Hypothyroidism..introduction prevalence clinical features instigation treatment and its effect on renal diseases

1. HYPOTHYROIDISM
DR Bibek Raj Parajuli
College of Medical
Sciences, Bharatpur
Nepal.
1

2. INTRODUCTION
 Hypothyroidism, also known as underactive
thyroid, is a condition where the thyroid gland
does not create enough of a thyroid hormone
called thyroxin
 abnormally low activity of the thyroid gland,
resulting in retardation of growth and mental
development in children and adults
 Cretinism is a neonatal form of hypo thyroidism
due to iodine deficiency during pregnancy. New
born is pale has puffy face, pot belly and mental
retardation.
2

3. 3

4. PREVALENCE
common disorder, esp. after the onset of middle age,
women > men ; is five to eight times more common in
women than men, increasing incidence with age.
more common in women with small body size at birth
and during childhood
In community surveys, the prevalence of overt
hypothyroidism varies from 0.1 to 2 percent
The prevalence of subclinical hypothyroidism is
higher, ranging from 4 to 10 percent of adults, with
possibly a higher frequency in elderly women
Iodine deficiency remains the most common cause
worldwide.
In areas of iodine sufficiency, autoimmune disease
and iatrogenic causes are most common.
4

5. In the United States National Health and Nutrition
Examination Survey (NHANES III), 13,344 people
without known thyroid disease or a family history of
thyroid disease had measurements of serum TSH, T4,
thyroglobulin antibodies, and thyroid peroxidase
antibodies with the following results:
Hypothyroidism was found in 4.6 percent (0.3 percent
overt and 4.3 percent subclinical).
Hyperthyroidism was found in 1.3 percent (0.5
percent overt and 0.7 percent subclinical).
Serum thyroid peroxidase antibody concentrations
were high in 11 percent.
Mean serum TSH concentrations were significantly
lower in blacks than in whites or Mexican-Americans.
Thus, a significant proportion of the US population
has laboratory evidence of thyroid disease,
suggesting that routine screening could be useful
5

6. CLASSIFICATION
•
time of onset (congenital or acquired)
• the level of endocrine dysfunction
(primary or secondary),
• severity (clinical /overt and subclinical / mild).
6

7. BY DEFINITION, SUBCLINICAL HYPOTHYROIDISM REFERS
TO BIOCHEMICAL EVIDENCE OF THYROID HORMONE
DEFICIENCY IN PATIENTS WHO HAVE FEW OR NO APPARENT
CLINICAL FEATURES OF HYPOTHYROIDISM.
THERE ARE NO UNIVERSALLY ACCEPTED
RECOMMENDATIONS FOR THE MANAGEMENT OF
SUBCLINICAL HYPOTHYROIDISM, BUT THE MOST RECENTLY
PUBLISHED GUIDELINES DO NOT RECOMMEND ROUTINE
TREATMENT WHEN TSH LEVELS ARE BELOW 10 MU/L.
SUBCLINICAL HYPOTHYRODISM7

8. ETIOLOGY:
Causes of Hypothyroidism
Primary
Autoimmune hypothyroidism: Hashimoto's
thyroiditis, atrophic thyroiditis
Iatrogenic: 131I treatment, subtotal or total
thyroidectomy, radiation
Drugs: iodine excess (iodine-containing contrast
media ,amiodarone), lithium, antithyroid drugs, p-
aminosalicylic acid, interferon- and other
cytokines, aminoglutethimide, sunitinib
Congenital hypothyroidism: absent or ectopic
thyroid gland, dyshormonogenesis, TSH-R
mutation
Iodine deficiency
Infiltrative disorders: amyloidosis, sarcoidosis,
hemochromatosis, scleroderma, cystinosis,
Riedel's thyroiditis
Overexpression of type 3 deoiodinase in infantile
hemangioma
8

9. Transient
Silent thyroiditis, including postpartum thyroiditis
Subacute thyroiditis
Withdrawal of thyroxine treatment in individuals
with an intact thyroid
After 131I treatment or subtotal thyroidectomy for
Graves' disease
Secondary
Hypopituitarism: tumors, pituitary surgery or
irradiation, infiltrative disorders, Sheehan's
syndrome, trauma, genetic forms of combined
pituitary hormone deficiencies
Isolated TSH deficiency or inactivity
Hypothalamic disease: tumors, trauma, infiltrative
disorders, idiopathic
9

10. THERE THE FOLLOWING 5 STEPS IN THE
HORMONOGENESIS
Iodine
from
dietary
Iodides
Trapping
of
inorganic
Activatio
n of
Iodine to
high
valance I2
Incorporatio
n of I2 into
Tyrosine of
Thyroid
Globulin
Coupling of
formed MIT
(monoiodoty
rosine) and
DIT
(diiodotyrosi
ne) to form
T4 & T3
Proteolysis of
Thyroglobulin
to release T4 &
T3
10

11. 11

12. THYROID REGULATION
PLASMA T4 + FT4
HYPOTHALAMUS - TRH
ANT. PITUITARY - TSH
THYROID T4 and T3
PLASMA T3 + FT3
TISSUES FT4 to FT3, rT3
12

13. T.F.T. in Progressive
Hypothyroidism
Normal Range
FREE
T4
FREE
T3
MILD MODERATE SEVERE
13

14. Clinical-features
Many of the manifestations of
hypothyroidism reflect one of
two changes induced by lack of
thyroid hormone
1.A generalized slowing of
metabolic processes :
This can lead to abnormalities
such as fatigue, slow movement
and slow speech, cold
intolerance, constipation, weight
gain (but not morbid obesity),
delayed relaxation of deep
tendon reflexes, and bradycardia
14

15. 2.Accumulation of matrix
glycosaminoglycans in the
interstitial spaces of many tissues
This can lead to coarse hair and
skin, puffy facies, enlargement of
the tongue, and hoarseness. These
changes are often more easily
recognized in young patients, and
they may be attributed to aging in
older patients
15

16. Mental slowness
Psychosis/dementia
Periorbital oedema
Ataxia
Deep voice
Poverty of movement (Goitre)
Deafness
Dry skin
Mild obesity
Pericardial effusion
Cold peripheries
Anaemia
SIGNS
16

17. Dry thin hair
Loss of eyebrows
Hypertension
Myotonia
Hypothermia
Muscular hypertrophy
Heart failure
Proximal myopathy
Bradycardia
Carpal tunnel syndrome
Oedema
Delayed tendon reflex relaxation
17

18. 18

19. INVESTIGATIONS:
Raised TSH: primary hypothyroidism irrespective
of its
cause and severity
• a free T4 level and increased TSH: clinical ~
• only free T4: will not detect subclinical ~
• secondary hypothyroidism: low free T4 level
regardless of TSH, investigation : pituitary
imaging, a
thyroid releasing hormone stimulation test to
assess TSH
responsiveness and other pituitary function
testing
should performed
• TPO : 90 to 95% of patients with autoimmune
hypothyroidism.
•goiter associated with hypothyroidism: FNAC
19

20. OTHER LABORATORY ABNORMALITIES:
• Anaemia: usually normochromic and
normocytic in type but may be macrocytic
(sometimes this is due to associated pernicious
anaemia) or microcytic (in women, due to
menorrhagia)
• increased serum AST levels, from muscle and/or
liver
• increased serum CK levels, with associated
myopathy
• hypercholesterolaemia
• hyponatraemia due to an increase in ADH and
impaired free water clearance
20

21. THYROID FUNCTION TESTS IN PATIENTS WITH
KIDNEY DISEASE
The kidney plays a role in clearance
of iodine, TSH, and thyrotropin-
releasing hormone.
However, most patients with CKD are
euthyroid, with normal TSH and free
T4 levels.
Patients with AKI and some with
advanced CKD may have changes in
thyroid function tests consistent with
the euthyroid sick syndrome; that is,
low T4, T3, and TSH concentrations.21

22. Cystatin C is a cysteine proteinase inhibitor that
is produced at a constant rate by most nucleated
cells, freely filtered at the glomerulus, and then
reabsorbed and metabolized by proximal tubular
epithelial cells
Somewhat surprisingly, studies in humans and
animals show that serum cystatin C levels
generally trend in the opposite direction to those
of creatinine that is, cystatin C is commonly
elevated in hyperthyroid patients and decreased
in hypothyroid patients.
hypothesized to be a direct effect of thyroid
hormone on cystatin C production, although the
exact mechanism is not known.
Cystatin C should not be used for assessment of
GFR in patients with thyroid disease.
22

23. THYROID DYSFUNCTION IN
KIDNEY DISEASES
23

24. Thyroid Dysfunction in Kidney
diseases
The kidney normally plays an important role in the
metabolism, degradation, and excretion of several thyroid
hormones.
Impairment in kidney function leads to disturbed thyroid
physiology.
All levels of the hypothalamic-pituitary-thyroid axis may be
involved, including alterations in hormone production,
distribution, and excretion.
Thyroid hormones (TH) are necessary for growth and
development of the kidney and for the maintenance of water
and electrolyte homeostasis. On the other hand, kidney is
involved in the metabolism and elimination of TH. From a
clinical practice viewpoint, it should be mentioned that both
hypothyroidism and hyperthyroidism are accompanied by
remarkable alterations in the metabolism of water and
electrolyte, as well as in cardiovascular function
24

25. Thyroid function also influences water and
electrolyte balance on different compartments of
the body.
The kidney also plays a role on the regulation of
metabolism and elimination of TH and is an
important target organ for TH actions.
The decrease in the activity of TH is accompanied
by an inability to excrete an oral water overload .
This effect is not due to an incomplete
suppression of vasopressin production, or a
decrease in the reabsorptive ability in the dilutor
segment of the kidney tubule, but rather to a
reduction in the glomerular filtration rate (GFR)
25

26. Thyroid Dysfunction in Glomerular
diseases
Both hypothyroidism and
hyperthyroidism can coincide with
different forms of glomerular disease
Proteinuria may promote the
development of primary hypothyroidism,
and the immune activation of the
thyroid or kidney disorders could induce
the formation of immunocomplexes .
Glomerular disease in general is
associated and occasionally caused by
autoimmune disease (e.g. lupus
nephritis, antineutrophil cytoplasmic
antibodies (ANCA) associated vasculitis)
that can be associated to autoimmune
thyroid disease.
26

27. Thyroid dysfunction in tubular
diseases
Less frequently than glomerular
disease
Isolated cases of hyperthyroidism
have been reported in association
with tubulointerstitial nephritis and
uveitis, a self-limited syndrome of
unknown etiology that responds to
glucocorticoids
27

28. Thyroid dysfunction in Nephrotic
Syndrome
associated with changes in serum TH levels,
reasons are:
Urinary losses of binding proteins
reduction in serum total thyroxine (T4) and, sometimes,
in total T3 levels
These hormonal changes are related both to the
degree of proteinuria and to serum albumin levels
However, patients often remain euthyroid, because
free T4 and T3 levels are usually normal
Thyroid is able to compensate for hormonal urinary
losses keeping the patient euthyroid.
However, in patients with low thyroid reserve overt
hypothyroidism can develop.
Similarly, NEPHROTIC SYNDROME may increase
the exogenous levothyroxine needs in patients with
hypothyroidism
28

29. Thyroid dysfunction in Acute Kidney
injury
Associated with abnormalities in
thyroid function tests similar to
those found in euthyroid sick
syndrome (ESS).
Contrary to the usual form of the
ESS, patients with AKI may not
exhibit an elevation or reverse
(r)T3levels
29

30. Euthyroid Sick Syndrome
tests that occur in the setting of a
nonthyroidal illness (NTI), without
preexisting hypothalamic-pituitary and
thyroid gland dysfunction.
After recovery from an NTI, these thyroid
function test result abnormalities should
be completely reversible
30

31. HYPOTHYROIDISM IN CHRONIC KIDNEY DISEASE
CKD affects both hypothalamus–pituitary–thyroid axis
and TH peripheral metabolism .
Uremiainfluences the function and size of the thyroid
Uraemic patients have an increased thyroid
volume compared with subjects with normal renal
function and a higher prevalence of goiter, mainly in
women .
Also, thyroid nodules and thyroid
carcinoma are more common in uraemic patients than
in the general population31

32. CAUSES OF THE HYPOTHYROIDISM IN CKD
1.INCREASED IODINE IN BODY
WOLF CHAIKOFF EFFECT
(HYPOTHYROIDISM)
2. ABNORMAL RESPONSE TO TSH
IMPAIRED CR ALTERED GLYCOSYLATION32

33. THE WOLFF–CHAIKOFF EFFECT (PRONOUNCED
"WOOLF' CHA'KOF"), DISCOVERED BY DRS. JAN
WOLFF AND ISRAEL LYON CHAIKOFF AT THE
UNIVERSITY OF CALIFORNIA, IS A REDUCTION
IN THYROID HORMONE LEVELS CAUSED BY
INGESTION OF A LARGE AMOUNT OF IODINE.
The Wolff–Chaikoff effect is an autoregulatory
phenomenon that inhibits organification in the thyroid
gland, the formation of thyroid hormones inside the
thyroid follicle, and the release of thyroid hormones into
the bloodstream
33

34. Low T3 levels —
Most patients with end stage renal disease have
decreased plasma levels of free triiodothyronine
(T3), which reflect diminished conversion of T4
(thyroxine) to T3 in the periphery.
This abnormality is not associated with increased
conversion of T4 to the metabolically inactive
reverse T3 (rT3), since plasma rT3 levels are
typically normal. This finding differentiates the
uremic patient from patients with chronic illness
In the latter setting, the conversion of T4 to T3 is
similarly reduced, but the generation of rT3 from
T4 is enhanced
34

35. Uremia influences the function and size of the
thyroid .
Uraemic patients have an increased thyroid
volume compared with subjects with normal renal
function and a higher prevalence of goiter, mainly
in women.
Also, thyroid nodules and thyroid carcinoma are
more common in uraemic patients than in the
general population.
35

36. 36

37. Hypothalamic-pituitary dysfunction —
The plasma concentration of thyroid stimulating
hormone (TSH) is usually normal in chronic
kidney disease .
However, the TSH response to exogenous
thyrotropin-releasing hormone (TRH) is often
blunted and delayed, with a prolonged time
required to return to baseline levels
Reduced renal clearance may contribute to
delayed recovery, since TSH and TRH are
normally cleared by the kidney. However, the
blunted hormone response also suggests
disordered function at the hypothalamic-pituitary
level that may be induced by uremic toxins.
When compared to normals, patients with chronic
kidney disease have an attenuated rise in TSH
levels during the evening hours and the normally
pulsatile secretion of TSH is smaller in amplitude
37

38. Figure 2 Effects of CKD on hypothalamus–pituitary–thyroid axis.
Iglesias P , and Díez J J Eur J Endocrinol 2009;160:503-515
© 2009 European Society of Endocrinology
38

39. CKD is associated with a higher prevalence of
primary hypothyroidism, both overt and subclinical,
but not with hyperthyroidism
In fact, the prevalence of primary hypothyroidism,
mainly in the subclinical form, increases as GFR
decreases .
A recent study has shown a prevalence of subclinical
hypothyroidism of 7% in patients with estimated GFR
90 ml/min per 1.73 m2 that increased to 17.9% in
subjects with GFR!60 ml/min per 1.73 m2 .
The prevalence of hypothyroidism is higher in women
and is associated with an increased frequency of high
titers of anti-thyroid antibodies
39

40. Serum iodine concentrations are high in CKD but
are not correlated with the degree of kidney
failure .
This iodine excess has been linked to increased
prevalence of goiter and hypothyroidism reported
in CKD.
A high exposure to iodine facilitates the
development of hypothyroidism in CKD patients
some authors have reported that a restriction of
dietary iodine in uraemic patients on HD can
correct the hypothyroidism avoiding the need for
hormone replacement with levothyroxine
40

41. Multiple direct and indireMultiple direct and indirect effects of thyroid hormone on GFR. NOS,
nitric oxide synthase; SVR, systemic vascular resistance; CO, cardiac output.
Multiple direct and indirect effects of thyroid hormone on GFR. NOS, nitric oxide synthase;
SVR, systemic vascular resistance; CO, cardiac output.
ct effects of thyroid hormone on GFR. NOS, nitric oxide synthase; SVR, systemic vascular
resistance; CO, cardiac output.
Laura H. Mariani, and Jeffrey S. Berns JASN 2012;23:22-26
©2012 by American Society of Nephrology
41

42. THYROID ABNORMALITIES IN CKD:
↓ T3,
normal total rT3,
T4 either low or normal
TSH normal, rises appropriately in
hypothyroidism
Slight ↑ incidence of goiter
Effect of Heparin(Used in dailysis):
Increased free T4 only
Displacement of T4 from TBG
(TSH normal)
42

43. TREATMENT OF
HYPOTHYRODISM
43

44. • ~ treated with thyroxine
• start slowly 50 μg/d for 3 weeks, then 100 μg/d
further 3 weeks and finally to 150 μg/d
• Thyroxine should always be taken as a single
daily dose as it has a plasma half-life of
approximately 7 days.
should be taken on an empty stomach, ideally an
hour before breakfast
• The dose is adjusted on the basis of TSH levels,
with the goal of treatment being a normal TSH,
ideally in the lower half of the reference range
44

45. TSH responses are gradual; measured 4-6
weeks after instituting treatment or after any
subsequent change in levothyroxine dosage.
• Patients may not experience full relief from
symptoms until 3 to 6 months after normal TSH
levels are restored.
• Adjustment of thyroxine dosage is made in
12.5- or 25-ug increments
• TSH levels are stable, follow-up measurement of
TSH is at annual intervals and may be extended
to every 2 to 3 years
45

46. Mechanism of Action of Thyroxine
T4 is converted to T3 in cells by a deiodinase
enzyme. T3 binds to nuclear receptors and
regulates gene transcription. This leads to
multiple metabolic actions. In some tissue (e.g.
the pituitary) there is an obligatory requirement
for a high percentage of T3 to be derived from
intracellular T4 conversion. For this reason, T4 is
a more effective hormone in suppression of TSH
than is T3 and is therefore the preferred thyroid
hormone for replacement
46

47. Pharmacokinetics
Both T4 and T3 are adequately absorbed following
oral administration. T4 has a half-life of about a
week and T3 about 2 days. Both undergo
conjugation in the liver and enterohepatic
circulation.
47

48. Adverse effects:
These are related to the physiological and
pharmacological actions of thyroid hormone.
Elderly patients, or those known to have
ischaemic heart disease, are given low initial
doses with slow increments because angina or
myocardial infarction can be precipitated.
Thyroid hormone excess produces the usual
clinical features of thyrotoxicosis
48

49. RAPID REVIEW PATHOLOGY THIRD
EDITION EDWARD F. GOLJAN, MD
HARRISON'S™ PRINCIPLES OF
INTERNAL MEDICINE
EIGHTEENTH EDITION
EUROPEAN JOURNAL OF
ENDOCRINOLOGY
JOURNAL OF THE AMERICAN SOCIETY
OF NEPHROLOGY
REFERENCES:
Update to date
49

50. THANK YOU
50