A 46-year-old man comes to the office due to a sensation of right upper-quadrant fullness. He has been obese since early adolescence. Past medical history is notable for type 2 diabetes mellitus and hypertension. His current medications include metformin, candesartan, and hydrochlorothiazide. The patient does not use tobacco, alcohol, or illicit drugs. His father has type 2 diabetes mellitus. Temperature is 36.7 C (98 F), blood pressure is 138/90 mm Hg, pulse is 72/min, and respirations are 16/min. BMI is 36 kg/m². On examination, the patient has acanthosis nigricans over the neck creases and hepatomegaly. Laboratory results are as follows: Viral hepatitis serologies, antimitochondrial antibodies, antinuclear antibodies, serum ceruloplasmin, and transferrin saturation are normal. Which of the following is the most likely pathophysiologic mechanism responsible for this patient's increased liver enzymes?

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11ec25c8_d2fc_0010_bc81_a7bc456cc82f_MD0003_00 This patient's presentation (hepatocellular injury in the absence of viral hepatitis or autoimmune disease) is most consistent with nonalcoholic fatty liver disease (NAFLD). Affected patients are typically middle-aged, obese, and have features of the metabolic syndrome (eg, central obesity, diabetes mellitus, hyperlipidemia, hypertension). NAFLD can range from bland steatosis to inflammation and necrosis (steatohepatitis) to fibrosis and cirrhosis. Histologically, NAFLD can resemble alcohol-induced liver disease (macrovesicular fat deposition, peripheral displacement of nuclei) but occurs in patients with minimal or no alcohol history. NAFLD can be due to increased transport of free fatty acids (FFA) from adipose tissue to the liver, decreased oxidation of FFA in the liver, or decreased clearance of FFA from the liver (due to decreased VLDL production). It is frequently related to peripheral insulin resistance leading to increased peripheral lipolysis, triglyceride synthesis, and hepatic uptake of fatty acids. Hepatic FFA increases oxidative stress and production of proinflammatory cytokines (eg, tumor necrosis factor-alpha). (Choice A) Insulin decreases lipolysis in adipose cells. Insulin resistance, as seen in most patients with NAFLD, leads to increased lipolysis and FFA release. FFA are then transported to the liver, where they participate in pathogenesis of NAFLD and further contribute to insulin resistance by impairing insulin-dependent glucose uptake and increasing hepatic gluconeogenesis. (Choice B) Some patients with type 2 diabetes can have increased glucagon production. Although glucagon increases gluconeogenesis and glycogenolysis, it does not play a role in hepatic fat accumulation. (Choice C) Cushing syndrome can contribute to insulin resistance and NAFLD, but it would be unlikely in this patient with near lifelong obesity. (Choice D) Hepatic glycogen synthesis is usually decreased in type 2 diabetes and does not play a role in hepatic steatosis. Educational objective: Nonalcoholic fatty liver disease resembles alcohol-induced liver disease but occurs in patients with minimal or no alcohol history. It is associated with insulin resistance. Severity can range from bland steatosis to steatohepatitis to fibrosis and cirrhosis. References: Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches. (http://www.ncbi.nlm.nih.gov/pubmed/23855299) The epidemiology, pathogenesis and histopathology of fatty liver disease. (http://www.ncbi.nlm.nih.gov/pubmed/22372457)

A 46-Year-Old Man Comes to the Office Due to a Sensation