Difference between revisions of "Parathyroid glands"

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[[Image:Parathyroid gland high mag.jpg|thumb|right|280px|[[Micrograph]] of a parathyroid gland. [[H&E stain]].]]
The '''parathyroid glands''' are an endocrine organ that is important in calcium regulation.  They often make an appearance in the context of [[thyroid surgery]].   
The '''parathyroid glands''' are an endocrine organ that is important in calcium regulation.  They often make an appearance in the context of [[thyroid surgery]].   
They produce parathyroid hormone (PTH). PTH acts to increase serum calcium and is important in the regulation of the calcium balance. 


=Clinical=
=Clinical=
==Overview - hyperparathyroidism==
==Hyperparathyroidism==
Classification:
*Definition: increased secretion of ''parathyroid hormone'' (PTH).<ref name=emed_hyperparathyroid>URL: [http://emedicine.medscape.com/article/127351-overview http://emedicine.medscape.com/article/127351-overview]. Accessed on: 24 January 2013.</ref>
*Primary.<ref name=Ref_PBoD8_1127>{{Ref PBoD8|1127}}</ref>
 
**~90% parathyroid adenoma, ~10% parathyroid hyperplasia, ~1% parathyroid carcinoma.
What PTH does:<ref name=emed_hyperparathyroid>URL: [http://emedicine.medscape.com/article/127351-overview http://emedicine.medscape.com/article/127351-overview]. Accessed on: 24 January 2013.</ref>
*Increase serum calcium.
*Decrease serum phosphate.
 
===Classification===
*Primary.
*Secondary.
*Secondary.
*Tertiary.  
*Tertiary.  
====Overview in a table====
{| class="wikitable sortable"
! Type
! PTH
! Calcium
! Common causes
|-
| Primary hyperparathyroidism
| high
| high
| [[parathyroid adenoma]] (~85-90% of cases), [[parathyroid hyperplasia]] (~10-15% of cases)
|-
| Secondary hyperparathyroidism
| high
| low or normal
| chronic renal failure, vitamin D deficiency<ref name=emed_hyperparathyroid_2ndary>URL: [http://emedicine.medscape.com/article/127351-overview#aw2aab6b5 http://emedicine.medscape.com/article/127351-overview#aw2aab6b5]. Accessed on: 24 January 2013.</ref>
|-
| Tertiary hyperparathyroidism
| high
| high
| persistent hyperparathyroidism after renal transplant;<ref name=emed_hyperparathyroid_tertiary>URL: [http://emedicine.medscape.com/article/127351-overview#aw2aab6b6 http://emedicine.medscape.com/article/127351-overview#aw2aab6b6]. Accessed on: 24 January 2013.</ref> arises in the context of secondary hyperparathyroidism<ref name=pmid26163537>{{Cite journal  | last1 = Duan | first1 = K. | last2 = Gomez Hernandez | first2 = K. | last3 = Mete | first3 = O. | title = Clinicopathological correlates of hyperparathyroidism. | journal = J Clin Pathol | volume = 68 | issue = 10 | pages = 771-87 | month = Oct | year = 2015 | doi = 10.1136/jclinpath-2015-203186 | PMID = 26163537 }}</ref>
|}
====Genetics====
Genes implicated in hyperparathyroidism:<ref name=pmid22187299>{{Cite journal  | last1 = Starker | first1 = LF. | last2 = Akerström | first2 = T. | last3 = Long | first3 = WD. | last4 = Delgado-Verdugo | first4 = A. | last5 = Donovan | first5 = P. | last6 = Udelsman | first6 = R. | last7 = Lifton | first7 = RP. | last8 = Carling | first8 = T. | title = Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. | journal = Horm Cancer | volume = 3 | issue = 1-2 | pages = 44-51 | month = Apr | year = 2012 | doi = 10.1007/s12672-011-0100-8 | PMID = 22187299 }}</ref><ref name=pmid23652676>{{Cite journal  | last1 = Hendy | first1 = GN. | last2 = Cole | first2 = DE. | title = Genetic defects associated with familial and sporadic hyperparathyroidism. | journal = Front Horm Res | volume = 41 | issue =  | pages = 149-65 | month =  | year = 2013 | doi = 10.1159/000345675 | PMID = 23652676 }}</ref>
*MEN1.
*CASR.
*HRPT2/CDC73.
*CDKN1B.
*RET.
====Hypercalcemia DDx====
Mnemonic ''GRIMED'':<ref>{{Ref TN2006| Emerg.}}</ref>
*Granulomatous disease ([[tuberculosis]], [[sarcoidosis]]).
*Renal disease.
*Immobility.
*Malignancy (esp. squamous cell carcinoma, [[plasmacytoma]]).
*Endocrine (primary hyperparathyroidism, tertiary hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH)).
*Drugs (thiazides ... others).
Note:
*Hyperparathyroidism and FHH are assoc. with an increased PTH.<ref name=Ref_PBoD8_1129>{{Ref PBoD8|1129}}</ref>
**Other causes are assoc. with a decreased PTH.
====Primary hyperparathyroidism====
Cause:<ref name=Ref_PBoD8_1127>{{Ref PBoD8|1127}}</ref>
*[[Parathyroid adenoma]] ~90%.
*[[Parathyroid hyperplasia]] ~10%.
*[[Parathyroid carcinoma]] ~1%.


Familial causes of primary hyperparathyroidism:
Familial causes of primary hyperparathyroidism:
*[[MEN 1]].
*[[MEN 1]].
*[[MEN 2]].
*[[MEN 2A]].
*Familial hypocalciuric hypercalcemia.
*Familial hypocalciuric hypercalcemia.
**Autosomal dominant.
**Autosomal dominant.
**CASR (calcium sensing receptor) gene defect.<ref name=omim601199>{{OMIM|601199}}</ref>   
**CASR (calcium sensing receptor) gene defect.<ref name=omim601199>{{OMIM|601199}}</ref>
 
Classic manifestations ''moans, stones, bones, (abdominal) groans, psychiatric overtones''.<ref>{{Cite journal | last1 = Lienert | first1 = D. | last2 = Rege | first2 = S. | title = Moans, stones, groans, bones and psychiatric overtones: lithium-induced hyperparathyroidism. | journal = Aust N Z J Psychiatry | volume = 42 | issue = 2 | pages = 171-3 | month = Feb | year = 2008 | doi =  | PMID = 18350681 }}
</ref><ref>URL: [http://www.usmleforum.com/files/forum/2010/1/505388.php http://www.usmleforum.com/files/forum/2010/1/505388.php]. Accessed on: 4 December 2011.</ref>
*Moans = bone pain.
*Stones = [[nephrolithiasis]] (kidney stones).
*Bones = bone pathology, e.g. osteitis fibrosa cystica.<ref>{{Cite journal  | last1 = França | first1 = TC. | last2 = Griz | first2 = L. | last3 = Pinho | first3 = J. | last4 = Diniz | first4 = ET. | last5 = Andrade | first5 = LD. | last6 = Lucena | first6 = CS. | last7 = Beserra | first7 = SR. | last8 = Asano | first8 = NM. | last9 = Duarte | first9 = AP. | title = Bisphosphonates can reduce bone hunger after parathyroidectomy in patients with primary hyperparathyroidism and osteitis fibrosa cystica. | journal = Rev Bras Reumatol | volume = 51 | issue = 2 | pages = 131-7 | month = Apr | year = 2011 | doi =  | PMID = 21584419 }}</ref>
*Groans = constipation.
*Psychiatric overtones = CNS pathology.
**Can include: lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.


==Hypercalcemia DDx==
==Hypoparathyroidism==
Mnemonic ''GRIMED'':<ref>TN06 Emerg.</ref>
*Rare vis-à-vis hyperparathyroidism.
*Granulomatous disease (tuberculosis, [[sarcoidosis]]).
*Classically iatrogenic, i.e. the surgeon removing 'em.<ref name=Ref_PBoD8_1129>{{Ref PBoD8|1129}}</ref>
*Renal disease.
 
*Immobility.
Other causes:<ref name=Ref_PBoD8_1130>{{Ref PBoD8|1130}}</ref>
*Malignancy (esp. squamous cell carcinoma, [[plasmacytoma]]).
*Autoimmune hypoparathyroidism.
*Endocrine (primary hyperparathyroidism - leads to brown cell tumour).
*Autosomal dominat hypoparathyroidism.
*Drugs (thiazides ... others).
*Familial isolated hypoparathyroidism.
*Congenital absence ([[DiGeorge syndrome]]).
*Drugs - [[proton pump inhibitors]].<ref name=pmid24736034>{{Cite journal  | last1 = Deroux | first1 = A. | last2 = Khouri | first2 = C. | last3 = Chabre | first3 = O. | last4 = Bouillet | first4 = L. | last5 = Casez | first5 = O. | title = Severe acute neurological symptoms related to proton pump inhibitors induced hypomagnesemia responsible for profound hypoparathyroidism with hypocalcemia. | journal = Clin Res Hepatol Gastroenterol | volume = 38 | issue = 5 | pages = e103-5 | month = Oct | year = 2014 | doi = 10.1016/j.clinre.2014.03.005 | PMID = 24736034 }}</ref><ref name=pmid25138239>{{Cite journal  | last1 = Toh | first1 = JW. | last2 = Ong | first2 = E. | last3 = Wilson | first3 = R. | title = Hypomagnesaemia associated with long-term use of proton pump inhibitors. | journal = Gastroenterol Rep (Oxf) | volume =  | issue =  | pages =  | month = Aug | year = 2014 | doi = 10.1093/gastro/gou054 | PMID = 25138239 }}</ref>


=Normal parathyroid glands=
=Normal parathyroid glands=
:The [[cytology]] is dealt with in ''[[normal parathyroid cytology]]''.
===General===
===General===
*Identification of normal can be tricky.
*Identification of normal can be tricky.
Line 44: Line 114:
***Chief cells - predominant cell type, small, cytoplasm has variable staining (hyperchromatic-clear-eosinophilic).
***Chief cells - predominant cell type, small, cytoplasm has variable staining (hyperchromatic-clear-eosinophilic).
***Oxyphil cells (''acid staining'' cells<ref>[http://dictionary.reference.com/search?q=oxyphil%20cell http://dictionary.reference.com/search?q=oxyphil%20cell]</ref>) - abundant cytoplasm.
***Oxyphil cells (''acid staining'' cells<ref>[http://dictionary.reference.com/search?q=oxyphil%20cell http://dictionary.reference.com/search?q=oxyphil%20cell]</ref>) - abundant cytoplasm.
***Adipocytes - increased with age, may be used to help differentiate from thyroid - '''key feature'''.
***Adipocytes - dependent on age, body habitus, PT hormone, size of gland.<ref name=pmid7551007>{{Cite journal  | last1 = Iwasaki | first1 = A. | last2 = Shan | first2 = L. | last3 = Kawano | first3 = I. | last4 = Nakamura | first4 = M. | last5 = Utsuno | first5 = H. | last6 = Kobayashi | first6 = A. | last7 = Kuma | first7 = K. | last8 = Kakudo | first8 = K. | title = Quantitative analysis of stromal fat content of human parathyroid glands associated with thyroid diseases using computer image analysis. | journal = Pathol Int | volume = 45 | issue = 7 | pages = 483-6 | month = Jul | year = 1995 | doi =  | PMID = 7551007 }}</ref>
****Increased with age, may be used to help differentiate from thyroid - '''key feature'''.


====Images====
<gallery>
Image:Parathyroid_gland_intermed_mag.jpg | Parathyroid gland - intermed. mag. (WC)
Image:Parathyroid_gland_high_mag.jpg | Parathyroid gland - cropped - high mag. (WC)
Image:Parathyroid_gland_high_mag_cropped.jpg | Parathyroid gland - high mag. (WC)
</gallery>
www:
*[http://library.med.utah.edu/WebPath/ENDOHTML/ENDO031.html Parathyroid - med.utah.edu].
*[http://pathology.mc.duke.edu/research/PTH225.html Histology - several images. - pathology.mc.duke.edu].


====Parathyroid cell types====
{| class="wikitable"
{| class="wikitable"
| '''Name''' || '''Staining (cytoplasm)''' || '''Quantity of cells''' ||  '''Cytoplasm (quantity)''' || '''Function'''
! Name
|-  
! Staining (cytoplasm)
| (parathyroid) chief cells  || intense hyperchromatic to eosinophilic (see note) || abundant || moderate || manufacture PTH  
! Quantity of cells  
|-  
! Cytoplasm (quantity)  
| oxyphil cells  || moderate/light hyperchromatic to eosinophilic || rare || abundant || ?
! Function
! Image
|-  
| (parathyroid) chief cells   
| intense hyperchromatic to eosinophilic (see note)  
| abundant  
| moderate  
| manufacture parathyroid <br>hormone (PTH)
| [[Image:Parathyroid adenoma - chief cells -- high mag.jpg|thumb|center|85px|Chief cells (WC)]]
|-  
| oxyphil cells   
| moderate/light hyperchromatic to eosinophilic  
| rare
| abundant
| ?
| [[Image:Parathyroid adenoma - oxyphil cells -- high mag.jpg|thumb|center|85px|Oxyphil cells (WC)]]
|}
|}
Notes:
Notes:
*Cytoplasmic staining varies considerably on H&E preparations - it may vary from hyperchromatic<ref>[http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg]</ref> to clear to eosinophilic<ref>[http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm]</ref>.
*Cytoplasmic staining varies considerably on H&E preparations - it may vary from hyperchromatic<ref>[http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg]</ref> to clear to eosinophilic.<ref>[http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm]</ref>
*Chief cells tend to stain more intensely than oxyphil cells.
*Chief cells tend to stain more intensely than oxyphil cells.


Thyroid vs. parathyroid (see: [http://instruction.cvhs.okstate.edu/Histology/HistologyReference/imagesco/parathyroid2F.jpg parathyroid image]):
====Thyroid versus parathyroid====
*Parathyroid cytoplasm:  
*Parathyroid cytoplasm:  
**Hyperchromatic.
**Hyperchromatic.


Parathyroid vs. lymphoid tissue (see [http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg parathyroid image]):
Notes:
*Thyroid often has birefringent (calcium oxalate) crystals (60 of 80 cases) whereas parathyroid less often does (2 or 20 cases).<ref name=pmid24618617>{{cite journal |authors=Wong KS, Lewis JS, Gottipati S, Chernock RD |title=Utility of birefringent crystal identification by polarized light microscopy in distinguishing thyroid from parathyroid tissue on intraoperative frozen sections |journal=Am J Surg Pathol |volume=38 |issue=9 |pages=1212–9 |date=September 2014 |pmid=24618617 |doi=10.1097/PAS.0000000000000204 |url=}}</ref>
*Thyroid usually follicular - though parathyroid occasionally is pseudofollicular.
 
====Parathyroid versus lymphoid tissue====
*Parathyroid:  
*Parathyroid:  
**No germinal centres.
**No germinal centres.
**Gland-like/follicular-like arrangement -- much smaller than normal follicles of
**Gland-like/follicular-like arrangement may be present but usually much smaller than normal thyroid follicles.
***May be confused with thyroid microfollicules.
**Occasional cell with rim of clear cytoplasm (oxyphil?).
**Occasional cell with rim of clear cytoplasm (oxyphil?).
**Nuclei are different:
***Slightly larger than in lymphocytes (1.2-1.5x the size)
***Stippled chromatin (unlike lymphocytes).


Images:
Images:
*[http://library.med.utah.edu/WebPath/ENDOHTML/ENDO031.html Parathyroid - med.utah.edu].
*[http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg Parathyroid image (deltagen.com)].
*[http://pathology.mc.duke.edu/research/PTH225.html Histology - several images. - pathology.mc.duke.edu].
*[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770637/figure/f1/ Parathyroid gland (nih.gov)].<ref name=pmid15790694>{{Cite journal  | last1 = Johnson | first1 = SJ. | last2 = Sheffield | first2 = EA. | last3 = McNicol | first3 = AM. | title = Best practice no 183. Examination of parathyroid gland specimens. | journal = J Clin Pathol | volume = 58 | issue = 4 | pages = 338-42 | month = Apr | year = 2005 | doi = 10.1136/jcp.2002.002550 | PMID = 15790694 | pmc = 1770637 }}</ref>
 
===IHC===
*GATA3 +ve (>98%<ref name=pmid27097544>{{Cite journal  | last1 = Takada | first1 = N. | last2 = Hirokawa | first2 = M. | last3 = Suzuki | first3 = A. | last4 = Higuchi | first4 = M. | last5 = Kuma | first5 = S. | last6 = Miyauchi | first6 = A. | title = Diagnostic value of GATA-3 in cytological identification of parathyroid tissues. | journal = Endocr J | volume = 63 | issue = 7 | pages = 621-6 | month = Jul | year = 2016 | doi = 10.1507/endocrj.EJ15-0700 | PMID = 27097544 }}</ref>).
*PTH -ve/+ve (~33%<ref name=pmid27097544/>).
*Chromogranin A +ve (~80%<ref name=pmid27097544/>).
*AE1/AE3 +ve.{{fact}}<!-- {{Cite journal  | last1 = Piciu | first1 = D. | last2 = Irimie | first2 = A. | last3 = Kontogeorgos | first3 = G. | last4 = Piciu | first4 = A. | last5 = Buiga | first5 = R. | title = Highly aggressive pathology of non-functional parathyroid carcinoma. | journal = Orphanet J Rare Dis | volume = 8 | issue =  | pages = 115 | month = Aug | year = 2013 | doi = 10.1186/1750-1172-8-115 | PMID = 23915575 }} -->


=Specific entities=
=Specific entities=
==Parathyroid hyperplasia==
==Parathyroid hyperplasia==
===General===
{{Main|Parathyroid hyperplasia}}
*Chief cell hyperplasia - associated with MEN 1, MEN 2A.<ref>URL: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970475-2 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970475-2]. Accessed on: 29 July 2010.</ref>
*Parathyroid hyperplasia - classically assoc. with renal failure.
 
*Classically all parathyroid glands are involved; however, some may be spared making it difficult to differentiate this from parathyroid adenoma.<ref name=Ref_PBoD8_1128>{{Ref PBoD8|1128}}</ref>
===Microscopic===
Features:<ref name=Ref_PBoD8_1128>{{Ref PBoD8|1128}}</ref>
*Similar to parathyroid adenoma.
*+/-Water-clear cells ("water-clear cell hyperplasia").


==Parathyroid adenoma==
==Parathyroid adenoma==
===General===
{{Main|Parathyroid adenoma}}
*One parathyroid is big... the others are small.
*Associated with [[MEN I]] and [[MEN]] IIa/b (II/III).
 
MEN I:
*[[Parathyroid adenoma]].
*Pancreatic neuroendocrine tumours.
*[[Pituitary adenoma]].
 
MEN IIa/IIb (II/III):
*Parathyroid adenoma.
*[[Medullary thyroid carcinoma]].
*[[Pheochromocytoma]].
 
Image: [http://library.med.utah.edu/WebPath/jpeg4/ENDO091.jpg Parathyroid adenoma (med.utah.edu)].<ref>URL: [http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/enfrm.html http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/enfrm.html]. Accessed on: 6 December 2010.</ref>
 
===Microscopic===
====Chief cell adenoma====
Features:<ref name=Ref_PBoD8_1127>{{Ref PBoD8|1127}}</ref>
*Chief cells:
**Small central nucleus.
**Moderate cytoplasm.
*+/-Scattered oxyphil cells:
**Large cells.
**Abundant cytoplasm.
 
====Oxyphil adenoma====
Features:<ref name=Ref_PBoD8_1127>{{Ref PBoD8|1127}}</ref>
*Oxyphil cells:
**Large cells.
**Abundant cytoplasm.
 
DDx:
*[[Hürthle cell adenoma]] of the [[thyroid gland]].


==Parathyroid carcinoma==
==Parathyroid carcinoma==
===General===
{{Main|Parathyroid carcinoma}}
*Extremely rare.
 
===Microscopic===
Features:<ref>{{Ref PBoD8|1128}}</ref>
*Histologically normal parathyroid cells.
**Cytologic features not reliable for diagnosis.
*Fibrous capsule.
*Invasion of surrounding tissue - '''key feature'''.
*+/-Metastasis - '''diagnostic feature'''.
 
Note:
*Diagnosis of ''parathyroid carcinoma'' is like that of ''malignant [[pheochromocytoma]]'' - cytology useless, tissue invasion and metastases are the key features.
 
Image:
*[http://emedicine.medscape.com/article/280908-overview Parathyroid carcinoma (medscape.com)].


=See also=
=See also=
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