7 A1c Goal <7% Can be unreliable if Alternative is fructosamine Blood transfusionDecreased RBC lifespanHemoglobinopathiesAlternative is fructosamine
8 Oral agents in diabetes Need to know contraindications and most side effects of different agentsMetformin, TZDs and sulfonylureas are roughly equivalent on ability to decrease A1cMetformin, TZDs and sulfonylureas are FDA approved for combination with insulinDDP-4 inhibitors (sitagliptin, etc) are NOT FDA approved for combination with insulin
9 Metformin TZDs Sulfonylurea DDP-4 inhibitors Only oral agent that is weight loss/weight neutralGenerally first line agentContraindicated if Cr >1.5 in men, >1.4 in femalesSulfonylureaInsulin secretagogueContraindicated in renal failureTZDsCan have fluid retention and edemaContrainidicated in NYC Class III and IV heart failureDDP-4 inhibitorsIncreases insulin production and sensitivityDelays gastric emptyingCan be used in CKD with dose reduction
10 Indications for insulin Significant hyperglycemia at presentationAcute decompensationSurgeryPregnancyRenal diseasePoor control despite oral agents
11 Diabetic ketoacidosis Total body potassium is lowEven if patient presents with hyperkalemiaMonitor potassium and replaceFollow bicarb and anion gapGenerally no need to follow ketones
12 Diabetes is not just hyperglycemia Keep blood pressure <130/80ACE inhibitor or ARB if proteinuriaManage any dyslipidemiaIf age >40, start statin even if LDL at goalScreen for complicationsUrine microalbumin, dilated eye examSmoking cessationImmunizations
13 Lipid goals in diabetes LDL< 100 for every diabetic< 70 if DM with CAD or CAD equivalent (PAD, AAA)First choice is statinTriglycerides<150First treatment is glycemic controlFenofibrate safer than gemfibrozil when in combo with statin (less rhabdo)Secondary target (treat LDL first) unless >500
14 Complications of diabetes Acute complicationsDKAHyperosmolar hyperglycemic nonketotic state (HHNS)MicrovascularRetinopathyNeuropathyNephropathyMacrovascularCADPVDCVDAtherosclerosis is most common cause of death
15 Diabetes in pregnancy Glargine and detemir are contraindicated Use NPH for basal insulinCan use regular for prandial/bolus insulinA1c < 7% before conception and keep it thereRetinopathy may worsen during pregnancyRemember: statins, ACEIs, and ARBs are contraindicated
17 Adjusting insulin Basal insulin—controls fasting glucoses If fasting hyperglycemia—increase doseIf fasting hypoglycemia—decrease dosePrandial insulin—controls post-prandial glucosesIf post-prandial hyperglycemia—increase doseIf post-prandial hypoglycemia—decrease doseAdjustments should be 10-20% of dose
18 A 58 yo WM with HTN and DM is followed in your clinic and previously had good control of his diabetes with A1c of 6.9 on Novolog 70/30, taking 35 units before breakfast and supper. Has had recently begun complaining of highly variable blood sugars:Pre-breakfast FSG –Pre-Lunch FSG –Pre-Supper FSG –Which of the following is the best next step in his management?Increase Novolog 70/30 dose in the evening to 40 units.Begin acarbose therapyIncrease Novolog 70/30 dose in the morning to 40 unitsCheck blood sugar at 3 AMChange the patient’s regiment to Lantus and Regular Insulin before each meal for better compliance.
19 Early morning hyperglycemia Dawn phenomenonRise in GH and cortisol lead to morning hyperglycemiaNo associated hypoglycemiaSomogy effectNocturnal hypoglycemia leads to morning hyperglycemiaOnly way to differentiate is to check 3 AM FSG
20 23-year-old man with 13-year history of type 1 DM is preparing for racquetball tournament. The first game of his tournament is at 8 AM and he asks for advice about his insulin regimen because he has never attempted to play racquetball so early in the day (usually plays late afternoon).Usual insulin dosage is 6 units NPH with 10 units insulin lispro with breakfast at 7 AM, 4 units insulin lispro with lunch at 12 PM, and 8 units NPH with 12 units insulin lispro with dinner at 6 PM. His last A1c was 6.4 and his fasting fingerstick readings at 7 AM ranges between 160 and 200 mg/dL.Assuming that his 7 AM glucose concentration is in usual range, which one of the following should he do?A. Not take his insulin or eat breakfast but drink 8oz of orange juice just before the gameB. Take his usual insulin and eat his usual breakfastC. Omit the insulin lispro but take the usual dose of NPH with breakfastOmit the NPH but take the usual dose of insulin lispro with breakfastDecrease the insulin lispro and NPH and eat his usual breakfast
27 Definition of hypoglycemia Whipple’s triadSymptoms, signs or both consistent with hypoglycemiaA low plasma glucose concentrationResolution of symptoms/signs after raising plasma glucose“In the absence of Whipple’s triad, the patient may be exposed to unnecessary evaluation, costs and potential harms, without expectation of benefit.”From “Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guidelines”
28 Insulinoma Extremely rare Typically fasting hypoglycemia Whipple’s triadSymptoms associated with hypoglycemiaGlucose <70 at time of symptomsRelief with glucose administrationHave elevated insulin and C-peptide levelsNegative sulfonylurea screen
29 Vitals are normal and physical exam is unremarkable. 18 yo woman evaluated for syncope. Has had 3 episodes in past month that resolved after she drank fruit juice with sugar. Has history of depression treated with citalopram and occasional insomnia treated with zolpidem as needed. Her mother has type 2 diabetes treated with NPH and glyburide.Several minutes into presentation, patient becomes confused and agitated with tachycardia and profuse sweating. Blood is drawn. IV glucose given with resolution of her symptoms.Vitals are normal and physical exam is unremarkable.Lab studies: C peptide 0.4 ( ), glucose 34, insulin 26 (2-20), sulfonylurea screen negative.What is most appropriate next step in management?Abdominal CTAbdominal octreotide scanningGastric emptying studyPsychiatric evaluation
30 Interpreting laboratory data Remember that hypoglycemia is result of low glucose production rather than high glucose utilization.Plasma insulin, C-peptide, and pro-insulin concentrations don’t have to be high relative to normal values.Can be “inappropriately normal” for hypoglycemiaGenerally, only interpret results if glucose is <55 mg/dL.A concurrent illness can complicate interpretation of results.
33 Lipid profile Ideally after 14 hour fast and no alcohol for 3 days LDL is calculatedTotal cholesterol – HDL – triglycerides/5Not accurate if triglycerides > 400VLDL and chylomicrons are rich in triglycerides
34 HyperlipidemiasMay be primary (genetic) or secondary (meds, other diseases).Hypercholesterolemia—elevated cholesterol with normal triglyceridesHypertriglyceridemia—elevated triglycerides with normal cholesterolMixed hyperlipidemia—elevated cholesterol and triglycerides
35 Familial hyperlipidemia Familial hypercholesterolemiaReduction or absence of LDL receptorTendinous xanthomasLipoprotein lipase (LPL) deficiencyCannot degrade chylomicrons and VLDLTriglycerides > 1000
36 Familial hyperlipidemia Familial combined hyperlipidemiaMost common genetic hyperlipidemia (1%)Increase ApoB 100 → ↑LDL and ↑ VLDLPremature CADNo risk for xanthomasFamilial dysbetalipoproteinemiaElevated IDL (total cholesterol and triglycerides)Associated with diabetes, obesity and alcohol abusePalmar xanthomas (“yellow hands”)
41 Elevated triglycerides Normal retinaLipemia retinalisElevated triglycerides
42 Lipid disorder scenarios Young child with TG of 8000, pancreatitis, eruptive xanthomas, lipemia retinalis, positive family history. Most likely diagnosis? 32 yo man with CAD, LDL 350, TG normal and tendon xanthomas. +Familly hx of premature CAD. Diagnosis? 48 yo woman with premature CAD and severe PVD. +Tuberous and palmar xanthomata. TC 380, TG 400, LDL 50. Diagnosis?Lipoprotein lipase deficiency – unable to degrade VLDL and chylomicrons.Familial hypercholesterolemia (LDL receptor defect; LDL >300).Autosomal dominant with variable penetrance.Familial dysbetalipoproteinemia—High levels of IDL cause severe PVD and early CAD. Treat with statins and fibrates. TC and TG roughly equal with low LDL.
44 Secondary hyperlipidemia Treat secondary causes FIRST!If hypothyroid, normalize TSH and then repeat lipid profile.If uncontrolled diabetes, normalize A1c and repeat lipid profile.If oral estrogens, change to patch or change method of birth control.If excessive alcohol intake, work on cessation
45 Treatment of hyperlipidemia LDLStatins +/- ezetimibeBile acid resinsTriglyceridesFibratesCombined hyperlipidemiaStatin and fenofibrate (safer than gemfibrozil)Niacin (best for HDL)
46 Other points Unless triglycerides >500, LDL is first target. In patients on HAART, use pravastatin.Not metabolized through cytochrome P450s.Statins are contraindicated in pregnancy.
51 Primary hyperparathyroidism Most frequent case of hypercalcemia as outpatientUsually asymptomaticCalcium level typically within 1 mg/dL of ULNSolitary adenoma (80%) >> four gland hyperplasia (15-20%) >> carcinoma (< 1%)PTH > 25 with high calcium consistent with primary hyperparathyroidismRemember “inappropriate normals”!!
52 Management—primary hyperparathyroidism Treatment any underlying vitamin D deficiencyVitamin D deficiency is secondary cause of hyperparathyroidismStop any offending medications (if possible)Thiazides, lithium, calcium carbonateTreat any hyperphosphatemiaHyperphosphatemia is secondary cause
53 Indications for parathyroidectomy Acute parathyroid crisisOsteitis fibrosa cysticaNephrolithiasisAzotemia with no other explanationDecreased bone mineral densityMyopathyPancreatitisSerum calcium >1 mg/dL above ULN24-hour urinary calcium >400 mgAge < 50
54 Parathyroidectomy Four-gland exploration Mandatory in familial forms of hyperparathyroidismNeed experienced surgeonMinimally invasive parathyroidectomySingle gland involvement (adenoma)Pre-operative imaging should be performedPre-operative localizationSestamibi scintigraphyNeck ultrasound
55 Malignancy-associated hypercalcemia Predominate symptoms are altered mental status and dehydration.Tends to progress rapidly and have serum calcium >12 mg/dL80% due to PTHrP productionHypercalcemia, hypophosphatemia, ↓PTHMost commonly associated malignancies:Squamous cell carcinoma of lung, esophagus, cervix, head/neckBreast cancerLymphomaCarcinoma of kidney, bladder and ovary
56 Malignancy-associated hypercalcemia Local osteolytic hypercalcemia remaining 20%Lytic metastasis with extensive destructionMediated by cytokinesMultiple myeloma and breast carcinomaRarely 1,25 (OH)2 vitamin D3 productionHodgkin, B cell lymphoma, HTLV-1Treatment: steroids
57 Familial hypocalciuric hypercalcemia Autosomal dominant mutation in calcium sensing receptorUsually asymptomaticPTH inappropriately normalCalcium clearance/creatinine clearance <0.01Treatment: LEAVE THEM ALONE!
58 Granulomatous disease Macrophages have 1-α-hydroxylase which produces 1,25 (OH)2 vitamin D3Seen in sarcoidosis, tuberculosis, histoplasmosis, leprosy, silicone-induced granulomatosisTreatment: steroids
59 Drug-induced hypercalcemia ThiazideIncreased urinary calcium reabsorptionLithiumResets calcium setpoint for PTHCalcium carbonate (milk-alkali syndrome)Generally >10 grams dailyBecoming more common (osteoporosis, ERSD)
60 Lab studies: BUN 37, calcium 15.7, creatinine 1.4, sodium 151. 62 yo woman evaluated for 1 week history of fatigue, lethargy, constipation and nocturnal polyuria and polydipsia. Patient has advanced breast cancer, which has metastasized to liver. Conventional therapy is no longer helpful and she is scheduled to see oncologist to discuss treatment.Physical exam shows pale and somnolent woman. BP 98/65 and resting pulse Mucous membranes dry. Liver edge palpated 3 cm below costal margin.Lab studies: BUN 37, calcium 15.7, creatinine 1.4, sodium 151.What is most appropriate immediate next step in treating this patient?IV bisphosphonateIV furosemideIV glucocorticoidsIV normal saline
61 Treatment of hypercalcemia Hydration, hydration, hydration!!Bisphosphonates: pamidronate and zoledronic acidPamidronate + calcitonin if calcium >15Steroids only for granulomatosis disease or hematologic malignanciesLasix is only for volume overload!!
62 Hypocalcemia Low vitamin D: ↓Ca ↓Phos ↑PTH Secondary hyperparathyroidism is compensatory mechanismTreatment: give vitamin DHypoparathyroidism: ↓ Ca ↑Phos ↓ PTHUsually complication of total thyroidectomyTreatment: calcium and calcitriolPseudohypoparathyroidism: ↓ Ca ↑Phos ↓ PTHDefect in PTH receptor → PTH resistanceCharacteristic phenotype: short, obese, round face, mental retardation, short 4th and 5th metacarpals and metatarsals
64 Hypocalcemia Give IV calcium if symptomatic Calcium gluconate preferred to calcium chlorideOtherwise, give oral calcium and vitamin DOnly treat to calcium ofEnough to prevent symptomsNot enough to cause hypercalciuria
65 Calcium scenarios64 yo man with Calcium 10.8, PTH 135 (10-65). Diagnosis? 64 yo man with Calcium 10.8, PTH 49 (10-65). Diagnosis? 70 yo smoker with dysphagia to solids, then liquids; presents with altered mental status and dehydration. Calcium 14, Albumin 2. Diagnosis?Primary HyperparathyroidismPrimary HyperparathyroidismPTH is inappropriately normal - If >25 with hypercalcemia, then primary HPTHypercalcemia of MalignancyBe alert for diabetes insipidus with hypercalcemia → hypercalcemic crisis.
66 Calcium scenarios42 yo with serum calcium of 10.9, phosphate normal, PTH normal and no kidney stones, normal bones; +Hx of hypercalcemia in the past. Best next test? 53 yo with calcium 12.3, Phos 5.9 and mediastinal lymphadenopathy. Best therapy?24 hour urine calcium/creatinine – Familial hypocalciuric hypercalcemia. Do NOT operate!Steroids – Sarcoidosis causes hypercalcemia by uncontrolled activation of Vitamin D.
67 Calcium scenarios65 year old health food fanatic ingests high dose vitamin A supplements “to help with my eyes.” Calcium 11.7 with low PTH. Diagnosis? 43 year old with PUD eats 15 tums BID due to dyspepsia. Calcium 12.3, PTH low, HCO Diagnosis?Vitamin A toxicity – Periosteal resorption if taking >5000 units/dayMilk-Alkali Syndrome – metabolic alkalosis and hypercalcemia
68 Calcium scenarios42 yo with osteopenia, microcytic anemia and Calcium of 7.6. PTH is 125. Next step? 63 yo drunkard found passed out… again… Calcium 7.3, PTH is 23. Next step?\Celiac Disease. Check 25-OH Vitamin D level and replace to >32. Look for dermatitis herpetiformis, Type I Diabetes Mellitus, Non-Hodgkins Lymphoma, Vitamin B or K deficienciesCheck for Hypomagnesemia causes reversible hypoparathyroidism. Replace magnesium to >2 mg/dL.
69 Calcium scenarios68 yo woman with newly diagnosed osteoporosis starts zoledronic acid therapy 2 days before presentation and presents to the ER with tetany and palpitations. What happened?Bisphosphonate Induced Hypocalcemia - Most common several days after infusion in Vitamin D deficient patients.Always replace Vitamin D to 30 before starting bisphosphonate therapy.Therapy – Replace calcium and Vitamin DPalpitations – QRS prolongation
70 Check phosphorus level. 72 yo woman s/p parathyroidectomy due to primary hyperparathyroidism develops calcium 6.9 on POD #1. Magnesium is normal pre-op. Next step? 20 yo with round face, short stature, mental retardation, obesity, basal ganglia calcifications, shortened 4th & 5th metacarpals. Calcium 6.9, Phos 5.5. Next step?Check phosphorus level.Low Phosphorus – Hungry Bone Syndrome – Give calcium/DHigh Phosphorus – Hypoparathyroidism – Give Calcium/RocaltrolCheck PTH levelLikely Pseudohypoparathyroidism (PTH resistance)Albright’s Hereditary OsteodystrophyTherapy is calcium and vitamin D supplementation
72 MEN I Have to have 2 out of 3 P’s Pituitary Pancreas Parathyroid Prolactinoma, acromegaly, Cushing’s diseasePancreasGastrinoma, insulinoma, glucagonoma, VIPomaParathyroidPrimary hyperparathyroidism (multifocal)
73 MEN 2 MEN 2B: MTC + ganglioneuromas and Marfaniod habitus Medullary thyroid cancer (MTC) present in 100%Always malignant; usually bilateralMEN 2A: MTC + parathyroid hyperplasiaMEN 2B: MTC + ganglioneuromas and Marfaniod habitusPerform genetic screening for RET mutations in all index patientsIf mutation found, screen family membersRule out pheo, then total thyroidectomy and cervical exploration