Keep in Mind…

1. Endocrine Emergencies8/23/19Norma Lopez, MDAssociate ProfessorDivision of Endocrinology and Metabolism

2. Keep in Mind… • You will see and treat an endocrine emergency at some point • You may not know it at the time • Supportive care is key

3. Case 1

4. Case 1 • 54 year old male presents to the emergency room with a 3 day history of new onset frontal headache • He describes the headache as 8/10, acute onset associated with nausea and vomiting and more recently with photophobia and diplopia. He took OTC pain meds but it did not help his symptoms. • In good health in the past and did not have any medical problems, did not take any meds other than MVI, denied use of tobacco, alcohol or illicit drugs • Patient denied any recent trauma or illness • He denied having any prior HA’s in the past similar to this episode

5. Case 1… • VS: Temp 100.2 RR 20 HR 110 BP 138/75 • PE: • In mod distress but alert and oriented • HEENT: Anicteric EOMI + Bitemporal hemianopsia • Neck was supple with minimal stiffness • CVS: Tachy but regular • Pulm: CTA B • ABD: Soft NT ND + BS • Rest of exam was normal • Prelim Blood tests showed WBC 14,000 Hgb and Plt WNL and BMP normal • MRI brain was ordered, next slides for normal MRI followed by patient’s MRI

6. Imaging: MRI Normal MRI of Pituitary and Surrounding Structures www.clevelandclinicmeded.com

7. Imaging: MRI Patient’s MRI www.clevelandclinicmeded.com

8. What is your diagnosis?

9. Pituitary Apoplexy • Rare clinical syndrome resulting from rapid expansion of the pituitary tumor secondary to hemorrhage. • Most cases occur spontaneously and in many cases such as in this one, the presence of the pituitary adenoma was not known prior to presentation • This diagnosis is a clinical diagnosis not a pathological one • Some describe this presentation as a “thunderclap headache” given sudden onset, and severity of the HA. Patients can present with both neurological and endocrine related signs and symptoms • Other DDx include subarachnoid hemorrhage, meningitis or encephalitis, cervico-cranial artery dissection, cerebral venous and dural sinus thrombosis, acute stroke or mass lesion. The imaging characteristics can provide a clue to the diagnosis.

10. What is the pathophysiology of the patient’s symptoms?

11. Pathophysiology • The HA and neuro/endo manifestations are due to hemorrhage of the adenoma causing sudden increase in intra-sellar pressure secondary to rapid expansion. This can lead to pituitary tissue compression and compromise of the blood supply to the pituitary which can lead to hypopituitarism with adrenal insufficiency being the main concern • Patients can have meningeal signs if the blood or necrotic tissue leaks into the subarachnoid space • The hemorrhage and increased pressure can also cause compromise of surrounding structures such as: • Laterally: cranial nerves III, IV, V and VI • Superiorly: Optic chiasm which can lead to bitemporal hemianopsia • Inferiorly: the increased pressure can cause CSF leak

12. What is your next step in managing this patient?

13. Management • Address systemic, neurological and endocrinological abnormalities • Two treatment options should be considered and the decision should be made based on severity of symptoms as well as presence of neurological compromise and evidence of progression of neurological compromise • Neurosurgical Evaluation: Documentation of VF defects is important and NS evaluation should be sought even if the second option is pursued. As in cases where there is significant neurological compromise or patient exhibits evidence of progression of neurological compromise then surgical decompression by an experienced surgeon is necessary • Conservative Medical Therapy: Serial evaluation and monitoring, corticosteroids and supportive therapy. The most important step is glucocorticoids as many patients can have compromise of the hypothalamic pituitary adrenal axis. The glucocorticoids can help control the inflammation and swelling.

14. What labs would you order?

15. 30 yo female 3rd trimester admitted for workup of HA . MRI noted 1.3cm pituitary lesion abutting chiasm, no sign of hemorrhage Component 7/22/2018 FREE T3 230 - 420 PG/DL 216 (L) FREE T4 0.8 - 1.7 NG/DL 0.6 (L) GROWTH HORMONE 0.0 - 3.6 1.7 PROLACTIN 3 - 29 NG/ML 88 (H) TSH 0.40 - 4.60 UU/ML 0.50 IGF-1 73 - 244 ng/mL 247 (H) ACTH <=46 pg/mL 30 CORTISOL 2.9 - 19.4 UG/DL 7.3

16. Check Pituitary Hormones • Impaired secretion of any of the hormones can be seen in this setting, partial or panhypopituitarism • ACTH/Cortisol, TSH/FT4,FT3, GH/IGF-1, Prolactin, Gonadal Axis, BMP • Pituitary function may return in certain cases • Pituitary axis should be re-evaluated a few weeks and months after the episode to see if pituitary function has returned

17. Test Questions • 64 year old male presents to the ER with sudden onset retro-orbital HA associated with dizziness and nausea • VS: 98 125/85 76 upon standing BP 100/60 100 • Main findings on exam include pale skin with fine wrinkles, Bitemporal hemianopsia, sparse body hair • MRI shows 1.9 cm sellar mass with compression of the optic chiasm, after administration of contrast there is evidence of hemorrhage within the mass • Of note patient with chronic fatigue for 2-3 years and was evaluated for hypogonadism 8 months prior to presentation

18. Test Questions • What is the most appropriate initial therapy? • A. Emergency Surgical Decompression of the sella • B. IV hydrocortisone 100mg Q 8 hrs • C. Hydrocortisone PO 20 mg in am and 10mg in pm • D. Levothyroxine 100mcg

19. Test Questions • Answer: B • The patient presents with pituitary apoplexy given presenting symptoms as well as MRI findings • The dizziness, nausea and orthostatic hypotension strongly suggest acute hypocortisolism • Full stress dose steroids would be the most appropriate initial therapy

20. CASE 2

21. Case 2 • 29 year old female was seen by her primary care doctor 1 yr ago with palpitations, tremors and weight loss, labs consistent with thyrotoxicosis and patient was referred to endocrinology • She was diagnosed with hyperthyroidism due to Grave’s Disease and after discussion regarding different treatment options patient opted to be treated with a thionamide ( methimazole ) • Unfortunately she was lost to follow up • During that time patient lost her job and insurance. Due to financial problems patient was not able to afford her medications including methimazole

22. Case 2 … • Patient with 50 lb weight loss, palpitations, tremors, diarrhea and developed proximal muscle weakness and returned for evaluation • Gen: Agitated • VS Temp 101 HR 140 RR 21 BP 155/60 • HEENT: + Temporal Wasting +Stare + B Proptosis • Thyroid Exam: 3 x Normal, Smooth without nodules + Bruit • CVS: Tachycardic, 1+ LE edema • Pulm: CTA B • ABD: Soft + BS • Skin: Warm and moist • Neuro: Motor 4/5 BUE and LE , DTR: Brisk B UE and LE + Fine Tremor B UE • Labs: TSH undetectable FT4 6.0 FT3 999

23. What is your diagnosis?

24. Thyroid Storm • Thyroid storm is defined as verysevere clinical hyperthyroidism or decompensated state of severe thyrotoxicosis presenting with marked tachycardia, fever,agitation, and weakness. It is a medical emergency with mortality of 10%. • While many patients with thyrotoxicosis can have palpitations and tremors the main features to look for in thyroid storm are: fever, tachycardia and altered mental state • It is a clinical diagnosis. Many patients have high thyroid hormone levels but are not in thyroid storm (exact mechanism as to why some get it and some don’t?) • Burch and Wartofsky have formulated a set of criteria and point system to diagnose thyroid storm

25. Precipitating Factors Most Common Etiology is History of Underlying Graves’ disease Chiha et al Journal of Intensive Care Medicine 2013

26. Criteria for Thyroid Storm ≥45 Highly suggestive of thyroid storm 25-44Supports the diagnosis <25 Thyroid storm unlikely Adapted from Burch HB, Wartofsky L. Endocrinol Metab Clin North Am 1993;22:263

27. Thyroid Storm • Thyroid Storm can develop in patients with longstanding untreated hyperthyroidism but most are precipitated by superimposed insult. • The elderly may present with apathetic hyperthyroidism, they have atypical symptoms presenting with apathy, obtundation, heart failure symptoms and with minimal signs of thyrotoxicosis.

28. What is your treatment approach and what medications would you use to treat this patient?

29. Treatment • Initiate treatment as soon as diagnosis suspected. • Supportive measures (intravenous fluids) should be initiated. Treatment of underlying infection or precipitator, if present, should be addressed. • Target the synthesis of hormone, release of hormone and attempt to minimize the affects of circulating hormone • Inhibiting new hormone synthesis: thionamides, PTU 250mg every 4 hours or Methimazole 60-120mg per day in 4-6 doses. • Both PTU and MMZ can be prepared in enemas and suppositories. Only MMZ can be prepared for IV.

30. Treatment Chiha et al. Journal of Intensive Care Medicine 2013

31. Treatment • Medications • Thionamide: Block new hormone synthesis within a few hours but do not effect the release of previously formed hormones • Propylthiouracil (PTU) is preferred as it also blocks T4T3 conversion however methimazole can be used as well (some physicians prefer it as it has a longer half life) • Iodine Solution: Block the release of thyroid hormone • Needs to be administered after thionamide therapy has been initiated to prevent the iodide from being used as a substrate for new hormone synthesis • SSKI or Lugol’s solution can be used • Glucocorticoids: Block T4 T3 Conversion and possibly treat the autoimmune process in Grave’s Disease

32. Supportive Measures • Treat fever, acetaminophen preferred over salicylates (can increase FT4 by decreasing binding to T4 binding globulin) • Hydration/IVF • Steroids may be given due to HPA axis impairment, decrease in adrenal reserve* • Therapeutic Plasma Exchange if conventional therapy fails *

33. Surgery • All measures must be employed to stabilize patient prior to emergent thyroid surgery • “Safe” level of free thyroid hormones may depend on the surgeon as well as risk/benefit assessment • Thionamide may be stopped right after surgery • B-blockade and steroid should be continued and slowly weaned

34. Test Q&A • 1. 38 y/o female with h/o Grave’s disease presents to the ER with tachycardia, fever and agitation. Upon further questioning of family members it is discovered that patient has been very noncompliant with her methimazole. Patient is diagnosed with thyroid storm and is admitted for further treatment. Which of the following treatment options is incorrect? • A. Iodine Solution before giving methimazole • B. Starting propranolol • C. Iodine Solution after giving methimazole • D. Starting steroids

35. Test Q&A • The correct answer is C • Treatment options for thyroid storm should include treatment with thionamide (PTU or Methimazole) to decrease new thyroid hormone synthesis. Also Beta blocker such as propranolol to help control heart rate and symptoms (it can also help block T4T3 conversion). Glucorticoids are used to also help block T4T3 conversion. • Iodine is used to block the release of thyroid hormone. However it should be given after starting treatment with thionamide as if it started before giving thionamide the iodine can be used as substrate for new hormone synthesis and worsen hyperthyroidism

36. Case 3

37. Case 3 • 75 year old male is seen in ED after he was found lethargic and almost unresponsive at the nursing home. His family had noted that when visiting him at the NH that the patient had become very slow at answering questions and not as energetic as he had been 2 months prior. • VS: Temp 96 HR 44 RR 15 BP 125/90 • Exam: Patient very lethargic, puffy face • HEENT: Anicteric with periorbital edema • Pulm: Poor respiratory effort but clear • CVS: Bradycardic but regular • Abd: Soft Hypoactive BS • Exts: Bilateral non-pitting edema • Skin: Cool and pale with yellowish tinge • Neuro: Limited exam secondary to poor effort, delayed relaxation phase of DTR’s

38. Case 3 • Labs: • CBC with elevated WBC and normocytic anemia • BMP remarkable for glucose of 68, hyponatremia, high bicarb and elevated Cr (1.9) • UA with elevated WBC, + LE and many bacteria • TSH 100 • Upon further review of med list from the NH family notices that LT4 is not on the list

39. What is your diagnosis?

40. Myxedema Coma • The rare syndrome of myxedema coma represents the extreme of hypothyroidism and is an endocrine emergency • The mortality rate remains high, may approach 60%. • Despite the name patients frequently do not present in coma but do manifest lesser degrees of altered consciousness. Usually confusion with lethargy and obtundation.

41. Myxedema Coma • Long-standing, unrecognized and poorly controlled hypothyroidism and often precipitated by a superimposed systemic illness. • Event such as infection, myocardial infarction, CVA, CHF, cold exposure, or the administration of sedative drugs, especially opiates may be the precipitating factor • The diagnosis initially based upon the history, physical examination, and exclusion of other causes of altered mental status • Features include (but not all are necessarily present) hypothermia, unconsciousness, bradycardia, pericardial effusion, hypotension leading to cardiovascular collapse, impaired water excretion with hyponatremia, paralytic ileus, and gastric atony

43. Diagnosis ≥60 highly suggestive, 25-59 is suggestive of risk, <25 unlikely Popoveniuc G et al Endocrine Practice August 2014

44. How would you treat this patient?

45. Treatment • Test adrenal axis prior to starting treatment with LT4 • If no evidence of adrenal insufficiency then thyroid hormone replacement with initial large doses of IV T4, T3, or both is initiated • Levothyroxine (T4) IV loading dose 200-400mcg followed by daily dose 1.6mcg/kg • Liothyronine (T3) 2.5-10mcg every 8 hours until clinical improvement noted • Oral treatment can be substituted when improvement is evident and sufficient gastrointestinal motility is present

46. Test Q&A • Correct answer is B Bok Choy (contains glucosinolates, a group of compounds that occur widely in the genus. Some of the breakdown products of glucosinolates, such as thiocyanates, nitriles, and oxazolidines) have been implicated for their inhibitory effects on the thyroid / inhibits thyroid hormone production

47. Test Questions • 2.When treating myxedema coma what is the best initial management? • A. PO Levothyroxine (T4) • B. IV Levothyroxine (T4) • C. PO Cytomel (T3) • D. Rewarming

48. Case 4 • 20 year old female college student presents to her primary care physician c/o extreme fatigue, lightheadedness, difficulty concentrating. While she has been stressed with her school work, her symptoms appear more severe than anticipated. • She denies any recent illness, denies being depressed, admits to lack of appetite and nausea, also with diffuse myalgias and arthralgias she has also noted that her skin has been getting darker for the past several months despite the fact that she has been in doors studying most of the time

49. Test Questions • The correct answer is IV levothyroxine • When treating myxedema coma, initially give IV T4 or T3 or both and later change to PO thyroid hormone replacement.

50. Case 4 • VS: Afebrile HR 102 RR 19 100/70 Sitting 75/50 Standing • GEN: ill appearing, thin and with skin hyperpigmentation (compared to prior photos) • HEENT: Anicteric EOMI thyroid not enlarged • CVS: Tachy but regular • Pulm: CTA B no w/r/r • ABD: Soft hypoactive BS NT • Exts: No Edema • Initial orders include labs to further evaluate symptoms … • Na 132 K 6.1 Glucose 65 Cr 1.1