Santral Tiroid Hormon Direnci Saptanan Olgularda Tiroid Hormon Reseptör Gen Analizi ve Periferik Direnç Eşliğinin Araştırılması.

Yıl 2020, Cilt: 14 Sayı: 1, 72 - 79, 27.01.2020

Rıza Taner Baran , Sema Akçurin Gayaz Akçurin , Esra Manguoğlu Sebahat Özdem

https://doi.org/10.12956/tchd.638141

Öz

Amaç: Hipofizer tiroid hormon (TH)
direnci düşünülen ve klinik bulguların ayırdettirici olmadığı çocuk olgularda
periferik direnç eşliğinin değerlendirilmesi ve TH β reseptörü (TRβ) mutasyon
sıklığının belirlenmesi amaçlanmıştır.

 Gereç
ve Yöntem: Hipofizer TH direnci tanısı ile izlenen ve yeterli dozda
levotiroksin (L-T4) tedavisi almalarına rağmen izlem süreçlerinde tiroid
stimülan hormon (TSH) düzeyleri baskılanamayan, 20 olgu (13 kız, ort yaş
7.03±2.72 yıl,) çalışmaya alınmıştır. TH periferik etkileri, suprafizyolojik
doz levotriiodotironin (L-T3) uygulaması öncesi ve sonrası serbest T3 (sT3),
serbest T4 (sT4), TSH, seks hormon bağlayıcı globulin (SHBG), total kolesterol,
alkalen fosfataz (ALP), osteokalsin, anjiotensin konverting enzim (ACE)
düzeyleri ve kreatin fosfokinaz (CPK), M-mod ve Doppler ekokardiyografi (EKO)
tetkikleri ile değerlendirilmiş ve TRβ gen analizleri yapılmıştır.

Bulgular: Olguların L-T3 öncesi ve
sonrası biyokimyasal ölçütleri karşılaştırıldığında SHBG, osteokalsin, ACE
düzeylerinde anlamlı artış, total kolesterol ve CPK düzeylerinde ise anlamlı
ölçüde azalma olduğu gözlenmiştir (p<0.001). ALP ve kardiyak parametrelerde
farklılık görülmemiştir.

TRβ gen analizinde, olguların
ikisinde homozigot, dördünde heterozigot rs3752874 ve iki hastada homozigot, 7
hastada heterozigot IVS8 -110 G>A değişimi saptanmıştır.

 Sonuç:
Olgularımızda suprafizyolojik L-T3 konsantrasyonlarına değişik derecelerde
periferik doku yanıtının gözlenmesi, yüksek T3 düzeylerine yanıtın korunduğunun
göstergesidir ve en yüksek yanıtın oluştuğu SHBG ve CPK değişimleri yol
gösterici olabilir. TRβ gen analizinde saptanan iki değişimin direnç
patogenezinde rolü olmadığı düşünülmüştür. Yeterli tedavi kriterleri
taşımalarına rağmen TSH düzeyleri ısrarlı yüksek seyreden doğumsal hipotiroid
olgularda genetik bir anomali eşliğinden çok, hipotalamus-hipofiz-tiroid
ekseninin intrauterin dönem olgunlaşma sürecindeki fonksiyonel bir hatanın
sorumlu olduğu düşünülebilir.

Aim:
This trial was designed to assess the concomitant peripheral resistance in
pediatric cases, who were considered to have pituitary thyroid hormone (TH)
resistance and exhibited indistinguishable clinical results and determine the
incidence of TH β receptor (TRβ) mutation in the “investigational group”.

 Matherials and Methods: 20 patients, monitored
with the diagnosis of pituitary TH resistance, in whom thyroid stimulating
hormone (TSH) level could not be suppressed during monitoring despite an
adequate dose of levothyroxine (L-T4) administered, were included in the trial
(13 girls, mean age: 7.03±2.72 years). TH peripheral effects were assessed
before and after liothyronine (L-T3) administration using free T4 (fT4), TSH,
sex hormone-binding globulin (SHBG), total cholesterol, alkalen fosfatase
(ALP), osteocalcin, anjiotensin coverting enzyme (ACE) levels and creatine
phosphokinase (CPK), M-mod and Doppler ECHO investigations and TRβ gene
analyses were performed.

Results:
The comparison of the pre-L-T3 and post-L-T3 biochemical measurements revealed
a significant increase in SHBG, osteocalcin and ACE levels and a significant
reduction in total cholesterol and CPK levels (p<0.001). No difference was
detected in ALP and cardiac parameters.

TRβ
gene analysis revealed homozygote and heterozygote rs3752874 changes in 2 and 4
patients respectively, and homozygote and heterozygote IVS8 -110 G>A changes
in 2 and 7 patients, respectively.

Conclusion:
Achievement of various degrees of peripheral tissue response to supraphysiological
L-T3 concentrations indicates that the response to high T3 levels is maintained
and the SHBG and CPK changes exhibiting the highest responses may be guiding.
The two changes detected in the TRβ gene analysis were considered not to be involved
in the pathogenesis of resistance. In patients with congenital hypothyroidism,
who sustain high levels of TSH despite meeting adequate therapeutic criteria,
the condition may be attributed to a functional defect in the intrauterine
growth process of the hypothalamic- pituitary-thyroid axis rather than a
concomitant genetic abnormality.

Anahtar Kelimeler

Hipotiroidi, tiroid hormon direnci, Hypothyroidism, Thyroid hormone resistance

Kaynakça

• 1. DiLaura R, De Felice M. Resistance to Thyroid Hormone. In: Degroot LJ, Jameson JL, editors. Endocrinology. 5th ed. Philadelphia: Saunders 2006; 2227- 37.
• 2. Akcurin S. Tiroid fonksiyonları bozuk olan çocuk. 14. Ulusal Pediatrik Endokrin ve Diabet Kongresi 4-10 Ekim 2010 Muğla; 81.
• 3. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metabol 2007; 21: 277-305.
• 4. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Five new families with resistance to thyroid hormone not caused by complete deletion of the protein coding region of the thyroid hormone receptor beta gene. J Clin Endocrinol Metab 1992; 74: 49- 55.
• 5. Ono S, Swartz ID, Mueller OT, Root AW, Usala SJ, Bercu BB. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. J Clin Endocrinol Metab 1991; 73: 990-4.
• 6. Weiss RE, Hayashi Y, Nagaya T, Petty KJ, Murata Y, Tunca H, Seo H, Refetoff S. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor. J Clin Endocrinol Metab 1996; 81: 4196-203.
• 7. Weiss RE, Refetoff S. Resistance to thyroid hormone. Rev Endocr Metab Disord 2000; 1: 97-108.
• 8. Kaplan MM, Swartz SL, Larsen PR. Partial peripheral resistance to thyroid hormone. Am J Med 1981; 70: 1115-21.
• 9. Fisher DA. Disorders of the thyroid in the newborn and infant. In: Sperling MA, editor. Pediatric Endocrinology. 2nd ed. Philadelphia: WB Saunders 2002; 161- 85.
• 10. Refetoff S,Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14: 348-99.
• 11. Ercan O. Thyroid hormone resistance. Pediatric Endocrine Reviews 2003;1(suppl 2): 191-8.
• 12. Chatterjee VK. Resistance to thyroid hormone. Horm Res 1997; 48 (suppl 4): 43- 6.
• 13. Kurtoglu S, Covut İE, Kendirci M, Uzum K, Durak AC, Kiris A. Normal thyroid volume of children in Turkey: Pilot study in Kayseri province. IDD Newsletter 1995; 11: 41-2.
• 14. Beck-Peccoz P, Roncoroni R, Mariotti S, Medri G, Marcocci C, Brabant G, Forloni F, Pinchera A, Faglia G. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol Metab 1990; 71: 19-25.
• 15. Beck-Peccoz P, Chatterjee VK. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994; 4: 225-32.
• 16. Weiss RE, Refetoff S. Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin North Am 1996; 25: 719-30.
• 17. Danzi S, Klein I. Thyroid hormone regulatde cardiac gene expression and cardiovascular disease. Tyhroid 2002; 12: 467-72.
• 18. Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, Hauser P, Wiggs E, Weintraub BD. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann Intern Med 1995; 123: 572-83.
• 19. Kahaly GJ, Matthews CH,Matthews CH,Mohr-Kahaly S, Richards CA,Chatterjee VKK. Cardiac involvement in thyroid hormone resistance. J Clin Endocrinol Metab 2002; 87: 204-12.
• 20. Sarne DH, Refetoff S, Rosenfield RL, Farriaux JP. Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration. J Clin Endocrinol Metab 1988; 66: 740-6.
• 21. Sorensen HG, Van der Deure WM, Hansen PS, Peeters RP, Breteler MM, Kyvik KO, Sorensen TI, Hegedüs L, Visser TJ. Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes. Thyroid 2008; 18: 1087-94.