Low LDL Cholesterol (Hypobetalipoproteinemia) Workup

Laboratory studies include the following:

• Routine complete blood cell count with differential, including platelet count - Some patients present with thrombocytopenia. In the absence of another obvious explanation, a low platelet count may be considered secondary to vitamin cofactor malabsorption, and one must consider the possibility of abetalipoproteinemia (ABL) and familial hypobetalipoproteinemia (FHBL).

• Blood smear to assess erythrocyte morphology - Acanthocytosis (burr cells) may be evident in patients with FHBL, but even when the erythrocytes appear normal, an exceptionally low sedimentation rate can be demonstrated. Patients with ABL uniformly demonstrate acanthocytosis. From 40-80% of erythrocytes are acanthocytic. Mild to moderate anemia with mild to moderate reticulocytosis may also be present.

• Basic chemistry (metabolic) panel - This test is used to exclude multisystem illness or evidence of malnutrition from another cause.

• Liver function tests, including transaminases - Hepatic transaminases have been reported to be elevated in patients with ABL and FHBL. The mechanism for this finding is unclear. ^[21]

• Stool studies - Search the stool for ova, parasites, and white blood cells in order to exclude other common causes of fat malabsorption.

• Fasting lipid profile - A fasting lipid profile should be obtained from patients and their first-degree relatives, in the latter case to assist in distinguishing between ABL and homozygous FHBL. The parents of a patient with ABL have normal cholesterol levels, while the parents of a patient with homozygous FHBL have lower-than-average cholesterol levels.

  • Heterozygous FHBL - Patients with heterozygous FHBL may have total cholesterol levels that are below the fifth percentile (and may be less than 100 mg/dL). Plasma low-density lipoprotein (LDL) cholesterol levels are also reduced by one half or more. High-density lipoprotein (HDL) cholesterol levels are normal or slightly increased. Plasma triglyceride levels are reduced in some kindreds.

  • Homozygous FHBL - Patients with homozygous FHBL show extremely low plasma cholesterol and triglyceride levels.

  • ABL - Characteristically, extremely low levels of plasma cholesterol (< 50 mg/dL) and triglycerides are detected in infants and young children. Patients who are obligate heterozygotes have normal cholesterol levels.

• ABL or homozygous FHBL diagnosis - This depends on finding acanthocytes in the peripheral blood and extremely low plasma levels of cholesterol (< 50 mg/dL). Chylomicrons (CMs) and very low-density lipoprotein (VLDL) are not detectable, and LDL is virtually absent.

Imaging studies include the following:

• Hepatic scan or ultrasonography to assess changes of fatty liver - Patients with liver enlargement, splenomegaly, or elevated levels of transaminases may need hepatic imaging studies to ascertain anatomy and function.

• Magnetic resonance imaging (MRI) of the spinocerebellar region - This may become necessary in patients presenting with ataxic gait or vision loss.

• Eye and retinal examination and imaging - An ophthalmic examination and retinal imaging may be needed in patients with visual disturbance and retinal degeneration.

The molecular diagnosis of familial hypobetalipoproteinemia can be performed only in specialized laboratories; it is accomplished through the examination of the plasma apoB, using gel electrophoresis or deoxyribonucleic acid (DNA) analysis to identify specific mutations.

The demonstration of the molecular defect in persons with abetalipoproteinemia requires a specialized laboratory for the detection of low or absent MTP in intestinal biopsy specimens or DNA analysis to identify specific mutations.

Intestinal biopsy may be needed, along with electron microscopy.

• The endoscopic appearance of the mucosa of the small intestine may be whitish, although this characteristic is usually limited to the villi.

• The diagnosis is confirmed by the typical hematologic finding of acanthocytosis and the appearance of the small-bowel biopsy specimen, in which the tip enterocytes are filled with lipid droplets. The villi are normal but are lined with fat-containing enterocytes (engorged with triglycerides) that constitute the lipid droplets.

• In specialized cases, light and transmission electron microscopy may show fat-loaded enterocytes (from marked triglyceride accumulation).

Liver biopsy is rarely needed but may become necessary to assess for fatty liver, chronic liver disease, or cirrhosis and to rule out other causes of hepatomegaly, fatty liver, and transaminase elevation.

Intestinal biopsy reveals the gross appearance of white mucosa, usually limited to the villi. Histologically, the villi are normal but are lined with fat-containing enterocytes (engorged with triglycerides). In specialized cases, light and transmission electron microscopy may show fat-loaded enterocytes.