What is Sitosterolemia?
Sitosterolemia is an inherited disorder in which waxy substances from plants are absorbed into the body and build up in the blood and arteries. These waxy substances are called “plant sterols.” The principle one is sitosterol. Usually, plant sterols are cleared from the intestine before ever entering the body. This is done by a protein “pump” called ABCG5/ABCG8. Sitosterolemia develops when the gene responsible for the creation of this pump is broken, leading to both increased absorption and decreased excretion of plant sterols.
Sitosterolemia is thought to be a rare disease, however it may be more common than we think. The condition is likely underdiagnosed because of variability in presenting signs and symptoms, as well as misdiagnosis with other cholesterol disorders. Recent studies estimate that it may affect as many as 1 in 200,000 individuals in the general population. If left untreated, sitosterolemia can lead to premature hardening of the arteries (atherosclerosis), so it is important to diagnose it and start treatment as soon as possible.
The condition is “recessive” which means that a broken copy of the gene must be inherited from each parent. The parents, who only have one broken copy of the gene, do not have the disorder.
What are the symptoms of sitosterolemia?
The buildup of plant sterols in different parts of the body leads to a variety of symptoms, which may vary from person to person. Plant sterols can deposit in the arteries of the heart, causing a heart attack at a very young age. It is common to see fatty deposits under the skin called “xanthomas” (zan-tho-muhs) on hands, elbows, knees, and the Achilles tendon above the heel. Another symptom can be anemia, caused by plant sterols in the walls of red blood cells making them likely to break apart. Platelets—the cells in the blood which help prevent bleeding—can also be low in number and larger than usual. Plant sterols may also build up in the joints, causing joint stiffness and pain.
How is sitosterolemia diagnosed?
Patients with sitosterolemia often have very high blood cholesterol levels, however levels may be normal or only moderately elevated. Patients with high cholesterol levels and xanthomas may be misdiagnosed as having familial hypercholesterolemia (FH), a genetic condition characterized by very high levels of a type of cholesterol called low-density lipoprotein cholesterol (LDL-C). Unlike patients with FH, those with sitosterolemia have a poor response to treatment with “statins,” the usual first-line treatment for high cholesterol levels, but respond unexpectedly well to treatment with a different cholesterol-lowering medication called “ezetimibe.” A dramatic fall in LDL-C levels upon dietary restriction of plant sterols also helps to support the diagnosis.
Routine laboratory tests do not measure plant sterols. When sitosterolemia is suspected, plant sterol levels in the blood should be measured using special tests. People with the condition have sitosterol levels 10-25 times higher than in healthy individuals. Normal values of plant sterols are less than 1 mg/dL. Genetic testing of mutations in ABCG5 and ABCG8 confirms the diagnosis.
Lifestyle Recommendations
Dietary changes are very effective in people with sitosterolemia and should focus on restriction of plant sterols. The following foods are high in plant sterols and should be avoided:
- Vegetable oils (olive, canola, corn, soybean, sunflower, palm)
- Margarine and shortening
- Wheat germ
- Nuts (almonds, walnuts, pecans, pistachios)
- Seeds (sesame, sunflower, pumpkin)
- Legumes (peanuts, dried peas, beans, lentils)
- Avocados
- Chocolate
- Shellfish (shrimp, scallops, clams, oysters)
- Products, such as milk or yogurt, labeled “fortified with sterols”
Treatment Options
Ezetimibe
Ezetimibe (Zetia) is the first-line treatment for people with sitosterolemia. It works by reducing plant sterol and cholesterol absorption from food in the gut to the bloodstream. Ezetimibe is a pill that can be taken once daily, with or without food. It is generally well-tolerated but side effects may include abdominal pain, flatulence, or diarrhea. Ezetimibe may lower blood levels of plant sterols by up to 50%. It can also decrease the size of xanthomas and improve the red blood cell and platelet abnormalities that may occur with the condition.
Bile Acid Sequestrants
Bile acid sequestrants, such as cholestyramine, are considered in those with an incomplete response to ezetimibe. These medications work by increasing the elimination of plant sterols and cholesterol in the stool. Bile acid sequestrants are commonly prescribed as a powder that can be mixed into juice, water, or semi-solid foods with a high liquid content, like applesauce. They are also available in pill form, but the pills are large and several are needed per dose. These medications should be taken one hour before or four to six hours after other medications to ensure that the other medications are properly absorbed. These medications are not absorbed and stay in the gut, which can lead to some side effects such as upset stomach, constipation, or heartburn. Bile acid sequestrants typically reduce plant sterol levels by about 30%, and decreased size of xanthomas can also be seen with this treatment.
Statins
Statins are medications that lower cholesterol and prevent heart attacks and strokes. Examples of statins include rosuvastatin, atorvastatin, simvastatin, pitavastatin, and pravastatin. The response to statins is typically poor in patients with sitosterolemia because statins do not decrease plant sterol levels. However, since statins may help to reduce LDL-C levels, they may be considered in individuals who have had a previous heart attack or stroke.
Jacob’s Story
A 58-year-old patient Jacob (name changed for patient’s privacy) was referred to Dr. Alan Brown’s lipid clinic in Chicago for statin intolerance and a history of “genetic hypercholesterolemia.” He had tendon xanthomas on his hands (see photo) and on his Achilles tendons (back of his heels) since childhood. Jacob had a biopsy of his Achilles tendon that revealed “cholesterol” deposits. He was not able to take statin therapy (simvastatin, atorvastatin, pravastatin, or rosuvastatin) that was prescribed to him because of the side effect of muscle aches.
Jacob was not on lipid-lowering drugs at the time of his first visit with Dr. Brown. At the time, his LDL (“bad”) cholesterol was 169 mg/dL. He had moderate build up of plaque in one of the arteries in his neck but had never had a heart attack or a stroke. He was a smoker and had a significant family history of premature heart attacks in several of his siblings. He was overweight. He did not have high blood pressure or diabetes.
Dr. Brown noted the xanthomas and the LDL cholesterol which was only moderately elevated and considered the possibility of sitosterolemia. Jacob was on ezetimibe, which, on average, lowers sitosterol levels in the blood by 44% when his sitosterol came back from the lab at 6.6 mg/dL. That means that his untreated would have been around 11.8 mg/dL. Normal sitosterol is under 0.5mg/dL so his untreated level was 20 times normal!
Although most of the patients with sitosterolemia who have been reported in medical journals were diagnosed in childhood, this case shows that the diagnosis can be missed well into adulthood.
A major clue to the diagnosis in this patient was that fact that he had xanthomas with only a very mildly elevated LDL cholesterol (169mg/dL). If this patient had the more typical cause of xanthomas- familial hypercholesterolemia- his LDL cholesterol would have been 250mg/dL or higher! There is also another very rare cause of xanthomas called cerebrotendinous xanthomatosis (CTX). CTX was ruled out because Jacob wasn’t experiencing any neurologic symptoms, diarrhea, cataracts or seizures, which are all common in people with CTX.
The normal range of sitosterol in the blood is up to 0.5 mg/dL or 5.0 mg/L. The difference is whether the amount present in 100 milliliters (one tenth of a liter) or 1000 milliliters (a full liter) is reported.
Caleb’s Story
When Caleb was five years old, his pediatrician checked his cholesterol level. It came back over 300mg/dL. This was a surprise to his parents since neither of them had high cholesterol. Although the pediatrician wanted to start a statin medication, his mother preferred to try diet first. In fact, the whole family went on a low cholesterol, low saturated fat diet. Caleb’s cholesterol dropped to 180! His mother felt like a supermom! As he got older it did go up but generally stayed in the 200 range.
However, when Caleb was 12, during kitchen remodeling, the family was eating a lot of fast food. A cholesterol check was 432 with this diet! At that point Caleb was put on a statin medication. It was expected that his cholesterol would fall into the low to mid 200 range with the statin but it remained in the 300s, despite going back on the healthy diet.
When Caleb was 13, his mother, frustrated by years of not knowing why Caleb had high cholesterol and uncertain how to make it better, began Googling cholesterol researchers. (She *is* a supermom!) She sent emails, not really expecting responses. However, she did get a response from Dr. Helen Hobbs in Texas who recommended Caleb be in a study. Blood samples were shipped to Dr. Hobbs and the diagnosis of sitosterolemia was made. His level of sitosterol was ten times normal.
At age 14, Caleb stopped taking the statin medication and started ezetimibe, a medication which blocks the absorption of both cholesterol and sitosterol. Caleb’s cholesterol dropped to normal and his sitosterol level dropped 40%. He also started a diet low in plant sterols.
Caleb is now a young adult and is doing well. He is appreciative of all his supermom did for him!
Caleb never had xanthomas- lumps of cholesterol on Achilles tendons or tendons of the hand. This is often seen in sitosterolemia patients but not necessary for the diagnosis.
A clue to the diagnosis of sitosterolemia was the wild swings in Caleb’s blood cholesterol with diet alone- no medication. Sitosterolemia patients dramatically over absorb both cholesterol and plant sterols so limiting cholesterol in the diet (or consuming too much) has much more effect than in other people.
Another clue was the fact that neither of his parents had high cholesterol. This makes his very high cholesterol “recessive”. Sitosterolemia is one of the recessive forms of high cholesterol.
Finally, his cholesterol did not respond well to statin medications which is also typical of sitosterolemia.
Finding a Specialist
Lipidology, or the treatment of high cholesterol, is a small but growing field in medicine. Some lipid specialists are cardiologists, some are endocrinologists, and some are internists with an interest in caring for patients with high cholesterol.
It can be challenging to find a lipid specialist. Your primary care provider may know the lipid specialists in your area. On the website for your health care system, review providers in cardiology and endocrinology and look for key interests like “lipid clinic”, “cholesterol”, or “preventive cardiology”, or search those terms under medical conditions the system treats. We recommend that if you are interested in additional patient educational materials you visit the Sitosterolemia Foundation at www.sitosterolemiafoundation.org.
References
- Liebeskind A, Peterson AL, Wilson D. Sitosterolemia. In: Feingold KR, Anawalt B, Blackman MR, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; March 10, 2023.
- Rocha VZ, Tada MT, Chacra APM, Miname MH, Mizuta MH. Update on Sitosterolemia and Atherosclerosis. Curr Atheroscler Rep. 2023;25(5):181-187. doi:10.1007/s11883-023-01092-4
- Tada H, Nomura A, Ogura M, et al. Diagnosis and Management of Sitosterolemia 2021. J Atheroscler Thromb. 2021;28(8):791-801. doi:10.5551/jat.RV17052
- Yoo EG. Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Ann Pediatr Endocrinol Metab. 2016;21(1):7-14. doi:10.6065/apem.2016.21.1.7
