Etiology Of Primary Hyperparathyroidism (PHPT)

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The exact cause of PHPT is unknown:
    • Although exposure to low-dose therapeutic ionizing radiation and familial predisposition account for some cases
    • Various diets and intermittent exposure to sunshine may also be related
    • Other causes include:
      • Renal leak of calcium
      • Declining renal function:
        • With age
      • Alteration in the sensitivity of parathyroid gland:
        • To be suppression by calcium
  • The latency period for development of PHPT after radiation exposure:
    • Is longer than that for the development of thyroid tumors:
      • With most cases occurring 30 to 40 years after exposure
    • Patients who have been exposed to radiation:
      • Have similar clinical presentations and calcium levels when compared to patients without a history of radiation exposure:
        • However, the former tend to have higher PTH levels and a higher incidence of concomitant thyroid neoplasms
  • Lithium therapy:
    • Has been known to shift the set point for PTH secretion in parathyroid cells:
      • Thereby resulting in elevated PTH levels and mild hypercalcemia
    • Lithium stimulates the growth of abnormal parathyroid glands in vitro and also in susceptible patients in vivo
  • PHPT results from the enlargement of a single gland or parathyroid adenoma:
    • In approximately 80% to 95% of cases
    • Multiple gland disease in seen in 15% to 20% of the cases:
      • Doble adenomas 6% to 9% of cases:
        • This entity is less common in younger patients but is more prevalent in older patients
      • Triple adenomas < 0.3% of cases
      • Four gland hyperplasia 3% of cases
    • Parathyroid carcinoma:
      • In 1% of patients
  • It should be emphasized that when more than one abnormal parathyroid gland is identified preoperatively or intraoperatively:
    • The patient has hyperplasia (all glands abnormal) until proven otherwise
  • Genetics of PHPT:
    • Most cases of PHPT are sporadic:
      • However, PHPT also occurs within the spectrum of a number of inherited disorders such as:
        • MEN1 (Wermers Syndrome)
        • MEN2A (Sipple Syndrome)
        • Isolated familial HPT
        • Familial HPT with jaw-tumor syndrome
      • All of these syndromes are inherited in an autosomal dominant fashion
    • MEN type 1 Wermers Syndrome:
      • PHPT is the earliest and most common manifestation of MEN1:
        • It develops in 80% to 100% of patients by age 40 years old
      • These patients also are prone to:
        • Pancreatic neuroendocrine tumors:
          • About 50% of patients develop gastrinomas:
            • Which often are multiple and metastatic at diagnosis
          • Insulinomas develop in 10% to 15% of cases
          • Whereas many patients have nonfunctional pancreatic endocrine tumors
        • Pituitary adenomas:
          • Prolactinomas occur in 10% to 50% of MEN1 patients and constitute the most common pituitary lesion
        • Less commonly, to:
          • Adrenocortical tumors
          • Lipomas
          • Skin angiomas
          • Carcinoid tumors of the bronchus, thymus, or stomach
      • MEN1 has been shown to result from germline mutations in the MEN1 gene:
        • A tumor suppressor gene:
          • Located on chromosome 11q12-13:
            • That encodes menin:
              • A protein that is postulated to interact with the transcription factors JunD and nuclear factor-κB in the nucleus, in addition to replication protein A and other proteins
        • Most MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene:
          • This makes presymptomatic screening for mutation carriers difficult
        • MEN1 mutations also have been found in kindreds initially suspected to represent isolated familial HPT
    • MEN type 2A Sippple Syndrome:
      • HPT develops in about 20% of patients with MEN2A:
        • It is generally is less severe
      • MEN2A is caused by germline mutations of the RET proto-oncogene:
        • Located on chromosome 10
      • In contrast to MEN1:
        • Genotype-phenotype correlations have been noted in this syndrome:
          • In that individuals with mutations at codon 634 are more likely to develop HPT
    • Patients with the familial HPT with jaw-tumor syndrome:
      • Have an increased predisposition to parathyroid carcinoma
      • This syndrome maps to a tumor suppressor locus HRPT2 (CDC73 or parafibromin):
        • On chromosome 1
    • Patients belonging to isolated HPT kindreds:
      • Also appear to demonstrate linkage to HRPT2
    • Approximately 25% to 40% of sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
      • Have loss of heterozygosity (LOH) at 11q13:
        • The site of the MEN1 gene
    • The parathyroid adenoma 1 oncogene (PRAD1):
      • Which encodes cyclin D1:
        • A cell cycle control protein:
          • Is overexpressed in about 18% of parathyroid adenomas
      • This was demonstrated to result from a rearrangement on chromosome 11 that places the PRAD1 gene:
        • Under the control of the PTH promoter
    • Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
      • 1p, 6q, and 15q
      • RET mutations are rare in sporadic parathyroid tumors
      • Sporadic parathyroid cancers:
        • Are characterized by uniform loss of the tumor suppressor gene RB:
          • Which is involved in cell cycle regulation
        • 60% have HRPT2 (CDC73) mutations
          • These alterations are rare in benign parathyroid tumors and may have implications for diagnosis
    • Whereas amplified regions suggesting oncogenes have been identified at 16p and 19p
    • The p53 tumor suppressor gene is also inactivated in a subset (30%) of parathyroid carcinomas
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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