THYROID STORM

Introduction

• Thyroid storm, also known by its synonyms thyroid crisis, thyrotoxic

storm, or thyrotoxic crisis,is an extremely rare but life-threatening
acute exaggerated clinical manifestation of thyrotoxic state
• Prompt diagnosis and vigorous therapy are required to avoid a fatal
outcome as the mortality rates of hospitalized patients ranged from
10% to 75%
Introduction

• Multiple system dysfunction is the commonest cause of death,

followed by heart failure, respiratory failure and sepsis
• It is rare occurs in 1– 2% of patients admitted for thyrotoxicosis and
occurs more commonly in women and in patients with Graves’
disease; autonomous nodules are the culprit in elderly patients
Pathophysiology

• To understand the pathophysiology and rationale of treatment for

thyroid storm, we need to understand the normal thyroid hormone
physiology.
• Normal thyroid function is under control of feedback mechanisms
between the hypothalamus, anterior pituitary and thyroid gland.
“Thyrotropin-releasing hormone” (TRH) stimulates anterior pituitary
to release “thyroid-stimulating hormone” (TSH), which binds to its
receptor on thyroid gland and stimulates the synthesis and secretion
of thyroid hormone.
Pathophysiology

The thyroid hormone synthesis is a five-step process comprising of:

• (a) iodide trapping
• (b) organification—oxidation and iodination
• (c) coupling
• (d) storage
• (e) release
• Twenty percent of T3 comes directly from thyroid gland and 80% of
circulating T3 comes from peripheral conversion of T4 to T3. The
entire process is controlled by a negative feedback loop with
peripheral thyroid hormone inhibiting the release and synthesis of
TSH and TRH.
• Majority of thyroid hormone is protein-bound (>99%) to TBG,
transthyretin, and albumin making a “circulating storage pool,” while
unbound or free hormone is available for uptake into the tissues.
Pathophysiology

• Peripheral conversion of T4 to T3 is done by the 5′-deiodinases. The

deiodinase D2 is active in euthyroid state whereas in hyperthyroid
state deiodinase D1 is more prevalent. The deiodinase D1 is
susceptible to inhibition by thionamide and propylthiouracil (PTU).
• Glucocorticoids and β-blockers inhibit peripheral conversion of T4 to
T3. This understanding will help us understand the rationale behind
use of various classes of drugs in the treatment of thyroid storm.
Pathophysiology

• Exact pathophysiology of thyroid storm is poorly understood. Several

hypotheses have been postulated for the storm, which are as follows:

1 Acute increase in release of T4 or T3 from thyroid gland

• Most important mechanism, acute increase in T4 or T3 hormones is seen after
radioiodine therapy, thyroidectomy, discontinuation of antithyroid drugs, and
administration of iodinated contrast agents or iodine.
• Rapid improvements in clinical condition after reduction in T4 or T3
concentration after peritoneal dialysis or plasmapheresis support this theory.
Pathophysiology

2 Decrease in protein binding of T4 and T3 in the serum

• Acute illnesses cause decrease in protein binding of T4 and T3, either
due to decrease in production of transthyretin or due to production of
inhibitors of T4 –and T3- binding protein.
• They lead to decrease in bound form of T4 and T3, which ultimately
leads to relative increase in the percentage and absolute serum
concentrations of fT4 and T3, which causes storm.
3. Role of sympathetic nervous system activation
•Many symptoms and signs of thyroid storm mimic those of
catecholamine excess, suggesting the role of sympathetic nervous
system activation.
•Dramatic improvement in symptoms following beta blocker
administration supports this hypothesis.
4.Augmentation of cellular responses to thyroid hormone
•In patients with condition of hypoxemia, ketoacidosis, lactic acidosis,
and infection, there is augmentation of cellular response to thyroid
hormone
•There is uncoupling of oxidative phosphorylation leading to
generation of ATP, which results in excess utilization of substrate,
increased oxygen consumption, thermogenesis, and hyperthermia.
•Excess heat is dissipated by increased sweating and cutaneous
vasodilation, the most common symptoms of thyroid storm.
Precipitating Factors

• There are triggers that can induce thyroid storm in patients with
unrecognized thyrotoxicosis, which includes nonthyroidal surgery,
parturition, major trauma, infection, or iodine exposure from
radiocontrast dyes or amiodarone.
• Infection is the most common precipitant of thyroid storm in the
hospitalized patients and no identifiable precipitating factor in about
25–43% of patients with TS.
Precipitating Factors
Clinical Features

• Hyperpyrexia(104–106°F
• Cardiovascular manifestations include
palpitations
tachycardia (HR > 140/min)
exercise intolerance
dyspnea on exertion
widened pulse pressure
myocardial ischemia
atrial fibrillation
CNS manifestations include
• agitation
• delirium
• confusion
• stupor
• obtundation
• coma
CNS involvement is a poor prognostic factor for mortality.
Gastrointestinal symptoms include
• nausea
• vomiting
• diarrhea
• abdominal pain
• intestinal obstruction
• acute hepatic failure
Clinical Features

• Liver dysfunction and hepatomegaly are due to hepatic congestion

and hypoperfusion, or directly due to hyperthyroidism. Jaundice is a
poor prognostic indicator.
• •Unusual presentations include acute abdomen, status epilepticus,
rhabdomyolysis, hypoglycemia, lactic acidosis, and disseminated
intravascular coagulation.
Investigation
• Thyroid function test
• LFT
• SEUCR, Calcium
• FBC
• FBS
• CXR
• ECG
Investigation

• Usual findings include ↑ serum levels of free T4 and T3 conc and ↓

TSH. T3 levels be may ↔ which is due to reduced deiodination or
conversion of T4 to T3 seen in the low T3 or euthyroid sick syndrome
and an elevated radioiodine uptake.
• Leukocytosis with a shift to left is common, even in the absence of
infection
Investigations

• Liver function abnormalities include elevated levels of transaminases,

bilirubin, LDH, creatine kinase and alkaline phosphate due to hepatic
dysfunction, serum alkaline phosphatase may be high as a result of
both increased osteoblastic activity and hepatic dysfunction.
• Hypercalcemia may be found due to the high bone resorption that
accompanies hyperthyroidism
• Hyperglycemia is due to a combination of increased catecholamine
inhibition of insulin release and increased gluconeogenesis.
• CXR-cardiomegaly, pulmonary oedema and / or evidence of infection.
Treatment
Management
•Immediate goals of therapy include
•Decrease thyroid hormone synthesis and release
•Decrease peripheral action of thyroid hormone and
•Treat the precipitating cause.
Treatment

Inhibiting new thyroid hormone synthesis:

•First line therapy utilizes thionamide which includes thiouracils (PTU)
and imidazoles (methimazole and carbimazole). They inhibit thyroid
peroxidase (TPO), thereby inhibiting formation of T3 and T4 from
thyroglobulin
•Both methimazole and PTU are used but PTU is favored during TS due
to its additional benefit of rapid onset of action and inhibition of
peripheral conversion of T4 to T3 In addition, can be safely used in
pregnancy.
Treatment

• The dose of PTU is 600–1500 mg/day in divided doses every 4–6 h

with a loading dose of 600 mg.
•Dose of methimazole is 80–120 mg daily in divided doses every 4–6 h
•The American Association of Clinical Endocrinologist/ American
Thyroid Association guidelines recommend 500–1000 mg loading dose
of PTU followed by 250 mg every 4 h and 60–80 mg/day of
methimazole in divided doses.
•Routes of administration include intravenous, enteral, and per rectal
as suppository or retention enema.
Treatment

• Non radioactive iodine also decreases new thyroid hormone

synthesis. It is due to the inhibition of organic binding of iodide to
thyroglobulin as plasma iodide levels reach a critical threshold, a
phenomenon known as the Wolff-Chaikoff effect.
• Inorganic iodine may be given orally as a saturated solution of
potassium iodide (SSKI) by administering five drops (0.25mL or
250mg) every 6hours Lugol’s solution (eight drops given every 6h).
• Routes can be enteral, rectal, or intravenous.
• Lithium may be substituted when iodine administration is not possible
or desired.

• Inhibiting thyroid hormone release

• The next line of treatment is inhibiting the release of preformed
hormone. Iodine administration, additionally, blocks the release of
preformed hormone by inhibiting the release of T3 and T4 from
thyroglobulin.
Inhibiting the peripheral effect of thyroid hormone
• Both α- and β-adrenergic stimulation are enhanced in thyroid storm.
Thus, adrenergic blockade is an integral part of the treatment.
• Propranolol is the most commonly usedβ-. Blocker due to its
nonselective β-adrenergic antagonism and its ability to block the
peripheral conversion of T4 to T3
• Cardioselective βblocker such as atenolol or metoprolol may be
administered in patients with reactive airway disease, and calcium
channel blockers such as diltiazem may be used when beta blockers
are contraindicated.
• The recommended dose is 60–120mg orally every 6hour by slow
intravenous infusion.
• For a more rapid effect, intravenous propranolol or a shorter acting β-
blocker such as esmolol can be used.
• Inhibiting enterohepatic circulation of thyroid hormone
• In severe and refractory cases cholestyramine is given which binds the
conjugation products and promotes their excretion, there by
decreasing thyroid hormone levels. The recommended dose is 1–4g
twice a day.
• Supportive and resuscitative measures
• Treat in ICU
• Correct hyperthermia [paracetamol and peripheral cooling],
dehydration, congestive heart failure, dysrhythmia, and prevent adrenal
crisis.
• Corticosteroids prevent adrenal insufficiency, and helps in decreasing
the peripheral conversion of T4 to T3
• Treat precipitating factors and correct metabolic abnormalities, like
DKA, stroke, or pulmonary emboli.
• Therapeutic plasma exchange
• In refractory cases plasmapheresis is effective in rapidly reducing
thyroid hormone levels.
• Surgical management: indicated in a subset of patients who fail
medical management despite all of the most aggressive treatment
modalities.
Prognosis

• Fatal if left untreated. Cause of death may be heart failure,

arrhythmias or multiple organ failure. Risk factors for poor prognosis
include:
• •Advanced age
• •Neurological deficits on admission
• •Failure to use beta-blockers and antithyroid medications
• •Need for dialysis and/or mechanical ventilation
Conclusion

• Thyroid storm is an endocrine emergency that is associated with high

morbidity and mortality if not promptly recognized and treated.
• Multidisciplinary treatment in an intensive care setting is usually
needed.
• FURTHER READING