Sitosterolemia
Encyclopedia
Sitosterolemia is a rare autosomal recessively inherited lipid
metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia
, tendon and tuberous xanthomas, premature development of atherosclerosis
, and abnormal hematologic and liver function test results.
(FH), such as the development of tendon xanthomas in the first 10 years of life and the development of premature atherosclerosis . However, in contrast to FH patients, sitosterolemia patients usually have normal to moderately elevated total sterol levels and very high levels of plant sterols (sitosterol, campesterol, stigmasterol, avenosterol) and 5α-saturated stanols in their plasma. Plasma sitosterol levels in sitosterolemia patients are 10–25 times higher than in normal individuals (8–60 mg/dl). Not all patients with sitosterolemia have tendon xanthomas, thus absence of this should not be used to exclude this diagnosis.
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.Decreased range of motion with possible redness, swelling, and warmth of joints due to arthritis
may be present.In addition, sitosterolemia patients may develop hemolytic episodes and splenomegaly
.
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
Sitosterolemia is inherited as a rare autosomal recessive condition.It has been shown to result from mutations in either of two adjacent and oppositely oriented genes (ABCG5 and ABCG8) located in chromosome 2 in band 2p21 and encode for ABC transporter proteins named sterolin-1 and sterolin-2, respectively. Thus, 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.
Patients have markedly reduced whole-body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte hydroxymethylglutaryl-coenzyme A reductase (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 low-density lipoprotein (LDL) receptor expression.
If dietary treatment alone is insufficient, bile acid-binding resins (eg, cholestyramine
, colestipol
) could be considered. In October 2002, a new cholesterol absorption inhibitor, ezetimibe
, received US Food and Drug Administration (FDA) approval for use in sitosterolemia. This drug is now the standard of care, as it blocks sterol entry and can be used in combination with bile-acid resins.
Finally, ileal bypass has been performed in select cases to decrease the levels of plant sterols in the body, though this therapy was undertaken prior to the advent of ezetimibe.
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, tendon and tuberous xanthomas, premature development of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, and abnormal hematologic and liver function test results.
Epidemiology
Only 45 cases have been reported in the literature worldwide, hence this condition appears to be relatively rare. More than likely, sitosterolemia is significantly underdiagnosed and many patients are probably misdiagnosed with hyperlipidemia.Signs and symptoms
Sitosterolemia may share several clinical characteristics with the well-characterized familial hypercholesterolemiaFamilial hypercholesterolemia
Familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...
(FH), such as the development of tendon xanthomas in the first 10 years of life and the development of premature atherosclerosis . However, in contrast to FH patients, sitosterolemia patients usually have normal to moderately elevated total sterol levels and very high levels of plant sterols (sitosterol, campesterol, stigmasterol, avenosterol) and 5α-saturated stanols in their plasma. Plasma sitosterol levels in sitosterolemia patients are 10–25 times higher than in normal individuals (8–60 mg/dl). Not all patients with sitosterolemia have tendon xanthomas, thus absence of this should not be used to exclude this diagnosis.
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.Decreased range of motion with possible redness, swelling, and warmth of joints due to arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
may be present.In addition, sitosterolemia patients may develop hemolytic episodes and splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
.
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
Pathogenesis
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 transporter (ABC transporter) proteins.Sitosterolemia is inherited as a rare autosomal recessive condition.It has been shown to result from mutations in either of two adjacent and oppositely oriented genes (ABCG5 and ABCG8) located in chromosome 2 in band 2p21 and encode for ABC transporter proteins named sterolin-1 and sterolin-2, respectively. Thus, 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.
Patients have markedly reduced whole-body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
), 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 low-density lipoprotein (LDL) receptor expression.
Treatment
The disorder is treated by strictly reducing the intake of foods rich in plant sterols (e.g., vegetable oils, olives and avocados). However, dietary therapy is never sufficient to control this disease since plant sterols are constituents of all plant-based foods. Statins have been used, and while these lower cholesterol levels and may ameliorate atherosclerotic disease, plant sterol levels are insufficiently lowered by their use alone.If dietary treatment alone is insufficient, bile acid-binding resins (eg, cholestyramine
Cholestyramine
Cholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
, colestipol
Colestipol
Colestipol is a bile acid sequestrant.It works in the gut trapping bile salts, and preventing them from being reabsorbed.This leads todecreased enterohepatic recirculation of bile salts,increased synthesis of new bile salts by the liver,...
) could be considered. In October 2002, a new cholesterol absorption inhibitor, ezetimibe
Ezetimibe
Ezetimibe is a drug that lowers cholesterol. It acts by decreasing cholesterol absorption in the intestine. It may be used alone , when other cholesterol-lowering medications are not tolerated, or together with statins when statins alone do not control cholesterol.Even though ezetimibe decreases...
, received US Food and Drug Administration (FDA) approval for use in sitosterolemia. This drug is now the standard of care, as it blocks sterol entry and can be used in combination with bile-acid resins.
Finally, ileal bypass has been performed in select cases to decrease the levels of plant sterols in the body, though this therapy was undertaken prior to the advent of ezetimibe.