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Lipid Disorders Main Page




Familial hypoalphalipoproteinemia
LCAT Deficiency
Chylomicron retention disease
Tangier disease
Familial combined hypolipidemia

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]; Aravind Kuchkuntla, M.B.B.S[3]; Tarek Nafee, M.D. [4] Synonyms and keywords: Hypolipidemia, low lipoprotein


Hypolipoproteinemia (also known as hypolipidemia or low lipoproteins) is defined as presence of low levels of one or more type of lipoproteins. Hypolipoproteinemia may present as primary genetic disorders or as a secondary complication of underlying medical conditions. After ruling out common secondary causes of hypolipoproteinemia, the clinician must begin the work-up for primary causes. Patients with hypoproteinemia may present with low LDL, or low HDL. Patients with low LDL commonly present with diarrhea, vomiting, or failure to thrive (in infanthood). Patients with primary low HDL are usually asymptomatic however, patients diagnosed with low HDL due to Tangier's disease, ApoA1 deficiency, or LCAT deficiency have specific clinical findings such as corneal opacities, xanthomas, and renal failure. Work up for primary hypolipoproteinemias begins with careful examination of the lipid panel and may involve screening of family members. Confirmatory gene sequencing is the gold standard diagnostic test for all hypolipoproteinemias.


The following are the list of conditions which can cause low LDL C and low HDL C levels:

Primary lipoprotein abnormalities

  • Hypoalphalipoproteinemia (Apolipoprotein A-1 deficiency). Low HDL
  • Hypobetalipoproteinemia and Abetalipoproteinemia. Low LDL and VLDL, but not low HDL
  • Chylomicron retention disease
  • Cholesteryl ester transfer protein (CETP) elevation
  • Familial combined hypolipidemia (does not increase risk of atherosclerosis)
  • LCAT deficiency
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) loss of function or deficiency
  • Adenosine triphosphate (ATP)-binding cassette transporter (ABCA1) gene mutations
    • Familial HDL deficiency. This is the most common cause of low HDL and coronary artery disease.
    • Tangier disease

Secondary causes


Based on the etiology hypolipoproteinemias are classified into primary and secondary hypolipoproteinemias. The following algorithm is a list of various etiologies under primary and secondary hypolipoproteinemias:

Apolipoprotein 1 deficiency
Chylomicron retention disease
Familial combined hypolipidemia
LCAT deficiency
Primary alphalipoproteinemia
PCSK9 deficiency
Tangier disease
Critical illness
Chronic inflammation
Chronic liver disease

Differential Diagnosis

The table below provides a brief synopsis of the lipid profile findings in several of the most common primary hypolipidemic disorders affecting the LDL C levels:

Abetalipoprotienemia Familial Homozygous


Familial Heterozygous


PCSK9 deficiency Chylomicron Retention


Familial Combined


LDL C ↓↓↓ (0) ↓↓↓ ↓↓ ↓↓
Apo B ↓↓↓( 0) ↓↓↓ N ↓↓ N
TG ↓↓↓ ↓↓↓ N
TC ↓↓↓ ↓↓↓ ↓↓
HDL ↓↓ ↓↓ N N ↓↓ ↓↓
VLDL ↓↓ ↓↓ N ↓↓
Apo A1 ↓↓ ↓↓ N ↓↓ N

The table below is a differential diagnosis for low HDL C disorders:

Familial LCAT


Fish Eye


Homozygous Tangier


Heterozygous Tangier


Apo A1 Deficiency
Gene Defect LCAT LCAT ABCA1 ABCA1 Apo A1
Inheritance Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Dominant
  • Loss of alpha and beta LCAT function
  • Failure of cholesterol ester formation.
Loss of alpha function only

Pre beta-1 HDL fails to picks up free cholesterol from cells due to mutation in ABCA1 transporter.

Similar to homozygous Defective synthesis of Apo A1 resulting in failure of maturation of HDL and defective reverse cholesterol transport.
Clinical Features
  • Annular corneal opacity
  • Anaemia
  • Progressive renal disease with proteinuria
  • Corneal opacities only
  • Normal renal function
  • Large yellow-orange tonsils
  • Dense central corneal opacity
  • Relapsing and remitting course of neuropathy
  • Corneal Opacities
  • Tuboeruptive, Planar and palmar Xanthomas
  • Premature Heart Disease
Lipid Panel
  • Elevated Free cholesterol
  • HDL-C < 10 mg/dL
  • Low Apo A1 and Apo AII
  • Elevated Apo E and Triglycerides
  • Low LDL C
  • Elevated free cholesterol
  • HDL C < 27 mg/dL
  • Apo A1<30mg/dl and low Apo A2
  • Elevated Apo E and Triglycerides
  • Normal LDL and VLDL
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
  • HDL C, Apo A1 and LDL 50% less than normal.
  • Undetectable Apo A1
  • HDL C less than 10mg/dl
  • Normal or low Apo AII
  • LDL C normal
  • Triglyceride normal or elevated
2D Gel Electrophoresis Pre β-1 and α-4 HDL, LDL with β mobility due to Lipoprotien-X Pre β-1and α-4 HDL with normal pre-β LDL. Only preβ-1 HDL present
  • Lack of large α-1 and α-2 HDL particles
  • Normal preβ-1 HDL
Lack of Apo A1 containing HDL particles.

Approch algorithm to a patient with low HDL C:[1]

HDL <20mg/dl in the absence of severe hypertriglyceridemia
Rule out secondary causes of low HDL C
Paraproteinemia from multiple myeloma
Anabolic steriod use
Fibrate use
Thiazolidinedione use
Consider Monogenic primary disorders
Order ApoA1
Undetectable or <5mg/dl
Familial LCAT deficiency
High plasma FC:CE ratio
2D electrophoresis: Prebeta and Alpha-4, Beta mobility of LDL
Do 2D Gel Electrophoresis with Apo A1 Immunoassay
Complete absence of Apo A1 containing HDL C
Only Pre-Beta HDL C
Apo A1 Deficiency
(Confirm with gene sequencing)
Homozygous Tangier Disease
(Confirm with gene sequencing)

Approach algorithm to a patient with low low LDL C:

Low LDL C <5th percentile
Rule out secondary causes of low LDL
Lipid panel
Normal Triglycerides
Low Triglycerides
Chlyomicron retention disease
(Confirm with gene sequencing)
Screen the lipid panel of the patient's parents
Normal Parental Lipid Panel
If Parental Lipid Panel <50% of Normal on:
*Total Cholesterol
(Confirm with gene sequencing)
Familial homozygous hypobetalipoproteinemia
(Confirm with gene sequencing)


  1. Rader DJ, deGoma EM (2012). "Approach to the patient with extremely low HDL-cholesterol". J Clin Endocrinol Metab. 97 (10): 3399–407. doi:10.1210/jc.2012-2185. PMC 3462950. PMID 23043194.

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