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Parathyroid & Adrenals

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Parathyroid & Adrenals Powered By Docstoc
					                 PARATHYROID

• 4 located within thyroid (2 on each side)
• composed mainly of Chief cells
      a) secrete PTH
• controlled mainly by blood Ca++ and NOT by
  any throphic hormone(s)
      a)  levels of free ionized Ca++ stimulate
         synthesis and secretion
• PTH receptor (G protein)
      a) activation of adenyl cyclase  cAMP
• PTH actions: ( calcium - hypercalcemia)
     a) activates osteoclasts
     b)  renal tubule Ca++ reabsorption
     c)  Vit D conversion to active form
     d)  GI absorption of Ca++
     e) these listed actions  Ca++
          i) negative feedback controls PTH
• hypercalcemia is common complications of
  malignancy
     a) most common cause of hypercalcemia
          i) poorest outcome (advanced cancers)
• primary hyperparathyroidism is, however, the
  most common cause of asymptomatic
  hypercalcemia
• Hyperparathyroidism
     a) 2 major forms – primary and secondary
        (less common is tertiary)
• Primary hyperparathyroidism
     a) autonomous overproduction of PTH
     b) one of most common endocrine disorders
           i) important cause of hypercalcemia
     c) typical causes:
           i) adenomas (~ 80% of cases)
           ii) 1O hyperplasia (diffuse or nodular)
           iii) parathyroid carcinoma (< 5%)
     d) female predominance (3:1)
     e) adult disease (50’s and >)
     f) over 95% due to sporadic adenoma/cell
g) genetic influences
      i) MEN-1 syndrome (discussed later)
      ii) MEN-2 syndrome (tyrosine kinase
          receptor mediated)
             - MEN-2A specific
      iii) familial hypocalciuric hypercalcemia
h) clinical presentation:
      i) asymptomatic -  Ca++ ;  PTH
         hypophosphatemia;  Urine
         excretion of both calcium and
         phosphate
      ii) PTH is low in hypercalcemia due to
         non parathyroid disease
iii) symptomatic “painful bones, renal
    stones, abdominal groans and
    psychic moans”
• Secondary hyperparathyroidism
     a) anything causing  plasma Ca++
          i) renal failure most common cause
                - chronic renal failure   serum
                  PO4  directly depress serum
                  Ca++   parathyroid activity
• Tertiary hyperparathyroidism
     a) in small number of cases, parathyroid
        gland may become autonomous and
        excessive
• Hypoparathyroidism
    a) less common than hyper-
    b) causes:
         i) surgical induced
         ii) congenital absence
         iii) familial hypoparathyroidism
         iv) idiopathic
    c) hypocalcemia is result and causes:
         i) tetany!! (hallmark)  characterized
            by neuromuscular irritability
                - Chvostek sign:  tapping along
                  the facial nerve  causes
                  contraction of muscles of eye,
                  mouth or nose
          - Trousseau sign: occluding circulation
             to forearm induces carpal spasms
          ii) emotional instability, anxiety,
              depression, hallucinations, etc…
          iii) CV – conduction abnormalities (i.e.,
               prolonged QT interval)
          iv) ocular disease – cataract formation
          v) dental – caries, etc…
• Pseudohypoparathyroidism
     a) end-organ resistance to PTH
                  ADRENALS

• Adrenal Cortex
• Adrenocortical Hyperfunction (hyperadrenalism)
• Adrenal secretes 3 major groups of steroid
  hormones
     a) glucocorticoids (cortisol) – Cushing
        Syndrome
     b) mineralocorticoids (aldosterone) –
        hyperaldosteronism
     c) androgens – virilizing syndromes
1.Cushing Syndrome

    a) any factor that causes  cortisol (i.e.,
       glucocorticoids)
         i) mainly due to administration of
            glucocorticoids (iatrogenic)
         ii) hypersecretion of ACTH
         iii) hyperplasia or neoplasia
         iv) ectopic secretion of ACTH
• In hypersecreting ACTH (ii above)  “Cushing
  Disease”
     a) more often in women
     b) 20-30 yrs
     c) in most patients, pituitary usually has
         small ACTH secreting adenoma
          i) less sensitive to (-) feedback control
             on ACTH release
     d) anterior pituitary has areas of
        corticotroph-cell hyperplasia without
        adenoma
     e)  CRH from hypothalamus
     f) neoplasia/hyperplasia  ~30% of cases
        of Cushing syndrome
     g) most other case caused by  ectopic
        sites of ACTH secretion (usually small
        carcinoma of lung)
           i) other sites have included pancreas,
              thyroid
• Clinical
     a) patients who have exogenous
        glucocorticoids (i.e., cortisol)
           i) adrenals are atrophied due to 
              ACTH release
     b) endogenous ACTH  adrenal hyperplasia
c) known affects of glucocorticoids
     i) hypertension
     ii) weight gain (“moon face” “buffalo
          hump”)
     iii) atrophy of fast (type II) twitch
           myofibers  muscle atrophy and
           limb weakness
     iv) hyperglycemia and glucosuria
     v) proteolysis and bone resorption
          (osteoporosis)
     vi) suppresses immune system  
           risk for infections
     vii) hirsuitism
     viii) CNS  mood changes
            Hyperaldosteronism

• Excessive levels of aldosterone
     a)  sodium retention
     b)  potassium excretion 
     c) which results in  BP and hypokalemia
• Primary or Secondary
     a) primary
          i) autonomous overproduction of
             aldosterone   renin-angiotensin
             system
          ii) caused by adrenocortical adenoma
              or by hyperplasia
         iii) primary aldosterone secreting
              adenoma (in >80%) – “Conn
             syndrome”
         iv) carcinomas are rare
         v) no ACTH (-) feedback; therefore
              other regions of adrenals are not
              atrophic
         vii) Conn syndrome more often in
              adults whereas hyperplasia occur
              more often in children
          Adrenogenital Syndrome
• Caused by variety of diseases
    a) primary gonadal disorders and 
    b) primary adrenal disorders

• Adrenal cortex
    a) secretes
          i) dehydroepiandrosterone
          ii) androstenedione
    b) both require conversion to testosterone
       in peripheral tissues
    c) these adrenal androgen formation
       requires ACTH
          i) secretion can occur de novo or
             through 
          ii) excess ACTH secretion (e.g.,
             Cushing Syndrome)
d) adrenal causes of  androgens
     i) neoplasms (more likely to be
        carcinomas)
     ii) adrenal hyperplasia
           - group of autosomal recessive
           disorders causing  cortisol
           production with feedback  in
           ACTH with resultant adrenal
           hyperplasia (e.g., congenital)
           - the most common enzymatic
           defect in congenital adrenal
           hyperplasia is 21-hydroxylase
           deficiency which accounts for
           ~95% of cases.
• Clinical:
     a) congenital adrenal hyperplasia
           i) bilateral adrenal hyperplasia
                  - driven by  ACTH
     b) hyperplasia of ACTH producing cells is
        present in anterior pituitary
     c) clinical manifestation determined by
        specific enzyme deficiency
           i) androgens
           ii) sodium homeostasis
           iii) depending on severity of diseases,
                S & S usually present during
                infancy and early childhood and
                less commonly during childhood.
d) 21-hydroxylase deficiency causes
   excessive androgenic activity
     i) masculinization in females
           - hirsutism
           - oligomenorrhea
     ii) in males, enlargement of external
        genitalia
e) some rare forms of congenital
   adrenal hyperplasia
     i) 17--hydroxylase deficiency
     ii) in other forms of congenital adrenal
         hyperplasia (e.g., 11-hydroxylase
         deficiency)
           - accumulated intermediates
            steroids have sodium retention
            properties and subsequent
            hypertension
f) congenital adrenal hyperplasia should be
  suspected in neonate with ambiguous
  genitalia
     i) severe enzyme deficiency in infancy
        can be life threatening
           - vomiting
           - diarrhea
           - sodium loss (dehydration)
     ii) in all cases, an androgen producing
         neoplasm in the ovary must be R/O
     Adrenal Insufficiency (adrenocortical
                   hypofunction)
• May reflect either primary adrenal disease (i.e.,
   primary hypoadrenalism) or secondary via
  decreased stimulation of the adrenals caused by
  ACTH deficiency (e.g., Sheehan syndrome,
  nonfunctioning pituitary adenomas and/or
  lesions of hypothalamus, etc.)
• Further divided (primary adrenocortical
  insufficiency)
      a) chronic primary adrenocortical
         insufficiency (Addison Disease) or
      b) acute primary adrenocortical insufficiency
        1. Addisons Disease (chronic)
• Progressive destruction of adrenal cortex
     a) S & S usually do not appear until ~90%
        of adrenal gland has been compromised
• Causes:
     a) autoimmune adrenalitis
          i) ~75-90% of all cases of Addison
              disease in developed countries
          ii) sporadically or familial component
          iii) In ~50% of patients, autoimmune
              cause affects only the adrenal
              glands whereas the remaining
              patients also exhibit other
              autoimmune disorders
     - Hashimoto
     - Pernicious anemia
     - Type I diabetes
     - idiopathic Hypoparathyroidism
iv) Type I and II polyglandular
    syndrome
     -Type I: - autosomal recessive;
                mutations located on
                chromosome 21q
     -Type II: - strong link to
                histocompatibility
                antigens (HLA-B8, HLA-
                DR3 and HLA-DQ5)
     v) circulating antibodies to several
         steroidal enzymes (e.g., 21 and
         17-hydroxylase) have been found
         in all types of autoimmune
         adrenalitis
b) Infections
     i) TB (accounted for ~90% of primary
        chronic adrenocortical insufficiency)
        antituberculosis drugs have  the
        incidence of Addisons disease
     ii) Fungi (Histoplasma capsulatum and
         coccidioides immitis)
     iii) AIDS, due to contracting a variety
          of infections
c) Metastatic neoplasms
    i) common site of metastatic
       disseminated carcinomas
    ii) carcinomas of breast and lung are
        source of majority of metastases in
        the adrenals
    iii) other neoplasms from GI,
        melanomas and hematopoietic
        neoplasms may also metastasize to
        the adrenals
• Clinical
     a) insidious onset with progressive
        weakness and easy fatigability
     b) GI disturbances are common complaint
          i) anorexia, vomiting, nausea, weight
             loss and diarrhea
     c) In patients with primary disease,
        melanocytes are stimulated with
        hyperpigmentation (via  ACTH precursor
        hormone stimulation)
          i) face, axilla,nipples, areola, perineum
          ii) hyperpigmentation is not seen in
              primary pituitary or hypothalamic
             disease
d) Primary adrenal insufficiency
     i)  aldosterone  Na+ loss; K+
        retention; volume depletion 
        hypotension
     ii) heart smaller than normal (?
         Chronic hypovolemia)
     iii) hypoglycemia (via glucocorticoid
          deficiency) and impaired
          gluconeogenesis
     iv) acute stress in the patients (e.g.,
          infections, surgical procedures,
          trauma) may initiate an “acute
          adrenal crisis”
               - intractable vomiting
               - abdominal pain
               - hypotension, vascular collapse,
               - coma
               - death unless corticosteroids are
                 replaced immediately.
    2. Acute Adrenocortical Insufficiency
• Rapid withdrawal of steroids (from previous
  treatment)
• Massive adrenal hemorrhage
     a) destroy adrenal cortex
          i) may occur in patients maintained on
             chronic anticoagulant therapy
          ii) pregnancy
iii) DIC
iv) overwhelming sepsis (i.e.,
    Waterhouse-Friderichsen syndrome)
      - classically associated with
        Nisseria meningitides septicemia
      - also can be caused by
        pneumococci, Haemophilus
        influenza and pseudomonas sp.
      - pathogenesis unclear (may
        involve ETX induced vascular
        damage?)
      - DIC, shock, skin purpura
      - more common in children
      - massive adrenal clots
            Adrenocortical Neoplasms
• May be responsible for a variety of
  hyperadrenalisms
     a) functional adenomas most commonly
          associated with hyperaldosteronism and
          Cushing syndrome
• A virilizing neoplasm  high incidence to be
  carcinogenic
• Functional and non-functional adrenocortical
  neoplasms cannot be differentiated solely on
  basis of morphology
     a) hormone measurements
     b) most adrenocortical adenomas do not
          cause hyperfunction
• Adrenocortical carcinomas are rare
     a) two rare inherited adrenal cortical
        carcinomas
          i) Li-Fraumeni syndrome
                - autosomal dominant
                - predisposition to develop other
                  cancers due to mutations in p53
          ii) Beckwith-Wiedemann syndrome
• Generally, adrenal adenomas are small (1-2cm)
  whereas adrenal carcinomas are large, invasive
  lesions
     a) adrenal carcinomas metastasize via
        lymphatics and inferior vena cava
          i) mean survival is ~2 yrs.
                Adrenal Medulla
• Most important diseases of adrenal
  medulla are the neoplasms
    a) neuronal
         i) neuroblastoma
         ii) mature ganglionic cell tumors
    b) chromaffin cells
         i) pheochromocytoma
• Pheochromocytoma
    a) neoplasm composed of chromaffin cells
         i) synthesize and release
             catecholamines
    b) familial syndromes (~10%)
     i) MEN2A and MEN2B
     ii) type I neurofibromatosis
     iii) Von Hippel-Lindau disease
     iv) Sturge-Weber syndrome
c) Extra-adrenal source (~10%)
     i) carotid body
     ii) organ of Zuckerkandl
d) are bilateral (~10%)
     i) may be as high as 50% in familial
        cases
e) malignant (~10%)
     i) more common when arise in extra-
        adrenal sites
f) clinical
      i) hypertension!
             - chronic, elevated BP (~70% of
               cases)
      ii) other hormones can be secreted
             - ACTH
             - somatostatin
      iii) dx   urinary excretion of
          catecholamines and metabolites
             - vanillylmandelic acid
             - metanephrines
      iv) isolated pheochromocytomas
          treated surgically
             - multifocal  medically treated
 Multiple Endrocrine Neoplasia Syndromes
                  (MEN)

• Group of inherited diseases
     a) hyperplasias, adenomas and carcinomas
        of multiple endocrine organs
          i) occur at younger age vs. cancers
          ii) arise in multiple endocrine organs
          iii) even in one organ, they are
               multifocal
          iv) tumors preceded by hyperplasia
          v) more aggressive and recur more
               frequently vs. sporadic tumors
• MEN-1
     a) inherited as autosomal dominant
     b) is a tumor suppressor gene
           i) loss of MEN-1 therefore causes
              tumor genesis
                 - parathyroid (95% involved)
                 - pancreas (>40%)
                 - pituitary (>30%)
• Parathyroid gland
     a) primary hyperparathyroidism arising from
        hyperplasia is a common feature of
        MEN-1
• Pancreas
     a) leading cause of death in MEN-1
     b) aggressive
     c) often functional tumors
          i) gastrinomas (Zollenger-Ellison
             syndrome)
          ii) insulinomas and resultant
              hypoglycemia
• Pituitary
     a) most common in MEN-1 is prolactinoma
• MEN-2b (William syndrome)
    a) involve also the thyroid
    b) adrenal (medulla)
    c) major differences between MEN-2a and
       MEN-2b is
         i) do not develop primary
             hyperparathyroidism (MEN-2b)
         ii) develop at extra endocrine sites
               - lips
               - tongue
               - GI tract
• MEN-2 carry RET Protooncogene
    a) persons are advised to have prophylactic
       thyroidectomy to prevent carcinoma.

				
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