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Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children
No full textIn their comment to our report (1), Fraser et al raise several issues that were not settled in our study. The first problem is the persistence into adulthood of the insulin resistance generated by intrauterine growth retardation (defined as small for gestational age) (SGA) and its potential for NAFLD. Very low birth weight confers an increased susceptibility to insulin resistance and metabolic diseases in adulthood (2), not attributable to body size composition or fat distribution. In adults born SGA, liver fat deposition and altered liver function tests may be part of a central axis of abdominal obesity. Dual-energy X-ray absorptiometry documented a moderately higher degree of abdominal obesity in young men born SGA, independently of BMI and waist-to-hip ratio, associated with an impairment of the insulin-stimulated glycolytic flux and a reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake (3). Ectopic fat accumulation in adults born SGA may thus derive from an abnormal function of the adipose tissue, suggested by hypoleptinemia, compared with individuals with normal weight at birth, even after correction for fat mass, gender and hyperinsulinemia (4).
A second issue regards a possible gender difference in the risk of NAFLD associated with several variables. On the basis of indirect evidence, we have previously speculated that the circulating levels of estrogens within the physiologic range might be responsible for a “protective” effect on the development of steatosis (due to both NAFLD and, presumably virus-related steatosis (5). This would imply that, similar to what happens in cardiovascular disease, women in the fertile age are more spared than men from the development of steatosis and that this protection vanes after the menopause. Whether this also happens in SGA steatosis and NAFLD occurring in childhood remains to be determined. The relatively small size of our cohort does not allow a robust analysis in relation to gender. Whereas in males the association of SGA with NAFLD is maintained (OR, 9.59; 95% confidence interval, 2.52-36.52), the association is no longer significant in females (OR, 4.21; 0.58-30.66), but less than 25% of our NAFLD females were in the postpubertal age
Is liver disease a threat to patients with metabolic disorders?
No full textSummary
The association of metabolic disorders with liver disease is receiving increasing attention in the gastroenterological community. Cohort studies have shown that advanced liver disease may stem from metabolic disorders, via fatty liver, non-alcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. In both obesity and diabetes, deaths for cirrhosis are higher than expected, mainly in subjects with no or moderate alcohol consumption, but high rates of fatty liver disease have been associated with all features of the metabolic syndrome. Also the risk of hepatocellular carcinoma is higher-than-normal, being BMI-dependent in obesity, and independent of age, BMI, gender and race in diabetes. Finally, metabolic liver disease may interact with hepatitis C virus infection, increasing the risk of steatosis and liver disease progression, as well as reducing the chances of an effective antiviral treatment. There is evidence that treatments aimed at reducing insulin resistance are also effective in improving liver histology. Although cardiovascular disease remains the major cause of increased morbidity and excess mortality in metabolic disorders, the risk of progressive liver disease should no longer be underestimated, being a threat to millions people at risk in the present epidemics of obesity and diabetes, and therapeutic strategies need to be tested
NASH and the risk of cirrhosis and hepatocellular carcinoma in Type 2 diabetes
No full textThe risk of chronic liver disease and liver-related mortality is increased in patients with type 2 diabetes mellitus. Several cohort studies have suggested a metabolic pathway from nonalcoholic fatty liver, nonalcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. Although cardiovascular risk remains the major cause for excess mortality in type 2 diabetes mellitus, the risk of progressive liver disease should no longer be underscored
Insulin resistance in nonalcoholic fatty liver disease
No full textAbstract: Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is considered the hepatic component of the metabolic syndrome and insulin resistance represents its pathophysiological hallmark. Insulin resistance in NAFLD is characterized by reduced whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanism(s) underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Liver fat is highly correlated with all the components of the metabolic syndrome, independent of obesity, and NAFLD may increase the risk of type 2 diabetes and atherosclerosis. Overproduction of glucose, very low-density lipoproteins, C-reactive protein and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease. The reason(s) why some patients will develop NASH are poorly understood. Circulating free fatty acids may be cytotoxic by inducing lipid peroxidation and hepatocyte apoptosis. Insulin resistance is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes may contribute liver damage and liver disease progression. Understanding the molecular mediators of liver injury would promote the development of mechanism-based therapeutic interventions. This article briefly summarizes the recent advances in our understanding of the relationship between NAFLD/NASH, insulin resistance and the metabolic syndrome
Insulin resistance: a metabolic pathway to chronic liver disease
No full textABSTRACT
Insulin resistance is the pathophysiologic hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. In this article, we review the definition, the methods for the quantitative assessment of insulin action, the pathophysiology of insulin resistance and its role in the pathogenesis of chronic liver disease. Increased free fatty acid (FFA) flux from adipose tissue to non-adipose organs, which is a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a pro-inflammatory state, which may be limited to the liver or more extensively expressed throughout the body. Insulin resistance is the common soil of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscle, pancreas, kidney, heart, and the immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances insulin resistance and the phenotypic expression of NAFLD in individual patients. Advanced fibrotic liver disease is associated with multiple features of the metabolic syndrome and the risk of progressive liver disease should no longer be underestimated in subjects with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing insulin resistance in the liver (metformin) and in the periphery (thiazolidinediones) are discussed
Iron depletion by phlebotomy improves insulin resistance in patients with non alcoholic fatty liver disease and hyperferritinemia ; evidence from a multicenter case control study
No full textNon-alcoholic fatty liver disease/Non-alcoholic steatohepatitis (NAFLD/NASH): treatment
No full textAbstract
Non-alcoholic fatty liver disease is now recognized as a cause of potentially-progressive liver damage, posing patients at risk of advanced liver failure. Unfortunately, the natural history of disease is only partly known, the disease is slowly progressive and therapeutic outcomes are difficult to define. These factors have limited therapeutic trials to pilot studies, and very few randomized-controlled studies are available. The concept that insulin-resistance, coupled with oxidative stress, may be the underlying mechanism responsible for fat accumulation and disease progression points to insulin-sensitizing agents (metformin, thiazolidinediones) as the most promising drugs. They proved effective in reducing enzyme levels in the short period, but very limited information is available on liver histology, not to say progression to liver cell failure. Large, long-term, placebo-controlled randomized studies are eagerly awaited. Outside controlled studies, nutritional counselling and physical exercise aimed at moderate weight loss remain the basis of any therapeutic intervention
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