1. Hypothyroidism/Myxedema Coma Megha Poddar PGY 5 ENDOCRINE EMERGENCIES

2. 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

3. Case J 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

4. 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

5. 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

6. 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)

7. 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

8. 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

10. Signs of Hypothyroidism FindingsHypothyroidism GeneralLethargic and slow VitalsHR: bradycardia BP: narrow pulse pressure (↑ DSP) Temp: hypothermic HandsCool, rough skin, yellow discolouration (carotene) H&NHair: coarse, thick Eyes:  Periorbital edema  Loss of lateral 1/3 eyebrows (Queen Anne’s sign) Mouth  Macroglossia SkinVitiligo, non-pitting edema CVSPericardial effusion, diastolic hypertension RespPleural effusions CNSProximal muscle weakness, Reflexes = delayed relaxation, carpal tunnel syndrome

11. 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

12. 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

14. Hypothyroidism vs. Myxedema Coma Metabolic and anatomic thyroid emergencies: a Review (Robert c. Smallridge) Critical Care Medicine, 1992

15. 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

16. Journal of Thyroid Research 2011

17. 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

18. 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

20. 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

21. Helpful Signs/Symptoms Previous history of thyroidal illness Significant hypothermia Bradycardia Non pitting edema Delayed/absent deep tendon reflexes

22. 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

23. 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)

24. 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

25. 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

26. 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)

27. 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!

28. 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

29. 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

30. Management Strategies - controversial T4: 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

31. 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

33. 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

35. Investigations Active 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

36. 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

37. 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

38. 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.

40. References 1. 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