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Low LDL Cholesterol (Hypobetalipoproteinemia): Differential Diagnoses & Workup

Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI, Director, Suncoast Cardiovascular Center; Chair, Cardiology Division and Cath Labs, Department of Medicine, Bayfront Medical Center; Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine
Coauthor(s): Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Contributor Information and Disclosures

Updated: Aug 4, 2009

Differential Diagnoses

Celiac Disease
Malabsorption
Cystic Fibrosis
Malnutrition
Failure to Thrive
Pancreatitis, Chronic
Fatty Liver
Sprue, Tropical
Inflammatory Bowel Disease
Vitamin E Deficiency
Intestinal Lymphangiectasia
Whipple Disease

Other Problems to Be Considered

Anderson disease (CM retention disease)15
Disorders of fat malabsorption
Ataxia
Spinocerebellar disorders
Retinal degeneration
Secondary cancers
Friedreich disease
Hereditary sensorimotor neuropathies
Combined neuropathy and ataxia
Familial vitamin E deficiency
Chronic cholestatic liver disease
Machado-Joseph disease

Workup

Laboratory Studies

  • 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.16
  • 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

  • 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.

Other Tests

  • 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.

Procedures

  • 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.

Histologic Findings

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.

More on Low LDL Cholesterol (Hypobetalipoproteinemia)

Overview: Low LDL Cholesterol (Hypobetalipoproteinemia)
Differential Diagnoses & Workup: Low LDL Cholesterol (Hypobetalipoproteinemia)
Treatment & Medication: Low LDL Cholesterol (Hypobetalipoproteinemia)
Follow-up: Low LDL Cholesterol (Hypobetalipoproteinemia)
References
Further Reading
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References

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Keywords

low LDL cholesterol, cholesterol, LDL, LDL cholesterol, ABL, abetalipoproteinemia, hypobetalipoproteinemia, cholesterol levels, good cholesterol, triglyceride, triglycerides, lipoprotein, lipoproteins, apolipoprotein, Bassen-Kornzweig syndrome, HBL, familial hypobetalipoproteinemia, FHBL, FH-beta, low low-density lipoprotein cholesterol, Anderson disease, Anderson's disease

chylomicron retention disease, chylomicron-retention disease, lipoprotein metabolism dysfunction, lipoprotein metabolism disorder, fat malabsorption, spinocerebellar degeneration, acanthocytosis, acanthocytic red blood cells, pigmented retinopathy, malabsorption syndrome, vitamin E deficiency, vitamin deficiency, failure to thrive, ataxia, steatorrhea, retinal degeneration, blindness, spinocellular degeneration, retinitis pigmentosa

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Contributor Information and Disclosures

Author

Vibhuti N Singh, MD, MPH, FACC, FSCAI, Director, Suncoast Cardiovascular Center; Chair, Cardiology Division and Cath Labs, Department of Medicine, Bayfront Medical Center; Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine
Vibhuti N Singh, MD, MPH, FACC, FSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Florida Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Udaya M Kabadi, MD, Professor, Department of Medicine, University of Iowa College of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Yoram Shenker, MD, Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison
Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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