ABIM Board Review Endocrinology 2005

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ABIM Board ReviewEndocrinology2005
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Strategies

• Prior to exam
• Focus on the testable material
• Avoid controversial areas
• Practice test questions
• Emphasize integrated questions
• Stay healthy
• Confidence (92 passed in 04)
• During Exam.
• Budget your time
• Mark harder questions to return to later
• Dont cheat
• Avoid irritating colleagues during breaks
• Confidence

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Endocrine Top 10

• Pituitary Disease
• Thyroid Function Testing
• Thyroid Nodules
• Adrenal hyper/hypofunction
• Adrenal incidentalomas
• Amenorrhea
• Diabetes
• Bone and Calcium Disorders
• SIADH
• Lipids

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PITUITARY
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• With exception of PRL, all anterior hormones are
  regulated by hypothalamic releasing hormones (via
  the stalk) and feedback by peripheral hormones
• AVP regulated by serum Osm, BP
• PRL unique because under tonic inhibition by
  Dopamine

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Pituitary Key Points

• Presentation of pituitary masses (hormone
  changes, mass effect, invasion, differences in
  men and women)
• Work-up suspected pituitary deficiency
• Distinguish prolactinoma hyperprolactinemia
• Factors that can elevate PRL
• Medical vs. surgical management of tumors
• Principles of panhypopituitarism
• Complications of acromegaly

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Anatomical Relationships
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THYROID
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Thyroid Physiology

• Uptake and concentration of Iodide ion
• Stimulated by TSH, Inhibited by perchlorate
• Thyroglobulin made in follicular cells,
• secreted into lumen, stored as colloid.
• In lumen, thyroid peroxidase oxidizes
• iodide and incorporates it into tyrosine
• residue of thyroglobulin protein
• The joining of mono and diiodotyrosine
• makes T4 and T3
• Under TSH, thyroglobulin molecules are
• retrieved via endocytosis into the follicular
• cell. There, lysosomal proteases release
• free T4 and T3 (101), which enter capillaries

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Euthyroid Sick

• Mild-moderate illness
• T3 decreases as a result of reduced conversion of
  T4 to T3 in peripheral tissues
• Serum free T4 usually normal TSH normal or
  elevated
• rT3 increases
• Severe illness
• T3 levels decrease further
• T4 also decreases because of decreased binding
  proteins and decreased TSH secretion
• How can euthyroid sick be distinguished from
  hypothyroidism?
• In hypothyrodism, both T4 and T3 will be low rT3
  is low
• In euthyroid sick, T3ltltT4 and rT3 is elevated
• Do not treat euthyroid sick. In hospitalized
  patients w/ abnormal TFTs,
• repeat approximately 6 weeks after discharge

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Radioiodine Uptake vs. Scan

• Tissues that take up trap iodine can be
  visualized and/or treated w/ RAI
• Although other tissues can take up I- , only
  differentiated thyroid tissue (normal or
  metastatic) can trap the RAI
• RAIU gives a number () of I- uptake. Used to
  determine whether patients with thyrotoxicosis
  have a high RAIU or a low RAIU disorder.
• A scan gives a picture of the I- distribution in
  the gland. Used to distinguish among the three
  types of high-RAIU thyrotoxicosis and to
  determine whether thyroid nodules are
  nonfunctioning (cold), or hyperfunctioning (hot)

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Radioiodine Uptake and Scan

• Only done when theres hyperthyrodism
• If low
• Thyroiditis
• Exogenous T4 ingestion
• Struma ovarii
• If high
• Graves, HCG, TSH adenoma
• Toxic nodule
• Multinodular goiter

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Thyroid Nodules

• Always get TSH and FT4
• If TSH suppressed, do RAIU and scan to r/o a hot
  nodule
• If TSH normal or elevated, then biopsy
• For boards, biopsy all palpable nodules and
  incidentalomas gt1.5 cm
• Hot nodules are virtually all benign
• Cancers are cold, although most cold nodules are
  benign

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Thyroid Cancer

• Thyroidectomy
• Suppression of TSH w/ Synthroid
• RAI ablation of remnant thyroid tissue
• Whole body scan w/ I131 6 months later
• Periodic surveillance with thyroglobulin
  measurements

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ADRENAL
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Cushings

• All of my patients look like they have Cushings!
  Are some
• clinical findings more specific than others?
• Sign/symptom Sensitivty () Specificity ()
• Hypokalemia 25 96
• Ecchymoses 53 94
• Osteoporosis 26 94
• Weakness 65 93
• DBP gt105 39 83
• -If clinically suspected, then confirm
  biochemically w/
• 24-hr urinary cortisol. (Elevated if 3x normal)
• -If ACTH is suppressed, then cause is either an
  adrenal
• neoplasm or exogenous steroids

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What if both Cortisol and ACTH are Elevated ?

• ACTH should normally be suppressed when Cortisol
  is high.
• If ACTH is detectable, then its either from
  pituitary or ectopic secretion
• In order to determine the source, do high-dose
  overnight Dex suppression. If AM cortisol
  decreases by 50 from baseline, then likely
  pituitary Cushings. Order MRI next.
• If cortsiol remains elevated, search for ectopic
  ACTH (lung cancer, carcinoid)

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Adrenal Insufficiency

• In primary AI, mineraldocorticoids,
  glucocorticoids and adrenal androgens are lost
• In secondary AI, mineraldocorticoids are
  preserved because they are under control of
  renin-angiotensin axis.
• Most commonly caused by exogenous steroids
• Other causes include pituitary adenomas,
  panhypopit, stalk disruption
• Diagnose primary AI with cosyntropin stim test
  (gt20ug/mL excludes diagnosis)
• Diagnose secondary AI with CRH stim test,
  metapyrone test or insulin-induced hypoglycemia

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Adrenal Incidentalomas

• Determine whether the lesion is hormonally active
  or nonfunctioning and
• whether it is malignant or benign.
• Size is best predictor of malignancy. Tumors gt6
  cm have high risk of malignancy lt4 cm rarely
  malignant.
• Most common hormonal disorder is subclinical
  Cushings
• All patients with an incidentaloma should have a
  1-mg dexamethasone suppression test and a
  measurement of plasma-free metanephrines.
• Patients with hypertension should also undergo
  measurement of serum potassium and plasma
  aldosterone concentration/plasma renin activity
  ratio.
• Indications for surgery
• Functional tumors
• All tumors gt6cm
• Tumors 4-6cm w/ features suggestive of cancer or
  rapid growth

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AMENORRHEA
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Amenorrhea

• Pregnancy
• Pituitary/hypothalamic
• -Prolactin (impairs GnRH)
• -Hypothyrodism (raises PRL)
• -GnRH deficiency or loss of pulsatility
  (anorexia, female athletic triad)
• -Gonadotropin deficiency (Kallmans syndrome)
• PCOS
• -increased LH/FSH
• Primary ovarian problem
• -Estrogen or progestin deficiency (diagnose by
  withdrawal testing)
• -Polyglandular deficiency (DM, Graves, vitiligo,
  AI)
• -Chemotherapy, XRT
• Plumbing
• -Anatomic problem (Ashermans syndrome)

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DIABETES
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Outpatient Diabetes

• Screening
• Current guidelines
• Use of oral agents
• Insulin regimens
• Gestational diabetes

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Who Should be Screened for Diabetes?

• ?45 years old repeat q 3 years
• Overweight (BMI 25 kg/m2)
• Physically inactive
• Have a first-degree relative with diabetes
• High-risk ethnic population
• h/o GDM or baby gt9 lbs
• HTN
• Hyperlipidemia
• PCOS
• Other sx of insulin resistance (acanthosis)
• h/o vascular disease

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Criteria for the diagnosis of diabetes

• Symptoms of diabetes and a casual plasma glucose
  200 mg/dl or..
• FPG 126 mg/dl ( no caloric intake for at least 8
  hr) or
• BS 200 mg/dl after OGTT (2 hr after 75 gm
  glucose).
• In the absence of unequivocal hyperglycemia,
  these
• criteria should be confirmed by repeat testing on
  a different
• day.
• OGTT is not recommended for routine clinical
• use, but may be required in the evaluation of
  patients with
• IFG or when diabetes is still suspected despite a
  
• normal FPG as with the postpartum evaluation of
  women
• with GDM.

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Recommendations for Adults w/ DM

• A1Clt7.0 (q 3 mo if uncontrolled twice yr if at
  goal)
• Preprandial BS 80-110 mg/dl (60-90 if pregnant)
• Postprandial BSlt140 mg/dl (lt120 if pregnant)
• Blood pressurelt130/80 mmHg
• LDLlt100 mg/dl
• Triglycerides lt150 mg/dl
• HDLgt40 mg/dl
• Annual influenza vaccine
• Pneumococcal vaccine for adults with diabetes
• Revaccination is for individuals gt64 if vaccine
  was administered gt5 years ago. Other indications
  for repeat vaccination include nephrotic
  syndrome, chronic renal disease, and other
  immunocompromised states, such as after
  transplantation.

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Health Maintainance

• SMBG TID w/ DM1 and GDM
• BP each visit
• Annual urinary microalbumin (lt30ug/mg)
• Annual lipids
• Annual optho exam starting 3-5 yrs after onset w/
  DM1, and upon diagnosis in DM 2
• Visual foot exam each visit. Comprehensive exam
  yearly (sensation, biomechanics, foot structure,
  vascular status and skin integrity)

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Mnemonic for Diabetes Office Visits
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Screening for Gestational Diabetes

• Risk assessment at first prenatal visit
• Low-risk status requires no glucose testing
• Age lt25 years
• Weight normal before pregnancy
• Member of an ethnic group with low prevalence
• No known diabetes in first-degree relatives
• No history of abnormal glucose tolerance
• No history of poor obstetric outcome
• High risk features (obesity, h/o GDM, glycosuria,
  or FH) should undergo glucose testing as soon as
  possible

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Diagnosis of GDM

• FPG 126 mg/dl or a casual plasma glucose 200
  mg/dl meets the threshold for the diagnosis of
  diabetes (confirm on subsequent day)
• High-risk women not found to have GDM at initial
  screening and average-risk women should be tested
  between 24 and 28 weeks of gestation. Testing
  should follow one of two approaches
• One-step approach 100-g OGTT
• 95 mg/dl fasting
• 180 mg/dl at 1 h
• 155 mg/dl at 2 h and 140 mg/dl at 3 h.
• Two or more of the plasma glucose values must be
  met or exceeded for a positive diagnosis
• Two-step approach perform an initial screening
  by measuring the plasma or serum glucose
  concentration 1 h after a 50-g oral glucose load
  and perform a diagnostic 100-g OGTT on that
  subset of women exceeding 140 mg/dl

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Oral Hypoglycemic Agents

Each will lower A1c by 1-2 compared to placebo.
When combined, efficacy typically is additive
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FDA-Approved Combination Therapies

• Sulfonylurea Metformin
• Sulfonylurea a-glucosidase inhibitors
• Sulfonylurea TZD
• Metformin Secretagogues
• Metformin TZD
• Insulin Sulfonylurea
• Insulin Metformin
• Insulin TZD

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Insulin

• Know the types of insulin and onset
• Know how to adjust insulin
• All regimens include basal and bolus

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Adjusting Insulin

• Make changes slowly, taking into account diet,
  activity, stress
• Asses the effectiveness of insulin at its peak
  time of action
• Increase short/rapid insulin based on
  post-prandial readings
• Increase long-acting when BG high fasting or
  throughout day
• Inject into subcutaneous abdomen and rotate sites

To ? pre-dinner BG.?AM intermediate-acting
(e.g., NPH) To ? fasting BG.. ?PM
long/intermediate-acting insulin (e.g., glargine,
NPH) To ? pre-lunch BG..?AM short/rapid-acting
insulin (e.g., regular, lispro, aspart) To ?
bedtime BG....?PM short/rapid-acting insulin
(regular, lispro, aspart)
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DKA

• Decreased insulin, high counterregulatory
  hormones (catecholamines, glucagon, GH,
  cortisol), leading to hyperglycemia, proteolysis,
  lipolysis ketone production
• Diagnostic Criteria
• hyperglycemia glucosegt250 mg/dl
• acidosis pH lt7.35 HCO3 lt 18
• ketosis (blood /or urine)
• Therapeutic Goals
• Improve circulating volume tissue perfusion
• Identify precipitating factors
• FLUIDS restores intravascular volume, decreases
  counterregulatory hormones and lowers glucose
  levels
• Reduce Gluc. serum osmolarity lytes q2,
  glucose q1
• Clear ketones, fix electrolytes

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BONE AND CALCIUM DISORDERS
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Hypercalcemia
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Treatment of Hypercalcemia

• Fluids then lasix once euvolemic
• Search for causes
• Antiresorptive therapies
• (Bisphosphonates, Calcitonin) if caused by high
  bone turnover
• Steroids if due to extra-renal vitamin D
  production (Sarcoidosis, lymphoma, TB)

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Indications for Parathyroidectomy

• Serum Ca ?1.0 mg/dL above the upper limit of
  normal
• Hypercalciuria (urinary Ca excretion gt400 mg/day
• Cr clearance ?30 of age-matched controls
• BMD T score lt-2.5
• Patients who are less than 50 years old
• Patients in whom periodic follow-up will be
  difficult
• 2002 NIH Workshop

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Osteoporosis

• Standard deviationdistribution about the mean in
  a set of data.
• T-score is the number of SD above/below mean for
  sex-matched, young adults for the site measured
  2.5 means 2.5 SD below the mean
• Z-score is the number of SD above/below mean for
  sex and age-matched controls
• Osteoporosis defined by T-score of -2.5 or lower,
  ie. 2.5 SD below the mean Osteopenia is -1.0-2.5
• Z-scores used to r/o accelerated osteoporosis
  such as w/ secondary causes

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Causes of Osteoporosis

• 1. Failure to achieve peak bone mass
• 2. Increased bone resorption
• 3. Inadequate replacement of lost bone
• Primary Osteoporosis bone loss that occurs
• during the normal aging process
• Secondary Osteoporosis due to a specific
• clinical disorder which decreases BMD

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Predictors of Low Bone Mass

• Female sex
• Advancing age
• Sex steroid deficiency
• White race
• Low body weight and BMI
• Family history
• Low calcium intake
• Smoking or excessive alcohol intake
• Low level of physical activity
• Chronic glucocorticoid use
• History of fracture

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Who Should be Worked up for Secondary Causes?

• No clear guidelines
• Suspect in younger patients with low trauma
  fracture or low BMD
• Common causes
• Hyperthyroidism
• Vitamin D deficiency
• Steroids

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Glucocorticoids

• Bone loss occurs w/ sustained doses (5 mg/day
  Predisone)
• Greater effects on axial skeleton (vertebral fx)
• Excessive inhaled steroids can decrease BMD
• Cause accelerated bone loss by increasing bone
  resorption and decreasing formation
• Decreased muscle mass contributes to falls

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Screening Guidelines
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Treatment Indications
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Treatment Options

• Should address the 3 causes
• of osteoporosis
• peak bone mass
• increased bone resorption
• inadequate replacement of lost bone)

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Calcium and Vitamin D

• Reduces rate of hip fractures in nursing home
  patients
• Indicated for all postmenopausal women and anyone
  at risk for osteoporosis
• Given along with any other osteoporosis treatment
  
• Dosages of 1000-1500mg/day of calcium and 400-800
  U of Vitamin D
• Calcium citrate may be more effective than
  carbonate and is preferred in patients with a
  history of renal stones

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Bisphosphonates

• Potent inhibitors of osteoclasts
• Reduce the rate of bone turnover
• Proven in prospective randomized trials to
  prevent bone loss, increase BMD at spine and hip
  and reduce fractures
• Prolonged action (weekly dosing)
• GI side effects

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Bisphosphonates
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Calcitonin

• Inhibits osteoclast-mediated bone resorption
• Increased BMD of spine and reduced incidence of
  new vertebral fractures by 33 in postmenopausal
  women with osteoporosis (5-year study)
• Has not been demonstrated to reduce hip and
  nonvertebral fractures
• Side effects include rhinitis, nose bleeding

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Raloxifine

• SERM (Selectieve Estrogen Receptor Modulator)
• Agonist in bone and lipoprotein antagonist in
  breast and uterus
• Indicated for prevention or treatment of
  osteoporosis
• Increases spine and femoral BMD
• Shown to reduce vertebral fractures in
  postmenopausal women

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Teriparatide

• Recombinant PTH
• Paradoxically increases BMD when given in pulse
  injections
• Stimulates new bone formation
• Increases spine and hip BMD
• Reduces risk of vertebral and nonvertebral
  fractures in postmenopausal women
• Risk of osteosarcoma in animal studies
• Contraindicated in children, adolescents,
  pregnancy, hypercalcemia and Pagets disease
• Only approved for 2 years

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Estrogen

• Suppresses osteoclast activity
• WHI showed estrogen plus progesterone increased
  BMD and reduced fractures in postmenopausal women
• Because of WHI, HRT is no longer recommended for
  prevention or treatment
• Ongoing studies looking at ultralow-dose estrogen
  and combination of low dose estrogen with
  bisphosophonates
• Stay tuned....

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Treatment Summary

• Post-menopausal women
• Alendronate and risedronate reduce hip and
  vertebral fracture risk
• Raloxifene and calcitonin reduce vertebral
  fracture risk
• Hormone replacement therapy reduces vertebral and
  hip fracture risk
• Men with osteoporosis
• Alendronate reduces vertebral fracture risk
• In glucocorticoid use
• Risedronate (and perhaps alendronate) reduces
  vertebral fracture risk

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Osteomalacia

• Poorly mineralized bone matrix caused by
  deficiency of Ca or PO42-
• Usually from vitamin D deficiency or phosphaturia
• Bone pain, muscle weakness
• Multiple fractures
• Diagnose w/ bone biopsy
• Vitamin D deficiency from low sun exposure, or
  malabsorption

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SIADH
SIADH
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SIADH

• Euvolemic hyponatremia
• Caused by ectopic secretion of ADH or diffuse
  input into the hypothalamus
• Must rule out other causes of free-water
  retention (adrenal insuff, hypothyroidism)
• Distinguish from psychogenic polydipsia by urine
  Osm (concentrated in SIADH)
• Can do a diagnostic volume stimulation test w/
  normal saline
• ?UNa ?PNa SIADH
• ?UNa ?PNa Dehydration

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SIADH Treatment

• Treatment depends on chronicity.
• If acute and severe symptoms, slowly raise Na w/
  3
• If chronic, then fluid restrict
• Demeclocycline inhibits activity of ADH
  (nephrotoxic)
• V2 antagonists currently in Phase 3 trials
• Greatest risk is central pontine demyelinosis
  from rapid correction
• Symptoms occur several days after correction.
• Fluctuating consciousness, convulsions,
  hypoventilation

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LIPIDS
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LDL Goals Based on Risk
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Criteria for Metabolic Syndrome
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Lipid Drugs
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