Familial Hypocalciuric Hypercalcemia vs Primary Hyperparathyroidism: Deciphering the Differences

Primary hyperparathyroidism (PHPT) is a relatively common disorder affecting 85 per 100,000 men, with three times higher prevalence in women and older individuals(1). Although the majority of cases are asymptomatic, symptoms of bone loss and nephrolithiasis are seen in 20% of cases with PHPT. Parathyroidectomy is curative in >95% of cases in symptomatic and asymptomatic PHPT in whom surgery is indicated. 

In contrast, familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant genetic disorder with high penetrance and a prevalence of about 1 in 78,000 individuals. Inactivating mutations of the calcium-sensing receptor (CaSR) and downstream signaling pathways, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) have been linked to FHH1, FHH2, and FHH3, respectively. FHH1 accounts for > 65% of cases and involves inactivating mutation of the CaSR gene that encodes the CaSR protein, which is predominantly expressed in the parathyroid tissue and renal tubules and is involved in the regulation of renal calcium excretion and PTH secretion (2). Dysregulation of CaSR leads to impaired calcium and magnesium excretion by the kidneys and decreased sensitivity of the parathyroid gland to changes in serum calcium, leading to impaired inhibition of PTH secretion. 

Deciphering the difference between PHPT and FHH is crucial as FHH is mostly a benign condition and rarely requires any therapeutic intervention, whereas parathyroidectomy in patients with classic and asymptomatic PHPT is curative in >95% of cases. Both PHPT and FHH are characterized by inappropriately normal (20-65 pg/ml) or elevated PTH (> 65 pg/ml) levels in the presence of hypercalcemia. Approximately 40% of patients with PHPT may have “normal” PTH levels. In contrast, 20% of patients with FHH may have high PTH levels. Although young age at diagnosis (<30 yrs) and family history of hypercalcemia is suggestive of FHH, differentiation of these two disorders is often based on calcium excretion in urine (table 1) (3). 

Clinical and Biochemical Parameters	Favors FHH	Favors PHPT
Young Age (<30)	Yes
Older Age (>50)		Yes
Family history of hypercalcemia	Yes
Elevated PTH levels		Yes
Hypermagnesemia		Yes
24h UCCR <0.01	Yes
24h UCCR >0.02		Yes
Elevated bone turnover markers(osteocalcin, bone specific ALP)		Yes
Pro FHH >0.928		Yes
Pro FHH <0.928	Yes

Table 1. Clinical and biochemical features that differentiate FHH from PHPT

The recommended test to differentiate these two disorders is the  24-hour urine calcium and creatinine clearance ratio (24h UCCR = Urine calcium x serum creatinine / Serum calcium x urine creatinine ). A 24h UCCR <0.01 is indicative of FHH, while a 24h UCCR >0.02 often suggests PHPT(4). However, there is considerable overlap in using 24h UCCR to differentiate FHH and PHPT. Around 20% of patients with FHH can have 24h UCCR >0.02. 24h UCCR <0.01 is estimated in approximately 10% (4-23%) of patients with surgically treated PHPT, with the causes being attributed to use of thiazide diuretics, lithium and more commonly, coexisting vitamin D deficiency, present in 60-80% of patients with PHPT. Low Vitamin D levels can increase the PTH levels by up to 27%, reduce urine calcium excretion by 25%, and are often associated with increased bone turnover markers (osteocalcin, bone specific alkaline phosphatase etc), reduced bone mass, and symptomatic PHPT(5). This deficiency must be treated in patients with suspected FHH or PHPT, particularly if the UCCR is <0.02, before a definitive diagnosis is considered. In patients with adequate vitamin D levels (25 OH vitamin D level >30 ng/ml) whose 24h UCCR remains <0.02, genetic testing may be recommended to rule out FHH and to avoid unnecessary surgery.

A recent French study group developed a statistical test called pro-FHH (protect FHH patients from surgery) to accurately predict whether patients with hypercalcemia and inappropriately “normal PTH” have PHPT or FHH with the aim of avoiding unnecessary genetic testing in all patients with suspected FHH with UCCR <0.02 and to avoid parathyroid surgery in patients with FHH (6). It requires measuring calcium and creatinine in blood and urine along with PTH and bone turnover markers (osteocalcin or bone-specific alkaline phosphatase).  Pro-FHH with a cut-off of >0.928 had higher AUROC (~0.95) compared with UCCR (~0.80) and 100% specificity and 100% positive predictive value for the diagnosis of PHPT. However, the validity of this test in differentiating FHH and PHPT with elevated PTH levels has not been studied. 

In summary, although 24h UCCR is the standard test to differentiate FHH from PHPT, it is essential to correct the underlying vitamin D deficiency before interpreting the results of this test. The new statistical test, pro-FHH, can be used to separate patients of FHH from PHPT in a subset of patients with hypercalcemia associated with normal PTH levels in order to avoid routine genetic testing and unnecessary parathyroid surgeries.