Hypothyroidism/Myxedema Coma

Megha PoddarPGY 5

ENDOCRINE EMERGENCIES

Objectives

1. Discuss the signs and symptoms of Hypothyroidism and Myxedema Coma through a case

2. Review definition, pathophysiology, diagnosis and management of Myxedema Coma

3. Review the difficulties with diagnosing Myxedema and Sick Euthyroid

4. Review specific management strategies

CaseJ Korean Med Sci. 2010 September; 25(9): 1394–1397

74yo woman presented to hospital with altered mental status, generalized edema, hypotension, hypothermia and respiratory distress. Found by a family member in bed unconscious.

•The initial diagnosis was a brain stem infarct • One week ago, facial edema started and she

complained of a dry cough and general weakness • No other medical, family, or social history was

reported, and no medication were known

Case…

• She arrived to the hospital after having been intubated in the field, had been given IV fluids and started on Levophed

• Vitals: BP 71/48 mmHg, Temp 36.0, HR 99 beats/min• Neuro Exam: pinpoint pupils and no brain stem

reflexes• Face and extremities non-pitting edema, skin dry,

cool, pale, obese • She was then transferred to a tertiary care hospital • Vitals on arrival: 70/40, 59bpm, temp: 34.8, slow

and shallow respirations

Investigations

• CT head negative

• WBC 8.7, hemoglobin 98, sodium 121 mEq/L, potassium 4.2 mEq/L, Cr 103, glucose 3.9 mmol/L, ALT 113 U/L, AST 74 U/L, albumin 33, CK 499 IU/L, troponin <0.01, lactate 1.2 mM/L

• Her blood pressure did not respond for 3days therefore additional blood work done

Free T4 0.64 (11.97-21.88 pmol/L)

TSH 30.12 (0.27-5.0 mU/L)

• Thyroid gland secretes mainly T4

• 20% of hormone secreted is T3

• Remainder of T3 converted in the peripheral tissue from T4

• T3 is more biologically active in tissue

• Free hormones bind to TSH recepters and initiate various physiological and biochemical responses

Thyroid Physiology

Etiology of Hypothyroidism

• Most common cause: Autoimmune thyroiditis

• Removal of gland

• Surgical

• RAI ablation

• Medications

• Lithium

• Amiodarone

• Anticonvulsants

• Iodine deprived areas (most common cause wordwide)

• Secondary/Central Hypothyroidism (5%)

• Hypopituitarism

• Hypothalamic disorders

Signs of HypothyroidismFindings Hypothyroidism

General Lethargic and slow

Vitals HR: bradycardiaBP: narrow pulse pressure (↑ DSP)Temp: hypothermic

Hands Cool, rough skin, yellow discolouration (carotene)

H&N Hair: coarse, thickEyes:Periorbital edemaLoss of lateral 1/3 eyebrows (Queen Anne’s sign)MouthMacroglossia

Skin Vitiligo, non-pitting edema

CVS Pericardial effusion, diastolic hypertension

Resp Pleural effusions

CNS Proximal muscle weakness, Reflexes = delayed relaxation, carpal tunnel syndrome

Myxedema Coma

• Extreme clinical expression of Hypothyroidism, terminal phase of severe or decompensated hypothyroidism• CNS disturbance, CV collapse, hypoventilation, metabolic

derangements

• EMERGENCY!

• High Mortality rate (40-60%)

• Rare (0.22/million ppl per yr (US))

• Most common amongst elderly women

• Poor prognostic indicators include advanced age, gender, presence of cardiac/resp complications, hypothermia

• Japanese study in Thyroid from 1999 – case study of 8 patients and Lit.Review (Yamamota et el)

• Higher doses of levothyroxine (500mcg) and T3 (75mcg) associated with increased mortality

• Usually precipitated by another event

• FIND THE CAUSE

• Clinical Clues

• Infection with no fever

• Any patient who is obtunded should be screened

Hypothyroidism vs. Myxedema Coma

Metabolic and anatomic thyroid emergencies: a Review (Robert c. Smallridge) Critical Care Medicine, 1992

Pathogenesis of Myxedema Coma

• Low intracellular T3 – suppresses cardiac activity, hypothermia – precipitating events leads to shock

• Compensation includes:• Peripheral vasoconstriction, diastolic HTN, low

blood volume

• Respiratory dysfunction: • Muscle weakness, obesity, pleural effusions,

infection, reduced lung volume

• Altered vascular permeability• Anasarca, effusions, hyponatremia

Journal of Thyroid Research 2011

Clinical Findings

• Hypothermia: <34 degrees Celsius • Resp : pleural effusion, hypoventilation• Neuro :Coma/deterioration of mental status• CVS: hypotension, bradycardia, CHF,

pericardial effusions• ECG changes include bradycardia, decreased

voltages, non-specific ST and T changes, varying types of block and a prolonged QT interval

• GI/GU: Ileus, urinary retention, ascites, high LFTS

Laboratory Findings• Alveolar Hypoventilation:

• High CO2 on ABG• Low O2 saturation

• Hyponatremia• Impaired renal water excretion• ? Low ANP• ? Inc ADH

• Anemia• Iron deficiency• Megaloblastic

• Coagulopathy and Bleeding• Reduced factors 5,7,8,9,10, acquired vWD

• Hypoglycemia: - Down-regulation of metabolism seen in hypothyroidism +/- adrenal insufficienency, sepsis etc

Pitfalls in Diagnosis

• Recognition of vague symptoms are difficult

• May be misdiagnosed initially as having a more common disorder (stroke, CHF, infection/delirium)

• Distinguishing sick euthyroid from true hypothyroidism

• Edema may be present in other causes• ** difference between pitting and non pitting• **Dependent vs non dependent areas

Helpful Signs/Symptoms

• Previous history of thyroidal illness

• Significant hypothermia

• Bradycardia

• Non pitting edema

• Delayed/absent deep tendon reflexes

Common Scenario:

• Elderly patients with mod to severe untreated hypothyroidism and a concomitant other illness bringing patient to the hospital

• ? How do you distinguish between sick euthyroid and severe hypothyroidism

Sick Euthyroid vs Hypothyroidism

• Low Free T3 in both cases – Sick Euthyroid: inhibition of conversion from T4 to T3, high amounts of rT3-Hypothyroidism: Low T3/T4, Low rT3-** rT3 not readily available

• Low Total T4 – inhibition of binding to proteins

• Free T4 may be high, low or normal

• TSH should be elevated in primary hypothyroidism, suppressed in severe illness•Increase may be suppressed by stress, meds (steroids, etc)

Sick Euthyroid

• Pathogenesis: cytokine mediated inhibition of 1 5’ deiodinase, medications used in critically ill patients (steroids, amio, dyes)

• Can occur in caloric restriction, malnutrition, acute or chronic illness

• Body is attempting to decrease excessive catabolism in a state of critical illness

• Difficult to distinguish between Sick euthyroid and secondary hypothyroidism

• Randomized prospective study:• response of hypothyroxinemic patients with severe

nonthyroidal illnesses to T4 therapy.

• Medical intensive care unit pts with total T4 < 5 micrograms/dl

• Randomly assigned to a control (12 patients) or a T4 treatment group (11 patients).

• L-T4 1.5 micrograms/kg was given iv each day for 2 weeks.

• Results: Mortality was equivalent in the 2 groups (75% control vs. 73% treatment).

• T4 therapy was not beneficial in this population of intensive care unit patients, and by inhibiting TSH secretion, it may suppress an important mechanism for normalization of thyroid function during recovery

Sick Euthyroid Treatment

ATA Guidelines 2012 – no clear evidence

- patients that are not clearly hypothyroid should wait until they are well to be treated

•Patients with refractory depression

•CABG Patients: “A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery.”• 170 pts post CABG, placebo vs T3 (0.6ug/kg plus

0.1ug/kg over 6 hours)

Management• ABC’s!

• Hemodynamic Monitoring

• Intubate early

• Restoration of circulatory volume

• Examine the GI tract!

• Search for Infection – cover empirically with antibiotics

• Electrolyte abnormality correction

• Urinary retention is common – needs a foley!

Glucocorticoids • Cover empirically: Because of the possibility of secondary

hypothyroidism and associated hypopituitarism or Addison's

• Failure to treat with hydrocortisone in the face of adrenal insufficiency may result in the precipitation of adrenal crisis!

• Hydrocortisone 100mg IV q8h or 50 mg IV q6h • give at least 1 hour prior to thyroid hormone

• Draw a random cortisol/ACTH level prior to therapy, and if normal d/c steroid

Thyroid Hormone Replacement

• Consider: • Absorption - ? Poor gut motility• 7 patient observational study showed oral absorption is

variable in myxedema patients, IV route results in higher peak free hormone levels

• Onset and Efficacy - ? Dose, route• Safety - ? Active angina, age• ? Potential for use of T3 – decreased peripheral

conversion

Management Strategies -

controversialT4:

•Treatment of Myxedema with IV levothyroxine

•Most frequently used

T3:

•? If neuropsychological symptoms predominate

•Careful with unpredictable fluctuations in free hormones

Combination:

•Potential use if refractory to T4 alone

•Half the recommended dose of T4 and T3

• L-T4• Slower onset, avoids peaks/troughs• IV 200-500 mcg IV bolus then 50-100 mcg IV daily• depends on weight, severity (caution if lighter, older, cardiac

conditions)

• IV:PO = 1:2 dosing

• Higher doses of levothyroxine (500mcg) and T3 (75mcg) associated with increased mortality (Japanese study)

• L-T3• Rapid onset of action, crosses BBB more rapidly• ? Increased risk of cardiac complications• 15-20 mcg then 10-25 mcg po q8h• continued until clinical improvement

Thyroid Hormone Replacement

Supportive Management Specifics

• Management• ICU, support ventilation, cardiac monitoring• External passive warming • NOT ACTIVE –can precipitate hypotension due to

vasodilation

• Monitor electrolytes and use fluids cautiously• Not hypotonic fluids/free water since low Na

• Antibiotics• Caution drug dosing – lower metabolism of

drugs

InvestigationsActive search for precipitating causes

• TSH, Free T4

• Thyroid Antibodies (TPO and Tg)

• CBC, lytes, renal, glucose, ABG, CK, trops, LFTS, lactate

• Blood and urine cultures, CXR

• Cortisol and ACTH

• ECG, ECHO (if cardiomegaly to r/o pericardial effusion), CT/MRI Head

Back to the case

• Unconscious, GCS 5, breathing was shallow• BP 71/48 mmHg, Temp 36.0, HR 99 beats/min • pinpoint pupils and a lack of brain stem reflexes,

• face and extremities non-pitting edema, skin dry, cool, pale, and slightly mottled and desquamated

• She was intubated, started on levophed drip, in ICU

• CT head negative

• WBC 8.7, hemoglobin 98, sodium 121 mEq/L, potassium 4.2 mEq/L, Cr 103, glucose 3.9 mmol/L, ALT 113 U/L, AST 74 U/L, albumin 33, CK 499 IU/L, troponin <0.01, lactate 1.2 mM/L

Summary

• Accurate diagnosis: careful history, physical examination and laboratory evaluation.

• Most important elements in treatment: early recognition, presumptive thyroid hormone replacement, hydrocortisone and appropriate supportive care.

References1. Front. Endocrinol., 01 July 2014 | doi: 10.3389/fendo.2014.00102 Clinical concepts on

thyroid emergencies Giampaolo Papi et al

2. Metabolic and anatomic thyroid emergencies: a Review (Robert c. Smallridge) Critical Care Medicine, 1992

3. Powerpoint Slides on UWO postgrad website

4. ATA Guidelines 2012.

5. Factors associated with mortality of myxedema coma: report of eight cases and literature survey. Yamamoto T, Fukuyama J, Fujiyoshi A.

6. Thyroxine therapy in patients with severe non thyroidal illness and low serum thyroxine concentration. G.Brent et al. JCEM 1986

7. Myxedema Coma: a new look into an old crisis. Mathew V. et al. Journal of Thyroid Research. 2011.

8. J Korean Med Sci. 2010 Sep;25(9):1394-7. doi: 10.3346/jkms.2010.25.9.1394. Epub 2010 Aug 16.A case of myxedema coma presenting as a brain stem infarct in a 74-year-old Korean woman.

9. UptoDate