Metabolic complications in liver transplant recipients

The metabolic syndrome(MS), which includes obesity,dyslipidaemia, hypertension and hyperglycaemia according to the most widely accepted definitions now used, is one of the most common post-transplant complications, with a prevalence of 44%-58%. The MS, together with the immunosuppression, is considered the main risk factor for the development of cardiovascular disease(CVD) in transplant recipients, which in turn accounts for 19%-42% of all deaths unrelated to the graft. The presence of MS represents a relative risk for the development of CVD and death of 1.78. On the other hand, non-alcoholic fatty liver disease(NAFLD), considered as the manifestation of the MS in the liver, is now the second leading reason for liver transplantation in the United States after hepatitis C and alcohol. NAFLD has a high rate of recurrence in the liver graft and a direct relation with the worsening of other metabolic disorders, such as insulin resistance or diabetes mellitus. Consequently, it is vitally important to identify and treat as soon as possible such modifiable factors as hypertension, overweight, hyperlipidaemia or diabetes in transplanted patients to thus minimise the impact on patient survival. Additionally, steroid-free regimens are favoured, with minimal immunosuppression to limit the possible effects on the development of the MS.     

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.     

“Weighing the risk”: Obesity and outcomes following liver transplantation

Obesity is on the rise worldwide. As a result, unprecedented rates of patients are presenting with end stage liver disease in the setting of non-alcoholic fatty liver disease(NAFLD) and are requiring liver transplantation. There are significant concerns that the risk factors associated with obesity and the metabolic syndrome might have a detrimental effect on the long term outcomes following liver transplantation. In general, short term patient and graft outcomes for both obese and morbidly obese patients are comparable with that of non-obese patients, however, several studies report an increase in peri-operative morbidity and increased length of stay. Continued studies documenting the long-term outcomes from liver transplantation are needed to further examine the risk of recurrent disease(NAFLD) and also further define the role risk factors such cardiovascular disease might play long term. Effective weight reduction in the post liver transplant setting may mitigate the risks associated with the metabolic syndrome long-term.     

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.     

Liver transplantation for patients with alcoholic liver disease: An open question

End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase.In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.     

Colorectal cancer after orthotopic liver transplantation

There is an increased incidence of de novo malignancies in post-liver transplant patients, commonly associated with chronic viral infection comprising lymphoproliferative disease and skin cancers, including squamous cell carcinoma and Kaposi's sarcoma. The overall incidence of colorectal cancer however in this population seems to be no different to the age and sex matched general population. In identified high risk patients like those with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the incidence of colorectal cancer appears to be higher. In IBD, like other pre-malignant conditions, the risk of developing malignancy increases exponentially with time, raising the question of whether the apparent increase in the incidence of colorectal cancer is the result of liver transplantation and immunosuppression or due to the natural history of IBD. For these PSC recipients, pre-transplant screening with colonoscopy and post-transplant surveillance for malignant change in the large bowel is crucial. The behaviour of inflammatory bowel disease post-liver transplant is largely unpredictable despite immunosuppression. Colorectal cancer when it occurs in the post-liver transplant patient should be managed according to current guidelines, stage for stage as for the population in general coupled with reduction in immunosuppression treatment.     

Strategies to reduce hepatitis C virus recurrence after liver transplantation

Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not retransplanting this patients, as lower patient and graftoutcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pretransplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of posttransplant HCV recurrence and strategies to reduce its impact on our patients.     

肝移植术后新发非酒精性脂肪肝的危险因素

目的探究肝移植术后新发非酒精性脂肪肝(non-alcoholic fatty liver disease NAFLD)的危险因素。方法收集2015年5月至2019年5月于解放军总医院第五医学中心136例行肝移植患者的临床资料。比较移植术后新发NAFLD患者与无NAFLD患者的临床资料。应用logistic回归分析移植术后新发NAFLD的危险因素。结果肝移植术后1年时新发NAFLD的发病率为11.03%(15/136)。新发NAFLD患者与无NAFLD患者比较,术前BMI(27.85比23.17,P=0.003)、酒精性肝硬化(66.7%比23.1%,P=0.001)、术前高血压病史(33.3%比5.4%,P=0.016),肝移植术后1年时的ALT水平(24.0 U/L比21.5 U/L,P=0.012)差异有统计学意义。Logistic回归分析结果显示,术前酒精性肝硬化(OR=4.79,95%CI:1.35~16.98)、术前高BMI(OR=1.23,95%CI:1.05~1.46)是术后新发NAFLD的危险因素。结论肝移植术前酒精性肝硬化和高BMI是术后新发NAFLD的危险因素。     

Metabolic syndrome and liver transplantation

Non-alcoholic fatty liver disease (NAFLD), an important consequence of the global epidemic of obesity, is a common indication of orthotopic liver transplantation in the western world. Currently, NAFLD is the fourth most common indication of liver transplantation in the United Stated with prediction for increase demand of liver transplantation for NAFLD cirrhosis in the next two decades to exceed that of liver transplantation for chronic hepatitis C virus infection. Given the advances in the efficacy and tolerability of immunosuppressive agents which have reduced the incidence of chronic rejection, long-term survival rates after liver transplantation have remarkably improved. Today, long-term graft loss and death after liver transplantation are commonly related to age-related complications, such as cardiovascular disease. Features of metabolic syndrome including obesity, hypertension, hyperglycemia and dyslipidemia are very prevalent and almost universal after liver transplantation. These metabolic derangements are intricately associated with cardiovascular events and have emerged as the leading cause of morbidity and mortality after liver transplantation. In addition, the international epidemic of obesity has negatively impacted the liver transplant candidacy. Because obesity is associated with poor postoperative outcome, many transplant centers decline liver transplantation for morbidly obese individuals above certain level of body mass index.     

Patient selection for liver transplantation

Improved outcomes in liver transplant recipients reflect advances in surgical technique, post-operative care, immunosuppression as well as better selection of potential candidates. The pre-transplant evaluation is a multidisciplinary process intended to recognize and treat important comorbid conditions that may impair outcomes during the peri- and post-transplant periods. Important psychosocial issues should also be ascertained and tackled early during the pre-transplant evaluation with an overarching intention to improve the success of liver transplantation.     

Risk factors for accelerated atherosclerosis in renal transplant recipients

The factors responsible for atherosclerosis in renal transplant recipients are not known. In the present study, cardiovascular disease was investigated in 403 patients who received 464 kidney transplants during a 10-year period. Among those who had no clinical evidence of vascular disease at the time of transplantation, atherosclerotic complications developed in 15.8 percent during the post-transplant follow-up period (46.1 +/- 36.2 months). Pre- and post-transplant vascular diseases were closely linked. However, after taking pre-transplant vascular disease into account, multivariate analysis showed that a number of known risk factors (age, sex, diabetes, cigarette smoking, hypertension, and serum cholesterol) were independently associated with post-transplant vascular disease. In addition, the number of acute rejection episodes (all treated with high doses of corticosteroids) was also independently linked to vascular disease. These results suggest that an increased prevalence of known risk factors, and events linked to allograft rejection, explain the high incidence of cardiovascular disease in renal transplant recipients.     

Non-alcoholic fatty liver disease: The diagnosis and management

Non-alcoholic fatty liver disease(NAFLD) is now the most frequent chronic liver disease that occurs across all age groups and is recognized to occur in 14%-30% of the general population, representing a serious and growing clinical problem due to the growing prevalence of obesity and overweight. Histologically, it resembles alcoholic liver injury but occurs in patients who deny significant alcohol consumption. NAFLD encompasses a spectrum of conditions, ranging from benign hepatocellular steatosisto inflammatory nonalcoholic steatohepatitis, fibrosis, and cirrhosis. The majority of hepatocellular lipids are stored as triglycerides, but other lipid metabolites, such as free fatty acids, cholesterol, and phospholipids, may also be present and play a role in disease progression. NAFLD is associated with obesity and insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies; however, staging the disease requires a liver biopsy. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and medications appear promising. The aim of this review is to highlight the current information regarding epidemiology, diagnosis, and management of NAFLD as well as new information about pathogenesis, diagnosis and management of this disease.     

Modern approach to the clinical management of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D₃. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease.     

Liver transplantation and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is an important health problem worldwide. NAFLD encompasses a histological spectrum ranging from bland liver steatosis to severe steatohepatitis (nonalcoholic steatohepatitis, NASH) with the potential of progressing to cirrhosis and its associated morbidity and mortality. NAFLD is thought to be the hepatic manifestation of insulin resistance (or the metabolic syndrome); its prevalence is increasing worldwide in parallel with the obesity epidemic. In many developed countries, NAFLD is the most common cause of liver disease and NASH related cirrhosis is currently the third most common indication for liver transplantation. NASH related cirrhosis is anticipated to become the leading indication for liver transplantation within the next one or two decades. In this review, we discuss how liver transplantation is affected by NAFLD, specifically the following: (1) the increasing need for liver transplantation due to NASH; (2) the impact of the increasing prevalence of NAFLD in the general population on the quality of deceased and live donor livers available for transplantation; (3) the long term graft and patient outcomes after liver transplantation for NASH, and finally; and (4) the de novo occurrence of NAFLD/NASH after liver transplantation and its impact on graft and patient outcomes.     

Colorectal disease in liver allograft recipients -- a clinicopathological study with follow-up

OBJECTIVE : To determine the spectrum and outcome of colorectal diseases occurring in adult liver allograft recipients. DESIGN : A retrospective cohort analysis of clinical, microbiological and histopathological data regarding colorectal disease. PATIENTS : Forty three out of 302 adult primary liver allograft recipients were transplanted and followed up (at median 42 months) at a tertiary referral centre/teaching hospital. RESULTS : Out of 302 patients, 43 (14%) were investigated (by endoscopy and/or laparotomy) for symptoms of colorectal disease after orthotopic liver transplantation. The symptoms were: diarrhoea (n = 31); per-rectal bleeding (n = 5); and symptoms relating to pre-transplant ulcerative colitis (n = 7). Among the patients without known ulcerative colitis, per-rectal bleeding occurring early after orthotopic liver transplantation was most commonly caused by cytomegalovirus colitis and carried a poor prognosis. Excluding ulcerative colitis, the commonest causes of diarrhoea were Clostridium difficile, cytomegalovirus infection and medications, particularly during the first 2 months after orthotopic liver transplantation. No cases of colorectal graft-versus-host disease, cryptosporidiosis, amoebiasis, atypical mycobacterial infection or post-transplant lymphoproliferative disease were demonstrated. The activity of pre-transplant ulcerative colitis was unchanged or increased after orthotopic liver transplantation. Two further patients developed new-onset ulcerative colitis after orthotopic liver transplantation. CONCLUSIONS : Ulcerative colitis, C. difficile, cytomegalovirus infection and medications are the commonest colorectal causes of morbidity after orthotopic liver transplantation. Adult liver allograft recipients are, however, unlikely to show certain large bowel diseases encountered in other immunosuppressed groups. Amongst non-ulcerative colitis patients, those presenting with diarrhoea show a good outcome with appropriate management, whereas those with per-rectal bleeding have a more guarded prognosis.     

Nonalcoholic fatty liver disease： An overview of current insights in pathogenesis, diagnosis and treatment

Estimates of people suffering from overweight （one billion） and obesity （300 million） are increasing. The accumulation of triglycerides in the liver, in the absence of excess alcohol intake, has been described in the early sixties. It was not until 1980, however, that Ludwig et al named this condition nonalcoholic steatohepatitis （NASH）. Subsequently, nonalcoholic fatty liver disease （NAFLD） has been used as a general name for conditions ranging from simple steatosis through steatohepatitis to end-stage liver disease （cirrhosis）. Many studies have demonstrated the significant correlation with obesity and insulin resistance. Other studies have revealed a signifi- cant correlation between hepatic steatosis, cardiovascu- lar disease and increased intima-media thickness. WHO estimated that at least two million patients will develop cirrhosis due to hepatic steatosis in the years to come. Longitudinal cohort studies have demonstrated that those patients with cirrhosis have a similar risk to devel- op hepatocellular carcinoma as those with other causes of cirrhosis. Taken all together, NAFLD has become the third most important indication for liver transplantation. There- fore, training programmes in internal medicine, gastroen- terology and hepatology should stress the importance of diagnosing this entity and treat properly those at risk for developing complications of portal hypertension and con- comittant cardiovascular disease. This review will focus on the clinical characteristics, pathophysiology, imaging tech- niques and the readily available therapeutic options.     

Cardiovascular risk,atherosclerosis and metabolic syndrome after liver transplantation: a mini review

Liver transplantation is the standard of care for acute and chronic end-stage liver disease. Advances in medical therapy and surgical techniques have transformed the long-term survival of liver-transplant (LT) recipients. The prevalence of post-transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. Currently, deaths related to cardiovascular complications are one of the main causes of long-term mortality in LT recipients, as cardiovascular disease is the reason of 19–42% of non-liver-related mortality after transplant. On the other hand, metabolic syndrome is common among LT recipients before and after transplantation. In fact, their components (abdominal obesity, diabetes mellitus, hypertension and dyslipidemia) are often exacerbated by transplant-specific factors, such as immunosuppression, inappropriate diet, smoking and a sedentary lifestyle, and add a significant risk of developing atherosclerosis. These aspects are discussed in this article.     

Nonalcoholic Steatohepatitis and Liver Transplantation

The growing epidemic of obesity has led to an increase in the number of patients developing end-stage liver disease related to nonalcoholic steatohepatitis (NASH). In fact, NASH is now the second-leading etiology for liver transplantation in the USA. In this context, interest is growing in understanding the outcomes of liver transplantation in patients with NASH. Current data suggest that the short- and medium-term outcomes for NASH patients post-transplantation are not different from those for other recipients. Nevertheless, patients with NASH and diabetes may have higher risk post-transplantation for de novo diabetes. Caregivers must be vigilant post-transplant for the development of de novo diabetes regardless of their pre-transplant status. NASH patients also seem to have a lower functional status post-transplant. There are conflicting data regarding the outcome of morbidly obese patients with NASH who undergo liver transplantation. The pre-transplant management of these patients with surgical weight loss is reported, but caution must be exercised in considering them for transplant.     

Obesity and liver cancer

Obesity prevalence is rapidly increasing worldwide. It is associated with huge economic and health costs due to its clinical consequences, which includes increased incidence of type 2 diabetes, cardiovascular diseases, and development of different malignancies. In particular, obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC). Indeed, obesity is highly prevalent in patients with non-alcoholic fatty liver disease (NAFLD) that is becoming one of the most frequent causes of liver disease worldwide. NAFLD-related HCC is the most rapidly growing indication for liver transplantation in many countries. The higher mortality rates found in obese HCC patients might be related not only to a worse outcome after HCC treatments, but also to a delayed diagnosis related to a low frequency and a poorer quality of abdominal ultrasonography surveillance that is the test universally used for HCC screening. Given its diffusion, obesity is frequently present in patients with chronic liver diseases related to different etiologies, and in these cases it may increase the HCC risk, acting as an additional co-factor. Indeed, growing evidence demonstrates that a healthy diet and regular physical activity may have an impact in reducing the overall HCC risk. Finally, an impact of obesity in the development of intrahepatic cholangiocarcinoma has been postulated, but more extensive studies are needed to definitively confirm this association.     

Antimitochondrial antibody serocoversion post-liver transplant during hepatitis C treatment with peginterferon α, ribavirin and telaprevir

Pegylated interferon alpha (PEG-IFN α), a key component of chronic hepatitis C therapy, has been linked to the development of auto-antibodies and autoimmune disease. We report the first case of antimitochondrial antibody (AMA) seroconversion during PEG-INF α based therapy after liver.1., 2., 3.^–4 transplantation. A fiftyseven year-old man five months after liver transplantation was initiated on hepatitis C triple therapy with PEG-INF α, ribavirin and telaprevir. He had failed previous PEG-IFN α and ribavirin 12 years pre-transplant and his AMA remained negative pre-transplant. After twelve weeks of antiviral therapy, he developed elevated liver enzyme tests associated with an AMA seroconversion to seropositivity. A liver biopsy failed to show histological evidence of primary biliary cirrhosis or graft rejection. He was initiated on urseodeoxy-cholic acid with subsequent improvement of his liver enzymes. This case demonstrates that despite adequate immunosuppression, AMA seroconversion may occur post-transplant during interferon-based therapy. As AMA seroconversion did not occur during the pre-transplant PEG-IFN therapy, we speculate that donor allograft antigens in combination with PEG-IFN may have been a factor in the post-transplant seroconversion.