Endocrinology

Endocrinology
Alison Schwartz
Shana McCormack
Elvira Isganaitis
Lynne L. Levitsky
Diabetes Mellitus
Definition
  • Fasting glucose ≥126 mg/dL, 2-hr OGTT (oral glucose tolerance test) glucose ≥200 mg/dL, or random glucose ≥200 mg/dL in the presence of symptoms. In absense of symptoms, level needs to be repeated on diff day.
Classification
  • Type 1 diabetes: Autoimmune disorder w/ T cell-mediated destruction of pancreatic islet cells, causing insulin deficiency. + pancreatic autoantibodies. Rx w/ insulin.
  • Type 2 diabetes: Peripheral resistance to insulin action and variably dysregulated/diminished insulin secretion. Rx w/ oral hypoglycemic agents and/or insulin.
  • Maturity-onset diabetes of the young (MODY): Heterogeneous group of genetic disorders caused by mutations in beta cell genes.
    • AD inheritance, mild to moderate hyperglycemia, absence of autoantibodies.
    • ∼1%–5% of diabetes. Rx w/ oral hypoglycemic agents and/or insulin.
  • Mitochondrial diabetes: Mitoc DNA mutations w/ hyperglycemia and other features, (e.g., Kearns-Sayre syndrome [diabetes, ophthalmoplegia, retinal degeneration, cardiomyopathy]), maternally-inherited diabetes and deafness syndrome (MIDD).
  • Secondary diabetes:
    • CF related DM: ↓ insulin secretion 2/2 pancreatic destruction and amyloid deposition.
    • Drug-induced: 2/2 meds, such as steroids, growth hormone, β-agonists, diazoxide, antiretroviral protease inhibitors, cyclosporine A, L-asparaginase.
    • Hemosiderosis/Hemochromatosis: Iron overload (chronic transfusion) ↓ secrete and ↑ resistance insulin
    • 2/2 genetic syndrome: Wolfram syndrome (a.k.a. DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, deafness), Prader-Willi, Bardet-Biedl, etc.
Diabetes Mellitus Type 1
(Contemporary Endo: Pediatric Endo: A Practical Clinical Guide Radovick and MacGillivray 2003;523)
Epidemiology
  • Prevalence in the U.S. is 1 in 400–500; increased in northern latitudes.
  • Age of onset has bimodal distribution (1st peak at 4–6 yo & 2nd at early puberty)
  • FHx of type 1 diabetes (1° relative) in 15% of patients
  • Concordance rates for monozygotic twins 21%–70%, implies roles for genetic factors (HLA genotype) and environmental triggers (possibly viral infxn, diet, toxins)
Clinical Manifestations
  • May be asymp and just incidental hyperglycemia on blood work
  • Classic symptoms: Polyuria and polydipsia (70%), weight loss (34%) often w/ inc appetite (polyphagia), lethargy (16%), and nocturnal enuresis
  • Diabetic ketoacidosis (DKA): Classic sx +/- vomiting and abdominal pain, fruity breath (ketones), Kussmaul respirations, obtundation, coma.
    • Frequency of DKA as initial presentation of diabetes is ∼25%
    • Inc incidence further from equator; more freq in very young children, in families w/o FHx of diabetes, and in families w/ lower socioeconomic status
  • Dehydration: Mild to severe, because of osmotic diuresis
  • Visual changes: 2/2 osmotic shifts in lens or cataracts if prolonged hyperglycemia
  • Candidal infections (more common in younger children)
Diagnostic Studies
  • Hemoglobin A1c: Glycosylated Hgb; good marker of serum glucose conc over 2–3 mo
    • Accuracy affected by hemolysis, inc RBC turnover, and hemoglobinopathies.
  • Anti-islet cell Ab (ICA), anti-insulin Ab (IAA; ideally obtained before admin insulin), anti-IA2 (islet antigen 2, a.k.a. ICA512) Ab, anti-GAD (glutamic acid decarboxylase, a.k.a. GAD65) Ab
  • Consider eval for other autoimmune conditions (Diabetes Care 2001;24:27)
    • Autoimmune thyroid dz (antithyroid peroxidase Ab, antithyroglobulin Ab), in up to 18% of newly dx’d DMI pts. Check TSH and free T4.
    • Celiac sprue (anti-TTG and anti-endomysial Ab), seen in up to 1–5% of newly dx’d DMI pts.
    • Also consider Addisons, Vitiligo, & Autoimmune Poly-endocrinopathies
Monitoring
(Diabetes Care 2005;28:186)
  • Blood glucose checked before meals and at bedtime. Consider testing at MN, at 2–4 am, and after meals shortly after dx or when altering regimens.
  • HgbA1c every 3 mo (see age specific goals, below)
  • Dilated retinal exam every year after age 10 yr
  • Fasting lipid panel at diagnosis and then q5 yr if normal
  • TSH, free T4 yearly; anti-TPO antibodies, anti-thyroglobulin antibodies initially
  • Celiac screening every 1–2 yr
  • Urine microalbumin: Creatinine ratio yearly after age 10 yr
Management
  • Insulin regimen requires estimation of total daily dose (TDD) of insulin.
  • Start dose btw 0.3 and 0.6 U/kg/d; prepubertal pts may need less (0.25–0.5 U/kg/d); pubertal pts and those who present in DKA may require more (0.5–0.75 U/kg/d)
  • Onset and action of insulins:
    Type Onset (hr) Peak (hr) Duration (hr) Comments
    Rapid-acting
    Lispro insulin (Humalog) 0.25 1 2–3  
    Insulin aspart (NovoLog) 0.25 1 2–3  
    Glulisine (Apidra) 0.25 1 2–3  
    Short-Acting
    Regular human insulin 0.5–1 2–4 4–6 Longer action if larger dose (mass action effect)Can be used intravenously
    Intermediate-Acting
    NPH human 0.5–1 4–6 8–16 Peak and duration quite variable
    Long-Acting
    Insulin glargine (Lantus) 0.5–1 None 23–26 Basal insulin: minimal or no peak.Cannot be mixed with other insulins
    Insulin detemir (Levemir) 0.5–1 None 5.7 (low dose) –26 (high dose) Basal insulin: minimal or no peakCannot be mixed with other insulins
  • Conventional insulin Rx (2–3 injections per d)
    • NPH at least b.i.d. (before breakfast w/ 2nd dose either before dinner or bedtime), w/ rapid-acting (i.e., lispro or aspart) or short-acting (“regular”) insulin 2–3×/d.
    • 2/3 TDD before breakfast (2/3 NPH and 1/3 rapid/short-acting) and 1/3 before dinner and bedtime (2/3–½ NPH bedtime and 1/3–½ rapid/short acting before dinner)
    • Requires fixed schedule of eating & insulin dosing and fixed amt of carbs at meals
  • Basal-Bolus (4+ injections/d) (Diabet Med 2006;23:285)
    • Assoc w/ improved HgbA1c, dec gluc fluctuations, and dec risk of hypoglycemia.
    • Lantus/Levemir 1–2×/d plus lispro or aspart insulin w/ meals
      • 50% of TDD is Lantus
      • 50% of TDD lispro/aspart – dose based on blood sugar and carb content
        • Estimate of correction factor: 1500–1800/TDD (some use 1650) gives amt by which serum glucose expected to dec, in mg/dL for 1 unit of rapid-acting insulin.
        • Estimating insulin: Carb ratio; 500/TDD gives # of grams of carbs that are covered by 1 unit of rapid-acting insulin.
    • Insulin pump: Cont basal insulin (lispro/aspart) w/ bolus for corrections & food.
      • Assoc w/ dec risk of hypoglycemia, improved HgbA1c compared to NPH-based regimens, and improvements in quality of life scales. (Diabetes Care 2008;31:S140)
  • Education regarding symptoms of hypoglyecemia is very important
Treatment goals:
Glycemic targets: HgbA1c/Plasma blood glucose goal range (mg/dL)
  Plasma Blood Glucose Goal Range (mg/dL)    
Values By Age Before Meals Bedtime/Overnight A1c Rationale
Toddlers and preschoolers (<6 yr) 100–180 110–200 <8.5% (but >7.5%) High risk and vulnerability to hypoglycemia
School age (6–12 yr) 90–180 100–180 <8% Hypoglycemia risk vs. relatively low risk of complications before puberty
Adolescents and young adults (13–19 yr) 90–130 90–150 <7.5%* Lower risk of hypoglycemiaDevelopmental and psychological issues
*A lower goal (<7.0%) is reasonable if it can be achieved without excessive hypoglycemia.
Complications
  • Hypoglycemia; Rx w/ PO glucose or IV dextrose bolus, consider 0.5–1 mg SC/IV glucagon
  • Microvascular complications (retinopathy, neuropathy, renal disease)
  • Macrovascular complications (coronary vascular disease, peripheral vascular disease)
    • DCCT w/ significant correlation btw HgbA1c and risk of both microvascular and macrovascular complications (N Engl J Med 2000;342:381)
Diabetes Mellitus Type 2
Epidemiology
(Lancet 2007;369:1823; Diabetes Care 2006;29:212)
  • U.S. prevalence ↑ing; past 3% new cases DM, now 15%–45% depending on location.
  • STOPP-T2D trial: ∼50% middle-school students w/ ↑BMI (≥85 percentile), 40% w/ fasting glucose ≥100 mg/dL, (only 0.4% >125 mg/dL, and 1/3 w/ hyperinsulinism w/ fasting insulin ≥30 μU/mL) and thus prediabetes. (Diabetes Care 2006;29:212)
Diagnostic Studies
(Pediatrics 2003;112:e328)
  • At dx, screen for proteinuria/microalbuminuria, dilated funduscopic exam by ophtho.
    • After metabolic stabilization (1–3 mo after dx): LFTs & fasting lipids
    • Repeat all preceding annually. (AAP guidelines for at-risk groups) HgbA1c q3 mo.
Complications (acute)
(Lancet 2007;369:1823)
  • Multi studies, 11%–25% of pts p/w DKA, more w/ ketonuria. (See section on DKA)
  • Hyperglycemic hyperosmolar state (glucose >600 mg/dL, osmolality >330 mOsm/L, mild acidosis w/ bicarbonate >15 mmol/L and mild ketonuria ≤15 mg/dL) 2/2 nonadherence to Rx, meds, and stresses (infections, substance abuse, chronic disease).
    • In one study at tertiary care facility, 3.7% of pts w/ T2DM had this presentation; case-mortality rates are high across studies, and range from 14%–42%.
Complications (chronic)
(Lancet 2007;369:1823)
  • Microalbuminuria and risk of AMI ↑ for pts w/ DM2 dx’d at younger ages.
  • HTN, dyslipidemia, retinopathy, nonalcoholic fatty liver dz, and neuropathy.
    • Nephropathy and retinal disease often present at diagnosis.
  • Poor glycemic control (by HgbA1c) & HTN predictive of subseq complications.
  • Complications progress more rapidly in kids and adolescents w/ DM2 than w/ DM1.
Treatment
  • Lifestyle Δ, diet modification, weight mgmt, exercise effective, adherence difficult.
  • Oral hypoglycemics; metformin (FDA approved). Dose can be titrated up slowly to avoid common side effects (headache, nausea).
  • Eventually may need initiation of insulin therapy
  • Surveillance as indicated above.
Diabetic Ketoacidosis
Definition
(Pediatrics 2004;113:e133)
  • ↓ effective circulating insulin and ↑ counterregulatory hormones (glucagon, epinephrine) leading to hyperglycemia and hyperosmolarity
  • Lipolysis leads to ketonemia and metabolic acidosis
  • Hyperglycemia and acidosis lead to osmotic diuresis, dehydration, electrolyte loss
  • Severity: Mild w/ venous pH <7.30, bicarbonate <15 mmol/L, moderate w/ venous pH <7.2, bicarbonate <10, severe w/ venous pH <7.1, bicarbonate <5
Epidemiology
(Pediatrics 2004;113:e133)
  • DKA as 1st presentation of DM1 more often in pts <4 yo, w/o a 1st-degree relative w/ DM1, and of lower socioeconomic status
  • 25% of new onset diabetes in children presents as DKA
  • Incidence 1%–10% per patient per yr in established DM1
  • Risk factors: Poor control, previous episodes of DKA, peripubertal or adolescent, psychiatric disorders, lower SES, insulin not administered by responsible adult, pump failure, inadequate insulin during intercurrent illness
Clinical Manifestations
(Pediatrics 2004;113:e133; Diabetes Care 2006;29:1150)
  • Confirm dx and determine cause (evidence of infection; recurrent DKA, insulin omission, failure to follow sick day/pump failure mgmt guidelines).
  • Exam: Weight (assess dehydration), fruity breath, acanthosis nigricans (suggests insulin resistance and DM2; may need higher insulin doses)
  • Assess severity of dehydration (UOP not reliable indicator of hydration in hyperosmolar states given osmotic diuresis); see FEN chapter
  • Level of consciousness (Glasgow coma scale)
  • Headache or focal neurologic signs (suggests cerebral edema)
Diagnostic Studies
(Pediatrics 2004;113:e133; Diabetes Care 2006;29:1150)
  • Labs: Blood gas, serum or plasma glucose (not just D-stick), lytes, BUN/Cr, Ca, Mg, Phos, CBC (↑ WBC can be 2/2 stress), HgbA1c, U/A (ketones), consider lactate if severe acidosis or not responding to insulin.
  • Assess for infectious trigger (blood, urine, and throat cx; consider CXR)
Treatment
(Pediatrics 2004;113:e133; Diabetes Care 2006;29:1150)
  • Fluids: Administer 10–20 cc/kg NS IV over 1–2 hr; repeat as necessary
    • Assume 5%–7% dehydration in mild-moderate DKA; assume 10% in severe DKA
      • Rate of IV fluids should be calculated to correct over 48 hr
      • Should not exceed 1.5–2× maintenance
      • Use 0.9% NS for 1st 4–6 hr; then transition to 0.45% or 0.9% NS w/ K; choose ↑ Na content if corrected Na low or dropping during initial resuscitation
  • Insulin: IV fluids can normalize hyperglycemia, insulin therapy essential for correcting acidosis (counteracts lipolysis and ketogenesis)
    • IV insulin 0.1 U/kg/hr; avoid bolus insulin dosing 2/2 inc risk of cerebral edema
    • Add dextrose to IVF if BG <300, or if BG dropping by >100 mg/dL per hour
    • May transition to SQ insulin once VBG pH >7.3 and pt able to eat
  • Monitoring: Initially q1h (more freq as needed) VS, neuro exam (cerebral edema; HA, vomiting, bradycardia, HTN, dec O2 sat, ΔMS, posturing, abn pupil resp, CN palsies), strict I’s and O’s, gases. (Check cap gases against VBG; cap gas inaccurate w/ poor periph perfusion, acidemia, extreme hyperglycemia.) Q1h D-sticks
    • Labs: Glucose, electrolytes, blood gas, Ca/Mg/Phos q2–4h (more often if unstable). BUN, creatinine, and hematocrit repeated q6–8h until normal.
    • Urine ketones until cleared.
  • Calculations: Anion gap = Na – (Cl + HCO3); normal is 12 ± 2 mmol/L
    • Corrected sodium = measured Na + 2.4 × [(glucose mg/dL – 100) ÷ 100] (Am J Med. 1999;106:399)
    • Effective osmolality = 2 × (Na + K) + glucose mmol/L (mg/dL ÷ 18)
  • Potassium: Total intracellular stores depleted but hyperkalemia 2/2 extracellular shift. Replete w/ 1/2 KPhos & 1/2 KCI
    • Once UOP; if initial K <3, add 40–60 mEq/L in IVF; if K is 3–4, add 30 mEq/L; if K 4–5, add 20 mEq/L; if K 5–6, add 10 mEq/L; if K >6, hold K replacement
  • Phosphate: Total body stores ↓. Rx hypophos if severe. Rx may result in HypoCa.
  • Acid-base status: Fluid and insulin replacement should treat metabolic acidosis.
    • Bicarb only if profound acidosis and likely to affect action epinephrine in a code
    • Bicarbonate use during the Rx of DKA associated w/ inc risk of cerebral edema.
Complications
(Pediatrics 2004;113:e133; Diabetes Care 2006;29:1150)
  • Mortality from DKA is 0.15% in the U.S.
  • 0.5–1% of episodes of DKA c/b cerebral edema; mortality risk of 20–25%.
    • Accounts for 60%–90% of DKA-related mortality.
    • Risk factors for cerebral edema: Bolus insulin attenuated rise or drop in serum Na, severity of acidosis or hypocapnia, elevated BUN, but NOT degree of hyperglycemia
  • Electrolyte abnormalities like hypokalemia and hyperkalemia also occur
  • Please see Neurology chapter section on treatment of cerebral edema
Prevention
(Pediatrics 2004;113:e133)
  • Earlier dx, pt, family, and community education, responsible adults administering insulin, establishing comprehensive treatment networks.
Hypoglycemia
(Pediatr Rev 1989;11:117)
Definition
  • Low serum glu (<45) + sx and resolution of sx after administration of glucose
  • Sx’s: Perspiration, tachycardia, pallor, paresthesia, tremor, weak, N/V
Pathophysiology
  • Nml fall in glucose → ↓ insulin secretion and ↑ counterregulatory hormones
  • Presence of insulin inhibits adipose tissue breakdown → no ketones
Etiology
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Jun 19, 2016 | Posted by in PEDIATRICS | Comments Off on Endocrinology

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