Patho II- Exam V

What is the most common cause of adult hypopituitarism?

Nonfunctioning pituitary adenoma

What is the most common cause of childhood hypopituitarism?

Craniopharyngioma

What is primary hypogonadism?

-the male testes and female ovaries *fail to secrete sufficient amounts of testosterone and estrogens*
-removes the negative feedback inhibition on the anterior pituitary gonadotropic cells, producing *elevated plasma levels of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH)*

What is secondary hypogonadism?

-the *anterior pituitary* gonadotropic cells are *unable to secrete sufficient amounts of FSH and LH*
-plasma levels are correspondingly low or unmeasurable, and the target organs (testes, ovaries) atrophy due to lack of hormonal stimulation.

What are the symptoms of hypogonadism?

• males: eunuchoid appearance (testosterone deficiency results in failure of epiphyseal closure), decreased libido, impotence
• females: amenorrhea

Which endocrinopathies are most common with craniopharyngioma?

•young children → *GH deficiency* is the most common leading to growth retardation and short stature
• older children and adolescents → *gonadotropin deficiency* leading to absent or arrested puberty is most common

What changes occur in serum prolactin and GnRH levels in prolactinoma?

· ↑ prolactin
· ↓ gonadotropin-releasing hormone (GnRH)

What are symptoms of a prolactinoma?

•earliest clinical sign in adults is hypogonadism
•females: amenorrhea, infertility, galactorrhea, estrogen deficiency; early osteoporosis
• males: decreased libido, impotence

What is the outcome of a functional somatotrophic adenoma in childhood and adolescence?

gigantism due to increased GH

What is the outcome of a functional somatotrophic adenoma in adulthood?

acromegaly due to GH

What are the symptoms acromegaly?

•mean age 40y/o with symptoms for 5-10 years
• chronic disabling and disfiguring disorder
• slowly progressive course with increased late morbidity and mortality
• gradual development of coarse facial features
• overgrowth of the mandible (prognathism) and maxilla; jaw protrudes forward and forehead slants forward
• spaces between upper incisor teeth
• thickened nose, nose may increase to twice normal size
• enlarged hands and feet; increased ring, glove, shoe, and hat size; hand twice as large as normal
• increased sweating, heat intolerance, oily skin, fatigue, weight gain, increased sleep requirement, headache (65%)
• paresthesias (70%), arthralgias (bone and cartilage overgrowth), degenerative arthritis
• hypertension (25%), cardiomegaly (15%); most common cause of fatality is heart failure due to cardiomegaly and hypertension
• glucose intolerance (50%), hyperinsulinism (70%)
• hypogonadism: females (60%), males (46%)
• hypercalciuria and renal stones (11%)

What labs may be abnormal in acromegaly?

· elevated postprandial glucose, increased serum insulin (70%)

How is acromegaly diagnosed?

• clinical features, radiographic location of tumor, increased GH secretion
• lack of suppression of GH secretion with the oral glucose tolerance test

What is the most common cause of fatality in acromegaly?

heart failure due to cardiomegaly and hypertension due to IG1 influence

Why might a patient experience glucose intolerance and hyperinsulinism due to acromegaly?

due to the influence of insulin like growth factor

What is neurogenic vs nephrogenic diabetes insipidus?

•Neurogenic: lack of production and/or secretion of vasopressin
•Nephrogenic: lack of renal response to vasopressin

Compare the symptoms of neurogenic vs nephrogenic diabetes insipidus?

Both polydipsia and polyuria

Compare the serum and urine osmolality in nephrogenic diabetes insipidus?

Serum: increased
Urine: low

Compare the serum and urine osmolality in neurogenic diabetes insipidus?

Serum: increased
Urine: low

Compare the serum vasopressin in neurogenic vs nephrogenic diabetes insipidus?

Neurogenic: low
Nephrogenic: normal to high

Compare the serum sodium in neurogenic vs nephrogenic diabetes insipidus?

Both: hypernatremia

After the water deprivation test, compare the changes in urine osmolality of neurogenic vs nephrogenic diabetes insipidus.

Pre vasopressin:
•Neurogenic: no increase
•Nephrogenic: little to no increase

Post vasopressin adminitration:
•Neurogenic: \>100% increase
•Nephrogenic: no change

After the water deprivation test, compare the changes in serum osmolality of neurogenic vs nephrogenic diabetes insipidus.

both increase

After the water deprivation test, compare the changes in serum vasopressin of neurogenic vs nephrogenic diabetes insipidus.

Neurogenic: stays low (

Describe the volume status of a patient with SIADH?

nonedematous, normovolemic hyponatremia

What change in serum sodium occurs in SIADH? What is the result?

•hyponatremia
•loss of sodium prevents volume overload and edema

Compare the serum vs urine osmolality in SIADH.

↓ serum osmolality
inappropriately ↑ urine osmolality

Describe the presentation of SIADH.

• hyponatremia
• AMS, lethargy, confusion
• neurologic dysfunction: stupor, neuromuscular hyperexcitability, seizures ("water intoxication"), coma
cerebral edema, central pontine myelinolysis

What causes pituitary dwarfism?

•deficiency of GH secretion during childhood
•body features develop in proportion to each other, but the rate of development is greatly decreased

What causes pituitary gigantism?

• production of excess quantities of GH cause all body tissues to grow rapidly, including the bones → intense acceleration of linear growth
• usually caused by tumor
• tumor growth will eventually destroy the gland resulting in hypopituitarism with death in early adulthood if untreated

What changes occur in TT4, FT4I, TSH, and RAIU levels in hyperthyroidism?

↑TT4, ↑FT4I, ↓TSH, ↑RAIU

What changes occur in TT4, FT4I, TSH, and RAIU levels in hypothyroidism?

↓TT4, ↓FT4I, ↑TSH, ↓RAIU

What are the 2 most common mechanisms of goiter?

• an absolute or relative *deficiency of TH*, resulting in increased stimulation by TSH
• thyroid-stimulating *autoantibodies* which stimulate the TSH receptor

What are the 3 major causes of nontoxic goiter?

• *iodine deficiency*
• *genetic defects* in TH synthesis
• sporadic goiter induced by antithyroid agents: *goitrogenic chemicals* (amioderone, lithium, sulfa drugs, antithyroid drugs) and *foods* which suppress thyroid hormone synthesis (cabbage, cauliflower, brussel sprout, turnips)

What changes occur in T4, T3 and TSH in idiopathic colloid goiter?

· normal levels of T4, T3, and TSH

What symptoms occur in idiopathic colloid goiter?

•usually asymptomatic, large mass in neck
•mass may exert pressure on surrounding structures: dysphagia, inspiratory stridor, venous congestion, hoarseness
•may progress to toxic form of disease

What are the common symptoms of hypothyroidism?

• extreme somnolence with sleeping 12-14 hr/day, tiredness, lethargy
• weakness, muscle cramps, fatigue
• slowed heart rate, decreased cardiac output, decreased blood volume
• weight gain (about 10% increase due to edema), constipation
• cold intolerance
• hair loss; dry, scaly skin; hoarseness; brittle nails

Compare serum TSH, TT4, FT4I, RAIU levels in primary and secondary hypothyroidism.

· Primary: ↓ TT4, ↓FT4I, ↓ RAIU, *↑ serum TSH*
· Secondary: *↓ to nl TSH*, ↓ FT4I, ↓ to nl TT4?, ↓RAIU?

What changes occur in T4, T3 and TSH in endemic colloid goiter?

↑ TSH, ↓T3 and T4

What are symptoms of endemic colloid goiter?

enlarged thyroid gland, Hypothyroidism?

What are the symptoms of developmental hypothyroidism?

First few weeks:
• infants are apathetic, sluggish, large abdomen
• low body temperature; pale, cold skin
• anemia, dilated heart

6 months:
• mental retardation, stunted growth
• characteristic facies: large tongue; flat, broad nose; periorbital edema
• low levels of T4 and T3, elevated TSH

What can occur if developmental hypothyroidism is not treated?

unless treated within a few months after birth, mental and physical growth are permanently retarded

What causes myxedema?

•almost total lack of thyroid function
•greatly increased quantities of proteoglycans collect in the interstitial spaces, forming an edema characterized by a myxomatous gel in the interstitial spaces

Describe myxedema coma.

• severe hypothermia, hypoventilation (hypoxia, hypercapnia), *hyponatremia*, hypotension, seizures
• may be precipitated by infection, cardiac or respiratory illness, cold exposure
• occurs most often in elderly women

What are the symptoms of myxedematous hypothyroidism?

• slowed speech, hoarseness, decreased sense of taste and smell
• facies: facial swelling, bagginess under eyes, periorbital puffiness
• pitting edema of hands and feet, thickened tongue
• cutaneous vasoconstriction: absence of sweating; pale, cool skin; hypothermia
• other lab findings: hyponatremia, hypoglycemia, anemia

What changes occur in the thyroid gland in hyperthyroidism?

· excessive production of thyroid hormones with hypertrophy and hyperplasia of the thyroid gland
• thyroid gland is 2-3 times normal size (goiter)
• extensive infolding of the follicular cell lining into the follicles
• number of cells is increased several times

What are the symptoms of hyperthyroidism?

• highly excitable state, irritability, nervousness, fatigue with inability to sleep
• heat intolerance; warm moist skin; diaphoresis
• muscular weakness, tremors
• mild to extreme weight loss, diarrhea
• menstrual irregularity
• tachycardia
• Graves' disease: goiter and exophthalmos (protrusion of eyeballs)

What is Plummer's disease?

• progression of nontoxic multinodular goiter after repeated episodes of stimulation and involution
• ten times more frequent in females, and more common in elderly with cardiac symptoms (CHF, AF)

What glandular changes occur in Plummer's disease?

• groups of large hyperplastic and hyperfunctional follicles mixed with other apparently inactive nodules

What are the symptoms of Plummer's syndrome?

• less severe symptoms of hyperthyroidism than Graves' disease and not accompanied by infiltrative ophthalmopathy or dermopathy

What changes occur in TT4, FT4I, RAIU, serum TSH, RAIU in Plummer's disease?

minimally ↑ TT4, FT4I
↑RAIU- patchy
↓TSH

What causes Grave's disease?

• autoimmune disorder (T cells become sensitized to thyroid antigens and stimulate B cells to produce autoantibodies) characterized by diffuse goiter, hyperthyroidism, and exophthalmos
• most frequent cause of hyperthyroidism in patients < 40 yr old in US and the most common cause of endogenous hyperthyroidism

What are associated symptoms of Grave's disease?

• *thyrotoxicosis*: gradual onset of nervousness, emotional lability, tremor, weakness, weight loss, heat intolerance, diaphoresis, tachycardia, palpitations, amenorrhea
• *goiter*: symmetrically enlarged gland
• ophthalmopathy (*exophthalmos, proptosis*)
• dermopathy (pretibial edema)
• clinical course: exacerbations and remissions

What changes in TT4, free T4, and FT4I, T3, serum TSH, and RAIU occur in Grave's disease?

• ↑: TT4, free T4, and FT4I; very large increase in T3
• ↓TSH
• ↑ diffuse uptake of radioactive iodine

What changes in ESR, FT4I, TSH, and RAIU occur in subacute thyroiditis?

• Initially ↑ ESR, ↑ FT4I, ↓ TSH
• ↓ RAIU since the gland is damaged
• eventually as the gland becomes depleted of stored TH, circulating T4 and T3 decrease and TSH beings to rise, a transient hypothyroid phase may occur until gland fully recovers

What is Hashimoto's thyroiditis and what glandular changes occur?

•goitrous hypothyroidism, high titers of circulating autoantibodies which are toxic to thyroid epithelial cells (bind to peroxidase or thyroglobulin)- evidence indicates that these autoantibodies are the result of, rather than the cause of, gland destruction

What changes occur in TH, TSH, and RAIU levels in the early phase of Hashimoto's thyroiditis?

•transient hyperthyroidism due to follicular disruption with release of thyroid hormone ("hashitoxicosis")
•both TSH and RAIU are suppressed

What changes occur in T4, T3 and TSH levels as Hashimoto's thyroiditis progresses?

• as the gland is destroyed, serum *T4 levels fall* and a compensatory *rise in TSH* levels occurs
• allows *T3 levels to remain near normal*

Describe the initial symptoms of Hashimoto's thyroiditis.

patients are clinically euthyroid (due to T3 levels) and asymptomatic except for *goiter*

What happens in TRH test in a euthyroid patients?

•The bolus of TRH stimulates secretion of TSH to *greater than twice the baseline* in normal subjects

Describe the levels of circulating thyroid hormones in hyperthyroidism.

excess T3 and T4

How does hyperthyroidism affect TRH and TSH levels?

•highly elevated levels of TH exert *negative feedback effects on TRH* secretion and TRH interaction with pituitary receptors
•TSH levels are usually below the normal range

How do hyperthyroid patients respond to the TRH test?

•Due to pituitary suppression by T3 and T4, the response to the TRH bolus is significantly blunted after TRH dosing, TSH levels are *less than twice the baseline values*

Describe the thyroid hormone levels and TSH levels in primary (thyroidal) hypothyroidism.

•little to no TH is secreted
•TSH levels are increased

How do primary (thyroidal) hypothyroid patients respond to the TRH test?

TSH levels are elevated above the normal range to *greater than twice the baseline value*

Describe the thyroid hormone levels and TSH levels in secondary (pituitary) hypothyroidism.

•decreased responsiveness to the effects of hypothalamic TRH
•*TSH* levels are usually near the *low end of the normal range*
•low T3 and T4

How do secondary (pituitary) hypothyroid patients respond to the TRH test?

the TRH bolus has little to no effect on TSH secretion; after TRH dosing, *TSH levels remain at the lower limit of the normal range* (less than twice the baseline value) with no peaks

Describe the thyroid hormone levels and TSH levels in tertiary (hypothalamic) hypothyroidism.

•there is a deficient endogenous source of TRH
•*TSH levels are at the lower end of the normal range*
•low T3 and T4

How do tertiary (hypothalamic) hypothyroid patients respond to the TRH test?

•the exogenous TRH bolus does stimulate TSH secretion
•TSH levels typically remain in the normal response range *(suppressed response) at about twice the baseline value*

What are the previous names of Type 1 and 2 diabetes?

•Type 1: Insulin-dependent/ Juvenile onset
•Type 2: Non-insulin dependent/ Maturity or Adult onset

What is the typical age of onset for Type 1 and type 2 diabetes?

•Type 1: Usually < 30 yr; peaks around 12-14 yr
•Type 2: Usually \> 30 yr; affects almost 10% of persons over 65 yr

Describe the pancreatic function in type 1 and 2 diabetes.

•Type 1: Usually none; some residual C-peptide may be present
•Type 2: Insulin levels may be low, normal, or high

Describe insulin dependence in type 1 and 2 diabetes.

•Type 1: Absolute (total lack of insulin)
•Type 2: Exogenous insulin not usually needed to maintain life, although it may help management of the disease in some cases

What is the etiology of Type 1 diabetes?

•Autoimmune destruction of beta cells
•may be triggered by viral infection, chemical or environmental insult in genetically susceptible individuals
•islet cell autoantibodies (50-85%) and sensitized cytotoxic T lymphocytes are frequently present at time of onset

What is the etiology of Type 2 diabetes?

•*Insulin resistance* (deficient number of insulin receptors), defect in insulin secretion, or a postreceptor defect
•< 10% incidence of autoantibodies

How important if family history and HLA association in type 1 and 2 diabetes?

•Type 1: Positive family history in 10% of cases; 50% concordance rates in twins; *associated with certain HLA types*
•Type 2: Positive family history in 30% of cases; 95-100% concordance rates in twins; precise mode of inheritance not defined; *no association with any HLA types*

How common is obesity in Type 1 and 2 diabetes?

•Type 1: uncommon
•Type 2: common- weight loss improves disease management

How likely is ketoacidosis to occur in Type 1 and 2 diabetes?

•Type 1: often, severe
•Type 2: rare

Describe the presentation of Type 1 Diabetes.

usually sudden onset; moderate to severe symptoms: polyuria, polydipsia, fatigue, weight loss, polyphagia, ketoacidosis (25% first time)

Describe the presentation of Type 2 Diabetes.

usually insidious onset; mild polyuria, fatigue, lethargy

How is type 1 diabetes treated?

Insulin (100%)
Diet
Exercise

How is type 2 diabetes treated?

Diet, Exercise
Oral Hypoglycemics
Insulin (33%)

What is the current ATPII and AHA criteria for fasting plasma glucose for metabolic syndrome?

- NCEP ATP III, *≥ 110 mg/dL*
- AHA, *≥ 100 mg/dL*

What is the relationship of insulin resistance and obesity to metabolic syndrome?

• central obesity- caused by overeating and inactivity - factors in producing insulin resistance
•insulin resistance causes glucose intolerance
•insulin resistance and central obesity appear to synergize each other's effects

What is the mechanism of progression of insulin resistance in metabolic syndrome?

•obesity factors in producing insulin resistance
•levels of intracellular TG may be markedly increased in muscle and liver in obesity due to excess deposition of free fatty acids (FFA); TG and FFA exert "lipotoxic" effects by interfering with insulin signaling mechanisms, resulting in insulin resistance

What is the mechanism of progression of glucose intolerance and hyperinsulinemia in metabolic syndrome?

• insulin resistance impairs glucose utilization in tissues and causes hyperglycemia → pancreas to produce more insulin to overcome the insulin resistance, producing elevated levels of both glucose (impaired glucose tolerance) and insulin (secondary hyperinsulinemia)

How are TG and FFA affected by metabolic syndrome?

• levels of *intracellular TG may be markedly increased* in muscle and liver in obesity due to *excess deposition of free fatty acids (FFA)*
• TG and FFA exert "lipotoxic" effects by *interfering with insulin signaling* mechanisms, resulting in insulin resistance

What is the triad of atherogenic dyslipidemia?

• The combination of ↑ TG, ↓ HDL, and smaller, more dense LDL (LDL particles are smaller than normal and densely packed, favoring atherogenesis)

What is the mechanism of metabolic syndrome?

• Insulin resistance impairs glucose utilization in tissues and causes hyperglycemia → stimulates the pancreas to produce more insulin to overcome the insulin resistance, ↑ glucose (impaired glucose tolerance) and insulin (secondary hyperinsulinemia).
• greatly increased risk of atherosclerotic vascular disease, similar to type 2 DM
• proinflammatory state, elevated levels of CRP
• in obesity, cytokine release from the adipose tissue causes inflammation, which leads to dyslipidemia and increased waist circumference

What are the 3 essential components of development of type 1 MD?

• *genetic*ally susceptible individual (HLA-DR3 or -DR4 allele, or both)
• *environmental insult* (microbial, chemical, dietary); congenital rubella infection is the only environmental agent clearly associated with type 1 DM
• triggered *autoimmune* response

Describe the autoimmune attack on islet beta cells in type 1 DM?

• *chronic autoimmune attack* on beta cells that begins many years before disease is evident
• both humoral (autoantibodies) and cell-mediated (cytotoxic T lymphocytes) responses directed against antigens (still poorly characterized) on islet beta cells
• inflammatory reaction in which the islets are infiltrated by lymphocytes (both CD4 Th1 and CD8 Tc), mononuclear cells, and neutrophils (*insulitis*) → locally produced *cytokines (IL1, TNF, IFNγ) damage the beta cells*

Describe the mechanism of compensated insulin resistance in type 2 diabetes.

• genetically predetermined peripheral insulin resistance in fat and muscle → decreased glucose uptake and utilization in metabolic tissues (muscle and fat) is the primary site of insulin resistance
• mechanisms: *decreased numbers of insulin receptors or postreceptor (transduction) defects*
• beta cells *compensate by producing more insulin* (secondary hyperinsulinemia) to maintain normal blood glucose

Describe the mechanism for impaired glucose tolerance in type 2 diabetes. What does it lead to?

• overeating and inactivity stimulate excessive amounts of insulin → insulin resistance
• beta cells gradually *fail to compensate* → low inulin secretion
- loss of the 1st phase (post prandial) of glucose-stimulated insulin secretion (peaking at 10 min)
- subsequent gradual loss of the second phase of insulin secretion (starting 30 min after glucose stimulation and peaking at 60 min)
•leads to *postprandial hyperglycemia*

Describe the beta cell dysfunction in type 2 diabetes.

• glucotoxicity due to chronic hyperglycemia
• ↓ insulin secretion (impaired beta cell sensitivity)
• ↓ insulin activity (by increasing insulin resistance)
• function of duration and magnitude of hyperglycemia

Describe the mechanism of fasting hyperglycemia in type 2 diabetes.

• excessive hepatic glucose production due to *inadequate suppression of hepatic gluconeogenesis* and markedly *increased postprandially*
• usually increased GI glucose absorption
• symptomatic, early-onset type 2 DM

What factors lead to hyperglycemia when there is an absence of insulin?

•glucose cannot enter the cells so it accumulates in the blood
•continuous glucose output from liver by gluconeogenesis (from amino acids) and glycogen breakdown

What are the effects of hormone-sensitive lipase when there is an absence of insulin?

• increased breakdown of triglycerides stored in adipose tissue to glycerol and fatty acids → increased mobilization of fatty acids

Describe the formation of ketone bodies in the absence of insulin.

• increased mobilization of fatty acids → increased formation of ketone bodies (acetoacetic acid, acetone, and beta-hydroxybutyric acid)

How can lack of insulin lead to hypercholesterolemia?

decreased LDL receptor availability → decreased serum cholesterol clearance

How does absence of insulin affect protein catabolism?

• *increased catabolism of proteins* from muscle and other tissues to supply amino acids for gluconeogenesis → muscle wasting