Nonalcoholic Fatty Liver Disease after Liver Transplant

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the world. The rising prevalence of nonalcoholic steatohepatitis (NASH) has led to a 170% increase in NASH cirrhosis as the listing indication for liver transplantation from 2004 to 2013. As of 2018, NASH has overtaken hepatitis C as an indication for liver transplantation in the USA. After liver transplantation, the allograft often develops recurrent NAFLD among patients with known NASH cirrhosis. In addition to recurrent disease, de novo NAFLD has been reported in patients with other indications for liver transplantation. In this review, we will discuss the risk factors associated with recurrent and de novo NAFLD, natural course of the disease, and management strategies after liver transplantation.     

Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) with its progressive form nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in western countries which is associated with end-stage liver disease and hepatocellular carcinoma (HCC). This entity is a consistently increasing indication for transplantation. However, data about postsurgery outcome and complications are still limited. Patients and Methods: Records of 432 consecutive transplanted patients between October 2007 and January 2011 were investigated retrospectively. Forty transplants were performed due to NASH-induced cirrhosis. Perioperative courses and short- and long-term outcomes were analyzed. Results: The NAFLD population consisted of 16 women and 24 men with a mean age of 55 years. The median MELD score was 27 at the time of liver transplantion. BMI before surgery ranged from 21 to 45 (mean 31). Sixteen of the initial 40 patients are still alive. Patients with sustained obesity and features of the metabolic syndrome had a worse 1-year mortality rate of 42%. Conclusions: A significant number of liver transplantations in our center was performed due to NASH; transplantation in this cohort was associated with high mortality and postoperative complications, most likely due to associated obesity and diabetes. Weight reduction prior to surgery may lead to a better outcome.     

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.     

Nonalcoholic fatty liver disease should be considered for treatment allocation in standard management algorithms for type 2 diabetes

Background and aimsType 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) often exist together. This is a high-risk population, as presence of T2D promotes the progression of NAFLD to more severe liver pathologies. There are several international guidelines for managing T2D, however guidance for management of NAFLD in individuals with T2D is scarce. In India, there is hardly any screening programme for identification of high-risk NAFLD individuals.MethodsA literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till October 2020, using relevant keywords (nonalcoholic fatty liver disease; NAFLD; nonalcoholic steatohepatitis; NASH screening and management; metabolic associated fatty liver disease) to extract relevant studies describing screening and management strategies of NAFLD/NASH, especially in patients with T2D.ResultsAn estimated 12.4 million Indian people are living with coexisting T2D and NAFLD-related advanced liver fibrosis, which is a major determinant of liver-related mortality in these individuals. Several studies have reported screening tools for identification of high risk NAFLD patients with coexisting T2D. The emphasis has been laid on the identification of advanced liver fibrosis and cirrhosis, using noninvasive tests at the primary level. For management, lifestyle measures and appropriate glucose-lowering medication have been proposed that help patients with coexisting T2D and NAFLD. Timely referral to specialists is also critical for preventing complications of cirrhosis.ConclusionsWhile current management algorithms for T2D include atherosclerotic cardiovascular disease, kidney dysfunction and obesity as co-morbidities to direct appropriate therapies, NAFLD should be considered as additional pathway to select appropriate treatment.     

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.     

Novel antidiabetic medications for non‐alcoholic fatty liver disease with type 2 diabetes mellitus

Liver‐related diseases are the leading causes of death in patients with type 2 diabetes mellitus (T2DM) in Japan. Type 2 diabetes mellitus is closely associated with non‐alcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Non‐alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma and hepatic failure. Non‐alcoholic steatohepatitis can be called “diabetic hepatopathy”. There are no established pharmacotherapies for NAFLD/NASH patients with T2DM. Although metformin is established as the first‐line therapy for T2DM, given its relative safety and beneficial effects on glycosylated hemoglobin, weight, and cardiovascular mortality, this agent is not recommended as specific therapy for NASH/NAFLD due to lack of clinical evidence. The effects of pioglitazone on NASH histology with T2DM have been extensively proved, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. In recent years, novel antidiabetic medications have been approved for T2DM, such as glucagon‐like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium/glucose cotransporter 2 inhibitors. A key clinical question for hepatologists is what kinds of antidiabetic medications are the most appropriate for the treatment of NAFLD accompanied by T2DM, to prevent progression of hepatic fibrosis resulting in HCC/liver‐related mortality without increased risk of cardiovascular events. This review focuses on novel antidiabetic agents and future perspectives on the treatment of NAFLD/NASH with T2DM.     

Bariatric surgery in patients with non-alcoholic fatty liver disease-from pathophysiology to clinical effects

Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.     

Nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2-4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.     

Cytokeratin-18 fragments and biomarkers of the metabolic syndrome in nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease （NAFLD） remains a leading cause of chronic liver disease. In the context of NAFLD, the presence of nonalcoholic steatohepatitis （NASH） portends an adverse prognosis with greater risk of liver fibrosis and cirrhosis. Although liver biopsy is the keystone of patient management in NAFLD, it is also increasingly clear that such evaluation has its limitations. The availability of biochemical markers of NAFLD and NASH has tremendous potential to radically alter management strategies for these conditions, as well as to monitor disease activity. Our article provides an overview of biomarker discovery and selection in the setting of NAFLD and highlights future directions in the field.     

The use of statins alone,or in combination with pioglitazone and other drugs,for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement

Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (> 5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without.The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD.Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients.     

Management of nonalcoholic steatohepatitis: an evidence-based approach

Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are an increasingly common cause of chronic liver disease in the developed world, with NASH projected to be the leading cause of liver transplantation in the United States by 2020. This review of NASH management addresses current data from the perspective of levels of evidence for therapeutic options in NASH, including lifestyle modification, drug therapies, and bariatric surgery. In particular, behavioral therapies to assist patients in adopting lifestyle changes are highlighted and a research agenda for future NASH management is presented.     

Role of diabetologists in the management of nonalcoholic fatty liver disease: Primary prevention and screening/management of fibrosis and cirrhosis

Background and aimsNonalcoholic fatty liver disease (NAFLD) is a common condition, especially among individuals with type 2 diabetes (T2D). Presence of T2D increases the risk of progression of simple steatosis to more severe liver conditions, such as nonalcoholic steatohepatitis (NASH) and fibrosis (NASH-fibrosis). Since majority of patients with T2D are managed by diabetologists (including physicians and endocrinologists), their roles in the management of coexisting NAFLD are not well defined, partly due to lack of unambiguous guidelines.MethodsA literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till January 2022, using relevant keywords (nonalcoholic fatty liver disease and diabetologist; screening of NASH; management of NASH) to extract relevant studies describing prevention and screening of NAFLD/NASH, especially in people with T2D.ResultsDiabetologists have two main roles for the management of patients with T2D and coexisting NAFLD. The most important role is to prevent the development of NASH-fibrosis in patients with simple steatosis (primary prevention). This can be achieved by reinforcing the importance of lifestyle measures, and by early use of glucose-lowering agents with beneficial effects on the liver. The second important role of diabetologists is to screen all patients with T2D for liver fibrosis and compensated cirrhosis, and provide appropriate referral for timely management of complications (secondary prevention).ConclusionDiabetologists can play a central role in mitigating the epidemic of NAFLD in individuals with T2D. However, diabetologists need to be aware about their roles in NASH-fibrosis prevention and screening. Furthermore, longitudinal studies should explore the role of newer glucose-lowering drugs in the primary prevention of NASH-fibrosis in individuals with coexisting T2D and simple steatosis.     

Hepatic Steatosis and Steatohepatitis: Are they Really Two Distinct Entities?

Non-alcoholic fatty liver disease affects nearly 30 % of Americans. A histopathological spectrum exists from simple steatosis to NASH which may progress to cirrhosis and HCC. NASH is currently the third most common indication for liver transplant with increasing incidence. Steatosis can be considered the hepatic manifestation of the metabolic syndrome as insulin resistance is a major risk factor for its development. While liver biopsy is the gold standard for diagnosis, non-invasive methods are currently being developed to appropriately determine who needs histologic evaluation. Management focuses on mitigation of risk factors, since targeted therapies to halt progression of fibrosis have not been validated. Simple steatosis does not affect overall survival, but NASH conveys increased mortality. Because of this, non-invasive strategies to diagnose patients and management algorithms are needed. This review supports the definitions of simple steatosis and NASH as two distinct entities based on pathophysiology, diagnosis, management, and prognosis.     

Nonalcoholic fatty liver disease and liver transplantation - Where do we stand?

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation(LT), on patients on the waiting list for transplant, on posttransplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome(Met S) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of Met S and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population.     

Nonalcoholic steatohepatitis

NASH is an important form of chronic liver disease that is increasingly recognized. The diagnosis is secured by biopsy findings with similarities to alcoholic hepatitis in a patient with a confirmed history of abstinence. Obesity is a major risk factor, but the disease also occurs in the nonobese. In 20% to 40% of patients the disease can progress to various stages of fibrosis and ultimately cause cirrhosis and death from end-stage liver disease. For this reason, recognition of NASH is important, and establishing the diagnosis provides a further impetus for performing a liver biopsy as part of the evaluation of unexplained liver abnormalities. The mainstay of treatment is weight reduction in the obese. For those individuals who are not obese, continued observation is the only option currently available. Patients who develop decompensated cirrhosis should be considered for liver transplantation unless advanced age or other underlying medical illnesses are a problem. With the increasing knowledge about the pathophysiology of hepatic steatosis, it is hoped that better diagnostic tests for specific causes of NASH will be available and lead to efficacious therapy.     

NASH – eine ungelöste therapeutische Herausforderung

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are closely associated with the metabolic syndrome and are regarded as very important conditions leading to chronic liver disease in western countries. Considering the constantly increasing incidence in obesity and type 2 diabetes mellitus, new therapeutic concepts especially in the treatment of NASH are urgently needed. Patients with NASH lacking characteristic features of the metabolic syndrome are particularly challenging in this context. In this review an overview of currently available data is provided that should be considered in the care of patients with NASH.     

Current and future perspectives on acute-on-chronic liver failure: Challenges of transplantation,machine perfusion,and beyond

Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in patients with chronic liver disease and is characterized by acute decompensation, organ failure and high short-term mortality. Partially due to the lack of universal diagnostic criteria, the actual ACLF prevalence remains unclear; nevertheless, it is expected to be a highly prevalent condition worldwide. Earlier transplantation is an effective protective measure for selected ACLF patients. Besides liver trans-plantation, diagnosing and treating precipitant events and providing supportive treatment for organ failures are currently the cornerstone of ACLF therapy. Although new clinical specific therapies have been researched, more studies are necessary to assess safety and efficacy. Therefore, future ACLF management strategies must consider measures to improve access to liver transplantation because the time window for this life-saving therapy is frequently narrow. Thus, an urgent and global discussion about allocation and prioritization for transplantation in critically ill ACLF patients is needed because there is evidence suggesting that the current model may not portray their waitlist mortality. In addition, while donor organ quality is meant to be a prognostic factor in the ACLF setting, recent evidence suggests that machine perfusion of the liver may be a safe tool to improve the donor organ pool and expedite liver transplantation in this scenario.     

Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist due to shared risk factors. Their rising prevalence parallels the growing epidemic of obesity and insulin resistance (IR). In patients with T2DM and biopsy-proven NAFLD, a significantly higher prevalence of nonalcoholic steatohepatitis (NASH) (63–87%), any fibrosis (22–60%), and advanced fibrosis (4–9%) is noted. Possible risk factors for more advanced liver disease include concomitant metabolic syndrome with three or more components, visceral obesity, older age, increased duration of diabetes, and family history of diabetes. Liver biopsy is strongly suggested in these patients. Cardiovascular disease (CVD) and malignancy are the leading causes of death in this population, but a growing body of evidence shows liver-related mortality as an important cause of death, including an increased rate of hepatocellular carcinoma (HCC) in diabetes. The presence of NAFLD in T2DM is also associated with increased overall mortality. We aim with this review to summarize the results from studies investigating NAFLD in T2DM and to outline the factors that predict more advanced liver histology as well as the impact of these hepatic changes on CVD, overall and liver-related mortality.