LMP301 2014 Lecture 9.pdf

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Laboratory Medicine and Pathobiology
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Kenneth Yip

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    Lecture  9  :  Thyroid  Diseases   Goiter   -­‐ Enlarged  thyroid  gland   o May  be  associated  with  hypo,  hyper  or  eu -­‐thyroid  (no  thyroid  problem)   o Malnutrition?  Thyroid  gland  would  try  to  enlarge  the  number  of  cells  to  produce  more   tissues  and  accumulate  more  iodine  from  diet   à  goiter  is  adaptation  to  environment     Thyroid  Gland  and  Thyroid  Hormones   -­‐ thyroid  gland  secretes  mostly  T4  and  some  T3   -­‐ the  peripheral  tissues  (e.g.  the  liver  and  kidney  –  can  convert  T4  to  T3)  deiodinate    T4  to   produce  2/3  of  the  circulating  T3  (peripheral  conversion)   -­‐ thyroid  hormones  bind  to  receptors  and  triggers  the  hormonal  effects   -­‐ T3  is  more  biologically  active  than  T4 ,  but  at  a  lower  concentration  in  plasma  (2nmol/L  for  T3   vs  100nmol/L  for  T4)   -­‐ Reverse  T3  (rT3)  is  an  inactive  form  metabolized  from  T4   -­‐ T3  binds  to  receptor  and  triggers  target  cell  to  promote  metabolism   -­‐ Local  thyroid  status  can  be  modulated  b y  the  relative  production  of  T3  and  rT3   -­‐ Thyroid  hormones  are  essential  for  the  normal  maturation  and  metabolism  of  all  tissues  in  the   body     Synthesis  of  Chemical   1) tyrosine  (amino  acid)  is  a  precursor   2) from  diet,  thyroid  gland  accumulates  iodine  à  gets   converted  to  a  more  active  form  so  it  can  bind  to  a   tyrosine  molecule   3) If  there  is  only  1  iodine  attached  =   monoiodotyrosine  (MIT)   • If  there  is  2  iodines  attached  =  diiodotyrosine   (DIT)   4) If  2  of  the  diiodotyorsine  is  coupled  together  =  T4   • There  are  4  iodines  attached  to  the  2  DITs   5) If  there  is  1  monoform  and  1  diiodoform  coupled   together  =  T3   • From  T4,  they  can  also  lose  one  of  the  iodine  to   form  T3   6) In  rT3,  iodine  is  in  a  different  position  and  one  is   active,  another  is  inactive   -­‐ peripheral  tissue  (by  adjusting  how  much   conversion  to  T3  or  rT3  =  fine  tuning  of  local  thyroid  hormone  effect)       Hypothalamus-­‐Pituitary-­‐Thyroid  Axis   1) hypothalamus  produces  TRH   2) TRH  stimulates  the  Anterior  Pituitary  to  release  TSH   3) TSH  goes  to  the  thyroid  gland  and  binds  the  TSH  receptor   à  promote  thyroid   gland  to  release  T4  and  T3   -­‐ thyroid  hormones  connect  the  feedback  to  the  pituitary  ad  hypothalamus   à   when  there  are  enough  thyroid  hormone  in  the  circulation,  they  will  reduce  TRH   and  TSH  production   -­‐ same  mechanism,  TSH  can  also  have  a  negat ive  feedback  to  the  hypothalamus  to   adjust  TRH  release   -­‐ fine  tuning  of  T3  and  rT3  production  in  peripheral  tissues   à  locally  adjust  response  to  thyroid  hormone     Total  vs.  Free   -­‐ in  the  circulation,  most  of  thyroid  hormones  bind  to  their  binding  proteins   -­‐ reversibly  bound  to  carrier  proteins   o e.g.  T4-­‐binding  globulin  (TBG),  some  will  bind  to  albumin       -­‐ only  very  small  fraction  is  unbound  and  free  for  biological  activity  à  these  are  the  active  hormones  à  bind  receptors   to  cause  biological  effect     • only  0.03%  of  T4’s  are  in  the  free  form   • 0.3%  of  T3’s  are  in  the  free  form   -­‐ alterations  in  the  concentration  or  affinity  of  binding  proteins  may  change  the  concentration  of  thyroid  hormones   o in  the  circulation,  if  there  is  a  change  in  the  binding  protein  concentration,  or   binding  protein  affinity  to  the   hormone  à  balance  between  bound  and  free  will  also  change   -­‐ FT4  and  FT3  vs.  total  T4  and  total  T3   –  which  are  the  better  markers  in  routine  assessment  of  thyroid  function?     Changes  of  TBH  Binding  Affects  Thyroid  Function  Tests   Cause   Compound   Effects   Increase  TBG   Estrogen   ↑  T4,  T3  /  ↔  FT4,  TSH   (by  increasing  liver  production)   -­‐  can  decrease  TBG  synthesis  in  the  liver   à  when  there  is  an  increase   -­‐  less  binding  protein  (less  T3  and  T4  bound  to  the  binding   level  of  TBG  in  the  circulation   protein  =  bound  form  is  decreased)   à  more  binding  protein  =  more   -­‐  but  because  the  normal  patient  with  functioning  thyroid  can   thyroid  hormone  bound     immediately  respond  to  change  of  hormone  status,  they  can   à  but  in  a  normal  patient  with   maintain  normal  thyroid  status   à  adjust  T4  level  to  be  normal   a  normal  thyroid  function,  they   à  total  hormone  (because  bound  fraction  has  been  decreased)   can  maintain  normal  thyroid   à  adjust  total  hormone  level  in  response  to  bound   hormone  status  =  free  T4  is   increase/decrease  à  maintain  free  hormone  to  be  normal   maintained  as  normal,  but  total   (therefore,  TSH  also  maintained  to  be  normal   à  feedback   hormone  level  is  increase   pathway)   (bound  is  increased)   Oral  contraceptive   Decrease  TBG   Androgen   ↓  T4,  T3  /  ↔  FT4,  TSH   Glucocorticoids   Inhibit  binding  of  T4/T3  to   Salicylates   ↓  T4  /  ↔  FT4   TBG   -­‐  medication   -­‐  inhibit  binding  of  thyroid  hormones  to  TBG  à  decrease  binding   affinity   -­‐  same  effect  as  decrease  in  binding  =  l ess  bound  form   -­‐  but  because  this  medication  has  nothing  to  do  with  the  thyroid   gland  à  assume  in  normal  subject,  the  thyroid  gland  can  respond   to  change  in  binding  to  return  free  t4  to  normal,  and  decrease   total  T4  levels   -­‐  free  hormone  is  more  important  to  biological  effect  of  thyroid   gland  and  thyroid  hormone  status   -­‐  the  total  hormone  fluctuates  through  the  binding  protein   change   -­‐  measure  FT4/FT3  in  the  laboratory   MYXEDEMA:  Dry,  Waxy  Swelling  of  the  Skin,  with  A bnormal  Deposits   of  Glucosaminoglycans  (unbranched  polysaccharides )   -­‐ change  in  the  appearance  of  an  untreated  hypothyroid   female  over  11  year  period   -­‐ this  dramatic  change  reflects  thyroid  function  (not  just  age)  -­‐   hypothyroidism   -­‐ myxedema:  skin  accumulates  in  deposits  of  unsaturated   polysaccharides     -­‐ enlarged  thyroid  gland  due  to  iodine  deficiency     Symptoms  and  Signs  of  Hypothyroidism  –  Hypometabolic  Syndrome   -­‐ low  thyroid  hormone     -­‐ symptoms  and  signs:   o weight  gain   o easy  fatigue  (less   energy  and   o depression   energy,  less  thyroid   metabolism)   hormone  to  produce   o lethargy       o cold  intolerance   o deep,  hoarse  voice   o Bradycardia  (slow   o hair  loss   o dry,  coarse  skin   heart  rate)  à  less   o constipation  (less   o myxedema   hormone  to  produce   intestine  movement)   o high  cholesterol   heart  beat  and  less   o growth  retardation   (decrease  in  LDL   metabolism in  children   receptors)     Cause  of  Hypothyroidism   -­‐ primary  hypothyroidism  (targets  endocrine  gland  –  thyroid  gland)   o autoimmune  destruction  of  the  thyroid  gland     § thyroid  gland  failed  to  produce  thyroid  hormone   § Hashimoto’s  Disease:  auto-­‐antibody  targets  the  thyroid  gland   • Destroys  the  thyroid  gland  so  it  cannot  function  and  produce  hormones   o Radioiodine  or  surgical  treatment  of  hypothyroidism   o Iodine  deficiency   o Congenital  defects  in  hormone  biosynthesis  and  action   o Transient  hypothyroidism  due  to  drug  therapy  (antithyroid  drugs)   § After  stop  of  treatment,  thyroid  gland  can  go  back  to  normal   -­‐ secondary  hypothyroidism  (targets  the  pituitary)   o pituitary  disease   o pituitary  fails  to  produce  TSH   à  thyroid  gland  does  not  get  enough  TSH   à  cannot  produce  hormone   o giving  TSH  =  thyroid  gland  goes  back  to  normal  to  produce  hormones   -­‐ tertiary  hypothyroidism   o hypothalamic  disease  (caused  by  the  hypothalamus)   o hypothalamus  fails  to  produce  TRH     Diagnostic  Strategy  for  Suspected   Hypothyroidism   -­‐ if  suspected  of  hypothyroidism,  screen   test  for  TSH  and  fT4   • high/normal  TSH  and  high   fT4  =  not  hypothyroid   • high  TSH  and  low  fT4  =   primary  hypothyroidism   § low  fT4  =  less  thyroid   hormone  =   hypothyroidism   § pituitary  is  functioning,  but  thyroid  gland  failed   • high  TSH  and  normal  fT4  =  subclinical  hypothyroidism   § not  hypothyroidism  yet   § but  high  TSH  –  fT4  not  enough  to  maintain  normal  thyroid  hormone  requirements   • low/normal  TSH  and  low  fT4  =  secondary  hypothyroidism   § caused  by  the  pituitary  =  secondary  hypothyroidism     § isn’t  enough  TSH  to  promote  T4  production     Complications  of  Hypothyroidism   -­‐ depending  on  when  during  life  a  patient  is  hypothyroid,  clinical  outcomes  vary   -­‐ pregnancy:  if  the  pregnant  women  develops  hypothyroidism  =  irreversible  fetal  malformation,  
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