ENDOCRINE

Question 1

Adrenal Cortex Origin

Answer 1

Mesoderm

Question 2

Anterior Pituitary Origin

Answer 2

Oral ectoderm (Rathke pouch)

Question 3

Anterior Pituitary Basophils

Answer 3

FSH

LH

ACTH

TSH

B-FLAT

Question 4

Anterior Pituitary Acidophils

Answer 4

GH

Prolactin

Question 5

Thyroid Follicular Cells Origin

Answer 5

Endoderm

Question 6

Paracrine Hormones

Answer 6

• Affect the neighboring cells via diffusion
• Example → D cells of the stomach produce somatostatin to inhibit neighboring G cells from secreting gastrin.

Question 7

Autocrine Hormones

Answer 7

• Affect the secreting cell itself
• Example → Autocrine signaling is particularly important for the self-renewal of embryonic stem cells.

Question 8

Endocrine Hormones

Answer 8

• Secreted into the bloodstream to reach their targets
• Example → Pancreatic β cells secrete insulin directly into the bloodstream to stimulate the uptake of glucose by the hepatic, muscle, and adipose tissue cells.

Question 9

Steroid Hormones

Answer 9

Derived from cholesterol

Examples:

1. Testosterone
2. Progesterone
3. Estrogen
4. Glucocorticoids
5. Mineralocorticoids

Question 10

Amine Hormones

Answer 10

Derived from a single amino acid such as phenylalanine, tyrosine, or tryptophan

Examples:

1. Catecholamines
2. Thyroid hormones (T3 and T4)

Question 11

Peptide/Protein Hormones

Answer 11

Derived from a few or many amino acids

Examples:

1. Oxytocin
2. Vasopressin
3. Prolactin
4. Glucagon
5. Insulin

Question 12

Lipophilic Hormones

Answer 12

• Diffuse through the lipid plasma membrane of cells, bind to intracellular receptors, and affect transcription
• Usually have long-term effects with delayed onset (e.g., sex hormones)
• Pass into the bloodstream once synthesized without being stored in cells.

1. Steroid hormones
2. Thyroid hormones

Question 13

Hydrophilic Hormones

Answer 13

• Water-soluble
• Bind to receptor proteins on the cellular membrane
• Stored in secretory granules and released when needed.

1. Amine and peptide hormones (except for thyroid hormones, which are lipophilic)

Question 14

Degradation of Steroid Hormones

Answer 14

Inactivation and conjugation in the liver and excretion in bile

Question 15

Degradation of Catecholamines

Answer 15

Enzymatic degradation and excretion in urine (e.g., vanillylmandelic acid)

Question 16

Degradation of Peptide/Protein Hormones

Answer 16

Proteolytic degradation mainly in the liver and kidneys

Question 17

GH (Growth hormone, Somatotropin) Function

Answer 17

Direct effects

1. ↓ Glucose uptake into cells (↑ insulin resistance)
2. ↑ Lipolysis
3. ↑ Protein synthesis in muscle
4. ↑ Amino acid uptake

Indirect effects → mediated by IGF-1 (insulin-like growth factor 1; originally called somatomedin C) (growth hormone stimulates the production of IGF-1 in the liver)

1. Growth stimulation
2. Anabolic effect on body
3. ↑ Amino acid uptake
4. ↑ Protein synthesis
5. ↑ DNA and RNA synthesis
6. ↑ Chondroitin sulfate
7. ↑ Collagen
8. ↑ Cell size and number

Growth hormone counters the effects of insulin on glucose and lipid metabolism but has an insulin agonist effect on protein metabolism.

Question 18

GH (Growth hormone, Somatotropin) Regulation

Answer 18

• ↑ GH secretion → exercise, deep sleep, puberty, hypoglycemia, CKD, thyroid hormone, estrogen, testosterone, and short-term glucocorticoid exposure (initial steroid exposure causes release of somatostatin, which decreases GH secretion. This is followed by a reflex increase in GHRH secretion that lasts for ∼ 12 hours (for dexamethasone), after which there is a drop in GH levels.)
• ↓ GH secretion → glucose, somatostatin, somatomedin, free fatty acids, and chronic glucocorticoid therapy (the inhibitory effect is seen with > 3 months of steroid therapy)

Question 19

Cortisol Function

Answer 19

• Metabolism → cortisol plays an important role in the mobilization of energy reserves.

1. ↑ Gluconeogenesis to maintain blood glucose levels
2. ↑ Glycogen synthesis to maintain glucose storage
3. ↑ Protein catabolism
4. ↑ Lipolysis
5. ↑ Appetite
6. ↑ Insulin resistance

• Immune system → antiinflammatory and immunosuppressive effects

1. Inhibits production of leukotrienes and prostaglandins ƒ
2. Inhibits WBC adhesion → neutrophilia ƒ
3. Blocks histamine release from mast cells ƒ
4. Eosinopenia, lymphopenia ƒ
5. Blocks IL-2 production
6. Wound healing → fibroblast inhibition → ↓ collagen synthesis → ↓ wound healing, ↑ striae

• Blood pressure → mild mineralocorticoid effect (stimulation of aldosterone receptors in high concentrations) and ↑ potassium excretion → ↑ blood pressure
• Upregulates α1-receptors on arterioles Žsensitivity to norepinephrine and epinephrine (permissive action)
• ↓ Bone formation (osteoblast activity)

Question 20

Cortisol Regulation

Answer 20

• Positive feedback → a number of stimuli can trigger CRH release.
  
  • Psychological/physical pain and stress
  • Pyrogens, epinephrine, histamine
  • Hypoglycemia
  • Hypotension
• Negative feedback → glucocorticoids themselves trigger a negative feedback loop that inhibits the secretion of CRH and ACTH.
• Circadian rhythm
  
  • Endogenous biological rhythm influences CRH secretion (impulses by the suprachiasmatic nucleus (SCN) trigger the rhythmic release of CRH. Moreover, the SCN transmits signals directly to the adrenal cortex via neural pathways. In the adrenal cortex, the intrinsic circadian oscillator modifies the efficiency with which cells respond to ACTH)
  • Cortisol levels are highest early in the morning and decrease during the day, until they drop sharply during the night and the early phase of sleep.

Question 21

Endocannabinoid

Answer 21

Regulation:

• Hunger Intake of fatty and sweet food

Effects:

• ↑ Appetite
• ↑ Dopamine release from nucleus accumbens (reward pathway)
• Exogenous cannabinoids are responsible for “the munchies” effect.

Question 22

Neuropeptide Y

Answer 22

Regulation:

• Hunger

Site of Production:

• Hypothalamus

Effects:

• ↑ Appetite
• Regulation of anxiety-related behavior
• Increased neuronal excitability

Question 23

Neuroendocrine Regulation of Satiety

Answer 23

1. Leptin
2. Cholecystokinin
3. GLP-1
4. Peptide YY
5. Amylin

Question 24

Neuroendocrine Regulation of Appetite

Answer 24

1. Ghrelin
2. Neuropeptide Y
3. Endocannabinoid

Question 25

Leptin

Answer 25

↓ Levels during:

• Starvation
• Sleep deprivation

↑ Levels in:

• Obesity (due to leptin resistance)
• Fed state

Source:

• Adipose tissue

Effects:

• ↓ Appetite (long term)
• ↓ Neuropeptide Y release

Leptin gene mutation causes obesity.

Question 26

Peptide YY

Answer 26

Regulation:

• Protein-rich chyme

Source:

• L cells of the small and large intestine

Effects:

• ↓ Appetite (short term)
• ↓ Gastric emptying

Question 27

Amylin

Answer 27

Regulation:

• Glucose (cosecreted with insulin)

Source:

• β cells of the pancreas

Effects:

• ↓ Appetite (short term)
• ↓ Gastric emptying
• ↓ Glucagon release

Question 28

Hormones with cAMP Signaling Pathway

Answer 28

FSH

LH

ACTH

TSH

CRH

hCG

ADH (V2- receptor)

MSH

PTH

Calcitonin

Histamine (H2-receptor)

Glucagon

GHRH

Question 29

Hormones with cGMP Signaling Pathway

Answer 29

BNP

ANP

EDRF (NO)

Question 30

Hormones with IP₃ Signaling Pathway

Answer 30

GnRH

ADH (V1-receptor)

TRH

Oxytocin

Gastrin

Angiotensin II

Histamine (H1-receptor)

Question 31

Hormones with Intracellular Receptors

Answer 31

Progesterone

Estrogen

Testosterone

Cortisol

Aldosterone

T3/T4

Vitamin D

Question 32

Hormones with Receptor Tyrosine Kinase

Answer 32

IGF-1

FGF

PDGF

EGF

Insulin

TGF-β

MAP kinase pathway

Question 33

Hormones with Nonreceptor Tyrosine Kinase

Answer 33

G-CSF

Erythropoietin

Thrombopoietin

Prolactin

Immunomodulators (eg, cytokines IL-2, IL-6, IFN)

GH

JAK/STAT pathway

Think acidophils and cytokines GET a JAKed PIG

Question 34

Adiponectin

Answer 34

• A hormone produced by adipose tissue.
• Modulates insulin sensitivity, enhances fatty acid breakdown and has anti-inflammatory effects.
• Inversely related to adiposity.

Question 35

HIV Associated Lipodistrophy

Answer 35

↓ leptin

↑ ghrelin and insulin

Question 36

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Etiology

Answer 36

Increased pituitary ADH secretion

1. CNS conditions
   
   • Stroke
   • Trauma, bleeding (subarachnoid hemorrhage)
   • Infection
   • Following neurosurgery (e.g., transsphenoidal pituitary surgery)
   • Psychosis
2. Chronic disease
   
   • Pulmonary (pneumonia, COPD)
   • HIV
   • Acute intermittent porphyria
3. Drugs

• Anticonvulsants (e.g., carbamazepine, valproate)
• Antidepressants
  
  • SSRIs (e.g., sertraline)
  • MAO inhibitors
  • TCAs (e.g., amitriptyline)
• Antineoplastic agents
  
  • Mitotic inhibitors (e.g., vincristine)
  • Alkylating agents (e.g., cyclophosphamide, cisplatin)
• Antipsychotics (e.g., haloperidol)
• Analgesics (e.g., NSAIDS, opioids)
• Illicit substances (e.g., MDMA)

Paraneoplastic ectopic ADH production

1. Small cell lung carcinoma
2. Head and neck cancer
3. Extrapulmonary small cell carcinoma
4. Olfactory neuroblastoma

Nephrogenic SIADH

• Mutation of vasopressin-2 receptor gene (gain of function mutation causes constitutive receptor activation)

Question 37

Central Diabetes Insipidus (CDI) Etiology

Answer 37

Most common form → caused by insufficient or absent hypothalamic synthesis or secretion of antidiuretic hormone (ADH) from the posterior pituitary

Types:

1. 1. Primary (∼ ⅓ of cases)
      * Most cases are idiopathic.
      * The hereditary form is rare.
      * Autoimmune etiology of primary CDI has been suggested
2. Secondary (∼ ⅔ of cases)
   
   • Brain tumors (especially craniopharyngioma) and cerebral metastasis (most common → lung cancer and leukemia/lymphoma)
   • Neurosurgery → usually after the removal of large adenomas
   • Traumatic brain injury, pituitary bleeding, subarachnoid hemorrhage
   • Pituitary ischemia (e.g., Sheehan syndrome, ischemic stroke)
   • Infection (e.g., meningitis)

Question 38

Nephrogenic Diabetes Insipidus (NDI) Etiology

Answer 38

Rare → caused by defective ADH receptors in the distal tubules and collecting ducts

Types:

1. Hereditary (mutation in ADH receptor) → very rare
2. Acquired
   
   • Adverse effect of medications (lithium, demeclocycline)
   • Hypokalemia, hypercalcemia (both lower responsiveness to ADH and sodium reabsorption)
   • Renal disease (e.g., autosomal dominant polycystic kidney disease, renal amyloidosis)
   • Pregnancy (due to transient ADH resistance in the 2nd half of pregnancy; called gestational diabetes insipidus)

Question 39

Primary Polydipsia (Psychogenic Polydipsia) Etiology

Answer 39

• Psychiatric diseases (e.g. schizophrenia, obsessive-compulsive disorder)
• Lesions in the hypothalamic thirst center

Question 40

Acquired Hypopituitarism Etiology

Answer 40

1. Intrasellar/parasellar masses (compress the pituitary gland and cause hypopituitarism)
   
   • Nonsecretory pituitary macroadenomas (≥ 10 mm in diameter) are the most common cause of hypopituitarism among adults (microadenomas (< 10 mm) are usually too small to cause hypopituitarism)
   • Less common → meningiomas, craniopharyngiomas, internal carotid artery aneurysms, Rathke cleft cyst (a benign, intrasellar/suprasellar cyst that arises from the remnants of the Rathke pouch) (the sella turcica, which contains the pituitary gland, is surrounded laterally by the cavernous sinus (which contains the internal carotid artery), superiorly by the diaphragma sellae (a fold of dural matter), and inferiorly by the sphenoid sinus and Rathke pouch)
2. Pituitary apoplexy
   
   • Infarction of the pituitary gland as a result of ischemia and/or hemorrhage
   • Most commonly occurs in patients with a preexisting pituitary adenoma
   • Primarily affects the anterior pituitary gland because it receives its blood supply from a relatively low-pressure arterial system and is, therefore, vulnerable to ischemia and infarction (in contrast, the posterior pituitary gland is thought to receive its blood supply from a higher-pressure arterial system. Accordingly, the posterior pituitary gland hormones, including antidiuretic hormone and oxytocin, are not typically affected in patients with pituitary apoplexy)
   • Sheehan syndrome → postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage.
     
     • During pregnancy, hypertrophy of prolactin-producing regions increases the size of the pituitary gland, making it very sensitive to ischemia.
     • Blood loss during delivery/postpartum hemorrhage → hypovolemia → vasospasm of hypophyseal vessels → ischemia of the pituitary gland → empty sella turcica on imaging
3. Traumatic brain injury (especially around the skull base)

Question 41

Congenital Hypopituitarism Etiology

Answer 41

1. Infiltration of the pituitary and/or hypothalamus
   
   • Hemochromatosis
   • Sarcoidosis
   • Lymphocytic histiocytosis (infiltration of plasma cells and other lymphocytes leading to autoimmune destruction of the pituitary gland; usually seen during late pregnancy or in the postpartum period)
   • Langerhans cell histiocytosis
   • Infections → meningitis, TB, tertiary syphilis, toxoplasmosis, fungi (e.g., histoplasmosis)
2. Empty sella syndrome
3. Congenital deficiency of hypothalamic hormones
   
   • GnRH deficiency (Kallmann syndrome)
   • Prader-Willi syndrome

Question 42

Iatrogenic Hypopituitarism Etiology

Answer 42

These procedures are performed to treat pituitary tumors

1. Hypophysectomy
2. Pituitary irradiation

Question 43

Pituitary Apoplexy

Answer 43

• Infarction of the pituitary gland as a result of ischemia and/or hemorrhage
• Most commonly occurs in patients with a preexisting pituitary adenoma
• Primarily affects the anterior pituitary gland because it receives its blood supply from a relatively low-pressure arterial system and is, therefore, vulnerable to ischemia and infarction (in contrast, the posterior pituitary gland is thought to receive its blood supply from a higher-pressure arterial system. Accordingly, the posterior pituitary gland hormones, including antidiuretic hormone and oxytocin, are not typically affected in patients with pituitary apoplexy)
• Sheehan syndrome → postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage.
• Manifests with acute onset of:
  
  1. Severe headache
  2. Hypopituitarism
  3. Bilateral hemianopia, diplopia (due to damage to CN III)
  4. Sudden hypotension, possibly shock

Question 44

Sheehan Syndrome

Answer 44

• Postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage.
• During pregnancy, hypertrophy of prolactin-producing regions increases the size of the pituitary gland, making it very sensitive to ischemia.
• Blood loss during delivery/postpartum hemorrhage → hypovolemia → vasospasm of hypophyseal vessels → ischemia of the pituitary gland → empty sella turcica on imaging

Question 45

Acromegaly Presentation

Answer 45

Tumor mass effects

• Headache, vision loss (bitemporal hemianopsia), cranial nerve palsies
• ♀ → Oligomenorrhea, secondary amenorrhea, galactorrhea, vaginal atrophy
• ♂ → Erectile dysfunction, decreased libido, ↓ testicular volume

Soft tissue effects

• Doughy skin texture, hyperhidrosis (caused by enlarged sweat glands)
• Deepeninf the voice, macroglossia with fissures, obstructive sleep apnea (caused by enlargement of larynx and pharynxg o in addition to macroglossia)

Skeletal effects

• Coarsening of facial features slowly progressing with age → enlarged nose, forehead, and jaw (macrognathia) with diastema (enlarged gap between the top incisors)
• Widened hands, fingers, and feet
• Painful arthropathy (ankles, knees, hips, spine)

Consider acromegaly in patients who report having had to increase hat, shoe, glove, and ring sizes in the past!

Question 46

Acromegaly Diagnosis

Answer 46

Hormone analysis

1. Serum IGF-1 concentration → the best single test (interpretation based on age-adapted IGF-1 levels, which are highest during puberty and decrease with age. Due to its half-life of several hours and constant secretion (as opposed to GH), a single test is already conclusive)
   
   • Elevated IGF-1 level → acromegaly suspected; conduct - oral glucose tolerance test (OGTT).
   • Normal IGF-1 level → acromegaly ruled out
2. Oral glucose tolerance test (OGTT) with baseline GH and measure GH after 2 hours → the most specific test (food intake elevates blood sugar levels, which leads to a physiological decrease in GH secretion. In patients with acromegaly, this regulatory mechanism has no effect on ectopic production of GH. Accordingly, acromegaly can be ruled out if GH is suppressed following a glucose load)
   
   • If GH suppressed → acromegaly ruled out
   • If GH not suppressed → confirmed acromegaly; conduct pituitary MRI to determine the source of excess GH Pituitary MRI

Imaging modality of choice

• Usually shows a visible mass → confirmed GH-secreting pituitary adenoma
• If normal → screen for an extrapituitary cause (e.g., CT scan of the chest and abdomen, measure GHRH)

Question 47

Acromegaly Treatment

Answer 47

• Transsphenoidal adenomectomy is the method of choice for treating acromegaly.
• In patients with inoperable tumors or unsuccessful surgery, medication and radiotherapy are indicated to reduce tumor size and limit the effects of GH and IGF-1 (adequate treatment may improve the prognosis by partially reversing and preventing complications of GH and IGF-1 (e.g., reduced soft tissue swelling improves sleep apnea))

Surgery

• Transsphenoidal adenomectomy (preferred method)
• Surgical debulking (in patients with parasellar disease and inoperable tumors)

Medication

• Somatostatin analogs (e.g., octreotide, lanreotide) (may reduce GH secretion and tumor size. However, not all pituitary adenomas respond)
• Dopamine agonists (e.g., cabergoline) → reduce tumor size and GH secretion
• GH receptor antagonists (e.g., pegvisomant) (bind to GH receptors without activating these, thereby inhibiting the effects of GH. However, tumor size is not decreased by receptor antagonists)

Radiotherapy

Question 48

Acromegaly Complications

Answer 48

Complications lead to increased mortality.

• Cardiovascular complications → the main cause of death

1. Hypertension (∼ 30% of cases) (the exact cause of hypertension in patients with acromegaly is unknown. Hypertrophy and cardiomyopathy are partially attributable to direct cell proliferation, and partially to hypertension)
2. Left ventricular hypertrophy and cardiomyopathy
3. Arrhythmia
4. Valvular disease Impaired glucose tolerance and diabetes mellitus (up to 50% of cases)

• Colorectal polyps and cancer
• Thyroid enlargement and cancer (despite the thyroid being enlarged, thyroid hormone levels are usually normal)
• Carpal tunnel syndrome (edematous swelling of the synovial tendon sheaths and local proliferation of connective tissue)
• Cerebral aneurysm
• Hypopituitarism
• Psychological impairment (↓ quality of life, anxiety, ↓ self-esteem)

Question 49

Congenital Hypothyroidism Etiology

Answer 49

1. 1. Sporadic (∼ 85% of cases)
      * Thyroid hypoplasia, dysplasia, or ectopy
      * Thyroid aplasia (athyroidism)
      * Transplacental transmission of maternal antithyroid antibodies Iodine deficiency
2. Hereditary (∼ 15% of cases)
   
   • Dyshormonogenetic goiter → defects in thyroid hormone synthesis (most commonly in thyroid peroxidase) lead to thyroid hyperplasia and goiter.
   • Peripheral resistance to thyroid hormones

Question 50

Acquired Hypothyroidism Etiology

Answer 50

• Primary hypothyroidism → insufficient thyroid hormone production
  
  1. Hashimoto thyroiditis
     
     • The most common cause of hypothyroidism in iodine-sufficient regions
     • Associated with other autoimmune diseases (e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus, and systemic lupus erythematosus)
  2. Postpartum thyroiditis (subacute lymphocytic thyroiditis)
  3. De Quervain thyroiditis (subacute granulomatous thyroiditis) → often subsequent to a flu-like illness
  4. Iatrogenic → e.g., post thyroidectomy, radioiodine therapy, antithyroid medication (e.g., amiodarone, lithium)
  5. Nutritional (insufficient intake of iodine) → the most common cause of hypothyroidism worldwide, particularly in iodine-deficient regions
  6. Riedel thyroiditis → occurs in IgG4-related systemic disease
  7. Wolff-Chaikoff effect
• Secondary hypothyroidism → pituitary disorders (e.g., pituitary adenoma) → TSH deficiency
• Tertiary hypothyroidism → hypothalamic disorders → TRH deficiency

Question 51

Effects of Hypothyroidism

Answer 51

• Generalized decrease in the basal metabolic rate → decreased oxygen and substrate consumption, leading to:

1. CNS → apathy, slowed cognition
2. Skin and appendages → skin dryness, alopecia
3. Lipid profile → ↑ low-density lipoproteins, ↑ triglycerides
4. Cold intolerance

• Decreased sympathetic activity leads to:

1. Decreased sweating
2. Cold skin (due to decreased blood flow)
3. Constipation (due to decreased gastrointestinal motility)
4. Bradycardia

• Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) → decreased cardiac output, myopathy
• Hyperprolactinemia → ↑ prolactin production is stimulated by TRH → suppression of LH, FSH, GnRH, and testosterone and stimulation of breast tissue growth
• Myxedema → due to accumulation of glycosaminoglycans and hyaluronic acid within the reticular layer of the dermis
  
  • Complex protein mucopolysaccharides bind water → nonpitting edema
  • Initially, edema is pretibial, but as the condition progresses it can generalize, resulting in a range of symptoms

Question 52

Hypothyroidism Presentation

Answer 52

• Symptoms related to decreased metabolic rate

1. Fatigue, decreased physical activity
2. Cold intolerance
3. Decreased sweating
4. Hair loss, brittle nails, and cold, dry skin
5. Weight gain (despite poor appetite)
6. Constipation
7. Bradycardia

• Hypothyroid myopathy (can manifest with elevated serum creatinine kinase levels), myalgia, stiffness, cramps
• Woltman sign → a delayed relaxation of the deep tendon reflexes, which is commonly seen in patients with hypothyroidism, but can also be associated with advanced age, pregnancy, and diabetes mellitus.
• Entrapment syndromes (e.g., carpal tunnel syndrome)
• Symptoms related to generalized myxedema
  
  • Doughy skin texture, puffy appearance
  • Myxedematous heart disease (dilated cardiomyopathy, bradycardia, dyspnea)
    
    • Hoarse voice, difficulty articulating words
    • Pretibial and periorbital edema
    • Myxedema coma
• Symptoms of hyperprolactinemia
  
  • Abnormal menstrual cycle (esp. secondary amenorrhea or menorrhagia)
  • Galactorrhea (lactation in individuals (both men and women) who are not breastfeeding)
  • Decreased libido, erectile dysfunction, delayed ejaculation, and infertility in men
• Further symptoms
  
  • Impaired cognition (concentration, memory), somnolence, depression (especially in elderly individuals)
  • Hypertension (hypothyroidism can increase peripheral vascular resistance and therefore elevate blood pressure, especially in hypertensive patients)
  • Goiter (in Hashimoto thyroiditis) or atrophic thyroid (in atrophic thyroiditis)
• Older patients may not have typical symptoms of hypothyroidism. Instead, they may appear to have dementia or depression.

Question 53

Congenital Hypothyroidism Presentation

Answer 53

• Children with congenital hypothyroidism may have general signs and symptoms of hypothyroidism in addition to those typical in neonates.

Postpartum

1. Umbilical hernia
2. Prolonged neonatal jaundice
3. Hypotonia
4. Decreased activity, poor feeding, and adipsia (absence of thirst, even in the case of dehydration)
5. Hoarse cry, macroglossia

• Congenital iodine deficiency syndrome → a complication of congenital hypothyroidism that manifests leads to an impaired development of the brain and skeleton, resulting in skeletal abnormalities (e.g., short stature and delayed fontanelle closure) and intellectual disabilities Most children with congenital hypothyroidism do not have symptoms at the time of birth because the placenta supplies the fetus with maternal thyroid hormone. For this reason, neonatal screening is vital even if children are asymptomatic. Irreversible intellectual disabilities can be avoided through early initiation of adequate therapy!

Question 54

Euthyroid Sick Syndrome (ESS) (Sick Euthyroid Syndrome (SES), Non-Thyroidal Illness Syndrome (NTI))

Answer 54

• Etiology → occurs in severe illness or severe physical stress (most common in intensive care patients)
• Normal thyroid function → no symptoms of hyperthyroidism or hypothyroidism
• Cytokines (e.g., interleukin 6) cause various changes in levels of circulating TSH and thyroid hormones.
• Altered deiodinase enzyme activity
  
  • ↓ Conversion of T4 to T3
  • ↑ Conversion of T4 to reverse T3 (rT3) by thyroxine 5-monodeiodinase
  • ↓ Thyroid binding globulin
• Clinical features → specific to underlying nonthyroidal illness
• Laboratory
  
  • Low T3 syndrome → decrease in both total and FT3 levels, normal FT4 and TSH, and increased reverse T3
  • Low T3 low T4 syndrome → FT4 levels may be low in prolonged courses of illness (indicates a poor prognosis)
• Treatment
  
  • Treat underlying illness
  • Thyroid hormone replacement is usually not recommended because thyroid function is normal (there is not conclusive evidence that thyroid hormone substitution is beneficial to patients with ESS)

Question 55

Thyroid Hormone Resistance

Answer 55

• Insufficient end-organ sensitivity to thyroid hormones
• Etiology → deficits in thyroid hormone metabolism, transport, or receptor interaction as a result of genetic mutations
• Clinical features → symptoms of both hypothyroidism and hyperthyroidism are possible.
• Laboratory → Persistently elevated FT4 and FT3 and absent TSH suppression is typical.
• Therapy → No causative therapy is available.

Question 56

L-thyroxine (levothyroxine, liothyronine) Interactions

Answer 56

Increased dosage necessary

1. Estrogen
2. SERM (increase thyroxin-binding globulin (TBG) in the serum)
3. Bile acid-binding resins
4. Omeprazole
5. Calcium carbonate (reduces gastrointestinal absorption of thyroid hormone)
6. Phenytoin
7. Carbamazepine (increases metabolism of thyroid hormones)
8. Propranolol (reduces conversion of T4 to T3)

Reduced dosage necessary → glucocorticoids (decrease TBG in the serum)

Question 57

Myxedema Coma

Answer 57

• Extremely rare condition caused by the decompensation of an existing thyroid hormone deficiency and can be triggered by infections, surgery, and trauma.
• Potentially life-threatening condition and, if left untreated, is fatal in ∼ 40% of cases.
• Clinical presentation
  
  • Cardinal symptoms → impaired mental status, hypothermia, and concurrent myxedema
  • Hypoventilation with hypercapnia
  • Hypotension (possibly shock) and bradycardia
• Diagnosis
  
  • TSH and T4 (to evaluate thyroid function)
  • Cortisol (to exclude concomitant adrenal insufficiency)
  • Hypoglycemia and hyponatremia (their presence can be due to hypothyroidism alone or also due concomitant adrenal insufficiency)
  • ↑ CK and LDH
  • ECG → low-voltage QRS complexes, flattened or inverted T waves
  • CSF analysis → slightly ↑ CSF protein
• Treatment:
  
  • IV combination of levothyroxine and liothyronine plus IV hydrocortisone (until concomitant adrenal insufficiency is ruled out)
  • Patients should be treated and monitored in an ICU.

Question 58

Hashimoto’s Thyroiditis (Chronic Autoimmune Thyroiditis) Findings

Answer 58

• Painless goiter
• Early-stage → rubbery and symmetrically enlarged
• Late-stage → normal-sized or small if extensive fibrosis has occurred Iodine uptake on scintigraphy → patchy and irregular
• Pathology findings:
  
  • Lymphocytic infiltration with germinal centers and oncocytic-metaplastic cells (Hurthle cells)

Question 59

Postpartum Thyroiditis Findings

Answer 59

• Diffuse and firm painless goiter Iodine uptake on scintigraphy → reduced
• Pathology findings:
  
  • Lymphocytic infiltration and disrupted thyroid follicles with occasional germinal center formation

Question 60

Subacute Granulomatous Thyroiditis (De Quervain) Findings

Answer 60

• Associated with HLA-B35
• Painful, diffuse and firm goiter
• Increase thyroglobulin
• Decrease blood flow on thyroid ultrasound
• ↑ ESR
• Iodine uptake on scintigraphy → reduced
• Pathology findings:
  
  • Multinucleated giant cells and granuloma formation

Question 61

Congenital Hypothyroidism Findings

Answer 61

• Painless diffuse or nodular goiter
• Iodine uptake on scintigraphy → absent or patchy
• Pathology findings:
  
  • Depend on the cause

Question 62

Riedel Thyroiditis Findings

Answer 62

• Painless, slowly growing and stone-hard goiter
• Iodine uptake on scintigraphy → normal or reduced
• Pathology findings:
  
  • Dense and white fibrotic tissue, macrophages, eosinophils

Question 63

Hot Nodule

Answer 63

• Hyperfunctioning tissue takes up large amounts of radioactive iodine
• The rest of the glandular tissue is suppressed and does not take up the RAI

Question 64

Cold Nodule

Answer 64

• Non-functioning nodules do not take up any radioactive iodine and appear “cold”, but the surrounding normal thyroid tissue takes up radioactive iodine and appears “warm”

Question 65

Thyroid Ultrasound with Doppler Findings

Answer 65

• Changes to morphology → diffuse enlargement or nodules
• Increased perfusion → either diffuse (Graves disease, toxic adenoma) or nodular (toxic MNG)
• Decreased perfusion → destructive causes of hyperthyroidism (e.g., subacute thyroiditis or postpartum destructive thyroiditis)
• Hypoechoic areas in acute thyroiditis and malignancy

Question 66

Thyroid Storm (Thyrotoxic Crisis) Etiology

Answer 66

• Iatrogenic
  
  • Thyroid surgery (manipulation of the thyroid causes the release of thyroid hormones. Pretreatment with beta blockers, antithyroid drugs, and potassium iodide has drastically decreased the incidence of thyroid storm in patients undergoing surgery)
  • Radioactive iodine ablation (RAIA)
  • Exogenous iodine from contrast media or amiodarone
  • Discontinuation of antithyroid medication (most commonly discontinuation of medication in Graves disease)
• Stress-related catecholamine surge (worsens the preexisting hyperadrenergic state of hyperthyroidism)
  
  • Nonthyroidal surgery
  • Anesthesia induction
  • Labor
  • Intercurrent illness, e.g., sepsis, myocardial infarction, diabetic ketoacidosis

Question 67

Thyroid Storm (Thyrotoxic Crisis) Presentation

Answer 67

• Hyperpyrexia with profuse sweating
• Tachycardia (> 140/minute) and (possibly severe) arrhythmia (e.g., atrial fibrillation), hypertension with wide pulse pressure, congestive cardiac failure (the cardiovascular system is often most severely affected)
• Hypotension/shock secondary to high output heart failure or hypovolemia as a result of GI and insensible losses
• Symptoms of thyrotoxicosis
  
  • Abdominal pain
  • Severe nausea, vomiting, diarrhea, possibly jaundice
  • Severe agitation and anxiety, delirium and psychoses, seizures, coma (neuropsychiatric symptoms are seen in most cases of thyroid storm)

Question 68

Antithyroid Drugs in Thyroid Storm

Answer 68

• Inhibition of thyroid hormone synthesis
  
  • First line → propylthiouracil (generally preferred over methimazole for the initial treatment of thyroid storm because it additionally inhibits peripheral conversion of T4 to T3)
  • Alternative → methimazole
• Inhibition of thyroid hormone release (through the Wolff-Chaikoff effect)
  
  1. First line → iodine solutions given at least 1 hour after antithyroid drugs (to avoid exacerbation of thyroid storm due to increased iodine uptake)
     
     • Potassium iodide solution
     • Lugol solution
  2. In patients with iodine allergy or iodine-induced thyrotoxicosis, lithium can be used.
• Inhibition of peripheral conversion of T4 to T3
  
  1. Propranolol (inhibition of peripheral T4 hormone conversion is a secondary effect or propranolol in addition to beta blockade)
  2. Glucocorticoids → can also treat concurrent adrenal insufficiency (relative adrenal insufficiency can occur during thyroid storm because of hypermetabolism and accelerated turnover of cortisol; cortisol levels are thus inappropriately low or normal compared to other situations with significant stress)
     
     • First line → hydrocortisone
     • Alternative → dexamethasone

Question 69

Graves Disease Findings

Answer 69

• Painless diffuse and smooth goiter
• Thyroid function tests → ↓/Undetectable TSH, ↑ T3/T4
• Antibodies → ↑ TRAbs, anti-TPO antibody, and anti-Tg
• Iodine uptake on scintigraphy → diffuse
• Pathologic findings:
  
  • Diffuse hyperplasia and hypertrophy of follicular cells

Question 70

Toxic Multinodular Goiter (Plummer Disease) Findings

Answer 70

• Painless multi nodular goiter
• Thyroid function tests → ↓ TSH, ↑ T3/T4 Antibodies → absent
• Iodine uptake on scintigraphy → multiple focal areas of increased uptake
• Pathologic findings:
  
  • Patches of enlarged follicular cells distended with colloid and flattened epithelium

Question 71

Subacute Lymphocytic Thyroiditis (silent thyroiditis) Findings

Answer 71

• Painless diffuse and firm goiter
• ↑ ESR
• Thyroid function tests:
  
  • Thyrotoxic phase → ↓ TSH, ↑ T3/T4, and ↑ thyroglobulin
  • Hypothyroid phase → ↑ TSH and ↓ T3/T4
• Antibodies → Anti-TPO antibody
• Iodine uptake on scintigraphy → reduced
• Pathologic findings:
  
  • Absence of germinal follicles, lymphocytic infiltration on histology

Question 72

Iodine-induced Hyperthyroidism Findings

Answer 72

• Painless goiter
• Thyroid function tests → ↓ TSH, ↑ T3/T4
• Antibodies → possible ↑ TRAb in patients with Graves disease
• Iodine uptake on scintigraphy → reduced
• Pathologic findings:
  
  • Depends on underlying thyroid disorder

Question 73

Thyroid Adenoma

Answer 73

• Follicular adenoma is the most common type of thyroid adenoma
• Clinical features
  
  • Often presents as a slow-growing solitary nodule
  • Patients are typically euthyroid.
  • In rare cases, patients can manifest with clinical features of hyperthyroidism (∼ 1% of follicular adenomas develop into toxic adenomas)
• Diagnostics
• Follicular adenoma is a histopathological diagnosis.
• Cytology alone cannot distinguish between adenoma and carcinoma.
• Thyroid function tests → TSH is typically normal.
• Thyroid ultrasound → may show sonographic signs of malignancy or appear benign
• FNAC
  
  • Follicular neoplasm or follicular lesion of undetermined significance
  • Cannot distinguish between follicular adenoma and carcinoma
• Confirmatory test
  
  • Surgical excision (e.g., hemithyroidectomy) with histologic analysis
  • Findings → normal follicular structure with no tumor invasion into the surrounding tissues (e.g., capsule, blood vessels)
• Treatment
  
  • Thyroid surgery is always indicated, both for definitive diagnosis and treatment.
  • Initial surgical excision shows no evidence of cancer → no further treatment required
  • If follicular cancer is identified on histopathology → completion thyroidectomy and adjuvant treatment of thyroid cancer as needed

Question 74

Toxic Thyroid Adenoma

Answer 74

• Third most common cause of hyperthyroidism
• Gain-of-function mutations of TSH receptor gene in a single precursor cell → autonomous functioning of the thyroid follicular cells of a single nodule → focal hyperplasia of thyroid follicular cells → toxic adenoma
• The autonomous thyroid nodule overproduces thyroid hormones → hyperthyroidism → decrease in pituitary TSH secretion → suppression of hormone production in the rest of the gland
• Clinical features
  
  • Palpable, usually painless nodule in otherwise normal gland
  • Symptoms of thyrotoxicosis
• Diagnostics
  
  • Thyroid function tests → ↑ T3 and ↓ TSH
  • Thyroid ultrasound → sonographic signs of a benign thyroid nodule; in some cases, increased perfusion
  • Thyroid scintigraphy → solitary, hot nodule; suppression of rest of the gland
  • FNAC → indicated not as a confirmatory test for toxic adenoma but to identify malignancy in suspicious nodules
• Treatment
  
  1. Initial management → treatment of hyperthyroidism
     
     • Beta blockers for symptom control
     • Antithyroid drugs to achieve euthyroidism
  2. Definitive treatment options
     
     • Hemithyroidectomy or isthmusectomy for a solitary toxic adenoma
     • Radioactive iodine ablation (RAIA)
       
       • Less invasive therapy (e.g., ethanol ablation, radiofrequency ablation, laser ablation) may be considered in patients who are neither candidates for surgery nor RAIA

Question 75

Toxic Multinodular Goiter

Answer 75

• Age → often > 60 years
• Second most common cause of hyperthyroidism
• Develops in 10% of patients with a long-standing nodular goiter
• More prevalent in iodine-deficient regions
• Chronic iodine deficiency/thyroid dysfunction → decreased hormone production → increased hypothalamic TRH secretion → persistent TSH stimulation of the thyroid gland → hyperplasia of thyroid nodules, some more active than others → multinodular goiter (nontoxic MNG)
• Multiple somatic mutations of TSH receptor occur in long-standing goiters (> 60% of cases) → autonomous functioning of some nodules (toxic MNG) → hyperthyroidism (due to ↑ release of both T3 and T4)
• Clinical features
  
  • Painless goiter with multiple palpable nodules
  • Symptoms of thyrotoxicosis
• Diagnostics
  
  • Thyroid function tests → ↑ T3 and ↓ TSH
  • Thyroid ultrasound → multiple nodules within the thyroid parenchyma; increased perfusion
  • Thyroid scintigraphy → increased radioiodine uptake by multiple hyperfunctioning (hot) nodules; decreased uptake (suppression) by the rest of the gland and intervening parenchyma; hypofunctioning or cold nodules may also be present in the multinodular gland.
  • FNAC → not routinely required
    
    • Histopathology of resected tissue → patches of enlarged follicular cells distended with colloid and with flattened epithelium
• Treatment
  
  • Initial management → treatment of hyperthyroidism
    
    1. Beta blockers for symptom control
    2. Antithyroid drugs to achieve euthyroidism
  • Definitive treatment options
    
    1. Total thyroidectomy or near-total thyroidectomy
    2. Radioactive iodine ablation

Question 76

Thyroid Cyst

Answer 76

• Simple cysts are exclusively fluid-filled nodules lined by benign epithelial cells.
• Complex cysts are partly solid and partly cystic and carry a 5–10% risk of malignancy. Malignancy risk is higher in cysts with a > 50% solid component.
• Most commonly due to cystic degeneration of thyroid tissue or involution of an adenoma
• Clinical features
  
  • Palpable thyroid nodule
  • Hemorrhage into a cyst → pain and rapid enlargement of the nodule
  • A large cyst or extensive hemorrhage can cause compression symptoms (e.g., hoarseness, dysphagia).
• Diagnostics
  
  • Thyroid function tests → typically normal
  • Thyroid ultrasound → cystic components appear anechoic; may be mixed with solid components
  • FNAC
    
    • Purely cystic nodule → diagnostic FNAC not recommended
    • Partly cystic nodule → low risk pattern (eccentric solid component) → FNAC if size is ≥ 1.5 cm; very low risk pattern → consider FNAC if size is ≥ 2 cm.
• Treatment
  
  • Benign cysts
    
    • Asymptomatic cysts → observation
    • Large or symptomatic cysts (or patient preference)
    1. Aspiration with/without ethanol ablation
    2. Surgery may be considered if aspiration is not effective

Question 77

Medullary Thyroid Carcinoma Etiology

Answer 77

• Associated with MEN2 (RET gene mutations) or familial medullary carcinoma

Question 78

Papillary Thyroid Carcinoma Etiology

Answer 78

• Associated with RET/PTC rearrangements and BRAF mutations - Ionizing Radiation (particularly during childhood) Incidence of thyroid cancer (especially papillary) increased after the atomic bombing of Hiroshima and Nagasaki, as well as after the Chernobyl disaster.

Question 79

Follicular Thyroid Carcinoma Etiology

Answer 79

• Associated with PAX8-PPAR-γ rearrangement and RAS mutation

Question 80

Undifferentiated/Anaplastic Thyroid Carcinoma Etiology

Answer 80

• Associated with TP53 mutation

Question 81

Hurthle Cells

Answer 81

• Large, polygonal epithelial cell with eosinophilic granular cytoplasm as a result of numerous altered mitochondria - Nonspecific -Observed in Hashimoto thyroiditis, Graves disease, previously-irradiated thyroid glands, and in Hurthle cell adenoma (no vascular or capsular invasion; no metastasis) - They are also found in the parathyroid glands, salivary glands, and kidneys

Question 82

Sonographic Signs of Thyroid Malignancy

Answer 82

• Solid or mostly solid hypoechoic nodule(s) (echogenicity of the nodule is evaluated relative to the adjacent strap muscles. Approximately 90% of thyroid cancers are solid (i.e., not cystic and not spongiform). Purely cystic or spongiform lesions are typically benign) - Irregular margins (irregular margins can be infiltrative, lobulated, or spiculated) - Microcalcifications within nodules - Nodules that are taller than wide (signifying growth unrestricted by anatomic planes) - Extrathyroidal growth

Question 83

Follicular Thyroid Cancer Tumor Marker

Answer 83

• Thyroglobulin (Tg) → precursor of thyroid hormones; produced exclusively by the thyroid gland - Indicated after total thyroidectomy or radioactive iodine ablation (RAIA) therapy (Tg levels should be undetectable after a successful total thyroidectomy or RAIA) - Baseline (pretreatment) levels are not routinely indicated.

Question 84

Papillary Thyroid Cancer Tumor Marker

Answer 84

• Thyroglobulin (Tg) → precursor of thyroid hormones; produced exclusively by the thyroid gland - Indicated after total thyroidectomy or radioactive iodine ablation (RAIA) therapy (Tg levels should be undetectable after a successful total thyroidectomy or RAIA) - Baseline (pretreatment) levels are not routinely indicated.

Question 85

Medullary Thyroid Carcinoma Tumor Marker

Answer 85

1. Calcitonin → hormone secreted by parafollicular cells, which is the tissue of origin of medullary carcinoma - Indicated preoperatively if FNAC is suspicious for medullary carcinoma (supportive diagnostic marker) - Used to monitor response to therapy 2. Carcinoembryonic antigen (CEA) → nonspecific marker, used in combination with calcitonin to monitor response to therapy

Question 86

“Orphan Annie” Eyes Nuclei

Answer 86

• Empty-appearing large oval nuclei with central clearing Occurrence 1. Papillary thyroid carcinomas 2. Autoimmune thyroiditis (e.g., Hashimoto disease, Grave disease)

Question 87

Nuclear Grooves

Answer 87

• Longitudinal invaginations of nuclear bilayer Occurrence: 1. Papillary thyroid carcinomas

Question 88

Papillary Thyroid Carcinoma Histology

Answer 88

1. “Orphan Annie” Eyes Nuclei - Empty-appearing large oval nuclei with central clearing 2. Nuclear Grooves - Longitudinal invaginations of nuclear bilayer 3. Psammoma bodies - Concentric lamellar calcifications - Seen in diseases associated with calcific degeneration

Question 89

Medullary Thyroid Carcinoma Histology

Answer 89

• Ovoid cells of C cell origin and therefore without follicle development - Amyloid in the stroma (stains with Congo red)

Question 90

Follicular Thyroid Carcinoma Histology

Answer 90

• Uniform follicles (absence of follicles and nuclear atypia are associated with poor prognosis) - Vascular and/or capsular invasion (to distinguish follicular adenoma, in which there is no invasion of the thyroid capsule)

Question 91

Undifferentiated/Anaplastic Thyroid Carcinoma

Answer 91

• Undifferentiated giant cell (i.e., osteoclast-like cell) - Areas of necrosis and hemorrhage

Question 92

Medullary Thyroid Carcinoma Treatment

Answer 92

1. Well-differentiated thyroid cancer Total thyroidectomy (with neck dissection as needed) 2. Poorly-differentiated thyroid cancer - Total thyroidectomy + neck dissection ± radiation therapy and/or systemic chemotherapy as needed (RAIA and TSH suppression therapy is not required in the management of medullary carcinoma as it does not arise from thyroid follicular cells. Thyroid hormone replacement will be required after total thyroidectomy.)

Question 93

Hypoparathyroidism Etiology

Answer 93

• Postoperative → most commonly occurs as the result of accidental injury to parathyroids (or their blood supply) during thyroidectomy, parathyroidectomy, or radical neck dissection - Autoimmune → second most common cause - Nonautoimmune destruction 1. Infiltration of parathyroid gland - Wilson disease - Hemochromatosis - Granulomas - Metastases 2. Radiation-induced destruction 3. Gram-negative sepsis 4. Toxic shock syndrome 5. HIV infection - Congenital 1. Parathyroid gland aplasia or hypoplasia (DiGeorge syndrome) 2. PTH gene mutation 3. Autosomal dominant hypocalcemia (mutation of calcium-sensing receptors that causes these receptors to be active even at normal calcium levels. These receptors then bind calcium, decreasing levels of free serum calcium.)

Question 94

Hypoparathyroidism Presentation

Answer 94

• Acute manifestations 1. Symptoms of hypocalcemia, such as tetany - Chronic manifestations 1. Extrapyramidal disorders (secondary to basal ganglia calcifications) - Parkinsonism - Dystonia - Hemiballismus - Choreoathetosis - Oculogyric crises - Dementia 2. Ocular disease - Cataracts - Keratoconjunctivitis 3. Skeletal manifestations - Increased bone mineral density - Osteosclerosis 4. Dental abnormalities - Dental hypoplasia - Failure of tooth eruption - Defective root formation 5. Cutaneous manifestations - Dry, puffy, coarse skin

Question 95

Hypoparathyroidism Findings

Answer 95

• Chvostek sign - Trousseau sign Laboratory tests - Hypocalcemia with low or inappropriately normal PTH - Hyperphosphatemia - Normal 25-hydroxyvitamin D (25[OH]D) - Normal or low 1,25-dihydroxyvitamin D (1,25[OH]2D) → low concentration of PTH cannot stimulate renal production of 1,25[OH]2D - Normal magnesium - Normal creatinine

Question 96

Pseudohypoparathyroidism type 1A (PHP1A)

Answer 96

• End-organ (i.e., bones and kidneys) resistance to parathyroid hormone (PTH) despite sufficient PTH synthesis due to a defective Gs protein α subunit - Autosomal dominant - Inherited from the mother (GNAS gene imprinting) - Mutations in GNAS1 → impaired encoding of α subunit → missing activation of adenylate cyclase when PTH binds to Gs → resistance to PTH in kidney and bone tissue Clinical features 1. Albright hereditary osteodystrophy (AHO) - Round face - Short stature - Obesity - Brachydactyly of the 4th and 5th fingers - Intellectual disability - Subcutaneous ossifications 2. Symptoms related to low calcium and high phosphate levels - Seizures - Numbness, tetany - Cataracts - Dental problems Diagnostics Persistent hypocalcemia despite ↑ PTH levels ↑ Phosphate levels

Question 97

Pseudopseudohypoparathyroidism

Answer 97

• Extremely rare condition that mimics PHP1A but without end-organ resistance to PTH - Autosomal dominant - Defective Gs protein α subunit is inherited from the father (GNAS gene imprinting). - The normal allele from the mother allows for maintaining the responsiveness of the kidneys to PTH. Clinical features: - Albright hereditary osteodystrophy (individuals affected by pseudopseudohypoparathyroidism show the clinical features of AHO, but do not experience symptoms related to low calcium and high phosphate levels, unlike in PHP1A) Diagnostics: Normal calcium, PTH, and phosphate

Question 98

Albright Hereditary Osteodystrophy (AHO)

Answer 98

• Round face - Short stature - Obesity - Brachydactyly of the 4th and 5th fingers - Intellectual disability - Subcutaneous ossifications

Question 99

Autosomal Dominant Hypocalcemia

Answer 99

Mutation of calcium-sensing receptors that causes these receptors to be active even at normal calcium levels. These receptors then bind calcium, decreasing levels of free serum calcium

Question 100

Primary Hyperparathyroidism (pHPT)

Answer 100

Hypercalcemia results from abnormally active parathyroid glands.

Question 101

Secondary Hyperparathyroidism (sHPT)

Answer 101

Hypocalcemia results in reactive overproduction of PTH.

Question 102

Tertiary Hyperparathyroidism (tHPT)

Answer 102

Hypercalcemia results from untreated sHPT, with continuously elevated PTH levels.

Question 103

Primary Hyperparathyroidism Etiology

Answer 103

1. Parathyroid gland adenoma (∼ 85%) → benign tumor of the parathyroid glands 2. Hyperplasia and multiple adenomas (∼ 15%) 3. In rare cases, carcinomas (∼ 0.5%) or idiopathic 4. MEN type 1 or 2 5. Lithium

Question 104

Secondary Hyperparathyroidism Etiology

Answer 104

1. Chronic kidney disease (most frequent cause) 2. Malnutrition 3. Vitamin D deficiency (e.g., reduced exposure to sunlight, nutritional deficiency, liver cirrhosis) 4. Cholestasis (bile is necessary for the absorption of fat in the intestines. Vitamin D3 is a fat-soluble agent and requires bile to be absorbed)

Question 105

Tertiary Hyperparathyroidism Etiology

Answer 105

Caused by persistent secondary hyperparathyroidism In longstanding secondary hyperparathyroidism, the parathyroid glands may become severely enlarged and continue to be overactive, even if the original stimulus (e.g., hypocalcemia) is no longer present.

Question 106

Maturity Onset Diabetes of the Young (MODY)

Answer 106

• Genetic defects in the β cell function
• Different forms of autosomal dominant inherited diabetes mellitus that manifest before the age of 25 years and are not associated with obesity or autoantibodies
• 6 subtypes, the most common being MODY II and MODY III
• Caused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α, respectively
• In contrast to all other subtypes, MODY II is not associated with an increased risk of microvascular disease and can be managed with diet alone, despite stable hyperglycemia and chronically elevated HbA1C levels
• All other subtypes require medical treatment, either with insulin or sulfonylureas

Question 107

Insulin Function

Answer 107

• Variety of metabolic effects on the body, primarily contributing to the generation of energy reserves and glycemic control. - Carbohydrate metabolism → insulin is the only hormone in the body that lowers the blood glucose level (stimulates glucose uptake into cells and glycogen production; inhibits glycogenolysis and gluconeogenesis) - Protein metabolism → stimulates protein synthesis (muscles). Stimulates amino acid uptake into cells; inhibits proteolysis - Lipid metabolism → maintains a fat depot and has an antiketogenic effect (stimulates fatty acid uptake into cells and lipogenesis; inhibits lipolysis and the β-oxidation of free fatty acids in the liver) - Electrolyte regulation → stimulates intracellular potassium accumulation (directly stimulates Na+/K+ ATPase and promotes intracellular alkalosis, reduces phosphate levels (glucose binds to phosphate in the cell), and stimulates magnesium uptake into cells). Increase Na retention in kidneys

Question 108

Type 2 Diabetes Pathophysiology

Answer 108

Two major mechanisms: 1. Peripheral insulin resistance - Numerous genetic and environmental factors – Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes (the absence of the insulin-dependent inhibition of hepatic glycogenolysis and gluconeogenesis further promotes hyperglycemia) – Increased serine kinase activity in liver, fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake 2. Pancreatic β cell dysfunction - Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production. - Peripheral insulin resistance creates a huge demand for glucose lowering hormones, resulting in increased production of pro-insulin and pro-amylin. The pancreatic proteolytic enzymes that convert pro-insulin and pro-amylin into insulin and amylin are not able to keep up with the high levels of secretion, which leads to the accumulation of pro-amylin. - The exact mechanism by which pro-amylin aggregates decrease insulin production is not completely understood. - Initially, insulin resistance is compensated by increased insulin and amylin secretion (postprandial hypoglycemia may occur due to reactively elevated insulin secretion, stimulating rapid glucose uptake into cells (regulatory hyperinsulinemia)) - Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines. - After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.

Question 109

Diabetes Mellitus Diagnosis

Answer 109

• A single random blood glucose level ≥ 200 mg/dL is sufficient for diagnosis - Fasting plasma glucose (FPG) in mg/dL (mmol/L) ≥ 126 (≥ 7.0) - 2-hour glucose value after oral glucose tolerance test (OGTT) in mg/dL (mmol/L) ≥ 200 (≥ 11.1) - Hemoglobin A1C (HbA1c or A1C) in % ≥ 6.5 Additional tests 1. Specific autoantibodies for diabetes mellitus type 1 - Anti-GAD antibodies - Anti-tyrosine phosphatase-related islet antigen (IA-2) - Islet cell surface antibody (ICSA; against ganglioside) (Anti-GAD and Anti-IA-2 are positive in > 90% of cases) 2. C-peptide - ↓ C-peptide levels indicate an absolute insulin deficiency → type 1 diabetes - ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes 3. Urine analysis - Microalbuminuria → an early sign of diabetic nephropathy (over the course of the disease, the level of albuminuria correlates with the risk of cardiovascular and renal complications) - Glucosuria → Testing urine for glucose does not suffice to establish the diagnosis of diabetes mellitus. The renal threshold for glucose is reached if the blood glucose level exceeds 150–180 mg/dL (8.3–10 mmol/L). Higher blood glucose levels lead to urinary glucose excretion. In some conditions, glucosuria may occur despite normoglycemia (e.g., tubulointerstitial nephritis, physiological in pregnancy). In addition, the renal threshold may be increased in diabetic kidney disease; glucosuria may be absent despite hyperglycemia as a result. Therefore, it is important to measure fasting glucose levels. - Ketone bodies (usually accompanied by glucosuria) → positive in acute metabolic decompensation in diabetes mellitus (diabetic ketoacidosis)

Question 110

Glucagonoma

Answer 110

• Rare neuroendocrine tumor of the pancreas that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis. Clinical Findings: - Nonspecific symptoms, weight loss (80%), necrolytic migratory erythema (70%), impaired glucose tolerance or diabetes mellitus (75–95%), chronic diarrhea (30%), deep vein thrombosis, and depression Diagnostics: Requires a high index of suspicion to make the diagnosis ↑ glucagon, ↑ blood glucose levels, normocytic normochromic anemia (90%) Imaging (CT) → locate the tumor Treatment - Glycemic control - Octreotide (somatostatin) - Pancreatic resection

Question 111

Necrolytic Migratory Erythema

Answer 111

• A cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma - Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities (nutritional deficiencies (e.g., decreased amino acid levels) are thought to be the underlying pathomechanism for the development of the erythema. On the other hand, zinc deficiency may result in similar skin lesions) - Develop into painful and pruritic crusty patches with central areas of bronze-colored induration - Tend to resolve and reappear in a different location - Skin biopsy shows epidermal necrosis

Question 112

Somatostatinoma

Answer 112

• Rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin. Clinical findings: - Abdominal pain - Weight loss - Classic triad 1. Glucose intolerance (due to inhibition of insulin secretion) 2. Cholelithiasis (due to inhibition of cholecystokinin-induced gallbladder contraction) 3. Steatorrhea (due to inhibition of exocrine pancreatic function) - Achlorhydria (due to inhibition of gastrin-induced proton secretion) Diagnostics: - ↑ somatostatin, ↑ blood glucose levels Imaging → locate the tumor Treatment: - Octreotide → inhibition of somatostatin secretion - Pancreatic resection → curative if no metastases are present - Chemotherapy

Question 113

Conditions that Require Insulin Adjustments

Answer 113

1. Physical activity → decreases insulin by 1–2 units per 20–30 minutes activity 2. Illness, stress, and changes in diet - Increase in insulin demand → many illnesses are associated with elevated blood glucose levels due to an acute stress reaction. The subsequent increase in insulin demand cannot be met by patients with insulin deficiency. A higher insulin dose is required. - Decrease in insulin demand → vomiting and diarrhea lead to decreased glucose uptake, increasing the risk of hypoglycemia. 3. Surgery → ⅓–½ of the usual daily requirement with frequent monitoring

Question 114

Diabetes Mellitus Complications

Answer 114

Macrovascular disease - More common in patients with type 2 diabetes - The major determinants are metabolic risk factors, which include obesity, dyslipidemia, and arterial hypertension. Hyperglycemia may be less related to the development of macrovascular disease. - Manifestations 1. Coronary heart disease (CHD) 2. Cerebrovascular disease 3. Peripheral artery disease (PAD) 4. Mönckeberg arteriosclerosis (medial calcific sclerosis = variant of PAD). PAD diagnostic tools are unreliable in patients with Mönckeberg’s arteriosclerosis Microvascular disease - Onset → typically arises 5–10 years after onset of disease - Chronic hyperglycemia is the primary factor influencing the development of microvascular disease; results in glycation of proteins and lipids with subsequent impaired protein and cell membrane function and tissue damage - Manifestations 1. Diabetic nephropathy 2. Diabetic retinopathy 3. Diabetic neuropathy 4. Diabetic foot Diabetic cardiomyopathy Diabetic fatty liver disease Hyporeninemic hypoaldosteronism Limited joint mobility (formerly known as diabetic cheiroarthropathy) (tight waxy skin, and stiffness of the small joints of the hand; prayer sign (inability to approximate the palms due to flexion contractures of the PIP and MCP joints)) Sialadenosis Increased risk of infection (Poor perfusion of tissue (macrovascular/microvascular disease) and a weak immune system may lead to a higher risk of infection. In addition, growth of bacteria and fungi (e.g., Candida albicans) occurs, likely due to hyperglycemia. Certain infections occur almost exclusively in diabetics (e.g., otitis externa maligna due to Pseudomonas aeruginosa)) Necrobiosis lipoidica Mucormycosis (zygomycosis)

Question 115

Diabetic Nephropathy

Answer 115

• Major cause of end stage renal disease (ESRD)
• Seen in patients with diabetes for > 10 years (usually develops after 5 years with diabetes mellitus; however, patients with type 2 diabetes may present with renal damage at diagnosis. Many patients with type 2 diabetes have additional risk factors for kidney disease (e.g., hypertension))
• Chronic hyperglycemia → glycation (also called non-enzymatic glycosylation or NEG) of the basement membrane (protein glycation) → increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole → hyperfiltration (increase in GFR) → increase in intraglomerular pressure (mechanism behind hyperfiltration is not fully understood; dilation of the afferent arterioles plays an important role) → progressive glomerular hypertrophy, increase in renal size, and glomerular scarring (glomerulosclerosis) → worsening of filtration capacity

Three major histological changes can be seen on LM (chronic hyperglycemia, hyperlipidemia, elevated levels of growth hormones, and intraglomerular hypertension are responsible for these changes)

1. Mesangial expansion
2. Glomerular basement membrane thickening
3. Glomerulosclerosis (later stages)
   
   • Diffuse hyalinization (most common)
   • Pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) [glomerular capillary hypertension and hyperfiltration → increase in mesangial matrix → eosinophilic hyaline material in the area of glomerular capillary loops; can progressively consume the entire glomerulus → hypofiltration (↓ GFR)]

Clinical features:

• Often asymptomatic; patients may complain of foamy urine
• Progressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy)
• Arterial hypertension
• Urine analysis → proteinuria. Initially moderately increased albuminuria (microalbuminuria); eventually significantly increased albuminuria (macroproteinuria) → nephrotic syndrome may develop.

Prevention and management

1. Stringent glycemic control (may delay the progression of microalbuminuria or partially reverse diabetic nephropathy)
2. Antihypertensive treatment → ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in patients with diabetes (prevent the progression of albuminuria and may protect against renal tubulointerstitial fibrosis)
   
   • Second line agents to be added to ACE inhibitors or ARBs to further control hypertension include diuretics or calcium channel blockers
3. Dietary modification → daily salt intake < 5–6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction (proteinuria (albuminuria) in diabetic nephropathy may be improved and the progression of renal insufficiency delayed by reducing protein consumption (max. 0.8–1 g/kg/day))

Question 116

Diabetic Retinopathy

Answer 116

• After 15 years with disease, approx. 90% of type 1 diabetic patients and approx. 25% of type 2 diabetic patients develop diabetic retinopathy.
• The most common cause of visual impairment and blindness in patients aged 25–74 years in the US
• Asymptomatic until very late stages of disease
  
  1. Visual impairment
  2. Progression to blindness

Ophthalmological findings and classification of diabetic retinopathy

1. Nonproliferative retinopathy (mild, moderate, severe) → accounts for most cases of diabetic retinopathy
   
   • Findings → intraretinal microvascular abnormalities (IRMA), including microaneurysms; caliber changes in venous vessels; intraretinal hemorrhage; hard exudates (lipid deposits in the retina), retinal edema, and cotton-wool spots (fluffy white patches on the retina; axoplasmic congestion due to retinal ischemia)
   • Visual loss, most commonly due to macular edema
2. Proliferative retinopathy
   
   • Findings → preretinal neovascularization is the hallmark of PDR (primarily arising from the optic disc and retinal vessels), fibrovascular proliferation (neovascularization and abnormal growth of connective tissue into the retina. Fibrosis may lead to traction retinal detachment), vitreous hemorrhage, traction retinal detachment (due to fibrosis of the vitreous body), rubeosis iridis (neovascularization of the iris; risk of hemorrhage and congestion of the trabecular meshwork) → secondary glaucoma. Additionally, findings of nonproliferative retinopathy are usually present.
   • Visual loss may be due to vitreous hemorrhage, retinal detachment, or neovascular glaucoma.
3. Macular edema
   
   • Findings → clinically significant retinal thickening and edema involving the macula, hard exudates, macular ischemia (avascular region in the area of the fovea due to capillary occlusion)
   • May occur in all stages of NPDR and PDR

Treatment

1. Nonproliferative retinopathy
   
   • Laser treatment → focal photocoagulation
   • Intravitreal anti-vascular endothelial growth factor (VEGF) injection
2. Proliferative retinopathy and severe nonproliferative retinopathy
   
   • Laser treatment → panretinal photocoagulation over the course of numerous appointments (destruction of ischemic areas of the retina prevents further neovascularization by reducing the production of VEGF by ischemic tissue). Risks associated with laser treatment → night vision impairment, visual field loss, further fibrosis of the vitreous body with risk of retinal detachment
   • Vitrectomy in case of traction retinal detachment and vitreal hemorrhage
3. Macular edema
   
   • VEGF inhibitors
   • Focal photocoagulation

Question 117

Diabetic Neuropathy

Answer 117

• Distal symmetric polyneuropathy
• Chronic hyperglycemia causes glycation of axon proteins with subsequent development of progressive sensomotoric neuropathy; typically affects multiple peripheral nerves
• Most common form of polyneuropathy in Western countries.

Clinical features

1. Early → progressive symmetric loss of sensation in the distal lower extremities (loss of vibration sense may be tested with a tuning fork)
   
   • A “stocking-glove” sensory loss pattern with proximal progression is typical
   • Dysesthesia (burning feet) may occur
   • A similar sensory loss pattern may occur in the upper extremities.
2. Late → pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia

Special types:

• Mononeuropathy
  
  1. Cranial mononeuropathy (cranial nerve III is most commonly involved → diabetic third nerve palsy presents with eye pain, diplopia, ptosis, and an inability to adduct the eye (pupils are spared!); mononeuropathy of the cranial nerves VI and IV may also occur)
  2. Peripheral mononeuropathy (the median, ulnar, and common peroneal nerves are often affected)
  3. Mononeuropathy multiplex → asymmetric neuropathy, affecting the multiple peripheral and cranial nerves
  4. Diabetic truncal neuropathy (involvement of intercostal nerves results in truncal pain)
  5. Diabetic lumbosacral plexopathy (severe deep thigh pain as well as weakness and atrophy of thigh and hip muscles)

Screening

• Tuning fork → decreased vibration sense
• Monofilament test → decreased pressure sense
• Pinprick (pain assessment) or temperature assessment → decreased sensation

Treatment

1. Optimal glycemic control (can prevent the onset and progression of diabetic neuropathy. However, once established, glycemic control cannot reverse diabetic neuropathy)
2. Pain management
   
   • Anticonvulsants → pregabalin (most effective; usually first-choice), gabapentin, and sodium valproate
   • Antidepressants
   1. Tricyclic antidepressants → amitriptyline
   2. SNRI → duloxetine, venlafaxine
3. Miscellaneous → lidocaine patch, capsaicin spray, isosorbide dinitrate spray
4. Opioids → dextromethorphan, morphine sulfate, tramadol, and oxycodone

Question 118

Diabetic Ketoacidosis (DKA) Etiology

Answer 118

1. Lack of or insufficient insulin replacement therapy
   
   • Undiagnosed, untreated diabetes mellitus
   • Treatment failure in known diabetics → insulin pump failure, forgotten insulin injection, noncompliance with insulin therapy
2. Increased insulin demand
   
   • Stress → infections, surgery, trauma, myocardial infarction
   • Drugs → glucocorticoid therapy, cocaine use, alcohol abuse
   • Hypovolemia resulting from diabetic ketoacidosis (DKA) can lead to acute kidney injury (AKI) due to decreased renal blood flow. Hypovolemic shock may also develop.
   • Intracellular potassium deficit (as a result of hyperglycemic hyperosmolality, potassium shifts along with water from inside cells to the extracellular space and is lost in the urine). Insulin normally promotes cellular potassium uptake but is absent in DKA, compounding the problem. A total body potassium deficit develops in the body, although serum potassium may be normal or even paradoxically elevated.
   • Insulin deficiency → hyperosmolality → K+ shift out of cells + lack of insulin to promote K+ uptake → intracellular K+depleted → total body K+ deficit despite normal or even elevated serum K+ - There is a total body potassium deficit. This becomes important during treatment, when insulin replacement leads to rapid potassium uptake by depleted cells and patients may require potassium replacement.

Question 119

Hyperosmolar Hyperglycemic State (HHS)

Answer 119

• Primarily affects patients with type 2 diabetes
• The pathophysiology of HHS is similar to that of DKA. However, in HHS, there are still small amounts of insulin being secreted by the pancreas, and this is sufficient to prevent DKA by suppressing lipolysis and, in turn, ketogenesis (for this reason, HHS typically occurs in patients with type 2 diabetes, as the condition involves a relative insulin deficiency, rather than the absolute insulin deficiency of type 1 diabetes. However, DKA can also occur in the advanced stages of type 2 diabetes, when beta cell function has declined so much that insulin levels are negligible)

Question 120

Diabetic Ketoacidosis (DKA) Presentation

Answer 120

• Rapid onset (< 24 h) in contrast to HHS

1. Polyuria
2. Polydipsia
3. Recent weight loss
4. Nausea and vomiting (vomiting expels gastric acid, shifting the acid-base balance of the body)
5. Signs of volume depletion (i.e., dry mucous membranes, decreased skin turgor), hypotension, circulatory collapse
6. Altered mental status
7. Lethargy
8. Coma
9. Other neurological exam abnormalities, e.g., blurred vision and weakness
10. Abdominal pain (the state of ketoacidosis leads to irritation of the peritoneum. This can cause diffuse abdominal tenderness on palpation with guarding, possibly even to the extent that an acute abdominal pathology is suspected)
11. Fruity odor on the breath (from exhaled acetone)
12. Hyperventilation → long, deep breaths (Kussmaul respirations) (respiratory compensation for the state of metabolic acidosis)

Question 121

Diabetic Ketoacidosis (DKA) Findings

Answer 121

1. Hyperglycemia
2. High anion gap metabolic acidosis
3. Ketonuria/ketonemia
4. Pregnancy and SGLT2-inhibitors can cause euglycemic DKA (i.e., high anion gap metabolic acidosis with normal or near-normal glucose).
5. Urine ketones → standard urine dipstick assays detect acetoacetate and acetone but not beta-hydroxybutyrate.
6. Serum beta-hydroxybutyrate (is the most common ketone produced in DKA. Serum measurement is more sensitive than urine ketone measurement and can also be used to monitor the response to therapy)
7. Hyponatremia is common, due to hypovolemic hyponatremia and hypertonic hyponatremia
8. Potassium → normal or elevated (despite a total body deficit)
9. Magnesium levels are typically low (due to osmotic diuresis)
10. Phosphorus levels may be falsely elevated despite a total body deficit.
11. BUN and creatinine are often elevated (↑ BUN and creatinine suggest AKI, which in hyperglycemic crisis is often due to osmotic diuresis and dehydration and typically responds to fluid resuscitation. Persistently elevated BUN and creatinine despite fluid resuscitation should prompt further investigation)
12. Leukocytosis may be present even in the absence of infection in patients with hyperglycemic crisis.
13. Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis.

Question 122

Diabetic Ketoacidosis (DKA) Management

Answer 122

• IV access with two large-bore peripheral IV lines
• Fluid resuscitation → initially with isotonic saline (0.9% NaCl), then 0.45% or 0.9% depending on corrected serum sodium
• Electrolyte repletion (especially potassium)
• Short-acting insulin (regular insulin) therapy (administration of insulin is essential in halting lipolysis and ketoacidosis in patients with DKA; halting ketone formation is far more important than rapidly decreasing the serum glucose level)
• IV bicarbonate (only in severe metabolic acidosis)
• Identify and treat the underlying cause.
• Consider admission to the ICU.
• Potassium levels must be ≥ 3.3 mEq/L before insulin therapy is initiated. If potassium level is < 3.3 mEq/L, potassium should be repleted and rechecked prior to giving any insulin (insulin causes an intracellular shift of K+, which can cause life-threatening hypokalemia)

Question 123

Hyperosmolar Hyperglycemic State (HHS) Presentation

Answer 123

• Characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycemia and osmotic diuresis.
• Symptoms typically begin more slowly and progress insidiously.

1. Polyuria
2. Polydipsia
3. Recent weight loss
4. Nausea and vomiting (vomiting expels gastric acid, shifting the acid-base balance of the body)
5. Signs of volume depletion (i.e., dry mucous membranes, decreased skin turgor), hypotension, circulatory collapse
6. Altered mental status
7. Lethargy
8. Coma
9. Other neurological exam abnormalities, e.g., blurred vision and weakness

Question 124

Hyperosmolar Hyperglycemic State (HHS) Findings

Answer 124

1. Hyperglycemia
2. Hyperosmolality
3. Dehydration without ketonuria
4. Hyponatremia is common due to hypovolemic hyponatremia and hypertonic hyponatremia
5. BUN and creatinine are often elevated (↑ BUN and creatinine suggest AKI, which in hyperglycemic crisis is often due to osmotic diuresis and dehydration and typically responds to fluid resuscitation. Persistently elevated BUN and creatinine despite fluid resuscitation should prompt further investigation)
6. Leukocytosis may be present even in the absence of infection in patients with hyperglycemic crisis. Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis.

Question 125

Hyperosmolar Hyperglycemic State (HHS) Management

Answer 125

• IV access with two large-bore peripheral IV lines
• Fluid resuscitation → initially with isotonic saline (0.9% NaCl), then 0.45% or 0.9% depending on corrected serum sodium
• Electrolyte repletion (especially potassium)
• Short-acting insulin (regular insulin) therapy
• Consider admission to the ICU.

Question 126

Ectopic ACTH Production

Answer 126

• Paraneoplastic syndrome → ↑ ACTH secretion → bilateral adrenal gland hyperplasia

Carcinomas include:

1. Small cell lung cancer
2. Renal cell carcinoma
3. Pancreatic or bronchial carcinoid tumors
4. Pheochromocytoma
5. Medullary thyroid carcinoma

Question 127

Cushing Syndrome Clinical Features

Answer 127

1. Skin
   
   • Thin, easily bruisable skin with ecchymoses
   • Stretch marks (classically purple abdominal striae)
   • Hirsutism
   • Acne
   • If secondary hypercortisolism → often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity). Caused by excessive ACTH production because melanocyte-stimulating hormone (MSH) is cleaved from the same precursor as ACTH called proopiomelanocortin (POMC). Not a feature of primary hypercortisolism
   • Delayed wound healing
   • Flushing of the face
2. Neuropsychological → lethargy, depression, sleep disturbance, psychosis
3. Musculoskeletal
   
   • Osteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head (due to inhibition of calcitriol synthesis by cortisol)
   • Muscle atrophy/weakness (catabolic effect on protein metabolism results in muscle atrophy and weakness. Proximal muscles are more commonly affected)
4. Endocrine and metabolic
   
   • Insulin resistance → hyperglycemia → mild polyuria in the case of severe hyperglycemia - Dyslipidemia (increased cortisol → increased lipolysis)
   • Weight gain characterized by central obesity, moon facies, and a buffalo hump (these symptoms result from the relocation of body fat from the body periphery to the body center)
   • ♂ → Decreased libido
   • ♀ → Decreased libido, virilization, and/or irregular menstrual cycles (e.g., amenorrhea) (hypercortisolism results in inhibition of gonadotropin release)
   • Growth delay (in children)
5. Other features
   
   • Secondary hypertension (∼ 90% of cases) (caused by the following pathophysiological effects → 1. Mineralocorticoid effect of cortisol (increased water and sodium retention with increased potassium excretion); 2. Enhanced sympathetic activity; 3. Amplified response to catecholamines; 4. Secretion of prehormones with mineralocorticoid effect; 5. Activation of the renin-angiotensin-aldosterone system (RAAS))
   • Increased susceptibility to infections (due to immunosuppression)
   • Peptic ulcer disease
   • Cataracts (prolonged hypercortisolism is typically associated with posterior subcapsular cataracts)

Question 128

Cushing Syndrome Findings

Answer 128

1. Hypernatremia, hypokalemia, metabolic alkalosis (11β-hydroxysteroid dehydrogenase converts cortisol to cortisone (which has lesser mineralocorticoid activity). The enzyme also prevents the binding of cortisol to the renal mineralocorticoid receptor. When cortisol levels surge (as occurs with ectopic ACTH production) the enzyme 11β-hydroxysteroid dehydrogenase becomes saturated. As a result, cortisol that is not inactivated is free to bind to mineralocorticoid receptors causing ↑ water and sodium retention, ↑ K+ excretion, and ↑ H+ excretion)
2. Hyperglycemia → due to stimulation of gluconeogenesis enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue
3. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia)
4. Leukocytosis (predominantly neutrophilic), eosinopenia (hypercortisolism causes the demargination of neutrophils from the endothelial lining of vessels. Therefore, no left shift is seen. The presence of a left shift along with leucocytosis may signify an infection)

Question 129

Nelson Syndrome

Answer 129

• Post adrenalectomy syndrome
• Etiology → bilateral adrenalectomy in patients with a previously undiscovered pituitary adenoma (bilateral adrenalectomy is no longer commonly performed as a treatment for Cushing syndrome)
• Bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on hypothalamus → increased CRH production → uncontrolled enlargement of preexisting ACTH-secreting pituitary adenoma → increased secretion of ACTH and MSH → symptoms of pituitary adenoma and ↑ MSH

Clinical Features

• Headaches, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation

Diagnostics

• High levels of beta-MSH and ACTH
• Pituitary adenoma on MRI confirms the diagnosis.

Treatment:

• Surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g, in the case of tumor residues after surgery)

Question 130

Primary adrenal insufficiency (Addison disease) Etiology

Answer 130

• Caused by abrupt destruction of the adrenal gland (acute adrenal insufficiency; e.g., due to massive adrenal hemorrhage) or by its gradual progressive destruction or atrophy (chronic adrenal insufficiency; e.g., due to autoimmune conditions, infection).

1. Autoimmune adrenalitis
   
   • Most common cause in the US (∼ 80–90% of all cases of primary adrenal insufficiency)
   • Associated with other autoimmune endocrinopathies
2. Infectious adrenalitis
   
   • Tuberculosis → most common cause worldwide, but rare in the US
   • CMV disease in immunosuppressed states (especially AIDS)
   • Histoplasmosis
3. Adrenal hemorrhage
   
   • Sepsis (especially meningococcal sepsis (endotoxic shock) → hemorrhagic necrosis (Waterhouse-Friderichsen syndrome))
   • Disseminated intravascular coagulation (DIC)
   • Anticoagulation (especially heparin (heparin-induced thrombocytopenia))
   • Venous thromboembolism, especially in antiphospholipid syndrome (APS). Recurrent thromboses are a typical manifestation of APS.
   • Adrenal tumor (most commonly pheochromocytoma) → intratumoral bleeding
   • Short-term steroid usage
   • Trauma (mostly blunt trauma, can also occur postoperatively)
   • In neonates → birth trauma, difficult labor (e.g., breech delivery, forceps/vacuum delivery, prolonged labor), maternal diabetes
4. Infiltration of the adrenal glands
   
   • Tumors (adrenocortical tumors, lymphomas, metastatic carcinoma)
   • Amyloidosis
   • Hemochromatosis
5. Adrenalectomy
6. Impaired activity of enzymes that are responsible for cortisol synthesis
   
   • Cortisol synthesis inhibitors (e.g., rifampin, fluconazole, phenytoin, ketoconazole) → drug-induced adrenal insufficiency
   • 21β-hydroxylase deficiency
7. Vitamin B5 deficiency (vitamin B5 increases production of glucocorticoids and other adrenal hormones. In vitamin B5 deficiency, adrenal function is impaired)

Question 131

Secondary Adrenal Insufficiency Etiology

Answer 131

• Caused by conditions that decrease ACTH production (impaired hypothalamic-pituitary-adrenal axis).

1. Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g., infection, trauma, surgery) during prolonged glucocorticoid therapy
   
   • Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis due to long-term cortisol therapy → ↓ CRH/ACTH release (negative feedback) → ↓ endogenous cortisol
   • Impaired endogenous cortisol production in addition to discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) → acute glucocorticoid deficiency
2. Hypopituitarism → ↓ ACTH → ↓ endogenous cortisol

Question 132

Tertiary Adrenal Insufficiency Etiology

Answer 132

• Caused by conditions that decrease CRH production.

1. The most common cause is sudden discontinuation of chronic glucocorticoid therapy.
2. Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia) → ↓ CRH → ↓ ACTH → ↓ cortisol release

Question 133

Adrenal Crisis (Addisonian Crisis)

Answer 133

• Acute, severe glucocorticoid deficiency that requires immediate emergency treatment.

Precipitating factors

1. Stress in patients with underlying adrenal insufficiency e.g.:
   
   • Gastrointestinal illness (most common)
   • Other infections
   • Perioperative period
   • Physical stress or pain
   • Psychological stress
2. Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy
3. Bilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome)
4. Pituitary apoplexy

Signs and symptoms

1. Hypotension, shock
2. Impaired consciousness, coma
3. Fever
4. Vomiting, diarrhea
5. Severe abdominal pain (which can resemble peritonitis)
6. Consider adrenal crisis in patients with severe hypotension refractory to fluid resuscitation and/or vasopressors.

Diagnosis

1. Hyponatremia
2. Hyperkalemia
3. Hypocalcemia
4. Hypoglycemia
5. Normal anion gap metabolic acidosis

Management

1. Adrenal crisis can be life-threatening, so treatment with high doses of hydrocortisone should be started immediately, without waiting for diagnostic confirmation of hypocortisolism
   
   • Hydrocortisone (preferred)
   • Prednisolone (alternative if hydrocortisone is unavailable)
   • Dexamethasone (least preferred alternative if hydrocortisone is unavailable) (has no mineralocorticoid activity and requires concurrent substitution with fludrocortisone)
2. Consider adding mineralocorticoid replacement, e.g., fludrocortisone (off-label) for the following:
   
   • Patients receiving glucocorticoids other than hydrocortisone
   • Patients with septic shock
3. Fluid resuscitation
4. Hypoglycemia → IV dextrose, e.g., 50% dextrose
5. Identify and treat underlying causes (e.g., sepsis).
6. Consider higher-level monitoring, e.g., intensive care

Question 134

Primary Hyperaldosteronism Etiology

Answer 134

• Caused by autonomous overproduction of aldosterone in the zona glomerulosa of one or both adrenal glands - Most commonly due to the following conditions: 1. Bilateral idiopathic hyperplasia of the adrenal glands (∼ 60%) (often manifests with only mild symptoms and normokalemia) 2. Aldosterone-producing adrenal adenoma (Conn syndrome) or aldosteronoma (∼ 30%) (usually manifests with marked hypokalemia and more severe symptoms than idiopathic hyperplasia of the adrenal glands) 3. Less common causes include: - Unilateral hyperplasia of one adrenal gland - Familial hyperaldosteronism - Aldosterone-secreting carcinomas of the adrenal cortex - Ectopic aldosterone-producing tumors (e.g., in the kidneys, ovaries)

Question 135

Neuroblastoma Etiology

Answer 135

• Cause → unclear
• Genetic associations → chromosomal abnormalities, especially deletions (found in ∼ 50% of neuroblastomas)

1. Deletions of 1p, 11q, and 14q chromosomosomal regions (deletion of the short arm of chromosome 1 (1p deletion) is the most common chromosomal alteration associated with neuroblastomas. The tumor suppressor gene KIF1B is present in this region)
2. Amplification and overexpression of oncogene MYCN (N-myc) (in approx. 25% of patients with neuroblastomas, the MYCN oncogene on chromosome 2p is replicated 50–100 times. These copies remain as extrachromosomal DNA (double minutes) or can be integrated into a chromosome, and result in overexpression of the growth-promoting transcription factor MYCN. The cause of this amplification is not completely understood)

• Risk factors

1. Maternal → gestational diabetes, opiates, folate deficiency
2. Congenital syndromes → Turner syndrome, neurofibromatosis, Hirschsprung’s disease, Beckwith-Wiedemann syndrome
3. Familial

Question 136

In adults, _________ is the most common tumor of the adrenal medulla, while in children it is _________.

Answer 136

Pheochromocytoma; neuroblastoma

Question 137

Neuroblastoma Clinical Features

Answer 137

General Symptoms

1. Failure to thrive or weight loss
2. Fever
3. Nausea, vomiting, loss of appetite
4. Hypertension (generally caused by renal artery compression)

Location of primary tumor

1. Abdomen (in > 60% of cases)
   
   • Palpable, firm, irregular abdominal mass that may cross the midline (in contrast to Wilms tumor, which is smooth and usually does not cross the midline)
   • Abdominal distension and pain
   • Hepatomegaly
   • Constipation
2. Chest (in ∼ 20% of cases) → particularly paravertebral ganglia
   
   • Spinal cord compression → back pain, weakness, numbness, ataxia, loss of bowel or bladder control
   • Scoliosis
   • Dyspnea, cough
   • Inspiratory stridor
3. Neck
   
   • Horner syndrome
   • Symptoms due to spinal cord compressions

Location of metastases

1. Orbit of the eye
   
   • Periorbital ecchymoses (“raccoon eyes”) (bleeding in the tissue surrounding the orbit of the eye)
   • Proptosis
2. Bones
   
   • Bone pain
   • Anemia (bone marrow suppression)
3. Skin
   
   • Subcutaneous nodules

Paraneoplastic syndromes

1. Chronic diarrhea → electrolyte imbalances (neuroblastomas may secrete vasoactive intestinal peptide (VIP))
2. Opsoclonus-myoclonus-ataxia → a paraneoplastic syndrome of unclear etiology characterized by rapid and multi-directional eye movements, rhythmic jerks of the limbs, and ataxia (dancing eyes dancing feet syndrome) (at least 50% of children with opsoclonus-myoclonus have an underlying neuroblastoma). Believed to be an autoantibody response to CNS antigens
3. Possibly hypertension, tachycardia, palpitations, sweating, flushing (due to tumor catecholamine secretion) (hypertension is more commonly seen in pheochromocytoma)

Question 138

Neuroblastoma Findings

Answer 138

• ↑ Catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in 24-hour urine

Blood

• ↑ Catecholamine metabolites (HVA/VMA)
• ↑ Lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE)
• Anemia suggests bone marrow suppression by tumor metastases

Imaging → to identify the primary site

• Abdominal ultrasound
• CT or MRI (depending on the presumable site of the lesion) Scintigraphy
• MIBG scan → Uptake scan of metaiodobenzylguanidine (MIBG) combined with a radioactive iodine tracer (MIBG is similar in structure to norepinephrine, so it is taken up by sympathetic nerve cells, including neuroblastoma or pheochromocytoma tumor cells, throughout the body. Certain radioactive iodine tracers have a therapeutic use)

Biopsy

1. Image-guided needle aspiration of the tumor or biopsy at the time of surgical tumor resection
   
   • Evaluation for MYCN gene amplification
   • Evaluation for DNA ploidy
2. Bilateral bone marrow biopsy of iliac crests

Pathology

1. Homer Wright rosettes → halo-like clusters of neuroblast cells surrounding a central pale area containing neuropil (associated with tumors of neuronal origin such as neuroblastoma, medulloblastoma, primitive neuroectodermal tumors, and pineoblastoma)
2. Small round blue cells with hyperchromatic nuclei
3. Bombesin and NSE positive (tumor marker for neuroblastoma, small cell carcinoma of the lung, pancreatic cancer, and gastric cancer)

Question 139

Pheochromocytomas Etiology

Answer 139

• The majority of pheochromocytomas are benign, unilateral, catecholamine-producing tumors, that rarely produce other hormones such as EPO.
• Tumors arise from chromaffin cells, which are derived from the neural crest.

Localization

• ∼ 90% adrenal medulla (physiologically activated by acetylcholine) (adrenal medulla is considered a modified sympathetic ganglion, which is innervated by sympathetic preganglionic neurons)
• ∼ 10% extra-adrenal in the sympathetic ganglia (also referred to as catecholamine-secreting paragangliomas)
• ∼ 10% at multiple locations

25% of pheochromocytomas are hereditary (germline mutations):

1. Multiple endocrine neoplasia type 2 (MEN 2A, MEN 2B)
2. Neurofibromatosis type 1 (NF1)
3. Von Hippel-Lindau disease (VHL)

Question 140

MEN 1 (formerly known as Wermer syndrome)

Answer 140

• Autosomal Dominant
• Mutation of the MEN1 gene (located on chromosome 11) → altered expression of menin protein

Principal Manifestation:

1. Primary hyperparathyroidism (parathyroid adenoma)

Further Manifestations:

1. Endocrine pancreatic tumors
   
   • Gastrinoma (most common)
   • Insulinoma
   • VIPoma
   • Glucagonoma (rare)
2. Pituitary adenoma → most commonly prolactinoma
3. Carcinoid tumors (∼ 10–15% of cases)
4. Nonendocrine tumors (e.g. angiofibromas, collagenomas, meningiomas)

Management:

1. Parathyroidectomy
2. Excision of pancreatic tumor
3. Transsphenoidal surgery for excision of pituitary adenoma

Question 141

MEN 2A (formerly known as Sipple syndrome)

Answer 141

• Autosomal Dominant
• Altered expression of the RET proto-oncogene → elevated tyrosine kinase activity

Principal Manifestation:

1. Medullary thyroid carcinoma

Further Manifestations:

1. Pheochromocytoma (∼ 40% of cases)
2. Primary hyperparathyroidism (∼ 20–30% of cases)

Management:

1. Thyroidectomy including cervical lymph nodes
   
   • Pheochromocytoma should first be ruled out (e.g., by measuring urine metanephrines) or treated before undergoing surgery (intraoperative catecholamines released from a pheochromocytoma could otherwise lead to hemodynamic instability during the procedure)
2. If pheochromocytoma → adrenalectomy
3. If hyperparathyroidism → parathyroidectomy

Question 142

MEN 2B

Answer 142

• Autosomal Dominant
• Altered expression of the RET proto-oncogene → elevated tyrosine kinase activity

Principal Manifestation:

1. Medullary thyroid carcinoma

Further Manifestations:

1. Pheochromocytoma (∼ 40% of cases)
2. Multiple neurinomas → mucosal neuromas (e.g., lips, tongue), intestinal ganglioneuromatosis) (polypoid growth from proliferating ganglion and Schwann cells)
3. Marfanoid habitus

Management:

1. Thyroidectomy including cervical lymph nodes
   
   • Pheochromocytoma should first be ruled out (e.g., by measuring urine metanephrines) or treated before undergoing surgery (intraoperative catecholamines released from a pheochromocytoma could otherwise lead to hemodynamic instability during the procedure)
2. If pheochromocytoma → adrenalectomy
3. If hyperparathyroidism → parathyroidectomy

Question 143

MEN 1 is formery known as __________.

Answer 143

Wermer syndrome

Question 144

MEN 2A is formerly known as __________.

Answer 144

Sipple syndrome

Question 145

Carcinoid Tumor

Answer 145

• Neuroendocrine tumors that arise from amine precursor uptake and decarboxylation (APUD) cells.
• ⅓ are Multiple
• ⅓ are associated with another Malignancy
• ⅓ Metastasize

Secretory Products:

• Carcinoid tumors can synthesize different hormones (most commonly serotonin).
• Serotonin is degraded via the following mechanisms:
  
  1. First-pass metabolism in the liver
  2. Monoamine oxidases in the lung
• Serotonin can reach systemic circulation under the following conditions:
  
  1. Intestinal carcinoid tumors with liver metastases (these tumors are usually asymptomatic because of the first-pass metabolism of the hormones in the liver. After the tumor has metastasized to the liver, first-pass metabolism is impaired)
  2. Extraintestinal carcinoid tumors (these tumors are more likely to be symptomatic due to the lack of first-pass metabolism)
• ↑ Serotonin in systemic circulation can lead to:
  
  1. Carcinoid syndrome
  2. Carcinoid heart disease
  3. Pellagra due to increased serotonin metabolism
• Carcinoid syndrome
  
  1. Diarrhea and abdominal cramps
  2. Cutaneous flushing (lasts up to 30 minutes and causes reddening of the face, neck, and chest. May be accompanied by a burning sensation). Possible triggers → alcohol consumption, food intake, stress. In severe cases, may be accompanied by tachycardia and fluctuating blood pressure
  3. Dyspnea, wheezing (asthma-like attacks)
  4. Palpitations
  5. Possible weight loss despite normal appetite
• Carcinoid heart disease (liver metastases of the carcinoid tumor produce serotonin which travels to the right heart via the inferior vena cava. This way, serotonin leads to endocardial fibrosis of the right heart)
  
  • Endocardial fibrosis that especially affects the right heart (left heart is better protected because of hormone inactivation in the lungs)
  • Tricuspid insufficiency and/or pulmonary stenosis
  • Symptoms of right-sided heart failure
  • Causes late complications in 20–70% of metastatic carcinoids
  • Other symptoms → abdominal pain (may be due to local tumor growth and/or fibrosis of the mesenteric vessels)

Biopsy

• Histology → prominent rosettes composed of numerous small monomorphic cells with salt-and-pepper chromatin
• Immunohistochemistry → immunostaining with synaptophysin, chromogranin A, and neuron-specific enolase (NSE) to confirm neuroendocrine origin

Question 146

VIPoma

Answer 146

• Neuroendocrine tumor that secretes excess VIP (vasoactive intestinal polypeptide)
• Associated with MEN1 syndrome (5% of cases)
• Excess VIP → ↑ relaxation of gastric and intestinal smooth muscles and cAMP activity (similar to cholera toxin) → secretory diarrhea and inhibition of gastric acid production
• VIP also stimulates vasodilation, bone resorption, and glycogenolysis
• Tumor location → the primary tumor is most frequently found in the pancreas (however, it arises from APUD cells rather than α or β pancreatic islet cells)

Clinical Features

• WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria) → tea-colored watery diarrhea (> 700 mL/day) → dehydration
• Weight loss
• Abdominal pain, nausea, vomiting
• Achlorhydria → ↓ iron and B12 absorption → anemia

Diagnostics

• ↑ Serum VIP concentration (> 75 pg/mL)
• Hypokalemia
• Hypercalcemia (manifests in almost 50% of all patients. The mechanism behind this is not yet understood)
• Hyperglycemia
• Gastric achlorhydria or hypochlorhydria (measured via nasogastric tube)
• CT scan to localize the primary tumor

Treatment

• Tumor resection
• Octreotide (inhibits VIP secretion)