A Brief review on thyroid abnormalities mainly hypothyroidism

1. Thyroid Gland Disorders
Dipesh Tamrakar
MSc. Clin. Biochemistry
1

2. Overview
• Factors affecting thyroid functions
• Extrathyroidal
• Non-thyroidal
• Hypothyroidism
• Causes and its effect
• Types
• Treatment
2

3. Brief
• The half-life of T4 is 5-7 days & of T3 is only 1 day.
• Approximately 99% of the circulating thyroid hormone is bound to
plasma protein and is metabolized primarily by the liver.
• The half life of plasma TSH is approximately 1 hour
• Changes in half-lives results in temporary non steady-state condition
of pituitary-thyroid axis
3

4. Extrathyroidal factors that may affect thyroid function
Fetus:
• Thyroxine and TSH are detectable in fetal plasma at 10 – 12 weeks of
gestation.
• Plasma concentrations of total and free T4, T3 and TBG increase
during gestation.
• The concentration of TSH also increases with gestational age but is
within or above the adult reference range throughout gestation.
• Marked time and organ-specific changes occur throughout gestation
in the expression of the deiodinases, which are thought to coordinate
the orderly maturation of enzyme systems responsible For
development of the brain and the other organ systems in the fetus.
4

5. Neonate:
• During the first 24 h after birth, there is a rapid transient increase in the
release of TSH, T3 and T4 that is considered to be an adaptive response to
birth.
• Thyroid stimulating hormone peaks during the first 30 min, which then
stimulates T3 and T4 production during the first 24–36 h of postnatal life.
• This effect may be attenuated in infants delivered prematurely. Screening for
congenital hypothyroidism should be carried out after at least three days to
avoid spurious results.
Infancy and childhood.
• Plasma concentrations of TSH are within the adult range but free T3 is higher
than in adults.
• Free T4 concentrations tend to be at the lower end of the adult range.
• This hormone pattern suggests it may arise as a result of increased D1
activity in children.
• After puberty, no major changes in thyroid function occur, except in the
pregnant woman.
5

6. Elderly.
• In old age, there is little change in thyroid function tests
• There is a modest decrease in T4 secretion but without an
accompanying change in circulating T4.
• A slight fall in T3 may occur in those over 80 years of age.
• In patients on T4 replacement, the dose of T4 may have to be
decreased with age.
• There is also increasing evidence that the normal TSH distribution
curves appear to be shifted towards higher value ranges in individuals
aged over 80.
6

7. Pregnancy
• In normal pregnancy, there is a large increase in plasma TBG
concentration that arises from both an oestrogen stimulated increase
in synthesis and diminished clearance of the protein.
• There is also an increase in the pool size of extrathyroidal T4
distribution and an increase in the deiodination of thyroid hormones
in the developing placenta.
• The result of these changes is that, during pregnancy, there is a
marked increase in the requirement for iodine and an approximately
50% increase in T4 production occurs if the supply of iodine is
adequate.
• In order to maintain homoeostasis, an increase in total T4 and total
T3 concentrations occurs, which reach a new steady state around
mid-gestation.
7

8. • This requirement for increased thyroid hormone production requires
an ideal iodine supply during pregnancy of approximately 250 μg/day.
• Similarly, women with hypothyroidism taking T4 replacement will
need an increase in the dose of T4 of approximately 25–50 μg/day
during pregnancy within the first six weeks of gestation, aiming for a
TSH no higher than 2.5 mIU/L.
• Some centres recommend that women double their pre-pregnancy
levothyroxine dose on two days a week as soon as pregnancy is
confirmed to reduce the risk of maternal hypothyroidism.
• Thyroxine replacement should be monitored carefully using both TSH
and free T4, since even modest degrees of hypothyroxinaemia in early
pregnancy have been associated with an impaired IQ in the infant
8

9. • Hyperemesis gravidarum (severe vomiting in the first trimester of
pregnancy) is associated with high plasma total and free thyroid hormone
and low TSH concentrations, making it difficult to distinguish this condition
from severe true thyrotoxicosis (thyroid crisis).
• It is believed that hCG is responsible for the thyroid stimulation; the
condition usually resolves by the second trimester.
• Thyroid stimulating hormone receptor antibodies are negative in patients
with hyperemesis but positive if the patient has Graves disease.
• Thyrotrophin releasing hormone can cross the placenta from mother to
fetus, but TSH does not.
• Thyroid hormones cross the placenta, but this transplacental flux is
regulated in part by changes in expression of placental deiodinase as
pregnancy progresses.
• A maternal supply of thyroid hormones (particularly T4) to the fetus is
particularly import in the first trimester until a functional fetal thyroid has
developed.
9

10. • initially show a slight rise, thought to be due to the weak thyroid
stimulating action of hCG, present in very high concentration in early
pregnancy.
• This increase in free hormones can lead to suppression of TSH, such that
low or sometimes undetectable concentrations may be found in up to 20%
of patients during the first trimester.
• As pregnancy progresses, the concentrations of free thyroid hormones fall
and TSH begins to rise, although rarely increasing above the reference
range seen in nonpregnant subjects.
• Free thyroid hormone concentration may be lower than those found in
non-pregnant women.
• It is important that trimester-related reference ranges are used or both TSH
and free thyroid hormones.
• Patients can usually return to their pre-pregnancy levothyroxine
replacement regimen immediately post-delivery; however, they should be
monitored to ensure that this is still the optimal dose.
10

11. Non-thyroidal illness
• Patients attending or admitted to hospital suffering from any of a wide
range of chronic or acute non-thyroidal illnesses (NTI), often have
abnormalities in thyroid function tests.
• A low T3 may often be found even though the patients are clinically
euthyroid; this has been termed the sick euthyroid syndrome. Several
mechanisms are involved, including:
• alterations in the hypothalamic–pituitary–thyroid axis leading to
decreased hypothalamic stores of TRH and suppression of TSH release
due to increased concentrations of dopamine, cytokines, cortisol and
somatostatin
• While the degree of TSH suppression in NTI is often not as great as that
found in hyperthyroidism, there is considerable overlap in TSH
concentrations found in the two conditions.
12

12. • changes in the affinity characteristics and in the plasma
concentrations of the thyroid hormone binding proteins.
• These changes give rise to alterations in the plasma concentrations of
both the free and total thyroid hormones
• impaired uptake of thyroid hormones by the tissues
• decreased production of T3 in the peripheral tissues
• changes in the T3 occupancy and function of the T3 receptors.
• Extrathyroidal conversion of T4–T3 is reduced, leading to a marked
decline in plasma total and free T3, which may all to undetectable
concentrations.
13

13. • Reverse T3 concentration increases, primarily owing to impaired
catabolism rather than increased synthesis.
• These changes are often considered to be an adaptive response or
energy conservation, as rT3 is not metabolically active.
• Concentrations of free atty acids and other substances that can
compete with thyroid hormones or binding to plasma proteins may
rise. This can produce a transient increase in free T4.
• Drugs that compete or T4 binding sites will have a similar effect.
Uptake of thyroid hormone into cells may be impaired, either directly
by endogenous inhibitors or indirectly as a result of impairment of the
active transport systems of the cells.
• Finally, administration of corticosteroids or dopamine may suppress
TSH release.
14

14. • The contribution of each of the above mechanisms may vary with the
severity and stage of the illness, and thus the pattern of thyroid
function tests may be extremely variable and may mimic the profile
seen in either primary or secondary thyroid disease.
• Interpretation of thyroid function tests is complicated further by the
effects of drugs and methodological problems associated with free
hormone measurements.
• Thyroid hormone metabolism is markedly affected by fasting and
illness, with the magnitude of these changes tending to be
proportional to the severity of the illness
15

15. HYPOTHYROIDISM
16

16. Definition
• Hypothyroidism is defined as a deficiency in thyroid hormone
secretion and action.
• This disorder occurs in 2 to 15% of the population, more commonly in
women than in men.
• The risk of developing hypothyroidism increases with age.
• When there is low thyroid hormone a variety of clinical signs and
symptoms of hypometabolism develops.
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17. 18

18. Effect on organ system
• Cardiovascular system
• Respiratory system
• Renal system
• Central nervous system
• Neuromuscular system
• Gastrointestinal system
• Hematology
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19. BMR
• The basal metabolic rate is the sum of the total daily energy
expenditure that is generally in the range of 60%, which includes the
energy required for physical activity (approximately 10 to 30% or
more), or from the thermogenic effect of food that includes another
10% or more.
• Hypothyroidism reduces the metabolic rate and impairs
thermogenesis and behavioral responses
• lower metabolic rates may develop a mild to moderate
hypoproliferative anemia causing weakness and fatique
•
20

20. 21

21. Cardiovascular system
• A reduction in resting cardiac output occurs.
• Cool peripheries are characteristic, owing to a reduction in cutaneous
blood flow, which contributes to the intolerance to cold that is so often
present.
• In the thorax, cardiac dilatation may be seen on chest X-ray and occurs
in association with pericardial effusion, which occasionally leads to
compromised myocardial function.
• Ischaemic chest pain is uncommon, more frequently being seen in
hypothyroid patients with coincidental ischaemic heart disease when
they first receive thyroid hormone replacement therapy. The cardiac
changes reverse with appropriate thyroid replacement therapy.
22

22. Gastrointestinal system
• Most individuals show a moderate weight gain despite reduced
appetite, primarily due to fluid retention.
• Intestinal absorption of nutrients may be affected both by reduced
absorption rates and increased intestinal transit time, but net
absorption may actually be reduced, normal or even increased.
• Results of biochemical liver function tests are usually normal.
23

23. Central & peripheral nervous system
• Deficiency of thyroid hormones in fetal or early neonatal life, if not
promptly treated, results in irreversible damage to the CNS, with structural
abnormalities evident on histological examination.
• The classic picture of congenital hypothyroidism is rarely seen
• In adult life, neurological defects resulting from hypothyroidism are usually
reversible.
• The characteristic features are of generalized slowing in intellectual
function, with inanition, slow mentation, somnolence, and occasionally, a
rankly psychotic state. Speech becomes slow and the voice, the latter in
part due to oedema within the vocal apparatus.
• Cerebellar ataxia may be seen with prolonged hypothyroidism and may
become irreversible with delay in treatment.
• Seizures may also occur in severe cases. Peripheral nervous system
manifestations are also common, with compression of the median nerve at
the wrist being perhaps the best known (carpal tunnel syndrome).
Relaxation of the tendon jerks is characteristically delayed. 24

24. Locomotor system
• Muscular stiffness is a particularly common complaint in
hypothyroidism and relates to reduced relaxation rate.
• The muscles show abnormal structure on microscopy, with loss of
striations, oedema, swelling of fibres and relative deficiency of type II
fibres.
• Muscular weakness is often evident clinically and plasma activities of
muscle enzymes such as creatine kinase may be raised.
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25. Respiratory system
• Fatigue
• Shortness of breath on exertion
• Rhinitis
• Decreased exercise capacity
• This may result from impaired respiratory function as well as
cardiovascular disease.
• Hypoventilation occurs because of respiratory muscle weakness and
reduced pulmonary responses to hypoxia and hypercapnia.
• abnormal muscle function leading, in patients with pre-existing lung
disease, to exacerbation of any carbon dioxide retention and sleep
apnoea.
• Chest X-ray show pleural effusions, though these are seldom large.
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26. Skin and hair
• Increased water binding occurs as a result of deposition of
mucopolysaccharides in the skin, in common with the other tissues.
• The indurated oedema that results gives rise to the ‘myxoedematous’
appearance of the typical hypothyroid patient.
• Associated anaemia and hypercarotenaemia through impaired
conversion of β-carotene into retinol may render the skin pale or
yellow, respectively.
• Body hair tends to be easily lost, though the classic description of loss
of the outer-third of the eyebrows is rarely seen.
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27. The Skeleton
• Thyroid hormone deficiency in early life leads to abnormalities of the
epiphyses with marked reduction in linear growth and stunted final height.
• Short stature may be an apparently isolated presentation of
hypothyroidism in childhood.
• In common with all systemic illnesses, prolonged hypothyroidism in
childhood leads to retardation of bone age compared with chronological
age.
• Rates of bone turnover are reduced, leading to a reduction in the pool of
exchangeable calcium.
• Plasma concentrations of calcium and phosphate remain normal. Alkaline
phosphatase activity tends to be low in children with hypothyroidism.
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28. The Kidneys
• Renal blood flow and glomerular filtration are both decreased, but
total body water has been shown to increase with hypothyroidism
• owing to impaired renal excretion of water that itself results from a
reduction in delivery to the distal tubule and abnormal
osmoregulatory function in the hypothalamus and posterior pituitary.
• Although exchangeable body sodium is increased, the dilutional effect
typically leads to a mild hyponatraemia.
• Plasma creatinine and urea concentrations remain normal.
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29. The Reproductive System
• In adults of both sexes, hypothyroidism leads to a reduction in libido
and subfertility.
• Menorrhagia due to failed progesterone secretion with anovulatory
cycles is common in the female, as is oligospermia in the male.
• These changes may be related to impaired luteinizing hormone
secretion, particularly in longstanding cases.
• Basal gonadotrophin concentrations are, however, typically within the
normal range, unless pituitary disease is responsible or the
hypothyroid state.
• A reduction in sex hormone binding globulin concentration leads to
an elevation in free sex hormone concentrations, with a reduction in
total concentrations of both oestrogen and testosterone following
from both this and alterations in sex steroid synthesis.
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30. Other systems
• Cortisol turnover is often reduced and, in some patients, the cortisol
response to hypoglycaemia is blunted
• Hyperprolactinaemia is a common finding, resulting from increased
TRH release.
• The hyperprolactinaemia correlates with the degree of elevation of
TSH, although rank galactorrhoea is only relatively in frequently
found.
• A normochromic anaemia, which may be either normo- or macrocytic
in nature, is often seen and is likely to reflect diminished production
of erythropoietin, with low red cell mass.
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31. • Macrocytosis is frequently ascribed to coincidental occurrence of
vitamin B12 deficiency due to autoimmune pernicious anaemia, but a
deficiency in the response to available B12 and concurrent
malabsorption of folate rom the gut may contribute.
• If menorrhagia has been prolonged or severe, microcytosis, rather
than macrocytosis, may be present as part of an iron deficiency state.
• Plasma concentrations of clotting factors VIII and IX may be reduced
in hypothyroidism and platelet adhesiveness reduced, causing a mild
bleeding tendency that may exacerbate the existing risk of anaemia.
• Glucose absorption from the gut and uptake by the tissues from
plasma are both delayed, but in patients with established diabetes, a
characteristic increase in sensitivity to exogenous insulin is seen,
probably due to decreased clearance of insulin.
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32. Causes
33

33. • Measurement of plasma TSH concentrations provides the cornerstone of
the biochemical evaluation of hypothyroidism.
• As circulating concentrations of thyroid hormone fall, TSH secretion
increases and is used to monitor thyroid status.
• Secretion of T3 is preferentially maintained in the presence of the high TSH
concentrations that accompany declining thyroid function.
• T3/T4 ratios, therefore, rise and plasma T4 concentrations correlate better
with thyroid activity than do plasma T3 concentrations.
• Replacement therapy for primary hypothyroidism can be monitored using
plasma TSH concentrations.
• It should be noted that not all raised concentrations of TSH equate to
hypothyroidism: of possible sources of error clinically, the most important
is hypoadrenalism, which results in a mild to moderately raised TSH (with
completely normal free T4) but treatment with thyroxine (rather than
steroids) will increase metabolism of any remaining cortisol and precipitate
a potentially fatal hypoadrenal crisis.
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34. Types
Primary hypothyroidism:
• Iodine deficiency
• Autoimmune thyroiditis
• Previous thyroidectomy,
• Previous radioiodine treatment,
• Previous external beam radiotherapy to the neck
• Drugs like Amiodarone, Lithium
Central hypothyroidism:
• Lesions compressing the pituitary (pituitary adenoma,
craniopharyngioma, meningioma) 35

35. Iodine deficiency hypothyroidism
• When iodine deficiency is more severe, thyroid hormone production falls
and the patient may experience a hypothyroid condition.
• In such cases, adults have the usual signs and symptoms of
hypothyroidism and may lead to myxedema
• However, congenital hypothyroidism (also known as cretinism) in fetuses
and young children prevents central nervous system development and
maturation, resulting in permanent mental retardation, neurologic
defects and growth abnormalities.
36

36. • Severe iodine deficiency results in impaired thyroid hormone synthesis
and thyroid enlargement (goiter).
• Population effects of severe iodine deficiency, termed iodine deficiency
disorders (IDDs), include
• Endemic goiter
• Hypothyroidism
• Cretinism
• Decreased fertility rate
• Increased infant mortality
• Mental retardation.
37

37. • A significant danger of iodine deficiency is maternal hypothyroidism
leading to an insufficient supply of thyroid hormone to the fetus in
the first half of gestation, when the fetus is entirely dependent on
maternal thyroid hormone.
• Thus maternal hypothyroidism can produce a reduction in the IQ of
the affected child.
• Maternal iodine deficiency will produce fetal iodine deficiency.
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38. Drug induce hypothyroidism
• Durgs such as thionamides or thioureas, propylthiouracil (PTU),
methimazole, and carbimazole inhibit the oxidation of iodide and the
subsequent binding of iodine to tyrosine residues in Tg
• Lithium, which is used in the treatment of bipolar disorder, can induce
hypothyroidism.
• The action of lithium appears similar to that of high-dose iodine,
inhibiting thyroid hormone release and organification of iodine.
• Prolonged use of nitroprusside may lead to hypothyroidism.
39

39. • Cyanide (CN−) released from nitroprusside is metabolically
converted to thiocyanate (SCN−), which inhibits iodide uptake by
the thyroid gland.
• Amiodarone is an antiarrhythmic drug that contains two iodine
atoms per molecule and can induce hypothyroidism or
hyperthyroidism.
• Various recombinant DNA-derived biologicals substance used to
treat chronic viral hepatitis or cancer have been found to cause
thyroid dysfunction like interferon-alpha, interleukin-2
40

40. Surgical and Radiation-Induced Hypothyroidism
• Although the hypothyroidism developing after surgery or iodine therapy
or Graves disease is usually permanent, it may be temporary, especially
in the first 3–4 months.
• If symptomatic at this early stage, patients should be treated with a
relatively small dose of thyroxine and the need or continued treatment
assessed at six months.
• If serum TSH remains elevated, thyroxine therapy will be required
lifelong.
• If at that stage serum TSH is normal or undetectable, stopping the
thyroxine for four weeks and retesting thyroid function would be the
appropriate action.
41

41. Autoimmune thyroid disease
• Hashimoto thyroiditis is characterized by the destruction of thyroid cells
by various cell- and antibody-mediated immune processes.
• Females are affected with greater frequency than males.
• The gland is typically enlarged but small and firm in early cases, with a
palpable pyramidal lobe.
• At this stage, hyperthyroidism may transiently occur, but further gland
damage rapidly leads to permanent hypothyroidism, at which stage
goitre regresses and the gland remnant is composed of fibrous tissue.
42

42. • Patients with Hashimoto thyroiditis have antibodies to various thyroid
antigens;
• anti-thyroid peroxidase (anti-TPO),
• antithyroglobulin (anti-Tg),
• TSH receptor-blocking antibodies (TBII).
• In about half of patients with Hashimoto thyroiditis, serum TSH is
elevated and T4 normal (subclinical hypothyroidism), the other patients
having overt thyroid failure.
43

43. Pathogenesis
• There is a marked lymphocytic infiltration of the thyroid with germinal
center formation, atrophy of the thyroid follicles, absence of colloid,
and mild to moderate fibrosis.
• In atrophic thyroiditis, the fibrosis is much more extensive, lymphocyte
infiltration is less pronounced, and thyroid follicles are almost
completely absent.
• Atrophic thyroiditis likely represents the end stage of Hashimoto's
thyroiditis rather than a distinct disorder.
44

44. • In Hashimoto disease destructive thyroiditis results from both a cell-
mediated and humoral attack on the thyroid tissue.
• The gland is typically enlarged but small and firm in early cases, with a
palpable pyramidal lobe.
• Hyperthyroidism may transiently occur.
• But further gland damage rapidly leads to permanent hypothyroidism
• Regression of Goiter and the gland remnant will composed of fibrous
tissue.
45

45. • The process gradually reduces thyroid function
• There is a phase of compensation when normal thyroid hormone
levels are maintained by rise in TSH.
• Later, T4 levels fall and TSH levels rises further
• Symptoms become more readily apparent at this stage which is
referred to as clinical hypothyroidism or overt hypothyroidism
46

46. Viral or Bacterial Thyroiditis
• occur very rarely
• De Quervain thyroiditis is an unusual condition, which often follows a viral
illness.
• Patients typically present with pain in the thyroid and neck region with ever
and malaise. Thyroid function tests may transiently become hyperthyroid,
then hypothyroid
• Riedel thyroiditis is a condition of unknown aetiology. Extensive
replacement of the thyroid with fibrous tissue causes the gland to become
stony hard. Hypothyroidism is a rare complication.
• Viral infection of the thyroid gland is termed subacute thyroiditis and can
produce generalized thyroid gland tenderness.
• Bacterial infection of the thyroid gland is termed acute thyroiditis and can
produce a thyroid abscess.
47

47. Central Hypothyroidism
• Central hypothyroidism is defined as hypothyroidism due to insufficient
stimulation of the thyroid gland by TSH.
• Secretion of TSH can be impaired at the hypothalamic or pituitary levels.
• Causes of central hypothyroidism include
1. tumor,
2. hemorrhage,
3. trauma,
4. malformation,
5. post-infectious damage, and
6. postsurgical damage.
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48. Congenital hypothyroidism
• Congenital hypothyroidism is inadequate
thyroid hormone production in newborn
infants.
• This can occur due to
• an anatomic defect in the gland,
• an inborn error of thyroid metabolism,
• iodine deficiency and ineffective
transport.
• Inability to organify trapped thyroidal
iodide
49

49. Secondary Hypothyroidism
• Loss of TSH drive to thyroid function may result from any of the causes
of pituitary gland hypo function.
• Recognition of the aetiology of this type of hypothyroidism is critical and
is usually made by observing a low T4 accompanied by an
inappropriately ‘normal’ TSH concentration.
• In some cases of secondary hypothyroidism, TSH may be slightly
increased.
• Increased T3:T4 ratios are not seen in this type of hypothyroidism as TSH
drive is absent.
50

50. Myxedema Coma
• Myxedema coma is life-threatening condition
• The term myxedema refers to the thickened, nonpitting edematous
changes to the soft tissues of patients in a markedly hypothyroid state.
• This is a relatively uncommon endocrine emergency that may be
triggered by factors such as infection, cold exposure, the use of sedative
medications or non-compliance with treatment
• It occurs late in the progression of hypothyroidism.
51

51. • The condition is seen typically in elderly women and is often
precipitated by infection, medication, environmental exposure, or
other metabolic-related stresses.
• Symptoms can manifest in all organ systems and range in severity
based on the degree of hormone deficiency.
• The classic presentation is that of decompensated hypothyroidism
with altered sensorium, marked bradycardia, hypothermia and
circulatory collapse
52

52. • The disease typically progresses over months to years onset of
disease is quick following cessation of thyroid replacement
medication or surgical removal of the thyroid gland.
• If condition of hypothyroid progress leads to
• Decreasing mental ability
• Cardio vascular collapse
• Severe electrolyte imbalance
• Cerebral hypoxia (elevated CO2 levels)
• Severe hypothermia
• Coma
53

53. Treatment:
Hormone replacement:
• Thyroxin, known as levothyroxine: In patients with hypopituitarism,
with both secondary adrenal and thyroid failure, it is important that
levothyroxine is not started before hydrocortisone replacement, as
this might precipitate adrenal crisis by increasing the metabolic rate in
a patient unable to secrete cortisol
• The response to treatment in patients with secondary hypothyroidism
should be based on FT4 measurements since TSH secretion is
deficient in pituitary disease.
• The therapeutic goal in such cases would be a FT4 in the upper-third
of the reference range.
• The combination of a raised serum T4 and TSH is suggestive of poor
compliance
54

54. Subclinical Hypothyroidism
• This is the term used to describe patients who are clinically euthyroid
with normal serum T4 concentration but raised TSH, usually <10 mU/L.
• There may be mild non-specific symptoms, such as tiredness, weight
gain and depression.
• Now viewed as the mildest form of thyroid failure, it is common
practice to treat with thyroxine if antibodies are positive and/or serum
TSH is >10 mU/L in order to ‘nip things in the bud’ before the
progression to overt thyroid failure (5% per year), and the possibility of
loss to follow-up and later presentation with severe hypothyroidism.
• Recovery from non-thyroidal illness should be excluded before a
diagnosis of subclinical hypothyroidism is made, emphasizing that in all
cases thyroid function tests should be repeated and confirmed as
remaining abnormal before initiating therapy.
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55. Indications
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56. THANK-YOU 58