Mini Primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is an endocrinological disease with parathormone (PTH) and calcium elevation. It is the most common form of hypercalcemia in the community. In this review, the de ﬁ nition, diagnosis, differential diagnosis and treatment of hyperparathyroidism are described.


Introduction
PHPT is characterized by increased PTH release from one or more parathyroid glands. It causes hypercalcemia. This hypercalcemia also leads to osteoporosis, bone fracture, urinary stone, kidney failure and adversely affects many systems. It is one of the most common endocrine diseases [1]. After 1970s, serum calcium entered the routine of measurement and the diagnosis of mild and / or symptomatic PHPT began to increase, not only symptomatic and severe PHPTs [2]. Nowadays, it presents in 3 ways: 1. Classic PHPT: condition with symptoms and signs specifi c to disease with high PTH and calcium [3].
2. Normocalcemic PHPT: Clinical form where total and ionized calcium levels are normal when PTH is high [3]. In order to make this sub-diagnosis, the level of vitamin D should be normal (> 20 ng/ml) and the other causes of secondary hyperparathyroidism ( [9]. Its incidence is 13-36 in 100000 patient years in women and 66 in men. It is about 4 times more common in women [8]. (In which patients genetic testing is required, the diagnosis section is mentioned below).

Clinical symptoms and signs
In symptomatic PHPT, symptoms / signs can develop in almost any system: Urinary system: polyuria, polydipsia, nephrolithiasis, nephrocalcinosis. PTH leads to an increase in calcium reabsorption and phosphorus excretion in the kidneys. In PHPT, when the fi lter calcium load exceeds its absorption capacity, it leads to hypercalciuria, which starts the formation of stones and calcinosis.
Gastointestinal tract: nausea, vomiting, acute pancreatitis, peptic ulcus. Peptic ulcus is generally seen in syndromic patients, especially in MEN1 and MEN4 because the frequency of gastrin-related tumors has increased in these syndromes.
Whether there is a causal relationship between PHPT and acute pancreatitis has not been established yet.
Musculoskeletal system: weakness, bone pain, osteopenia / osteoporosis, brown tumor (osteitis fi brosa cystica). Chronic PTH elevation, through receptor activator of nuclear factor-к ligand (RANKL), particularly affects distal radius, leading to bone loss, osteoporosis and pathological fractures. Osteitis fi brosa cystica occurs in 6.1% of patients. Recently, it is a less common bone complication characterized by bone loss, fi brosis and bone cyst.
Cardiovascular system: hypertension, arrhythmia, left ventricular hyperplasia. These fi ndings are more common with PTH and calcium elevation. In asymptomatic / mild disease, the opposite is the case.

Differential diagnosis
PHPT is a disease with normal / high calcium and normal / high PTH. In differential diagnosis, especially malignancy, familial hypocalciuric hypercalcemia (FHH), drugs and secondary HPT should be taken into consideration.
Hypercalcemia can be seen in many types of malignancy, especially solid organ tumors [13]. In malignancies, both the cancer's self clinic and hypercalcemia clinic are faster and more severe, calcium is higher, especially PTH is too low or undetectable, these make it easy to distinguish from PHPT [14]. It occurs due to inactivating mutation in calcium sensing receptors in parathyroid glands and kidneys. In these cases, the family story is positive. Genetic diagnosis is possible. Since it does not require treatment, differential diagnosis with PHPT is mandatory [15,16].
Lithium can cause downstream in calcium sensing receptors, similar to FHH, leading to a picture with hypercalcemia and hypocalciuria. With the discontinuation of the drug, the picture returns in most patients. Thiazide diuretics may decrease urinary calcium excretion and cause mild hypercalcemia.
Calcium level returns to normal following discontinuation of the drug [17,18].
Secondary hyperparathyroidism is an increase in PTH secretion from parathyroid glands due to a decrease in extracellular calcium level. When PTH is high, serum calcium or ionized calcium is low or at the low normal limit. It is seen in cases of malabsorption, vitamin D defi ciency (<20 ng/ml), bariatric surgery, kidney failure, loop diuretics, pseudohyperparathyroidism (genetic resistance to PTH, hypocalcemia, elevated PTH), hungry bone syndrome, antiresorptive agents (bisphosponat, denosumab) [4,19,20].

Treatment and follow up
In patients with a diagnosis of PHPT, the necessity for surgery should fi rst be decided for treatment. Surgical treatment is indicated if there is nephrolithiasis, low creatinine clearance (GFR) unexplained for other reasons, presence of hyperparathyroidic bone disease, signs of hypercalcemia and/or life-threatening attacks of hypercalcemia. Unless asymptomatic PHPT was treated, an increased risk of vertebral fracture and kidney stone was found. Thus asymptomatic patients should be screened for these complications (4). In asymptomatic PHPT, surgery is indicated if one of the following is present: age <50 years, serum calcium with 1 mg/dl above the upper limit, GFR is lower than 60 ml/minutes, vertebra, hip or distal radius T score <-2.5 in DXA, vertebral fracture, urinary calcium excretion> 400 mg / day, nephrolithiasis or nephrocalcinosis [21,22].
The standard surgical procedure is bilateral cervical exploration with a 95-98% cure rate. This method should be preferred in PHPTH associated with genetic syndrome or where the lesion location cannot be detected or multigland involvement. Minimally invasive parathyroidectomy can be selected in single adenoma operation if intraoperative PTH can be performed and the surgical team is experienced. In these cases, endoscopic methods may also be an option [22,23].
Mortality rate is low but it can be seen up to 10% in the elderly [22,24].
HBS is a complication after parathyroidectomy with a frequency of 13%. Impaired balance between bone  [25,26].
Medical treatment indications in PHPT are: > 50 years of age, the patient is minimally symptomatic or asymptomatic, calcium is <1.0 mg / dl higher than the normal upper limit, has no surgical indication or the patient does not want surgery or the patient is not suitable for surgery. In these situations, patients are followed up by medical monitoring [11,22].
There is no need for calcium restriction in the diet.
Abundant daily hydration is recommended. If vitamin D is low, it is recommended to be replaced. The risk of hypercalcemia is low. It provides a slight drop in PTH [27].
Antiresorptive agents (estrogen receptor-targeted drugs, biphosphonates) can be used in the presence of osteopenia / osteoporosis, these drugs provide a slight drop in calcium.
Treatment of bone loss caused by the disease is also provided [28,29].
Sinekalset, which is a calcimimetic agent, normalizes 80%-90% in serum calcium and provides an increase in phosphorus.
Urinary calcium is reduced. It does not affect bone mineral density [27].
Patients who do not receive surgical or medical treatment should be followed up periodically, and should be applied without delay when treatment indication develops. Biochemical tests (serum calcium, creatinine, GFR) of these patients are recommended to be performed annually, BMD follow-up is performed once in 1 or 2 years [30][31][32][33][34][35].