One-quarter of the global population is estimated to have nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20% [14]. The incidence of nonalcoholic steatohepatitis (NASH) is projected to increase by up to 56% in the next 10 years [10]. Recently, the SAF score emerged as a new algorithm to assess NAFLD and diagnose NASH. Initially, this score was developed for classifying NAFLD in morbidly obese patients [12], but it has now been validated in a cohort of patients with NAFLD and metabolic syndrome [9]. The SAF score separates steatosis from parenchymal necro-inflammation, two features that may have distinct prognostic potential.

Interestingly, independent from the classification of whether NASH is present, the overall histological severity of disease is scored separately as mild disease (A < 2, F < 2) or significant disease (A ≥ 2, F ≥ 2), also considering fibrosis staging. Therefore, NAFLD patients with less fat but still advanced fibrosis, and without steato-hepatitis, would be classified as having “significant disease,” even though they did not fulfill the criteria of NASH. Thus, the fibrosis component has an impact on the SAF score that may be relevant for long-term prognostication, although the association between the SAF score and long-term liver-related mortality has not yet been evaluated.

In our prospective cross-sectional study, the multivariate analysis showed that steatosis is an independent and significant factor associated with the degree of liver fibrosis. The more is the steatosis degree, the worse is the fibrosis. Interestingly, steatosis in HCV patients has also been associated with more severe histological injury and higher fibrosis scores, suggesting that fat in the liver is a biologically active tissue [15]. Steatosis can be significantly and independently associated with fibrosis in chronic hepatitis C. Insulin resistance (IR) is the possible link between the metabolic abnormalities in HCV patients with steatosis and the progression of hepatic fibrosis. Hyperinsulinemia in HCV patients may potentially promote fibrogenesis through either altered cytokine production, including TNF α, or by its direct effect on hepatic stellate cells [16, 17].

Although the mechanisms underlying the development of parenchymal steatosis in HCV infection are not exactly known, there are some findings to describe the mechanism of fat accumulation. The first series of mechanisms basically focuses on HCV proteins as the first step of the damage sequence. At least two HCV proteins (core protein and NS5A) are suspected to interact with the cell machinery involved in lipid metabolism [15].

Both HCV and steatosis are two synchronized factors causing fibrosis. The conflicting results of the previous studies that discuss the relation between steatosis and fibrosis may be due to the variation of the studied population and the abundance of risk factors [18,19,20,21].

In our study, baseline HCV genotyping was not performed, as it is assumed that more than 90% of HCV-infected patients in Egypt are infected with HCV-G4, and the remaining patients are infected with HCV-G1, with genotypes 2, 3, 5, and 6 almost non-existent and this analysis assumes that almost all patients are infected with HCV-G4 [22, 23]. HCV-G4 is known to induce less steatosis than genotype 3. However, it was found in an Egyptian study that HCV genotype 4 was associated with steatosis in more than half the patients, even in the absence of risk factors for metabolic steatosis. This was independent of the viral load but positively correlated with fibrosis and inflammation in these patients. This type of steatosis is possibly viral-induced (VAFLD) [24].

We found in our results that the degree of fibrosis increased with the progress of age. In agreement with our results, in a recent study, 25 patients with NAFL and 45 patients with NASH and/or advanced fibrosis were followed with repeated liver biopsy for an average of 3.7 years. Among the patients with NAFL, 16 patients (64%) developed NASH, eight of which had severe ballooning and six showing bridging fibrosis. Mild lobular inflammation or any degree of fibrosis conveyed a higher risk of progression than simple steatosis alone. Older age and deterioration of metabolic risk factors were associated with a more rapid progression [25].

A recent meta-analysis evaluated 411 patients with biopsy-proven NAFLD from 11 cohort studies (150 patients with NAFL and 261 patients with NASH). In the whole cohort, 33.6% of patients had fibrosis progression. This result was also observed in patients with NAFL but at a slower rate. In those with NAFL, it took an average of 14.3 years to progress one stage in fibrosis score; however, in those with NASH, the time to progress with one stage was halved to 7.1 years [26]. Taken together, the data indicate that fibrosis progression is also observed in patients with NAFL, particularly in those with mild inflammatory changes, delicate fibrosis, older age, or deterioration of metabolic risk factors. However, patients with NASH have a more rapid course, with a significant risk for liver-related mortality [27].

In our study, both ALT and/or AST were found to progressively increase from F1 to F3. ALT showed a significant correlation with activity degree of SAF scoring system. However, AST/ALT ratio showed no significant relation to the activity or fibrosis degree of SAF score. In a recent study, they found that clinical predictors of advanced fibrosis in NAFLD are male sex, Caucasian ethnicity, diabetes mellitus, obesity, and increased AST or ALT levels [8, 28]. However, there was a poor correlation between ALT levels and NASH, or the stage of fibrosis [29]. In a study of 222 patients with NAFLD, 23% had normal ALT. The proportion of patients with advanced fibrosis was similar among those with normal and elevated ALT [26]. Contrary to our results, another study found that AST was a better predictor for advanced fibrosis than ALT. In early studies on NAFLD, an AST/ALT ratio > 1 was found to be associated with advanced fibrosis [8]. Another test that includes AST is the AST/platelet ratio index (APRI) [27] and had a negative predictive value of 94% to exclude advanced fibrosis (F3–4) in NAFLD. In a Chinese study, Zou et al. reported that AST/ALT ratio is often less than 1 in NASH, whereas a ratio above 1 would suggest an alcoholic steatohepatitis or evolution toward liver cirrhosis. In this respect, the higher AST levels would reflect more extensive mitochondrial damages [30].

We found that there is no significant correlation between SAF score and BMI (< 30 and 30 or more). Variation in body fat distribution in relation to histology is evident. As the overall fat mass measured by DXA decreased, both hepatic steatosis grade and disease severity worsened. In contrast, an increased trunk: limb ratio of fat was associated with increased steatosis grade. Finally, adipocyte size and volume from the abdominal wall biopsies showed a linear correlation with increased severity of histological diagnosis of NAFLD, but only in women. For unclear reasons, this did not hold true in the men and is an area worth further evaluation [31].

Our study showed no significant correlation between insulin resistance (IR) and BMI. Vadukoot et al. in 2016 [32] found that although IR was significantly higher in obese patients with NASH as compared to lean NASH (BMI < 23 kg/m2), there was no significant difference in the correlation of IR with histology between these 2 groups. No significant difference was observed with regard to IR level with SAF. Fasting insulin level was comparable among patients with lean and obese NASH. No significant correlation was found between fibrosis of SAF score and between other risk factors increasing fibrosis such as HCV-RNA-PCR, age, MS, or IR.

Our study had been done on homogenous genotype 4 HCV non-cirrhotic, nonalcoholic Egyptian patients; however, the study had limitations including the relatively small number of patients, being conducted at the era of starting the use of DAA with difficulty to enrol new patients who agree to undergo liver biopsy. Also, most of our patients had early hepatic affection. Only 20% of our patients had advanced fibrosis (F3). Also, 60% of our patients had low BMI (below 30) and half showed no steatosis, which could affect our results.

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