KORELACJE POMIĘDZY WSKAŹNIKAMI METABOLIZMU LIPIDÓW U PACJENTÓW Z NADCIŚNIENIEM TĘTNICZYM I NIEDOCZYNNOŚCIĄ TARCZYCY
Lyubov V. Olenych, Lesya I. Pylypiv, Nataliya S. Bek, Olena M. Radchenko
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
Introduction: Hypertension is a major reason behind morbidity, disability and mortality. Elevated blood pressure is a huge risk factor for cardio-vascular diseases. Almost 90% of hypertension patients have internal comorbidities, in particular hypothyroidism. For now, however, the specificities of the clinical course of hypertension in hypothyroid patients are understudied and the data on lipid metabolism in patients with primary hypothyroidism and hypertension are inconclusive.
The study aims at establishing the effect of the lipid metabolism indices in hypertensive patients with hypothyroidism using correlation analysis.
Materials and methods: The total of 198 patients with stage 1 and stage 2 hypertension were examined. The patients were divided into two groups based on whether they have hypothyroidism or normal thyroid function.
Results: The study revealed that in patients with hypertension and hypothyroidism, hypercholesterolemia is associated with hypocoagulation, hyperkalaemia, decreased bilirubin levels and adrenal cortex activation. Hyperbetalipoproteinemia is linked to the reduced thyroid gland, activation of the lymphocytic component of the inflammatory response, predisposition to hypocoagulation, probable unfavourable acute stress response and development of the eccentric hypertrophy of the left ventricle myocardium. Elevated triglycerides have an effect on the progression of arterial hypertension and are associated with diastolic dysfunction of the left ventricle and hepatic dysfunction.
Conclusion: The combination of hypothyroidism and hypertension is an unfavourable factor in the development and progression of dyslipidaemia, which, in its turn, can cause blood coagulation disorders, adrenal glands activation, cardiac, renal and hepatic damage, and negative adaptive responses.
Wiad Lek 2018, 71, 2 cz. I, -284
Arterial hypertension (AH) and dyslipoproteinemia are the major risk factors for cardiovascular disorders, which entail early disability and mortality. 4% of AH patients are diagnosed with obesity, 67% have hypercholesterolemia, one in four patients manifests a low level of high density lipoproteins (HDL), almost every fifth patient is diagnosed with hypertriglyceridemia . The most significant hypertension risk factor is dyslipidaemia, which is often associated with the thyroid gland (TG) disorders .
The category of the conditions connected with the lipid metabolism disturbance includes primary hypothyroidism, diagnosed in 11.8% of patients . For instance, a raise of TSH level by 1 mIU/L is accompanied by an increase in the body mass by 0.9 kg and in body mass index (BMI) by 0.3 kg/m2 in women and by 0.8 kg and 0.2 kg/m2 in men, respectively. Half the patients with TG hypofunction have increased body weight, total cholesterol level (TCL) and low-density lipoproteins (LDL) level [4, 5]. This results from the reduced synthesis of fat acids and lipolysis, which is directly proportional to the level of thyroid-stimulating hormone (TSH) and in inverse proportion to the thyroxin level. Reduced levels of TG hormones also inhibit the activity of lipoprotein lipase, an enzyme that is responsible for triglycerides synthesis, which causes their increased levels [6, 7]. TSH effect on the receptors of the adipose tissue cells induces the differentiation of рreadipocytes into adipocytes, which stimulates adipogenesis and adipocytokines production, in particular leptin [8, 9]. Leptin stimulates thyroliberin secretion, this leading to increased TSH levels, while the levels of triiodothyronine (Т3) and thyroxin (T4) remain normal or slightly raised [10, 11].
The study revealed the effect of TG hormones on the distribution of the adipose tissue. The amount of the subcutaneous fat and the ratio of the subcutaneous fat to the visceral fat are inversely proportional to Т4 level, whereas TSH level is in a positive correlation with the subcutaneous fat thickness. Some studies showed that the expression of the thyroid receptors -α and -α1 is stronger in the adipose tissue as compared to the visceral fat in the patients with obesity, while the TSH receptor expression in the adipose tissue correlates with the body mass index .
Recently, the correlation between the thyroid stimulating hormone and the adipose tissue has been the subject-matter of numerous studies. It was found out that in obese persons TSH level is much more often at the upper reference range limit and is higher than in non-overweight patients. For elevated TSH in obese patients, TSH receptors expression in the adipocytes is weaker than in non-obese persons. This can result in a reduced stimulation of the thyroid hormone receptors and suppression of TG hormones, which, in its turn, causes increased TSH and T3 levels. This is how peripheral resistance to the thyroid hormones develops and TSH biological activity changes . This vicious circle is broken when the body weight decreases and the size and function of the mature adipocytes are restored, which leads to TSH level normalization.
Cardiovascular manifestations belong to the top-important symptoms of hypothyroidism; they are detected by the direct and indirect effects that the thyroid hormones have on the heart and blood vessels. Elevated blood pressure is diagnosed in over 50% of hypothyroid patients. Fairly often, it is one of the first clinical symptoms of hypothyroidism. So far, the controversy regarding the reasons for AH in hypothyroid patients has not been solved. Some researchers believe AH to be a disease that develops independently of hypothyroidism, reporting, however, BP stabilization as a result of the adequate replacement therapy by thyroxin .
Therefore, arterial hypertension, hypothyroidism and dyslipidaemia are correlated, have common etiological factors and pathophysiological mechanisms, due to which search for the links between the lipid metabolism indices and clinical, laboratory and instrumental parameters in patients with hypertension and hypothyroidism remains a topical problem.
The aim of the research is to explore the effect of the lipid metabolism indices in hypertension patients with hypothyroidism by means of correlation analysis.
Materials and methods
The total of 198 patients with stage 1 and stage 2 hypertension enrolled in the study were split into two groups. Group 1 comprised hypothyroid patients and Group 2 was made of patients with the preserved TG function. The enrolees in each group had comparable age, gender composition, AH duration, stage and degree, and comorbidities. Group 1 consisted of 162 patients aged 53.00±9.67; Group 2 included 36 patients aged 61.00±11.54 (p>0.05). The diagnosis of hypothyroidism was established on the grounds of the patients’ complaints, anamneses, objective examinations, increased TSH>4.0 mIU/mL, reduced free T4<10.0 pmol/mL and T3<4.0 pmol/mL. In addition to the standard tests in compliance with the protocol, the study relied on measuring the body mass index, waist circumference (WC), hip circumference (HC) and waist-to-hip ratio, as well as on the calculation of glomerular filtration rate and left ventricular muscle mass index. Levels of TSH, T3, T4 and cortisol were measured using the enzyme-linked immunosorbent assay. The results were processed with Statistica for Windows 10.0 standard package for calculating the median (M), standard deviation (σ), upper and lower quartiles; the correlations were estimated using the Kendall rank correlation coefficient; the probability value was assumed to be p<0.05.
As expected, the lipid profile parameters correlated between themselves. For instance, in the hypertensive and hypothyroid patients there was a direct correlation between TCL and β–lipoprotein (β-LP), LDL, triglycerides (TG) (τ = 0.39; р<0.001, τ = 0.90; р = 0.004, τ = 0.29; р<0.001), while TG correlated with the atherogenic index (AI) (τ = 0.81; р<0.001). At the same time, in the patients with the normal thyroid gland function, there was no correlation of TG with TCL and AI.
Group 1 patients displayed direct correlations of TCL with the systolic blood pressure (SBP) and pulse pressure (PP) (τ = 0.14; р = 0.001 and τ = 0.13; р = 0.014, respectively), which confirms the role that hypercholesterinemia plays in the development and progression of arterial hypertension. Importantly, an increased SBP necessitates a raised dose of levothyroxine used as a replacement therapy (τ = 0.21; р = 0.013). Besides, an inverse correlation between SBP and Т4 level was established (τ = -0.24; р = 0.022), both of them correlating with BMI
(SBP: τ = 0.14; р = 0.031, Т4: τ = -0.26; р = 0.036).
For hypothyroid patients TCL was inversely correlated with the total bilirubin level (τ = -0.19; р = 0.026), prothrombin index (τ = -0.39; р = 0.002) and directly correlated with the cortisol blood level (τ = 0.56; р = 0.016), potassium level (τ = 0.22; р = 0.03), aorta diameter (τ = -0.44; р = 0.002) and urine protein level (τ = 0.22; р = 0.047), which was not observed for the normothyroid patients. In other words, if hypertension is comorbid with hypothyroidism, hypercholesterinemia is associated with hypocoagulation, hyperkalaemia, decreased levels of antioxidant bilirubin, impaired renal function and activation of the adrenal cortex.
In the hypothyroid patients, β-LP inversely correlated with the thyroid volume (τ = -0.27; р = 0.003), prothrombin index (τ = -0.32; р = 0.009) and segmented neutrophil count (τ = -0.24; р = 0.007). Besides, increased β-LP levels were associated with raised peripheral lymphocyte counts (τ = 0.24; р = 0.006), increased adaptation index (τ = 0.26; р = 0.004), potassium level (τ = 0.27; р = 0.009), left ventricular posterior wall (LVPW) thickness (τ = 0.30; р = 0.047) and right kidney size (τ = 0.57; р = 0.047), which was not observed for the normothyroid patients. Therefore, in patients with hypothyroidism and hypertension, hyperbetalipoproteinemia, which may play a role in atherosclerotic processes, is associated with the reduced size of the thyroid gland, activation of the lymphocytic component of the inflammatory response, predisposition to hypocoagulation, probable unfavourable acute stress response, which is characterized by an excessive increase in the adaptation index and development of the eccentric hypertrophy of the left ventricle myocardium.
For patients with hypothyroidism and hypertension, triglycerides were associated with the age (τ = 0.16; р = 0.013), BMI and WC (τ = 0.19; р = 0.007 and τ = 0.59; р = 0.003, respectively), which suggests their pathogenic involvement in the abdominal obesity development. There was also revealed a direct correlation of TG with the blood pressure (SBP: τ = 0.14; р = 0.028 and DBP: τ = 0.14; р = 0.038), level of alanine aminotransferase (ALT) (τ = 0.18; р = 0.014), peripheral segmented neutrophil count (τ = 0.23; р = 0.024), erythrocyte sedimentation rate (τ = 0.23; р = 0.003), left ventricle size (τ = 0.39; р = 0.019) and liver dimensions (τ = 0.51; р = 0.041). Therefore, if hypertension is comorbid with hypothyroidism, increased triglyceridemia is associated with progressive arterial hypertension, left ventricular diastolic dysfunction and inflammatory responses activation in the body, in particular in the liver.
Impaired blood pressure control occurs in parallel with further suppression of the thyroid gland function and further weight gain leading to obesity. Other authors also confirm the role of hypothyroidism in the development and progression of hypertension and obesity , , .
If hypertension is comorbid with hypothyroidism, hypercholesterinemia and hyperbetalipoproteinemia are associated with hypocoagulation. According to the literature, hypothyroidism is associated with hypocoagulation and the formation of Acquired Willebrand syndrome , , which coincides with our study. This requires an additional study of the feasibility of antiplatelet therapy in patients with hypothyroidism and hypertension.
The functional state of the thyroid gland affects the emergence of various types of adaptive reactions. In patients with pathology of the thyroid gland, the stress reaction and the acute stress response are accompanied by symptoms of inhibition of functional properties of the gland. The peculiarities of the adaptive reaction of the organism against the background of hypothyroidism are the predominance of reactions of increased activation and acute stress response, indicating the strain of regulatory mechanisms . Our study found that in patients with hypothyroidism and hypertension, hyperbetalipoproteinemia, which may play a role in atherosclerotic processes, is associated with the probable unfavourable acute stress response, which is characterized by an excessive increase in the adaptation index, which coincides with the data of literature.
We investigated that hypercholesterinemia in patients with hypothyroidism and hypertension is also associated with hyperkalaemia, decreased levels of antioxidant bilirubin, impaired renal function and activation of the adrenal cortex. However, no literary sources were found to confirm or rebut this data, which requires additional research.
In patients with hypothyroidism and hypertension, hypercholesterolemia is associated with progressive hypertension (based on SBP and PP), while impaired blood pressure control occurs concurrently with even more pronounced suppression of the thyroid gland function and body weight gain leading to obesity. Hypercholesterolemia and hyperbetalipoproteinemia can be considered risk factors for increased hypocoagulation (based on prothrombin index), hyperkalaemia, impaired renal function (based on the urine protein level) and activation of the adrenal cortex (based on the cortisol level). Hyperbetalipoproteinemia is linked to the activation of the lymphocytic component of the inflammatory response, probable unfavourable acute stress response, whereas an increased triglycerides level influences the progression of arterial hypertension and is associated with left ventricular diastolic dysfunction and development of hepatic dysfunction.
1. Kovalenko V. M., Dorohoy A. P. Sertsevo-sudynni khvoroby: medychno-sotsial’ne znachennya ta stratehiya rozvytku kardiolohiyi v Ukrayini. Ukrayins’kyy kardiolohichnyy zhurnal. 2016; 4(1): 5-14.
2. Taylor P. N., Razvi S., Pearce S. H. et al. Clinical review: A review of the clinical consequences of variation in thyroid function within the reference range. Journal of Clinical Endocrinology and Metabolism. 2013; 98: 3562–3571.
3. Pan’kiv V. I. Sympozium «Syndrom hipotyreozu». Mizhnarodnyy endokrynolohichnyy zhurnal. 2012; 5(45): 136-148.
4. Pearce E. N. Thyroid hormone and obesity. Current Opinion in Endocrinology, Diabetes and Obesity. 2012; 19(5): 408-413.
5. Zakharova S. M. Savel’eva L. V., Fadeeva M. Y. Ozhyrenye y hipotyreoz. Ozhyrenye y metabolyzm. 2013; 2: 54-58.
6. Abramova N. O. Osoblyvosti lipidnoho obminu u osib iz metabolichnym syndromom na tli porushenoho tyreoyidnoho homeostazu. Klinichna ta eksperymental’na patolohiya. 2013; 1(43): 11-14.
7. Chen Y., Wu X., Wu R. et al. Changes in profile of lipids and adipokines in patients with newly diagnosed hypothyroidism and hyperthyroidism. Scientific Reports. 2016; 6: 1-7. doi 10.1038/srep26174.
8. Duntas L.H., Biondi B. The interconnections between obesity, thyroid function, and autoimmunity: the multifold role of leptin. Thyroid. 2013; 23(6): 646-653.
9. Lucas A., Granada М. L., Olaizola I. et al. Leptin and Thyrotropin Relationship Is Modulated by Smoking Status in Euthyroid Subjects. Thyroid. 2013; 23(8): 964-970.
10. Sanyal D., Raychaudhuri M. Hypothyroidism and obesity: An intriguing link. Indian Journal of Endocrinology and Metabolism. 2016; 20: 554-557.
11. Guzel S., Seven A., Guzel Е. С. et al. Visfatin, Leptin, and TNF-a: Interrelated Adipokines in Insulin-Resistant Clinical and Subclinical Hypothyroidism. Endocrine Research. 2013; 28(3): 184-194.
12. Saito І., Ito K., Saruta T. Hypothyroidismas a cause of hypertension. Hypertension. 2014; 5(1): 112-115.
13. Stabouli S., Papakatsika S., Kotsis V. Hypothyroidism and Hypertension. Expert Reviews Cardiovascular Therapy. 2010; 8: 1559-1565.
14. Lison S., Dietrich W., Spannagl M. Review article: unexpected bleeding in the operating room: the role of acquired von Willebrand disease. Anesthesia and Analgesia. 2012; 114(1):73-81.
15. Egoreva E.N. Gemostaticheskaya funktsiya u bolnyih s zabolevaniyami schitovidnoy jelez. Translyatsionnaya meditsina. 2014; 2: 20-22.
16. Olenovych O. A. Nespetsyfichni adaptatsiini reaktsii orhanizmu khvorykh na hipotyreoz za intehralnymy hematolohichnymy pokaznykamy. Klinichna ta eksperymentalna patolohiia. 2014; 13(1): 89-93.
The work is performed within the framework of the research work of the Department of Internal Medicine №2 «Metabolic predictors of the course of diseases of the internal organs against the background of obesity and their predictive value». State registration number: 0107U001050.
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