LMP301 2014 Lecture 12.pdf

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Laboratory Medicine and Pathobiology
Kenneth Yip

  Lecture  12:  Calcium,  Vitamin  D  &  Parathyroid   Calcium  Fluxes  in  a  Normal  Adult   -­‐ calcium  balanced  is  maintained  by  intake  of  food     -­‐ then  active  exchange  of  intake  through  blood  circulation  and   exchange  between  the  bones   -­‐ some  are  excreted  through  kidney  (c annot  be  absorbed  or   exchanged  by  extracellular  fluid)   -­‐ overall,  intake  =  excretion  balanced  for  healthy  bones     Hormone  Regulation  of   Calcium  Homeostasis   -­‐ parathyroid   hormone  (PTH)   -­‐ 1,25  (OH)  vitD   2 -­‐ calcitonin     Parathyroid  Glands  and  Parathyroid  Hormone  (PTH)   -­‐ PTH  produced  by  parathyroid  glands   -­‐ 4  glands  that  surround  the  thyroid  glands   –  they  produce  PTH     Responses  to  a  Change  of  Serum   [Ca2+]   -­‐ ↓  in  calcium  =  ↑  in  PTH   -­‐ ↑  in  calcium  =  ↓  in  PTH   -­‐ PTH:   o Effect  on  the  bone:  ↑  in  bone  reabsorption   § More  calcium  released  from  bones   § Bones  are  the  largest  storage  of  calcium   o Effect  on  the  kidney:  ↑  in  Ca2+  reabsorption,   ↑  in  1-­‐hydroxylase  and   1,25(OH)2vitD,  ↓  in  phosphate  reabsorption   § Opposite  –  increase  calcium,  decrease   phosphate   § increase  in  1-­‐hydroxylase  in  the  kidney,   and  increase  in   1,25(OH)2vitD       Vitamin  D  and  its  Metabolites   -­‐ humans  get  it  from  precursor  7 -­‐ Dehydrocholesterol  provitamin  D3   -­‐ through  the  skin,  under  UV  stimulation,  we  can   synthesis  Vitamin  D   -­‐ goes  to  the  liver  through  circulation,  the  liver  has   the  enzyme  25-­‐hydroxylase  à  synthesize  25-­‐ hydroxyVitD   -­‐ in  the  kidney,  it  produces  1-­‐alpha-­‐hydroxylase  to   convert  25-­‐OH-­‐D3  to  1,25dihydroxy-­‐VitD   -­‐ 1,25dihydroxy-­‐VitD  is  the  active  hormone   o can  be  further  metabolized  by  24-­‐ hydroxylase  to  become  inactive  and   excreted     -­‐ we  get  out  vitamin  D  through  the  sun,  milk,  fish   -­‐ 1,25dihydroxy-­‐VitD  functions:  regulate  calcium  balance   (homeostasis),  maintain  bone  and  muscle  health,  functions   as  immnomodulators  (to  prevent  immune  disease),   paracrine  and  autocrine  functions   -­‐ endocrine:  hormones  secreted  into  the  blood   -­‐ paracrine  and  autocrines:  affect  nearby/own  cells  to   regulate  function   -­‐ pancreas,  prostate,  breast,  colon   –  all  of  these  tissues       contain  1-­‐hydroxylase  à  they  can  convert  25(OH)D3  to  1,25dihydroxy -­‐VitD  à  these  tissues  can  affect  their  own  cells   and  near  by  cells  (wont  have  overall  circulation  concentration,  but  can  have  a  local  concentration  of  the  hormone  to   regulate  cell  growth)   o patients  with  higher  vitamin  D  levels  =  lower  risk  of  cancer   o vitamin  D  supplements  =  cancer  prevention     1,25  (OH) 2  vitD  –  Hormonal  Effects   -­‐ Effect  on  intestine:     o ↑Ca2+  absorption   o ↑phosphate  absorption   -­‐ Effect  on  bone:     o ↑bone  resorption   -­‐ Effect  on  parathyroid  gland:   o ↓PTH  synthesis  and  secretion   -­‐ Inhibits  its  own  synthesis  and  stimulates  its  metabolism   o If  there  is  enough  1,25 2(OH)  vitD,  it  will  decrease  1-­‐hydroxylase  expression  and  increase  24 -­‐hydrozylase   secretion   o Decrease  synthesis,  increased  metabolism   -­‐ Most  of  the  1,25  2OH)  vitD  is  bound  to  vitamin  D-­‐binding  protein  in  the  circulation  (they  are  steroid  horones)   -­‐ Actions  via  specific  nuclear  vitamin  D  receptor   o binds  gene  response  element   o affects  gene  expression  à  how  VitD  affects  gene  expression     Calcitonin   -­‐ effects  calcium  concentration,  but  in  normal  subjects,  it  is  not  a  major  force  of  hormonal  regulation  of  calcium   -­‐ 32-­‐amino  acid  peptide,  secreted  by  the  parafollicular  or  C  cells  of  thyroid  gland   -­‐ Stimulated  by  high  [Ca2+],  and  GI  hormones  (e.g.  gastrin  and  pentagastrin)   -­‐ Effect  on  serum  [Ca]:  Ca ↓ 4  PO ↓   o its  function  is  usually  not  significant  in  the  regulation  of  normal  calcium  homeostasis   -­‐ Inhibits  bone  resorption  by  osteoclasts     o used  for  treatment  of  postmenopausal  osteoporosis,  Paget’s  disease,  etc.   -­‐ Tumour  marker   o medullary  thyroid  carcinoma  (a  tumour  of  the  C  cells)     Clinical  Significance  of  Calcium   -­‐ Hypocalcemia     o presents  with  neuromuscular  hyperexcitability,  such  as  tetany,  Trousseau’s  sign   o TETANY:  a  syndrome  manifested  by  sharp  flexion  of  the  wrist  and  ankle   joints,  muscle  twitching   and  cramps   -­‐ Hypercalcemia     o presents  with  reduced  neuromuscular  excitability   o causes    fatigue,  weakness,  depression,  inability  to  concentrate   o may  induce  mild  nephrogenic  diabetes  insipidus  with  thirst,  polydipsia  and  polyuria  (ADH  resistance)   § abnormal  potassium  concentration  will  also  cause  ADH  resistance     § here  polydipsia  and  polyuria  is  due  to  hypercalcemia   § renal  stone  from  chronic  hypercalcemia  and  hypercalciuria   • lots  of  calcium  excreted  in  urine     Causes  of  Hypocalcemia   -­‐ Hypoparathyroidism:  idiopathic,  postsurgical     o Parathyroid  glands  fail  to  produce  PTH   -­‐ Pseudohypoparathyroidism  (PTH  resistance)     o PTH  receptor  deficiency  or  defect   o Receptor  cannot  response  to  PTH   o But  feedback  will  increase  PTH  express,  but  no  downstream   response   o Patient  will  have  hypothyroidism  with  high  PTH  levels   o PTH  level  is  high,  low  calcium   -­‐ Magnesium  deficiency     o Magnesium  influences  the  secretion  of  PTH  (PTH  relies  on  magnesium)       o Severe  hypomagnesemia  may  cause  hypoparathyroidism   § Deficiency  in  magnesium  =  parathyroid  gland  cannot  secrete  PTH   § In  order  to  treat  this  type  of  hypocalcaemia,  have  t  give  magnesium     -­‐ Renal  failure     o Can  cause  hypocalcaemia  à  renal  disease  causes  renal  tissue  to  have  problems  in  producing  1 -­‐ hydroxylase  and  failure  in  excreting  p hosphate   o due  to  phosphate  retention  and  1,25(OH)2 vitD  deficiency   -­‐ Vitamin  D  deficiency  –  causes  hypocalcaemia:     o dietary     o lack  of  sun  exposure   o malabsorption  (cannot  efficiency  absorb  from  diet)   o chronic  liver  disease  –  liver  cells  cannot  convert  vitamin  D  into 21,25  (OH)  vitD  =  vitamin  D  deficiency       o chronic  renal  disease   o vitamin-­‐D  dependent  rickets  –  causes  hypocalcaemia  as  well     What  are  the  Calcium  and  PTH  levels  in  Renal  Failure  and  Vitamin  D    ciency? -­‐ low  calcium,  high  PTH   What  are  the  causes  of  Secondary  Hyperparathyroidism?   -­‐ renal  failure  and  vitamin  D  deficiency  can  cause  secondary  hyperparathyroidism     o secondary:  causes  outside  the  parathyroid  glands   o these  causes  are  outside  –  nothing  to  do  with  parathyr oid  gland   o parathyroid  gland  is  healthy,  respond  to  low  calcium  to  increase  PTH  secretion   -­‐ over  secretion  of  PTH  by  the  parathyroid  glands  =  primary  hyperparathyroidism       Causes  of  Hypercalcemia   -­‐ Mechanisms:     o Increased  intestinal  absorption:  e.g.  Vit  D  intoxication   o Enhanced  renal  retention  of  calcium   o Increased  bone  resorption:  e.g.  immobilization   o combination  of  above   -­‐ Primary  hyperparathyroidism     -­‐ Malignancies:  cancer  with  or  w/o  bone  metastases  (e.g.  PTHrP)   o Some  cancer  cells  can  produce  PTHrP  (parathyroid  hormone  related  peptide)   à  peptide  is  produced  by  a   different  gene  (not  the  PTH  gene)   o But  this  peptide  shares  the  same  N -­‐terminal  as  PTH  =  can  bind  to  PTH  receptors  to  mimic  PTH  function   à   increase  calcium  resorption  from  the  kidney  and  incre ase  phosphate  excretion   o But  this  peptide  CANNOT  increase  1-­‐hydroxylse  expression  à  no  increase  of  1,25  (OH)  vitD   2 o Patients  with  abonormally  high  PTHrP:  hypercalcemia  and  low  phosphate   o This  hormone  is  also  expressed  on  normal  tissues,  not  only  on  tumors à  but  expression  is  much  higher  in   tumors  à  enough  to  cause  hypercalemia     • Derived  from  a  gene  on  chromosome  12,   distinct  from  PTH  gene  on  chromosome  11   • N-­‐terminal  end  showing  close  homology  to  PTH  (8  of  the  first  13  amino  acids),  the  remainder  with  little   homology   • Binding  to  PTH  receptor,  mimi cking  biological  actions  of  PTH   • PTH
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