Hypolipoproteinemia

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Lipid Disorders Main Page

Overview

Causes

Classification

Abetalipoproteinemia
Hypobetalipoproteinemia
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

Overview

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.

Causes

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

Classification

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:

 
 
 
 
 
 
Hypolipoproteinemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary
(Genetic)
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abetalipoproteinemia
Apolipoprotein 1 deficiency
Chylomicron retention disease
Familial combined hypolipidemia
Hypobetalipoproteinemia
LCAT deficiency
Primary alphalipoproteinemia
PCSK9 deficiency
Tangier disease
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia
Critical illness
Chronic inflammation
Chronic liver disease
Hyperthyroidism
Infection
Malabsorption
Malignancy

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

Hypobetalipoproteinemia

Familial Heterozygous

Hypobetalipoproteinemia

PCSK9 deficiency Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

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

Deficiency

Fish Eye

Disease

Homozygous Tangier

Disease

Heterozygous Tangier

Disease

Apo A1 Deficiency
Gene Defect LCAT LCAT ABCA1 ABCA1 Apo A1
Inheritance Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Dominant
Pathogenesis
  • 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
Asymptomatic
  • 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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>5mg/dl
 
 
 
 
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:
*LDL
*Total Cholesterol
*Triglycerides
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abetalipoproteinemia
(Confirm with gene sequencing)
 
 
Familial homozygous hypobetalipoproteinemia
(Confirm with gene sequencing)

References

  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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