Early Detection of Familial Hypercholesterolemia in Children in Tarragona Province
Conditions: Familial Hypercholesterolemia, Familial Hypercholesterolemia - Heterozygous, Familial Hypercholesterolemia - Homozygous
Sponsor: Institut Investigacio Sanitaria Pere Virgili

 
 
 
EARLY DETECTION OF FAMILIAL 
HYPERCHOLESTEROLEMIA IN CHILDREN 
 
Acronym: DECOPIN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol version 1.2 (25/10/18) approved for local Ethic Committee (Comité ètic d’investigació amb 
medicament - CEIM; Reus-Tarragona; Spain); number: 176/2018  

 
 
 
Principal Investigators: 
Dra. Núria Plana  
Dr. Albert Feliu 
 
Collaborating researchers: 
Dr. Raimon Ferré  
Dr. Daiana Ibarretxe 
Mrs. Cèlia Rodríguez  
Dr. Josefa Girona 
Mrs. Anna Varela  
Dr. Joaquin Escribano 
Dr. Lluís Masana 
 
In addition, the Primary Care Pediatricians involved in the project (DECOPIN GROUP) 
 
 
 
 
 
Núria Plana 
nplana@grupsagessa.cat 

INTRODUCTION 
 
The most prevalent cause of hypercholesterolemia in childhood is Heterozygous 
Familial Hypercholesterolemia (HeFH). 
It is a monogenic disorder that is transmitted of autosomal dominant way and 
affects 50% of offspring. It is characterized by the increase of low-density lipoproteins 
(LDL-C), which can be detected from birth. It is mostly caused by mutations in the gene 
that encodes the LDL receptor (LDLr) located in the short arm of chromosome 19. 
Nowadays, more than 1500 different mutations have been described worldwide. Less 
common are the ApoB3500 Family Defect, caused by the mutation of the Apolipoprotein B 
gene (APOB) that is located on chromosome 2, and the mutation of the gene encoding 
PCSK9 (proprotein convertase subtilisin-kexin type 9) located on the chromosome 1p32.2. 
These three entities are clinically expressed in the same way and only the genetic study 
will allow us to differentiate them. 
HeFH has a prevalence of 1 for every 250 individuals in the European population, 
therefore it is the most frequent genetic disease, which is a major public health problem 
as it is associated with high cardiovascular risk (CVR). In spite of the current knowledge 
and the diagnostic techniques, it continues being an unknown disease and therefore is 
underdiagnosed and under-treated. In countries with active screening projects of HeFH 
detection, only 20% are diagnosed. In Catalonia, in order to get free access to  lipid 
lowering therapy, a register was started in 2004. In November 2012, a total of 2,981 
patients were registered in Catalonia, representing 19.53% of expected HeFH patients in 
Catalonia. Only 108 children were included, in the age group 0 to 14 years, 
In clinical practice, DLCN criteria (clinical criteria of Dutch Lipids Units) is used as a 
diagnostic tool, but these clinical criteria cannot be applied to the children. The criteria are 
based on family history, personal history, physical examination and LDL-C levels. A definite 
clinical diagnosis of HeFH is considered when the score obtained is equal to or greater 
than 8 points, it´s probable when the score obtained is between 6-7 points and possible 
when it is between 3-5 points (table 1). In these clinical criteria, the presence of tendinous 
xanthomas and the corneal arch are very important. These two stigmas are not present in 
HeFH children, and we will only find xanthomas in Homozygous Familial 
Hypercholesterolemia (HoFH). This form of the disease is very serious and the prevalence 

is low, 1 per 300,000-400,000 habitants. 
We suspect HeFH when  we observe LDL levels >135 mg/dL in children with a 
family history of premature cardiovascular disease (men < 55 y/o and women < 65 y/o) in 
first-degree relatives, or a parent with LDL levels> 240 mg/dL (according to data published 
in adult HeFH population in the Spanish population)1. 
At present, there are clear evidences that high LDL-C levels in children induce the 
formation and development of atheromatous lesion2. This lesion can be initiated during 
the first years of life by cholesterol deposit, causing an increase in the carotid intimate-
medium thickness (cIMT), progressing silently until adulthood. 
It has been observed in children over 5 years of age that high cholesterol levels 
cause alterations in endothelial function of the arterial wall, measured by flow-mediated 
dilation (FMD)3. Wigman and colleagues observed that cIMT of HeFH children between 8 - 
18 years H was higher than the control children population, estimating cIMT growth in 
around 0.0047 mm/year; in front of 0.0003 mm/year in the control group4. Dalmau and 
colleagues evaluated the cIMT of 88 HeFH children between 2 and 19 years and described 
a faster cIMT increase with age particularly after 12 years old, regardless of gender and 
other analytical parameters related to CVR5. 
Statin intervention studies, have described that reductions between 30 and 40% in 
LDL-C levels lead to an improvement in endothelial function measured by FMD6,7 and cIMT 
8,9. Núñez et al, have also observed that arterial stiffness was increased in children with 
CVR compared to children without CVR10. 
There is evidence suggesting that HeFH children have a pro-inflammatory and pro-
oxidant state that could accelerate the atherosclerosis process and increase CVR11. Recent 
studies from our group have shown that E-selectin, sVCAM or oxLDL/LDL are associated 
with lower post-ischemia reactivity in small arteries in patients with high CVR12.  
Statin intervention studies in HeFH children have proven that these drugs are safe 
and effective. LDL-C reduction is associated to a reduction in cIMT13. An early lipid 
lowering therapy decrease the lifelong CVR.14. 
The first clinical guidelines addressing familial hypercholesterolemia (FH) in 
children were published in 1992 by National Cholesterol Education Program (NCEP)15. 
Since then, many Scientific Societies have given recommendations about detection, 
diagnosis and treatment16-21. All guides reinforce the importance of an early detection. 

The most conflicting point between the different panels of experts is the type of 
screening. The National Heart Lung and Blood Institute (NHLBI) recommends universal 
screening between 9 and 11 years, in the context of the comprehensive management of 
CVR factors in childhood, and selective screening between 2 and 8 years17. Other 
guidelines recommend selective screening based on family history and the presence of 
CVR factors18-21. 
A recent study has shown that screening based on lipid profile may be insufficient 
to detect HeFH population. A genetic study of 215 members of 24 families with RLDL 
mutations showed  that 7% of the members wear the mutation despite a normal lipid 
profile22. 
The Netherlands is one of the countries with a more active health policies to detect 
the HeFH population. For many years, they have established a National Program based in 
cascade screening of all first-degree relatives of diagnosed FH patients. They propose a 
general screening of the children population between 1 and 9 years. This type of screening 
has a greater sensitivity and specificity23. Universal screening together with selective 
screening would be the most efficient method to detect FH patients, but this goal can only 
be achieved by activating specific healthcare strategies in the usual clinical practice. 
Avis et al. assessed the degree of control and follow-up of 207 HeFH children (0-18 
y/o) from January 2007 to May 2008. Only 62% had received a lifestyle change advice, 16% 
took functional foods every day with stanols or sterols and only 26% were taking statin 
therapy. Their conclusions were that a screening program is necessary but this programme 
should be accompanied by a proper follow-up with a multidisciplinary health group 
(nurses, pediatricians, dietitians and specialists involved in the management of severe 
hypercholesterolemia)24. 
Previously, different studies had observed that 50% of men and 20% of woman 
with FH don’t received adequate treatment increasing the risk of coronary episodes 
before 50 years old25. Nowadays, it has been shown that the intensive treatment of FH 
patients reduce cardiovascular mortality, reaching the same proportion as the general 
population26. 
According the official data from the “Generalitat of Catalonia” the province of 
Tarragona has a population of 71,186 children between the ages of 0 and 14. The aim of 
this project is detecting FH children early to improve their CVR in adulthood. 

 
HYPOTHESIS 
HeFH is an underdiagnosed disease in the paediatric population. Its early detection, 
would allow us to initiate lifestyle therapeutical changes and early pharmacological 
therapy if necessary. This is a key fact to reduce atherosclerosis progression and CVR in 
adulthood. Moreover, it will allow, detecting the first and second degree affected 
relatives. 
 
1-OBJECTIVES: 
Main 
1- Early detection of FH in the children population by:  
 Increasing 
paediatric 
awareness 
and 
cholesterol 
measurements 
(oportunistic screening). 
 Reverse cascade screening: Confirmation of FH in one of the progenitors of 
suspicious children, by positive mutation or clinical criteria (DLCN ≥8 
points).  
 Direct cascade screening: Studing children from FH families 
2- Comprehensive phenotype characterization. Including new plasma biomarkers      
of cardiometabolic risk 
3- Follow-up of FH children to assess the impact of lifestyle therapeutic changes or 
lipid lowering therapy if indicated.  
 
Secondary aims 
1- To study subclinical atherosclerosis parameters of the FH child population and 
compare it with non-FH child population, using non-invasive techniques such as the 
measurement of the cIMT and the rigidity determination of the arterial wall at baseline. 
This study will be repeated every two years, at the fifth year and later every 5 years, in FH 
children and in children with Polygenic Hypercholesterolaemia (PHC). This follow-up will 
allow study the progression of two lipid disorders and study the relation with 
atherosclerosis. 
2- To determinate the Achilles tendons thickness of FH children and compare it 
with the non-FH children at basal time. This study will be repeated over the next year, 

after two years, at the fifth year and every 5 years after. This study only will do in FH and 
PHC children. This follow-up will allow seeing if there are differences between the two 
pathologies. 
3- To determine biochemical parameters and complete lipid profile by NMR and 
new biomarkers of children at basal time. Annual and follow-up will be determinate in FH 
and PHC children. 
4- To collect the anthropometric and clinical data of all children at baseline.  FH and 
PHC children will be monitored annually. 
5- To study the pro inflammatory and oxidant status of the FH children and 
compare it with the non-FH children at basal time. This study will be repeated in the fifth 
year to children diagnosed with FH and PHC. 
6- To study the parameters of aortic arterial elasticity in all the children at basal 
time. This study will be repeated over the next year, after two years, at the fifth year and 
every 5 years after children diagnosed with FH and PHC. This follow-up will allow to study 
if there are differences between the two pathologies. 
7- To study the lifestyle of all the children before explanations about 
recommendations of lifestyle changes and verify their compliance after one year. Every 
year we will study the healthy patterns of children with FH and PHC.  
8- To start selective screening cascade of the first and second degree relatives after 
receiving the results of the genetic study in the index patient (progenitor). 
9- To compare all the results of FH children at basal time and follow-up.  
 
 
2- MATERIAL AND METHODS 
2.1-Patients of the study:  
Inclusion criteria: 
Children between 2 and 18 years of age who have a LDL-C level above 135 mg/dL 
will be referred to the Unit of Vascular Medicine and Metabolism (UVASMET) of the Sant 
Joan University Hospital. Previously, the pediatrician will have discarded secondary causes 
of hypercholesterolaemia such as hypothyroidism, nephrotic syndrome, diabetes, renal 
insufficiency (table 2). 
After confirmation that one of the parents has a genetic mutation 

(Lipoxip/Liponext) or clinical diagnosis (DLCN ≥ 8), the child will be studied. The progenitor 
with hypercholesterolemia will be considered as an index case, in this way we will 
demonstrate the vertical transmission of the genetic disease. 
 
Exclusion criteria 
The child population under 2 and over the age of 18 and children with secondary 
hypercholesterolaemia. 
 
Procedures: 
The detailed clinical history of the index case, including the history of 
cardiovascular disease in first and second degree relatives, personal history of 
cardiovascular disease as well as the presence of other CVR factors, anthropometric data 
and usual treatment will be collected. 
The family history, personal, anthropometric data, CVR factors of all affected or 
unfocused children of FH related in first or second degree will be collected. 
A semi-quantitative assessment of the consumption of different food groups and 
physical activity (Minnesota Test) will be done. 
To all of them, carotid ultrasound will be performed to determine the cIMT at the 
level of the common, bulb and internal portion of the right and left side (a total of six 
determinations). 
The rigidity of the arterial wall, determined by the central velocity of the pole wave 
(PWV), the distensibility and the rate of increase (IAx) at the level of the common portion 
of the carotid artery will be studied. 
For ultrasound, the Achilles tendon thickness will be measured and the presence of 
hypo-echogenic areas compatible with tendon xanthomas will be recorded. 
For transthoracic echocardiography, the parameters of aortic arterial elasticity will 
be measured. 
Control population will be considered to all those relatives of the case that do not 
present diagnostic criteria of the disease and are in the age of inclusion of the study or 
those candidates with relevant age who are referred to the UVASMET for suspicion of FH 
in which the diagnosis is not confirmed. 
 

2- Assessment of the lifestyle 
A semi-quantitative assessment of the consumption of different food groups will 
be carried out using a frequency questionnaire validated by the Spanish population27. This 
questionnaire consists of 137 food items and will be obtained by the dietitian of our Unit 
(see annex). A review will be added for those foods enriched with phytosterols and that 
can influence the levels of cholesterol. These data, we can assess the effect of different 
groups of foods or specific foods on cholesterol levels. In addition, it will allow us to see 
which patterns of food consumption can influence, positively or negatively, on the levels 
of cholesterol in the child population carrying the genetic alteration. 
The child population and/or their parents will be instructed on how to fill the data 
in the food diary for a period of 3 days, in order to be able to analyse the nutritional 
composition of the intake and the effect on the lipid profile. The first food register, will be 
obtained at the collection visit before starting any type of treatment. Another food diary 
will be included after one year. 
Physical activity will be collected from the Minnesota Test and we will ask about 
the consumption of tobacco. 
 
2.3-Biochemical analysis 
A fasting analysis will be performed which will include blood count, glycemia, total 
cholesterol, HDL-C, LDL-C, triglycerides, ApoA, ApoB, Lp(a), ApoE genotype, GOT, GPT , 
GGT, alkaline phosphatases, total and direct bilirubin, calcium, CPK, TSH, Vitamin D, 
creatinine and proteinuria. 
Complete lipid profile by NMR will be also determined. 
Selective determination of specific mutation (RLDL, ApoB, PCSK9) in the case of a 
positive outcome of the index case. 
Plasma concentrations of E-selectin and oxLDL will be determined by commercial 
ELISA kit: E-selectin (R & D Systems) and oxLDL (Mercodia). 
 
2.4-Collection of samples 
An additional sample of 10cc of venous blood will be collected that will be 
processed in plasma and serum aliquots according to the protocol of the METBANC-HFH 
collection that is part of the BIOBANC of the Pere Virgili Health Research Institute (IISPV). 

In the child population diagnosed with FH and PHC a new additional sample will be 
included in the follow-up year, at two and five years and later every five years. 
 
3- DETERMINATION OF SUBCLINICAL ATHEROSCLEROSIS IN CHILDREN'S POPULATION 
WITH AND WITHOUT FH. 
 
3.1 Determination of the intima-medium thickness of the carotid artery (cIMT). 
The cIMT determination is a reliable, standardized, reproducible and validated 
method that use ultrasounds, allows quantitative measurements of the bulk of the carotid 
artery wall. It is a non-invasive technique that has proven to be directly associated with 
CVR factors and to be useful in predicting the future incidence of cardiovascular events. 
This measure allows quantifying the vascular damage caused by CVR factors over time. 
The technique will be carried out according to the recommendations of the Consensus of 
the American Society of Ecography28. It will be carried out in the external consultations 
(UVASMET) of the Sant Joan University Hospital, by the same operator to minimize the 
variability and we use Esaote My-Lab 60 X-Vision (Esaote SpA, Italy) that allows to 
determine the cIMT for a semi-automatic method in live and radio frequency images. 
Images of the posterior wall of the common carotid artery, 1 cm proximal to the carotid 
bifurcation and 1 cm distal to the division corresponding to the internal carotid will be 
obtained. 
The existence of an atheroma plaque will be considered when protrusion of the 
wall towards the light that is higher than 1.5 mm thick or when the thickness is greater 
than 50% of the surrounding area. The average cIMT will be the result of the average of 
both cIMT of the common carotids and the maximum cIMT will be the one that 
corresponds to the maximum of cIMT of the 6 studied territories (the two common 
carotids, the 2 branches and the 2 internal carotids). 
 
3.2. Measurement of the elasticity of the carotid arterial wall: 
The loss of arterial elasticity is one of the mechanisms that most alarmingly warn of 
damage to the arteries. There are several parameters that evaluate the arterial elasticity: 
The pulse wave velocity (PWV) is one in which the energy wave caused by the 
cardiac systole travels through the arterial wall. At higher speeds, greater rigidity of the 

wall and also higher pulse wave transmission speed. This variable corresponds mainly to 
the rigidity of large arteries, such as the aorta and its main forks, which are the main 
responsible for the damping of the energy caused by cardiac contraction. It is expressed in 
m/sec, the values of normality vary according to age, gender and blood pressure. 
The increase index (AIx) corresponds to the interaction between the incident pulse 
wave that comes from the cardiac systole and the reflex wave, which occurs when the 
incident bounces in the middle artery divisions and small diameter and arterioles. The 
pulse wave detected by tonometry is the result of the interaction of these two. It is 
defined as the percentage of the distance between the inflection point corresponding to 
the confluence of the incident wave and the one that returns with respect to the distance 
between the maximum point of the pulse wave (systolic blood pressure) and the base of 
the wave (diastolic blood pressure). This measure correlates with the cardiovascular risk 
and expresses the rigidity not only of large arteries but also of those of small size, which 
reflects the elasticity of the entire arterial tree. 
The arterial distensibility is the fluctuation of the size of the arterial light when 
receiving the impulse of the blood column mobilized by the cardiac contraction. Increased 
arterial stiffness less complacency or viscoelasticity of the arterial wall. 
All these variables are measured by arterial tonometry and radio frequency. In the 
present study, they will be measured using the My-Lab 60 X-Vision device (Esaote S.p.A., 
Italy) at the level of the common portion of the carotid arteries. 
 
3.3 Determination of the thickness of the Achilles tendons: 
The determination of the thickness of the Achilles tendons will be carried out in the 
HFH child population and in the non-HFH child population participating in the study. 
To measure the Achilles tendons, the participants will be placed in a position with a 
folded ankle beyond the test bed and with the feet at 90° of flexion. The high resolution 
linear probe will be placed perpendicular to the tendon at 2 cm from the proximal zone of 
the insertion of the calcaneus. Once the image is obtained, it will freeze and be measured 
in a transverse manner in the tendon. When the upper and lower limits of the tendon 
walls are clearly observed, three determinations will be made at the maximum thickness 
point and separated by 0.5 cm. The Achilles tendom thickness of each foot will be the 
result of the average of the three determinations. We will consider that there is an 

increase in the thickness of the tendon when it is greater than 5.3 mm in men <45 years of 
age and more than 5.7 mm in men over 45 years of age. In women, we will consider 
xanthomas when the thickness of the aquiline tendon is greater than 4.8 mm in age under 
50 and 4.9 mm in over 50 years. At the same time, the presence of xanthomas will be 
assessed for the presence of hypo-echogenic areas and for the ecological deconstruction 
of the tendon29. In the child population, the values of normality of the Achilles tendon 
thickness are described based on age and sex. 
 
3.4 Determination of aortic arterial elasticity by transthoracic echocardiography: 
The echocardiography is an innocuous, painless technique that does not require 
sedation for its realization. 
The echocardiography will be performed with a General Electrocardiograph E9, 
with a 5 Mhz transducer suitable for paediatrics. The measures will be carried out with the 
patient placed in the left lateral position, and in the absence thereof, if by age of the 
patient it is not possible, in supine order. 
The measures of structures and standard flows will be carried out as well as 
measures to determine the arterial elasticity. The standard measures will be carried out as 
described in the paediatric echocardiography guides. 
The diameters of the aorta will be carried out in three locations: 
1. In the long parasternal axis, with M mode, 0.5 cm above the sinus-tubular 
junction. 
2. From the super sternal axis to the ascending aorta just before the exit of the first 
brachiocephalic trunk, both by 2D and by mode M. 
3. Short axis at the level of the right pulmonary artery. 
The systolic diameter will be measured at the point of maximum previous 
movement of the aorta, and the diastolic diameter will be measured at the peak of 
the QRS in the simultaneous ECG. 
 
Aortic distensibility (DA) will be calculated according to the formula: DA = 2x (AoS- 
AoD) (AoDxPP) (cm2dyn-1x10-6). 
Aortic rigidity will be calculated according to the formula: RA = (ln (PAS / PAD)) / 
((AoS- AoD) / (AoD)). 

Likewise, a determination of the blood pressure will be made with the supine 
patients, after a rest period of 15 minutes. The measurement will be done with an 
automatic tensiometer with a handle adapted to its age and condition. 
Pressure of dust (PP) will be calculated with the difference between systolic and 
diastolic blood pressure. 
In the event that any structural or functional anomaly is detected, the patient will 
be referred to the pediatric cardiology questionnaire for appropriate follow-up. 
 
4. SIZE OF THE SAMPLE AND STATISTICAL ANALYSIS: 
The population of the demarcation of Tarragona between 2 and 18 years old is 
71,186 children. We know that the prevalence of HeFH is 1/200-300 habitants, therefore 
we have a population of 355 to 237 HeFH children in the province of Tarragona. 
Statistical analysis will be carried out through the SPSS statistical program (version 
19.0) through a specific database for this study. 
The normal distribution of the continuous variables by the Kolmogorov-Smirnoff 
test will be studied. For the categorical variables and comparisons of frequencies between 
groups, the chi square test will be used to compare continuous variables between groups 
and with normal distribution the Student T test or the U Mann-Whitney test in the case of 
Non-normal distribution variables. In order to associate variables, Pearson or Spearman 
correlations will be made between normal or non-normal continuous variables 
respectively. Multivariate analysis will be done with logistic or linear regressions 
depending on whether the variables are dichotomous or continuous. 
 
5. INFORMED CONSENT: 
The study procedure will be explained to the parents of FH and non-FH children. 
Parents, as legal guardians, must sign the consent informed and confidentiality procedures 
will be given a patient information sheet detailing all the procedures of the study. A copy 
of the informed consent will also be given (see annex). This study has beeb approved by 
the clinical research ethics committee (CEIC) of the Sant Joan University Hospital. 
 
6. GOOD CLINICAL PRACTICE: 
All the clinical procedures will be in accordance with the current international 

regulations on good clinical practices, in accordance with the Provisions of the 
International Conference Harmonization on Good Clinical Practices (ICH-GCP) and the 
principles established by the 18th International Medical Association (Helsinki, 1964). 
 
7. WORK PLANNING  
Clinical visit: 
The child population between 2 to 18 years old with LDL-C levels >135 mg/dL 
and/or progenitor with cholesterol levels >300 mg/dL or with hypolipemiant treatment, or 
a history of premature cardiovascular disease in relatives of first or second degree (<55 
years men and <65 years in women), will be referred to external consultations of 
endocrinology with Dr. Feliu. 
Dr. Feliu is responsible to assess the inclusion criteria and if the child and the 
parent can be FH, they will be sent to UVASMET. In there, the responsible staff  will 
explain the reasons for the study again and insisting on the importance of early detection 
to reduce CV risk. The informed consent will be collected, filed and kept under key in the 
Clinical Investigation Unit (UIC). Family history, personal history, anthropometric data, 
physical examination and current treatment data will be collected under the supervision 
of Dr. Plana. 
All researchers will participate in the analysis and discussion  of the results. 
 
Evaluation of the lifestyle: 
The semi-quantitative assessment of the consumption of the different food groups 
will be carried out in UVASMET (Sant Joan University Hospital, Reus). Children and his 
families will be informed about foods with low cholesterol content. Recommendations will 
be made and "cardiosaludable" habits will be stimulated. Support documentation will be 
provided. 
The annual follow-up visit will evaluate compliance with the recommendations 
made and the frequency questionnaire for food consumption will be collected again. Mrs. 
Cèlia Rodríguez will be the nutritionist-dietician in charge of this task. 
All researchers will participate in the analysis and discussion  of the results. 
 
Vascular study: 

The study of subclinical arteriosclerosis will be carried out in UVASMET (Sant Joan 
University Hospital, Reus). An ultrasound will be performed at levels of the carotid arteries 
and levels of Achilles tendons. Team work will be supervised by Dr. Ferré and Dr. 
Ibarretxe. 
Echocardiography will be carried out by Dr. Marimon. 
All researchers will participate in the analysis and discussion  of the results. 
Blood extraction: 
Blood samples will be obtained after 8-hours fasting in UVASMET (Sant Joan 
University Hospital, Reus) premises. Mrs. Anna Varela will be the nurse in charge of 
processing and distributing samples.  Several plasma, serum and WBC aliquots will be 
stored in the BioBanc of the Hospital Research Institute (IISPV). 
An aliquot will be sent to the laboratory of the San Juan Hospital for routine 
biochemical parameters measurement.  
A complete lipid profile by NMR will be analysed in Biosfer Teslab. 
(www.biosferteslab.com) 
If the genetic study is indicated, a DNA sample will be sent to the Hospital de Sant 
Pau in Barcelona, that centralize these genetic studies in Catalonia. 
   
All the members of the team of researchers will participate in the analysis of the 
results 
 
Determination of inflammatory parameters: 
Inflammation, oxidation and other biomarkers determination will be carried out in 
the Research Unit on Lipids and Arteriosclerosis (URLA) located at the Faculty of Medicine 
of Reus of the Rovira i Virgili University (URV) at the end of the recruitment of the child 
population. Dra. Josefa Girona will be responsible. 
All the members of the team of researchers will participate in the analysis of the 
results. 
 
 
The Dra. Plana and Dr. Feliu will be in charge of supervising and coordinating the 
team of researchers as well as analyzing the results and the possible publication. Drs NP, 

AF, RF, DI, JG, CR, CM, LM will participate actively in the elaboration of manuscripts 
derived from the study.  
All pediatricians involved in the DECOPIN group will be present in all the 
publications derived from the study. 

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ANNEXES 
 
Table 1. Clinical criteria diagnosis of HFH according to DLCN 
 
Family History:  
 
 
 
 
 
 
Score if is affirmative 
I.- First-degree family with precocious disease and / or vascular .   
..... 1 point  
II.- First-degree family member with c-LDL 210 mg/dL  
 
 
..... 1 point  
III.- First degree family with xanthoma and / or corneal arch  
 
..... 2 points  
IV.- Child under 18 with c-LDL 150 mg/dL   
 
 
 
..... 2 points 
 
Personal History: 
I.- Antecedent of precocious coronary disease 
 
 
 
..... 2 points 
II.- Antecedent of peripheral vascular disease and/or precocious cerebral ..... 1 point 
 
Physical examination 
I.- Tendinous Xanthome  
 
 
 
 
 
 
... 6 points 
II.- Corneal arc before age 45 
Fasting analytics 
I.-  LDL-C   330 mg/dL 
...... 8 points 
II.- LDL-C  250 - 329 mg/dL 
..…. 5 points 
III.-LDL-C  190 - 249 mg/dL 
......3 points 
IV.-LDL-C  155 - 189 mg/dL                                                                          
.......1 point 
 
TRUE DIAGNOSIS: ≥8 points, PROBABLE DIAGNOSIS: 6-7, POSIBLE DIAGNOSIS: 3-5 Points 
 
 

Table 2. Causes of secondary dyslipidemia in the child population 
 
Pure Hypercholesterolemia 
 Nephrotic syndrome 
 Hypothyroidism, hypopituitarism, idiopathic hypercalcemia 
 Drugs: corticosteroids, retinoic acid 
 Anorexia nervosa, Kawasaki's disease 
 
Mixed dyslipemia 
 Diabetes type 1 and type 2, metabolic syndrome, obesity, lipodystrophy 
 Drugs: antiretrovirals, oral contraceptives, anabolizers 
 Ketogenic diets, alcohol. 
 Chronic renal or hepatic insufficiency 
 Pregnancy 
 Turner Syndrome or Klineffelter 
 Lupus erythematosus, rheumatoid arthritis 
 Glucogenosis (type I), sphingolipidosis (Niemann-Pick) 
 

 
SUSPECT CRITERIA IN HeFH CHILDREN'S POPULATION 
 
 Child with LDLC ≥ 135 mg / dL. 
+ 
 Antecedents of early cardiovascular disease (<55 years in men or <65 years of age 
in women) in relatives of first or second degree. 
O 
 Progenitor with CT levels> 300 mg / dL or in hypolipemiant treatment. O 
 Progenitors of unknown origin (Child adopted). 
 
 
 
 
 
 
CRITERIA OF DERIVATION TO PEDIATRIC ENDOCRINOLOGY 
 
 Child with confirmed hypercholesterolaemia. 
 Discard causes of secondary hypercholesterolaemia. 
 
Confirmation of hypercholesterolemia in progenitor. 

 
How will we do universal screening? 
 We will take the opportunity to request CT and TG in all analyzes that ask the 
child population between 2 and 14 years. 
 If CT levels> 200 mg / dL, we will repeat the analytic after one month to confirm 
the finding and we will request a complete lipid profile (CT, HDL, LDL, TG), TSH 
to rule out hypothyroidism, liver profile and kidney We will discard proteinuria 
in urine. 
 
 
If LDL-C >135 mg/dL 
 Lifestyle changes 
Family screening 
If LDL-C <135 mg/dL 
 Lifestyle changes 
Lipid Profile 
Yes, cLDL> 135 mg / dL 
+ 
Parents with CT> 300 mg / dL  
or 
History of precocious CV disease 
or 
Unknown progenitors 
Send to Pediatric Endocrinology 
Service 
UVASMET 

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El dictamen del CElm respecte a l'anomenat projecte en el forrnat actual és favorable.
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Código: DECOPTN
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se cumplen los requisitos necesarios de idoneidad del protocolo en relación con los objetivos del estudio
y están justificados los riesgos y molestias ¡lrevisibles para el sujeto.
La capacidad del investigador y los medios disponibles son apropiados para lleva a cakro el estudio.
Son adecuados tanto el procedimiento para obtener el consentimiento informado como la compensación
prevista para los sujétos por daños que puclieran derivarse de su participación en el estudio.
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éticos.
Este comité elcpte que dicho estudio sea realizado en el Hospital Universitari Sant.loan de Reus por
la Dra. Núria Plana Gil del Servicio de Medicina Interna
En el caso que se evolúe olgún proyecto en el que participe como investigador/colaboroctor olgún miembro
de este comité, se ousentaró de la reunión durante la discusión del estudio.
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Presidente
Dra. Maria Teresa Auguet euintilla
servicio de Medicina lnterna. Hospitot Llniversitari Joon xXill. Representonte de la comisión de
lnvestigación,
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Dr. Josep Ma Alegret Colomé
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Dr. Xavier Ruiz Plazas
LJrólogo. servicic¡ de Medicina lnterno del,tlospital Llniversitari Joon XXlll.
Sra. Montserrat Boj Borbonés
servicio de Farmacío del Hospitot tJniversitari sant Joon de Reus.
Sra. Anna Borrurel Llovera
D i p I o m o d a U n iv e rs ita ri o e n E nfe rm e rí o. IJ ll IJ
Sra. lmmaculada de Molina Fernández
Diplomada universitaría en Enfermería. Haspitat lJniversitari Joan xxttt.
Dr, Joaquín Escribano Súbias.
Médico del Servicio de Pediotría. Representonte de ta Comisión de Bioética Assitencial. Miembro de
Com isión de I nvestigació n.
Dr. Joan Fernánclez Ballart
catedrótico de Medicino Preventiva i satud Púbtico. Focultdd de Medicina i ciéncies de to solut.
Universitot Rovira i Virgili.
Sra. M. Mar Granell Barceló
Abogada i Asesora Jurídica del Comité.
Dr. Josep M. Crespo Bernabeu
Servicio de Farmacia del Hospitat l.Jniversitari Joan XXtil.
Dr. Jesús Miguel López-Dupla
Servicio de Medic:inq lnterna Hospital lJniversitari Joan XXttt
Sr. JordiMallol Mirón
cqtedrético de Formocología, Facultod de Medicino, lJniversitat Rovira ivirqili.
Sra. lsabel Rosich Martí
Fa rmacé utico Ate nció p ri ma ri o
Sr. Francesc Xavier Sureda Batlle
Profesor Titular de Formacología. lJniversitat Rovira i Virgili.
Dr. Vicente Valentí Moreno
Oncólogo. Hospital Sant pou i Santa Tecla.
Dra. Elisabet Vilella Cuadrada
Departomento de Formación e tnvestigación det Hosptal Psiquidtric lJniversitari lnstitut pere Mata.
Representante de la Comisión de tnvestigoción.
Sra. Mercé Vilella papaseit
Representante de la Sociedad Civil.
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Edifici de Nutr¡c¡ó i Salut
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Tel. 977 75 93 94
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