Hypolipoproteinemia

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:

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

• Anemia
• Chronic inflammation
• Chronic liver disease
• Critical illness
• Hyperthyroidism
• Infection
• Malabsorption
• Malignancy

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:

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)