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Unit 5 > Pathology - endocrine > Flashcards

Pathology - endocrine Flashcards

1
Q

Hormones released by the anterior pituitary (6)

A
  1. Prolactin
  2. GH
  3. TSH
  4. ACTH
  5. FSH
  6. LH
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2
Q

What structure lies in sella turcica? What structure is above that? (anatomy)

A

Pituitary sits in the sella turcica, above which lies the optic chiasm

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3
Q

Pituitary adenoma

A

Benign tumor of anterior pituitary cells

Separated into functional (hormone-producing) and nonfunctional (silent)

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4
Q

Pituitary adenoma - nonfunctional - pathogenesis

A

Primarily due to mass effect. As the tumor grows it can cause:

  • bitemporal hemianopsia – due to compression of the optic chiasm
  • hypopituitarism – compression of the normal pituitary tissue that causes damage
  • headache
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5
Q

Pituitary adenoma - functional - pathogenesis (general)

A

Features are based on the type of hormones produced.

Hormones produced: prolactin, GH, ACTH, TSH, LH and FSH

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6
Q

Most common pituitary adenoma

A

Prolactinoma

  • presents as:
    • Female: galactorrhea and amenorrhea
    • Male: decreased libido and headache
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7
Q

Prolactinoma

A

Characterized by increased levels of prolactin

presents as:

  • Female: galactorrhea (prolactin) and amenorrhea (prolactin inhibits GnRH synthesis –> decreased FSH and LH)
  • Male: decreased libido (inhibition of GnRH synthesis) and headache

Most common pituitary adenoma

Treatment is dopamine agonists (ie bromocriptine or cabergoline) to suppress prolactin production (shrinks tumor) or surgery for larger lesions

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8
Q

Prolactinoma - treatment

A

Treatment is dopamine agonists (ie bromocriptine or cabergoline) to suppress prolactin production (shrinks tumor) or surgery for larger lesions

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9
Q

Prolactinoma - clinical presentation

A

Female: galactorrhea (prolactin) and amenorrhea (prolactin inhibits GnRH synthesis –> decreased FSH and LH)

Male: decreased libido (inhibition of GnRH synthesis) and headache

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10
Q

What (compounds) are involved in breast milk production and let down? Where is each produced?

A

Prolactin - milk production (produced and secreted from the anterior pituitary)

Oxytocin - milk let down, induced via suckling (produced in the hypothalamus, stored and released from the posterior pituitary)

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11
Q

Relationship between prolactin and dopamine?

A

Prolactin feedbacks onto the hypothalamus to secrete dopamine which inhibits further prolactin synthesis.

This is why dopamine agonists (ie bromocriptine or cabergoline) are used to treat prolactinomas

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12
Q

What does increased levels of prolactin cause? Why?

A

Prolactin causes milk production –> galactorrhea in females.

  • Does not occur in males because lack of lobular units. Men only have terminal ducts

Prolactin feeds back onto the hypothalamus to decrease GnRH synthesis –> decreased FSH and LH secretions from anterior pituitary –> amenorrhea in females and decreased libido in males

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13
Q

Growth hormone cell adenoma - clinical presentation

A

GH induces the production of IGF-1 which mediates the growth of tissues. It causes:

  • Gigantism in children (increased linear bone growth as epiphyses are not fused yet)
  • Acromegaly in adults
    • enlarged bones of hands, feet and jaw
    • growth of visceral organs leading to dysfunction (ie cardiac failure – most common cause of death in these patients)
    • enlarged tongue

Secondary diabetes mellitus often common

  • GH induces live gluconeogenesis and also decreased glucose uptake causing high glucose levels characteristic of diabetes
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14
Q

Growth hormone cell adenoma - pathogenesis

A

Characterized by secretion of GH: which induces production of IGF-1.

  • IGF-1 (insulin like growth factor) is responsible for mediating the growth of tissues

GH also feeds back to decrease glucose uptake and increased liver gluconeogenesis to cause secondary diabetes mellitus

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15
Q

Growth hormone cell adenoma - what happens in children? (before epiphyses fusion)

A

Gigantism

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16
Q

Growth hormone cell adenoma - what happens to adults? (after fusion of epiphyses)

A

Acromegaly characterized by:

  • enlarged bones of hands, feet and jaw
  • growth visceral organs leading to dysfunction (ie cardiac failure)
  • enlarged tongue
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17
Q

Most common cause of death in patients with growth hormone cell adenoma?

A

Cardiac failure – due to growth of visceral organs leading to dysfunction

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18
Q

How does patients with GH cell adenoma get diabetes mellitus?

A

GH induces liver gluconeogenesis

GH decreases glucose uptake

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19
Q

Growth hormone cell adenoma - treatment

A
  1. Octreotide (somatostatin analog that suppresses GH release)
  2. GH receptor antagonists
  3. surgery
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20
Q

ACTH cell adenomas

A

Secrete ACTH leading to Cushing syndrome

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21
Q

Most common pituitary adenomas

A

List is in order of greatest or least occurence.

  1. Prolactinoma
  2. GH adenoma
  3. ACTH adenoma
  4. TSH, LH, FSH adenomas – rare
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22
Q

Hypopituitarism

A

Insufficient production of hormones by the anterior pituitary gland

Symptoms arise when >75% of pituitary parenchyma is lost

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23
Q

Hypopituitarism - when do symptoms arise?

A

when there is >75% loss of pituitary parenchyma

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24
Q

Hypopituitarism - causes

A
  1. mass effect
    • Pituitary adenoma (adults) or craniopharyngioma (children)
  2. pituitary apoplexy (sudden onset of sudden neurologic impairment due to pituitary hemorrhage or infarction)
  3. Sheehan syndrome
    • pregnancy-related infarction of the pituitary gland
    • gland doubles in size during pregnancy without much increase in blood supply. Any kind of blood loss (ie during parturition) precipitates infarction
  4. Empty sella syndrome
    • Due to congenital defect of the sella or secondary loss due to trauma
      • herniation of the arachnoid and CSF int he sella compresses and destroys the pituitary gland
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25
Q

What kind of mass effects can cause the loss of the pituitary gland?

A

Typically due to something else being present so the pituitary is compressed or completely fails to develop. Can also be caused by blood/CSF hemorrhage

  • Pituitary adenomas (adults) or craniopharyngioma (children)
  • pituitary apoplexy
  • Empty sella syndrome
    • secondary to trauma
    • herniation of the arachnoid and CSF into the sella
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26
Q

pituitary apoplexy

A

Apoplexy refers to the sudden onset of neurologic impairment.

Pituitary apoplexy is characterized by a sudden onset of headache, visual symptoms, altered mental status, and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland.

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27
Q

Pituitary apoplexy - clinical symptoms

A
  • sudden onset of headache
  • visual symptoms
  • altered mental status
  • hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland.
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28
Q

Sheehan syndrome

A
  1. Pregnancy-related infarction of the pituitary gland
  2. Gland doubles in size during pregnancy due to increased demand of hormones (FSH, LH) however the blood supply does not increase significantly.
  3. Blood loss during parturition or via other modalities precipitates infarction

Presents as:

  • poor lactation
  • loss of pubic hair
    • ​pubic hair depends on androgens which arise due to LH.
  • fatigue
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29
Q

What is the association between pregnancy and pituitary infarction? What is this syndrome called?

A

Pituitary gland doubles in size during pregnancy due to increased demand of hormones (FSH, LH) however the blood supply does not increase significantly.

  • Blood loss during parturition or via other modalities precipitates infarction

This syndrome is referred to as Sheehan syndrome

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30
Q

Clinical association with Sheehan syndrome

A

Remember this is the loss of the pituitary due to infarction precipitated by blood loss

Presents as: poor lactation (prolactin), loss of pubic hair (LH), and fatigue

Fatigue can be nonspecific. Poor lactation is hard to tell unless the baby is born and may not be noticeable. Loss of pubic hair is the key association in this disease

  • Androgens are responsible for the growth of hair which is induced by the presence of LH.
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31
Q

Why is there a loss of hair in Sheehan syndrome?

A

Androgens are responsible for the growth of hair which is induced by the presence of LH.

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32
Q

Empty sella syndrome - causes

A

2 main causes: trauma or herniation

  • secondary loss of pituitary due to trauma
  • herniation of arachnoid and CSF into sella compresses and destroys the gland
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33
Q

empty sella syndrome - diagnosis

A

Pituitary gland is “absent” (empty sella) on imaging

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34
Q

Posterior pituitary gland - what hormones is it responsible for? Where are they produced?

A

ADH (antidiuretic hormone aka vasopressin) and oxytocin

  • ADH - acts on distal tubules and collecting ducts of the kidney to promote free water retention
  • oxytocin - mediates uterine contraction during labor and release of breast milk (let-down) in lactating mothers

both are made in the hypothalamus and transported via axons to the posterior pituitary for release

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35
Q

Central diabetes insipidus

A

ADH deficiency

Due to hypothalamic or posterior pituitary pathology (ie tumor, trauma, infection or inflammation)

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36
Q

Central diabetes insipidus - clinical features

A

All based on loss of free water

  • polyuria and polydipsia w/ risk of life-threatening dehydration
  • hypernatremia and high serum osmolality
  • Low urine osmolality and specific gravity
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37
Q

Central diabetes insipidus - diagnosis

A

Water deprivation test fails to increase urine osmolality

  • remember that normally if you water deprive someone, the normal physiological response is to secrete ADH to retain water and concentrate the urine. No response will be seen in a patient with this disease
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38
Q

Central diabetes insipidus - treatment

A

Desmopressin (ADH analog)

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39
Q

Nephrogenic diabetes insipidus

A
  • Impaired renal response of ADH
  • Due to inherited mutations or drugs (ie lithium or demeclocycline)
  • Clinical features are similar to central diabetes insipidus, but there is no response to desmopressin
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40
Q

What are the 2 types of diabetes insipidus? What makes them different? what makes them similar?

How do you tell them apart clinically?

A

Similar in that they both result in the body’s inability to control movement of free water

Central = due to ADH deficiency –> hypothalamic of posterior pituitary pathology

Nephrogenic = due to impaired renal response to ADH

Clinically can be separated out as only central will respond to desmopressin or any other ADH analogs

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41
Q

Syndrome of inappropriate ADH (SIADH) secretion

A

Excessive ADH secretion –> holding onto free H2O

Most often due to ectopic production (ie small cell carcinoma of the lung)

Other causes: CNS trauma, pulmonary infection, drugs (ie cyclophosphamide)

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42
Q

SIADH - causes

A

Most often due to ectopic production (ie small cell carcinoma of the lung)

Other causes: CNS trauma, pulmonary infection, drugs (ie cyclophosphamide)

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43
Q

SIADH - clinical features

A

All based on the retention of free water

  • hyponatremia and low serum osmolality
  • mental status changes and seizures – hyponatremia leads to neuronal swelling and cerebral edema
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44
Q

Why are there mental status changes associated with SIADH secretion? What is the mechanism?

A

Too much ADH dilutes the blood causing hyponatremia.

Hyponatremia leads to neuronal swelling and cerebral edema

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45
Q

SIADH - treatment

A
  • Free water restriction
  • demeclocycline (antibiotic that reduces the responsiveness of the collecting duct to ADH)
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46
Q

Development of the thyroid gland

A

Develops at the base of tongue and then travels along the thyroglossal duct to the anterior neck

  • Thyroglossal duct normally involutes
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47
Q

What is the thyroglossal duct? Purpose?

A

The duct is created when the thyroid descends from the base of the tongue to the anterior neck.

A persistent duct, may undergo cystic dilation

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48
Q

What the pathology behind a persistent thyroglossal duct?

A

It may undergo cystic dilation –> anterior neck mass

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49
Q

persistent thyroglossal duct - clinical presentation

A

anterior neck mass

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50
Q

Thyroglossal duct cyst

A

Cystic dilation of thyroglossal duct remnant

Presents as an anterior neck mass

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51
Q

Lingual thyroid

A

Persistence of thyroid tissue at the base of the tongue

Presents as a base of tongue mass

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52
Q

Lingual thyroid - presentation

A

base of tongue mass

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53
Q

Pathology associated with embryological development of the thyroid

A

Thyroid develops at the base of the tongue and descends creating a thyroglossal duct that normally degenerates over time.

  1. Thryoglossal duct cyst – develops if there is cystic dilation of a remnant thyroglossal duct
  2. Lingual thyroid – develops if not all of the thyroid descends and leaves some at the base of the tongue.
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54
Q

Hyperthyroidism

A

Increased level of circulating thyroid hormone

  • increases BMR (via increased synthesis of Na/K ATPase)
  • increases sympathetic nervous system activity (due to increased expression of β1-adrenergic receptors)
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55
Q

Why is there an increase in BMR in hyperthyroidism?

A

Due to increased synthesis of Na+/K+ ATPase

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56
Q

Why is there an increased sympathetic nervous system activity in hyperthyroidism?

A

Increased expression of β1-adrenergic expression

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57
Q

Hyperthyroidism - clinical features

A

All the features are associated with the increased BMR and increased sympathetic activity

  1. Weight loss despite increased appetite
  2. heat intolerance and sweating (burning a lot ATP –> sweating)
  3. tachycardia w/ increased cardiac output (increased sympathetics)
  4. arrhythmia (ie afib) especially in elderly
  5. tremor, anxiety, insomnia, and heightened emotions
  6. staring gaze w/ lid lag
  7. diarrhea w/ malabsorption (gut moving faster as well)
  8. oligomenorrhea
  9. bone resorption w/ hypercalcemia –> increased risk for osteoporosis
  10. decreased muscle mass w/ weakness
  11. hypocholesterolemia
  12. hyperglycemia (due to gluconeogenesis and glycogenolysis)
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58
Q

What 2 high yield features associated with hyperthyroidism? Why are they associated with this disease state?

A
  1. Hypocholesterolemia – due to thyroid hormone stimulating glycogenolysis
  2. Hyperglycemia – due to thyroid hormone stimulating gluconeogenesis
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59
Q

Why are hypocholesterolemia and hyperglycemia associated with hyperthyroidism?

A

Hypocholesterolemia – due to thyroid hormone stimulating glycogenolysis

Hyperglycemia – due to thyroid hormone stimulating gluconeogenesis

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60
Q

Graves disease

A
  • Autoantibody (IgG) that stimulates TSH receptor (Typer II hypersensitivity)
  • Leads to increased synthesis and release of thyroid hormone
  • Most common cause of hyper thyroidism
  • classically occurs in women of childbearing age (20-40 years old)
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61
Q

Most common cause of hyperthyroidism

A

Graves disease

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62
Q

What is the classic demographic for an autoimmune disease? Why?

A

Classical demographic is women of childbearing age (20-40 years)

  • The reason is still unclear, but it is believed that during this age, women have a more complex immune system due to excess the need for excess regulation during pregnancy. Because it is more complex, it is easier to be broken hence why they are almost 10x more likely to develop certain autoimmune diseases
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63
Q

What type of hypersensitivity is associated with Graves disease?

A

Type II hypersensitivity – antibody mediated

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64
Q

Graves disease - clinical features

A
  1. hyperthyroidism
  2. diffuse goiter (constant and diffuse TSH stimulation leads to thyroid hyperplasia and hypertrophy)
  3. exophthalmos and pretibial myxedema
    • fibroblasts behind the orbit and overlying the shin express the TSH receptor
    • TSH activation resulting in glycosaminoglycan (chondroitin sulfate and hyaluronic acid) buildup, inflammation, fibrosis and edema leading to these features
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65
Q

Myxedema

A

Referring to the swelling/edema of skin. However, normal edema is caused by fluid buildup (water mainly or inflammatory debris). This is due to myxoid substance mainly consisting of glycosaminoglycans (chondroitin sulfate and hyaluronic acid)

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66
Q

What substance if found in myxedema? What is it made of?

A

Glycosaminoglycans – made up of chondroitin sulfate and hyaluronic acid

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67
Q

Why is there exophthalmos and pretibial myxedema in Graves disease?

A

Fibroblasts behind the orbit and overlying the shin express the TSH receptor – activation of which causes the buildup of glycosaminoglycans followed by inflammation, fibrosis and edema.

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68
Q

Graves disease - classical histological finding

A

Irregular follicles w/ scalloped colloid

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69
Q

Graves disease - laboratory findings

A
  1. Increased total and free T4 (free T3 downregulates TRH receptors in the anterior pituitary (AP) to decrease TSH release)
  2. hypocholesterolemia – increased glycogenolysis
  3. hyperglycemia – increased gluconeogenesis
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70
Q

Graves disease - treatment and why is each drug used?

A
  1. β-blockers (block the effect on the sympathetics)
  2. thioamide (block peroxidases which catalyzes the organification, oxidation and coupling steps in the production of thyroid hormone)
  3. radioiodine ablation (idea here is to let the thyroid incorporate radioactive iodine which will ultimately kill off some of the overactive thyroid)
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71
Q

What is the importance of thyroid peroxidases? What are their functions? Why are they important?

A
  • There are several peroxidase in the thyroid. They are all responsible for the organification, oxidation and coupling steps in the production of thyroid hormone.
  • They are important because they are important pharmaceutical targets (ie thioamid and propylthiouracil)
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72
Q

Potentially fatal complication of Graves Disease

A

Thyroid storm - basically due to the exposure of excess thyroid hormone (T3) to the body

Usually in response to stress (ie surgery or childbirth)

Presents as

  • arrhythmia, hyperthermia and vomiting w/ hypovolemic shock

Treatment: propylthiouracil (PTU), β-blockers and steroids

  • PTU inhibits peroxidase-mediated oxidation, organification and coupling steps of thyroid hormone synthesis as well as peripheral conversion of T4 to T3.
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73
Q

Thyroid storm - treatment

A
  1. propylthiouracil (PTU)
    • PTU inhibits peroxidase-mediated oxidation, organification and coupling steps of thyroid hormone synthesis as well as peripheral conversion of T4 to T3.
  2. β-blockers - blocks/reduces sympathetic activity
  3. steroids - reduces inflammation (esp if this is associated with graves disease when the underlying cause is inflammation)
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74
Q

what disease is thyroid storm associated with?

A

Graves Disease

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75
Q

Thyroid storm - clinical presentation

A
  1. arrhythmia
  2. hyperthermia
  3. vomiting w/ hypovolemic shock
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76
Q

Multinodular goiter

A
  • Enlarged thyroid gland w/ multiple nodules
  • Due to relative iodine deficiency
  • usually nontoxic (euthyroid or having a normally functioning thyroid)
  • Rarely, regions become TSH-independent leading to T4 release and hyperthyroidism (toxic goiter)
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77
Q

Propylthiouracil (PTU) - What is it? What is it used to treat? Why?

A

PTU inhibits peroxidase-mediated oxidation, organification and coupling steps of thyroid hormone synthesis

Also inhibits peripheral conversion of T4 to T3

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78
Q

Toxic goiter

A

Excretion of excess thyroid hromone but not under the control of TSH

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79
Q

Cretinism

A

Hypothyroidism in neonates and infants

Characterized by

  • mental retardation
  • short stature w/ skeletal abnormalities
  • coarse facial features
  • enlarged tongue
  • umbilical hernia
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80
Q

What role does thyroid hormone play in embyro development?

A

Associated with normal brain and skeletal development

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81
Q

Cretinism - causes

A
  • maternal hypothyroidism during early pregnancy (when fetus can’t produce its own hormones)
  • thyroid agenesis
  • dyshormonogenetic goiter (deficiency in ability to produce thyroid hormone – most common enzyme deficiency is thyroid peroxidase)
  • iodine deficiency
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82
Q

dyshormonogenetic goiter

A

deficiency in ability to produce thyroid hormone

Most common deficiency: thyroid peroxidase

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83
Q

dyshormonogenetic goiter - most common enzyme deficiency

A

thyroid peroxidase (responsible for the organification, oxidation and coupling steps in the production of thyroid hormone)

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84
Q

Myxedema

A

Hypothyroidism in older children or adults

Clinical features based on decreased BMR and decreased sympathetic nervous system activity

  • myxedema – accumulation of glycosaminoglycans in the skin and soft tissue; results in deepening of voice and large tongue
  • weight gain despite normal appetite
  • slowing mental activity
  • muscle weakness
  • cold intolerance w/ decreased sweating
  • bradycardia w/ decreased cardiac output –> SOB and fatigue
  • oligomenorrhea
  • hypercholesterolemia
  • constipation (decreased gut movements)
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85
Q

Myxedema (hypothyroidism) - clinical features

A
  • myxedema – accumulation of glycosaminoglycans in the skin and soft tissue; results in deepening of voice and large tongue
  • weight gain despite normal appetite
  • slowing mental activity
  • muscle weakness
  • cold intolerance w/ decreased sweating
  • bradycardia w/ decreased cardiac output –> SOB and fatigue
  • oligomenorrhea
  • hypercholesterolemia
  • constipation (decreased gut movements)
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86
Q

Why is there a deepening of the voice and large tongue associated with myxedema?

A

The accumulation of glycosaminoglycans preferentially occurs in the larynx and tongue causing changes in voice and enlarged tongue

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87
Q

What happens to gut during hyper vs hypothyroidism?

A

Hyper –> increased stimulation –> increased gut movement –> diarrhea

Hypo –> decreased “ “ –> constipation

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88
Q

Myxedema (hypothyroidism) - most common causes

A
  • iodine deficiency (where iodine levels are inadequate) or Hashimoto thyroiditis (where iodine levels are sufficient)

Other causes

  • drugs (ie lithium)
  • surgical removal or radioablation of the thyroid (a treatment for acne in children)
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89
Q

Cold and heat intolerance? Which is associated with hypo vs hyperthyroidism?

A

Heat intolerance associated with hyperthyroidism

Cold intolerance – hypothyroidism

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90
Q

Hypothyroidism in neonates & infants vs older children & adults - medical terminology

A

In neonates & infants: cretinism

In older children and adults: myxedema

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91
Q

Thyroiditis (3)

A

Inflammation of thyroid

  1. Hashimoto thyroiditis
  2. Subacute (DeQuervain) granulomatous thyroiditis
  3. Riedel fibrosing thyroiditis
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92
Q

Hashimoto Thyroiditis

A

Autoimmune destruction of the thyroid gland

Associated with HLD-DR5

Most common cause of hypothyroidism in regions where iodine levels are adequate

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93
Q

Hashimoto thyroiditis - clinical features

A
  1. Initially may present as hyperthyroidism (due to follicle damage leaking out excess thyroid hormone)
  2. Progresses to hypothyroidism: decreased T4 and increased TSH
  3. Antithyroglobulin and antithyroid peroxidase antibodies are often present (sign of thyroid damage – does NOT mediate the disease, only an indicator)
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94
Q

Hashimoto thyroiditis - what happens to T4 and TSH levels?

A

Once it gets to the hypothyroidism state:

  • Decreased T4
  • Increased TSH (T4 controls the # of TRH receptors on the anterior pituitary. Decreased T4 will increase receptors and increase secretion of TSH)
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95
Q

Hashimoto thyroiditis - what gene is it associated with?

A

HLA-DR5

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96
Q

Signs of thyroid damage in Hashimoto Thyroiditis

A
  • Remember that this is an autoimmune destruction of the thyroid gland
  • Antithyroglobulin and antithyroid peroxidase Abs are often present
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97
Q

Hashimoto thyroiditis - histological characteristics

A

Chronic inflammation w/ germinal centers and Hurthle cells (eosinophilic metaplasia of cells that line follicles)

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98
Q

Hurthle cells

A

A term used to describe follicular-derived epithelial cells with oncotic cytology

Most commonly seen in Hashimoto thyroiditis and follicular thyroid carcinoma

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99
Q

What complication do you have to be concerned about in patients w/ Hashimoto thyroiditis? What does it present as?

A

Increased risk for B-cell lymphoma(located in the marginal zones that develop in this disease)

Presents as an enlarging thyroid gland late in disease course

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100
Q

Subacute (DeQuervain) granulomatous thyroiditis

A

Subacute – follows acute process

granulomatous – forms granulomas

Thyroiditis – inflammation of the thyroid

  • Follows a viral infection
  • Presents as a tender thyroid w/ transient hyperthyroidism
  • Self-limited; rarely (15%) may progress to hypothyroidism
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101
Q

Subacute (DeQuervain) granulomatous thyroiditis - potential complication

A

Rarely (15%) may progress to hypothyroidism (destruction of the thyroid due to the inflammation)

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102
Q

Subacute (DeQuervain) granulomatous thyroiditis - clinical presentation

A

Tender thyroid w/ transient hyperthyroidism

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103
Q

What disease presents w/ tender thyroid?

A

Subacute (DeQuervain) granulomatous thyroiditis

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104
Q

Riedel fibrosing thyroiditis

A

Chronic inflammation w/ extensive fibrosis of the thyroid gland

Presents as hypothyroidism w/ ‘hard as wood’ nontender thyroid gland

  • Classically seen in young female

Fibrosis may extend to involve local structures (ie airway)

  • clinically mimics anaplastic carcinoma, but patients are younger (40s) and malignant cells are absent
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105
Q

Riedel fibrosing thyroiditis - what other clinical disease does this mimic? How do you separate them?

A

Clinically mimics anaplastic carcinoma

Distinguished because patients are usually younger in Riedel’s, and malignant cells are absent

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106
Q

What disease presents as ‘hard as wood’ nontender thyroid? What disease is tender thyroid?

A

‘hard as wood’ nontender = Riedel fibrosing thyroiditis

tender thyroid = subacute granulomatous thyroiditis

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107
Q

Hashimoto vs Grave’s disease

A

Both autoimmune.

Graves produces IgG Abs that stimulate the TSH receptors (type II hypersensitivity)

Hashimoto is autoimmune destruction of the thyroid –> hypothyroidism

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108
Q

Thyroid neoplasia - presentation (most are the same)

A

Usually presents as a distinct, solitary nodule

more like to be benign than malignant

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109
Q

Thyroid neoplasia - how are nodules characterized once discovered?

A

via I131 radioactive uptake studies

  • Increased uptake (‘hot’ nodule) is seen in Graves disease or nodular goiter
  • Decreased uptake (‘cold’ nodule) is seen in adenoma and carcinoma; often warrants biopsy

Biopsys are done via fine needle aspiration

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110
Q

How are biopsy’s of the thyroid done? Why?

A

Done using fine needle aspirations (FNAs)

This is because the gland is very bloody as well as small, so you want to disrupt as little as possible. Additionally, you do not want disrupt too many of the follicles as it may result in leakage of the thyroid hormone out

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111
Q

Follicular adenoma

A

Benign proliferation of follicles surrounded by a fibrous capsule

Usually nonfunctional.

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112
Q

hallmark of follicular adenoma

A

proliferation of follicles surrounded by a fibrous capsule

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113
Q

4 major thyroid carcinomas

A
  1. papillary
  2. follicular
  3. medullary
  4. anaplastic
114
Q

Most common type of thyroid carcinoma (80% of cases)

A

Papillary carcinoma

115
Q

Papillary carcinoma of the thyroid

A

Comprised of papillae lined by cells w/ clear “Orphan Annie eye’ nuclei and nuclear grooves

  • papillae are often associated w/ psammoma bodies
  • often spreads to cervical (neck) LNs, but prognosis is still excellent (10 year survival >95%)

Major risk factor: exposure to ionizing radiation in childhood (ie acne treatments)

116
Q

Papillary carcinoma of the thyroid - major risk factor

A

Exposure to ionizing radiation ( ie children treated with radiation for acne)

117
Q

Papillary carcinoma of the thyroid - where does it often spread to? How does it affect the prognosis?

A

Often spread ot cervical (neck) lymph nodes

Prognosis is still excellent w/ 10 year survival > 95%

118
Q

Follicular carcinoma of the thyroid

A

Malignant proliferation of follicles surrounded by a fibrous capsule w/ invasion through the capsule

  • Entire capsule must be examined microscopically
  • Metastasis generally occurs hematogenously (carcinoma normally lieks to spread via LNs)
119
Q

How do you distinguish between follicular adenoma and follicular carcinoma of the thyroid?

A

Adenoma is benign and is characterized by a fibrous capsule.

Follicular carcinoma is malignant with the same fibrous capsule, however there IS invasion through the fibrous capsule.

  • Need to examine the entire capsule microscopically in order to confirm this.

Additionally, this distinction CANNOT be made by FNA because FNA only examines cells and not the capsule.

120
Q

Why can’t a FNA (fine needle aspiration) distinguish between adenoma and carcinoma of the thyroid?

A

FNA only examines cells and not the capsule.

121
Q

How does follicular carcinoma of the thyroid like to metastasize? (mode of spreading)

A

Hematogenously

122
Q

What is the normal method of metastasis of carcinomas? What are the exceptions (4)?

A

Carcinomas normally metastasize via lymphatics.

4 general exceptions to the rule

  • Renal cell carcinoma –> renal vein
  • hepatic cellular carcinoma –> hepatic vein
  • follicular carcinoma
  • choriocarcinoma
123
Q

Medullary carcinoma of the thyroid

A

Malignant proliferation of parafollicular C cells (~5% of thyroid carcinomas)

  • C cells are neuroendocrine cells that secrete calcitonin
  • Calcitonin lowers serum calcium by increasing renal calcium excretion but is inactive at normal physiologic levels
  • High levels of calcitonin produced by tumor may lead to hypocalcemia
  • calcitonin often deposits within the tumor as amyloid
124
Q

What is the function of calcitonin? What cells produce it?

A

C cells are neuroendocrine cells that secrete calcitonin

Calcitonin lowers serum calcium by increasing renal calcium excretion but is inactive at normal physiologic levels

125
Q

Pathogenesis of medullary carcinoma of the thyroid

A

Medullary carcinoma is the malignant proliferation of the parafollicular C cells

  1. C cells are neuroendocrine cells that secrete calcitonin
  2. Calcitonin lowers serum calcium by increasing renal calcium exceretion but is inactive at normal physiologic levels
  3. High levels of calcitonin produced by tumor may lead to hypocalcemia
  4. calcitonin often deposits within the tumor as amyloid
126
Q

What cancer is associated with malignant proliferation of parafollicular C cells?

A

Medullary carcinoma

127
Q

Medullary carcinoma of thyroid - what do you expect on biopsy?

A

sheets of malignant cells in an amyloid stroma

128
Q

Medullary carcinoma of thyroid - if it is familial, what is it associated with?

A

Multiple endocrine neoplasia (MEN) 2A and 2B

  • Associated with mutations in the RET oncogene
129
Q

What gene is associated with MEN 2A and 2B? (Multiple Endocrine Neoplasia)

A

RET oncogene.

Detection of RET mutation often warrants prophylactic thyroidectomy

130
Q

MEN 2A

A

Associated with RET mutation

Involves:

  • Medullary carcinoma
  • pheochromocytoma
  • parathyroid adenoma
131
Q

MEN 2B

A

Associated with RET mutation

Involves:

  • Medullary carcinoma
  • pheochromocytoma
  • ganglioneuromas of the oral mucosa
132
Q

Anaplastic carcinoma of the thyroid

A
  • Undifferentiated malignant tumor of the thyroid
  • usually seen in the elderly
  • Often invades local structures –> dysphagia and/or respiratory compromise
  • Poor prognosis
133
Q

What does anaplastic carcinoma of the thyroid often look like? (what disease does it mimic) How do you distinguish them apart?

A

Clinically mimics Reidel’s Fibrosing Thyroiditis

Anaplastic carcinoma however appears in elderly and has a poor prognosis (malignant) while Reidel’s has good prognosis (not a tumor) and affects primarily the young

134
Q

“Orphan Annie Eye” nuclei and nuclear grooves and lines on histology – what is the diagnosis?

A

Papillary carcinoma

135
Q

What is the role of PTH? What cells produce PTH?

A

PTH (parathyroid hormone) regulates free (ionized) calcium.

PTH is produced by Chief cells

136
Q

Mechanism of PTH (3)

A
  1. Increases bone osteoclast activity (indirectly via the direct activation of osteoblasts)
    • releases calcium and phosphate
  2. increases small bowel absorption of calcium and phosphate (indirectly by activating vitamine D)
  3. increases renal calcium reabsorption (distal tubule) and decreases phosphate reabsorption (proximal tubule)

Of all 3 mechanisms above, ONLY the renal handling of calcium and phosphate results in increased free calcium.

  • Increased serum ionized calcium levels provide negative feedback to decease PTH
137
Q

Of all the mechanisms that PTH works, what actually increases the free calcium in the blood? Why?

A

Only the renal handling of calcium and phosphate mediated by PTH (increased calcium reabsorption and decreased phosphate reabsorption)

All other methods increase both calcium and phosphate which increases bound calcium as phosphate loves to bind calcium.

138
Q

Primary hyperparathyroidism

A

Excess PTH due to a disorder of the parathyroid gland itself

Most common cause (>80% of cases) is parathyroid adenoma.

  • other causes: sporadic parathyroid hyperplasia and parathyroid carcinoma
139
Q

Primary hyperparathyroidism - most common causes

A
  1. parathyroid adenoma (>80% of cases)
  2. sporadic parathyroid hyperplasia
  3. parathyroid carcinoma
140
Q

How many parathyroid glands do humans have?

A

4

141
Q

Parathyroid adenoma

A

Benign neoplasm usually involving one gland

Usually asymptomatic, but if there are symptoms they are due to

  • increased PTH
  • hypercalcemia
142
Q

Parathyroid adenoma - clinical symptoms (if there are any)

A

Usually asymptomatic, but if they are present, they are due to increased PTH and hypercalcemia

  • Nephrolithiasis (calcium oxalate stones)
  • Nephrocalcinosis – metastatic calcification of renal tubules potentially leading to renal insufficiency and polyuria
  • CNS disturbances (ie depression and seizures)
  • Constipation, peptic ulcer disease, and acute pancreatitis
  • Osteitis fibrosa cystica - constant resorption of bone results in fibrosis and cystic spaces
143
Q

Nephrocalcinosis

A
  • Refers to the deposition of calcium inside tissues due to high levels in the blood (hypercalcemia)
  • Could be a result of hyperparathyroidism (ie via parathyroid adenomas) which can cause metastatic calcification of renal tubules potentially leading to renal insufficiency and polyuria
144
Q

How does parathyroid adenoma increase risk of acute pancreatitis?

A

May cause hypercalcemia which is an enzyme activator. The inadvertent activation of pancreatic enzymes may result in acute pancreatitis

145
Q

Parathyroid adenoma - clinical findings

(PTH, Calcium, phosphate, urinary cAMP, alkaline phosphatase)

A
  • Increased serum PTH
  • Increased serum calcium
  • decreased serum phosphate (remember excreted out via renal system)
  • increased urinary cAMP (PTH activates a Gs protein that activates adenylate cyclase which converts ATP to cAMP. cAMP is the mediator of all the effects of PTH and may leak out into the urine)
  • increased serum alkaline phosphatase (PTH directly activates osteoblasts which secrete this in order to create the alkaline environment needed to lay down bone)
146
Q

Why is there increased urinary cAMP in parathyroid adenoma?

A

PTH activates a Gs protein that activates adenylate cyclase which converts ATP to cAMP. cAMP is the mediator of all the effects of PTH and may leak out into the urine

147
Q

Parathyroid adenoma - why is there increased serum alkaline phosphatase?

A

PTH directly activates osteoblasts which then activate the osteoclasts.

For osteoblasts to lay down bone requires an alkaline environment so they secrete alkaline phosphatase to create that environment

148
Q

Parathyroid adenoma - treatment

A

Surgical removal of affected gland

149
Q

Secondary hyperparathyroidism

A

Excess production of PTH due to a disease process extrinsic to the parathyroid gland

Most common cause is chronic renal failure

150
Q

Most common cause of secondary hyperparathyroidism. Why?

A

Chronic renal failure

  1. renal insufficiency leads to decreased phosphate excretion
  2. increased serum phosphate binds free calcium
  3. decreased free calcium stimulates all 4 of the parathyroid glands to increase PTH
  4. increased PTH leads to bone resorption (contributing to renal osteodystrophy)

Lab findings: increased PTH, serum phosphate and alkaline phosphatase. Decreased serum calcium

151
Q

Secondary hyperparathyroidism - laboratory findings

A
  • Increased PTH
  • Increased serum phosphate
  • increased alkaline phosphatase
  • decreased free serum calcium
152
Q

Hypoparathyroidism

A

Low PTH

causes include

  • autoimmune damage to the parathyroids
  • surgical excision
  • DiGeorge Syndrome

Presents with: (all related to low serum calcium)

  • Numbness and tingling (particularly circumoral aka around the mouth)
  • Muscle spasms (tetany) – may be elicited with filling of a blood pressure cuff (Trousseau sign) or tapping of the facial nerve (Chvostek sign)
153
Q

Hypoparathyroidism - main causes (3)

A
  • autoimmune damage to the parathyroids
  • surgical excision
  • DiGeorge Syndrome (failure of development of the 3rd and 4th pharyngeal pouches)
154
Q

Hypoparathyroidism - clinical presentation

A

Presents with: (all related to low serum calcium)

  • Numbness and tingling (particularly circumoral aka around the mouth)
  • Muscle spasms (tetany) – may be elicited with filling of a blood pressure cuff (Trousseau sign) or tapping of the facial nerve (Chvostek sign)
155
Q

Tetany

A

a condition marked by intermittent muscular spasms, caused by malfunction of the parathyroid glands and a consequent deficiency of calcium.

156
Q

Trousseau sign

A
  • Muscle spasms with filling of a blood pressure cuff.
  • lack of blood flow exacerbates the existing calcium deficiency in the distal arm causing spasms of the arm and forearm muscles
    • Results in: wrist and metacarpal phalangeal flexion, proximal and distal interphalangeal extension, and finger adduction
  • Much more sensitive (94%) than the Chvostek sign (29%) for hypocalcemia
157
Q

Chvostek sign

A
  • Muscle spasms illicited via tapping of the facial nerve.
  • Demonstrates the hypersensitivity of the muscles due to hypocalcemia.
  • Tapping of the facial nerve will cause contraction of the ipsilateral masseter muscle
158
Q

What is the better test for checking for hypocalcemia?

A

Goal is to illicit muscle spasms.

Trousseau sign much more sensitive (94%) than the Chvostek sign (29%) for hypocalcemia

  • Trousseau – illicited via filling of a blood pressure cough
  • Chvostek sign – illicited via tapping of the facial nerve
159
Q

Hypoparathyroidism - laboratory findings

A

decreased PTH levels

decreased serum calcium

160
Q

pseudohypoparathyroidism

A

End organ resistance to PTH

Labs will show hypocalcemia w/ increased PTH levels

Most common due to a defect in the Gs protein (autosomal dominant) which would normally activate adenyl cyclase and convert ATP to cAMP

161
Q

what chemical messenger is responsible for mediating the downstream effects of PTH?

A

cAMP – created by adenylate cyclase (convert ATP –> cAMP)

162
Q

Pancreas is split up into 2 divisions. What are they? What are each respective roles?

A

Endocrine pancreas – responsible for production of insulin, glucagon, amylin and CCK (somatostatin)

Exocrine pancrease – responsible for the production of gastric enzymes such as gastrin, and VIP (vasoactive intestinal peptide)

163
Q

Functional unit of the endocrine pancreas

A

Islets of Langerhans

A single islet consists of multiple cell types each producing one type of hormone

  • Alpha cells producing glucagon (15–20% of total islet cells)
  • Beta cells producing insulin and amylin (65–80%)
  • Delta cells producing somatostatin (3–10%)
  • PP cells (gamma cells) producing pancreatic polypeptide (3–5%)
  • Epsilon cells producing ghrelin (<1%)
164
Q

Where and what is insulin made by? What is its mechanism of action?

A

Made and secreted by beta cells which lie at the center of islets

Insuline is a major anabolic hormone

Mechanism:

  1. upregulates insulin-dependent glucose transporter (GLUT4) on skeletal muscle and adipose tissue
    • glucose uptake by GLUT4 decreases serum glucose
  2. Increased glucose uptake by tissues leads to increased glycogen, protein and lipid synthesis
165
Q

How does insulin decrease serum glucose?

A
  • insulin upregulates insulin-dependent glucose transporter (GLUT4) on skeletal muscle and adipose tissue
  • glucose uptake by GLUT4 decreases serum glucose
166
Q

Why is insulin a major anabolic hormone?

A

It causes glycogen synthesis (increased energy), protein synthesis (increased muscle) and lipogenesis (increased fat)

167
Q

Where and what is glucagon made by? What is its mechanism of action?

A

Secreted by alpha cells that surround the Beta cells (typically around the periphery)

Acts to oppose insulin in order to increase blood glucose levels (ie in states of fasting) via glycogenolysis and lipolysis

168
Q

Type 1 diabetes

A

Insulin deficiency leading to a metabolic disorder characterized by hyperglycemia

Due to autoimmune destruction of beta cells by T lymphocytes (Type IV hypersensitivity)

  • characterized by inflammation of islets
  • associated with HLA-DR3 and HLA-DR4
  • autoAbs against insulin are often present (sign of damage) and may be seen years before clinical disease develops
169
Q

Type 1 diabetes - what type of hypersensitivity is associated with this disease?

A

Type IV hypersensitivity is what causes the destruction of beta cells by T lymphocytes

170
Q

Type 1 diabetes - what genes is it associated with?

A

HLA-DR3 and HLA-DR4

171
Q

Type 1 diabetes - defining characteristic on histology

A

Inflammation of islets

172
Q

Type 1 diabetes - clinical presentation

A

​Manifests in childhood w/ clinical features of insulin deficiency

  1. high serum glucose – lack of insulin leads to decreased glucose uptake by fat and skeletal muscle
  2. Weight loss, low muscle mass, polyphagia (excessive hunger or increased appetite)
    • unopposed glucagon leads to gluconeogenesis, glycogenolysis and lipolysis which further exacerbates hyperglycemia
  3. Polyuria, polydipsia, and glycosuria – hyperglycemia exceeds renal ability to resorb glucose –> excess filtered glucose leads to osmotic diuresis
173
Q

Type 1 diabetes - treatment

A

lifelong insulin

174
Q

Diabetic ketoacidosis (DKA)

A

characterized by excessive serum ketones

Often arises with stress (ie infection) – release of epinephrine in stress stimulates glucagon secretion which increases lipolysis (as well as gluconeogenesis and glycogenolysis).

  • increased lipolysis leads to increased free fatty acids (FFAs)
  • liver converts FFAs to ketone bodies (β-hydroxybutyric acid and acetoacetic acid)
    • These acids are the hallmarks of DKA
175
Q

DKA - mechanism

A

Often arises with stress (ie infection) – release of epinephrine in stress stimulates glucagon secretion which increases lipolysis (as well as gluconeogenesis and glycogenolysis).

  • increased lipolysis leads to increased free fatty acids (FFAs)
  • liver converts FFAs to ketone bodies (β-hydroxybutyric acid and acetoacetic acid)
    • These acids are the hallmarks of DKA
176
Q

What is the primary chemical responsible for DKA?

A

Glucagon

If unopposed by insulin, it results in increased lipolysis which results in FFAs that will be converted into ketone bodies by the liver

177
Q

What results from DKA? (laboratory findings)

A
  1. Hyperglycemia (>300 mg/dL) – due to glucagon still inducing gluconeogenesis and glycogenolysis
  2. Anion gap metabolic acidosis – ketone acids floating in blood
  3. hyperkalemia (2 mechanisms)
    • insulin helps to K+ into the cells . Without insulin, there is excess in the blood
    • when there is acidosis, one of our bodies mechanisms of buffering the acidosis is to pump H+ ions into the cells and K+ out (to balance the charge)
178
Q

What happens to the K+ levels in patients with DKA? What is the mechanism?

A

Results in hyperkalemia

  • insulin helps to K+ into the cells . Without insulin, there is excess in the blood
  • when there is acidosis, one of our bodies mechanisms of buffering the acidosis is to pump H+ ions into the cells and K+ out (to balance the charge)

While there is excess K+ in the blood, there actually is overall less in the body because the K+ is being excreted (via renal handling). Careful for the excessive loss of potassium when correcting DKA

179
Q

DKA - clinical presentation

A
  1. Kussmaul respirations (deep and labored breathing in an attempt to blow off the acidosis)
  2. dehydration (hyperglycemia results in increased urination)
  3. N&V
  4. mental status changes
  5. fruity smelling breath (due to acetone)
180
Q

DKA - treatment

A
  1. Fluids (corrects dehydration from polyuria)
  2. insulin (counter effects of glucagon)
  3. replacement of electrolytes (replace the K+ lost in the urine and also to counter the effect of giving insulin which will push more K+ into the cells)
181
Q

Type 2 diabetes

A

End-organ insulin resistance leading to a metabolic disorder characterized by hyperglycemia

Most common type of diabetes (90% of cases) – affects 5-10% of the US population

  • incidence is rising

Arises in middle-aged, obese adults

  • obesity leads to decreased number of insulin receptors (obesity results from constant eating of mainly sugars –> high levels of insulin –> insulin desensitization –> decreased insulin receptors
  • strong genetic predisposition exists (stronger than Type 1 diabetes)
182
Q

Most common type of diabetes

A

Type II – insulin resistance

>90% of cases

5-10% of US populations has Type II

183
Q

What population is Type II diabetes most prevalent in?

A

Middle-aged obese adults

184
Q

What role does obesity play in diabetes?

A

Causes type II diabetes

Obesity is a result from overeating. Overeating naturally causes increased level of insulin = constant elevated levels of insulin results in insulin desensitization –> decreased insulin receptors

185
Q

Type 2 diabetes - pathogenesis

A

Obesity –> increased glucose levels –> increased insulin –> insulin desensitization = decreased insulin receptors –> body compensates by pumping more insulin –> beta cell exhaustion

histology reveals amyloid deposition in the islets

186
Q

Type 2 diabetes - histology

A

Amyloid deposition in the islets

187
Q

Type 2 diabetes - clinical features

A
  • polyuria
  • polydipsia
  • hyperglycemia

disease is often clinically silent

188
Q

Type 2 diabetes - how is diagnosis made?

A
  • Random glucose > 200mg/dL
  • fasting glucose > 126mg/dL
  • glucose tolerance test w/ a serum glucose level > 200 mg/dL two hours after glucose loading
189
Q

Type 2 diabetes - treatment

A

First line: diet and exercise

Drug therapy to counter insulin resistance (if needed – ie sulfonylureas, metformin)

exogenous insulin after exhaustion of beta cells

190
Q

Type 2 diabetes - complications

A

Risk for hyperosmolar non-ketotic coma

  • high glucose (>500mg/dL) leads to life-threatening diuresis w/ hypotension and coma
  • ketones are absent due to small amounts of circulating insulin (sufficient enough to counter glucagon – which is the cause of DKA)
191
Q

hyperosmolar non-ketotic coma

A
  • high glucose (>500mg/dL) leads to life-threatening diuresis w/ hypotension and coma
  • ketones are absent due to small amounts of circulating insulin (sufficient enough to counter glucagon – which is the cause of DKA)

A result of type 2 diabetes

192
Q

Long term consequence of diabetes (2)

A
  1. Nonenzymatic glycosylation (NEG) of vascular basement membranes
    • NEG of large and medium sized vessels –> atherosclerosis
      • Cardiovascular disease (leading cause of death among diabetics)
      • Peripheral vascular disease (leading cause of non-traumatic amputations in diabetics)
    • NEG of small vessels (arterioles) –> hyaline arteriolosclerosis
      • Preferentially affects efferent arterioles but can affect afferent
        • afferent effected –> decreased GFR –> gluomerulosclerosis –> small scarred kidneys w/ a granular surface
        • efferent effected –> hyperfiltration injury with microalbuminuria that progresses to nephrotic syndrome – characterized by Kimmelstiel-Wilson nodules in glomeruli
    • NEG of hemoglobin produces glycated Hb (HbA1C) – a marker of glycemic control
  2. Osmotic damage
    • Glucose freely enters (independent of insulin) 3 cells types
      1. Schwann cells –> peripheral neuropathy
      2. pericytes of retinal blood vessels –> blindness
      3. Lens –> cataracts
    • Aldose reductase converts the glucose into sorbitol, which causes osmotic damage
193
Q

NEG of large to medium vessels causes what?

A

Atherosclerosis

  • cardiovascular disease
  • peripheral vascular disease
194
Q

NEG of small vessels cause what? Where does it preferentially hit?

A

Hyaline arteriolosclerosis of the efferent arterioles in the kidney.

  • If efferent arterioles are affected –> hyperfiltration injury w/ microalbuminuria that progresses to nephrotic syndrome
    • characterized by Kimmelstein-Wilson nodules
  • If afferent arterioles are affected –> glomerulosclerosis due to decreased GFR –> small scarred kidneys w/ a granular surface
195
Q

How do you detect for NEG?

A

Look at HbA1C – a marker for glycemic control b/c Hb has a half-life of 120days so basically it is a measure of the average sugar in your blood over that period of time

196
Q

2 types of damage caused by hyperglycemia (long term)

A
  1. NEG
  2. Osmotic damage (due to conversion of glucose into sorbitol via aldose reductase)
197
Q

What is the mechanism of action of osmotic damage cause by hyperglycemia? How does it come about? What is the result?

A

Glucose is converted into sorbitol which can cause osmotic damage to cells.

This occurs when there is excess glucose in cells, especially in cells that uptake glucose in an insulin-indepedent manner. 3 cell types that do this:

  1. Schwann cells –> peripheral neuropathy
  2. pericytes of retinal blood vessels –> blindness
  3. Lens –> cataracts
198
Q

Osmotic damage to the body due to hyperglycemia in diabetes causes what?

A

Schwann cells –> peripheral neuropathy

pericytes of retinal blood vessels –> blindness

Lens –> cataracts

199
Q

Leading cause of blindness in the developed world? what is the mechanism by which this blindness occurs?

A

Diabetes – due to uptake of glucose in an insulin-independent manner in pericytes of retinal blood vessels. Osmotic damage occurs when the glucose is converted into sorbitol via aldose reductase

200
Q

What enzyme is responsible for osmotic damage in diabetic patients?

A

Aldose reductase – converts glucose to sorbitol which causes the damage to cells

201
Q

Pancreatic endocrine neoplasms (4)

A

Tumor of islet cells: (<5% of pancreatic neoplasms) – often a component of MEN 1

  1. Insulinomas
  2. Gastrinomas
  3. Somatostatinomas
  4. VIPomas (vasoactive intestinal peptide)
202
Q

MEN1 - what neoplasms are involved?

A

parathyroid hyperplasia

pituitary adenoma

pancreatic endocrine tumor

203
Q

Insulinomas - presentation

A

Present as episodic hypoglycemia w/ mental status changes that are relieved by adminstration of glucose

Diagnosed by

  • decreased serum glucose levels (usually < 50 mg/dL)
  • increased insulin
  • increased C-peptide (note that only insulin made in our bodies comes with C-peptide which is cleaved upon activation/released. If there is no C-peptide, need to be careful for injected or non-natural insulin)
204
Q

diagnosis of insulinomas

A
  • decreased serum glucose levels (usually < 50 mg/dL)
  • increased insulin
  • increased C-peptide (note that only insulin made in our bodies comes with C-peptide which is cleaved upon activation/released. If there is no C-peptide, need to be careful for injected or non-natural insulin)
205
Q

Gastrinomas

A

Presents as treatment-resistant peptic ulcers (Zollinger-Ellison syndrome)

  • gastrin induces production/secretion of H+ ions by the parietal cells

ulcers may be multiple and can extend into the jejunum

206
Q

Somatostatinomas - presentation

A

Presents as

  • achlorhydria - low acid production (due to inhibition of gastrin)
  • cholelithiasis with steatorrhea (due to inhibition of cholecystokinin – CCK responsible for contraction of gallbladder which releases enzymes for digestion of fats)
    • increased risk for steatorrhea
    • increased risk for gallstones
207
Q

VIPomas - presentation

A

Excessive secretion of VIP which presents as (VIP or vasoactive intestinal peptide inhibits gastric secretion and a bunch of other things)

  • watery diarrhea
  • hypokalemia
  • achlorhydria (low acid)
208
Q

Function of VIP (vasoactive intestinal peptide)

A

With respect to the digestive system

  • smooth muscle relaxation (of the lower esophageal sphincter,stomach, gallbladder)
  • stimulates secretion of water into pancreatic juice and bile
  • inhibition of gastric acid secretion and absorption from the intestinal lumen
  • stimulates pepsinogen secretion by chief cells
209
Q

3 layers of the adrenal cortex and what does each layer produce

A

GFR (outside –> inside)

  • Glomerulosa – produces mineralocorticoids (ie aldosterone)
  • Fasciculata – produces glucocorticoids (ie cortisol)
  • Reticularis – produces androgens (ie DHEA)
  • Medulla –> produces catecholamines (ie epinephrine and NE)

Ways to remember:

  • Sweeter as it gets deepers
  • Salt, Sugar, Sex
210
Q

What is the precursor to the cortical hormones?

A

Cholesterol

211
Q

Function of aldosterone

A

Acts on the late distal tubule and the collecting duct on the following cells to:

  • Principal cells – grab sodium, dump potassium
  • α-intercalated cells – dump H+
  • β-intercalated cells – dump bicarbonate

When there is excess aldosterone:

  • grabbing sodium –> hypernatremia
  • dumping potassium –> hypokalemia
  • dumping H+ –> metabolic alkalosis
  • hypernatremia (water follows) –> volume expansion –> HTN
212
Q

What happens in hyperaldosteronism?

A

When there is excess aldosterone:

  • grabbing sodium –> hypernatremia
  • dumping potassium –> hypokalemia
  • dumping H+ –> metabolic alkalosis
  • hypernatremia (water follows) –> volume expansion –> HTN
213
Q

What is the function of principal cells under the effect of aldosterone?

A

Grab sodium

Dump potassium

214
Q

What is the function of α-intercalated cells under the effect of aldosterone?

A

dump H+ causing metabolic alkalosis

215
Q

What is the function of β-intercalated cells under the effect of aldosterone?

A

dump bicarbonate –> metabolic acidosis

216
Q

Most common cause of primary hyperaldosteronism

A

bilateral adrenal hyperplasia

217
Q

Causes of hyperaldosteronism

A

bilateral adrenal hyperplasia (most common)

Other causes: adrenal adenoma (Conn Syndrome) and adrenal carcinoma

218
Q

Conn Syndrome - what is it?

A

Refers to hyperaldosteronism due to an adrenal aldosteronoma

219
Q

Hyperaldosteronism - what happens to renin? why?

A

Renin decreased. Increased aldosterone increases uptake of salt –> volume increase –> decreased renin secretion from the JGA

220
Q

hyperaldosteronism - treatment

A

First line: mineralocorticoid receptor antagonist (ie spironolactone or eplerenone)

adenomas are surgically resected

221
Q

Secondary hyperaldosteronism - cause?

A

Due to the activation of the renin-angiotensin system (ie renovascular HTN or CHF)

222
Q

Secondary hyperaldosteronism - (2) common diseases associated with this

A

Renovascular HTN

CHF

both activate the renin-angiotensin system

223
Q

How do you distinguish between primary and secondary hyperaldosteronism?

A

Both result in high aldostern.

Primary –> low renin

Secondary –> high renin (the cause of secondary is b/c of the activation of the renin-angiotensin)

224
Q

Why does activation of the renin-angiotensin system cause secondary hyperaldosteronism?

A

Angiotensin II causes the release of aldosterone

225
Q

Familial hyperaldosteronism

A

Can be rarely due to glucocorticoid-remediable aldosteronism (GRA)

  • aberrant expression (AD) of aldosterone synthase in the fasciculata
  • presents in children as HTN, hypokalemia (+/-), high aldosterone, and low renin
  • Responds to dexamethasone – confirmed with genetic testing
226
Q

Liddle syndrome

A
  • Mimics hyperaldosteronism
  • mutation to sodium channels that causes decreased degradation of sodium channels (AD) in collecting tubules
  • Classically presents as HTN, hypokalemia, and metabolic alkalosis in a young patient
  • Low aldosterone and low renin
  • Treatment is potassium-sparing diuretics (ie amiloride or triamterene) which block tubular sodium channels – spironolactone not effective (low aldosterone)
227
Q

Liddle syndrome - cause?

A

mutation to sodium channels that causes decreased degradation of sodium channels (AD) in collecting tubules

228
Q

Liddle syndrome - presentation

A

Classically presents as

  • HTN (increased NA)
  • hypokalemia (increased water –> dilution of salts, potassium secretion stimulated by increased Na+)
  • metabolic alkalosis (stimulated by increased Na+ reabsorption)

Note: the uptake of Na+ creates a lumen-negative electrical gradient​ that is balanced by the increased excretion of H+ and K+)

Classically affects young patients

  • Low aldosterone and low renin
229
Q

Liddle syndrome (what are the aldosterone and renin levels)? Why?

A

Low to normal aldosterone

low renin

Remember this syndrome is due to increased reabsorption of sodium –> HTN –> low renin –> low aldosterone

230
Q

Liddle syndrome - treatment

A

Potassium-sparing diuretics (ie amiloride or triamterene)

Spironolactone and epnerolone will not work due to low aldosterone

231
Q

Cushing syndrome

A

Characterized by excess cortisol (hypercortisolism)

Clinical features

  • muscle weakness w/ thin extremities
  • moon facies, buffalo hump, and truncal obesity
  • abdominal striae
  • hypertension often w/ hypokalemia and metabolic alkalosis
  • Osteoporosis
  • immune suppression
232
Q

Cushing syndrome - clinical features

A
  1. muscle weakness w/ thin extremities
    • cortisol breaks down muscle to produce amino acids for gluconeogenesis
  2. moon facies, buffalo hump, and truncal obesity
    • high cortisol –> high glucose –> high insulin –> increased storage of fat centrally
  3. abdominal striae
    • cortisol impairs collagen synthesis –> thinning of skin –> blood vessels rupture easily –> striae
  4. hypertension often w/ hypokalemia and metabolic alkalosis
    • High cortisol increases sensitivity of peripheral vessels to catecholamines (via upregulation of α1 receptors)
    • at very high levels cortisol cross-reacts w/ mineralocorticoid receptors (aldosterone is not increased)
  5. Osteoporosis
    • cortisol inhibits the function of osteoblasts
  6. immune suppression
    • inhibition of phospholipase A2 – can’t make arachodonic acid and its derivatives
    • inhibition of IL-2 (important T-cell growth factor)
    • inhibition of release of histamine from mast cells (essential for vasodilation and increased vascular permeability)
233
Q

Cushing syndrome - why is there muscle weakness w/ thin extremities?

A

cortisol breaks down muscle to produce amino acids for gluconeogenesis

234
Q

Cushing syndrome - why is there moon facies, buffalo hump and truncal obesity?

A

high cortisol –> high glucose –> high insulin –> increased storage of fat centrally

235
Q

Cushing syndrome - Why is there abdominal striae?

A

cortisol impairs collagen synthesis –> thinning of skin –> blood vessels rupture easily –> striae

236
Q

Cushing syndrome - why is there HTN often w/ hypokalemia and metabolic alkalosis?

A
  • High cortisol increases sensitivity of peripheral vessels to catecholamines (via upregulation of α1 receptors)
  • at very high levels cortisol cross-reacts w/ mineralocorticoid receptors (aldosterone is not increased)
237
Q

Cushing syndrome - why is there osteoporosis?

A

cortisol inhibits the function of osteoblasts

238
Q

Cushing syndrome - why is there immune suppression? Mechanism?

A
  • inhibition of phospholipase A2 – can’t make arachodonic acid and its derivatives
  • inhibition of IL-2 (important T-cell growth factor)
  • inhibition of release of histamine from mast cells (essential for vasodilation and increased vascular permeability)
239
Q

Cushing syndrome - diagnosis?

A

Based on

  • 24-hour urine cortisol level (increased)
  • Late night salivary cortisol level (increased)
  • low dose dexamethasone suppression test
240
Q

Cushing syndrome - how do you distinguish Cushing syndrome from ACTH-independent causes?

A

Plasma ACTH distinguishes ACTH-dependent causes of Cushing syndrome from ACTH-independent causes

  • If ACTH-independent, next step is to CT to look for an adrenal lesion
  • If ACTH-dependent, next step is high-dose dexamethasone test
241
Q

What is the purpose of the dexamethasone test? Why is it used? What is difference between the low-dose and high-dose test?

A

Dexamethasone is a cortisol analog.

  • At low doses: it will suppress cortisol in normal individuals but fails to suppress cortisol in all causes of Cushing syndrome (hence it is used for diagnosis of Cushings)
  • At high doses: it is capable of suppressing ACTH production by a pituitary adenoma (ie will lower serum cortisol) but does not suppress ectopic ACTH production (ie via paraneoplastic syndromes)
242
Q

Steroidogenesis

A
243
Q

Steroidogenesis - What is decreased and what is elevated when there is loss of 21-hydroxylase?

A

Lost ability to produce mineralocorticoids (aldosterone) and glucocorticoids (cortisol)

Increased shunting toward the production of androgens (ie DHEA and androstenedione)

244
Q

Steroidogenesis - What is decreased and what is elevated when there is loss of 11-hydroxylase?

A

This disease is bascially same as 21-hydroxylase deficiency. The only difference is that there is now production of weak mineralocorticoids so there is less salt wasting.

  • Lost ability to produce aldosterone/corticosterone (mineralocorticoids) and cortisol (glucocorticoid)
  • Increased production of 11-deoxycorticosterone (a weak mineralocorticoid)
  • Increased production of androstenedione
    • Increased shunting to the production of androgens
245
Q

Steroidogenesis - What is decreased and what is elevated when there is loss of 17-hydroxylase?

A

Increased mineralocorticoids (aldosterone)

Decreased glucocorticoids (cortisol)

Decreased androgens (DHEA and androstenedione)

246
Q

Most common iatrogenic cause of Cushing syndrome

A

exogenous glucocorticoids

247
Q

Common causes of Cushings Syndrome (4)

A
  1. Exogenous glucocorticoids
  2. ACTH-secreting pituitary adenoma
  3. Ectopic ACTH secretion (paraneoplastic)
  4. primary adrenal adenoma, hyperplasia or carcinoma
248
Q

How do you distinguish different causes of Cushing syndrome?

A

1 is only one to cause bilateral adrenal atrophy

  1. Exogenous glucocorticoids
  2. ACTH-secreting pituitary adenoma
  3. Ectopic ACTH secretion (paraneoplastic)
  4. primary adrenal adenoma, hyperplasia or carcinoma
249
Q

Congential adrenal hyperplasia (CAH)

A

Characterized by enzymatic defects in cortisol production (autosomal recessive)

  • High ACTH (due to decreased negative feedback from lack of cortisol production but depends on the enzyme deficiency) –> results in bilateral adrenal hyperplasia
  • mineralocorticoids and androgens may be increased depending the on the defect

Most common cause: 21-hydroxylase deficiency (90% of cases)

  • aldosterone and cortisol are decreased; steroidogenesis is shunted towards androgens
  • Classic form presents in neonates as
    • hyponatremia (decreased aldosterone –> increased salt wasting)
    • hypovolemia with life-threatening hypotension (due to both increased salt wasting which loses water and the loss of cortisol which causes loss of vascular tone)
    • females have clitoral enlargement (genital ambiguity) due to increased androgens
    • males have precocious puberty
250
Q

Congential adrenal hyperplasia (CAH) - why is there hyperplasia of adrenals?

A

In all forms of CAH, there is a loss of the production of one of the cortisol which causes the loss of negative feedback on the pituitary to stop secreting ACTH.

This loss of negative feedback causes constant release of ACTH which causes the adrenal hyperplasia seen in this disease

251
Q

Congential adrenal hyperplasia (CAH) - most common enzyme deficiency? What is increased and what is lost/decreased?

A

21-hydroxylase deficiency (90% of cases)

hyponatremia (decreased aldosterone –> increased salt wasting)

hypovolemia with life-threatening hypotension (due to both increased salt wasting which loses water and the loss of cortisol which causes loss of vascular tone)

females have clitoral enlargement (genital ambiguity) due to increased androgens

males have precocious puberty

  • Decreased/lost production of aldosterone and cortisol
  • Steroidogenesis is shunted toward androgens (increased)
252
Q

21-hydroxylase deficiency - clinical presentation

A
  • hyponatremia (decreased aldosterone –> increased salt wasting)
  • hypovolemia with life-threatening hypotension (due to both increased salt wasting which loses water and the loss of cortisol which causes loss of vascular tone)
  • females have clitoral enlargement (genital ambiguity) and/or hirsuitism due to increased androgens
  • males have precocious puberty
253
Q

CAH - what are the enzyme deficiencies (3)

A
  • 21-hydroxylase – loss of glucocorticoids and mineralocorticoids
  • 11-hydroxylase – same as 21-hydroxylase deficiency, but there is production of weak mineralocorticoids so no salt wasting
  • 17-hydroxylase – loss of androgens and glucocorticoids
254
Q

11-hydroxylase deficiency

A

Biochemically similar to 21-hydroxylase deficiency, but weak mineralocorticoids (11-deoxycorticosterone) are present (less salt wasting rather causes almost a weak version of hyperaldosteronism)

  • leads to HTN (sodium retention) with mild hypokalemia
  • renin and aldosterone low (low b/c the weak mineralocorticoids act on the aldosterone receptors to ultimately cause decrease in renin and aldosterone)
  • loss of cortisol still present
255
Q

How does cortisol cause HTN? What disease is this associated with?

A
  1. Cortisol increases sensitivity of peripheral vessels to catecholamines via the upregulation of α1 receptors
  2. At high concentrations, cortisol cross-reacts with mineralocorticoid receptors (increased salt uptake –> HTN)

Cushing Syndrome

256
Q

17-hydroxylase deficiency

A

Leads to decreases glucocorticoids and androgens

  • increased mineralocorticoids –> HTN, hypokalemia, metabolic alkalosis
  • decreased cortisol (glucocorticoids) –> HTN, weakness (loss of glucose), N&V, hyperpigmentation
  • decreased androgens –> primary amenorrhea and lack of pubic hair in females or pseudohermaphroditism in males
    • sexual infantism in XX females
    • genital ambiguity in XY males
257
Q

Screening for Congential Adrenal Hyperplasia (CAH)

A

Involves serum 17-hydroxyprogesterone levels

  • increased in 21- and 11- hydroxylase deficiency
  • decreased in 17-hydroxylase deficiency
258
Q

Congenital Adrenal Hyperplasia - treatment

A

Glucocorticoids and:

  • Mineralocorticoids (21-hydroxylase deficiency)
  • sex steroids (17 hydroxylase deficiency)
259
Q

Adrenal insufficiency - most common cause?

A

Most commonly arises secondary to abrupt withdrawal of glucocorticoids

Presents as weakness and hypotension (loss of vascular tone –> shock)

260
Q

Adrenal insufficiency - classic presentation and why?

A

weakness (low glucose)

hypotenson (loss of vascular tone)

Both caused by the acute loss of cortisol

261
Q

Waterhouse-Friderichsen syndrome

A

hemorrhagic necrosis of the adrenal glands

classically due to DIC in young children w/ Neisseria meningitidis infection

262
Q

Waterhouse-Friderichsen syndrome - pathogenesis

A
  • infection causes DIC
  • DIC –> loss of platelet and coagulation factors –> massive bleeding (into adrenals) –> hemorrhagic necrosis –> loss of adrenals
  • Loss of adrenals –> loss of cortisol –> exacerbates the hypotension (that originally resulted from bleeding due to DIC) –> death
263
Q

Addison’s Disease

A

Chronic adrenal insufficiency due to progressive destruction of the adrenal glands

Classically presents with:

  • hypotension (decreased cortisol and decreased aldosterone)
  • hyponatremia (decreased aldosterone)
  • hypovolemia (decreased aldosterone)
  • hyperkalemia (decreased aldosterone)
  • metabolic acidosis (decreased aldosterone – responsible for pushing out H+)
  • weakness
  • hyperpigmentation (low cortisol causes production of ACTH. ACTH is synthesized from POMC. Another derivative of POMC is MSH – melanocyte stimulating hormone – which then causes hyperpigmentation)
  • vomiting and diarrhea (decreased cortisol)
264
Q

Addison’s Disease - most common causes

A
  1. Autoimmune (western world)
  2. TB (developing world)
  3. metastatic carcinoma (lung cancer loves to go the adrenals)
265
Q

Addison’s disease - clinical features

A
  • hypotension (decreased cortisol and decreased aldosterone)
  • hyponatremia (decreased aldosterone)
  • hypovolemia (decreased aldosterone)
  • hyperkalemia (decreased aldosterone)
  • metabolic acidosis (decreased aldosterone – responsible for pushing out H+)
  • weakness
  • hyperpigmentation (low cortisol causes production of ACTH. ACTH is synthesized from POMC. Another derivative of POMC is MSH – melanocyte stimulating hormone – which then causes hyperpigmentation)
  • vomiting and diarrhea (decreased cortisol)
266
Q

Why is hyperpigmentation associated with Addison’s Disease?

A

low cortisol causes production of ACTH. ACTH is synthesized from POMC. Another derivative of POMC is MSH – melanocyte stimulating hormone – which then causes hyperpigmentation

267
Q

How do you distinguish primary from secondary adrenal insufficiency?

A

Hyperpigmentation and hyperkalemia

Primary – loss of adrenal functions –> hyperpigmentation (increased ACTH) and hyperkalemia (due to loss of mineralocorticoids)

In secondary, there is usually low ACTH and mineralocorticoids are still able to be released with minimal cortisol

268
Q

What cells are in the adrenal medulla? What is their function? Where are they derived from?

A

Chromaffin cells

Main physiologic source of catecholamines (epinephrine and NE)

Derived from the neural crest

269
Q

What is a tumor of the adrenal medulla called?

A

Pheochromocytoma

270
Q

Pheochromocytoma - clincial features

A
  • Episodic HTN
  • headache
  • palpitations
  • tachycardia
  • sweating

All based on increased serum catecholamines

271
Q

Pheochromocytoma - diagnosis

A

Increased serum metanephrines and increased 24-hour urine metanephrines and vanillylmandelic acid (VMA)

  • Metanephrine and normetanephrine are breakdown products of E and NE
  • VMA is a breakdown products of metanephrine and normetanephrine
272
Q

What are metanephrines? What is VMA (vanillylmandelic acid)? Where are they from and what are their purpose?

A

Metanephrine and Normetanephrine are breakdown products of epinephrine and norepinephrine

VMA is a further breakdown of the metanephrines via MAO (monoamine oxidase)

These compounds are used for diagnostic purposes to determine if there is ever a pheochromocytoma

273
Q

Pheochromocytoma - treatment

A

Surgical excision

  • Phenoxybenzamine (irreversible α-blocker) is adminstered perioperatively to prevent a hypertensive crisis (may leak out catecholamines when touching/squeezing the tumor
274
Q

What is adminstered before ever surgically removing the adrenals?

A

Phenoxybenzamine (irreversible α-blocker) is adminstered perioperatively to prevent a hypertensive crisis (may leak out catecholamines when touching/squeezing the tumor

275
Q

Pheochromocytoma - rule of 10

A
  • 10% bilateral (90% unilateral)
  • 10% familial (90% sporadic)
  • 10% malignant (90% benign)
  • 10% located outside adrenal (ie bladder wall or organ of Zuckerkandl at the IMA root)
276
Q

Where does pheochromocytoma like to present other than the adrenal? How does it present?

A

Bladder wall

Presents as HTN on urination

277
Q

What diseases are pheochromocytoma’s associated with?

A
  • MEN2A and 2B
  • von Hippel-Lindau disease
  • neurofibromatosis type 1
278
Q

What gene is MEN2A and 2B associated with (when it is familial causes)? What is the treatment? Why?

A

RET mutation

If detected, prophylactic thyroidectomy is done. This is because the most common cause of the death is the medulary carcinoma of the thyroid.

279
Q

Why are peptic ulcers seen in hyperparathyroidism?

A

Hyperparathyroid –> high calcium –> increased levels of gastrin –> increased gastric acid secretion –> increased risk for peptic ulcers

280
Q

Signs & symptoms of congential hypothyroidism

A
  • slugglishness
  • large abdomen with umbilical herniation
  • low anemia
  • refractory anemia

Later on, will get:

  • mental retardation
  • stunted growth
  • characteristic facies
281
Q
A

Unit 5 (5 decks)

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