Subclinical hypothyroidism

sub clinical hypothyroidism is increasing day by day, a brief discussion about pathogenesis incidence and management

1. Subclinical Hypothyroidism

2. Background Hypothalamic Pituitary Thyroid Axis

3. Thyroid Hormone Synthesis and Secretion

4. Background Effects of Thyroid Hormones in Health & Diseases

5. Definitions Subclinical hypothyroidism (SCH) is defined as a serum thyroid-stimulating hormone (TSH) level above the upper limit of normal despite normal levels of serum free thyroxine for a given population reference. Overt hypothyroidism is defined as a serum thyroid-stimulating hormone (TSH) level above the upper limit of normal with decreased levels of serum free thyroxin for a given population reference.

6. Spectrum of Thyroid Diseases Diseases TSH (0.45 – 4.5 mIU/L) Free T4 (9.0 – 25.0 pmol/L)
Free T3 (3.5 – 7.8 pmol/L) Overt Hypothyroid High or Very High Low Subclinical Hypothyroid High Normal Euthyroid Normal Normal Subclinical Hyperthyroid Low Normal Overt Hyperthyroid Low or Very Low High Thyroid Hormone Resistance Normal High or Normal

7. Epidemiology Subclinical hypothyroidism or mild thyroid failure is a common problem, with a prevalence of 3% to 8% in the population without known thyroid disease. The prevalence increases with age and is higher in women. After the sixth decade of life, the prevalence in men approaches that of women, with a combined prevalence of 10%.

8. Risk Factors Family history of thyroid disease Personal history of thyroid disease Presence of antithyroid antibodies Radiation treatment to head, neck or chest Other autoimmune disease Medications: lithium, amiodarone (Cordarone), iodine Old age

9. Causes Chronic autoimmune thyroiditis Treated Graves' disease Radioactive iodine therapy Subtotal thyroidectomy Antithyroid drugs Head and neck surgery Radiation therapy to the head, neck or chest area Iodine deficiency Medications: lithium, iodine, amiodarone (Cordarone) Idiopathic Congenital

10. Course of Disease In some cases, the TSH level will be normal if measured again several months later; we would then attribute the initial elevation to laboratory error or, perhaps, to an episode of silent thyroiditis with a transient hypothyroid phase. In other cases, the subclinical hypothyroidism remains unchanged and doesn’t progress. Patients with SCH have a high rate of progression to clinically overt hypothyroidism, 2.6% each year if thyroperoxidase (TPO) antibodies are absent and 4.3% if they are present. In a study in men and women older than 55 years with a mean follow-up of 32 months, the TSH level normalized in 52% of those with a serum TSH of less than 10 mIU/L. [JCEM 2004]

11. Natural History of disease Progression of euthyroid state to subclinical hypothyroidism and to overt hypothyroidism depending on serum TSH levels and antithyroid antibody status

12. Clinical Diagnosis The clinical signs and symptoms of hypothyroidism manifest when the disease is fully developed. But even in the earliest (subclinical stage), one or more of these findings may occur.  Dry skin, cold intolerance and easy fatigability are significantly more common in the patients with raised TSH levels, and these symptoms improve after treatment with thyroid hormone. [ Annals of Internal Medicine 2004] Some patients with subclinical hypothyroidism do indeed have clinical manifestations of mild thyroid failure in relation to their serum TSH levels. Progression to overt disease can manifest with menorrhagia, neck swelling, delayed relaxation of deep tendon reflexes and bradycardia.

13. Symptoms & Signs A study conducted in Mumbai compares symptoms and signs of thyroid disease among two groups; euthyroid status (blue) and subclinical hypothyroidism (red). [IJEM 2013]

14. Complications Progression to overt hypothyroidism with systemic manifestations of the disease leading to thyroid failure . Increase risk of metabolic syndrome.[ IJEM 2010, CSHR 2017] Cardiac dysfunction in form of slow LV relaxation time, LV systolic dysfunction and impaired endothelial function eventually leading to IHD and Cardiomyopathies [Thyroid 2007] Neuromuscular dysfunction [Endocrinologist 2004] Psychiatric and Cognitive dysfunction in form of depression, bipolar disorder [IJPM2000]

15. Question A 64 year old women is referred for possible hypothyroidism, after her primary care provider ordered a serum TSH for screening. She feels well and has no major medical problems. She is taking no medications. PE: P 80 BP 140/70 Wt 65 kg. The thyroid is normal to palpation. Skin cool, dry. Reflexes normal. Serum TSH 5.5, repeat 6.1 mU/l, FT4 12.87 pmol/L; antiTPO antibodies are negative Should she be treated with L-thyroxine?

16. Laboratory Diagnosis Patients with subclinical hypothyroidism can be categorized into those with mildly elevated TSH (4.5–10 mIU/L), and those with markedly increased serum TSH levels (>10 mIU/L), along with free T4/T3 levels within the reference range for the population. Elevated serum TSH on two separate occasions 6 weeks apart is required for diagnosis of SCH. Antithyroperoxidase antibodies USG neck for thyroid swelling Thyroid scan with radioactive iodine

17. Management Management of SCH differs depending on whether the serum TSH concentration is 5.0 to 10 mIU/L, or higher than 10 mIU/L. Most thyroidologists agree that all patients with SCH and a serum TSH level above 10 mIU/L should be treated with levothyroxine. [JCEM 2001] Studies have shown that levothyroxine therapy results in an 8-mg reduction in low-density lipoprotein levels. [JCEM 2000] Levothyroxine therapy has been also shown to reduce neuromuscular dysfunction, psychiatric and cognitive dysfunction.

18. Management  Clinical Condition Strength of association Benefits of treatment Progression to overt hypothyroidism Good Variable Adverse cardiac end points Insufficient No evidence Elevation in serum total cholesterol and LDL-C levels Insufficient Insufficient Cardiac dysfunction Insufficient Insufficient Systemic hypothyroid symptoms No clear evidence Insufficient Psychiatric symptoms No clear evidence Insufficient Large-scale randomized studies to conclusively show reduction of cholesterol with levothyroxine therapy in this subgroup are lacking. Quality of Evidence on the Strength of Association and Risks/Benefits of Levothyroxine Treatment of Subclinical Hypothyroidism for Patients With a Serum TSH Level of 5.0 to 10.0 mIU/L [JCEM 2001]

19. Management Pregnancy or intention of pregnancy Goiter Therapeutic trial for possible hypothyroid symptoms Childhood and adolescence TSH levels >4.5 mIU/L on 2 occasions Bipolar disorder, depression Infertility Presence of antithyroid antibodies Progressive TSH increase Ovulatory dysfunction Young age of the patient Hyperlipidemia? Factors Favoring Levothyroxine Therapy in Patients With a Thyroid-Stimulating Hormone (TSH) Level of 4.5 to 10 mIU/L [JCEM 2001]

20. Management For all patients with SCH and a serum TSH concentration above 10 mIU/L and for patients with serum TSH concentrations of 4.5 to 10.0 mIU/L in whom individualized decision for therapy is made, therapy should be started with levothyroxine. Daily dose of levothyroxine is 1.5mcg/kg Dose should be titrated according to patients age, serum TSH levels and serum free T4 levels. In old patients with cardiac comorbidities levothyroxine should be started in minimal dose; 25 – 50 mcg/day and gradually escalated to achieve the target response. Thyroid profile should be checked every 8 weeks. Once a normal TSH level is achieved it should be checked every 6 months thereafter..

21. Management European Thyroid Association Guidelines 2013

22. Subclinical Hypothyroidism in Pregnancy Prevalence of thyroid dysfunction in pregnancy [JCEM 2012, IJEM 2013]

23. Subclinical Hypothyroidism in Pregnancy A seminal study by Haddow et al showed a 7-point reduction in intelligence quotient in children aged 7 to 9 years whose mothers had SCH at pregnancy compared with the children of euthyroid mothers. [NEJM 1999] Although this was a single study, it nevertheless points to the need for screening of pregnant women and therapy for mild thyroid failure in women who are pregnant or planning on becoming pregnant. SCH is associated with multiple adverse outcomes in the mother and fetus including spontaneous abortion, preeclampsia, gestational hypertension, gestational diabetes, preterm delivery, and decreased intelligence quotient (IQ) in the offspring. [Oxf Clin Endocr 2003]

24. Subclinical Hypothyroidism in Pregnancy Recent Endocrine Society guidelines also suggested 0.1-2.5 mIU/L as the “normal” range for TSH values in the first trimester and <3 mIU/L in the second and third trimester. [BMJ 2015] Adequate levothyroxine replacement in early pregnancy with SCH can reduce chances of preterm delivery. But there is no conclusive evidence of reduced chances of other fetal & maternal complications with the therapy. [Thyroid 2002] The Indian guideline is still not clear about treating women with TSH between 2.5 and 4.5 μIU/ml, but Indian Thyroid Society guidelines have suggested that universal screening for thyroid profile during pregnancy at the first antenatal visit should be the norm. [Ind J Endocr Metab 2013]

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