AUTHOR INFORMATION

Section 1 of 11

Authored by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital

Coauthored by Patricia Campbell, MD, Staff Physician, Department of Pediatrics, Doernbecher Children's Hospital

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, American Medical Association, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Robert D Steiner, MD
Editor's Email:	Ian Krantz, MD

eMedicine Journal, July 1 2005, VOLUME 6, Number 7

INTRODUCTION

Section 2 of 11

Background: Sitosterolemia is a rare inherited plant sterol storage disease. Bhattacharyya and Connor first described this disease in 1974. 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. 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.

Pathophysiology: The metabolic defect in the affected patient causes hyperabsorption of sitosterol from the gastrointestinal 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. 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. Normally, plant sterols are poorly absorbed from the gastrointestinal tract; fewer than 5% of plant sterols are absorbed compared to 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. 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.

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.

The ability of the liver to preferentially excrete plant sterols into the bile is apparently impaired. While 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 to 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.

Frequency:

• Internationally: Sitosterolemia is thought to be a very rare disorder. As of 2000, only approximately 40 patients had been identified worldwide. 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 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. Episodic hemolysis has been reported in several patients. Erythrocytes have been shown to contain increased amounts of sitosterol, rendering the cell membrane more rigid and, therefore, more prone to lysis and rupture.
  
  
• Arthritis occurs 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.

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 appears to exist for sitosterolemia, though the small number of patients diagnosed makes it premature to draw any conclusions. Sitosterolemia has been described in Amish, Japanese, and Chinese patients, as well as in other patient population groups.

Sex: Sitosterolemia is an autosomal recessive genetic condition; therefore, no sex predilection exists. 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.

CLINICAL

Section 3 of 11

History:

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

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.

DIFFERENTIALS

Section 4 of 11

Lipid Storage Disorders

Other Problems to be Considered:

Familial hypercholesterolemia
Pseudohomozygous familial hypercholesterolemia
Cerebrotendinous xanthomatosis

WORKUP

Section 5 of 11

Lab Studies:

• Plasma lipoprotein profile, plasma cholesterol level


• • 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 (up to 9 mg/dL according to the literature and 13 mg/dL or higher 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.

  
  
  
  • 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 theoretically possible.
  
  
  
• Complete blood cell count is indicated.


• • Hemolytic anemia, either chronic or episodic, may be present.
  
  
  
  • Platelet abnormalities, such as thrombocytopenia, may be present.
  
  
  

Imaging Studies:

• Coronary angiography may be useful in select cases.

Procedures:

• Arteriography


• • Once sitosterolemia is diagnosed, depending on the patient's age, coronary arteriography may be indicated.
  
  
  
  • Arteriography may show coronary artery stenosis.
  
  
  

TREATMENT

Section 6 of 11

Medical Care:

• Treatment 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.



• Arthritis may require treatment.



• Treat chronic anemia and/or thrombocytopenia if present.

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

Consultations:

• 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:

• 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.


• • Bhattacharrya AK, Connor WE. Familial diseases with storage of sterols other than cholesterol:
    Cerebrotendinous xanthomatosis, and beta-sitosterolemia, and xanthomatosis. In: Stanbury B, Wyngaarden, Fredrickson DS, eds. The Metabolic Basis of Inherited Disease, 4th ed. New York: McGraw-Hill, 1978: 656-87.

  • Kuksis I, Myher JJ, Marai L, et al. Fatty acid composition of individual plasma steryl esters in phytosterolemia and xanthomatosis. Lipids 1986; 21: 371-7.
  
  
  

MEDICATION

Section 7 of 11

Medications are occasionally used in the treatment of sitosterolemia. Attempt dietary therapy first in most cases. If dietary treatment alone is insufficient, bile acid-binding resins (eg, cholestyramine, colestipol) or competitive inhibitory agents (eg, sitostanol) 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.

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 (Salen, 2004). Limited studies have been conducted on sitostanol in this context. Information on the use of medications other than cholestyramine (and, more recently, ezetimibe) in sitosterolemia is limited; therefore, colestipol and sitostanol cannot generally be recommended.

Drug Category: Bile acid-binding resins -- 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 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.

Drug Name	Cholestyramine (Prevalite, Questran, LoCHOLEST) -- 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 orally as slurry in water, juice, or milk before meals; chewable bars are also available.
Adult Dose	3-4 g/d PO tid; not to exceed 32 g/d
Pediatric Dose	240 mg/kg/d PO divided tid; not to exceed 12 g/d
Contraindications	Documented hypersensitivity
Interactions	Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Be aware of theoretical risk for fat-soluble vitamin deficiency; monitor serum concentrations of erythrocyte folate and of fat-soluble vitamins A, D, and E; perform basic metabolic profile, liver function tests, and CBC annually; administer a daily supplement of multivitamins containing both iron and folic acid; hyperchloremic acidosis may occur with prolonged use; caution with phenylketonuria, avoid aspartame containing products (eg, LoCHOLEST Light)

Drug Category: Cholesterol absorption inhibitors -- Inhibits dietary cholesterol absorption.

Drug Name	Ezetimibe (Zetia) -- First in new class of cholesterol-lowering agents that inhibits intestinal absorption of cholesterol.
Adult Dose	10 mg/d PO
Pediatric Dose	<10 years: Not established >10 years: Limited data exist; administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Cholestyramine decreases bioavailability; fenofibrate and gemfibrozil increase bioavailability; cyclosporine may increase bioavailability
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in moderate-to-severe hepatic impairment

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Inpatient care is usually not necessary unless significant heart disease, hemolysis, or severe arthritis is present.

Further Outpatient Care:

• Monitor plant sterol levels in plasma to assess treatment efficacy.

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.

Complications:

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

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 eMedicine’s Cholesterol Center and Statins Center. Also, see eMedicine’s patient education articles High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Sitosterolemia is often likely to be misdiagnosed as hyperlipidemia. Sitosterolemia can also be misdiagnosed as pseudohomozygous familial hypercholesterolemia.



• Test patients who have hypercholesterolemia and do not respond to statins for sitosterolemia.



• Cholesterol levels may be in the range observed in homozygous familial hypercholesterolemia, which may be extremely high.



• An accurate diagnosis requires plant sterol levels analysis.



• Patients receiving total parenteral nutrition may have high levels of plant sterols in plasma.



• Infants consuming infant formulas may have high levels of plant sterols.

Special Concerns:

• Early diagnosis and treatment is essential.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is a typical physical finding in patients with sitosterolemia?

A: Hepatomegaly
B: Corneal clouding
C: Xanthomas
D: Orange tonsils
E: Cleft palate

The correct answer is C: Xanthomas are common in sitosterolemia. Cleft palate is a feature of Smith-Lemli-Opitz syndrome. Orange tonsils are observed in Tangier disease.

CME Question 2: Which of the following needs to be tested for diagnosis of sitosterolemia?

A: Lipoprotein levels
B: Plasma sterol levels
C: Blood and urine bile acids
D: Cholesterol level
E: 7-dehydrocholesterol level

The correct answer is B: The only diagnostic test for sitosterolemia is a plasma sterol levels analysis. This is a specialized test available in only a few laboratories. A lipid profile is not diagnostic, though some of these patients may have very high cholesterol levels. The elevated levels of plasma sterols in the blood that are diagnostic are not identified by a cholesterol level test or a lipid profile. Answer E, a 7-dehydrocholesterol test, is the test for Smith-Lemli-Opitz syndrome, not sitosterolemia.

Pearl Question 1 (T/F): Sitosterolemia can be misdiagnosed as pseudohomozygous familial hypercholesterolemia.

The correct answer is True: Cholesterol levels in children with sitosterolemia can be extremely high. Parents of children with sitosterolemia usually have normal cholesterol levels. Therefore, sitosterolemia is one cause of pseudohomozygous hypercholesterolemia.

Pearl Question 2 (T/F): No treatment for sitosterolemia exists.

The correct answer is False: Treatment may include dietary changes, pharmacologic agents, surgical interventions, or all three. A diet low in plant sterols may be recommended. Bile acid-binding resins and/or ezetimibe may be administered. An ileal bypass may be indicated.

Pearl Question 3 (T/F): The cause of morbidity and mortality in sitosterolemia is atherosclerosis.

The correct answer is True: Atherosclerosis leads to coronary heart disease. Coronary heart disease and its inherent health consequences are the primary causes of illness and premature death in sitosterolemia.

Pearl Question 4 (T/F): Sitosterolemia is an autosomal dominant condition.

The correct answer is False: Sitosterolemia is inherited in an autosomal recessive manner. 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 a common regulatory control.

BIBLIOGRAPHY

Section 11 of 11

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