How Low Is Safe? The Frontier of Very Low (<30 mg/dL) LDL Cholesterol

Angelos D. Karagiannis; Anurag Mehta; Devinder S. Dhindsa; Salim S. Virani; Carl E. Orringer; Roger S. Blumenthal; Neil J. Stone; Laurence S. Sperling

Disclosures

Eur Heart J. 2021;42(22):2154-2169. 

In This Article

Genetic Conditions Associated With Very Low LDL-C

Six genetic conditions (PCSK9 loss-of-function mutations, abetalipoproteinemia, familial hypobetalipoproteinemia, familial combined hypolipidemia, chylomicron retention disease, and Smith–Lemli–Opitz syndrome) are associated with very low LDL-C levels (Figure 2). Healthy human neonates have baseline low LDL-C (30–70 mg/dL)[42] and a percentage of healthy neonates are found with LDL-C levels even <30 mg/dL.[43,44]

Figure 2.

Genetic conditions associated with very low LDL-C. Thus far, six different genetic conditions associated with very low (<30 mg/dL) LDL-C have been identified. Analysis of individuals living with these conditions may help in better understanding potential benefits and side effects of living with very low LDL-C long term.

PCSK9 is a serine protease that tightly binds to the LDL receptor (LDL-R) and subsequently chaperones the LDL-R to the intracellular degradative organelles for dismantling.[45] Individuals with PCSK9 loss-of-function mutations have increased numbers of LDL-R on the surface of their hepatocytes that promotes robust LDL-C clearance from the circulation leading to lifelong reduction in LDL-C. Such individuals are healthy, do not have any apparent secondary morbidities, and experience a significant reduction in cardiovascular events over long-term follow-up.[9,46,47]

Although PCSK9 is expressed in the brain, liver, intestine and kidneys, a compound heterozygote for loss-of-function PCSK9 mutations with 14 mg/dL serum LDL-C was found to be healthy, fertile and without any neurocognitive impairment.[48] One study showed that PCSK9 variants have an LDL-C-dependent risk for developing diabetes; for each 10 mg/dL LDL-C decrease, there is an 11% increase in diabetes risk.[46] On the contrary, another study did not support any correlation between low LDL-C and type 2 diabetes in individuals with the most frequent PCSK9 loss-of-function variant.[49]

Abetalipoproteinemia is a rare autosomal recessive disorder resulting from mutation of the microsomal triglyceride transfer protein (MTP), which is essential for assembling all apoB lipoproteins. Abetalipoproteinemia is characterized by the absence of serum apoB-containing lipoproteins, undetectable LDL-C, in addition to deficiency of lipid soluble vitamins (A, D, E, K).[50] Affected individuals present with severe neurological manifestations including retinal degeneration, spinocerebellar ataxia, peripheral neuropathy, and posterior column neuropathy, as well as steatorrhoea, hepatic steatosis, myositis, and acanthocytosis. The demyelination that leads to aforementioned neurological presentation seems to be associated with vitamin E deficiency and not related to absence of LDL-C.[51] Lifelong supplementation with high-dose vitamin E appears to halt further neurological degeneration.[52] Other manifestations associated with the condition (myalgias/myositis) are also LDL-C independent as they improve with high doses of fat-soluble vitamins[52] and, thus far, absent serum LDL-C has not been identified as a cause of any specific adverse consequences in abetalipoproteinemia patients.[50]

Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disorder caused by mutations of the apoB gene, which results in decreased lipidation and secretion of apoB-containing lipoproteins from hepatocytes to the circulation.[53] FHBL is associated with LDL-C typically between 20 and 50 mg/dL, although affected individuals have been found with LDL-C as low as 17 mg/dL.[53] Heterozygotes with FHBL are usually asymptomatic but can develop hepatic steatosis and subsequent liver cirrhosis. Hepatic steatosis is most likely secondary to the accumulation of apoB-containing lipoproteins in the hepatocytes but should be further investigated if hepatosteatosis is also related to decreased hepatocellular ApoB lipoproteins production and subsequently very low LDL-C.[54] Eighty-two patients with FHBL were found to have reduced arterial wall stiffness, although this study did not evaluate whether the observed reduced arterial stiffness was directly correlated with lower LDL-C per se.[54]

Familial combined hypolipidaemia (FHBL2) and chylomicron retention disease (CRD) are very rare genetic conditions caused by mutations in Angiopoietin-like 3 (ANGPTL3) and SAR1B proteins, respectively. Individuals with FHBL2 are found to have a significant reduction of all apoB- and apoAI-containing lipoproteins with some homozygous carriers having LDL-C as low as 27 mg/dL.[55] Two studies of FHBL2 patients showed no diabetes or cardiovascular disease among a small sample of homozygous carriers.[55,56] Studies have also demonstrated that individuals with ANGPTL3 loss-of-function mutations have decreased odds of developing ASCVD.[56,57] CRD is characterized by hypocholesterolaemia in the presence of normal triglycerides.[58] Affected individuals with CRD present with steatorrhoea, decreased bone density, demyelinating sensory neuropathy and abnormal visual evoked potentials; all aforementioned signs/symptoms are in the setting of fat and fat-soluble vitamin malabsorption and are not associated with the low LDL-C.[58]

Smith–Lemli–Opitz syndrome (SLOS) is a congenital syndrome caused by the deficiency of 7-dehydrocholesterol (7-DHC) reductase enzyme, which is necessary for cholesterol synthesis.[59,60] The clinical spectrum and severity of presentation varies; patients with SLOS can present with prenatal and postnatal growth restriction, moderate-to-severe intellectual disability, distinctive facial features, cardiac defects, underdeveloped external genitalia in males and 2–3 syndactyly of the toes.[60] Laboratory findings are significant for elevated 7-DHC and usually low serum total cholesterol and LDL-C (some patients have even LDL-C < 30 mg/dL), albeit many patients will have normal cholesterol and LDL-C levels.[61] It is unclear if syndrome's pathophysiology is secondary to decreased cholesterol synthesis (e.g. reduced local de novo cholesterol production in the central nervous system), or to lower cholesterol levels or to toxic accumulation of the prodrome 7-DHC.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....