Sitosterolemia (Phytosterolemia) 

Updated: May 24, 2019
Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

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]

See the image below.

Tuberous xanthomas. Courtesy of Duke University Me Tuberous xanthomas. Courtesy of Duke University Medical Center.

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 death 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.

Pathophysiology

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]

Hyperabsorption

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.

Reduced cholesterol synthesis

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 enzymes 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.

Epidemiology

Frequency

International

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.

Mortality/Morbidity

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[15] at least once with successful treatment by liver transplant.[16] Heterozygotes are likely healthy,[17] although an elevated plasma plant sterol concentration of 3.07 mg/dL was found in one heterozygote.[18]

Race

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.

Sex

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

Age

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

Prognosis

The prognosis for patients with sitosterolemia is not clear, given the extreme rarity of the disease. Early diagnosis and treatment correlate with a better outcome. Left untreated, sitosterolemia has significant morbidity and increased risk of early mortality. The availability of ezetimibe may dramatically improve the prognosis.

Patient Education

Dietary instruction by a licensed dietitian is helpful.

For excellent patient education resources, visit eMedicineHealth's Cholesterol Center. Also, see eMedicineHealth's patient education articles High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

 

Presentation

History

The history of patients with sitosterolemia may include lumps or bumps on the skin, chest pain, or myocardial infarction related to early coronary vascular disease.

Angina may be present.

Hemolytic episodes may occur.

History of arthralgias or arthritis, especially of the knees and ankles, may be present.

Individuals with sitosterolemia, especially young children, may present with extremely high LDL and total cholesterol levels. This is one cause of pseudohomozygous familial hypercholesterolemia.[19]

Physical

Xanthomas may appear at any age, even in childhood. These may be present as subcutaneous xanthomas on the buttocks in children or in usual locations (eg, Achilles tendon, extensor tendons of the hand) in children and adults.

Xanthelasma and corneal arcus are less common.

Signs of premature coronary vascular disease, such as congestive heart failure, may be present if a patient has had previous myocardial infarction.

Decreased range of motion with possible redness, swelling, and warmth of joints due to arthritis may be present.

Splenomegaly may be present.

Causes

Genetic evaluation of familial recurrences identified sitosterolemia as an autosomal recessive disorder. A disease locus was mapped to band 2p21 in 1998. The causative mutated genes for sitosterolemia, ABCG8 and ABCG5, were identified 2 years later. Interestingly, these 2 genes both map to band 2p21 directly adjacent to each other in opposite orientation and seem to be under common regulatory control.

No other locus is suspected given the different racial origins of the families and the fact that no evidence of genetic heterogeneity has been found.

Complications

Complications may include myocardial infarction, sudden cardiac death, painful hemolysis, and arthritis.

 

DDx

 

Workup

Laboratory Studies

The following studies are indicated in suspected or diagnosed sitosterolemia:

Plasma lipoprotein profile and plasma cholesterol levels should be obtained. The cholesterol level may be elevated or normal (in approximately 50% of patients). Many of the common assays for cholesterol level do not differentiate between cholesterol and plant sterols. Normally, cholesterol represents more than 99% of plasma sterols. Approximately 0.2% of plasma sterols is cholestanol, and another 0.2% is plant sterols. In sitosterolemia, cholesterol represents approximately 80% of total plasma sterols and plant sterols represent approximately 20%.

Blood plant sterol levels are ascertained by gas-liquid chromatography (GLC), gas chromatography/mass spectrometry (GC/MS), or high-pressure liquid chromatography (HPLC). Plant sterols, especially sitosterol, and the 5-alpha derivatives of plant sterols are dramatically elevated in patients with sitosterolemia. Care must be taken when evaluating infants because infants taking commercial formulas with large amounts of vegetable oil may have elevated sitosterol levels (≤ 9 mg/dL according to the literature, and ≥ 13 mg/dL based on personal experience).

Children with parenteral nutrition associated cholestasis may have plasma concentrations of plant sterols as high as those seen in patients with hereditary sitosterolemia (ie, total plant phytosterols of 1.3-1.8 mmol/L). Intralipid typically contains cholesterol, sitosterol, campesterol, and stigmasterol, the latter 3 of which are plant sterols. Adults receiving parenteral nutrition may also have elevated plasma plant sterol levels.[20]

Chromatographic analysis of sterols is the only reliable diagnostic test for this condition; however, with the recent identification of the disease genes (ie, ABCG8, ABCG5), molecular diagnosis is now possible and useful in diagnostic confirmation. Next-generation sequencing can prove useful in differentiating sitosterolemia from other conditions when hyperlipidemia and/or xanthomas are present.[21]

CBC count is indicated. Hemolytic anemia, either chronic or episodic, and sometimes with stomatocytosis may be present; platelet abnormalities, such as thrombocytopenia especially macrothrombocytopenia, are sometimes encountered.[22]

Liver function testing is indicated.

Imaging Studies

Coronary angiography may be useful in select cases.

Procedures

Once sitosterolemia is diagnosed, depending on the patient's age, coronary arteriography may be indicated.

Arteriography may reveal coronary artery stenosis.

Histologic Findings

Biopsies of xanthomas in patients with sitosterolemia contain increased levels of plant sterols.

Liver histology has been normal to date in reported cases.

The changes of atherosclerotic coronary artery disease are observed.

 

Treatment

Approach Considerations

Treatment of sitosterolemia may include dietary changes, pharmacologic agents, and/or surgical intervention. A diet low in plant sterols may be recommended. Bile acid-binding resins may be administered. An ileal bypass may be indicated. However, even with treatment, plant sterol levels may not be reduced to normal.[23] Ezetimibe has become the treatment of choice. After 3 years of treatment in a young child, carotid artery intima media thickness (cIMT) was stable in diameter and arterial wall echogenicity had improved.[24] Arthritis may require treatment. Treat chronic anemia and/or thrombocytopenia, if present.

Medical Care

Medications are occasionally used in the treatment of sitosterolemia. Dietary therapy was formerly the recommended initial treatment, but newer therapies (see below) have supplanted dietary therapy. If dietary treatment alone is attempted and insufficient, bile acid-binding resins (eg, cholestyramine) could be considered.

In October 2002, a new cholesterol absorption inhibitor, ezetimibe, received US Food and Drug Administration (FDA) approval for use in sitosterolemia. Because the mechanism by which it inhibits cholesterol absorption is quite specific, the adverse effects and drug interactions associated with the resins should not be expected.

Ezetimibe can increase platelet count and decrease mean platelet volume, thereby potentially reducing the risk for bleeding in sitosterolemia.[25]

A multiple center collaborative randomized placebo-controlled study of ezetimibe 10 mg/d in patients aged 10 years and older determined that ezetimibe was well tolerated and efficacious in reducing plant sterol levels compared with a placebo.[26] Plasma cholesterol levels, if elevated, fall dramatically in patients treated with ezetimibe. Plasma plant sterol levels fall also but often not to normal levels.

A study in China documented the successful use of ezetimibe in several young children, although a child younger than 2 years did not initially respond.[5] The long-term efficacy and safety of ezetimibe in sitosterolemia have been documented.[27] In contrast with patients with adult sitosterolemia who typically reached full treatment response within 2–8 weeks of treatment,[26] 4 months of treatment was required to significantly lower the sterols in the children reported in the study in China.

Little data on the use of ezetimibe in children younger than 10 years are available. Information on the use of medications other than cholestyramine and ezetimibe in sitosterolemia is limited. Recently, administration of ezetimibe added to cholestyramine was reported in a patient with sitosterolemia with remarkably positive results.[28]

Surgical Care

Ileal bypass has been performed in select cases to decrease the levels of plant sterols in the body.

Consultations

See the list below:

  • Cardiologist - For assistance with treatment and evaluation of coronary artery disease

  • Lipid disorder specialist - May assist with diagnosis and treatment

  • Dietitian - To educate patient regarding low plant sterol diet

  • Medical geneticist, metabolic disease specialist, or both - Helpful in establishing diagnosis, coordinating molecular testing of causative genes, providing potential genetic counseling, and implementing treatment (With identification of disease genes, prenatal counseling and diagnosis may become available.)

  • Rheumatologist - Optional depending on if arthritic symptoms exist

  • Hematologist - Optional depending on if hemolysis, anemia, thrombocytopenia, or hypersplenism exists

Diet

With the advent of treatment with ezetimibe, dietary therapy may not be needed.

If dietary therapy is indicated, a diet with the lowest possible amounts of plant sterols is advised. Guidelines are as follows:

  • Eliminate all sources of vegetable fats.

  • Avoid all plant foods high in fat, such as olives and avocados.

  • Eliminate vegetable oils, shortening, and margarine.

  • Eliminate nuts, seeds, and chocolate.

  • Avoid shellfish.

  • Cereal products without germ are allowed.

  • Food derived from animal sources with cholesterol as the dominant sterol is allowed.

Diet is quite restrictive, but references for acceptable commercial products, possible menus, and recipes are available.[29, 30]

Long-Term Monitoring

Monitor plant sterol levels in plasma to assess treatment efficacy.

Further Inpatient Care

Inpatient care is usually not necessary in patients with sitosterolemia unless significant heart disease, hemolysis, or severe arthritis is present.

Transfer

Blood sterol analysis, which is the only diagnostic test for sitosterolemia, is a specialized test available in only a few laboratories. Transfer of the patient or a specimen may be warranted.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Ezetimibe improves VLDL and HDL subfraction distribution, thereby reducing the atherogenic lipid profile, thus providing potential clinical benefit in sitosterolemia even beyond cholesterol and plant sterol reduction.[31]

Bile acid-binding resins

Class Summary

These agents are used as lipid-regulating drugs to modify blood lipid concentrations. They are used in the management of hyperlipidemias and for the reduction of cardiovascular risk. They lower cholesterol by combining with bile acids in the gastrointestinal tract, thus preventing their reabsorption. This leads to increased cholesterol oxidation to replace the lost bile acids and increased hepatocyte low-density lipoprotein (LDL)-receptor synthesis, which results in reduced LDL-cholesterol levels.

Reductions of approximately 45% in cholesterol and plant sterols have been achieved with administration of bile acid-binding resins. Three of five Chinese patients received cholestyramine with a very good response initially, but all discontinued therapy due to poor compliance.[5]

Cholestyramine (Prevalite, Questran)

Bile acid sequestrant shown to lower plasma sterol levels in sitosterolemia. Dosage is, in part, determined by clinical and biochemical response. Pediatric doses up to 12 g/d have been used in sitosterolemia.

Start with low dose; administer PO as slurry in water, juice, or milk before meals; chewable bars are also available.

Antilipemic Agent, 2-Azetidinone

Class Summary

These agents inhibit dietary cholesterol absorption from the small intestine.

Ezetimibe (Zetia)

First in new class of cholesterol-lowering agents that inhibits intestinal absorption of cholesterol. Targets the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.

 

Questions & Answers

Overview

What is sitosterolemia (phytosterolemia)?

What is the pathophysiology of sitosterolemia (phytosterolemia)?

What is the role of hyperabsorption in the pathophysiology of sitosterolemia (phytosterolemia)?

What is the role of reduced cholesterol synthesis in the pathophysiology of sitosterolemia (phytosterolemia)?

What is the prevalence of sitosterolemia (phytosterolemia)?

What is the mortality and morbidity associated with sitosterolemia (phytosterolemia)?

What are the racial predilections of sitosterolemia (phytosterolemia)?

What are the sexual predilections of sitosterolemia (phytosterolemia)?

At what age does sitosterolemia (phytosterolemia) typically present?

What is the prognosis of sitosterolemia (phytosterolemia)?

What is included in patient education about sitosterolemia (phytosterolemia)?

Presentation

Which clinical history findings are characteristic of sitosterolemia (phytosterolemia)?

Which physical findings are characteristic of sitosterolemia (phytosterolemia)?

What causes sitosterolemia (phytosterolemia)?

What are the possible complications of sitosterolemia (phytosterolemia)?

DDX

What are the differential diagnoses for Sitosterolemia (Phytosterolemia)?

Workup

What is the role of lab tests in the workup of sitosterolemia (phytosterolemia)?

What is the role of imaging studies in the workup of sitosterolemia (phytosterolemia)?

What is the role of arteriography in the workup of sitosterolemia (phytosterolemia)?

Which histologic findings are characteristic of sitosterolemia (phytosterolemia)?

Treatment

How is sitosterolemia (phytosterolemia) treated?

Which medications are used to supplement dietary therapy for sitosterolemia (phytosterolemia)?

What is the role of ezetimibe in the treatment of sitosterolemia (phytosterolemia)?

What is the role of surgery in the treatment of sitosterolemia (phytosterolemia)?

Which specialist consultations are beneficial to patients with sitosterolemia (phytosterolemia)?

Which dietary modifications are used in the treatment of sitosterolemia (phytosterolemia)?

What is included in the long-term monitoring of sitosterolemia (phytosterolemia)?

When is inpatient care indicated for the treatment of sitosterolemia (phytosterolemia)?

When is patient transfer indicated for the treatment of sitosterolemia (phytosterolemia)?

Medications

What is the role of medications in the treatment of sitosterolemia (phytosterolemia)?

Which medications in the drug class Antilipemic Agent, 2-Azetidinone are used in the treatment of Sitosterolemia (Phytosterolemia)?

Which medications in the drug class Bile acid-binding resins are used in the treatment of Sitosterolemia (Phytosterolemia)?