The principal findings of this study are that FIB-4 scores increased over time, and dyslipidemia was a major deteriorating factor for hepatic fibrosis, as shown in Table 3. Therefore, regardless of whether an individual has hepatic steatosis or non-alcoholic steatohepatitis (NASH), all NAFLD patients should be followed-up and assessed for dyslipidemia to prevent further deterioration of hepatic fibrosis.
The impact of chronic liver disease on hepatic lipid metabolism has been mentioned in several studies (10, 11). One important finding in this study is that patients with severe NAFLD, as indicated by a FIB-4 score greater than 2.67, were found to have lower lipid levels, specifically total cholesterol and LDL, than patients with moderate and mild FIB-4 scores. The improvement in dyslipidemia in patients with lower FIB-4 scores can possibly be explained by hepatic synthetic failure in patients with cirrhosis (12, 13), under the assumption that patients with more severe FIB-4 scores were mostly cirrhotic. However, it is important to note that NAFLD is comprised of a spectrum of conditions ranging from steatosis to NASH, and that the decline in serum total cholesterol, TG, or LDL may indicate that the patient is already pre-cirrhotic or cirrhotic. Furthermore, the amount of decrement in serum total cholesterol, LDL, and HDL have a positive correlation with the severity of liver damage. It is well known that in advanced cirrhosis, the levels of total cholesterol are decreased. In this study, we found that levels of total and LDL cholesterol were both decreased. From a clinically practical standpoint, this could possibly mask the severity of patients’ cardiovascular risk due to the improvement in blood lipid tests.
Another interesting finding is that fasting glucose was higher in the mild versus moderate NAFLD group (p < 0.05), as shown in Table 1. Although the relationship between the metabolism of glucose and chronic liver disease is not fully understood, there have been several proposed mechanisms for glucose homeostasis in NAFLD (11). A possible explanation for a lower fasting glucose in moderate versus mild NAFLD group is that the liver’s ability to mobilize and distribute glucose to peripheral tissues is diminished, this is especially seen in patients with cirrhosis where their liver is severely dysfunctional (14).
Dyslipidemia, characterized by lower levels of HDL, and higher levels of LDL and TG, along with metabolic syndrome, insulin resistance, have long been known to be associated with NAFLD (2, 15, 16). However, the exact pathogenesis and progression of non-alcoholic fatty liver still remains to be uncovered. In our study, we found that dyslipidemia was a significant factor that increased the FIB-4 score in patients from their first and last visits. Dyslipidemia is most likely an end result of inflammation and oxidative stress on the liver, which is an oversimplified explanation of the several proposed complex mechanisms and pathways that cause an accumulation of triglycerides in the liver (17). An important metabolic change that plays a part in the pathogenesis of NAFLD is hyperinsulinemia, which increases fatty acid uptake (18), transcriptionally upregulates de novo lipogenesis in the liver (19), and heightens production rates of very-low-density lipoprotein (VLDL) particles (20). These VLDL particles, a major source of circulating TG, may be one of the causes of high TG commonly seen in NAFLD (21). Consequently, the failure of insulin to suppress VLDL secretion leads to dyslipidemia, and overproduction of TG worsens the present steatosis. In essence, dyslipidemia is both a cause and result of NAFLD. Moreover, the increase in VLDL secretion does not compensate for the overproduction of the TG because the free fatty acids incorporated into VLDL particles are from intracellular storage rather than de novo synthesis (20, 22). These metabolic changes listed above are also discussed on a molecular level (23), but are beyond the scope of our study.
In summary, these mechanisms can all be attributed to insulin resistance (15), which causes a diminished response to insulin in patients with NAFLD. Therefore, it is evident that conditions affiliated with insulin resistance such as obesity and metabolic syndrome are also strongly associated with fatty liver and should be treated along with NAFLD. Given the finding that FIB-4 scores increased over time, we recommend all patients with NAFLD, whether it’s simple steatosis or NASH, be regularly followed-up. Although the natural history of NAFLD generally starts from steatosis to NASH, cirrhosis, and even hepatocellular carcinoma (HCC), there have been reports of the development of HCC without apparent cirrhosis (24). More importantly, NAFLD is associated with many hepatic and extrahepatic complications and morbidities (25, 26), and this calls for more adequate surveillance of fatty liver patients to prevent further deterioration of their FIB-4 scores.