**5.3 Tertiary HPT**

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

parathyroid gland (13%) or carcinoma (1%) can occur. Parathyroid adenoma is the most common clinical presentation in primary HPT. It usually presents with only one adenoma, but it can manifest in more than one parathyroid, known as multiple adenomas [20–22]. Structural genetic mutations are associated with the etiology of the adenoma, although it can also occur after exposure to neck irradiation, treatment with lithium, or thiazide diuretics [20, 23]. The consequence is the disorderly overproduction of PTH, increasing osteoclastic activity and therefore raising calcium levels in the body. PTH also stimulates renal calcium reabsorption and acts on the activation of vitamin D, increasing intestinal calcium absorption. Most are asymptomatic; however the patient may develop clinical manifestations. The most frequent consequence of primary HPT is nephrolithiasis that develops in almost 15–20% of cases. Nevertheless, HPT is found in just 5% of patients with nephrolithiasis. Osteoporosis, fibrous osteitis, and peptic disease may be also found in these patients. Neuropsychiatric and neuromuscular disorders such as asthenia, weakness, and mild depression can be found less frequently [24]. In rare presentations, brown tumors may be formed, the etiology of which is associated with the disruption of bone turnover between osteoblastic and osteoclastic activity, resulting in benign bone tumors. Sporadic presentation is more frequent; however, family forms may be associated. The main familial manifestations are multiple endocrine neoplasia (MEN) type I, or Werner's syndrome (HPT, pancreatic tumor and pituitary tumor), and type IIA, or Sipple's syndrome (HPT, medullary thyroid carcinoma and pheochromocytoma), and are associated with the expression of the

Other existing familial forms described are primary neonatal HPT, familial hypocalciuric hypercalcemia, jaw tumor HPT syndrome, and isolated familial HPT [26]. Associated with primary HPT is the parathyroid carcinoma, a rare presentation, less than 1% of cases. It is suspected when there are high levels of serum calcium and PTH and may also have a palpable cervical mass on the thyroid gland topography. HPT in patients, if not treated quickly and efficiently, can progress rapidly to complications secondary to hypercalcemia and may progress to death [20, 26, 27].

Secondary HPT, unlike primary HPT, is a systemic and non-intrinsic pathology of the parathyroid gland, the consequence of which affects the functioning and metabolism of the parathyroid glands. It is the result of a parathyroid response to a tendency of hypocalcemia in order to maintain calcium homeostasis. It occurs due to low calcium absorption and vitamin D deficiency. Hypovitaminosis D is the main cause of secondary HPT in developed countries, in which confinement and low sun exposure occur frequently. As a result, there is a decrease in intestinal calcium absorption and a tendency towards serum hypocalcemia. The feedback mechanism stimulates the parathyroid glands and increases PTH synthesis, mobilizing calcium from the bones to maintain intravascular calcium homeostasis. Another important cause of secondary HPT is CKD, in which the kidney injury generates low calcium reabsorption in the distal renal tubules with consequent hypocalcemia. It is also in the kidney that the conversion of vitamin D (cholecalciferol) to its active form (calcitriol) occurs through the enzyme alpha1-hydroxylase. In CKD, this conversion is impaired and shows a consequent decrease in serum calcitriol rates and intestinal calcium absorption. As a result, there is an increase in PTH production and osteoclastic activity to try to normalize serum calcium levels. In advanced cases, there is intense damage to bone health, with osteoporosis, severe bone pain, fibrous osteitis, and even pathological fractures [16, 28, 29]. At the same time, renal injury causes

phosphate retention, with an increase in serum inorganic phosphate.

**74**

RET proto-oncogene [24, 25].

**5.2 Secondary HPT**

Tertiary HPT manifests itself through an evolution of secondary HPT. In these cases, the continuous stimulus to the overproduction of PTH leads the autonomy of the parathyroid glands to produce PTH in high amounts. In the case of CKD, many patients undergo kidney transplants, expecting normalization of calcium reabsorption, conversion of vitamin D to its active form (calcitriol), and a consequent drop in PTH levels and normalization of the calcium rates. However, autonomous parathyroid glands maintain PTH overproduction even with renal calcium reabsorption normalized. The main consequence is the increase of the calcium serum levels. Most patients are asymptomatic, although some maintained bone pain and risk of fractures. In these cases, persistent hypercalcemia, chronic renal graft dysfunction, bone disease progression, cardiovascular events, and the risk of developing nephrolithiasis in the transplanted renal graft justify the early treatment of the disease [7, 30].
