August 16th, 2012

Children Should Have Their Cholesterol Checked

Dr. James H. Stein, in his recent post on CardioExchange, presents several arguments against cholesterol screening  in childhood. I would like to present the view of those who drafted the document and suggest that some of Dr. Stein’s arguments are incorrect.

First, given that conflicts of interest were part of his argument, I must be transparent about mine. I have never participated in a drug-industry-sponsored trial of a cholesterol-lowering medication. I had no conflicts with industry until late 2009, after the main work on the guideline was complete. Both of these are related to evidence gaps identified in the literature review for the guideline. The first is as a member of the Data and Safety Monitoring Board for a trial of losartan to lower blood pressure in severely hypertensive children younger than 6 years of age. The reimbursement for this work is deposited into a research fund for medical students and residents who lack another source of support for their research. The second is to conduct a clinical trial of fish oil for elevated triglycerides in adolescents. No clinical trial data on medication use for elevated triglycerides in children exist, and the NHLBI-sponsored statement made no recommendations about use of medications for this purpose. This money is provided as a grant, the trial is completely of my design, and my research program manages the trial without input from the company. The company has no oversight role for the trial, other than that I have to recruit a specified number of patients and complete a manuscript to receive payment.  My reimbursement from the grant is for managing the coordinating center of the trial (there are 3 sites), analyzing the data, and performing various medical duties in conducting the trial.

The NHLBI guideline was strictly conducted according to the recommendations of the Institute of Medicine (IOM) and other bodies that are interested in guideline integrity. Several thousand research papers meeting preselected criteria as evidence were considered in the evaluation of recommendations for 14 different risk factors.  A paper describing the panel’s process has recently been published. The Lipid section of the guideline was drafted by the three members of the panel who have the most knowledge about lipids.  However, this group’s recommendation was debated and voted on by the entire committee, which had a diverse composition, consistent with IOM recommendations. NHLBI officials, cognizant of conflict of interest issues, were also present and contributed to the discussion.  With one exception, none of the other 11 committee members had participated in an industry-sponsored cholesterol-drug trial.

All the arguments discussed in critiques of the guideline emerged in this debate; in fact, the committee felt so strongly about the evidence limitations that a specific chapter of the guideline was written to include them, particularly the cost issue. Nonetheless, the committee, with one exception, voted for universal screening because the weight of the evidence review favored this decision despite evidence gaps. The weight came from these facts: atherosclerosis begins in the second decade of life; this atherosclerosis (including future atherosclerosis) is strongly related to non-HDL cholesterol levels; a small but significant number of children can be identified with high cardiovascular risk; treatments highly likely to be successful are available; and genetic diseases causing both high and low LDL cholesterol were highly suggestive of the risk of high LDL cholesterol and of the benefit of  lifetime low LDL cholesterol levels.

It is inaccurate of Dr. Stein to say that the evidence evaluation for the cholesterol treatment recommendation does not reflect the types of studies included to support the recommendation. The grade given is B (not A): evidence from clinical trials with potential flaws, high-quality and consistent observational studies, and Mendelian randomization (genetic research). I hope that the guideline will ultimately lead to high-quality clinical trials of lipid-lowering treatment, initiated by sponsors other than industry.

Included in guideline development (and recommended by the IOM) was a period for public comment, review by several interested professional organizations, and internal review by both NHLBI and DHHS. Notably, despite receiving over a thousand critiques, only one challenged the universal screening for cholesterol recommendation, and that critique presented only opinion rather than evidence against the recommendation. Given the committee’s deliberations and the extensive external review prior to publication, it is my opinion that the argument against cholesterol screening in children is a well-considered — but a minority — position.

I would like to challenge several other arguments in Dr. Stein’s post — as the extensive evidence review, conducted using a process now considered “state of the art,” did not support these assertions. Most important, no published evidence of harm from cholesterol screening exists. Guidelines regarding cholesterol testing have been in place for about 20 years, with no research demonstrating harm from this practice. In West Virginia, where universal screening of cholesterol occurs in schools voluntarily, over 60% of children consent to testing, and no harm has been identified in this program. Our evidence review specifically sought publications with side effects or unintended consequences of screening — and none were found. The age for cholesterol screening was chosen partly because most states require a medical examination for admission to a public school, and blood is often drawn for other purposes. Girls, on average, do have slightly higher total-cholesterol levels than boys — but women have equal rates of heart disease as men, only at slightly older ages. The number of cases of familial hypercholesterolemia missed by current guidelines is significant. Indeed, one of the reasons for the universal screening recommendation was that numerous studies conducted since the 1992 guideline was published suggest that 25% to 30% of cases are missed by selective screening. Given the frequency of 1:300-500 in the population, this is not a trivial number (and there is no gender bias in these levels). The dietary guidelines presented are for all children, not just those with high cholesterol. One of the reasons for delay in publication was the need to synchronize the recommendations with the evidence-based 2010 Dietary Guidelines for Americans.

The cardiovascular health of children has deteriorated significantly, principally because of the obesity epidemic and poor nutrition habits. Many, indeed almost one third of U.S. children, have a different type of dyslipidemia (low HDL cholesterol and high triglycerides), and it has been recommended, prior to the publication of the universal screening recommendations, that these children have their lipids checked. I am concerned that the debate about the usefulness of checking cholesterol might send the wrong message to the general population — namely, that accurately knowing your cardiovascular risk is not useful for this vulnerable population.

A key tenet of the IOM recommendations for development of guidelines is that they undergo periodic review with reconsideration of the evidence. For the lipid section in particular, the evidence gaps identified by Dr. Stein and others cited in his post had insufficient weight as evidence compared with the many studies supporting the final recommendations. Nonetheless, the current guideline should not be the last word. Evidence gaps point the way for future research, and this new work should inform future deliberations about this important issue.

Note: In addition to James Stein’s post,  Larry Husten has written a post on industry PR efforts to influence the debate on cholesterol screening for children.

7 Responses to “Children Should Have Their Cholesterol Checked”

  1. Steven Greer, MD says:

    All of these essays for and against screening of children for elevated cholesterol are too lengthy. It is very simple.

    Do we have any studies in children to support the screening with mortality or CV outcomes? No.

    Do adult screenings of LDL and prescribing of statins in low risk factor adults confer mortality or CV risk benefit? Nope.

    Are statins drugs wit serious side effects like muscle damage, weakness, liver toxicity, and forgetfulness? Yes.

    Are statins over prescribed? yes, according to Eric Topol and others.

    Should LDL be abandoned as a surrogate endpoint used to guide statin therapy? Yes, according to Krumholz et al.

    Are the authors of the pediatric screening guidelines receiving significant cash from the statin makers? Yes.

    Follow the money, folks. Follow the money.

  2. Steven Greer, MD says:

    Harlan Krumholz explains in our video interview why LDL should be abandoned as the surrogate market to guide statin therapy and as the endpoint in trials

  3. Uffe Ravnskov, MD, PhD says:

    Obviously the main purpose with child screening is to identify individuals with familial hypercholesterolemia in order to introduce cholesterol lowering measures for the rest of their life. However, to screen by analyzing cholesterol is a questionable method, because one of the most surprising facts about FH is that high cholesterol is not a risk factor for these people. At least six studies including only people with FH 
have shown that both the prevalence and future cardiovascular disease are independent on their blood cholesterol level (1-6); in one of the studies mean cholesterol was even lowest in those who had CHD (5).

    The risk factors are instead high fibrinogen, high factor VIII, and high prothrombin, because a few individuals with FH may have other genetic 
aberrations as well (5-7). This interpretation fits well with the fact 
that atherosclerosis in FH is mainly located to arteries that are exposed to 
mechanical forces, while premature atherosclerosis is absent in the cerebral
 arteries, even in homozygous FH (8,9).

 more surprising is that according to the The Simon Broome FH Register Group,
the mean life expectancy in FH is as long as for other people; more die from
 CHD at a young age, but fewer die from cancer and other diseases later in life (10).
These calculations were based on a selection of FH people with close relatives,
who had died early, and the authors therefore assumed that the prognosis would 
have been even better for unselected individuals. Also, before 1900 their life 
expectancy was longer than for the general population (11), probably 
because high cholesterol protects against infectious diseases (12), the
 commonest cause of death at that time. The reason is that lipoproteins partake in the immune system by binding and inactivating bacteria, viruses and their toxic products. This is little known, although it has been demonstrated by a dozen research groups (13).

    There is also evidence from several cholesterol lowering trials, and from cohort and case-control studies that low cholesterol may increase the risk of cancer (14). The reason is probably that about 20 % of all cancers are caused by viruses.

    Is it really a good idea to lower children´s cholesterol?

    1. Miettinen TA, Gylling H. Arterioscler 1988;8:163-7.
    2. Hill JS et al. Arterioscler Thromb 1991;11:290-7.
    3. Ferrieres J et al. Circulation 1995; 92:290-5.
    4. Kroon AA et al. J Intern Med 1995;238:451-9.
    5. Hopkins PN et al. Am J Cardiol 2001;87:47-553.
    6. Jansen AC et al. Arterioscler Thromb Vasc Biol 2005;25:1475-81.
    7. Sugrue
DD et al.. Br Heart J 1985;53:265-8.
    8. Postiglione A et al. Atherosclerosis 1991;90:23-30.
    9. Rodriguez G et al. Stroke 1994;25:831-6.
    10. Neil HA et al. 2005;179:293-7.
    11. Sijbrands EJ et al. BMJ 2001;322:1019-23.
    12. Ravnskov U. QJM 2003;96:927-34.
    13. Ravnskov U, McCully KM. Ann Clin Lab Sci 2009;39:3-16.
    14. Ravnskov U et al. QJM doi:10.1093/qjmed/hcr243

    I have given more details about this issue in my most recent book “Ignore the Awkward!”

  4. I’m afraid I’m biased on this issue, since I have FH in my family. In addition, members of my husband’s family have suffered fatal MIs as early as 35 and 40.

    If we are honest, we must acknowledge that screening children for cholesterol will cause a certain amount of overtreatment. It is uncertain even for children with FH whether treating children during childhood prevents more morbidity and mortality than waiting until adulthood. In addition, there is no data that shows what age in childhood treatment should start, or how intensive the treatment should be. Cholesterol screening will identify many children with less severe lipid abnormalities and many of these kids will end up being treated with medication. The AAP guidelines recommend treating as early as age 8. In my opinion, there is no need to treat that early except in unusual cases.

    On the other hand, the benefit of universal screening will be to identify children with FH who otherwise would be missed. If there was some way to institute a screening program in early adulthood these children could be identified at that time. However, in the fragmented U.S. health system it is not clear how this would be accomplished.

    There is no clear right answer. The reduction in morbidity and mortality from identifying FH patients who otherwise might not be identified until their 30s or later must be weighed against the risk of overtreatment. Ideally, the pediatrician would have a discussion with the parents (and child if old enough) and make the decision through shared decision making. For parents who decline to have their child screened at age 9, the issue could be raised again when the child is a teenager.

    In addition, the issue of when to start treatment should also be decided through shared decision making. In my opinion, it is perfectly reasonable to wait until the child is a teenager to start medication, even in the case of kids with FH, except in unusual cases.

    Marilyn Mann

  5. Travs Harrell, MD says:

    If the major driver for universal screening is identification of Familial Hypercholesterolemia (FH), why don’t we just use a qualitative screen for FH (i.e. positive or negative for FH)? Otherwise, the absolute total cholesterol level and its breakdown into HDL and non-HDL cholesterol are not very helpful in guiding treatment decisions in children. Am I missing something from the debate and articles cited?

  6. The case of Marylin Mann points to strong family history. The family history is the strongest risk factor for atherosclerosis. This probably applies to her family where high cholesterol is just one biochemical value in accordance with the genetic profile of the family. (Otherwise there would uniformly high CV mortality occur in FH patients, yet there is considerable variation in the rate of progression of atherosclerosis among FH patients, despite uniformly elevated LDL levels.)

  7. Neville Wilson, M.B., Ch.B., D.Fam. Med., M.Sc., D.Obs (COG) SA., B.A. says:

    I agree with Milan. The variations in rate of atherosclerosis progression, regardless of uniformly elevated LDL levels, as observed and reported by Brown and Goldstein (1) suggest that factors other than dyslipidaemia are significant agents in cardiovascular mortality.
    Dr. Eric Sijbrands came to similar conclusions after observing that life spans for FH family members were quite normal prior to 1915, with mortality variations occurring only after that date, again suggesting that factors other than high cholesterol were implicated in CVD.
    Sijbrands concluded that the significant variability in mortality risks among FH persons may point to a strong interaction with environmental factors.(2)
    It would be a worthwhile exercise to explore the subsequent changes in environmental factors that may underlie these variations in mortality rate, and which may in some cases give rise to a secondary dyslipidaemia.
    Dr. Ravnskov’s conclusion that high cholesterol is a secondary phenomenon, and not the cause of atherosclerosis is supported by these observations.
    1. Ann Rev Biochem 52,223-61,1983
    2.BMJ 322,1019-1023,2001.