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  1. 1. The Mis-Interpretation of Endocrine Laboratory Results A Primer on the Thought Process of the Endocrinologist Alexander Karmazin, MD, FAAP, FACE Pediatric Endocrinologist Sanford Children’s Specialty Clinic Assistant Professor of Pediatrics Sanford USD School of Medicine
  2. 2. Learning Objectives • Identify laboratory values that might not be normal, despite being within the reference range on the laboratory report • Identify laboratory values that might be normal, despite not being within the reference range on the laboratory report • Recognize situations in which exam findings provide more information than laboratory test results • Understand that age, gender, and Tanner stage may significantly influence a laboratory test’s reference range
  3. 3. Areas To Be Covered • Growth • Thyroid function • Puberty • Calcium/Vitamin D metabolism
  4. 4. Growth Evaluation • Bone age X-rays • Serum growth hormone • IGF-1 • IGF BP-3
  5. 5. Bone Age X-Rays • Inexpensive, informative, predictive • Subjective and interpreter-dependent • Should never be interpreted as either “normal” or “abnormal” • Cannot differentiate between certain diagnoses – growth hormone deficiency vs. constitutional delay of growth
  6. 6. Normal (bad) vs. Abnormal (good)
  7. 7. Growth hormone • Random values not reliable for diagnosis of either GH deficiency or excess (diurnal variability) • Usually requires prolonged sampling under either a provocative test or inhibitory protocol using oral glucose
  8. 8. IGF-1 and IGF BP-3 • Values highly dependent on age, gender, and Tanner stage • Regulated by growth hormone production and nutritional intake • Normal reference ranges, particularly in adolescents are wide
  9. 9. A Clinical Example (A Recent Patient Seen in Clinic) • 6-4/12 y.o. male referred for short stature • Limited growth data available, but apparently no change in height in past 8 months • BMP, CBC, TSH obtained locally all normal • PMH: Asthma; Meds: Singulair, Flovent, Albuterol MDI PRN • Physical exam unremarkable • Bone age = 4 years (1 S.D. for age = 9.3 months) • TSH = 3.38 mcIU/mL (0.4-5), free T4 = 0.9 ng/dL (0.7-1.5), sed rate = 11 mm/hr (0-22), IGF-1 = 17 ng/mL (60-228), IGF BP-3 = 1.3 mg/L (1.5-3.4), celiac screen – strongly positive
  10. 10. A Clinical Example (A Recent Patient Seen in Clinic) • Why did I repeat thyroid functions when the TSH value was normal locally? • Does this child’s combination of bone age delay and low IGF-1/IGF BP-3 values indicate a diagnosis of growth hormone deficiency despite his small bowel biopsy showing villous atrophy & increased epithelial lymphocytes?
  11. 11. Thyroid Function Testing • TSH • Total and free T4 • Total and free T3 • T3 resin uptake (T3RU) • Reverse T3 • Thyroglobulin
  12. 12. Thyroid Stimulating Hormone • Very difficult (but not impossible) for a laboratory to perform incorrectly • Values generally stable over the lifespan • An excellent screen for primary hypothyroidism • Alone, an inadequate screen for secondary or tertiary hypothyroidism • Not useful for ongoing monitoring of patients with panhypopituitarism on thyroid replacement • If mildly elevated (5-10 mcIU/mL), should not be blamed for rapid weight gain or other significant symptoms of hypothyroidism
  13. 13. Total T4 • A measure of all tetraiodothyronine in the bloodstream • All but 99.97% is bound to proteins and thus inactive • Dependent on thyroxine binding globulin concentration • Values relatively stable over the lifespan, however children under 2 tend to have slightly higher reference ranges
  14. 14. Free T4 • Usually performed by an indirect method that can rarely be affected by non-specific absorption of free T4 to matrix reagents • Can be performed by a direct method called equilibrium (direct) dialysis • Values from one laboratory cannot be compared to those from another – Reference ranges can vary from 0.59-1.17 ng/dL to 1.1-1.8 ng/dL
  15. 15. Free T4, continued • Eliminates issues of TBG deficiency and TBG excess • Generally should be obtained with TSH in patients with primary hypothyroidism on thyroid replacement • Can be used alone to monitor therapy for those with central hypothyroidism/ hypopituitarism • Should make sense when interpreted together with the TSH value
  16. 16. Total and Free T3 • Mostly made by deiodination from T4, though some is made directly in the thyroid gland • Values generally decrease slightly over the lifespan • Free T3 values are not well established in the pediatric population • Most useful in evaluation of possible pure T3 toxicosis – suppressed TSH and normal or close to normal free T4
  17. 17. T3 Resin Uptake • Historically was used as an indirect measure of free T4 concentration by assessing T4 protein binding • Says absolutely nothing about T3 concentration • Since the development of free T4 assays, is generally relegated to the medical history books
  18. 18. Reverse T3 • A metabolically inert product of deiodination of T4 • Usually elevated in cases of non-thyroidal illness (euthyroid sick syndrome) as deiodination to T3 is inhibited • Euthyroid sick syndrome can be associated with a variety of conditions – Fasting, malnutrition, trauma, surgery, severe systemic illness, poorly controlled diabetes • Rarely if ever ordered by pediatric endocrinologists
  19. 19. Thyroglobulin • Precursor molecule for thyroid hormone mostly stored as colloid • Note that this is note the same as thyroglobulin antibodies • Mostly used for post-operative monitoring in thyroid cancer • Can be used to distinguish between endogenous and exogenous hyperthyroidism
  20. 20. A Clinical Example • 12 y.o. female referred for “abnormal thyroid function tests” and recent weight gain • Locally: TSH = 6.2 mcIU/mL (0.35-4.94), free T4 = 1 ng/dL (0.7-1.5) • Height points consistently at the 75th percentile • PMH: Negative; Meds: None • FH: No family history of thyroid disease • Exam: No thyromegaly, otherwise normal
  21. 21. A Clinical Example • Should this patient be started on thyroid replacement? • If not, what is the next step? • If thyroid functions should be repeated, when? • Would thyroid antibodies be helpful? • Any role for thyroid ultrasound?
  22. 22. The Pituitary-Gonadal Axis • FSH • LH • Testosterone • Free testosterone • Estradiol • Other serum and urine estrogens
  23. 23. Gonadotropins (FSH & LH) • Both boys and girls go through a “mini- puberty” of infancy – LH values begin to increase two weeks after birth and decline to pre-pubertal values by 1 year of age – FSH values also begin to increase two weeks after birth and decline to pre- pubertal levels by 1 year of age in boys and 2 years of age in girls
  24. 24. Gonadotropins (FSH & LH) • Low values in the early to mid-teen years cannot distinguish between hypogonadotropic hypogonadism and simple pubertal delay • High values indicative of gonadal failure cannot be expected until the end of the first decade of life
  25. 25. Gonadotropins (FSH & LH) • Reference ranges are available by age, Tanner stage, and gender • In pediatrics, testing should occur in a laboratory with expertise in analysis of pediatric samples and established reference ranges for children
  26. 26. Testosterone • Remember the “mini-puberty” phenomenon – In boys, levels are elevated (75-400 ng/dL) at birth, decrease rapidly during the first week (20-50 ng/dL), increase to a peak during days 20-60 (60-400 ng/dL), then decline to a pre-pubertal level (<10 ng/dL) by 7 months of age
  27. 27. Testosterone • Standard laboratories often cannot detect testosterone concentrations <40 ng/dL • Pediatric samples thus should be processed at endocrine-specific laboratories that can detect concentrations as low as 3 ng/dL • The generally accepted cut-off of pre- vs. in puberty testosterone values is 10 ng/dL
  28. 28. Free Testosterone • In most cases, offers little if any advantage over total testosterone • May offer greater sensitivity in the evaluation of hyperandrogenemic girls because androgen excess lowers levels of circulating SHBG (sex hormone binding globulin)
  29. 29. Estradiol • The “mini-puberty” phenomenon is back one more time – Levels are markedly elevated at birth, fall rapidly during the first week to pre-pubertal levels, increase between 30 and 60 days (1.0-3.2 ng/dL for males, 0.5-5.0 ng/dL for females), and decline to pre-pubertal levels again by six months in boys and by 1 year in girls
  30. 30. Estradiol • Different laboratories (even endocrine specific ones) may use different units of measure for estradiol assays – Quest Diagnositics uses pg/mL – Esoterix uses ng/dL – There is a 10-fold difference between them • Low values may not be helpful in females because of the cyclic nature of hormone production
  31. 31. Other serum and urine estrogens • In the general pediatric and pediatric endocrinology practices, provide no additional information or benefit in the detailed evaluation of the pituitary- gonadal axis
  32. 32. A Clinical Example • 15-1/2 year old male presents for evaluation of delayed puberty • No significant past medical history • Height at the 10th percentile • Exam shows normal pre-pubertal male genitalia with testicular volume of 3 mL • Labs: TSH = 1.5 mcIU/mL (0.4-5); FSH = 0.65 IU/L (0.81-8.18 for 15-18 y.o. males), LH = 0.14 IU/L (0.69-7.15 for 15-18 y.o. males), testosterone = 12 mg/dL (220-880 for 15-17 y.o. males) • What is the most likely diagnosis?
  33. 33. Calcium Metabolism • Parathyroid Hormone (PTH) • Calcium • Ionized calcium • Phosphorus • Vitamin D – 25-Hydroxy – 1,25-Dihydroxy
  34. 34. Parathyroid Hormone • Should be measured as the intact 84 amino acid molecule • Reference range is generally unchanged over one’s lifetime • Cannot be interpreted in isolation from calcium or ionized calcium values (many labs automatically perform a serum calcium when PTH is ordered)
  35. 35. Parathyroid Hormone • Normal PTH levels in the face of hypocalcemia are “inappropriately normal” – i.e. LOW – and may be indicative of either hypoparathyroidism or a gain-of-function mutation in the calcium sensing receptor (autosomal dominant hypoparathyroidism)
  36. 36. Parathyroid Hormone • Normal PTH levels in the face of hypercalcemia are “inappropriately normal” – i.e. HIGH – and may be indicative of either hyperparathyroidism or a loss-of-function mutation in the calcium sensing receptor (familial hypocalciuric hypercalcemia)
  37. 37. Calcium and Ionized Calcium • Reference range is slightly higher during the first decade of life – Total calcium • Full term-<10 days 7.6-10.4 mg/dL • 10 days-2 years 9.0-11.0 mg/dL • 2-12 years 8.8-10.8 mg/dL • Adult 8.6-10 mg/dL – Source: Harriet Lane Handbook – Ionized values show a similar pattern
  38. 38. Ionized Calcium • Represents the concentration of free and biologically active calcium in blood • Calcium circulates in approximately equal free and bound fractions • Permits a more accurate assessment of hypo- and hypercalcemic states in the presence of abnormal albumin levels
  39. 39. Phosphorus • Levels are significantly higher in the first decade compared to later in life – Newborn 4.5-9.0 mg/dL – 10 days-24 months 4.5-6.7 mg/dL – 24 months-12 years 4.5-5.5 mg/dL – >12 years 2.7-4.5 mg/dL • Source: Harriet Lane Handbook
  40. 40. Phosphorus • Values typically low in all causes of rickets • Values typically inverse to those of calcium in parathyroid disorders (hypopara, hyperpara, pseudohypopara) – PTH increases calcium resorption and phosphorus excretion
  41. 41. 25-Hydroxy Vitamin D • The test best reflective of total body vitamin D stores • Sometimes reported separately as vitamin D2 (plant sources) and vitamin D3 (animal sources and skin production) • Optimal value is ≥32 ng/mL, no matter what the laboratory reports as the reference range
  42. 42. 1,25-Dihydroxy Vitamin D • The active form of vitamin D • Stored 25-Hydroxy Vitamin D is 1- hydroxylated by the kidney in a tightly regulated fashion • Tends to be elevated in hyperparathyroid and early rachitic states; decreased in renal failure and late rachitic states
  43. 43. A Clinical Example • An infant in the NICU has been having seizures • She is also known to have a ventricular septal defect • Labs – Calcium = 6.1 mg/dL (7.6-10.4) – Ionized calcium = 0.88 mmol/L (1.1-1.42) – Phosphorus = 8.6 mg/dL (4.5-9 for newborn, 4.5-6.7 after 10 days of age) – PTH = 38 pg/mL (9-59) – 25-OH vitamin D = 41 ng/mL (32-?) • What is the most likely diagnosis? • What other test should be obtained?
  44. 44. Summary • Endocrine laboratory tests must be interpreted in light of the patients clinical presentation and physical exam findings • Some endocrine laboratory tests cannot be interpreted in isolation from others • Reference range based on age, gender, and Tanner stage is often vital in order to properly interpret endocrine results