Non-Alcoholic Fatty Liver disease (NAFLD) is being recognized as a major global health issue in both alcoholic and non-alcoholic persons, affecting all populations irrespective of age, gender, BMI and ethnicity[i]. It is one of the three most common chronic liver diseases worldwide, the other two being alcoholic liver diseases and viral hepatitis[ii]. Apparently taken as benign disease, NAFLD has now become one of the common indications for liver transplantation in the western world[iii]. Various diagnostic tests have been used for the diagnosis of NAFLD and assessment of severity like US, CT, MR, and fibroscan[iv]. Liver biopsy still remains the gold standard for diagnosing and identifying NAFLD and NASH. Albeit it is seldom used[v] because of invasiveness, correct assessment of time of use and affected persons’ will. Attempts are in progress to develop noninvasive methods to predict NAFLD. This has become more important due to the fact that numerous drug trials are underway, some in phase IV. Follow up of these cases is not feasible with multiple biopsies. FLD is a slow progressing disease which rarely exhibits any discomfort. This leads to an un-noticed pathological / biochemical change in liver parenchyma of affected individual that culminates into serious outcomes. The chemical variable selected for this study represented glycemic control (HbA1C) one of the advanced glycation end-products (AGEs).
Advance Glycosylation end-products (AGE) are implicated in development of DM and coronary artery disease[vi]. HbA1C is produced in direct proportions of blood glucose concentrations[vii]. Deranged carbohydrate metabolism, also effects lipid metabolism and results in increased synthesis of triacylglycerol (TAG) that tends to deposit in various tissues of body including liver. TAG deposition in adipose tissue increases BMI while in liver parenchyma it leads to fatty liver. DM has strongly been linked with fatty deposition in liver and HbA1C may be causally associated with NAFLD[viii]. On the other hand obesity in absence of DM also relates to increased fat content of the body tissues. Higher BMI has been associated with insulin resistance and increases in HbA1C [ix]. Patient suffering from NAFLD show a higher level of HbA1C independent of DM[x]. Various body measurements along with different chemical markers have been used in different combinations to develop noninvasive diagnostic tools like fatty liver index (FLI), Bard score, Fib4, Steatosis score, NAFLD fibrsosis score, NAFLD liver fat score and APRI score17 with variable sensitivity and specificity.
Present study reports significantly higher HbA1C levels in individuals with NAFLD (p<0.001, Table-1) that increased with grades of severity (Table-2). Chronic hyperglycemia results in non-enzymatic glycosylation of various proteins that may trigger the immune response with consequent subclinical inflammation of soft tissues including liver[xi]. Glycosylated Hemoglobin reflecting long term glycemic control has been studied for its association with NAFLD. A study has reported conflicting results that “increased pancreatic echogenicity is associated with deteriorating glycemic parameters and higher risk of glycemic progression and incident diabetes, independent of HbA1C concentration and NAFLD”[xii]. Recently it has been claimed that hemoglobin glycation index (difference between observed and predicted HbA1C levels based on plasma glucose levels) can identify the non-diabetic individuals at higher risk of developing fatty liver[xiii]. Present study reports a significant association of HbA1C with NAFLD .This association was positive both in diabetic and non-diabetic, obese and lean persons (cOR=4.12, p<0.001). This indicates that those who have HbA1C higher than 5.7% are 4 time more prone to develop fatty liver disease. Similarly a Chinese study has also reported HbA1C as an independent risk factor for development of NAFLD in elderly people16. Moreover 11.55% (52 individuals) of the study sample were diagnosed as Type II diabetic at the time of recruitment and in concordance with others7 more than 90 % of individuals with Type II DM had NAFLD. While 99 (66%) had more than normal HbA1C (Table-1). This indicates that more than half of the individuals did not know about their high HbA1C which may have been in pre-dibetic17 group and continued with their lifestyle and ended up in FLD. This finding signifies need of more studies to establish the importance of routine HbA1C examination even in otherwise adult healthy individuals.
Various studies have demonstrated variable results when comparing effect of age, gender, BMI & Obesity. There are opinions that BMI is not a good indicator of chronic disease association as compared to abdominal fatness[xiv] (central obesity represented by WC). Excess abnormal fat predisposes to obesity related disease regardless of total body fat. Present study found both BMI and WC significantly different (p<0.001) with presence of NAFLD in both genders (Table-1) while WHR was significantly different only in males. All of these indices were significantly associated with NAFLD (Table-3). However when it was adjusted for other parameters, this association became weaker whereas association with WC remained significant both in males and females (aOR 2.91, 4.28, p<0.001 respectively). This indicates that abdominal obesity is more associated with presence of NAFLD. It has been reported that people with central obesity have less activity index[xv]. Central obesity has been found more prevalent in subcontinent[xvi],[xvii].Even the patients, who are lean, develop fatty liver if they have central obesity[xviii]. Both of these conditions are associated with insulin resistance and hence high HbA1C may be a common link between NAFLD and DM /center obesity. Insulin resistance predisposes to type 2 DM, Obesity, Central Obesity and increased TAG. The results of this study also depicted that as compared to male patients, females had higher central obesity (Table-1) and NAFLD. Present study demonstrates that NAFLD can be predicted by a combination of HbA1C and WC both in males (AUC=0.706 & 0.681) and in females (AUC= 0.800 & 0.632 respectively). It is in concordance to others who claimed that a combination of age, sex, waist circumference, ALT, HbA1C, and HOMA-IR with an AUC of 0.87 can best predict NAFLD[xix].
This study also demonstrated significant increases in various severity grades of fatty liver with the rise in HbA1C levels, BMI and WC (Table-2). Increasing insulin resistance has been reported with higher grades of NAFLD in diabetic and pre-diabetic individuals[xx] while other have claimed that glyacated albumin/glycated hemoglobin is inversely proportional to the severity grades of NAFLD[xxi]. With this data it is tempting to speculate that investigation of HbA1C and central obesity may give an insight to the presence of NAFLD well before it is diagnosed.