Transplant Outcomes in Older Patients With Nonalcoholic Steatohepatitis Compared to Alcohol-related Liver Disease and Hepatitis C.

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) are waitlisted at older ages than individuals with other liver diseases, but the effect of age on liver transplantation (LT) outcomes in this population and whether it differs from other etiologies is not known. We aimed to evaluate the impact of age on LT outcomes in NASH. METHODS: The United Network for Organ Sharing database was used to identify adults with NASH, hepatitis C virus (HCV) infection, and alcohol-related liver disease (ALD) listed for LT during 2004-2017. Patients were split into age groups (18-49, 50-54, 55-59, 60-64, 65-69, ≥70), and their outcomes were compared. RESULTS: From 2004 to 2017, 14 197 adults with NASH were waitlisted, and the proportion ≥65 increased from 15.8% to 28.9%. NASH patients ages 65-69 had an increased risk of waitlist and posttransplant mortality compared to younger groups, whereas the outcomes in ages 60-64 and 55-59 were similar. The outcomes of individuals with NASH were similar to patients of the same age group with ALD or HCV. Functional status and dialysis were predictors of posttransplant mortality in individuals ≥65 with NASH, and cardiovascular disease was the leading cause of death. CONCLUSIONS: Older NASH patients (≥65) have an increased risk of waitlist and posttransplant mortality compared to younger individuals, although outcomes were similar to patients with ALD or HCV of corresponding age. These individuals should be carefully evaluated prior to LT, considering their functional status, renal function, and cardiovascular risk. Further studies are needed to optimize outcomes in this growing population of transplant candidates.

Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.

BACKGROUND & AIMS: With the rising prevalence of alcoholism, obesity and metabolic syndrome, steatohepatitis will become the leading cause of end-stage liver disease and hepatocellular carcinoma in the United States by 2025. Patients with non-alcoholic steatohepatitis and alcoholic liver disease have similar clinical and histopathological presentations, whether these similarities persist in non-alcoholic steatohepatitis and alcoholic liver disease patients with hepatocellular carcinoma remains unknown. METHODS: A retrospective analysis of the clinical features of adult patients from a large transplant center who underwent liver transplantation for steatohepatitis due to non-alcoholic steatohepatitis and alcoholic causes (alcoholic liver disease) between 1/1/02 and 1/1/12 was performed. Clinical features, explant histopathology, and clinical outcomes were compared. RESULTS: Hepatocellular carcinoma was present in 80 of 317 patients, who underwent liver transplantation for steatohepatitis with equivalent distribution in non-alcoholic steatohepatitis and alcoholic liver disease patients (24% vs 26%; P = 0.8). On multivariate analysis, significant predictors of hepatocellular carcinoma included age, ethnicity (Hispanic), and diabetes, but not BMI, hypertension or smoking. A lower risk of hepatocellular carcinoma was associated with a clinical history of hyperlipidemia. Clinical parameters were similar between patients with alcoholic liver disease - hepatocellular carcinoma and non-alcoholic steatohepatitis-hepatocellular carcinoma, except sex and presence of metabolic syndrome. non-alcoholic steatohepatitis-hepatocellular carcinoma livers retained histopathological features of non-alcoholic steatohepatitis such as ballooning and Mallory bodies, while alcoholic liver disease-hepatocellular carcinoma livers did not. There were no significant differences in hepatocellular carcinoma recurrence rates or post-transplant overall survival. CONCLUSIONS: We report the largest single-center study evaluating clinical, histopathological and outcome measures of patients undergoing liver transplantation for steatohepatitis. Older patients, diabetics, and Hispanics may warrant more frequent cancer screening due to increased risk of hepatocellular carcinoma.

Both α-1-antitrypsin Z phenotypes and low caeruloplasmin levels are over-represented in alcohol and nonalcoholic fatty liver disease cirrhotic patients undergoing liver transplant in Ireland.

OBJECTIVES: Alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) are steatotic liver diseases and major causes of cirrhosis. Only a minority of patients with risk factors develop cirrhosis and genetic cofactors may be important in pathogenesis. Mutations in the Wilson's and α-1-antitrypsin genes are not uncommon and we speculated that they may act as cofactors. METHODS: We investigated α-1-antitrypsin phenotyes and caeruloplasmin levels in patients undergoing elective liver transplantation. We compared patients with alcohol and NAFLD with nonsteatotic liver disease patients: viral hepatitis B or C, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. RESULTS: Two hundred and thirty-one patients were included in the study. Pretransplant caeruloplasmin levels and α-1-antitrypsin phenotypes were available in 197 and 112 patients, respectively. α-1-Antitrypsin Z phenotypes were significantly more common in the alcohol and NAFLD group: 12/56 versus 3/56 (P<0.05). Serum caeruloplasmin (0.3±0.01 vs. 0.39±0.01 g/l, P<0.01) and serum copper levels (13.5±0.9 vs. 19.3±0.9 µmol/l, P<0.01) were significantly lower in the alcohol and NAFLD patients compared with the viral and autoimmune patients. CONCLUSION: In this study, we found the α-1-antitrypsin Z phenotype was more common, and serum caeruloplasmin and copper levels were lower in patients with fatty liver diseases. We suggest that mutations in the α-1-antitrypsin and Wilson's genes may act as cofactors in the pathogenesis of fatty liver diseases.

Liver Transplantation for Alcoholic and Nonalcoholic Fatty Liver Disease: Pretransplant Selection and Posttransplant Management.

Alcoholic fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are common causes of chronic liver disease throughout the world. Although they have similar histologic features, a diagnosis of NAFLD requires the absence of significant alcohol use. ALD is seen commonly in patients with a long-standing history of excessive alcohol use, whereas NAFLD is encountered commonly in patients who have developed complications of obesity, such as insulin resistance, hypertension, and dyslipidemia. Lifestyle contributes to the development and progression of both diseases. Although alcohol abstinence can cause regression of ALD, and weight loss can cause regression of NAFLD, many patients with these diseases develop cirrhosis. ALD and NAFLD account for nearly 30% of liver transplants performed in the United States. Patients receiving liver transplants for ALD or NAFLD have similar survival times as patients receiving transplants for other liver disorders. Although ALD and NAFLD recur frequently after liver transplantation, graft loss from disease recurrence after transplantation is uncommon. Cardiovascular disease and de novo malignancy are leading causes of long-term mortality in liver transplant recipients with ALD or NAFLD.

Autoimmune hepatitis-primary biliary cirrhosis concurrent with biliary stricture after liver transplantation.

Although the development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults, autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome has rarely been seen in liver transplant recipients. Here, we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 years after LT. Standard autoimmune serological tests were positive for anti-nuclear and anti-mitochondrial antibodies, and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus. Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis, which confirmed the diagnosis of AIH-PBC overlap syndrome. We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome; a novel type of autoimmune overlap syndrome.

Suramin decreases injury and improves regeneration of ethanol-induced steatotic partial liver grafts.

Steatotic grafts are excluded for use in partial liver transplantation (LT) because of the increased risk of primary nonfunction. This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT. Rat livers were harvested after acute ethanol treatment (6 g/kg, intragastric administration), reduced in size to ≈ 1/3, and transplanted. Serum alanine aminotransferase (ALT) and total bilirubin levels as well as hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG). Suramin (5 mg/kg, i.p.) decreased ALT by ≈ 60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation. Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 hours, and the mitotic index increased to 7% in LPG but was only 0.2% in FPG, indicating suppressed regeneration in FPG. Suramin increased BrdU incorporation and the mitotic index to 43% and 9%, respectively, in FPG. All FPG recipients died within 5 days. Suramin recovered survival of FPG to 62%. Tumor necrosis factor-α (TNF-α) mRNA was 2.2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and caspase-3 in FPG. Suramin decreased TNF-α and caspase activation in FPG. Transforming growth factor-ß (TGF-ß), phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-ß formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNF-α and TGF-ß formation.

Infrahepatic terminolateral cavocavostomy: a case report.

Infrahepatic vena cavocavostomy has been reported to be a rescue therapy when venous outflow from a liver allograft is obstructed due to stenosis of a piggyback anastomosis. The authors have described herein two consecutive adult liver transplantations using this technique as the primary venous anastomosis. Using a caval clamp positioned above the retrohepatic portion, partial hemodynamic obstruction of caval flow was well tolerated, avoiding use of a venovenous bypass. Although additional studies regarding this technique are needed, we believe that an infrahepatic vena cavocavostomy should be considered to be an alternative technique in carefully selected cases.

Outcome after liver transplantation for NASH cirrhosis.

Nonalcoholic steatohepatitis (NASH) associated cirrhosis is an increasing indication for liver transplant (LT). The aim of this study was to determine outcome and poor predictive factors after LT for NASH cirrhosis. We analyzed patients undergoing LT from 1997 to 2008 at a single center. NASH was diagnosed on histopathology. LT recipients with hepatitis C, alcoholic or cholestatic liver disease and cryptogenic cirrhosis acted as matched controls. Ninety-eight LT recipients were identified with NASH cirrhosis. Compared to controls, NASH patients had a higher BMI (mean 32.3 kg/m2), and were more likely to be diabetic and hypertensive. Mortality after transplant was similar between NASH patients and controls but there was a tendency for higher earlier mortality in NASH patients (30-day mortality 6.1%, 1-year mortality 21.4%). Sepsis accounted for half of all deaths in NASH patients, significantly higher than controls. NASH patients > or =60 years, BMI > or =30 kg/m2 with diabetes and hypertension (HTN) had a 50% 1-year mortality. In conclusion, patients undergoing LT for NASH cirrhosis have a similar outcome to patients undergoing LT for other indications. The combination of older age, higher BMI, diabetes and HTN are associated with poor outcome after LT. Careful consideration is warranted before offering LT to these high-risk patients.

Micro- and macrovesicular steatotic liver model for transplantation induced by ethanol and protein-deficient diet.

Steatotic liver grafts are associated with a high incidence of primary nonfunction and initial poor function. Due to the increasing number of liver transplant candidates, centers are inclined to accept marginal donors more frequently. For a lack of a reliable fatty liver model, preservation concepts for fatty livers have hardly been evaluated. Moreover, there is an ongoing debate on the relevance and impact of micro- versus macrovesicular steatotic organs. We therefore intended to establish a steatotic liver model in pigs comprising both micro- and macrovesicular steatotic livers. Five groups of pigs received daily 1 to 6 g ethanol/kg body weight and/or a protein-deficient diet for up to 72 days. Liver biopsy was carried out at days 24, 48, and 72. With an increasing amount and duration of ethanol intake, higher levels of microvesicular steatosis were induced. Ethanol and protein deficient diet resulted in more than 60% microvesicular steatosis after 72 days. Exclusively protein-deficient diet without ethanol induced macrovesicular steatosis of more than 70% after 72 days. For the first time, we established a porcine model of hepatic steatosis that comprises both histologic types of fatty liver: micro- and macrovesicular steatosis induced by ethanol and a protein-deficient diet. We would like to conclude that our model is particularly qualified to study new concepts of preservation for steatotic livers to improve on the posttransplant outcome.

Role of free radicals in failure of fatty liver grafts caused by ethanol.

Alcohol is associated with accidental deaths and suicides leading to organ donation, and hepatic steatosis is an important risk factor for initial poor function and failure of human liver grafts. Mechanisms of fatty graft failure are not fully understood, but increased oxidative stress may be a major factor. To characterize the role of free radical stress and the efficacy of antioxidant treatments in fatty liver graft injury, donors for orthotopic rat liver transplantation were treated chronically (3 or more weeks) and acutely (single dose) with ethanol. After transplantation, necrosis and alanine aminotransferase release were threefold to fourfold higher in recipients of fatty grafts from donors treated with ethanol either acutely or chronically compared with findings for recipients of grafts from untreated donors. Moreover, graft survival decreased from nearly 100% to less than 20%. Free radical adducts, as measured by electron spin resonance spectroscopy, were detected in the blood and bile of rats receiving fatty grafts caused by ethanol. Markers of lipid peroxidation also increased after transplantation. Destruction of Kupffer cells with gadolinium chloride decreased free radical production and improved graft survival. Leukocyte adhesion increased beginning early after implantation, and adherent white blood cells obtained from transplanted fatty livers produced the same free radical species as were detected in blood. Therefore, Kupffer cells and adherent white blood cells are important sources of free radicals. Free radicals not only damage fatty grafts directly but also lead to enhanced inflammation and disturbed microcirculation. Delivery of superoxide dismutase-1 and superoxide dismutase-2 genes, free radical-scavenging polyphenols, and antioxidant-containing Carolina Rinse solution reduced injury and improved survival of fatty grafts caused by ethanol. Taken together, these findings indicate that free radicals increase in fatty grafts after transplantation and play an important role in injury of fatty grafts obtained from ethanol-exposed donors. Treatment of fatty donor livers with antioxidants and free radical scavengers may thus be an effective clinical therapy to prevent failure of fatty grafts.

Therapeutic potential of interleukin-6 in preventing obesity- and alcohol-associated fatty liver transplant failure.

Donor organ shortage significantly hinders orthotopic liver transplantation therapy, the only effective treatment for chronic end-stage liver disease and acute liver failure. Further complicating this matter is the prevalence of steatosis in 13% to 50% of donor livers obtained from obese and alcoholic individuals. When transplanted, these livers are associated with primary nonfunction and an elevated risk of dysfunction. New therapeutic approaches to render marginal fatty livers worthy for clinical transplantation are actively being sought. Study findings obtained from my group show that in vitro treatment with interleukin-6 (IL-6) dramatically reduces mortality, liver injury, and necrapoptosis in steatotic Zucker rat liver isografts. Findings of additional studies indicate that IL-6 induces hepatoprotection of steatotic liver isografts by preventing sinusoidal endothelial cell damage and, consequently, the amelioration of hepatic microcirculation, and by protecting against hepatocyte death, which is likely mediated through activation of signal transducer and activator of transcription 3/Bcl-x(L). Finally, in vitro IL-6 treatment also prevents mortality associated with alcoholic fatty liver transplants. Relative to the protective effect of IL-6 on steatotic Zucker rat liver, IL-6 is less effective in alcoholic fatty livers, which may be due to the inhibitory effects of ethanol on IL-6 activation of signal transducer and activator of transcription 3 in hepatocytes and sinusoidal endothelial cells. Collectively, these results support the assertion that in vitro IL-6 treatment of steatotic livers may render allografts usable for clinical transplantation, thereby decreasing the gap between the short supply of cadaver liver allografts and high demands for replacement livers. Higher concentrations of IL-6 may be required to protect against alcoholic fatty liver isograft injury because alcohol inhibits IL-6 signaling in the liver.

In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats.

BACKGROUND & AIMS: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. METHODS: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL-6)-treated steatotic isografts. RESULTS: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. CONCLUSIONS: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.