Thyroid Physiology and
NonThyroidal Illness
Gita Majdi
March 2014
Outline
• Thyroid hormone synthesis
• Action of thyroid hormone
• Nonthyroidal Illness
Thyroid
35-30 grams in adults
Thyroid Follicle
Thyroid gland consists of numerous spherical
follicles .
Interior of the follicle is filled with the clear,
proteinaceous material colloid, containing
large amounts of thyroglobulin.
T4
•
Daily synthesis of 110 nmol/lit (85 mcg)
of T4
From the apex of follicular cells, numerous
microvilli extend into the follicle.
Apical membrane : iodination, exocytosis and
initial phase of hormone secretion occur
Specific tyrosine residues of TG homodimers
are iodinated at the apical borders of thyroid
cells to form MIT & DIT.
T4 &T3 are transported out of the
phagolysosomes and across the basolateral
cell membrane, exit the cell, and enter
circulation.
Thyroid Hormone synthesis
• Formation of normal quantities of thyroid hormone requires the
availability of exogenous iodine.
• At least 100 microgram of Iodine per day is required to eliminate all
signs of iodine deficiency.
• In healthy adult, absorption of iodide(I- ) is 90%.
• Plasma iodide is completely filterable.(60-70% of filtered Ioad
reabsorbed ).
• The concentration of iodide in the extracelluar fluid is 10-15 mcg/lit.
• Thyroid contains 8000 mcg of iodine.
Clinical Pearls
Antithyroid drugs : Methimazole,
Carbimazole and PTU inhibit TPO,so
intrathyroidal iodine deficiency will happen.
TSH Receptor
TSH Receptor has seven
transmembrane domain , a large
extracellular domain and a small
intracellular domain.
After activation receptor cleaves into α
and β subunits.
The α subunits is shed from the cell
surface.
The α subunit has TSH binding activity
and it is water soluble.
Thyroid hormones in
Peripheral tissue
T4 concentration is highest and only
arises from thyroid.
80% of T3 is derived from the
peripheral tissues by enzymatic
removal of a single 5’iodine atom
from T4.
The Plasma proteins with which T4
is mainly associated are TBG ,
transthyretin(TTR, formerly T4
binding pre albumin and albumin.
TBG
Thyroxine Binding Globulin is a
glycoprotein .
There is one iodothyronine binding site per
TBG molecule.
TBG concentration is 270 nmol/lit ( 1.5
mcg/dl)
The half life of protein in plasma is 5 days.
Estrogen and acute hepatitis will increase
TBG.
TBG binding site has an affinity for T3 that
is 20 fold less than that for T4.
Binding of T4&T3 by TBG is inhibited by
phenytoin, salicylate and furosemide .
Patients receiving these medications have
low total hormones.
• Parameter
T3
T4
• Production rate (nmol/day)
50
110
•
Fraction from thyroid
0.2
1
• Relative metabolic potency
• Serum concentration
• Total (nmol/L)
1
0.3
1.8
100
•
Free (pmol/L)
• Distribution volume (L)
5
20
40
10
• Fraction intracellular
0.64
0.15
• Half-life (days)
0.75
6.7
Thyroid hormones in
peripheral Tissue
Cellular uptake and efflux of thyroid
hormone is mediated by transporter
proteins.
Thyroid hormone transporter for T3 ,T4, rT3
and T2 : MCT 8 & OATP
(monocarboxylate transporter )
OATP= organic anion transporting
polypeptide
Mutation in MCT8 gene has shown to cause
severe developmental neurologic phenotype
Thyroid hormone in
peripheral Tissues.
T4
D1 & D2
T3
The T3 produced by D2(close to the nucleus)
is especially effective In entering the nucleus
and binding to thyroid hormone receptor.
D2 serves the special purpose of prviding
nuclear T3 from intracellular T4.
T4 by D3 converts to rT3.
T3 by D3 converts to T2.
D3 is thyroid hormone inactivating enzyme .
Highest D3 activity reported in infantile
hemangioma (consumptive Hypothyroidism)
D1,D2 and D3 contain rare amino acid
selenocysteine.
Preferred substrate for D1 is rT3.
D1 is inhibited by PTU.
Thyroid hormone acts by binding to a specific
nuclear receptors(TR) which inturn binds to
DNA as a heterodimer with retinoid X
receptor (RXR)at specific elements called
TREs.(thyroid hormone response elements)
T3 has a 15 fold higher affinity for TR than
T4.
In humans there are two TR genes, TRα and
TRβ. (chromosome 17 &3)
Thyroid Receptor
The active proteins are TRα and TR β1, Tβ2
and TRβ3.
There are tissue specific preferences in
expressions of the various TR.
in human families with resistance to thyroid
hormone, a condition in which TRβ mutations
markedly reduce the binding affinity of TRβ
for T3 were identified.
Thyroid hormone action
Thyroid hormones are critical determinants
of brain and somatic development in infants
and of metabolic activity in adults; they also
affect the function of virtually every organ
system. Thyroid hormones must be
constantly available to perform these
functions.
Thyroid hormone
Action:
There are two thyroid hormone nuclear
receptors (TR), alpha and beta . T3 binds to
these TRs, and the T3-TR complexes then
bind to regulatory regions contained in the
genes that are responsive to thyroid
hormone. TRs without T3 bind to nuclear
receptor co-repressors and then to
regulatory regions of genes normally induced
by T3, resulting in repression of gene
expression
Thyroid hormone, in the form of
triiodothyronine (T3), acts by modifying
gene transcription in virtually all tissues to
alter rates of protein synthesis and
substrate turnover.
T3 has different actions in different
tissues. These differences are
determined by variations in both local
production of T3 and the tissue
distribution and content of TR isoforms.
The deiodinases that convert the
prohormone T4 to the active hormone T3
and convert T3 to diiodothyronines are
also expressed in a development- and
tissue-specific pattern
Thyroid Hormone Action
• Thyroid hormones stimulate diverse metabolic activities most tissues,
leading to an increase in basal metabolic rate.
• One consequence of this activity is to increase body heat production,
which seems to result, at least in part, from increased oxygen consumption
and rates of ATP hydrolysis.
• Lipid metabolism: Increased thyroid hormone levels stimulate fat
mobilization, leading to increased concentrations of fatty acids in plasma.
• They also enhance oxidation of fatty acids in many tissues.
• Finally, plasma concentrations of cholesterol and triglycerides are inversely
correlated with thyroid hormone levels - one diagnostic indication of
hypothyroidism is increased blood cholesterol concentration.
Clinical Pearls
• The identification of development- and tissue-specific pathways of
thyroid hormone action is being translated into novel therapies.
• Hypercholesterolemic patients not at LDL target levels while on
statins were given eprotirome (KB2115), a TR-beta selective agonist.
Treatment for 12 weeks resulted in reduced total and LDL-cholesterol
in all patients and also reduced triglycerides in those individuals with
elevated baseline triglyceride levels.
• A cardio-selective thyroid hormone analog, DITPA, has had some
utility in treatment of congestive heart failure, although a longer
study resulted in significant toxicity, especially metabolic, and the trial
was stopped.
Thyroid hormone Action:
• Carbohydrate metabolism: Thyroid hormones stimulate almost
all aspects of carbohydrate metabolism, including enhancement
of insulin-dependent entry of glucose into cells and increased
gluconeogenesis and glycogenolysis to generate free glucose.
• Growth: Thyroid hormones are clearly necessary for normal
growth in children and young animals, as evidenced by the
growth-retardation observed in thyroid deficiency.
• The growth-promoting effect of thyroid hormones is intimately
intertwined with that of growth hormone, a clear indication that
complex physiologic processes like growth depend upon
multiple endocrine controls.
Thyroid Hormone Action:
• Development: Normal levels of thyroid hormone are essential to the
development of the fetal and neonatal brain.
• Cardiovascular system: Thyroid hormones increases heart rate, cardiac
contractility and cardiac output. They also promote vasodilation, which
leads to enhanced blood flow to many organs.
• Central nervous system: Both decreased and increased concentrations of
thyroid hormones lead to alterations in mental state. Too little thyroid
hormone, and the individual tends to feel mentally sluggish, while too
much induces anxiety and nervousness.
• Reproductive system: Normal reproductive behavior and physiology is
dependent on having essentially normal levels of thyroid hormone.
Hypothyroidism in particular is commonly associated with infertility.
Thyroid Function in NonThyroidal Illness
• Assessment of thyroid function in patients with nonthyroidal illness is
difficult, especially among those hospitalized in an intensive care unit.
• Many of them have low T4 andT3 and their serum thyrotropin TSH
concentration also may be low.
• Previously, these patients were thought to be euthyroid, and the
term euthyroid-sick syndrome was used to describe the laboratory
abnormalities .
• There is some evidence that these patients may have acquired transient
central hypothyroidism .
• Despite these abnormalities, treatment of these patients with thyroid
hormone, while controversial, appears to be of little benefit, and may be
harmful.
• It is possible that the changes in thyroid function during severe illness
are protective in that they prevent excessive tissue catabolism.
NonThyroial Illness
• Thyroid function should not be assessed in seriously ill patients unless
there is a strong suspicion of thyroid dysfunction.
• When thyroid dysfunction is suspected in critically ill patients,
measurement of serum TSH alone is inadequate for the
evaluation of thyroid function.
Low T3
The majority of hospitalized patients have
low serum T3 concentrations, as do some
outpatients who are ill.
Unlike T4, which is produced solely within the
thyroid, 80 percent of circulating T3 is produced by
the peripheral 5'-deiodination of T4 to T3, a reaction
catalyzed by 5'-monodeiodinases in organs such as
the liver and kidney.
5'-monodeiodination decreases whenever caloric
intake is low and in any nonthyroidal illness, even
mild illness.
Reverse T3 (rT3) is the product of 5monodeiodination of T4 (type III T4-5-deiodinase).
The clearance of reverse T3 to diiodothyronine (T2)
is reduced in nonthyroidal illness because of
inhibition of the 5'-monodeiodinase activity As a
result, serum rT3 concentrations are high in patients
with nonthyroidal illnesses , except in those with
renal failure and some with AIDS
• Mechanisms of inhibition of 5'-monodeiodination and therefore
low serum T3 concentrations in patients with nonthyroidal
illness:
1-High endogenous serum cortisol concentrations and
exogenous glucocorticoid therapy
2- Circulating inhibitors of deiodinase activity, such as free (nonesterified) fatty acids
3-Treatment with drugs that inhibit 5'-monodeiodinase activity
such as amiodarone and high doses of propranolol.
4-Cytokines (such as tumor necrosis factor, interferon-alfa and
interleukin-6).
FT4
Small reductions in binding proteins should
not alter serum free T4 index or direct free
T4 values, and these values are usually
normal in patients whose illness is not
severe.
Low T4
From 15 to 20 percent of hospitalized
patients and up to 50 percent of patients
in intensive care units have low serum T4
concentrations (low T4 syndrome).
The concentrations are low primarily
because of reductions in the serum
concentrations of one or more of the
three thyroid hormone-binding proteins.
thyroxine-binding globulin (TBG),
transthyretin (TTR, or thyroxine-binding
prealbumin [TBPA]), and albumin.
FT4
Despite the theoretical attraction of
measuring the concentration of free or
biologically active hormone, it remains
uncertain whether current free T4
methodology is any improvement over an
uncontentious measurement of total T4“.
Possible contributing factors for decreased T4 and free T4: inhibitors of T4 binding
• Some data support the possibility that high serum free fatty
acid concentrations inhibit T4 binding to serum proteins.
• Serum free fatty acid, particularly oleic acid concentrations, may
be high in critically ill patients and their effect on T4 binding may
be increased because of hypoalbuminemia.
• Albumin is the major carrier of free fatty acids in serum.
However, this phenomenon may be an in vitro effect of fatty
acids released during collection and transport of the serum
sample.
Transient Central Hypothyroidism (1)
• Patients with severe nonthyroidal illness may have acquired transient
central hypothyroidism. This suggestion is supported by the following
observations:
• A prospective study evaluated changes in thyroid function in patients
undergoing bone marrow transplantation: serum TSH concentrations fell
coincident with declines in serum T4 concentrations.
• A study of critically ill patients recovering from nonthyroidal illness
demonstrated that a rise in serum TSH concentration (which transiently
reached supranormal values in some patients) preceded normalization of
serum T4 concentrations.
• Patients with nonthyroidal illness, similar to those with central
hypothyroidism from other causes, have a blunted nocturnal rise in serum
TSH concentrations, but usually have a normal serum TSH response to
thyrotropin-releasing hormone (TRH) .
Central Hypothyroidism (2)
• Abnormalities in TSH glycosylation that may decrease TSH bioactivity have
been found in patients with nonthyroidal illness , and also in patients with
central hypothyroidism.
• TRH mRNA in the paraventricular nucleus of the hypothalamus was
reduced in patients who died with nonthyroidal illness in one report, and
was correlated with premortem serum T3 and TSH concentrations .
• TRH infusion in patients with critical illness raises serum TSH, T4, and T3
concentrations.
• Infusion of interferon-alfa to eight normal men caused a fall in serum TSH
and T3 concentrations as well as a rise in the serum concentrations of rT3
and interleukin-6, thus mimicking the thyroid metabolic changes of serious
illness, except that there was no fall in the serum T4 concentration.
Serum TSH
• SERUM TSH — Serum TSH assays that have a detection limit of
0.01 mU/L should be used in assessing thyroid function in critically ill
patients. TSH results should be interpreted as follows:
• Low but detectable — Almost all patients who have a subnormal but
detectable serum TSH concentration (greater than 0.05 mU/L and less
than 0.3 mU/L) will be euthyroid when reassessed after recovery from
their illness.
• Undetectable — In contrast, approximately 75 percent of patients
with undetectable serum TSH concentrations (<0.01 mU/L) have
hyperthyroidism.
High TSH
• Some hospitalized patients have transient elevations in serum
TSH concentrations (up to 20 mU/L) during recovery from
nonthyroidal illness.
• Few of these patients prove to have hypothyroidism when
reevaluated after recovery from their illness.
• Patients with serum TSH concentrations over 20 mU/L usually
have permanent hypothyroidism.
Prognosis
• The magnitude of the changes in thyroid function in patients with
nonthyroidal illness varies with the severity of the illness .
• The serum T4 value correlates with outcome.
• Similar findings were reported in a randomized trial of early versus
late parenteral nutrition in critically ill ICU patients :
- The patients who tolerated the nutritional deficit for one week had
lower TSH, T4, T3, and T3/rT3 ratios . Lower T3, but higher T4 was
associated with a higher likelihood of early alive ICU discharge.
• These data suggest that inactivation of T4 to T3 conversion during
starvation and illness may be a beneficial adaptation, while very low
T4 levels in more critically ill patients are associated with deleterious
outcomes.
TREATMENT
• Thyroid hormone replacement has not been shown to be effective for
patients with critical illness and low T3 and/or T4, or for patients
undergoing cardiopulmonary bypass.
• In a randomized trial of burn patients with low free T4 index and free
T3 index levels, T3 replacement had no effect on mortality or
metabolic rate when compared with placebo.
• In a second trial, administration of T4 to 23 critically ill patients with
low serum T4 concentrations did not alter either mortality or
outcome.
CABG
• During and after cardiopulmonary bypass, there is a transient decrease in serum T3
concentrations.
• While animal data and anecdotal clinical experience had suggested that T3 repletion
might improve outcomes after cardiopulmonary bypass , clinical trials have not
demonstrated such a benefit.
• In a systematic review of 14 randomized trials evaluating the administration of T3 in
euthyroid adult patients in the immediate postoperative period (13 cardiac surgery, one
renal transplantation), intravenous (IV) T3 administration increased cardiac index .
• Mortality was not affected by high-dose IV T3 and could not be assessed for low dose IV
or oral T3.
• In one of the trials included in the meta-analysis, 142 patients with coronary heart
disease undergoing coronary artery bypass surgery (CABG) were randomly assigned to
intravenous T3 therapy (0.8 mcg/kg bolus followed by an infusion of
0.113mcg/kg/hour for six hours) at the completion of surgery or placebo . Although the
mean cardiac index was higher and systemic vascular resistance was lower in the T3
group compared with placebo, there were no differences in the incidence of arrhythmia,
need for inotropic or vasodilator drugs during the 24 hours after surgery, or
in perioperative morbidity and mortality.
Summmary
• there is no evidence that thyroid hormone replacement is beneficial for
patients with critical illness who have low serum T4 or T3 concentrations,
or for patients undergoing CABG, whose serum T3 concentrations are
known to decrease in the perioperative period. If, however, there is
evidence to support a diagnosis of hypothyroidism (such as a TSH over
20 mU/L with low free T4 and/or history, symptoms, and signs of
hypothyroidism), cautious administration of thyroid hormone is
appropriate.
RECOMMENDATIONS
• Assessment of thyroid function in patients with nonthyroidal illness is
difficult, especially among those hospitalized in an intensive care unit.
Many of them have low serum concentrations of thyroxine (T4), free T4,
and triiodothyronine (T3) and their serum thyrotropin (TSH) concentrations
may also be low.
• When to test
• Thyroid function tests should not be measured on seriously ill
patients unless there is a strong suspicion of thyroid dysfunction.
• What to test
• When thyroid dysfunction is suspected in critically ill patients,
measurement of serum TSH alone is inadequate for the evaluation of
thyroid function. Measurement of a full thyroid panel including a
total T4, a free T4, and a T3 is recommended.
• However, the diagnosis may still be in doubt. All methods for
assessing free T4 levels are unreliable in severe critical illness; a free
T4 by equilibrium dialysis sent to a reference lab would be the least
likely to provide spurious results. Some experts argue a total T4 is of
similar utility, at considerably less cost.
Treatment
• In critically ill patients with low serum T3 and/or low T4 concentrations and
no other clinical signs of hypothyroidism, we suggest not treating with
thyroid hormone (Grade 2B).
• In previously euthyroid patients undergoing CABG, we
recommend not treating with thyroid hormone in the immediate postoperative period (Grade 1A).
• If there is additional evidence to suggest a diagnosis of hypothyroidism in
critically ill patients, we suggest that patients receive thyroid hormone
replacement (Grade 2C). In the absence of suspected myxedema coma,
repletion should be cautious, beginning with approximately half the
expected full replacement dose of levothyroxine.
Sources:
• Williams Textbook of Endocrinology, 12th Edition
• Harrison Endocrinology, 16th Edition
• UPtodate