NAFLD is characterized by excess fat (triglyceride) accumulation in >5 % of hepatocytes in the absence of other causes such as excess alcohol intake. It comprises a spectrum of disease ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), a more aggressive form that is characterized by hepatocellular injury (ballooning), and liver cirrhosis. The only curative treatment for end-stage cirrhosis is liver transplantation, for which NAFLD is currently the most rapidly increasing indication. NAFLD is also the most common cause hepatocellular carcinoma (HCC). In addition to liver disease, NAFLD increases the risk of type 2 diabetes and cardiovascular disease, even independently of obesity.
NAFLD is commonly asymptomatic, even at the stage of advanced fibrosis. There is urgent need to develop non-invasive laboratory tests and imaging tools.
The gold standard method for diagnosis of NAFLD is liver biopsy, which provides quantification of all qualities of the disease: steatosis, hepatocellular injury (NASH) and fibrosis, i.e. the degree of scarring in the liver. Despite being highly informative, the utility of liver biopsy is limited by its invasiveness, especially considering the high prevalence of the disease.
In addition to liver biopsy, steatosis can be assessed with non-invasive imaging modalities such as ultrasound or proton magnetic resonance spectroscopy. Fibrosis, which is the most important determinant of long-term outcome in NAFLD, can be assessed non-invasively using transient elastography (Fibroscan®) or magnetic resonance elastography. In high risk groups, such as patients with type 2 diabetes over the age 50, advanced fibrosis can be found in up to 10% of subjects.
Standard laboratory tests, such as liver enzymes ALT and AST, are too insensitive and inprecise to be used to diagnose NAFLD. To improve this unmet need, we and others have developed several non-invasive laboratory biomarkers to detect NAFLD and NASH.
Noninvasive Detection of Nonalcoholic Steatohepatitis Using Clinical Markers and Circulating Levels of Lipids and Metabolites. Zhou Y, Orešič M, Leivonen M, Gopalacharyulu P, Hyysalo J, Arola J, Verrijken A, Francque S, Van Gaal L, Hyötyläinen T, Yki-Järvinen H. Clin Gastroenterol Hepatol. 2016 Oct;14(10):1463-1472.e6.
Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study. Isokuortti E, Zhou Y, Peltonen M, Bugianesi E, Clement K, Bonnefont-Rousselot D, Lacorte JM, Gastaldelli A, Schuppan D, Schattenberg JM, Hakkarainen A, Lundbom N, Jousilahti P, Männistö S, Keinänen-Kiukaanniemi S, Saltevo J, Anstee QM, Yki-Järvinen H. Diabetologia. 2017 Oct;60(10):1873-1882.
Phosphorylated IGFBP-1 as a non-invasive predictor of liver fat in NAFLD. Petäjä EM, Zhou Y, Havana M, Hakkarainen A, Lundbom N, Ihalainen J, Yki-Järvinen H. Sci Rep. 2016 Apr 19;6:24740
The prevalence and severity of NAFLD is closely correlated with obesity, insulin resistance and the features of the metabolic syndrome (i.e. waist circumference, hypertension, and plasma glucose, triglyceride and low HDL cholesterol concentrations). The prevalence increases with age, and NAFLD is more common in men than in women.
In obesity, weight gain is commonly associated with adipose tissue inflammation resulting in increased lipolysis, i.e. release of fatty acids and glycerol into the circulation. These fatty acids are used for synthesis of intrahepatic triglycerides (IHTG), i.e. liver fat, the hallmark of NAFLD. In addition, dietary substrates contribute to the accumulation of IHTG. Dietary fat is partially taken up by the liver, and the liver itself can produce fatty acids from non-lipid substrates, such as sugars and amino acids via the de novo lipogenesis (DNL) pathway. DNL is upregulated by hyperinsulinemia and dietary substrates such as simple sugars.
The liver is the main organ producing glucose. Impaired insulin inhibition of hepatic glucose production is impaired in NAFLD, leading to hyperglycemia. Hyperglycemia stimulates insulin secretion by the pancreas, leading to hyperinsulinemia. If this compensatory capacity of the pancreas is exceeded, hyperglycemia and frank type 2 diabetes occurs.
The liver is also the main organ producing circulating lipids. IHTG are exported into the circulation as very low-density lipoprotein triglycerides, which are overproduced in NAFLD. This results in atherogenic dyslipidemia, i.e. high plasma triglycerides and a low HDL cholesterol concentration. Together with the overproduction of coagulation factors in NAFLD, these mechanisms contribute to the increased risk of cardiovascular disease in NAFLD.
NAFLD can progress from simple steatosis to a more advanced stage. According to a recent meta-analysis the rate of disease progression in slower in patients with NAFL (one fibrosis stage over 14.3 years) compared to patients with NASH (7.1 years). This future progression is predicted by the degree of steatosis at baseline.
Genetic factors also play a major role in NAFLD. Variant alleles in three genes, i.e. the patatin-like phospholipase domain containing 3 (PNPLA3), the transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound O-acyltransferase containing 7 (MBOAT7), have been associated in multiple cohorts with increased IHTG content and with progression to advanced liver disease. Interestingly, these variants are not associated with insulin resistance, features of the metabolic syndrome, or increased risk of diabetes or cardiovascular disease. The study of subjects carrying these genetic variants have allowed us to dissect the fundamental mechanisms in the pathophysiology of NAFLD
Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Yki-Järvinen H. Lancet Diabetes Endocrinol. 2014 Nov;2(11):901-10.
Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) - an 11-Year Prospective Study. Lallukka S, Sädevirta S, Kallio MT, Luukkonen PK, Zhou Y, Hakkarainen A, Lundbom N, Orho-Melander M, Yki-Järvinen H. Sci Rep. 2017 Nov 6;7(1):14561
Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans. Lallukka S, Luukkonen PK, Zhou Y, Isokuortti E, Leivonen M, Juuti A, Hakkarainen A, Orho-Melander M, Lundbom N, Olkkonen VM, Lassila R, Yki-Järvinen H. Thromb Haemost. 2017 Jan 26;117(2):286-294.
Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. Luukkonen PK, Zhou Y, Sädevirta S, Leivonen M, Arola J, Orešič M, Hyötyläinen T, Yki-Järvinen H. J Hepatol. 2016 May;64(5):1167-1175.
NAFLD can be both prevented and treated by lifestyle intervention. Weight loss by caloric restriction and/or exercise is beneficial and the degree of both metabolic and histological improvement is proportional to the amount of weight lost. In NASH, a loss of 10 % body weight is associated with histological improvement, and even a weight loss of a few percents can decrease IHTG by over 10%.
In addition to energy content, also the dietary composition is important. It seems that particularly diets containing excess carbohydrated and saturated fatty acids increase liver fat content and deteriorate insulin sensitivity. In contrast, the Mediterranean diet is associated with reduced liver fat and improved insulin sensitivity independently of weight loss.
Available pharmaceutical treatments include pioglitazone, vitamin E and obeticholic acid, none of which are approved by pharmaceutical agencies. Multiple drug trials for treatment of NASH are ongoing.
In carefully selected subjects, bariatric surgery is an effective treatment for NAFLD, with proven improvements in all features of the disease, including fibrosis.