INTRODUCTION

The global obesity epidemic has dramatically increased the prevalence of NAFLD and made it the leading cause of chronic liver disease in Western nations. NAFLD is considered the hepatic manifestation of the metabolic syndrome and shares a strong association with type 2 diabetes mellitus, obstructive sleep apnea (OSA), and cardiovascular disease. Although cardiovascular disease is the leading cause of death in patients with NAFLD, the subset of patients who meet histopathologic criteria for NASH are those at greatest risk of liver-related morbidity and mortality. Ludwig and colleagues coined the term NASH in 1980 to describe a cohort of middle-aged patients with elevated serum liver enzyme levels who had evidence of alcohol-associated hepatitis on biopsy specimens in the absence of alcohol consumption. Subsequent study led to the proposed “2-hit” hypothesis in which a sequential progression from isolated fatty liver (IFL) to NASH involved the initial “hit” of hepatic steatosis followed by a second “hit” of oxidative stress resulting in liver injury. It was subsequently recognized that patients who have steatohepatitis on a liver biopsy specimen are at greatest risk for progression to cirrhosis compared with those who have IFL. Correspondingly, our understanding of the pathogenesis of NAFLD has evolved from the 2-hit hypothesis. NASH is expected to become the most common cause of cirrhosis and the leading indication for LT in the USA in the 2020s. As a major public health concern, an understanding of its epidemiology and pathogenesis is paramount to facilitate our ability to effectively diagnose and treat patients with NAFLD and NASH.

EPIDEMIOLOGY

NAFLD is an increasingly frequent cause of cirrhosis and HCC. In fact, a report published in 2018 listed NAFLD as the second leading non-neoplastic indication for LT in adults in the USA, following alcohol-associated liver disease. Obesity (BMI ≥30 kg/m2) and type 2 diabetes mellitus are commonly encountered in patients with NAFLD; these 2 diseases have been recognized as risk factors for HCC, irrespective of the presence or etiology of cirrhosis. Although BMI is not necessarily a reliable indicator of adiposity in patients with end-stage liver disease, particularly in those with fluid retention and ascites, it is commonly used by many LT centers during the patient selection process. Morbid obesity (BMI ≥40 kg/m2 without significant obesity-related comorbidities or BMI ≥35 kg/m2 associated with obesity-related comorbidities) is commonly regarded as a relative contraindication to LT; however, data from the Organ Procurement and Transplantation Network demonstrate that 16.5% and 5% of patients who underwent LT in 2016 had a BMI greater than or equal to 35 kg/m2 and greater than or equal to 40 kg/m2, respectively.

NAFLD and Liver Transplantation

Analysis of data from the UNOS registry has suggested that the risk of primary graft nonfunction is increased and short- and long-term survival is poorer in morbidly obese liver transplant recipients with various causes of end-stage liver disease. However, when analyzed as an entire cohort and not stratified by BMI, patients with NAFLD have patient and graft survival rates that are comparable to those for other indications for LT. Many of the key precipitants of NAFLD (obesity, hyperlipidemia, and insulin resistance) are exacerbated by immunosuppression. Recurrence of NAFLD after LT causes graft injury, although graft loss does not typically occur. De novo NAFLD after LT has also been described. In the absence of specific therapy for NAFLD, therapeutic efforts after LT should center on weight control, optimal diabetic management, and use of a lipid-lowering agent, if indicated. Intensive noninvasive weight loss interventions pre-LT appear to be successful (reduction of BMI to <35 kg/m2) in a large proportion of patients (84%) enrolled in carefully monitored multidisciplinary protocols; however, 60% of patients regained weight to a BMI ≥35 kg/m2 post-LT. Although bariatric surgery is feasible in selected patients with NAFLD, this intervention is typically reserved for patients with early stages of liver disease and, as is the case for many other abdominal surgical procedures, is contraindicated in those with decompensated cirrhosis because of high morbidity and mortality. A strategy of combining LT with sleeve gastrectomy during the same operation has only been evaluated in small prospective series. The mean surgical time was not significantly different between LT and combined LT/sleeve gastrectomy, and the mean BMI reduction with the combined surgical approach was 20 kg/m2. Metabolic complications, such as post-transplant diabetes mellitus, as well as steatosis of the graft noted by US were significantly less frequent in patients undergoing LT/sleeve gastrectomy compared with patients who lost weight noninvasively pre-LT. The safety and efficacy of this combined surgical approach and other combinations of less invasive weight loss interventions, such as endoscopic techniques, pre-LT must be confirmed by large prospective studies before they can be recommended. Bariatric interventions are still an option post-LT; however, the procedure should be performed by an experienced surgeon, and the role of less invasive endoscopic techniques postLT is still under investigation.

Sleeve Gastrectomy vs NAFLD

Bariatric surgery leads to substantial weight loss that results in improved metabolic parameters and hepatic histology in patients with NAFLD, according to numerous large retrospective and prospective cohort studies. In one study of 109 patients with NASH who underwent follow-up liver biopsy one year after bariatric surgery, 85% of patients had resolution of NASH, and 33% had improvement in fibrosis. Initial concerns that fibrosis would worsen with rapid weight loss were unfounded, as demonstrated in a meta-analysis in which fibrosis improved by 11.9% from baseline after bariatric surgery. Although bariatric surgery is not recommended as a treatment for NASH, the abundant positive data in its favor suggest that surgical weight loss is a viable option for patients with comorbid conditions that would warrant the surgery for other reasons. Patients with NASH cirrhosis are at potentially higher risk for surgical complications, although some centers have demonstrated encouraging results with sleeve gastrectomy in patients with Child-Pugh class A cirrhosis.