Thyroid disorders , recent advances for better management are discussed.

1. DR.S.Sethupathy M.D.,Ph.D.,
Professor and Head,
Dept. of Biochemistry,
Rajah Muthiah Medical Colllege, AU

2.  Thyroid hormones and their functions
 Synthesis and storage of thyroid hormones
 Regulation of thyroid hormone synthesis
 Mechanism of thyroid hormone action
 Hypothyroidism, clinical features and
complications
 Hyperthyroidism, clinical features and
complications
 Lab investigations
 Management

7.  Receptors for thyroid hormones are intracellular
DNA-binding proteins
 Thyroid hormones enter cells through
membrane transporter proteins.
 Inside the nucleus, the hormone binds its
receptor, and the hormone-receptor complex
interacts with specific sequences of DNA.
 The effect of the hormone-receptor complex
binding to DNA is to modulate gene
expression , either by stimulating or inhibiting
transcription of specific genes.

8.  The iodothyronine deiodinases include two
activating enzymes, D1 and D2
 D1 functions predominantly as a scavenger
enzyme that deiodinates sulfatedTH
 D3 is expressed in the placenta, where it can
protect foetus from excessTH
 D1 is expressed at high levels in the liver, kidney,
and thyroid; D2 in brain, pituitary, thyroid, and
BAT;
 D3 in the skin, vascular tissue, and placenta.

9.  D1 and D3 – cell membrane
 D2 in the endoplasmic reticulum
 Selenium deficiency is also associated with
reduced deiodinase activity expression in
hypoxia - mediated by hypoxia-inducible
factor (HIF-1)
 Polymorphisms in the D2 gene have been
associated with type 2 diabetes, insulin
resistance, and obesity in some studies.

10.  EachTR isoform has several splice products
 TR α1 and α2 andTR β1 and β2 .
 TRα2 does not bindT3, and acts to reduce
T3 action.
 TR β2 is predominantly expressed in the brain
and pituitary

11.  Multiple transporters with the ability to
transport thyroid hormone, including the
monocarboxylate and organic ion transporter
families;
 Genetic disorder Allan-Herndon-Dudley
Syndrome, with serum thyroid hormone
abnormalities, low serumT4, and elevated
serumT3, and severe neurologic deficits, was
shown to be due to a mutation in the
monocarboxylate transporter 8 (MCT8) gene.

12.  Lipid metabolism:
 Thyroid hormone levels promote lipolysis and
increase free fatty acids in plasma.
 They enhance oxidation of fatty acids in many
tissues.
 Thyroxine increase LDL receptor expression.
 In hypothyroidism blood cholesterol increases.
 Carbohydrate metabolism:
 Enhance insulin-dependent entry of glucose
into cells
 Increase gluconeogenesis and glycogenolysis to
generate free glucose.

13.  After entering thyroid follicular cell) via a
Na+/I− symporter (NIS) on the basolateral side,
iodide is shuttled across the apical membrane into
the colloid via pendrin.
 Thyroid peroxidase oxidizes iodide to atomic
iodine (I) or iodinium (I+).
 The "organification of iodine," the incorporation of
iodine into thyroglobulin for the production of
thyroid hormone, is nonspecific.

17.  L-Tyrosine+ I− + H+ + H2O2 ⇒ 3-Iodo-L-Tyrosine+ 2
H2O
 Iodide is oxidized to iodine radical which immediately
reacts with tyrosine.
 3-Iodo-L-Tyrosine + I− + H+ + H2O2 ⇒ 3,5-Diiodo-L-
Tyrosine + 2 H2O
 The second iodine atom is added in similar manner to
the reaction intermediate 3-iodotyrosine.

19.  There is noTPO-bound intermediate,
but iodination occurs via reactive iodine
species released fromTPO.
 The chemical reactions catalyzed by
thyroid peroxidase occur on the outer
apical membrane surface
 Mediated by hydrogen peroxide.

20.  TPO is stimulated byTSH which up-
regulates gene expression.
 TPO is inhibited by the thioamide drugs,
such as propylthiouracil and methimazole
 In laboratory rats with insufficient iodine
intake, genistein has demonstrated
inhibition ofTPO.

21.  Thyroid peroxidase is a frequent epitope of
autoantibodies in autoimmune thyroid disease
 Called anti-thyroid peroxidase antibodies (anti-
TPO antibodies).
 Most commonly associated with Hashimoto's
thyroiditis.
 Antibody titer used to assess disease activity in
patients
 Expression of thyroid peroxidase (TPO) is lost in
papillary thyroid carcinoma.

22.  The determination ofTPO antibody levels is the
most sensitive test for detecting autoimmune
thyroid disease
 eg, Hashimoto thyroiditis, idiopathic
myxedema, and Graves disease
 The highestTPO antibody levels are observed in
Hashimoto thyroiditis. - 90% of cases
 It occur (60%–80%) in the course of Graves
disease.
 In subclinical hypothyroidism, the presence of
TPO antibodies is associated with an increased
risk of developing overt hypothyroidism.

23.  Detectable anti-TPO observed in 10%
to 12% in a healthy population with
normal thyroid.
 Moderately increasedTPO antibodies
may be found in non-thyroid
autoimmune disease such as pernicious
anemia, type I diabetes, or other
disorders that activate immune system

28.  Perchlorate and thiocyanate- inhibitors
of anion transport
 TPO inhibitor- Propyl thiouracil,
methimazole
 Colloid resorption- colchine. Li, iodide
 Deiodination of MIT,DIT –
Dinitrotyrosine
 Deiodination ofT4 –propylthiouracil

29.  They are autoantibodies targeted
against one or more components of
thyroid gland.
 Antithyroperoxidase (AntiTPO)
antibodies
 Thyroglobulin antibodies
 Thyrotropin receptor antibodies
(TRABs)

30.  10-20% of healthy individuals have
detectable antithyroglobulin levels.
 FollicularThyroid carcinoma,
 PapillaryThyroid Carcinoma
 Hashimoto thyroiditis
 Chronic urticaria

34.  Thyrotropin releasing hormone
(TRH) – a tripeptide –stimulates
anterior thyroid to releaseTSH
 TSH – a glycoprotein – feedback
inhibited by thyroid hormones

35.  Cells of the thyroid gland containTSH
receptors.
 Binding ofTSH to its receptors activates the
enzyme adenylate cyclase which increase
intracellular cAMP.
 Most ofTSH actions are mediated through
cAMP
 But some depend on stimulation of cell
membrane phospholipids.

36.  The major secreted product -T4 but T3 only in
small amounts .
 One third of circulatingT4 is converted toT3 in
peripheral tissues.
 T3 is less tightly bound to plasma proteins than T4
 T3 more readily available for cellular uptake.
 The free hormone is biologically active
 It interacts with specific receptors localized in the
membrane, mitochondria, cytoplasm and nucleus
of responsive cells.

37.  T3 binds to nuclear receptors to a much
greater extent thanT4, henceT3 is more
rapidly and biologically active thanT4.
 T3 andT4 are deiodinated and deaminated in
the tissues.
 In the liver, they are conjugated, pass into the
bile and are excreted into the intestine.
 Conjugated and free hormones are also
excreted by the kidney.

38.  Autoimmune thyrotoxicosis (Graves disease,
Hashitoxicosis, neonatal thyrotoxicosis) are
caused by the production ofTSHR-
stimulating autoantibodies.
 Long-acting-thyroid-stimulator (LATS) or
thyroid-stimulating immunoglobulins (TSI),
bind to the receptor and transactivate it
 Independent of the normal feedback-
regulated thyrotropin (TSH) stimulation

39.  It is a seven transmembrane G protein coupled
receptor
 Activating antibodies (associated with
hyperthyroidism)
 Blocking antibodies (associated with thyroiditis)
 Neutral antibodies (no effect on receptor).
 TRAbs are present in 70-100% of Graves' disease
 85-100% for activating antibodies
 1-2% of normal individuals.

40.  It accelerates clearance of cholesterol by
the liver by increasing the high-density
lipoprotein (HDL) receptor called
scavenger receptor B1(SR-B1)
 Increase the activity of cholesterol 7α-
hydroxylase and increase fecal excretion
of cholesterol and bile acids.

41.  TR β selective thyromimetics- KB-141.
 KB-141 increased metabolic rate with a 10-fold
selectivity
 Lowered cholesterol with a 27-fold selectivity as
compared with tachycardia.
 Cholesterol, Lp(a) , body weight reduced much
after 1 week of treatment, without tachycardia
or cardiac hypertrophy
 SelectiveTR β agonists - novel class of drugs for
the treatment of obesity, hypercholesterolemia
and elevated Lp(a) and for patients with
metabolic syndrome

42.  Another thyroid analogue -TR β1 selective in
the range of seven to 18–times
 More than 10-fold preference forTR β1 in
transactivation.
 Its selective tissue uptake may also play a role
in itsTR β1selectivity.
 GC-1 treatment reduced serum cholesterol
levels by 25% and serum triglycerides by 75%
in diet-induced hypercholesterolemic mice

43.  Affinity for the triiodothyronine receptorTR β
isoform.
 In a 2-week clinical trial, eprotirome was reported to
reduce the levels of serum total and LDL cholesterol
and apolipoprotein B without evident side-effects.
 Further reductions in serum LDL cholesterol levels in
patients who are already receiving statins.
 Lower apolipoprotein B, triglycerides and Lp(a)
lipoprotein
 No adverse effects on the heart or bone.
 Impact cardiovascular disease incidence – to be
studied.

44.  Uncoupling of oxidative phosporylation in
brown adipose tissue for whichTR β is
predominantly responsible
 BothTR α andTR β are essential for
synergism betweenTH and adrenergic signals
for lipolysis

45.  SuppressTSH
 Used in thyroid hormone resistance
syndrome along with levothyroxine in
patients with thyroid cancer.
 It has been widely marketed for weight loss
drug
 FDA warning for adverse effects including
heart attacks and strokes

46.  Maternal administration of DIMIT in
significant enhancement of fetal
lung phospholipid synthesis and
accelerated lung maturity.
 It also ameliorates maternal
hyperglycemia.

47.  Selectively enter hypatocytes
and cleaved intoTRβ agonist
 Has lipid lowering properties.
 Has antisteatotic activity and
reduce hepatic triglyceride levels

48.  For treatment of CHF - use of
selectiveTR modulator - 3,5-
diiodothyropropionic acid
(DITPA).
 DITPA works as a thyromimetic
agent.

49.  Potential antiarrhythmic agents, particularly
TR α1-selective antagonists.
 Tetrac- Deaminated derivative ofT4,
tetraiodothyroacetic acid
 Blocks binding and actions ofT4 andT3 at the
receptor

52.  Hypothyroidism is the result from any condition that
results inTH deficiency.
 Iodine deficiency
 Primary thyroid disease: Inflammatory diseases of the
thyroid that destroy parts of the gland are clearly an
important cause of hypothyroidism.
 Symptoms of hypothyroidism
 Lethargy, fatigue, cold-intolerance, weakness, hair
loss and reproductive failure.
 If these signs are severe, the clinical condition is
called myxedema.
 congenital thyroid deficiency- cretinism, a form of
irreversible growth and mental retardation.

53.  Thyroid hormone can be started at anticipated full
replacement doses in individuals who are young and
otherwise healthy.
 In elderly patients and those with known ischemic heart
disease, treatment should begin with one fourth to one
half the expected dosage, and the dosage should be
adjusted in small increments after no less than 4-6 weeks.
 For most cases of mild to moderate hypothyroidism, a
starting levothyroxine dosage of 50-75 µg/day will suffice.
 Clinical benefits begin in 3-5 days and level off after 4-6
weeks.
 Treatment with LT4, dosing changes should be made
every 6-8 weeks tillTSH is in target range.

54.  In patients with central (ie, pituitary or
hypothalamic) hypothyroidism,T4 levels guide
treatment
 Monitored with annual or semiannual clinical
evaluations andTSH monitoring.
 Patients should be monitored for symptoms and
signs of overtreatment, which include the
following:
 Tachycardia , Palpitations, Atrial fibrillation ,
Nervousness ,Tiredness , Headache
 Increased excitability , Sleeplessness ,Tremors
 Possible angina

55.  Helicobacter pylori –related gastritis, atrophic
gastritis, or celiac disease - such disorders -
levothyroxine dosage.
 Initiation or discontinuation of estrogen and
androgens -Reassessment of serumTSH
 SerumTSH monitoring is advisable when
medications such as phenobarbital,
phenytoin, carbamazepine, rifampin, and
sertraline started.

56.  Pregnant women with overt hypothyroidism should
receive levothyroxine replacement therapy with the
dose titrated to achieve aTSH concentration within
the trimester-specific range
 SerumTSH levels should be assessed every 4 weeks
during the first half of pregnancy
 SerumTSH should be reassessed during the second
half of pregnancy.
 In women already taking levothyroxine, 2 additional
doses per week of the current levothyroxine dose,
given as one extra dose twice weekly with several
days’ separation as soon as pregnancy is confirmed.

57.  Adverse effects of hypothyroidism in
pregnancy
 Preeclampsia
 Anemia
 Postpartum hemorrhage
 Cardiac ventricular dysfunction
 Increased risk of spontaneous abortion
 Low birth weight
 Impaired cognitive development in the fetus
 Fetal mortality

58.  TSH levels of 5.5-10 mIU/L.
 T4 replacement in pregnant women with
subclinical hypothyroidism.
 Ultrasonographic thyroid scan showed diffuse
hypoechogenicity (an indication of chronic
thyroiditis).
 Treatment of subclinical hypothyroidism -to
reduce total cholesterol, non-HDL cholesterol,
and apolipoprotein B levels and to decrease
arterial stiffness and systolic blood pressure.

59.  Patients with concomitant subclinical
hypothyroidism and iron deficiency anemia,
iron supplementation may be ineffective if
LT4 is not given.
 With goiter or positive anti-TPO antibodies-
mostly progress to overt hypothyroidism.
 An initial LT4 dosage of 50-75 µg/day can be
used, which can be titrated every 6-8 weeks
to achieve a targetTSH of between 0.3 and 3
mIU/L.

60.  Hyperthyroidism results from excess
secretion of thyroid hormones.
 Less common than hypothyroidism.
 Graves disease, an immune disease in which
autoantibodies bind to and activate the
thyroid-stimulating hormone receptor
 Hamburger thyrotoxicosis.
 Symptoms include nervousness, insomnia,
high heart rate, eye disease and anxiety.

61.  Hyperthyroidism results from excess
secretion of thyroid hormones.
 Less common than hypothyroidism.
 Graves disease, an immune disease in which
autoantibodies bind to and activate the
thyroid-stimulating hormone receptor
 Hamburger thyrotoxicosis.
 Symptoms include nervousness, insomnia,
high heart rate, eye disease and anxiety.

62.  Common signs of thyrotoxicosis :
 Tachycardia or atrial arrhythmia
 Systolic hypertension with wide pulse pressure
 Warm, moist, smooth skin
 Lid lag
 Stare
 Hand tremor
 Muscle weakness
 Weight loss despite increased appetite
 Reduction in menstrual flow or oligomenorrhea

64.  Graves disease is an autoimmune disease, and
patients often have a family history or past medical
history of autoimmune disease (eg, rheumatoid
arthritis, vitiligo, pernicious anemia).
 Graves disease often have more marked symptoms
 Evidence of thyroid eye disease exists, including
periorbital edema, diplopia, or proptosis.
 Toxic multinodular goiters -Patients have emigrated
from regions of the world with borderline- low iodine
intake or have a strong family history of nontoxic
goiter.

66.  FreeT4 (FT4) and totalT3 increased
 TSH is low
 Anti –TPO antibody elevated in the most common
type of hyperthyroidism, Graves thyrotoxicosis
 Usually are low or absent in toxic multinodular goiter
and toxic adenoma.
 Healthy people without active thyroid disease have
mildly positive anti-TPO antibody titers; So not for
screening .
 The thyroid-stimulating immunoglobulin (TSI) level, if
elevated, helps to establish the diagnosis of Graves
disease.
 Anti-TG antibodies may be present in normal persons

67.  Subclinical hyperthyroidism, defined as a low
thyroid-stimulating hormone (TSH) level with
normal free thyroxine (FT4) and free
triiodothyronine (FT3) levels
 Atrial fibrillation, osteoporosis, or
hypercalcemia may suggest the possibility of
thyrotoxicosis.
 Risk of atrial fibrillation.
 Incidence of subclinical HyperT- 2% in the
general population.

68.  Scintigraphy. Iodine-123 (123 I) or technetium-
99m (99m Tc) can be used for thyroid scanning.
 Normally, the isotope distributes
homogeneously throughout both lobes of the
thyroid gland
 Radioactive iodine uptake (RAIU) also varies
with different conditions.
 Normal RAIU is approximately 5-20%

70.  After 4-6 weeks, antithyroid medications
usually must be reduced;
 Since the patient becomes hypothyroid
 Initially, the patient should have thyroid
function tests performed every 4-6 weeks
until thyroid hormone levels are stabilized on
a low dosage of antithyroid medication.

71.  In patients with Graves disease, antithyroid
medication should be stopped or decreased
after 12-18 months to remission.
 Remission is defined as a normalTSH level
after cessation of antithyroid drug therapy
 20% become hypothyroid over subsequent
years as a consequence of autoimmune
destruction of the gland.

72.  Surgery
 Radioactive ablation
 Ablation of the gland occurs over 2-5 months
after radioactive iodine therapy.
 Most patients become hypothyroid.
 Checking thyroid functions every 4-6 weeks
 Then stop antithyroid and start low dose
thyroxine

73.  Methimazole or propylthiouracil to maintain a
euthyroid state;
 Free thyroxine (FT4)/total thyroxine (T4) andTSH
should be monitored approximately every 4
weeks;
 Lowest effective dose of methimazole or
propylthiouracil, targeting maternal serum free
thyroxine (FT4)/total thyroxine (T4) at the upper
limit of reference range.

76. Thank you