Medication
Treatment with medications is primarily aimed at improving liver disease and is generally limited to those with biopsy-proven NASH and fibrosis.No medicines specifically for NAFLD or NASH had received approval, as of 2018, although anti-diabetic medications may help in liver fat loss. While many treatments appear to improve biochemical markers such as alanine transaminase levels, most do not reverse histological abnormalities or improve outcomes.Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) and liraglutide are not specifically recommended for NAFLD as they do not directly improve the liver condition. They can be indicated for diabetic individuals, after a careful assessment of risks, to reduce insulin resistance and risks of complications. Indeed, the side effects associated with thiazolidinedione medications, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure, bladder cancer, and long-term weight gain, have limited their adoption. Due to these side effects, the AASLD recommends the use of pioglitazone only for individuals with biopsy-proven NASH, and the Asia-Pacific Work Group recommends them only for individuals with NAFLD with known diabetic issues. However, the AASLD advises against the use of metformin as studies were inconclusive about the improvement of the livers histological condition. Although there was an improvement in insulin resistance and serum aminotransferases, this did not translate into NASH improvements.
Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of NAFLD.Once NAFLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect the liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver, anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in NAFLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver. Dysbiosis
Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals).