Thyroid Hormones

Jason Ryan, MD, MPH

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 Thyroid Hormones
• Produced by the thyroid gland
• Triiodothyronine (T3) and thyroxine (T4) Tyrosine

• Both synthesized from tyrosine and iodine

Triiodothyronine (T3) Thyroxine (T4)

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 Thyroid Hormones
• Contain the element iodine
• Iodized salt
• Table salt (NaCl) mixed with small minute amount of iodine
• Done in many countries to prevent iodine deficiency
• Added to salt in US in 1924
• For thyroid hormone, iodine in our diet needs to be:
• Oxidized to I2 (“oxidation”)
• Added to organic/carbon structures (“organification”)

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 TPO
Thyroid Peroxidase
• Multifunctional enzyme
• Catalyzes several steps in thyroid hormone synthesis
• Oxidation of iodine
• Organification of iodine into MIT/DIT
• Coupling of MIT/DIT into T3/T4
• TPO antibodies common in autoimmune thyroid disease

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 Thyroid Peroxidase
TPO

Monoiodotyrosine
(MIT)
Tyrosine Triiodothyronine (T3)
TPO TPO
+

Iodine (I2)

TPO

I- I- Diiodotyrosine
(DIT) Thyroxine (T4)

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 Thyroglobulin
• Protein produced by thyroid follicular cells
• Contains numerous tyrosine molecules
• Tyrosine → MIT/DIT → T3/T4
• Thyroglobulin antibodies in autoimmune thyroid disease

Tyrosine Tyrosine Tyrosine

Tyrosine
Tyrosine

Thyroglobulin

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 Thyroid Hormones
• Thyroxine (T4) is major hormone produced by thyroid gland
• Over 90% of thyroid hormone produced is T4
• Triiodothyronine (T3) more potent hormone
• 5’ deiodinase converts T4 → T3
• Most conversion occurs in peripheral tissues

Iodine

5’-deiodinase
Thyroxine (T4) Triiodothyronine (T3)

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 Wolff-Chaikoff Effect
• Excessive iodine in diet could lead to hyperthyroidism
• Thyroid protects itself via Wolff-Chaikoff Effect
• Iodine inhibits synthesis of thyroid hormone
• Organification inhibited by ↑ iodine
• Less synthesis of MIT/DIT
• Normal patients “escape” with time

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 Wolff-Chaikoff Effect
• “Failure to escape”
• Iodine → prolonged ↓ hormone → hypothyroidism
• Occurs in amiodarone-induced hypothyroidism
• May also occur in autoimmune thyroid disease
• Jod-Basedow phenomenon
• Lack of Wolff-Chaikoff effect
• Excess iodine → hyperthyroidism
• Occurs in patients with toxic adenomas

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 Thyroid Hormone Regulation
• Hypothalamus releases thyroid releasing hormone (TRH)
• Anterior pituitary releases thyrotropin (TSH)
• Thyroid gland releases T3 and T4
• Feedback on pituitary and hypothalamus

Shutterstock

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 TBG
Thyroxine-Binding Globulin
• Thyroid hormones poorly soluble in water
• Circulates bound to TBG (produced in liver)
• Most plasma thyroid hormone is T4
• Almost all T4 is bound to TBG
• Bound T4 does not exert hormone effects
• Small amount of “free T4” produces hormone effects

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 Thyroid Panel
• Four standard measurements to assess thyroid

Test Normal Value

TSH 0.5 to 5.0 mU/L
Total T4 60 to 145 nmol/L
Total T3 1.1 to 3 nmol/L
Free T4 0.01-0.03nmol/L

Note:
T4 > T3
Total T4 >> Free T4
(most bound to TBG)

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 TBG
Thyroxine-Binding Globulin
• Increased production due to estrogen
• Occurs in pregnancy
• Contraceptives or hormone replacement
• Raise total T4
• TSH and free T4 will be normal
• Classic findings high estrogen states
• Elevated total T4
• Normal TSH and free T4
• Does not indicate thyroid disease

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 Thyroid Hormones
Pregnancy
• Rise in TBG levels (estrogen)
• Rise in total T4 level
• hCG stimulates thyroid (same alpha unit as TSH)
• Raises free T4 → lower TSH

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 Thyroid Hormone Effects
• Major regulator of metabolic activity and growth
• Glucose and lipid metabolism
• Cardiac function
• Bone growth
• CNS development

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 Thyroid Hormone
Metabolic Effects
• ↑ carbohydrate metabolism
• ↑ glycogenolysis, gluconeogenesis
• ↑ serum glucose
• ↑ lipid metabolism
• ↓ concentrations of cholesterol, triglycerides
• Hypothyroid patients: ↑ cholesterol
• Check TSH in hyperlipidemic patients
• Hyperthyroid patients: hyperglycemia Cholesterol

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 Thyroid Hormone
Metabolic Effects
• ↑ basal metabolic rate
• Basal rate of energy use per time
• Amount of energy burned if you slept all day
• ↑ Na/K ATPase pumps
• More pumps = more ATP consumed
• ↑ oxygen demand to replenish ATP
• ↑ respiratory rate
• ↑ body temperature
• Hypothyroid patients: weight gain
• Hyperthyroid patients: weight loss

Wikipedia/Public Domain

McDonough AA, et al. Thyroid hormone coordinately regulates Na+-K+-ATPase alpha- and beta-subunit
mRNA levels in kidney. Am J Physiol. 1988 Feb;254(2 Pt 1):C323-9.

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 Thyroid Hormone
Cardiac Effects
• ↑ β1 receptors in heart
• ↑ cardiac output and heart rate
• Hypothyroid patients: bradycardia
• Hyperthyroid patients: tachycardia or arrhythmias
Tachycardia

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 Thyroid Hormone
Bone effects
• Thyroid hormones increase bone turnover
• Stimulates bone resorption
• Hyperthyroidism: osteoporosis and hypercalcemia

Wikipedia/Public Domain

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 Thyroid Hormone
CNS and Bone Development
• TH required for normal bone growth/CNS maturation
• Childhood hypothyroidism → cretinism
• Stunted growth
• Intellectual disability
• Large tongue
• Umbilical hernia
• Causes
• Iodine deficiency
• Congenital thyroid disease

Wellcome Images/Wikipedia

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 Hypothyroidism
Jason Ryan, MD, MPH

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 Hypothyroidism
• Underproduction of thyroid hormone by thyroid gland
• Metabolism SLOWS DOWN
• Highly variable clinical features
• Symptoms can be subtle
• Some patients have minimal symptoms

Pixabay.com

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 Hypothyroidism
Clinical Features
• Lethargy and fatigue
• Weakness
• Cold intolerance
• Weight gain with loss of appetite
• Constipation
• Hyporeflexia
• Dry, cool skin Sinus Bradycardia
• Coarse, brittle hair
• Bradycardia

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 Hypothyroidism
Clinical Features
• Hyperlipidemia
• ↑ total cholesterol
• ↑ LDL cholesterol
• TSH often checked in hyperlipidemia
• Myopathy
• Muscle symptoms common in hypothyroid
• Weakness, cramps, myalgias
• ↑ serum creatine kinase (CK) common (up to 90%)
• Hyponatremia
• High levels of ADH (SIADH)

Wikipedia/Public Domain

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 Hypothyroidism
Clinical Features
• Infertility
• Associated with increased prolactin
• Low FSH/LH
• Disruption of menstrual cycle
• Low sperm count
• Cognitive impairment
• Depression
• Hypertension
• Causes aortic stiffness

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 Myxedema
Thyroid dermopathy
• Non-pitting edema of the skin from hypothyroidism
• Hyaluronic acid deposits in dermis
• Draws water out → swelling
• Usually facial/periorbital swelling
• Pretibial myxedema
• Special form of myxedema over shin
• Seen in Graves’ disease (hyperthyroidism)
• Myxedema coma = coma from hypothyroidism

Herbert L. Fred, MD and Hendrik A. van Dijk

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 Hypothyroidism
Subtypes
• Primary hypothyroidism
• Most common form
• Failure of thyroid gland function due to disease or iodine deficiency
• TSH will be high
• Central hypothyroidism: rare
• Failure of pituitary gland or hypothalamus
• Same causes as hypopituitarism
• Usually occurs with deficiency of other pituitary hormones
• Workup usually involves MRI of brain
• TSH will be low or inappropriately normal

Shutterstock

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 Hypothyroidism
Lab Findings

Test Normal Value Primary Central

TSH 0.5 to 5.0 mU/L HIGH LOW or NL
Total T4 60 to 145 nmol/L Low Low
Total T3 1.1 to 3 nmol/L Low Low
Free T4 0.01-0.03nmol/L Low Low

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 Goiter
• Enlarged thyroid
• Mild forms detected on physical exam
• Normal thyroid = 15 to 25 grams
• Caused by excess stimulation of thyroid gland
• Primary hypothyroidism
• High TSH, inability to produce T3/T4
• Hyperthyroidism due to Graves’ disease
• Thyroid stimulating antibodies

Wikipedia/Public Domain

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 Subclinical Hypothyroidism
• Normal free T4
• Increased TSH
• Generally asymptomatic
• Often identified on routine lab work
• Same causes as overt hypothyroidism
• Treated only if TSH > 10 mU/L
• High risk of and progression to symptoms
• Also risk of atherosclerosis and myocardial infarction

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 Thyroid Function in Illness
Euthyroid Sick Syndrome
• Thyroid hormone levels often abnormal in critically-ill patients
• Related to underlying illness with no treatment required
• Levels only checked if strong suspicion of thyroid disease
• Low T3: low conversion T4 → T3 (cortisol, cytokines)
• May also see low TSH → Low T3/T4
• Early: low T3; low-normal TSH and T4
• Late: Low TSH, T3 and T4

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 Thyroid Function in Illness
Euthyroid Sick Syndrome
• Key test: reverse T3 (rT3)
• Isomer of T3
• Level rises in critical illness due to impaired clearance
• Critically ill patient with low TSH/T4/T3
• Check rT3
• Low → central hypothyroidism
• High → sick euthyroid syndrome (no treatment)

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 Primary Hypothyroidism
Causes, demographics and workup
• Most common cause worldwide: iodine deficiency
• Rare in US due to iodized salt
• Most common cause US: autoimmune thyroiditis
• Prevalence increases with age
• More common in women
• Diagnosis by lab testing (TSH, T3, T4)
• Additional testing usually not performed
• Antibody testing or nuclear scans only used in select cases

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 Primary Hypothyroidism
Treatment
• Levothyroxine
• Synthetic T4
• Check TSH in 6 weeks
• Titrate dose to normal TSH (0.5 to 5.0 mU/L)
• Treat all symptomatic patients
• Subclinical patients: TSH concentrations >10 mU/L

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 Primary Hypothyroidism
Treatment
• Higher dosages required with higher TBG levels
• Occurs in high estrogen states
• Pregnancy
• Hormone replacement therapy

Øyvind Holmstad/Wikipedia

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 Myxedema Coma
• Severe hypothyroidism
• Altered mental status, hypothermia and organ dysfunction
• Hypoventilation, bradycardia
• Hyponatremia
• May be due to severe, longstanding hypothyroidism
• Or caused by an acute event in poorly-controlled hypothyroidism
• Infection, myocardial infarction, surgery
• Administration of sedatives (e.g., opioids)

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 Myxedema Coma
Diagnosis and Treatment
• Diagnosis: TSH and thyroid hormone levels
• Intravenous combined therapy: T4 (levothyroxine) and T3 (liothyronine)
• Stress-dose glucocorticoids
• Often IV hydrocortisone 100 mg every eight hours
• Mechanical ventilation
• Intravenous fluids

Hydrocortisone

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 Primary Hypothyroidism
Causes
• Chronic lymphocytic thyroiditis
• Other forms of thyroiditis
• Iodine deficiency
• Drugs

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 Thyroiditis
• Thyroid gland inflammation
• Painful when caused by infection, radiation or trauma
• Painless when caused by autoimmune disease or medications
• May initially cause hyperthyroidism → hypothyroidism
• Most common form: chronic lymphocytic thyroiditis

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 Chronic Lymphocytic Thyroiditis
Hashimoto’s Thyroiditis
• Most common cause of hypothyroidism in the US
• Infiltration of thyroid gland by lymphocytes Lymphocyte
• Autoimmune disorder
• HLA-DR3, HLA-DR5 and others
• Antibodies produced
• Anti-TPO
• Anti-thyroglobulin
• Not required to begin treatment
• Can be used to confirm the diagnosis

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 Chronic Lymphocytic Thyroiditis
Hashimoto’s Thyroiditis
• More common among middle-aged women
• Can occur at any age or in men
• Enlarged non-tender thyroid gland
• Gradual loss of thyroid function → symptoms
• Symptoms and labs consistent with hypothyroidism
• Treatment: thyroid hormone replacement
• Increased risk of non-Hodgkin B cell lymphoma

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 Subacute Thyroiditis
de Quervain’s Thyroiditis/Granulomatous Thyroiditis
• Post-viral inflammation of thyroid
• Most common cause of thyroid pain
• Occurs in young women
• Tender, enlarged thyroid gland
• Variable lab findings
• Hyperthyroid → euthyroid → hypothyroid
• Thyroid symptoms usually mild (no treatment)
• Elevated ESR and CRP

Shutterstock

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 Subacute Thyroiditis
de Quervain’s Thyroiditis/Granulomatous Thyroiditis
Radioactive Iodine Uptake Scan
• Clinical diagnosis
• Neck pain with tender, enlarged thyroid
• Low thyroid radioiodine uptake
• Usually less than 1 to 3 percent
• Inflammation interferes with uptake
• Treatment:
• Anti-inflammatories (aspirin, NSAIDs, steroids)
• Usually resolves in few weeks

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 Subacute Lymphocytic Thyroiditis
Painless Thyroiditis
• Variant of Hashimoto’s
• Lymphocytic infiltration of thyroid gland
• Transient mild hyperthyroidism
• Resembles Graves’ disease without eye/skin findings
• Serum thyroid stimulating immunoglobulins not elevated
• Radioiodine uptake low when hyperthyroid
• Contrast with Graves’ disease: upper normal or high
• Rarely can be followed by hypothyroidism
• Usually self-limited – resolves over weeks

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 Postpartum Thyroiditis
• Similar to painless thyroiditis
• By definition occurs within one year after pregnancy
• Delivery of baby or after spontaneous/induced abortion
• Self-limited

PxHere.com

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 Fibrous Thyroiditis
Riedel’s Thyroiditis
• Fibroblast activation and proliferation
• Fibrous tissue (collagen) deposition in thyroid
• “Rock hard” thyroid
• Often extends beyond the thyroid
• Parathyroid glands → hypoparathyroidism
• Recurrent laryngeal nerves → hoarseness
• Trachea compression → difficulty breathing

Shutterstock

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 Fibrous Thyroiditis
Riedel’s Thyroiditis
• Associated with IgG4 plasma cells
• IgG4 plasma cells identified in biopsy specimens
• Diagnosis: biopsy
• Treatment: thyroid hormone replacement
• Surgery often required to relieve thoracic compression Plasma Cell

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 Infiltrative Thyroid Disease
Amyloidosis
• Fibrous thyroiditis
• Amyloidosis
• Sarcoidosis
• Hereditary hemochromatosis

Ed Uthman, MD

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 Iodine Deficiency
• Constant elevation of TSH → enlarged thyroid
• “Endemic goiter”
• Goiter in regions with widespread iodine deficiency

Wellcome Images

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 Goitrogens
• Substances that inhibit thyroid hormone production
• Lithium (inhibits release of thyroid hormone)
• Amiodarone

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 Amiodarone
• Antiarrhythmic drug
• May cause hypothyroidism
• Excess iodine → Wolff-Chaikoff Effect
• Normal patients “escape” in few weeks
• Pre-existing subclinical thyroid disease → “failure to escape”
• Also inhibits conversion of T4 → T3
• May also cause hyperthyroidism
• Increased iodine → increase hormone synthesis
• May also cause thyroiditis → hyperthyroidism
• Must check TSH prior to starting therapy

Amiodarone

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 Iatrogenic Hypothyroidism
• Thyroid surgery
• Treatment for Graves’ or malignancy
• Radioiodine therapy
• I131 administered orally as solution or capsule
• Beta-emissions → tissue damage
• Ablation of thyroid function over weeks
• Treatment for Graves’ or malignancy
• Neck radiation
• Hodgkin’s lymphoma
• Head and neck cancer

Public Domain

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 Hyperthyroidism
Jason Ryan, MD, MPH

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 Hyperthyroidism
• Overproduction of thyroid hormone by thyroid gland
• Metabolism SPEEDS UP
• Hyperactivity
• Heat intolerance
• Weight loss with increased appetite
• Diarrhea
• Hyperreflexia
• Warm, moist skin
• Fine hair
• Tachycardia (atrial fibrillation)

Shutterstock

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 Hyperthyroidism
Subtypes
• Primary hyperthyroidism
• Most common form
• Overactivity of thyroid gland not due to high TSH
• Low TSH with high T3/T4
• Central hyperthyroidism: rare
• Excess TSH from pituitary gland
• High TSH and high T3/T4
• Neoplastic: pituitary tumor (TSHoma)
• Non-neoplastic: pituitary resistance to thyroid hormone

Shutterstock

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 Hyperthyroidism
Lab Findings

Test Normal Value Primary Central

TSH 0.5 to 5.0 mU/L LOW NL or HIGH
Total T4 60 to 145 nmol/L High High
Total T3 1.1 to 3 nmol/L High High
Free T4 0.01-0.03nmol/L High High

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 Primary Hyperthyroidism
Causes
• Graves’ disease (most common)
• Multinodular goiter
• Toxic adenoma
• Iodine-induced
• Amiodarone
• Thyroiditis
• Levothyroxine

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 Graves’ Disease
• Autoimmune disease
• Thyroid stimulating antibodies produced
• Symptoms of hyperthyroidism occur
• Large non-nodular thyroid

Shutterstock

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 Graves’ Disease
Special features
• Exophthalmos (bulging eyes)
• Proptosis (protrusion of eye) and periorbital edema
• Retroocular fibroblast and adipocyte activation
• Pretibial myxedema (shins)
• Fibroblasts contain TSH receptor
• Stimulation → secretion of glycosaminoglycans
• Draws in water → swelling

Herbert L. Fred, MD and Hendrik A. van Dijk

Jonathan Trobe, M.D./Wikipedia

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 Graves’ Disease
Diagnosis
• Often clinical: hyperthyroid symptoms and labs, goiter plus exophthalmos
• TSH receptor antibodies Radioactive Iodine Uptake Scan
• Thyrotropin receptor antibodies (TRAb)
• Also called TSIs: “Thyroid stimulating immunoglobulins”
• Radioactive iodine uptake
• Increased due to overactive thyroid

TELEGRAM: @EMEDICALLIBRARY

03/10/2022
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 Graves’ Disease
Treatment
• Symptom control: beta blockers
• Used for initial treatment of symptoms
• Improves tachycardia
• Usually atenolol – once daily dosing
• Decrease thyroid hormone synthesis
• Thionamides
• Radioiodine thyroid ablation
• Surgery

Public Domain

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 Thionamides
• Inhibit production of thyroid hormone
• Used initially to improve moderate to severe symptoms
• Methimazole
• Most commonly used drug
• Once daily dosing - usually well tolerated
• Propylthiouracil
• Main use is 1st trimester of pregnancy
• Lower risk of adverse fetal effects
• Also used in thyroid storm

Public Domain

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 Thionamides Agranulocytosis
Adverse Effects
• Agranulocytosis
• Rare drop in WBC
• May present as fever, infection after starting drug
• WBC improves with stopping drug
• Aplastic anemia cases reported
• Hepatotoxicity
• Baseline testing: CBC and LFTs
• Monitoring WBC: controversial
• Not recommended by American Thyroid Association guidelines
• Most clinicians advise patients to report any signs of infection
• Signs of infection → stop drug → check CBC

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 Graves’ Disease
Treatment
• Radioiodine ablation
• Usually given as oral capsule
• Concentrated in thyroid → ablation
• Requires lifelong replacement therapy
• Associated with increase in TRAb
• May lead to worsening orbitopathy
• Surgery (thyroidectomy)
• May cause hypoparathyroidism
• May cause recurrent laryngeal nerve damage
• Associated with a fall in TRAb
• Does not worsen orbitopathy

Shutterstock

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 Thyroidectomy
Post-operative hypocalcemia
• Common complications of thyroidectomy
• Paresthesias of lips, mouth, hands and feet
• Muscle twitches or cramps
• Rarely trismus (lockjaw) or tetany
• Reduced serum calcium
• Treatment: IV calcium gluconate

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 Graves’ Orbitopathy
• Can cause irritation, excessive tearing or eye pain
• Symptoms often worsened by cold air, wind or bright lights
• Immune-mediated process
• Mainstay of treatment when severe: glucocorticoids
• Other immunosuppressants may be used
• Also treated with radiation or surgery

Jonathan Trobe, M.D./Wikipedia

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 Toxic Adenomas
Multinodular Goiter
• Thyroid nodules
• Function independently
• Usually contain mutated TSH receptor
• No response to TSH
• One nodule: toxic adenoma
• Multiple: toxic multinodular goiter
• Findings:
• Palpable nodule(s) or nodular goiter
• Hyperthyroidism symptoms/labs
• Increased uptake of radioiodine in nodule(s)

Public Domain

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 Toxic Adenomas
Treatment
• Initial symptom control: beta blockers and thionamides
• Preferred therapy for most patients: radioiodine ablation
• Accumulates in hyperfunctioning nodules
• Underactive surrounding tissue not affected
• Patient may become euthryoid and avoid thyroid replacement
• Surgery in select patients
• Large, obstructive goiters
• Coexisting thyroid malignancy

Shutterstock

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 Iodine-Induced Hyperthyroidism
Jod-Basedow Phenomenon
• Wolff-Chaikoff effect: excess iodine → decreased hormone production
• Some patients “escape” the Wolff-Chaikoff effect
• Called the Jod-Basedow Phenomenon
• Excess iodine → hyperthyroidism

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 Iodine-Induced Hyperthyroidism
Jod-Basedow Phenomenon
• Often occurs in regions of iodine deficiency
• Introduction of iodine → hyperthyroidism
• Often occurs in patients with toxic adenomas
• Drugs administered with high iodine content
• Expectorants (potassium iodide), CT contrast dye
• Amiodarone

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 Amiodarone
Hyperthyroidism
• Type I
• Occurs in patients with pre-existing thyroid disease
• Graves’ or Multi-nodular goiter
• Amiodarone provides iodine → excess hormone production
• Increased radioiodine uptake
• Type II Amiodarone
• Destructive thyroiditis
• Excess release T4/ T3 (no ↑ hormone synthesis)
• Direct toxic effect of drug
• Can occur in patients without pre-existing thyroid illness
• Decreased radioiodine uptake

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 Amiodarone
Hyperthyroidism Management
• Stop amiodarone if possible
• Radioiodine uptake test to distinguish type I from type II
• Type I: beta blockers, thionamides, ablation or surgery
• Type II (thyroiditis): glucocorticoids Amiodarone

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 Hyperthyroidism
Other Causes
• Early thyroiditis
• Low radioiodine uptake
• High serum thyroglobulin concentration
• Exogenous hyperthyroidism
• Excess levothyroxine
• Supplements with thyroid hormone
• Low radioiodine uptake
• Low serum thyroglobulin concentration

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 Hyperthyroidism
Workup

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 Thyroid Storm
• Life-threatening hyperthyroidism
• Usually precipitated by acute event
• Patient with pre-existing hyperthyroid disease
• Graves’ or toxic multinodular goiter
• Surgery, trauma, infection
• Massive catecholamine surge
• Acute increase in thyroid hormone levels

Pixabay.com

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 Thyroid Storm
Clinical Features
• Fever (up to 106⁰F)
• Delirium
• Tachycardia with possible death from arrhythmia
• Warm skin
• Tremor
• Hyperglycemia (catecholamines/thyroid hormone)
• Hypercalcemia (bone turnover)
• Diagnosis: increased free T4 and T3; low TSH

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 Thyroid Storm Iodine

Treatment
• Propranolol
• Beta blocker → improves symptoms
• Also blocks T4 → T3 conversion
Thyroxine (T4)
• Propylthiouracil
• Preferred over methimazole
• Decreases T4 → T3 conversion 5’-deiodinase
Peripheral Tissues
• Glucocorticoids
• Decreases T4 → T3 conversion
• Reduces inflammation if Graves' disease present

Triiodothyronine (T3) – More Potent

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 Thyroid Storm
Treatment
• Iodine
• Potassium iodide-iodine (Lugol’s) solution
• Blocks release of T4 and T3 from thyroid gland
• ICU level care

Public Domain

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 Thyroid Nodules
Jason Ryan, MD, MPH

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 Thyroid Nodules
• Identified by patients or detected on physical exam by clinician
• Incidental finding on imaging
• Carotid ultrasound
• Neck or chest CT
• May have benign cause
• Cyst, adenoma
• Major clinical concern: thyroid cancer
• Cause of about 5 to 10% nodules

Shutterstock

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 Thyroid Nodules
Workup
• TSH
• Thyroid ultrasound
• Radioactive iodine uptake scan
• Fine needle aspiration

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 Thyroid Nodules
TSH Measurement
• Low TSH
• Overt or subclinical hyperthyroidism
• Suggests hyperfunctioning nodule
• Also T3/T4 measurement for hyperthyroidism
• Risk of malignancy low
• Normal or high TSH
• Possibly malignant nodule
• Higher TSH = higher likelihood cancer

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 Thyroid Nodules
Radioactive iodine scan
• Hyperfunctioning (“hot”) nodule
• Greater uptake than surrounding tissue
• Evaluate for hyperthyroidism
• Risk of malignancy low
• FNA not required Normal
• Nonfunctioning (“cold”) nodule
• Less uptake than surrounding tissue
• Follow-up testing with ultrasound
• May require FNA

Cold Nodule Hot Nodule

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 Thyroid Nodules
Thyroid Ultrasound
• Purely cystic lesions are almost always benign
• Suspicious lesions followed by FNA
• Large nodules (≥ 2 cm)
• Micro calcifications
• Irregular margins
• Extrathyroidal invasion

Public Domain

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 Thyroid Nodules
Workup

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 Thyroid Nodules
Fine Needle Aspiration
• Usually performed under US guidance
• Six categories of results based on Bethesda classification system
Class Description Follow-up
I Non-diagnostic Repeat FNA
II Benign Reassurance and periodic US follow-up
III Atypia of undetermined significance Variable
IV Suspicious for follicular neoplasm Variable
V Suspicious for malignancy Surgery
VI Malignant Surgery

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 Thyroid Cancer
• Papillary
• Follicular
• Medullary
• Anaplastic
• Lymphoma

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 Papillary Carcinoma
• Most common form thyroid cancer (~ 80%)
• Increased risk with prior radiation exposure
• Childhood chest radiation for mediastinal malignancy Papillary Carcinoma
• Survivors of atomic bomb detonation (Japan)
• Nuclear power plant accidents (Chernobyl)
• Median age at diagnosis is 51 years
• Presents as thyroid nodule
• Sometimes identified on imaging (CT/MRI)
• Diagnosis made after fine needle aspiration (FNA)

KGH/Wikipedia

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 Papillary Carcinoma
• Excellent prognosis
• Treated with surgery
• Total thyroidectomy or lobectomy
• Based on size and degree of spread
• Post-operative T4 (levothyroxine)
• Prevent hypothyroidism
• Prevent TSH rise → cancer growth
• Radioactive iodine ablation
• Based on patient risk category
• Ablate residual normal thyroid tissue
• Eliminate metastatic cells

Public Domain

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 Follicular Carcinoma
• Malignancy of follicular epithelial cells
• Similar to follicular adenoma
• Breaks through (“invades”) fibrous capsule
• FNA cannot distinguish between adenomas/cancer Follicular Carcinoma
• Many similarities with papillary carcinoma
• Similar age and risk factors
• Treatment similar to papillary carcinoma
• Thyroidectomy
• Radioiodine ablation of remaining tissue or metastasis

Nephron/Wikipedia

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 Medullary Carcinoma
• Cancer of parafollicular cells (C cells)
• Produces calcitonin Medullary Carcinoma
• Lowers serum calcium
• Normally minimal effect on calcium levels
• Used for monitoring
• Amyloid protein deposits in thyroid
• Treatment: total thyroidectomy
• Most patients have bilateral disease
• Serial calcitonin monitoring

Nephron/Wikipedia

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 MEN Syndromes
Multiple Endocrine Neoplasia
• Gene mutations that run in families
• Cause multiple endocrine tumors
• MEN 2A and 2B associated with medullary carcinoma
• Caused by RET oncogene mutation
• Some patients have elective thyroidectomy
• Sometimes at a young age

Mikael Häggström

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 Anaplastic Carcinoma
Undifferentiated Carcinoma
• Occurs in elderly
• Highly malignant - invades local tissues
• Dysphagia (esophagus)
• Hoarseness (recurrent laryngeal nerve)
• Dyspnea (trachea)
• Don’t confuse with Riedel’s (“rock hard” thyroid/young pt)
• Poor prognosis
• Treatment: surgery (local disease only), chemotherapy and radiation

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 Primary Thyroid Lymphoma
• Rare B-cell lymphoma arising in thyroid gland
• Associated with chronic lymphocytic thyroiditis (Hashimoto’s)

Shutterstock

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 Hyperaldosteronism
Jason Ryan, MD, MPH

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 Primary Hyperaldosteronism
• Excessive levels of aldosterone secretion
• Not due to increased activity of RAAS
• Adrenal adenoma (Conn’s syndrome)
• Bilateral idiopathic adrenal hyperplasia
• Rarely adrenal carcinoma (~1%)

Wikipedia /Public Domain

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 Primary Hyperaldosteronism
• ↑ Na reabsorption distal nephron
• ↑ circulating volume → hypertension
• ↑ K excretion → hypokalemia
• ↑ H+ excretion → metabolic alkalosis
• High serum bicarbonate

Acid (H+)
Potassium (K+)
BLOOD URINE
Sodium (Na+)

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 Aldosterone Escape
• Excess aldosterone does not lead to volume overload
• Usually no pitting edema, rales, increased JVP
• Na and water retention → hypertension
• Compensatory mechanisms activated
• Increased ANP
• Increased sodium and free water excretion
• Result: diuresis → normal volume status

Pixabay

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 Primary Hyperaldosteronism
Clinical Features
• Resistant hypertension
• Possible hypokalemia
• Inconsistent finding
• Less than 30% in some studies
• Normal volume status on physical exam

Shutterstock

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 Primary Hyperaldosteronism
Diagnosis
• Renin-independent aldosterone secretion
• Plasma renin activity (PRA)
• Low in primary hyperaldosteronism
• Usually than 1 ng/mL per hour
• Plasma aldosterone concentration (PAC)
• High in primary hyperaldosteronism
• Greater than 15 ng/dL
• Ratio of PAC:PRA
• Greater than 20 suggest primary hyperaldosteronism

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 Primary Hyperaldosteronism
Confirmatory Testing
• Demonstration of inappropriate aldosterone secretion
• Oral sodium load or sodium infusion
• Should suppress aldosterone release
• Measure urinary aldosterone excretion or plasma aldosterone concentration
• Increased aldosterone after sodium load = positive test

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 Primary Hyperaldosteronism
Determination of cause
• Abdominal CT scan
• Adrenal mass
• Bilateral adrenal enlargement
• Adrenal vein sampling
• Interventional radiology procedure
• Separate blood sample from each vein
• Measurement of aldosterone in samples
• Distinguishes unilateral from bilateral disease

Metastatic adenocarcinoma within a functioning adrenal adenoma: A case report - Scientific Figure on ResearchGate.
https://www.researchgate.net/figure/Abdominal-CT-scan-arrow-depicts-right-adrenal-mass_fig5_38012436 [accessed 21 Jan, 2021]

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 Primary Hyperaldosteronism
Treatment
• Unilateral disease: surgical adrenalectomy
• Bilateral disease: medical therapy
• Drugs of choice: spironolactone/eplerenone
• Aldosterone antagonists Spironolactone
• ACE inhibitors and ARBs: no effect
• AII levels already very low (↓ RAAS activity)
• Aldosterone release not dependent on AII stimulation

Eplerenone

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 SAME
Syndrome of Apparent Mineralocorticoid Excess
• Cortisol binds to renal aldosterone receptors
• Cortisol → cortisone by renal cells
• Enzyme: 11-β-hydroxysteroid dehydrogenase
• SAME: deficiency 11-β-hydroxysteroid dehydrogenase
• Cortisol produces aldosterone effects

11-β-hydroxysteroid
Cortisol dehydrogenase Cortisone

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 SAME
Syndrome of Apparent Mineralocorticoid Excess
• Presents in children/adolescents
• Similar clinical syndrome to hyperaldosteronism
• Hypertension
• Hypokalemia
• Metabolic alkalosis
• Low plasma renin activity
• Low plasma aldosterone levels
• Treatment: potassium-sparing diuretics
• Amiloride, spironolactone
• Inhibit mineralocorticoid effects

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 Licorice
• Contains glycyrrhetinic acid (a steroid)
• Weak mineralocorticoid effect
• Inhibits renal 11-beta-hydroxysteroid dehydrogenase
• Large amounts may cause disease
• Hypertension, hypokalemia, metabolic alkalosis
• Low plasma renin activity
• Low plasma aldosterone levels

Pikaluk/Flikr

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 Secondary Hyperaldosteronism
• Hyperreninemic hyperaldosteronism
• Elevated plasma renin activity
• Limited renal perfusion
• Renal artery stenosis
• Heart failure
• Cirrhosis
• Renin-secreting tumor (rare)

Public Domain

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 Cushing’s Syndrome
Jason Ryan, MD, MPH

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 Cushing’s Syndrome
Hypercortisolism
• Clinical syndrome of excess effects of cortisol
• Cortisol: steroid hormone
• “Glucocorticoid:” raises serum glucose
• Synthesized by adrenal glands

Cortisol

Wikipedia /Public Domain

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 Pituitary-Adrenal Axis
• Controls cortisol secretion
• Hypothalamus: CRH
• Corticotropin releasing hormone
• Acts of pituitary gland
• Anterior pituitary: ACTH
• Adrenocorticotropic hormone
• Acts on adrenal gland
• Adrenal: cortisol

Drosenbach/Wikipedia

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 Excess Cortisol
Major Effects
• Immunosuppression
• Hyperglycemia
• Hypertension
• Fat deposition
• Muscle, bone and skin changes
• Reproductive effects

Cortisol

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 Cortisol
Immunosuppressive Effects
• Reduces T and B cell levels in plasma
• Sequesters lymphocytes in spleen/nodes Neutrophils
• Impairs neutrophils
• Blocks neutrophil migration
• Increases peripheral neutrophil count
• Raises the white blood cell count
• Mast cells: blocks histamine release
• Reduces eosinophil counts
• Basis for corticosteroids as immunosuppressive therapy

Dr Graham Beards/Wikipedia

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 Corticosteroid Drugs
“Steroids” or “Glucocorticoids”
Cortisol

Dexamethasone
Prednisone Cortisone

Hydrocortisone

Triamcinolone Betamethasone Methylprednisolone

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 Cortisol
Glucose Effects
• Increases liver gluconeogenesis
• More glucose produced by liver
• May cause insulin resistance
• Increases serum glucose
• Cortisol excess: hyperglycemia
• May worsen diabetes

Shutterstock

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 Cortisol
Blood Pressure Effects
• Maintains blood pressure
• Modifies vascular smooth muscle tone
• ↑ cortisol: hypertension (Cushing’s syndrome)
• ↓ cortisol: hypotension (adrenal insufficiency)

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 Cortisol
Lipid Effects
• Activation of lipolysis in adipocytes
• Can increase total cholesterol and triglycerides
• Stimulate adipocyte growth
• Key effect: fat deposition
• Face (“Moon face”)
• Trunk
• Upper back (“Buffalo hump”)

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 Cortisol
Muscle, Skin and Bone Effects
• Muscle atrophy
• Thin arms and legs Striae
• Thin skin
• Easy bruising
• Striae
• Osteopenia and osteoporosis
• Inhibits osteoblasts

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 Cortisol
Reproductive Effects
• Supresses GnRH release → ↓ LH and FSH
• Hypogonadotropic hypogonadism
• Women: irregular menses
• Men: low testosterone

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 Cushing’s Syndrome
Common Clinical Features
• Weight gain
• Hypertension
• Hyperglycemia
• Round face
• Menstrual irregularities
• Thin skin
• Bruising and striae

Shutterstock

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 Cushing’s Syndrome
Special Clinical Features
• Skin hyperpigmentation
• Only occurs in ACTH-dependent Cushing’s syndrome
• Caused by ↑ ACTH not cortisol
• ↑ ACTH → ↑ MSH
• Also seen in adrenal insufficiency
• Loss of cortisol → ↑ ACTH

Wikipedia/Public Domain

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 Cushing’s Syndrome
Special Clinical Features
• Androgen excess
• Occurs in some adrenal carcinomas Hirsutism
• Tumor secretes cortisol and androgens
• May cause acne
• Women: hirsutism

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 Cushing’s Syndrome
Causes
• Most common cause: exogenous glucocorticoids
• Commonly oral prednisone
• Administered for immunosuppressive effects
• Many indications
• Rare causes:
• Overproduction of ACTH by pituitary (Cushing’s disease)
• Ectopic ACTH syndrome (tumor)
• Adrenal adenoma

‫املكتبة الطبية اإللكترونية‬

03/10/2022
Wikipedia /Public Domain

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 Cushing’s Syndrome
Causes
• ACTH-dependent
• High ACTH level → hypercortisolism
• Cushing’s disease
• Ectopic ACTH syndrome
• ACTH-independent
• Low ACTH level
• Adrenal adenoma

Wikipedia /Public Domain

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 Cushing’s Syndrome
Workup
• Step 1: exclude exogenous glucocorticoids
• Step 2: diagnosis of hypercortisolism
• Twenty-four-hour urinary cortisol excretion
• Late-night salivary cortisol
• Late-night serum cortisol
• Low-dose dexamethasone suppression test
• If clinical suspicion high, sometimes 2 tests done (false negatives)
• Step 3: plasma ACTH

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 Cushing’s Syndrome
Low dose dexamethasone suppression test
• Screening test for hypercortisolism
• 1mg dexamethasone (“low dose”) administered at bedtime
• Suppresses normal pituitary ACTH release
• Morning blood test → cortisol level should be low (suppressed)
• Cushing’s syndrome: cortisol will be high
• ACTH production not suppressed from pituitary adenomas or ectopic tumors
• Cortisol production not suppressed from adrenal adenomas

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 Cushing’s Syndrome
Plasma ACTH
• Low plasma ACTH concentration
• ACTH-independent disease
• Suggests adrenal tumor
• Next best test: CT scan of adrenal glands
• Normal or high ACTH concentration
• ACTH-dependent disease
• Pituitary tumor or ectopic production
• Next best test: determine source of ACTH production
• High dose dexamethasone test
• CRH stimulation test
• Petrosal vein sampling

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 Cushing’s Syndrome
Source of ACTH production
• High dose dexamethasone test (8mg)
• Differentiates causes of high ACTH Cushing’s syndrome
• Will suppress cortisol in pituitary adenomas
• Will not suppress cortisol from ACTH tumors

AM Cortisol After Dexamethasone

Low Dose High Dose
Normal ↓ ↓
Pituitary Adenoma -- ↓
ACTH Tumor -- --

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 Cushing’s Syndrome
Source of ACTH production
• CRH stimulation test
• Pituitary tumor: ACTH and cortisol increases after CRH administration
• Pituitary cells actively synthesizing ACTH
• Release can be increased by surge of CRH
• Ectopic tumors: no response
• Pituitary cells NOT synthesizing ACTH
• Pituitary cells inactive
• Minimal or no response to surge in CRH

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 Cushing’s Syndrome
Source of ACTH production
• Petrosal venous sampling
• Petrosal venous sinus drains pituitary gland
• Venous blood sample obtained via catheter
• Gradient of central to peripheral ACTH measured
• Pituitary ACTH source: high central-to-peripheral ACTH gradient

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 Cushing’s Syndrome
Workup

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 Cushing’s Syndrome
Medical Therapy
• Cushing syndrome usually treated with surgery
• May be treated medically
• Often done while awaiting surgery or surgery contraindicated
• Ketoconazole
• Adrenal enzyme inhibitor
• Decreases adrenal cortisol synthesis Ketoconazole
• May cause hepatoxicity
• Strong inhibitor of cytochrome P450 enzymes
• May prolong Qt interval

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 Cushing’s Disease
Pituitary ACTH Release
• Usually caused by benign pituitary adenomas
• Usually microadenomas (< 10 mm in diameter)
• May be too small to identify by MRI
• Treatment: transsphenoidal surgery
• Main complication: diabetes insipidus (rarely permanent)
• Radiation if surgery unsuccessful

Shutterstock

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 Cushing’s Syndrome
Ectopic ACTH Release
• Small cell lung cancer
• Carcinoid tumors of lung
• Islet cell tumors of pancreas
• Medullary thyroid carcinoma
• Thymus gland tumors
• Treatment: surgical resection of tumor

Public Domain

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 Cushing’s Syndrome
Adrenal Adenoma Treatment
• Unilateral adrenalectomy
• Refractory disease (any cause): bilateral adrenalectomy
• Lifelong glucocorticoid and mineralocorticoid replacement

Wikipedia /Public Domain

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 Cushing’s Disease Cabergoline
ACTH Medical Treatments
• Used if surgery unsuccessful or not possible
• Cabergoline
• Dopamine agonist
• Used to treat hyperprolactinemia
• Also suppresses ACTH release
• Pasireotide
• Somatostatin analogue
• Blocks the release of ACTH

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 Adrenal Insufficiency
Jason Ryan, MD, MPH

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 Adrenal Insufficiency
• Loss of adrenal function
• Loss of one or more adrenal hormones
• Glucocorticoids: cortisol
• Mineralocorticoids: aldosterone
• Androgens: dehydroepiandrosterone (DHEA)

Wikipedia /Public Domain

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 Adrenal Insufficiency
Types
• Primary adrenal insufficiency
• “Addison’s disease”
• Destruction of adrenal gland tissue
• Loss of cortisol, aldosterone and androgens
• Secondary or tertiary (central)
• Loss of ACTH from pituitary (secondary)
• Loss of CRH from hypothalamus (tertiary)
• Loss of cortisol only

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 Glucocorticoid Deficiency
Clinical Features
• Fatigue
• Weight loss
• Gastrointestinal symptoms
• Usually nausea
• Sometimes vomiting, abdominal pain or diarrhea
• Hypotension +/- syncope
• Cortisol maintains vascular tone
• Often orthostatic hypotension
• Muscle and joint pain Cortisol
• Hyponatremia (↑ ADH release)

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 Mineralocorticoid Deficiency
Clinical Features
• Hypovolemia
• “Salt wasting” – patient may crave salty foods
• Loss of sodium and water in urine
• May lead to hypovolemic shock
• Hyponatremia
• High ADH from hypovolemia
• Retention of free water
• Hyperkalemia Aldosterone
• Decreased urinary potassium
• Metabolic acidosis Acid (H+)
• Decreased urinary acid excretion Potassium (K+)
BLOOD URINE
Sodium (Na+)

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 Androgen Deficiency
Clinical Features
• No significant impact in males (testes)
• Decreased axillary and pubic hair in females

Dehydroepiandrosterone
(DHEA)

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 Primary Adrenal Insufficiency
Clinical Presentation
• Fatigue Eosinophil
• Weight loss
• Nausea, vomiting and abdominal pain
• Muscle and joint pain
• Postural hypotension
• Salt craving
• Hyponatremia
• Hyperkalemia
• Eosinophilia

Bobjgalindo/Wikipedia

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 Primary Adrenal Insufficiency
Skin Hyperpigmentation
• ACTH is high in primary adrenal insufficiency
• ↑ melanocyte stimulating hormone (MSH)
• Common precursor in pituitary with ACTH
• Proopiomelanocortin (POMC)
• ↑ ACTH → ↑ MSH → ↑ melanin synthesis
• Most obvious in sun-exposed areas
• Face, neck, backs of hands
• May also occur on mucous membranes

Wikipedia/Public Domain

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 Primary Adrenal Insufficiency
Diagnosis
• Morning cortisol
• Cortisol concentration higher in early morning
• Low value at this time suggests adrenal insufficiency
• Plasma ACTH
• Low cortisol + high ACTH = primary disease
• Low cortisol + low ACTH = central disease
• Cosyntropin stimulation test
• Used to quickly exclude adrenal insufficiency

Shutterstock

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 Cosyntropin Stimulation Test
• Cosyntropin: synthetic ACTH
• Standard high-dose test: 250 mcg
• Normal response: rise in serum cortisol
• Measured after 30 or 60 minutes
• Should peak at ≥ 18 to 20 mcg/dL
• Normal response rules out primary adrenal insufficiency
• Rules out most forms of central adrenal insufficiency
• Abnormal response = adrenal insufficiency
• Primary disease: blunted rise due to adrenal pathology
• Central disease: blunted rise due to adrenal atrophy

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 Primary Adrenal Insufficiency
Causes
• Autoimmune adrenalitis
• Suggested by other autoimmune disorders
• Infectious adrenalitis Neisseria Meningitis
• Tuberculosis, HIV
• Disseminated fungal infections
• Hemorrhagic infarction
• Associated with meningococcemia
• Waterhouse-Friderichsen syndrome
• Increased risk with anticoagulant use
• Metastatic cancer

CDC/Public Domain

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 Primary Adrenal Insufficiency
Determination of cause
• Cause may be evident from history and exam CT Abdomen
• Tuberculosis, HIV or meningococcemia
• Antibodies against 21-hydroxylase
• Autoimmune adrenalitis
• CT abdomen
• Infection, hemorrhage or malignancy
• CT-directed fine needle aspiration
• Infection or malignancy

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 Primary Adrenal Insufficiency
Treatment
• Corticosteroids
• Dexamethasone, prednisone or hydrocortisone
• Mineralocorticoids
• Fludrocortisone

Fludricortisone

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 Central Adrenal Insufficiency
Clinical Features
• Weakness and fatigue
• Muscle and joint pain
• Hypotension (less prominent)
• Decreased vascular tone only
• No loss of mineralocorticoids Hypothalamus and Pituitary Gland
• Hyponatremia (but less common)
• Intact mineralocorticoids
• Low cortisol →↑ ADH
• No skin hyperpigmentation (low ACTH)
• Diagnostic testing consistent with central disease

Shutterstock

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 Central Adrenal Insufficiency
Evaluation and Treatment Head MRI
• Head MRI
• CRH stimulation test
• Differentiates 2∘ from 3∘
• No cortisol rise after CRH: 2∘ (pituitary failure)
• Cortisol rise after CRH: 3∘ (hypothalamic failure)
• Treatment: glucocorticoids

Public Domain

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 Adrenal Insufficiency
Workup

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 Central Adrenal Insufficiency
Patients on Chronic Glucocorticoids
• Suppression of HPA axis
• ↓ CRH and ↓ ACTH
• Adrenal atrophy
• Impaired ability to produce cortisol
• Cortisol effects entirely from drugs
• Mineralocorticoids intact from RAAS
• Patient dependent on exogenous glucocorticoids
• Cessation or underdosing → deficiency state

Drosenbach/Wikipedia

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 Central Adrenal Insufficiency
Patients on Chronic Glucocorticoids
• Longer duration therapy requires tapering of dose (“weaning”)
• Various regimens to prevent symptoms of adrenal insufficiency
• Usually a small decrease in dose every one to two weeks
• Suppression of HPA axis unlikely if treatment under three weeks

Wikipedia /Public Domain

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 Adrenal Crisis
• Acute-onset, life-threatening condition
• Shock due to sudden loss of adrenal hormones
• Poorly-responsive to fluids alone
• Resolves with glucocorticoid administration
• Consider in any hypotensive patient

Picpedia/Public Domain

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 Adrenal Crisis
Causes
• Occurs with underlying adrenal disease and acute stressor
• Chronic primary adrenal insufficiency (possible initial presentation)
• Chronic glucocorticoid therapy and adrenal atrophy
• Adrenal function unable to increase in response to stressor
• Stressors: trauma, surgery or major illness
• Also occurs with acute-onset adrenal gland destruction
• Bilateral hemorrhage

Picpedia/Public Domain

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 Adrenal Crisis
Treatment and Prevention
• “Stress dose steroids”
• Hydrocortisone intravenous bolus
• Regular intravenous doses every few hours or infusion
• Prevention: stress dose steroids in patients on chronic glucocorticoids
• High daily dose for more than 3 weeks
• Prior to major surgery
• After trauma
• During major illness
• Not necessary for minor surgical procedures or low daily doses

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 Diabetes Mellitus
Jason Ryan, MD, MPH

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 Diabetes Mellitus
• Chronic disorder of elevated blood glucose levels
• Lack of insulin or poor response to insulin (“insulin resistance”)
• Can lead to symptoms of hyperglycemia
• Many long-term complications
• Vascular disease
• Kidney disease
• Blindness

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 Diabetes Mellitus
Symptoms
• May be asymptomatic
• “Silent killer”
• No symptoms until complications develop
• Basis for screening
• Classic hyperglycemia symptoms
• Polyuria (osmotic diuresis from glucose)
• Polydipsia (thirst to replace lost fluids)
• Can present with diabetic ketoacidosis

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 Diabetes Mellitus
Diagnosis
• Symptomatic (polyuria, polydipsia, DKA)
• Symptoms plus glucose > 200 mg/dl = diabetes
• Asymptomatic
• Fasting blood glucose level (no food for 8 hours)
• Hemoglobin A1c > 6.5%
• Two-hour plasma glucose ≥ 200 mg/dL after 75 g oral glucose tolerance test

State Fasting plasma glucose

Normal < 100 mgl/dl
Pre-diabetes 100 to 125 mg/dl
Diabetes >= 126 mg/dl

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 Diabetes Mellitus
Stress hyperglycemia
• Occurs in normal individuals without diabetes
• Infection, trauma, surgery, burns
• Cortisol, epinephrine
• Does not indicate diabetes
• Diagnosis not usually done during in illness/stress

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 Hemoglobin A1C
Hemoglobin
• Small fraction of hemoglobin is “glycated”
• Glucose combines with alpha/beta chains
• Amount of HbA1c measured in diabetes
• Reflects average glucose over past 3 months
• Normal < 5.7%
• Pre-diabetes: 5.7 to 6.4%
• Diabetes: >= 6.5%
• Used for diagnosis and monitoring therapy

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 Hemoglobin A1C
Treatment Goals
• Lower value = better control of blood sugar
• Type I diabetes: < 7.0%
• Type II diabetes: < 7.0% for average adult patient
• Higher goal (< 8.0%) for older patients
• Avoid hypoglycemia
• Limited life expectancy for complications

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 Glucose Tolerance Test
• Oral glucose load administered
• Plasma glucose measured 1-3 hours later
• High glucose indicates diabetes
• Often used to screen for gestational diabetes
• Some insulin resistance normal in pregnancy
• Fasting glucose and A1c not reliable
• Need to study response to glucose load for diagnosis

Pixabay.com

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 Type 1 Diabetes
• Autoimmune disorder
• Type IV hypersensitivity reaction
• Immune-mediated destruction of beta cells
• Loss of insulin
• Multifactorial etiology
• Genetics, environment
• Only major risk factor: family history

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 Type 1 Diabetes
• Mostly a childhood disorder
• Bimodal distribution
• Peak at 4-6 years
• 2nd peak 10 to 14 years of age
• Presents with hyperglycemia symptoms
• Polyuria
• Polydipsia
• Glucose in urine
• Diabetic ketoacidosis

Wikipedia/Public Domain

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 Type 1 Diabetes
Diagnosis and treatment
• No standard screening
• Diagnosis usually made when symptoms occur
• Treatment: insulin

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 Type 2 Diabetes
• Complex disorder of insulin resistance
• Reduced response to insulin → hyperglycemia
• Pancreas initially responds with ↑ insulin
• Eventually pancreas can fail → ↓ insulin
• Most common form of diabetes
• Common in adults
• Also becoming more common among children

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 Type 2 Diabetes
Risk Factors
• Major risk factor: obesity
• Central or abdominal obesity carries greatest risk
• Weight loss improves glucose levels
• Family history
• Strong genetic component (more than type I)
• Any first degree relative with T2DM: ↑ 2-3x risk
• Sedentary lifestyle
• Smoking

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 Type 2 Diabetes
Screening
• Guidelines vary slightly by expert groups
• American Diabetes Association
• Screening for most patients beginning age 45
• Earlier screening in high-risk groups
• Repeat screening every 3 years
• US Preventive Services Task Force
• Patients 40 to 70 who are overweight or obese
• Repeat screening every 3 years

Picpedia

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 Type I versus Type II
Diagnosis
• Usually distinguished by clinical features
• Type I:
• Childhood onset
• Rapid onset with severe hyperglycemia
• Obesity less likely (~ 20%)
• Type II:
• Puberty or adulthood
• Often insidious onset (screening, polyuria/polydipsia)
• Family history more likely
• Obesity common (~ 80%)
• Islet-specific pancreatic autoantibodies in some cases of type I (not reliable)

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 Type 2 Diabetes
Management
• All patients: maintain healthy weight and exercise
• Can be done prior to medical therapy in select cases
• For highly motivated patients with A1C near target
• Usually 3- to 6-month trial of lifestyle modification
• Most common initial therapy: metformin
• May add additional agents to achieve target A1c
• After failure of two or more agents consider insulin
• If severely elevated A1c (> 9.5%) consider insulin

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 Bariatric Surgery
• Indicated for obese patients with type II diabetes
• Long-term remission up to 60% in some studies
• Reduced risk of diabetes complications
• Indicated for any patient with diabetes and BMI > 35
• Or 30 to 34.9 if hyperglycemia inadequately controlled

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 Acanthosis Nigricans
• Hyperpigmented plaques on skin
• Intertriginous sites (folds)
• Classically neck and axillae
• Associated with insulin resistance
• Often seen in obesity, diabetes
• Much more common type II
• Rarely associated with malignancy
• Gastric adenocarcinoma most common

Madhero88/Dermnet.com

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 Diabetes Complications
Jason Ryan, MD, MPH

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 Diabetes Mellitus
Complications
• Chronic hyperglycemia → complications
• Vascular disease
• Kidney disease
• Neuropathy
• Ocular disease (blindness)

Shutterstock

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 Diabetic Macroangiopathy
Atherosclerosis
• Coronary artery disease
• Most common cause of death in diabetes
• Stroke and TIA
• Peripheral vascular disease

BruceBlaus/Wikipedia

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 Diabetic Macroangiopathy
Atherosclerosis
• Screening lipid panel
• At time of diagnosis
• At least every five years thereafter
• Statin therapy
• US Preventive Services Task Force guidelines
• Diabetes + age > 40 + 10-year risk > 10%
• Regardless of LDL level
• Routine EKG, stress test, imaging not indicated

BruceBlaus/Wikipedia

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 Diabetic Kidney Disease
Diabetic Microangiopathy
• Damage to glomeruli and arterioles
• Efferent arteriole glycosylation
• Hyperfiltration
• Basement membrane damage
• Mesangial and glomeruli sclerosis
• Causes albuminuria
• May lead to end-stage kidney disease

Public Domain

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 Diabetic Kidney Disease
Screening and Prevention
• Annual urine albumin-to-creatinine ratio
• Measurement correlated to 24-hour urine values (mg/day)
• Normal rate: less than 30 mg/day
• Above 30 mg/day indicates diabetic nephropathy
• ACE inhibitors and ARBs
• Indicated for albuminuria
• Even if blood pressure is not elevated
• Shown to reduce progression to ESRD
• Slows progression of nephropathy
• Hypertension goal: < 130/80 mmHg

Public Domain

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 Diabetic Peripheral Neuropathy
• Most common form of diabetic neuropathy
• “Distal symmetric polyneuropathy”
• “Stocking-glove" sensory loss
• Progressive loss of sensation: distal → proximal
• Severe cases: motor weakness

Large Myelinated Fibers Small Myelinated Fibers

Function Proprioception/Pressure Pain
Symptoms Numbness, loss of balance Burning, electric shocks
Reduced ankle reflexes Loss of pinprick
Exam Findings Reduced vibration Loss of hot/cold
Reduced proprioception discrimination

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 Diabetic Peripheral Neuropathy
Foot Ulcers
• Common problem in diabetes
• Loss of sensation → tissue damage
• Vascular disease → impaired healing
• May be painless
• Patients should check feet daily
• Annual foot exam and sensory testing
• Monofilament testing (pressure)
• Vibratory testing
• Pinprick testing
• Ankle reflexes

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 Diabetic Peripheral Neuropathy
Management
• Generally not reversible
• Glucose control slows progression
• Pain in feet (burning or stabbing)
• SNRIs: duloxetine or venlafaxine
• TCAs: amitriptyline, desipramine or nortriptyline
• AEDs: pregabalin or gabapentin

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 Diabetic Autonomic Neuropathy
• Abnormal function of autonomic nerves
• GU system: bladder dysfunction, erectile dysfunction
• GI: gastroparesis
• CV: orthostatic hypotension, silent ischemia

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 Diabetic Eye Disease
• Cataracts
• Glaucoma
• Diabetic retinopathy
• Diabetic macular edema
• Annual screening for prevention
• Dilated fundus examination by trained specialist
• Usually ophthalmologist or optometrist

Petr Novák, Wikipedia

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 Diabetic Eye Disease
Cataracts
• Increased risk with diabetes
• Sorbitol accumulates in lens
• Increased osmolarity
• Fluid into lens
• Opacification over time

Rakesh Ahuja, MD/Wikipedia

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 Diabetic Eye Disease
Retinopathy
• Can cause blindness
• Nonproliferative retinopathy Cotton Wool Spots
• Microaneurysms or hemorrhages
• Exudates: leakage of proteins and lipids
• Cotton-wool spots (nerve infarctions)
• Proliferative retinopathy
• Retinal ischemia → new vessel growth
• “Neovascularization”
• Treated with photocoagulation (laser)
• Also intraocular anti-VEGF agents

Public Domain

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 Diabetes Mellitus
Benefits of lowering blood glucose
• Several large, randomized trials of intensive glycemic control
• Comparisons of lower versus higher A1c targets
• Type 2 diabetes
• Lower risk of microvascular complications
• Mostly retinopathy and nephropathy
• Little impact on macrovascular disease (MI, stroke)
• ACCORD trial: A1c 6.0 to 6.5% → increased mortality
• Type 1 diabetes
• Lower risk of most complications
• Microvascular and macrovascular

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 Diabetic Ketoacidosis
Jason Ryan, MD, MPH

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 Diabetic Ketoacidosis
DKA
• Life-threatening complication of diabetes
• Biochemical derangement: hyperglycemia, acidosis
• Requires very low insulin effects
• More common in type 1
• Common type 1 initial presentation
• Often precipitated by infection or trauma (↑ epinephrine)
• Can occur with missed insulin dose in type 1 diabetes (↓ insulin)
Epinephrine

Insulin

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 Diabetic Ketoacidosis
DKA
• ↑ epinephrine or ↓ insulin → increased glucose
• Very low insulin effects → liver ketone synthesis
• Net result: hyperglycemia + ketones
• Osmotic diuresis (glucose) → volume depletion Hyperglycemia
• High ketones = anion gap metabolic acidosis Low bicarbonate
• Acidosis → hyperkalemia Hyperkalemia
Volume depletion

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 Diabetic Ketoacidosis
Clinical Presentation
• Abdominal pain, nausea and vomiting
• Volume depletion
• Dry mucous membranes
• Low blood pressure
• Hyperglycemia
• Low bicarbonate
• Hyperkalemia

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 Diabetic Ketoacidosis Metabolic Acidosis
Bicarbonate
Clinical Presentation
• Elevated plasma and urine ketones
• Glucose in urine
• Anion gap metabolic acidosis (↓ bicarbonate)
• Kussmaul breathing: deep, labored breathing
• Hyperventilation to blow off CO2 and raise pH
• Fruity smell on breath (acetone)

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 Diabetic Ketoacidosis
Phosphate
• Risk of hypophosphatemia
• Phosphaturia caused by osmotic diuresis
• Loss of ATP
• Muscle weakness (respiratory failure)
• Heart failure (↓ contractility)

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 Diabetic Ketoacidosis
Other features
• Arrhythmias (hyperkalemia)
• Cerebral edema
• Mechanism poorly understood
• Common cause of death in children with DKA

_DJ_/Wikipedia

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 Diabetic Ketoacidosis
Diagnostic Criteria
• Triad: hyperglycemia, anion gap acidosis and ketones

Measurement Criteria
Glucose > 250 mg/dL
Arterial pH < 7.30
Bicarbonate < 18 mEq/L
Urine ketones Positive
Serum ketones Positive

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 Diabetic Ketoacidosis
Treatment
• IV Fluids
• Volume replacement
• Usually normal saline
• Usually infused continuously
• IV Insulin
• Lowers blood glucose levels
• Inhibits liver production of ketones
• Shifts potassium into cells
• Bolus plus continuous drip

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 Diabetic Ketoacidosis
Treatment - Potassium
• Total body potassium is low from loss of potassium in urine
• Hyperkalemia presents initially due to acidosis/low insulin
• Potassium shifted out of cells into plasma
• Hypokalemia may develop from insulin infusion
• Add potassium to IV fluids when potassium less than 5.3 mEq/L
• Normal potassium: 3.6 to 5.2 mEq/L

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 Diabetic Ketoacidosis
Treatment – other electrolytes
• Monitor magnesium, calcium and phosphate
• Levels may fall due to loss in urine
• Replete as needed

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 Diabetic Ketoacidosis
Treatment - bicarbonate infusion
• Usually not necessary
• Arterial pH will increase with DKA treatment
• Only indicated with pH < 6.9 (impaired cardiac function)

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 Diabetic Ketoacidosis
Treatment monitoring
• Close monitoring of serum glucose and electrolytes
• When glucose approaches 200 mg/dL add 5% dextrose to saline infusion
• Allows continued insulin infusion to suppress ketones
• Avoids hypoglycemia
• Can also decrease insulin infusion rate
• DKA resolves when:
• Anion gap normalizes (less than 12 mEq/L)
• Beta-hydroxybutyrate absent (if available)
• Patient can eat

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 HHS
Hyperglycemic Hyperosmolar Syndrome
• Life-threatening complication of diabetes
• More common in type 2
• Markedly elevated glucose (can be >1000)
• High glucose → diuresis and volume depletion
• High osmolarity → CNS dysfunction
• Usually no acidosis

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 HHS
Hyperglycemic Hyperosmolar Syndrome
• Very high serum osmolarity → CNS dysfunction
• Caused by very high glucose (can be > 1000)
• Normal plasma osmolarity: less than 300 mOsm/kg
• HHS: usually above 320 mOsm/kg
• Few or no ketone bodies (insulin present)
• Usually no acidosis
• Different from DKA

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 HHS
Clinical features and diagnosis
• Polyuria, polydipsia
• Volume depletion
• Mental status changes
• Confusion, even coma
• Diagnosis: serum glucose

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 HHS
Treatment
• Similar to DKA
• Insulin, fluids
• Resolved when:
• Plasma osmolality below 315 mOsmol/kg
• Patients alert and able to eat

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 Insulin
Jason Ryan, MD, MPH

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 Type 1 and Type 2
• Type 1 diabetes treated mainly with insulin
• Type 2 diabetes: oral or SQ drugs +/- insulin
• Initial stages: oral and/or SQ drugs
• Advanced disease: insulin

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 Insulin
• Many different types available for diabetes therapy
• All vary by time to peak and duration of action
• Also vary by peak effect

Rapid
Regular NPH
Acting Basal Insulins
Insulin Insulin
Insulin

Fast Peak Slow Peak

Short Duration Long Duration

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 Insulin Hexamers
• Insulin forms hexamers in the body
• Six insulin molecules linked together
• Stable structure
• Insulin usually administered subcutaneously
• Activity related to speed of absorption
• Insulin hexamers → slower onset of action
• Insulin monomers → faster onset of action

Isaac Yonemoto /Wikipedia

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 Rapid-acting Insulin
Lispro, Aspart, and Glulisine
• Modified human insulin
• Insulin with modified amino acids
• Reduced hexamer/polymer formation
• Rapid absorption, fast action, short duration
• Onset: 15 minutes
• Peak: 1 hour
• Duration: 2 to 4 hours
• Often used pre-meal

Pixabay

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 Insulin
Rapid

2 4 6 8 10 12 14 16 18 20 22 24

Hours After Administration

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 Regular Insulin
• Synthetic analog of human insulin
• Made by recombinant DNA techniques
• Onset: 30 minutes
• Peak: 2 to 4 hours
• Duration: 3 to 6 hours

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 Regular Insulin
• Only type of insulin that is given IV
• IV regular insulin used in DKA/HHS
• Used to treat hyperkalemia
• Given IV with glucose to prevent hypoglycemia

Wikipedia/Public Domain

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 NPH Insulin
Neutral Protamine Hagedorn
• Regular insulin combined with neutral protamine
• Slows absorption
• Peak: ~ 8 hours
• Duration: 12-16 hours

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 Basal insulin analogs
Glargine, Detemir, Degludec
• Insulin with modified chemical structure
• Provide low, continuous insulin effects
• Onset: ~ 2 hours
• Duration: up to 24 hours or more
• Glargine and Detemir: up to 24 hours
• Degludec: > 40 hours
• Often given once daily

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 Insulin
Administration
• Subcutaneous (SQ)
• Continuous infusion
• Infusion pump
• Rapid-acting insulin

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 Hypoglycemia
• Major adverse effect of all insulin regimens
• Tremor, palpitations, sweating, anxiety
• If severe: seizure, coma
• Always check blood sugar in unconscious patients
• Dosages, frequency adjusted to avoid low glucose

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 Weight Gain
• Occurs in most patients on insulin
• Insulin promotes fatty acid and protein synthesis

Wikipedia/Public Domain

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 Insulin
Hypersensitivity Reactions
• Immediate
• IgE-mediated type I hypersensitivity reactions
• Occur within 1 hour of injection
• Local skin reactions: erythema, wheals, pruritus
• Systemic reactions: generalized urticaria and angioedema
• Treatment: antihistamines, glucocorticoids; epinephrine if anaphylaxis
• Delayed
• More than one hour after injection
• Induration and nodules at injection sites
• Contact dermatitis
• Treatment: topical corticosteroids

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 Insulin
Subcutaneous fat changes
• Lipohypertrophy: swelling of fatty tissue at injection sites
• Insulin alters fatty tissue growth
• Lipoatrophy: loss of fatty tissue Lipohypertrophy Lipoatrophy
• Prevention: rotate injection sites

Mokta JK, Mokta KK, Panda P. Insulin lipodystrophy and lipohypertrophy. Indian J Endocrinol Metab. 2013 Jul;17(4):773-4.

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 Diabetes Treatment
Jason Ryan, MD, MPH

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 Type 1 and Type 2 Treatment
• Type 1 diabetes treated mainly with insulin
• Type 2 diabetes: oral or SQ drugs +/- insulin
• Most common initial therapy: metformin
• Advanced disease: insulin

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 Hemoglobin A1C
Treatment Goals
• Type I diabetes: < 7.0%
• Type II diabetes: < 7.0% for average adult patient
• Higher goal (< 8.0%) for older patients
• Lower value = lower average blood glucose levels
• Reduced risk of diabetes complications
• Type I: most complications
• Type II: microvascular complications
• Especially retinopathy and nephropathy
• May not reduce risk of macrovascular complications

Shutterstock

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 Antidiabetic Agents
Oral or Subcutaneous
• Biguanides (Metformin)
• Sulfonylureas
• Glitazones
• Glucosidase Inhibitors
• GLP-1 Analogs
• DPP-4 Inhibitors
• SGLT2 inhibitors

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 Metformin
Biguanide
• Oral medication
• Exact mechanism unknown
• Multiple metabolic effects
• ↓ hepatic glucose production
• Inhibits gluconeogenesis
• ↑ insulin effects
• ↑ insulin sensitivity

Metformin

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 Metformin
Benefits and Adverse Effects
• Usually first line in type 2 diabetes
• Associated with weight loss
• Rarely causes hypoglycemia
• Does not depend on beta cells
• Can be used in advanced diabetes
• Most common adverse effect is GI upset
• Nausea, abdominal pain
• Can cause a metallic taste in the mouth

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 Metformin
Lactic Acidosis
• Rare, life-threatening adverse effect of metformin
• Exact mechanism unclear/controversial
• Metformin can increase conversion of glucose to lactate
• Beneficial for lowering glucose levels
• Too much → lactic acidosis
• Can be life threatening

Lactic Acid
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 Metformin
Lactic Acidosis
• Almost always occurs associated with other illness
• Renal insufficiency
• Liver disease or heavy alcohol use
• Acute heart failure
• Hypoxia
• Serious acute illness
• Metformin not used in patients with low GFR
• Often “held” when patients acutely ill
• Also held during IV contrast tests

Public Domain

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 Sulfonylureas
• ↑ insulin release
• Bind to sulfonylurea receptor in pancreas
• Close K+ channels in beta cells
• Beta cells more sensitive to glucose/amino acids
Urea
• “Insulin secretagogues”
• Used when metformin contraindicated (renal failure)
• Or side effects on metformin (GI upset)
• Can be added to metformin

Sulfonylurea

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 Sulfonylureas
• Oral medications
• Each generation more potent
• ↓ dosage used → ↓ side effects
• First generation: tolbutamide, chlorpropamide, tolazamide
• Second generation: glyburide, glipizide
• Third generation: glimepiride

Needpix.com

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 Sulfonylureas
Adverse Effects
• Hypoglycemia
• Most common adverse effect
• Sweating, palpitations
• May occur with exercise or skipping meals
• Can also cause weight gain
• More insulin release
• Insulin causes weight gain

Wikipedia/Public Domain

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 Sulfonylureas
Adverse Effects - Chlorpropamide
• Flushing with alcohol consumption
• Inhibits acetaldehyde dehydrogenase (disulfiram effect)
• Hyponatremia (↑ADH activity)

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 Meglitinides
Repaglinide, Nateglinide
• Oral medications
• Similar mechanism but different chemical structure from sulfonylureas
• Close K+ channels → ↑ insulin secretion
• Short acting → given prior to meals
• Major side effect is hypoglycemia
• No sulfa group → can be used in sulfa allergy
• Added to metformin if sulfa allergy

Repaglinide

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 Thiazolidinediones
Pioglitazone, Rosiglitazone
• Oral medications
• Decrease insulin resistance
• Act on PPAR-γ receptors
• Highest levels in adipose tissue
• Also found in muscle, liver, other tissues
• Modulate expression of genes

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 Thiazolidinediones Pulmonary Edema
Adverse Effects
• Weight gain
• Proliferation of adipocytes plus fluid retention
• Risk of hepatotoxicity
• Troglitazone removed from market due to liver failure
• Edema
• Occurs in ~ 5% patients
• Due to PPAR-γ effects in nephron → ↑ Na retention
• Risk of pulmonary edema
• Not used in patients with advanced heart failure
• Pioglitazone not used with active bladder cancer
• Potential small increased risk of bladder cancer

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 Glucosidase Inhibitors
Acarbose, Miglitol, Voglibose
• Competitive inhibitors of intestinal α-glucosidases
• Enzymes of brush border of intestinal cells
• Hydrolyze starches, oligosaccharides, disaccharides
• Slows and limits absorption of glucose
• Taken orally before meals
• Less increase in glucose after meals
• Main side effect: GI upset
• Especially flatulence
• Diarrhea

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 GLP-1 Analogs
Exenatide, Liraglutide, Dulaglutide
• GLP-1 (glucagon-like peptide-1)
• Produced by L-cells of small intestine
• Secreted after meals
• Stimulates insulin release
• Also blunts glucagon release, slows gastric emptying
• Subcutaneous drugs
• Exenatide: twice daily or weekly
• Liraglutide: once daily
• Dulaglutide: once weekly

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 GLP-1 Analogs
Exenatide, Liraglutide, Dulaglutide
• Usually not used as initial therapy
• Add-on therapy in multi-drug regimens
• Do not usually cause hypoglycemia
• Associated with weight loss
• Reduce mortality in patients with cardiovascular disease
• GI side effects: nausea, vomiting, diarrhea

Pixabay

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 DPP-4 Inhibitors
Sitagliptin, Linagliptin, Saxagliptin
• DPP-4: Dipeptidyl peptidase 4
• Enzyme expressed on many cells
• Inhibits release GLP-1
• Inhibition → ↑ GLP-1
• Oral drugs
• Side effects: infections
• May depress immune function
• ↑ risk nasopharyngitis and respiratory infections
• Weight neutral; not associated with hypoglycemia

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 SGLT2 Inhibitors
Canagliflozin, Dapagliflozin
• SGLT2: renal glucose transporter
• Expressed in proximal tubule
• Reabsorbs sodium and glucose
• Reabsorbs ~ 90% percent filtered glucose Glucose
• Inhibition → loss of glucose in urine SGLT2
• Lowers glucose levels
• Also causes mild osmotic diuresis

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 SGLT2 Inhibitors
Canagliflozin, Dapagliflozin
• Oral medications
• Lead to mild weight loss
• Adverse effects
• Vulvovaginal candidiasis
• UTIs
• May lead to volume depletion
• Not used advanced renal disease (low GFR)
• Shown to improve outcomes in systolic heart failure

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 Diabetes Therapy
Helpful Tips
• Renal failure: avoid metformin
• May cause lactic acidosis
• Advanced heart failure
• Avoid glitazones (fluid retention)
• Avoid metformin (lactic acidosis)
• Insulin generally safe with any comorbidity
• Patients with cardiovascular disease
• GLP-1 agonists (reduce mortality)
• SGLT2 inhibitors (systolic heart failure)

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 Diabetes Therapy
Helpful Tips
• Hospitalized patients
• Oral antidiabetic agents often held/avoided
• Most patients treated with insulin
• Most oral agents decrease A1c by 0.5 to 1.5%
• Metformin 1 to 1.5%
• Markedly elevated A1c % usually requires insulin
• Insulin used at diagnosis when Hgb A1c > 9.5%

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 Pituitary Gland
Jason Ryan, MD, MPH

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 Pituitary Gland
• “Master gland”
• Controls other endocrine organs
• Located at base of brain
• Sits in small cavity of sphenoid bone: sella turcica

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 Pituitary Gland
• Posterior pituitary
• Antidiuretic hormone (ADH; vasopressin)
• Oxytocin
• Anterior pituitary
• Adrenocorticotropic hormone (ACTH)
• Follicle-stimulating hormone (FSH)
• Luteinizing hormone (LH)
• Growth hormone (GH)
• Thyroid-stimulating hormone (TSH)
• Prolactin

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 Hypothalamus
• Controls anterior pituitary gland
• Delivers releasing/inhibiting hormones via hypothalamic portal system

Hypothalamus Pituitary
Corticotropin-releasing hormone (CRH) ACTH
Thyrotropin-releasing hormone (TRH) TSH
Gonadotropin-releasing hormone (GnRH) LH/FSH
Growth hormone–releasing hormone (GHRH) GH
Dopamine Prolactin
Somatostatin GH, TSH

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 Pituitary Adenomas
• Benign tumors of the anterior pituitary
• May produce hormones → hormone excess syndromes
• May compress nearby CNS structures → neurologic symptoms
• Classified by cell type of origin and size
• Microadenoma: < 10 mm in size
• Macroadenoma: > 10 mm in size

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 Pituitary Adenomas
Cell types

Cell Type Hormone Adenoma

Lactotrophs Prolactin Hyperprolactinemia
Corticotrophs Adrenocorticotropic hormone (ACTH) Cushing’s disease
Thyrotrophs Thyroid-stimulating hormone (TSH) Central hyperthyroidism
Somatotrophs Growth hormone (GH) Acromegaly
Luteinizing hormone (LH)
Gonadotrophs Usually non-functioning
Follicle-stimulating hormone (FSH)

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 Pituitary Adenomas
Clinical presentation
• Most patients present with features of hormone hypersecretion
• Hyperprolactinemia, hypercortisolism, growth hormone excess, etc.
• Non-functioning adenomas: about 30% of adenomas
• Do not produce hormones
• Usually gonadotroph adenomas
• Usually identified as macroadenomas
• Present with neurologic symptoms from mass effect
• Or incidental finding on imaging
• May grow large enough to cause hypopituitarism

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 Pituitary Adenomas
Mass effect symptoms
• Headaches
• Classic cause of bitemporal hemianopsia
• Compression of optic chiasm

JFW/Wikipedia

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 Prolactinoma
• Most common functional pituitary adenoma
• Excess pituitary production of prolactin
• Normal: less than 20 ng/mL
• Small prolactinoma < 1 cm: up to 200
• Large prolactinoma over 2 cm: > 1000
• Hypogonadism
• Prolactin → ↓ LH/FSH
• Women: amenorrhea
• Men: low testosterone
• Galactorrhea (uncommon)

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 Hyperprolactinemia
Clinical features and diagnosis
• Postmenopausal women: usually no symptoms from high prolactin
• Diagnosis: serum prolactin level

Premenopausal Women Men

Fatigue
Oligomenorrhea
Loss of libido
Amenorrhea
Decreased muscle mass
Infertility
Decreased body hair
Decreased bone density
Infertility
Galactorrhea
Galactorrhea*
*less common due to less breast tissue

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 Hyperprolactinemia
Differential diagnosis
• Prolactinoma
• Dopamine-blocking drugs
• Antipsychotic drugs
• Usually mild and asymptomatic
• Usually no treatment required

Procedureready/Wikipedia

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 Hyperprolactinemia
Differential diagnosis
• Primary hypothyroidism
• Increases TSH and TRH
• Chronic renal failure
• Decreased clearance
• Hypothalamic disease
• Tumors
• Infiltrative disease (sarcoid)
• Damage to pituitary stalk (trauma)
• Pregnancy or stress (physiologic)

Procedureready/Wikipedia

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 Hyperprolactinemia
Workup
• History
• Symptoms and medication review
• Exam
• Visual field defects
• Signs of hypothyroidism
• Lab testing
• Thyroid: TSH
• Renal: BUN/Cr
• Pituitary MRI

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 Prolactinoma
Management
• Small, asymptomatic adenomas → observation
• Cabergoline or bromocriptine
• Treat symptoms of hyperprolactinemia
• Hypogonadism or galactorrhea
• Dopamine agonists
• Will decrease prolactin release
• Transsphenoidal surgical resection
• If medical management fails
• Large adenomas with neurologic symptoms

Cabergoline

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 Somatotroph Adenoma
• Causes excess growth hormone
• Children: gigantism
• Adults: acromegaly
• Growth hormone → IGF-1 secretion
• Insulin-like growth factor 1
• Secreted by liver
• Causes many clinical manifestations

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 Acromegaly
Clinical features
• Clinical syndrome of growth hormone excess
• Insidious onset
• Average duration symptoms → diagnosis = 12 years
• Enlarged jaw
• Coarse facial features
• Enlargement of nose, frontal bones
• Enlarged hands and feet
• Increasing glove or shoe size
• Rings that no longer fit

Philippe Chanson and Sylvie Salenave

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 Acromegaly
Insulin effects
• Growth hormone oppose insulin effects
• Insulin resistance → diabetes
• Diabetes in 10-15% of patients
• Abnormal glucose tolerance in 50% of patients

Insulin
Glucagon
Cortisol
Epinephrine
Growth Hormone

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 Acromegaly
Other clinical features
• Visceral organ enlargement
• Thyroid, heart, liver, lungs, kidneys, prostate
• Synovial tissue/cartilage enlargement
• Joint pain in knees, ankles, hips, spine
• Common presenting complaint is joint pain
• Cardiovascular disease
• Hypertension, left ventricular hypertrophy
• Diastolic dysfunction and arrhythmias
• Mortality increased in acromegaly due to CV disease

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 Acromegaly
Diagnosis
• Serum IGF-1 concentration
• IGF-1 level is constant (contrast with GH)
• Oral glucose tolerance testing
• Glucose should suppress growth hormone levels
• Normal subjects: GH falls within two hours
• Acromegaly: GH levels not supressed
• CNS imaging (MRI)

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 Acromegaly
Treatment
• Preferred treatment: surgery
• Medical therapy less effective
• Octreotide and lanreotide
• Analog of somatostatin
• Suppress somatotroph growth
• Suppress release of growth hormone
• Monitoring: IGF-1
• Goal level within reference range
• Bony abnormalities do not regress
• Joint symptoms often continue

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 Pituitary Incidentaloma
Common testing
• Prolactin
• Cortisol testing
• IGF-1
• TSH and free T4
• LH and FSH
• Testosterone (men)
• Estradiol (women)

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 Hypopituitarism
• Decreased secretion of pituitary hormones

Hormone Clinical Features

Adrenocorticotropic hormone (ACTH) Adrenal insufficiency
Thyroid-stimulating hormone (TSH) Hypothyroidism
Luteinizing hormone (LH)
Hypogonadism
Follicle-stimulating hormone (FSH)
Short stature in children
Growth hormone (GH)
Adults: ↓ lean mass ↑ fat mass
Prolactin Inability to lactate postpartum

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 Hypopituitarism
Diagnostic testing

Hormone Testing
Adrenocorticotropic hormone (ACTH) Measuring serum cortisol
Thyroid-stimulating hormone (TSH) Free T4 or total T4
Luteinizing hormone (LH) Testosterone (males)
Follicle-stimulating hormone (FSH) Estradiol (females)
Growth hormone (GH) IGF-1
Prolactin Levels variable

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 Hypopituitarism
Causes
• Hypothalamic disease
• Tumors, trauma, stroke
• Pituitary disease
• Mass lesions especially macroadenomas
• Radiation
• Damage to hypothalamus or pituitary gland
• Pituitary infarction
• Pituitary apoplexy

Shutterstock

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 Pituitary Infarction
Sheehan syndrome
• Ischemia and infarction of pituitary gland
• Occurs after postpartum hemorrhage
• Pituitary gland increases in size during pregnancy
• Estrogen stimulates lactotrophs growth (prolactin)
• Postpartum hemorrhage/shock → infarction

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 Pituitary Infarction
Clinical features
• Variable based on degree of infarction
• Lethargy, anorexia and weight loss (cortisol, thyroid)
• Inability to lactate (prolactin)
• Failure to resume menses (LH/FSH)

Anton Nossik/Wikipedia

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 Pituitary Apoplexy
• Sudden hemorrhage into pituitary gland
• Most often into a pituitary adenoma
• Abrupt onset of severe headache, visual loss and diplopia Pituitary Apoplexy
• Hypopituitarism: usually laboratory evidence only
• Diagnosis: head MRI or CT
• Treatment: surgical decompression of pituitary

Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 17664

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 Hypopituitarism
Treatment

Deficient Hormone Treatment

Adrenocorticotropic hormone (ACTH) Glucocorticoids
Thyroid-stimulating hormone (TSH) Levothyroxine
Luteinizing hormone (LH) Testosterone (males)
Follicle-stimulating hormone (FSH) Estrogens and progestins (females)
Replacement in children
Growth hormone (GH)
Usually no replacement in adults
Prolactin No replacement

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 Hyperparathyroidism
Jason Ryan, MD, MPH

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 Parathyroid Glands
• Four endocrine glands
• Located behind thyroid
• Secrete parathyroid hormone (PTH)
• Important for calcium and phosphate balance

Wikipedia/Public Domain

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 Parathyroid Hormone
Net effects
• ↑ plasma Ca2+
• ↓ plasma P043-
• Some effects due to direct action PTH
• Some due to activation of vitamin D (indirect)

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 Parathyroid Hormone
Stimuli for secretion
• Major stimulus: ↓ plasma Ca2+
• ↑ plasma P043-
• ↓ 1,25-(0H)2 vitamin D

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 Parathyroid Hormone
Systemic effects
• Kidney
• ↑ Ca2+ reabsorption (less urinary calcium)
• ↓ P043- reabsorption (more urinary phosphate)
• ↑ 1,25-(0H)2 vitamin D production
• GI tract
• ↑ Ca2+ and P043- absorption (via vitamin D)
• Bone
• ↑ Ca2+ and P043- reabsorption (direct and via vitamin D)

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 Hyperparathyroidism
• Excess release of PTH
• Primary: overactive glands
• Secondary: caused by hypocalcemia
• Tertiary: occurs in chronic kidney disease

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 Primary Hyperparathyroidism
• Inappropriate secretion of PTH not due to low calcium
• ↑ PTH → ↑ Ca
• Most common cause of outpatient hypercalcemia
• Malignancy most common cause in hospitalized patients
• Most common in postmenopausal women
• Diagnosis: serum calcium and PTH
• Must have hypercalcemia
• PTH may be elevated
• PTH may be inappropriately normal for high calcium

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 Primary Hyperparathyroidism
Causes Parathyroid Adenoma
• Most common cause: adenoma (85% of cases)
• Hypertrophy of all four glands
• Multiple adenomas
• Rarely parathyroid carcinoma

BruceBlaus/Wikipedia

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 Primary Hyperparathyroidism
Signs and symptoms
• Often incidental finding when asymptomatic
• Recurrent kidney stones
• “Stones, bones, groans, and psychiatric overtones”
• Largely historical Kidney Stones
• Modern era, most patients diagnosed early

Shutterstock

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 Osteitis Fibrosa Cystica
• Classic bone disease of hyperparathyroidism
• Clinical features: bone pain and fractures Brown Tumors
• Subperiosteal bone resorption Brown Tumors
• Commonly seen in bones of fingers
• Irregular or indented edges to bones
• Brown tumors (osteoclastoma)
• Appear as black spaces in bone on x ray

Frank Gaillard/Wikipedia

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 Primary Hyperparathyroidism
Diagnosis and workup
• Diagnosis: calcium and PTH
• 24-hour urinary calcium excretion
• Maye be high, normal or low
• Not required for diagnosis
• Used to estimate risk of renal complications
• Elevated urinary calcium excludes FHH
• Familial Hypocalciuric Hypercalcemia
• Disorder of excess renal resorption of calcium
• Also causes hypercalcemia but low urinary calcium

Wikipedia/Public Domain

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 Primary Hyperparathyroidism
Localization studies
Parathyroid MIBI Scan
• Used to identify hyperfunctioning tissue
• Done only if surgery being planned
• Not used for diagnosis
• Sestamibi scintigraphy
• Technetium-99m-sestamibi (MIBI)
• Concentrates in parathyroid glands
• Alternatives: ultrasound or CT-scan

Public Domain

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 Primary Hyperparathyroidism
Treatment
• Definitive treatment: parathyroidectomy
• Pre-op nuclear imaging often done to identify hyperfunctioning tissue
• Focused parathyroidectomy: remove adenoma only
• Bilateral hyperplasia: remove 3.5 glands
• Or remove 4 glands and implant tissue in arm
• Resolves symptoms of hypercalcemia (if present)
• Decreases risk of kidney stones
• Improves bone mineral density

Public Domain

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 Primary Hyperparathyroidism
Parathyroidectomy indications
• Indicated for all symptomatic patients
• Asymptomatic patients*:
• Age less than 50 years (lower surgical risk; more likely to progress)
• Calcium more than 1.0 mg/dL above normal (~ 11.5 or higher)
• Osteoporosis by DXA scan
• GFR < 60 mL/min
• Many patients are older and asymptomatic
• Often do not require surgery

* Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism 2014 guidelines

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 Primary Hyperparathyroidism
Parathyroidectomy complications
• Risks of recurrent laryngeal nerve damage
• May result in hoarseness
• Post-op hypocalcemia
• Remaining parathyroid glands may be suppressed
• Numbness or tingling in fingertips, toes, hands
• If severe: twitching or cramping of muscles
• Treat with calcium supplementation

Shutterstock

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 Primary Hyperparathyroidism
Medical therapy
• Used in poor surgical candidates with symptoms
• Bisphosphonates
• Cinacalcet
• “Calcimimetic”
• Activate calcium receptor in parathyroid glands
• Inhibits PTH secretion

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 Secondary Hyperparathyroidism
• Occurs in chronic kidney disease
• Chronically low serum calcium → ↑ PTH
• No symptoms of hypercalcemia
• Results in renal osteodystrophy
• Bone pain (predominant symptom)
• Fractures (weak bones 2° chronic high PTH levels)
• If severe, untreated can lead to osteitis fibrosa cystica

↑PTH ↓Ca
Public Domain

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 Secondary Hyperparathyroidism
Chronic Kidney Disease

↑ Phosphate ↓ 1,25-OH2 Vitamin D

↓ Ca from plasma ↓ Ca from gut

Hypocalcemia

↑PTH

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 Secondary Hyperparathyroidism
Monitoring, treatment and prevention
• Standard monitoring in patients with low GFR
• Calcium and phosphate
• Vitamin D
• PTH level
• Hyperphosphatemia: phosphate binders
• Calcium-containing binders: calcium carbonate and acetate
• Non-calcium-containing binders: sevelamer and lanthanum
• Treat vitamin D deficiency with supplementation
• Persistently elevated PTH: calcitriol

Public Domain

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 Tertiary Hyperparathyroidism
• Consequence of chronic kidney disease
• Chronically low calcium → chronically ↑ PTH
• Parathyroid hyperplasia
• Parathyroid gland becomes autonomous
• VERY high PTH levels
• Calcium may become elevated
• Often requires parathyroidectomy

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 FHH
Familial Hypocalciuric Hypercalcemia
• Rare, autosomal dominant disorder
• Abnormal calcium sensing
• Abnormal calcium sensing receptors (CaSRs)
• Found in parathyroid glands and also kidneys
• Higher than normal set point for calcium
• Normal PTH → ↑ calcium
• More renal resorption of calcium
• Low urinary calcium

Smith KA, Ayon RJ, Tang H, Makino A, Yuan JX. Calcium-Sensing Receptor Regulates Cytosolic [Ca 2+ ] and
Plays a Major Role in the Development of Pulmonary Hypertension. Front Physiol. 2016 Nov 4;7:517.

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 FHH
Clinical features
• Mildly elevated serum calcium
• Usually normal PTH
• Low urinary calcium (key finding!)
• Often looks like 1o hyperparathyroidism
• Real world distinction from 1o disease difficult
• Genetic testing available
• Usually does not require treatment

Wikipedia/Public Domain

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 PTHrP
Parathyroid hormone-related protein
• Synthesized in large amounts by some tumors Lung Cancer
• Renal cell carcinoma, squamous cell lung cancer, others
• Leads to hypercalcemia of malignancy
• Increased calcium
• Low PTH
• Elevated serum PTHrP
• Normal or low 1,25 vitamin D
• PTHrP does not activate vitamin D

Public Domain

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 Hypercalcemia
↑ Calcium

PTH

Low
Normal or High
PTH
PTH
Malignancy likely
Urinary Calcium
Check PTHrP
Alk Phos Low Normal/High
↑ Calcitriol (lymphoma, granulomas)
Rare causes
Consider FHH Primary or Tertiary
Hyperparathyroidism

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 Hypoparathyroidism
and Vitamin D
Jason Ryan, MD, MPH

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 Hypoparathyroidism
• Inappropriately low PTH secretion
• Not due to hypercalcemia
• Causes hypocalcemia

↓PTH ↓Ca

Wikipedia/Public Domain

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 Hypocalcemia
Causes
• Hypoparathyroidism – low serum PTH
• Hypomagnesemia
• Very low Mg inhibits PTH release
• High serum PTH – normal response to hypocalcemia
• PTH unable to raise serum calcium
• Vitamin D deficiency
• Chronic kidney disease (↓ active vitamin D)
• Resistance to PHT (pseduohypoparathyroidism)
• Key tests: Mg, PTH level, vitamin D, BUN/Cr

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 Hypocalcemia
Signs and symptoms
• Tetany
• Muscle spasms
• Tingling of fingers, toes, around mouth
• Perioral numbness
• Trousseau's sign: hand spasm with BP cuff inflation
• Chvostek's sign: facial contraction with tapping on nerve
• Seizures
• Prolonged Qt interval

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 Hypoparathyroidism
Causes
• Surgical excision
• Often accidental after thyroid or neck surgery
• Common after parathyroid surgery
• Post-op tingling, muscle spasms
• Autoimmune and genetic disorders
• Infiltrative diseases
• Hemochromatosis, Wilson's
• Metastatic cancer
• Radiation

Public Domain

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 Hypoparathyroidism
Management of hypocalcemia
• Goal: low normal serum calcium
• Normal range for total calcium: 8.5 to 10.0 mEq/L
• Acute or highly symptomatic
• Tetany, seizures, prolonged Qt interval
• Often post-op after thyroidectomy or other surgery
• Intravenous calcium (calcium gluconate)
• Chronic or minimal symptoms
• Oral calcium and vitamin D supplementation
• Rare cases: recombinant human PTH (teriparatide)

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 APS-I Oral Candidiasis
Autoimmune Polyglandular Syndrome Type 1
• Rare autosomal recessive disorder
• Mutations of autoimmune regulator (AIRE) gene
• Triad:
• Mucocutaneous candidiasis
• Candida infections of skin, nails, and mucous membranes
• Autoimmune hypoparathyroidism
• Adrenal insufficiency
• Hypoparathyroidism usually occurs before age 10
• Diagnosis: genetic testing

James Heilman, MD

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 DiGeorge Syndrome
• Immunodeficiency syndrome due to chromosomal deletion at 22q11.2
• Failure of 3rd/4th pharyngeal pouch to form
• Classic triad:
• Loss of thymus (loss of T-cells, recurrent infections)
• Loss of parathyroid glands (hypocalcemia, tetany)
• Congenital heart defects
• Presents in infancy/childhood with:
• Hypocalcemia (hypoparathyroidism)
• Recurrent infections
• Congenital heart disease

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 Pseudohypoparathyroidism
PHP
• Group of congenital disorders PTH Receptor
• Kidney and bone unresponsiveness to PTH
• PTH resistance
• Abnormal PTH receptor function (various subtypes)
• Usually presents in childhood
• Hypocalcemia
• Hyperphosphatemia
• Elevated PTH (appropriate)
• Normal vitamin D and renal function

Thomas J. Gardella, and Jean-Pierre Vilardaga

Pharmacol Rev 2015;67:310-337

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 AHO
Albright's Hereditary Osteodystrophy
• Type 1a form of pseudohypoparathyroidism
• Autosomal dominant GNA1 gene mutation
• Inability to produce cAMP after PTH binds receptor
• Hypocalcemia, hyperphosphatemia, ↑ PTH
• Collection of clinical features
• Short stature
• Shortened fourth and fifth metacarpals
• Rounded facies
• Mild intellectual impairment

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 Vitamin D
• Raises serum calcium and phosphate
• Activated by parathyroid hormone
• Gastrointestinal tract: ↑ Ca2+ and P043- absorption
• Bone: ↑ Ca2+ and P043- resorption
• Deficiency: hypocalcemia and hypophosphatemia

Wikipedia/Public Domain

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 Vitamin D
Forms
• Vitamin D2 (ergocalciferol): found in plants
• Vitamin D3 (cholecalciferol): found in fortified milk
• Skin synthesizes vitamin D3 D2 D3
• Requires sunlight
• Lack of sun exposure can lead to deficiency
• More common in winter months

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 Vitamin D 25carbon

Activation
• Dietary or skin-produced vitamin must be activated
• Requires hydroxylation to become active
• Step 1: 25 hydroxylation - occurs in liver
• Constant activity
• Step 2: 1 hydroxylation - occurs in kidney
• Regulated by PTH

1 carbon

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 Vitamin D
Activated forms Nephron – Proximal Tubule
• 25-OH Vitamin D: calcidiol
• Produced by liver
• Long half life
• Storage form
• Available for activation as needed
• 1,25-OH2 Vitamin D: calcitriol
• Produced by kidneys (proximal tubule)
• Active form
• Binds vitamin D receptors
• Levels vary based on PTH
• ↓ 1,25-OH2 vitamin D in CKD → hypocalcemia

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 Vitamin D
Clinical importance of subtypes
• Determination of vitamin D status: 25-OH Vitamin D (calcidiol)
• Level of storage form
• Level based on dietary intake and skin/sunlight
• Replacement in patients with no liver/kidney disease
• Vitamin D3 (cholecalciferol)
• Vitamin D2 (ergocalciferol)
• Replacement in advanced CKD: 1,25-OH2 Vitamin D (calcitriol)
• Active form - restores vitamin D activity
• Overcomes inability of kidneys to active vitamin D

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 Vitamin D
Deficiency
• Normal 25-OH vitamin D level: 20 to 40 ng/mL
• Deficiency: less than 20 ng/mL
• Most patients asymptomatic
• Elevated PTH level often maintains serum calcium
• Major adverse outcome is bone disease
• Severe cases: hypocalcemia

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 Vitamin D Deficiency Rickets
Bone disorders
• Osteomalacia
• Softening of bones
• ↓ vitamin D → low calcium → ↑ PTH → ↓ bone mineralization
• Bone pain or tenderness
• Fractures
• Rickets
• Occurs in children
• Deficient mineralization of growth plate
• Bone pain
• Distal forearm/knee most affected (rapid growth)
• Bowing of femur/tibia (classic X-ray finding)

Michael L. Richardson, M.D./Wikipedia

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 Vitamin D Deficiency
Treatment
• Cholecalciferol
• Vitamin D3
• Used in patients with low 25-OH vitamin D
• Improves vitamin D3 stores
• Requires activation by kidneys
• Calcitriol
• Active form of vitamin D3
• Used in patients with renal disease and high PTH
• Calcium supplementation

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 Vitamin D
Screening
• Sometimes done in high-risk groups
• Limited sun exposure
• Institutionalized (nursing home residents)
• Osteoporosis
• Malabsorption

Pixnio

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 Vitamin D
Breast feeding
• Breast milk low in vitamin D
• Even if mother has sufficient levels
• Most infants get little sun exposure
• Exclusively breastfed infants → supplementation
• 400 international units (drops)
• Beginning a few days after birth

Public Domain/Wikipedia

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 Hypocalcemia ↓ Calcium*

Magnesium * corrected for albumin

Low Normal

Correct Mg PTH
Vitamin D, Phos, Cr

↑ PTH ↓ PTH
Elevated Cr
↑ Phos ↓ Phos ↑ Phos
↓ 25 Vit D Nl 25-Vit D Hypoparathyroidism
DiGeorge
APS-1
CKD Vit D PHP
↓ 1,25 VitD Deficiency
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 Osteoporosis
Jason Ryan, MD, MPH

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 Osteoporosis
• Porous bone
• Low bone mass and bone density
• Weak bones prone to fracture
• Usually no clinical symptoms until fracture

BruceBlaus/Wikipedia

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 Osteoporosis
Diagnosis
• Fragility fracture
• Fall from standing height or less
• Not from major trauma (i.e. MVA)
• Spine, hip, wrist, humerus, rib, or pelvis
• Also a spontaneous vertebral “compression” fracture
• T score of -2.5 or lower

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 DXA
Dual-energy X-ray absorptiometry
• Two X-rays of different energy levels aimed at bones
• T score
• Patient BMD vs. healthy 30-year-old BMD
• Normal: -1.0 or higher (least fractures)
• Osteopenia: -1.0 to -2.5
• Osteoporosis: -2.5 or lower (most fractures)
• Screening in women
• Every 3 to 5 years
• All women > 65 years old
• Women < 65 with risk factors
• Screening not recommended in men

Nick Smith photography/Wikipedia

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 Bone Mass
• Peak bone mass occurs in young adulthood
• Many influences: sex, genetics, diet
• Decreases slowly thereafter
• Each resorption/formation cycle → some bone loss
• Males achieve higher peak bone mass
• Menopause accelerates bone loss
• Caused by decreased estrogen levels
• Female osteoporosis >> male osteoporosis
• Weight-bearing activity → ↑ bone mass

OpenStax College/Wikipedia

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 Osteoporosis
Selected Risk Factors
• Alcohol
• Heavy use associated with osteoporosis
• Moderate use effects not clear
• Smoking
• Accelerates bone loss
• Low body weight (< 127 lbs)
• Advanced age

Pixabay/Public Domain

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 Osteoporosis
Subtypes
• Primary osteoporosis
• Most common form
• Postmenopausal osteoporosis (type I) – estrogen deficiency
• Senile osteoporosis (type II) – age-related bone loss (men and women)
• Secondary osteoporosis
• Not related to menopause or aging
• Suspected in pre-menopausal women
• Caused by drugs or another medical disorder

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 Secondary Osteoporosis
Glucocorticoids
• Affect osteoblasts and osteoclasts
• Increase bone resorption
• Reduce bone formation

Shutterstock

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 Secondary Osteoporosis
Antiepileptic Drugs
• Phenobarbital, Phenytoin, Carbamazepine
• Used to treat seizures and epilepsy
• Risk of osteoporosis with long term therapy
• Increase activity of P450 enzymes
• Increases breakdown of vitamin D
• Less calcium → increased PTH → bone loss

Pixabay/Public Domain

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 Secondary Osteoporosis
Unfractionated Heparin
• Only with long term use
• Decreases bone formation
• Increases resorption
• Low molecular weight heparin: unclear bone effects

Unfractionated Heparin

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 Secondary Osteoporosis Cushing’s Syndrome
Endocrine isorders
• Cushing’s syndrome or disease (↑ cortisol)
• Hyperthyroidism
• Hyperparathyroidism
• Hypogonadism (↓ estrogen)

Shutterstock

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 Secondary Osteoporosis
Nutritional Associations
• Vitamin D deficiency
• Calcium deficiency Vitamin D3
• Malabsorption (celiac disease)

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 Secondary Osteoporosis
Selected Testing
• Suspected in premenopausal women
• History and physical exam may be used to guide testing

Disorder Testing
Celiac Disease CBC (anemia)
Calcium deficiency Serum calcium
Vitamin D deficiency 25-hydroxyvitamin D
Hyperthyroidism TSH
Hyperparathyroidism Calcium, phosphate +/- PTH
Chronic renal/liver disease Creatinine and LFTs

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 Osteoporosis
Treatment
• Lifestyle modification
• Weight-bearing exercise
• Exercise while standing and bearing body weight
• Walking, hiking, jogging, playing tennis, etc.
• Not swimming, cycling, rowing
• Avoidance of heavy alcohol use
• Smoking cessation
• Calcium and vitamin D supplementation
• Calcium 1200 mg daily
• Vitamin D 800 international units daily

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 Bisphosphonate
Bisphosphonates
Alendronate, Risedronate, Zoledronate, Ibandronate
• First line medical therapy
• Analogs of pyrophosphate
• Two phosphonate (PO3) groups attached to carbon
• Vary by side chains (R1 and R2)
• Inhibit osteoclasts
• Oral and IV drugs

Wikipedia/Public Domain

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 Bisphosphonates
Common adverse effects
• Oral drugs: alendronate and risedronate
• Upper GI upset
• Reflux, esophagitis, esophageal ulcers
• Local effects of bisphosphonates on mucosa
• Not used in patients with esophageal disease
• Often taken weekly
• Take with water on empty stomach
• Remain upright for 30 minutes

Pixabay.com

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 Bisphosphonates
Common adverse effects
• IV drugs: zoledronate and ibandronate
• Flu-like symptoms
• 24 to 72 hours after infusion
• Low-grade fever, myalgias
• Treated with ibuprofen and acetaminophen
• Long dosing intervals: 3-months to annually

Shutterstock

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 Bisphosphonates
Rare, serious adverse effects
• Atypical femur fractures
• Below lesser trochanter
• No or minimal trauma
• Usually occur after 5 years of therapy
• Osteonecrosis of the jaw
• Pain, swelling of mandible
• May lead to exposed bone, local infection
• May cause pathologic fracture of jaw
• Often occurs in patients with cancer

Wikipedia/Public Domain

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 Bisphosphonates
Other Indications Spinal Bone Mets MRI
• Hypercalcemia
• ↓ bone resorption → ↓ serum calcium
• Paget’s disease of bone
• Metastatic bone disease
• Improve outcomes
• ↓ pathologic fractures and spinal cord compression
• ↓ hypercalcemia of malignancy
• ↓ need for radiation or bone surgery

Wikipedia/Public Domain

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 Osteoporosis
Other Treatments
• Used in patients who cannot take bisphosphonates
• Or who do not respond to bisphosphonates
• Teriparatide
• Raloxifene
• Calcitonin
• Denosumab

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 Teriparatide
• Recombinant human parathyroid hormone (PTH)
• Continuous administration of PTH
• Bone resorption →↑ serum calcium
• Important physiologically
• Low dose once daily bolus administration
• Increased bone mass
• Increased osteoblast bone formation
• Teriparatide: subcutaneous daily injection

Wikipedia/Public Domain

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 Teriparatide
Adverse Events
• Generally well tolerated
• May cause nausea or dizziness
• Transient hypercalcemia
• Brief rise in serum calcium
• Drug has quick on/off effect over hours
• Rarely leads to very high levels or symptoms
• Levels return to baseline within four hours

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 Raloxifene
SERM (Selective Estrogen Receptor Modulator)
• Estrogen actions on bone
• Anti-estrogen in breast
• Reduces risk of breast cancer
• May cause hot flashes
• Associated with DVT/PE
• Minimal effects on uterus
• Not associated with bleeding, hyperplasia/cancer

Raloxifene

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 Calcitonin
• Hormone produced by thyroid
• Binds to osteoclasts
• Inhibits bone resorption
• Salmon calcitonin used for osteoporosis
• Second-line therapy
• Intranasal administration
• May cause hypocalcemia
• May cause rhinitis

Wikipedia/Public Domain

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 Denosumab
• Monoclonal RANK-L antibody
• Blocks osteoblast activation of osteoclasts
• Given subcutaneously every six months
• Usually well-tolerated with few adverse effects

Osteoblast

R
Osteoclast
RANK-L RANK

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