Endocrine Outline PDF

Type II Diabetes Mellitus Diabetes Mellitus: Metabolic dz characterized by hyperglycemia Type 1A: (95%) – D/t autoimmune B cell destruction usually leading to absolute insulin deficiency Type 1B: (5%) – idiopathic Type 2: D/t progressive loss of B cell insulin secretion w/ variable degree...

Type II Diabetes Mellitus Diabetes Mellitus: Metabolic dz characterized by hyperglycemia Type 1A: (95%) – D/t autoimmune B cell destruction usually leading to absolute insulin deficiency Type 1B: (5%) – idiopathic Type 2: D/t progressive loss of B cell insulin secretion w/ variable degree of tissue insensitivity to insulin Gestational Diabetes Mellitus (GDM): Dx in the 2nd or 3rd trimester of pregnancy w/o evidence of diabetes prior to pregnancy Maturity-Onset Diabetes of the Young (MODY): Genetic defects of pancreatic B cell function (several types) Latent Autoimmune Diabetes in Adults (LADA): Slowly developing T1DM in older adults ~ initially have NO insulin-dependence & ketoacidosis but develop insulin-dependence over time as B cells diminish T2DM Overview: o Pathophys: Insulin resistance o Etiology: Genetics + pancreatic exhaustion o Prevalence: Over 90-95% of all diabetes = in the US (very prevalent – most pts with diabetes have type 2) o Lab Diagnostics: Clinical, fasting plasma glucose (FPG), random plasma glucose (RPG), A1C, C-Peptide, Insulin levels o Treatment Gold Standard: Diet/Exercise, Metformin, Stepwise tx approach o Very expensive disease ($327 billion per year in 2017) T2DM PATHOPHYSIOLOGY: o Insulin facilitates movement of glucose from blood -> cells for energy use ~ helps transport glucose to liver & muscles for energy utilization; also stores glucose in fat tissue ▪ Released by pancreas in response to carbs consumed in diet o T2DM - Produce insulin but often not enough for the body’s needs, & may also struggle to use produced insulin effectively ▪ Insulin levels sufficient to prevent ketoacidosis but NOT hyperglycemia ▪ Microvascular Complications: Retinopathy, Neuropathy, Nephropathy ▪ Macrovascular Complications: Coronary artery dz, peripheral arterial dz, stroke  T2DM ETIOLOGY: o Genetic AND environmental factors o Genetic – High heritability (30-70%) w/ >60 genetic variants (but don’t usually test for genetic variant in dx) o Environmental ▪ Obesity = HIGHEST ABSOLUTE RISK FACTOR (regardless of FHx) Visceral or central obesity ▪ Also d/t reduced activity, age, poor diet, prior gestational diabetes T2DM EPIDEMIOLOGY: o Highest prevalence in US = American-Indian & Alaskan o Highest prevalence overall = China o Highest in certain pacific islands & middle east; intermediate in countries like India & US o Peak incidence in minority groups: >45 y/o (slightly younger than white onset) o Male > female (slightly) T2DM CLINICAL PRESENTATION: o SYMPTOMS: ▪ Often asymptomatic ~ insidious dz onset ▪ Overweight, obese ▪ Occasionally incr. urination & thirst ▪ Neuro or cardiovasc abnormalities possible if prolonged undetected/untreated dz o SIGNS: ▪ Chronic skin infx = immune system dysfunction ▪ Chronic yeast infx = immune system dysfunction (vulvovaginitis in women, foreskin & glans penis inflamm in men) Makes sense bc yeast loves sugar, & T2DM has high sugars ▪ Incr. centripetal fat distribution:  Men = Waist circ >40 in Women = Waist circ >35 in ▪ Acanthosis nigricans – Darkening of skin w/in skin folds; skin tags ~ assoc. w/ significant insulin resistance ▪ Eruptive xanthomas – hyperchylomicronemia (incr. triglycerides) WHY SCREEN FOR T2DM? o Many asymptomatic & unaware they have the dz o Prevent complications (some T2DM pts have 1+ diabetes-specific complications at time of dx) o Prevent worsening/progression of dz ▪ Early intervention -> superior outcomes o Dx of prediabetes should incr. efforts for diabetes prevention o Cost-effectiveness WHO TO SCREEN FOR T2DM? o Overweight or obese w/1+ of these risks: ▪ FHx of diabetes; Certain ethnic groups (e.g., African American, Latino, Asian, etc.); HTN; Low HDL or high triglycerides; PCOS or acanthosis nigricans; Heart dz hx; Physical inactivity; Insulin resistance (e.g., severe obesity) o Test yearly if previously dx w/ high blood sugar (IFG, IGT, A1C 5.7-6.4%) o Test women w/ past gestational diabetes every 3 years o Start testing everyone at 45 years old, every 3 years o Test people with HIV T2DM DIAGNOSTIC EVALUATION: o 3 Broad Categories for Glucose Tolerance = Normal glucose homeostasis, impaired glucose homeostasis, diabetes mellitus o Dx of T2DM in nonpregnant pt based on any 1 of 4 abnormalities – ▪ Elevated fasting plasma glucose (FPG) ▪ Random elevated glucose w/ sx ▪ Elevated HgB A1C ▪ Abnormal oral glucose tolerance test (OGTT) o Plasma/Serum Glucose – ▪ Better than blood glucose bc it avoids interference from RBC conc. (Hct), so it gives more accurate measure of the glucose conc. the body tissues are actually exposed to Concentration of glucose in plasma/serum typically 10-15% higher than in whole blood o Glycosylated HgB (HgbA1c): Glucose irreversibly attaches to beta chain of Hgb A ▪ HgbA1c levels = avg blood glucose over prior 6-12 wks More heavily influenced by glucose levels in prior 4 wks ▪ Increased HgbA1c predicts risk of microvascular complications  ▪ Not appropriate to use in populations w/ high prevalence of hemoglobinopathies or in conditions w/ increased red cell turnover o Oral glucose tolerance test - ▪ Consume 150-200 g of carbs per day x3 days preceding test ▪ NPO past midnight prior to test day ▪ Perform test in AM to avoid diurnal variation in glucose tolerance ▪ Give 75g of glucose/300 mL of water PO & consumed w/in 5 min ▪ Obtain plasma glucose levels at 0 hrs (fasting) & 2 hrs ▪ MC done in pregnancy A1C ≥ 6.5% = Diabetes o Urine Tests – ▪ Urine glucose – urine dipstick for glucose (detects >100 mg/dL of glucose) ▪ Urine & blood ketones – urine dipstick helps with early detection of ketoacidosis but does NOT detect beta-hydroxybutyric acid (main ketone in DKA) -> therefore this doesn’t tell you pt is in DKA, but can estimate ketonuria Should not be excreting glucose in urine – if you are, likely diagnostic of hyperglycemia Do blood eval to assess for the important ketones o T2DM DIAGNOSIS CONFIRMATION – ▪ If there is no clear symptomatic hyperglycemia, confirm dx by repeating the same test on a different day OR by performing 2 confirmatory tests on the same day ▪ Preferred tests (d/t convenience) = fasting plasma glucose (FPG) & A1C  T2DM TREATMENT: o Goals = eliminate hyperglycemia sx, reduce/eliminate long- term micro/macrovascular complications of DM, & allow pt to achieve as normal a lifestyle as possible o FIRST LINE = Diet & Exercise (plus metformin) ▪ 5-10% weight loss assoc. w/ significant improvement in cardiac risk factors ▪ Diet = decr. carb intake to promotes decr. TGs & incr. HDL (good cholesterol) ▪ Exercise = aerobic & resistance training DAILY 150 min/week (distributed over 3+ days) of moderate aerobic physical activity w/ no gaps > 2 days ▪ Metformin (Glucophage) – FIRST LINE initial tx for T2DM Start pharm tx at dx (DON’T wait to see whether pt can achieve target glycemic control w/ weight management & exercise) MOA: Biguanide; acts as an antihyperglycemic o ↓ hepatic glucose production, ↓ intestinal glucose absorption, & ↑ insulin sensitivity by ↑ peripheral glucose uptake & utilization o HgbA1C Reduction = 1-2% o ↓TGs in obese patients & promotes weight loss o Low risk of hypoglycemia o Long-term use assoc. w/ ↓ micro- & macrovascular complications Dosage 2000 mg PO daily Side Effects = GI upset Contraindications = Alcohol, Liver dz, unstable CHF = Lactic Acidosis (D/C drug if suspected) o i.e. do NOT give metformin to pts w/ lactic acidosis!!! CKD = Severe renal impairment (eGFR < 30, Elevated Cr), DKA o i.e. do NOT give metformin to pts w/ GFR 140/90 should, in addition to lifestyle therapy, start pharmacotherapy ▪ Lifestyle Therapy = Wt loss (if needed), DASH diet (↓ Na, ↑ K), alcohol moderation, ↑ physical activity ▪ Pharmacotherapy – include Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blocker (ARB) Multiple drug therapy generally required o Monitoring Cholesterol in T2DM ▪ Statin therapy recommended in ALL pts w/ DM >40 y/o regardless of presence/absence of CVD risk factors ▪ 1 of 4 “statin benefit groups” - Persons w/ DM who are 40-75 y/o w/ LDL-C levels of 70-189 but w/o known CVD benefit from statin therapy ▪ Diabetic dyslipidemia = characteristic of insulin resistance syndrome ▪ Circulating lipoprotein levels are dependent on insulin (just like glucose) GUIDELINES FOR ONGOING COMPREHENSIVE CARE FOR PTS W/ DM: o Individualized glycemic goal & tx plan o Self-monitor blood glucose based on personal needs (fingerstick or continuous monitoring) o Test HbA1c 2-4x/ year o Manage diabetes with lifestyle changes: Diabetes education & support, Nutrition therapy, Physical activity, Mental health support (depression, anxiety) o Detection, prevention, or management of diabetes-related complications, s/a: Eye exams (annual or biannual), Foot exams (1-2 times/yr by provider, daily by pt), Neuropathy exams (annual), Kidney dz testing (annual). o Monitor & manage other diabetes-related conditions: BP (check 2-4x/year), Lipids (check 1-2 x/year), Consider antiplatelet therapy w/ low-dose aspirin, Vaccines (flu, pneumonia, hepatitis B, COVID-19) T2DM COMPLICATIONS: o Retinopathy: Vascular damage to the retina ▪ #1 cause of blindness in people 20-74 yrs in the US ▪ Early Stages: Can be asx, but earliest clinical signs = microaneurysms  ▪ Later sx: Floaters, distortion, blurred vision ▪ Macular edema – MC cause of vision loss in pts w/ nonproliferative diabetic retinopathy ▪ All T1D’s must get yearly fundoscopic exams ▪ Prevention = Glucose/A1c control ▪ Buzz Word: Cotton Wool Spots! o Nephropathy: #1 cause of chronic kidney & end stage renal dz in US (1st sign = microalbuminuria) ▪ Damage to glomeruli (capillaries), persistent albuminuria (>300 mg/d or >200 µg/min confirmed 2+ times 3-6 mos apart), progressive ↓ in GFR, ↑ arterial BP Nephropathy in T2DM differs from that of T1DM: o Albuminuria may be present when T2DM is dx, reflecting its long asx period o HTN more often contributes to albuminuria & ↓ GFR Once there is marked albuminuria & ↓ GFR, pathologic changes are likely irreversible ▪ Tx/Monitoring: Prevention = optimal tx ~ yearly measurement of creatinine, urinary albumin excretion, K Improve glycemic control, strict BP management, consider ACEI/ARB, insulin dose adjust based on GFR & refer to nephrology if GFR non-healing foot ulcers, amputations -> ref to wound care or podiatry! ▪ Autonomic Neuropathy – Generalized ~ Ataxia, gait instability Gastrointestinal ~ Constipation (MC GI manifestation), dysphagia, abd pain, n/v, diarrhea, fecal incontinence, gastroparesis (may -> poor glucose control; may improv w/ diet changes & prokinetic agents s/a erythromycin, cisapride, domperidone; anti-emetics; metoclopramide for severe cases only) Cardiovascular ~ Persistent sinus tach, orthostasis, exercise intolerance  GU ~ Bladder neuropathy (poor urinary stream/straining; feeling of incomplete emptying; recurrent UTI, pyelo; incontinence), ED, retrograde ejaculation Sudomotor Neuropathy ~ Heavy sweating of upper body/anhidrosis of lower, gustatory sweating o Hyperglycemia Hyperosmolar State (HHS) – 2nd MC form of hyperglycemic coma, & a serious acute complication ▪ Severe hyperglycemia in the absence of significant ketoacidosis, w/ hyperosmolality & dehydration leading to AMS ▪ Etiology: T2DM + illness – fluid intake NO ketosis! There is insulin onboard w/ T2DM, unlike T1DM, but not enough to prevent hyperglycemia ▪ Pathophysiology: ↓ insulin -> ↑ in counterregulatory hormones -> ↓ glucose utilization & ↑ gluconeogenesis -> hyperglycemia -> osmotic diuresis -> dehydration -> limited access to H2O, so body is going to hold onto the water -> hyperosmolar state ▪ S/Sx: develops over weeks-days; polyuria +/- polydipsia, wt loss, weakness, tachycardia, HoTN, dry skin & mucous membranes, poor skin turgor, AMS w/o Kussmaul respirations o Nonketotic Hyperosmolar State ▪ Dx: Plasma glucose >600; Serum osmolality >320 (normal level = 280-290); profound dehydration up to an avg of 9L (BUN/creatinine ↑ ↑/↑ ~ dehydration -> poor perfusion); NO significant acidosis (serum pH >7.3, Bicarb conc >15, small ketonuria & absent-to-low ketonemia; may have some ketosis from not eating) ▪ Tx: Rehydrate, correct hyperglycemia, treat underlying illness; may require insulin T2DM WRAP-UP: o Every T2DM needs - ▪ Multidisciplinary team working w/ both pt & pt’s family ▪ A WRITTEN PLAN that encompasses meds, diet/exercise, & goal setting ▪ Medications (w/ adequate refills) Most pt’s w/ T2DM are on multiple medications Make sure they know how to use devices (i.e. pens) & have them DEMONSTRATE ▪ Blood glucose monitoring through some sort of device +/- testing strips (which are expensive), lacets for the meter, skin adhesives for CGM’s  ▪ Psychosocial Counseling - Screen for psychosocial problems s/a depression, diabetes- related distress, anxiety, eating disorders, & cognitive impairment (esp if > 65yo) ▪ Quarterly to yearly visits including appropriate monitoring of complications Monogenic Diabetes (Subgroup: Maturity Onset Diabetes of the Young) (MODY) Single gene disorders -> genetic defects of pancreatic B cell function o Genes involved control pancreatic beta cell development, function, & regulation ~ mutations in these genes cause impaired glucose sensing & insulin secretion w/ minimal or no defect in insulin Non-insulin requiring diabetes (typically, but some forms of MODY to require insulin) MC form of monogenic diabetes -> 2-5% of diabetes Age of onset = ≤25 y/o w/ lack of autoantibodies (differentiates MODY from T1DM) Autosomal dominant inheritance – multiple gene abnormalities on diff chromosomes o MC cause = GCK (glucokinase) & HNF (hepatocyte nuclear factor) mutations ▪ GCK mutation: Causes mild asymptomatic stable fasting hyperglycemia Sensor in molecules for glucose is defective, so plasma glucose levels need to be higher in order to stimulate insulin secretion Resulting hyperglycemia often stable & mild -> therefore not associated with the vascular complications common in other types of diabetes NO tx required ▪ HNF mutation: Causes a progressive pancreatic beta cell dysfunction & hyperglycemia that can cause microvascular complications Can be controlled well w/ a sulfonylurea Hepatocyte nuclear factor 4- alpha (MODY1): Pts are at risk for hyperglycemia-assoc. microvascular & macrovascular complications of diabetes  Hepatocyte nuclear factor-1 (MODY3): (MC form) MC among Europeans. Prior to diabetes onset, mutation carriers have detectable glycosuria provoked by glucose loading o Initially, pts w/ MODY3 are responsive to sulfonylurea therapy but eventual progressive beta cell failure -> eventual need for insulin therapy MODY CLINCIAL PRESENTATION: o Quite heterogeneous ~ May not be reliable in predicting underlying pathogenesis o Mild, stable, fasting hyperglycemia ▪ Can also have renal cysts, mild pancreatic exocrine insufficiency, & abnormal LFTs o Typically NO obesity o Often have 1 or more of the following – ▪ Strong FHx of diabetes (bc autosomal dominant) of any type (2 generations) ▪ Insulin independence Lack of ketoacidosis when insulin stopped outside 5 yrs following dx ▪ Absence of autoantibodies for pancreatic antigens (bc MODY not autoimmune dz) ▪ Evidence of endogenous insulin production Insulin resistance is NOT a feature of MODY C-Peptide: Byproduct of insulin production – its levels can indicate how much insulin body is producing ~ ↑ C-peptide levels indicate ↑ levels of endogenous insulin production MODY DIAGNOSTIC EVALUATION: o More difficult to differentiate MODY from T2DM d/t lack of autoantibodies among both types o Presence of autoantibodies makes MODY very unlikely -> before genetic testing, measure serum antibodies – ▪ Islet Cell Cytoplasmic Autoantibodies (ICA) ▪ Glutamic Acid Decarboxylase Autoantibodies (GADA) ▪ Insulinoma-Associated-2 Autoantibodies (IA-2A) ▪ Insulin Autoantibodies (IAA) ▪ Zinc Transporter-8 Autoantibodies (ZnT8A) o Genetic testing by direct sequencing of the gene ▪ Genetic testing allows for optimal tx of pts, identification of family members at risk, identify those at risk for diabetes complications which varies w/ type Pts w/ MODY d/t HNF1A or HNF4A mutations are frequently misdiagnosed as having insulin-requiring T1DM bc they present at an early age & are not obese, but many of these pts can be successfully managed w/sulfonylureas monotherapy In all pts, need detailed hx of diabetes at dx (age, BMI, & presenting sx) o Also need to ascertain insulin dependency & presence/absence of FHx of diabetes  Typically perform genetic testing for MODY when there’s a high index of suspicion (familial diabetes w/ autosomal dominant pattern of inheritance [>2 generations], onset 35 y/o & in 25% o Obesity does not exclude LADA o Obese DM II pts with islet antibodies show progressive beta-cell failure Can affect children too, but mostly just adults Shares genetic features of T1&2DM On the spectrum of insulin deficiency btw T1&2DM LADA DIAGNOSIS: o Measure autoantibodies when dx of T1/T2DM uncertain by clinical presentation (pt thin w/ poor response to initial tx w/ sulfonylureas or metformin, Personal/FHx of  autoimmune dz, Overweight/obese children/adolescents presenting w/ apparent T2DM who in actuality may have an early presentation of T1DM) ▪ 5 of the MC Diabetes-related autoantibody tests = Islet Cell Cytoplasmic Autoantibodies (ICA) Glutamic Acid Decarboxylase Autoantibodies (GADA) Insulinoma-Associated-2 Autoantibodies (IA-2A) Insulin Autoantibodies (IAA) Zinc Transporter-8 Autoantibodies (ZnT8A) ▪ Measuring >1 antibody ↑ likelihood of (+) value, but costly Insulin antibodies should NOT be measured if pt has received insulin therapy for ≥ 2 wks bc this will generate insulin antibodies o Autoantibodies ↓ when you put insulin in body, so want to make sure pt not on insulin when testing for autoantibodies If ≤1 antibodies present → pt should be presumed to have T1DM Tx w/ insulin replacement therapy, as these pts respond poorly to diet & oral hypoglycemic drug therapy o During early stages in the development of T1DM, intensive insulin therapy prolongs beta cell function LADA TREATMENT: o Like that of T1DM ▪ Obese LADA pts benefit from calorie restriction & physical activity ▪ Metformin thought to be useful in these pts!!! ▪ Insulin = TX OF CHOICE at dx!!! o D/t the slow progression of ß-cell failure, pts w/ autoimmune diabetes (LADA) = candidates for immunomodulation Gestational Diabetes & Pregnancy Hormones in pregnancy are assoc. w/ insulin resistance o Metabolic changes of pregnancy can precipitate hyperglycemia requiring ↑ insulin needs o Pregnancy w/ insulin resistance = mediated by placental secretion of diabetogenic hormones s/a growth hormone, corticotropin releasing hormone, placental lactogen, prolactin, & progesterone ~ changes more prominent in the 3rd trimester o Gestational DM develops in people whose pancreatic function is not sufficient to overcome the insulin resistance assoc. w/ the pregnancy Diabetes in the second or third trimester of pregnancy in pts not previously diabetic Pregnant women are screened between 24 & 28 weeks Rates of GDM increasing d/t ↑ in obesity & mean maternal age  GESTATIONAL DIABETES IMPLICATIONS: o Large for gestational age infant (LGA) infant: Fetal/neonatal weight at/above 90th percentile for gestational age ▪ Macrosomia: Birth age ≥4000 g ▪ Can cause increased maternal & perinatal morbidity ▪ ↑ risk of operative delivery cesarean or instrumental vaginal ▪ Adverse neonatal outcomes = Shoulder dystocia & its assoc. complications (brachial plexus injury, fx) o Preeclampsia & Gestational Hypertension o Polyhydramnios: MC in pts w/ GDM; ↑ glucose causes ↑ in polyuria -> ↑ amniotic fluid o Stillbirth: ↑ risk w/ GDM & suboptimal glucose control GESTATIONAL DIABETES COMPLICATIONS: o Neonatal morbidity - ▪ ↑ risk of hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, polycythemia, respiratory distress, &/or cardiomyopathy ▪ Delayed pulmonary, hepatic, & neurologic organ maturity ▪ Congenital defects - heart, neural tube, renal ▪ Abnormal fetal HR patterns ▪ Intrauterine fetal growth retardation & intrauterine fetal distress o Maternal infx o Maternal hypoglycemia, diabetic coma, ketoacidosis o Maternal cardiac, renal, ophthalmic, & peripheral vascular injuries o LONG TERM CONSEQUENCES OF GDM: ▪ GDM = strong marker for maternal development of T2DM, including diabetes- related vascular dz ▪ GDM ↑ offspring’s risk for developing obesity impaired glucose tolerance, & diabetes GESTATIONAL DIABETES RISK FACTORS: o Personal hx of impaired glucose tolerance ~ Hgb A1c>5.7 o FHx of diabetes, esp 1st degree relatives o Pre-pregnancy BMI >30, weight gain in early adulthood, btw pregnancies, or btw 18 & 24 wks of pregnancy o Older maternal age >40 GESTATIONAL DIABETES SCREENING: o Obtain Hgb A1c as part of prenatal laboratory studies at the initial visit -> Manage as diabetic if >6.5 o Targeted screening at 24-28 weeks gestational age with oral 1 hour glucose tolerance test: ▪ 50-g 1-hr oral glucose challenge test (OGCT) w/o PO intake restriction 50g for screening, 100g for diagnostic ▪ 1 hr serum glucose >140 mg/dl = abnormal → 3-hour OGTT  ▪ 1 hr serum glucose >200 mg/dl = GDM (3-hour OGTT not performed) o 3-hr OGTT (if screen is abnormal, after overnight fast) ▪ FBS obtained prior to start of test ▪ 100g oral glucose load ▪ ≥2 abnormal values = GDM GESTATIONAL DIABETES MANAGEMENT: o Team Approach: Pt, OB, maternal fetal medicine specialist, nutritionist o Goal = Euglycemia: ▪ FBS Proceed w/ 2 hr OGTT (75g glucose load) Glucose < 140: normal Glucose ≥ 200: Type II DM Glucose 141-199: Impaired glucose tolerance o Also obtain - ▪ Lipid panel (fasting) ▪ CMP - evaluate renal & liver functions ▪ UA - proteinuria assess for renal damage (HTN & DM) ▪ TSH & free T4 - possible cause of obesity ▪ Uric acid - ↑risk of metabolic syndrome with hyperuricemia  o Also consider - ▪ Sleep study - Symptoms of OSA ▪ PCOS - suspected based on clinical features & anovulation - testosterone, LH, & FSH o Suggested approach: ▪ Treat all CVD risk factors individually & aggressively ▪ Achieving this goal removes the need for a Dx of metabolic syndrome o Criteria based on NCEP: ATP III 2001 Guidelines, requires 3 or more of the following – ▪ Central obesity: Waist circumference >102 cm/40in (males), >88 cm/35 in (females) ▪ Hypertriglyceridemia: Triglyceride level ≥150 mg/dL or on medication for high TGs ▪ Low HDL cholesterol: 35 kg/m2 w/ comorbidities ▪ Evolving application - pts with a BMI as low as 30 kg/m2 & T2DM ▪ Surgical options = Gastric bypass, vertical sleeve gastrectomy o Insulin resistance & hyperglycemia -> Metformin, Pioglitazone, Rosiglitazone o Dyslipidemia -> Statins, Other lipid-lowering drugs (many choices) o HTN -> Lifestyle modification, Antihypertensive Meds (many choices) ▪ +/-Low-dose aspirin (81 mg PO daily) – Risk of bleeding vs benefit  Metabolic syndrome = pro-thrombotic & pro-inflammatory state (more likely to be atherosclerotic/have CVD events) CLINICAL IMPLICATIONS OF METABOLIC SYNDROME: o Fatty liver dz w/ steatosis, leading to fibrosis, & cirrhosis o Hepatocellular carcinoma & intrahepatic cholangiocarcinoma o Chronic kidney disease (CKD = GFR < 60 mL/min per 1.73 m2) o Polycystic ovary syndrome o Male Hypogonadism o Sleep-disordered breathing, including OSA o Hyperuricemia & gout o ↑ risk of cognitive decline & dementia Obesity BMI: Measure of excess adipose tissue; = weight (kg)/height (m)2 BMI classifications: o 18.5-24.9 = Normal o 25-29.9 = Overweight o 30-34.9 = Class I obesity o 35-39.9 = Class II obesity o >40 = Extreme obesity BMI used > 100 yrs. to calculate whether people are over or under weight BMI does not distinguish btw muscle & fat BMI 18.5 – 24.99 = considered to be healthy: o Some people are healthy w/ other BMIs o Some people are unhealthy in this BMI range  Obesity -> ↑ risk of - o HTN o Diabetes o Dyslipidemia o Obstructive sleep apnea o Nonalcoholic fatty liver disease o Some malignancies o Centripetal Obesity (>40 inches in men, >35 inches in women) leads to: ↑ DM, ↑ CVA, ↑ CAD, ↑ Early death Upper body obesity (abd & flank) = greater health risk vs. lower body (buttocks & thighs) obesity OBESITY EPIDEMIOLOGY: o American adults – ▪ 30.7% = overweight ▪ 42.4% = obese ▪ 9.2% = Severe obesity ▪ 60% w/ obesity have metabolic syndrome ▪ 40-70% of obesity = genetic influences ▪ < 1% = secondary obesity (hypothyroid, Cushing syn.) o ↑ prevalence over last 3 decades, esp w/ ages 20-60 y/o (peaks at 60 then slightly declines) OBESITY PATIENT EVALUATION: o 1. Focused hx ▪ Hx considerations = What factors contribute to the pt’s obesity? How is the obesity affecting the pt’s health? What is the pt’s level of risk from obesity? What does the pt find difficult about managing weight? What are the pt’s goals & expectations? Is the pt motivated to begin a weight management program? What kind of help does the pt need? o 2. Physical exam to determine the degree & type of obesity o 3. Assessment of comorbid conditions o 4. Determination of fitness level o 5. Assessment of the pt’s readiness to adopt lifestyle changes o H&P – ▪ FHx obesity (If negative search for extraneous causes) ▪ Wt gain Hx (over time): Recent vs. chronic ▪ Diet & exercise routine: Sedentary vs. active vs. athletic ▪ Degree & distribution of body fat: ↑health risks w/ centripetal obesity  ▪ Signs of secondary obesity: Cushing syndrome – round face, buffalo hump, striae Hypothyroidism – depression, fatigue, constipation, cold intolerance, etc. OBESITY DIAGNOSTIC EVALUATION: o Measurements: ▪ BP ▪ Weight & height → Calculate BMI ▪ Waist circumference o Labs: ▪ TSH & Free T4 ▪ Fasting lipid panel ▪ Fasting Glucose OBESITY DIFFERENTIAL DX: o ↑ caloric intake (life changes) o Fluid retention (heart failure, cirrhosis, renal failure) o Hypothyroidism o DM (type 2) o Drugs (antipsychotics, antidepressants, corticosteroids) o Insulinoma o Binge eating disorder OBESITY TREATMENT: o Primary Approach = If no underlying condition: DIET & EXERCISE! o Goal = ↓ in 10% body wt over 6 mos or 1-2lbs per wk o Reassess Tx plan after 6 mos o DIET: ▪ General guidelines for weight loss: Aim for a 500-750 kcal/day deficit from habitual diet For women: Consume 1200-1700 kcal/day For men: Consume 1500-1800 kcal/day Caloric intake should be adjusted based on the individual’s body weight ▪ No single diet is proven superior for long-term wt loss (>1 year). Mediterranean diet may reduce ASCVD risk ▪ Low-carb, high-protein diets show ↑ wt loss at 6 mos o EXERCISE:  ▪ Best approach: Combine diet & exercise for effective long-term wt loss Exercise alone is usually not enough for maintaining wt loss beyond 1 year ▪ Physical Activity Guidelines: 150 min of moderate-intensity or 75 minutes of vigorous activity per wk performed for at least 10 min & spread throughout the wk ▪ Simple activities: Brisk walking, using stairs, housework, & sports Use pedometers or accelerometers to track steps & activity Step counts are highly correlated w/ overall activity level o Adjunctive Behavioral Therapy: CBT strategies to help change & reinforce new dietary & physical activity behaviors ▪ Self-monitoring techniques (e.g., journaling, weighing, & measuring food & activity); Stress management; stimulus control (e.g., using smaller plates, not eating in front of the television or in the car); social support; problem solving; cognitive restructuring to help pts develop more positive & realistic thoughts about themselves o Adjunctive Pharmacological Tx: ▪ Considered for pts w/: BMI ≥30 kg/m2 BMI ≥27 kg/m2 w/ concomitant obesity-related dz & for whom dietary & physical activity therapy has not been successful ▪ GI fat blockers - Orlistat (Xenical, Alli) (120 mg PO TID w/ meals) 5% body wt. loss MOA: ↓ fat absorption in GIT Side Effects: May cause GI distress (diarrhea, cramping, flatulence) o Low fat diet reduces Sx = can motivate pt to stay on diet ▪ Appetite suppressants (anorexiants) – Lorcaserin (Belviq) (10 mg PO BID) o 5% body wt. loss o MOA: may promote satiety through serotonin agonist activity o Side Effects: Possible breast tumors, valvular heart dz, psychiatric problems Phentermine + topiramate o 5-10% wt. loss o MOA: Amphetamine + anticonvulsant o Side Effects: Addictive potential, HTN, tachycardia o Distribution in US restricted (class IV drug) Naltrexone + bupropion o 2-4% wt. loss o MOA: Opioid antagonist + NE-dopamine reuptake inhibitor  o Side Effects: Possible suicide, seizures, HTN, tachycardia Liraglutide (Saxenda, Victoza) o 3-4% wt. loss o MOA: Injectable glucagon-like peptide-1 receptor agonist (regulates appetite & caloric intake) o Concerns = Thyroid tumors, pancreatitis, gallbladder disease, renal impairment, tachycardia, suicidal thoughts o Side Effects: N/V/D, constipation, hypoglycemia o Bariatric Surgery: ▪ Considered for patients w/ - Severe obesity (BMI, ≥40) Moderate obesity (BMI, ≥35) assoc w/ serious medical conditions/co-morbidities o Obesity co-morbidities: Joint dz, OSA, DM, HTN, GERD ▪ Surgical Procedures Include: Roux-en-Y gastric bypass; Gastric banding; Sleeve gastrectomy, intraluminal gastric balloon Intraluminal Gastric Balloon = Gastric balloon devices placed in stomach endoscopically o 2 devices approved - RESHAPE (consists of 2 silicone balloons attached to a central silicone shaft) & ORBERA (single-balloon device) ▪ Mean wt loss of 7.2 kg & 8.8 kg, respectively, was seen for these devices in short-term pivotal trials ▪ Both systems are approved only for ≤ 6 mos of use in adults with a BMI of 30–40 o Adverse effects: N/V, abdominal pain ▪ Complications: infx, hernia, nutritional def., neuropathy, blood clots ▪ Mortality – 1% risk in postop period; higher rate w/in 1st year after sx ▪ Multidisciplinary approach: Diet, exercise, behavior modification, social support, pre- meal planning OBESITY OUTCOMES & PROGNOSIS: o HTN & Hyperlipidemia o CAD o T2DM o DJD o Psychosocial disability o ↑ Cancers (colon, rectum, prostate, uterus, biliary tract, breast, ovary) o Thromboembolic disorders (MI, CVA, PE) o Digestive tract diseases (gallstones, reflux esophagitis) o Skin disorders (Hidradenitis suppurativa, striae, acanthosis nigricans, delayed wound healing, infx) o 20% lose 20 lbs. & maintain loss > 2 yrs; 5% lose 40 lbs. & maintain > 2 yrs o Very low-calorie diets -> 2 lbs/wk wt. loss (length of time varies)  o Stop daily 16 0z. Soda -> 20 lbs. wt. loss/yr ▪ Diet soda = weight gain or loss o Orlistat (Xenical, Alli) -> 4-8 lbs. wt. loss over 2 yrs o Roux-en-Y gastric bypass -> 50% initial body wt. loss ▪ 50% wt. regain by 5 yrs. Hirsutism Excessive male-pattern hair growth in women of reproductive age Affects 5-10% of females of reproductive age MC cause = PCOS HIRSUTISM EPIDEMIOLOGY: o 20% American women have hirsutism o 80% of women w/ androgen excess have hirsutism (not all) o Extent of terminal hair varies by ethnic background: ▪ East Asian & Native American women: < body hair ▪ Southern European women (Mediterranean): > body hair o Hirsutism may occur with virilization: ▪ Male pattern alopecia, voice deepening, ↑muscle bulk, clitoromegaly ▪ Virilization = moderate/severe androgen excess HIRSUTISM ETIOLOGY: o Idiopathic Hirsutism: ▪ Females w/ hirsutism ▪ Normal androgen concentrations ▪ No menstrual irregularities ▪ No identifiable cause of the hirsutism o Hirsutism is caused by the interaction of circulating serum androgens & hair follicle sensitivity to those androgens, as well as local growth factors  ▪ Key Androgens = Testosterone: Primarily from ovaries Dehydroepiandrosterone sulfate (DHEAS): From adrenal glands Androstenedione: From adrenal or ovarian sources o Hair grows on scalp, eyebrows, & eyelashes w/o androgens o Androgens ↑ hair growth on other body areas (face, arms, legs, trunk) ▪ Androgens cause larger follicles, thicker hair, & longer growth (anagen) phase ▪ Excess androgens in females lead to hair growth in sensitive areas (lip, chin, back) ▪ Scalp hair loss occurs due to shorter growth (anagen) phase in androgen excess o Nonclassical Adrenal Hyperplasia: ▪ Characterized by excess androgens (seen in congenital adrenal hyperplasia) ▪ Usually recognized at birth or early infancy ▪ Nonclassical form (primary 21-hydroxylase deficiency) manifests as - Females w/ hirsutism at puberty, menstrual irregularities, or primary amenorrhea No cortisol deficiency o Females w/ Virilization or Severe Hyperandrogenemia ▪ Rapid virilization: Sudden onset of masculine traits in females, often from excess adrenal androgens ▪ Common causes: Androgen-secreting tumors (ovarian, adrenal) or ovarian hyperthecosis Ovarian hyperthecosis: Thecal cell hyperplasia in ovaries leads to excess testosterone, causing hirsutism and virilization. o Nonmalignant ovarian disorder w/ ↑ testosterone from luteinized thecal cells o Testosterone levels often > 700 (i.e. markedly ↑) o Unclear if distinct or part of PCO o Mostly affects postmenopausal women but can occur in premenopausal women Androgen Secreting Tumors: o Usually occurs later in life & progresses rapidly compared to PCOS o ~5% of ovarian tumors o Identified by pathology (biopsy/sx) or transvaginal ultrasound o Most females have testosterone levels > 150-200 & present w/ virilization o Rare cause of androgen excess o Adenomas secrete testosterone o Carcinomas secrete DHEA, DHEAS, & cortisol o Symptoms: Androgen excess, Cushing syndrome. o Elevated DHEAS suggests adrenal carcinoma o Uncommon Causes of Hirsutism: ▪ Hyperprolactinemia (pituitary adenoma) ▪ Acromegaly (pituitary adenoma) ▪ Hypothyroidism  ▪ Severe Insulin resistance ▪ Drugs: Androgen therapy (testosterone, DHEA), Danazol (used to treat endometriosis) HIRSUTISM CLINICAL PRESENTATION: o Mild to moderate hirsutism: ▪ Regular menses, no clear cause → Think Idiopathic hirsutism o Hirsutism with: ▪ Acne, male pattern alopecia, acanthosis nigricans, obesity, &/or oligomenorrhea ( excess cortisol & antigens o ↑PRL: Galactorrhea, vision changes, infertility, oligo/amenorrhea o CAH: Menstrual abnormalities, virilization, ↑DHEA/DHEA-S/androstenedione o Androgen-secreting tumor: Older age, rapid progression, virilization o Ovarian hyperthecosis: Older age, intense slow- progressing hirsutism HIRSUTISM DIAGNOSTIC EVALUATION: o Idiopathic hirsutism: ▪ Total testosterone = Normal o Polycystic ovarian syndrome (PCOS): ▪ Total testosterone = usually Elevated ▪ Trans Vaginal US o Androgen secreting tumor: ▪ Total testosterone = elevated ≥ 2x normal values ▪ Get: DHEAS (primarily adrenal origin) & androstenedione (primarily ovarian origin) ▪ Pelvic ultrasound ▪ CT of abdomen & pelvis HIRSUTISM TREATMENT: o Treat underlying cause: Remove tumor, block androgen production (oral contraceptive pills suppress GnRH, LH, & FSH = ↓ovarian androgens) o Block androgen response: ▪ Spironolactone (androgen antagonist; recommended) ▪ Finasteride (inhibits 5-alpha-reductase type 2 – enzyme that converts testosterone to DHT; concerns about its use inadvertently in pregnancy) ▪ Flutamide (non-steroidal androgen receptor antagonist ~ prostate cancer drug used off label)  ▪ Antiandrogens contraindicated in pregnancy o Block hair growth: Vaniqa (retards hair growth) o Hair removal: ▪ Depilatory creams (Nair) ▪ Electrolysis, laser ablation ▪ Manual (plucking) HIRSUTISM URGENT CONSIDERATIONS: o Rapid Virilization ▪ Evaluate for tumor ▪ Adrenal gland-CT ▪ Ovarian–transvaginal US Polycystic Ovarian Syndrome (PCOS) MC endocrine disorder in reproductive-age women (5-10%) 90% of hyperandrogenism in women Prevalence does NOT vary across diff regions of the world Causes menstrual irregularity & androgen excess Symptoms: Hirsutism, Irregular menses, Polycystic ovarian morphology on transvaginal ultrasound PCOS ETIOLOGY: o Unknown etiology: Multiple systems involved; primary defect unclear o Theories: ▪ Hypothalamic-pituitary axis defect → ↑ amp/freq of LH pulses → ↑ gonadal androgens ▪ Intrinsic ovarian defect → androgen overproduction & anovulation ▪ Defects in insulin sensitivity = insulin resistance → hyperinsulinemia o Pathophysiology: Not well understood, multiple mechanisms possible PCOS RISK FACTORS: o FHx: PCOS inherited as a common complex disorder (multiple genes involved) o Premature Adrenarche (before age 8 in girls) PCOS SIGNS/SYMPTOMS: o Menstrual Dysfunction: Delayed menarche, oligomenorrhea (irregular flow), amenorrhea (no menses for 3+ months) o Hyperandrogenism: Hirsutism, acne, male pattern hair loss; most have elevated androgens o Hirsutism o Polycystic Ovaries: Seen on TVUS o Metabolic/Cardiovascular risks: ▪ 40-85% are overweight/obese  ▪ Insulin resistance, T2DM, CAD, sleep apnea, nonalcoholic fatty liver disease o Mood: Linked to depression, anxiety, impaired quality of life, eating disorders o Symptoms: Hirsutism 60%, Acne 20%, Scalp hair loss 5%, Oligomenorrhea (< 6-8 menses/yr), Amenorrhea (no menses), Irregular menses, Weight gain, Infertility o PE: Hirsutism, Acne, Alopecia, Possible HTN, Acanthosis nigricans, Sweating, Oily skin PCOS DIFFERENTIAL DX: o CAH = 21 hydroxylase deficiency - MC cause of congenital adrenal hyperplasia ~ missing enzyme -> overproduction of adrenal hormones o Thyroid dysfunction o Hyperprolactinemia o Cushing syndrome (rare) o Androgen secreting neoplasm PCOS DIAGNOSTIC EVALUATION: o Rotterdam Criteria (Preferred) – 2 of 3 Required – ▪ Oligo- &/or anovulation ▪ Clinical &/or biochemical signs of hyperandrogenism ▪ Polycystic ovaries (by ultrasound) ▪ Diagnosis confirmed after excluding other conditions (thyroid dz, nonclassic congenital adrenal hyperplasia (NCCAH), hyperprolactinemia, androgen-secreting tumors) o Serum total testosterone ▪ Measure if evidence of androgen excess ▪ Upper limit of normal for woman is 45-60 ▪ Levels > 150 require eval for ovarian or adrenal androgen secreting tumor or ovarian hyperthecosis o DHEAS - not suggested for everyone ▪ Measure for sx of severe hyperandrogenism ▪ Can be extremely ↑ in pts w/ adrenal carcinoma o Androstenedione: Role unclear in eval of PCOS (mixed results) o Serum 17-hydroyprogersone ▪ Measure morning level in early follicular phase to rule out congenital adrenal hyperplasia d/t 21-hydroxylase deficiency ▪ >800 = adrenal hyperplasia o FSH & estradiol: High in premature ovarian insufficiency (also have low estradiol) o TSH: Check for thyroid abnormalities (also cause irregular menses/ovulation) o ↑ Prolactin: Pituitary adenoma causes irregular menses, ovulation, galactorrhea o Cushing Syndrome: If suspected, perform 24-hr urine cortisol or dexamethasone test (shared sx: oligomenorrhea, hirsutism, obesity, HTN, striae, muscle weakness)  o Transvaginal US (TVUS): Used to check for polycystic ovarian morphology (PCOM) ▪ Not all suspected PCOS patients need ultrasound. ▪ If oligomenorrhea & hyperandrogenism are present, PCOS can be dx w/o US ▪ TVUS is used in hyperandrogenic women with normal menstrual cycles to check for PCOM o Pelvic ultrasound: ▪ ≥ 12 follicles in either ovary 2-9mm diameter OR Ovarian volume > 10 o Basal body temperature chart: ▪ Absence of biphasic pattern = anovulation ▪ Rarely used now o Other Considerations: ▪ BP/BMI/Waist circumference - CVD risk ▪ Fasting lipid profile ▪ 2-hour OGTT or fasting glucose & hgbA1C ▪ Screen for OSA ▪ Liver enzymes (not recommended to use US to screen for fatty liver) ▪ Screen for depression & anxiety disorders PCOS TREATMENT: o Obese patients: Wt loss & exercise can reverse metabolic issues & induce ovulation o Non-pregnancy patients: ▪ First-line: Combined hormonal OCPs for hyperandrogenism & menstrual irregularities ▪ Alternatives: Intermittent or continuous progestin therapy or hormonal IUD for endometrial protection ▪ Metformin: Second line - Improves menstrual function; no effect on hirsutism, acne, or infertility; used for glucose issues. ▪ Medroxyprogesterone (Provera) (10 mg q.d. PO for the 1st 10 days of each month) Only initiates & regulates menses but does not inhibit androgen excess ▪ Low-dose combination OCPs Use low androgenic activity progestins Regulates menses & may decrease androgens while preventing pregnancy o Pts who desire pregnancy: ▪ Ovary stimulation Letrozole (first line) Clomiphene Increased risk of twins w/ ovarian stimulation o Hirsutism: ▪ Low-dose combination OCPs 6 -12 mos ▪ If not improved, add spironolactone 25 mg PO tid (only use with contraception) ▪ Topical eflornithine (Vaniqa) cream applied to face BID x6 mos ▪ Electrolysis/laser therapy PRN  PCOS PROGNOSIS: o Insulin resistance & hyperinsulinemia = ↑ T2DM o Anovulation causes unopposed estrogen = ↑endometrial CA o Pregnancy desired: 20-40% live birth with Clomiphene Tx o