HYPOTHYROIDISM

HYPOTHYROIDISM
DR LAVANYA BONNY
SR, DEPT OF ENDOCRINOLOGY
ST JOHNS MEDICAL COLLEGE
BANGALORE

DEFINITION
• syndrome characterized by the clinical and biochemical manifestations
of thyroid hormone deficiency in the target tissues of thyroid hormone
• denotes deficient thyroid gland production of thyroid hormone.

DEFINITION
• This deficiency may be caused
• by an abnormality in the thyroid gland itself (primary hypothyroidism) or
• by insufficient TSH stimulation of the thyroid gland resulting from an
abnormality in the pituitary gland or hypothalamus (secondary and
tertiary, or central, hypothyroidism).

HISTORY
• Described in 1874 by Gull under the name of myxedema in view of the
swollen skin (edema) and its excessive content of mucin (myx-)
• 1883-Semon noted striking similarities between patients with
myxedema and patients who had undergone total thyroidectomy
• 1891-Murray reported cure of myxedema by hypodermic injections of
sheep thyroid extract

HISTORY
• Active principle of thyroid extract was isolated by Kendall in 1914 and
was named thyroxine
• Harrington elucidated the precise constitution of thyroxine in 1926 and
was able to synthesize it.
• Desiccated thyroid, made from animal thyroid glands, remained the
main form of therapy until about 1960

HISTORY
• Synthetic preparations of L-T3 were available in 1956
• synthetic preparations of L-T4 became accessible in 1958

EPIDEMIOLOGY
• Mean age at diagnosis of hypothyroidism in women is 60 years
• Probability of spontaneous hypothyroidism developing in women at a
particular time increases with age
• from 1.4 per 1000 per year at 20 to 25 years of age, to 14 per 1000 per
year at 75 to 80 years of age

EPIDEMIOLOGY
• Risk factors for progression to overt hypothyroidism include the
presence of thyroid autoantibodies and an already elevated TSH

NORMAL RANGE OF TSH
• NHANES III - 95% of adult subjects have a serum TSH within the range
of 0.45 to 4.12 mU/L
• National Academy of Clinical Biochemists in the United States - 95% of
individuals without evidence of thyroid disease will have TSH below 2.5
mU/L

NORMAL RANGE OF TSH
• Genetic variants in the phosphodiesterase 8B gene and in the TSH
receptor may also influence the setpoint of the hypothalamic-pituitary-
thyroid axis
• Serum TSH level is higher in white populations than in black ones -
genetic and ethnic influence
• age effect - 97.5th percentile of serum TSH noted to increase by 0.3
mU/L every 10 years after the age of 30 to 39 years

NORMAL RANGE OF TSH
• slightly increased serum TSH might not always reflect mild thyroid
hormone deficiency in healthy elderly subjects
• Effect of BMI - TSH is higher in overweight and obese individuals than in
lean subjects.
• MECH – leptin stimulates release of TRH by the paraventricular nucleus
of the hypothalamus

ETIOLOGY
• Transient and persistent adult hypothyroidism
• Transient hypothyroidism is defined as a period of reduced thyroid
function with elevated TSH, which is followed by recovery to a euthyroid
state

ETIOLOGY OF TRANSIENT
HYPOTHYROIDISM

PERSISTENT HYPOTHYROIDISM
• persistent subclinical and overt hypothyroidism is defined by the
presence of a permanent reduced secretion of thyroid hormones by the
thyroid gland
• Iodine deficiency - MC cause of persistent hypothyroidism in the world
• Hashimoto’s thyroiditis - MC cause of acquired subclinical or overt
hypothyroidism in adults in areas of iodine sufficiency

ETIOLOGY OF PERSISTENT
HYPOTHYROIDISM

CENTRAL HYPOTHYROIDISM
• Reduced T4 secretion in central hypothyroidism is due to insufficient
stimulation of the thyroid gland by TSH
• caused by lesions in the pituitary gland (secondary hypothyroidism) or
the hypothalamus (tertiary hypothyroidism) resulting from deficient TRH
release.

• Basal serum TSH values in central hypothyroidism can be low, normal, or
even slightly elevated (up to 10 mU/L)
• reduced biological activity of TSH in these patients related to abnormal
sialylation of TSH.
• Also a/w decreased nocturnal TSH surge (because of loss of the usual
nocturnal increase in TSH pulse amplitude)

• Prevalence-0.005% in general population
• Peaks in childhood and in adults 30 to 60 years of age.

Congenital causes –
• Pituitary hypoplasia
• Midline defects such as septo-optic dysplasia (TSH deficiency in 20%)
• Rathke’s pouch cysts
• Rare loss-of-function mutations in genes encoding for TRH receptors,
the TSH-β subunit, or pituitary transcription factors

• Childhood cases are caused most often by craniopharyngioma (TSH
deficiency in 53%) or cranial irradiation for brain tumors (TSH deficiency
in 6%).
• Adult cases most frequently are due to pituitary macroadenomas
(hypothyroidism in 10% to 25%) and pituitary surgery or irradiation

• Less common causes include TBI and SAH, ischemic necrosis from
postpartum hemorrhage (Sheehan’s syndrome) and severe shock,
infiltrative diseases, and lymphocytic hypophysitis
• TSH deficiency caused by loss of functional tissue usually becomes
manifest after the development of growth hormone and gonadotropin
deficiency

• In critically ill patients receiving dopamine, serum TSH and the T4
production rate decrease by 60% and 56%, respectively, as a result of
direct inhibition of pituitary TSH
• Glucocorticoid excess dampens pulsatile TSH release, which rarely
results in decreased serum FT4
• High doses of bexarotene cause central hypothyroidism by strongly
inhibiting TSH secretion

CHRONIC AUTOIMMUNE THYROIDITIS
• Hypothyroidism secondary to chronic autoimmune thyroiditis is caused
mainly by destruction of thyrocytes.
• Goitrous variant (hypothyroid Hashimoto’s goiter) is characterized by
massive lymphocytic infiltration of the thyroid gland
• characterized by a diffuse goiter of firm rubbery consistency
• goiter does not regress despite T4 treatment in 43% of cases

• Atrophic variant (atrophic myxedema)- fibrosis is the predominant
feature, along with lymphocytic infiltration
• Destruction of thyrocytes is mediated by cytotoxic T cells and cytokines
(especially IF-γ and TNF) released by infiltrating T cells and macrophages
• TPO antibodies may contribute via antibody-dependent, cell-mediated
cytotoxicity, complement-mediated cytotoxicity, and inhibition of TPO
enzymatic activity

• TSH receptor–blocking antibodies enhance thyroid atrophy and
hypothyroidism, possibly also by inducing apoptosis
• Autoimmune thyroid disease runs in families (80% of patients have a
positive family history) and is four to ten times more common in women
• weakly associated with HLA-DR3, CTLA4, PTPN22 and Tg polymorphisms

• prevalence of autoimmune hypothyroidism is higher in iodine-replete
areas
• Smoking decreases the risk for developing TPO antibodies and overt
autoimmune hypothyroidism

• Histopathology
• Classical Hashimoto thyroiditis (originally termed struma lymphomatosa)
- thyroid gland may be diffusely enlarged or nodular
• diffuse lymphocytic infiltration with germinal center formation and
obliteration of thyroid follicles, accompanied by a variable degree of
fibrosis

• Histopathology
• atrophic thyroiditis or primary myxedema-the gland is atrophied and
consists of extensive fibrotic tissue, moderate lymphocytic infiltration,
and widespread loss of thyroid follicles
• IgG4 thyroiditis : Subtype of Hashimoto’s with high circulating levels of
IgG4 and increased numbers of IgG4-positive plasma cells in the thyroid.
• Characterized pathologically by a greater degree of stromal fibrosis,
lymphoplasmacytic infiltration, and hypothyroidism

REVERSIBLE AUTOIMMUNE
HYPOTHYROIDISM
• Chronic Autoimmune Thyroiditis
• may evert spontaneously into euthyroidism with the disappearance of
TSHR–blocking antibodies.
• presence of a goiter and high thyroidal radioiodine uptake increase the
likelihood of spontaneous recovery

HYPOTHYROIDISM
• incidence of spontaneous recovery is about 5%
• in Japan—in the face of a high ambient iodine intake—iodine restriction
alone restores euthyroidism in one third of patients

HYPOTHYROIDISM
• Peculiar cases of alternating hypothyroidism and hyperthyroidism are
explained by changes in coexisting TSH receptor–blocking and TSH
receptor– stimulating antibodies.

HYPOTHYROIDISM
• Silent and Postpartum Thyroiditis
• Silent or painless thyroiditis and postpartum thyroiditis are variant forms
of chronic autoimmune thyroiditis.
• autoimmune attack is intense (mainly T cell–mediated destructive
thyroiditis) but transient

HYPOTHYROIDISM
• Transient thyrotoxicosis followed by transient hypothyroidism in the
recovery stage.
• Each stage lasts 2 to 8 weeks
• Most patients remain asymptomatic and revert spontaneously to
euthyroidism

HYPOTHYROIDISM
• Thyrotoxicosis alone occurs in 38%, thyrotoxicosis followed by
hypothyroidism occurs in 26%, and hypothyroidism alone occurs in 36%.
• Women with postpartum thyroiditis are at risk for recurrent postpartum
thyroiditis after delivery (about 40%) and for permanent hypothyroidism
(20% to 30% after 5 years)
• TPO antibodies of 100 kU/L or greater at 12 weeks’ gestation can predict
postpartum thyroiditis

HYPOTHYROIDISM
• Cytokine-Induced Thyroiditis
• Treatment with IL-2 or IF-α is causally related to the de novo occurrence
of TPO antibodies
• sudden onset, biphasic pattern of thyrotoxicosis followed by
hypothyroidism (although hypothyroidism alone is most frequent), and
spontaneous resolution after discontinuation of treatment.
• The incidence is about 6%; risk factors include female sex and
preexisting TPO antibodies

POSTOPERATIVE AND POSTIRRADIATION
HYPOTHYROIDISM
• Surgery
• Total thyroidectomy results in overt hypothyroidism within 1 month.
• Subtotal thyroidectomy for Graves’ hyperthyroidism is followed by
hypothyroidism in 40% after 10 years
• Immediate postoperative hypothyroidism does not always indicate
permanent hypothyroidism; it may resolve spontaneously by 6 months

HYPOTHYROIDISM
• Surgery
• risk factors include a small thyroid remnant, lymphocytic infiltration, and
subsequent exposure to iodine.
• Subtotal thyroidectomy for (toxic) nodular goiter carries a much lower
risk (about 15%) for postoperative hypothyroidism

HYPOTHYROIDISM
• Radioactive Iodine
• cumulative incidence of hypothyroidism of 70% after 10 years after
treatment for Graves disease
• Most cases occur in the first year
• thereafter the annual incidence of hypothyroidism is 0.5% to 2%
• Hypothyroidism after 131I treatment for TNG is less common (6% to
13%).

HYPOTHYROIDISM
• External Irradiation
• radiotherapy of the neck for Hodgkin’s or non- Hodgkin’s lymphoma
causes hypothyroidism in 25% to 50% of patients
• risk is decreased when the thyroid is shielded
• External radiotherapy for head and neck cancer has a risk of 40% for the
development of SCH and 15% for overt hypothyroidism 3 years after
treatment

INFILTRATIVE AND INFECTIOUS DISEASES
• invasive fibrous thyroiditis of Riedel, progressive systemic sclerosis, and
amyloidosis can cause hypothyroidism.
• Infections of the thyroid gland are rare and are associated with
preexisting thyroid disease and immunocompromising conditions

IODINE EXCESS
• Inorganic iodide in excess of daily doses of 500 to 1000 mcg inhibits
organification of iodide
• thyroid gland escapes the Wolff-Chaikoff effect after several weeks
because autoregulatory mechanisms inhibit thyroid iodide transport
• Failure to escape results in hypothyroidism
• This occurs in the presence of underlying thyroid disease, such as
chronic autoimmune thyroiditis, previous thyroiditis, and 131I or surgical
therapy

CLINICAL FEATURES
• Systemic manifestations vary considerably, depending on the cause,
duration, and severity of the hypothyroid state.
• The characteristic clinical finding is slowing of physical and mental
activity and many organ functions.

CLINICAL FEATURES
• Energy and Nutrient Metabolism
• slowing of metabolic processes results in decreased resting energy
expenditure, oxygen consumption
• Reduced thermogenesis is related to the characteristic cold intolerance
of hypothyroid patients
• decline in metabolic rate and substrate use contributes to decreased
appetite and food intake

CLINICAL FEATURES
• Body weight increases on average by 10% because of an increase in
body fat and retention of water and salt
• Serum concentrations of the adipocytokines may be decreased- leptin
mostly unchanged –resistin, adiponectin
• or elevated- visfatin which is directly associated with insulin resistance
and body mass index

CLINICAL FEATURES
• Synthesis and the degradation of protein are decreased
• Decrease in protein synthesis - retardation of both skeletal and soft
tissue growth
• Permeability of capillaries to protein is increased - high levels of protein
in effusions
• Albumin pool is increased because of the greater decrease in albumin
degradation compared to albumin synthesis

CLINICAL FEATURES
• reduction in glucose disposal to skeletal muscle and adipose tissue
• reduced gluconeogenesis.
• The net effect of these influences is usually a minimal effect on serum
glucose levels
• Degradation of insulin is slowed and the sensitivity to exogenous insulin
may be increased

CLINICAL FEATURES
• synthesis and the degradation of lipid are depressed
• Degradation is affected more
• net effect of accumulation of LDL and triglycerides
• Mobilization of free fatty acids in response to fasting, catecholamines,
and growth hormone is impaired

CLINICAL FEATURES
• Reduction in LDL with T4 therapy is related to the original magnitude of
LDL and TSH elevation
• the higher the initial levels, the greater the reduction in LDL that is
observed.
• A typical reduction in LDL is 5% to 10% of the original level

CLINICAL FEATURES
• Skin and Appendages
• accumulation of hyaluronic acid and other GAGs in interstitial tissue
• related to loss of the inhibitory effects of thyroid hormone on the
synthesis of hyaluronate, fibronectin, and collagen by fibroblasts.
• The hydrophilic properties of GAGs - mucinous nonpitting edema
(myxedema) that is most obvious in the dermis but can be present in
many organs.

CLINICAL FEATURES
• tissue is characteristically boggy and nonpitting and is apparent around
the eyes, on the dorsa of the hands and feet, and in the supraclavicular
fossae
• enlargement of the tongue and thickening of the pharyngeal and
laryngeal mucous membranes

CLINICAL FEATURES
• skin is pale and cool as a result of cutaneous vasoconstriction
• secretions of the sweat glands and sebaceous glands are reduced,
leading to dryness and coarseness of the skin
• Easy bruising is due to an increase in capillary fragility.
• Head and body hair is dry and brittle, lacks luster, and tends to fall out.

CLINICAL FEATURES
• Hair may be lost from the temporal aspects of the eyebrows
• nails are brittle and grow slowly
• Vitiligo may also be seen in patients with Hashimotos thyroiditis
• Yellowish discoloration of the skin may be present, especially on the
palms and soles, because of the deposition of carotene, which is
converted to a lesser extent to vitamin A

CLINICAL FEATURES
• The thick rough skin with scales is caused by mucinous swelling of the
dermis and hyperkeratosis of the stratum corneum in the epidermis.

CLINICAL FEATURES
• Central and Peripheral Nervous Systems
• Deficiency in fetal life or at birth impairs neurologic development,
including hypoplasia of cortical neurons with poor development of
cellular processes, retarded myelination, and reduced vascularity

CLINICAL FEATURES
• In adult hypothyroid patients - low-voltage EEG, prolonged central
motor conduction time, and reduced visual and somatosensory-evoked
potential amplitude with longer latency
• Functional MRI studies have linked poorer memory states to specific
brain areas and reduced hippocampal volume.
• PET scans have demonstrated lower glucose metabolism in brain areas
regulating affect and cognition

CLINICAL FEATURES
• All intellectual functions, including speech, are slowed
• Loss of initiative is present and memory defects are common, lethargy
and somnolence are prominent
• Hearing can be impaired.
• rare but treatable cause of dementia

CLINICAL FEATURES
• Psychiatric disorders are common and are usually of the paranoid or
depressive type and may induce agitation (myxedema madness)
• Depression is likely related to reduced synthesis and turnover of brain 5-
HT
• Seizures tend to occur in myxedema coma.
• Night blindness can occur

CLINICAL FEATURES
• Hearing loss - due to myxedema of the eighth cranial nerve and serous
otitis media
• Thick, slurred speech and hoarseness are due to myxedematous
infiltration of the tongue and larynx
• Cerebellar ataxia may occur, especially in older adults

CLINICAL FEATURES
• Compression byGAG deposits around the median nerve - carpal tunnel
syndrome
• Tendon reflexes are slow, especially during the relaxation phase - hung-
up reflexes
• due to a decrease in the rate of muscle contraction and relaxation, rather
than a delay in nerve conduction.

CLINICAL FEATURES
• Muscular System
• Stiffness and aching of muscles are worsened by cold temperatures.
• Muscle mass may be slightly increased, and the muscles tend to be firm.
• Rarely, a profound increase in muscle mass with slowness of muscular
activity may be the predominant manifestation (the Kocher-Debré-
Sémélaigne, or Hoffmann, syndrome).

CLINICAL FEATURES
• Muscular System
• Myoclonus may be present.
• increase in the inorganic phosphate–to–ATP ratio in resting muscle
• decrease in phosphocreatine in working hypothyroid muscle with a
greater decrease in intracellular pH

CLINICAL FEATURES
• Muscular System
• Impairment of mitochondrial oxidative metabolism
• Transition from white fast type II to red slow type I muscle fibers
• The histopathology varies; most common is type II fiber atrophy
• but fiber hypertrophy may be present along with interstitial edema and
sarcoplasmic degeneration

CLINICAL FEATURES
• Skeletal System
• Growth failure is due both to impaired general protein synthesis and to a
reduction in GH, but especially of IGF-1
• Deficiency of thyroid hormone in early life leads to both a delay in
development and an abnormal, stippled appearance of the epiphyseal
centers of ossification (epiphyseal dysgenesis)
• Impairment of linear growth is seen

CLINICAL FEATURES
• Skeletal System
• Because of decreased bone resorption, serum calcium levels are
decreased slightly
• This is followed by an increase in PTH and 1,25-di OH Vit D and an
increase in intestinal calcium absorption.
• Calcium losses in urine and feces are decreased.

CLINICAL FEATURES
• Cardiovascular System
• cardiac output at rest is decreased because of reduction in both stroke
volume and heart rate
• Peripheral vascular resistance at rest is increased
• Leads to narrowing of pulse pressure, prolongation of circulation time,
and decrease in blood flow to the tissues.

CLINICAL FEATURES
• hemodynamic alterations at rest resemble those of congestive heart
failure.
• However cardiac output increases and peripheral vascular resistance
decreases normally in response to exercise
• Cardiac silhouette is enlarged, and the heart sounds are diminished in
intensity in severe hypothyroidism

CLINICAL FEATURES
• These findings are d/t effusion into the pericardial sac
• Pericardial effusion is rarely of sufficient magnitude to cause tamponade

CLINICAL FEATURES
• ECG - sinus bradycardia, PR prolongation, low amplitude of the P wave
and QRS complex, alterations of the ST segment, and flattened or
inverted T waves
• Serum levels of homocysteine, creatine kinase, AST, and may be
increased
• combination of large heart, hemodynamic and electrocardiographic
alterations, and the serum enzyme changes - myxedema heart

CLINICAL FEATURES
• atherogenic profile of serum lipids and the hyperhomocystenemia - risk
factor for cardiovascular disease
• improvement from treatment of hypothyroidism, especially SCH, is
primarily in those who are middle age and not older individuals

CLINICAL FEATURES
• Respiratory System
• Pleural effusions - usually only on radiologic examination
• Lung volumes are usually normal, but maximal breathing capacity and
diffusing capacity are reduced.

CLINICAL FEATURES
• Respiratory System
• In severe hypothyroidism, myxedematous involvement of respiratory
muscles and depression of both the hypoxic and the hypercapnic
ventilatory drives may cause alveolar hypoventilation and carbon
dioxide retention
• Increased prevalence of OSA - usually reversible

CLINICAL FEATURES
• Renal Function
• Reversible reductions in renal blood flow, GFR, and tubular reabsorptive
and secretory maxima are seen
• Serum creatinine is increased by 10% to 20%
• delay in water excretion appears to be due to decreased volume delivery
to the distal diluting segment of the nephron

CLINICAL FEATURES
• Renal Function
• Increase in total body water-accounts for the hyponatremia occasionally
noted
• High prevalence of hypothyroidism in patients with chronic kidney
disease
• improvement in renal function has been demonstrated with T4
treatment

CLINICAL FEATURES
• Alimentary System
• Constipation – decreased peristaltic activity and decreased food intake
• Gaseous distention of the abdomen (myxedema ileus), if accompanied
by colicky pain and vomiting, may mimic mechanical ileus
• fecal impaction - myxedema megacolon

CLINICAL FEATURES
• Achlorhydria may be seen
• Circulating antibodies against gastric parietal cells - in one third of
patients
• Overt pernicious anemia - in about 12% of patients
• Hypothyroid patients with positive parietal cell antibodies have a higher
T4 requirement compared with antibody-negative patients

CLINICAL FEATURES
• Levels of aminotransaminases may be elevated, probably because of
impaired clearance.
• The gallbladder contracts sluggishly and may be distended
• 3.8-fold increased risk of cholelithiasis

CLINICAL FEATURES
• Hematopoietic System
• Diminished oxygen requirements and decreased production of
erythropoietin - RBC mass is decreased
• mild normocytic, normochromic anemia occurs
• Less commonly, the anemia is macrocytic- due to associated pernicious
anemia and Folate deficiency from malabsorption
• microcytic, hypochromic anemia may be seen-due to mennorhagia and
iron deficiency due to achlorhydria

CLINICAL FEATURES
• Platelet adhesiveness may be impaired
• intrinsic clotting mechanism may be defective because of decreased
concentrations in plasma of factors VIII and IX
• increase in capillary fragility is seen
• Accounts for the bleeding tendencies

CLINICAL FEATURES
• Thrombin activatable fibrinolysis inhibitor (TAFIa)–dependent
prolongation of clot lysis is reduced.
• Bleeding time in vivo and clotting time in vitro are prolonged.
• There is also decreased von Willebrand factor antigen and activity.

CLINICAL FEATURES
• The prevalence of acquired von Willebrand syndrome in overt
hypothyroidism is 33%; but most cases are mild.
• Desmopressin rapidly reduces these abnormalities and may be valuable
for the acute treatment of bleeding or as cover for surgery

CLINICAL FEATURES
• Pituitary and Adrenocortical Function
• long-standing primary hypothyroidism, hyperplasia of the thyrotropes
may cause the pituitary gland to be enlarged
• severe hypothyroidism may have increased serum prolactin levels,
stimulated by the elevation in TRH
• Leas to galactorrhoea and ammenorhea

CLINICAL FEATURES
• The decrease in GH secretion in hypothyroidism is related to an increase
in hypothalamic somatostatinergic tone
• results in low IGF-1 serum concentrations.
• It may cause dramatic growth retardation in hypothyroid children.
• Serum IGF-2, IGFBP-1, and IGFBP-3 are also decreased, whereas IGFBP-2
is increased; these changes are reversed with T4 treatment

CLINICAL FEATURES
• decreased rate of turnover of cortisol due to decreased hepatic 11β-
HSD-1
• Plasma cortisol is usually normal
• Hypocortisolemia by itself may cause slightly elevated TSH levels that
return to normal with glucocorticoid replacement
• adrenal insufficiency may be precipitated by rapid replacement therapy
with thyroid hormone

CLINICAL FEATURES
• Hypothyroidism decreases angiotensinogen production in the liver and
serum angiotensin-converting enzyme and plasma renin activity.
• Serum aldosterone remains normal
• The decrease in clearance is neutralized by a decrease in secretion.
• The effects of these changes in the RAAS are minimal

CLINICAL FEATURES
• Sympathoadrenal System
• Serum norepinephrine concentrations are increased in hypothyroid
patients because of an increased production rate
• The increased central sympathetic output seems to be compensatory for
the reduced response to catecholamines in target tissues such as the
heart
• Mechanisms involved include a reduced number of β-adrenergic
receptors and postreceptor defects, which contributes to impaired
lipolysis, glycogenolysis, and gluconeogenesis.

CLINICAL FEATURES
• Reproductive Function
• Juvenile hypothyroidism causes a delay in the onset of puberty followed
by anovulatory cycles.
• may also rarely cause precocious sexual development and galactorrhea -
due to “spillover” of elevated TSH stimulating the LH receptor and
elevated TRH initiating excess prolactin release

CLINICAL FEATURES
• adult women - severe hypothyroidism may be associated with
diminished libido and failure of ovulation
• Secretion of progesterone is inadequate, and endometrial proliferation
persists, resulting in excessive and irregular breakthrough menstrual
bleeding.
• These changes may be due to deficient secretion of LH

CLINICAL FEATURES
• Fertility is reduced, and there is an increase in spontaneous abortion and
preterm delivery
• Primary ovarian failure can also be seen in patients with Hashimoto
thyroiditis as part of an autoimmune polyendocrine syndrome

CLINICAL FEATURES
• in men may cause diminished libido, erectile dysfunction, and
oligospermia
• Secretion of androgens is decreased
• SHBG in plasma is decreased - plasma concentrations of both
testosterone and estradiol are decreased

HYPOTHYROIDISM - 2
DIAGNOSIS AND MANAGEMENT

DIAGNOSIS
• Overt hypothyroidism is a clinical condition and can be suspected in the
presence of specific symptoms of thyroid hormone deficiency
• several rating scales have been proposed for the diagnosis of
hypothyroidism
• none of the symptoms or signs of hypothyroidism is sufficiently sensitive
or specific

DIAGNOSIS
• Onset of clinical symptoms influenced by
• severity of disease
• Duration
• Age - Elderly may be minimally or completely asymptomatic
• individual sensitivity to thyroid hormone deficiency

A SCORE OF +25 OR MORE SUGGESTS HYPOTHYROIDISM,
WHILE A SCORE OF -30 OR LESS EXCLUDES THE DISEASE.

DIAGNOSIS
• serum TSH - most sensitive and specific test in the presence of an intact
HPT
• immunometric assays for TSH - 99% sensitivity and specificity
• Elevated TSH and decreased FT4 - classical combination indicating
primary hypothyroidism

DIAGNOSIS
• Serum FT3 evaluation is only marginally useful in diagnosing
hypothyroidism
• low serum levels only in severe hypothyroidism
• Early stages have compensatory increase in hepatic T4 to T3 conversion
and residual thyroidal T3 secretion

DIAGNOSIS
• Serum TSH should be reevaluated after 3 to 6 months in the event of
slightly increased values
• to exclude a laboratory error or a transient TSH increase due to
temporary thyroiditis recovery from systemic illness or drugs

DIAGNOSIS
• A laboratory pattern indistinguishable from SHypo may be rarely seen in patients with TSH
receptor mutations causing mild TSH resistance.
• have f/h/o raised serum TSH but an absence of h/o thyroid autoimmunity

DIAGNOSIS
• Pituitary resistance to thyroid hormones and thyrotropin secreting pituitary adenoma may
have slightly increased TSH
• both of these conditions are characterized by raised serum free thyroid hormone levels.

DIAGNOSIS
• serum TSH assay alone may be insufficiently sensitive for the diagnosis of
• 1) CH due to hypothalamic or pituitary disorders
• 2) subjects recovering from nonthyroidal illnesses
• 3) drugs that can suppress TSH
• 4) overweight and obese subjects

DIAGNOSIS
• serum TSH assay alone may be insufficiently sensitive for the diagnosis of
• 5) short-term withdrawal of thyroid hormone therapy in euthyroid subjects
• 6) presence of heterophilic antibodies against mouse proteins in some immunoassays that
may falsely raise serum TSH
• 7) patients with untreated adrenal insufficiency.

DIAGNOSIS – EFFECT OF DRUGS
• drugs that suppress TSH at the level of the hypothalamus or pituitary
• Glucocorticoids
• dopamine, and dopamine agonists (bromocriptine and cabergoline)
• somatostatin analogs (octreotide)
• Dobutamine
• Retinoids
metformin can also lower serum TSH – shown in a small study

DIAGNOSIS
• During the recovery phase from nonthyroidal illness :
• serum TSH levels may be increased to levels above normal (usu. no higher than 20 mU/L)

DIAGNOSIS - ANTIBODIES
• About 90% of patients with Hashimoto’s thyroiditis have detectable anti-TPO and anti-Tg
antibodies
• useful to confirm the diagnosis of autoimmune hypothyroidism

DIAGNOSIS - ANTIBODIES
• Can also predict the subsequent development of overt hypothyroidism in
• patients with SCH
• pregnant women
• postpartum period
• presence of other AI disease
• during treatment with drugs such as lithium, interferon-, and amiodarone or exposure to
excessive amounts of iodine

DIAGNOSIS – OTHER LAB FINDINGS
• Hypercholesterolemia
• Hypertriglyceridemia
• Hyperprolactinemia
• hyperhomocysteinemia
• Hyponatremia
• Anemia
• elevated creatine phosphokinase levels

DIAGNOSIS – ROLE OF USG
• The hypoechogenicity of the thyroid gland can identify individuals with
autoimmune thyroiditis
• may provide a correct diagnosis in about 10% of patients with no
detectable thyroid autoantibodies

DIAGNOSIS – CENTRAL
HYPOTHYROIDISM
CH can be suspected
• in the presence of other pituitary hormone deficiency
• in the presence of a history of pituitary gland tumors and surgery
• pituitary inflammatory and infiltrative disorders

DIAGNOSIS – CENTRAL
HYPOTHYROIDISM
• low or low-normal serum T4 with a low or low-normal serum TSH
• can have a modestly elevated serum TSH (e.g., 5 to 7 mU/L)
• This is due to the secretion of TSH that is immunoreactive but less
biologically active

DIAGNOSIS
• TSH is preferable when detection of SCH is important or when both
hypothyroidism and thyrotoxicosis must be excluded.
• free T 4 should be used when central hypothyroidism is a possibility.
• If either test result is abnormal, the other measurement should be done
before any intervention is undertaken

TREATMENT
Thyroid hormone formulations: pharmacokinetics and
pharmacodynamics
2 categories
• Natural hormonal preparations derived from animal thyroid
• Synthetic preparations

THYROID EXTRACTS
• Natural preparations include desiccated thyroid and Tg.
• Desiccated thyroid products (dried and powdered) are derived from the
thyroid glands of domesticated animals that are used for food by man
(either beef, or sheep)
• Contains approximately 80% T4 and 20% T3 as well as other iodinated
compounds (eg, diiodotyrosine and monoiodotyrosine).

THYROID EXTRACTS
• bioavailability of T3 in desiccated thyroid is comparable to that of orally
administered synthetic T3
• most commonly used form of desiccated thyroid-Armour Thyroid, is of
porcine origin
• mixture of T3 and T4 (1 grain, about 60 mg desiccated pig thyroid
extract is approximately equivalent to 88 g L-T4 )

THYROID EXTRACTS
• RCT comparing dessicated thyroid with LT4
• treatment with desiccated thyroid hormone did not improve the QOL
• 48.6% of patients preferred this therapy vs L-T4 because it was a/w weight loss

THYROID EXTRACTS
• LIMITATIONS
• Inappropriate use of thyroid extracts in euthyroid and hypothyroid patients can result in
thyrotoxic symptoms and severe adverse effects
• thyroid storm has been reported
• no evidence to support using desiccated thyroid hormone in preference to L-T4 -
particularly due to content of a nonphysiological proportion of T3

LEVOTHYROXINE
• Plasma T4 reaches a peak concentration 2 to 4 hours after oral
administration
• once daily dose of L-T4 each morning provides stable and relatively
constant blood levels of T4
• long half life (about 7 days)

LEVOTHYROXINE
• ABSORPTION
• takes place through the intestinal mucosa within the first 90 minutes
• 21% in the duodenum, 45% in the upper jejunum, and 34% in the lower jejunum and ileum
• only 70% to 80% of the administered dose is absorbed

LEVOTHYROXINE
• METABOLISM
• Thyroid hormones are metabolized by the liver and mainly eliminated by the kidneys.
• portion of the conjugated hormone reaches the colon unchanged.
• Approximately 20% of T4 is eliminated in the stool.
• Physiological amounts of T3 are generated by the monodeiodination of T4 in target tissues

DIFFERENT T4 FORMULATIONS
• Two medicinal products containing the same active substance are
considered bioequivalent if they are pharmaceutically equivalent or
pharmaceutical alternatives with a similar record of safety and efficacy
• Therapeutic equivalence permits substitution of one drug for another
with the expectation of similar clinical effects with the expectation that
strict follow-up testing would not be required

• ,L-T4 is a drug with a narrow therapeutic index
• Has the potential of significant clinical consequences with minor
degrees of excessive or inadequate dosage

ADMINISTRATION AND INTERACTIONS
• It can be given 60 minutes before breakfast or 3 hours after dinner
• Other medications like PPI , Calcium and iron supplements , sevelamer ,
sucralfate , cholestyramine can interfere with absorption of levothyroxine

• FDA requires that the 90% CIs of the generic’s pharmacokinetic
properties fall within the 80% to 125% range of that of the brand
• AUC and the maximum T4 concentration are used
• pharmacokinetic method used by the FDA to assess bioequivalence was
too insensitive to assess therapeutic equivalence for L-T4

• using current FDA methodology, a difference of 25% to 33% of the
administered L-T4 dose might not be detected
• even after correction for baseline endogenous T4 levels, a difference of
12.5% would not be identified
• especially dangerous in patients who require precise dose titration such
as children, patients with thyroid cancer, pregnant women, elderly
patients, and patients with heart or bone disease

• Patients should be instructed to avoid switching between branded L-T4
products
• If there is a switch, TFT should be repeated within 4 to 8 weeks and
dosage retitrated to achieve the therapeutic target with the new
preparation

LIQUID FORMULATION
• Preliminary small studies – LT4 dissolved in glycerin and supplied in
gelatin capsules may be better absorbed than standard LT4
• potential utility in patients affected by changes in gastric pH (chronic
gastritis or lactose intolerance or those on H2 blockers and PPI)
• may allow 100% absorption from the GIT with relatively immediate
dissolution apparently unaffected by pH

LIQUID FORMULATION
• However, the present lack of controlled long-term outcome studies does
not support a recommendation

LIOTHYRONINE
• T3 - affinity for the nuclear receptor is 10- to 20-fold that of T4
• The ratio of T4 to T3 in the human thyroid gland is approximately 15:1

LIOTHYRONINE
• T3 has a relatively short half-life
• available formulations of L-T3 are rapidly absorbed
• Typically after T3 administration, supraphysiological serum T3
concentrations were maintained for several hours followed by a rapid
decline

LIOTHYRONINE
• USES
• as a second line drug for conditions such as myxedema coma
• or as short-term therapy in patients with DTC when L-T4 therapy is being
withdrawn or restarted in preparation for radioiodine therapy

EVIDENCE FOR TREATMENT
• OVERT HYPOTHYROIDISM
• should be treated to prevent the risk of progression to a more severe
disease and to avoid the risk of adverse cardiovascular events
• Untreated overt hypothyroidism can lead to an increased risk of
atherosclerosis, CAD, HF, pericardial and pleural effusion, and ventricular
arrhythmias

• OVERT HYPOTHYROIDISM
• During pregnancy, hypothyroidism should be treated to avoid adverse
obstetric outcomes and impaired neuropsychological development in
the offspring

• SUBCLINICAL HYPOTHYROIDISM
• Increased risk of progression to overt hypothyroidism
• may have an increased risk of HF and CHD events and mortality
• study by Díez et al, TSH levels greater than 10 to 15 mU/L were
associated with HR of 9.69 for the development of overt disease

• Risk of CAD increases with the severity of thyroid hormone deficiency
and was even higher when TSH values were above 10 mU/L
• Studies show increased incidence of HF observed in patients with TSH
concentrations of more than 7 to 10 mU/L

• Metaanalyses show definite benefit of treatment of patients with SHypo
having a serum TSH level above 10 mU/L to reduce the risk of CHD and
HF

• BENEFIT OF TREATMENT WITH REPLACEMENT DOSES OF L-T4
• beneficial effects on mood, cognition, and symptoms in patients with
SHypo are most apparent when serum TSH>10 mU/L
• beneficial effects on lipid levels were proportional to both the severity of
hypothyroidism and the magnitude of the elevation in lipid levels

• BENEFIT OF TREATMENT WITH REPLACEMENT DOSES OF L-T4
• L-T4 treatment is associated with lower all-cause mortality in patients
with moderate hypothyroidism
• Risk of HF events was significantly lower in L-T4–treated patients with
TSH>10 mU/L in the Cardiovascular Heart Study

• MANAGEMENT OF PATIENTS WITH MINIMALLY INCREASED SERUM
TSH
• Patients with SHypo and new onset of symptoms or depression, goiter,
or CV risk factors might benefit from treatment
• treatment may be indicated in patients with positive antithyroid
antibody tests and a progressively rising TSH level

• MANAGEMENT OF PATIENTS WITH MINIMALLY INCREASED SERUM TSH
• SHypo may be transient in some patients with an initial slightly increased TSH
• TSH could be assessed at yearly intervals to avoid the risk associated with unnecessary
treatment
• Young patients with TSH from 3 to 4.5 mU/L - monitored with periodic TFTs, particularly if
they have positive TPOAbs

• MANAGEMENT OF PATIENTS WITH MINIMALLY INCREASED SERUM TSH
• TRUST trial indicated that treatment with LT4 in older persons with SCH provided no
symptomatic benefits.

DETERMINANTS OF L-T4 REQUIREMENTS
AND STARTING DOSE OF L-T4
• Dose requirement of L-T4 is higher in infants and children and is usually higher in younger
compared with elderly patients
• Body weight and body composition influences the requirement.

• dosage correlates best with lean body mass rather than TBW
• suggests that adipose tissue is less metabolically responsive to L-T4 than muscle
• age-related decrease in L-T4 requirement is mediated by alterations in body weight and
body composition

• Most patients are well treated with a narrow dose window
• varies from 1.6 to 1.8 mcg/kg/d for replacement therapy in young and middle-aged
patients with primary hypothyroidism
• 2.0 to 2.5g/kg/d when suppressive doses of L-T4 are desired

SPECIAL SITUATIONS
• Patients with nephrotic syndrome and other severe illnesses may have
an altered clearance of L-T4 and require a higher dose
• GI diseases may reduce L-T4 absorption

SPECIAL SITUATIONS
• Patients with D2 polymorphism (threonine 92 alanine) may also need
higher doses of L-T4 to restore euthyroidism

SPECIAL SITUATIONS
• Emergency CABG in patients with unstable angina or LMCA occlusion
may be safely performed while the patient is still moderately to severely
hypothyroid
• patients at risk of adrenal insufficiency should be treated with clinically
appropriate doses of hydrocortisone until adrenal insufficiency is ruled
out

TARGET SERUM TSH IN PATIENTS RECEIVING
REPLACEMENT THERAPY WITH L-T4
• TSH levels will decline within a month after starting L-T4 therapy.
• Dose adjustments are usually guided by serum TSH determinations
every 4 to 8 weeks to give sufficient time to reset the pituitary gland
between dosage changes.
• Changes of about 12.5 to 25 microg/d are initially made

• In patients with primary hypothyroidism, TSH levels should be
normalized to a target level within the reference range
• Periodic follow-up evaluations with repeated TSH testing at 6- and 12-
month intervals are appropriate in patients with stable euthyroidism

• Lower target of 1 to 2.5 mU/L in young patients - data is lacking.
• age-adjusted serum TSH should be targeted in middle aged and elderly
patients

• More frequent evaluations
• in pregnant patients
• in patients receiving drugs that can interfere with thyroid function
• those with malabsorption
• those losing or increasing their body weight

• FT4 targeting the mid reference range should be considered when
monitoring L-T4 therapy.
• FT3 levels may remain in the low-normal reference range in a significant
subset of thyroidectomized patients receiving replacement doses of L-T4

MANAGEMENT OF PERSISTENT TSH
ELEVATION IN PATIENTS ON HIGH-DOSE L-
T4 REPLACEMENT THERAPY
• 1) poor patient compliance
• 2) inadequate or incorrect L-T4 dosage and/or administration
• 3) increased turnover or excretion of L-T4 related to drugs administered for concomitant
illnesses
• 4) heterophile antibody interference with the laboratory test (antimouse antibodies, RA,
and autoimmune anti-TSH antibodies)-false high TSH

MANAGEMENT OF PERSISTENT TSH
ELEVATION IN PATIENTS ON HIGH-DOSE L-
T4 REPLACEMENT THERAPY
• 5) L-T4 malabsorption due to the coexistence of celiac disease,
autoimmune gastritis, or administration of drugs that may interfere with
L-T4 absorption (eg, calcium, iron, and H2-blockers)
• 6) coexistence with thyroid hormone resistance
• 7) coexistence with adrenal insufficiency

TIMING
• Optimal absorption of L-T4 occurs with fasting
• reduction of 40% to 80% during food and drink administration
• calcium and iron supplements should not be taken until 3 to 4 hours after L-T4 is taken
• dose of L-T4 may need to be increased by 20% to 30% in patients taking these drugs,

DAILY VS WEEKLY
• once-weekly administration of L-T4 was effective and well-tolerated in
studies
• However, TSH levels were increased during the weekly regimen
compared with daily dose regimen
• should be avoided in patients with underlying heart disease because of
the transient supraphysiological hormone conc in the first 1 or 2 days

INTRAVENOUS LT4
• should be considered when oral administration cannot be used in
patients with severe hypothyroidism
• should initially receive 70% or less of their usual dose
• once daily as a bolus injection.

INTRAVENOUS LT4
• Adjunctive iv administration of T3 advocated for the treatment of MC
• Because 90% to 100% of orally administered T3 is absorbed, the iv dose
would not need to be reduced

ABSORPTION TEST
• in pseudomalabsorption,
• administration of a single large dose of T4, ie, 1000 mcg given in the morning after fasting
overnight
• serial blood sampling for thyroid function tests at 2, 4, and 6 hours after L-T4
administration

ABSORPTION TEST
• FT4 peak at 2 hours rising above the ULN (25pmol/L) with an increment of more than 20
pmol/L suggests poor adherence to treatment

ADVERSE EFFECTS OF LT4 THERAPY
• The hypermetabolic state associated with undetectable serum TSH can
impair psychological, social, and physical QOL
• may be a/w development of some important CV risk factors
• Elderly patients may be asymptomatic for specific symptoms of thyroid
hormone excess compared with younger patients

• remains to be established whether or not ExoSHyper and EndoSHyper
exert the same adverse effects
• because T3 levels are higher in patients with EndoSHyper, whereas FT4 is
often elevated in patients undergoing L-T4-suppressive therapy with a
greater T4 to T3 ratio

• Higher doses - 2 to 3-fold increased risk of fractures
• Lower doses should be used in postmenopausal women and in the
presence of risk factors for bone fractures.

T3 AND T4 COMBINATION THERAPY
• The addition of T3 to T4 monotherapy should be restricted to
persistently symptomatic hypothyroid patients despite their biochemical
euthyroidism during L-T4 replacement therapy
• goal of achieving improved QOL

INTERACTIONS WITH OTHER PITUITARY
HORMONE DEFICIENCIES AND HORMONE
REPLACEMENT
• Women under estrogen treatment and patients under GH treatment
often will need a higher T4 dose for serum FT4 levels to remain in the
euthyroid range
• In adrenal insufficiency, steroid replacement should accompany L-T4
replacement with establishment of a euadrenal state before achieving
euthyroidism

REPLACEMENT
• rhGH treatment may interfere with the activity of the HPT axis
• In euthyroid individuals, rhGH induces a slight reduction of serum T4, an
increase in serum T3, and a decrease in serum TSH without changes in
rT3
• Also augments peripheral deiodination of T4 to T3 and the secretion of
somatostatin, which in turn reduces pituitary TSH secretion

REPLACEMENT
• GH deficiency may mask subclinical forms of CH
• patients on rhGH replacement therapy often require higher replacement
doses of L-T4

ANALOGS OF THYROID HORMONE
• thyromimetics might be useful for the treatment of obesity and
dyslipidemia.
• Selective thyromimetics are synthetic analogs of thyroid hormones that
can selectively stimulate TR beta, avoiding harmful effects on the heart
and bone

• 3,5,3-Triiodothyroacetic acid (TRIAC: tiratricol)
• Product of decarboxylation and deamination of thyroid hormone
• affinity for TR some 10 to 20 times that of T3.
• has been administered to patients with isolated pituitary resistance to
thyroid hormone and was thought to have TSH-suppressive effects
greater than T4

• 3,5,3-Triiodothyroacetic acid (TRIAC: tiratricol)
• Not FDA approved

• SOBETIROME
• binds TR beta with an affinity similar to T3 but binds TR alpha with a 10-
fold lower affinity
• initially was thought to have a promising role as an antiobesity agent
because it is able to induce a 20% decrease in fat mass and improve
lipid profile without reduction in food intake and without affecting the
heart or BMD

• SOBETIROME
• Later found to have no effect

• EPROTIROME
• TR Beta-selective ligand that is preferentially taken up by the liver
• Eprotirome induced a 23% to 29% decrease in LDL and a 22% to 38%
lowering in TG with a 37% to 45% decrease in apolipoprotein A1 and
apolipoprotein B

• EPROTIROME
• cartilage damage in long-term dog models led to the withdrawal of
eprotirome from clinical trial

• 3,5-Diiodothyropropionic acid (DITPA)
• has cardiac inotropic selectivity compared with thyroid hormone with
minimal effects on heart rate and metabolic activity
• has been used to treat CHF with promising preliminary results

• 3,5-Diiodothyropropionic acid (DITPA)
• also stimulates coronary arteriolar growth without inducing cardiac
hypertrophy by upregulating key angiogenic growth factors
• DITPA induced suppression of the HPT axis and had a negative effect on
bone due to increased bone turnover – SO withdrawn from trials

HYPOTHYROIDISM

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