reference to late biliary anastomotic strictures (LBAS). METHODS: A total of 688 consecutive adult LT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005 were reviewed. Biliary anastomotic stricture was confirmed by endoscopic retrograde cholangiopancreatography. LBAS was defined as stricture that occurred 30 days or more after LT. Early HCV recurrence was defined as recurrence within 6 months after LT. RESULTS: LBAS occurred in 55 patients (8% of total). Patients with HCV infection had a higher occurrence of LBAS than non-HCV patients (11% vs. 5%, P=0.0093). Among HCV patients, those with early HCV recurrence had an exceedingly high rate of LBAS (16%). In multivariate analyses, early recurrence of hepatitis C (P<0.0001), as well as occurrence of hepatic artery thrombosis (P=0.0018) and prolonged cold ischemic time (P=0.034), were independent risk factors affecting LBAS. Among HCV patients, those with LBAS had a significantly higher hepatitis activity index score (3.1 vs. 1.4, P<0.0001) and fibrosis stage (0.9 vs. 0.4, P<0.0001) as compared to patients without LBAS. CONCLUSION: Patients with early recurrence of HCV have increased occurrence of late biliary anastomotic stricture after liver transplantation.

Viral hepatitis: manifestations and management strategy.

Viral hepatitis is the third most common cause of liver disease in allogeneic transplant recipients and causes significant morbidity and mortality. When treating patients with hematological malignancies, an emphasis should be placed on identification of patients at risk for viral hepatitis with appropriate screening. Initial screening serology should include anti-HCV, HBsAg, anti-HBs, and anti-HBc testing. When hepatitis B exposure has been documented, prophylaxis of viral reactivation for all HBsAg-positive patients with a nucleoside analogue should be implemented. HCV infection appears to have little short-term impact on survival after bone marrow transplantation, but is a risk factor for veno-occlusive disease (VOD) and graft-versus-host disease (GVHD). In the long-term survivor, HCV infection can lead to significant morbidity and mortality due to the development of cirrhosis, decompensation, and liver cancer. Since effective antiviral therapies are available for both hepatitis B and C, routine screening and selected intervention is recommended once reactivation and disease recurrence is documented. In this chapter we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.

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 (CL(Cr)) below 60 ml/min/1.73 m2, and stage 4 chronic renal disease (CRD-4) was defined by an estimated CL(Cr) below 30 mL/min/1.73 m2 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 CL(Cr) 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.