Sitosterolemia (Phytosterolemia)

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Sitosterolemia, also known as phytosterolemia, is a rare inherited plant sterol storage disease. Bhattacharyya and Connor first described this disease in 1974. [1, 2] The original report detailed 2 sisters who presented with extensive tendon xanthomas but normal plasma cholesterol levels. Subsequently, they were found to have significantly elevated plasma levels of plant sterols in the form of beta-sitosterol, campesterol, and stigmasterol.

Sitosterolemia is characterized by tendon and tuberous xanthomas and by a strong propensity toward premature coronary atherosclerosis. [3, 4]

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Significant increases of plant sterols (ie, phytosterols) are found in blood and various tissues. Arteries and xanthomas in patients with sitosterolemia contain increased amounts of these sterols, particularly sitosterol, stigmasterol, campesterol, and their 5-alpha derivatives.

Untreated, the condition causes a significant increase in morbidity and mortality. Coronary heart disease and its inherent health consequences are the primary causes of illness and premature in untreated patients. With treatment, cholesterol levels can normalize, and xanthomas can completely regress.

A clue to sitosterolemia diagnosis in a patient with highly elevated plasma cholesterol level is parents with normal cholesterol levels.

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 . [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 . 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 . The pathophysiologic causes of coronary heart disease in sitosterolemia, especially concerning the effects of plant sterol and stanol intake, have been debated. [8]

The intestinal pathway for cholesterol absorption is beginning to be elucidated. Mutations in the ABCG8 and ABCG5 genes were recently identified as the underlying cause of sitosterolemia. The active pumping back into the intestine of passively absorbed plant sterols is disrupted, and hepatic secretion of the resultant accumulation of these sterols is decreased. Animal studies have revealed that expression of G5 and G8 in either intestine or liver is sufficient to limit accumulation of plasma phytosterols in animal models of sitosterolemia, but expression in both tissues is required to maintain the very low levels observed in wild type animals. [9]

The ability of the liver to preferentially excrete plant sterols into the bile is apparently impaired. Although bile acid synthesis remains the same as in healthy people, the total excretion of sterols in the bile is reportedly less than 50% in subjects with sitosterolemia compared with control subjects. The mechanism for decreased hepatic secretion is unknown.

Sitosterolemia was originally thought to be associated with a single inherited defect in the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase gene, but more recent studies suggest that inadequate cholesterol production in sitosterolemia is due to abnormal down-regulation of early, intermediate, and late in the cholesterol biosynthetic pathway.

Patients have markedly reduced whole-body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte HMG-CoA reductase, the rate-controlling enzyme in the cholesterol biosynthetic pathway.

Whether or not the down-regulation is due to accumulated sitosterol is still debatable, but most recent data indicate that secondary effects of unknown regulators other than sitosterol can lead to reduced HMG-CoA reductase activity in the disease. This is coupled with significantly increased LDL receptor expression.

The precise relationship between enhanced sterol absorption, hepatic sterol retention, and down-regulation of cholesterol biosynthesis underlying the disorder remains unknown; however, identification of these processes as characteristics of the disorder has led to viable treatment options.


Sitosterolemia is thought to be a very rare disorder. Only approximately 40 patients had been identified worldwide by 2000. More than likely, sitosterolemia is significantly underdiagnosed. Many patients are probably misdiagnosed with hyperlipidemia; therefore, assay of plasma sterol levels, the definitive diagnostic test for sitosterolemia, is not performed.

Little toxicity occurs, and no obvious adverse effects are associated with phytosterols in healthy individuals. However, when individuals have sitosterolemia, they have significant morbidity and increased risk for premature mortality. Coronary heart disease and its inherent health consequences are the primary causes of illness and premature death in patients with sitosterolemia.

Xanthomas occur most prominently in the extensor tendons of the hands and Achilles tendon. They can cause significant discomfort, interfere with mobility, and have cosmetic implications. One case of spinal cord compression secondary to multiple intradural extramedullary xanthomas has been reported.

Males with sitosterolemia have a high prevalence of accelerated atherosclerosis leading to coronary heart disease and subsequent premature death. The high content of plant sterols in the circulatory lipoproteins has been postulated to possibly promote their deposition in the arterial walls. Deaths have been reported in adolescent males as young as 13 years caused by coronary arthrosclerosis and secondary infarction. Angina pectoris has been reported in a 12-year-old girl.

Hemolysis and platelet abnormalities, including thrombocytopenia, have been described. Ezetimibe ameliorates the effect on platelets. [10] Episodic hemolysis has been reported in several patients. Stomatocytes and giant platelets may be seen. [11] Erythrocytes have been shown to contain increased amounts of sitosterol, rendering the cell membrane more rigid and, therefore, more prone to lysis and rupture.

The clinical, biochemical, and molecular genetic features (mainly manifested by hematologic abnormalities) of a Chinese family with sitosterolemia were reported. [12] The main clinical features of these patients were hemolysis and macrothrombocytopenia. The authors suggested that blood cells could be a target for the toxic effect of plant sterols in blood. Another report of a case with macrothrombocytopenia, stomatocytic hemolysis, and splenomegaly without other obvious features of the condition was described. [13]

Arthralgias and arthritis can occur particularly in the knee and ankle joints.

Trace amounts of unsaturated plant sterols and cholesterol have been found in the brain tissue of people with sitosterolemia. The only identified neurological complication to date is one reported case of paraplegia secondary to spinal cord compression by multiple intradural extramedullary xanthomas.

In patients with sitosterolemia, 5α-stanol accumulation may be associated with thyroid function. Ezetimibe reduces circulating 5α-stanol levels while increasing levels of FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. [14]

Abnormal liver function test results can be observed, and liver cirrhosis has been reported at least once with successful treatment by liver transplant. [15] Heterozygotes are likely healthy, [16] although an elevated plasma plant sterol concentration of 3.07 mg/dL was found in one heterozygote. [17]

Only approximately 40 patients with sitosterolemia had been reported worldwide as of the year 2000; therefore, very little information on racial or ethnic predilection is available, especially because bias of ascertainment is likely. No ethnic predilection is apparent in sitosterolemia, although the small number of patients diagnosed makes it premature to draw any conclusions.

Sitosterolemia has been described in Amish, Hutterite, Japanese, and Chinese patients, as well as in other patient population groups.

Sitosterolemia is an autosomal recessive genetic condition; therefore, no sex predilection is noted. Males may be more prone to the severe complications of sitosterolemia.

The condition can manifest at any age. Xanthomas have been reported in patients as young as 18 months.

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Robert D Steiner, MD Chief Medical Officer, PreventionGenetics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Americal College of Medical Genetics, Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma; Biomarin; PreventionGenetics<br/>Received research grant from: Alexion<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma; Biomarin; Prevention Genetics<br/>Travel Support for: Pfizer.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Luis O Rohena, MD, FAAP, FACMG Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Patricia Campbell, MD, to the original writing and development of this article.

Sitosterolemia (Phytosterolemia)

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