Impact of Graft Steatosis on Post-operative Complications After Liver Transplantation

Introduction Solid organ transplantation has become the standard of care for selected patients with end-stage organ dysfunction. With improved surgical techniques, more effective immunosuppressive therapies, and better anti-infective medications, outcomes after solid organ transplantation have improved over the last several years.

The excellent survival rates reported after orthotopic liver transplantation (OLT) have increased the demand for liver transplants and have enhanced the disparity between the number of available donor organs and the need for such organs.

The lack of available organs for liver transplantation (LT) associated with the increased death rates among patients on most waiting lists for LT has triggered the use of so-called extended criteria donor (ECD) grafts, previously called ''suboptimal grafts''. Among the wide range of these ECD livers, hepatic steatosis is one of the most frequent disorders, which is mostly related to an increasing prevalence of non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is increasingly significant in healthy individuals for its high worldwide prevalence, an association with the metabolic syndrome such as insulin resistance, diabetes, dyslipidemia and obesity, and an association with liver-related morbidity and mortality.

Clinical evaluation and current imaging modalities, and serological and laboratory tests can be strongly suggestive of the presence of hepatic steatosis, but none of these is capable of distinguishing steatohepatitis (SH) from uncomplicated steatosis; likewise, these evaluations can generally detect advanced liver disease (e.g. portal hypertension), but none can truly assess the degree of liver necroinflammatory injury, lesser stages of fibrosis and architectural remodeling. Liver biopsy evaluation, therefore, remains the 'gold standard' to unequivocally diagnose SH and to document the severity of hepatic injury and fibrosis.

Steatosis is assessed according to the pattern and the amount of fatty infiltration in hepatic tissue sections. Traditionally, fatty accumulation has been classified morphologically as macrovesicular or microvesicular. Macrovesicular steatosis is characterized by a single, bulky fat vacuole in the hepatocyte that displaces the nucleus to the edge of the cell. The less conspicuous microvesicular steatosis, usually related to toxins or metabolic disorders, is characterized by accumulation of tiny lipid vesicles in the cytoplasm of hepatocytes without nuclear dislocation. Current quantification and grading of liver steatosis originates from studies performed in the early 1990s, when steatosis was classified as mild, moderate, or severe if, less than 30%, 30-60%, or more than 60% of hepatocytes, respectively, display fatty infiltrations.

Although usually benign, fatty liver may associate with serious injury, with inflammation and hepatocyte necro-apoptosis, non-alcoholic steatohepatitis (NASH), in 20-30% of subjects. Those patients are at risk of developing fibrosis, one fifth progressing to liver cirrhosis. It is apparently more slowly progressive than other chronic liver diseases, such as alcohol or viral-induced disease. Moreover, the problem of hepatocytes being fatty, overcomes the liver itself, as it increases the risk for cardiovascular disease and death and duplicates the risk for type 2 diabetes mellitus (T2DM), independently of the severity of liver injury.

Severe fatty livers are more susceptible to warm and cold ischemia reperfusion injury than normal ones. The type of damage is not through the pathway of cellular apoptosis, but necrosis.

The use of steatotic grafts for orthotopic liver transplantation (OLT) is associated with a high rate of primary graft dysfunction and decreased graft and patient survival particularly with macro-steatosis.