1. Mariana Purice, I.H. Ursu, A. Goldstein
National Institute of Endocrinology “C.I. Parhon”, Bucharest, Romania
HYPERHOMOCYSTEINEMIA, A RISK FACTOR INTERACTING IN MODERATE AND SEVER HYPOTHYROIDISM
1. Thyroid status is an important determinant of plasma tHcy and affects serum folate levels .
2. Significantly lower serum folate in the study group is pleading for the role of folate deficiency in hyperhomocysteinemia induced by hypothyroidism.
3. High prevalence of hyperhomocysteinemia in hypothyroid patients represent an argument to associate folate supplementation to levothyroxine therapy, especially in patients with other risk factors for cardiovascular disease.
4. Dynamic evaluation of plasmatic homocysteine levels in correlation with Folic Acid and standard laboratory parameters is important for the estimation of supplementary risk factor and follow up of the specific therapy in hypothyroid patients.
CONCLUSIONS
DISCUSSION
Moderate hyperhomocysteinemia was frequent in our study groups: 68% in group 1 and 76% in group 2. Borderline (10-12 µmol/L) values were found in 24 % in group 1 and 28 % in group 2.
Mean serum folate was significantly lower in group 1 versus control (5.9 ng/ml versus 9.1ng/ml) and NS lower in group 2
Both serum cholesterol and LDL cholesterol were significant higher in the study groups before treatment. Serum creatinine was in the normal range in both groups.
After six months of folate therapy associated with levothyroxine therapy, plasma homocysteine decreased significantly in the moderate hypothyroid patients from µmol/L to 8.17 and
from 16.9 to 7.9 in the sever iatrogenic hypothyroidism.
Epidemiologic evidences show that mild hyperhomocysteinemia (>12 μmol/L) is an independent risk factor for atherosclerotic and
atherothrombotic vascular disease. Between 5-10 % of normal population and more then 40% of patients with cardiovascular
diseases have hyperhomocysteinemia (HHcy).
Additional risk factors and endocrine disorders (diabetes, hypothyroidism) may additively or by interacting with
hyperhomocysteinemia, increase overall risk.
Hypothyroidism is associated with increased cardiovascular morbidity which might be explained by the atherogenic lipid profile
and/or hyperhomocysteinemia. This may exacerbate the risk of cardiovascular disease in hypothyroidism that is traditionally
attributed to lipid changes.
Study groups:
25 patients with primary hypothyroidism before and during levotyroxine treatment. We measured plasma tHcy , serum folate, TSH, T3, T4 and cholesterol, LDL, HDL, , creatinine. We found moderate low level of serum folate (5.84 ng/ml) .Only 20% of subjects had basal tHcy < 10 μmol/L while 44% had plasma tHcy between μmol/L and 36 % had tHcy >17 μmol /L, significant elevated cholesterol, HDL cholesterol at medium risk level . Mean TSH concentration was μUI/ml. After achieving an euthyroid status, tHcy, folate and hormons leveles were evaluated before and after three and six month of daily folate supplementation therapy (5 mg/day). In 76% of the subjects with basal level t Hcy> 10 μmol/lL, a significant decrease (p<0.001) was achieved in correlation with normalization of TSH and cholesterol levels.
25 patients with postoperative hypothyroidism after thyroidectomy for thyroid cancer. Before radioiodine therapy, they discontinued levotyroxine substitution during 6 weeks. With mean TSH concentration of 29.9 μU/ml and mean cholesterol of mg/ml , we considered them in a sever hypothyroidism state. The tHct was ± 3.93 μmol/L significantly higher then for control group (p< 0.001). Only 24% had tHcy < 10 μmol/L, while 28% had tHcy: μmol/L and 48% had tHcy > 20μmol/L. High values of tHcy was correlated with high levels of thyroglobuline (> 2 ng/ml) for 10 patients with thyroid cancer metastasis. Normal folate serum mean level was found (7.89 ng/ml). Carotidian ultrasound for measuring the intima - media thickness (IMT) was done. We evaluated the patients after 3 month and 6 month of folic acid administration (5 mg/day) together with levotyroxine substitution, observing significant decrease of tHcy (p<0.002) while IMT remained almost unchanged.
ABSTRACT
INTRODUCTION
Moderately elevated plasma homocysteine is highly prevalent in the general population, being a risk factor for cardiovascular disease and is caused by hormonal, nutritional and genetic factors.
The elevated plasma homocysteine may exacerbate the risk of cardiovascular disease in hypothyroidism that is traditionally attributed to lipid changes.
Aims of Study
1. Evaluate the prevalence of moderate hyerhomocysteinemia and of borderline values (10-12 µmol/L ) in hypothyroid patients and in thyroidectomized patients for thyroid cancer before L-Thyroxine treatment
2. Evaluate the effect of Folic Acid supplementation in patients with plasma homocysteine over 10 µmol/L.
3. Evaluate the prevalence of concomitant increase plasma homocysteine and serum lipids as vascular risk factors in hypothyroid patients before levothyroxine treatment.
METHODS
STUDY GROUPS
Group
Thyroid Status n
Gender
Age
Basal TSH
Therapy
Group1:
Moderate Hypothyroidism 25
F=23
M=2
52-80
>10 µIU/ml
Levo thyroxine: µg/day
Folic acid : 5 mg/day
Group 2:
Sever Hypothyroidism
postoperative hypothyroidism after thyroidectomy for thyroid cancer before radiotherapy.
F=20
M=5
52-73
>50 µIU/ml
Levo thyroxine: µg/day
Folic acid: 5 mg/day
Control
euthyroid status 32
M=12
35-50
2.2 µIU/ml
Total homocysteine ( tHcy) was assayed with ELISA method(DRG) after a reduction and enzymatic conversion steps .
Reference values
tHcy < 10 µmol/L SAFE
tHcy : µmol/L Tolerated: normal subjects
Therapy recommended (ac folic +/- Vit B) for subjects with high risk factors
tHcy : > µmol/L moderate Hyperhomocysteinemy
tHcy : > µmol/L intermediate Hyperhomocysteinemy
tHcy : > 100 µmol/L sever Hyperhomocysteinemia
Folic acid: chemiluminiscence, ACS -180 Bayer
Serum cholesterol, HDL, LDL, creatinine: colorimetric (Roche, HITACHI 912)
Serum hormones : TSH, T3, T4, FT4 ( RIA/ IRMA, ADALTIS)
Results were subjected to non parametric tests (Mann-Whitney U test) and data are expressed as media+/- SD.
Correlations were tested by Spearman correlation test
All statistical procedure were performed using the SPSS ( for Social Sciences Statistical Package).
Statistical analysis
After therapy
RESULTS
GROUP 2
Fig. 4. Homocystein concentration distribution
24%
28%
48%
tHcy<10 mol/l
tHcy: mol/l
tHcy > 20 mol/l
Fg. 6. Serum colesterol, HDL and LDL before treatment
Fg. 5. Homocystein and Folic acid before treatment
GROUP 1
Fig.3.
Homocystein
and Folic acid levels in group 1 and
control 2 4 6 8 10 12 14 16
Hcy
FolicAcid
9.32
11.9
14.27
5.81
Hypothyr
Before therapy
GROUP 1
GROUP 2