Serum Cholesterol
Blood Tests

Author: Gianpiero Pescarmona
Date: 24/01/2010

Description

DEFINITION

Serum cholesterol level is dependent on a number of agents involved in Cholesterol Serum Influx/Efflux

ANALYTICAL METHOD

  • Total Cholesterol
  • HDL Cholesterol
  • LDL Cholesterol

ANALYTICAL TRICKS AND TIPS

THE BIOLOGICAL CONTEXT

Google:cholesterol circadian rhythm

Hunt Study Shows Thyroid Prevents Heart Attacks

Subclinical Hypothyroidism

Endocrine and liver interaction: the role of endocrine pathways in NASH, 2009

  • We also showed that human LXR-alpha gene expression and promoter activities were up-regulated by thyroid hormone.

Liver X receptor-alpha gene expression is positively regulated by thyroid hormone. 2007

DIAGNOSTIC USE

Issues

Statistics

Cholesterol as Risk Factor (before statins)

As you can see, those with serum cholesterol levels below 5mmol/L made up 10% of the population yet represented less than 3% of total coronary heart disease deaths. Those with serum cholesterol levels above 8mmol/L made up slightly more than 10% of the total population but accounted for over a quarter of coronary heart disease deaths.

In addition, mean serum cholesterol levels increase in the average population by age, in particular in women

Low Cholesterol

Is this figure true?

Specificity, sensitivity etc.

Diagnostic Algorithms

PROs and CONTROs

Open Questions

Working Hypothesis

Age distribution

Hypocholesterolemia

out of a sample of around 2000 patients

Grafici colesterolo

J Am Geriatr Soc. 2003 Jan;51(1):80-4.
Does inflammation or undernutrition explain the low cholesterol-mortality association in high-functioning older persons? MacArthur studies of successful aging.

Hu P, Seeman TE, Harris TB, Reuben DB.

Multicampus Program in Geriatric Medicine and Gerontology, UCLA School of Medicine, Los Angeles, California 90095, USA. phu@mednet.ucla.edu

Comment in:

* J Am Geriatr Soc. 2004 Mar;52(3):469-70; author reply 471.

OBJECTIVES: To explore the effect of inflammation and undernutrition on the association between hypocholesterolemia and higher overall mortality in high-functioning older persons. DESIGN: Prospective cohort study. SETTING: Three U.S. communities. PARTICIPANTS: A cohort of 870 participants from the MacArthur Studies of Successful Aging. MEASUREMENTS: Baseline information was obtained for serum levels of cholesterol, C-reactive protein, interleukin-6, and albumin; body mass index; prevalent medical conditions; health behaviors; and medications. Crude and multivariate logistic regression analyses were used to examine the association between serum total cholesterol levels and 7-year all-cause mortality, while adjusting for potential confounders. RESULTS: In univariate analysis, the risk ratio of low serum total cholesterol level (<169 mg/dL) for 7-year total mortality was 1.90 (95% confidence interval (CI) = 1.18-3.07). The multiple adjusted risk ratios were 1.82 (95% CI = 1.10-3.00) after controlling for markers of inflammation and nutrition and 1.39 (95% CI = 0.80-2.40) after adjustment for additional cardiovascular risk factors. Sex was an important confounding variable that contributed to the observed inverse association between low serum cholesterol and overall mortality in univariate analysis. CONCLUSIONS: Hypocholesterolemia is not an independent risk factor for increased overall mortality in high-functioning community-dwelling older men and women. The association between low total cholesterol and high mortality observed in crude analysis is mainly confounded by common cardiovascular risk factors, rather than underlying inflammation or undernutrition.

Premeditated aggression is associated with serum cholesterol in abstinent drug and alcohol dependent men 2008

an inverse association between lower cholesterol and higher impulsivity and anxiety.

Serum leptin and cholesterol values in suicide attempters. 2002

Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Gecici O, Firidin B.

Department of Psychiatry, Medical Faculty, Firat University, Elazig, Turkey. matmaca_p@yahoo.com
Abstract

The growing number of studies examining the relationship between suicide and lipid metabolism are based upon studies suggesting that cholesterol-lowering procedures may increase the risk of death due to suicide or impulsive-aggressive behavior. Leptin seems to be strongly associated with lipid metabolism. In the present study, serum total cholesterol and leptin levels were compared in 24 suicide attempters and 24 healthy controls. The patients with suicide attempts had significantly lower serum cholesterol and leptin levels than controls. There was a positive correlation between cholesterol and leptin levels in both groups. Our results suggest that suicide attempts seem to be associated with decreased serum cholesterol and leptin levels. Copyright 2002 S. Karger AG, Basel

Eureka

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review , 2016

Evacetrapib

un altro fallimento l'evacetrapib;

Gli inibitori della CETP¹ (proteina di trasferimento degli esteri del colesterolo), nonostante la diminuzione del colesterolo LDL e l’aumento del colesterolo HDL, non sono riusciti ad ottenere risultati clinici.

Nello studio ACCELERATE è stato testato un altro inibitore della CEPT, l’evacetrapib, confrontandolo con placebo in pazienti ad alto rischio cardio-vascolare in trattamento standard. Lo studio, sponsorizzato dall’industria farmaceutica, ha riguardato 12.092 soggetti, un terzo dei quali era andato incontro ad un evento coronarico acuto nei 6 mesi precedenti.

Quasi tutti erano in terapia con statine. Lo studio, internazionale, è stato interrotto per futilità dopo un follow-up medio di 28 mesi. I livelli delle LDL erano notevolmente differenti tra i gruppi: con l’evacetrapib risultavano diminuite del 31% a fronte di un aumento del 6% con il placebo.

A livello delle HDL si è avuto un aumento del 133% con l’evacetrapib, contro il 2% con il placebo. Da questi esiti biochimici ci si sarebbero attesi risultati clinici degni di nota, invece gli endpoint considerati (decessi da cause cardio-vascolari, infarti, rivascolarizzazioni coronariche, stroke, angine instabili) si sono verificati del 12.9% dei soggetti trattati con il farmaco e nel 12.8% dei soggetti trattati con il placebo.

¹ La funzione della CETP consiste nella redistribuzione del colesterolo esterificato e dei trigliceridi tra le lipoproteine circolanti. Il punto centrale è il trasferimento di colesterolo dalle HDL alle LDL in cambio di trigliceridi. La sua inibizione pertanto provoca una diminuzione delle LDL ed un aumento delle HDL.

Comments
2010-06-13T16:32:47 - Gianpiero Pescarmona

Familial Hypercholesterolemia

Dan Med Bull. 2002 Nov;49(4):318-45.
The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark.
Jensen HK.

Department of Medicine and Cardiology, Aarhus Amtssygehus, Research Unit for Molecular Medicine, Skejby Sygehus, Aarhus.
Abstract
Normal function of the hepatic low-density lipoprotein (LDL) receptor is obligate for normal levels of plasma LDL cholesterol. The LDL receptor regulates the concentration of plasma LDL cholesterol by internalizing apolipoprotein B-100- and apolipoprotein E-containing lipoproteins by receptor-mediated endocytosis. Mutations in the gene encoding the LDL receptor protein give rise to one of the most common classical autosomal dominant inherited disorders in man, familial hypercholesterolemia (FH). The estimated prevalence of heterozygous FH is 0.2% (1:500) in most populations of the world including the Danish. Worldwide, an estimated ten million people are afflicted with FH and in Denmark there are approximately 10,000 subjects with heterozygous FH. Persons with heterozygous FH are characterized by a severely elevated concentration of LDL cholesterol in plasma starting in early childhood, tendon xanthomas and a markedly increased risk of premature coronary heart disease (CHD). Adequate control of plasma LDL cholesterol levels can be achieved in most patients with heterozygous FH, and to a lesser extent in the very rare cases with homozygous FH, using combinations of diet, drug therapy and selective LDL-apheresis. So, it is very important that physicians be aware of this relatively common disorder since there is good evidence that early diagnosis and cholesterol-lowering therapy will delay or even prevent CHD in persons with FH. A large majority of these persons, however, are still not diagnosed or adequately treated. It is believed that the diagnostic abilities molecular biology has to offer will provide the impetus for correcting this situation. The aims of the studies behind the present thesis, therefore, were to obtain important knowledge about current mutation detection technology, prevalence and spectrum of LDL receptor gene mutations in Denmark, methods to evaluate pathogenicity of LDL receptor gene mutations, relationship between FH genotype-phenotype, and clinical versus DNA diagnosis in the Danish FH population. Among different relative laborious and expensive scanning methods for unknown gene mutations we have shown that the polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) analysis is a highly efficient and sensitive technique for detection of mutations in the 18 exons including intronic splice-site sequences and the promoter region of the LDL receptor gene, reserving DNA sequencing to the exons revealing variant SSCP patterns. Southern blot analysis or long distance PCR analysis are necessary to identify large gene re-arrangements in the LDL receptor gene in FH patients in whom SSCP analysis did not reveal any smaller sequence alterations. Worldwide, about 700 different mutations in the LDL receptor gene have been reported and in the Danish FH population we have so far identified 60 different mutations localized throughout the LDL receptor gene. In certain populations a small number of mutations predominate due to founder effects. The spectrum of LDL receptor mutations in Danish FH patients is intermediate between such specific founder populations with 5 predominant mutations (W23X, W66G, W556S, 313 + 1G-->A, 1846-1G-->A) accounting for about 40-50% of FH. These frequent mutations can easily and inexpensively be tested for by specific PCR based assays using restriction enzyme cleavage. Future analysis of LDL receptor mutations in heterozygous FH subjects, therefore, should be based on the mutational spectrum present in each relevant specific subset. Most mutations in the LDL receptor gene cause the classical heterozygous form of FH, but a small proportion seem to result in mild or moderate forms of autosomal, dominantly inherited hypercholesterolemia. Differentiation between harmless sequence variations and disease-causing mutations is not always easy without additional work. We have experienced that large re-arrangements, frame-shift and nonsense mutations obviously are pathogenic, but full pathogenicity should not be ascribed to missense mutations and small in-frame deletions, e.g. the N543H and 2393del9 mutations, unless in vitro gene expression in eukaryotic cells have been studied, or to splice-site mutations, e.g. the 1592 + 5G-->A mutation, before mRNA studies in patient cells have been performed. The cumulated LDL cholesterol exposure, mainly determined by the defect LDL receptor, plays a crucial role for the clinical manifestation of FH. The phenotypic expression of homozygous FH appears to be dominated by the consequences of the LDL receptor gene mutations. In heterozygous FH, however, the underlying mutational LDL receptor type determines only to a much lesser extent, if any, the variable phenotypic expression as seen in Danish patients. Extreme low fat dietary habits or major gene interactions may influence the lipid profile and the excess cardiovascular mortality observed in heterozygous FH, whereas minor gene determinants do not seem to play any significant role. The clinical diagnosis of heterozygous FH should be based on an elevated plasma LDL cholesterol concentration above the 95th percentiles for the general population together with either the presence of tendon xanthomas or an autosomal dominant transmission of hypercholesterolemia in the family or a child with hypercholesterolemia. Our studies illustrate clearly that molecular genetics can strengthen an equivocal clinical diagnosis and assist decision-making in diagnosis and tracing family members. If demonstration of a pathogenic mutation in the LDL receptor gene fails, other causes of autosomal dominant inherited hypercholesterolemia should be sought. Familial defective apolipoprotein B (FDB) caused by the R3500Q apolipoprotein B gene mutation may mimic FH but the clinical course, however, is often milder than that seen in patients with LDL receptor gene mutations. A newly discovered third major locus at chromosome 1 may also be of future diagnostic importance although the exact gene remains to be identified. The overall molecular genetic knowledge obtained about FH in Denmark forms the basis for the implementation and use of molecular genetic diagnostics of FH in daily clinical practice.

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