Wednesday, November 29, 2023
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Paris, France; Friday, April 15, 2005 -- Nonalcoholic fatty liver disease (NAFLD) has recently emerged as the most common cause of abnormal liver function tests seen in patients presenting to practicing gastroenterologists and hepatologists, with the overall prevalence of NAFLD in the developed world estimated to be between 20% and 30%. The realization that a proportion of patients with NAFLD can progress through steatohepatitis and fibrosis to full-blown cirrhosis and liver cancer has further focused the attention of the liver community on this condition, previously considered to be benign. At present, the 2 most important clinical problems faced by clinicians managing patients with NAFLD are: (a) how to distinguish patients with progressive disease from those with "simple" fatty liver without resorting to an invasive and potentially life-threatening liver biopsy, and (b) how to treat patients with advanced disease. Several presentations at this year's meeting of the European Association for the Study of the Liver (EASL) focused on these 2 issues and are the focus of this commentary.
It has been appreciated for some time that structural and functional alterations of mitochondria have been described in humans with nonalcoholic steatohepatitis (NASH) and in animal models of disease. (NASH is a histology-based diagnosis and is thus part of a spectrum of fatty conditions of the liver referred to collectively as NAFLD.) Portincasa and colleagues[1] demonstrated that a simple breath test of mitochondrial function (13C- ketoisocaproate [KICA]) could discriminate obese patients with NASH from healthy controls and obese patients with normal livers. Lemoine and colleagues[2] exploited the fact that a variety of cytokines released by adipose tissue -- so-called adipokines -- are considered to play a role in the pathogenesis of NASH, and determined whether serum levels of different adipokines could predict disease severity in patients with NAFLD. They reported that when combined with an index of insulin resistance -- the HOMA index -- the ratio of adiponectin to leptin had a sensitivity of 90% and a specificity of 88% for the diagnosis of NASH, whereas the serum level of another adipokine, interleukin-6, was associated with the stage of fibrosis and the patient's age. The association of the adiponectin/leptin ratio with disease stage was also reported by Day and colleagues,[3] who also showed that serum levels of soluble tumor necrosis factor (TNF) receptor 2 (sTNFR2) increased with the histologic severity of NAFLD.
These reports, considered together with earlier studies in the literature, suggest that serum adipokines may offer real potential for the noninvasive assessment of NAFLD.
Dr. G.I. Shulman from Yale University in his State-of-the-Art lecture on insulin resistance and the liver,[4] described the crucial role of hepatic and muscle fat accumulation in the pathogenesis of insulin resistance, hyperglycemia, and diabetes associated with obesity and aging. He also discussed a recent study[5] demonstrating that in obese patients, weight loss of as little as 8 kg is enough to completely clear fat from the liver, improve insulin sensitivity, and return fasting blood glucose to normal -- providing further rationale for advocating weight loss as the central strategy for the management of patients with NAFLD.
Additional support for this strategy came from a study from Israel[6] reporting that weight loss, based on a 25 kcal/kg ideal body weight/day diet for 6 months, resulted in a significant reduction in hepatic steatosis (60% to 30%) and fibrosis in 48 patients with primary NAFLD. Some of these patients also received the pancreatic lipase inhibitor orlistat, although there did not appear to be any additional benefit from the use of this drug.
Shulman also referred to studies in diabetics showing a reduction of liver fat following treatment with the thiazolidinedione, rosiglitazone, as well as to pilot (nonrandomized, noncontrolled) studies in patients with NASH with both rosiglitazone and pioglitazone, showing a reduction in hepatic steatosis, necroinflammation, and fibrosis. No human studies on the thiazolidinediones were reported at this year's EASL meeting, although 1 study from France conducted in patients with NASH demonstrated that the hepatic expression levels of the target for the thiazolidinediones -- the transcription factor PPAR (peroxisome proliferator activated receptors)-gamma -- correlated with the severity of steatosis,[7] suggesting that this class of drugs may actually worsen hepatic steatosis. Clearly, data from large, randomized, controlled trials of these drugs in patients with NAFLD are required before they can be routinely recommended for the treatment of nondiabetics with NAFLD. Such trials are currently ongoing in the United States.
As a further way of reducing insulin sensitivity, Guzzo and colleagues,[8] treated patients with NAFLD with phlebotomy until iron depletion was reached, with the rationale that this strategy may improve insulin sensitivity and, therefore, NAFLD. Insulin sensitivity, assessed by the HOMA method and liver function tests, improved significantly after phlebotomy in patients maintained on a weight-reducing hypocaloric diet. This finding confirms a previous Italian study and suggests that phlebotomy is worth subjecting to a formal randomized controlled clinical trial in patients with NAFLD.
Finally, a study from the United Kingdom[3] provided evidence that gut bacteria may play a role in both disease progression in NAFLD as well as the development of insulin resistance and the other features of the metabolic syndrome. Blood levels of endotoxin -- a constituent of gut bacterial cell walls -- were higher in patients with NAFLD than controls, and correlated with markers of systemic inflammation and the presence of diabetes. These findings clearly suggest the possibility that strategies aimed at reducing this bacteria -- such as the use of anti- or probiotics -- may be worthy of consideration in the treatment of NASH/NAFLD.
As evidenced by key presentations at this year's EASL meeting, issues in NAFLD/NASH remain a formidable challenge for the practicing gastroenterologist/hepatologist. It is hoped that the above discussion helps to contextualize these issues in the appropriate clinical setting, and offers a view regarding future directions in the field.
