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Hyperparathyroidism Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Classification

Classification of hyperparathyridism
Features Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism
Pathology Hyperfunction of parathyroid cells due to hyperplasia, adenoma or carcinoma. Physiological stimulation of parathyroid in response to hypocalcaemia. Following long term physiological stimulation leading to hyperplasia.
Cause
Associations May be associated with multiple endocrine neoplasia. Usually due to chronic renal failure or other causes of Vitamin D deficiency. Seen in chronic renal failure.
Serum calcium High Low/Normal High
Serum phosphate Low/Normal High High
Management Usually surgery if symptomatic. Cincacalcet can be considered in those not fit for surgery. Treatment of underlying cause. Usually cinacalcet or surgery in those that don't respond.

Causes

Genetic causes

  • HRPT2 gene mutations:[1]
    • HRPT2 gene code for parafibromin protein.
    • HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
    • HRTP2 gene mutations increases risk of parathyroid carcinoma.
  • Cyclin D1 gene (CCND1)/PRAD1 gene:[2][3]
    • PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
    • Cyclin D1 gene translocation and oncogene action observerd in 8% of adenomas
    • Cyclin D1 gene overexpression is pbserved in 20% to 40% of parathyroid adenomas
  • MEN1 gene:[2][4]
    • MEN1 is a tumor supressor gene on chronosome 11q13.
    • Somatic loss of single MEN1 allele is observed in 25% to 40% of sporadic parathyroid adenomas.

Pathogenesis

Associated conditions

  • Hypercalcemia
  • Chronic renal failure
  • Osteitis fibrous cystica
  • Osteoporosis
  • Osteomalacia
  • Osteoarthritis
  • Brown tumor
  • Multiple endocrine neoplasia type 1, type 2A, and type 4
  • Familial isolated hyperparathyroidism
  • Neonatal severe hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
  • Hyperparathyroid-jaw tumor syndrome
  • Pancreatitis[5]

ECG

There are no CT scan findings associated with hyperparathyroidism. However, a CT scan may be helpful in the diagnosis of cardiac complications of hyperparathyroidism. Findings on ECG are due to hypercalcemia and includes:[6]

  • ST segment - ST segment is short in patients with hyperparathyroidism when compared to normocalcemic patients. This represents a decrease in systolic interval.
  • QRS complex - QRS complex has an increased amplitudein patients with hyperparathyroidism when compared to normocalcemic patients. This represents an increase in ventricular muscle mass.
  • T wave - T wave is prolonged in patients with hyperparathyroidism when compared to normocalcemic patients.

X-ray

CT scan

MRI

Ultrasound

TC-99m Sestamibi Scintigraphy

  • Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) scintigraphy is the most popular investigation for preoperative localization of hyper-functioning parathyroid glands.[7]
  • Most of the sestamibi is retained in mitochondria of thyroid and abnormal parathyroid tissue and is a function of mitochondrial activity.[8]
  • The basis of this "single-isotope, double-phase technique" is that sestamibi washes out of the thyroid more rapidly than from abnormal parathyroid tissue.[9]
  • Multiple planar images are obtained, typically one shortly after injection of 99mTc-sestamibi and another after two hours to identify the foci of retained sestamibi showing hyper-functioning parathyroid tissue.
  • As all parathyroid lesions does not retain sestamibi nor all thyroid tissue washes out quickly, subtraction imaging may be beneficial.[10]
  • Subtraction technique uses dual contrast Tc-99m sestamibi along with iodine-123 or 99m-technicium pertechnetate which is taken by thyroid tissue only. Iodine-123/99m-technicium pertechnetate images of thyroid are later digitally subtracted from Tc-99m sestamibi images leading to visualization of parathyroid tissue only.[11]
  • Presence of solid thyroid nodule is the most common cause of false positive results. Other causes of false positive results may include thyroid carcinoma, lymphoma, and lymphadenopathy.
  • The sensitivity of sestamibi scintigraphy can be increased by using it concomitantly with neck ultrasound and/or SPECT. [12][13]
  • The sensitivity of sestamibi scintigraphy is 80% - 90%.[14][15][16]
Dual tracer Tc-99m sestamibi scintigraphy - A nuclear medicine parathyroid scan demonstrates a parathyroid adenoma adjacent to the left inferior pole of the thyroid gland. The above study was performed with Technetium-Sestamibi (1st column) and Iodine-123 (2nd column) simultaneous imaging and the subtraction technique (3rd column). -- Source:Myohan at en.wikipedia, via Wikimedia Commons
Tc-99m sestamibi scan - Parathyroid adenomas typically retain activity on late scans after wash-out in the thyroid has occurred. - Source:Case courtesy of Dr Roberto Schubert, Radiopaedia.org, rID: 16675

SPECT

  • Single positron emission computed tomography may be used along with Tc-99m sestamibi scintigraphy for preoperative evaluation of hyper-functioning parathyroid gland.[17][18]
  • Sestamibi-SPECT is also called pinhone-SPECT (P-SPECT). P-SPECT uses cone beam collimator in contrast to parallel-hole collimator used in SPECT. cone bean collimator possess more suitable geometric properties leading to high spatial resolution.[19][20]
  • Using SPECT with sestamibi scintigraphy improves detection and localization of hyper-functioning parathyroid gland.[21][22]
  • SPECT provides more precise result of sestamibi scitigraphy allowing surgeon to choose best route for surgical intervention.
  • P-SPECT may detect glands not visible on planer images leading to increased sensitivity. It is very useful in case of uncertain result from conventional sestamibi scitigraphy.[23][24]
  • P-SPECT also enables accurate interpretation sestamibi uptake in upper mediastinum leading to a higher specificity.
  • In difficult cases, P-SPECT may also be adjuncted with subtraction Tc-99m sestamibi and I-123 scintigraphy or positron emission tomography.[25]
  • P-SPECT is approximately 84% sensitive, 91% specific with positive predictive value of around 91% and negative predictive value of around 84%.[26]
  • Fusion images of CT-MIBI-SPECT is superior to CT or MIBI-SPECT alone in preoperative localization of hyper-functioning parathyroid gland.[27]

PET

  • 11C-methionine PET along with CT scan (MET-PET/CT) may be used for preoperative localization of hyper-functioning gland.[28][29]
  • MET-PET/CT may be used as an complimentary imaging modality for localizing hyper-functioning parathyroid glands in patients with negative Tc-99m sestamibi scintigraphy/SPECT results.[30]

DXA

  • Low bone mineral density (BMD) is caused by primary hyperparathyroidism. Distal forearm is affected most commonly.
  • DXA of distal forearm should be done in all patients of primary hyperparathyroidism. Worst T-score of distal forearm is observed in patients with primary hyperparathyroidism.[31]

Other diagnostic studies

Intraoperative parathyroid hormone (IOPTH)

  • Measurement of intraoperative parathyroid hormone (IOPTH) by using a modified sensitive assay (immunoradiometric assay) is beneficial for long term surgical outcomes.Post-surgical success is defined as postoperative normocalcemia.
  • Patients with hyperparathyroidism due to lesion in a single gland shows a rapid decline of intact parathyroid hormone. The levels of intact parathyroid hormone reached to indetectable levels within hours of resection.[32]
  • After resection of parathyroid adenoma, intact parathyroid hormone levels decrease by 85% is observed in first 15 minutes. This fall in parathyroid hormone levels is due to short half-life of parathyroid hormone.[33]
  • The fall in parathyroid hormone level is significantly more after resection of parathyroid adenoma than after resection of parathyroid hyperplasia.
  • A fall in level of parathyroid hormone 15 minutes after resection of hyper-functioning parathyroid glands may help differentiating sigle gland disease from multi gland disease.[34][35]
  • IOPTH monitoring has a predictive accuracy of 97%. [36]

Technique for intraoperative parathyroid hormone (IOPTH) monitoring

  • When the enlarged parathyroid gland is first visualized intraoperatively, the baseline sample should be obtained.[37]
  • The baseline samples should never be obtained before induction of anesthesia. It is due to the fact that an increase in parathyroid hormone level may be observed after general anesthesia.
  • After excision of enlarged gland, 2nd and 3rd samples are collected at 5 and 10 minutes respectively.
  • Several criteria are used for predicting post-operative normocalcemia including:
    • A decline in parathyroid hormone levels of ≥60% from baseline value at 15 minutes.
    • A decline in parathyroid hormone levels of ≥50% from baseline value at 10 minutes.

Super Selective Venous Sampling

Selective arteriography

  • Selective transarterial hypocalcemic stimulation is combined with nonselective venous sampling to perform selective arteriography.[38]
  • Sodium citrate is injected to induce hypocalcemia. Simultaneous arteriography is performed.
  • Samples are taken for superior vena cava at basaeline and timed intervals (20 sec, 40 sec, and 60 sec).
  • An increase in the parathyroid hormone level to 1.4 times above the baseline or a clear blush observed on arteriography is considered as positive localization.
  • Arterial stimulation venous sampling is performed simultaneously with arteriogram due to similarly high PPV.

Angiography

  • Superselective arterial digital subtraction angiography (DSA) and superselective conventional angiography (CA) may be used for preoperative localization of hyper-functioning parathyroid glands in which noninvasive imaging modalities are negative or inconclusive.[39]
  • Sensitivity of superselective digital subtraction angiography appears to be similar to conventional angiography.
  • Superselective arterial digital subtraction angiography may be more sensitive than conventional angiography for preoperative localization of mediastinal hyper-functioning parathyroid glands.

References

  1. ↑ Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D; et al. (2003). "Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma". N Engl J Med. 349 (18): 1722–9. doi:10.1056/NEJMoa031237. PMID 14585940.
  2. ↑ 2.0 2.1 Westin G, Björklund P, Akerström G (2009). "Molecular genetics of parathyroid disease". World J Surg. 33 (11): 2224–33. doi:10.1007/s00268-009-0022-6. PMID 19373510.
  3. ↑ Hsi ED, Zukerberg LR, Yang WI, Arnold A (1996). "Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study". J Clin Endocrinol Metab. 81 (5): 1736–9. doi:10.1210/jcem.81.5.8626826. PMID 8626826.
  4. ↑ Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC; et al. (1997). "Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states". Hum Mol Genet. 6 (7): 1169–75. PMID 9215689.
  5. ↑ Bai HX, Giefer M, Patel M, Orabi AI, Husain SZ (2012). "The association of primary hyperparathyroidism with pancreatitis". J. Clin. Gastroenterol. 46 (8): 656–61. doi:10.1097/MCG.0b013e31825c446c. PMC 4428665. PMID 22874807.
  6. ↑ Lind L, Ljunghall S (1994). "Serum calcium and the ECG in patients with primary hyperparathyroidism". J Electrocardiol. 27 (2): 99–103. PMID 8201301.
  7. ↑ Palestro CJ, Tomas MB, Tronco GG (2005). "Radionuclide imaging of the parathyroid glands". Semin Nucl Med. 35 (4): 266–76. doi:10.1053/j.semnuclmed.2005.06.001. PMID 16150247.
  8. ↑ Hetrakul N, Civelek AC, Stagg CA, Udelsman R (2001). "In vitro accumulation of technetium-99m-sestamibi in human parathyroid mitochondria". Surgery. 130 (6): 1011–8. doi:10.1067/msy.2001.118371. PMID 11742331.
  9. ↑ Taillefer R, Boucher Y, Potvin C, Lambert R (1992). "Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium-99m-sestamibi (double-phase study)". J Nucl Med. 33 (10): 1801–7. PMID 1328564.
  10. ↑ Thulé P, Thakore K, Vansant J, McGarity W, Weber C, Phillips LS (1994). "Preoperative localization of parathyroid tissue with technetium-99m sestamibi 123I subtraction scanning". J Clin Endocrinol Metab. 78 (1): 77–82. doi:10.1210/jcem.78.1.8288719. PMID 8288719.
  11. ↑ Ryhänen EM, Schildt J, Heiskanen I, Väisänen M, Ahonen A, Löyttyniemi E; et al. (2015). "(99m)Technetium Sestamibi-(123)Iodine Scintigraphy Is More Accurate Than (99m)Technetium Sestamibi Alone before Surgery for Primary Hyperparathyroidism". Int J Mol Imaging. 2015: 391625. doi:10.1155/2015/391625. PMC 4333274. PMID 25722888.
  12. ↑ Eslamy HK, Ziessman HA (2008). "Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT". Radiographics. 28 (5): 1461–76. doi:10.1148/rg.285075055. PMID 18794320.
  13. ↑ Haber RS, Kim CK, Inabnet WB (2002). "Ultrasonography for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism: comparison with (99m)technetium sestamibi scintigraphy". Clin Endocrinol (Oxf). 57 (2): 241–9. PMID 12153604.
  14. ↑ Chapuis Y, Fulla Y, Bonnichon P, Tarla E, Abboud B, Pitre J, Richard B (1996). "Values of ultrasonography, sestamibi scintigraphy, and intraoperative measurement of 1-84 PTH for unilateral neck exploration of primary hyperparathyroidism". World J Surg. 20 (7): 835–9, discussion 839–40. PMID 8678959.
  15. ↑ Prasannan S, Davies G, Bochner M, Kollias J, Malycha P (2007). "Minimally invasive parathyroidectomy using surgeon-performed ultrasound and sestamibi". ANZ J Surg. 77 (9): 774–7. doi:10.1111/j.1445-2197.2007.04227.x. PMID 17685957.
  16. ↑ Gómez-Ramírez J, Sancho-Insenser JJ, Pereira JA, Jimeno J, Munné A, Sitges-Serra A (2010). "Impact of thyroid nodular disease on 99mTc-sestamibi scintigraphy in patients with primary hyperparathyroidism". Langenbecks Arch Surg. 395 (7): 929–33. doi:10.1007/s00423-010-0680-8. PMID 20625763.
  17. ↑ Billotey C, Sarfati E, Aurengo A, Duet M, Mündler O, Toubert ME; et al. (1996). "Advantages of SPECT in technetium-99m-sestamibi parathyroid scintigraphy". J Nucl Med. 37 (11): 1773–8. PMID 8917173.
  18. ↑ Civelek AC, Ozalp E, Donovan P, Udelsman R (2002). "Prospective evaluation of delayed technetium-99m sestamibi SPECT scintigraphy for preoperative localization of primary hyperparathyroidism". Surgery. 131 (2): 149–57. PMID 11854692.
  19. ↑ Strand SE, Ivanovic M, Erlandsson K, Franceschi D, Button T, Sjögren K; et al. (1994). "Small animal imaging with pinhole single-photon emission computed tomography". Cancer. 73 (3 Suppl): 981–4. PMID 8306288.
  20. ↑ Jaszczak RJ, Li J, Wang H, Zalutsky MR, Coleman RE (1994). "Pinhole collimation for ultra-high-resolution, small-field-of-view SPECT". Phys Med Biol. 39 (3): 425–37. PMID 15551591.
  21. ↑ Schachter PP, Issa N, Shimonov M, Czerniak A, Lorberboym M (2004). "Early, postinjection MIBI-SPECT as the only preoperative localizing study for minimally invasive parathyroidectomy". Arch Surg. 139 (4): 433–7. doi:10.1001/archsurg.139.4.433. PMID 15078713.
  22. ↑ Perez-Monte JE, Brown ML, Shah AN, Ranger NT, Watson CG, Carty SE; et al. (1996). "Parathyroid adenomas: accurate detection and localization with Tc-99m sestamibi SPECT". Radiology. 201 (1): 85–91. doi:10.1148/radiology.201.1.8816526. PMID 8816526.
  23. ↑ Spanu A, Falchi A, Manca A, Marongiu P, Cossu A, Pisu N; et al. (2004). "The usefulness of neck pinhole SPECT as a complementary tool to planar scintigraphy in primary and secondary hyperparathyroidism". J Nucl Med. 45 (1): 40–8. PMID 14734671.
  24. ↑ Carlier T, Oudoux A, Mirallié E, Seret A, Daumy I, Leux C, Bodet-Milin C, Kraeber-Bodéré F, Ansquer C (2008). "99mTc-MIBI pinhole SPECT in primary hyperparathyroidism: comparison with conventional SPECT, planar scintigraphy and ultrasonography". Eur. J. Nucl. Med. Mol. Imaging. 35 (3): 637–43. doi:10.1007/s00259-007-0625-9. PMC 2964350. PMID 17960377.
  25. ↑ Nguyen BD (1999). "Parathyroid imaging with Tc-99m sestamibi planar and SPECT scintigraphy". Radiographics. 19 (3): 601–14, discussion 615-6. doi:10.1148/radiographics.19.3.g99ma10601. PMID 10336191.
  26. ↑ Lindqvist V, Jacobsson H, Chandanos E, Bäckdahl M, Kjellman M, Wallin G (2009). "Preoperative 99Tc(m)-sestamibi scintigraphy with SPECT localizes most pathologic parathyroid glands". Langenbecks Arch Surg. 394 (5): 811–5. doi:10.1007/s00423-009-0536-2. PMID 19578871.
  27. ↑ Wimmer G, Profanter C, Kovacs P, Sieb M, Gabriel M, Putzer D; et al. (2010). "CT-MIBI-SPECT image fusion predicts multiglandular disease in hyperparathyroidism". Langenbecks Arch Surg. 395 (1): 73–80. doi:10.1007/s00423-009-0545-1. PMID 19705144.
  28. ↑ Tang BN, Moreno-Reyes R, Blocklet D, Corvilain B, Cappello M, Delpierre I; et al. (2008). "Accurate pre-operative localization of pathological parathyroid glands using 11C-methionine PET/CT". Contrast Media Mol Imaging. 3 (4): 157–63. doi:10.1002/cmmi.243. PMID 18781582.
  29. ↑ Weber T, Maier-Funk C, Ohlhauser D, Hillenbrand A, Cammerer G, Barth TF; et al. (2013). "Accurate preoperative localization of parathyroid adenomas with C-11 methionine PET/CT". Ann Surg. 257 (6): 1124–8. doi:10.1097/SLA.0b013e318289b345. PMID 23478517.
  30. ↑ Traub-Weidinger T, Mayerhoefer ME, Koperek O, Mitterhauser M, Duan H, Karanikas G; et al. (2014). "11C-methionine PET/CT imaging of 99mTc-MIBI-SPECT/CT-negative patients with primary hyperparathyroidism and previous neck surgery". J Clin Endocrinol Metab. 99 (11): 4199–205. doi:10.1210/jc.2014-1267. PMID 25029418.
  31. ↑ Wood K, Dhital S, Chen H, Sippel RS (2012). "What is the utility of distal forearm DXA in primary hyperparathyroidism?". Oncologist. 17 (3): 322–5. doi:10.1634/theoncologist.2011-0285. PMC 3316917. PMID 22258698.
  32. ↑ Nussbaum SR, Thompson AR, Hutcheson KA, Gaz RD, Wang CA (1988). "Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism". Surgery. 104 (6): 1121–7. PMID 3194839.
  33. ↑ Bergenfelz A, Isaksson A, Ahrén B (1994). "Intraoperative monitoring of intact PTH during surgery for primary hyperparathyroidism". Langenbecks Arch Chir. 379 (1): 50–3. PMID 8145618.
  34. ↑ Irvin III, George L.; Dembrow, Victor D.; Prudhomme, David L. (December 1993). "Clinical usefulness of an intraoperative "quick parathyroid hormone" assay". Surgery. 114 (6): 1019–1023.
  35. ↑ Bergenfelz A, Isaksson A, Lindblom P, Westerdahl J, Tibblin S (1998). "Measurement of parathyroid hormone in patients with primary hyperparathyroidism undergoing first and reoperative surgery". Br J Surg. 85 (8): 1129–32. doi:10.1046/j.1365-2168.1998.00824.x. PMID 9718013.
  36. ↑ Boggs JE, Irvin GL, Molinari AS, Deriso GT (1996). "Intraoperative parathyroid hormone monitoring as an adjunct to parathyroidectomy" (PDF). Surgery. 120 (6): 954–8. doi:10.1016/S0039-6060(96)80040-7. PMID 8957480.
  37. ↑ Westerdahl J, Lindblom P, Bergenfelz A (2002). "Measurement of intraoperative parathyroid hormone predicts long-term operative success". Arch Surg. 137 (2): 186–90. doi:10.1001/archsurg.137.2.186. PMID 11822958.
  38. ↑ Powell AC, Alexander HR, Chang R, Marx SJ, Skarulis M, Pingpank JF; et al. (2009). "Reoperation for parathyroid adenoma: a contemporary experience". Surgery. 146 (6): 1144–55. doi:10.1016/j.surg.2009.09.015. PMC 3467310. PMID 19958942.
  39. ↑ Miller DL, Chang R, Doppman JL, Norton JA (1989). "Localization of parathyroid adenomas: superselective arterial DSA versus superselective conventional angiography". Radiology. 170 (3 Pt 2): 1003–6. doi:10.1148/radiology.170.3.2644666. PMID 2644666.
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