The topic of fatty liver/elevated liver enzymes comes up a lot here, so I thought I'd post an interesting article I ran across. It discusses a study that points to a link between fatty liver and insulin resistance, and suggests insulin resistance itself, apart from obesity, as a cause for fatty liver. Later in the article, it suggests that insulin-sensitizing agents such as Metformin may actually be helpful in treating the condition of NAFLD (Non-Alcoholic Fatty Liver Disease). By the way, this condition is also associated with iron overload, and I read on another site that women with PCOS are especially vulnerable to this and that we should be careful not to take supplements containing iron (unless one is diagnosed with iron deficiency):
http://www.medforum.nl/idm/fatty_liv...istance___.htm
Fatty liver, hepatic insulin resistance and the metabolic syndrome
Original article:
Nonalcoholic fatty liver disease. A feature of the
metabolic syndrome. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Diabetes 2001; 50: 1844–50.
Summary
In order to test the hypothesis that non-alcoholic fatty liver disease (NAFLD) might represent another feature of the metabolic syndrome, with decreased insulin sensitivity being the common factor, Marchesini and colleagues measured insulin sensitivity by means of the euglycaemic clamp technique in a group of 30 patients with NAFLD, and compared the results with values obtained in 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects used as controls.
Of those subjects with NAFLD, nine had pure fatty liver and 21 had evidence of steatohepatitis. Most patients with NAFLD had central fat accumulation, increased triglyceride and uric acid levels, and low HDL cholesterol concentrations, irrespective of BMI.
Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, to an extent similar to that of type 2 diabetic patients (Fig. 1A).
Fig. 1: (A) Glucose disposal during the euglycaemic clamp and (B) hepatic glucose production in control subjects (n = 5), patients with type 2 diabetes (n = 5) and NAFLD subjects (n = 10); and (C) plasma FFA concentrations in control subjects (n = 10), patients with type 2 diabetes (n = 10) and NAFLD subjects (n = 30). Data are presented as means and 95% CI.
Postabsorptive hepatic glucose production (HGP), measured by [6,6-2H2]glucose, was normal. However, in response to insulin infusion, HGP decreased by only 63% of basal values in NAFLD vs. 84% in control subjects (p = 0.002), an impairment similar to that seen in type 2 diabetic patients (Fig. 1B). In NAFLD patients, basal free fatty acid (FFA) levels were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs. -84% in control subjects; p = 0.003). Again, the latter abnormalities were similar in NAFLD subjects and diabetic patients (Fig. 1C). There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological and biochemical data (including insulin sensitivity) were not correlated with iron status.
The authors concluded that NAFLD, even in the presence of normoglycaemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance.
Comment
The presence of fatty liver in patients with obesity and type 2 diabetes has long been reported. Patients with fatty liver and hepatitis are identified as having non-alcoholic steatohepatitis (NASH), a condition which has been found to be associated with clinical and biological markers of the metabolic syndrome [1, 2]. Interestingly, several studies have demonstrated that weight loss is associated with a parallel regression of biological markers of NASH (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) and biological markers of the insulin resistance syndrome (hyperinsulinaemia, high triglyceride levels, low HDL cholesterol concentrations and hyperuricaemia) [3].
The present study confirms that NAFLD is characterized by a remarkable reduction in insulin sensitivity, with decreased insulin effects on both glucose and lipid metabolism. Such a defect is not exclusively associated with abnormal glucose regulation and/or overweight as is frequently observed in NAFLD, but also extends to subjects with normal glucose tolerance and normal weight. Indeed, to rule out diabetes as a primary cause of insulin resistance, only NAFLD subjects with normal fasting glucose and glucose tolerance were selected for the present study. In addition, although total fat mass and intra-abdominal fat were not quantitatively measured, one-third of NAFLD patients had normal body weight, and there was no significant difference in glucose disposal during the clamp between normal-weight and overweight NAFLD subjects, a finding which rules out the possibility that obesity plays a significant role in the present study. Taken together, these data suggest that insulin resistance in NAFLD might be a primary phenomenon, sometimes in addition to obesity- and diabetes-associated insulin resistance.
In NAFLD patients, HGP was normal or high-normal in the fasting state, despite basal hyperinsulinaemia, and liver did not switch off glucose production in response to insulin infusion, indicating the presence of liver insulin resistance. Comparing NAFLD with type 2 diabetes, it appears that the two conditions are very similar in the presence of different fasting glucose levels and overall glucose metabolism. Liver insulin resistance in NAFLD might theoretically derive from liver damage itself, as is commonly observed in patients with cirrhosis, but this is not the case in the present study. It might also result from hypertriglyceridaemia and high FFA levels: a striking lipid abnormality in NAFLD patients was the higher basal FFA concentrations and the lower-than-normal decrease in plasma FFA levels in response to insulin infusion, a finding which may be associated with
relatively increased visceral adiposity found in most NAFLD patients even in the presence of normal body weight. Finally, hepatic insulin resistance might be related to iron overload. The present study confirmed that serum indices of iron overload (increased ferritin, low unsaturated transferrin and higher-than-normal transferrin saturation) are present in most patients with NAFLD. In addition, an appreciable proportion of these patients (4 out of 30) was heterozygous for mutation His63Asp of the hemochromatosis gene HFE. However, iron status did not classify patients according to the histological severity of their liver disease, and serum indices of iron overload did not correlate with measures of insulin sensitivity. Accordingly, hepatic iron might be one but not the only agent causing hepatic insulin resistance and ongoing fatty liver disease in these patients.
The possible relevance of impaired insulin sensitivity in the pathogenesis of NAFLD has potential therapeutic implications that must be tested in clinical studies. In obese subjects, a weight-reducing intervention programme is likely to reduce the obesity-related insulin resistance, which might be partly responsible for liver fat deposition. A parallel reversibility of biological markers of the metabolic syndrome and histological findings of liver steatosis was observed after gastroplasty-induced weight loss in severe obesity [3]. Alternatively, insulin sensitizer agents, such as metformin and thiazolidinediones, might break the vicious circle linking hyperinsulinaemia and insulin resistance to elevated triglyceride and FFA concentrations, and NAFLD, including progressive steatosis, inflammatory reactions (NASH), ultrastructural mitochondrial lesions in the hepatocytes, and ultimately hepatocyte death. A pilot study demonstrated an early and significant response by ALT and AST measurements in 10 NASH patients treated with the first available thiazolidinedione, troglitazone [4]. However, this was associated with only mild improvement in necroinflammatory grade, and all of the biochemical responders showed persistent steatohepatitis in the follow-up liver biopsies. Considering the well-known hepatotoxicity related to troglitazone (which resulted in the withdrawal of the drug from the market), and even if this liver complication does not appear to be shared by rosiglitazone and pioglitazone [5], such pharmacological intervention with glitazones in NAFLD should be considered with caution and must first be validated in large, prospective, controlled clinical trials.
Linda