Prevalence and Metabolic Impact of Non-alcoholic Fatty Liver Disease in Patients With Type 2 Diabetes With Normal Renal Function or Chronic Kidney Disease

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries affecting approximately 30 % of the general adult population. The disease is defined by an increased fat accumulation in the liver cells (>5 %), not caused by excessive alcohol intake (a threshold of 20 g per day for women and 30 g per day for men), autoimmunity, drugs or viral hepatitis. The histological spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). Simple steatosis defined as steatosis without injury of the hepatocytes in form of ballooning and NASH defined as the presence of hepatic steatosis and inflammation with ballooned hepatocytes with or without fibrosis. The degree of fibrosis is an important prognostic factor and is related to liver related complications and mortality.

Diabetes is the single most important cause of end-stage renal disease (ESRD). Furthermore, more than 25 % of patients with moderate to severe chronic kidney disease (CKD) have pre-diabetic characteristics such as impaired glucose tolerance or impaired fasting glucose. NAFLD represents an important pathogenic factor in the development of type 2-diabetes and is associated with an increased risk of cardiovascular disease, insulin resistance and overweight.

Previous studies of patients with CKD with/without diabetes demonstrated, with less sensitive ultrasonic methods than what we plan to use in the present project, a high prevalence of NAFLD. Furthermore, the presence of both NAFLD and CKD is likely to increase the risk for cardiovascular diseases and mortality, particular among overweight patients. NAFLD is present in both diabetic and nondiabetic patients with ESRD. The co-existence of CKD, NAFLD and gluco-metabolic disturbances, including diabetes, is a research topic with increasing focus on. Co-morbidities in CKD such as impaired insulin sensitivity, diabetes, impaired calcium-phosphate metabolism, hypertension and hypertriglyceridemia constitute risk factors for NAFLD. Unfortunately, several treatments of CKD, including kidney transplantation, have been shown to impair lipid metabolism and increase insulin resistance especially in the liver. Importantly, lifestyle changes and medical treatment modalities have been shown to have only minor impact on reducing the prevalence of these disturbances in patients with CKD.

In patients with NAFLD, either due to metabolic stress (obesity) or toxic substances (immunosuppressive treatment), liver damage and the impact on insulin resistance is reflected in characteristic modifications of metabolites and lipids in liver tissue, as well as in circulating blood, which may help to identify and interpret the pathogenesis of liver damage in the setting of CKD. One recent hypothesis for linking liver damage and CKD involves a change in gut microbiota due to impaired renal function, leading to a leaky gut with damage of the gut-blood barrier. This transfers gut microbiota metabolites to the blood, leading to a pathogen-associated molecular pattern, reflected in changes in lipidomic and metabolomic profile in the blood. Such changes have in other conditions been associated with insulin resistance and have been linked to liver damage leading to NAFLD and later potentially fibrosis.