Primary Hyperparathyroidism

• Primary hyperparathyroidism (PHPT):
  • Is caused by an increased secretion of parathyroid hormone (PTH) by the parathyroid gland(s):
    • Which leads to an elevated serum calcium level
• The overproduction of parathyroid hormone (PTH):
  • Termed hyperparathyroidism (HPT), can be categorized as:
    • Primary
    • Secondary
    • Tertiary
• Primary hyperparathyroidism (PHPT);
  • Arises from an unregulated overproduction of PTH from an abnormal parathyroid gland
• Increased PTH levels may also occur as a compensatory response to hypocalcemic states resulting from:
  • Chronic renal failure or gastrointestinal (GI) malabsorption of calcium:
    • This secondary HPT can be reversed by the correction of the underlying problem:
      • For example kidney transplantation for chronic renal failure
• However, chronically stimulated parathyroid glands:
  • May occasionally become autonomous:
    • Resulting in the persistence or recurrence of the hypercalcemia after successful renal transplantation:
      • Resulting in tertiary HPT
• PHPT is defined as:
  • Hypercalcemia or widely fluctuating levels of serum calcium resulting from:
    • The inappropriate or autogenous secretion of PTH:
      • By one or more parathyroid glands:
        • In the absence of a known or recognized stimulus
• The most common cause of hypercalcemia in the outpatient setting is:
  • Primary hyperparathyroidism (PHPT):
    • With approximately 100,000 new cases per year reported in the United States
• Since the advent of routine laboratory testing:
  • The prevalence of the disease has increased from:
    • 0.1% to 0.4%:
      • One to seven cases per 1000 adults
• In a study by Yeh et al:
  • The incidence of PHPT fluctuated between:
    • 36.3 and 120.2 cases per 100,000 women-years
    • 13.4 and 35.6 in 100,000 men-years
• PHPT may present at any age:
  • With the vast majority of cases occurring in patients older than 45 years of age
  • The mean age at diagnosis has remained between:
    • 52 and 56 years
• Women have consistently made up the preponderance of cases:
  • With a female-to-male ratio of:
    • 3:1 to 4:1
  • Based on a population based study from Rochester Minnesota:
    • The higher incidence of this could be secondary (hypothetically) to:
      • Estrogen deficiency after menopause:
        • That reveals underlying HPT
• The precise origin of PHPT is unknown:
  • Although exposure to low-dose therapeutic ionizing radiation and familial predisposition account for some cases:
    • Irradiation for acne could have accounted for a 2 to 3-fold increase in the incidence of this disease at some point in time, and a 4-fold increase was noted in survivors of the atomic bomb
  • Schneider et al., in their study of 2555 patients followed for 50 years, even low doses of radiation exposure during the teenage years:
    • Was associated with a slight risk of developing PHPT
    • In this study a dose response was documented in people receiving external-beam radiotherapy for benign diseases before their 16th birthday
    • The latency period for the 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 radiated have similar clinical manifestations and serum 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
• Certain medications have been implicated in the development of hypercalcemia:
  • 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
  • Unusual metabolic features associated with lithium use include:
    • Low urinary calcium excretion
    • Normal cyclic AMP excretion
    • Lack of calcic nephrolithiasis
  • The mechanism probably results from:
    • Lithium linking with the calcium sensing receptor on the parathyroid glands resulting in PTH secretion
• Elevated serum calcium levels have been associated with thiazide diuretic:
  • The overall annual age- and sex-adjusted (to 2000 U.S. whites) incidence was:
    • 7.7 (95% CI, 5.9 to 9.5) per 100,000 individuals
  • The average 24-hour plasma calcium concentrations are increased with thiazide diuretic use:
    • But the mean 24-hour PTH levels remain unchanged in subjects with normal baseline PTH levels and no evidence of hypercalciuria
  • Thiazides diuretics have several metabolic effects that may contribute to increased calcium levels:
    • A decrease in urine calcium excretion is the most likely cause:
      • But in some cases diuretic use has been associates with a metabolic alkalosis:
        • That could also increase the total serum calcium levels through a pH-dependent increase in protein-bound calcium
    • Although plasma 1,25 (OH) vitamin D levels are unchanged:
      • Increased intestinal calcium absorption in response to thiazide diurectic use:
        • Has been noted and could also contribute to an increase in serum calcium
    • One last possible explanation for the elevated serum calcium levels associated with thiazide diuretic use is:
      • Hemoconcentration associated with dieresis
• Numerous genetic abnormalities have been identified in the development of PHPT, including:
  • Anomalies in tumor suppressor genes and proto-oncogenes
  • Specific DNA mutations in a parathyroid cell:
    • May confer a proliferative advantage over normal neighboring cells:
      • Thus allowing for clonal growth:
        • Large populations of these altered cells containing the same mutation within hyper functioning parathyroid tissue:
          • Suggest that such glands are a result of clonal expansion
  • The majority of PHPT cases are:
    • Sporadic
  • Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
    • Multiple endocrine neoplasia syndromes (MEN):
      • MEN type 1 (Wermer Syndrome)
      • MEN type 2A (Sipple Syndrome)
    • Isolated familial HPT
    • Familial HPT with jaw-tumor syndrome
  • All of these are inherited in an:
    • Autosomal dominant fashion
• The earliest and most common presentation of MEN type 1 (Wermer Syndrome):
  • Is PHPT:
    • Develops in approximately 80% to 100% of patients by age 40 years
  • These patients also are predisposed to the development of:
    • Pancreatic neuroendocrine tumors
    • Pituitary adenomas
    • Less frequently:
      • Skin angiomas
      • Lipomas
      • Adrenocortical tumors
      • Neuroendocrine tumors of the:
        • Thymus
        • Bronchus
        • Stomach
    • MEN type 1 has been shown to result from:
      • A germline mutation in a tumor suppressor gene:
        • Called MEN1 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
    • Pre-symptomatic screening for mutation carriers for MEN type 1:
      • Is difficult because generally MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene
    • MEN1 mutations also have been found in kindred’s initially suspected to represent isolated familial HPT
    • Screening for mutation carriers for MEN type 1 has a very high detection rate greater than 94%, and is used in Sweden for patients with:
      • PHPT with a first-degree relative with a major endocrine tumor, age of onset is less than 30 years and / or if multiple pancreatic tumors / parathyroid hyperplasia is detected
• Approximately 20% of patients with MEN type 2A (Sipple Syndrome):
  • Develop PHPT:
    • Which is usually less severe
  • MEN type 2A is caused by:
    • A germline mutation of the RET proto-oncogene:
      • Located on chromosome 10
  • Genotype and phenotype correlations have been noted in this syndrome:
    • In that individuals with mutations at codon 634:
      • Are more likely to develop PHPT
• 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 (parafibromin):
    • On chromosome 1
• Sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
  • Have loss of heterozygosity (LOH) at 11q13:
    • The site of the MEN1 gene in approximately 25% to 40% of the cases
• Over expression of PRAD1:
  • Which encodes cyclin D1:
    • A cell cycle control protein:
      • Is found approximately 18% of parathyroid adenomas
  • This was proven 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
  • 15q
• Amplified regions suggesting oncogenes have been identified at:
  • 16p
  • 19p
• RET mutations:
  • Are unusual 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 located in chromosome 1:
    • Encodes the protein Parafibromin
  • These alterations are rare in benign parathyroid tumors;
    • May have implications for diagnosis
  • The p53 tumor suppressor gene:
    • Is also inactivated in a subset (30%) of parathyroid carcinomas
• Single gland adenoma:
  • Is the most common cause (75% to 90%) of PHPT
• Lower pole adenomas (in relation to the thyroid):
  • Are more common than are upper pole adenomas
• Sizes range from 1 cm to 3 cm:
  • The normal parathyroid gland measures approximately 6 mm X 4 mm X 2 mm
• The weight of parathyroid adenomas vary between:
  • 553.7 mg +/- 520.5 mg (range, 66-2536):
    • The normal weight of a parathyroid gland is:
      • Approximately 40 mg to 50 mg
• Ectopic glands can be present:
  • 4% to 16% of cases
• PHPT is caused by multiple adenomas or hyperplasia in:
  • 15% to 25% of the cases
• Parathyroid carcinoma as the cause of PHPT:
  • Is extremely rare in most parts of the world (~1%)
• Multi-gland adenoma arises in a significant number of patients:
  • Double adenomas are seen in approximately:
    • 2% to 12% of the cases
  • Triple adenomas:
    • In less than 1% the cases
  • Four adenomas or parathyroid gland hyperplasia:
    • In less than 3% to 15% of the cases
• Most parathyroid adenomas:
  • Consist of parathyroid chief cells
  • They are usually encapsulated
  • In 50% of the cases they are surrounded by normal parathyroid tissue
  • Some adenomas, nevertheless, are composed of oxyphil cells:
    • These adenomas are usually larger than chief cell adenomas
• Parathyroid adenomas are sometimes located within the thymus:
  • They express a parathyroid-specific gene:
    • GCMB
  • Contrasting with the normal thymus:
    • Which does not neither express PTH nor GCMB
• In a study by Ruda et al:
  • 225 patients with PHPT:
    • Parathyroid hyperplasia accounted for approximately 6% of cases
• In parathyroid hyperplasia all four glands are enlarged:
  • With the lower glands typically being larger than the upper time
  • The glands are usually composed of:
    • Chief cells
  • Clear cell hyperplasia is very rare and is the only one in which the upper parathyroid glands are larger than the lower ones

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