LMP301 2014 Lecture 10.pdf

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University of Toronto St. George
Laboratory Medicine and Pathobiology
Kenneth Yip

  Lecture  10:  Adrenal  Disease   Adrenal  Glands  and  Hormones     -­‐ small  triangular  shaped  glands  situated  just  above  the  kidney   -­‐ they  enlarge  in  chronic  stress   -­‐ the  hormones  of  the  adrenal  glands  are  essential  for  survival     -­‐ adrenal  gland  can  be  separated  into  2  layers:   1) outside  layer:  cortex   -­‐ can  be  separated  into  3  layers:   1. zona  glomerulosa:  most  outside  layer   à  produces  aldosterone   2. zona  fasciculate,  and  zona  reticularis :  inside  layers  à   produces  cortisol,  adrenal  androgens,  and  estrogens   2) inside  layer:  medulla   -­‐  produces  neuroendocrine  hormones   à  epinephrine,   norepinephrine,  and  dopamine     Biosynthesis  of  Steroid  Hormones   -­‐ all  of  these  hormones  start  from  a  common  precursor  –   cholesterol   -­‐ cortisol  and  aldosterone  and  androgens  goes  through   pathways  that  require  cholesterol   -­‐ because  aldosterone  is  from  the  most  outside  layer  of  the   adrenal  gland,  they  require  unique  enzymes  (18  OH ’ase  à   absent  in  other  layers)  à  reason  why  only  the  most  outside   layer  (zona  glomerulosa)  can  produce  aldosterone   -­‐ ACTH  is  the  main  driving  force  for  cortisol  and  androgens   -­‐ For  aldosterone,  there  are  different  regulation  pathways   (ACTH  also  involved,  but  not  important)   -­‐ Since  aldosterone  and  cortisol  share  the  same  enzyme,  their   precursors  may  share  similar  biological  functions     Cortical-­‐Physiology   -­‐ effects  on  metabolism:   o carbohydrate  –  promotion  of  gluconeogenesis  in  liver  (stimulates  liver  to  synthesize  glucose  release  to   circulation),  reduction  in  glucose  use  and  uptake  in  peripheral  tissues   o protein  –  increase  of  muscle  proteolysis   o fat  –  activation  of  lipolysis  and  release  of  free  fatty  acids  into  circulation   § when  present  in  excess:  glucocorticoids  cause  central  distribution  of  fat   –  face,  neck,  and  trunk   -­‐ circulating  forms:   o most  cortisol  circulating  are  bound,  free  cortisol  are  the  biologically  active  ones   o 90-­‐98%  protein  bound  to  cortisol -­‐binding  globulin  (CBG)  and  albumin   o CBG  synthesis  is  increased  in  pregnancy  and  estrogen  treatment  =  increasing  total  cortisol   -­‐ Metabolic  fate:  after  liver  conjugation,  cortisol  is  excreted  in  urine   o Excessive  cortisol  produced?  Free  cortisol  can  also  be  excreted  in  urine   à  present  in  some  disorders     Regulation  of  Cortisol   -­‐ hypothalamus  produce  CRH   -­‐ CRH  stimulates  pituitary  to  produce  ACTH   -­‐ ACTH  stimulates  adrenal  cortex  to  produce  cortisol   -­‐ Cortisol  can  have  negative  feedback  to  hypothalamus  and  pituitary   –   central  hypothalamus-­‐pituitary  axis   -­‐ Stress  and  sleep/wake  cycle  can  als o  affect  cortisol  levels   -­‐ Under  stress,  cortisol  synthesis  and  release  will  increase   o Patients  with  chronic  stress  will  have  enlarged  adrenal   glands  à  increase  of  cortisol  synthesis  =  cortisol  excess       Cushing’s  Syndrome   -­‐ results  from  prolonged  excessive  exposure  of  body  tissues  to       cortisol  or  other  glucocorticoid     -­‐ Causes:   -­‐ Pituitary  ACTH-­‐producing  tumor:  Cushing’s  disease  à  specific  to  pituitary  ACTH-­‐producing  tumors   -­‐ Ectopic  ACTH-­‐producing  tumor:  ACTH  produced  by  cells  other  than  pituitary   § e.g.  small  cell  carcinoma  in  the  lunch  may  secrete  ACTH   • if  the  tumors  produce  a  large  amount  of  ACTH,  you  can  expect  patient  (under  ACTH   stimulation)  to  have  a  lot  of  cortisol  produced   • tumors  producing  ACTH  can  cause  cortisol  excess  =  Cushing’s  syndrome   -­‐ Adrenal  cortisol-­‐producing  tumor  (Adenoma  or  carcinoma)  à  local  tumors  producing  cortisol  à  cause  of   Cushing’s  syndrome   -­‐ Exogenous  glucocorticoids  (taken  orally,  inhaled  or  applied  topically)  à  therapy  for  asthma,  skin  problems,   etc.  will  receive  a  large  dose  of  exogenous  glucocorticoids   à  can  cause  Cushing’s  Syndrome     Clinical  Features  of  Cushing’s  Syndrome   -­‐ common  features  we  see  in  patients  with  Cushing’s  syndrome:   -­‐ moon  shaped  face   -­‐ acne  on  face   -­‐ buffalo  hump  (fat  redistribution  in  the  back)   -­‐ abdominal  affect  redistribution   -­‐ may  present  skin  thinning   à  accumulation  of  fat  in   abdominal  area  will  stretch  the  skin  (thin  is  so  thin,   blood  vessels  are  visible)  =  abdominal  striae   -­‐ osteoporosis  –  cortisol  can  promote  bone  breakdown   and  stop  bone  regrowth  à  loss  of  bone  mass   -­‐ hypertension   -­‐ muscle  weakness  à  protein  breakdown     Diagnosis  of  Cushing’s  Syndrome   -­‐ need  more  than  50%  reduction  in  cortisol  to  say  there  is  enough   suppression   -­‐ screening  test:  24hour  urinary  free  cortisol   -­‐ cortisol  is  usually  bound  to  its  protein  in  the  circulation,   but  if  there  is  too  much  cortisol,  it  can  exceed  the  binding  capacity,  therefore,  increasing  plasma  cortisol   levels   -­‐ cortisol  exceeds  the  plasma  protein  binding  capacity,  so  unbo und  cortisol  is  filtered  into  urine   –  elevated   free  cortisol  in  Cushing’s;  but  stress  and  obesity  can  cause  false  positive  results   -­‐ plasma  cortisol:  measured  at  8am  and  10pm   -­‐ cortisol  produces  at  the  same  time  as  ACTH   à  follow  24  hour  circadian  rhythm   -­‐ high  peak  in  morning  (8am)  and  lowest  at  the  mid  of  night  (10pm)   -­‐ dramatic  difference  between  2  levels   à  cortisol  production  still  follows  normal  circadian  rhythm   à  can   rule  out  Cushing’s   -­‐ the  normal  ACTH  DEPENDENT  circadian  rhythm  (high  peak  in  the  morning)  is   not  apparent  in  the  patient   with  Cushing’s   -­‐ however,  in  Cushing’s  patients,  cortisol  production  is  not  controlled  =  do  not  follow  circadian  rhythm  =  no   difference  in  cortisol  levels  in  morning  and  night   -­‐ low  dose  (1mg)  dexamethasone  (cortisol  analogue)  test:  suppresses  cortisol  production  (>50%)  in  normal  subject   but  not  in  patients  with  Cushing’s  syndrome   -­‐ more  potent  than  cortisol   -­‐ if  you  measure  cortisol,  you  wont  detect  dexamethasone  (wont  interfere  with  assay)   -­‐ cortisol-­‐like  compound  à  should  be  able  to  suppress  ACTH  production  and  internal  cortisol  production  in   normal  subjects   -­‐ in  Cushing’s,  this  low  dose  dexamethasone  is  not  strong  enough  to  suppress  Cushing’s  syndrome   -­‐ if  you  do  not  see  expected  suppression  =  patient  may  have  Cushing’ s  syndrome   -­‐ cause  cannot  be  determined  with  this  test   -­‐ High  dose  dexamethasone  test   –  for  differential  the  cause  of  Cushing’s   -­‐ Suppresses  cortisol  production  (>50%)  in  Cushing’s   disease  but  not  in  other  Cushing’s  syndrome   caused  by  adrenal  adenoma  or  carcinom a,  ectopic  production  of  ACTH   -­‐ Strong  enough  to  suppress  the  pituitary  ACTH  producing  tumor,  but  not  strong  enough  to  suppress  ectopic   and  adrenal  ACTH  producing  tumor       -­‐ High  dose  dexamethasone  test  differentiates  between  Cushing’s  disease  and  other  causes  of  Cushing’s   syndrome   -­‐ Plasma  ACTH:  suppressed  in  adrenal  tumors  and  very  high  in  ectopic  ACTH  secreting  tumors   -­‐ Differentiates  between  ectopic  production  of  ACTH  and  adrenal  tumor  caused  syndrome   -­‐ ectopic  production  of  ACTH  in  cancer  patients:  their  ACTH  level  =  high   -­‐ adrenal  tumor  caused  syndrome:  tumor  producing  large  amount  of  cortisol,  local  ACTH  production  in   pituitary  will  be  low  à  negative  feedback  suppresses  pituitary  to  produce  ACTH     Case  1:  30  year  old  man  with  Cushing’s   -­‐ clinical  presentation:  obese,  hypertensive,  glucose  intolerance,  wasting  of  proximal  limb  muscles,  and  abdominal   striae   -­‐ laboratory  findings:   1) screening:  plasma  cortisol  concentrations  measured  at  8am  was  400nmol/L,  and  at  10pm  it  was  400nmol/L   -­‐  no  difference  between  morning  and  night  =  Cushing’s   2) conformation  of  Cushing’s:  low  dose  dexamethasone  test:  baseline  420nmol/L,  post  410nmol/L   -­‐  no  suppression  –  Cushing’s  syndrome  (do  not  know  cause)     3) differential  diagnosis  of  cause  of  Cushing’s:   -­‐ high  does  dexamethasone  test:  baseline  420nmol/L,  post  400nmol/L   -­‐ no  suppression  –  exclude  Cushing’s  disease  (Cushing’s  disease  caused  by  pituitary  ACTH  producing   tumor  with  large  dose  of  dexamethasone  –  large  dose  is  strong  enough  to  suppress  Cortisol  production   -­‐ don’t  see  suppression,  so  patient  has  either  adrenal  tumor  or  ectopic  ACTH  tumor   -­‐ plasma  ACTH:  at  8am,  150ng/L  (normal  range:  7-­‐51)   -­‐ significantly  elevated   -­‐ diagnosis:  ectopic  ACTH  producing  tumor   -­‐ glucose  intolerance  –  patient  with  excessive  cortisol  producti on  à  cortisol  affects  glucose  metabolism,   increase  liver  synthesis  of  glucose,  and  reduce  peripheral  tissue  uptake  of  glucose   § glucose  levels  increased  in  these  patients   § cortisol  is  a  counter-­‐hormone  of  insulin  (causes  glucose  uptake  by  cells)         • note*  the  4  counter  hormones  of  insulin:   1) cortisol   2) growth  hormone   3) produces  catecholamine’s  (epinephrine’s  and  norepinephrine’s)   4) glucagon   -­‐ all  can  increase  glucose  levels   -­‐ when  patient  has  hypoglycemia,  these  4  hormones  kick  in  and  quickly  increase  glucose  levels   -­‐ hypoglycemia  is  life  threatening     Aldosterone  –  Physiology     -­‐ produced  exclusively  by  the  zona  glomerulosa  (because  of  the  unique  enzyme)   -­‐ lacks  17-­‐  hydroxylase  but  has  18-­‐hydroxylase  and  18-­‐hydroxysteroid  dehydrogena se  for  aldosterone   biosynthesis   -­‐ Regulation  of  synthesis  and  secretion:   primarily  by  the  renin-­‐ angiotensin  system   -­‐ Other  factors,  including  AC TH,  potassium  are  also  involved   -­‐ Biological  effect:     -­‐ Regulates  water  and  electrolytes   -­‐ Increase  sodium  and  water  retention   -­‐ Promote  potassium  and  hydrogen  ion  secretion   -­‐ Sodium  and  water  retention  à  Raises  BP   -­‐ Patients  with  aldosterone  excess  will  have  high  blood   pressure  (hypertension)  à  like  patients  with  Cushing’s  also   have  hypertension  (during  cortisol  synthesis  pathways,  all   the  precursors  after  the  enzyme  21  OH’ase  share  the  same   biological  effect  with  aldosterone   à  aldosterone-­‐like  effect   -­‐ All  of  the  21-­‐hydroxylated  steroids  (e.g.  cortisol  precursors)
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