CONTENTS

• Rapid Reference 🚀
• Diagnosis
  • Epidemiology (including triggers)
  • Recognition of the clinical syndrome
  • Catalog of potential findings
  • Investigations
  • Definition & differential
• Treatment
  • Treatment of cause
  • Supportive care
  • Hormonal manipulations
    • Stress dose steroid
    • T4 (levothyroxine)
    • T3 (liothyronine)
  • Followup

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rapid reference

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basic workup should include:

• Endocrine evaluation:
  • TSH & free T4.
  • Random serum cortisol.
• Infectious workup:
  • Blood cultures.
  • Urinalysis +/- urine culture.
  • Chest radiograph.
• POCUS (patients may have pericardial effusion, cardiomyopathy).

treatment for decompensated hypothyroidism:

• IV dextrose if hypoglycemic.
• Steroid: 100 mg IV hydrocortisone q8hr (alternative: 60 mg IV methylprednisolone daily).
• IV levothyroxine (T4): Loading dose ~250 mcg IV.
• Antibiotics: consider empiric therapy if sepsis is possible.
• Liothyronine (T3): consider in the sickest patients. 📖

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epidemiology

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Decompensated hypothyroidism is generally caused by a combination of severe hypothyroidism plus a triggering event. Unfortunately, this may be the initial presentation of hypothyroidism.

triggering event

• Thyroid supplementation nonadherence.
• Medications:
  • Sedatives.
  • Opioids.
  • Diuretics.
  • Beta-blockers.
  • Amiodarone.
  • Antipsychotics.
  • Lithium.
  • Checkpoint inhibitors, tyrosine kinase inhibitors.
• Infection.
• Surgery, trauma, burns.
• MI or heart failure.
• Cerebrovascular accident (CVA).
• GI bleed.
• Some iodinated contrast dyes may cause transient thyroid suppression.
• Physical stress (including cold exposure).

epidemiology

• Patients are typically female and elderly.
• The majority of cases occur during the winter.

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recognition of the clinical syndrome

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core features that may help suggest decompensated hypothyroidism:

• (1) Altered mental status:
  • Usually not frankly comatose, most patients have hypoactive delirium.
  • Rarely, may see an activated form known as “myxedema madness.”
• (2) Presence of one of the following two cardinal features:
  • Hypothermia (may be severe).
  • Bradycardia.

may also see:

• Features of precipitating event.
• Hypoglycemia.
• Hyponatremia.
• Hypoventilation.
• Reduced bowel & bladder motility.

clues to the diagnosis of hypothyroidism:

• Any history of prior thyroid disease (either hyper- or hypothyroid).
• Thyroidectomy scar or goiter.
• Myxedema:
  • Non-pitting edema of hands, ankles, face.
  • Hoarseness, macroglossia.
• Hair loss, loss of outer third of the eyebrows.
• Cold intolerance.

Myoedema may be a sign of myopathy due to hypothyroidism. When stimulated, the muscle tissue contracts locally (video above).

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catalog of potential findings

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cardiovascular

• Bradycardia
• Pericardial effusion.
• Cardiogenic shock (late finding)
  • Hypothyroid patients often have diastolic hypertension. When the diastolic blood pressure starts falling, this may be a poor sign.
  • Shock may result from some combination of bradycardia, pericardial effusion, impaired contractility, and/or peripheral vasoconstriction.
  • Hypothyroidism can cause vasopressor-refractory shock (which will start responding to therapy once thyroid replacement is administered).
• Torsades de Pointes can occur.

neurologic

• Delirium or coma is a core feature.
• Seizures can occur, including status epilepticus (potentially exacerbated by hyponatremia).

pulmonary

• Hypoventilation may result from central reduction in respiratory drive, as well as from muscular weakness.
• Pleural effusions may promote hypoxemia.
• Edema of the tongue can complicate intubation.

hematologic

• Acquired von Willebrand syndrome may occur, due to reduced synthesis of von Willebrand's factor. Additionally, factors V, VII, VIII, IX, and X may be reduced.(31424777)
  • May be treated with desmopressin (DDAVP).(7750191)
• Anemia is common.

renal

• Hyponatremia usually results from excessive levels of antidiuretic hormone (ADH).
• Acute kidney injury may result from hypoperfusion and possibly also from rhabdomyolysis.
• Reduced bladder motility may cause urinary retention.

gastrointestinal

• Ileus may cause nausea and vomiting.
• Hypothyroidism may lead to megacolon.
• Ascites can occur, but isn't common.
• Gastrointestinal bleeding may occur as a result of coagulopathy (see above).

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investigations

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thyroid labs

• Check: TSH, free T4, and random serum cortisol.
• Findings in decompensated hypothyroidism:
  • TSH will generally be markedly elevated (although this may not occur with central hypothyroidism due to pituitary insufficiency).
  • Free T4 should be decreased.
• The extent of laboratory abnormalities doesn't differentiate compensated vs. decompensated hypothyroidism.
  • Labs will show hypothyroidism, but labs cannot diagnose decompensated hypothyroidism.
  • A wide range of labs are seen in decompensated hypothyroidism, possibly because this may itself suppress hypothalamic function (thereby reducing the TSH level).
  • Decompensated hypothyroidism is a clinical diagnosis based on clinical features in the context of hypothyroidism.

other lab abnormalities which may be seen in hypothyroidism:

• Elevated creatinine kinase (CK).
• Leukopenia can occur.

EKG findings

• Rhythm abnormalities: Sinus bradycardia (most often), conduction blocks.
• QTc may be prolonged, potentially leading to Torsades de Pointes.
• Low voltage complexes.

evaluation for triggers

• Infectious evaluation (CXR, Blood cultures, urinalysis).
• Head CT scan.
• Lumbar puncture (decompensated hypothyroidism may cause a slight increase in protein level due to increased vascular permeability).

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definition & differential

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operational definition of decompensated hypothyroidism?

• “Myxedema Coma” is a misleading term:
  • i) Most patients aren't truly comatose (but they are generally delirious).
  • ii) Most patients don't have myxedema.
  • The construct of “myxedema coma” sets clinicians up for diagnostic failure.
• Decompensated hypothyroidism may be conceptualized as hypothyroidism causing organ failure.
  • The first organ to fail is generally the brain. Thus, a clinical hallmark of decompensated hypothyroidism is delirium.

differential diagnostic considerations include

• Adrenal crisis.
• Septic shock.
• Meningitis.
• Hypothermia of other etiology. 📖
• Hypoglycemia due to another etiology.
• Cerebrovascular accident.
• Drug intoxication (e.g. carbon monoxide, clonidine, beta-blocker or calcium channel blocker).
• Malnutrition.

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treatment of cause

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The trigger of decompensated hypothyroidism should be aggressively investigated and treated. This most often may involve…

sepsis

• Consider empiric therapy for sepsis.
• Decompensated hypothyroidism can mask may features of sepsis (including fever and leukocytosis).

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supportive care

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hypothermia management

• Provide supportive care as described in the hypothermia chapter: 📖.

hypoglycemia

• May require IV dextrose; follow serial glucose levels.
• Hypoglycemic should improve somewhat with steroid administration.

hyponatremia

• Severe hyponatremia may be a contributory factor towards seizure and delirium. This should be treated as described in the hyponatremia chapter: 📖.
• Mild hyponatremia will resolve with thyroid supplementation.

respiratory support

• Intubation and mechanical ventilation may be required due to coma.
• Macroglossia may make intubation more challenging.

cardiovascular support

• Tamponade may rarely require drainage. However, these patients tend to bleed and pericardial effusions will improve over time following treatment with thyroid hormone. Therefore, if it's possible to avoid pericardiocentesis, this may be wise. (28255471)
• Patients may be volume depleted, so titrated fluid resuscitation may be helpful.
• Shock may be pressor-refractory until thyroid hormone is administered.

hematologic support

• For hemorrhage, consider addition of desmopressin 0.3 mcg/kg IV.(7750191) von Willebrand syndrome won't cause alteration in standard coagulation labs, so empiric therapy may be needed.

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stress dose steroid

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• Rationale: Hypothyroidism may associate with adrenal insufficiency, either due to pituitary disease or as a multifocal autoimmune disorder.
  • Giving thyroid hormone without steroid can precipitate adrenal crisis.
• Hydrocortisone 100 mg IV q8hr is the standard therapy here.
• Hydrocortisone should be given prior to thyroid hormone administration (although this is could be less important for levothyroxine, which takes hours to work).
• Patients may be weaned off steroid fairly rapidly, once they are hemodynamically stable and improving.

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T4 (levothyroxine)

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contraindications, drug interactions, side effects 👎

contraindications

• Untreated adrenal insufficiency (may precipitate adrenal crisis; steroid replacement must precede thyroid hormone administration).
• Excipient hypersensitivity: Levothyroxine is a naturally occurring body chemical, so it's impossible to be allergic to levothyroxine itself. Allergy may rarely occur to excipients in tablets or capsules. This may be managed by using a different product.
• Oral levothyroxine is contraindicated in decompensated hypothyroidism (because GI absorption is unpredictable).
• Cautions:
  • Acute myocardial infarction (may increase myocardial oxygen demand).
  • Arrhythmias (can exacerbate).

drug-drug interactions

• Drugs that reduce oral bioavailability:
  • Calcium carbonate.
  • Antacids (aluminum/magnesium hydroxides).
  • Ferrous sulfate.
  • Bile acid sequestrants (cholestyramine, colestipol).
  • Phosphate binders (e.g., sevelamer).
  • Sucralfate.
  • Simethicone.
  • Proton pump inhibitors (liquid formulation may be better absorbed).
  • Cation exchange resins (kayexalate).
• Hepatic enzyme inducers may accelerate metabolism (e.g., phenobarbital, phenytoin, carbamazepine, and rifampin), requiring a 20-50% dose escalation.
• Tyrosine kinase inhibitors (e.g., sorafenib) increase thyroid hormone catabolism.
• Drugs that inhibit peripheral conversion of T4 to T3 may blunt the clinical effects (e.g., amiodarone, high-dose glucocorticoids, and high-dose propranolol).
• Hypothyroidism affects the metabolism and pharmacodynamics of numerous drugs (e.g., digoxin, warfarin, insulin, sympathomimetics and sympatholytics). Monitor drug levels and pharmacokinetics carefully as patients are treated for hypothyroidism.

side effects

• Precipitation of adrenal crisis (if underlying adrenal insufficiency).
• Precipitation of angina or arrhythmia.
• Hyperthyroidism (if dosed excessively).

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indications, advantages 👍

• Hypothyroidism.

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dosing of levothyroxine (T4)

levothyroxine dose in decompensated hypothyroidism

• Loading dose of 200-400 micrograms IV push. (25266247)
  • Consider using the lower end of the dose range in patients who are elderly, have low body weight, or have a history of coronary artery disease or arrhythmia.
  • This dose replenishes the peripheral hormone pool.
• IV levothyroxine is safe to give empirically (e.g., if there is a delay in labs returning).
  • T4 is the inactive form of thyroid hormone, so this won't cause any immediate effects.
  • The normal amount of circulating T4 is ~1,000 mcg. So, if the patient doesn't actually have hypothyroidism, giving 200-400 mcg of levothyroxine won't have much effect.
• Subsequently, the maintenance dose is 1.2 micrograms/kg IV daily. (25266247) Alternatively, simply a dose of 100 mcg IV daily may be reasonable for most patients. 
• Oral thyroid replacement shouldn't be used in decompensated hypothyroidism, because GI absorption may be erratic in this situation.

levothyroxine in hypothyroidism (in general)

• The full replacement dose for adults is ~1.6 mcg/kg/day PO (or ~1.1 mcg/kg/day in older adults).
• The usual dose range is 50-200 mcg daily.
• For patients >50YO with mild/moderate hypothyroidism, a starting dose of 25-50 mcg/day is reasonable.
• Morbid obesity: dose based on lean body mass, not actual body weight.
• Renal failure: no dose adjustment.
• Dose adjustments:
  • Often made by increments of 12.5-25 mcg/day.
  • Adjustments may be made every ~4-6 weeks.

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monitoring

• Discussed below.

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pharmacology of levothyroxine (T4)

• Chemical properties:
  • Molecular weight: 799 g/mol.
  • LogP: 2.5
• Absorption:
  • PO:
    • Oral bioavailability of a levothyroxine tablet is ~40-80%.
    • The bioavailability of oral levothyroxine suspension may be slightly higher (especially in the presence of reduced gastric acidity, for example, due to proton pump inhibitors).
    • Ideally, take in the AM on an empty stomach (this may improve absorption and reduce insomnia).
    • Levothyroxine is absorbed mainly in the jejunum and upper ileum of the small intestine.
    • Several medications may reduce absorption (listed above as drug-drug interactions).
    • In decompensated hypothyroidism, oral bioavailability is unreliable, so levothyroxine should be given intravenously. However, a recent study did find that the absorption of levothyroxine was sufficient for the treatment of decompensated hypothyroidism (using a specifically designed tapering dose: see 33777819). If oral levothyroxine is being utilized, consider the addition of adjunctive oral liothyronine (since the bioavailability of liothyronine is higher than the bioavailability of levothyroxine).  
  • IV dose:
    • The IV dose may be estimated as ~75% of the PO dose (sources vary somewhat in the PO/IV conversion; 50-75% might be reasonable).
• Distribution:
  • Protein binding is >99.9% to plasma proteins, including thyroxine-binding globulin (TBG), prealbumin, and albumin.
  • Vd is 11-15 liters (~extracellular fluid volume).
  • High protein binding contributes to thyroxine's long half-life.
  • Only the free hormone is biologically active to enter cells.
• Metabolism:
  • Levothyroxine is metabolized by sequential deiodination.
  • ~80% of circulating T3 is generated via peripheral monodeiodination of T4 (normally, the thyroid gland also secretes some T3).
  • Inner ring deiodination yields inactive reverse T3 (rT3).
  • Some T4 is also metabolized via glucuronidation and sulfation, with subsequent biliary and gut excretion (including enterohepatic recirculation).
• Elimination:
  • ~80% is excreted in the urine (as metabolites).
  • ~20% is eliminated in the feces (including conjugated metabolites).
• Half-life & duration of action:
  • Half-life varies depending on thyroid status:
    • Euthyroid patients: half-life of ~6-7 days.
    • Hypothyroid patients: half-life of ~9-10 days.
    • Hyperthyroid patients: half-life of ~3-4 days.
• Mechanism of action:
  • Levothyroxine is chemically identical to endogenous thyroxine (T4).

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T3 (liothyronine)

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contraindications, drug interactions, side effects 👎

contraindications

• These are the same as contraindications to levothyroxine (above).

drug-drug interactions

• Oral bioavailability may be reduced by cholestyramine or sevelamer (but this seems to be less problematic overall than the oral bioavailability of levothyroxine, as discussed above).
• Warfarin: Liothyronine potentiates warfarin's effects.
• Insulin: Liothyronine reduces insulin sensitivity.
• Digoxin: Liothyronine decreases serum digoxin levels.

side effects

• These are the same as side effects from levothyroxine (above).

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indications: role for liothyronine in decompensated hypothyroidism? 👍

• T3 is the activated form of thyroid hormone. Because liothyronine doesn't require activation, it has a faster onset of action.
• Normally, the body converts T4 into T3, but this conversion can be impaired in decompensated hypothyroidism. Therefore, T3 could be beneficial in combination with T4 to accelerate recovery.
• Old, retrospective, small studies have correlated the administration of massive doses of liothyronine (>75 mcg/day) with mortality. (10646654) This isn't necessarily surprising since it's a massive dose of liothyronine, which was utilized in the sickest patients.
• Bottom line: Liothyronine isn't necessarily mandatory, but it may be given as adjunctive therapy in combination with thyroxine. It's probably sensible to reserve liothyronine for more severe situations (e.g., intubated or shocky patients). ( 25266247)

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dosing of liothyronine in decompensated hypothyroidism

dosing of liothyronine in decompensated hypothyroidism

• Dosing when combined with IV T4 therapy (as above):
  • Loading dose of 5-20 micrograms IV.
  • Maintenance dose of 2.5-10 micrograms IV q8hr. (25266247)
  • Use the lower end of the dose range in smaller, older patients, as well as in those with a history of coronary disease or arrhythmia. (25266247)
• Discontinue once the patient is recovering (e.g., improved consciousness) or if T3 levels become elevated.
• If you don't have IV liothyronine, oral liothyronine may be used as an alternative, but absorption is unclear (discussion of oral bioavailability below).

dosing of liothyronine as thyroid replacement for hypothyroidism (in general)

• A typical starting dose in hypothyroidism is 25 mcg once daily, with increases of 12.5-25 mcg/day every 1-2 weeks. However, in elderly patients or patients with cardiac disease, an initial dose may be 5 mcg/day with titration in 5 mcg increments.
• The usual maintenance dose is 25-75 mcg daily.
• Twice daily dosing is often preferred to minimize peak-trough variability.
• When substituting liothyronine for levothyroxine, a 1:3 ratio is generally used (e.g., 25 mcg of liothyronine is equivalent to 75 mcg of levothyroxine).

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monitoring

• Discussed below.

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pharmacology

• Chemical properties:
  • Molecular weight: 672 g/mol.
  • LogP: 2.4
• Enteral absorption:
  • Rapidly and nearly completely absorbed (95% within 4 hours).
  • The onset of activity begins within hours.
  • Unlike levothyroxine, absorption isn't affected by gastric pH or binding agents.
  • Absorption in the context of decompensated hypothyroidism is unclear and shouldn't be assumed to be adequate. However, based on extrapolation from one study on levothyroxine (which has lower bioavailability than liothyronine), the absorption of liothyronine might be sufficient. (33777819)
• Distribution:
  • Less heavily protein-bound in the plasma compared to levothyroxine (99.5% vs. 99.96%).
  • Vd is 0.1-0.2 L/kg (extracellular fluid distribution).
  • This results in a higher level of free liothyronine with a more rapid onset of action.
• Metabolism:
  • The primary pathway of metabolism involves sequential deiodination, yielding diiodothyronine (T2).
  • The liver is the primary site of metabolism.
  • Some additional metabolism occurs via glucuronidation and sulfation, followed by biliary excretion and enterohepatic recirculation.
• Elimination:
  • 80% is cleared by the kidneys (mostly as metabolites).
  • 20% is excreted in feces.
• Half-life & duration of action:
  • Biological half-life is ~2.5 days.

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followup

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check thyroid hormones every 1-2 days (TSH, free T4, T3).

• TIMING OF LAB DRAW:
  • Shortly after administering exogenous thyroid hormones, peak levels will be elevated.
  • Thyroid hormone levels should ideally be checked as a trough level.
• TSH:
  • If TSH fails to decrease, the patient may require higher dosing of thyroid hormone.
  • However, TSH typically falls at a rate of ~50% per week.
• Free T4:
  • Free T4 should normalize within four days of starting therapy. (31424777)
  • Some drugs may cause protein-binding site displacement, causing an initial transient increase in free T4 (>80 mg IV furosemide, heparin, fosphenytoin, NSAIDs, high-dose salicylates).
• T3:
  • High T3 suggests excess administration of liothyronine. If T3 levels elevate, this indicates that T3 should be discontinued.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Mostly diagnostic problems:
  • Failure to consider decompensated hypothyroidism in a patient with altered mental status.
  • Satisfaction of search: after finding decompensated hypothyroidism, don't forget to look for a cause (e.g., sepsis).
• Avoid any potentially sedating medications, as these patients may have very tenuous mental status.

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