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the accurate measurement and appropriate control of the serum parathyroid hormone ( pth ) concentration is essential in the management of uremic secondary hyperparathyroidism ( shpt ) .
the so - called third generation pth assay that can exclusively detect pth ( 184 ) , a full - length pth fragment , has become widely available .
the value measured by the second generation assay is usually higher than that measured by the third generation assay , because the former assay can detect both pth ( 184 ) and pth ( 784 ) , . as a result , the whole pth / intact pth ratio is theoretically < 1.0 .
several investigators have recently reported that there are quite a few patients with hyperparathyroidism or parathyroid cancer , whose whole pth / intact pth ratio is > 1.0 [ 47 ] .
the relative increase of n - terminus pth ( n - pth ) is thought to be the cause of the abnormal pth ratio in these rare cases .
n - pth , a full - length pth ( 184 ) first identified through high - performance liquid chromatography fractionation by d'amour et al .
, is reported to have post - translational modification at the site where the first antibody to the intact pth assay recognizes [ 7 , 9 ] .
the whole pth assay can detect n - pth , but the intact pth assay can not because of the structural modification of n - pth and the difference in the recognition sites between intact pth assay and whole pth assay .
thus , the abnormal pth ratio can theoretically occur in cases with high serum n - pth value compared with serum pth ( 784 ) .
however , whether there are any specific biological and histological features in the causative parathyroid gland ( ptg ) showing the abnormal pth ratio remains undetermined . in this report
, we describe a hemodialysis patient with shpt whose abnormal whole pth / intact pth ratio became normalized immediately after the largest ptg was surgically removed .
we also discuss the possible underlying mechanism of the abnormal whole pth / intact pth ratio by comparing the immunohistochemical features of the causative ptg with those of the other ptgs in the patient .
a 34-year - old woman under 5 years of hemodialysis therapy was hospitalized for the treatment of uncontrollable shpt .
total parathyroidectomy with forearm auto - transplantation was scheduled , because intravenous calcitriol therapy over 4 years failed to control shpt .
the corrected serum calcium ( ca ) at the time of admission was 3.1 mmol / l , phosphorus 2.0 mmol / l , alkaline phosphatase ( alp ) 345 u / l , bone - specific alp 35.6u / ml , intact pth 84.9 pmol / l ( 801 pg / ml ) ( elecsys pth ; roche diagnostics ) , whole pth 96.6 pmol / l ( 901 pg / ml ) ( whole pth ; scantibodies laboratories ) ; the whole pth / intact pth ratio was 1.14 .
neck ultrasonography revealed four ptgs , while no ectopic ptgs were detected by tc - methoxyisobutyl - isonitrile scintigraphy .
total parathyroidectomy resected all the four ptgs in the order of ptg4 , ptg3 , ptg2 and ptg1 : the smallest gland ( ptg1 ) was auto - transplanted in the right forearm ( figure  1a ) .
the patient 's serum was obtained 5min after each ptg was removed ; each ptg was resected at an 5 min interval .
the serial changes in the serum whole pth , intact pth and the whole pth / intact pth ratio are shown in figure  1b .
the pth ratio decreased immediately after the left lower ptg ( ptg4 ) was removed , and the ratio was maintained at < 1.0 after all the four ptgs were resected ( ratio : 1.14  0.41 ) .
pmol / l ( 58 pg / ml ) , respectively , 3 years after surgery ; the pth ratio was 0.48 . 

1.(a ) a schematic presentation of the four parathyroid glands and their macroscopic photographs and weights measured after parathyroidectomy .
( b ) the serial changes in the intact pth , whole pth and whole pth / intact pth ratio during surgery .
( a ) a schematic presentation of the four parathyroid glands and their macroscopic photographs and weights measured after parathyroidectomy .
( b ) the serial changes in the intact pth , whole pth and whole pth / intact pth ratio during surgery .
eosin staining showed that the smallest ptg ( ptg1 ) was diffuse hyperplastic , and the remaining three ptgs were nodular hyperplastic ( figure  2a ) .
immunohistochemistry was performed for the following ptg - related proteins : ca - sensing receptor ( casr ) , vitamin d receptor , ki-67 , parafibromin and galectin-3 .
the number of ki-67-positive cells was greater and the galectin-3 positive areas were larger in ptg3 and ptg4 than those observed in ptg1 and ptg2 ( supplementary figure s1a and b ) .
as for the vitamin d receptor , the expression of vdr in ptg3 and ptg4 was decreased compared with that observed in ptg1 and ptg2 ( supplementary figure s1c ) .
however , these markers could not be used to differentiate between ptg3 and ptg4 . as shown in figure  2b and c , the expression of casr and parafibromin in ptg4
was extremely diminished in comparison with the other three ptgs , distinguishing ptg4 from other ptgs and indicating the possible involvement of casr and parafibromin in the pathogenesis of the abnormal pth ratio in this patient . 

immunohistochemical staining of ( b ) the calcium - sensing receptor ( original magnification 200 ) and ( c ) parafibromin ( original magnification 100 , 200 ) .
immunohistochemical staining of ( b ) the calcium - sensing receptor ( original magnification 200 ) and ( c ) parafibromin ( original magnification 100 , 200 ) .
n - pth is constitutively produced and secreted into the serum in the normal and proliferative ptgs , although the amount of n - pth production is relatively small ; the proportion of n - pth among all forms of serum pth fragments is usually low , and the whole pth / intact pth is < 1.0 .
n - pth can only be detected by the third - generation assay , not by the second - generation assay   because 1020 amino acid sites from the n - terminus are reported to be modified by unknown mechanisms [ 7 , 9 ] .
therefore , the amount of n - pth is theoretically higher than that of pth ( 784 ) in patients with an abnormal whole pth / intact pth ratio .
although the current study did not directly demonstrate the increase of n - pth by high - performance liquid chromatography , the normalization of the whole pth / intact pth ratio after removal of the largest ptg strongly suggests that the largest ptg was secreting a relatively large amount of n - pth , thus leading to the abnormal pth ratio .
the possible mechanisms of the abnormal whole pth / intact pth ratio can be theoretically due to either hypersecretion of n - pth in the ptg or decreased clearance of serum n - pth .
the present case demonstrated that the whole pth / intact pth ratio was normalized after the removal of largest ptg , indicating that the clearance of n - pth from serum did not contribute to the abnormal pth ratio .
reported in their in vitro study that low ca concentration in the medium increases the proportion of n - pth and decreases the proportion of pth ( 184 ) , followed by the increase of the whole pth / intact pth ratio .
in addition , komaba et al .   reported that cinacalcet hydrochloride , an allosteric modulator of casr , lowers the whole pth / intact pth ratio , and the ratio returns to an abnormal level after the discontinuation of cinacalcet treatment , thereby indicating the involvement of casr signaling in the modulation of the whole pth / intact pth ratio .
the expression of casr as determined by immunohistochemistry was extremely reduced in the largest ptg in the current case , suggesting that casr signaling could have been decreased in the same ptg , leading to the increase of the whole pth / intact pth ratio .
although it is undetermined how casr signaling is involved in the regulation of the whole pth / intact pth ratio , one possibility is that casr signaling plays a crucial role in the degradation of pth fragment or in the stabilization of pth mrna .
the diminished expression of parafibromin can partially explain the mechanism of the abnormal whole pth / intact pth ratio .
parafibromin is a protein that regulates the cell cycle by suppressing the expression of cyclin d1 and other cell cycle - dependent proteins .
the loss of parafibromin is also reported to be involved in the development of sporadic parathyroid carcinoma and primary hyperparathyroidism [ 13 , 14 ] . in some cases with parathyroid carcinoma , a diminished expression of parafibromin in the glands with the abnormal whole pth
/ intact pth ratio was reported , indicating the possible involvement of parafibromin in the pathogenesis of the abnormal pth ratio .
furthermore , the loss of parafibromin is also highly associated with downregulation of casr in parathyroid carcinoma .
in addition , a mouse model of cyclin d1 overexpression in the ptg demonstrated casr downregulation in the ptg .
these results suggest that a diminished expression of parafibromin in the ptg decreases casr signaling via cyclin d1 upregulation , leading to a decrease in n - pth degradation and a relative increase in the n - pth fraction and the whole pth / intact pth ratio .
why only limited cases exhibit abnormal pth levels remains unclear , although the casr on the ptg is often observed to decrease in patients with severe shpt .
one possible factor is that the pattern of the whole pth / intact pth ratio in shpt patients has not been fully investigated .
indeed , recent clinical studies have shown that many shpt patients exhibit an inverse whole pth / intact pth ratio .
another possible explanation is that a decrease in the casr protein expression is only a necessary condition , not a sufficient condition .
hence , we speculate that parafibromin is a possible factor that is directly or indirectly involved in the pathogenesis of the abnormal whole pth / intact pth ratios in shpt patients . finally , the biologic features of n - pth remain to be elucidated .
previous reports show that patients with an abnormal pth ratio tend to show relatively high - bone turnover with severe hyperparathyroidism [ 5 , 6 ] .
the bone turnover as demonstrated by the serum bone - specific alp level and bone scintigraphy seemed high in the present case .
although there has been no experimental data that examined the biologic activity of n - pth , given that pth ( 784 ) was historically identified as having antagonistic action against the pth receptor , it is plausible that n - pth has an unknown biologic effect apart from pth ( 184 ) . the present study is associated with several limitations .
because the ionized ca level can influence the whole pth / intact pth ratio , a further evaluation of the effects of ionized ca on serial changes in the pth ratio during ptx should be conducted . secondly
, we can not explain why calcimimetics do not affect the whole pth / intact pth ratio in patients with parathyroid carcinoma .
therefore , the present immunohistochemical results can not be easily generalized to other patients with the inverse whole pth / intact pth ratios , and causal inference remains in the range of speculation .
further studies are needed to clearly determine the effects of casr and parafibromin in the pathogenesis of the abnormal whole pth / intact pth ratios in dialysis patients . in summary , this report presented the case of an shpt patient with an abnormal whole pth / intact pth ratio , which normalized immediately after the largest ptg was surgically resected .
an immunohistochemical analysis revealed that the expression of the casr and parafibromin were extremely decreased in the most advanced form of ptg .
this case supports the hypothesis that a diminished expression of the casr and parafibromin in the advanced form of ptg is involved in the pathogenesis of an abnormal whole pth / intact pth ratio in severe shpt patients .
a 34-year - old female hemodialysis patient with an abnormal whole parathyroid hormone ( pth)/intact pth ratio ( ratio = 1.14 ) underwent parathyroidectomy for advanced secondary hyperparathyroidism . 
 the abnormal pth ratio indicated a relative increase in the serum n - terminus pth , a new molecular form of pth . the abnormal ratio normalized immediately after the largest parathyroid gland ( ptg ) 
 was removed , proving the largest ptg as causative . 
 an immunohistochemical analysis revealed extremely decreased expression of the calcium - sensing receptor and parafibromin in the largest ptg in comparison with the other ptgs . 
 this case indicated the possible involvement of decreased calcium - sensing receptor and parafibromin signaling in the development of the abnormal pth ratio .