Pbl Exam 5 Case 2

Front 1

1. The interaction of thyroid hormone w/its nuclear thyroid hormone receptor results in the formation of...?

Back 1

A multi-protein receptor complex that binds to thyroid hormone response elements (TREs) in target genes, regulating their transcription.

Front 2

2. From where does the thyroid gland develop?

Back 2

The thyroid develops from an evagination of the developing pharyngeal epithelium that descends as part of the thyroglossal duct from the foramen cecum at the base of the tongue to its normal position in the anterior neck.

This pattern of descent explains the occasional presence of ectopic thyroid tissue, most commonly located at the base of the tongue or at other sites abnormally high in the neck.

Front 3

3. During puberty, pregnancy and physiologic stress from any source, what happens to the thyroid?

What happens when the stress abates?

Back 3

The gland increases in size and becomes more active.

This functional lability is reflected in transient hyperplasia of the thyroidal epithelium.

At this time, thyroglobulin is resorbed, and the follicular cells become tall and more columnar, sometimes forming small, infolded buds or papillae.

When the stress abates, involution occurs, that is the height of the epithelium falls, colloid accumulates, and the follicular cells resume their normal size and architecture.

Front 4

3. What is hyperthyroidism?

What is primary/secondary hyperthyroidism?

Back 4

Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T₃ and T₄.

Thowever, hyperthyroidism is only one cause of thyrotoxicosis. The terms primary and secondary hyperthyroidism are used to designate hyperthyroidism arising from an intrinsic thyroid abnormality and that arising form processes outside of the thyroid.

Front 5

4. What are the three most common causes of thyrotoxicosis that are also associated w/hyperfunction of the gland?

Back 5

1. Diffuse hyperplasia of the thyroid associated w/Graves disease (85%)
2. Hyperfunctional multinodular goiter
3. Hyperfunctional adenoma of the thyroid

Front 6

5. What is the clinical course of hyperthyroidism?

Back 6

1. Hypermetabolic state as well as overactivity of the sympathetic nervous system
2. Increase in the basal metabolic rate
3. Cardiac manifestations are among the earliest and most common features of hyperthyroidism
4. Ocular changes
5. GI problems
6. Osteoporosis and skeletal problems

Front 7

6. What is thyrotoxic dilated cardiomyopathy?

Back 7

Some patients with thyrotoxicosis develop a reversible diastolic dysfunction and a "low-output" failure, so-so called thyrotoxic dilated cardiomyopathy

Front 8

7. What is thyroid myopathy?

Back 8

Proximal muscle weakness is common w/decreased muscle mass in thyrotoxicosis.

Front 9

8. What is thyroid storm?

Back 9

Thyroid storm is used to designate the abrupt onset of sever hyperthyroidism. This condition occurs most commonly in patients w/underlying Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or any form of stress.

Patients are often febrile and present w/tachycardia out of proportion to the fever.

Thyroid storm is a medical emergence; death can ensue if untreated.

Front 10

9. What is apathetic hyperthyroidism?

Back 10

This refers to thyrotoxicosis occurring in the elderly, in whom old age and various comorbiities may blunt the typical features of thyroid hormone excess seen in younger patients.

The Dx of thyrotoxicosis in these patients if often made during laboratory workup for unexplained weight loss or worsening cardiovascular disease.

Front 11

10. How is the Dx of hyperthyroidism made?

Back 11

The measurement of serum TSH concentration using sensitive TSH (sTSH) assays provides the most useful single screening test for hyperthyroidism. A low TSH value is usually confirmed w/measurement of free T₄, which is expectedly increased.

Determining TSH levels after the injection of TRH (TRH stimulation test) is used in the evaluation of cases of suspected hyperthyroidism with equivocal changes in the baseline serum TSH level. A normal rise in the TSH after administration of TRH excludes secondary hyperthyroidism.

Front 12

11. What is T₃ toxicosis?

Back 12

In an occasional patient, hyperthyroidism results predominantly from increased circulating levels of T₃.

In these cases, free T₄ levels may be decreased, and direct measurement of serum T₃ may be useful.

Front 13

12. How are radioactive iodine uptake measurements useful?

Back 13

They are useful in determining the etiology. For example, there may be diffusely increased uptake in the whole gland (Graves), increased uptake in a solitary nodule (toxic adenoma), or decreased uptake (thyroiditis).

Front 14

13. What is hypothyroidism? What is the most common form?

Back 14

Hypothyroidism is caused by any structural or functional derangement that interferes w/the production of adequate levels of thyroid hormone. It can result from a defect anywhere in the HPA axis.

Primary hypothyroidism accounts for the vast majority of cases of hypothyroidism. It can be thyroprivic (due to absence or loss of thyroid parenchyma) or goitrous (due to enlargement of the thyroid gland under the influence of TSH).

Front 15

14. What are the causes of primary hypothyroidism?

Back 15

1. Developmental (thyroid dysgenesis: PAX-8, TTF-2, TSH-receptor mutations)
2. Thyroid hormone resistance syndrome
3. Post ablative (surgery, radioiodine therapy, or external radiation)
4. Autoimmune hypothyroidism (Hashimoto's)
5. Iodine deficiency
6. Drugs (lithium, iodides)
7. Congenital biosynthetic defect (dyshormonogenetic goiter)

Front 16

15. What is Pendred syndrome?

How is it different from goitrous hypothyroidism?

Back 16

Organification of iodine involves binding of oxidized iodide w/tyrosyl residues in thyroglobulin, and this process is deficient in patients w/Pendred syndrome, wherein goitrous hypothyroidism is accompanied by sensorinoral deafness.

Front 17

16. What causes dyshormonogenetic goiter?

Back 17

Inborn errors of thyroid metabolism are an uncommon cause of goitrous hypothyroidism.

Front 18

17. What is thyroid hormone resistance syndrome?

Back 18

It is a rare autosomal dominant disorder caused by inherited mutations in the thyroid hormone receptor, which abolish the ability of the receptor to bind thyroid hormones.

Patients demonstrate a generalized resistance to thyroid hormone, despite high circulating levels of T₃ and T₄. Since the pituitary is also resistant to feedback from thyroid hormones, TSH levels tend to be high as well.

Front 19

18. What causes thyroid agenesis or thyroid hypoplasia?

Back 19

Mutations in the TSH receptor are a newly recognized cause of congenital hypothyroidism associated w/a hypoplastic thyroid gland.

Recently, mutations in two transcription factors that are expressed in the developing thyroid and regulate follicular differentiation - thyroid transcription factor-2 (TTF-2) and paired homeobox-8 (PAX-8) - have been reported in patients w/thyroid agenesis.

*Thyroid agenesis caused by TTF-2 mutations is usually associated w/a cleft palate.

Front 20

19. What causes secondary and tertiary hypothyroidism?

Back 20

Secondary hypothyroidism is caused by TSH deficiency. Frequently, the cause is a pituitary tumor; other causes include postpartum pituitary necrosis, trauma, and nonpituitary tumors.

Tertiary (central) hypothyroidism is caused by TRH deficiency. Causes include any disorder that damages the hypothalamus or interferes with hypothalamic pituitary portal blood flow, thereby preventing delivery of TRH to the pituitary.

Front 21

20. What is cretinism?

Back 21

Cretinism refers to hypothyroidism that develops in infancy or early childhood.

Clinical features include impaired development of the skeletal system and CNS, manifested by severe mental retardation, short stature, course facial features, a protruding tongue, and umbilical hernia.

The severity fot he mental impairment appears to be related to the time at which thyroid deficiency occurs in utero.

If there is maternal thyroid deficiency before the development of the fetal thyroid gland, mental retardation is severe. However, reduction in maternal hormones later in pregnancy after the fetal thyroid has developed, allows normal brain development.

Front 22

21. What is myxedema?

Back 22

The term myxedema is applied to hypothyroidism in the older child or adult.

Clinical features are characterized by a slowing of physical and mental activity.

HIstologically, there is an accumulation of matrix substances, such as GAGs and hyaluronic acid, in skin, subcutaneous tissues, and a number of visceral sites. This results in edema, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice.

Front 23

22. How is the Dx of hypothyroidism made?

Back 23

Measurements of the serum TSH level is the most sensitive screening test for this disorder.

The TSH level is increased in primary hypothyroidism due to a loss of feedback inhibition of TRH and TSH production by the hypothalamus and pituitary, respectively.

The TSH level is not increased in patients w/hypothyroidism due to primary hypothalamic or pituitary disease.

T₄ levels are decreased in patients w/hypothyroidism of any origin.

Front 24

23. What is thyroiditis?

Back 24

Inflammation of the thyroid gland,. These diseases include conditions that result in acute illness with sever thyroid pain (e.g. infectious thyroiditis, subacute granulomatous thyroiditis) and disorders in which there is relatively little inflammation and the illness is manifested primarily by thyroid dysfunction (subacute lymphocytic thyroiditis and fibrous thyroiditis).

Front 25

24. What is infectious thyroiditis?

Back 25

Can be acute or chronic. Acute infections can reach the thyroid via hematogenous spread or through direct seeding of the gland, such as via a fistula from the piriform sinus adjacent o the larynx.

Other infections of the thyroid, including mycobacterial, fungal, and Pneumocystis infections, are more chronic and frequently occur in immunocompromised patients.

Whatever the cause, the inflammatory involvement may cause sudden onset of neck pain and tenderness in the area of the gland and is accompanied by fever, chills, and other signs of infection.

Thyroid function is usually not significantly affected, and there are few residual effects except for possible small foci of scarring.

Front 26

25. What is Hashimoto's thyroiditis?

Back 26

AKA chronic lymphocytic thyroiditis

This is the msot common cause of hypothyroidism in the areas of the world where iodine levels are sufficient.

This disorder is most prevalent between 45-65 y/o and is more common in women.

Front 27

26. What are the causes of Hashimoto's?

Back 27

There is a significant genetic component.

Several chromosomal abnormalities ahve been associated w/thyroid autoimmunity; those with Turner's syndrome and trisomy 21 have an increased risk for developing Hashimotos.

Also, polymorphisisms in the HLA locus, specifically the HLA-DR3 and HLA-DR5 alleles, are linked to Hashimoto's. Further, areas on chromosomes 6p and 12q may harbor genes predisposing to this disorder.

Front 28

27. What is the pathogenesis of Hashimoto's?

What is the overriding feature?

What is the initiating event?

Back 28

Hashimoto's is an autoimmune disease in which the immune system reacts against a variety of thyroid antigens.

The overriding feature of Hashimotos is progressive depletion of thyroid epithelial cells (thyrocytes), which are gradually replaced by mononuclear cell infiltration and fibrosis.

Sensitization of autoreactive CD4+ T helper cells to thyroid antigens appears to be the initiating event.

Front 29

27. What are the three effector mechanisms in thyrocyte death?

Back 29

1. CD8+ cytotoxic T cell mediated cell death: CD8+ cells may cause destruction by exocytosis of perforin/granzyme granules or engagement of death receptors, specifically CD95 on the target cell.

2. Cytokine-mediated cell death: CD4+ T cells produce inflammatory cytokines such as IFN-gamma in the immediate thyrocyte milieu, with resultant recruitment and activation of macrophages and damage to follicles.

3. Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, and antithyroid peroxidase antibodies), followed by antibody dependent cell mediated cytotoxicity.

Front 30

28. What are the morphological characteristics of Hashimoto thyroiditis?

Back 30

The thyroid is often diffusely enlarged. The capsule is intact, and the gland is well demarcated. The cut surface is pale, yellow-tan, firm, and somewhat nodular.

Microscopic exam reveals extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well developed germinal centers.

The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hürthle cells.

Front 31

29. What is the characteristic appearance of Hashimoto's in fine needle aspiration?

Back 31

The presence of Hürthle cells in conjunction with a heterogeneous population of lymphocytes is characteristic of Hashimoto's.

In "classic" Hashimoto's, interstitial connective tissue is increased and may be abundant.

Front 32

30. What is the fibrous variant of Hashimoto's?

Back 32

The fibrous variant is characterized by sever thyroid follicular atrophy and dense "keloid-like" fibrosis, w/broad bands of aceullar collagen encompassing residual thyroid tissue. Unlike Reidel thyroiditis, the fibrosis does not extend beyond the capsule of the gland. The remnant thyroid parenchyma demonstrates features of chronic lympocytic thyroidits.

Front 33

31. What is the enlargement of the thyroid like in Hashimotos?

Back 33

The enlargement of the gland is usually symmetric and diffuse, but in some cases, it may be sufficiently localized to raise a suspicion of a neoplasm.

Front 34

32. What is hashitoxicosis?

Back 34

Hashimoto's may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, w/secondary release of thyroid hormones.

During this phase, free T₄ and T₃ levels are elevated, TSH is diminished, and radioactive iodine uptake is decreased.

After this phase, as hypothyroidism supervenes, T₄ and T₃ levels progressively fall, accompanied by an increase in TSH.

Front 35

33. What is subacute (granulomatous) thyroiditis?

Back 35

AKA granulomatous thyroiditis or De Quervain thyroiditis, occurs much less freq than Hashimotos.

The disorder is most common between the ages of 30 and 50 and affects women considerably more often than men.

Front 36

34. What is the pathogenesis of subacute (granulomatous) thyroiditis?

Back 36

It is believed to be caused by a viral infection or a postviral inflammatory process. The majority of patients have a history of an URI just before the onset of thyroidits.

Clusters of cases have been reported in association w/coxsackievirus, mumps, measles, adenovirus, and other viral illnesses.

It appears that the viral infection provides an antigen that is released secondary to virus induced host tissue damage. This antigen stimulates cytotoxic T lymphocytes, which then damage thyroid follicular cells.

Front 37

35. What is the morphology of subacute (granulomatous) thyroiditis?

Back 37

The gland may be unilaterally or bilaterally enlarged and firm, with an intact capsule. On cut section, the involved areas are firm and yellow-white and stand out from the more rubbery, normal brown thyroid substance.

Histologically, the changes are patchy and depend on the stage of the disease. Early, scattered follicles may be entirely disrupted and replaced by neutrophils forming microabscesses.

Later, the more characteristic features appear in the form of aggregations of lymphocytes, histiocytes, and plasma cells about collapsed and damaged thyroid follicles. *Multinucleate giant cells enclose naked pools or fragments of colloid.

Front 38

36. What is the clinical course of subacute (granulomatous) thyroiditis?

Back 38

The presentation may be sudden or gradual. It is characterized by pain in the neck which may radiate to the upper neck, jaw, throat, or ears, particularly when swallowing. Fever, fatigue, malaise, anorexia, and myalgia accompany a variable enlargement of the thyroid.

Thyroid inflammation and hyperthyroidism are transient, usually diminishing in 2-6 weeks.

Front 39

37. In transient hyperthyroidism due to subacute (granulomatous) thyroiditis, what are the serum thyroid levels like?

Back 39

Nearly all patients have high serum T₄ and T₃ levels and low serum TSH levels. Radioactive iodine uptake is low b/c of suppression of TSH.

The serum T₄ and T₃ levels are only modestly elevated. After recovery, normal thyroid function returns.

Front 40

38. What is subacute lymphocytic (painless) thyroiditis?

Back 40

Subacute lymphocytic (painless) thyroiditis is an uncommon cause of hyperthyroidism. It usually comes to attention b/c of mild hyperthyroidism, goitrous enlargement of the gland, or both.

It can occur at any age, but it is most often seen in middle aged adults and is more common in women, especially during the postpartum period.

An autoimmune basis has been suggested b/c some patients have elevated levels of antibodies to thyroglobulin and thyroid peroxidase or a family history of thyroid autoimmune disease.

Front 41

39. What is the morphology of subacute lymphocytic (painless) thyroiditis?

Back 41

Except for possible mild symmetric enlargement, the thyroid appears normal on gross inspection.

THe most specific histologic features consist of lymphocytic infiltration w/hyperplastic germinal centers within the thyroid parenchyma and patch disruption and collapse of thyroid follicles.

Front 42

40. What is the clinical course in subacute lymphocytic (painless) thyroiditis?

Back 42

Symptoms usually develop over 1-2 weeks and last from 2-8 weeks before subsiding.

The patient usually has symptoms of hyperthyroidism. Infiltrative ophthalmopathy and other manifestations of Graves disease are not present.

Lab findings during periods of thyrotoxicosis include elevated levels of T₄ and T₃ and depressed levels of TSH.

Front 43

41. What is Riedel thyroiditis?

Back 43

Riedel thyroiditis is a rare disorder of unknown etiology characterized by extensive fibrosis involving the thyroid and contiguous neck structures.

The presence of a hard and fixed thyroid mass clinically simulates a thyroid carcinoma. The presence of circulating antithyroid antibodies in most patients suggests an autoimmune etiology.

Front 44

42. What is palpation thyroiditis?

Back 44

Palpation thyroiditis is caused by vigorous clinical palpation of the thyroid, resulting in multifocal follicular disruption associated w/chronic inflammatory cells and occasional giant cell formation.

Front 45

43. What is Graves disease, and what is the clinical triad associated with it?

Back 45

Graves disease is the most common cause of endogenous hyperthyroidism. It is characterized by a clinical triad:
1. Hyperthyroidism owing to hyperfunction, diffuse enlargement of the gland
2. Infiltrative ophthalmopathy with resultant exopthalmos
3. Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which is present in a minority of patients.

Front 46

44. Prevalence of Graves disease

Back 46

Graves has a peak incidence between ages 20-40, women being affected up to 7x more frequently than men.

The disorder is present in 1.5-2.0% of women in the US.

Front 47

45. Genetic susceptibility to Graves disease

Back 47

Associated w/the presence of certain major histocompatiblity haplotypes, specifically HLA-B8 and -DR3.

Polymorphisms in the cytotoxic T-lymphocytes-associated-4 (CTLA-4) gene are also linked to Graves.

Recall that the HLA proteins are a critical component of antigen presentation to T cells, while CTLA-4 is an inhibitory receptor that prevents T-cell responses to self-antigens.

Front 48

46. Pathogenesis of Graves disease

Back 48

Graves disease is an autoimmune disorder in which a variety of antibodies may be present in the serum, including antibodies to the TSH receptor, thyroid peroxisomes, and thyroglobulin.

*Of these, autoantibodies to the TSH receptor are central to disease pathogenesis.

Front 49

47. What is the important of thyroid stimulating immunoglobulin (TSI) in Graves?

Back 49

Almost all patients with Graves disease have detectable levels of this autoantibody to the TSH receptor.

TSI is relatively specific for graves disease.

Front 50

48. Why do some patients with Graves disease have spontaneously episodes of hypothyroidism?

Back 50

TSH binding inhibitor immunoglobulins (TBII); these anti-TSH receptor antibodies prevent TSH from binding normally to its receptor on thyroid epithelial cells. In doing so, some forms of TBII's mimic the action of TSH, resulting in the stimulation of thyroid epithelial cell activity, whereas other forms may actually inhibit thyroid cell function.

It is not unusual to find the coexistence of stimulating and inhibiting immunoglobulins in the serum of the same patient, thus explaining why spontaneous episodes of hypothyroidism develop.

Front 51

49. What is the importance of anti-TSH receptor antibodies in the pathogenesis of Graves disease?

Back 51

Immunization of mice w/the TSH receptor results in generation of antibodies that cause thyroid stimulation, thyroid enlargement w/lymphocytic infiltration, elevated thyroxine levels, and Graves ophthalmopathy.

Front 52

50. What about T cell mediated autoimmunity and Graves disease?

Back 52

A T-cell mediated autoimmune phenomenal is also important in the development of the infiltrative ophthalmopathy that is characteristic of Graves disease.

In Graves opthalmopathy, the volume of the retro-orbital connective tissues and extraocular muscles is increased owing to several causes.

Front 53

51. What are the four causes of Graves opthalmopathy?

Back 53

1. Marked infiltration fo the retro-orbital space of mononuclear cells, predominantly T cells
2. Inflammatory edema and swelling of extraocular muscles
3. Accumulation of extracellular matrix components such as GAGs, and hyaluronic acid
4. Increased numbers of adipocytes, which displaces the eyeball forward

*Orbital preadipocyte fibroblasts express the TSH receptor and thus become targets of an autoimmune attack.

Front 54

52. What is the morphology of Graves disease?

Back 54

The thyroid gland is usually symmetrically enlarged b/c of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. The gland is usually smooth and soft, and its capsule is intact.

On cut section, the parenchyma has a soft, meaty appearance resembling normal muscle. Histologically the dominant feature is too many cells. This crowding often results in the formation of small papillae, which project into the follicular lumen and encroach on the colloid, sometimes filling the follicles. Such papillae lack fibrovascular cores.

The colloid within the follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting predominantly of T cells, with fewer B cells and mature plasma cells, are present throughout the interstitium; germinal centers are common.

Front 55

53. Why is is impossible to perform histologic exam of surgical specifics in pre-treated patients?

Back 55

Preoperative therapy alters the morphology of the thyroid in Graves.

Preoperative admin of iodine causes involution of the epithelium and the accumulation of colloid by blocking thyroglobulin secretion.

Treatment w/the antithyroid drugs propylthiouracil exaggerates the epithelial hypertrophy and hyperplasia by stimulating TSH secretion.

Front 56

54. What is the clinical course in Graves disease?

Back 56

The clinical findings include changes referable to thyrotoxicosis as well as those associated uniquely w/Graves disease: diffuse hyperplasia of the thyroid, opthalmopathy, and dermopathy.

The thyroid enlargement is present in all cases and may be accompanied by increased blood flow through the hyperactive gland, producing an audible bruit.

Lab findings include elevated free T₄ and T₃ levels and depressed TSH levels. B/c of ongoing stimulation of the thyroid follicles by thyroid stimulating immunoglobulins, radioactive iodine uptake is increased, and radioiodine scans show a diffuse uptake of iodine.

Front 57

55. Diffuse and multinodular goiters

Back 57

Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease.

Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency.

The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency.

Front 58

56. Diffuse nontoxic (simple) goiter

Back 58

Refers to a form of goiter that diffusely involves the entire gland without producing nodularity. B/c the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition. It occurs in both an endemic and a sporadic distribution.

Front 59

56. What are the two phases of diffuse nontoxic goiters?

Back 59

1. Hyperplastic phase
2. Colloid involution phase

Front 60

57. Morphology of diffuse nontoxic goiters

Back 60

In the hyperplastic phase, the thyroid is diffusely and symmetrically enlarged. The follicles are lined by crowded columnar cells, which may pile up and form projections similar to those seen in Graves disease.

If dietary iodine subsequently increases or if the demand for thyroid hormone decreases, the stimulated follicular epithelium involutes to form an enlarged colloid rich gland.

In these cases, the cut surface of the thyroid is usually brown, somewhat glassy, and translucent.

Histologically, the follicular epithelium is flattened and cuboidal, and colloid is abundant during periods of involution.

Front 61

58. What is multinodular goiter?

Back 61

Multinodular goiters produce the most extreme thyroid enlargements are are more frequently mistaken for neoplastic involvement that any other form of thyroid disease.

They occur in both sporadic and endemic forms having the same male to female distribution but affecting older individuals b/c they are late complications.

Front 62

59. How do multinodular goiters form?

Back 62

It is believed that arise b/c of variations among follicular cells in responses to external stimuli, such as trophic hormones.

Mutations in proteins of the TSH-signaling pathway that lead to constitutive activation of this pathways have been identified in a subset of autonomous thyroid nodules.

Front 63

60. What is the morphology of multinodular goiters?

Back 63

Multinodular goiters are multilobulated, asymmetrically enlarged glands that can achieve a weight of more than 2 kg.
The pattern of enlargement may involve one lobe more than the other, producing lateral pressure on midline structures.

On cut section, irregular nodules containing variable amounts of brown, gelatinous colloid are present. Regressive changes occur frequently, particularly in older lesions and include areas of hemorrhage, fibrosis, calcification, and cystic change.

The microscopic appearance includes colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular epithelial hypertrophy and hyperplasia, accompanied by degenerative changes.

Front 64

61. What is the clinical course of multinodular goiters?

What is Plummer syndrome?

Back 64

The dominant clinical features of goiter are those caused by the mass effects of the enlarged gland.

Most patients are euthryoid, but in a substantial minority of patients, a hyperfunctioning nodule may develop within a long-standing goiter, resulting in hyperthyroidism (toxic multinodular goiter). This condition, known as Plummer syndrome, is not accompanied by the infiltrative opthalmopathy and dermopathy of Graves disease.

Radioiodine uptake in uneven; hyperfunctioning nodules may appear hot by concentrating radioiodine.

Front 65

62. What are five clinical criteria that may provide clues to the nature of a given thyroid nodule?

Back 65

1. Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules
2. Nodules in younger patients are more likely to be neoplastic than are those in older patients
3. Nodules in males are more likely to be neoplastic than are those in females
4. A history of radiation treatment to the head and neck region is associated w/an increased incidence of thyroid malignancy
5. Nodules that take up radioactive iodine in imaging studies (hot nodules) are more likely to be benign than malignant.

Front 66

63. Pathogenesis of thyroid adenomas

Back 66

The TSH receptor signaling pathway paths an important role int eh pathogenesis of toxic adenomas. Activating "gain of function" somatic mutations in one of the two components of this signaling system, most often the TSH receptor itself or the alpha subunit of Gs- cause chronic overproduction of cAMP, generating cells that acquire a growth advantage.

Overall, mutations leading to constitutive activation of the cAMP pathway appear to be the cause of a proportion (10-75%) of autonomously functioning thyroid adenomas.

Front 67

64. Morphology of follicular thyroid adenoma #1

Back 67

The morphology of typical thyroid adenoma is a solitary, spherical, encapsulated lesion that is well demarcated from the surrounding thyroid parenchyma.

The color ranges from gray-which to red-brown, depending on the cellularity of the adenoma and it scolloid content. The neoplastic cells are demarcted from teh adjacent parenchym by a well-defined, intake capsule.

*These features are important in making the distinction from multinodular goiters.

Front 68

65. How are multinodular goiters similar/different to follicular thyroid adenomas?

Back 68

Areas of hemorrhage, fibrosis, calcification, and cystic change, similar to those encountered in multinodular goiters, are common in follicular adenomas, particularly with larger lesions.

However, multinodular goiters produce less compression of the adjacent thyroid parenchyma, and lack a well formed capsule.

*Also, the follicular growth pattern within the adenoma is usually quite distinct from the adjacent non-neoplastic thyroid.

Front 69

66. Morphology of follicular thyroid adenoma #2

Back 69

Microscopically, the constituent cells often form uniform-appearing follicles that contain colloid. Follicular growth pattern is observed.

The epithelial cells composing the follicular adenoma reveal little variation in cell and nuclear morphology. Mitotic figures are rare.

Occasionally, the neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change); the clinical presentation and behavior of a follicular adenoma with oxyphilia (Hürthle cell adenoma) is no different from that of a conventional adenoma.

Front 70

67. Variants of follicular adenomas

Back 70

Other variants have extensive clear cell change of the cytoplasm (clear cell follicular adenoma) and adenomas w/"signet-ring" features (signet-ring cell follicular adenomas).

Similar to endocrine tumors at other sites, even benign follicular adenomas may exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli (endocrine atypia).

Front 71

68. Atypical follicular adenomas (morphology)

Back 71

Infrequently, adenomas can demonstrate increase cellularity, more extensive variation in cellular size and nuclear morphology and even mitotic activity.

These adenomas have been called atypical follicular adenomas and warrant careful exam of the tumor capsule to exclude capsular and/or vascular invasion.

Front 72

69. What is the hallmark of all follicular adenomas?

Back 72

The presence of an intact, well-formed capsule encircling the tumor. Careful evaluation of the integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular carcinomas, which demonstrate capsular and/or vascular invasion.

Front 73

70. Clinical features of follicular adenomas?

Back 73

Most adenomas take up less radioactive iodine than does normal thyroid parenchyma. On radionuclide scanning, therefore, adenomas usually appear as cold nodules relative to the adjacent thyroid tissues.

Thyroid adenomas, including atypical adenomas, have an excellent prognosis and do not recur or metastasize.

Front 74

71. What are the genetic alterations involved in follicular adenomas?

Back 74

About 20% of follicular adenomas have point mutations in the RAS family of oncogenes, which have also been identified in 30-40% of follicular carcinomas.

This finding raises the possibility that some adenomas may progress to carcinomas.

Front 75

72. Other benign tumors of the thyroid

Back 75

These may prove to be cysts. A great amount of these lesions represent cystic degeneration of a follicular adenoma; the remainder probably arise in multinodular goiters.

They are often filled with a brown, turbid fluid containing blood, hemosiderin pigment, and cell debris.

Front 76

73. What are the major subtypes of thyroid carcinomas, and which is the most common?

Back 76

1. Papillary carcinoma (75-85%)
2. Follicular carcinoma (10-20%)
3. Medullary carcinoma (5%)
4. Anaplastic carcinoma (<5%)

Front 77

74. Genetic factors in follicular thyroid carcinomas

Back 77

Approximately half of follicular thyroid carcinomas harbor mutations in the RAS family of oncogenes (HRAS, NRAS, and KRAS), with NRAS mutations being the most common.

PAX8-PPARγ1 fusion is present in approximately 1/3 of follicular thyroid carcinomas.

Front 78

75. Genetic factors in papillary thyroid carcinomas

Back 78

One pathway involves rearrangements of the tyrosine kinase receptors RET or NTRK1, and another involves activating mutations in the BRAF oncogene.
A third pathway involves RAS mutations.

In papillary thyroid cancers, either a paracentric inversion of chromosome 10 or a reciprocal translocation between chromosomes 10 and 17 places the tyrosine kinase domain of RET under the trasncriptional control of constitutively active genes on these two chromosomes.

The novel fusion genes that are so formed are known as ret/PTC and are present in approx 1/5 of papillary thyroid cancers.

Front 79

76. Genetic factors in medullary thyroid carcinomas

Back 79

Medullary carcinomas arise from the parafollicular C cells in the thyroid.

Familial medullary thyroid carcinomas occur in MEN-2 and as associated w/germ line RET protooncogene mutations that affect residues in the cysteine rich extracellular or the intracellular tyrosine kinase domains, leading to constitutive activation of the receptor.

RET mutations are detectable in approx 95% of families w/MEN-2.

Front 80

77. Genetic factors in anaplastic carcinomas

Back 80

Inactivating point mutations in the p53 tumor suppressor gene are rare in well-differentiated carcinomas but common in anaplastic tumors.

Front 81

78. What are papillary carcinomas?

Back 81

Papillary carcinomas are the most common form of thyroid cancer. They occur at any age but most often in the 20-40 y/o's, and account for the majority of thyroid carcinomas associated w/previous exposure to ionizing radiation.

Front 82

79. What is the morphology of papillary carcinomas?

Back 82

May be solitary or multifocal lesions. Some tumors may be well-circumscribed and even encapsulated, others may infiltrate the adjacent parenchyma with ill-defined margins.

The lesions may contain areas of fibrosis and calcification and are often cystic. On the cut surface, they may appear granular and may sometimes contain grossly discernible papillary foci.

Front 83

80. What are the four characteristic hallmarks of papillary neoplasms?

Back 83

1. Contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells. In contrast to hyperplastic papillary lesions, the neoplastic papillae are more complex and have dense fibrovascular cores.
2. The nuclei cells contain finely dispersed chromatin, which imparts an optically clear or empty appearance, giving rise to the designation ground glass or Orphan Annie eye nuclei.
3. Concentrically calcified structures termed psammoma bodies are often present within the lesion, usually w/in the cores of papillae.
4. Foci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon.

Front 84

81. Encapsulated variant of papillary carcinomas

Back 84

The encapsulated variant constitutes about 10% of all papillary neoplasms.

It is usually confined to the thyroid, is well encapsulated, and rarely presents with vascular or lymph node dissemination and so it can easily be confused with a benign adenoma. Prognosis is excellent

Front 85

82. Follicular variant of papillary carcinomas

Back 85

The follicular variant has the characterstic nuclei of papillary carcinoma but has an almost totally follicular architecture.

Grossly, the tumor may be encapsulated, and focally, psammoma bodies may be seen.

Front 86

83. Tall cell variant of papillary carcinomas

Back 86

The tall cell variant is marked by tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures.

Typically, the cells are at least twice as tall as they are wide.

These tumors tend to occur in older individuals and are usually large with prominent vascular invasion, extrathyroidal extension, and cervical and distant metastases.

More than half the tall cell variants harbor a ret/PTC translocation that confers greater mitogenic potential than the ret/PTC observed in usual papillary thyroid cancers.

Front 87

84. Diffuse sclerosing variant of papillary carcinomas

Back 87

These tumors occur in younger individuals, including children. They do not present with a mass, but rather with a bilateral goiter.

There is a characteristic "gritty" sensation to the cut surface of the lesion due to the presence of abundant psammoma bodies.

The tumor demonstrates a prominent papillary growth pattern, intermixed with solid areas containing nests of squamous cells (squamous morules) The neoplastic cells exhibit classic nuclear features of a papillary neoplasm.

There is extensive, diffuse fibrosis throughout the thyroid gland, often associated w/a prominent lymphocytic infiltrate.

Nodal metastases are present in almost all cases.

Front 88

85. Hyalinizing trabecular tumors

Back 88

These tumors have been reconsidered as a variant of papillary carcinomas based on the presence of ret/PTC gene rearrangements in 30-60% of these tumors.

They are characterized by an "organoid" growth pattern, with nests and trabeculae of elongated tumor cells within a fibrovascular stroma.

Both intracellular and extracellular hyalinization are prominent and confer a pink hue on the tumor on low power exam.

The nuclear features resemble those seen in classic papillary carcinomas and psammoma bodies may be present.

These tumors are well encapsulated.

Front 89

86. What are follicular carcinomas?

Back 89

Follicular carcinomas are the second most common form of thyroid cancer. They tend to present in women and at an older age than do papillary carcinomas with a peak incidence in the forties and fifties.

The high frequency of RAS mutations in follicular adenomas and carcinomas suggests that the two may be related.

Front 90

87. Morphology of follicular carcinoma

Back 90

They are single nodules that may be well circumscribed or widely infiltrative.

They are gray to tan to pink on the cut section, and on occasion, are somewhat translucent when large, colloid-filled follicles are present. Degenerative changes, such as central fibrosis and foci of calcification are sometimes present.

Microscopically, most are composed of fairly uniform cells forming small follicles containing colloid.

*The nuclei lack the features typical of papillary carcinoma and psammoma bodies are absent.

Front 91

88. Minimally invasive follicular carcinomas vs. widely invasive follicular carcinomas

Back 91

In contrast to minimally invasive follicular cancer, extensive invasion of adjacent thyroid parenchyma or extrathyroidial tissue makes the Dx of carcinomas obvious in widely invasive follicular carcinomas.

Histologically, these cancers tend to have a greater proportion of solid or trabecular growth pattern, less evidence of follicular differentiation, and increased mitotic activity.

Front 92

89. What is medullary carcinoma?

Back 92

Medullary carcinomas of the thyroid are neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid.

These cells of the tumor secrete calcitonin, or other polypeptide hormones, such as somatostatin, serotonin, and VIP.

The tumors arise sporadically in about 80% of cases. The remainder occurs in the setting of MEN syndrome 2A or 2B or as familial tumors (familial medullary thyroid carcinoma).

Front 93

90. What is the morphology of medullary carcinoma?

Back 93

Can arise as a solitary nodule or may be present as multiple lesions involving both lobes of the thyroid.

The sporadic neoplasms tend to originate in one lobe. In contrast, bilaterality and multicentricity are common in familiarl cases. Larger lesions often contain areas of necrosis and hemorrhage and may extend through the capsule of the thyroid.

The tumor tissue is firm, pale gray to tan, and infiltrative. There may be foci of hemorrhage and necrosis in the larger lesions.

Microscopically, they are composed of polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles.

Acellular amyloid deposits, derived form calcitonin molecules are present in the adjacent stroma in many cases. Calcitonin is readily demonstrable within the cytoplasm of the tumor cells as well as in the stromal amyloid by immunohistochemical methods.

Electron microscopy reveals variable numbers of membrane-bound electron dense granules within the cytoplasm of the neoplastic cells.

Front 94

91. How can one tell the difference between familial medullary carcinomas and sporadic ones?

Back 94

One of the peculiar features of familial medullary cancers is the present of multicentric C-cell hyperplasia in the surrounding thyroid parenchyma, a feature that is usually absent in sporadic lesions.

Also, sporadic medullary carcinomas are lesions of adulthood, with a peak incidence in the 40's and 50's.

Front 95

92. Morphology of anaplastic carcinomas

Back 95

Microscopically, these neoplasms are composed of highly anaplastic cells, which may take one of several histologic patterns:
1. Large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells
2. Spindle cells w/a sarcomatous appearance
3. Mixed spindle and giant cells
4. Small cells resembling those seen in small cell carcinomas arising at other sites

Foci of papillary or follicular differentiation may be present in some tumors, suggesting origin from a better differentiated carcinoma.

Prognosis = bad

Front 96

93. Congenital anomalies involving the thyroid

Back 96

Thyroglossal duct or cyst is the most common clinically significant congenital anomaly of the thyroid.

Segments of the duct and cysts that occur high in the neck are lined by stratified squamous epithelium, which is essentially identical with that covering the posterior portion of the tongue in the region of the foramen cecum.

The anomalies that occur in the lower neck more proximal to the thyroid gland are lined by epithelium resembling the thyroidal acinar epithelium.

Characteristically, subjacent to the lining epithelium, there is an intense lymphocytic infiltrate. Superimposed infection may convert these lesions into abscess cavities, and rarely, they give rise to cancers.

Front 97

94. What are the earliest clinical manifestations of pituitary tumors?

Back 97

Usually the characteristic signs and symptoms caused by the hormone hypersecretion.

Subsequently, if the tumor is large, local manifestations of tumor enlargement may develop. Pressure on surrounding structures can cause signs and symptoms of large pituitary adenomas. Headache is a freq symptom.

If the tumor extends into the suprasellar space, the optic chiasm may be compressed which results in bi-temporal hemianopia.

Front 98

95. Destructive pituitary lesions result in hormone loss, and follows what particular pattern?

Back 98

Initially GH secretion is reduced, followed by LH and FSH, then TSH, and lastly ACTH.

Front 99

96. How is the presence of a pituitary tumor confirmed?

Back 99

Via pituitary MRI. The contrast agent gadolinium is used to help differentiate small pituitary lesions from normal anterior pituitary tissue.

Front 100

97. What is the most common cause of an enlarged sella?

Back 100

A primary congenital defect or herniation of the arachnoid membrane through an incompetent diaphragma sellae, either after pituitary surgery or radiation, can cause empty sella syndrome, the most common cause of an enlarged sella.

Front 101

98. Where does GH bind?

Back 101

GH binds to receptors in the liver and induces secretion of IGF-1, which circulates in the blood bound to binding proteins, the most important of which is IGF-BP3.

Front 102

99. What is the gold standard for assessing GH reserve?

Back 102

Insulin induced hypoglycemia (ITT) is the gold standard.

Insulin is administered via IV to reduce the patients blood glucose levels to 50% of initial blood glucose or to 40 mg/dL.

Hypoglycemia is a potent stimulus for GH secretion, and a normal response is a peak GH level in excess of 5 ng/mL at 60 minutes.

Front 103

100. What other test is as sensitive and specific as insulin induced hypoglycemia in stimulating GH secretion in adulthood?

Back 103

Combined infusion of GHRH and arginine.

Front 104

101. What other tests evaluate GH reserve?

Back 104

Oral propranolol and L-dopa, a precursor of dopamine and norepinephrine, also stimulate GH secretion from the pituitary somatotroph and are used to evaluate childhood GH deficiency, but they lack sensitivity in adult GH deficiency.

Front 105

102. What hormone levels can be used as a screening test for GH deficiency?

Back 105

IGF-1 levels can be used as a screening test for GH deficiency b/c GH regulates IGF-1 levels.

GH deficiency is associated w/low IGF-1. Low IGF-1 levels indicate the need to perform provocative testing of GH secretion.

Front 106

103. Which is more valuable, dynamic or single random GH levels in determining GH levels?

What other serum indicator does not fluctuate throughout the day?

Back 106

GH is secreted in a pulsatile manner, and thus dynamic GH testing is more valuable than the measurement of a single, random GH level.

However, measurement of serum IGF-1 is a useful indicator of GH hypersecretion b/c this level does not fluctuate through the day. (IGF-1 levels are elevated in almost all patients w/GH hypersecretion.

Front 107

104. What is a simple and specific dynamic test for GH hypersecretion?

Back 107

The administration of oral glucose, in which 100 g of glucose administered orally suppresses GH levels to less than 1 ng/mL after 2 hours in healthy individuals.

In patients w/acromegaly, GH levels may increase, remain unchanged, or decrease after an oral glucose load.

If no pituitary mass is detected than an extrapituitary source of ectopic GH or GHRH should be sough through imaging studies of the chest and abdomen.

Front 108

105. Adult growth hormone deficiency

Back 108

Adult GH deficiency is exhibitied as increased abdominal adiposity, reduced muscle strength and exercise capacity, decreased lean body mass and increased fat mass, reduced bone mineral density, glucose intolerance and insulin resistance, abnormal lipid profile, and impaired psychosocial well being.

Front 109

106. What is the treatment for adult GH deficiency?

Back 109

GH is administered in adulthood as a subcutaneous daily injection.

GH replacement therapy in adults decreases fat mass, increases lean body mass and BMD, and is associated w/improved cardiovascular risk factors.

Front 110

107. Acromegaly and tumor sizes

Where can ectopic GH/GHRH secretion occur?

Back 110

Approximately 70% of patients w/acromegaly have tumors larger than 1 cm.

Ectopic GHRH secretion can occur with pancreatic islet cell tumors and bronchial or intestinal carcinoids.

Ectopic GH secretion occurs very rarely with pancreas, breast and lung tumors.

Front 111

108. Prognosis or treatment with acromegaly

Back 111

Cure rates are proportional to preoperative tumor size w/a 90% success rate for patients w/microadenomas.

LFT's and pituitary adenoma size must be monitored on a long term basis.

Front 112

109. What is the function of different hormones on prolactin secretion?

Back 112

TRH and VIP are PRL releasing factors.

Estrogens increase basal and stimulated PRL secretion.

Glucocorticoids and TSH blunt TRH-induced PRL secretion.

PRL levels increase during pregnancy.

Front 113

110. What causes increased PRL secretion?

How does one confirm the Dx of a prolactinoma?

Back 113

Several physiologic conditions as well as certain medications and pathologic states (hypothyroidism, chronic renal failure, chest wall lesions), increase PRL secretion.

These conditions may be associated w/mildly elevated PRL levels; however, basal PRL levels in excess of 200 ng/mL usually imply prolactinoma.

MRI will confirm Dx.

Front 114

111. What is the treatment for prolactinomas?

Back 114

Medical management w/a dopamine agonist (e.g. bromocriptine, cabergoline) restores gonadal function and fertility in the majority of patients.

Dopamine agonists cause tumor shrinkage in a significant number of patients w/macroadenomas.

Trans-sphenoidal surgery is indicated in patients who are intolerant or resistant to medical treatment.

Front 115

112. How is TSH secretion evaluated?

High TSH vs. low TSH levels mean what?

Back 115

TSH is measured by ultrasensitive assays (immunoradiometric assay), which can accurately distinguish low, normal, and high TSH levels.

In a patient w/hypothyroidism, a suppressed TSH level indicates central (secondary) hypothyroidism and an elevated level indicates primary hypothyroidism.

Front 116

113. How does one differentiate between secondary hypothyroidism as a result of HPA dysfunction from primary hypothyroidism?

Back 116

The present of low-circulating TSH levels in the presence of low thyroid hormone levels differentiates secondary hypothyroidism as a result of hypothalamic-pituitary dysfunction from primary hypothyroidism.

Front 117

114. What is the treatment for TSH deficiency?

How does one assess the adequacy of thyroid replacement?

Back 117

Patients w/central hypothyroidism are treated w/thyroxine in doses of 75 to 150 mcg/day.

Measuring the serum FT4 level, which should be in the mid to normal range, assesses the adequacy of thyroid replacement.

TSH levels are low-to-normal in central hypopituitarism; thus TSH levels cannot be used to monitor thyroid hormone replacement dosage in secondary hypothyroidism.

Front 118

115. Thryotropin-secreting pituitary tumors

Back 118

Thyrotropin-secreting pituitary tumors are are, exhibiting hyperthyroidism, goiter, and inappropriately elevated serum thyroid hormone levels.

TSH-secreting tumors are usually plurihormonal, secreting GH PRL, and the glycoprotein hormone alpha subunit, as well as TSH.

These tumors are often resistant to removal, which necessitates several surgical procedures or radiotherapy.

Octreotide can be useful to shrink tumor size and decrease TSH secretion. Iodine-131 thyroid ablation or thyroid surgery may be needed to control thyrotoxicosis.

Front 119

116. ACTH secretion

Back 119

ACTH stimulates cortisol synthesis and secretion from the adrenal gland.

Cortisol exerts a negative feedback on ACTH and CRH secretion.

ACTH is secreted in pulses and is under circadian control, reaching max levels in the last hours before awakening, followed by a steady decline to a nadir in the evening.

Front 120

117. How does one evaluate basal ACTH levels?

Back 120

Random basal ACTH measurements are unreliable b/c of the short palsma half-life and pulsatile secretion of the hormone.

B/c ACTH regulates cortisol secretion, plasma cortisol levels better reflect HPA function.

Front 121

118. How does one differentiate primary from secondary adrenal insufficiency?

Back 121

ACTH levels can be used to differentiate primary from secondary adrenal insufficiency.

Plasma ACTH levels are normal to high in adrenal insufficiency b/c of a primary adrenal disorder and are low to absent in adrenal insufficiency secondary to hypothalamic-pituitary hypofunction.

Front 122

119. How does one evaluate ACTH reserve?

Back 122

Provocative testing is performed. The insulin induced hypoglycemia test is the most reliable test of the ACTH secretory response to stress.

The test is contraindicated in older patients and in patients with cerebrovascular disorders, seizure disorders, or cardiovascular disease.

Front 123

120. What is another test used to evaluate ACTH reserve?

Back 123

Metyrapone (30 mg/kg orally at midnight) inhibits the 11-beta hydroxylase enzyme in the adrenal gland, which converts 11-deoxycortisol to cortisol.

Low cortisol stimulates CRH and ACTH. An 11-deoxycortisol level greater than 7 mg/dL, with a simultaneous serum cortisol less than 5 mcg/dL, the morning after metyrapone administration, indicates an adequate response.

Front 124

121. What is the purpose of cortrosyn?

Back 124

Prolonged ACTH deficiency results in adrenal atrophy, and thus ACTH status can be assessed indirectly by measuring adrenal cortisol reserve. Cortrosyn correlates well w/the ITT test.

Approx 250 mcg cosyntropin administered via IV results in a peak cortisol level of more than 20 mcg/dL within 60 minutes in normal individuals.

An inadequate response implies either impaired pituitary ACTH secretion or primary adrenal failure.

Numerous studies suggest than low-dose (1 mcg) ACTH stimulation provides a more sensitive test than the 250 mcg does.

Front 125

122. How does one assess ACTH hypersecretion?

Back 125

Initially a Dx of hypercortisolemia must first be confirmed by measuring 24 hour urinary free cortisol levels, midnight plasma cortisol levels, or lack of suppression of an 8am serum cortisol after 1 mg of dexamethasone administered at 11pm on the night before.

After confirming Cushing's syndrome and hypercortisolemia, plasma ACTH levels are measured to differentiate between ACTH dependent Cushing's syndrome (pituitary or ectopic ACTH secretion) and ACTH independent Cushing's syndrome (adrenal adenoma or hyperplasia).

Front 126

123. What is ACTH deficiency?

Back 126

ACTH deficiency results in adrenal failure, causing lethargy, weakness, nausea, vomiting, dehydration, orthostatic hypotension, coma, and, if untreated, death.

Front 127

124. What is the treatment for ACTH deficiency?

Back 127

Patients w/adrenal insufficiency should be treated w/hydrocortisone, 15 to 25 mg/day in two divided doses or equivalent.

The dose should be increased 5-10x in times of stress. Stress doses of hydrocortisone should be administered if the patient undergoes surgery with rapid tapering of the dose postoperatively.

Mineralocorticoid replacement is not required w/central adrenal insufficiency b/c the renin-aldosterone system is intact.

Front 128

125. ACTH-secreting pituitary tumors

Back 128

ACTH-secreting pituitary tumors result in hypercortisolemia associated w/obesity, moon facies, cervicodorsal dysplasia, striae, thinning of the skin, hirsutism, hypertension, menstrual irregularities, glucose intolerance, mood changes, proximal myopathy, and osteopenia.

Front 129

126. What is the treatment for ACTH-secreting pituitary tumors?

Back 129

Treatment modalities include trans-sphenoidal resection, radiation therapy, and medical therapy.

Drugs that block steroid synthesis include ketoconazole, metyrapone and aminoglutethimide, RU-476, and trilostane.

Treatment of ectopic ACTH syndrome is designed to remove the ectopic tumor if possible.

Front 130

127. What does LH do?

Back 130

LH stimulates sex steroid secretion.

It stimulates gonadal steroid secretion by testicular Leydig cells and by the ovarian follicles.

In women, the ovulatory LH surge results in rupture of the follicle and then luteinization.

Front 131

128. What does FSH do?

Back 131

FSH stimulates gametogenesis.

FSH stimulates Sertoli cell spermatogenesis in men and follicular development in women.

Front 132

129. How does one evaluate the hypothalamic pituitary gonadal axis?

Back 132

LH and RSH levels in men are measured by three pooled samples drawn 20 min apart, which compensates for the normal pulsatile secretion.

Gonadotropin and sex steroid estimation in women are more complex. In women with amenorrhea, measurement of serum LH, FSH, estradiol, PRL, and hCG can differentiate among (1) primary ovarian failure, with elevated FSH and LGH levels and normal PRL levels; (2) hyperprolactinemia, with elevated PRL and normal to low follicular phase LH, FSH, and estradiol levels; and (3) pregnancy, with a positive hCG, normal to high PRL, normal LH and high estradiol.

Front 133

130. How does one measure gonadotropin deficiency?

Back 133

Best diagnosed by concurrent measurement of serum gonadotropins and gonadal steroid concentrations.

Low or normal GSH and LH levels in the presence of a low testosterone level (in men) or a low estrodiol level (in women) confirm the Dx of gonadotropin deficiency.

Low levels of gonadal steroids in the presence of elevated gonadotropin levels suggest primary gonadal failure.

Front 134

131. What is the treatment for gonadotropin deficiency?

Back 134

Androgen replacement therapy is recommended in men w/central hypogonadism. Testosterone can be administered.

Premenopausal women w/central hypogonadism should receive estrogen replacement therapy, and, if they have a uterus, they should receive progesterone either continuously or cyclically to protect the uterine lining.

Estrogen-progesterone replacement therapy recommendations for postmenopausal hypopituitary women are the same as for postmenopausal women w/o hypopituitarism.

Front 135

132. Gonadotropin secreting pituitary tumors

Back 135

Gonadotropin secreting pituitary tumors are rare and have been reported mainly in men.

The majority of tumors are large at the time of presentation and hypersecrete only FSH.

Patients usually have signs and symptoms of local pressure, such as visual impairment. Patients may also exhibit hypogonadism w/low or normal testosterone levels or low or normal sperm counts.

This results from inhibitory effects of chronically high levels or gonadotropins (LH and FSH) on the testicles.

Front 136

133. What is the most frequent cause of hypothalamic dysfunction in children and young adults?

In adulthood?

Back 136

Craniopharyngiomas in the young.

Primary CNS tumors, pinealomas, and dermoid and epidermoid tumors also cause hypothalamic dysfunction in adulthood.

Front 137

134. What are the results of hypothalamic disturbances?

Back 137

Include disorders of thirst (polydipsia, polyuria, dehydration), appetite (e.g. hyperphagia, obesity), temp regulation, and consciousness (e.g. somnolence, emotional lability).

Diabetes insipidus is a common manifestation of hypothalamic lesions but rarely occurs w/primary pituitary lesions.

An MRI can confirm the diagnosis. B/c hypopituitarism occurs freq with hypothalamic lesions, anterior pituitary function should be assessed.

Front 138

135. What causes hypopituitarism?

Back 138

Results either from anterior pituitary gland destruction or dysfunction secondary to deficient hypothalamic stimulatory-inhibitor factors that normally regulate pituitary function.

Congenital or acquired lesions can also cause hypopituitarism.

Front 139

136. What is the treatment for hypopituitarism?

Back 139

Patients must have adequate replacement of thyroxine, glucocorticoids, and appropriate sex steroids.

In patients w/combined TSH and ACTH deficiency, glucocorticoids should be replaced before thyroxine b/c thyroxine may aggravate adrenal insufficiency and may precipitate acute adrenal failure.

Front 140

137. How can one distinguish patients w/diabetes insipidus?

Back 140

On distinguishing feature is that patients w/diabetes insipidus prefer cold beverages.

Front 141

138. How can one tell the differences between central or nephrogenic diabetes?

Back 141

The primary test used to differentiate the causes of polyuria is the water deprivation test.

A normal response is a decrease in urine output as well as an increase in urine concentration to greater than that of plasma.

Patients w/diabetes insipidus (either central or nephrogenic) maintain a high urine output, which continues to be dilute despite water deprivation. Water deprivation is continued until the urine osmolarity plateaus. At that point, vasopressin is administered and the urine osmolarity is measured after 1 hour.

In patients w/complete central diabetes insipidus, urine osmolarity increases above plasma osmolarity, whereas in nephrogenic diabetes insipidus, the urine osmolarity increases less than 50% in response to ADH.

Front 142

139. ADH levels and water deprivation test

Back 142

ADH levels should be measured during the water deprivation test.

Patients w/nephrogenic diabetes insipidus have normal or increased levels of ADH during water deprivation.

Front 143

140. What is the treatment for central diabetes insipidus?

Nephrogenic?

Back 143

Desmopressin acetate (DDAVP), a synthetic analog of ADH, is usually administered intranasally or orally in the treatment of diabetes insipidus.

The underlying disease process must be reversed in nephrogenic diabetes insipidus. Specific treatment is designed to maintain a state of mild sodium depletion with reduction in the solute load on the kidneys and subsequent increased proximal tubular reabsorption. Diuretics coupled w/dietary salt restriction can be used to achieve this goal.

Front 144

141. How do you determine the total concentration of solutes in the ECF? (i.e. the osmolarity)

Back 144

= (amount of solute) / (volume of the ECF)

Front 145

142. What regulates the ECF sodium concentration and osmolarity?

Back 145

The amount of extracellular water in the body.

Front 146

143. What two things regulates the extracellular body water?

Back 146

1. Fluid intake, which is regulated by factors that determine thirst

2. Renal excretion of water, which is controlled by multiple factors that influence glomerular filtration and tubular reabsorption.

Front 147

144. Ability of the kidneys to dilute urine

Back 147

The kidney has a tremendous capability to vary the relative proportions of solutes and water in the urine in response to various challenges.

When there is excess water in the body and body fluid osmolarity is reduced, the kidney can excrete urine w/an osmolarity as low as 50 mOsm/L

When there is a deficit of water and ECF osmolarity is high, the kidney can excrete urine w/a concentration of 1200-1400 mOsm/L.

Front 148

145. What controls urine concentration?

Back 148

Antidiuretic (ADH) hormone.

There is a powerful feedback system for regulating plasma osmolarity and sodium concentration that operates by altering renal excretion of water independently of the rate of solute excretion. A primary effector of this feedback is ADH.

Front 149

146. ADH secretion when the osmolarity of the body fluids increases above normal

Back 149

When osmolarity of the body fluids increases above normal, the posterior pituitary gland secretes more ADH, which increases the permeability of the distal tubules and collecting ducts to water.

This allows large amts of water to be reabsorbed and decreases urine volume but does not markedly alter the rate of renal excretion of the solutes.

Front 150

147. ADH secretion when the osmolarity of the body fluids is reduced

Back 150

The secretion of ADH by the posterior pituitary decreases, thereby reducing the permeability of the distal tubule and collecting ducts to water, which causes large amounts of dilute urine to be excreted.

Front 151

148. How does the kidney excrete a dilute urine?

Where does this occur in the kidney?

Back 151

The kidney continues to reabsorb solutes while failing to reabsorb large amount of water in the distal parts of the nephron, including the late distal tubule and the collecting ducts.

Front 152

149. What is the concentration of solutes in relation to the plasma in the proximal tubules?

What about in the descending loop of Henle?

Back 152

Tubular fluid remains isosmotic in the proximal tubules.

Then, as fluid passes down the descending loop of Henle, water is reabsorbed by osmosis and the tubular fluid reaches equilibrium w/the surrounding interstitial fluid of the renal medulla, which is very hypertonic.

Therefore, the tubular fluid becomes more concentrated as it flows into the inner medulla.

Front 153

150. What happens to the tubular fluid in the ascending loop of Henle?

Back 153

Tubular fluid becomes dilute in the ascending loop of Henle.

In the ascending loop, especially in the thick segment, sodium, potassiu, and chloride are avidly reabsorbed.

However, this portion of the tubular segment is impermeable to water, even in the presence of large amts of ADH.

Front 154

151. What is the osmolarity of the fluid leaving the early distal tubule in relation to the plasma osmolarity?

Back 154

Regardless of whether or not ADH is present, fluid leaving the early distal tubular segment is hypo-osmotic, with an osmolarity of only about 1/3 the osmolarity of plasma.

Front 155

152. What happens to the fluid osmolarity in the late distal convoluted tubule, cortical collecting duct, and collecting duct in the absence of ADH?

Back 155

Tubular fluid is further diluted in the absence of ADH. There is additional reabsorption of sodium chloride.

In the absence of ADH, this portion of the tubule is also impermeable to water, and the additional reabsorption of solutes causes the tubular fluid to become even more dilute. This leads to a large volume of dilute urine.

Front 156

153. How do the kidneys conserve water?

Back 156

By excreting a concentrated urine. Fluid intake is supposed to match the loss of water, but the ability of the kidney to form a small volume of concentrated urine minimizes the intake of fluid required to maintain homeostasis.

With a water deficit in the body, the kidney forms concentrated urine by continuing to excrete solutes while increasing water reabsorption of decreasing the volume of urine formed.

Front 157

154. Human kidneys vs. desert animals

Back 157

The human kidney can produce a maximal urine concentration of 1200-1400 mOsm/L, 4-5 the osmolarity of plasma.

Desert animals can concentrate their urine to as high as 10,000 mOsm/L

Front 158

155. What dictates how much urine volume must be excreted each day to rid the body of waste products?

Back 158

The maximal concentrating ability of the kidney.

A normal 70 kg human must excrete about 500 mOsm of solute each day.

Front 159

156. What is the obligatory urine volume, and how is it calculated?

Back 159

If maximal urine concentrating ability is 1200 mOsm/L, the minimal volume of urine that must be excreted, called the obligatory urine volume, can be calculated as 0.5 L/day.

(600 mOsm/day) / (1200 mOsm/L) = 0.5 L/day

Front 160

157. Why do humans become severely dehydrated after drinking sea water?

Back 160

The limited ability of the human kidney to concentrate urine to a maximal concentration of 1200 mOsm/L is the reason.

Drinking 1 L of sea water with a concentration of 1200 mOsm/L would provide a total sodium chloride intake of 1200 mOsm.

Since max urine concentration is only 1200 mOsm/L, the amt of urine volume needed to excrete 1200 mOsm would be 1 L.

However, the kidney must also excrete other solutes, especially urea, which contribute about 600 mOsm/L.

Thus, for every liter of seawater ingested, 2 L of urine volume would be required to rid the body of 1200 mOsm of NaCl ingested in addition to other solutes (approx 2000 mOsm).

This would result in a net fluid loss of 1 L for every liter of sea water drunk.

Front 161

158. What are the two requirements for excreting a concentrated urine?

Back 161

1. A high level of ADH, which increases the permeability of the distal tubules and the collecting ducts to water, thereby allowing these tubular segments to avidly reabsorb water

2. A high osmolarity of the renal medullary interstitial fluid, which provides the osmotic gradient necessary for water reabsorption to occur in the presence of high levels of ADH.

Front 162

159. How does the renal medullary interstitial fluid become hyperosmotic?

Back 162

The countercurrent mechanism.

This mechanism depends on the special anatomical arrangement of the loops of Henle and the vasa recta, the specialized peritubular capillaries of the renal medulla.

Front 163

160. Comparison of the medullary interstitial fluid osmolarity to other parts of the body

Back 163

The osmolarity of the interstitial fluid in the medulla of the kidney is much higher, increasing progressively to about 1200-1400 mOsm/L in the pelvic tip of the medulla.

Once the high solute concentration in the medulla is achieved, it is maintained by a balanced inflow and outflow of solutes and water in the medulla.

Front 164

161. What are the four major factors that contribute to the buildup of solute concentration in the renal medulla?

Back 164

1. Active transport of sodium ions and co-transport of potassium, chloride, and other ions out of the thick portion of the ascending limb of the loop of Henle into the medullary interstitium.
2. Active transport of ions from the collecting ducts into the medullary interstitium
3. Facilitated diffusion of large amounts of urea from the inner medullary collecting ducts into the medullary interstitium.
4. Diffusion of only small amts of water from the medullary tubules into the medullary interstitium, far less than the reabsorption of solutes into the medullary interstitium

Front 165

162. What is the most important cause of the high medullary osmolarity?

Back 165

Active transport of sodium and co-transport of potassium, chloride, and other ions from the thick portion of the ascending limb of the loop of Henle into the medullary interstitium.

This pump is capable of establishing about a 200 mOsm concentration gradient between the tubular lumen and the interstitial fluid.

Front 166

163. Why is there a limit of 200 mOsm/L to the gradient?

Back 166

The limit to the gradient is about 200 mOsm/L b/c paracellular diffusion of ions back into the tubule eventually counterbalances transport of ions out of the lumen when the 200 mOsm/L concentration gradient is achieved.

Front 167

164. What is the countercurrent multiplier system?

Back 167

The countercurrent multiplier gradually traps solutes in the medulla and multiplies the concentration gradient established by the active pumping of ions out of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to 1200-1400 mOsm/L.

Thus, the repetitive reabsorption of NaCl by the TAL of Henle and continued inflow of new NaCl from the proximal tubule into the loop of Henle is called the countercurrent multiplier.

The NaCl reabsorbed from the ascending loop of Henle keeps adding to the newly arrived NaCl, thus, multiplying its concentration in the medullary interstitium.

Front 168

165. What is the role of the distal tubule and collecting ducts?

Back 168

The early distal tubule further dilutes the tubular fluid b/c this segment, like the ascending loop of Henle, actively transports NaCl out of the tubule but is relatively impermeable to water.

Very highly sensitive to concentration of ADH.

Front 169

166. What helps preserve the high medullary interstitial fluid osmolarity?

Back 169

The fact that large amounts of water are reabsorbed from the tubule into the cortex interstitium, rather than into the renal medulla, helps to preserve the high medullary interstitial fluid osmolarity

Front 170

167. What about urea and its contribution to urine osmolarity?

Back 170

Urea contributes about 40-50% of the osmolarity of the renal medullary interstitium when the kidney is forming a max concentrated urine.

Unlike NaCl, urea is passively reabsorbed from the tubule. When there is a deficit of water and blood concentrations of ADH are high, large amts of urea are passively reabsorbed from the inner medullary collecting ducts into the interstitium.

Front 171

168. What is the mechanism for reabsorption of urea into the renal medulla?

Back 171

As water flows up the ascending loop of Henle and into the distal and cortical collecting tubules, little urea is reabsorbed b/c these segments are impermeable to urea.

In the presence of high concentrations of ADH, water is reabsorbed rapidly and the urea concentration increases rapidly b/c urea is not very permeant. Then, as the tubular fluid flows into the inner medullary collecting ducts, still more water is reabsorbed, causing the urea concentration to rise higher.

This high concentration of urea in the tubular fluid of the inner medullary collecting duct causes urea to diffuse out of the tubule into the renal interstitium.

Front 172

169. What helps facilitate the diffusion of urea?

Back 172

Specific urea transporters, e.g. UT-AI, which is activated by ADH, and causes increased transport of urea out of the inner medullary collecting duct even more when ADH levels are elevated.

This helps maintain a high concentration of urea in the urine.

Front 173

170. High-protein diets and urea excretion

Back 173

People who ingest a high-protein diet yield large amounts of urea as waste and can concentrate their urine much better than people whose protein intake and urea production are low.

Front 174

171. What two factors determine the rate of urea excretion?

Back 174

1. The concentration of urea in the plasma

2. The GFR

Front 175

172. Does the urea pass through the terminal parts of the tubular system only once?

Back 175

No, urea can recirculate through the terminal parts of the tubular system several times before it is excreted.

Each time around the circuit contributes to a higher concentration of urea.

Front 176

173. What is the importance of the medullary blood flow system?

Back 176

Blood flow must be provided to the renal medulla to supply the metabolic needs of the cells in this part of the kidney.

W/o a special medullary blood flow system, the solutes pumped into the renal medulla by the countercurrent multiplier system would be rapidly dissipated.

Front 177

174. What are the two special features of the renal medullary blood flow that contribute to the preservation of the high solute concentrations?

Back 177

1. The medullary blood flow is low, accounting for less than 5% of the total renal blood flow. This sluggish blood flow is sufficient to supply the metabolic needs of the tissues but helps to minimize solute loss from the medullary interstitium

2. The vasa recta serve as countercurrent exchangers, minimizing washout of solutes form the medullary interstitium.

Front 178

175. How do the vasa recta serve as countercurrent exchangers?

Back 178

Although there is a large amt of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid at each level of the renal medulla b/c of the U shape of the vasa recta capillaries, which act as countercurrent exchangers.

Thus, the vasa recta do not create the medullary hyperosmolarity, but they do prevent it from being dissipated.

Under steady-state conditions, the vasa recta carry away only as much solute and water as is absorbed from the medullary tubules, and the high concentration of solutes established by the countercurrent mechanism is maintained.

Front 179

176. What is the result of increased medullary blood flow?

Back 179

Increased medullary blood flow can reduce urine concentrating ability.

Vasodilators and large increases in arterial pressure can increase the blood flow of the renal medulla to a greater extent than in other regions of the kidney and tend to wash out the hyperosmotic interstitium, thereby decreasing urine concentrating ability.

Even w/max levels of ADH, urine concentrating ability will be reduced if medullary blood flow increases enough to reduce the hyperosmolarity in the renal medulla.

Front 180

177. What is an important point regarding urine concentration and NaCl concentration?

Back 180

The kidney can, when needed, excrete a highly concentrated urine that contains little NaCl.

The hyperosmolarity fo the urine in these circumstances is due to high concentrations of other solutes, such as urea.

This occurs in dehydration accompanied by low sodium intake.

Front 181

178. What is another important point regarding urine concentration and sodium concentration?

Back 181

Large quantities of dilute urine can be excreted w/o increasing the excretion of sodium

This is accomplished by decreasing ADH secretion, which reduces water reabsorption in the more distal tubular segments w/o significantly altering sodium reabsorption.

Front 182

179. What is the osmolar clearance?

Back 182

The total clearance of solutes from the blood can be expressed as the osmolar clearance; this is the volume of plasma cleared of solutes each minute.

Calculated as:

C = (U x V) / P

Where C is the osmolar clearance, U is the urine osmolarity, V is the urine flow rate, and P is the plasma osmolarity.

Front 183

180. What is free-water clearance?

Back 183

Free water clearance is calculated as the difference between water excretion (urine flow rate) and osmolar clearance.

Ch2o = V - C

Where Ch2o is the free-water clearance, V is the urine flow rate, and C is the osmolar clearance.

Front 184

181. In sum, what does the free-water clearance represent?

Back 184

The free-water clearance represents the rate at which solute-free water is excreted by the kidneys.

When free-water clearance is positive, excess water is being excreted; when it is negative, excess solutes are being removed from the blood by the kidneys and water is begin conserved.

Front 185

182. So how does urine osmolarity and plasma osmolarity related to free-water clearance?

Back 185

Whenever urine osmolarity is greater than plasma osmolarity, free-water clearance will be negative, indicating water conservation.

Front 186

183. What are the three abnormalities that cause disorders of urinary concentrating ability?

Back 186

1. Inappropriate secretion of ADH
2. Impairment of the countercurrent mechanism
3. Inability of the distal tubule, collecting tubule, and the collecting ducts to respond to ADH

Front 187

184. What is "central" diabetes insipidus?

Back 187

Failure to produce ADH.

Can result from inability to produce or release ADH from the posterior pituitary caused by injury or infections.

This results in the formation of a large volume dilute urine, and excessive thirst.

As long as the person drinks lots of water, dehydration will not occur. However, if water intake is restricted, severe dehydration can occur.

Front 188

185. What is the treatment for central diabetes insipidus?

Back 188

Treatment is administration of synthetic analogue of ADH, desmopressin, which acts to increase water permeability in the late distal and collecting tubules.

Front 189

186. What is "nephrogenic" diabetes insipidus?

Back 189

Nephrogenic diabetes is when normal or elevated levels of ADH are present but the renal tubular segments cannot respond appropriately.

This abnormality can be due to either failure of the countercurrent mechanism to form a hyperosmotic renal medullary interstitium or failure of the distal and collecting tubules and collecting ducts to respond to ADH.

In either case, large volumes of dilute urine are formed, which tends to cause dehydration unless fluid intake is increased by the same amount as urine volume is increased.

Front 190

187. How can one tell the difference between nephrogenic diabetes insipidus and central diabetes insipidus?

Back 190

Via administration of desmopression, the synthetic analog of ADH.

Lack of a prompt decrease in urine volume and an increase in urine osmolarity within 2 hours after injection of desmopressin is strongly suggestive of nephrogenic diabetes insipidus.

Front 191

188. What is the treatment for nephrogenic diabetes?

Back 191

The treatment is to correct, if possible, the underlying renal disorder.

The hypernatremia can also be attenuated by a low-sodium diet and administration of a diuretic that enhances renal sodium excretion, such as a thiazide diuretic.

Front 192

189. How does one estimate plasma osmolarity from plasma sodium concentration?

Back 192

B/c sodium and its associated anions account for about 94% of the solute in the ECF compartment, plasma osmolarity can be roughly approximated as:

P = 2.1 x Plasma sodium concentration

Front 193

190. Why do you use sodium ion concentration instead of other ions?

Back 193

Sodium ions represent about 84% of the extracellular osmoles, with glucose and urea contributing about 3-5% of the total osmoles.

However, b/c urea easily permeates most cell membranes, it exerts little effective osmotic pressure under steady-state conditions.

Therefore, sodium ions in the ECF and associated ions are the principal determinants of fluid movement across the cell membrane.

Front 194

191. What two primary systems are involved in regulating the concentration of sodium and osmolarity of the ECF?

Back 194

1. The osmoreceptor-ADH system
2. The thirst mechanism

Front 195

192. What is the order of the osmoreceptor feedback mechanism if there is a water deficit?

Back 195

1. Water deficit
2. ↑ Extracellular osmolarity
3. ↑ ADH secretion via posterior pituitary
4. ↑ Plasma ADH
5. ↑ H₂O permeability in distal tubules, collecting ducts
6. ↑ H₂O reabsorption
7. ↓ H₂O excretion

Front 196

193. Where is ADH synthesized and released?

Back 196

The hypothalamus contains two types of mancocellular neurons that synthesize ADH in the supraoptic and paraventricular nuclei of the hypothalamus.

About 5/6'ths in the supraoptic nuclei and about 1/6'th in the paraventricular nuclei.

Both of these nuclei have axonal extensions to the posterior pituitary. Once ADH is synthesized, it is transported down the axons into the posterior pituitary gland. The released ADH is then carried away in the capillary blood of the posterior pituitary into the systemic circulation.

Front 197

194. What is another neuronal area that is important in controlling osmolarity and ADH secretion

Back 197

Located along the anteroventral region of the third ventricle, called the AV3V region.

At the upper part of the region is a structure called the subfornical organ, and at the inferior part is another structure called the organum vasculosum of the lamina terminalis.

Between these two organs is the median preoptic nucleus, which has multiple nerve connections w/the two organs as well as with the supraoptic nuclei and the BP control centers of the brain.

Front 198

195. What occurs with lesions to the AV3V region?

What occurs with electrical stimulation here?

Back 198

Lesions of this region cause multiple deficits in the control of ADH secretion, thirst, sodium appetite, and BP.

Electrical stimulation of this region of stimulation by angiotensin II can alter ADH secretion, thirst, and sodium appetite.

Front 199

196. What does an increase in ECF osmolarity cause in this region?

Back 199

In the vicinity of the AV3V region and the supraoptic nuclei are neuronal cells that are excited by small increases in ECF osmolarity; hence, the term osmoreceptors is used to describe these neurons.

These cells send nerve signals to the supraoptic nuclei to control their firing and secretion of ADH.

It is also likely that they induce thirst in response to increased ECF osmolarity.

Front 200

197. What is special about the subfornical organs and the organum vasculosum of the lamina terminalis?

Back 200

These organs have vascular supplies that lack the typical blood-brain barrier that impedes the diffusion of most ions form the blood into the brain tissue.

This makes it possible for ions and other solutes to cross between the blood and the local interstitial fluid in this region.

As a result, the osmoreceptors rapidly respond to changes in osmolarity of the ECF, exerting powerful control over the secretion of ADH and over thirst.

Front 201

198. How does the cardiovascular system control ADH release?

Back 201

Cardiovascular reflexes that respond to decreases in BP and/or blood volume, include:

1. Arterial baroreceptor reflexes
2. The cardiopulmonary reflexes

Afferent stimuli are carried by the vagus and glossopharyngeal nerves w/synapses in the nuclei of the tractus solitarius.

Projections from these nuclei relay signals to the hypothalamic nuclei that control ADH synthesis and secretion.

Front 202

199. In addition to increased osmolarity, what two other 'obvious' stimuli increase ADH secretion?

Back 202

1. Decreased arterial pressure
2. Decreased blood volume

Front 203

200. Which is ADH more sensitive to - small changes in osmolarity or small changes in blood volume?

What about with large changes?

Back 203

ADH secretion is considerably more sensitive to small changes in osmolarity than to similar changes in blood volume.

With further decreases in blood volume, however, ADH levels rapidly increase. Thus, with severe decreases in blood volume, the cardiovascular reflex play a major role in stimulating ADH secretion.

Front 204

201. What other things stimulate/inhibit ADH secretion?

Back 204

Nausea is a potent stimulus for ADH release.

Drugs such as nicotine and morphine stimulate ADH release, whereas some drugs, such as alcohol, inhibit ADH release. The marked diuresis that occurs after ingestion of alcohol is due in part to inhibition of ADH release.

Front 205

202. What are the CNS centers for thirst?

Back 205

The same area along the anteroventral wall of the third ventricle that promotes ADH release also stimulates thirst.

Located anterolaterally in the preoptic nucleus is another small area that, when stimulated electrically, causes immediate drinking. All these areas together are called the thirst center.

Front 206

203. What do the neurons in the thirst center respond to?

Back 206

They respond to injections of hypertonic salt solutions. These cells almost certainly function as osmoreceptors to activate the thirst mechanism.

Increased osmolarity of the CSF in the third ventricle has essentially the same effect to promote drinking.

Front 207

204. What mediates the thirst center?

Back 207

It is likely that the organum vasculosum of the lamina terminalis, which lies immediately beneath the ventricular surface at the inferior end of the AV3V region, is intimately involved in mediating the thirst response.

Front 208

205. What is one of the most important stimuli for increase thirst?

Back 208

The most important is increased ECF osmolarity, which causes intracellular dehydration in the thirst centers.

Front 209

206. What four other things can stimulate/decrease thirst?

Back 209

1. Decreases in ECF volume and arterial pressure
2. Increases in angiotensin II
3. Dryness of the mouth and mucous membranes of the esophagus
4. GI and pharyngeal stimuli (can decrease thirst w/gastric distention)

Front 210

207. Why is the ability of animals and humans to meter fluid intake important?

Back 210

Important b/c it prevents overhydration. If it were not there, a person would continue to drink more and more, eventually leading to overhydration and excess dilution of the body fluids.

Front 211

208. What is the threshold for the osmolar stimulus for drinking?

Back 211

When the sodium concentration increases only about 2 mEq/L above normal, the thirst mechanism is activated, causing a desire to drink.

Front 212

209. When either the ADH or the thirst mechanism fails, but not both, what happens?

What happens when both mechanisms fail?

Back 212

The other system can still control ECF osmolarity and sodium concentration with reasonable effectiveness, so long as there is enough fluid intake to balance the daily obligatory urine volume and water losses.

However, if both the ADH and thirst mechanism fail simultaneously, plasma sodium concentration and osmolarity are very poorly controlled.

Front 213

210. What is the extent of the effect that angiotensin II and aldosterone have on sodium concentration?

Back 213

Although these hormones increase the amt of sodium in the ECF, they also increase the ECF volume by increasing reabsorption of water along w/the sodium.

Thus, angiotensin II and aldosterone have little effect on sodium concentration, except under extreme conditions.

Front 214

211. What are the two primary reasons why changes in angiotensin II and aldosterone do not have a major effect on plasma sodium concentration?

Back 214

1. Angiotensin II and aldosterone increase the ECF volume by increasing reabsorption of water along w/the sodium, so little change in sodium concentration occurs.

2. As long as the ADH-thirst mechanism is functional any tendency toward increased plasma sodium concentration is compensated for by increased water intake or increase plasma ADH secretion, which tends to dilute the ECF back toward normal.

Front 215

212. Which system is more powerful in regulating sodium concentration in normal conditions?

Back 215

The ADH-thirst mechanism far overshadows the angiotensin II and aldosterone systems in regulating sodium concentration in normal conditions.

Front 216

213. Under extreme conditions, such as in patients with Addison's disease, what happens to the sodium concentration? Why?

Back 216

There is tremendous loss of sodium by the kidneys which can lead to reductions in plasma sodium concentration.

One of the reasons for this is that large losses of sodium eventually cause severe volume depletion and decreased blood pressure, which can activate the thirst mechanism through the cardiovascular reflexes.

This leads to a further dilution of the plasma sodium concentration, even through the increased water intake helps to minimize the decrease in body fluid volumes under these conditions.

Front 217

214. What are the two primary stimuli believed to increase salt appetite?

Back 217

1. Decreased ECF sodium concentration
2. Decreased blood volume or BP, associated w/circulatory insufficiency.

Some of the same neuronal centers in the AV3V regions of the brain seem to be involved.

Front 218

215. What is a diuretic?

Back 218

A diuretic is a substance tha tincreases the rate of urine volume output.

Most diuretics also increase urinary excretion of solutes, especially sodium and chloride.

In fact, most diuretics that are used clinically act by decreasing the rate of sodium reabsorption from the tubules, which causes natriuresis, which in turn causes diuresis.

Front 219

216. How do diuretics cause increased water output?

Back 219

In most cases, increased water output occurs secondary to inhibition of tubular sodium reabsorption, because sodium remaining in the tubules acts osmotically to decrease water reabsorption.

B/c the renal tubular reabsorption of many solutes, such as potassium, chloride, magnesium, and calcium, is also influenced secondarily by sodium reabsorption, many diuretics raise renal output of these solutes as well.

Front 220

217. Length of time a diuretic works

Back 220

Some diuretics can increase urine output more than 20x within a few minutes after they are administered.

However, the effect of most diuretics on renal output of salt and water subsides within a few days.

This is due to other compensatory mechanisms initiated by the decreased ECF volume.

For example, a decreased ECF often reduces arterial pressure and GFR and increases renin secretion and angiotensin II formation. All these responses, together, eventually override the chronic effects of the diuretic on urine output.

Front 221

218. How do osmotic diuretics decrease water reabsorption?

Back 221

Osmotic diuretics decrease water reabsorption by increasing osmotic pressure of tubular fluid.

Injection into the blood stream of substances that are not easily reabsorbed by the renal tubules, such as urea, mannitol, and sucrose, causes a marked increase in the concentration of osmotically active molecules in the tubules. The osmotic pressure of these solutes then greatly reduces water reabsorption, flushing large amounts of tubular fluid into the urine.

Front 222

219. How do loop diuretics work?

Back 222

Furosemide, ethacrynic acid, and bumetanide are powerful loop diuretics that decrease active reabsorption in the thick ascending limb of the loop of Henle by blocking the 1-sodium, 2-chloride, 1-potassium co-transporter located in the luminal membrane of the epithelial cells.

These diuretics are among the most powerful of the clinically used diuretics.

Front 223

220. What are the two reasons for loop diuretics raising urine output of Cl, Na, K, and other electrolytes as well as water?

Back 223

1. They greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these act as osmotic agents to prevent water reabsorption as well.

2. They disrupt the countercurrent multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid. B/c of this effect, loop diuretics impair the ability of the kidneys to either concentrate or dilute the urine.

Front 224

221. Why is urinary dilution impaired with loop diuretics?

Back 224

Urinary dilution is impaired b/c the inhibition of sodium and chloride reabsorption in the loop of Henle causes more of these ions to be excreted along with increased water excretion.

Front 225

222. Why is urinary concentration impaired with loop diuretics?

Back 225

Urinary concentration is impaired b/c the renal medullary interstitial fluid concentration of these ions, and therefore renal medullary osmolarity, is reduced.

Consequently, reabsorption of fluid from the collecting ducts is decreased, so that the maximal concentrating ability of the kidneys is also greatly reduced.

Front 226

223. Loop diuretic summary

Back 226

B/c of these multiple effect, 20-30% of the glomerular filtrate may be delivered into the urine, causing, under acute conditions, urine output to be as great as 25x normal for at least a few minutes.

Front 227

224. How do thiazide diuretics work?

Back 227

Thiazide diuretics inhibit NaCl reabsorption in the early distal tubule.

The thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the NaCl co-transporter in the luminal membrane of the tubular cells.

Under favorable conditions, these agents cause 5-10% of the glomerular filtrate to pass into the urine. This is about the same amount of sodium normally reabsorbed by the distal tubules.

Front 228

225. How do carbonic anhydrase inhibitors work?

Back 228

Carbonic anhydrase inhibitors block sodium-bicarbonate reabsorption in the proximal tubules.

Front 229

226. Acetazolamide

Back 229

Acetazolamide inhibits the enzyme carbonic anhydrase, which is critical for the reabsorption of bicarb int he proximal tubule.

Front 230

227. Where is carbonic anhydrase located?

Back 230

Carbonic anhydrase is abundant in the proximal tubule, the primary site of action of carbonic anhydrase inhibitors. Some carbonic anhydrase is also present in other tubular cells, such as the intercalatated cells of the collecting tubule.

Front 231

228. How is sodium reabsorption decreased with carbonic anhydrase inhibitors?

Back 231

B/c hydrogen ion secretion and bicarb reabsorption in the proximal tubules are couples to sodium reabsorption through the sodium-hydrogen ion counter-transport mechanism in the luminal membrane, decreasing bicarb reabsorption also reduces sodium reabsorption.

The blockage of sodium and bicarb reabsorption from the tubular fluid causes these ions to remain in the tubules and act as an osmotic diuretic.

Front 232

229. What is a disadvantage of the carbonic anhydrase inhibitors?

Back 232

They cause some degree of acidosis b/c of the excessive loss of bicarb in the urine.

Front 233

230. How do competitive inhibitors of aldosterone work?

Back 233

Competitive inhibitors of aldosterone decrease sodium reabsorption from and potassium secretion into the cortical collecting tubule.

Front 234

231. Spironolactone and eplerenone are....

Back 234

Spironolactone and eplerenone are aldosterone antagonists that compete with aldosterone for receptor sites in the cortical collecting tubule epithelial cells and, therefore, can decrease the reabsorption of sodium and secretion of potassium in this tubular segment.

As a consequence, sodium remains in the tubules and acts as an osmotic diuretic, causing increased excretion of water as well as sodium.

Front 235

232. How are adosterone inhibitors potassium sparing diuretics?

Back 235

B/c these drugs also block the effect of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium.

Aldosterone antagonists also cause movement of potassium from the cells to the ECF. In some instances, this causes the ECF potassium concentration to increase excessively.

For this reason, spironolactone and other aldosterone inhibitors are referred to as potassium sparing diuretics.

Front 236

233. Amiloride and triamterene are...?

Back 236

Amiloride and triamterene also inhibit sodium reabsorption and potassiium secretion in the collecting tubules, similar to the effects of spironolactone.

However, at the cellular level, these drugs act directly to block the entry of sodium into the sodium channels of the luminal membrane of the collecting tubule epithelial cells. B/c of this decreased sodium entry into the epithelial cells, there is also decreased sodium transport across the cells' basolateral membranes and, therefore, decreased activity of the sodium-potassium ATP pump.

Front 237

234. How are sodium channel blockers also potassium sparing diuretics?

Back 237

The decreased activity of the sodium-potassium ATP pump reduces the transport of sodium into the cells and ultimately decreases the secretion of potassium into the tubular fluid.

For this reason, the sodium channel blockers are also potassium sparing diuretics and decrease the urinary excretion rate of potassium.

Front 238

235. What are the two main categories of severe kidney disease?

Back 238

1. Acute renal failure, in which the kidneys abruptly stop working entirely or almost entirely but may eventually recover nearly normal function

2. Chronic renal failure, in which there is progressive loss of function of more and more nephrons that gradually decreases overall kidney function.

Front 239

236. What are the three main categories of causes for acute renal failure

Back 239

1. Acute renal failure resulting from decreased blood supply to the kidneys; this condition is often referred to as prerenal acute renal failure - can be a consequence of heart failure with reduced cardiac output and low BP

2. Intrarenal acute renal failure resulting from abnormalities within the kidney itself, including those that affect the blood vessels, glomeruli, or tubules.

3. Postrenal acute renal failure, resulting from obstruction of the urinary collecting system anywhere from the calyces to the outflow from the bladder. Common causes are kidney stones.

Front 240

237. Prerenal acute renal failure is caused by...?

Back 240

Caused by decreased blood flow to the kidney.

The main purpose of high blood flow to the kidneys is to provide enough plasma for the high rates of glomerular filtration needed for effective regulation of body fluid volumes and solute concentration.

Therefore, decreased renal blood flow is usually accompanied by decreased GFR and decreased urine output of water and solutes.

Front 241

238. How can acute renal failure be reversed?

Back 241

s long as renal blood flow does not fall below about 20-25% normal, acute renal failure can ususally be reversed if the cause of the ischemia is corrected before damage to the renal cells has occurred.

Unlike some tissues, the kidney can endure a relatively large reduction in blood flow before actual damage to the renal cells occurs.

Front 242

239. Reason for kidney being able to endure a large reduction in blood flow

Back 242

As renal blood flow is reduced, the GFR and the amount of sodium chloride filtered by the glomeruli are reduced.

This decreases the amt of sodium chloride that must be reabsorbed by the tubules, which uses most of the energy and oxygen consumed by the normal kidney. Therefore, as renal blood flow and GFR fall, the requirement for renal oxygen consumption is also reduced.

As the GFR approaches zero, oxygen consumption of the kidney approaches the rate that is required to keep the renal tubular cells alive even when they are not reabsorbing sodium.

Front 243

240. What happens when blood flow is less than 20-25x the normal renal blood flow?

Back 243

When blood flow is reduced below this basal requirement, the renal cells start to become hypoxic and further decreases in renal blood flow, if prolonged, will cause damage or even death of the renal cells, especially the tubular epithelial cells.

If the cause of the prerenal acute renal failure is not corrected and ischemia persists longer than a few hours, it can lead to intrarenal acute renal failure.

Front 244

241. Intrarenal acute renal failure

Back 244

Abnormalities that originate within the kidney and that abruptly diminish urine output fall into the general category of intrarenal acute renal failure.

Front 245

242. What are the three categories of acute renal failure?

Back 245

1. Conditions that injure the glomerular capillaries or other small renal vessels

2. Conditions that damage the renal tubular epithelium

3. Conditions that cause damage to the renal interstitium

Front 246

243. Glomerulonephritis and acute renal failure

Back 246

Acute glomerulonephritis is a type of intrarenal acute renal failure usually caused by an abnormal immune reaction that damages the glomeruli.

It is related to infections caused by a certain type of group A beta streptococci.

It is not the infection that damages the kidneys.

Instead, over a few weeks, as antibodies develop against the stretococcal antigen, the antibodies develop against the streptococcal antigen, the antibodies and antigen react with each other to form an insoluble immune complex that becomes entrapped in the glomeruli, especially in the basement membrane portion of the glomeruli.

Front 247

244. What happens once the immune complex has deposited int he glomeruli?

Back 247

Many of the cells of the glomeruli begin to proliferate, but mainly the mesangial cells that lie between the endothelium and the epithelium.

In addition, large numbers of WBCs become entrapped in the glomeruli. Many of the glomeruli become blcoked by this inflammatory reaction, and those that are not blocked ususally become excessively permeable, allowing both protein and RBCs to leak from the blood of the glomerular capillaries into the glomerular filtrate.

In severe cases, either total or almost complete renal shutdown occurs.

Front 248

245. How long does the acute inflammation of the glomeruli last?

Back 248

The acute inflammation of the glomeruli usually subsides in about 2 weeks, and in most patients, the kidneys return to almost normal function within the next few weeks to few months.

Sometimes, however, many of the glomeruli are destroyed beyond repair, and in a small percentage of patients, progressive renal deterioration continues indefinitely, leading to chronic renal failure.

Front 249

246. Tubular necrosis as a cause of acute renal failure

Back 249

Another cause of intrarenal acute renal failure is tubular necrosis, which means destruction of epithelial cells in the tubules.

Front 250

247. What are two common causes of tubular necrosis?

Back 250

1. Severe ischemia and inadequate supply of oxygen and nutrients to the tubular epithelial cells

2. Poisons, toxins, or medications that destroy the tubular epithelial cells

Front 251

248. Acute tubular necrosis caused by severe renal ischemia

Back 251

Severe ischemia of the kidney can result from circulatory shock or another other disturbance that severely impairs the blood supply to the kidney. If the ischemia is severe enough to seriously impair the delivery of nutrients and oxygen to the renal tubular epithelial cells, and if the insult is prolonged, damage or eventual destruction of the epithelial cells can occur.

When this happens, tubular cells slough off and plug many of the nephrons, so that there is not urine output from the blocked nephrons; the affected nephrons often fail to excrete urine even when renal blood flow is restored to normal, as long as the tubules remain plugged.

Front 252

249. What are the most common causes of ischemic damage to the tubular epithelium?

Back 252

The most common causes of ischemic damage to the tubular epithelium are the prerenal causes of acute renal failure associated with circulatory shock.

Front 253

250. Acute tubular necrosis caused by toxins or medications

Back 253

Some of these are carbon tetrachloride, heavy metals, ethylene glycol, various insecticides, various medications used as antibiotics, and cis-platinum.

Each of these substances has a specific toxic action on the renal tubular epithelial cells, causing death of many of them. As a result, the epithelial cells slough away from the basement membrane and plug the tubules. In some instances, the basement membrane also is destroyed. If the basement membrane remains intact, new tubular epithelial cells can grow along the surface of the membrane, so that the tubule repairs itself within 10-20 days.

Front 254

251. Postrenal acute renal failure caused by abnormalities of the lower urinary tract

Back 254

Multiple abnormalities of the lower urinary tract can block or partially block urine flow and therefore lead to acute renal failure even when the kidney's blood supply and other functions are initially normal.

Chronic obstruction of the urinary tract, lasting for several days or weeks, can lead to irreversible kidney damage.

Front 255

252. What are some causes of postrenal acute kidney failure?

Back 255

1. Bilateral obstruction of the ureters or renal pelvises caused by large stones or blood clots
2. Bladder obstruction
3. Obstruction of the urethra

Front 256

253. What are the major physiologic effects of acute renal failure?

Back 256

A major physiologic effect of acute renal failure is retention in the blood and extracellular fluid of water, waste products of metabolism, and electrolytes. This can lead to water and salt overload, which in turn can lead to edema and hypertension.

Excessive retention of potassium, however, is often a more serious threat to patients with acute renal failure, b/c hyperkalemia can be fatal.

B/c the kidneys are also unable to excrete sufficient hydrogen ions, patients with acute renal failure develop metabolic acidosis, which in itself can be lethal or can aggravate the hyperkalemia.

Front 257

254. Chronic renal failure

Back 257

Chronic renal failure results from progressive and irreversible loss of large numbers of functioning nephrons. Serious clinical symptoms often do not occur until the number of functional nephrons falls to at least 70-75% below normal.

In general, chronic renal failure can occur b/c of disorders of the blood vessels, glomeruli, tubules, renal interstitium, and lower urinary tract.

The end result is essentially the same - decrease in the number of functional nephrons.

Front 258

255. End stage renal disease

Back 258

In many cases, an inital insult to the kidney leads to progressive deterioration of kidney function and further loss of nephrons to the point where the person must be placed on dialysis treatment or transplanted with a functional kidney to survive. This condition is referred to as end-stage renal disease.

Front 259

256. What is the vicious circle of chronic renal failure?

Back 259

Loss of nephrons because of disease may increase pressure and flow in the surviving glomerular capillaries, which in turn may eventually injure these "normal" capillaries as well, thus causing progressive sclerosis and eventual loss of these glomeruli.

Front 260

257. Sclerotic lesions in renal disease

Back 260

These sclerotic lesions can eentually obliterate the glomerulus, leading to further reduction in kidney function, further adaptive changes in the remaining nephrons, and a slowly progressing vicious circle that eventually terminates in end-stage renal disease.

Front 261

258. What is the only proven method of slowing down the progressive loss of kidney function in end-stage renal disease?

Back 261

Only was is to lower arterial pressure and glomerular hydrostatic pressure, especially by using drugs such as angiotensin-converting enzyme inhibitors or angiotensin II antagonists.

Front 262

259. What are the four most common causes of end stage renal disease?

Back 262

Glomerulonephritis
Diabetes
Hypertension
Polycystic kidney disease

Front 263

260. What types of vascular lesions can lead to ischemia and death of kidney tissue?

Back 263

1. Atherosclerosis of the larger renal arteries, with progressive sclerotic constriction of the vessels

2. Fibromuscular hyperplasia of one or more of the large arteries, which also causes occlusion of the vessels

3. Nephrosclerosis caused by sclerotic lesions of the smaller arteries, arterioles, and glomeruli.

Front 264

261. Benign nephrosclerosis

Back 264

Benign nephrosclerosis is the most common form of kidney disease and is seen at least some extent in about 70% of postmortem exams in people who die after teh age of 60.

This type of vascular lesion occurs in the smaller interlobular arteries and in the afferent arterioles of the kidney. It is believed to begin with the leakage of plasma through the intimal membrane of these vessels. This causes fibrinoid deposits to develop in the medial layers of these vessels, followed by progressive thickening of the vessel wall that eventually constricts the vessels, and in some cases, occludes them.

Therefore, much of the kidney tissue becomes replaced by small amounts of fibrous tissue.

Front 265

262. Prevalence of nephrosclerosis and glomerulosclerosis

Back 265

Nephrosclerosis and glomerulosclerosis occur to some extent in most people after the foruth decade of life, causing about 10% decrease in the number of functional nephrons each 10 years after age 40.

This loss of glomeruli and overall nephron function is reflected by a progressive decrease in both renal blood flow and GFR.

Even in normal people, kidney plasma flow and GFR decrease by 40-50% by age 80.

Front 266

263. What can increase the frequency and severity of nephrosclerosis and glomerulosclerosis?

Back 266

The frequency and severity of nephrosclerosis and glomerulosclerosis are greatly increased by concurrent hypertension or diabetes.

In fact, DM and hypertension are the two most important causes of end-stage renal disease.

Front 267

264. Malignant nephrosclerosis

Back 267

Benign nephrosclerosis in association with severe hypertension can lead to a rapidly progressing malignant nephrosclerosis.

The characteristic histological features of malignant nephrosclerosis include large amounts of fibrinoid deposits in the arterioles and progressive thickening of the vessels, with sever ischemia occurring in the affected nephrons.

Front 268

265. Chronic glomerulonephritis

Back 268

In contrast to the acute form, chronic glomerulonephritis is a slowly progressive disease that often leads to irreversible renal failure. It may be primary kidney disease, following acute glomerulonephritis, or it may be secondary to systemic diseases, such as SLE.

Front 269

266. How does chronic glomerulonephritis form?

Back 269

In most cases, chronic glomerulonephritis begins with accumulation of precipitated antigen-antibody complexes in the glomerular membrane.

The results of the accumulation of antigen-antibody complex in the glomerular membranes are inflammation, progressive thickening of the membranes and eventual invasion of the glomeruli by fibrous tissue.

In later stages of the disease, the glomerular capillary filtration coefficient becomes greatly reduced b/c of decreased numbers of filtering capillaries in the glomerular tufts and b/c of thickened glomerular membranes.

Front 270

267. What is interstitial nephritis?

Back 270

Primary or secondary disease of the renal interstitium is referred to as interstitial nephritis.

In general this can result from vascular, glomerular, or tubular damage that destroys individual nephrons, or it can involve primary damage to the renal interstitium by poisons, drugs, and bacterial infections.

Front 271

268. What is pyelonephritis?

Back 271

Renal interstitial injury caused by bacterial infection is called pyelonephritis. The infection can result from different types of bacteria but especially from E. coli that originate from fecal contamination of the urinary tract.

These bacteria reach the kidneys either by way of the blood stream or, more commonly, by ascension from the lower urinary tract by way of the ureters to the kidneys.

Front 272

269. What are the two general clinical conditions that may interfere with the normal flushing of bacteria from the bladder?

Back 272

1. The inability of the bladder to empty completely, leaving residual urine in the bladder

2. The existence of obstruction of urine outflow. Can result form cystitis.

Front 273

270. What is vesicoureteral reflux?

Back 273

Once cystitis has occurred, it may remain localized w/o ascending to the kidney, or in some people, bacteria may reach the renal pelvis b/c of a pathological condition in which urine is propelled up on one or both of the ureters during micturition.

As a result, some of the urine is propelled upward toward the kidney, carrying with it bacteria that can reach the renal pelvis and renal medulla, where they can initiate the infection and inflammation associated with pyelonephritis.

Front 274

271. Progression of pyelonephritis

Back 274

Pyelonephritis begins in the renal medulla and therefore usually affects the function of the medulla more than it affects the cortex, at least in the initial stages.

B/c one of the primary functions of the medulla is to provide the countercurrent mechanism for concentrating urine, patients with pyelonephritis freq have markedly impaired ability to concentrate the urine.

Front 275

272. Long standing pyelonephritis

Back 275

With long-standing pyelonephritis, invasion of the kidneys by bacteria not only causes damage to the renal tubules, glomeruli, and other structures throughout the kidney.

Consequently, large parts of functional renal tissue are lost, and chronic renal failure can develop.

Front 276

273. What is nephrotic syndrome?

Back 276

Nephrotic syndrome is characterized by loss of large quantities of plasma proteins into the urine. In some instances, this occurs without evidence of other major abnormalities of kidney function, but more often it is associated w/some degree of renal failure.

Front 277

274. What is the cause of the protein loss in the urine in nephrotic syndrome?

Back 277

The cause is increased permeability of the glomerular membrane.

Therefore, any disease that increase the permeability of this membrane can cause the nephrotic syndrome.

Front 278

275. What three conditions can cause nephrotic syndrome?

Back 278

1. Chronic glomerulonephritis, which affect primarily the glomeruli and often causes greatly increase permeability of the glomerular membrane.

2. Amyloidosis, which results from deposition of an abnormal proteinoid substance in the walls of the blood vessels and seriously damages the basement membrane of the glomeruli.

3. Minimal change nephrotic syndrome, which is associated w/no major abnormality in the glomerular capillary membrane that can be detected w/light microscopy.

Front 279

276. What causes the minimal change nephropathy

Back 279

Minimal change nephropathy has been found to be associated w/loss of the negative charges that are normally present in the glomerular capillary basement membrane.

This loss of negative charges may have resulted from antibody attack on the membrane. Loss of normal negative charges in the basement membrane of the glomerular capillaries allows proteins, esp albumin, to pass thru the glomerular membrane w/ease b/c the negative charges in the basement membrane normally repel the negatively charged plasma proteins.

Can lead to severe edema.

Front 280

277. Loss of function nephrons causes...

Back 280

Causes the surviving nephrons to excrete more water and solutes.

However, metabolic waste products such as creatinine and urea accumulate in direct proportion to the number of nephrons destroyed.

Front 281

278. Why do these other substances accumulate when water and electrolytes do not?

Back 281

Substances such as creatinine and urea depend largely on glomerular filtration for their excretion, and they are not reabsorbed as avidly as the electrolytes.

Creatinine, for example, is not reabsorbed at all, and the excretion rate is equal to the rate at which it is filtered.

Front 282

279. Equation for creatinine filtration and excretion rate

Back 282

Creatinine filtration rate =

= GFR x Plasma creatinine concentration

= Creatinine excretion rate

Front 283

280. What happens when the GFR decreases?

Back 283

If the GFR decreases, the creatinine excretion rate also transiently decreases, causing accumulation of creatinine in the body fluids and raising plasma concentration until the excretion rate of creatinine returns to normal - the same rate at which creatinine is produced in the body.

Thus, under steady state conditions, the creatinine excretion rate equals the rate of creatinine production, despite reductions in GFR; however, this normal rate of creatinine excretion occurs at the expense of elevated plasma creatinine concentration.

Front 284

281. Phosphate, urate, and hydrogen ions and GFR

Back 284

Some solutes, such as phosphate, urate, and hydrogen ions, are often maintained near the normal range until GFR fall below 20-30% of normal.

Thereafter, the plasma concentrations of these substances rise, but not in proportion to the fall in GFR.

Maintenance of relatively constant plasma concentrations of these solutes as GFR declines is accomplished by excreting progressively larger fractions of the amounts of these solutes that are filtered at the glomerular capillaries; this occurs by decreasing the rate of tubular reabsorption or, in some instances, by increasing tubular secretion rates.

Front 285

282. What about sodium and chloride ions?

Back 285

Their plasma concentrations are maintained virtually constant even with severe decreases in GFR.

This is accomplished by greatly decreasing tubular reabsorption of these electrolytes.

For example, with a 75% loss of functional nephrons, each surviving nephron must excrete 4x as much Na and 4x as much volume as under normal conditions.

Front 286

283. What causes this adaptation of the nephrons?

Back 286

Part of this adaptation occurs b/c of increased blood flow and increased GFR in each of the surviving nephrons, owing to hypertrophy of the blood vessels and glomeruli, as well as functional changes that cause the blood vessels to vasodilate.

Even with large decreases in the total GFR, normal rates of renal excretion can still be maintained by decreasing the rate at which the tubules reabsorb water and solutes.

Front 287

284. What is isosthenuria?

Back 287

Isosthenuria is the inability of the kidney to concentrate or dilute the urine.

One important effect of the rapid rate of tubular flow that occurs in the remaining nephrons of diseased kidneys is that the renal tubules lose their ability to concentrate or dilute the urine.

Front 288

285. Why is the concentrating ability of the kidney impaired in diseased kidneys?

Two reasons...

Back 288

1. The rapid flow of tubular fluid through the collecting ducts prevents adequate water reabsorption

2. The rapid flow through both the loop of Henle and the collecting ducts prevents the countercurrent mechanism from operating effectively to concentrate the medullary interstitial fluid solutes.

Therefore, as progressively more nephrons are destroyed, the max concentrating ability of the kidney declines, and urine osmolarity and specific gravity approach the osmolarity and specific gravity of the glomerular filtrate.

Front 289

286. Why is the diluting mechanism in diseased kidneys also impaired?

Back 289

The diluting mechanism in the kidney is also impaired when the number of nephrons decreases b/c the rapid flushing of fluid through the loops of Henle and the high load of solutes such as urea cause a relatively high solute concentration in the tubular fluid of this part of the nephron.

As a consequence, the diluting capacity of the kidney is impaired, and the minimal urine osmolaity and specific gravity approach those of the glomerular filtrate.

Front 290

287. Which is more indicative of renal function when a person's water intake is restricted for 12+ hours?

Back 290

B/c the concentrating mechanisms becomes impaired to a greater extent than does the diluting mechanism in chronic renal failure, an important clinical test of renal function is to determine how well the kidneys can concentrate urine when a person's water intake is restricted for 12 or more hours.

Front 291

288. The effect of complete renal failure on the body fluids depends on what two things?

Back 291

1. Water and food intake
2. The degree of impairment of renal function.

Front 292

289. What are the four effects of renal failure on the body fluids (AKA uremia)?

Back 292

1. Generalized edema resultign from water and salt retention
2. Acidosis resulting from failure of the kidneys to rid the body of nromal acidic products
3. High concentration fo the nonprotein nitrogens - especially urea, creatinine, and uric acid- resulting from failure of teh body to excrete the metabolic end products of proteins
4. High concentrations of other substances excreted by the kidney, including phenols, sulfates, phosphates, potassium and guanidine bases.

Front 293

290. Water retention and development of edema in renal failure

Back 293

Edema usually does not become severe until kidney function falls to 25% of normal or lower.

Even the small fluid retention that does occur, along with increased secretion of renin and angiotensin II that usually occurs in ischemic kidney diseases, often causes severe hypertension in chronic renal failure.

Thus, dialysis is usually required to preserve life but it usually results in hypertension. In most of these patients, severe reduction of salt intake or removal of ECF by dialysis can control the hypertension.

Front 294

291. Uremia and azotemia

Back 294

The nonprotein nitrogens include urea, uric acid, creatinine, and others. These end products must be removed from the body to ensure continued normal protein metabolism in the cells.

The concentrations of these, particularly of urea, can rise to as high as 10x normal during 1-2 weeks of total renal failure. With chronic renal failure, the concentrations rise appox in proportion to the degree of reduction in functional nephrons.

Thus, measures of urea and creatinine provide an important means for assessing the degree of renal failure.

Front 295

292. What causes acidosis in renal failure?

Back 295

When the kidneys fail to function, acid accumulates in the body fluids. The buffers of the body can be overwhelmed and the blood pH falls drastically.

Front 296

293. What causes anemia in those with chronic renal failure?

Back 296

Patients with severe chronic renal failure almost always develop anemia.

The most important cause of this is decreased renal secretion of erythropoietin, which leads to diminished RBC production.

Front 297

294. What causes osteomalacia in chronic renal failure?

Back 297

Serious damage to the kidney greatly reduces the blood concentration of active vitamin D, which in turn decreases intestinal absorption of calcium and the availability of calcium to the bones.

Another cause is the rise in serum phosphate concentration that occurs as a result of decreased GFR, which leads to increased in PTH secretion - thus causing secondary hyperparathyroidism.

Front 298

295. How do renal lesions caused hypertension?

Back 298

Renal lesions either decrease GFR OR increase tubular reabsorption usually lead to hypertension of varying degrees.

Front 299

296. Three types of renal abnormalities that can cause hypertension

Back 299

1. Increased renal vascular resistance (renal artery stenosis)
2. Decreased glomerular capillary filtration coefficient (glomerulonephritis)
3. Excessive tubular sodium reabsorption (hyperadosteronism)

Front 300

297. What are the most likely sequence of events that cause hypertension in patchy renal damage?

Back 300

1. Ischemic kidney tissue itself excretes less than normal amts of water and salt
2. The renin secreted by the ischemic kidney and subsequent increased angiotensin II formation, affects the nonischemic kidney tissue, causing it to also retain salt and water
3. Excess salt and water cause hypertension in the usual manner.

Front 301

298. What kind of kidney disease cause loss of entire nephrons leads to renal failure but may not cause hypertension?

Back 301

With minimal salt intake, this condition might not cause clinically significant hypertension, b/c even a slight rise in BP will raise the GFR and decrease tubular sodium reabsorption sufficiently to promote enough water and salt excretion in the urine, even with the few nephrons that remain intact.

However, the patient with this type of abnormality may develop hypertension if salt intake increases.

Front 302

299. What is renal glycosuria?

Back 302

Failure of the kidneys to reabsorb glucose.

The blood glucose concentration may be normal, but the transport mechanisms for tubular reabsorption of glucose is greatly limited or absent.

Consequently, large amts of glucose pass into the urine each day. Diabetes is associated with this as well, so renal glycosuria must be ruled out first.

Front 303

300. What is aminoaciduria?

Back 303

Failure of the kidneys to reabsorb AAs.

Rarely, a condition called generalized aminoaciduria results from deficient reabsorption of all AAs; more frequently, deficiencies of specific carrier systems may result in:

1. Essential cystinuria, in which large amts of cystine failt to be reabsorbed and often form kidney stones
2. Simple glycinuria, in which glycine fails to be absorbed
3. Beta-aminoisobutyricaciduria, which occurs in about 5% of all people but has not clinical significance.

Front 304

301. What is renal hypophosphatemia?

Back 304

Failure of the kidneys to reabsorb phosphate.

Usually not clinically significant in the short term but over a long period, a low phosphate level can cause diminished calcification of the bones, causing the person to develop vitamin D resistant rickets.

Front 305

302. What causes renal tubular acidosis?

Back 305

Failure of the tubules to secrete hydrogen ions. As a result, large amts of sodium bicarb are continually lost in the urine. This causes a continued state of metabolic acidosis.

Front 306

303. What is nephrogenic diabetes insipidus?

Back 306

Failure of the kidneys to respond to ADH.

This causes large quantities of dilute urine to be excreted. As long as the person is supplied with plenty of water, the person is OK. However, with dehydration, it can become problematic.

Front 307

304. What is Fanconi's syndrome?

Back 307

A generalized reabsorptive defect of the renal tubules.

Fanconi's syndrome is usually associated with increased urinary excretion of virtually all AAs, glucose, and phosphate. It can also cause:
1. failure to reabsorb bicarb, which causes metabolic acidosis
2. increased excretion of potassium and sometimes calcium
3. nephrogrenic diabetes insipidus

Front 308

305. What are three causes of Fanconi's syndrome?

What part of the kidneys is especially affected in Fanconi's syndrome?

Back 308

1. Hereditary defects in cells transport mechanisms
2. Toxins or drugs that injure the renal tubular epithelial cells
3. Injury to the renal tubular cells as a result of ischemia

The proximal tubular cells are especially affected in Fanconi's syndrome caused by tubular injury, b/c these cells reabsorb and secrete many of the drugs and toxins that can cause damage.

Front 309

306. The rate of movement of solute across the dialyzing membrane depends on what four things?

Back 309

1. Concentration gradient of the solute between the two solutions
2. Permeability of the membrane to the solute
3. Surface area of the membrane
4. Length of time that the blood and fluid remain in contact w/the membrane

Front 310

307. blank

Back 310

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Front 311

308. blank

Back 311

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Front 312

309. Antidiuretic hormone (ADH)

Back 312

In response to decreased intravascular volume, peripheral nervous system cells lining the atria and pulmonary vasculature transmit a signal to noradrenergic neurons in the medulla of the CNS.

This signal is relayed to the hypothalamus, resulting in increased secretion of ADH from the posterior pituitary gland.

ADH maintains distal tissue perfusion.

Front 313

310. What is the juxtaglomerular apparatus?

Back 313

Renin is an aspartyl protease produced and secreted by the juxtaglomerular apparatus, a specialized set of smooth muscle cells that line the afferent and efferent arterioles of the renal glomerulus.

Front 314

311. What is the result of renal secretion?

Back 314

The ultimate result of renin secretion is vasoconstriction and Na retention, actions that maintain tissue perfusion and increase ECF volume.

Front 315

312. What three mechanisms control juxtaglomerular cell release of renin?

Back 315

1. A direct pressure sensing mechanism of the afferent arteriole increases juxtaglomerular cell release of renin in response to decreased tension.

2. Sympathetic innervation of juxtaglomerular cells promotes renin release via β₁-adrenoceptor signaling.

3. An autoregulatory mechanism known as tubuloglomerular geedback sesnse distal nephron sodium delivery and modulates renin release.

Front 316

313. What is the macula densa?

Back 316

Macula densa cells of the cortical thick ascending limb respond to increased luminal NaCl delivery by increasing EC adenosine in the juxtoglomerular interstitium and thereby activating A₁ receptors on the juxtaglomerular mesangial cells.

Front 317

314. What are the four physiologic actions of angiotensin II?

Back 317

1. Stimulation of aldosterone secretion by zona glomerulosa cells of the adrenal glands.

2. Increased reabsorption of NaCl at the proximal tubule and other nephron segments

3. Stimulation of thirst and ADH secretion

4. Arteriolar vasoconstriction

Front 318

315. What mediates the actions of angiotensin II?

Back 318

All of the actions of AT II are mediated by its binding to the AT II receptor subtype 1 (AT₁ receptor), a G protein coupled receptor.

Front 319

316. ANP, BNP, CNP

Back 319

Three natriuretic peptides have been identified: A-type is released primarily by the atria, while B-type is released mainly by the ventricles. C-type is released by vascular endothelial cells.

Natriuretic peptides are released in repsonse to increased intravascular volume.

Front 320

317. What do ANP, BNP, and CNP bind to?

Back 320

Circulating natriuretic peptides bind to one of three receptors, termed NPR-A, NPR-B, and NPR-C.

Front 321

318. What modulates urine and plasma osmolality?

Back 321

Regulation of renal water reabsorption in the collecting duct modulates urine and plasma osmalality, and serves as a reserve mechanism for increasing intravascular volume in situations of severe dehydration.

Front 322

319. What occurs in the proximal tubule?

Back 322

The proximal tubule is the first reabsorptive site in the nephron. It is responsible for approx 2/3's of sodium reabsorption, 85-90% of bicarbonate reabsorption, and 60% of chloride reabsorption.

Specific sodium coupled symporters in the proximal tubule apical membrane drive renal reabsorption of glucose, AAs, phosphate, and sulfate. The proximal tubule also mediates secretion and reabsorption of weak organic acids and bases coupled to sodium or proton symport or antiport, or to anion exchange mechanisms.

Front 323

320. What does carbonic anhydrase IV do?

Back 323

CAIV converts luminal HCO₃⁻ to CO₂ and OH⁻.

Then, the OH⁻ is rapidly hydrated to water by the abundance of local protons, and the CO₂ freely diffuses into the cytoplasm of the proximal tubular epithelial cell.

Front 324

321. What does carbonic anhydrase II do?

Back 324

CAII rapidly rehydrates the intracellular CO₂ to HCO₃⁻.

The HCO₃⁻ produced by the CAII reaction is then cotransported with sodium across the basolateral membrane of the epithelial cell using the Na⁺/HCO₃⁻ cotransporter (NBC1).

Front 325

322. What is the importance of aquaporins?

Back 325

Data from mice genetically modified to lack the aquaporin water channel (AQP1) demonstrate that most proximal tubular water reabsorption is transcellular.

The important role of aquaporins in transepithelial water permeability seems to hold true for all water-permeable nephron segments.

Front 326

323. What occurs in the thick ascending limb of the loop of Henle (TAL)?

Back 326

The tubular fluid emerging from the thin ascending limb is hypertonic and has an elevated NaCl concentration. The TAL reabsorbs NaCl without accompanying water, diluting the tubular fluid.

The TAL reabsorbs between 25-35% of the filtered sodium load by means of the membrane Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2)

Front 327

324. What is the energy requirement of the TAL?

Back 327

The TAL, working at maximal capacity, can consume up to 25% of the body's total ATP production, ~65 moles/day at rest.

Front 328

325. What occurs in the distal convoluted tubule?

Back 328

This continuation of the diluting segment actively reabsorbs between 2-100% of the filtered NaCl load, while remaining impermeable to luminal water.

Front 329

326. What occurs in the collecting ducts?

Back 329

The terminal portion of the nephron is divided into cortical, outer medullary, and inner medullary collecting duct segments.

These collecting ducts account for 4-5% of the kidney's reabsorption of sodium and 5% of the kidney's reabsorption of water. At times of extreme dehydration, over 24% of the filtered water may be reabsorbed in the collecting duct system.

*They are extremely sensitive to ADH.

The collecting duct system participates in the regulation of other electrolytes, including chloride, potassium, hydrogen ions, and bicarbonate.

Front 330

327. How does ADH affect the collecting duct system?

Back 330

In the absence of ADH, water in the renal filtrate is left alone to enter the urine, promoting diuresis.

When ADH is present, aquaporins allow for the reabsorption of this water, thereby inhibiting diuresis.

Front 331

328. What are the three pharmacologic strategies for interruption of the renin-angiotensin system?

Back 331

1. ACE inhibitors interrupt the conversion of angiotensin I to angiotensin II

2. Angiotensin receptor antagonists are competitive antagonists of the AT₁ receptor, and thus inhibit the target-organ effects of angiotensin II.

3. Antagonists of the mineralocorticoid receptor block aldosterone action at the nephron collecting duct.

Front 332

329. What are ACE inhibitors?

Back 332

B/c angiotensin II is the primary mediator of the activity of the renin-angtiotensin-aldosterone system, decreased conversion of ATI to ATII inhibits arteriolar vasoconstriction, decreases aldosterone synthesis, inhibits renal proximal tubule NaCl reabsorption, and decreases ADH release.

All of these actions result in decreased BP and increased natriuresis. In addition, b/c ACE proteolytically cleaves bradykinin, ACE inhibitors increase bradykinin levels, leading to vascular smooth muscle relaxation and increased NO production.

Front 333

330. What are the names of the ACE inhibitors?

Back 333

1. Captopril
2. Enalopril
3. Ramipril
4. Benazepril
5. Fosinopril
6. Moexipril
7. Perindopril
8. Quinapril
9. Trandolapril
10. Lisinopril

Front 334

331. ACE inhibitors MOA and PURPOSE

Back 334

MOA: By inhibiting ACE, decrease conversion of ATI to ATII, and thereby decrease arteriolar vasoconstriction, aldosterone synthesis, renal proximal tubule NaCl reabsorption, and ADH release. ACE also inhibits the degradation of bradykinin, and thereby increase vasodilation.

PURPOSE: hypertension, heart failure, diabetic nephropathy, and MI

Front 335

332. ACE inhibitors ADVERSE and CONTRA

Back 335

ADVERSE: Angioedema (more frequent in Black patients), agranulocytosis, neutropenia, cough, edema, hypertension, rash, gynecomastia, hyperkalemia, proteinuria

CONTRA: History of angioedema, bilateral renal artery stenosis, renal failure, and *pregnancy.

*Causes major fetal malformations

Front 336

333. What are the three patterns of metabolism in ACE inhibitors?

Back 336

1. The first pattern is exemplified by the prototypical ACE inhibitor, captopril - it is active as administered, but is also processed to an active metabolite.

2. The most common pattern, exemplified by enalapril and ramipril, is that of an ester prodrug converted in the plasma to an active metabolite.

3. Lisinopril is the sole example of the third pattern, in which the drug is administered in active form and excreted unchanged by the kidneys.

Front 337

334. What causes the cough and angioedema in ACE inhibitors?

Back 337

Cough and angioedema are caused by bradykinin action; angioedema occurs within the first week of therapy in 0.1-0.2% of patients and can be potentially life threatening.

Front 338

335. ACE inhibitor NOTES

Back 338

NOTES: First does hypotension and/or acute renal failure are more common in patients with bilateral renal artery stenosis; *hyperkalemia is more common when ACE inhibitors are used in combo with potassium sparing diuretics

ACE inhibitors delay progression of cardiac contractile dysfunction in heart failure and after MI, and delay progression of diabetic nephropathy.

A few case reports suggest that coadministration of allopurinol may predispose to hypersensitivity reactions, including Stevens-Johnson syndrome and anaphylaxis.

Front 339

336. What are angiotensin II receptor antagonists?

How do they compare to ACE inhibitors?

Back 339

AT₁ receptor antagonists, such as losartan and valsartan, inhibit the action of AT II at its receptor.

Compared to ACE inhibitors, AT₁ receptor antagonists may allow more complete inhibition of ATII's actions, b/c ACE is not the only enzyme that can generate ATII.

In addition, b/c AT₁ receptor antagonists have not effect on bradykinin metabolism, their use may minimize the incidence of drug induced cough and angioedema.

However, they may be less effective vasodilation than ACE inhibitors.

Front 340

337. What are the angiotensin II receptor antagonists?

Back 340

1. Candesartan
2. Irbesartan
3. Losartan
4. Telmisartan
5. Valsartan

Front 341

338. Angiotensin II receptor antagonists

Back 341

MOA: Antagonize action of ATII at AT₁ receptor, may also indirectly increase vasorelaxant AT2 receptor activity

PURPOSE: hypertension, diabetic nephropathy, heart failure, MI, prevention of stroke

ADVERSE: Rare thrombocytopenia, rhabdomyolysis, rare angioedema, hypotension, diarrhea, asthenia, dizziness

CONTRA: Bilateral artery stenosis and pregnancy.

NOTES: Also called ARBs. In combo with ACE inhibitors, may provide survival benefit in severe heart failure; AT₁ receptor antagonists may also protect against stroke.

Initially only prescribed for patients with intolerable reaction to ACE inhibitors, but are now considered potential first-line treatments for hypertension.

Front 342

339. What is B-type natriuretic peptide?

Back 342

Nesiritide, a recombinant human-sequence B-type natriuretic peptide (BNP), has recently been approved for short term management of decompensated HF.

IN clinincal trials, it results in decreased pumonary capillary wedge pressure, decreased systemic vascular resistance, and improved cardiac stroke volume.

B/c it is a peptide, it is ineffective when given orally.

Front 343

340. Nesiritide

Back 343

MOA: Increases intracellular concentration of cGMP by binding to the particulate guanylyl cyclase receptor of vascular smooth muscle and endothelial cells, resulting in smooth muscle relaxation

PURPOSE: Acutely decompensated heart failure

ADVERSE: Hypotension, cardiac arrhythmia, renal dysfunction, headache, confusion, somnolence, tremor, pruritus, nausea.

CONTRA: Cardiogenic shock or systolic BP less than 90 mm Hg.

NOTES: May be associated with a lower incidence of arrhythmias than dobutamine. The risk of hypotension is increased by coadministration with ACE inhibitors. Nesiritide treatment is also associated with an increased risk of renal dysfunction.

Front 344

341. What are vasopressin receptor 2 (V2) antagonists?

Back 344

These antidiuretic hormone antagonists prevent vasopressin-stimulated water reabsorption via V2 coupled aquaporin channels in apical membranes of collecting duct cells.

These include:
1. Conivaptan
2. Lixivaptan
3. Tolvaptan

Front 345

342. Vasopressin receptor 2 (V2) antagonists

Back 345

MOA: Potent antagonists activity at V2 and weaker antagonist activity at V1, preventing vasopressin-stimulated water reabsorption via V2 coupled aquaporin channels in apical membranes of collecting duct cells.

PURPOSE: Euvolemic hyponatremia, SIADH, heart failure, cirrhotic ascites, autosomal dominant polycystic kidney disease

ADVERSE: Atrial fibrillation, orthostatic hypotension, hypertension, peripheral edema, injection-site reaction, hypokalemia, thirst, dyspepsia, headache, polyuria

CONTRA: Concurrent use of potent P450 3A4 inhibitors, and hypovolemic hyponatremia

NOTES: Approval of the orally bioavailable, V2-selective agents tolvaptan and lixivaptan is anticipated. V2 receptor antagonists are under eval as agents to retard vasopressin driven renal cyst growth in polycystic kidney disease

Front 346

343. Specific notes about conivaptan

Back 346

Conivaptan is the first specific non-peptide vasopressin receptor antagonist approved for treatment of euvolemic hyponatremias (SIADH).

Conivaptan is relatively nonselective for V2 and V1 receptors and MUST be administered via IV.

Front 347

344. What are carbonic anhydrase inhibitors?

Back 347

Carbonic anhydrase inhibitors, specifically acetazolamide, inhibit sodium reabsorption by noncompetitively and reversibly inhibiting proximal-tubule cytoplasmic carbonic anhydrase II and luminal carbonic anhydrase IV.

Inhibition of carbonic anhydrase leads to increased delivery of sodium bicarbonate to more distal segments of the nephron. Much of this sodium bicarbonate is initially excreted, however, over the course of several days of therapy, the diuretic effect of the drug is diminished by compensatory up-regulation of NaHCO₃ reabsorption, and by increased NaCl reabsorption across more distal nephron segments.

Front 348

345. Acetazolamide

Back 348

MOA: Inhibits sodium reabsorption by noncompetitively and reversibly inhibiting proximal-tubule cytoplasmic carbonic anhydrase II and luminal carbonic anhydrase IV, leading to increased delivery of sodium bicarbonate to more distal segments of the nephron.

PURPOSE: High altitude sickness, heart failure, epilepsy, glaucoma

ADVERSE: Metabolic acidosis, sulfonamide adverse reaction, diarrhea, weight and appetite loss, tinnitus, nausea, vomiting, paresthesia, somnolence, polyuria.

CONTRA: Adrenal gland failure, chronic angle-closure glaucoma, cirrhosis, hyponatremia, hypokalemia, hyperchloremic acidosis, and severe hepatic or renal disease.

Front 349

346. Acetazolamide notes

Back 349

NOTES on acetazolamide:
1. Clinical use is associated w/mild-to-moderate metabolic acidosis
2. Used occasionally in heart failure to restore acid-base balance
3. Carbonic anhydrase inhibition of ciliary process of the eye reduces secretion of aqueous humor and may thereby reduce elevated intraocular pressure in glaucoma
4. Can be used prophylactically against acute mountain sickness, presumably owing to the drug's effects on choroid plexus and ependyma, respiratory centers of the brain, and blood-brain barrier
5. These agents alkalinize urine (especially iwth oral bicarbonate) and increase urinary excretion of endogenous (uric acid) and exogenous (aspirin) organic acid anions; can be used in the treatment of hyperuricemia or gout
6. Aspirin increases plasma concentrations of acetazolamide, potentially leading to CNS toxicity.

Front 350

347. What are osmotic diuretics?

Back 350

Osmotic diuretics, such as mannitol, are small molecules that are filtered at the glomerulus but not subsequently reabsorbed in the nephron. Thus, they constitute an intraluminal osmotic force limiting reabsorption of water across water permeable nephron segments.

The effect of osmotic agents is greatest in the proximal tubule, where most iso-osmotic reabsorption of water takes place.

Front 351

348. Mannitol

Back 351

MOA: Act as an osmole, filtered at the glomerulus but not subsequently reabsorbed in the nephron; exert an intraluminal osmotic force limiting reabsorption of water across water permeable nephron segments.

PURPOSE: Cerebral edema, increased intraocular pressure, prophylaxis of oliguria in acute renal failure

ADVERSE: Thrombophlebitis, acidosis, seizure, urinary retention, pulmonary edema, hypotension, palpitations, fluid and/or electrolyte imbalance, diarrhea, nausea, rhinitis.

CONTRA: anuria, severe dehydration, heart failure, pulmonary congestion, or renal dysfunction after initiation of mannitol

Front 352

349. Mannitol notes

Back 352

Mannitol notes:

1. Promotes vigorous natriuresis; requires careful monitoring of volume status

2. Water loss in excess of sodium excretion can lead to unintended hypernatremia

3. Used primarily for rapid reduction of intracranial pressure in the setting of head trauma, brain hemorrhage, or symptomatic cerebral mass; also used rarely in treatment of compartment syndrome.

Front 353

350. Radiocontrast agents as osmotic diuretics

Back 353

Radiocontrast agents are filtered at the glomerulus but not reabsorbed by the tubular epithelium. Thus, the dyes constitute an osmotic load and can produce osmotic diuresis.

In patients with borderline cardiovascular status, the consequent reduction in intravascular volume can lead to hypotension or to renal and/or cardiac insufficiency secondary to reduced organ perfusion.

Front 354

351. What are loop diuretics?

Back 354

MOA: Loop diuretics at the TAL of the loop of Henle. These agents reversible and competitively inhibit the Na⁺-K⁺-2Cl⁻ cotransporter NKCC2 in the apical (luminal) membrane of TAL epithelial cells.

They also inhibit transcellular transport of NaCl which also reduces or abolishes the lumen-positive transeptihelial potential difference across the TAL.

Front 355

352. What is the prototypical loop diuretic?

Back 355

The prototypical loop diuretic is furosemide.

Other drugs in this class include bumetanide, torsemide, and ethacrynic acid.

Front 356

353. Loop diuretics (PURPOSE, ADVERSE)

Back 356

PURPOSE: hypertension, acute pulmonary edema, edema associated with congestive heart failure, hepatic cirrhosis, or renal dysfunction, hypercalcemia, hyperkalemia.

ADVERSE: hypotension, erythema multiforme, Stevens-Johnson syndrome, pancreatitis, aplastic or hemolytic anemia, leukopenia, thrombocytopenia, volume contraction, alkalosis, ototoxicity (dose related), hypokalemia, hyperuricemia, hypomagnesmia, hyperglycemia, rash, cramps, spasticity, headache, blurred vision, dyspepsia, glycosuria

Front 357

354. Loop diuretics (CONTRA)

Back 357

CONTRA: Hypersensitivity to sulfonamides (contraindication for furosemide, bumetanide, and torsemide), anuria, coadministration with aminoglycosides increases ototoxicity and nephrotoxicity

Front 358

355. Loop diuretics NOTES

Back 358

NOTES:

Bumetanide is approx 40x more potent than the other loop diuretics; furosemide, bumetanide, and torsemide are all sulfonamide derivatives, while ethacrynic acid is not.

Front line therapy for acute relief of pulmonary and peripheral edema in heart failure. Edematous states can be treated with low-dose loop diuretics.

Also used to counteract hypercalcemic and hyperkalemic states.

Front 359

356. What are thiazides?

Back 359

Thiazide diuretics inhibit sodium chloride reabsorption in the distal convoluted tubule.

These agents cause a modest reduction in intravascular volume, and decreases systemic BP.

As such, they are first line agents for treatment of hypertension

Front 360

357. What are the names of the thiazides?

Back 360

1. Hydrochlorothiazide
2. Bendroflumethiazide
3. Hydroflumethizide
4. Polythiazide
5. Chlorthalidone
6. Metolazone
7. Indapamide

Front 361

358. Hydrochlorthiazide

Back 361

Hydrochlorthiazide is the prototypical thiazide diuretic. In addition to its effects on renal electrolyte handling, Hydrochlorthiazide decreases glucose tolerance and may unmask diabetes in patients at risk for impaired glucose metabolism.

Front 362

359. Thiazides

Back 362

MOA: These agents act from the apical (luminal) side as competitive antagonists of the NCC1 Na⁺-Cl⁻ cotransporter in the luminal membrane of distal convoluted tubule cells.

PURPOSE: Hypertension, adjunct in edema states associated with congestive heart failure, hepatic cirrhosis, renal dysfunction, corticosteroid and estrogen therapy

ADVERSE: cardiac arrhythmias, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, hepatotocitiy, SLE, hypotension, vasculitis, photosensitivity, electrolyte abnormalities, hypokalemic metabolic alkalosis, hyperglycemia, hyperuricemia, dyspepsia, headache, blurred vision, impotence, restlessness.

CONTRA: Anuria, hypersensitivity to sulfonamides, coadministration with agents that prolong QT interval

Front 363

360. Thiazide NOTES

Back 363

Thiazide NOTES:

1. First line agents for treatment of hypertension

2. Used to diminish hypercalciuria in patients at risk for kidney stones and rarely to decrease urinary calcium wasting in osteoporosis

3. Should not be administered concurrently with antiarrhythmic agents that prolong the QT interval

4. In patients with nephrogenic diabetes insipidus, thiazide diuretics can paradoxically produce a modest decrease in urine flow.

Front 364

361. What are the collecting duct (potassium sparing) diuretics?

Back 364

In contrast to all other diuretic classes, potassium sparing diuretics increase nephron reabsorption of potassium.

Agents in this class interrupt collecting-duct principal cell Na reabsorption.

Front 365

362. Spironolactone and epleronone

Back 365

MOA: Inhibits aldosterone action by binding to and preventing nuclear translocation of the mineralocorticoid receptor.
Inhibits the biosynthesis of new Na channels in the principal cells.

PURPOSE: Hypertension, edema associated with congestive heart failure, liver cirrhosis (w/ or w/o ascites), or nephrotic syndrome, hypokalemia, primary aldostgeronism, acne vulgaris (spironoloactone), female hirsutism (spironoloactone)

ADVERSE: Hyperkalemic metabolic acidsosis, GI hemorrhage, agranulocytosis, SLE, breast cancer, gynecomastia, dyspepsia, lethargy, abnormal menstruation, impotence, rash

CONTRA: Anuria, hyperkalemia, acute renal insufficiency

Front 366

363. Spironolactone and epleronone NOTES

Back 366

Spironolactone and epleronone NOTES:

1. Potassium sparing diuretics are mild diuretics when used in isolation, but can potentiate the action or more proximally acting loop diuretics
2. Occasionally used in combo with thiazides to counteract potassium wasting effect of thiazide
3. Spironolactone also antagonizes the androgen receptor, can cause impotence and gynecomastia in men but confers therapeutic advantage in women with acne and hirsutism; eplerenone has less anti-androgenic activity
4. Used to treat hypokalemic alkalotic states secondary to mineralocorticoid excess in heart failure, hepatic failure, and other disease states associated with diminished aldosterone metabolism.
5. Both spironolactone and epleronone reduce mortality in patients with heart failure; the mechanism may be related to inhibition of cardiac fibrosis resulting from a paracrine aldosterone-signaling pathway.

Front 367

364. Amiloride and triamterene

Back 367

MOA: Competitive inhibitors of the principal cell apical membrane ENaC sodium channel

PURPOSE: Hypertension and Liddle syndrome

ADVERSE: disease of the hematopoietic system, nephrotoxicity (triamterene), hyperkalemic metabolic acidosis, orthostatic hypotension, hyperkalemia, dyspepsia, headache

CONTRA: anuria, hyperkalemia, acute renal insufficiency

NOTES: Amiloride and triameterene are drugs of choice for treatment of Liddle syndrome, a rare, Mendelian form of hypertension resulting from gain-of-function mutations in the β or γ subunit of the ENaC sodium channel.