Bioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Liver Disease

Background

Non-Alcoholic Fatty Liver Disease (NAFLD), including its more pathologic consequence, non-alcoholic steatohepatitis (NASH), is believed to be the most common chronic liver disease worldwide, affecting between 6 to 37% of the population. NAFLD is a so called 'silent killer', as clinical symptoms only surface at late stages of the disease, when it is no longer treatable. Untreated, NAFLD/NASH can lead to cirrhosis and hepatocellular carcinoma, culminating in liver failure. Several factors may contribute to the pathogenesis of NAFLD, including genetic assessment and mitochondrial dysfunction. Genetic factors might affect the pathophysiological aspects of NAFLD and its natural history. The European population appears to host genetic variants which can play a role in this respect. Recently, the common variant p.I148M of the enzyme adiponutrin (PNPLA3) has emerged as a major genetic determinant of hepatic steatosis and non-alcoholic steatohepatitis as well as its pathobiological sequelae fibrosis, cirrhosis, and hepatocellular cancer. PNPLA3 encodes a lipid droplet-associated, carbohydrate-regulated lipogenic and/or lipolytic enzyme. Homozygous carriers of the PNPLA3 variant (i.e. the presence of the PNPLA3 allele [M]) are prone to develop cirrhosis in the absence of other risk factors such as alcohol or viral hepatitis. Moreover, PNPLA3 p.I148M variant is associated with greater reduction of liver fat content after bariatric surgery, in comparison to carriers of PNPLA3 wild-type alleles.

Other variants might also play a role and include transmembrane 6 superfamily member 2 (TM6SF2) p.E167K, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738. Neither PNPLA3 nor TM6SF2 risk alleles impair the response to dietetic intervention in NAFLD. MBOAT7 polymorphism is associated with increased triglyceride, total cholesterol, low density lipoprotein, and serum glucose levels, all factors associated with metabolic syndrome and liver steatosis.

Patients with NAFLD/NASH display disturbances of intestinal permeability, and gut microbiota. In most cases, NAFLD/NASH is strongly linked to other metabolic conditions, including visceral adiposity.

Liver biopsy is the gold standard for the diagnosis and staging of NAFLD but is invasive in nature and not easily usable as screening tool. Other imaging techniques include ultrasonography which is non-invasive, can detect hepatic steatosis (>20%-30%) and can be easily used in follow-up studies. Computerized tomography, magnetic resonance imaging, and spectroscopy are alternative imaging techniques used for the detection of hepatic steatosis. However, they have failed to show better accuracy, are expensive and can bring adverse effects (e.g., radiation). Therefore they are not feasible as screening tools. Liver enzymes represent surrogate markers of liver disease but have limited accuracy. By ultrasound, NAFLD prevalence ranges from 11%-30%. In the United States, ultrasonographic NAFLD appears to range between 5%-33%. Liver fibrosis may be non-invasively assessed by acoustic radiation force impulse imaging (ARFI), an ultrasound-based approach for estimating liver stiffness, a surrogate marker of liver fibrosis. ARFI imaging is based on short-duration, high-intensity acoustic pulses to produce mechanical excitation in tissue. Localized tissue displacement and shear wave propagation follow the tissue excitation. The velocity of the waves correlates with the degree of fibrosis, implying that the shear wave velocity increases as the amount of fibrosis increases. Optimal cut-off values are provided by various studies. In the study by Crespo et al. (2012), the sensitivity of ARFI imaging in 88 patients for ≥F2 fibrosis was 85% using a cut-off of 1.44 m/s and for F4 fibrosis was 92 percent using a cut-off of 1.9 m/s. The corresponding specificities were 76 and 87 percent, respectively. In another study, ARFI was compared with ultrasound-based transient elastography in 321 patients undergoing liver biopsy for chronic liver disease. No difference was found between ARFI and ultrasound-based transient elastography for the diagnosis of cirrhosis or severe fibrosis and ARFI was better in lean patients. Among non-obese patients the area under the receiver operating characteristic (ROC) curves for cirrhosis and severe fibrosis were 0.92 and 0.91, respectively. For obese patients they were 0.63 and 0.63, respectively.