Background (cdc.gov/diabetes)

Definition: Diabetes is a metabolic disorder characterized by hyperglycemia due to problems with insulin secretion and/or response to insulin in target tissues

Epidemiology: Diabetes affects 9.3% of all US adults, 26% of people

>65 y; 28% of people are undiagnosed; 95% of cases are DM2; 3× ↑ in DM2 prevalence over past 30 y, primarily due to lifestyle changes: Diet (↑ CHO, ↑ calories), physical inactivity, & obesity; DM1 also ↑ in all ages (JAMA 2014;131:1778)

Complications: Microvascular disease (nephropathy, peripheral & autonomic neuropathy, retinopathy), macrovascular disease (CAD, stroke, PVD), impaired wound healing, & immunodeficiency; DM is the leading US cause of ESRD, lower-limb amputations, & blindness Glycemic Control: Despite treatable nature of DM, 23% of US diabetes pts have A1c >8% and 13% have A1c >9; many disparities in DM control and complications (cdc.gov/diabetes)

General approach: Tx is multifaceted; requires focus on glycemic control to prevent complications, screening for/management of complications, and ↓ CV risk

Classification (Diabetes Care 2017;40:s1; Lancet 2009;373:1773)

 

Selected Glycemic Disorders (Diabetes Care 2013;36:S67)
Disorder	Notes
DM2 (90–95%)	Assoc w/ insulin resistance in target organs & relative insulin deficiency; tx targets resistance and/or deficiency
DM1 (5–10%)	Autoimmune d/o against pancreatic β cells → insulin deficiency; typically presents prior to puberty, but can occur in adulthood: Suspect in thin, ⊕ FHx of other autoimmune disease, ⊖ DM2 FHx, or extreme hyperglycemia despite tx w/ oral agents shortly after dx; ⊕ pancreatic autoantibodies (GAD, ICA, IA2, or insulin); ∼30% present with DKA

 

Prediabetes	On spectrum with DM2; affects 35% of US adults; equivalent to “impaired fasting glucose” or “impaired glucose tolerance”  (reflect test used to dx prediabetes); defined as: FBG 100–125 mg/dL, HbA1c 5.7–6.4%, or OGTT 2 h BG 140–199 mg/dL after 75 g glucose challenge; 5 y risk of progression to DM2 ∼15– 30% (cdc.gov/diabetes; Diabetes Care 2004;27:S47)
Other syndromes	Ketosis-prone “Flatbush” DM: Characterized by severe, reversible β-cell dysfunction: Demographics ≈ DM2 (obese, racial/ethnic minorities) but p/w ⊕DKA; with aggressive control, some β-cell function restored & insulin/med needs ↓↓ (Diabetes Care 2006;29:2755) MODY (Mature Onset DM of the Young) = monogenic diabetes; rare, presents in young, generally normal BMI, ⊕ FHx autosomal dominant inheritance (Diabetes Care 2011;34:1878)
Secondary DM	Etiologies incl hemochromatosis, CF-related DM, pancreatic CA, surgical resection, Cushing’s, chronic pancreatitis
Medication-induced	Can ↓ glucose tolerance or impair insulin secretion: corticosteroids, protease inhibitors, atypical antipsychotics, HCTZ, tacrolimus

 

TYPE  2 DIABETES

 

Prevention

Risk factors: Assoc w/ obesity, inactivity, ⊕ FHx, PCOS, HTN, CVD, HLD, hx GDM; hx prediabetes, ↑ prevalence in African-American, Latino, Native American, Pacific Islander

Lifestyle: In pts with prediabetes, wt loss (5–10% of total body weight), diet, & exercise (150 min/wk mod exercise, e.g., walking) ↓ risk of developing DM2 by 58% over 3 y period (DPP, NEJM 2002;346:393) Metformin: In same study, metformin (850 mg PO BID) reduced risk of DM2 by 31%; ADA recommends for those at “very high risk” for developing DM in addition to lifestyle tx

Surgery: For obese pts (BMI >34 in ♂, >38 in ♀) bariatric surgery ↓ incidence of DM2 (NEJM 2012;367:695); not considered a 1° indication for surgery (see “Obesity”)

Diagnosis (Diabetes Care 2017;40:s1; Annals Int Med 2015;163:861)

Hemoglobin A1c >6.5% (preferred), random glucose >200 mg/dL +

 

symptoms of hyperglycemia, FBG ≥126 mg/dL, or OGTT 2 h-BG >200 mg/dL after 75 g glucose challenge; initial ⊕ tests should be repeated to confirm unless pt p/w sx of hyperglycemia (e.g., polydipsia, polyuria, unexplained wt loss)

Screening: (see “Disease Screening”) USPSTF: 40–70 y with BMI ≥25; ADA: All adults >45 and if ≤45 y, screen if BMI ≥25 and add’l risk factors (76% of US adults meet ADA criteria (JGIM 2015;30:612)); screen q3y, shorter interval if prior values approach DM or prediabetes threshold

Evaluation (Diabetes Care 2017;40:s1)

General approach: For initial eval of pts w/ known DM, hx key to assessing DM-related behaviors, disease severity and risk for/presence of complications; will guide tx approach

History:

Diabetes history: Age at onset (disease duration), medications used, prior glycemic control, known complications Behaviors: Physical activity, dietary habits (incl juice/sweetened beverages, meal patterns) Social context: Financial, housing

Medications: Adherence, side effects

Hyperglycemia s/sx: Polyuria, polydipsia, vision changes

Home glucose readings: All pts on insulin; ask pt to bring glucometer to every visit; examine for highs/lows/patterns, if lows assess hypoglycemia awareness (see “Hypoglycemia”); management below Complications risk/presence: CV: Known CAD, angina, claudication, CV risk factors/comorbidities (HTN, stroke, smoking)

Ophtho: Vision changes/decreased visual acuity

Renal: CKD risk factors (HTN), review prior urine alb/Cr ratios, Cr Peripheral neuropathy: Often starts w/ feet burning at night, (see “Peripheral Neuropathy”) Autonomic neuropathy: ED, orthostatic HoTN, gastroparesis – if ⊕, strongly assoc w/ CAD

Exam: BMI, BP; Derm: Acanthosis nigricans, CV: distal pulses, carotid bruits, Foot: PAD, callus, deformity, tinea, Neuro: Monofilament, vibratory, cold/pinprick testing, ankle DTRs

Hemoglobin A1c: (% of Hgb molecules which are glycosylated) estimates mean glucose over preceding 90 d, weighted toward the last 30 d; can be affected by states which alter RBC turnover, e.g.,

 

hemoglobinopathies, hemolysis, pregnancy, significant blood loss/anemia, CKD/ESRD; if in doubt correlate w/ glucometer readings

Frequency: Repeat q3mo if above target A1c, q6mo if at goal Interpretation: HbA1c 7% ≈ mean glucose 154 mg/dL; for every 1% HbA1c ↑ mean glucose ↑ ∼30 mg/dL; e.g., HbA1c 8% ≈ 180 mg/dL

Other labs: Yearly urine microalb/Cr ratio and creatinine; baseline & q5y lipids

Cardiac testing: Baseline ECG (no further cardiac testing warranted if asx & nl ECG, although may consider if starting vigorous exercise regimen; see “CP & Noninvasive Testing”)

Management: Behavioral (NEJM 2012;366:1319 & 2013;368:1613; Ann Intern Med

2011;154:554)

Behavioral tx: Improves glycemic control (which ↓ microvascular complications) and ↓ CV risk; recommended for all patients

Diet: Low-carbohydrate or Mediterranean recommended; “Plate method” = ½ nonstarchy vegetables, ¼ lean meat/protein, ¼ whole grains; heart-healthy diet low in saturated/trans fats; monitoring & awareness of CHO intake, esp in items of low nutritional value; reframe soda as (reframe as “liquid candy”) see sugarstacks.com for visuals) Weight loss: 5–10% body wt loss good initial target in the obese; see “Obesity”

Exercise: 36% of pts with DM are physically inactive (cdc.gov/diabetes); exercise improves glycemic control independent of wt loss, ↓ CV risk factors; goal is 30 min, 5×/wk, at 50–70% max HR (max HR ≈ 220 – age, e.g., for 60 yo, max HR = 160, target HR ≈ 115) should be strenuous enough, pt is “able to talk but not sing” Education: Self-mgmt education by trained professional (can be RN, PharmD, CDE) shown to help pts ↓ HbA1c, prevent/manage complications, address psychosocial aspects of DM2, & ↑ quality of life; cost-effective (Diabetes Care 2013;36:S11)

Management: Complications

Cardiovascular risk: Pts w/ DM have 2–4× ↑ risk of MI, stroke, & death compared to otherwise similar pts of same age; CV events responsible for majority of deaths in pts w/ DM; aggressive mgmt of

 

CV risk factors in diabetes pts (lipids, BP, smoking cessation) can ↓ risk

(BMJ 1998;317:703; Lancet 2008;371:116; Chest 2007;131:446)

HLD: 43% of pts not at target LDL; goal LDL <100, HDL 40, TG

<150; however, all pts >40 or w/ ASCVD risk factors (LDL >100, HTN, ⊕ tob, ⊕ FHx CVD, CKD incl proteinuria) should be on mod- high intensity statin, consider ezetimibe + mod-intensity if cannot tolerate high-dose statin Hypertension: 28–48% of pts not at target BP; goal <140/90 mmHg recommended by ACCORD trial and JNC8 (NEJM 2010;362:1575; JAMA 2014;311:515); consider ↓ systolic target if high-risk CVD or younger pts/on individual basis (Diabetes Care 2017;40:S75); BP control more important than Rx choice Smoking: 22% of pts w/ DM smoke; accounts for ∼1/2 of their CV risk; see “Tobacco”

 

Pharmacologic Management of CV Risk Factors in Diabetes
Rx	Notes/Indications
ASA 81 mg	All pts w/ known ASCVD; consider for 1° prevention if ≥50 y with 1 other ASCVD risk factor unless ↑ bleeding risk
Mod-high intensity statin	All pts w/DM ≥40 y, regardless of lipid levels Pts <40 w/ ASCVD risk factors; see “Lipids” 10–20 mg atorvastatin = moderate, 40–80 mg atorvastatin = high
HTN Rx	First-line agents the same (ACEI/ARB, CCB, thiazide) unless evidence of CKD (by ↓Cr or ⊕ microalbuminuria) → ACEI/ARB 1st-line; proven to ↓ progression of CKD

Immunizations: PPSV23, annual influenza, hep B series (recommended for pts <60 y, consider in pts ≥60 y; see “Immunizations”)

Complications Screening: Start at time of DM2 dx, 5 y after dx for DM1

 

Complications Screening/Management
Screening should be performed annually unless otherwise noted Risk of all below complications ↓ w/ glycemic control
Retinopathy	Retinal exam; may space to q2y if multiple nl exams Retinal photography (interpreted by ophthalmologist) appropriate

 

	alternative to in-person visit if no abnormalities on comprehensive ophtho exam
Nephropathy	Urine alb/cr ratio & GFR; ACEI/ARB for all pts with microalbuminuria Treatment of HTN (↑↑ risk of CKD progression)
Peripheral neuropathy	History: (“Any numbness or burning/tingling in your feet at night?”) Exam: Monofilament, vibratory, and pinprick/cold sensory testing; for pinprick, apply disposable pin proximal to hallux proximal nail fold, using just enough pressure to deform skin Pregabalin or duloxetine 1st-line for sx; see “Peripheral Neuropathy”
Foot ulcers, amputations	Foot exam (above); Rx tinea pedis to ↓DFI risk Counsel all pts re: appropriate footwear (e.g., avoid open-toed shoes) Pts who smoke, have hx LE complications, ↓ sensation, deformity or PAD → podiatry referral; Rx Diabetic footwear if ↑ risk
Monofilament Testing Autonomic neuropathy: Screen for s/sx in all pts w/ microvascular neuropathic complications

 

(From Boulton AJM, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment. Diabetes Care 2008;31(8):1679–1685. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.)

Management: Glycemic

Glycemic control: Primary purpose is to ↓ microvascular complications; intensive control not shown to ↓ risk of CV disease or mortality in DM2 (ACCORD NEJM 2011;364:818)

Target HbA1c: Generally <7%; however, should individualize; consider less intensive goals (e.g., HbA1c <8, FBG 100–150 mg/dL) in older pts

 

or those w/ significant comorbidities, advanced complications, ↑ risk hypoglycemia, or ↓ life expectancy; discuss target w/ pts & incorporate their preferences into goal-setting (Diabetes Care 2012;35:1364)

Target fasting blood glucose: 80–130 mg/dL; may adjust lower end of target to 70–90 depending on individual pt’s risk of hypoglycemia or glycemic goal)

Target postprandial blood glucose: <180 mg/dL, check 1–2 h after beginning of meal (Diabetes Care 2013;36:S11);

Home glucose monitoring: Indicated for pts on insulin or at risk of hypoglycemia; have pts bring glucometer or glucose log to each visit

Noninsulin regimens: Not shown to improve outcomes (BMJ 2008;336:1174; JAMA 2017;177:920); can be used PRN to monitor for hypoglycemia (if on hypoglycemic PO regimen) or illustrate effect of various behaviors/foods on blood glucose Single-dose insulin: AM fasting & after biggest meal of the day and/or before bed Multiple–dose insulin: Prior to meals/snacks, at bedtime, prior to exercise or critical tasks, and if suspect hypoglycemia; ± postprandial

Monitoring supplies: Rx for (1) glucometer, (2) test strips, & (3) lancets

DIABETES MEDICATIONS

 

Metformin: Biguanide (↑ insulin Se & ↓ gluconeogenesis); 1st-line Rx for DM2 → 1–2% avg ↓ in HbA1c, wt loss common, hypoglycemia rare,

↓CVD events;

Dosing: start 500 mg QD–BID, uptitrate to 1 g BID, take w/ meals (↑ absorption) S/e: GI upset common, minimize by starting at low dose, taking with food, & titrate ↑; lactic acidosis (type B, very rare (Cochrane Data System Rev 2010;20:CD002967), B12 deficiency; caution in CHF, ESLD; max dose 1000 mg daily if CrCl <45 mL/min/1.73 m2

Contraindications: CrCl <30 mL/min/1.73 m2; hold in AKI

 

Class (e.g.)	Mechanism	Notes
Sulfonylureas (glipizide— shorter t½, cleared by liver; also: Glyburide, glimepiride)	↑ β cell sensitivity to glucose, ↑ insulin release	High failure rate over time due to ↓ β cell function; long t½, elderly/CKD at ↑ risk of hypoglycemia, esp w/ glyburide s/e: Hypoglycemia, wt gain; caution in liver & renal dz; contraindicated if sulfa allergy
GLP-1 receptor agonists (exenatide, liraglutide)	⊕ Insulin secretion & delays gastric emptying	Injectable, expensive Assoc w/ wt loss, hypoglycemia rare; can → N/V, pancreatitis; adjust dose in CKD; ↑ C-cell hyperplasia/medullary thyroid tumors in animals Liraglutide assoc w/ ↓CVD events in pts w/ CVD (NEJM 2016;375:311;322)
Thiazolidinediones, (TZDs) (pioglitazone)	↑ Insulin sensitivity	Assoc w/ wt gain, CHF exacerbation, ↑ fractures, hepatotoxicity; monitor LFTs
α-Glucosidase inhibitor (acarbose)	Inhibits GI tract CHO metabolism	GI intolerance common
Meglitinides (repaglinide, nateglinide)	↑ β cell insulin secretion	Like sulfonylureas but shorter duration of action; can → wt gain & hypoglycemia Expensive
DPP-4 inhibitor (sitagliptin)	Blocks inactivation of incretins, e.g., GLP-1	Dose adjustment in CKD Wt neutral, assoc w/ pancreatitis, expensive
Amylin analogue (pramlintide)	↓ CHO absorption & GI motility	Injectable; expensive; assoc w/ wt loss; use w/ insulin can → severe hypoglycemia; avoid in pts w/ gastroparesis, osteopenia
SGLT2 inhibitor (empagliflozin)	Blocks renal glucose reabsorption → ↑glucosuria	Expensive; assoc w/ wt loss, ↓BP, ↓CVD events in pts with CVD (NEJM 2015;373:2117),↑GU infections, polyuria, vol depletion, normoglycemic DKA

 

Insulin

Indications: Pts with DM2 with HbA1c >10% or on 3 meds with HbA1c

>goal on 2 occasions, 3 mos apart, performing self-testing with a glucometer

Advantages: Less expensive than brand-name newer agents, no dose limit

Disadvantages: Wt gain, hypoglycemia, requires regular BG monitoring

Administration: SC in adipose areas (abdomen, thighs); site of injection should be rotated to avoid lipoatrophy

 

Pharmacokinetics of Selected Insulin Analogs (Adapted from JAMA 2003;289:2254)
Class	Name (Brand)	Onset	Peak	Duration
Long-Acting	Glargine (Lantus) Detemir (Levemir)	∼2 h	Minimal	20–24 h
Rapid-Acting	Aspart (NovoLog) Lispro (Humalog)	5–15 min	30–90 min	5 h
Short-Acting	Regular (Humulin R, Novolin R)	30–60 min	2–3 h	5–8 h
Intermediate- Acting	NPH (Humulin N, Novolin N)	2–4 h	4–10 h	10–16 h

 

Insulin Troubleshooting
Problem	Strategy
am glucose ↑↑	↑ Glargine or evening NPH; consider ✓ 2 am BG to r/o overnight hypoglycemia (can → rebound hyperglycemia)
Prelunch glucose ↑↑	Add/↑ breakfast insulin
Predinner glucose ↑↑	Add/↑ am NPH or add/↑ lunchtime insulin
Insulin Delivery Method: Choose One (below)
Pens/Cartridges: Carry insulin in self-contained cartridge, “dial in” desired dose; more convenient but less often covered by insurance; ↑ risk needle stick if injection given by another person; disposable pens come w/ single cartridge but still need to change needle, more $$; 1 pen cartridge = 300 units, 1 box = 5 pens = 1500 units; Sample Rx: Lantus SoloSTAR or Novolin N Pen—2 boxes for 1 mo/5 boxes for 3 mos; pen needles are a

 

Figure 4-1. Hyperglycemia management in type 2 diabetes.

 

 

 

 

Insulin Initiation

Step 1: Start basal insulin (0.1 mg/kg/d); usually safe to start glargine 10 units QHS, increase by 2 units Q3rd night until FSBG <130; can usually start w/ 20 units if BMI >30 & all blood sugars are ≥200; instruct pt to take the same time each evening, within 1 h; Continue metformin

+/− other agents based on cost, complexity

Step 2: Add prandial insulin with largest meal OR GLP-1 receptor agonist (Diabetes Care 2014;37:2763; Lancet 2014;384:2228); indicated when HbA1c > goal & postprandial hyperglycemia despite fasting sugars at goal; usually safe to start w/ 4 units insulin/meal, ↑ by 2 units every 3rd d until postprandial BG <180; d/c sulfonylurea before starting prandial insulin; combo formulations GLP-1 RA + basal insulin available ($$$) Step 3: Add prandial insulin before all meals if HbA1c goal not met w/ Step 2; stop GLP-1 RA if started; consider carb counting (→ nutritionist referral)

 

3 Common Basal + Prandial Insulin Regimens

NPH with breakfast and dinner (1/2 total daily insulin dose) + regular insulin* with meals (1/2 total dose)

Glargine QHS or QAM (1/2 total dose) + lispro* with meals (1/2 total dose)

“70/30” (Premixed 70% NPH/30% regular insulin) before breakfast (2/3 total dose) + 70/30 before dinner (1/3 total dose)

*Multiple combinations of basal + prandial Rx, including different prandial w/ this basal agent

When to Refer

Podiatry: Pts who smoke, have hx of lower-extremity complications, loss of protective sensation/neuropathy, structural abnormalities or PAD

Nutrition: Baseline and PRN, including if adding carb-counting Renal: All pts w/ stage IV CKD, pts w/ stage III CKD and uncertainty about etiology, difficulty w/ management, or rapid progression of CKD, persistent urine alb/cr >300 mg/g

Ophthalmology: Annually (can → q2–3y if >1 nl exam)

Endocrinology: If pt requiring >80 units of basal insulin w/o adequate

 

control of fasting glucose; persistent, frequent episodes of hypoglycemia; suspect late-onset DM1

Surgery: Bariatric surgery for obese pts can improve glycemic control,

↓ number of DM agents, increase wt loss & induce remission as c/w medical/lifestyle tx alone (NEJM 2012;366:1567; 2014;370:2002); rec if BMI ≥40 (≥37.5 in Asian-Americans) or if BMI 35–39.9; if uncontrolled DM (32.5–

37.4 in Asian Americans); consider for patients with T2D and BMI 30.0–

34.9 (27.5–32.4 in Asian Americans) if hyperglycemia uncontrolled despite optimal tx; long-term effects unknown; surgery has perioperative risk & possible complications; (see “Obesity”)

HYPOGLYCEMIA

 

Background (Diabetes Care 2017;40:155)

Definition: Serum glucose ≤70 mg/dL = glucose alert value; <54 mg/dL

= clinically significant hypoglycemia; may be +/− sx, considered severe if ⊕ CNS sx (confusion, seizure, coma) necessitating tx from another person (i.e., unable to self-tx); relative hypoglycemia: Sx of hypoglycemia in pt w/ chronic hyperglycemia as glucose approaches 70; likely not dangerous but can be distressing to pt; hypoglycemia unawareness: Inability to sense ↓ glucose at safe threshold, screen all pts on insulin

Overview: Serum glucose affected by food intake, exercise, drug interactions, EtOH use, insulin absorption, clearance. Occurs in pts on insulin or insulin-secreting agents (e.g., sulfonylureas); should not occur in pts only on insulin-sensitizing agents (e.g., metformin) Morbidity: Severe hypoglycemia assoc w/ ↑ risk of macrovascular, microvascular events, & 3.3× ↑ risk death (NEJM 2010;363:1410) Pathophysiology: In DM pts, physiologic response to hypoglycemia impaired: Insulin levels do not ↓, glucagon does not ↑, & attenuated ↑ in epinephrine; DM pts w/ prior hypoglycemic episodes less likely to have hypoglycemic sx; some of this likely reversible

Risk factors: ↑ Age, ↑ duration of DM, ↑ Cr, liver disease, ↓ cognitive function, insulin or >2 oral hypoglycemic agents, DM1, hx of chronic pancreatitis or pancreatectomy (glucagon def), ⊕ tobacco, PMHx microvascular disease, intensive glucose control; episodes may occur

 

at any HbA1c in pts on hypoglycemic agents (NEJM 2010;363:1410; BMJ

2010;340:b5444)

Clinical manifestations: Sx may be diverse but are often individually consistent; Autonomic: Palpitations, sweating, tremor, hunger; Neuroglycopenic: Primarily altered mental status, can → to sz, coma, even death (Diabetes Care 2005;28:1245)

Treatment

Counseling: Counsel all pts re: precipitants & potential consequences (incl driving); should have plan in place if develop sx (i.e., glucose tabs available); screen for hypoglycemia unawareness by determining threshold at which sx sensed; if level is <60 mg/dL, relax glycemic targets & recommend checking BG before driving or other dangerous activity

Prevention: Modify glycemic target/meds if risk of hypoglycemia > benefit of regimen

Episode management: At onset of suspected hypoglycemic episode, advise pt to check serum glucose (if feasible) & ingest ∼15 g carbohydrate ≈ ½ cup fruit juice/sugar soda (not diet) ≈ 4 glucose tabs

≈ 1 Tbs sugar/honey; recheck glucose in 15 min; if still <70, repeat glucose load; counsel pts to call provider if recurrent episodes/unclear precipitant; prescribe glucagon kit to pts at ↑ risk of clinically significant hypoglycemia

 

Background (cdc.gov; NEJM 2016;374:254; Osteoporosis Int 2014;25:239)

Osteoporosis is a condition of ↑ bone fragility which is major cause of fractures in adults; it can be prevented, diagnosed, & treated prior to fracture; screening plays critical role in ↓ disease burden, as disease is clinically silent until fracture

Physiology: Multiple determinants of bone strength: Size/shape of bone, BMD, mineralization, bone turnover, & microarchitecture Definitions: 1° osteoporosis: Occurs w/ advanced age

2° osteoporosis: Due to medications, endocrinopathy, toxins, or systemic disease Fragility fracture: Bone fracture caused by low-

 

trauma activity (e.g., fall from ≤standing height) which presumably would not occur w/o underlying bone weakness = pathognemonic for osteoporosis, regardless of BMD; represents majority of fractures in ≥50 y; however, only 23% of women >67 w/ fragility fx received osteoporosis tx or DXA in 6 mos after fx Major osteoporotic fracture: Affecting hip, spine, proximal humerus, or forearm

Epidemiology: Osteoporosis affects 2% of men & 10% of US women

≥50 y; 49% of adults over 50 y have e/o osteopenia by DXA (at femoral neck and/or lumbar spine); ethnic variation in prevalence (Asian, Hispanic > white > African-Americans); 50% of white women & 20% of white men will have osteoporotic fracture in their lifetime; highest RR if osteoporosis, but most fractures occur in pts w/ osteopenia

Disease burden: Hip fx major source of ↑ mortality in elderly; only 40% regain prior functioning after fx, and pts have 2.5× ↑ risk of future fx; vertebral fx can → pain & disability; → importance of early detection & tx to ↓ risk

Evaluation (Ann Intern Med 2011;154:356; 2011;155:ITC1–1; JCEM 2012;97:1802)

General approach: All pts should be assessed for presence of risk factors (below); if present → FRAX ± BMD testing

History: Screening: All adult pts should be assessed for risk factors for osteoporosis, incl history of any fractures after age 50 y, any fragility fractures (above) and risk factors

Patients with osteoporosis dx: Determine underlying etiology or assess for contributing factors (below), review prior treatment, assess for presence of complications

 

Selected Risk Factors for Osteoporosis & Fractures
Risk Factors	Screening Recommendation
Personal characteristics	↑ Age, wt <59 kg (women)
Medications (Am J Med 2010;0123:877)	Glucocorticoids (>5 mg prednisone QD or equivalent for >3 mos), GnRH agonists, medication-induced hypogonadism (aromatase inhibitors, androgen-deprivation tx), HAART, high- dose thyroxine
Medical history	RA, IBD, any prior fracture (as adult), celiac disease, s/p gastric bypass, HIV, ESLD, COPD, CHF, MM/MGUS

 

Diet/lifestyle	↓ Ca intake, inadequate Vit D, lack of wt-bearing activity, heavy EtOH use, tobacco
Genetics	⊕ FHx, CF, hemochromatosis
Endocrinopathy	Hypogonadism (e.g., anorexia, ↑ PRL, POI, early menopause), DM1, DM2, ↓ or ↑ cortisol, ↑ thyroid

(Adapted from Nat’l Osteoporosis Foundation, 2014 Clinician’s guide)

Exam: Height (watch for ↓), weight, BMI, signs of medical conditions (above), presence of complications (kyphosis, focal back pain suggestive of compression fx), & fall risk (evaluate gait & balance; see “Falls”)

Labs: For pts w/ new dx: CBC, Ca, phos, Cr, LFTs, 25OH-Vit D, PTH, TSH, spot urine Ca/Cr; further/specific studies as dictated by findings (see “Anemia,” “Hyperprolactinemia,” “Celiac Disease,” “Cushing Disease,” & “Male Hypogonadism”)

Determining fracture risk: Myriad risk factors play a role in bone density & risk of fracture; fracture risk assessment tool (FRAX) available at shef.ac.uk/FRAX/ estimates 10 y risk of major osteoporotic fx if pt untreated; can be used w/ or w/o BMD info; does not account for nonmeasured RF (e.g., fall risk, # of fractures) (Osteoporos Int

2008;19:385)

Bone Mineral Density: Assessed via dual-energy x-ray absorptiometry (DXA); process similar to standard radiograph (quick, painless)

Indications: Screening: All women >65 (USPSTF), men >70 (ACP, Nat’l Osteoporosis Foundation, Endocrine Society), & younger adults at equivalently ↑ risk of fracture by FRAX (∼9.3% over 10 y) Fracture hx: All pts w/ fracture after age ≥50 (w/ exception of traumatic fx of face, skull, fingers, toes) and all adult pts w/ suspected fragility fx Treatment: Anyone being considered for or being treated for osteoporosis

DXA Interpretation:

Skeletal site: Best assesses risk of fracture at that site: Density of femoral neck is standard; vertebral assessment recommended in pts at higher risk, age, if prior fracture, height loss >1.5 cm (can be difficult to interpret if prior compression fracture, osteophytes, or scoliosis) Scoring: Density of skeletal area compared & reported as standard deviations T-score: “Compared to the best”; bone density as compared to average 30 yo adult: Should not be used

 

to dx osteoporosis in premenopausal ♀ or ♂ <50 y Z-score: “Compared to a peer”; Bone density as compared to average person of pt’s age & gender; useful in eval of premenopausal ♀ or

♂ <50 y; low Z-score for any pt raises suspicion of 2° etiology Which score to use: When multiple sites measured, category of bone fragility typically determined by lowest (“worst”) T-score Classification: (For postmenopausal ♀ and ♂ ≥50) Normal: T– score ≥–1; Osteopenia: T-score between –1 & –2.5; Osteoporosis: T-score ≤–2.5 (WHO 2004; who.int/chp/topics/Osteoporosis.pdf)

DXA for monitoring response to treatment: No clear consensus; reasonable to repeat 2 y after initiation of tx; expectation is that BMD stable or improved → less frequent checks; if worsened BMD, warrants further eval/referral

Treatment (NEJM 2010;363:2027)

Nonpharmacologic therapy: Indicated for all pts w/ ↓ BMD or fragility fracture

Calcium: Carbonate or citrate; citrate can be taken w/ or w/o food & w/ PPI; goal is 1000–1200 mg total daily calcium intake either through dietary sources or supplements Vit D: Replete to serum

>20 ng/mL; typical dose 1000 IU daily (JCEM 2011;96:53) Exercise (e.g., walking; even 1 h walking/wk → 20% reduction in risk of hip fx compared with no activity; ↑ benefit w/ ↑ activity) (JAMA 2002;288:2300) Smoking cessation: Can → improved BMD (J Womens Health 2006;15:1141) Limit EtOH: ↓ BMD & ↑ fall risk; >3 drinks/d → 38%↑ fx risk (Osteoporos Int 2005;16:737) Fall prevention: In those at ↑ risk (see “Fall Prevention”)

Pharmacologic therapy: Indicated in all pts with osteoporosis (incl hx of fragility fracture) or osteopenia and (10 y risk of hip fx ≥3% or 10 y risk of major osteoporotic fractures ≥20% per FRAX algorithm) (Osteoporos Int 2010;21:41); n.b. premenopausal women or men under 50 merit endocrinology referral

Bisphosphonates: Oral = 1st-line tx for most patients; documented

↓ incidence of hip & vertebral fractures w/ generic alendronate & risedronate; prior to initiation of bisphosphonates ensure vit D replete (above) to avoid ↓Ca; risk ↑ w/ IV bisphosphonates

 

PO Bisphosphonate Properties (NEJM 2010;363:2027)
Sample Rx	Alendronate 70 mg/wk Risedronate 35 mg/wk or 150 mg/mo
Pt instructions	Should be taken in am 30 min prior to meds or food; take w/ 8 oz water & remain upright for 30 min to ↓ esophagitis
Contraindications	CrCl <35 (consider dose adjustment if stage III CKD), pts w/ dysphagia or gastric motility d/o, Vit D deficiency or hypocalcemia
Side effects	Esophagitis, ONJ (0.01–0.1% annual incidence, 95% of cases occur in CA pts on 10× ↑ doses), atypical femur fx (absolute risk very low, likely ↑ w/ Rx duration >5 y) hypocalcemia (↑ risk if Vit D deficient; ensure replete prior to initiating tx) (JBMR 2014;29:1)
Duration of Rx	Bisphosphonates have a prolonged duration of action (continue to work after Rx d/c’ed); consider drug holiday after 5 y if T-score > –2.5, no prior fx, or relatively low risk for future fx; after 10 y if ↑ risk of fx; consider alt tx (JBMR 2016;31:1910)

Intravenous bisphosphonate: Consider if pt has esophagitis/GERD with PO tx or otherwise unable to tolerate PO; Zoledronic acid 5 mg is annual dose; s/e similar to PO (minus esophagitis) + myalgias w/ infusion

Raloxifene: SERM; less effective than bisphosphonates but can be considered in postmenopausal women who cannot use bisphosphonates (e.g., CKD) or who have ⊕ FHx breast CA (raloxifene

↓ risk of ED + breast CA) (JAMA 1999;281:2189); s/e: DVT/PE, peripheral

edema, hot flushes, muscle cramps

Other: (Rx’ed by endocrinology) includes rPTH (teriparatide), RANKL Ab (denosumab); emerging therapeutic options include rPTH-rP (abaloparatide), (JAMA 2016;316:722) and sclerostin antibody (romosozumab), (NEJM 2016;375:1532)

When To Refer Endocrinology referral:

Early: Men <50 or premenopausal women with osteoporosis

Unusual/difficult to interpret: Hx fragility fracture + nl BMD

Severe or refractory disease: Recurrent fractures or ↓ BMD despite tx above Medical: Endocrinopathy or other condition that complicates mgmt options Advanced therapies: Consideration of other therapies (above)

 

 

Background  (NEJM 2011;365:2389)

Definition: Abnormal serum calcium determined by elevated ionized (free) Ca, which is physiologically active; total Ca (mg/dL) also measures Ca bound to albumin → value affected by ↓↑ albumin; to adjust for this, must calculate:

Albumin − corrected total Ca = [measured Ca] + 0.8 × (4 − [albumin]) Physiology: Ca homeostasis tightly regulated; serum Ca derived from diet, bone turnover, & reabsorption by kidneys; hypocalcemia → ↑ PTH

→ ↑ Ca (also ↓ phosphate) via ↑ bone release & ↑ renal reabsorption; ↑

production in 1,25OH Vit D → ↑ Ca by ↑ GI absorption

HYPERCALCEMIA

 

Etiology: In outpt setting, most commonly 2/2 primary hyperparathyroidism (primary HPT): Overactive parathyroid gland secreting excess PTH despite ↑ or ↑-nl Ca; most commonly due to benign adenoma (80%) > 4-gland hyperplasia (15–20%) > carcinoma (∼1%)

Epidemiology: Incidence peaks age 70–79, ♂ > ♀ ∼3:1 (♂ = ♀ at

younger ages); ∼5% hereditary (e.g., MEN-1, MEN-2a, FHH, hyperparathyroidism-jaw tumor syndrome)

 

Etiologies of Hypercalcemia (JCEM 2005;90:6316)
Cause	Examples/Mechanisms
1° HPT	See above
Meds (usually mild)	Lithium (via ↑ PTH), thiazides, excess Vit D, Ca, or Vit A, t
Malignancy	Solid organ tumors (PTH-rP production &/or local osteolysis >> ectopic PTH); MM (cytokines); lymphoma (1,25(OH)2D- production)
Granulomatous diseases	Sarcoid, TB (25OH Vit D → 1,25(OH)2 Vit D w/in granuloma)
Renal disease (2ç and 3ç HPT)	Early: 2° HPT; ↓ conversion 1,25 D by kidneys → ↑ PTH often p/w low Ca) Late: 3° HPT; Over time, stimulated parathyroid gland

 

	→ autonomous PTH production (“tertiary hyperparathyroidism”)
Other	Thyrotoxicosis, immobilization (esp w/ Paget), milk-alkali syndrome; adrenal insufficiency; familial hypocalciuric hypercalcemia (FHH, inactivating mutation of CaSR)

Evaluation (AFP 2003;67:1959)

General approach: Determine if pt symptomatic; if so, consider admission; otherwise continue outpt w/u; if suspect medication- induced, d/c med if possible, then recheck Ca

Signs and symptoms: Dehydration (↑ urinary Ca excretion → polyuria), hx nephrolithiasis, CKD, constipation, bone pain, weakness, nausea, can also cause → fatigue, mood, or cognitive changes; severe disease can p/w somnolence, large peaked T waves on ECG

Labs: Obtain PTH and vit D on all pts, PTH values guide Ddx

Suppressed PTH: Malignancy or excess Vit D ingestion/production (unregulated Ca release from bone by lytic lesions or PTH-rP production) Normal/elevated PTH: 1° or 3° HPT (distinguished by

⊕ hx longstanding CKD in 3° disease) or familial hypocalciuric

hypercalcemia (FHH) 25OH Vit D: ↑↑ In excess intake

1,25OH Vit D: ↑ If increased conversion (granulomatous disease, lymphoma) 24-h Urine Ca/Cr: Check if PTH nl/increased → if Ca/Cr low, suggest FHH

Other labs: If PTH is suppressed, consider SPEP, PTH-rP, TSH, LFTs

Management (NEJM 2005;352:373; JCEM 2009;94:335; JCEM 2014;99:3561)

Severe disease (e.g., Ca > 14 or significant sx) → IV fluids and ED referral, regardless of etiology

1 HPT: Parathyroidectomy by experienced surgeon definitive tx; indicated if sx or: Age < 50, Ca >1 mg/dL above ULN, T-score < –2.5, clinical or radiographic nephrolithiasis;

If medical mgmt: Serial monitoring of Ca (at least q12mos), avoid overrepleting Vit D, thiazides; avoid dehydration; bisphosphonates if ↓ BMD; consider cinacalcet (no improvement in bone health when used in 1° HPT)

3° HPT (see “Chronic Kidney Disease”)

Hypercalcemia of malignancy: Typically managed by oncology; tx

 

often includes bisphosphonates (e.g., zoledronate); nadir 4–7 d after infusion, response lasts 1–3 wk; can use denosumab for cases refractory to IV bisphosphonates

Exogenous Vit D or ↑ conversion: Treat underlying cause; low-Ca diet; glucocorticoids can ↓ conversion to 1,25OH Vit D, consider endocrine referral

Endocrine referral: If dx uncertain, ↑ Ca persists despite tx of presumed cause

HYPOCALCEMIA

 

Etiologies (NEJM 2008;359:391)

Hypoparathyroidism: Acquired: most common, s/p thyroidectomy or other neck surgery; infiltrative (hemochromatosis, Wilson, metastases); genetic: DiGeorge, 22q11.2 microdeletion, autosomal dominant hypocalcemia; severe Mg deficiency (↓ PTH secretion & ↑ resistance) Inadequate Vitamin D: Severe Vit D deficiency, CKD (2° HPT), ESLD, INH, ketoconazole (see “Vitamin D Deficiency”)

Other: Bisphosphonates or denosumab (if Vit D deficient & CKD), s/p parathyroidectomy, genetic resistance to PTH (pseudohypoparathyroidism, ↓ Ca despite ↑ PTH) or Vit D

Evaluation (Curr Opin Endocrinol Diabetes Obes 2012;19:435; NEJM 2012;367:e15)

Signs and symptoms: Muscle cramping, numbness, paresthesias; ⊕ Chvostek sign: Tap cheek over facial nerve; ⊕ if → ipsilateral twitching of upper lip (90/66% Se/Sp); ⊕ Trousseau sign: Inflate BP cuff >SBP × 3 min; ⊕ if → carpal spasm (94/99% Se/Sp); severe disease can p/w seizures, CHF, stridor/laryngospasm

Diagnostic studies: iCa (or Ca & albumin), Phos, Mg, BUN/Cr, PTH, Vit D, consider 24-h urine Ca

 

Expected Labs by Etiology
Diagnosis	Lab Studies
Hypoparathyroidism	↓ Ca, ↑ Phos, ↓ PTH
Vitamin D deficiency	↓ Ca, ↓ Phos, ↑ PTH
Pseudohypoparathyroidism	↓ Ca, ↑ Phos, ↑↑ PTH

 

Treatment

Severe disease or symptoms → ED for IV Ca bolus followed by infusion

Correct Vitamin D deficiency (see “Vitamin D”); for CKD, see “Chronic Kidney Disease”

Primary hypoparathyroid patients: Goal is sx relief, w/ total Ca in low–nl range (i.e., 7.5–8.5 mg/dL) to avoid hypercalciuria; treat with oral Ca (if on PPI, citrate is preferred, e.g., 500 mg elemental Ca TID) & 1,25OH Vit D (e.g., calcitriol 0.25 μg BID) significant variability in dosing requirements; pts w/ 1° hypoparathyroidism should have medical alert bracelets; PTH replacement now approved (JCEM 2016;101:2273)

If hypercalciuria (>300 mg Ca/d), consider thiazide to ↓ risk of nephrolithiasis

 

Background (NEJM 2007;357:266; 2011;364:248)

Definitions: Deficiency: Serum 25OH Vit D <20 ng/mL; Insufficiency; 25OH Vit D 20–29 ng/mL

Physiology: Vitamin D is a hormone which ↑ GI absorption & ↓ renal excretion of Ca, ↓ PTH production, & contributes to nl bone growth/mineralization

Complications: Inadequate Vit D causes 2° hyperparathyroidism & inadequate bone mineralization (→ osteomalacia), can ↑ fracture risk &

↑ falls in elderly; has also been assoc w/ myriad extraskeletal disease, including DM, cancer, & MS, although these are controversial & RCTs demonstrating extraskeletal benefits of supplementation are lacking Metabolism: Dietary intake of Vit D₂ (ergocalciferol = from plants) or

Vit D₃ (cholecalciferol = from animals) as well as synthesized D₃ (created in UV-exposed skin) converted to 25OH Vit D by the liver → converted to 1,25OH Vit D by the kidney; this final step is regulated by Ca, PTH, & phosphate levels

Vitamin D deficiency can occur with ↓ intake (↓ dietary intake, GI

absorption, or UV exposure), impaired hepatic conversion to 25OH Vit

 

D (rare), and/or impaired renal conversion to 1,25OH Vit D (common, seen in CKD)

Epidemiology: 33% of US population have Vit D <20; 6–8% of adult men & 10–12% of adult women have Vit D <12 ng/mL (cdc.gov; NCHS

2011:59)

Risk Factors: Elderly (↓ skin production), inhabitants of Northern climates, African-American or Hispanic background, obese (Vit D sequestered in adipose tissue) homebound, institutionalized, or otherwise inadequate sun exposure, no milk intake, postmenopausal ♀, GI disease (↓ absorption: IBD, celiac, biliary disease, s/p Roux-en-Y gastric bypass), medications (e.g., phenytoin, glucocorticoids, rifampin, cholestyramine)

Evaluation (Mayo Clin Proc 2011;86:50)

Screening: Some debate about merits of screening asx individuals; however, many (including AACE) suggest clinically screening all pts to find those at ↑ risk, & then to test Vit D in this population

Labs: Obtaining 25OH Vit D generally sufficient; in pts w/ ESRD, also

• PTH & 1,25OH Vit D (they may have insufficiency despite adequate 25OH Vit D due to ↓ renal conversion)

Treatment (NEJM 2007;357:266; JCEM 2011;96:53)

Vitamin D deficiency: Ergocalciferol 50,000 IU weekly for 8–12 wk; obese patients, malabsorption, or extreme deficiency may require longer course

Vitamin D insufficiency: 800–2000 IU QD will replete levels in an avg adult by 3 mos

Prevention: The IOM recommends 600 IU of Vit D & 1000 mg Ca daily intake for all adults, and 800 IU of Vit D & 1200 mg Ca for adults

>70 y; upper level of Vit D intake (above which ↑ risk of harm) set at

>4000 IU daily for all adults (www.nap.edu/catalog.php? record_id=13050)

Special populations: Osteoporosis: (See “Osteoporosis”); CKD: Repletion based on GFR & PTH; refer to practice guidelines (www.kidney.org/professionals/kdoqi/guidelines.cfm)

Vit D₂ vs. Vit D₃: D₂ (ergocalciferol) available by Rx in high-dose formulations for weekly/monthly repletion, not animal-based for pts w/

 

objections; D₃ (cholecalciferol) appears to ↑ serum Vit D levels higher at equivalent dose, although unknown if differences in adherence (JCEM 2011;96:E447; 2011;96:981)

Calcitriol: Use restricted to CKD pts w/ hypocalcemia or parathyroid

disease

Referral: Consider referral if low Vit D is refractory or if etiology unclear

 

Background (Lancet 2004;363:793; AFP 2012;86:244)

Thyroid hormones: Myriad functions, including calorigenesis, potentiating SNS tone, turnover/clearance of nutrients (lipids, CHO, vitamins) & tissues (muscles, bone)

Inappropriate thyroid hormone levels affect every organ system, with presentation ranging from subtle/asx to life-threatening (myxedema coma or thyroid storm)

Thyrotropin-releasing hormone (TRH): Secreted by hypothalamus, responsible for ⊕ anterior pituitary to release TSH

Thyroid-secreting hormone (TSH): Secreted by pituitary, responsible for ⊕ thyroid gland synthesis, storage, & release of thyroid hormones (T4 > T3); best representation of amt of hormone available to tissues, since it ↑ quickly and logarithmically with ↓ in thyroid hormone Thyroxine (T4): Has 4 iodine molecules; made only in the thyroid; T_1/2

= 7 d; has some biologic activity but primary is pro-hormone for T3 Triiodothyronine (T3): Has 3 iodine molecules; 4× more potent than T4; can be made from T4 in thyroid or in target tissues by removing one outer iodine (deiodination); regulates gene transcription in target tissues; T_1/2 = 1 d

Plasma concentrations: >99% of T3 & T4 bound to proteins in serum (mostly to TBG); ∴ Change in serum-binding proteins will result in change in serum total [T3] and [T4]; free concentrations of T3 & T4 = biologically active, unaffected by changes in protein levels

HYPOTHYROIDISM

 

Background (JCEM 2009;94:1853; 2002;87:489)

Epidemiology: Affects 3–8% of the US population; ↑ incidence in elderly, ♀ > ♂, white/Hispanic > African-Americans; Risk Factors: Postpartum, hx autoimmune disease, Turner/Down syndromes, childhood obesity, ⊕ FHx thyroid disease, chest/neck XRT

 

Etiology of Hypothyroidism (Endocr Practice 2012;18:988)
Etiology	Disease
Autoimmune	Chronic autoimmune thyroiditis (Hashimoto’s) = most common
Iatrogenic	S/p tx for hyperthyroidism or thyroid CA (RAIU, surgery); neck XRT
Central	CNS tumor, inflammatory, infiltrative disease, Sheehan’s, surgery, or XRT
Thyroiditis	Postpartum thyroiditis, subacute painless or granulomatous thyroiditis
Infiltration	Amyloid, hemochromatosis, sarcoidosis, sclerosing thyroiditis
Medications	Lithium, amiodarone, thioamides, tyrosine kinase inhibitors, immune modulators (IFNa, IL-2, anti-PD1)
Other	Iodine deficiency (Rare in US; most common cause worldwide) or excess, congenital (all US newborns screened), thyroid hormone resistance

Evaluation

General approach: Dx made by TSH + fT4; sx often subtle or nonspecific, tx effective, & ↑ prevalence; but, no evidence that screening asx, nonpregnant people improves outcomes; clinical guidelines differ in recs (see “Disease Screening”); test patients if ↑ risk, s/sx of disease

History/Exam: If pt c/o s/sx consistent w/ hypothyroidism, assess “Thyroid ROS”: Recognizing that sx highly variable & nonspecific (esp. if TSH ↑ is mild)

 

Hypothyroidism Manifestations/“Review of Systems”
Constitutional: Wt gain, fatigue, cold intolerance HEENT: Voice Δ, goiter, periorbital edema Pulm: Sleep apnea, hypoventilation CV: Diastolic HTN, bradycardia	Heme: Anemia MSK: Carpal tunnel syndrome, myalgias Neuro: Delayed DTR relaxation (↑ Sp) Endo: Dyslipidemia Ext: Nonpitting edema

 

GI: Constipation GU: Decreased libido, menstrual irregularities Renal: ↓ GFR & water clearance, ↓Na

Derm: Brittle hair/nails, cool, dry/rough skin, lateral brow loss

Labs: TSH best initial test; if TSH ↑ obtain free T4 (fT4); (always check TSH & fT4 if suspected pituitary disease); if TSH ↑ and fT4 ↓, no further testing indicated; T3 not indicated (poor assay Se/Sp) Additional testing/special populations:

Pts w/ history of pituitary disease or suspect 2° hypothyroidism:

Always ✓ TSH and fT4

Pts w/ subclinical hypothyroidism: If TSH borderline, repeat as 62% normalize on recheck (Arch Int Med 2007;167:1533) consider anti-TPO Abs; if ⊕ predicts progression to overt hypothyroidism

Lab abnormalities associated with hypothyroidism: ↑ LDL, ↓ HDL, anemia, ↑ CK, mild ↓Na, & hypoglycemia; however, these should not be ordered for dx

 

Interpretation of TFTs in Hypothyroidism
Etiology	TFT Pattern
Primary (usually autoimmune)	↑TSH, ↓fT4; TPO Ab often ⊕ but not needed
Subclinical (variant of primary)	↑TSH, nl fT4;
Central (pituitary/hypothalamic)	↓ or nl TSH, ↓fT4; <1% of cases (JCEM 2012;97:3068)

Treatment (Endocr Pract 2012;18:988; Thyroid 2014;24:12)

Primary: Uncomplicated 1° can be managed by PCP with levothyroxine (below)

Subclinical hypothyroidism: TSH >10 (and possibly >7) assoc w/ ↑ CAD events/mortality (JAMA 2010;304:1365) & CHF (Lancet 2012;379:1142); TSH 5–10 may be protective in elderly >70 (Arch Int Med 2009;169:2011); Tx if TSH

>10, consider tx if TSH >7–10, comorbidities, or ⊕ Anti-TPO; have a

much higher threshold to tx in elderly; follow same dosing guidelines below for tx

 

Prescribing Levothyroxine (synthetic T4)
Choice of Rx	All T4 brand & generic formulations are effective; mild difference in kinetics & bioavailability (AFP 2012;86:244); T3 is rarely needed
Initial dosing	Weight-based dose = 1.6 μg/kg/d (∼110 μg for 70 kg pt); for

 

	healthy younger adults, okay to start at ½ or full dose; for elderly or pts w/ CAD, start 25–50 μg & slowly uptitrate (T4 ↑ myocyte O2 demand)
Administration	In am 60 min prior to food (missed pill can be taken later/next day), 3–4 h apart from Ca or iron; if QHS, dose 3 h after last meal
Monitoring	Recheck TSH in 6–8 wk (T4 T1/2 7 d = 4–6 wk for steady state) after initiation, dose changes, or formulation changes; once at goal, ✓ q6–12mos; assess sx (see “Symptoms/Pt Education”)
Goal	TSH in nl range; TSH <2.5 for child-bearing age ♀; aim for high end of the normal range for elderly (overtreatment is common)
Titration	Change by 12.5–25 μg increments depending on proximity to goal
Tx interruptions	Avoid if possible; if <6 wk, usually ok to resume prior dose if low CVD risk or significant wt loss (Endocr Pract 2012;18:988)
Persistent or new ↑ TSH on Tx	Assess for adherence (most common), timing of dose & meals, meds that interfere with absorbance/metabolism (e.g., Calcium, iron, PPI, phos binders, bile acid sequestrants, raloxifene), formulation change, weight gain, malabsorption (e.g., Celiac)

Symptoms/Patient Education: Counsel pts that sx may take months– years to improve proportional to severity/duration of hypothyroidism; unfortunately, many pts with Hashimoto’s have ↓ QOL and persistent “hypothyroid” sx despite nl TSH; further T4 dose ↑ usually not helpful

(Thyroid 2011;21:161)

When to refer

Endocrine: Difficulty achieving euthyroid state, cardiac disease, planning pregnancy (or currently pregnant), thyroid structural abnormalities, central hypothyroidism, other endocrine d/o (adrenal, pituitary), labs difficult to interpret, unusual cause suspected, consideration of using T3 tx (e.g., postthyroidectomy 2/2 deiodinase polymorphism)

Emergency Department: Extreme/prolonged hypothyroidism + stressor (trauma, infection, drugs) can → myxedema coma (hypothermia, diffuse edema, HoTN, AMS, hypoventilation)

HYPERTHYROIDISM

 

Background (JCEM 2002;87:489; AFP 2005;72:623)

Epidemiology: 1.2% of US population (0.5% overt & 0.7% subclinical); 5× as common in ♀

Etiology: Graves disease (autoimmune d/o with TSH-receptor stimulating Abs) most common (60–80% of cases); subacute thyroiditis (lymphocytic/painless or granulomatous/painful), toxic adenoma, toxic multinodular goiter (TMNG) 5% (pts often older w/ longstanding goiter); meds (excess thyroxine, amiodarone); gestational hyperthyroidism; rare causes incl TSH-secreting pituitary tumor, hCG-secreting tumors, struma ovarii, widely metastatic follicular thyroid cancer

Evaluation (Endocr Pract 2011;17:e1; Thyroid 2016;26:1343)

General Approach: Hyperthyroidism dx made by TFTs; presentation of variable severity, most result from high adrenergic tone; may be atypical or “apathetic” in elderly (J Am Geriatr Soc 1996;44:50): Order TSH & reflective fT4, tT3 to confirm, and RAIU to help clarify etiology History/Exam: If suspicion for hyperthyroidism, evaluate other s/sx (below); additional history: Onset/duration of s/sx, as well as complete medication & supplement list, recent iodine exposure (e.g., CT contrast);

 

Hyperthyroidism Manifestations/“Review of Systems”
Constitutional: Diaphoresis, wt loss, insomnia,	Heme: Anemia
heat intolerance HEENT: Stare, lid lag,	Endo: ↓ BMD, hyperglycemia
exophthalmos (Graves’)	Pulm: DOE, ↑RR
Thyroid: enlarged, tender, or nodular	CV: ↑HR, AF, systolic HTN
Derm: Onycholysis, hyperpigmentation,	GI: Hyperdefecation
pruritus, thinning hair Neuro: Tremor,	GU: Menstrual irregularities
anxiety, hyperreflexia	Ext: Pretibial myxedema (Graves’)

Labs: TSH best initial test: if TSH ↓, then obtain total T3 (tT3) & fT4; if hx suspicious for Graves’, send thyroid receptor antibodies (TRAbs): TSII and TBII have Se/Sp >97% for overt Graves’ (JCEM 2013;98:2247); Radioactive iodine uptake and scan (RAIU): Order if labs above abnl to characterize hyperthyroid etiology; best test if no recent iodine exposure (will falsely lower uptake);

Additional testing/special populations:

Subclinical hyperthyroidism: If ↓ TSH with nl fT4 and tT3 levels and

 

asx, recheck in 2–3 mos Thyroid nodule on exam: Thyroid U/S (see “Thyroid Nodules”) Concern for exogenous T4 overdose: Thyroglobulin (will be ↓ instead of ↑)

Lab abnormalities associated with hyperthyroidism: ↓ LDL, ↓ HDL, anemia (↑ RBC mass, but ↑↑ plasma volume), ↑ AΦ; however, these should not be used for diagnosis

 

TFT Interpretation in Hyperthyroidism
Etiology	TFT Pattern
Primary (usually Graves’)	↓TSH, ↑fT4, ↑tT3 (↑↑tT3 suggests Graves’)
Subclinical (variant of primary)	↓TSH, nl fT4, nl tT3
Central (pituitary, extremely rare)	↑TSH, ↑fT4, ↑tT3

 

Radioactive Iodine Uptake Interpretation
Low Uptake	High Uptake
Subacute thyroiditis	Graves disease (diffuse uptake)
Exogenous hormone	Toxic multinodular adenoma (multiple foci)
Struma ovarii	Toxic adenoma (one focus)
Iodine exposure (amiodarone, contrast)	Gestational/trophoblastic hyperthyroidism

Treatment (Endocr Pract 2011;17:e1; Thyroid 2016;26:1343)

General approach: All hyperthyroid pts → endocrine referral for management; acute mgmt may be initiated by PCP (below) Graves disease: Multiple effective tx choices include antithyroid medication (thionamides), 131I tx, or surgery; mod–severe Graves ophthalmopathy: Options include glucocorticoids and surgery Acute mgmt: βB (e.g., propranolol 10–40 mg BID) are effective

immediately and indicated for all pts w/ sx, especially if CAD, resting pulse >90 or elderly; Methimazole 10–40 mg daily with baseline CBC/LFTs (risk of agranulocytosis, cholestasis ↑ with dose) Subclinical hyperthyroidism: If asx, repeat TSH, fT4, tT3 at 2–3 mos to document persistence vs. resolution, as 51% normalize w/ recheck; If sx or persistent, obtain RAIU; tx decision guided by (1) risk category: High-risk = postmenopausal women, elderly, pts w/ CV disease and (2) degree of TSH suppression (If TSH <0.1 and >60 y, atrial fibrillation risk

↑ 3× (NEJM 1994;331:1249), also ↑ osteoporosis and fracture risk)

 

TSH <0.1: High risk = tx; low risk = consider tx TSH 0.1–0.5: High risk

= consider tx (and/or tx βB, bisphosphonate); low risk = observe

When to Refer

Endocrinology: All hyperthyroid patients

Emergency Department: Extreme/prolonged hyperthyroidism + stressor (trauma, infection, drugs) can → thyroid storm (hyperthermia, HoTN or HTN, tachycardia +/− arrhythmias, AMS)

 

Background (NEJM 2004;351:1764)

Definition: Discrete mass w/in thyroid gland, palpated or visualized on imaging

Epidemiology: 4–7% of adults have palpable nodule; 50% of pts >60 y have nodule evident on autopsy; ∼5% of nodules are malignant

Evaluation (Endocr Pract 2010;16(Suppl1):1; Thyroid 2016;26:1)

History/Exam: Full hx & physical w/ special attention to thyroid exam & paracervical LN; assess for s/sx of hyper-or hypothyroidism, factors which suggest ↑ likelihood of malignancy (below)

 

Features Associated with Increased Risk of Malignancy
History	Exam, Imaging
Hx childhood head & neck XRT Hx accidental radiation exposure Hx total body XRT ⊕ FHx thyroid Ca or Ca syndrome (e.g., MEN2a, MEN2b, FAP, Cowden’s) Rapid growth of mass/nodule Hoarseness	Vocal cord paralysis Fixed nodule, lateral cervical LAD Suspicious U/S features: Hypoechoic irregular margins, microcalcifications, taller- than-wide, interrupted rim calcifications, extrathyroidal extension

Diagnostics: All patients w/ nodule should undergo dedicated thyroid U/S and TSH; those who meet criteria should undergo Fine Needle Aspiration (FNA): Can be done by endocrinology or radiology; offers cytology (but not histology)

 

 

 

 

 

Management

General approach: PCP surveillance of pts at avg malignancy risk with nl or not-indicated FNA appropriate; endocrine referral for anyone at ↑ malignancy risk or w/ abnl FNA results; consider endocrine referral for pts w/ multiple nodules, ambiguous RAIU results

Repeat FNA: Indicated if high risk (above), or if nodule grows by 20% or more in 2 dimensions, develops new suspicious features, or new sx; if two benign FNAs are obtained, surveillance usually no longer required

 

Management of Ultrasound Results: Nodule Surveillance
Classification (see algorithm above)	Management
Does not meet size criteria for FNA	Repeat U/S in 6–12 mos
Cyst	No follow-up needed
Very low risk	Repeat U/S in 2–4 y
Low or intermediate risk	Repeat U/S in 1–2 y
High risk	Repeat U/S and FNA in 6–12 mos
“Bethesda System” FNA Results and Management
Benign	U/S surveillance
Nondiagnostic (ND)	Repeat FNA; if ND again → close f/u or

 

	surgery
Indeterminate (AUS, FLUS, SFN)*	Repeat FNA w/in 3 mo; if indeterminate again → molecular testing or surgery; If FLUS/SFN, consider RAIU if TSH low-nl (hyperfunctioning = benign)
Suspicious for malignancy	Thyroidectomy
Papillary thyroid cancer	Thyroidectomy

*Atypia of undetermined significance, follicular lesion of undetermined significance, suspicious for follicular neoplasm

 

Background (NEJM 1996;335:1206; J Intern Med 2014;275:104; Lancet 2014;383:2152)

Definition: Inability of the adrenal glands to produce the amt of cortisol required for degree of stress; acute AI can present w/ adrenal crisis, but chronic AI is often subtle and making the dx requires clinician to consider it in Ddx for many common outpatient s/sx

1o (adrenal cause): (♀ > ♂, incidence ↑ 30–50 y) Addison disease, most commonly autoimmune (anti-21-hydroxylase antibodies ⊕ in 86%), infectious (TB, CMV, histo), bilateral adrenal hemorrhage (N. meningitidis and other pathogens, DIC, APLAS, anticoagulation), cancer (metastases, lymphoma), meds (→ ↓ adrenal steroid synthesis: ketoconazole, fluconazole, etomidate), genetic (CAH, adrenal leukodystrophy)

2o (hypothalamus/pituitary cause): (♀ > ♂, incidence ↑ 60–69 y) Meds (→ to HPA axis suppression: Corticosteroids, opioids, megestrol, medroxyprogesterone); hypopituitarism (mass lesions, infiltrative dz, infarction, hx head trauma, pituitary surgery/rads, postpartum pituitary necrosis)

Exogenous glucocorticoids most common cause of AI: Cases have been reported by transdermal, inhaled, rectal, and intra-articular routes Patient may tolerate partially compensated AI until a stressor results in profound symptoms ± hypotension (adrenal crisis)

Evaluation (JCEM 2016;101:364; Ann Clin Biochem 2009;46:351)

General approach: If suspicion for AI in stable pt, start w/ cosyntropin

 

stimulation test when possible (↑Se/Sp), if not then 6–8 AM plasma and ACTH levels; for pts w/ suspected adrenal crisis → avoid diagnostic delay in tx/ER (obtain single ACTH/cortisol value prior to tx if possible) History/exam: Assess for s/sx suggestive of either 1o or 2o insufficiency: weakness, fatigue, anorexia, N/V, abd pain, wt loss, orthostatic hypotension, hypotension, hyponatremia, hypoglycemia, hypercalcemia, anemia, eosinophilia

1o only: hyperkalemia, salt craving (↓aldosteronism), hyperpigmentation at mucous membranes, creases, pressure areas (↑ACTH precursor → ↑melanin), other autoimmune disease 2o only: S/sx of hypopituitarism (hypogonadism, hypothyroidism,

↑PRL)

Labs: Cortisol measured in corticotropin stimulation test (preferred) or AM cortisol testing; serum cortisol = bound + free cortisol; free = biologically active, ∴ serum measurement may be misleading when CBG is ↓ or ↑; ACTH should be measured with cosyntropin stim or AM cortisol test; ACTH >2× ULN c/w 1o AI, ↓ACTH c/w 2o AI

 

Corticotropin Stimulation Test (JCEM 2016;101:364)
Test administration	(1)  ✓ serum ACTH and cortisol (2)  give cosyntropin (ACTH analogue) 250 μg IV/IM (3)  ✓ cortisol 30 and 60 min later
Interpretation	Normal response: Peak serum cortisol level ≥18 μg/dL Abnormal response: In 1o AI due to adrenal gland destruction; in 2o AI due to adrenal gland atrophy False ⊕: Liver disease, critical illness (↓CBG) False ⊖: Pregnancy, OCPs (↑CBG); acute 2o AI (no time for adrenal atrophy)

6–8 AM cortisol: (Serum cortisol usually at its highest in early AM): Definite AI if ≤3 μg/dL (100% Sp); rules out AI if ≥18 μg/dL (JCEM 2003;88:4193); if equivocal → corticotropin stim test

If abnl cosyntropin stim test, ✓ aldosterone;

↑ACTH, ↓ aldosterone: 1o AI → 21-hydroxylase antibody testing → if (−), adrenal CT

↓ACTH, nl aldosterone: 2o AI → assess for culprit medications, pituitary MRI

Treatment (JCEM 2016;101:364; JAMA 2009;301:2362)

 

Endocrine referral: For all pts w/ confirmed or suspected AI, however, PCPs may initiate/complete w/u (above), triage acute AI, and should be aware of steroid mgmt in situations such as drug–drug interactions, outpatient illness

Acute AI: → ER for steroid replacement, volume repletion, and w/u for underlying trigger

Chronic AI: Titrate dose to s/sx (e.g., blood pressure, body weight, energy level); counsel pts on 100% adherence, “sick dose” rules, med alert bracelet

Glucocorticoids: Hydrocortisone 15–25 mg daily in 2–3 divided doses (e.g., 10 mg q AM, 5 mg q 2 PM) or prednisone 3–5 mg q AM

Mineralocorticoids (for 1o only): Fludrocortisone 0.05–0.1 mg q AM

Stress dosing: Glucocorticoid requirements ↑ during stressor like illness, surgery; for outpt illness or minor procedure, double or triple dose (see “Preoperative Medicine”)

Drug–drug interactions: Major glucocorticoid drug interactions – dose adjustments may be needed

CYP3A4 inhibitors: ↑ Levels (lower dose needed): Clarithromycin, ketoconazole, isoniazid, HIV/HCV antivirals (e.g., ritonavir, lopinavir), cyclosporine CYP3A4 inducers: ↓ Levels (higher dose needed): Carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, rifampin, St. John’s wort

 

Background (Eur J Endocrinol 2003;149:273; AFP 2010;81:1361; NEJM 2007;356:601)

Definition: Mass lesion ≥1 cm visualized by imaging, usually incidentally during evaluation of unrelated process (“incidentaloma”) Epidemiology: Incidence 8.7% in autopsy series (Br J Surg 1993;80:422); 4.4% in those undergoing unrelated abdominal CT (J Endocrinol Invest 2006;29:298); prevalence ↑ w/ age

Risk factors for malignancy: Hx of extra-adrenal malignancy; lesion

>4 cm in size, radiographic density >10 Hounsfield units, <50% washout at 10 min

 

Etiology of Adrenal Incidentaloma (Eur J Endocrinol 2009;161:513)
Malignant (3%)	Primary adrenal carcinoma (ACC, 2%) Metastases (1%)*
Benign (97%)	Nonfunctional adrenocortical adenoma (90%) Subclinical Cushing syndrome (6%) Pheochromocytoma (3%) Aldosteronoma (1%) Myelolipoma, cyst

*For pts w/ current/prior CA hx, 52% of adrenal incidentalomas = metastases (Surgery 2001;6:1060)

Evaluation (Endocr Pract 2009;15:S1; NEJM 2007;356:601)

General approach: Seek to answer 2 questions: Is nodule malignant, and/or is it functioning (producing hormones)?

History/Exam: Evaluate for malignancy (mets) and for s/sx functioning lesion;

Hypercortisolism (Cushing syndrome): Wt gain, central obesity, facial rounding, Δ cognition, HTN, DM2, HL, osteopenia Excess catecholamines (pheochromocytoma): HTN (paroxysmal or sustained), palpitations, headaches, diaphoresis Hyperaldosteronism (Conn syndrome): HTN, hypokalemia, muscle cramps

Labs: Always screen for Cushing’s and pheochromocytoma; screen for Conn/ aldosteronoma only if pt also has HTN

Excess cortisol (Cushing’s) screening: 1 mg dexamethasone suppression test; ⊕ if AM cortisol ≥1.8 μg/dL; ↑Se, ↓Sp (many false ⊕, can be due to obesity, stress, ↑EtOH use, psychiatric disease, OCPs (↑ CBG), AEDs (↑ dexamethasone clearance)

Excess catecholamines (pheochromocytoma) screening: 24-h urine metanephrines and catecholamines; plasma metanephrines (plasma assay > false ⊕, can be due to stress, illness, psychoactive agents (TCAs, amphetamines, etc.), decongestants, clonidine w/d Excess aldosterone (Conn) screening: AM plasma aldosterone concentration (PAC) and plasma renin activity (PRA); ⊕ if PAC ≥15 ng/dL and PAC/PRA ≥20

Treatment (J Am Coll Radiol 2010;7:754; Endocr Pract 2009;15:S1)

Endocrine referral: If any of hormonal screening tests ⊕, refer for

 

confirmatory testing

Surveillance: If <4 cm, benign appearance, and nonfunctioning: (1) serial imaging at 3–6 mos, 12 mos, and 24 mos; (2) Hormonal evaluation annually for up to 5 y; interval growth of >1 cm or hormonal screen ⊕ → surgical evaluation

Surgery referral: For excision (or biopsy) if size >4 cm (PPV 16% for

malignancy; JCEM 2000;85:637), malignant imaging characteristics, or pt history of malignancy; consider referral at smaller size for younger pts whose surgical risks are lower

Surgical excision should be considered for all hormonally active lesions, particularly pheo given risk of CV complications; medical management for hyperaldosteronism may be preferred to surgery in individuals with comorbidities

 

Background (Endocrinol Metab Clin N Am 2008;37:151)

Pituitary incidentaloma: Pituitary lesion discovered on imaging performed for other reasons (macro: ≥1 cm, micro: <1 cm)

10% of adult population have pituitary abnormalities on MRI compatible w/ pituitary adenoma (Ann Intern Med 1994;120:817)

 

Etiology of Pituitary Lesions
Pituitary adenomas	Inflammatory	Metastases
Nonfunctioning	Lymphocytic hypophysitis	Breast
Functioning (PRL most	Sarcoidosis	CNS lymphoma
common)	Wegener granulomatosis	Lung
Cystic	Infectious	Prostate
Rathke cleft cyst	Bacterial	Vascular
Craniopharyngioma	Syphilis	Carotid aneurysm
Nonadenomatous	Tuberculosis	Miscellaneous
neoplasms		Hyperplasia
Meningioma
Germinoma

(JCEM 2011;96:1633)

Evaluation (JCEM 2011;96:894)

General approach: Goal is to identify hormone hypersecretion &

 

hypopituitarism

History/Exam: Assess symptoms of excess/deficiency of pituitary axes (below) and any CNS complaints (HA, Δ vision)

 

Clinical Manifestations of Pituitary Dysfunction
Hormone	Hypo-and Hypersecretion Manifestations
Prolactin	Low: Generally asx High: Galactorrhea, menstrual irregularities; see “Hyperprolactinemia”
ACTH	Low: Fatigue, anorexia, orthostatic HoTN; see “Adrenal insufficiency” High (Cushing disease): Wt gain (esp central), facial rounding, supraclavicular fullness, fatigue, depression, ↑glucose, HTN, ecchymoses, hirsutism, myopathy
LH, FSH	Low: ♀: Menstrual irregularities, hot flashes; ♂: ↓ Libido; see “Male Hypogonadism” High: Generally asx
Growth hormone	Low: Generally asx; may have ↓ muscle mass, ↓ BMD High: ↑ Size of hands and feet, frontal bossing, macrognathia, macroglossia, spaces between teeth, carpal tunnel, deepening of voice, OSA, skin tags, hyperhidrosis
TSH	Low: Fatigue, wt gain, constipation, delayed DTRs; see “Thyroid disorders” High: Heat intolerance, palpitations, hyperdefecation, tremor, anxiety

Pituitary MRI to further characterize lesion if identified by CT

Hormone evaluation: Assess both hypo-and hyperfunction

Hypofunction (esp if macro): ✓ AM cortisol or cosyntropin stimulation test (see Adrenal Insufficiency), TSH, fT4, FSH/LH, testosterone (if

♂), IGF-1

Hyperfunction: ✓ PRL, IGF-1 (assess hypo-and hyperfunction), consider 24 h urine-free cortisol or late night salivary cortisol if any sx c/w ↑ ACTH (JCEM 2008;93:1526); if ↑ PRL mild but macroadenoma, repeat PRL assay w/ 1:100 sample dilution (can be falsely ↓ 2/2 “hook effect”) (JCEM 2011;96:273)

Ophtho referral: Visual field testing for lesions abutting optic nerves or chiasm on imaging

Biopsy (infrequent) in cases of diagnostic uncertainty

 

Treatment (JCEM 2011;96:894; Lancet 2016;388:2403)

Endocrine referral: If hyper-or hypofunction detected; see Adrenal Insufficiency, Thyroid Disorders; if both ↓ TSH and ↓ ACTH, cortisol replaced prior to thyroid hormone (concern for precipitating adrenal crisis)

Surgery referral: Any evidence of mass effect (VF deficit, ophthalmoplegia, lesion abutting optic nerves/chiasm, or hyperfunctioning); consider referral if HA, considering pregnancy, any lesion growth, or hypopituitarism

Surveillance: If no evidence of pituitary dysfunction and no mass effect

(1) MRI in 6 mos if macro or 12 mos if micro, then repeated annually for at least 3 y (2) Hormonal evaluation in 6 mos, and then annually if macroadenoma

 

Background (AFP 2010;81:617; JCEM 2011;96:273)

Physiology: Prolactin (PRL) is a hormone secreted by lactotrophs of anterior pituitary to induce lactation; tonically ↓ by hypothalamic dopamine (DA) and ↑ by estrogen and TRH

Signs/symptoms: Oligomenorrhea, amenorrhea, infertility (even if regular menses given luteal phase abnormalities), galactorrhea, male hypogonadism, erectile dysfunction

 

Etiology of Hyperprolactinemia
Class	Examples
Physiologic	Pregnancy, lactation (normalizes by 12 wk postpartum due to ↓ estradiol), smaller ↑ seen in nipple stimulation in lactating ♀, stress, exercise, sleep
Medical conditions	CKD (2/2 ↓PRL clearance), cirrhosis, PCOS, 1ç hypothyroidism (2/2 pituitary hyperplasia)
Medications	(Interfere with DA inhibition, usually PRL <200 ng/mL) antipsychotics (esp risperidone), TCAs, metoclopramide, opiates
CNS pathology	(Interfere w/ DA inhibition) Craniopharyngioma, trauma, cranial XRT, sarcoid

 

Pituitary adenoma	Lactotroph adenoma = 40% of pituitary adenomas, PRL level correlates w/ tumor size; other pituitary adenomas may disrupt DA inhibition and → ↑PRL as well
Spurious	Macroprolactin complex (biologically inactive but detectable on PRL assay)
Idiopathic	May reflect a microadenoma too small to detect

Evaluation (NEJM 2010;362:1219; JCEM 2011;96:273)

General approach: First exclude pharmacologic or extrapituitary causes, then proceed w/ pituitary MRI

Hx/PE: Review medications, comorbidities and assess for other findings suggestive of pituitary adenoma, ask about ↑PRL symptoms (premenopausal ♀: Oligomenorrhea, galactorrhea, ♂: Hypogonadal sx) Serum PRL: Repeat if mild elevation to confirm persistence or w/ dilution if concern for “hook effect” (see “Pituitary Lesions”); if med- induced suspected, d/c meds for 3 d then repeat (if cannot safely d/c meds → pituitary MRI)

Other labs: β-hCG (if reproductive-aged ♀), TSH, FT4, Cr, LFTs, macroprolactin (if no sx), FSH/LH/T/SHBG (if ♂); consider macroprolactin assay if pt asx

Pituitary MRI: For all pts with ↑PRL that is not medication-induced or if

>100–200 ng/dL

Treatment (JCEM 2011;96:273; Clin Endocrinol 2006;65:265; NEJM 2010;362:1219)

Referral to endocrine: If prolactinoma detected (see “Pituitary Lesions”); or if symptomatic or desiring pregnancy

Medication-induced: Stop drug if clinically feasible; if not feasible, use estrogen or testosterone replacement for sx hypogonadism; avoid DA agonists (may ⊕ psychosis)

Prolactinoma tx: Macroadenoma: DA agonist cabergoline 1st-line to

normalize PRL and ↓ tumor size (1st-line); s/e: Nausea, HA, orthostatic HoTN, nasal congestion, fatigue), may ↑risky behaviors (rare); estrogen/testosterone therapy; transsphenoidal surgery for macroadenoma in select cases

Microadenoma: Does not need Rx if asx and stable; if sx or enlarging, DA agonists (1st-line), estrogen/testosterone therapy PRN

Surveillance: No guideline consensus; one approach for

 

microadenomas if asx and not on tx, ✓ PRL and MRI annually × 3 y, then q2y (NEJM 2010;362:1219); 95% of microprolactinomas do not enlarge over 4–6 y of observation (JCEM 1989;68:412)