Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society
Authors: Luis Masana
Raul D Santos
Alberico L Catapano
Marja-Riitta Taskinen
Catherine Boileau
Albert Wiegman
Olov Wiklund
Steve E Humphries
Maurizio Averna
Gerald F Watts
G Kees Hovingh
Erik Stroes
Joep C Defesche
M John Chapman
Børge G Nordestgaard
European Atherosclerosis Society Consensus Panel
Robert A Hegele
Anton F H Stalenhoef
Eric Bruckert
Anne Tybjærg-Hansen
Olivier S Descamps
Kausik Ray
Jan Borén
Klaus G Parhofer
Jan Albert Kuivenhoven
Frederick J Raal
Petri T Kovanen
Henry N Ginsberg
Päivi Pajukanta
Journal: European Heart Journal (2013)
Discipline: CLINICAL MEDICINE
Keywords: Atherosclerosis; Cardiovascular disease; Cholesterol; Coronary heart disease; Low-density lipoprotein.
Affiliations: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2730 Herlev, Copenhagen, Denmark.

Abstract:  Aims: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results: Of the theoretical estimated prevalence of 1/500 for heterozygous FH, &lt;1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are &lt;3.5 mmol/L(&lt;135 mg/dL) for children, &lt;2.5 mmol/L(&lt;100 mg/dL) for adults, and &lt;1.8 mmol/L(&lt;70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion: Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition. 

Retracted: No

PubPeer comments:
 This 2013 paper [1] is involved in nested citation inaccuracies. This is Part 2. ([Part 1] is related and involves a 2014 corrigendum [2]; see PubPeer comment, https: pubpeer.com publications D69DE2E1620A86BE30004C0E458326#1.) Here is a brief review of Part 1 combined with an introduction to Part 2. ![file] **Background:** This 2013 paper cites a prevalence for familial hypercholesterolemia (FH) which is more than twice the established estimate. Although this 2013 paper only cites a previous 2012 paper [3] and conducts no prevalence study of its own, this 2013 claim is widely circulated as the authority on issues of prevalence and underdiagnosis. References to this paper are found in SEC filed corporate documents, FDA documents, marketing literature, and online social media. It has gathered more than 2,000 citations over the last 8 years. **Detail:** The prevalence claim in this 2013 paper is followed by reference *number 10* in superscript. ![file] It is natural to assume that, if we made the extra effort, reference *number 10* would guide us to a study which supported the result of 1 200 as claimed. However, reference *number 10* refers to a 2012 paper, and this paper does not claim a result of 1 200. It claims 1 137. ![file] Immediately in front of citation *number 10* is a reference to Figure 2. It is easy and natural to assume that the reference to Figure 2 would guide us to an *illustration* of the result, and not to the actual source for that result. Indeed, the illustration does provide a breakdown of the result into related categories, but meeting our expectations with the illustration is part of the problem: will we bother reading the caption? **Buried within this caption is the real source for the result of 1 200.** ![file] Here is the relevant text from the caption. u201cThis was originally reported as 1 137 but recalculation suggested that the prevalence of definite or probable familial hypercholesterolaemia combined is closer to 1 200 (personal communication Bu00f8rge G Nordestgaard). FH, familial hypercholesterolaemia. Adapted from Benn et al.u201c u201cAdapted from Benn et alu201d is a euphemism for u201ccorrection,u201d and a caption to a figure is a very unusual place to find *corrigenda.* With this new information, we moved from 1 137 in the external 2012 source up to 1 200 in this internal 2013 caption, a gap of about 45%. How many of the *more experienced* readers would not feel it necessary to read this caption, being able to work immediately with the same type of basic illustration that they are accustomed to? The estimate of 1 200 is the cornerstone to the conclusion of this paper: u201cunderdiagnosis.u201d And yet the source to that claim is found on page 5, in figure 2, at the bottom of a caption. The u201cpersonal communicationu201d with the lead author is both equivocal and ironic. First, the equivocal: there is no preposition between u201cpersonal communicationu201d and the name of the lead author, and so we donu2019t know who talked to whom. The individual in question is not only the lead author of the 2013 paper making this citation; he is also one of the authors on the cited 2012 paper. As lead author in the 2013 paper, is he relaying a personal communication he had with one of his co-authors in the 2012 paper? Or could it be that another author in this 2013 paper consulted *him*, and this other person is responsible for inserting the correction in Figure 2? And can we eliminate the possibility that the lead author simply thought to himself and then cited himself, since he is on both papers? With what was given, we cannot know the answers to these questions. Now for the irony: a correction was eventually issued for this 2013 paper in 2020. [4] ![file] Relevant Text: u201cThe Editors and authors wish to acknowledge that the information presented in Figure 1 about Switzerland has been cast into doubt as it has not been formally published in a data set but communicated verbally by an officer of the WHO to the senior author.u201d So a relatively minor support for the 2013 paper is called into question because it had not been u201cformally published in a data set but communicated verbally,u201d while the cornerstone support for the 2013 paper **also had not been formally published and also was merely a personal communication.** Here are cascading screen shots, the top with the 2020 correction and beneath it, the last sentences to the caption to Figure 2 on page 5 of the original 2013 document. ![file] The following overlay of three screenshots from the original 2013 document shows the lopsided influence of the two identical infractions, only one of which is issued a correction. ![file] If reliance on personal communication was wrong with the reference to the Swiss information, then the caption to Figure 2 is a confession of the same unreliability. **Conclusion:** When we read a claim *within* a document, that claim is of course an *internal* event. When that internal claim is followed by a reference to an external document, we expect to see the basis for that claim in that external document. Here, however, the internal claim merely *signals* an external document, while simultaneously leaving the true source camouflaged within the sort of text usually assigned to a different task, an otherwise routine caption describing a figure. The presentation of the source for u201c1 200u201d is equivocal -- the external source is not the source, and the internal figure is not just a figure; itu2019s the source. **References** [1] tB. G. Nordestgaard, M. J. Chapman, S. E. Humphries, H. N. Ginsberg, L. Masana, O. S. Descamps, O. Wiklund, R. A. Hegele, F. J. Raal, J. C. Defesche, A. Wiegman, R. D. Santos, G. F. Watts, K. G. Parhofer and others,  Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society, vol. 34, no. 45, pp. 3478-3490, 2013. [2] tM. Benn, G. F. Watts, A. Tybjaerg-Hansen and B. G. Nordestgaard,  Corrigendum: Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication, vol. 99, no. 12, pp. 4758-4759, 2014. [3] tM. Benn, G. F. Watts, A. Tybjaerg-Hansen and B. G. Nordestgaard,  Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication, vol. 97, no. 11, pp. 3956-3964, 2012. [4] tEditors, B. G. Nordestgaard, M. J. Chapman, S. E. Humphries, H. N. Ginsberg, L. Masana, O. S. Descamps, O. Wiklund, R. A. Hegele, F. J. Raal, J. C. Defesche, A. Wiegman, R. D. Santos, G. F. Watts and others,  Correction: Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease : Consensus Statement of the European Atherosclerosis Society, vol. 41, no. 47, p. 4517, 2020. , 
 In this *2013 paper*, reference number 10 is a piece to a larger puzzle. **Methods:** In this passage, reference number 10 suggests that Table 1 and *2012 Benn et al* [1] will lead us to the methodology which accounts for the prevalence result of 1 200. ![file] Pointing to Table 1, while using citation 10 suggests that the threshold of 6 had been used to derive the results. We know now, after reconciling the 2012 paper with its 2014 Corrigendum [2], that the 2012 paperu2019s result was actually derived from the off-text use of the number 5 as the threshold: u201c6u201d and u201c 5u201d were *printed* as the DLCN cutoff point, but 5 was actually *used* off-text. The result was 1 137. This presentation in the 2013 report further obfuscates the original problems with both the 2012 report and its 2014 Corrigendum. For a detailed reconciliation of the 2012 report with the 2014 Corrigendum, see PubPeer comment: https: pubpeer.com publications D69DE2E1620A86BE30004C0E458326#1. **Review of Comment #1:** In the 2013 paper, this passage and Figure 2 constitute an *impromptu correction* of the 2012 paper cited. The *new* result of 1 200, *inserted in this 2013 paper,* then becomes the cornerstone support to self-same paperu2019s stated aim and conclusion. 1 200 is a *departure* from its purported source. It is an internal self-citation. (See the previous PubPeer [comment #1 above]( ) for the more influential, and erroneous, use of this citation.) Reference [1] tM. Benn, G. F. Watts, A. Tybjaerg-Hansen and B. G. Nordestgaard,  Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication, vol. 97, no. 11, 2012. [2] tM. Benn, G. F. Watts, A. Tybjaerg-Hansen and B. G. Nordestgaard,  Corrigendum: Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication, vol. 97, no. 11, 2014. ,