Download Sick Euthyroid syndrome

SICK EUTHYROID SYNDROME
- DR. MUNIRA DILAWER GHEEWALA
NORMAL THYROID HORMONE SECRETION
 T3
– metabolically active hormone – exerts its action via
binding to chromatin bound nuclear receptors and
regulating gene transcription.
 Half lives of circulating T4 – 5 to 8 days
T3 – 1.3 to 3 days.
 Both T4 and T3 circulate in serum as bound hormones to
several proteins synthesized by the liver
 Thyroxine Binding Globulin is the predominant transport
protein (binds 80% of circulating serum thyroid hormone.)
 Affinity of T4 is 10 times more than T3. Hence circulating
levels of T4 are higher than T3.
 Other serum binding proteins – transthyretin (15% of T4,
but little of T3), prealbumin.
 41%
of T4 is converted to T3, 38% to rT3, 21% is
metabolized by other pathways like conjugation in liver and
excretion in bile.
 10% of circulating T3 is secreted directly by thyroid while
>80% of T3 is from conversion from T4 in peripheral
tissues.
FREE HORMONE CONCEPT
 Only
the free hormone present in the circulation has
any metabolic effect.
 Under the regulation of pituitary, overall thyroid
function is affected when there are any changes in free
hormone concentrations.
 Changes in either the concentrations of binding
proteins or the binding affinity of thyroid hormone to
the serum-binding proteins, have significant effects on
the total serum thyroid hormone levels due to the high
degree of binding of T4 and T3 to these proteins.
 Despite these changes, this does not necessarily
translate into thyroid dysfunction.
SICK EUTHYROID SYNDROME
Severe illness, Caloric deprivation, Physical trauma, Physiological
stress may result in,
1. Altered regulation of TSH secretion
TSH decreases markedly at 24-48 hrs, then tends to return to normal
2. Peripheral conversion of T3 to rT3
inhibitor of peripheral 5-monodeiodination - cortisol, starvation
3. Protein binding of thyroid hormones
There are circulating inhibitors of thyroid hormone binding to TBG's
Artefactual decrease in resin uptake of T3 & the FTI is also low
4. FT4 levels are low/normal & plasma t½b ~ 1-5 days
5. Euthyroid state is maintained by increased tissue T3 receptors
CHANGES IN CRITICALLY ILL PATIENT
 These
1.
2.
3.
changes occur due to :
Alterations in peripheral metabolism of thyroid
Alterations in TSH regulation
Alterations in binding of thyroid hormone to TBG.
PATHOPHYSIOLOGY
 Cytokines
 De-iodination.
 Inhibition
of TSH, Type 1 deiodinase, Factors inhibiting
binding of T4 to TBG
ROLE OF CYTOKINES IN PATHOPHYSIOLOGY OF SICK
EUTHYROID DISEASE
 TNF-α, IL-1, and IL-6 concentrations are increased in systemic
illness and are implicated as mediators of endotoxemia-induced
shock, fever, and metabolic acidosis.
 Serum concentrations of these cytokines have shown to be
inversely proportional to serum T3 concentrations in children
(IL-6 and TNF-α);postoperative patients (IL-6); hospitalized
patients, including those with acute myocardial infarction (IL-6)
and after bone marrow transplant (IL-6 and TNF-α); and
nursing home patients (TNF-α).
 TNF-α causes an acute decrease in both serum T3 and TSH
concentrations and a rise in serum rT3 concentrations.
 Several components of the thyroid hormone synthesis pathway
are down-regulated by cytokines directly on the level of
thyrocyte, eventually leading to decreased secretion of T4 and
T3.
DEIODINATION
1. T YPE 1 DEIODINASE
 T4
to T3 is by sequential monodeiodination. Removal
of outer ring iodine by type 1 iodothyronine 5’
deiodinase (type1 deiodinase, D1). It is the “activating”
metabolic pathway.
 Type 1 deiodinase found abundantly in liver, kidney,
and thyroid. Upregulated in hyperthyroidism and
downregulated in hypothyroid.
 Nonthyroidal illness induces a marked decrease in
liver type 1 deiodinase mRNA expression and its
activity in critically ill patients
 Peripheral deiodination of T4 to T3 is impaired in
critically ill, secondary to decreased activity of type 1
deiodinase enzyme, which deiodinates T4 to T3.
2. T YPE 2 DEIODINASE
 Type
2 deiodinase enzyme is localized in the
endoplasmic reticulum of the cells and deiodinates T4
into biologically active T3.
 Type 2 deiodinase is the main enzyme involved in the
production of tissue T3 and is largely involved in local
thyroid hormone metabolism.
 There is a major role of type 2 deiodinase in the
central part of hypothalamic-pituitary-thyroid axis that
is altered during illness.
3. T YPE 3 DEIODINASE
 Type
3 deiodinase is present in the plasma membrane
of cells and can be considered as the major thyroid
hormone–inactivating enzyme, as it catalyzes innerring deiodination of both T4 and T3, resulting in the
production of biologically inactive rT3 and rT2.
 Removal of the iodine by type 3 deiodinase D3 leads
to formation of reverse T3→ “inactivating” pathway.
 Type 3 deiodinase is expressed in brain, skin, placenta
and chorionic membranes.
 Increased type 3 deiodinase activity is observed in
severely ill patients.
 In
acute illness – acute inhibition of D1 resulting in
impairment of T4 to T3 conversion.
↓
Acute decrease in T3 production
Also there is increased deiodination by D3 resulting in
increased levels of rT3.
 TSH levels are initially normal early in acute illness. They
often fall as the illness progresses due to effects of
inhibitory factors.
INHIBITION OF TSH, T YPE 1 DEIODINASE, FACTORS
INHIBITING BINDING OF T4 TO TBG
1. FACTORS THAT DECREASE D1 ACTIVITY
Acute and chronic illness
 Caloric deprivation
 Malnutrition
 Glucocorticoids
 ß- blockers
 Oral cholecystographic agents (iopanoic acid, sodium ipodate.)
 Amiodarone
 Propylthiouracil
 Fatty acids
 Fetal/ neonatal period
 Selenium deficiency
 Cytokines (IL-1, IL-6).

2. FACTORS THAT ALTER TSH SECRETION
Increase
 Chlorpromazine
 Cimetidine
 Domperidone
 Dopamine antagonists
 Haloperidol
 Iodide
 Lithium
 Metoclopramide
 Sulfapyridine
 Radiographic contrast agents
Decrease
 Acute & chronic illness
 Adrenergic agonists
 Caloric restriction
 Carbamazepine
 Clofibrate
 Cyproheptidine
 Dopamine and dopamine agonist
 Endogenous depression
 Glucocorticoids
 Insulin like growth factor-1 agents
 Opiates
 Phenytoin
 Somatostatin
 Serotonin
 Surgical stress
3. FACTORS AFFECTING BINDING TO T4 TO TBG
Increase
 Estrogen
 Methadone
 Clofibrate
 5-fluorouracil
 Heroin
 Tamoxifen
 Raloxifen
 Liver disease
 Porphyria
 HIV infection
 inherited
Decrease
 Glucocorticoids
 Androgen
 L-asparaginase
 Salicylates
 Mefenamic acid
 Antiseizure medication
(phenytoin, tegretol)
 Furosemide
 Heparin
 Inherited
 Acute illness
 Non-esterified free fatty
STAGES OF SICK THYROID SYNDROME
 Low T3
state
 High T4
 Low T4
 Recovery
state
SPECIFIC ILLNESSES
1. CALORIC DEFICIENCY:
 Most, if not all, non-thyroidal illness is associated with
decreased caloric intake, catabolism, and/or malnutrition.
 Caloric deprivation is the most common inhibitory factor of
type 1 5′-deiodinase.
 The decrease in serum T3 levels may possibly be an adaptive
response in order to preserve the total body protein stores.
Restoring the serum T3 to normal during starvation results
in a marked increase in urinary nitrogen excretion. Thus, the
inhibition of T4 to T3 conversion in starvation can be viewed
as a condition of adaptive hypothyroidism.
2. HIV INFECTION
A
progressive increase in TBG levels is commonly observed
and T4 levels rarely decrease below the normal range.
 Serum T3 levels remain in the normal range despite
progression of the HIV infection and are only mildly decreased
in the critically ill AIDS patient, suggesting that these
“inappropriately normal” T3 levels play a role in the wasting
and weight loss seen in the terminal phases of this disease.
 In contrast to T4 levels in the sick euthyroid syndrome, it is
the decreased serum T3 levels in AIDS patients admitted to the
ICU with Pneumocystis carinii infections that correlate with
increased mortality.
3. LIVER DISEASES
 Individuals
suffering from acute and chronic hepatocellular
dysfunction often have marked elevations in total T4 levels
similar to those seen in patients with thyrotoxicosis.
 T3 levels are also higher than expected with illness and tend
to fall late in the course of terminal liver disease.
 The etiology of these increased thyroid hormone
concentrations is the increased discharge of TBG following
destruction of hepatocytes.
 Free hormone measurements remain in the normal range.
 Low T4 levels are seen in patients with cirrhosis and
associated with increased mortality.
4. CARDIAC DISEASES
 Cardiac
contractility, systolic time intervals, and heart rate
are all increased in thyrotoxicosis and decreased in
hypothyroidism.
 A significant inverse relationship between free T3 and global
oxygen consumption has been demonstrated after coronary
artery bypass grafting with and without cardiopulmonary
bypass.
 In contrast to other medical illnesses where serum T4 levels
are correlated with prognosis, serum T3 concentrations are a
negative prognostic factor in patients with congestive heart
failure and with coronary artery disease
MANAGEMENT
 Evaluation
 Diagnosis
 Prognosis
 Treatment
EVALUATION
 Primary
1.
2.

1.
2.
tests :
Sensitive thyrotropin assay : lower limit of 0.01 to
0.03 mU per L which is 20-30 fold lower than lower
limit of normal range – improved sensitivity.
Serum T4 assays: free T4 index, free T4, free T3
which represent estimates of the free hormone
concentration.
Secondary tests:
Serum T3 & rT3 assay : done only if thyrotoxicosis is
clinically suspected.
Serum thyroid autoantibodies: Antibodies to
thyroglobulin and thyroid peroxidase
 Imaging
:
Functional analysis of thyroid using radioisotope I123 in
patients suspected with thyrotoxicosis.
Anatomical studies like USG, CT, MRI, Isotopic
imaging are rarely used in critically ill patients.
DIAGNOSIS
 Single
best test to screen for thyroid dysfunction is either free T4
index or the free T4, realizing subtle changes in thyroid function.
 Assessment of the TSH & FT4 or free T4 index values in the context
of the duration, severity, and stage of illness of the patient will allow
the correct diagnosis in most patients.
 E.g. : a mildly elevated TSH coupled with a low free T4 index or free
T4 is more likely to indicate primary hypothyroidism early in an
acute illness as opposed to the same values obtained during the
recovery phase of the illness.
 If the diagnosis is still unclear, measurement of thyroid antibodies is
helpful as a marker of intrinsic thyroid disease and increases the
sensitivity of both the free T4 index or free T4 and the TSH.
PROGNOSIS
 Both
serum T4 and serum T3 concentrations have been associated as
negative indicators of prognosis when they are low.
 A direct relationship exists between low serum T4 levels and poor
outcomes in critically ill patient.
 In acutely ill older patients with non-thyroidal illness syndrome,
mortality rate was significantly higher, with an inverse relationship
between free T3 values and death rate.
 In patients on mechanical ventilation, patients with low free T3 had
higher mortality rate and longer duration of mechanical ventilation
and ICU length of stay .
 In different types of cardiac disease the prognostic value of low T3 is
poor, including coronary artery disease and chronic heart failure.
TREATMENT
General ICU patients :
 No benefit of L-T4 on general medical patients ,patients
with acute renal failure , or renal transplant .
 No benefit of L-T3 on burn patients.
Premature infants :
 No benefit of L-T4 on developmental indices of
premature infants at 26–28 weeks’ gestation.
 Possible beneficial effect of L-T4 on infants of at 25–26
weeks’ gestation but possible deleterious effects on infants
of 27–30 weeks’ gestation .
 No benefit of L-T3.
 Meta-analysis shows no significant effects of thyroid
hormone treatment of premature infants.
Cardiac surgery patients :
 Small studies suggest improved hemodynamic parameters with L-T3.
 Large trials show no benefit of L-T3 noted in patients undergoing cardiac
bypass.
 Possible improvement in hemodynamic parameters and hospital stay with
L-T3 in children undergoing cardiac surgery.
Cardiac donors:
 Variable results on the effects of LT3 in preserving function of normal
hearts in brain-dead cardiac donors prior to transplantation.
 Possible benefits of L-T3 in improving function of impaired hearts prior to
transplant, potentially increasing the pool of organs available for
transplantation.
 Consensus conferences recommend the use of L-T3 as part of the
hormonal resuscitation in donors whose cardiac ejection fraction is <
45%.
Congestive heart failure :
 Small uncontrolled study suggested short term L-T4 therapy
increased cardiac output and functional capacity and decreased
systemic vascular resistance .
 Improved hemodynamic parameters and neurohumoral profiles
with short term intravenous L-T3 infusion, possibly requiring
supra physiologic concentrations