Thyroid emergencies are an interesting class of disorders. They’re rare, but are an acute, life-threatening group of syndromes. This is in contrast to the vast majority of thyroid cases that often present with minor symptoms (or found on routine labs), only requiring outpatient treatment and medications. Thyroid emergencies are the extreme versions of these thyroid disorders. They fall into two categories: “too low” of thyroid hormone (myxedema coma) and “too high” of thyroid hormone (thyroid storm). The post starts with some background anatomy and physiology, and then dives into each disorder separately. Also briefly discusses Levothyroxine overdose.
Background Anatomy and Physiology
Hypothalamus-Pituitary-Thyroid Axis
- The hypothalamus releases TRH (thyroid releasing hormone) to stimulate the anterior pituitary to release TSH
- TSH stimulates production of T4 (thyroxine) and T3 (triiodothyronine) synthesis in the thyroid gland
- T3 is 3-4x more potent than T4
- All T4 is produced in the thyroid gland, while the vast majority of T3 (~80%) is synthesized in extra-thyroidal tissue (primarily liver, brain, brown adipose tissue, and muscle) by the conversion of released T4 into T3
- T4 and T3 in the bloodstream then produce negative feedback on the hypothalamus and thyroid gland
Synthesis of Thyroid Hormone
- Iodine is the main substrate needed for production of thyroid hormone. It is absorbed via a sodium/iodide symporter in the follicular cells of thyroid tissue
- Iodide is then oxidized by TPO (thyroid peroxidase) and attached to thyroglobulin molecules to produce MIT (monoiodotyrosine) and DIT (diiodotyrosine)
- These molecules are then coupled together to make T4 (DIT + DIT molecules) or T3 (DIT + MIT molecules)
Myxedema Coma
Background
- As the name implies, its main defining features include: myxedema (non-pitting edema) and coma (altered mental status). It is further described as a SEVERE, life-threatening state with decompensated low levels of thyroid hormone
- Mortality can range from 25-60% despite treatment
- It is more common in elderly women with long-standing pre-existing hypothyroidism
- It typically occurs in patients with untreated or undiagnosed hypothyroidism who bear an insulting trigger (see below) that pushes the patient into a decompensated state of low thyroid hormone
- Common triggers include: cold temperature, infection, stroke (or other CVA), heart failure, and medications (e.g. analgesics, sedatives, antipsychotics, amiodarone, or lithium)
- Also found a case report of a patient ingesting too much bok choy
Symptoms and Lab Findings
- Many of the symptoms of myxedema coma are similar to that of generic hypothyroidism: thinning of hair, hair loss, enlarged thyroid, constipation, infertility (menstrual abnormalities), cold intolerance, possible carpal tunnel syndrome, hyporeflexia
- Again, myxedema coma will also have diffuse non-pitting edema with possible altered mental status including coma
- Their vitals will often show a “slowing/lowering” including:
- Hypothermia: often severe, near 26.7 C which is unusual in most cases of environmental hypothermia
- The degree of hypothermia correlates with the risk of mortality
- Hypotension (typically from co-associated adrenal insufficiency)
- Bradycardia: often from hypothermia. I could not find literature whether Osborne Waves that we associate with environmental hypothermia would be present
- EKG will also show relative bradycardia with prolonged QTc (which could push them into torsades or Vtach)
- Bradypnea: often leading to hypercapnia/respiratory acidosis and hypoxia
- Hypothermia: often severe, near 26.7 C which is unusual in most cases of environmental hypothermia
- Common Lab Findings
- Hypoglycemia: from low PO intake (AMS) and adrenal insufficiency
- Metabolic and Respiratory acidosis: from hypoglycemia, poor PO intake, and bradypnea
- Cardiac Ultrasound: may show pericardial effusion which may also contribute to hypotension and poor cardiac output
- Renal insufficiency with electrolyte abnormalities including altered K and Mg
- Hyponatremia is very common (~50%): from both SIADH and interrupted water diuresis
- Low Cortisol: co-associated adrenal insufficiency is common
- Elevated CK: rhabdomyolysis from hypothyroid myopathy vs. prolonged immobile state
Differential, Work-Up, and Treatment
- These are challenging patients. They are often altered, clearly sick, and without much history. From as soon as we walk in the room, we know that they are “sick.”
- As with any altered patient, we want to go through our normal algorithm by starting with the quick fixes. I think a lot of us use “DONT”–dextrose, oxygen, narcan, thiamine + hypercapnia. These patients often will have hypoglycemia, hypotension, hypoxia, hypothermia, and hypercapnia, which will be important to fix from the get-go as likely contributing factors to acute AMS and illness
- Hypotension so want to start fluids
- Hypercapnia and Hypoxia:
- Depending on the level of their AMS, hypoxia, acidemia/hypercapnia, will likely require intubation (and should consider early as these patients will likely need a trip to CT scanner for Head CT). These patients are unlikely to tolerate Bi-Pap
- Hypothermia: remove wet clothing, warm blankets, bear hugger, warm fluids. Want to gradually increase temperature. If raise temp too quickly, can induce vasodilation and capillary leak resulting in worsening hypotension
- Now that our patient is stabilized, we want to start our work-up and definitive treatments. As ER doctors, we want to keep a broad differential. It is easy, from the vitals and presentation, to jump to sepsis or environmental hypothermia, but is important to keep a wide differential. Also as pointed out earlier, there are lots of co-associated issues with myxedema coma so it will be important to work these up in the process as well.
- Sepsis: CBC, CXR, blood cultures, UA, Ur Cx, lactate
- possible meningitis: LP
- stroke/CVA: Head CT
- MI/CHF/Pericardial Effusion: troponin, BNP, cardiac ultrasound
- Electrolyte abnormalities including Mg: often prolonged QTc, hyponatremia, altered K and Mg
- Adrenal insufficiency: cortisol level
- Rhabdomyolysis: CK level
- overdose/Tox/Medication changes: pharm review, UDS
- Myxedema Coma: TSH with T3/T4
- TSH should be considered in patients with profound hypothermia <32 C, and especially if co-associated AMS.
- Sepsis: CBC, CXR, blood cultures, UA, Ur Cx, lactate
- Supportive Treatment
- Broad-spectrum antibiotics until sepsis/infection ruled out
- gradual rewarming, correct hypotension
- Correct electrolyte abnormalities: hyponatremia, altered K, Mg, and hypoglycemia
- Definitive Treatment
- IV Thyroxine (T4)
- PO thyroxine should be avoided at presentation even if tolerating PO. This is because hypothyroidism causes constipation and capillary leak which can lead to intestinal edema, which will impede its absorption
- T4 is readily available (onset of action 6-8 hours), less potent than T3 so relatively smooth and gradual onset
- Possible disadvantage is that extra-thyroidal conversion of T4 to T3 may be inhibited in myxedema coma by lowered metabolism, which may make T4 less effective
- Most protocols I found did the following dosing
- Loading Dose 200 ug followed by 100 ug in 24 hours. Thereafter 50 ug per day until oral medication is tolerated.
- Max loading dose of 400 ug
- Typically can convert to PO thyroxine by day 2-3. Would need to convert this dose to higher PO dosing
- Loading Dose 200 ug followed by 100 ug in 24 hours. Thereafter 50 ug per day until oral medication is tolerated.
- T3 Supplementation
- As mentioned above, T3 is more potent than T4, which lends itself to causing more side effects–most often dysrhythmias. Therefore, it is reserved for severe cases of myxedema coma where patient is unconscious or with severe respiratory compromise.
- Due to its ability to induce dysrhythmias, it is contraindicated in the elderly or patients with CAD.
- Advantages are more rapid onset of action (2-4 hours) but needs to be dosed more often (q8 hours)
- Should receive serial EKGs for risk of arrhythmia
- Loading dose 20 ug IV, followed by 10 ug q8h IV. It is given until the patient is no longer comatose or breathing improves
- Hydrocortisone (if refractory hypotension or co-associated adrenal insufficiency)
- Hydrocortisone 100-200 mg q8h IV
- Give if refractory hypotension or low cortisol level
- Endocrine Consult and MICU admission
- IV Thyroxine (T4)
- On the floor/Future Testing…
- T3/T4 tested every 1-2 days
- If giving T3, then T3/T4 testing should be done at least 1 hr after giving T3 as can cause falsely elevated levels
- TSH typically falls 50% after 1 week of supplementation. Adjust accordingly if not at goal
Thyroid Storm
Background
- Hyperthyroidism refers to excess thyroid hormone produced from the thyroid, while thyrotoxicosis refers to excess thyroid hormone from any source
- Essentially, it is the opposite presentation and spectrum of disease from myxedema coma. Therefore, thyroid storm is defined as an acute, SEVERE, life-threatening hypermetabolic, decompensated state
- Mortality without treatment is 80-100%, and with treatment ranges from 15-50%
- Thyroid storm (much like myxedema coma) often occurs in patients with undiagnosed or untreated thyrotoxicosis that is pushed into a decompensated state by an insulting trigger.
- Common insulting triggers include: infection/sepsis, trauma, general surgery, DKA/HHS, medications (iodine, levothyroxine, amiodarone), MI, PE, CVA, parturition, eclampsia.
- No identifiable trigger occurs in 25% of cases
Causes of Hyperthyroidism
- Graves Disease (85% of cases): associated with diffuse goiter, exophthalmos, pretibial myxedema, 10x more common in women. Caused by thyroid stimulating antibody which can be tested for
- Toxic Multinodular Goiter (2nd most common)
- Toxic Nodular Goiter
- Thyroiditis
- Transient Hashimoto’s Thyroiditis
- Subacute Painful de Quervain’s Thyroiditis
- Subacute Painless Thyroiditis
- Radiation Thyroiditis
- Thyrotropin-secreting Pituitary Adenoma: defined as secondary hyperthyroidism that can be differentiate from above by high TSH and high T3/T4
Causes of Extrathyroidal Thyrotoxicosis
- Ectopic thyroid tissue (struma ovarii)/teratoma
- Metastatic thyroid disease
- Hydatidiform mole (HCG)
- Iodine-Induced Thyrotoxicosis (Jod-Basedow Disease)
- Medications (amiodarone, alpha-interferon, IL-2)
- Thyrotoxicosis Factitia (purposeful ingestion of Levothyroxin)
Symptoms and Lab Findings
- Symptoms can include hyperthermia, agitation, anxiety, psychosis, seizures, coma, tachycardia, palpitations, edema, arrhythmia, nausea/vomiting, diarrhea, abdominal pain, jaundice, hyperreflexia, and tremor
- Hyperthermia can be profound (often 104-106 F)
- Atrial fibrillation is most common arrhythmia (10-35% of cases)
- Most common symptoms are palpitations, tachycardia, tremor, and dyspnea.
- For all our score keepers out there… of course there is a clinical scale called The Burch-Wartofsky-Score
Differential
- Much like myxedema coma, these patients can present altered with significantly abnormal vitals. Again, it is important to keep a wide differential, because it is easy to jump to sepsis or heat stroke, but thyroid storm should also be on your differential
- Since this is often found in younger patients compared to myxedema coma, drugs/toxicology should be a mainstay of the differential. Common toxidromes with similar presentation include: delirium tremens, opiate withdrawal, cocaine toxicity, organophosphate poisoning, malignant hyperthermia, serotonin syndrome, neuroleptic malignant syndrome
- Can also consider pheochromocytoma in certain presentations
Work-Up
- Vitals can show hyperthermia, tachycardia, tachypnea, and often hypotension (from high output heart failure or co-associated adrenal insufficiency)
- POC glucose can be high, normal, or low. It depends on how long the thyrotoxicosis has been present but most often it is low
- Low glucose (prolonged presentation): occurs from depleted glycogen stores and high metabolic rate. Also can have co-associated adrenal insufficiency which can contribute
- High glucose (acute presentation): occurs from “stressed state” produced by high circulating thyroid hormone levels, which leads to increased intrinsic steroid production. This would likely indicate that there is no associated adrenal insufficiency
- EKG is extremely important as patients are prone to arrhythmia and atrial fibrillation, and will dictate much of treatment
- VBG lactate may show lactic acidosis if shock is present. Often will show concomitant respiratory alkalosis from tachypnea
- CXR, cardiac ultrasound, troponin, BNP: look for co-associated heart failure, MI as cause, pulmonary effusions
- Sepsis work-up as etiology: blood cultures, UA, urine culture, etc.
- Cortisol level for co-associated adrenal insufficiency
- CBC and CMP likely to show: mild leukocytosis with left shift, mild hypercalcemia, and mild elevation of LFTs
- On floor: will get thyroid ultrasound and possibly urine metanephrines for pheochromocytoma work-up
Treatment
- Supportive Care
- Airway Management for AMS
- Fever: externally cool, Tylenol 650 mg q4-6h
- Fun: aspirin is contraindicated in thyroid storm as can cause release of more thyroid hormone. This is for everyone who is giving aspirin for their fevers.
- IVF (high insensible losses from n/v, diarrhea, hyperthermia, tachypnea)
- Even pts with signs of heart failure will likely need aliquots of fluid
- Dextrose or Dextrose containing fluids: for hypoglycemia from hypermetabolic demands
- Control agitation: Benzodiazepines in ED. In ICU, can consider low-dose Precedex drip
- Inhibit New Thyroid Hormone Synthesis
- PTU (propylthiouracil) is 1st-line in thyroid storm
- 1st line because also inhibits T4 to T3 conversion in extrathyroidal tissue. In fact, PTU decreases T3 levels by ~45% within 24 hrs while Methimazole only decreases T3 level by 10-15% within 24 hrs.
- Typically not seen in outpatient setting as requires more frequent dosing and higher side effect profile (mainly acute liver injury). However, it is often cheaper so may see in certain settings.
- Loading dose 600-1000 mg PO or Rectal (no IV form available). Followed by 200-250 mg q4h
- Methimazole
- more often used in outpatient setting as requires less frequent dosing and also has lower side effect profile
- Contraindicated in 1st trimester of pregnancy
- Both drugs are contraindicated in liver failure/cirrhosis and can lead to agranulocytosis, therefore, require serial CBC and LFT surveillance while receiving
- PTU (propylthiouracil) is 1st-line in thyroid storm
- Inhibit Thyroid Hormone Release
- These drugs are given at least 1 hr after PTU/methimazole. This is because if given before this time, then the iodine could theoretically be used as a substrate for thyroid synthesis. Therefore, must give PTU/methimazole to inhibit this process before giving the iodine
- Giving large levels of iodine can inhibit the release of thyroid hormone (called “Wolf-Chaikoff Effect”). This effect only lasts ~10 days.
- Depending on severity of thyroid storm, should consult endocrinology prior to giving iodine load. The iodine can interfere with radioactive iodine uptake test or ablation if needed later on. Obviously, if pt is crashing, then should be given
- 3 main ways to give:
- SSKI (saturated solution potassium iodide) 5 drops PO q6h
- Lugol Solution 8-10 drops PO q6-q8h
- Lithium carbonate (if allergy to iodine) 300 mg PO q6h with goal serum level 1 mEq/L
- Inhibit Thyroid Hormone Reabsorption
- Cholestyramine 4 grams PO q6h: inhibits enterohepatic circulation of thyroid hormone
- Beta Blockade
- Propranolol is considered 1st line and is likely the right answer on board tests. It helps treat tachycardia (and if coexisting Atrial Fibrillation), tremor, anxiety, and has some inhibitory effects of T4 to T3 conversion
- Propranolol 0.5-1.0 mg IV to start
- Propranolol 60-80 mg PO q6h
- Inhibit Peripheral Conversion of T4 to T3
- This can also help treat co-associated adrenal insufficiency if present
- Hydrocortisone 100 mg IV q8h
- or Dexamethasone 2 mg IV q6h
- Treat precipitating cause
- infection is common cause and due to concern for sepsis, should start broad spectrum antibiotics
- Special Cases
- Co-associated Afib with RVR or Heart Failure
- would recommend starting esmolol drip in place of propranolol. Their tachycardia may be compensatory, therefore, it would likely be beneficial to use a short-acting drug that is easily titratable in place of propranolol. May require increased doses of benzodiazepines for tremor/anxiety.
- Also in patients with Afib with heart failure or hypotension, I think most would consider amiodarone as rate-control would be relatively avoided. However, amiodarone can worsen thyroid storm so should be avoided in these patients. I could not find much literature on this, but most suggested digoxin as first consideration
- Conflicting data on whether to anticoagulate these patients, but theoretically Afib should resolve with treatment of thyroid storm so unlikely to need to initiate in ED.
- Concomitant hepatic failure
- Plasmapheresis: PTU and methimazole are both contraindicated in hepatic failure/cirrhosis, therefore, can perform plasmapheresis which can remove thyroid hormone, cytokines, and culprit antibodies. Plasmapheresis is often bridge to below
- Co-associated Afib with RVR or Heart Failure
- Definitive Treatment
- Radioactive iodine ablation or surgery. Often the goal is to perform this after 5-7 days of above treatment. This is because the iodine load that inhibits thyroid hormone release stops working around Day 10.
Levothyroxine Overdose
- Good news… it is extremely hard to overdose from levothyroxine
- When symptoms do occur, they do not occur until the 24 hr mark because requires metabolic conversion of T4 to T3
- Most ingestions can be treated with low dose propranolol for tachycardia/tremor/anxiety and benzodiazepines for agitation PRN
- In severe ingestions, can consider activated charcoal if present early after ingestion. Could also consider cholestyramine to decrease enterohepatic circulation
- And as any toxidrome, call poison control.