Why do Obesity TDM and Nafld Cluster The Liver as the Metabolic Sensor of Lipotoxicity

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lifespan of patients with NAFLD is significantly shortened not only by a liver-related morbidity but also by a higher incidence of CVD (285, 286).

As with obesity and T2DM, there is also considerable concern that NAFLD and NASH are reaching epidemic proportions (287) . However, the true magnitude of the disease is not appreciated by many clinicians because the majority (~70%) of patients affected have normal liver enzymes (279, 288-290). It has been recently estimated that fatty liver disease affects ~1/3 of the adult population or ~80 million Americans, and as many as ~2/3 of obese subjects in the United States (278, 279, 288). In a large population-based study (n = 2,287 subjects) performed in Dallas, Texas, in which liver fat was evaluated by means of the gold-standard MRS technique, 34% of the population had a fatty liver, being much more common in Hispanics (45%) compared to whites (33%) and African-Americans (22%) (288). That adult Hispanic are affected more than Caucasians and African-Americans has been confirmed by others even after adjusting for major confounding variables (94, 96, 99, 101, 291-294). Recent studies indicate that the prevalence of NAFLD is also rapidly increasing in children and adolescents, particularly in those of Hispanic ancestry (94, 291, 293), being strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia (105).

While obese patients with the MS and T2DM are more prone to fatty liver and develop more severe disease (NASH), the reasons are unclear and most other aspects of the disease in T2DM remain poorly understood. It is tempting to speculate that the liver is like a "metabolic sensor" with the degree of steatosis being a reflection of the ability of the body to cope with a lipotoxic environment. There is an increasing awareness that insulin resistance, lipotoxicity, and T2DM are major risk factors for fatty liver disease, necroinflammation, and fibrosis. Still the information available on the natural history of the disease with paired biopsies is limited to a handful of small studies (281-284). In these studies, involving from 22 to 103 patients with an average follow-up ranging from 3.2 (283) to 13.8 years (284), fibrosis progressed over time in 32-41% of patients with NAFLD (281-284). However, disease remained stable in 34-50% of patients and even improved in a minority. This has brought attention to try to dissect and understand better the prognostic factors that may lead to disease progression over time. Obesity (281-284) and T2DM (281-284) have been the two most prominent factors of poor prognosis, while elevated liver enzymes (ALT (aldnine aminotransferase) or AST (aspartate)/ALT ratio) have been of much less value to predict future disease, with levels frequently being normal even in cases of advanced disease. Some studies have compared subjects with NAFLD who had chronically elevated plasma ALT concentrations to individuals with persistently normal ALT levels and found that the prevalence of advanced fibrosis and cirrhosis was similar in both groups (295, 296). Consistent with this, others have reported that in the setting of diabetes liver enzymes are poor predictors of disease activity (297, 298). Complicating the issue is the accepted finding that AST tends to fall over time with the progression of fibrosis and development of cirrhosis (283), making liver transaminases unreliable to identify patients at greater risk of advanced disease or to monitor therapy.

Many studies have reported that long-term prognosis in NAFLD varies widely depending upon the initial stage at diagnosis and the presence or not of obesity, MS, or T2DM. For example, the vast majority of patients with cryptogenic cirrhosis are obese or have T2DM (299). Several studies have confirmed the strong impact of both factors, but in particular diabetes, to the progression of disease (e.g., fibrosis) (280-284, 295-298, 300-305). Angulo et al. found that the combination of diabetes and obesity were predictors of advanced fibrosis in 66% of patients (300). Hyperglycemia was identified as a key factor in disease progression in large early studies by Marceau et al. (n = 551) (303) and Luyckx et al. (n = 505) (304). Dixon et al. (302) reported that 60% of patients with T2DM and NAFLD had biopsy-proven NASH, and that advanced fibrosis was present in 75% of those with diabetes and hypertension vs. 7% without either condition. Haukeland et al. (305) reported that the presence of diabetes or impaired glucose tolerance (IGT) increased by 3.8-fold the risk of fibrosis in patients with an unexplained elevation in LFT, diabetes being the only independent risk factor for NASH. Mofrad et al. (295) found that in patients with NAFLD and normal LFTs, 24% had severe fibrosis and >10% cirrhosis, concluding that normal plasma ALT levels does not guarantee freedom from underlying advanced fibrosis. Again, in this study diabetes was the only factor independently associated with increased risk of advanced fibrosis. Even if a low initial fibrosis stage is found, the presence of diabetes per se is a risk factor for progression (283).

Given the poor prognosis that the combination of T2DM and NAFLD have, it is quite surprising that few studies have focused on screening patients with diabetes for NASH. A prospective study conducted by Gupte et al. (306) reported biopsy-proven NASH in 87% of diabetics, 22% having moderate to severe disease. In a retrospective analysis of 44 patients with T2DM worked-up for NAFLD, Younussi et al. also found that cirrhosis was more prevalent in diabetics vs. nondiabetics (25% vs. 10%, p < 0.001) (301). More importantly, diabetics had increased not only liver-related mortality but also CV mortality was increased as well, consistent with recent epidemiological studies (285, 286, 307). Moreover, by logistic regression analysis, the severity of histological features of NAFLD independently predicted carotid intima medial thickness or CIMT (a marker of atherosclerosis burden) (p < 0.001) after adjustment for all potential confounders .307) . In another study in 38 patients with NAFLD, in the absence of morbid obesity, hypertension, and diabetes, had altered left ventricular geometry and early features of left ventricular diastolic dysfunction (308). While patients with T2DM are known to have increased CVD (309), long-term studies have indicated that CVD is also the most common cause of death of patients with NAFLD, even after adjusting for classical CV risk factors (284). NAFLD may increase CVD in T2DM by promoting a number of atherogenic risk factors, including chronic hyperinsulinemia (insulin resistance per se is known to be atherogenic) (40, 310-312), by promoting atherogenic dyslipidemia (increased VLDL production, leading to a lowering HDL-C and small dense LDL-C) (86, 313, 314), and by the induction of systemic inflammation (64, 223, 315).

It has also been postulated that insulin resistance and/or its clinical correlate of the MS are the most reliable indicators of disease severity and future progression (289, 316). In a study by Sorrentino et al. (296) in 80 patients with NAFLD but normal liver enzymes, 65% had NASH and 35% fibrosis, with the presence of the MS and long-standing history of obesity being the strongest predictors of disease, but not liver transaminase levels. Recently, Gholam et al. (317) reported in 97 obese individuals a 36% prevalence of NASH and 25% of fibrosis with hyperglycemia (A1c level), insulin resistance, and the MS, but not BMI, being strongly associated with NASH and fibrosis. Even modest increases in body weight and plasma triglycerides appear to support the role of insulin resistance in NAFLD, as suggested in an elegant study by Ratziu et al. (318) that found that a BMI >28 kg/m2 and elevated triglycerides >145 mg/dL were both useful predictors of the severity of liver fibrosis. Even in nonobese, nondiabetic patients, the presence and severity of NAFLD can be strongly predicted on the basis of insulin resistance, central obesity, and elevated triglycerides (319).

In summary, obese insulin-resistant T2DM patients are at the highest risk of fatty liver disease and progression to NASH and that NAFLD should be aggressively pursued in this population, although still today little is done to identify patients with the condition in routine clinical practice. The clustering of MS, T2DM, and NAFLD does not occur by chance, these conditions being tied together by the lipotoxi-city brought about by adipose tissue insulin resistance. Lipotoxicity creates a permissive environment for NAFLD. However, despite the accepted role of excessive fat supply and inflammation to the pathogenesis of NAFLD, we cannot satisfactorily explain why some lean subjects develop NASH or some obese (or T2DM) individuals are spared from developing a fatty liver. Moreover, why fatty liver evolves into NASH in only ~30-40% of patients or cirrhosis in just ~10% is puzzling. It is possible that if more careful measures of insulin resistance and/or FFA metabolism are done we will be able to identify a profile of subjects prone to NAFLD and/or NASH, although it is likely that development of disease will depend on the adaptive flexibility of target tissues, primarily the liver, to adapt to the insult.

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