Type III Hyperlipoproteinemia: Still Worth Considering?

    Type III hypercholesterolemia: still worth considering? Conrad B. Blum PII: DOI: Reference:

S0033-0620(16)30071-8 doi: 10.1016/j.pcad.2016.07.007 YPCAD 745

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Progress in Cardiovascular Diseases

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Please cite this article as: Blum Conrad B., Type III hypercholesterolemia: still worth considering?, Progress in Cardiovascular Diseases (2016), doi: 10.1016/j.pcad.2016.07.007

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TYPE III HYPERCHOLESTEROLEMIA: STILL WORTH CONSIDERING?

Conrad B. Blum, MD

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Professor of Medicine at Columbia University Medical Center Columbia University College of Physicians and Surgeons

Conrad B. Blum, MD

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Corresponding Author:

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New York, NY 10019

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Professor of Medicine at Columbia University Medical Center Columbia University College of Physicians and Surgeons New York, NY 10019

[email protected]

Disclosures: None.

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TYPE III HYPERLIPOPROTEINEMIA: STILL WORTH CONSIDERING?

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ABSTRACT:

Familial type III hyperlipoproteinemia (HLP) was first recognized as a distinct entity

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over 60 years ago. Since then, it has proven to be instructive in identifying the key role of

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apolipoprotein E (apoE)in removal of the remnants of very low density and chylomicrons produced by the action of lipoprotein lipase on these triglyceride-transporting lipoproteins. It

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has additionally shed light on the potent atherogenicity of the remnant lipoproteins. This review describes the history of development of our understanding of this fascinating

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disorder, discusses the several genetic variants of apoE that play roles in the genesis of

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type III HLP, and describes the remarkable responsiveness of this fascinating disorder to lifestyle modification, especially carbohydrate restriction and calorie restriction, and, when

(125 words)

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required, the addition of pharmacotherapy.

KEY WORDS: Type III hyperlipoproteinemia, dysbetalipoproteinemia, apolipoprotein E, remnant lipoproteins Disclosures/COI :None Abbreviations: apo = Apolipoprotein CHD = Coronary heart disease CM = Chylomicron

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FCH = Familial combined hyperlipidemia HDL-C = High-density lipoprotein cholesterol

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HLP = Hyperlipoproteinemia

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HSPG = Heparan sulfate proteoglycan

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LDL = Low-density lipoprotein LDL-C = Low-density lipoprotein cholesterol

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LDLR = Low-density lipoprotein receptor LPL = Lipoprotein lipase

PAD = Peripheral arterial disease

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LRP = Low-density lipoprotein receptor like protein

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T2DM = Type 2 diabetes mellitus

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TG = Triglyceride

TGRL = Triglyceride rich lipoprotein

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VLDL =Very low density lipoprotein

Familial type III hyperlipoproteinemia ( HLP), also called dysbetalipoprotenemia, is characterized by hyperlipidemia due to accumulation of remnants of the triglyceride (TG)rich lipoproteins (TGRL), very low density lipoproteins (VLDL) and chylomicrons (CM) in response to dysfunctional genetic variants of apolipoprotein (apo) E or absence of apo E.

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HISTORY OF DIAGNOSTIC APPROACH TO TYPE III HYPERLIPOPROTEINEMIA

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The modern era in the study of lipid transport in plasma began in the late 1940s

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when Gofman and colleagues began studying plasma lipoproteins with the analytical ultracentrifuge which had recently become commercially available (1). In a 1952 report on

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14 patients with xanthomatous disorders, they noted that until then although there had been ‘intensive investigations of the blood lipids…little attention [had been directed to] the

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lipoprotein molecules which contain most of the blood lipids’ (2). That report focused on 14 patients with tuberous or planar xanthomas of the skin or tendon sheath xanthomas.

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Lipoproteins were characterized according to rates of flotation (Sf values; S honoring

force.

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Theodore Svedberg, the inventor of the ultracentrifuge) when subjected to high centrifugal They recognized 2 conditions with distinct patterns of xanthomas and with distinct

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patterns of lipoprotein abnormalities. The first, with xanthomas arising from tendon sheaths,

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was associated with increased concentrations of lipoproteins Sf 6-20, subsequently found to correspond to low density lipoproteins (LDL) and was associated with an increased frequency of atherosclerotic disease.

The second condition, with tuberous and planar

xanthomas arising from the skin, demonstrated ‘extreme increases in the concentration of Sf 10-20 and Sf 20-40 classes of lipoproteins’, subsequently found to correspond primarily to remnants of TGRL. These patients evidenced a very high prevalence of atherosclerotic disease.

In 1967, Fredrickson, Levy, and Lees presented a phenotyping system for hyperlipoproteinemias (3). They gave the appellation type III HLP to patients evidencing mixed hypercholesterolemia and hypertriglyceridemia who had VLDL with beta

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electrophoretic mobility (as compared to normal VLDL with pre-beta mobility). They recognized this disorder as probably identical to xanthoma tuberosum described by Gofman

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and colleagues over a decade earlier, and the identity of these 2 conditions was confirmed

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shortly thereafter (4).

In 1972, having previously noted that CMs from patients with type III HLP were

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cholesterol-rich (5), Hazzard et al. observed an increased ratio of cholesterol/triglyceride in the VLDL of patients with type III HLP (6). They proposed this as an improved diagnostic

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criterion for this condition although the metabolic basis for the cholesterol-enrichment of VLDL was not defined. Concurrently, it was becoming apparent that an accumulation of

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remnants formed from VLDL and CMs by lipoprotein lipase (LPL)-mediated hydrolysis of TG

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was the cause of the relative cholesterol-enrichment of TGRL (7).

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Shortly afterwards, Havel and Kane noted a predominance of apoE in the TGRL of patients

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with type III HLP (8), and then Utermann reported that patients with type III HLP exhibited a genetic variant of apoE in these patients (9). The nature of this variant (homozygosity for the 2 variant of the APOE gene, which encodes apoE2) was made clear by Zannis and Breslow (10). Three common variants of apoE can be discerned according to their isoelectric points; they are termed apoE2, apoE3, and apoE4. The normal variant is apoE3; while homozygosity for apoE2 is found in >90% of patients with type III HLP, apoE4 is associated with Alzheimer’s disease. The underlying basis for the classic 2 variant of APOE was determined by Mahley and coworkers to be a single base substitution resulting in the amino acid substitution of cysteine for arginine at residue 158 (11). However, it soon became apparent that a small minority of patients with type III HLP had other variants of

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APOE or produced no apoE at all. All variants of apoE associated with type III HLP share one crucial characteristic: they interact poorly with the LDL receptor (12, 13).

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Thus, a contemporary definition of type III HLP is hyperlipidemia due to

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accumulation of remnants of TGRL in response to dysfunctional genetic variants of

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apolipoprotein E or absence of apolipoprotein E. Unfortunately, identification of an accumulation of remnant lipoproteins has generally involved chemical analysis of VLDL after

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it has been isolated by preparative ultracentrifugation, a labor-intensive procedure not generally available in clinical laboratories. Therefore, efforts have been made to infer

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remnant lipoprotein accumulation from measurements on whole plasma or serum. The best such procedure requires measurement of the concentrations of apoB, cholesterol and TG in

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a fasting sample of plasma or serum (14). A diagnosis of type III HLP is made when plasma

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TG > 160 mg/dl and the ratios of total cholesterol (mM /L)/apoB (g/L) ≥ 6.2 and TG (mM/L)/apoB (g/L) <10. These ratios convert to the following when cholesterol, TG, and

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apoB are expressed as mg/dL: total cholesterol/apoB ≥ 2.4, and TG/apoB < 8.85. These

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criteria were highly sensitive and specific in the population from which they were derived: 1771 consecutive patients in a tertiary lipid clinic including 38 patients with type III HLP. When applied to a different population of 3695 consecutive individuals and compared with an ultracentrifugation-based diagnostic procedure, the method of Sniderman appeared to lack specificity (16 cases identified by ultracentrifugation [prevalence 0.4%] compared with 53 cases identified by the method of Sniderman [prevalence 1.4%]). Concordance improved considerably if the method of Sniderman was modified to require TG >200 mg/dl rather than 160 mg/dl, yielding 93% sensitivity and 99.5% specificity compared to ultracentrifugation (15). Other readily available measurements may provide hints to consider type III HLP in the differential diagnosis, but are not themselves diagnostic. These include the presence of

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mixed hyperlipidemia with roughly similar elevations of cholesterol and TG, or mixed hyperlipidemia with TG elevated out of proportion to cholesterol. Additionally, a

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discrepancy between the LDL-cholesterol( LDL-C) level calculated by the Friedewald

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equation and a lower LDL-Cmeasured by a homogeneous assay (so-called “direct” LDL-C)

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should suggest the possibility of type III HLP (16).

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PATHOPHYSIOLOGY OF TYPE III HYPERLIPOPROTEINEMIA

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ApoE is the recognition site for receptors involved in the clearance of remnants of VLDL and chylomicrons. These remnants are formed by hydrolysis of much of the TG and

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phospholipid of VLDL and chylomicrons and the associated transfer of C apoproteins to

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HDL. The changes in lipid content of TGRL and the reduction of C apoproteins occurring in the course of remnant formation cause a conformational change in apoE allowing its

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receptor recognition domain to be recognized by the LDL receptor (LDLR), by the low

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affinity high capacity heparan sulfate proteoglycans (HSPG) receptors responsible for clearing these remnants and by the LDLR like protein (LRP). The HSPG receptors either internalize the bound remnant particles themselves or hand these particles to the LRP, which effects internalization of the remnants into an endocytic vesicle (17, 18). Alleles of APOE producing variant forms of apoE protein that are poorly recognized by these receptors cause accumulation of remnants and underlie the genesis of type III HLP. The commonest apoE variant in type III HLP (termed apoE2) bears the arginine158cysteine mutation, and accounts for >90% of cases of type III HLP. Expression of type III HLP in patients is autosomal recessive with low penetrance. Heterozygotes do not develop type III HLP. Homozygosity for the arginine158cysteine variant occurs in about 1% of the population, but type III HLP occurs in less than 5% of these homozygotes.

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An additional metabolic insult involving either increased synthesis of VLDL or impaired clearance of remnants must coincide with apoE2 homozygosity for type III HLP to

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supervene. These additional insults include: (a) conditions yielding increased synthesis of

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VLDL: obesity and insulin resistance, type 2 diabetes mellitus (T2DM), alcohol consumption,

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pregnancy, certain medications (e.g., exogenous estrogens and atypical antipsychotics such as olanzapine), and (b) conditions yielding decreased clearance of TGRL and/or

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remnants:polymorphisms of lipolysis genes, increased age, menopause. In one reported case, pregnancy resulted in such severe hypertriglyceridemia in a woman with apoE2

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homozygosity as to cause pancreatitis (19).

Approximately 10% of patients with type III HLP have other variants of apoE or a

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complete absence of apoE. Some of these rare variants of apoE will cause type III HLP

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with only a single allele of the mutant APOE gene ( [arginine142cysteine with cysteine112arginine], arginine145cysteine, lysine146glutamine, lysine146glutamic acid,

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arginine136serine, arginine136cysteine, lysine146aspartamine with

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arginine147tryptophan [cysteine112arginine with 7 amino acid tandem insertion residues 121-127] named apoE3Leiden)(20). In these, type III HLP is a dominant trait with high penetrance. It is easy to understand how absence of apoE may cause this condition: when the ligand is absent, receptor binding must also be absent. However, it seems paradoxical that a single defective allele would cause dominant expression with high penetrance because heterozygotes with only 1 normal allele coding apoE3 and a null mutation of the other allele do not develop type III HLP. Furthermore, heterozygotes with the most common apoE2 mutation (arginine158cysteine ) and one normal allele coding apoE3 do not develop type III HLP. These facts would lead one to consider that a single copy of the wild-type allele coding apoE3 should be sufficient.

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The paradox is resolved by the observation that the apoE variants causing autosomal dominant transmission of type III HLP with high penetrance all have 1 or more of the

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following characteristics: (1) a greater affinity for TGRL than apoE2 (arginine158cysteine)

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or the wild-type apoE3, (2) greater impairment of binding to HSPG, and (3) absent or

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diminished modulation of receptor binding by LPL-induced changes in TGRL composition (13). Since these variants have a higher affinity for TGRL, they may be the predominant

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species of apoE in VLDL particles. The key role of HSPG in remnant clearance provides an

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explanation for an adverse impact of apoE variants with weaker binding to HSPG.

PREVALENCE OF TYPE III HYPERLIPOPROTEINEMIA

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The sole population-based study of the prevalence of type III HLP is the Lipid

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Research Clinics Prevalence Study (21). This involved 10 well-defined North American populations studied 1972-1976. Type III HLP was diagnosed when VLDL with beta

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electrophoretic mobility was present and the ratio of VLDL cholesterol (mg/dl) to total

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plasma TG (mg/dl) was >0.3. The prevalence of type III HLP was reported as 0.4% in men ≥20 years of age, 0.1% in men <20 years of age, and 0-0.2% in women. The prevalence of apoE2 homozygosity (apoE2/2 phenotype) is about 1% in most countries where it has been studied. Exceptions are Finland (0.3%, n=615), Turkey (0.5%, n=8366) (20). The arginine145cysteine variant, responsible for an autosomal dominant form of type III HLP, is particularly common in sub-Saharan Africa, where the allele frequency is 5-12%. Not surprisingly, it was also found to be common in New York African Americans (allele frequency 4.3%), while it was rare in New York whites (0.1%). New York African Americans carrying this allele had fasting plasma TG levels 52% higher than New York African American controls (22).

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Some patients characterized as having mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia (FCH) may actually have type III HLP. When 279

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consecutive patients with a clinical diagnosis of FCH were studied with APOE genotyping in

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a lipid clinic in Zaragoza, Spain, it was found that 5 of these (1.8%) had the

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arginine136serine mutation and evidence of increased remnant particles. These newly found patients with type III HLP substantially increased the known number of cases of type

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III in the clinic (23).

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CLINICAL MANIFESTATIONS

Cardiovascular Disease: Atherosclerotic cardiovascular disease and xanthomatosis

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are the main clinical manifestations of type III HLP. Remnants of VLDL and CMs are highly

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atherogenic and remnant cholesterol appears to confer greater risk than a similar concentration of LDL-C (24, 25).

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A summary of pooled data from 181 patients with type III HLP indicates a prevalence

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of 28% for coronary heart disease (CHD) and 21% for peripheral arterial disease (PAD)(20). The high frequency of PAD relative to CHD is quite striking. In contrast, in a study of 119 kindreds with familial hypercholesterolemia, manifested by elevation of LDL-C, Stone et al. found a 30% prevalence of CHD and only a 4% prevalence of PAD (26). A contemporary European cross-sectional study of 305 patients with type III HLP in Norway, Spain, Italy, and Netherlands was recently reported (27). Lipid lowering medication had been prescribed for 74% of these prior to their initial clinic visits. The mean age was 61 years, and 66% were male. CHD was present in 19%, PAD in 11%, cerebrovascular disease in 4%, and abdominal aortic aneurysm in 2%. Xanthomatosis: Palmar xanthomas (also called palmar planar xanthomas or xanthoma striata palmaris) are considered to be virtually pathognomonic for type III HLP.

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They present as yellow nodular deposits in the palmar creases; in mild form, they may appear as yellowing of the palmar creases without nodularity. Tuberous xanthomas (hard or

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soft pedunculated nodules) or tuboeruptive xanthomas (aggregates of eruptive xanthomas

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resulting in larger lesions raised above the plane of the skin) are common in untreated type

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III HLP. They tend to occur over the tibial tuberosity, the elbows, and the buttocks. In the NIH series of 47 patients with type III HLP, the prevalence of xanthomatosis was: palmar

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xanthomas 64%, tendon xanthomas 23%, tuberous or tuboeruptive xanthomas 51%, eruptive xanthomas 4%. These patients had mean plasma cholesterol 453 mg/dl and mean

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plasma TG 699 mg/dl (28).

Associated metabolic disorders: In the NIH series, hyperuricemia was present in

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43% of patients but there was a history of gout in only 4%. Similarly, T2DM was present in

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only 4%. However, in the contemporary European cross-sectional study of 305 patients with type III HLP, the prevalence of T2DM was 29%. The mean body mass index was

TREATMENT

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study)(27).

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similar in the 2 studies (27.9 in the NIH series and 28.5 in the European cross-sectional

Type III HLP responds exquisitely to lifestyle treatment and pharmacotherapy. Therefore, considering type III HLP in the differential diagnosis of a patient with mixed hypercholesterolemia and hypertriglyceridemia is important. Morganroth reported that dietary therapy induced an approximately 60% reduction in total cholesterol and non- high-density lipoprotein cholesterol(HDL-C) as well as an 80% reduction in TG (Table 1). Patients with type III HLP tend to be very sensitive to caloric balance and large increases in dietary carbohydrate (28). Diets for these patients should focus on calorie restriction to achieve ideal weight and alcohol restriction. Saturated fats,

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trans fats, and cholesterol should be limited as for the general population. Because many of these patients will develop normal lipid profiles with diet as the sole therapy, dietary

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treatment should almost always precede drug therapy in patients with type III HLP.

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A comparison of a ‘standard lipid lowering diet (reduced total and saturated fats

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increased fiber, and restricted sugar and alcohol) with a high glycemic index diet and a low glycemic index diet was carried out in 16 patients with type III HLP (29). Each of these diets

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reflected a reduction in energy intake compared to baseline (baseline 2777 kCal, standard lipid lowering 1985 kCal, high glycemic index 2340 kCal, low glycemic index1759 kCal).

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Baseline serum cholesterol was 182 mg/dl, TG 221 mg/dl, and HDL-C 50 mg/dl. Total serum cholesterol was reduced by 19% with the standard lipid lowering diet, 15% with the

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high glycemic index diet, and 26% with the low glycemic index diet. Because of the varying

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energy content of the 3 diets, it is not possible to determine how much of the benefit is related to dietary composition vs how much is related to calorie restriction.

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Statins, fibrates, and nicotinic acid yield excellent lipid responses in patients with type

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III HLP (Table 2)(30-35). Statins should be considered the first-line drugs for type III HLP because of their superior efficacy in controlling non-HDL-C and remnant cholesterol. Fibric acid derivatives were the first drugs shown to be effective in type III HLP, and an early study demonstrated improved peripheral arterial circulation in response to 3-6 months of treatment with clofibrate and diet (36). More recently, Cho reported the disappearance of cutaneous xanthomas, the disappearance of exertional angina, and the normalization of initially ischemic results of treadmill stress testing, along with dramatic reductions in total plasma cholesterol (747 mg/dl to 157 mg/dl) and TG (1,315 mg/dl to 108 mg/dl) with 1 year of treatment with fenofibrate and atorvastatin plus diet (37). The response of type III HLP to treatment with inhibitors of proprotein convertase subtilisin kexin type 9 has not been studied.

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CONCLUSION

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Type III HLP has been a valuable condition for what it has taught us about the

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physiology of lipid transport in lipoproteins. It is a rewarding condition to identify because of

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its dramatic response to treatment.

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TABLE 1. Response to Diet and Type III Hyperlipoproteinemia: NIH Experience (26) After diet

% Change

Cholesterol

453

185

-59

HDL-C

38

40

Non-HDL-C

415

145

Triglyceride

699

131

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5

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Concentrations reported as mg/dl

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Baseline

-65 -81

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Percent Reduction apoB

-21

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-55

-11

-44

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-56

-31

-35

-56

—

-44

-64

-17

-43

-48

—

-41

-46

-28

-33

-52

-66

-56

-52

28

-46

-53

-40

-43

-17

9

-38

5

-27

6

-36

5

4

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6

-34

non-HDLc

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10

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Gemfibrozil 600 mg bid (27) Fenofibrate 200/100 mg bid (28) Gemfibrozil 600 mg bid (29) Bezafibrate 400 mg/d (30) Nicotinic acid 3 g/d (mean of 1.5 g bid and 1 g tid) (29) Atorvastatin 10 mg/d (30) Atorvastatin 20 mg/d (31) Atorvastatin 40 mg/d (32)

Triglyceride

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Cholesterol

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N

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Drug

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Table 2. Type III Hyperlipoproteinemia: Response to Medications

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