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Fatty liver phenotypes can help assess cardiometabolic risk in prediabetic patients

Insulin secretion failure, visceral obesity and fatty liver are three at risk phenotypes in people with diabetes.

Fatty change represents the intracytoplasmatic accumulation of triglycerides (neutral fats). At the beginning, the hepatocytes present small fat vacuoles (liposomes) around the nucleus (microvesicular fatty change). In this stage, liver cells are filled with multiple fat droplets that do not displace the centrally located nucleus. In the late stages, the size of the vacuoles increases, pushing the nucleus to the periphery of the cell, giving characteristic signet ring appearance (macrovesicular fatty change).

These vesicles are well-delineated and optically “empty” because fats dissolve during tissue processing. Large vacuoles may coalesce and produce fatty cysts, which are irreversible lesions. Macrovesicular steatosis is the most common form and is typically associated with alcohol, diabetes, obesity, and corticosteroids. Acute fatty liver of pregnancy and Reye’s syndromeare examples of severe liver disease caused by microvesicular fatty change.[6] The diagnosis of steatosis is made when fat in the liver exceeds 5–10% by weight.[1][7][8]

Mechanism leading to hepatic steatosis

Defects in fatty acid metabolism are responsible for pathogenesis of FLD, which may be due to imbalance in energy consumption and its combustion, resulting in lipid storage, or can be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased.[1][9]

Impairment or inhibition of receptor molecules (PPAR-α, PPAR-γ and SREBP1) that control the enzymes responsible for the oxidation and synthesis of fatty acids appears to contribute to fat accumulation. In addition, alcoholism is known to damage mitochondria and other cellular structures, further impairing cellular energy mechanism. On the other hand, non-alcoholic FLD may begin as excess of unmetabolised energy in liver cells. Hepatic steatosis is considered reversible and to some extent nonprogressive if the underlying cause is reduced or removed.

Micrograph of inflamed fatty liver (steatohepatitis)

Severe fatty liver is sometimes accompanied by inflammation, a situation referred to as steatohepatitis. Progression to alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH) depends on the persistence or severity of the inciting cause. Pathological lesions in both conditions are similar. However, the extent of inflammatory response varies widely and does not always correlate with degree of fat accumulation. Steatosis (retention of lipid) and onset of steatohepatitis may represent successive stages in FLD progression.[10]

Liver disease with extensive inflammation and a high degree of steatosis often progresses to more severe forms of the disease.[11] Hepatocyte ballooning and necrosis of varying degrees are often present at this stage. Liver cell death and inflammatory responses lead to the activation of hepatic stellate cells, which play a pivotal role in hepatic fibrosis. The extent of fibrosis varies widely. Perisinusoidal fibrosis is most common, especially in adults, and predominates in zone 3 around the terminal hepatic veins.[12]

The progression to cirrhosis may be influenced by the amount of fat and degree of steatohepatitis and by a variety of other sensitizing factors. In alcoholic FLD, the transition to cirrhosis related to continued alcohol consumption is well-documented, but the process involved in non-alcoholic FLD is less clear.

  • Non-alcoholic fatty liver disease (NAFLD) affects up to 25 percent of Americans, including children

  • If you have NAFLD, the first step for treatment should be to limit your fructose consumption to under 15 grams per day (including fruits)

  • Fructose is, in many ways, very similar to alcohol in the damage that it can do to your body… and your liver.

  • Eating right and exercising can often prevent this condition and may even reverse it in its early stages

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  • His findings were published in the Journal of the Academy of Nutrition and Dietetics,4 where Dr. Lustig explained the three similarities between fructose and its fermentation byproduct, ethanol (alcohol):
    1. Your liver’s metabolism of fructose is similar to alcohol, as they both serve as substrates for converting dietary carbohydrate into fat, which promotes insulin resistance, dyslipidemia (abnormal fat levels in the bloodstream), and fatty liver
    2. Fructose undergoes the Maillard reaction with proteins, leading to the formation of superoxide free radicals that can result in liver inflammation similar to acetaldehyde, an intermediary metabolite of ethanol
    3. By “stimulating the ‘hedonic pathway’ of the brain both directly and indirectly,” Dr. Lustig noted, “fructose creates habituation, and possibly dependence; also paralleling ethanol.”