I have no financial disclosures ENDOCRINE Hilary Thomas, MD - - PowerPoint PPT Presentation

7/8/15 1

ENDOCRINE

Hilary Thomas, MD

Assistant Clinical Professor of Medicine, UCSF Division of Endocrinology, SFGH July 8, 2015

I have no financial disclosures

2

7/8/15 2

Case 1

3

64 yo M with HTN, CAD, and prior episode of pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for another reason. An A1C was obtained and was 6.4%. The patient has no symptoms such as polyuria, polydipsia or polyphagia.

Does he meet the criteria for the diagnosis of diabetes?

• 1. Yes
• 2. No

Case 1

4

64 yo M with HTN, CAD, and prior episode of pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for another reason. An A1C was obtained and was 6.4%. The patient has no symptoms such as polyuria, polydipsia or polyphagia.

Does he meet the criteria for the diagnosis of diabetes?

• 1. Yes
• 2. No

7/8/15 3

Diagnosis of Diabetes

• 1. Fasting plasma glucose (FPG) ≥ 126 mg/dl*

OR

• 2. Plasma glucose ≥ 200 mg/dl 2h post 75 g oral

glucose load (OGTT)* OR

• 3. A1C ≥ 6.5%* OR
• 4. Random plasma glucose ≥ 200 mg/dl with

symptoms of hyperglycemia

*should be confirmed with same test unless has symptoms of hyperglycemia

5

Case 2

6

64 yo M with HTN, CAD, and a prior episode of pancreatitis is found to have a random plasma glucose of 205 without polyuria or polydipsia. You obtain a fasting BG which is 154 mg/dl confirming the diagnosis of diabetes mellitus. LABS: A1C = 8.5%, 140 111 28 4.5 28 1.3 MEDS: ASA 81 mg; lisinopril 40 mg; metoprolol 100 mg BID EXAM: 100 kg BMI 32 145/94 82 acanthosis nigricans

• therwise unremarkable

7/8/15 4

What’s the best initial therapy?

7

• 1. metformin
• 2. exenatide
• 3. pioglitazone
• 4. glipizide
• 5. diet and exercise alone

What’s the best initial therapy?

8

• 1. metformin
• 2. exenatide
• 3. pioglitazone
• 4. glipizide
• 5. diet and exercise alone

7/8/15 5

DM2 Therapy Pearls

§ Lots of different practice styles § Focus on CONTRAINDICATIONS § Some delay in test question writing so newest medications unlikely to be on the test § For T2D, always treat with metformin first unless contraindicated

9

Figure 7.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations (15). The order in the chart was determined by historical

10

Diabetes Care, 2015; 38(Suppl 1)

7/8/15 6

Metformin

Mechanism of action Inhibits liver gluconeogenesis (targets fasting BG) ê HbA1c 1.5 – 2% Benefits Weight loss No hypoglycemia CVD benefit Side Effects Nausea/diarrhea Impaired B12 absorption (>5% of patients) Contraindications eGFR < 30 OR do not initiate if unstable kidney function Severely impaired liver function (AST/ALT > 3X ULN) Decompensated heart failure Contrast studies

11

Metformin

Mechanism of action Inhibits liver gluconeogenesis (targets fasting BG) ê HbA1c 1.5 – 2% Benefits Weight loss No hypoglycemia CVD benefit Side Effects Nausea/diarrhea Impaired B12 absorption (>5% of patients) Contraindications eGFR < 30 (do not initiate if unstable kidney function) Severely impaired liver function (AST/ALT > 3X ULN) Decompensated heart failure Contrast studies

12

FIRST LINE AGENT

7/8/15 7

Medication by HbA1c Lowering

Medication Change in HbA1c Biguanides (Metformin) 1.5 - 2% Sulfonylureas 1 - 2% Glinides 1 - 1.5% GLP-1 agonists 0.5 – 1.5% PPARg agonists/TZDs 0.5 – 1.4% SGLT2 Inhibitors 0.5 – 1% DPP-IV Inhibitors 0.5 – 0.8%

13

Sulfonylureas

Glyburide, Glipizide, Glimepiride

14

Mechanism of Action Stimulate insulin release ê HbA1c 1 - 2% Benefits Targets post prandial BG Side Effects Hypoglycemia Weight gain Contraindications Caution in renal failure

7/8/15 8

Sulfonylureas – Dosing/Cautions

§ Glyburide

• Non-linear dose response (more effect of 1.25 to 2.5

than 10 to 20)

• Caution in renal failure and in elderly

§ Glipizide

• Better in renal impairment
• ? Increased CV risk

§ Glimepiride

• Caution in renal failure, liver failure, elderly

15

Typically discontinued when patient on prandial insulin

Glinides

Repaglinide, Nateglinide

Mechanism of Action Stimulate insulin release ê HbA1c 1 – 1.5% Benefits Targets post prandial BG Short acting – can skip if not eating Side Effects Hypoglycemia Weight gain TID dosing Contraindications Can use in renal failure (repaglinide) Caution with meds that affect CYP2C8 and

CYP3A4 activity

16

7/8/15 9

Case 3

§ You see an active 72yo F with a history of

• steoporosis, T2D, and HTN for follow up.

Her diabetes was controlled with metformin 1g bid, but her labs now show a HbA1c of 7.8%. Her Cr is 1.3 with eGFR of 50. She does not want to take injections.

What should you do?

• 1. Do nothing - a HbA1c of 7.8% is at goal
• 2. Add glyburide
• 3. Add pioglitazone
• 4. Add renally dosed sitaglipitin

17

Case 3

§ You see an active 72yo F with a history of

• steoporosis, T2D, and HTN for follow up.

Her diabetes was controlled with metformin 1g bid, but her labs now show a HbA1c of 7.8%. Her Cr is 1.3 with eGFR of 50. She does not want to take injections.

What should you do?

• 1. Do nothing - a HbA1c of 7.8% is at goal
• 2. Add glyburide
• 3. Add pioglitazone
• 4. Add renally dosed sitaglipitin

18

7/8/15 10

PPAR-γ Agonists

Pioglitazone, rosiglitazone

Mechanism of Action Improve insulin sensitivity ê HbA1c 0.5 – 1.4% Benefits Minimal hypoglycemia Improves lipid panel* Side Effects Weight gain/edema Increased risk of CHF (rosi) Increased fracture risk* Increased risk of bladder cancer* Contraindications

CHF (NYHA Class III/IV)

19

*pioglitazone only

The GLP-1 Effect

20

GLP-1 (exenatide) Inactive GLP-1

DPP-IV

(Sitagliptin)

7/8/15 11

GLP-1 agonists

exenatide, liraglutide, dulaglutide, albiglutide

Mechanism of Action Delays gastric emptying Increases glucose dependent insulin release Inhibits post-prandial glucagon release ê HbA1c 0.5 – 1.5% Benefits Weight loss (2-3kg) Minimal hypoglycemia Side Effects Injectable Nausea/vomiting Contraindications

Prior pancreatitis Medullary thyroid cancer (personal or family history) eGFR < 30 Caution in gastroparesis

21

DPP-IV Inhibitors

sitagliptin, saxagliptin, linagliptin, alogliptin

Mechanism of Action Increases GLP-1 and GIP levels ê HbA1c 0.5 – 0.8% Benefits Weight neutral Minimal hypoglycemia* Can dose reduce in renal failure Side Effects Nausea/vomiting Can increase URIs ? Increase heart failure hospitalizations Contraindications

Prior pancreatitis History of hypersensitivity reactions

22

*unless given with insulin, sulfonylurea or glinide

7/8/15 12

SGLT2 Inhibitors

dapagliflozin, canagliflozin, empagloflozin

Mechanism of Action Impairs renal absorption of glucose ê HbA1c 0.5 - 1% Benefits Weight loss Decrease BP Minimal hypoglycemia Can dose reduce in renal failure Side Effects GU infections/UTI Dehydration/dizziness Hyperkalemia/elevated Cr Contraindications eGFR <45 Severe liver failure Active bladder cancer

23

You are asked to see a 72 year old man with CHF with previously well controlled DM2, but now a HbA1c of 9.1% complicated by gastroparesis. He is on glyburide and metformin at max doses.

Case 4

How should you change his regimen?

• 1. Add pioglitazone
• 2. Add basal insulin (NPH or glargine)
• 3. Add exenatide
• 4. Add saxagliptin

7/8/15 13

You are asked to see a 72 year old man with CHF with previously well controlled DM2, but now a HbA1c of 9.1%. He is on glyburide and metformin at max doses. How should you change his regimen?

• 1. Add pioglitazone – CHF
• 2. Add basal insulin (NPH or glargine)
• 3. Add exenatide – gastroparesis
• 4. Add saxagliptin - minimal HbA1c change

Case 4

Medication by HbA1c Lowering

Medication Change in HbA1c Biguanides (Metformin) 1.5 - 2% Sulfonylureas 1 - 2% Glinides 1 - 1.5% GLP-1 agonists 0.5 – 1.5% PPARg agonists 0.5 – 1.4% SGLT2 Inhibitors 0.5 – 1% DPP-IV Inhibitors 0.5 – 0.8%

26

7/8/15 14

Case 5

27

66yo M with DM2 for 5 years started on insulin 2 years ago but still can’t get A1C below 8.5%. Patient reports no symptomatic lows. DM Meds: Metformin 1 gm BID NPH 20 units am, 10 units at bedtime Regular 5 units before each meal BS records: fasting 115-150 pre-lunch 85 -155 pre-dinner 92 - 145 bedtime 170-290

What would be the best first next step for improving A1C? a) Change NPH to glargine 30 units b) Increase morning NPH dose to 25 units c) Increase bedtime NPH dose 15 units d) Increase meal time R insulin dose to 8 units before each meal e) Increase dinner time R insulin to 8 units

Case 5

28

66yo M with DM2 for 5 years started on insulin 2 years ago but still can’t get A1C below 8.5%. Patient reports no symptomatic lows. DM Meds: Metformin 1 gm BID NPH 20 units am, 10 units at bedtime Regular 5 units before each meal BS records: fasting 115-150 pre-lunch 85 -155 pre-dinner 92 - 145 bedtime 170-290

What would be the best first next step for improving A1C? a) Change NPH to glargine 30 units b) Increase morning NPH dose to 25 units c) Increase bedtime NPH dose 15 units d) Increase meal time R insulin dose to 8 units before each meal e) Increase dinner time R insulin to 8 units

7/8/15 15

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239 0600 0600

Time of day

20 40 60 80 100 B L D

Normal Plasma Insulin Profile

B=breakfast; L=lunch; D=dinner 0800 1800 1200 2400

Insulin µU/mL

Basal insulin

• Near-constant levels
• Important during night/between meals
• 50% or more of daily needs

Mealtime/Bolus insulin

• Limits hyperglycemia after meals
• Rise and peak post meal

Types of Insulin

§ Basal Insulin

• NPH, BID dosing, peaks 4-8 hrs
• glargine (lantus), once daily dosing, no peak, can’t mix with
• ther insulins
• detemir (levemir), BID dosing, no peak, can’t mix

§ Mealtime/Bolus Insulin

• Regular (humalin R, novalin R), take 30m premeal
• Aspart (novolog), take 5-20 m premeal
• Lispro (humalog)
• Glulisine (apidra)

§ Combination Insulin

• 70/30 (70%N, 30% R; 70% intermediate, 30% aspart)
• 75/25 (75% intermediate; 25% lispro)

30

7/8/15 16

0600 0800 1800 1200 2400 0600

Time of day

20 40 60 80 100 B L D

Basal-Bolus Insulin Treatment

B=breakfast; L=lunch; D=dinner

Meal time insulin Normal pattern

µU/mL

NPH NPH at bedtime

0600 0800 1800 1200 2400 0600

Time of day

20 40 60 80 100 B L D

Basal-Bolus Insulin Treatment

B=breakfast; L=lunch; D=dinner

Glargine Meal time insulin Normal pattern

µU/mL

7/8/15 17

A 64yo W with DM2 presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesn’t check BS at other times of the day. Medicines include metformin 1g BID and glipizide 20 mg BID. A1c is 9.1%. Of the options listed below, which is the most appropriate therapy for this patient?

• 1. Start morning NPH or glargine and discontinue all oral agents
• 2. Start morning NPH or glargine, maintain sulfonylurea and

discontinue metformin

• 3. Start bedtime NPH or insulin glargine, discontinue metformin

and continue sulfonylurea.

• 4. Start bedtime NPH or glargine, maintain oral agents

Case 6

A 64yo W with DM2 presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesn’t check BS at other times of the day. Medicines include metformin 1g BID and glipizide 20 mg BID. A1C 9.1%. Of the options listed below, which is the most appropriate therapy for this patient?

• 1. Start morning NPH or glargine and discontinue all oral agents
• 2. Start morning NPH or glargine, maintain sulfonylurea and

discontinue metformin

• 3. Start bedtime NPH or insulin glargine, discontinue metformin

and continue sulfonylurea

• 4. Start bedtime NPH or glargine, maintain oral agents

Case 6

7/8/15 18

Case 7

55yo W with DM2, HTN and obesity complains

• f fatigue, depressive symptoms and weight

gain. What should you check?

Case 7

55 yo W with DM2, HTN and obesity complains of fatigue, depressive symptoms and weight gain Exam: 80 kg, BMI 32, dry skin

36

TSH 8.9 H (0.45-4.20) repeat TSH 35 H (0.45-4.20) FT4 0.63 L (0.65-1.78)

Dx - Hypothyroid

TSH T4/T3

7/8/15 19

Hypothyroidism

• 2% of adult women
• Etiology
• Hashimoto’s thyroiditis
• post surgery/radiation/XRT
• drugs (lithium, amiodarone, interferon)
• Treated with L-thyroxine
• Recheck/adjust dose in 6-8 weeks
• Calcium, iron interfere with absorption

37

Case 8

55yo F with DM2, HTN and obesity complains

• f fatigue, depressive symptoms and weight

gain. Exam: 80 kg, BMI 32, dry skin

38

TSH 8.9 H (0.45-4.20) TSH 12 H (0.45-4.20) FT4 1.1 (0.65-1.78) Subclinical Hypothyroidism What now?

7/8/15 20

Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat

• Prevent progression to frank hypothyroidism

(especially if + TPO)

• Improve symptoms
• Improve lipids/CV risk profile
• Woman of childbearing age (target TSH < 2.5)

39

• Never treat based on a single value
• Treat most patients with TSH > 10

Case 9

35yo F complains of fatigue, documented weight gain, cold intolerance and amenorrhea. TSH 1 (0.45-4.20) FT4 0.3 L (0.65-1.78)

Does this patient have primary hypothyroidism?

a) Yes b) No

40

7/8/15 21

Case 9

35yo F complains of fatigue, documented weight gain, cold intolerance and amenorrhea. TSH 1 (0.45-4.20) FT4 0.3 L (0.65-1.78)

Does this patient have primary hypothyroidism? a) Yes b) No – This patient needs to have their pituitary function tested and imaged. REFER TO ENDO!

41

TSH T4/T3

Case 10

29yo F with h/o anxiety, tremor and weight loss for 6 months TSH < 0.01 H (0.45-4.20) TSH < 0.01 H (0.45-4.20) FT4 1.76 (0.65-1.78)

What about a total T4 or T4 index? What about Free T3? What about thyroid antibodies?

42

7/8/15 22

Thyroid Lab Testing

§ Total T4

• Inferior tests for assessing thyroid function and used only in special

situations (pregnancy); Free T4 preferred

§ Free T3

• Can be elevated with fT4 in normal range (T3 toxicosis)
• Most useful in a patient with a suppressed TSH and

normal free T4

§ Antibodies

• TSH receptor antibodies: Graves (92-98% Sn)
• TSI (thyroid stimulating immunoglobulin): Graves (92% Sn,

99% Sp)

• anti-TPO (thyroid peroxidase) antibodies: Autoimmune

thyroid disease (Hashimoto’s + Graves, + in 10-15% of euthyroid patients)

• Anti-thyroglobulin: used for thyroid cancer

43

Case 10

29yo F with ten pound weight loss, tremor, insomnia and just not feeling right for 6 months. On exam she is tachycardic to 115, is noted to have scleral injection bilaterally with mild proptosis and an enlarged, non- tender thyroid. She denies any recent URIs. Labs: TSH < 0.01 H (0.45-4.20) FT4 1.76 (0.65-1.78) FT3 5.3 H (2.3-4.2)

What would you do next?

• 1. Order TSH Receptor Antibody
• 2. Order thyroid ultrasound
• 3. Order I-123 uptake scan

44

7/8/15 23

Case 10

29yo F with ten pound weight loss, tremor, insomnia and just not feeling right for 6 months. On exam she is tachycardic to 115, is noted to have scleral injection bilaterally with mild proptosis and an enlarged, non- tender thyroid. She denies any recent URIs. Labs: TSH < 0.01 H (0.45-4.20) FT4 1.76 (0.65-1.78) FT3 5.3 H (2.3-4.2)

What would you do next?

• 1. Order TSH Receptor Antibody
• 2. Order thyroid ultrasound
• 3. Order I-123 uptake scan

45

Hyperthyroidism

Differential Diagnosis

§ Graves’ Disease (60-80%) § Toxic Multi-Nodular Goiter § Toxic Adenoma § Exogenous thyroid § Thyroiditis

• Subacute thyroiditis –

fever, tender thyroid, viral prodrome

• Painless/silent thyroiditis
• Postpartum thyroiditis

46

§ Rare

• Struma Ovarii
• Hydatiform mole,

choriocarcinoma

• TSH secreting tumor
• Pituitary resistance to

thyroid hormone

• Thyroid cancer

7/8/15 24

Graves/TMNG/Toxic Adenoma

Treatment Options § Medication

• Methimazole – Liver failure, rash, agranulocytosis
• Beta-blockers – for symptoms, may need more frequent

dosing

• PTU – oldest, black box warning for liver failure, agranulocytosis;

use only in 1st trimester of pregnancy or allergic to methimazole

§ Radioactive Iodine (I-131) Ablation

• Treatment of choice for toxic adenoma, toxic multinodular

goiter

§ Surgery

• Not very common in US

47

Hyperthyroid Take Home Points

48

Persistent hyperthyroid (not thought to be thyroiditis) Check TSI or TSHrAb Treat for Graves disease

• ++

Order I-123 uptake scan Palpable Nodule? Order I-123 uptake scan HOT: NO FNA COLD: FNA

7/8/15 25

Case 11

29yo F with 5lb pound weight loss, tremor, insomnia and just not feeling right for 1 month since having a URI. Labs: I-123 Radioiodine Scan: TSH < 0.01 L (0.45-4.20) decreased uptake (5%) at 24 FT4 4.59 H (0.65-1.78) hrs (normal 15-30%)

49

What is the most likely diagnosis?

• 1. Toxic nodule
• 2. Thyroiditis
• 3. Graves’ disease
• 4. TSH secreting tumor

Case 11

29yo F with 5lb pound weight loss, tremor, insomnia and just not feeling right for 1 month since having a URI. Labs: I-123 Radioiodine Scan: TSH < 0.01 L (0.45-4.20) decreased uptake (5%) at 24 FT4 4.59 H (0.65-1.78) hrs (normal 15-30%)

50

What is the most likely diagnosis?

• 1. Toxic nodule
• 2. Thyroiditis
• 3. Graves’ disease
• 4. TSH secreting tumor

7/8/15 26

I-123 Thyroid Uptake and Scan

Decreased Uptake Diffusely Increased Uptake Heterogeneous Uptake Thyroiditis Graves’ Dz Multinodular goiter (hot and cold) Exogenous hyperthyroidism TSH secreting tumor Solitary Toxic nodule (hot) Struma Ovarii Cancer (cold)

Case 11b

What is the best treatment for this patient?

• 1. Methimazole and a beta-blocker
• 2. I-131 ablation
• 3. NSAIDs, beta-blocker and time
• 4. Surgery

52

7/8/15 27

Case 11b

What is the best treatment for this patient?

• 1. Methimazole and a beta-blocker
• 2. I-131 ablation
• 3. NSAIDs, beta-blocker and time
• 4. Surgery

53

A 65 year old man is referred for a palpable right thyroid

• nodule. Ultrasound confirms a 1.0cm R thyroid nodule with
• microcalcifications. He has no family history of thyroid

cancer or history of radiation exposure. TSH = 3.5 (0.45-4.20) The next step is to

• a. Place patient on L thyroxine suppressive

treatment

• b. Refer him to a thyroid surgeon
• c. Obtain a fine needle aspiration biopsy
• d. Arrange for a radionucleotide uptake scan

Case 12

7/8/15 28

A 65 year old man is referred for a palpable right thyroid

• nodule. Ultrasound confirms a 1.0cm R thyroid nodule with
• microcalcifications. He has no family history of thyroid

cancer or history of radiation exposure. TSH = 3.5 (0.45-4.20) The next step is to

• a. Place patient on L thyroxine suppressive

treatment

• b. Refer him to a thyroid surgeon
• c. Obtain a fine needle aspiration biopsy
• d. Arrange for a radionucleotide uptake scan

Case 12 Which thyroid nodules to FNA

ATA Guidelines on Thyroid Nodules, 2009

*suspicious features: hypoechoic, taller than wide, irregular borders, increased vascularity High Clinical Risk (FHx, XRT) Others

• 1. All sizes if have abnormal

cervical LNs

• 2. >0.5cm with suspicious

features*

• 1. > 1cm: solid or has

microcalcifications

• 2. >1.5cm: with suspicious

features*

• 3. > 2cm: all unless

completely cystic

7/8/15 29

Thyroid Cancer

§ Differentiated thyroid cancers (90%): Papillary, follicular, excellent prognosis § Medullary (5%): Tumor of parafollicular cells. Secretes calcitonin. Associated with RET-gene mutation

• familial medullary thyroid cancer
• MEN 2A
• MEN 2B

§ Anaplastic: very poor prognosis

75 yo M is in the ICU with urosepsis complicated by hypotension and aspiration pneumonia. Patient intubated and on pressors. Thyroid function tests are obtained because patient is obese. LABS: TSH 1.0 (0.45-4.2) FT4 0.75 ng/dl (0.8-2) FT3 2.0 pg/ml (2.5-3.9) Which of the following is the most likely explanation of these test results?

• 1. Pituitary tumor
• 2. Hashimoto’s thyroiditis
• 3. Myxedema
• 4. Euthyroid sick syndrome

Case 13

7/8/15 30

75 yo M is in the ICU with urosepsis complicated by hypotension and aspiration pneumonia. Patient intubated and on pressors. Thyroid function tests are obtained because patient is obese. LABS: TSH 1.0 (0.45-4.2) FT4 0.75 ng/dl (0.8-2) FT3 2.0 pg/ml (2.5-3.9) Which of the following is the most likely explanation of these test results?

• 1. Pituitary tumor
• 2. Hashimoto’s thyroiditis
• 3. Myxedema
• 4. Euthyroid sick syndrome

Case 13

75 yo man is in the ICU. Patient improves considerably over the next

• week. Are the following labs are consistent with your diagnosis?

LABS INITIAL: TSH 1.0 (0.45-4.2) FT4 0.75 ng/dl (0.8-2) FT3 2.0 pg/ml (2.5-3.9)

Case 13

LABS ONE WEEK LATER: TSH 22 (0.45-4.2) FT4 1.2 ng/dl (0.8-2) FT3 2.7 pg/ml (2.5-3.9)

7/8/15 31

Euthyroid Sick Syndrome

§ AKA non thyroidal illness § Adaptive process to conserve energy in severely ill patients § Hallmark is low T3 (decreased T4 -> T3 conversion) § TSH levels can be anywhere

• Low-normal acutely
• Can be frankly elevated in recovery phase

§ Treatment with thyroid hormone has not been shown to be of benefit

Adrenals

62

7/8/15 32

Case 14

A 38 year old man had an abdominal CT scan for evaluation of right abdominal pain. An incidental 5 cm left adrenal mass was discovered. The patient is otherwise healthy with normal exam and no symptoms. What biochemical testing is warranted?

63

• 1. Plasma catecholamines
• 2. Plasma catecholamines, aldosterone and renin, and

1 mg dexamethasone suppression test

• 3. Plasma metanephrines and 1 mg dexamethasone

suppression test

• 4. No testing required

Case 14

A 38 year old man had an abdominal CT scan for evaluation of right abdominal pain. An incidental 5 cm left adrenal mass was discovered. The patient is otherwise healthy with normal exam and no symptoms. What biochemical testing is warranted?

64

• 1. Plasma catecholamines
• 2. Plasma catecholamines, aldosterone and renin, and

1 mg dexamethasone suppression test

• 3. Plasma metanephrines and 1 mg dexamethasone

suppression test

• 4. No testing required

7/8/15 33

Adrenal Incidentalomas

§ Very common (5% of people, more as age) § Why should we care?

• Hormone producing (15%)
• Cortisol causing Cushings’ syndrome
• Aldosterone causing primary hyperaldosteronism
• Catecholamines (pheochromocytoma)
• Rare – androgens, other weird stuff
• Malignant (5%)
• Metastatic disease
• Adrenal carcinoma

Incidentaloma Evaluation

§ All patients:

• Screen for pheochromocytoma and Cushing’s syndrome:
• Evaluate at future time point for growth

§ Patients with hypertension:

• Must additionally screen for primary aldosteronism:

aldosterone, PRA

§ Imaging Characteristics

• Benign adenomas have low density (<10HU) and high

washout (>50%)

• 4 cm more worrisome for malignancy

** NEVER BIOPSY AN ADRENAL LESION UNTIL PHEOCHROMOCYTOMA IS RULED OUT

7/8/15 34

67

Disease Clinical signs Diagnostic Test Management Pheochromocytoma Headache Palpitations Tremor Anxiety Hypertension Abdominal pain Plasma metanephrines* or 24h urine metanephrines* Alpha blockade -> resection

68

Disease Clinical signs Diagnostic Test Management Pheochromocytoma Headache Palpitations Tremor Anxiety Hypertension Abdominal pain Plasma metanephrines* or 24h urine metanephrines* Alpha blockade -> resection Cushings’ Syndrome Facial plethora Abdominal adiposity Thin skin/ ecchymoses/ violaceous striae Hyperglycemia 1mg dexamethasone suppression test or 24h urine free cortisol If confirm adrenal

• rigin, resection

7/8/15 35

69

Disease Clinical signs Diagnostic Test Management Pheochromocytoma Headache Palpitations Tremor Anxiety Hypertension Abdominal pain Plasma metanephrines* or 24h urine metanephrines* Alpha blockade -> resection Cushings’ Syndrome Facial plethora Abdominal adiposity Thin skin/ ecchymoses/ violaceous striae Hyperglycemia 1mg dexamethasone suppression test or 24h urine free cortisol If confirm adrenal

• rigin, resection

Primary hyperaldosteronism Hypertension (> 3 agents or young age) Hypokalemia (60%) Plasma aldosterone and plasma renin activity

• 1. Surgical

resection OR

• 2. Aldosterone

receptor blocker (spironolactone/ eplerenone)

A 35yo M with one yr h/o hypertension. Despite treatment with β-blocker, calcium channel blocker and ACE inhibitor, his blood pressure remains elevated. EXAM: 210/110; Fundi – grade III retinopathy. PMH: none FH: no h/o hypertension LABS: Na: 142, K: 3.3, Creatinine: 1.2 What is the next step?

• 1. Plasma renin activity and plasma aldosterone concentration
• 2. CT scan of the adrenals
• 3. 24 hr urine for VMA
• 4. 24 hr urine for catecholamines and metanephrines

CASE 15

7/8/15 36

A 35yo M with one yr h/o hypertension. Despite treatment with β-blocker, calcium channel blocker and ACE inhibitor, his blood pressure remains elevated. EXAM: 210/110; Fundi – grade III retinopathy. PMH: none FH: no h/o hypertension LABS: Na: 142, K: 3.3, Creatinine: 1.2 What is the next step?

• 1. Plasma renin activity and plasma aldosterone concentration
• 2. CT scan of the adrenals
• 3. 24 hr urine for VMA
• 4. 24 hr urine for catecholamines and metanephrines

CASE 15

• 1. AI can occur in both autoimmune polyglandular

syndrome type 1 and type 2

• 2. Bilateral adrenal hemorrhage is now a relatively

common cause of adrenal insufficiency

• 3. A normal cortisol value excludes the diagnosis
• 4. Postural hypotension is often a feature
• 5. Eosinophilia is a feature of Addison’s disease

In primary adrenal insufficiency, which

• ne of the following statements is false:

7/8/15 37

• 1. AI can occur in both autoimmune polyglandular

syndrome type 1 and type 2

• 2. Bilateral adrenal hemorrhage is now a relatively

common cause of adrenal insufficiency

• 3. A normal cortisol value excludes the diagnosis
• 4. Postural hypotension is often a feature
• 5. Eosinophilia is a feature of Addison’s disease

In primary adrenal insufficiency, which one of the following statements is false:

Adrenal Insufficiency

§ Primary AI (adrenal problem):

• Autoimmune destruction
• Gland infiltration or destruction
• Metastases, lymphoma
• Hemorrhage
• Amyloid, hemochromatosis
• Infections
• Drugs: ketoconazole, etomidate
• Rare: congenital adrenal hyperplasia, adrenal

leukodystrophy

§ Secondary AI (pituitary problem):

• Iatrogenic: glucocorticoids & anabolic steroids
• Pituitary or hypothalamic tumors

7/8/15 38

§ Symptoms: Weakness, fatigue, anorexia, weight loss, nausea, vomiting, diarrhea, unexplained abdominal pain, postural lightheadedness, hyperpigmentation (primary adrenal insufficiency

• nly)

§ Labs:

• ↓ Na+, ↑ K+ (in primary)
• eosinophilia
• mild metabolic acidosis

Adrenal Insufficiency

Adrenal Insufficiency

Diagnosis

1) Establish diagnosis – can rule AI out if:

• random cortisol ≥ 18 µg/dl
• cosyntropin stimulated cortisol ≥ 18 µg

2) Use ACTH to determine primary (high) versus secondary (normal or low) adrenal insufficiency 3) Image as appropriate

76

baseline cortisol/ACTH-> cosyntrosin 250 µg IM/IV -> cortisol (60 min)

7/8/15 39

Calcium Disorders

Ca2+

77

A 62 yo man with a history of prostate cancer is referred because on routine laboratories, he was noted to have a serum calcium of 10.8 mg/dL (8.7-10.1). He denies constipation, abdominal discomfort, confusion or a history of renal stones. What laboratory tests would you order next?

• a. PTHrP
• b. PTH
• c. calcium, phosphorus, and PTH
• d. 25 hydroxy vitamin D and PTH
• e. 1,25 di-hydroxy vitamin D and PTH

CASE 16

7/8/15 40

A 62 yo man with a history of prostate cancer is referred because on routine laboratories, he was noted to have a serum calcium of 10.8 mg/dL (8.7-10.1). He denies constipation, abdominal discomfort, confusion or a history of renal stones. What laboratory tests would you order next?

• a. PTHrP
• b. PTH
• c. calcium, phosphorus, and PTH
• d. 25 hydroxy vitamin D and PTH
• e. 1,25 di-hydroxy vitamin D and PTH

CASE 16

PTH can ONLY be interpreted with a simultaneous calcium level

Hypercalcemia

§ 80% pts asymptomatic § 20% symptomatic (nephrolithiasis) § Differential:

PTH mediated

• Primary

hyperparathyroidism

• Familial hypocalciuric

hypercalcemia (mutation in CaS receptor on parathyroids) PTH independent

• Vitamin D toxicity
• 1,25(OH) D

(granulomatous disease or lymphoma)

• Malignancy (PTHrp or
• steolytic lesions)

7/8/15 41

Primary Hyperparathyroidism

§ é é PTH, é é Ca, ê ê Phos § More common in women § Single adenoma 80%, 4 gland hyperplasia 20% § When to refer for surgery:

Calcium 1.0 mg/dL above ULN Skeletal

• 1. BMD < -2.5 (osteoporosis)
• 2. Fragility fracture or vertebral fracture

Renal

• 1. CrCl < 60ml/min
• 2. Nephrolithiasis
• 3. 24h U Ca > 400 mg

Age <50 years

Calcium/PTH

82

• a. PTH 95 H (10-65)

Ca 8.6 (8.5-10.1) Phos 2.4 (2.4-4.6)

• c. PTH 95 H (10-65)

Ca 10.5 H (8.5-10.1) Phos 2.4 (2.4-4.6)

• d. PTH 2 L (10-65)

Ca 12.5 H (8.5-10.1) Phos 5.6 H (2.4-4.6)

• b. PTH 2 L (10-65)

Ca 12.5 H (8.5-10.1) Phos 2.4 (2.4-4.6)

• 1. Primary hyperparathyroidism
• 2. vitamin D deficiency
• 3. vitamin D intoxication
• 4. malignancy/high PTHrP

7/8/15 42

Calcium PTH

83

• a. PTH 95 H (10-65)

Ca 8.6 (8.5-10.1) Phos 2.4 (2.4-4.6)

• c. PTH 95 H (10-65)

Ca 10.5 H (8.5-10.1) Phos 2.4 (2.4-4.6)

• d. PTH 2 L (10-65)

Ca 12.5 H (8.5-10.1) Phos 5.6 H (2.4-4.6)

• b. PTH 2 L (10-65)

Ca 12.5 H (8.5-10.1) Phos 2.4 (2.4-4.6)

• 2. Vitamin D deficiency
• 4. malignancy/high PTHrP
• 1. Primary

hyperparathyroidism

• 3. Vitamin D intoxication

A 56 yr old African American man is referred because a DXA scan demonstrated T score of -2.8 at the spine. He complains of aches in his upper and lower extremities. There was no history of fractures

• r kidney stones. He has lactose intolerance, and is not on any

medications or supplements. LABS: Calcium 8.9 (8.7-10.1), phosphorus 2.4 (2.4-4.6) What would be a reasonable next step?

• a. Give a bisphosphonate, calcium and vitamin D
• b. Check 25 OHD, iPTH and testosterone level
• c. Check a 1, 25 OHD level
• d. Give Raloxifene, calcium and Vitamin D

Case 17

7/8/15 43

A 56 yr old African American man is referred because a DXA scan demonstrated T score of -2.8 (< -2.5 indicates osteoporosis) at the

• spine. He complains of aches in his upper and lower extremities.

There was no history of fractures or kidney stones. He has lactose intolerance, and is not on any medications or supplements. LABS: Calcium 8.9 (8.7-10.1), phosphorus 2.4 (2.4-4.6) What would be a reasonable next step?

• a. Give a bisphosphonate, calcium and vitamin D
• b. Check 25 OHD level, iPTH and testosterone
• c. Check a 1, 25 OHD level
• d. Give Raloxifene, calcium and Vitamin D

Case 17 Secondary (not idiopathic)

• steoporosis

§ Vitamin D deficiency § Hypogonadism § Primary hyperparathyroidism § Chronic tobacco or alcohol use § Malignancy § Hyperthyroidism § Drugs: glucocorticoids, anticonvulsants, immunosuppressants, tenofovir, lithium, chemotherapy § Inflammatory disease (RA, IBD)

7/8/15 44

Case 18

56yo M with HTN and hyperlipidemia is complaining of loss of morning erections and

• weakness. He saw a commercial about “low T”

and wants his checked.

• 1. Do you check it?

87

Case 18

56yo M with HTN and hyperlipidemia is complaining

• f loss of morning erections and weakness. He saw a

commercial about “low T” and wants his checked. Testosterone at 3pm is 180ng/dL (reference range) Now what?

• 1. Prescribe androgel
• 2. Check a pituitary MRI
• 3. Prescribe DHEA-S
• 4. Check morning testosterone and LH

88

7/8/15 45

Case 18

56yo M with HTN and hyperlipidemia is complaining

• f loss of morning erections and weakness. He saw a

commercial about “low T” and wants his checked. Testosterone at 3pm is 180ng/dL Now what?

• 1. Prescribe androgel
• 2. Check a pituitary MRI
• 3. Prescribe DHEA-S
• 4. Check morning testosterone and LH

89

§ Only test if clinical symptoms of hypogonadism § Check AM testosterone (release is cyclical) and always confirm with 2nd measurement § Evaluate for primary (gonads) vs secondary (pituitary) hypogonadism with LH

90

“Low T” – Now What?

Low Testosterone 2° Hypogonadism (low/normal LH)

• Idiopathic hypogonadotrophic

hypogonadism

• Systemic illness
• Opioids
• Alcoholism
• Panhypopituitarism
• LH and FSH deficiency

1° Hypogonadism (high LH)

• Klinefelter’s Syndrome
• Testicular damage
• Andropause

7/8/15 46

• 1. Repeat the prolactin in 3 months
• 2. Refer to neurosurgery
• 3. Initiate treatment with bromocriptine or cabergoline
• 4. Check a TSH and Free T4 level

A 32 yr old woman presents to her gynecologist with a 3 month history of fatigue, some weight gain and amenorrhea. Exam reveals dry skin, coarse hair and delayed DTR relaxation and galactorrhea. LABS: Prolactin 58 ng/ml (<20); urine HCG negative Pituitary MRI: enlarged pituitary gland without any obvious adenoma What is the appropriate next step?

CASE 19

• a. Repeat the prolactin in 3 months
• b. Refer to neurosurgery
• c. Initiate treatment with bromocriptine or cabergoline
• d. Check a TSH and Free T4 level

A 32 yr old woman presents to her gynecologist with a 6 month history of fatigue, some weight gain and amenorrhea. Exam reveals dry skin, coarse hair and delayed DTR relaxation and galactorrhea. LABS: Prolactin 58 ng/ml (<20); u preg negative Pituitary MRI: enlarged pituitary gland without any obvious adenoma What is the appropriate next step?

CASE 19

7/8/15 47

Hyperprolactinemia

§ Physiologic:

• Pregnancy
• Lactation or even nipple

stimulation

§ Pathologic:

• Pituitary tumors
• Hypothyroidism
• Hypothalamic lesions

§ Pharmacologic:

• Estrogen
• Psychiatric meds

(antipsychotic dopamine antagonists, SSRIs, TCAs)

• H2 blockers (ranitidine,

cimetidine)

• Diagnosis:
• High prolactin X 2
• Rule out pregnancy and

hypothyroid

• Medication List
• Pituitary MRI if PRL > 100
• Treatment: dopamine

agonists (bromocriptine/ cabergoline) in most cases

Case 20

65yo M evaluated in the ED for a crushing headache and double vision. He reports a 6 month history of erectile dysfunction, fatigue and weight gain. BP 90/50, HR 90, R18 Physical Exam: ill appearing, + bitemporal hemianopia Labs: Na 128 CT head: 3cm heterogeneous sellar mass with compression of optic chiasm In addition to consulting neurosurgery, what is the next most important step?

• 1. Adminstering glucocorticoids
• 2. Lumbar puncture
• 3. Checking GH and prolactin levels

94

7/8/15 48

Case 20

65yo M evaluated in the ED for a crushing headache and double vision. He reports a 6 month history of erectile dysfunction, fatigue and weight gain. BP 90/50, HR 90, R18 Physical Exam: ill appearing, + bitemporal hemianopia Labs: Na 128 CT head: 3cm heterogeneous sellar mass with compression of optic chiasm In addition to consulting neurosurgery, what is the next most important step?

• 1. Adminstering glucocorticoids
• 2. Lumbar puncture
• 3. Checking GH and prolactin levels

95

Anterior Pituitary

96

PROLACTIN LH/FSH -> gonads TSH -> thyroid GROWTH HORMONE ACTH -> adrenals

• Pituitary adenomas can overproduce any of these hormones
• Pituitary adenomas can cause deficiency of any of these

hormones *** ALWAYS CONSIDER ADRENAL

INSUFFICIENCY AND TREAT IT FIRST

7/8/15 49

ENDOCRINE TRIVIA

97

Diagnosing etiology of polyuria

Test Central DI Nephrogenic DI Primary Polydipsia Random plasma osmolality

Nl-é é Nl-é é ê ê

Random urine osmolality

ê ê ê ê ê ê

Urine osmolality during water deprivation No Change No Change

é é

Urine osmolality after IV DDAVP

é é

No Change

é é

Plasma ADH

ê ê

Normal to é

é ê ê

7/8/15 50

MEN 1 – the three Ps

§ HyperParathyroidism – hyperplasia of parathyroids § EnteroPancreatic tumors – gastrinomas, insulinomas § Pituitary tumors – prolactinoma, GH, nonfunctional, ACTH § Others – carcinoid, adrenal adenomas, subcutaneous lipomas, facial angiofibromas § Autosomal dominant, MENIN gene mutation

MEN 2

§ Mutations in RET proto-oncogene § Autosomal dominant

MEN 2A MEN 2B Medullary carcinoma of the thyroid Medullary carcinoma of the thyroid Pheochromocytoma Pheochromocytoma Hyperparathyroidism Mucosal neuromas Marfanoid habitus, Ganglioneuromatosis of the bowel