What is the pathophysiology of sitosterolemia (phytosterolemia)?

Updated: May 24, 2019
  • Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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The metabolic defect in the affected patient causes hyperabsorption of sitosterol from the GI tract, decreased hepatic secretion of sitosterol with subsequent decreased elimination, and altered cholesterol synthesis.

The defect associated with sitosterolemia manifests at 3 levels, culminating in greatly increased plasma sitosterol levels. Levels typically range from 10-65 mg/dL, with an average of 35 mg/dL. The reference range is 0.3-1 mg/dL but may increase to 9 mg/dL in infants fed commercial formulas high in vegetable oils. One report revealed extremely elevated plasma cholesterol in an affected breastfeeding infant. [5] Expanded total exchangeable pools of sitosterol (average 3500-6200 mg, with a reference range of 120-290 mg) are also evident.

Plant sterols are not synthesized endogenously in humans, including patients with sitosterolemia, but are derived entirely from the diet. Plant sterols are structurally similar to cholesterol except for substitutions at the C24 position on the sterol side-chain. Sitosterol has an added ethyl group.

Mammalian cells cannot use plant sterols. Plant sterols may normally be excluded because they are toxic in high doses. [6] Normally, plant sterols are poorly absorbed from the GI tract; fewer than 5% of plant sterols are absorbed compared with approximately 40% of cholesterol absorbed. The liver preferentially excretes plant sterols over cholesterol. Dietary sterols have recently been shown to passively enter intestinal cells, and, subsequently, the vast majority are pumped back into the gut lumen by ATP-binding cassette (ABC) transporter proteins.

Sitosterolemia has been shown to result from mutations in either of the genes for 2 proteins (ABCG5 or ABCG8). These ABC transporters preferentially pump plant sterols out of intestinal cells into the gut lumen and out of liver cells into the bile ducts, thereby decreasing sterol absorption. Consequently, the body absorbs only a small percentage of the plant sterols that reach the intestine. Absorbed sterols are packaged into chylomicrons for transport to the liver. In the liver, cholesterol and plant sterols may be transported to peripheral tissues by very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), converted to bile acids, or transported out of the liver into the bile for excretion.

In peripheral tissues, the ABC1 transporter (defective in Tangier disease) delivers cholesterol to high-density lipoprotein (HDL) for return to the liver. Phytosterols are metabolized in the liver into C21 bile acids via liver enzymes. Phytosterols have been shown to reduce serum and plasma total cholesterol and LDL levels in healthy individuals. [7] Little toxicity occurs, and no obvious adverse effects are associated with phytosterols when present in healthy individuals; however, in the disease state, toxicity is manifested by significant morbidity and increased risk for premature death. The pathophysiologic causes of coronary heart disease in sitosterolemia, especially concerning the effects of plant sterol and stanol intake, have been debated. [8]

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