Risk Assessment of Cardiovascular Atherogenicity in Growth Hormone-Deficient Children
By Fatimah Javaid Qureshi1,2, Muhammad Anwar1, Muhammad Asif Nawaz2, Mehnaz Omer2, Sanober Hameed2, Saqibah Rehman3Affiliations
doi: 10.29271/jcpsp.2025.10.1284ABSTRACT
Objective: To assess cardiovascular atherogenic risk in children with growth hormone deficiency (GHD) by comparing lipid profiles and plasma atherogenic indices (PAI) with those of healthy controls.
Study Design: A comparative cross-sectional study.
Place and Duration of the Study: Department of Chemical Pathology, the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from February to July 2024.
Methodology: Ninety children with short stature, aged 3–12 years were evaluated. They were categorised into the growth hormone–deficient group (GHD group) and the healthy control group (Control group) based on the insulin tolerance test, IGF-1, and IGFBP-3 levels. Fasting lipid profiles were assessed, including total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and non-HDL cholesterol. The PAI was calculated as log (TG/HDL). Data were analysed using SPSS version 23. The independent t-test and Mann–Whitney U test were used to compare continuous variables between the two groups, whilst the Chi-square test was applied for categorical variables. Statistical significance was set at p ≤0.05.
Results: Among the 90 participants, 48 exhibited GHD and 42 were healthy. Children with GHD showed markedly increased TC, TG, LDL, non-HDL cholesterol, and PAI values (p <0.001). Their HDL levels were also reduced compared with those of the healthy controls. A substantial proportion of GHD children (77.8%) were classified as high-risk based on PAI, whilst 100% of those with elevated non-HDL cholesterol were GHD. Atherogenic lipid parameters demonstrated a negative correlation with IGF-1 levels (p <0.001). IGF-1 concentrations correlated favourably with GH and HDL basal concentrations.
Conclusion: Children with GHD exhibited dyslipidaemia and elevated atherogenic risk markers, indicating a predisposition to premature atherosclerosis.
Key Words: Cardiovascular disease, Growth hormone, Dyslipidaemia, Plasma atherogenic indices.
INTRODUCTION
Growth hormone (GH) is a major mediator of development and somatic growth in humans. It executes its actions either directly or through insulin-like growth factor-1 (IGF-1), which is synthesised in the liver. This GH–IGF-1 axis plays a crucial role in cardiac contractility and the vascular system, regulating vascular tone and peripheral resistance.1 GH exerts a notable lipid-lowering effect, likely mediated by β-adrenergic activation, which stimulates hormone-sensitive lipase and indirectly enhances fat breakdown and fatty acid oxidation.2
Two to three hundred individuals per million of the population suffer from growth hormone deficiency (GHD), a unique clinical condition.3 In Pakistan, the prevalence of GHD is reported as 6.1%, indicating a considerable disease burden.4 GHD not only causes stunted growth in children but also has adverse effects on lipid metabolism by reducing lipolysis, thereby decreasing fat breakdown and increasing fat storage. It impairs body composition, particularly visceral adipose tissue, and causes insulin resistance. Moreover, it has also been linked to chronic low-grade inflammation, dyslipidaemia, endothelial dysfunction, impaired glucose metabolism, and oxidative stress—all of which increase the risk of cardiovascular disease (CVD).3,5
Compared with patients with adult-onset GHD, those with childhood-onset GHD that persists into adulthood exhibit more severe clinical symptoms, characterised by increased visceral adipose tissue and reduced lean body mass.6 The dyslipidaemia observed in individuals with GHD is primarily defined by elevated total cholesterol (TC) and low-density lipoprotein (LDL) levels, both of which are well-recognised risk factors for the development of atherosclerotic CVD in adults.7
The onset of dyslipidaemia and atherosclerosis occurs in childhood, often seen as fatty streaks in major vessels, which may be accelerated by GHD. There are limited data available regarding lipid abnormalities and cardiovascular risk associated with GHD in the young. Therefore, the study aimed to biochemically evaluate dyslipidaemia and CVD risk in children with GHD compared to the healthy controls. Early identification of GHD children at high risk for cardiovascular atherogenicity will facilitate timely medical intervention, and continuous monitoring of their cardiac profile may improve out- comes.
METHODOLOGY
It was a comparative cross-sectional study, which was executed at the Department of Chemical Pathology and Endocrinology, the Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan, from February to July 2024. Ethical approval was obtained from the Institutional Ethical Review Board (IRB No. MP-CHP22-10/READ/23/1741). Non-probability consecutive sampling was conducted, and the sample size was determined via the WHO sample size calculator with a 95% confidence interval, a 5% margin of error, and a prevalence of 6.1%.4
Ninety short-statured children (aged 3-12 years, both genders) presenting to the Endocrine Clinic at the AFIP for growth hormone evaluation were included in the study. Demographic details, family history, and birth and developmental histories were recorded. Anthropometric data were recorded, and detailed systemic examination was performed. Children were categorised into the GH-deficient group (GHD group) and the healthy control group (Control group; physiological short stature) on the basis of the insulin tolerance test (ITT), IGF-1, and IGF-BP3 levels. Informed consent was obtained from the parents of children, and fasting blood samples for lipid profile assessment were collected. Children receiving growth hormone replacement therapy, those having acute illness, familial hypercholesterolaemia, or genetic syndromes were excluded.
Among the lipid profile parameters, TC, triglyceride (TG), and high-density lipoprotein (HDL) were tested on a chemistry auto-analyser using their respective enzymatic methods. LDL was calculated via the Friedewald equation. GH, IGF-1, and IGF-BP3 were measured by electrochemiluminescence on an immunoassay auto-analyser. Cut-off values for dyslipidaemias were established in accordance with the National Cholesterol Education Programme (NCEP) guidelines. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from TC. Values <3.1 mmol/L were considered acceptable, 3.1-3.7 mmol/L were considered borderline, and >3.7 mmol/L were considered high.8 The plasma atherogenic indices (PAI) were determined by calculating logarithm of the TG/HDL ratio. PAI values <0.1 indicated low atherogenic risk, 0.1-0.24 were considered as moderate risk, and values >0.24 were considered as high risk.9
The data analysis was performed on the Statistical Package for the Social Sciences (SPSS), version 23.0. The distribution of the data was assessed using the Shapiro–Wilk test. Baseline characteristics and biochemical parameters were summarised descriptively. Frequencies and percentages were calculated for categorical variables (e.g., gender, height percentile, bone age, PAI categories, and non-HDL cholesterol categories). Means and standard deviations (SD) were calculated for continuous variables with a normal distribution, while the median and interquartile range (IQR) were used for non-normally distributed continuous variables. The Chi-square test was applied to examine the association between GH status and categorical variables, including gender, height percentile, bone age, PAI categories, and non-HDL cholesterol categories. For comparisons of continuous variables between the GHD group and the Control group, the independent t-test was applied for normally distributed variables, while the Mann–Whitney U test was applied for non-normally distributed variables. Additionally, Spearman’s correlation analysis was performed to assess the relationship between IGF-1 levels and lipid profile components (TC, TG, HDL, LDL), PAI, and non-HDL cholesterol, as well as basal GH levels. A p-value of ≤0.05 was considered statistically significant.
RESULTS
A total of 90 individuals participated in the study. The mean age of the subjects was 9.26 ± 2.90 years for 57 (63.3%) males and 8.96 ± 2.01 years for 33 (36.7%) females. Out of the 90 participants, 48 (53.3%) were GH-deficient, while 42 (46.7%) had normal GH status.
Table I examines the association between GH status and key demographic and clinical variables in children. No significant association was observed between gender and GH status (p = 0.347). Notable variations, however, were noted in height percentiles, as the GHD group was more likely to have lower percentiles (p = 0.001). Bone age was also significantly associated with GH status, as delayed bone age was more prevalent in the GHD group compared to the Control group (p <0.001). PAI showed a strong association with GH status, indicating higher cardiovascular risk in the GHD group (p <0.001). Similarly, non-HDL cholesterol levels were significantly associated with GH status, as the GHD group exhibited higher non-HDL cholesterol levels compared to the Control group (p <0.001).
The anthropometric and biochemical parameters between the GHD group and the Control group are compared in Table II. No significant differences in mean age and weight were found between the two groups (p = 0.942 and p = 0.333, respectively). The GHD group had significantly reduced IGF-1 and IGFBP-3 levels compared to the Control group (p <0.001). Lipid profile showed higher TC, TG, LDL, and non-HDL cholesterol levels in the GHD group (p <0.001). The PAI was elevated in the GHD group (p <0.001). The GHD group demonstrated decreased HDL levels as compared to the Control group (p <0.001).
Table I: Comparison of demographic and clinical characteristics by GH status.
|
Variables |
GH status |
Total |
p-values* |
||
|
GHD Group |
Control Group |
||||
|
Gender |
Male |
29 (50.9%) |
28 (49.1%) |
57 (63.3%) |
0.347 |
|
Female |
19 (57.6%) |
14 (42.4%) |
33 (36.7%) |
||
|
Total |
48 (53.3%) |
42 (46.7%) |
90 (100%) |
||
|
Height percentile |
<3 percentile |
37 (67.3%) |
18 (32.7%) |
55 (61.1%) |
0.001 |
|
3-10 percentile |
11(31.4%) |
24 (68.6%) |
35 (38.9%) |
||
|
Total |
48 (53.3%) |
42 (46.7%) |
90 (100%) |
||
|
Bone age |
Delayed |
40 (69.0%) |
18 (31.0%) |
58 (64.4%) |
<0.001 |
|
Normal |
8 (25.0%) |
24 (75.0%) |
32 (35.6%) |
||
|
Total |
48 (53.3%) |
42 (46.7%) |
90 (100%) |
||
|
PAI |
Low risk |
9 (28.1%) |
23 (71.9%) |
32 (35.6%) |
<0.001 |
|
Moderate risk |
11 (50.0%) |
11 (50.0%) |
22 (24.4%) |
||
|
High risk |
28 (77.8%) |
8 (22.2%) |
36 (40.0%) |
||
|
Total |
48 (53.3%) |
42 (46.7%) |
90 (100%) |
||
|
Non-HDL cholesterol |
Acceptable |
13 (24.5%) |
40 (75.5%) |
53 (58.9%) |
<0.001 |
|
Borderline |
17 (89.5%) |
2 (10.5%) |
19 (21.1%) |
||
|
High |
18 (100%) |
0 |
18 (20.0%) |
||
|
Total |
48 (53.3%) |
42 (46.7%) |
90 (100%) |
||
|
*p-value was calculated by the Chi-square test. GH: Growth hormone; PAI: Plasma atherogenic indices. |
|||||
Table II: Comparison of biochemical and anthropometric parameters by GH status.
|
Variables |
GH status |
p-values |
|
|
GHD Group |
Control Group |
||
|
Age |
9.42 ± 2.37 |
9.38 ± 2.22 |
0.942* |
|
Weight |
20.34 ± 6.20 |
21.55 ± 5.54 |
0.333* |
|
LDL |
2.33 ± 0.63 |
1.41 ± 0.62 |
<0.001* |
|
IGF-1 |
8.40 (10.88-5.61) |
27.50 (45.00-20.90) |
<0.001** |
|
IGFBP-3 |
2.10 (3.20-1.33) |
7.40 (9.13-4.58) |
<0.001** |
|
TC |
4.48 (4.86-3.82) |
3.00 (3.46-2.62) |
<0.001** |
|
TG |
1.67 (3.18-1.40) |
1.22 (1.50-1.00) |
<0.001** |
|
HDL |
0.90 (1.00-0.80) |
1.10 (1.20-0.97) |
<0.001** |
|
PAI |
0.28 (0.55-0.15) |
0.07 (0.17-0.00) |
<0.001** |
|
Non-HDL cholesterol |
3.58 (4.04-2.87) |
1.78 (2.53-1.38) |
<0.001** |
|
p-value was calculated by the Independent t-test for normally distributed parameters,* and Mann-Whitney U test for non-normally distributed parameters.** GH: Growth hormone; LDL: Low-density lipoprotein; IGF-1: Insulin-like growth factor-1: IGFBP-3: Insulin-like growth factor binding protein-3; TC: Total cholesterol; TG: Triglyceride; HDL: High-density lipoprotein; PAI: Plasma atherogenic indices. |
|||
Figure 1: Association of GH status with PAI risk categories.
Figure 1 illustrates that 28 (77.9%) children of the GHD group were classified as having a high CVD risk, with PAI >0.24. In contrast, 23 (71.9%) children of the Control group exhibited a low CVD risk, with PAI <0.10. Figure 2 demonstrates that all children (n = 18; 100%) with elevated non-HDL cholesterol levels had GHD, whereas the majority of children (40; 75.5%) with acceptable non-HDL cholesterol levels were in the Control group. IGF-1 showed a significant negative correlation with TC: -0.619, TG: -0.387, LDL: -0.513, PAI: -0.475, and non-HDL: -0.674, and a significant positive association with HDL levels (p <0.001).
Figure 2: Relationship between GH status and non-HDL cholesterol categories.
DISCUSSION
Despite the rarity of atherosclerotic cardiovascular events in children, strong clinical, imaging, and post-mortem evidence has shown that the atherosclerosis process in high-risk individuals begins in childhood. This highlights the need to identify dyslipidaemias in children with GHD and to prevent early cardiovascular events by prompt and efficient treatment.10
This study demonstrated that children with GHD exhibited significantly elevated lipid profiles in comparison to their counterparts with normal GH status. Specifically, the GHD group had higher median levels of TC, LDL, and TG, alongside lower median levels of HDL, compared to the Control group.
All children with elevated non-HDL cholesterol levels (>3.7 mmol/L) were found to be GH-deficient. Non-HDL Cholesterol indicates the TC content of all pro-atherogenic lipoproteins, such as very low-density lipoprotein (VLDL), intermediate- density lipoprotein (IDL), LDL, and lipoprotein(a). It is considered an independent risk factor for CVD.11
A study conducted by Gupta et al. reported that children with GHD had elevated levels of TC (p = 0.02), non-HDL cholesterol (p = 0.02), C-reactive protein (CRP) (p = 0.01), pro-brain natriuretic peptide (pro-BNP) (p = 0.04), and serum homocysteine (p <0.001), in comparison to healthy subjects, supporting the findings of the present study. GHD children also had substantially reduced thickness of the ventricular septum and left ventricular mass (p = 0.04 and p = 0.02, respectively).12 However, no correlation was observed between IGF-1 and echocardiographic parameters.13
Another study reported that the proportion of LDL increased in male GHD patients compared with healthy controls, resulting in elevated TC (p <0.01). Patients of both genders reported notable increases in the TC/HDL ratio, which is particularly crucial for assessing CVD risk. Both male and female patients had higher TG levels than the healthy controls.14
A similar study by Fukuoka et al. evaluated the most prevalent complications of untreated GHD and found dyslipidaemia to be the most frequent (22%), followed by diabetes mellitus (9.3%) and osteoporosis (4.76%).15
This study further categorised the GHD children into low CVD risk, moderate, and high CVD risk groups based on the PAI, which is the ratio of TG to HDL cholesterol in molar concentration that may be analytically computed as log (TG/HDL). The PAI is a significant predictor of atherosclerosis and coronary heart disease, and can therefore be effectively used as a screening test for major cardiovascular events.16 In this study, it was found that children with GHD constituted the majority (77.9%) of the high CVD risk group, with PAI >0.24. In contrast, the low-risk group (PAI <0.10) predominantly comprised children with normal growth hormone status.
Regarding the effects of growth hormone replacement therapy (GHRT) on lipid levels, two meta-analyses indicated that LDL levels significantly decreased after GHRT, and one of them also found a reduction in TC levels. However, neither study showed an increase in HDL levels.17,18 Another study by Scarano et al. evaluated the effects of long-term GHRT and recorded changes in lipid parameters at baseline and after seven years of therapy. The results suggested that TC and LDL were significantly reduced (p = 0.006 and p = 0.048, respectively) after seven years of treatment, and HDL also increased as a result of long-term GH therapy (p = 0.02).19 GHRT in obese children led to a decrease in BMI as well.20
This study has several potential limitations. It was a cross- sectional study conducted at one point in time and did not follow GHD children over time. Additionally, the assessment of CVD risk was limited to biochemical parameters, without including radiological or cardiological evaluations. Larger, multicentre studies with proper follow-up for the possible complications are needed to better establish CVD risk in GHD children.
CONCLUSION
Children with GHD demonstrated elevated TC, TG, and LDL, along with reduced HDL levels. They also exhibited high non-HDL cholesterol and elevated PAI values, indicating increased CVD risk. These findings suggest that GHD in children is associated with dyslipidaemias from an early age, placing them at higher risk for premature atherosclerosis compared to healthy peers.
ETHICAL APPROVAL:
Ethical approval was obtained from the Institutional Review Board and Ethical Committee of the Armed Forces Institute of Pathology, Rawalpindi, Pakistan (IRB No: MP-CHP22-10/ READ/23/1741).
PATIENTS’ CONSENT:
Informed written consent was obtained from all the study patients.
COMPETING INTEREST:
The authors declared no conflict of interest.
AUTHORS’ CONTRIBUTION:
FJQ: Data collection, processing, analysis, literature search, and manuscript writing.
MA: Project conception, design, and interpretation of the results.
MAN: Drafting of manuscript and critical review.
MO: Project development and interpretation of data.
SH: Statistical analysis and critical review of the manuscript.
SR: Literature review and interpretation of the results.
All authors approved the final version of the manuscript to be published.
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