Approach to the Patient with Extremely Low HDL-Cholesterol

Abstract

Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear. Therapeutic interventions address reversible causes of low HDL-C, multiorgan abnormalities that may accompany primary disorders and cardiovascular risk modification when appropriate. Uncommon encounters with patients exhibiting extremely low HDL-C provide an opportunity to directly observe the role of HDL metabolism in atherosclerosis and beyond the vascular system.

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Learning Objectives

Upon completion of this educational activity, participants should be able to:

• Distinguish between artifactual, primary, and secondary causes of very low HDL-cholesterol.

• Assess and manage cardiovascular risk and non-cardiovascular morbidity associated with very low HDL-cholesterol.

Target Audience

This Journal-based CME activity should be of substantial interest to endocrinologists.

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Daniel J. Rader, M.D., Emil M. deGoma, M.D., and Editor-in-Chief, Leonard Wartofsky, M.D., reported no relevant financial relationships.

Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.

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Activity release date: October 2012

Activity expiration date: October 2014

The Case

A 22-yr-old South Asian male college student was referred to our lipid clinic for a high-density lipoprotein-cholesterol (HDL-C) of 6 mg/dl observed by homogeneous assay. The remainder of the lipid panel showed a total cholesterol of 92 mg/dl, triglycerides of 184 mg/dl, and a low-density lipoprotein-cholesterol (LDL-C) of 49 mg/dl. He had no prior assessment of his lipids. He was asymptomatic and described no prior medical or surgical history. He reported a family history of mildly reduced HDL-C, with his mother and father demonstrating levels of 26 and 22 mg/dl, respectively. He had no family history of cardiovascular disease. He denied taking prescription medications or over-the-counter supplements. Physical examination revealed enlarged orange tonsils, no xanthomas or corneal opacification, and normal sensation and reflexes. β-Quantification confirmed extremely low levels of HDL-C (3 mg/dl) and apolipoprotein A-I (apoA-I) (8 mg/dl). Two-dimensional gel electrophoresis followed by immunoblotting with anti-apoA-I antibodies demonstrated only a preβ-HDL band; α-HDL subpopulations were absent. Carotid ultrasonography showed no plaque and a lower risk carotid intima-media thickness. He was diagnosed with Tangier disease and will follow up for surveillance of peripheral neuropathy and serial assessment of atherosclerotic risk.

Background

One of the first risk factors identified for coronary heart disease (CHD) (1), low HDL-C levels rank among the most common lipid abnormalities (2), particularly in patients with diabetes or CHD. Low HDL-C is currently defined as an HDL-C value below 40 mg/dl for men or below 50 mg/dl for women, corresponding to approximately the 50th percentile (3). Patients exhibiting extremely low HDL-C, defined in this review as levels below 20 mg/dl, often have severe hypertriglyceridemia (triglyceride >500 mg/dl). Patients with HDL-C less than 20 mg/dl in the absence of severe hypertriglyceridemia are infrequently encountered in clinical practice. Such extreme values well below the 5th percentile (3) arise from severe perturbations in the metabolic pathways of HDL (Fig. 1).

Fig. 1.

HDL metabolism and monogenic extremely low HDL-C disorders. ABC, ATP-binding cassette transporter; CETP, cholesteryl ester transfer protein; LDL-R, LDL receptor. [Reproduced from E. M. Degoma and D. J. Rader: Novel HDL-directed pharmacotherapeutic strategies. Nat Rev Cardiol 8:266–277, 2011 (4) with permission. © Nature Publishing Group.]

In normal HDL metabolism, apoA-I is synthesized by the liver and the intestine (4). After secretion, apoA-I forms nascent preβ-HDL by acquiring phospholipid and unesterified cholesterol. These components are transferred to apoA-I from the liver and intestine via ATP-binding cassette transporter A1 (ABCA1) and from triglyceride-rich lipoproteins via plasma phospholipid transfer protein after lipolysis mediated by lipoprotein lipase. Preβ-HDL serves as the acceptor of free cholesterol efflux from peripheral cells, initiating the first step of reverse cholesterol transport. Lecithin-cholesterol acyltransferase (LCAT) esterifies the free cholesterol in HDL to form cholesteryl esters, which migrate to the core of the HDL particle, resulting in formation of α-HDL. These mature HDL particles acquire additional lipid via efflux mediated by ATP-binding cassette transporter G1 and potentially scavenger receptor class B type I (SR-BI). Cholesteryl ester transfer protein mediates exchange of cholesteryl esters for triglycerides with very low-density lipoprotein (VLDL) or LDL, effecting depletion in cholesteryl esters and enrichment in triglycerides of HDL. The resulting HDL particles can be modified by hepatic lipase (HL) and endothelial lipase. HL hydrolyzes triglycerides and phospholipids within HDL, converting lipid-rich large HDL₂ to smaller, more dense HDL₃, which is more rapidly catabolized. Endothelial lipase preferentially hydrolyzes HDL phospholipids, releasing lipid-poor apoA-I, which can be filtered by the glomeruli and degraded by cubilin/megalin in the proximal renal tubule. HDL-C can be taken up by the liver via SR-BI-mediated selective uptake or by a holoparticle uptake mechanism that is poorly understood. Although multiple processes can result in low HDL-C levels, extremely low HDL-C in the absence of severe hypertriglyceridemia is generally a result of impaired HDL biogenesis.

Differential diagnosis of extremely low HDL-C in the absence of hypertriglyceridemia

Extremely low HDL-C may be artifactual due to assay interference from paraproteinemia, secondary to drugs or malignancy, or primary resulting from monogenic disorders, namely apoA-I deficiency, Tangier disease, or LCAT deficiency (Table 1).

Table 1.

Differential diagnosis of extremely low HDL-C levels (<20 mg/dl)

Artifactual cause

Paraproteinemia from immunoproliferative disorders such as multiple myeloma

Secondary causes

Anabolic androgenic steroids

Fibrates

TZD in combination with fibrates

Malignancy

Primary (monogenic) causes

ApoA-I deficiency

ApoA-I structural mutations

Tangier disease

Heterozygous deficiency of ABCA1

LCAT deficiency

Artifactual cause

Paraproteinemia

Many clinical laboratories currently use direct or homogeneous assays to quantify HDL-C. These techniques measure the cholesterol content of the HDL fraction without the need for labor-intensive pretreatment or separation, thereby permitting automated, high-throughput analysis (5). Paraproteinemia due to immunoproliferative disorders may interfere with the initial reagents used in several direct HDL-C assays that block detection of cholesterol in apolipoprotein-B-containing lipoproteins (6). The interaction, which remains poorly characterized, may result in artifactual extremely low and even undetectable HDL-C levels, and frequently low LDL-C as well. The hallmark of artifactual lipid abnormalities associated with multiple myeloma is normal lipid levels measured via ultracentrifugation, chemical precipitation, or electrophoresis, assays unaffected by the presence of excessive amounts of monoclonal gammaglobulin (6). Treatment of multiple myeloma results in normalization of the artifactual extremely low HDL-C observed with direct HDL-C assays (6).

Secondary causes

Androgenic anabolic steroids

Androgenic anabolic steroids used medically for catabolic diseases such as malignancy and AIDS or recreationally in weight-lifters may result in extremely low levels of HDL-C (7). Higher doses of steroids, 17α-alkylated compounds, and oral administration have been associated with profound HDL-C suppression exceeding 50%, as well as significant increases in LDL-C (7). The timing of HDL-C decline may occur within days of initiating these agents. Normalization of lipid parameters occurs after 1–3 months of steroid withdrawal. Androgens exert their HDL-lowering effects at least in part by enhancing the activity of HL, thereby accelerating the catabolic rate of HDL (7).

Paradoxical response to peroxisome proliferator-activated receptor (PPAR) agonists

Treatment with either fibrates (PPARα agonists) or thiazolidinediones (TZD; PPARγ agonists) generally yields an average increase in HDL-C of 5–20% (8) or 5–10% (9), respectively. Paradoxical and severe decreases in HDL-C to below 20 mg/dl have been reported after fibrate administration or in the setting of concurrent fibrate and TZD use (10, 11). The prevalence of this idiosyncratic response remains unknown. A review of 54,000 patients followed in the primary care setting observed reductions in HDL-C to below 17 mg/dl in 0.02% of patients treated with fibrates alone and 1.39% of patients treated with the combination of fibrate and TZD (10). A referral lipid clinic observed a higher prevalence (7.4%) of transient low HDL-C below 20 mg/dl among patients receiving fibrates (11). The reported onset of HDL-C depression varies from weeks to years after initiation of fibrate or fibrate-TZD therapy; on the other hand, resolution after withdrawal of the offending medication more consistently occurred within 1 month. Significant reductions in HDL-C do not appear to be a class effect. Not only are gemfibrozil and pioglitazone rarely implicated in extremely low HDL-C, but case reports describe resolution of severe reductions in HDL-C after switching from other fibrates or TZD to these drugs (12). The mechanism of the paradoxical, reversible HDL-C depression remains uncertain. One kinetic study in a patient who exhibited extreme lowering of HDL-C with ciprofibrate suggested increased clearance of apoA-I as a contributing factor (13).

Malignancy

Case reports have described extremely low HDL-C levels in the setting of lymphoma (14). A sudden, dramatic decline in HDL-C may precede overt clinical manifestations of hematological malignancy. The mechanism underlying HDL-C suppression remains unknown, and the phenomenon does not appear to be related to paraproteinemia. A recent study identified antibodies specific for LCAT as the cause of a significant decrease in HDL-C in a patient with lymphoma (15). Successful treatment of the lymphoma resulted in clearance of the antibody and correction of HDL-C levels.

Primary causes

Monogenic disorders associated with low HDL-C, although rare in the overall population (16), are more frequently observed among individuals with extremely low HDL-C. An analysis of the Dallas Heart Study identified monogenic low HDL-C disorders in one of six black and white men and women with HDL-C below the 5th percentile, approximately 30 mg/dl (3). The extremely low HDL-C group is undoubtedly further enriched for variants in three key genes involved in HDL metabolism, as described below.

ApoA-I deficiency or structural mutations

The major protein constituent of HDL, apoA-I, provides structure to the HDL particle, mediates the initial required step in HDL assembly, lipidation by ABCA1, and promotes activation of LCAT. ApoA-I deficiency is due to deletions of the apoA-I gene (17) or nonsense mutations early in the coding portion of the gene (18) in both apoA-I alleles. As a result, the apoA-I protein is not synthesized or secreted, leading to absent apoA-I in plasma and very low levels of HDL-C. Patients with apoA-I deficiency may present with cutaneous xanthomas or mild corneal opacification due to accumulation of cholesterol from impaired peripheral cellular efflux (Fig. 2) (19). Determining the cardiovascular risk associated with monogenic extremely low HDL-C disorders is complicated by the rarity of cases, referral bias, and the reliance in most kindred analyses on clinical events, which in younger individuals may not capture extensive premature atherosclerosis. With these caveats, the weight of evidence supports a high risk of early-onset CHD among patients homozygous or compound heterozygous for apoA-I deficiency. The association, however, is not invariant. A notable case of a 69-yr-old woman with apoA-I deficiency, HDL-C level of 5 mg/dl, LDL-C level of 196 mg/dl, hypertension, and impaired fasting glucose demonstrated a striking absence of significant atherosclerotic disease, with only mild plaque observed on carotid ultrasonography and an unremarkable exercise electrocardiogram (20). Similarly, a 39-yr-old man with apoA-I deficiency, HDL-C of 6 mg/dl, and LDL-C of 175 mg/dl exhibited no subclinical plaque on coronary iv ultrasound (21). Among apoA-I-deficient patients without clinical cardiovascular disease, lower LDL-C has been suggested as a possible protective trait (22). The aforementioned cases suggest additional mechanisms underlying the variable vascular phenotype in patients with extremely low HDL-C from apoA-I deficiency.

Fig. 2.

Physical examination findings in monogenic extremely low HDL-C disorders. Patients with apoA-I deficiency may manifest xanthomas (A) and mild corneal clouding (B). [Reproduced from E. J. Schaefer et al.: Marked HDL deficiency and premature coronary heart disease. Curr Opin Lipidol 21:289, 2010 (19), with permission. © Lippincott Williams & Wilkins.] The hallmark physical findings in Tangier disease are enlarged yellow-orange tonsils (C). [Reproduced from T. Sampietro et al.: Images in cardiovascular medicine. Tangier disease in severely progressive coronary and peripheral artery disease. Circulation 119:2741, 2009 (26), with permission. © American Heart Association.] Patients with LCAT deficiency exhibit age-dependent corneal opacification. Eyes from a 32-yr-old patient (D) and a 67-yr-old (E) patient are shown. [Reproduced from A. von Eckardstein: Differential diagnosis of familial high density lipoprotein deficiency syndromes. Atherosclerosis 186:231, 2006 (16), with permission. © Elsevier.]

In contrast, apoA-I structural mutations are caused by missense mutations in the apoA-I that result in the insertion of an alternate amino acid. This affects the structure of the apoA-I protein, often leading to impaired function and/or increased catabolism. The first apoA-I structural variant described was apoA-I Milano (23), and many others have since been described (19). Patients are almost always heterozygous for the mutation, and thus have one normal apoA-I allele. Like apoA-I Milano, most (but not all) apoA-I structural variants are not associated with increased cardiovascular risk, despite causing reduced HDL-C levels that are often below 20 mg/dl. A subset of apoA-I structural variants cause hereditary amyloidosis due to deposition of the mutant apoA-I in amyloid plaque (19).

Tangier disease

Tangier disease bears the name of the small island residence of the two siblings first identified with extremely low HDL-C, subsequently shown to be due to mutations in both alleles of the ABCA1 gene (24). Subsequent case reports have described the rare autosomal recessive monogenic disorder in a number of races throughout the world (16). The ABCA1 protein transports cellular cholesterol and phospholipids to the extracellular acceptor free apoA-I to form nascent HDL. Tangier patients carry two defective ABCA1 alleles resulting in very low or undetectable cellular ABCA1 activity. Levels of apoA-I are extremely low due to rapid catabolism of the apolipoprotein as a result of being poorly lipidated. Up to 50% lower LDL-C levels may be observed in Tangier patients due to increased clearance via up-regulated LDL-receptor expression (25). Preclinical data point to enhanced VLDL production as the cause of elevated triglyceride that may be seen in Tangier disease (25).

Hyperplastic foam cells are a characteristic feature of Tangier disease, resulting from the inability to efflux cholesterol via ABCA1. Lipid-laden cells of the reticuloendothelial system manifest as tonsillar enlargement and hepatosplenomegaly. Yellow-orange discoloration of the tonsils and rectal mucosa results from intracellular accumulation of lipophilic retinyl esters and carotenoids (Fig. 2) (26).

Peripheral neuropathy, observed in over 50% of Tangier patients (16), represents the most frequent reason for clinical presentation. Nerve dysfunction more commonly manifests as a remitting-relapsing multifocal neuropathy with sensory abnormalities. Lipid accumulation in the paranodal regions of myelinating Schwann cells has been implicated in the pathogenesis of nerve conduction delay or block (27). Rarely, Tangier disease has been associated with a debilitating syringomyelia-like neuropathy in which muscle wasting and anesthesia involve the face and the upper limbs before extending downward to the trunk and lower extremities. The mechanism remains uncertain but appears to involve primary neuronopathy of the dorsal roots (27).

The association of premature atherosclerosis with Tangier disease is surprisingly tenuous despite the defect in cellular cholesterol efflux and the very low levels of HDL-C and apoA-I. Early CHD has been observed in some kindreds but not in others (28). The incongruous cardiovascular risk in Tangier patients with extremely low HDL-C has previously been attributed to concurrently low LDL-C. However, high LDL-C levels have been observed in Tangier patients in the absence of clinical or subclinical cardiovascular disease, implicating additional mechanisms for the apparent paradox. One hypothesis is that the absence of hepatic ABCA1 may be atheroprotective, counterbalancing the impaired peripheral cholesterol efflux due to macrophage ABCA1 deficiency (29). Hepatic ABCA1 diverts cholesterol from the terminal step of reverse cholesterol transport, excretion into bile, by transporting cholesterol back into the circulation.

Individuals who are heterozygous for ABCA1 mutations have low levels of HDL-C that can be below 20 mg/dl. Indeed, in a family in which there appears to be dominant transmission of a low HDL-C trait, an ABCA1 mutation should be considered in the differential (30). As with Tangier disease, heterozygous ABCA1 deficiency is not uniformly associated with increased cardiovascular risk, and population-based studies have suggested that a low HDL-C due to ABCA1 mutations does not confer increased cardiovascular risk (31).

LCAT deficiency

After apoA-I acquires free cholesterol from ABCA1-mediated efflux, the next obligate step in HDL maturation requires LCAT. LCAT catalyzes conversion of free cholesterol to cholesteryl esters that migrate into the hydrophobic core of HDL, forming spherical α-HDL. Genetic deficiency of LCAT presents as one of two related autosomal recessive disorders, both exhibiting extremely low HDL-C. Patients with familial LCAT deficiency (FLD), characterized by essentially complete LCAT deficiency, develop corneal opacification, anemia, and progressive renal disease (32). Patients with fish-eye disease (FED) present with corneal opacification but are spared the anemia and renal disease and have evidence of some LCAT activity in the blood, generally associated with apoB-containing lipoproteins (33). Both disorders, however, are due to loss-of-function mutations in both LCAT alleles; FED can simply be thought of as a milder form of LCAT deficiency. In FLD and FED, apoB-containing lipoproteins may be elevated and are highly abnormal. VLDL is typically enriched for free cholesterol and relatively devoid of protein. The low-density fraction may contain normal LDL as well as lipoproteins predominantly consisting of free cholesterol, phospholipid, and apolipoprotein C, resembling the lipoprotein X observed in biliary obstruction (16).

Corneal opacification, the hallmark physical finding in LCAT deficiency states, is more severe than the corneal cholesterol accumulation that may sporadically be observed in apoA-I deficiency and Tangier disease. FLD and FED patients develop slowly progressive corneal clouding accompanied by a white or gray ring in the corneal margin similar to arcus senilis (Fig. 2) (16). Despite the dramatic appearance, vision remains intact in most cases. Among FLD patients, the major cause of morbidity and mortality is renal failure. Proteinuria manifesting in childhood gradually progresses to nephrotic syndrome and end-stage chronic kidney disease (34). Why kidney function deteriorates in FLD remains unknown. Heterogenous glomerular pathology implicates several possible mechanisms including trapping of abnormal LDL and deposition of complement C3 (35). Mild normochromic, normocytic anemia to a hemoglobin of 10 g/dl has been attributed to increased erythrocyte fragility due to abnormal lipid composition in the membrane (36).

Limited data available from kindreds with FLD and FED reveal no clear evidence of increased risk of premature atherosclerotic disease (37). Assessment of carotid intima-media thickness, a surrogate imaging measure of cardiovascular risk, also suggests no significant worsening of vascular phenotype among individuals homozygous for LCAT mutations. Patients with FLD and FED exhibited comparable or even reduced carotid intima-media thickness compared with controls (38).

Diagnostic Testing

Initial evaluation of patients with extremely low HDL-C focuses on eliminating severe hypertriglyceridemia as the cause and then classifying the dyslipidemia as artifactual, secondary, or primary. Normalization of an extremely low HDL-C on β-quantification, electrophoresis, or precipitation techniques suggests artifactually low HDL-C from paraproteinemia. Confirmation requires identification of monoclonal gammaglobulin by serum or urine protein electrophoresis. Serial lipid values, if available, are helpful, with previously normal HDL-C levels excluding a primary monogenic etiology. A detailed family history, with a focus on HDL-C levels, is important in assessing the potential for a familial condition. A complete medication history, including over-the-counter therapies and nutritional supplements, should be elicited in an attempt to identify secondary culprit drugs. In the setting of a sudden decrease in HDL-C below 20 mg/dl, if the aforementioned assessment is unrevealing, it is prudent to conduct a comprehensive evaluation for occult malignancy. Physical examination findings, as described above, can suggest a particular monogenic etiology, with special attention to the skin, eyes, tonsils, and spleen.

For suspected primary causes, workup involves additional biochemical and genetic assessment (Table 2). Plasma apoA-I levels should be obtained and can be useful diagnostically. Patients with apoA-I deficiency have undetectable plasma apoA-I, and Tangier disease patients have extremely low apoA-I levels (<5 mg/dl). In contrast, patients with LCAT deficiency, structural apoA-I mutations, and heterozygous ABCA1 deficiency have apoA-I levels that, although low compared with normal, are considerably higher. Measurement of plasma free (unesterified) cholesterol can be useful in that both forms of LCAT deficiency have a much higher ratio of free:total cholesterol in plasma due to the defect in cholesterol esterification. Specialized measurements of LCAT activity in plasma can be diagnostic for LCAT deficiency, although more definitive for FLD than for FED where residual LCAT activity can confound the interpretation. Two-dimensional gel electrophoresis of plasma followed by immunoblotting with antibodies specific for apoA-I separates lipid-poor preβ-HDL from lipid-rich α-HDL. In normal individuals, the former contributes a minor subfraction of the total apoA-I population. Plasma from Tangier patients, on the other hand, exhibits only preβ-HDL-migrating apoA-I; no α-HDL fraction is observed due to absent ABCA1-mediated conversion of preβ-HDL to α-HDL. Both FLD and FED have an absence of HDL particles larger than α-4 HDL, the farthest migrating α-HDL subspecies on two-dimensional gel electrophoresis (Fig. 3) (19). Examination of the peripheral blood smear in FLD may reveal target cells, anisopoikilocytosis, and evidence of hemolysis. The diagnosis of Tangier disease is generally made on clinical grounds, but rectal histological evaluation as well as skin fibroblast cholesterol efflux assays may provide confirmatory evidence. Biopsy of the rectum frequently reveals large lipid-laden foam cells in the mucosa and submucosa. Definitive molecular diagnosis of these conditions requires sequencing of the exons of the suspected gene to look for causal mutations, but the presumptive diagnoses can often be made on clinical grounds.

Table 2.

Overview of findings in monogenic extremely low HDL-C disorders

	ApoA-I mutations		ABCA1 mutations		LCAT mutations
	ApoA-I deficiency	ApoA-I structural mutations	Tangier disease	Heterozygous ABCA1 deficiency	FLD	FED
Physical examination	Xanthomas	Xanthomas	Enlarged, yellow-orange tonsils	None	Corneal opacification	Corneal opacification
	Mild corneal opacification	Mild corneal opacification	Peripheral neuropathy		Hepatosplenomegaly
			Hepatosplenomegaly
			Yellow-orange studded rectal mucosa
Laboratory assessment
LDL-C	Normal	Normal	Low	Normal	May be high	May be high
					LDL structurally resembles lipoprotein X	LDL structurally resembles lipoprotein X
Triglycerides	Isolated apoA-I deficiency: normal	Normal	High	Normal	High	High
	ApoA-I/C-III/A-IV deletion: low
ApoA-I	0–1 mg/dl	10–20 mg/dl	0–5 mg/dl	10–20 mg/dl	30–50 mg/dl	30–50 mg/dl
Two-dimensional gel electrophoresis	No apoA-I	Low apoA-I	Preβ-HDL: present	Preβ-HDL: present	Preβ-HDL: present	Preβ-HDL: present
			Any α-HDL: absent	Any α-HDL: low	α4-HDL: present	α4-HDL: present
					Larger α-HDL: absent	Larger α-HDL: absent
Additional lipid- related testing			Fibroblast efflux of radiolabeled cholesterol:low	Fibroblast efflux of radiolabeled cholesterol: low	LCAT mass/activity: absent	LCAT mass/activity: low
			Rectal biopsy: lipid-laden foam cells	Rectal biopsy: lipid- laden foam cells	Cholesterol ester/total cholesterol: very low	Cholesterol ester/total cholesterol: normal
Other					Proteinuria
					Reduced creatinine clearance
					Anemia with target cells and evidence of normocytic, nonimmune hemolysis
Association with premature atherosclerotic disease	++	+/−	+/−	+/−	−	−

Fig. 3.

Two-dimensional gel electrophoresis of monogenic extremely low HDL-C disorders. A composite is shown of the HDL gel patterns observed in a normal subject, a homozygote with apoA-I deficiency, a Tangier patient, and an individual with LCAT deficiency. [Reproduced from E. J. Schaefer et al.: Marked HDL deficiency and premature coronary heart disease. Curr Opin Lipidol 21:289–297, 2010 (19) with permission. © Lippincott Williams & Wilkins.]

Therapeutic Strategies

Management of secondary causes of extremely low HDL-C involves removal of the offending drug or treatment of the underlying disease. Evaluation and management of cardiovascular risk plays a central role, particularly for monogenic extremely low HDL-C disorders. Manifest cardiovascular disease warrants comprehensive secondary prevention measures, including achieving an LDL-C well below 70 mg/dl with high-dose statin therapy. In the primary prevention setting, in addition to optimizing identifiable traditional risk factors, subclinical atherosclerosis imaging with coronary artery calcium scanning or carotid intima-media thickness assessment may be helpful to refine risk and establish targets for lipid-lowering therapy.

ApoA-I deficiency is generally associated with markedly increased atherosclerotic cardiovascular disease and should be managed with aggressive reduction of LDL-C and non-HDL-C. Therapies such as repeated apoA-I infusion are being developed and could be useful for this condition in the future. apoA-I structural variants are not generally associated with clinical sequelae requiring specific treatment. In Tangier patients, hyperplastic tonsils are usually asymptomatic but in children may cause pharyngeal obstruction requiring tonsillectomy. Neuropathy is the major clinical issue, but to date, no therapeutic intervention has proven effective in treating the neuropathy of Tangier disease. Rarely, severe corneal opacification in patients with FLD or FED may interfere with vision, necessitating corneal transplantation. Management of FLD centers on the preservation of renal function. Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and in some cases steroid therapy have demonstrated efficacy in treating proteinuria and slowing progression of renal failure (39). Patients with end-stage renal disease have undergone renal transplantation; however, disease has been reported to reoccur in the allograft (40). Repeated infusion of recombinant LCAT is being developed as a therapy for this condition, and even gene therapy is a possibility for the future.

Summary

Extremely low HDL-C below 20 mg/dl may be an artifact of homogeneous assays in the setting of multiple myeloma; secondary to androgenic anabolic steroids, fibrates, TZD, or malignancy; or primary resulting from genetic disorders. Each of the three known monogenic disorders in which patients manifest extremely low HDL-C—apoA-I deficiency or structural mutations, Tangier disease, and LCAT deficiency—presents with a unique constellation of physical and biochemical findings. The association between extremely low HDL-C and premature atherosclerosis is surprisingly inconsistent, an observation that remains incompletely explained. Evaluation and management of the risk for atherosclerotic cardiovascular diseases plays a central role in the care of these patients, as well as addressing extravascular manifestations of abnormal HDL metabolism.