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Case Study II: Hereditary Sitosterolemia


President, Midwest Lipid Association
Director, Midwest Heart Disease Prevention Center
Assistant Professor, Loyola Stritch School of Medicine
Naperville, IL
Diplomate, American Board of Clinical Lipidology

This 58-year-old patient was referred to the lipid clinic for statin intolerance and a history of "genetic hypercholesterolemia." The patient has had tendon xanthomas on the extensor surface of his hands and on his Achilles tendons since childhood just like his brother and sister. Both siblings have expired prematurely due to coronary artery disease. He states that he has had a biopsy of his Achilles tendon that revealed "cholesterol" deposition by pathology per his surgeon. The patient was not able to take simvastatin, atorvastatin, pravastatin, or rosuvastatin due to significant myalgias and, hence, was referred for initiation of lipid-lowering therapy. He was not on lipidlowering drugs at the time of his initial visit.

His past medical history was remarkable only for inguinal hernia repair and dyslipidemia. He also has a history of moderate carotid atherosclerosis. Family history was remarkable. His father died at 85-years-old of CAD. Two brothers died of MIs at ages 59 and 53 respectively. A sister died of CAD at age 56. At least two of his siblings had similar xanthomas. Social history is remarkable for an 82 packs-per-year smoking history and rare alcohol. He works as a highway maintenance worker. Allergies include cephalosporins, quinolones, and sulfa. Home medications at the time of his initial visit included fexofenadine and clindamycin. Vital signs were blood pressure 120/72, pulse 84, respirations 18, and afebrile height 66 inches, weight 189 lbs., BMI 30.6.

His physical exam was remarkable for xanthomas on the extensor surface of his hands and on his Achilles tendons as shown in the photos. The remainder of his physical was unremarkable.

Lab results were as follows: Cholesterol 231; HDL 35 mg/dL, LDL 169 mg/dL; Triglycerides 137mg/dL; Fasting Glucose 80 mg; TSH 0.96 IU CBC and remainder of his chemistry testing was normal.

The differential diagnosis included functional Familial Hypercholesterolemia (FH), CTX (cerebrotendinous xanthomatosis), and hereditary beta sitosterolemia.

FH was ruled out due to the relatively low serum cholesterol levels. CTX was ruled out due to the absence of any neurologic symptoms, diarrhea, cataracts or seizures. A presumptive diagnosis of Hereditary Sitosterolemia was made.

Serum sitosterol levels were drawn and the results were as follows (note that patient had already been started on ezetemibe before blood draw):
Lathosterol 9.8
(Normal range 0.0-5.0)mg/dL?
Campesterol 9.1
(Normal range 0.0-7.0)mg/dL?
Sitosterol 6.6
(Normal range 0.0-5.0)mg/dL?

These elevations in plasma sterols despite initiation of ezetemibe as well as the clinical presentation were strongly suggestive of a diagnosis of Hereditary Sitosterolemia.

Hereditary beta sitosterolemia is a very rare autosomal recessive disorder. As of the year 2000, only 40 cases had been reported. It is likely that the disorder is underreported due to missed diagnosis. The clinical manifestations include xanthomatosis and premature coronary artery disease. The disorder can superficially mimic FH on physical exam with extensor tendon xanthomas on the hands and Achilles tendons leading to misdiagnosis, as in the case of our patient. The cholesterol levels can be mildly elevated or low in contrast to FH, providing a clue to the diagnosis.

Patients may also have painful and inflamed joints, particularly in the knees and ankles. Hemolysis and platelet abnormalities such as thrombocytopenia have also been reported. It is thought that incorporation of plant sterols into erythrocytes makes them more rigid and more susceptible to hemolysis. The pathophysiology of this disorder stems from a mutation in the ABCG5 or ABCG8 transporter proteins in the intestinal mucosal cell. Sterols (including cholesterol and plant sterols) are transported from the intestinal lumen into the mucosal cell via the NP1L1 (Neimann Pick 1L1) protein. The absorbed cholesterol and usually minimal amounts of plant sterol are then packaged into chylomicrons which are secreted from the mucosal cell into the lymphatic system. The majority of potentially toxic plant sterols are pumped out of the intestinal mucosal cell and back into the intestinal lumen by the ABC G5/G8 proteins to avoid their absorption into the circulation. In patients with sitosterolemia, a mutation in the ABCG5 or ABCG8 proteins causes inability to pump plant sterols back into the intestinal lumen for disposal and hence high levels are incorporated into chylomicrons and absorbed into the bloodstream. These high levels of circulating plant sterols lead to a marked increase in atherosclerosis, likely due to the incorporation of increased levels of plant sterols into VLDL and increase deposition into the arterial wall. The definitive diagnosis is made by the finding of elevated levels of plant sterols in the serum as analyzed using chromatography:

  • Treatment includes ezetemibe which blocks absorption of plant sterols into the intestinal mucosal cell by inhibiting the activity of the NP1L1 sterol transporter protein. In addition, bile acid resins can be used and in rare cases, ileal bypass surgery has been utilized.
  • Patients should be placed on a diet low in plant sterols. Dietary recommendations include an attempt to eliminate vegetable fat in the diet. Olives and avocados should be avoided due to high levels of vegetable fat. Nuts, seeds, and chocolate as well as vegetable oils, margarine and shortening should be avoided. Shellfish should also be avoided. A consult with a dietitian is recommended to help instruct patients on a low plant sterol diet.
  • Appropriate consultations would include cardiology for evaluation of atherosclerosis, hematology for hemolysis, and possibly rheumatology for arthritis. A lipidology consult would also obviously be recommended. A geneticist evaluation, if available, would also be optimal and screening of extended family members for xanthomas is appropriate.

Disclosure statement: Dr. Brown has received honoraria for serving on the advisory board of Kowa Pharmaceuticals.

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by Dr. Radut.