Pth, Dm, Osteoporosis

Subject: MEDICINE Topic: DM, PARATHYROID,BONE,etc. Lecturer: dr. Fuentes Shifting /Date: 4th/ January 15, 2009 Trans group: AM, Alphe, Riz PARATHYROID GLAND  four parathyroid glands are located posterior to the thyroid gland, producing parathyroid hormone (PTH), which is the primary regulator of calcium physiology.  PTH acts directly on bone, where it induces calcium resorption, and on the kidney, where it stimulates calcium reabsorption and synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D], a hormone that stimulates gastrointestinal calcium absorption.  Calcium, acting through the calcium-sensing receptor, and vitamin D, acting through its nuclear receptor, inhibit PTH release and synthesis.

Classification of Causes of Hypercalcemia I. Parathyroid-related A. Primary hyperparathyroidism 1. Solitary adenomas 2. Multiple endocrine neoplasia B. Lithium therapy C. Familial hypocalciuric hypercalcemia II. Malignancy-related A. Solid tumor with metastases (breast) B. Solid tumor with humoral mediation of hypercalcemia (lung, kidney)

HYPERCALCEMIA

C. Hematologic malignancies (multiple myeloma, lymphoma, leukemia) III. Vitamin D–related A. Vitamin D intoxication B. 1,25(OH)2D; sarcoidosis and other granulomatous diseases C. Idiopathic hypercalcemia of infancy IV. Associated with high bone turnover A. Hyperthyroidism B. Immobilization C. Thiazides D. Vitamin A intoxication V. Associated with renal failure A. Severe secondary hyperparathyroidism B. Aluminum intoxication C. Milk-alkali syndrome

MARY YVETTE ALLAIN TINA RALPH SHERYL BART HEINRICH PIPOY KC JAM CECILLE DENESSE VINCE HOOPS CES XTIAN LAINEY RIZ KIX EZRA GOLDIE BUFF MONA AM MAAN ADI KC PENG KARLA ALPHE AARON KYTH ANNE EISA KRING CANDY ISAY MARCO JOSHUA FARS RAIN JASSIE MIKA SHAR ERIKA MACKY VIKI JOAN PREI KATE BAM AMS HANNAH MEMAY PAU RACHE ESTHER JOEL GLENN TONI

Subject: Medicine Topic: endocrine Page 2 of 13

**excerpt from the book:  Hypercalcemia in an adult who is asymptomatic is usually due to primary hyperparathyroidism.  Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urination, a short QT interval in the electrocardiogram, and, in some patients, cardiac arrhythmias.  Generally, symptoms are more common at calcium levels >2.9–3 mmol/L (11.5–12.0 mg/dL), but some patients, even at this level, are asymptomatic.  When the calcium level is >3.2 mmol/L (13 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal function.  Severe hypercalcemia, usually defined as 3.7–4.5 mmol/L (15–18 mg/dL), can be a medical emergency; coma and cardiac arrest can occur. Hypercalcemia Crisis: RX 1. Volume: IV NS 300-500cc/hr (slower if elderly, cardiac or renal dse) 2. Loop diuretics: only give if ECFv overloaded. Lasix 20-40mg IV q4-6h. monitor I/O 3. Replace electrolyte depletion from saline dieresis as needed (K, Mg, Pi, etc.) 4. Calcitonin: a. 1IU SC test dose skin rxn by 15min b. 4IU kg SC/IM q12h c. If no response by 24-48hr increase to max dose 8IU/kg q6hr d. Rapid effect (begins 4-6hr) but transient (2-3d) due to tachyphylaxis e. Effective in 60-70% of cases, lowers Ca by 0.3-0.5mM 5. Bisphosphonates: a. Pamidronate- Ca<3.0mM 30mg in 500cc NS IV over 4h; Ca<3.0mM 60-90mg in 500cc IV over 24h b. Effect peaks at 2-4d, last 1-6wk (can retreat q1-6wk) 6. Steroids a. Useful in Vitamin D intoxication, granuloma, lymphoproliferative disorders b. Prednisone 40-80mg/d c. Take 5-10d to see treatment effect Hypercalcemia ddx:  PTH mediated o 1°HPT: PTHadenoma/hyperplasia/carcinoma o 3°HPT o Familial Hypocalciuric Hypercalcemia (FHH)

o Lithium  Non-PTH mediated PTH- mediated: Familial Hypocalciuric Hypercalcemia  Inactivating mutation of Calcium sensor: o Parathyroid cell: higher serum Ca needed to shut off PTH secretion o Renal tubular cell increase urinary Ca reabsorption  Autosomal dominant inheritance o Homozygous severe neonatal hypercalcemia o Heterozygotes asymptomatic mild hypercalcemia  Distinguish HPT from FHH by FECa o FHH: FECa <0.01 o HPT: FECa >0.01-0.02  Autosomal dominant hypocalcemia o Activating mutation of Ca sensor o Mirror image of FHH FECa = CaCl / CrCl = CaU x CreatS CreatU x CaS CaU: urine Ca (mmol/d) CaS: serum Ca (mmol/L) CreatS: serum creatinine (mmol/L) CreatU: urine creat (mmol/d) Non-PTH mediated  Malignancy o PTHr-P (SCC, hypernephroma, etc) o Osteolysis (myeloma, breast CA) o 1-alpha hydroxylase of Vitamin D (lymphoma)  Granulomatous Disease  Drugs o Vitamin D, A o Calcium antacids (milk alkali) o Thiazides  Al, Pheo, Thyrotoxicosis, Paget’s (immobility)  ARF 1°HPT  Etiology o Single Adenoma 85% o Multiple adenomas 5% o Hyperplasia 10% o Carcinoma <1%  Incidence: 42/100,000  Prevalence1/1000  Female:Male= 2-3:1  Incidence increases with age  Postmenopausal women: o Incidence 5x general population o Prevalence 4/1000

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1°HPT 2°HPT 3°HPT

Ca ↑ ↓ ↑

HPT: 1° vs 2° vs 3° Pi PTH ↓ ↑ ↑ ↑↑ ↑ ↑↑

1,25-D ↑ ↓ ↓

*2°HPT is a physiologic response to the dec. level of Ca

HPT diagnosis  Elevated serum Ca (total, ionized)  Serum intact PTH: o Double-antibody immunoassays (IRMA or ICMA) o Elevated or inappropriately high normal o Normal 10-65 pg/ml (1.2-7.6 pmol/L)  Serum Pi decreased, serum ALP increased  Hyperchloremic metabolic acidosis  Urine Ca normal (1-7.5mM/d) to slight increased o FECa >0.01-0.02 o Urinary Ca less than that of non-PTH mediated hypercalcemic patient with an equivalent serum calcium 1. Dual Phase exam 10-20mCi Technetium-99m (Tc99m) Sestamibi. Scan neck and chest at 15min and 2-4hr post injection. Agent clears faster from thyroid than parathyroid so PTH adenoma more clear on the 24hr scan. SEN 45-95% (ave 73%). PPV 97%. 2. Subtraction Exam Tc99m-pertechnetate outlines the thyroid only and this image is subtracted from the Tc99m-sestamibi image; N 89%

HPT clinical manifestations  Hypercalcemic crisis  Renal disease  Bone disease  Gastrointestinal  Neuromuscular  Neuropsychiatric

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HTN (↑risk CV mortality?) Corneal deposition CaPO4 (band keratopathy Pruritis Asymptomatic

Hypercalcemic/Parathyroid Crisis  Pathogenesis poorly understood  47% have intercurrent illness and / or predisposition for dehydration  In a few pxs, the crisis was ascribed to infarction of a parathyroid adenoma  PTH usually 20x ULN  Marked symptoms from ↑serum Ca: especially CNS dysfunction  Polyuria → ECFv contraction → renal insufficiency PARATHYROID CARCINOMA  Approx 400 reported cases since 1920  Mean age presentation 44-54 years  More likely to have symptoms than PTH adenoma o 65-75% have serum Ca>3.7-4.0mM o 12% present with hypercalcemicparathyroid crisis o 34-52% have a neck mass o 34-73% have bone disease o 32-70% have renal disease o Only 2-7% asymptomatic Diagnosis of Parathyroid CA  Diagnosis based on histology o Uniform sheets of cells o Arranged in lobular pattern separated by dense fibrous trabeculae o Capsular and avascular invasion (sometimes seen in adenomas)  Local invasion, lymohnode or distant metastases  Pathogenesis: RB gene, p53 gene  Hypercalcemia principle cause of M&M o 5year survival 50-70%, 10yr survival 1335% NEPHROCALCINOSIS  Development of renal insufficiency in 1°HPT is related to degree & duration of hypercalcemia  Long standing hypercalcemia & hypercalciurialeads to chronic nephropathy  Calcification, degeneration, and necrosis of the tubular cells leads to cell sloughing and eventual tubular atrophy and interstitial fibrosis and calcification (nephrocalcinosis) Clinical manifestations: Bone disease: oteitis fibrosa cystic, osteopenia/osteoporosis (cortical>trabecular), pathologic fracture, dental resorption of lamina densa GI:constipation, N/V, indigestion, PUD, pancreatitis

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Neuromuscular: fatigue, apathy, prox muscle weakness/ atrophy Treatment  Surgery (treatment of choice) o 95% success rate o Vocal cord paralysis 1%, permanent hypoparathyroidism 4%  Medical o Bisphosphonates  IV for acute severe hypercalcemia  Some trials showing benefit with oral biphosphonates o Oral phosphate (may precipitate calciphylaxsis) o Postmenopausal woman: HRT? o Calcimimetic agents: Ca receptor agonists NIH CONSENSUS for Asymptomatic HPT 1991 2002 Serum Ca >2.85-3.0mM >2.85mM CAcL <70% normal <70% normal 24hr urinary Ca >10mmol/d >10mmol/d BMD <2SD(z-score) <2.5SD(t-score) Age <50 <50 CALCIPHYLAXIS  Associated with but not just metatatic sof-tissue calcifications  Systemic medial calcification of the arteries and tissue ischemia  Calcium phosphate Product o Serum Ca x Pi <5

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ESRD, HPT at greatest risk Clinical manifestations: o Ischemic necrosis of skin, subQ fat, les often muscle/viscera o Livedo reticularis →plaques/papules→ischemic/necrotic ulcers o Ischemic myopathy without skin necrosis can occur (rare) o High mortality (50%) due to sepsis o Calcified heart myocardium, cardiac vessels o Calcification of coronary artery o Most common in patient with end stage renal disease, hyperPTH

**excerpt from the book: Hypercalcemia Associated with Renal Failure: Severe Secondary Hyperparathyroidism  Secondary hyperparathyroidism occurs when partial resistance to the metabolic actions of PTH leads to excessive production of the hormone.  Parathyroid gland hyperplasia occurs because resistance to the normal level of PTH leads to hypocalcemia, which, in turn, is a stimulus to parathyroid gland enlargement.  Secondary hyperparathyroidism occurs not only in patients with renal failure but also in those with osteomalacia due to multiple causes including deficiency of vitamin D action, and PHP (deficient response to PTH at the level of the receptor).  Medical therapy to reverse secondary hyperparathyroidism includes reduction of excessive blood phosphate by restriction of dietary phosphate, the use of nonabsorbable antacids, and careful, selective addition of calcitriol (0.25–2.0 g/d); calcium carbonate had been preferred over aluminum-containing antacids to prevent aluminum toxicity. HYPOCALCEMIA  2° to thyroidectomy or parathyroidectomy  Chronic hypocalcemia is less common than hypercalcemia; causes include chronic renal failure, hereditary and acquired hypoparathyroidism, vitamin D deficiency, PHP, and hypomagnesemia.  Transient hypocalcemia is seen with severe sepsis, burns, acute renal failure, and extensive transfusions with citrated blood.  Patients with severe sepsis may have a decrease in ionized calcium (true hypocalcemia), but in other severely ill individuals, hypoalbuminemia is the primary cause of the reduced total calcium concentration.  Medications such as protamine, heparin, and glucagon may cause transient hypocalcemia. These forms of hypocalcemia are usually not associated with tetany and resolve with improvement in the overall medical condition. The

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hypocalcemia after repeated transfusions of citrated blood usually resolves quickly. Signs and symptoms of chronic hypocalcemia: - muscle spasms - carpopedal spasm - facial grimacing - laryngeal spasm and convulsions - Respiratory arrest may occur - Increased intracranial pressure occurs in some patients with long-standing hypocalcemia, often in association with papilledema - Mental changes include irritability, depression, and psychosis - The QT interval on the electrocardiogram is prolonged, in contrast to its shortening with hypercalcemia. - Arrhythmias occur, and digitalis effectiveness may be reduced. - Intestinal cramps and chronic malabsorption Treatment of Hypocalcemic sate:  vitamin D or vitamin D metabolites and calcium supplementation[at least 2000 U/d (5 g/d) (higher levels required in older persons)]  Calcitriol (0.25–1.0 g/d) is more rapid in onset of action and also has a short biologic half-life; required to prevent rickets in normal individuals.  Patients with hypoparathyroidism should be given 2–3 g elemental calcium PO each day.  If hypocalcemia alternates with episodes of hypercalcemia in more brittle patients with hypoparathyroidism, administration of calcitriol and use of thiazides, may make management easier DIABETES MELITUS - A group of metabolic diseases characterized by hyperglycemia resulting from defect in insulin secretion, insulin resistance or both. “New” classification of diabetes mellitus • Type 1: Immune mediated DM Idiopathic DM • Type 2: Impaired glucose tolerance (IGT) Impaired fasting glucose Gestational DM Pathophysio of DMI Antibodies attack islets! DM classification-continued • Slow onset of insulin dependent DM (SIDDM) or • Later autoimmune Diabetes in Adults (LADA) • Autoantibodies to glutamic acid decarboxylase (anti-GAD) proposed as an early differentiating

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marker of type I diabetes in those individuals for whom there is a question of whether they have type 1 or type 2 Diabetes A correlation has been found between individuals originally classified as type 2 requiring insulin and anti-GAD Possible early test to identify those with type 2 diabetes who eventually require insulin

TYPE 2 DIABETES • May range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance • Individuals who usually have insulin resistance and usually have relative insulin deficiency • At least initially, and often throughout their lifetime, do not need insulin treatment to survive • Ketoacidosis seldom occurs spontaneously Pathophysiology of type 2 DM Lifted from the book.. Type 2 DM1 is characterized by three pathophysiologic abnormalities: impaired insulin secretion, peripheral insulin resistance, and excessive hepatic glucose production. Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is very common in type 2 DM. Adipocytes secrete a number of biologic products (leptin, TFN-a12, free fatty acids, resistin, and adiponectin) that modulate insulin secretion, insulin action, and body weight and may contribute to the insulin resistance. In the early stages of the disorder, glucose tolerance remains normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin output . As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT2, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue. Markers of inflammation such as IL13-6 and C-reactive protein are often elevated in type 2 diabetes. Metabolic abnormalities: insulin resistance, impaired insulin secretion, increased hepatic glucose production Risk Factors for the Development of Type 2 DM Genetic : Family history, race Environmental : • Age > 45 y/o • Obesity > 130% of IBW • Gestational DM • IGT Other Diagnostic Prompts...DM • Positive family history • Overweight/obesity

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• Elderly • Genital itching • Impairment of visual acuity • Repeated skin sepsis • Unaccountable pains/ paresthesia in the limbs • Long term use of steroids/ diuretics Criteria for testing DM in asymptomatic, undiagnosed individuals 1. Testing for Diabetes should be considered in all individuals at age 45 and above, and if normal, it should be repeated at 3-yr interval 2. Testing should be considered at a younger age or be carried out more frequently in individuals who: *are obese (≥ 120% OBW or BMI ≥27) *Have first degree relative who have diabetes Are members of a high-risk ethnic population (ex. African American, Hispanic, native American, Asian) Criteria for Diagnosis of DM • Casual is defined as any time of the day w/o regard to time since last meal • Fasting is defined as no caloric intake for at least 8 hrs • Symptoms of Diabetes include polys and unexplained weight loss 1. Symptoms of DM plus casual plasma glucose concentration ≥200 mg/dl (11.1 mmol/L) 2. FPG ≥126 mg/dl (7mmol/L) 3. 2 hPG ≥200 mg/dl during an OGTT **for exam purpose this values will be used (from 16th ed.) however, there is new values for criteria of DM (Normal blood glucose: 100 mg/dl, cut off FPG: 120 mg/dl)

Worldwide: Current estimate ~ 140 M people

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By 2025 estimated ~300 M afflicted Reasons for Increasing incidence Aging population Direct proportion to aging people living longer Change in eating habits

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Factors Responsible for Maintenance of Normal Glucose Tolerance 1. Hepatic glucose production 2. Peripheral glucose utilization 3. Insulin secretion @@@@@@@@@@@@@@@@@@@@@@@@@@@@@ FILLER =)

Doc Go:  how to pass exam?



Open your book and lie down on it and expect to absorb everything by diffusion: from the area of higher concentration to area of lower concentration Many of you will go to the other side. Don’t yell on nurses, because we’re like Nervous System, we should coordinate with them. You are the foundation of the hierarchy.

 Doc So:  You will enjoy your clerkship. I promise that.

**** lapit na tyo pumunta sa “the other side..****

Metabolic Staging of Type 2 DM

Classic Symptoms of DM • Thirst • Polyuria

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Normal

Weight loss Stage 0

IGT and IFG • Metabolic stage intermediate between normal glucose homeostasis and diabetes • IFG- Individuals with fasting glucose levels ≥ 110 mg/dl but < 126 mg/dl • IGT-indivduals whose 2’ PGBS levels ≥ 140 mg/dl but < 200 mg/dl • Metabolic stage intermediate between normal glucose homeostasis and diabetes FPG

Normal <110 mg/dl

2 hrs PG

<140 mg/dl

IGT/IFG ≥ 110 mg/dl but < 126 mg/dl ≥ 140 mg/dl but < 200 mg/dl

DM ≥126 mg/dl ≥200mg/dl

Peripheral insulin resistance

Hyperinsulinemia

Impaired Glucose

B cell failure

Stage 1

Stage 2Early Diabetes Stage 4

Incidence

Late diabetes Stage 5

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Mechanisms to lower glucose • Stimulate insulin secretion: sulfonylureas and ripaglinide • Increase Muscle glucose uptake: thiazolidinediones or biguanides • Decrease Glucose production: biguanides or (±thiazolidinediones) • Retard carbohydrate absorption: Alpha glucosidase inhibitors • Correct insulin analogues: Insulin or Insulin analogues Sites of action of currently available therapeutic options 1. Liver: for glucose production Metformin, thiazolidinediones 2. Intestine: glucose absorption Alpha glucosidase inhibitors 3. Pancreas: insulin secretion Sulfonylureas, glyburide, gliclizide, glimepizide, Non ST secretagogues, ripaglinide, nateglinide 4. Adipose tissue and muscle: peripheral glucose uptake Metformin, thiazolidinediones UKPDS: the bottom line Main Message for Management of type 2 Diabetes • Sulfonylureas, insulin and metformin are effective in reducing risk of complications by reducing risk of complications by improving glycemic control • No evidence of increased risk of complications for any single therapy • Combination therapy required almost from the outset to achieve near-normoglycemia • Much earlier use of Insulin Rx in mist patients as • expected therapy in the progressive management of Type 2 Diabetes Standard Approach to the management of Type 2 DM: treatment intensification Insulin Oral+ Insulin Oral combination Diet exercise + Oral monotherapy-Metformin

Nutrition therapy, exercise and lifestyle changes 1. Nutrition therapy • Decrease fat content and reduce total calories • Decrease saturated fat • Decrease salt • Healthy diet

• Moderate weight reduction if obese 2. Exercise • Increase energy expenditure w/ moderate intensity exercise 3. Lifestyle changes to reduce CV factors • Smoking cessation etc 4. Training in self management/ SMBG Add oral pharmacologic therapy 1. Monotherapy • Sulfonylureas • Biguanides • Alpha glucosidase inhibitors • Prandins 2. Combinations of above • Add or change to insulin • Bedtime intermediate or long acting insulin + daytime OHA • Intermediate + short acting insulins BID or premixed insulins BID Diabetes Complications: Macrovascular stroke Heart disease and hypertension 2-4x increased risk Peripheral vascular disease Foot problems

Microvascular Diabetic eye disease (retinopathy and cataracts) Renal disease Erectile dysfunction Peripheral neuropathy

Disease Burden of Diabetes Mellitus • Leading cause of blindness (12.5 % of cases) • Leading cause of ESRD (42% of cases) • 50% of all non traumatic amputations • 2.5x increase risk of stroke • 2-4x increase in cardiovascular mortality • DM responsible for 25% of cardiac surgeries • Mortality in DM: 70% due to cardio vascular disease *In a study conducted by Kaplan-Menier, it has been shown that there is decreased survival in px with type 2 DM after having myocardial infarction DM nephropathy • Stage 1-5 • Stage 2-microalbuminuria • Stage 3-proteinuria • Microalbuminuria-30-300 mg/dl (20-200µg/min) • Macroalbuminuria>300 mg/dl (>200µg/min) Reducing risk in diabetes Glycemic control • New insulins • New oral agents

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CBG testing: new sites (forearm, smarter monitors)

BP control ACE inhibitors Cholesterol control Aspirin Smoking cessation ***Future... • Noninvasive BS testing • Continuous BS monitor + insulin pump o “artificial pancreas” • Islet cell transplants o Stem cell research • Energy homeostasis breakthroughs Gestational DM (GDM) • Glucose intolerance with onset or discovery during pregnancy o Some T2DM picked up during pregnancy o Rarely some T1DM may present during pregnancy • Prevalence higher than previously thought in Canada • 3.5-3.8% non-aboriginal (but multi-ethnic population) • 8-18% aboriginal **Additional Notes: In DM, the BP target is 130/80 If there’s microalbuminuria, the BP target is <125/80 In DM LDL target: <100 TG: <70 Prior “selective screening” resulted in missed cases Caucasians < 25 y/o No personal or family hx of DM No prior infant with birth weight of >4kg Treatment of GDM= reduced perinatal morbidity Diagnosis of GDM= increased maternal anxiety? Evidence controversial for this Therefore, all women should be screened ***Future… • Non-invasive BS testing • Continuous monitor + insulin pump o “artificial pump” • Islet cell transplants o Stem cell research • Energy homeostasis breakthroughs… GDM (continued) • “Glucose intolerance with onset/ discovery during pregnancy’ o Some T2DM picked up during pregnancy o Rarely some T1DM may present during pregnancy • Prevalence higher than previously thought in Canada: o 3.5-3.8% non-Aboriginal (but multi-ethnic)

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o 8.0-18.0% Aboriginal Prior “selective screening” resulted in missed cases: o Caucasians <25 y.o. o No personal or FHx of DM o No prior infant with birth weight >4kg Treatment of GDM reduces perinatal morbidity Diagnosis GDM ↑maternal anxiety? o Evidence controversial for this Therefore all women must be screened Screening for and diagnosis of GDM 24th and 28th week of gestation If multiple risk factors for GDM are present, screen during the first trimester of pregnancy and reassess during subsequent trimesters 1hPG following a 50g glucose load given at any time of day

1hr PG≥ 10.3mmol/L

1hr PG= 7.8- 10.2mmol/L 75g OGTT Measure FPG, 1h PG and 2h PG levels

GDH

IGT of pregnancy

FPG≥5.3 mmol/L 1h PG≥ 10.6 mmol/L 2h PG≥ 8.9 mmol/L

If 2 values are met or exceeded

If 1 value is met or exceeded

Risk Factors for GDM  Previous diagnosis of GDM  Previous delivery of macrosomic infant  Member of high-risk population eg. women of Aboriginal, Hispanic, South-Asian, Asian or African descent  Age ≥ 35 years  Obesity (BMI≥30 kg/m2)  Polycystic ovary syndromeand/or hirsutism  Acathosis nigracans  Corticosteroid use GDM: Morbidity Maternal Macrosomia (birth trauma, cesarian) Preeclampsia

Fetal/ Neonate Macrosomia (shoulder dystocia) RDS

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Polyhydramnios Perinatal mortality(fetus) Postpartum IFG, IGT, DM 3-6 mos: 16-20% Lifetime: 30-50%

Neonatal hypoglycemia Neonatal hypocalcemia Neonatal jaundice Obesity later in life? IGT, IFG, or DM later in life?

Treatment of GDM  CBG qid: FBS, 1-2h pc  Dietary: 3 small meals, 3small snacks  If glycemic targets not met: insulin o Multiple Daily Injection (MDI) best o Insulins: regular, lispro, aspart? (still new) o No glargine (stimulates IGF-1 receptors) Recommended glycemic targets for women with GDM Target PG (mmol/L) Preprandial <5.3 1h postprandial <7.8 2h postprandial <6.7  No OHA’s, not standard care yet  Glyburide o Minimal crossing of placenta, 3rd trimester most organogenesis complete o 1 randomized control trial (RCT): 404 women, mild GDM, glyburide vs insulin, no difference in outcomes o Further study before safety established  Metformin o Retrospective cohort;  ↑preeclampsia and stillbirth  Bias: DM women older, more obese DKA A collection of severe and potentially life-threatening metabolic disturbances:  Hyperglycemia Osmotic dieresis o Urinary loss of fluids and electrolytes Fat cell:TG o ECFv contraction + of total body K stores (even Glucose o Depletion Ketoacids though may be hyperkalemic 2ᴼ to HSL cell intracellular shift)  Ketone production  metabolic acidosis FFA PFK o Compensatory Respiratory alkalosis (hopefully!!!)  Uncontrolled lipolysis  severe ↑TG Pyruvate DKA Pathophysiology

Kreb’s cycle

Fatty Acyl-Coa Acetyl CoA VLDL

DKA Risk factors  T1DM

o 1st presentation o o

Acute illness Insulin omission (inappropriate sick-day management, noncompliance, eating disorders)

 T2DM o During stress o Ethnicity: African-American; Hispanic  Extremes of ages  Poor glycemic control  MDI with CSII

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DKA Precipitating Factors Insulin omission: 33% Infection: 20-38% New onset DM: 10-20% Acute illness/stress: 5-39%

DKA: Diagnosis  Symptoms and signs o Polyuria, polydipsia, weight loss o Fatigue o N/V, abdominal pain o ECFv, Kussmaul’s, acetone breath, mild impairment in cognition  Laboratory o pH <7.3, serum HCO3 <15mEq/L, anion gap (AG)>14mM o raised serum ketones (and urine ketones) o BS> 14mM (occasionally normal or only mild inc BS) DKA: Management 1. Monitoring *Consider ICU

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o pH<6.9, inadequate respiratory compensation o decreased LOC o severe K disturbance (K<3.0 or 6.0 mEq/L) *Stepdown/telemetry: all others *Wards o only very mild DKA o pH>7.2, serum HCO3 >20mEq/L, AG<14mM o ECFv near normal o Not elderly, no high-risk DKA precipitant (ex. MI) *CBG q1-2h on IV insulin gtt *q2h: serum lytes, creatinine,glucose *q4-6h: o pH>7.2, serum HCO3 >20mEq/L, AG<15mM o ECFv stable and IV fluids @ maintenance rates o Normal K *Calcium profile o Initially, then q12-24h unless abnormal o Phosphate levels can be high at 1st drop with Rx of DKA *Flow charts to record biochemical *parameters shown to be useful *EKG, cardiac enzymes: r/o ACS (silent MI) *septic work-up: cultures, CXR, urinalysis, etc *consider pulmonary embolism?

2. IV fluid resuscitation (3-9L deficit) *IV NS 0.5-1L/h x 1-2h or longer so no more tachycardia, hypotension, orthostatic changes, low JVP *Then change to ½ NS o 200-500cc/h over 12h in order to replace ½ estimated deficit o Then lower to 100-150cc/h until deficit restored and eating/drinking well *If hypotension recalcitrant to fluids consider AI (Schmidt PGAS II) and send stat plasma cortisol and ACTH, then give solucortef 100mg IVq8h

3. Potassium (“no pee no K”) o K deficit 3-5mEq/kg 4. IV insulin o 0.2-0.3units per kgBW initially; double dose if unresponsive 5. Identify and Rx underlying cause  Noncompliance, infection, MI, etc DKA: Mortality  Adults 2-4% o Hypokalemia

MI, CVA, pneumonia, pulmonary mbolism, etc  Kids 0.2-0.4% o Cerebral edema o

DKA: IV Insulin  Might delay starting IV insulin for a few hours if K severely low (<3.0mEq/L) and metabolic acidosis not severe (pH>7.0)  Humulin R or Novolin Toronto  Bolus 0.1-0.2 U/kg IV  Then IV gtt @ 0.1-0.2U/kg/h (50 U of regular insulin in 500cc D5W; 1U/10cc)  Aim is to demonstrate correction of AG and decrease BS 4.4mM/L/h  Monitoring serial serum ketones NOT useful as most assays measure acetoacetate only  Using insulin to treat 2 different and separate metabolic disturbances in DKA: o Ketoacidosis o Hyperglycemia DKA: Switch to S.C. Insulin  Can consider to switch to SC insulin when: o AG normalized o BS<15mM o Insulin IV gttrequirements < 2U/h o Patient able to eat

 Overlap insulin IV gtt with 1st SC insulin by 2-4h, to avoid recurrent ketosis  T2DM persists with DKA o Don’t necessarily have to d/c on insulin SC o Once acute stress resolve, many do well on OHA DKA: Other Rx  Bicarbonate o May exacerbate hypokalemia o Only give if pH<6.9 and evidence of cardiovascular instability (arrhythmia, CHf, hypotension) o 1-2 amps of HCO3 in 1L D5W IV with 1020mEq of added KCl over 2h or until pH >7.1  Phosphate o Routine IV not recommended o Rx symptomatic hypophosphatemia (rhabdo, unexplained CHF or respiratory failure, severe confusion) o 10cc K Phos soln (3.0mEq Pi and 4.4mEq K/cc) in 1L NS IV over 8-12h  Cerebral edema o Usually only kids

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o o o o

Persistent decreased LOC standard rx of DKA CT scan to confirm diagnosis Decadron 10mg IV Mannitol 25mg IV

despite

DKA Rx: Evidence-Based Mgt  In patients not in shock, recovery is more rapid with slower rates of IV fuids (500mL/h x4h, then 250mL/h)  Low-dose insulin (0.1-0.2 U/kg bolus, then rate of 0.1-0.2 U/kg/h) has similar rate of recovery and less hypokalemia than high-dose insulin (50150U/h)  No clinical benefit to giving IV HCO3  No clinical benefit to giving IV PO4 Hyperosmolar Non-Ketotic Coma (HONC)  T2DM, elderly (mean age 60-73), F>M  Pathogenesis poorly understood  Mild ECFv↓ instigating factor  Insulin/Glucagon ratio, sufficient to limit DKA  Diminished thirst or access to water  Vicious cycle develops HONC Hyperglycemia

Pre-renal azotemia

Osmotic diuresis

Volume contraction HONC: Diagnosis  Signs and symptoms o Polyuria, polydipsia, fatigue x weeks/ months o N/V (< in DKA) o Dehydration  overt shock o Fever 50% o Decreased LOC: confusion/lethargy (4050%), stupor, coma (27-54%)  Laboratory o BS>33mM, serum OSM >320mM o pH >7.3, HCO3> 20mEq/L, ketones negative (33% cases mild DKA, hi-AG acidosis for other reasons) HONC: Precipitating Factors  Acute illness (MI, trauma): 10-15%

 New onset DM: 33%  Infection: 40-60%  Noncompliance: 5-15% HONC: Management 1. Coma management o ABCs, O2, narcan, D50W, thiamine, etc 2. Monitoring a. ICU or Stepdown best b. Vitals q1h c. Lytes, creatinine, glucose q2-4h d. Serum OSM, urine OSM/USG e. Cultures, EKG, cardiac enzymes f. CT brain (R/O CVA, SDH, etc) g. Consider pulmonary embolism 3. IV fluid resuscitation (10L free water deficit) o 25% body water lost (deficit 4-12L) o If hypotensive: Start with NS: 1L/h x 1-2h o Once ECFv normal change to ½ NS: IV 200-500 cc/h initially Correct ½ deficit over 1st 12h Correct total deficit by 36h o Lower fluid rates if elderly or known CHF 4. Insulin?  Patients can be treated successfully without insulin  If IV fluids inadequate BS and serum OSM will not drop despite insulin  Majority of studies used insulin  Hi-dose insulin: severe hypokalemia, shock  Therefore if going to use insulin, use low doses: o Bolus 0.1 U/kg, rate 1-2U/h (or 0.1U/kg/h) 5. Potassium (deficit 300-500mEq) 6. Identify and Rx underlying precipitant! HONC: Prognosis  Hi-mortality o Earlier series 58% o Recent studies 12-17% (but some mixed DKA)  30% complicating illness: o LRTI, GI bleed, ARF, CVA, MI, Pulmonary embolism o DVT prophylaxis beneficial?  Independent mortality predictors: o Advanced age o High osmolality, elevated ureas  After recovery: o Discharged or Insulin or OHA (Dr. Fuentes prefer Insulin!)

Subject: Medicine Topic: endocrine Page 12 of 13

o

Monitor closely for water intake/dehydration (esp. nursing home patients)

HYPOGLYCEMIA -is most commonly the result of taking drugs used to treat diabetes mellitus or other drugs, including alcohol. -sometimes defined as a plasma glucose level <2.5 to 2.8 mmol/L (<45 to 50 mg/dL) -Whipple’s triad: (1) symptoms consistent with hypoglycemia, (2) a low plasma glucose concentration, and (3) relief of symptoms after the plasma glucose level is raised. Causes of Hypoglycemia Drugs Especially insulin, sulfonylureas, ethanol Sometimes pentamidine, quinine Rarely salicylates, sulfonamides, and others Critical illnesses Hepatic, renal, or cardiac failure Sepsis Starvation and inanition Endocrine deficiencies Cortisol, growth hormone Glucagon and epinephrine (type 1 diabetes) Non-B-cell tumors Fibrosarcoma, mesothelioma, rhabdomyosarcoma, liposarcoma, other sarcomas Hepatoma, adrenocortical tumors, carcinoid Leukemia, lymphoma, melanoma, teratoma Endogenous hyperinsulinism Insulinoma Other B cell disorders Secretagogue (sulfonylurea) Autoimmune (autoantibodies to insulin, insulin receptor, _ cell?) Ectopic insulin secretion Disorders of infancy or childhood Transient intolerance of fasting Infants of diabetic mothers (hyperinsulinism) Congenital hyperinsulinism Inherited enzyme defects Postprandial Reactive (after gastric surgery) Ethanol-induced Autonomic symptoms without true hypoglycemia Factitious Insulin, sulfonylureas

Overview of glucose metabolism and pathways of counterregulatory responses to fasting and hypoglycemia. Symptoms of hypoglycemia 1. Neuroglycopenic -direct result of CNS neuronal glucose deprivation. -behavioral changes, confusion, fatigue, seizure, loss of consciousness, and, if hypoglycemia is severe and prolonged, death. 2. neurogenic (or autonomic) responses. -include adrenergic symptoms such as palpitations, tremor, and anxiety as well as cholinergic symptoms such as sweating, hunger, and paresthesia. -Adrenergic symptoms are mediated by norepinephrine released from sympathetic postganglionic neurons and the release of epinephrine from the adrenal medullae. -Increased sweating is mediated by cholinergic sympathetic nerve fibers. -Symptoms may be less pronounced with repeated hypoglycemic episodes Signs of hypoglycemia -pallor and diaphoresis -Heart rate and the systolic blood pressure are typically raised, but may not be prominent -neuroglycopenic manifestations are valuable, albeit nonspecific, signs -Transient focal neurologic deficits occur occasionally. URGENT TREATMENT  Oral treatment with glucose tablets or glucosecontaining fluids, candy, or food is appropriate if the patient is able and willing to take these  Reasonable initial dose is 20 g of glucose  If neuroglycopenia precludes oral feedings, parenteral therapy is necessary  IV glucose (25g) should be given using a 50% solution followed by a constant infusion of 5 or 10% dextrose  If IV therapy is not practical, S.C. or IM glucagon can be used, particularly in patients with type 1 DM.  Because it acts primarily by stimulating glycogenolysis, glucagon is ineffective in glycogen-depleted individuals (e.g., those with alcohol-induced hypoglycemia). It also stimulates insulin secretion and is therefore less useful in type 2 DM.  These treatments raise plasma glucose concentrations only transiently, and patients should be encouraged to eat as soon as practical to replete glycogen stores. End of trans FILLER =) Humility simply means we hold an accurate and unbiased assessment of our strengths and weaknesses. We understand our shape and our gifts, and we’re aware of, but not

Subject: Medicine Topic: endocrine Page 13 of 13 fretting over, our limitations. We see everything we have as a gift from God, and we know that without him we have nothing. You don’t have to live on overload. You don’t have to live in survival mode. Begin today to build a buffer around your schedule. Then enjoy the benefits of margin and see what God does next! Simplifying YOUR LIFE is really about choices – prioritizing what is important – and then sticking to those choices no matter how tempting it is to add more to your to-do list. In fact, take those tempting activities and put them on a list of things not to do. SURVIVING YOUR SCHEDULE 1. Line up your prorities Its useless to waste time on useless projects . You make your plans, but God directs your actions -Proverbs 12:11 2. Lighten up your attitude Worry weighs a person down, an encouraging word cheers a person up-Proverbs 12:25 A relaxed attitude lengthens life, jealousy rots it away -Proverbs 14:30 A cheerful heart is good medicine but a broken spirit saps a person’s strength-Proverbs 17:22 3. Look up to God Fear of the Lord lengthens one’s life but the years of the wicked are cut short-Proverbs 10:27 Those who fear the Lord are secure, he will be a place of refuge for these children -Proverbs 14:26