Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Transplantation for Nonalcoholic Steatohepatitis
Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease and as an Indication for Liver Transplantation
A recent cross-sectional study of patients in a large outpatient general medical clinic setting observed the prevalence of nonalcoholic fatty liver disease (NAFLD) to be 46%, with nonalcoholic steatohepatitis (NASH) observed in 12.2% of the total cohort, making NASH the most common liver disease in North America. The prevalence of advanced fibrosis due to NASH in the United States should thus be between 3 and 8 million cases. The precise frequency of liver disease related to NASH as a primary or secondary indication for liver transplantation is difficult to know because, unlike other indications such as hepatocellular carcinoma, there are no rigorous diagnostic criteria required for assigning NASH as an indication for liver transplantation. Based on data from the Scientific Registry of Transplant Recipients (SRTR) and the United Network for Organ Sharing (UNOS), NASH is the third most common indication for liver transplantation, after hepatitis C virus (HCV) and alcohol, with the proportion of transplants performed for NASH increasing from 1.2% in 2001 to 9.7% in 2009 ( Fig. 22-1 ). In the setting of a continuing increase in the prevalence and severity of obesity in North America and worldwide, combined with younger age of onset, the frequency of NASH as an indication for liver transplantation seems likely to increase further. These epidemiological trends for obesity and steatosis and NASH also have implications for donor livers. The prevalences of steatosis and NASH among living donors has been reported to range from 12% to 51% and 2% to 15%, respectively. Living donor grafts with steatosis have been reported to be at increased risk for ischemia reperfusion injury, possibly related to reduced hepatic microcirculation secondary to sinusoidal space compression by the ballooned fatty and inflamed hepatocytes or oxidative stress–induced susceptibility to hypoxia.
Clinical Features and diagnosis of Nash Cirrhosis
Most patients who are ultimately diagnosed with NASH are referred for evaluation of abnormal liver biochemistry values, often detected serendipitously. In contrast to the ratio seen in alcoholic liver disease, aminotransferase levels are typically four times the upper limit of normal or less, with alanine aminotransferase (ALT) usually greater than aspartate aminotransferase. Alkaline phosphatase level is usually normal or mildly elevated, twice normal or less, with bilirubin levels usually within the normal range. About one in six patients with NASH have normal liver biochemistry values.
Ascites can be difficult to detect clinically in patients with cirrhosis secondary to NASH in the context of a high body mass index (BMI), particularly when the fat distribution is truncal. An apron of adipose can preclude accurate examination of the abdominal cavity, and the presence of omental adipose can mimic ascites. A detailed history is essential in order to exclude, or otherwise, the presence of excessive alcohol consumption, steatohepatitis-inducing pharmacotherapy, surgical procedures, and occupational exposure to hepatotoxins. Of the clinical conditions that are associated with NASH that cannot be excluded by simple history taking, Wilson’s disease, viral hepatitis, and autoimmune liver disease require specific serological/biochemical exclusion. The great majority of patients with NAFLD will concomitantly have one or more features of the metabolic syndrome (increased waist circumference, hypertriglyceridemia, low level of high-density lipoprotein cholesterol, hypertension, and a fasting glucose level of 110 mg/dL or higher). A nutritional history, particularly of rapid weight gain or loss, is also important. Bariatric surgery in patients with unsuspected NASH cirrhosis can produce postoperative hepatic decompensation. The typical picture is of rapidly progressive cholestasis with encephalopathy. Post–bariatric surgery hepatic decompensation is probably secondary to the oxidative injury associated with the rapid and large mobilization of peripheral free fatty acids (FFAs) that inevitably occurs following bariatric surgery. Hyperalimentation is a cornerstone of treatment (to decrease mobilization of FFAs). The benefits of ursodeoxycholic acid and antioxidants such as betaine and N -acetylcysteine are unknown in this setting.
Because steatosis may resolve following the development of cirrhosis because of increased oxidation of FFAs, with the loss of steatosis following histological progression to cirrhosis being well described, a firm pretransplant diagnosis is often difficult.
Compared to patients transplanted for other indications, NASH patients are older (58.5 ± 8 years versus 53 ± 9 years); more likely to be overweight with BMI of 30 kg/m or higher (63% versus 32%), diabetic (53% versus 24%), and hypertensive (41% versus 22%); and less likely to have hepatocellular carcinoma (12% versus 19%). There is a high prevalence of MZ (17%) α 1 -antitrypsin phenotypes among patients with NASH evaluated for liver transplantation. Patients with panhypopituitarism may develop NASH that is rapidly progressive, leading to cirrhosis within the second or third decade of life, and is relatively commonly associated with severe hepatopulmonary syndrome.
Interactions Between the Pathobiology of NAFLD/NASH and Posttransplant Management
Obesity, which increases in prevalence and severity following liver transplantation, is associated with a number of metabolic effects relevant to the development of hepatic steatosis. These include increased absolute hepatic FFA uptake, increased esterification of hepatic FFAs to form triglycerides, increased FFA synthesis from cytosolic substrates, decreased apolipoprotein B-100 synthesis with subsequent decreased export of FFAs and triglycerides, decreased hydrolysis of triglycerides and diminished hepatic triglyceride and FFA export, and increased beta oxidation of mitochondrial long-chain fatty acids. Although the relative contribution of these effects to the net retention of fat within hepatocytes is not known, each of these potential contributing mechanisms to hepatic steatosis might be predicted to occur more commonly following liver transplantation.
Obesity is also strongly correlated with insulin resistance, particularly when central or truncal (a distribution that is favored by corticosteroid use). Obesity is generally associated with multiple acquired factors predisposing to insulin resistance, including sedentary lifestyle, high-fat diets, medications (e.g., cyclosporine and sirolimus), and glucose toxicity. Although the precise mechanism of truncal obesity–associated insulin resistance is not known, release of FFAs from abdominal adipocytes into the portal circulation with subsequent induction of hepatic insulin resistance and stimulation of glucose are likely to contribute.
In addition to the metabolic effects of obesity earlier, liver transplantation alters circulating levels of leptin (increased) and adiponectin (decreased), changes that may contribute to posttransplant obesity and metabolic syndrome. Tumor necrosis factor (TNF)-α, which downregulates insulin-induced phosphorylation of insulin receptor substrate 1 and reduces the expression of the insulin-dependent glucose-transport molecule Glut 4, may also be involved in posttransplant NAFLD/NASH and associated insulin resistance.
Susceptibility to steatosis in obese people has been recently found to genotype for adiponutrin or patatin-like phospholipase domain containing 3 (PNPLA3), which normally regulates hydrolysis of triglycerides to FFAs in the adipocytes. Polymorphisms of this gene are associated with NAFLD, NASH, and advanced fibrosis with GG genotype at risk compared to CC genotype. The impact of donor versus recipient genotype for PNPLA3 on posttransplant NAFLD/NASH and metabolic complications of transplantation is not known.
Although the link(s) between hepatic steatosis, inflammation, and fibrosis are not well established, increased oxidative stress, a feature of both animal models of steatohepatitis and humans with NAFLD, and mitochondrial function derangement play an important role. Oxidative stress can occur as a result of steatosis by lipid peroxidation by unsaturated FFA–mediated induction of hepatic microsomal cytochromes CYP2E1 and CYP4A. When pro-oxidant pathways generate more reactive species than can be consumed by antioxidant pathways (e.g., via protein disulfide isomerase or reduced glutathione [GSH] peroxidase), oxidative stress occurs, with resulting accumulation of reactive oxygen species (chiefly superoxide and hydroxyl radicals plus hydrogen peroxide) and mitochondrial injury. Mitochondrial injury (as manifest by megamitochondrion) is a hallmark of NAFLD. Increased oxidative stress usually results in increased synthesis of protective antioxidant pathways and reactive oxygen species scavengers. Almost all liver transplant recipients are maintained on a calcineurin inhibitor. Both cyclosporine and tacrolimus are associated with resultant increased generation of reactive oxygen species, mitochondrial dysfunction, and lipid peroxidation. This may have important implications for the natural history of recurrence of NAFLD following liver transplantation. Whether calcineurin inhibitor dosing should be minimized in patients with recurrence of NASH is not known, but there exists a theoretical possibility for such an approach to recurrence of NASH following liver transplantation.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here