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Sitosterolemia, increasingly called Phytosterolemia or Xenosterolemia, is an inherited condition that can lead to premature heart disease and other complications. It is characterized by excess accumulation of plant sterols in the blood. Once clinically recognized, it can be diagnosed with laboratory testing and treated with a combination of medications and lifestyle modification.


  • Outline the etiology of sitosterolemia.
  • Review clinical signs which can help physicians identify sitosterolemia.
  • Describe the diagnostic criteria for sitosterolemia.
  • Summarize the treatment options available for patients for management by the interprofessional team.


Sitosterolemia is a rare lipid disorder that is characterized by the accumulation of plant sterols in the blood. It is autosomal recessive and often presents in early childhood. Clinically, it can be misdiagnosed as familial hypercholesterolemia, and overlap between the two disorders creates a diagnostic challenge for physicians. Those with sitosterolemia absorb significantly higher amounts of plant sterols and stanols than healthy patients.[1][2] This can lead to hypercholesterolemia and subsequent premature atherosclerosis. Patients can develop severe coronary artery disease, myocardial infarction, and other complications quite early in life if this condition is left untreated.[3] 

Due to its low prevalence and lack of unique clinical features, it is an underdiagnosed condition. Diagnostic testing is done by measuring a serum plant sterol level with subsequent genetic testing.[4] Once diagnosed, it is a treatable condition with a combination of dietary modifications and medication. Elimination of plant sterols in the diet and treatment with ezetimibe generally leads to a major reduction in serum plant sterol levels.


Sitosterolemia is a rare condition in which the body absorbs an excessive amount of plant sterols.[5] A healthy person only absorbs a tiny percentage of ingested plant sterols. Once the sterols enter the gastrointestinal cells, they are then transported into the gut lumen.[6] This mechanism occurs through the ATP-binding cassette transporter (ABC transporter) proteins. However, in a person with sitosterolemia, the ABC transporter is defective. Therefore, the plant sterols are not effectively transported into the gut lumen. In addition, the liver cannot excrete sterols into the bile as effectively. The result is excessive accumulation of plant sterols in the individual's blood.

The pathophysiologic mechanism of sitosterolemia is the result of a genetic mutation. The genes ABCG5 and ABCG8 encode for the ABC transporter proteins. Specifically, they encode for sterolin-1 and sterolin-2. If a mutation exists in either of these two genes, the ABC transporter may become defunct. This condition is an autosomal recessive disorder.[1]


Over 100 cases have been reported in the literature at the global level. However, due to its overlapping features with other lipid disorders, it is likely underdiagnosed. Given the lack of testing for this condition, the true prevalence remains unknown. Some estimates show the prevalence may be as high as 1 in 50,000.

Given that clinical signs often appear early in life, patients are generally diagnosed in the first two decades of life. Delayed diagnosis can mean that patients may not be diagnosed until after suffering a cardiac event. In addition, given the widespread use of ezetimibe as a lipid therapy medication, false-negative testing may also occur in affected patients.

History and Physical

Sitosterolemia generally has many clinical features which overlap with other lipid disorders. Patients often develop tendon xanthomas, a key finding also found in those with familial hypercholesterolemia. They can also develop corneal arcus and xanthelasma, though these are not as commonly seen. Other symptoms are generally nonspecific, such as abdominal pain and arthralgia. Depending on the timeline of the disease, splenomegaly and hepatomegaly may also be seen.[7] Physicians should also inquire into the patient's dietary habits to assess the level of plant sterol intake.


Laboratory evaluation is required to make the diagnosis of sitosterolemia. Clinical suspicion of a cholesterol disorder often prompts a standard lipid panel to be ordered. Depending on the institution, this will usually include a total cholesterol level, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride level. Patients with sitosterolemia may have elevated total cholesterol, but otherwise, the standard lipid panel does not provide specific diagnostic information. In contrast to familial hypercholesterolemia, there is a significant lowering of serum cholesterol levels once plant sterols are minimized in the diet. As well, sitosterolemia patients often have a poor clinical response to statins.[8]

A serum plant sterol level is the standard method of diagnosing sitosterolemia.[9] This test is generally a panel that looks at the levels of sitosterol, campesterol, and stigmasterol. Patients with this condition will have over 30 times the level of plant sterols in their blood than healthy patients. A healthy individual generally has serum plant sterol levels that make up less than one percent of their serum cholesterol. For affected individuals, serum levels are often in the range of 10 to 65 mg/dL depending on the severity of the disease. Tests can be falsely negative if a patient is using ezetimibe or a bile acid-binding resin medication. In addition, false negatives occur if the patient is on a low plant sterol diet. False-positive results have been reported in cases of cholestasis and also consumption of infant formulas containing plant sterols. Generally, elevated serum levels may be considered diagnostic depending on the clinical scenario, but genetic testing can be done for confirmation. Specifically, pathogenic variants in ABCG5 or ABCG8 are identified on genetic testing.[10] Some labs may report a ratio of sitosterol to total cholesterol. This is less validated and less significant when making clinical decisions for patients. Absolute concentrations of sitosterol range depending on laboratory, but a level of sitosterol > 7 mg/L would be at the 99th percentile. A normal range for sitosterol would be 1.7 - 3.0 mg/L (most labs do not report as mg/dL). Those with total loss of function of ABCG5 or G8 (homozygous phytosterolemia) have 99.9th percentile levels of > 20-30 mg/L or higher. Lesser concentrations are usually partial ABCG5 or G8 loss of function. 

There are additional laboratory and diagnostic test abnormalities that are commonly noted. This includes hemolytic anemia and thrombocytopenia. A complete blood count (CBC) and hemolysis diagnostic evaluation are generally sufficient to diagnose this. Patients may also have liver disease with an unknown etiology which may present as transaminitis with a negative comprehensive diagnostic workup.  As a result of uncontrolled disease, premature atherosclerosis may also be discovered. Given the major association of sitosterolemia with premature atherosclerosis and cardiac valvular disease, it is generally reasonable to pursue diagnostic evaluation in the form of coronary imaging with computed tomography (CT), calcium scoring, and echocardiography.

Treatment / Management

The first step in treatment is significant dietary modifications. This includes a major reduction in the intake of plant sterols and shellfish sterols. Common examples include vegetable oils, nuts, and avocados. Patients often experience a measurable reduction in serum sterol levels and cholesterol levels following the dietary intervention.

Medications are generally required to fully control the chronic disease process of sitosterolemia. At a dosage of 10 mg per day, ezetimibe is approved by the United States Food and Drug Administration (FDA) for the treatment of sitosterolemia. It works directly by blocking plant sterol entry and consequently lowers serum plant sterol levels. Other medication options include bile-acid binding resins such as cholestyramine. However, this would only be used in conjunction with ezetimibe. Prior to the approval of ezetimibe, surgical intervention with an ileal bypass was reserved for severe cases.[1]

Statin therapy is not directly indicated for the treatment of sitosterolemia. Likely, it would be prescribed for affected patients given its cardioprotective effect in the setting of atherosclerosis. It would also help optimize the lipid profile of the patient to minimize other cardiac risks. However, it would not lower plant sterol serum levels, and hence statin therapy alone is not an appropriate treatment for sitosterolemia.[11] Patients who have already developed heart disease should be concurrently managed with standard of care guidelines in addition to therapy for sitosterolemia.

Differential Diagnosis

  • Familial hypercholesterolemia - Overlapping clinical features with sitosterolemia but features very high LDL levels
  • Lecithin-cholesterol acyltransferase (LCAT) deficiency - Features very low HDL, elevated very-low-density lipoprotein (VLDL), and hypertriglyceridemia[12]
  • Tangier disease - HDL levels are severely low, which is not seen in sitosterolemia [13]
  • Cerebrotendinous xanthomatosis
  • Familial dysbetalipoproteinemia
  • Familial hypertriglyceridemia


Untreated sitosterolemia can lead to premature coronary artery disease and death; given that the disease onsets early in life, timely diagnosis is required to prevent atherosclerosis. A definitive prognosis is not known at this time due to the rarity of the disease. Improved knowledge of this disorder could help improve the total number of diagnosed cases and increase the understanding of the prognosis. 


  • Atherosclerosis and coronary artery disease
  • Myocardial infarction
  • Aortic stenosis
  • Premature cardiac death
  • Hemolytic anemia
  • Thrombocytopenia
  • Splenomegaly
  • Liver disease and cirrhosis
  • Arthritis and arthralgia


Given the low prevalence of this disease, consultation with a lipidologist would be recommended. If a lipidologist is not available, consultation with a cardiologist or physician interested in lipid disorders would likely help to improve the patient outcome. In addition, a discussion with a genetics counselor would likely be warranted as well to evaluate family member carrier testing.

Deterrence and Patient Education

A critical component of the management of sitosterolemia is compliance with dietary modifications. Restriction of plant sterol intake must be emphasized during patient education, and patients must be made aware of the severe risks of complications associated with consuming plant sterols. Patients should be offered a consultation with a dietician given the importance of maintaining a plant sterol-free diet. 

Given that sitosterolemia generally presents earlier in life, this presents an additional challenge. Counseling will generally involve the patient's family members to help ensure a full understanding of the dietary restrictions. Intuitively, the foods which are restricted in these patients may not be inherently unhealthy, and hence additional education is often required.

Enhancing Healthcare Team Outcomes

Management of sitosterolemia requires an interprofessional approach to achieve optimal outcomes. Primary care clinicians would be the initial point of contact for patients. Identifying this disorder by a primary care provider is likely to lead to timely diagnosis and treatment, potentially improving the end outcome. Further management would generally require a lipidologist, dietician, and genetics counselor. Nursing can provide patient counseling, and the pharmacist can perform medication reconciliation and answer drug therapy questions. If the patient is in the pediatric age group, family members will also be a critical component of the team to help ensure dietary and medication compliance. The interprofessional team approach can help ensure the most optimal end outcome. [Level 5]

Article Details

Article Author

Khashayar Farzam

Article Editor:

Ryan T. Morgan


12/27/2022 10:50:06 PM



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