Primary hypobetalipoproteinemia

I see countless patients with severe refractory hyperlipidemia who do not respond to, or do not tolerate, lipid-lowering therapy.

Much less often I see patients with low cholesterol. A primary care physician called to ask if I would be interested in seeing a 50-something-year-old man with a long history of low total and LDL cholesterol.

“Of course I would!” I responded.

At our initial consultation the patient explained that he had had low cholesterol for as long as he could remember, and no one knew why.

“Years ago, one doctor told me it was impossible for me to have cholesterol so low. He said if I did I would be dead,” he told me.

The patient’s most recent lipid profile was: total cholesterol, 58 mg/dL; triglycerides, 14 mg/dL; direct LDL, 14 mg/dL and HDL, 48 mg/dL. Not surprisingly, apolipoprotein-B (apoB) was also very low at 24 mg/dL (48 – 124 mg/dL).

Low levels of the apo-B-containing lipoproteins can be due to either secondary or genetic causes. Whenever someone presents with low total and LDLcholesterol, secondary causes, including chronic liver disease, gastrointestinal malabsorption, malnutrition, malignancy and other explanations, must be ruled out. This patient had slightly elevated hepatic transaminases, which prior evaluation had revealed to be due to mild fatty liver disease. Evaluation for other secondary causes of low cholesterol was negative.

There are two primary causes of low total and LDL cholesterol: mutations in the gene encoding MTP (microsomal transfer protein) and mutations in the gene encoding APOB (apolipoprotein B).

MTP gene mutations can result in extremely low or absent levels of apo-B, total cholesterol and LDL , known as abetalipoproteinemia. Because MTP is necessary for the creation and secretion of chylomicrons, malabsorption of fat, especially of long-chain fatty acids, and of fat soluble vitamins, can occur. As a result, disease may be more severe and present in childhood. Patients develop neurologic complications related to vitamin E deficiency, including spinocerebellar degeneration. They may have deficiency of other fat soluble vitamins, including vitamin A and vitamin K. Some patients go on to develop retinal disease, including retinitis pigmentosa that sometimes progresses to blindness. Other features include abnormal erythrocytes (burr cells) and fatty liver disease. Abetalipoproteinemia is rare, occurring in about one in a million or less.

Low total and LDL cholesterol can also be due to familial hypobetalipoproteinemia, an autosomal dominant disorder due to mutations in the gene encoding APOB. Although homozygotes are rare, occurring in about one in 1 million, heterozygotes are more common, about one in 500. Fat malabsorption, fatty liver disease, complications due to deficiency of vitamin E and other fat soluble vitamins can also occur, especially in homozygotes. Heterozygotes present with low total (<100 mg/dL) and low LDLcholesterol (<50 mg/dL) but may otherwise be clinically silent. As expected, the rate of cardiovascular events is low.

After ruling out secondary causes of low cholesterol, all patients with abetalipoproteinemia or familial hypobetalipoproteinemia should be evaluated for fat-soluble vitamin deficiencies as well as the associated neurologic and ocular complications. Patients can be managed with a low-fat diet rich in medium-chain fatty acids and high-dose supplementation of vitamin E and other fat-soluble vitamins.

More than likely, our patient has heterozygous familial hypobetalipoproteinemia. He only had low-normal vitamin E, occasional loose stools and mild fatty liver disease; otherwise, there appeared to be no other sequelae of the disorder. I advised him to take 800 IU of vitamin E per day. This is lower than the high-dose vitamin E supplementation (over 100 mg/kg/day) recommended for those with more severe disease. However, because his disease is mild, it makes sense to treat somewhat more conservatively with close monitoring. There are simply no evidence-based guidelines for the management of people with rare disorders such as this.

For more information:

Linton MF. J Lipid Res. 1993;34(4):521-541.

Sankatsing RR.. Arterioscler Thromb Vasc Biol. 2005;25(9):1979-1984.

Schonfeld G. J Lipid Res. 2003;44(5):878-883.