Primary hyperparathyroidism

 

DEFINITION

•  Hypersecretion of PTH relative to calcemia due to abnormal regulation, excluding FHH. 
  

EPIDEMIOLOGY

• Prevalence about 1/430 ♀ - 1/1250 ♂, Peak age 50-65
  
• 85% single parathyroid adenoma, 5% multiple adenomas, <10% hyperplasia, <1% carcinoma. 

ETIOLOGY

• Mostly unknown. 
• Radiation, dose-dependent, only significant in Chernobyl or similar. 
• Genes: proto-oncogene gain-of-function: RET, cyclin D1/PRAD1 or tumor-supression gene lose-of-function: MEN1, CDC73. 
• Familial conditions (rare): MEN1 (menin), familial isolated hyperparathyroidism FIHP (unknown genetics, maybe hotchpotch), HPT-JT (CDC73), MEN2A (RET), familial hypocalciuric hypercalcemia FHH (CaSR).

CLINICAL PRESENTATION

• 80% asymptomatic hypercalcemia <1 mg/dL above upper limit.
• Remaining 20%:
• Normocalcemic PHPT. Elevated PTH + normal total and ionized calcium, excluded secondary HPT (see DD, mostly vit D deficiency and CKD). Considered initial form of PTPT, some develop hypercalcemia or bone/kidney damage. 
• Parathyroid crisis: severe and symptomatic hypercalcemia. Rare, 1-2%.
• Classical form (rare): Kidney stones or rarely nephrocalcinosis + osteitis fibrosa cystica + neuromuscular symptoms.
  

DIAGNOSIS

• Percent undiagnosed and time from onset to diagnosis: unknown, but high % and long prediagnosis time suspected based on hypercalcemia without further investigation in medical records.
  

• Disgnostic workup is biochemistry based:
• Serum calcium: elevated, except in normocalcemic HPT. Ionized Ca little value except in normocalcemic HPT to exclude hypercalcemia.
  
• Serum PTH: 80-90% modestly elevated, 10-20% normal range, usually upper half.
• 24h-urinary calcium: Not always required for diagnosis. 40% of PHPT >200 mg. <200 mg if low vitD or Ca intake, but poses DD with FHH (75% <100 mg).
• Ca/Cr clearance ratio = 24hCa x serumCr / 24hCr x serum Ca (spot urine not validated): <0.01 suggests (not confirm) FHH, especially in vitD depleted, 0.01-0.02 may be FHH or PHPT (genetic testing for CaSR in selected individuals), >0.02 is PHPT. 
• 25OH-D useful in two cases:
• ↑serum PTH and Ca + not elevated 24h Ca: DD PHPT+vitD deficiency vs. FHH
• normal serum Ca + ↑PTH: DD normocalcemic HPT vs. secondary HPT. 
• Not needed for diagnosis but for management plan (surgical criteria):
• eGFR (<60 mL/min→surgery)
  
• Renal imaging if surgical criteria not met (usually US, also CT or plain RX) finds stones in 7-21%, rarer calcinosis. 
• BMD in spine, hip and distal forearm. 
• Vertebral imaging by RX or Vertebral Fracture Assessment (VFA) for unnoticed fracture.
  
• DD:
• Malignancy: PTH is low.
  
• FHH: mild↑serumCa + normal/mildly ↑PTH + low 24hCa + family history + no symptoms.
  
• Drugs: thiazides (renal action) and lithium (↓CaSR activity mimicking FHH)
  
• Secondary HPT: low or normal serum Ca:
• CKD
• ↓Calcemia: low intake, malabsorption (including vitD deficiency), renal loss (hypercalciuria, loop diuretics)
• Low bone resorption: biphosphonates, denosumab, hungry bone.
  

 HEALTH IMPACT

• Mortality: ↑ in severe, unclear in mild cases. 
• Morbidity:
• Kidney
• Stones in 15-20%, calcium oxalate. Nephrocalcinosis is rare.
• GFR decline: Up to 17%, only in long-term important hypercalcemia.
  
• Bone 
• Fractures ↑ risk 2-3 fold. Despite preserved cancellous and affected cortical bones, vertebral fracture is more frequent, but all fracture sites are ↑, particularly in aged ♀.
• Chondrocalcinosis in severe cases: wrist and knees. 
  
• Neuromuscular-psychiatric symptoms. Present in severe cases. In remaining, just mildly in any case and no clear response to therapy.
  
• CV risk. Hypertension, arrhytmia, ventricular hypertrophy, vascular stiffening, vascular-valvular calcification. No proved ↑ CV death. Hypertension present even in mild cases, no proved causal relationship.
  
• Overweight and hyperglycemia mildly ↑, no proved causal relationship
• Estimated morbidity in undiagnosed cases: unknow, probably low because they are probably the mildest cases. 
  

MANAGEMENT

• Symptomatic patients (fractures, kidney stones, symptomatic hypercalcemia): surgery is indicated. It has proved:
• Nephrolithiasis improvement (not operated worsen)
• BMD improvement
• So far not proved but possible fracture reduction
• Some QoL improvement. 

Note: mild symptoms like fatigue, weakness, depression or memory impairment are vague and not indication for surgery. 

• Asymptomatic patients. Most do not progress (hypercalcemia or -calciuria, stones, fracture) but up to 1/3 do, and long-term data (>8y) show BMD worsening in most asymptomatic patients. Forth International Workshop for Asymptomatic Primary Hyperparathyroidism guidelines advise surgery for patients with high progression risk:
• Serum Ca >=1 mg/dL above upper normal range. 
• BMD TScore <2.5 at any site or vertabral fracture.
• eGFR <60, nephrolitiasis or -calcinosis, or 24h calcium > 400 mg (arbitrary cut-point not supported by evidence). 
• Age <50. 
• Any patient that prefers operation. 
  
• Effects of surgery:
• Neuropsychiatric symptoms: very low quality evidence of improvement. 
• Subclinical kidney disease (stones, hypercalciuria, eGFR<60):
• eGFR neither decline in untreated nor improve in treated. 
• Observational studies show that parathyroidectomy may reduce stone formation but do not prevent them completely.
  
• CV events: not all studies show mortality reduction. In rest of parameters no or weak evidence of improvement. Hypertension usually persists. 
• Bone: BMD mildly modestly at all sites 1-2 y after parathyroidism compared to observation, where it remains stable the first 5y, then there may be a decline. Fractures may modestly improve with surgery.
• Calcemia: little effect of surgery in follow-up except in younger patients that progress more if no treated. 
• Types of surgery: classical (bilateral neck exploration BNE) or minimally invasive parathyroidectomy (MIP) based in preoperative localization. Both similar success (95-100%) and risks when expert surgeon. 
• Preoperative localization studies are needed to MIP. The most frequently used is 99Tc-sestaMIBI (plain, spect or spect-CT) because of its high sensitivity, followed by US, 4d-CT, MRI, and invasive techniques (arteriography, venous sampling)
• If negative, BNE is performed because 20-40% are hyperplasia or multiple adenoma. 
• In reoperation, studies are mandatory, usually two (sestamibi+other depending of local experience). 
• BNE is recommended in young males (hereditary form suspected), or if studies show 0 or >1 affected gland.
  
• Conservative follow-up in patient not candidate to surgery:
• General measures:
• avoid thiazide and lithium
• encourage exercise, avoid >1g dietary calcium
• moderate dietary vit D 400-800 UI (maintain 20-30 ng/mL)
• encourage hydration. 
• Annual eGFR and calcium. 
• 2-3 yearly BMD
• Renal imaging not indicated unless clinical suspicion. 
• Surgical candidates not operated due to refusal / contraindications:
• Cinacalcet if hypercalcemia as surgical indication:
• Typical dose 30 mg/12h
  
• ↓Ca in most patients, mean 7%, normalize in 75%, irrespective of severity
• No efect in PTH, BMD or 24hCa, unknown effect in stone and neurocognitive symptoms (not indicated in asymptomatic PHPT)
  
• Frequent adverse effects: nausea and arthralgia (1/3), diarrhea, myalgia and paresthesia (1/5).
  
• Biphosphonates if osteoporosis as surgical indication (alendronate most experience), they improve BMD but not proved ↓fracture. 
• Cina + biph if ↑Ca+osteoporosis, but no RCT evidence of efficacy and safety.
  
• In other cases no treatment. Umproved therapies are:
• Estrogen-progestin, denosumab or raloxifen for OP, no proven fracture effect. 
• Vitamin D. Expert opinion, not evidence, recommend treat to >20, but careful if high hypercalciuria because it can worsen. Otherwise it seems safe but no proven benefit. Presurgical replacement advised to avoid postoperatory hypocalcemia.
  
• Normocalcemic HPT. Same criteria than hypercalcemic:
• Symptomatic patients: operation
• Asymtomatic, parathyroidectomy if 4th IWAPH criteria met. 
• Preoperative localization (US, sestamibi, CT, MRI), if + MIP, if - clasical surgery. Some prefer BP if negative localization and OP as indication. 
• Pregnancy
• Rare, but case reports included hyperemesis, nephrolitiasis, pancreatitis, miscarriage, and neonatal hypocalcemia due to fetal PTH suppression. 
• Surgery in 2nd trimester is recommended except mild cases, where observation is preferable. 
• Rely on ionized calcium, total is lower than normal due to ↓albumin.