Clinical considerations in the management of non-alcoholic steatohepatitis cirrhosis pre-and post-transplant: A multi-system challenge

Non-alcoholic steatohepatitis(NASH) is the most common chronic liver disease worldwide, and the fastest growing indication for liver transplantation in the United States. NASH is now the leading etiology for liver transplantation in women, the second leading indication for men, and the most common cause amongst recipients aged 65 years and older. Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases, including obesity, type 2 diabetes(T2 D), and hypertension. These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality. Furthermore, these patients carry considerable risk of morbidity and mortality both before after liver transplantation, with high rates of T2 D, cardiovascular disease, chronic kidney disease, poor nutrition, and disease recurrence. Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure. Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation, control of diabetes, nutritional support, and even, potentially, consultation with a bariatric surgeon. This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.     

Metabolic syndrome and non‐alcoholic fatty liver disease after liver or kidney transplantation

Transplantation is a definitive treatment option for patients with end‐stage liver disease, and for some patients with acute liver failure, hepatocellular carcinoma or end‐stage renal disease. Long‐term post‐transplantation complications have become an important medical issue, and cardiovascular diseases (CVD) are now the leading cause of mortality in liver or kidney transplant recipients. The increased prevalence of metabolic syndrome (MS) likely plays a role in the high incidence of post‐transplantation CVD. MS and its hepatic manifestation, non‐alcoholic fatty liver disease (NAFLD), are prevalent among the general population and in pre‐ and post‐transplantation settings. MS components are associated with recurrent or de novo NAFLD in transplant recipients, potentially influencing post‐transplantation survival. Moreover, recent data reveal an important association between NAFLD and risk of incident of chronic kidney disease (CKD). Therefore, NAFLD identification could represent an additional clinical feature for improving the stratification of liver and kidney transplant recipients with regards to risks of CVD, CKD and renal allograft dysfunction. All MS components are potentially modifiable; therefore, it is crucial that hepatologists, nephrologists and primary care physicians become more engaged in managing post‐transplantation metabolic complications. The present review discusses the recent clinical evidence regarding the importance of MS and its components after liver and kidney transplantation, as well as the link between MS and NAFLD after liver and kidney transplantation.     

Ethnic and Racial Differences in the Natural History of Hepatitis C

Hepatitis C virus (HCV) infection is common in the United States and affects all ethnic groups. Important ethnic disparities exist in HCV severity, response to treatment, and progression after liver transplantation. Among patients with chronic HCV, African Americans tend to have less severe disease histologically, whereas Hispanics appear to have a more aggressive disease course compared with non-Hispanic Whites. In contrast, new data suggest that African Americans have more rapid HCV progression after liver transplantation relative to other ethnic groups. African Americans and Hispanics have lower sustained virologic response rates to pegylated interferon and ribavirin compared with non-Hispanic Whites. Awareness of these differences will help clinicians counsel diverse populations of patients on risk of progression, treatment outcome, and expectations after liver transplant. Future investigations of these differences should help in identifying mechanisms behind observed disparities and interventions to improve outcomes.     

原发性胆汁性胆管炎肝移植术后预后研究现状与挑战

原发性胆汁性胆管炎(PBC)是一种病因尚不明确的慢性胆汁淤积性肝病。熊去氧胆酸、奥贝胆酸等药物治疗不佳的患者最终发展为肝硬化,甚至肝衰竭。目前,肝移植是治疗PBC的唯一有效手段。主要阐述了PBC患者进行肝移植的概况、肝移植术后生存期、并发症、PBC复发以及肝移植治疗前景及挑战,为PBC移植术后的临床转归及治疗提供参考。     

Cardiovascular risk factors following orthotopic liver transplantation: predisposing factors,incidence and management

Background: Liver transplantation is the standard of care for acute and chronic causes of end‐stage liver disease. Advances in medical therapy and surgical techniques have led to improvement of patient and graft survival rates following orthotopic liver transplantation. However, the prevalence of post‐transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. Aims: To determine the incidences, risk factors, and treatment for hypertension, hyperlipidaemia, diabetes, and obesity in the post‐liver transplantation population. Methods: We performed a review of relevant studies available on the PubMed database that provided information on the incidence, risk factors and treatment for cardiovascular complications that develop in the post‐liver transplantation population. Results: Current immunosuppressive agents have improved patient and graft survival rates. However, long‐term exposure to these agents has been associated with development of systemic and metabolic complications including hypertension, hyperlipidaemia, diabetes mellitus and obesity. Cardiovascular disease remains one of the most common causes of death in liver transplant patients with functional grafts. Conclusions: Liver transplant recipients have a higher risk of cardiovascular complications compared with the nontransplant population. Post‐transplant cardiac risk stratification and aggressive treatment of cardiovascular complications, including modification of risk factors and tailoring of immunosuppressive regimen, is imperative to prevent serious complications.     

Long-term liver allograft fibrosis: A review with emphasis on idiopathic post-transplant hepatitis and chronic antibody mediated rejection

Liver transplantation (LT) is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease. With improvements in organ preservation techniques, perioperative care, and immunosuppression, there is better patient and graft survival following LT, and assessment of the liver allograft in long-term survivors is becoming increasingly important. Recurrent or de novo viral or autoimmune injury remains the most common causes of chronic hepatitis and fibrosis following liver transplantation in adults. However, no obvious cause can be identified in many adults with controlled recurrent disease and the majority of pediatric LT recipients, as they have been transplanted for non-recurrent liver diseases. Serial surveillance liver biopsies post LT have been evaluated in several adult and pediatric centers to identify long-term pathological changes. Pathological findings are frequently present in liver biopsies obtained after a year post LT. The significance of these findings is uncertain as many of these are seen in protocol liver biopsies from patients with clinically good allograft function and normal liver chemistry parameters. This narrative review summaries the factors predisposing to long-term liver allograft fibrosis, highlighting the putative role of idiopathic post-LT hepatitis and chronic antibody mediated rejection in its pathogenesis.     

肝移植后乙型肝炎病毒再感染的预防与治疗

目的；研究肝移植后再感染的预防和治疗。方法：19例患者包括慢性乙型重型肝炎，终末期肝硬化和肝硬化合并肝癌患者，移植前，后给予抗,乏昔洛韦4例，拉米夫定13例，拉米夫定＋乙型肝炎免疫球蛋白（HBIg) 2例，观察临床表现，血HBV M及肝活检免疫组织化学等指标。结果：应用乏昔洛韦治疗的4例患者全部再感染，血清HBsAg,HBeAg和HBV DNA均阳性，3例患者肝活检免疫组织化学表现有HBsAg ,HBcAg表达，随病程延长而增多。1例发生了典型病毒性肝炎发病。4例中3例死亡，拉米夫定的治疗组13例，经治疗后仅有7例HBsAg阳性，2例HBV DNA阳性，4例肝组织免疫组织化学有HBsAg或HBcAg表达，治疗中1例有肝炎复发。拉米夫定＋HBIg治疗2例患者1例血清抗－HBc阳性，另1例HBV M均阴性。免疫组织化学检测亦未见阳性结果。结论：HBV感染相关疾病终末期肝病应作为肝移植的适应证，肝移植后抗病毒治疗可预防再感染，改善再感染者的预后。     

Disorders of respiration in patients before and after liver transplantation

In 61 patients with chronic hepatic insufficiency parameters of regulation of ventilation, mechanics of breathing and gas exchange were determined pre and in 16 patients post liver transplantation. Preoperatively disturbances of control with increased central respiratory drive resulting in chronic hyperventilation and maladaptation of perfusion to ventilation were found. Successful liver transplantation resulted in regression of these disturbances to different degrees. We therefore conclude that disturbances of respiration in patients with chronic hepatic insufficiency are reversible after successful liver transplantation.     

Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation

This report describes a patient with marked hypoxemia caused by intrapulmonary shunt associated with primary biliary cirrhosis. Liver transplantation resulted in resolution of digital clubbing and reduction of intrapulmonary shunt as demonstrated by normalization of room air arterial blood gases, reduction in shunt fraction and normalization of the indocyanine-enhanced echocardiogram and perfusion lung scan. This patient's course challenges the conventional notion that intrapulmonary shunting associated with chronic liver disease does not reverse after liver transplantation.     

Management of the liver transplant patient

Liver transplantation is currently the definitive treatment of end-stage liver disease. This article reviews the complex multidisciplinary care of the liver transplant recipient beginning immediately after transplantation but extending into the long term. The presentation, evaluation and treatment of common post-transplant complications are outlined. Importantly, immunosuppression strategies along with the issues of acute and chronic rejection are discussed in detail with an emphasis on how practice has evolved over time. The spectrum of infectious problems is systematically presented, based on the time since transplantation and the institution of immunosuppression. Finally, the substantial challenges of recurrent disease and long-term medical comorbidities are addressed as these are clearly the primary issues that threaten the longevity and wellbeing of the liver transplant recipient.     

Assessment of adult patients with chronic liver failure for liver transplantation in 2015: who and when?

In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post‐liver transplant is excellent, with 1‐year survival rate >90% and 5‐year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child‐Turcotte Pugh score ≥9 or a model for end‐stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1‐year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra‐hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non‐alcoholic fatty liver disease‐associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future.     

Quantifying changes in innate immune function following liver transplantation for chronic liver disease

BackgroundLiver transplantation (LT) offers patients with cirrhosis long-term survival, however many die from sepsis whilst awaiting LT. The liver's role in innate immunity may be key to improving outcomes, but the immune effects of LT have not been quantified.MethodsInnate immune capacity was assessed by clearance of ^99mTc-Albumin nanospheres in patients with chronic liver failure before and after LT.ResultsTwenty-eight patients with chronic liver disease on the LT waiting list entered the study during the twelve-month study period and nine patients underwent LT and completed the study protocol. One patient developed hepatic artery thrombosis in <7 days and was excluded from the study. Innate immune function was significantly impaired in patients with chronic liver disease on the LT waiting list and this was directly correlated with MELD score. LT normalised innate immune function by day 1 post LT with further improvement occurring by day 7 post LT. Donor liver weight was the only factor correlated with innate immune function at day 1 post LT but this effect was negated by day 7 post LT.ConclusionRecognising the immune effects of LT may facilitate treatment of cirrhosis and inform development of extracorporeal liver support systems.     

HCV In At Risk Populations: Who Can be Treated and How?

Hepatitis C virus (HCV), a major cause of chronic liver disease, affects an estimated 5 million people in the Unites States [1] and close to 170 million people worldwide. Certain subpopulations including injection drug users, prison inmates, the homeless, ethnic minorities, American veterans, and HIV co-infected patients are considered high risk for viral acquisition and are disproportionately affected by HCV. This review describes the prevalence of HCV in these at-risk populations including those with cirrhosis, chronic kidney disease (CKD), solid organ transplantation and presents current treatment options.     

Gastroenterologic findings in graft versus host disease after allogenic bone marrow transplantation

We are reporting on a 25 years old patient with acute myelogenous leukemia, who developed an acute graft-versus-host disease (GVHD) 43 days after allogeneic bone marrow transplantation (BMT). The clinical symptoms included exanthema, diarrhea and abdominal cramps. The patient was treated with cyclosporine A and prednisone and the clinical symptoms disappeared subsequently. At day 225 post BMT the patient became icteric as the clinical manifestation of chronic GVHD. We describe in this case report endoscopical and histological findings during the episodes of acute and chronic graft-versus-host disease. The results obtained by sigmoidoscopy and liver biopsy confirmed the clinical diagnosis. The clinical work up of patients with acute or/and chronic GVHD should also include sigmoidoscopy in order to verify this transplantation related complication.     

Non-alcoholic fatty liver disease and liver transplantation:Outcomes and advances

Non-alcoholic fatty liver disease(NAFLD)is one of the most prevalent causes of chronic liver disease worldwide.In the last decade it has become the third most common indication for liver transplantation in the United States.Increasing prevalence of NAFLD in the general population also poses a risk to organ donation,as allograft steatosis can be associated with non-function of the graft.Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease,although long term outcomes beyond 10 year are lacking.NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted.De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease.Predictors for NAFLD post-transplant recurrence include obesity,hyperlipidemia and diabetes as well as steroid dose after liver transplantation.A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk.Although immunosuppression side effects potentiate obesity and the metabolic syndrome,studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population.Based on pre-transplant data,sustained weight loss through diet and exercise is the most effective therapy for NAFLD.Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents.Studies of these therapies are lacking in the post-transplant population.A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD.     

Liver transplantation in Wilson’s disease: Single center experience from Saudi Arabia

AIM: To determine liver transplantation outcomes in Wilson’s disease (WD) patients, focusing on neurological manifestations.METHODS: This retrospective study assessed data from 16 WD patients (nine males, 56%) who had liver transplants between 1991 and 2007. Survival, graft function, and neurological complications were assessed during a follow-up period of up to 15 years. In addition, each patient’s medical record was reviewed in detail to find the type of Wilson’s disease (hepatic or hepatic plus neurological WD), indication for liver transplantation, use of chelating agents prior to transplantation, immediate and long term complications following transplantation, the donor details, and the pathology of explanted liver.RESULTS: End-stage liver disease was the indication for transplantation in all 16 WD patients. Four patients displayed WD-related neurological symptoms in addition to liver disease. Living-related liver transplantation was done in three cases. One patient died on postoperative day 6 due to primary graft non-function. One-year post liver transplant survival was 94%. Neurological manifestations of all four patients disappeared during their follow-up. Four patients developed acute cellular rejection, but all responded to treatment. One patient developed chronic ductopenic rejection after 15 years post-transplantation and their graft failed; this patient is currently waiting for re-transplantation. Fourteen patients (88%) are still living. The long-term average survival is currently 10.5 years, with a current median survival of 8 years. Long-term graft survival is currently 81%.CONCLUSION: Short- and long-term survival in WD patient liver transplantation was excellent, and neurological and psychological WD manifestations disappeared during long-term follow-up.     

Liver transplantation for viral hepatitis in 2015

Liver transplantation(LT) is a life-saving treatment forpatients with end-stage liver disease and for patients with liver cell cancer related to liver disease. Acute and chronic liver diseases related to hepatitis viruses are between the main indications for liver transplantation. The risk of viral reinfection after transplantation is the main limiting factor in these indications. Before the availability of antiviral prophylaxis, hepatitis B virus(HBV) recurrence was universal in patients who were HBV DNA-positive before transplantation. The natural history of recurrent HBV was accelerated by immunosuppression, and it progressed rapidly to graft failure and death. Introduction of post-transplant prophylaxis with immunoglobulin alone first, and associated to antiviral drugs later, drastically reduced HBV recurrence, resulting in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Overall, patient and graft survival after LT for hepatitis C virus(HCV)-associated cirrhosis is inferior compared with other indications. However, successful pretransplant or post transplant antiviral therapy has been associated with increased graft and overall survival. Until recently, the combination of pegylated interferon and ribavirin was the standard of care for the treatment of patients with chronic hepatitis C. Highly active antiviral compounds have been developed over the past decade, thanks to new in vitro systems to study HCV entry, replication, assembly, and release.     

Primary sclerosing cholangitis is a premalignant condition

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown aetiology. The course of the disease is usually progressive with the development of liver cirrhosis leading to death or liver transplantation within an average of 12 years. To date it is well known that the development of hepatobiliary malignancies and the rate of colonic mucosal dysplasia and carcinoma in patients with concomitant ulcerative colitis are greatly enhanced in patients with PSC. PSC can therefore be regarded as a premalignant condition. The following review will focus on the development of cholangiocellular carcinoma in patients with PSC and the associated diagnostic and therapeutic challenges.     

Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation

OBJECTIVES: Thrombopoietin (TPO), the key regulator of platelet production, is mainly produced by the liver and reduced expression of TPO could cause thrombocytopenia in liver cirrhosis. Reversal of thrombocytopenia by orthotopic liver transplantation seems to be mediated through an increase in TPO plasma levels after transplantation, but other cytokines with thrombopoietic activity could augment the actions of TPO on post transplant platelet recovery. DESIGN: Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. METHODS: TPO, interleukin-3 (IL-3), IL-6, and IL-11 plasma levels as well as peripheral platelet count were analysed in thrombocytopenic patients with liver disease undergoing orthotopic liver transplantation (17 patients) and followed for 14 days after the intervention. RESULTS: Before liver transplantation, TPO plasma levels were undetectable and IL-3, IL-6, and IL-11 levels were normal. Sixteen out of 17 patients showed a significant rise of TPO levels within 2 days after transplantation, with a peak between days 4 and 6, while IL-3 and IL-6 levels did not show a significant rise. IL-11 levels remained normal. Platelet counts were significantly higher than pretransplantation levels by day 14 post transplantation. CONCLUSION: Restitution of normal TPO production by liver replacement seems to be of key importance for reversal of thrombocytopenia in liver disease. The early acting thrombopoietic factor IL-3 and the late acting factors IL-6 and IL-11 do not play a major role for recovery of peripheral platelet count after orthotopic liver transplantation.     

Normalization of menstrual cycles and pregnancy after liver transplantation

The objective of the present study is to evaluate the effects of successful liver transplantation on menstrual cycles abnormalities and on reproductive function of women with chronic liver disease. Twelve women with age between 17 and 54 years who underwent liver transplantation were evaluated. The following variables were analyzed: age, etiology of chronic liver disease, pattern of menstrual function and period of amenorrhea before and after transplantation, and occurrence of pregnancy after transplantation. The mean age of patients was 36 +/- 12.6 years. Patients with primary biliary cirrhosis did not have menstrual abnormalities before transplantation. The other patients presented amenorrhea for 3 months to 11 years before the transplantation. Rapid recovery of menstrual function was observed in all patients after the transplantation (3.1 +/- 1.2 months). Two patients became pregnant one and three years after the transplantation. It is concluded from this study that most women who present amenorrhea secondary to chronic liver disease have normal menstrual cycles in approximately three months following liver transplantation and they may become pregnant.