Upsala J Med Sci 87: 215-222, 1982 Evaluation of Parathyroid Function in Patients with Hypergastrinaemia and Pernicious Anaemia 0. Selking’, K. Borch2, H. Johansson’, S . Ljunghal13 and L. Wide4 From the Departments of Surgery’, Medicine’ and Clinical Chemistry4, University Hospital, U p p s a l a , and the Department of Surgery’, Central Hospital, Eskilstuna, Sweden ABSTRACT I n o r d e r t o e v a l u a t e t h e p o s s i b l e c a u s a l r e l a t i o n s h i p between r a i s e d serum g a s t r i n l e v e l s and t h e development o f p r i m a r y h y p e r p a r a t h y r o i d i s m (HPT) w h i c h i s suggested f r o m e x p e r i m e n t a l s t u d i e s we e v a l u a t e d p a r a t h y r o i d f u n c t i o n i n a group o f 3 2 p a t i e n t s w i t h h y p e r g a s t r i n a e m i a and p e r n i c i o u s anaemia. The v a l u e s f o r serum c a l c i u m and p a r a t h y r o i d hormone were d e t e r m i n e d as w e l l as t h e f a s t i n g u r i n a r y e x c r e t i o n s o f c y c l i c AMP and c a l c i u m . There was no r e l a t i o n s h i p between t h e serum a a s t r i n l e v e l s and any o f t h e o t h e r s t u d i e d p a r a m e t e r s and t h e r e was no c o n s i s t e n t p a t t e r n s u g g e s t i n g p a r a t h y r o i d h y p e r f u n c t i o n . A r e t r o s p e c t i v e a n a l y s i s o f h o s p i t a l r e c o r d s f r o m 441 p a t i e n t s o p e r a t e d f o r p r i m a r y HPT showed a p r e v a l e n c e o f p e r n i c i o u s anaemia o f 1.8 %. T h i s f i g u r e i s h i g h e r t h a n t h a t f o u n d i n t h e u n s e l e c t e d age-matched p o p u l a t i o n (0.31 % I . How- ever, t a k e n t o g e t h e r t h i s s t u d y does n o t s u p p o r t t h e h y p o t h e s i s t h a t h y p e r - g a s t r i n a e m i a i s o f p a r t i c u l a r i m p o r t a n c e f o r t h e p a t h o g e n e s i s o f p r i m a r y HPT. INTRODUCTION S e v e r a l p i e c e s o f e v i d e n c e s u g g e s t t h a t g a s t r i n m i g h t be i n v o l v e d i n t h e p a t h o g e n e s i s o f p r i m a r y h y p e r p a r a t h y r o i d i s m (HPT). I n p a t i e n t s w i t h p r i m a r y HPT r a i s e d g a s t r i n l e v e l s have been f o u n d i n an i n c r e a s e d f r e q u e n c y o f t e n p e r s i s t i n g even a f t e r p a r a t h y r o i d e c t o m y (5, 10, 16, 2 1 ) . When h y p e r g a s t r i n a e m i a was e x p e r i m e n t a l l y i n d u c e d i n r a t s h y p e r p l a s i a o f t h e parenchymal c e l l s o f t h e p a r a t h y r o i d s was seen ( 7 ) and i n - v i t r o s t u d i e s s u g g e s t t h a t g a s t r i n m i g h t be a s t i m u l u s f o r s e c r e t i o n o f p a r a t h y r o i d hormone (PTH) (22). I n o r d e r t o f u r t h e r e v a l u a t e t h e p o s s i b l e r e l a t i o n s h i p between h y p e r - g a s t r i n a e m i a and p r i m a r y HPT we s t u d i e d p a r a t h y r o i d f u n c t i o n i n a group o f p a t i e n t s w i t h p e r n i c i o u s anaemia where a c h l o r h y d r i a and h y p e r g a s t r i n a e m i a i s an o b l i g a t o r y f i n d i n g . I n a d d i t i o n , t h e p r e v a l e n c e o f p e r n i c i o u s anaemia was d e t e r m i n e d among p a t i e n t s w i t h p r i m a r y HPT. 215 PATIENTS AND METHODS Altogether 32 p a t i e n t s (13 males, 19 females) w i t h a mean age of 67 2 10 ( S D ) (range 44-82) years were studied. They a l l h a d a verified history of perni- cious anaemia based on typical haematological findings including marrow biopsy and a f u l l response t o treatment w i t h vitamin B12. Their d u r a t i o n of disease was from 1 t o 2 1 years (mean 9.8 2 6.9 y e a r s ) . Gastric acid secretion was investigated i n 27 p a t i e n t s and they were found t o have achlorhydria. All p a t i e n t s except one had normal values f o r serum c r e a t i n i n e , 4 h a d diabetes and 3 received regular treatment w i t h thiazides. The patients were studied as out-patients (Central Hospital, Eskil s t u n a ) , where they reported a f t e r an overnight ( 1 2 hours) fasting. Blood samples were taken i n evacuated tubes, whenever possible w i t h o u t tourniquet. Urine was collected d u r i n g a 2-hour period as previously described (11). Blood samples were centrifuged and serum was decanted. Serum was frozen a t -8O'C and urine was frozen a t -2O'C until analyzed. Calcium, c r e a t i n i n e and albumin concentrations were determined as p a r t of the c l i n i c a l routine a t t h e Department of Clinical Chemistry. The serum calcium concentrations were adjusted for variations of the serum albumin content, the correction f a c t o r being n.019 mnol/l f o r each g/1 t h a t the individual albumin concentration deviated from the normal mean of 46 g/1. W i t h t h i s correction the normal range in our laboratory i s 2.20-2.60 mnol/l. ( 1 3 ) w i t h the g a s t r i n antibodies coupled t o bromcyanide-activated cellulose. The antiserum used was a generous g i f t from Professor J Rehfeld, Copenhagen, Denmark, and has been characterized previously (15). Synthetic Human Gastrin I (SHG ICI Chemicals, U . K . ) was used f o r preparation of standards and f o r 1251-labelling w i t h the Chloramine-T method. The r e s u l t s are presented as pmol equivalents of SHG/1. The normal value f o r serum gastrin i n our laboratory i s l e s s than 55 pmol/l . Immunoreactive PTH concentrations were measured by a radioimmunoassay method employing 1251-labelled bovine PTH (Inolex) and sheep antiserum (S478) against porcine and bovine PTH. This assay measures i n t a c t human PTH and the C-terminal 2/3 of the molecule. The antiserum r e a c t s predominantly w i t h a mid- portion (44-68) of the hormone b u t not w i t h a N-terminal (1-34) fragment or a small C-terminal (53-84) fragment ( 9 ) . The reference range, as estimated from 50 healthy individuals i s 0.4-1.2 a r b i t r a r y units (arb. U/l) per l i t r e , whereas among 40 consecutive p a t i e n t s w i t h verified primary HPT t h e mean value was 2.3 1.6 arb. U/l ( 1 2 ) . descrihed (23). The normal range f o r the f a s t i n g urinary CAMP i s 0.2-0.7 Serum gastrin concentrations were determined by a radioimnunosorbent method Urinary cyclic AMP was determined by a radioimmunoassay method as previously 216 lreol/mnol c r e a t i n i n e and f o r the f a s t i n g urinary calcium 0.05-0.50 mmol/mmol c r e a t i n i ne (11 1. A retrospective study of hospital records was also carried out of a l l p a t i e n t s operated a t our hospital d u r i n g the years 1959-1979 for primary HPT ( 1 ) . The prevalence of pernicious anaemia in t h i s material of 441 p a t i e n t s was compared t o figures from a recent survey of the apparently healthy population of approximately 20,700 individuals i n a nearby rural Swedish d i s t r i c t (18). RESULTS All p a t i e n t s w i t h pernicious anaemia had c l e a r l y elevated l e v e l s of g a s t r i n , which ranged from 80 t o 5500 pmol/l w i t h a mean (+ SD) of 2000 1200 pmol/l. In 2 4 of t h e 32 cases values above 1000 pmol/l were detected. The mean values f o r serum calcium a n d PTH a s well as f o r urinary cAMP and f a s t i n g calcium excretion a l l f e l l w i t h i n the normal range (Table 1). Table 1. in urine in p a t i e n t s w i t h pernicious anaemia and hypergastrinaemia. Mean values ( + ) SD of parathyroid hormone ( P T H ) and i n serum and of f a s t i n g excretions of cyclic AMP and calcium Serum values Urine values PTH Calcium cAMP Calcium ( a r b . U/l) (nmol/l) ( pmol /mol (mnol /mol 0.84 + 0.61 2.45 + 0.09 0.61 + 0.41 0.25 - + 0.17 c r e a t ) c r e a t ) - - - Pa ti en t s Normal range 0.40 - 1-20 2.20 - 2.60 0.17 - 0.67 0.05 - 0.50 There was no relationship between gastrin and PTH concentrations ( F i g . 1 ) nor between g a s t r i n and calcium values (Fia. 2 ) . Neither was there any relationship between gastrin a n d f a s t i n g urinary calcium or CAMP. Two p a t i e n t s had serum calcium concentrations j u s t above the upper normal limit(2.62 mmol/l i n both cases) and one of them had also a s l i g h t l y elevated value f o r urinary CAMP. In 2 nomocalcaemic individuals raised l e v e l s f o r PTH were found (1.31 and 3.55 a r b . U/l) and i n 2 others an elevated urinary cAMP (1.3 a n d 2.6 pmol/mmol c r e a t i n i n e ) b u t they had normal values for t h e f a s t i n g urinary calcium. Among the 441 p a t i e n t s operated f o r primary HPT altogether 8 individuals (1.8 % I , mostly elderly females, had a verified diagnosis of pernicious anaemia. Diagnosis of the blood disorder h a d preceded the detection of HPT w i t h periods from 2 t o 29 years. In the p o p u l a t i o n study 0.31 % o f a l l individuals had a diagnosis of pernicious anaemia (18) (Table 2 ) . This difference is s t a t i s t i c a l l y s i g n i f i c a n t ( p <0.001. Fisher's exact t e s t ) . 217 T 3-5 t 1.3 I 0 0 . I L J I 0 0 0 I- Q 5 0.7 Q) 0 v) 0 0.5 O 0 0 0 0 a 8 ° p o 0 0 0 0 0 0 0 L 0 0 0 80 200 500 1000 2000 4000 6000 Serum gastrin (pmolll) Fig. 1 R e l a t i o n s h i p between t h e serum c o n c e n t r a t i o n s o f g a s t r i n and p a r a t h y r o i d hormone ( P T H ) i n p a t i e n t s with p e r n i c i o u s anaemia ( r = -0.0616, p> 0 . 7 ) . 0 0 0 0 0 0 0 0 0 0 0 .- 0 ([I 0 0 0 5 L 2.1 a, v) 80 200 500 1000 2000 40006000 Serum gastrin (pmol/l) Fig. 2 R e l a t i o n s h i p between t h e serum c o n c e n t r a t i o n s o f g a s t r i n and calcium in p a t i e n t s with p e r n i c i o u s anaemia ( r = - 0 . 1 0 , p = 0 . 5 8 ) . 218 II:5 T a b l e 2. h y p e r p a r a t h y r o i d i s m (HPT) i n U p p s a l a 1959-1979 compared t o d a t a f r o m a p o p u l a t i o n s u r v e y ( 1 8 ) . P r e v a l e n c e o f p e r n i c i o u s anaemia i n p a t i e n t s o p e r a t e d f o r p r i m a r y HPT p a t i e n t s ( n = 4 4 1 ) Ma1 es Females Ma1 e s Females n % n % n % n % P o p u l a t i o n s t u d y ( n = 20 7 0 0 ) 15-44 2 0.1 45-64 5 0.2 7 0.3 65-74 1 4.2 4 4 8 0.7 7 0.6 75- 3 4.2 1 4 1.7 22 2.2 A l l ages 1 0.9 7 2.2 29 0.3 36 0.4 D I S C U S S I O N G a s t r i n bas been shown t o have t r o p h i c a c t i o n s b e s i d e s i t s s t i m u l a t o r y e f f e c t on t h e a c i d - s e c r e t i n g p a r i e t a l c e l l s . It s t i m u l a t e s RNA, DNA and p r o t e i n s y n t h e s i s i n t h e mucosa a l o n g t h e i n t e s t i n a l t r a c t w i t h t h e e x c e p t i o n o f oesophagus and antrum. A l s o t h e p a n c r e a s i s a t a r g e t o r g a n f o r t h e t r o p h i c a c t i o n o f g a s t r i n ( 6 , 8 ) . P r e v i o u s e x p e r i m e n t a l work i n o u r group ( 7 1 s u g g e s t e d t h a t , i n t h e r a t , h y p e r g a s t r i n a e m i a c o u l d s t i m u l a t e t o p a r a t h y r o i d h y p e r p l a s i a . I n t h e s e e x p e r i m e n t s , t h e i n d u c t i o n o f h y p e r g a s t r i n a e r n i a t h r o u g h a n t r a l e x c l u s i o n was a s s o c i a t e d w i t h an i n c r e a s e d volume o f t h e p a r a t h y r o i d s owing t o h y p e r p l a s i a o f t h e parenchymal c e l l s . However, t h e serum c a l c i u m l e v e l s were n o t a f f e c t e d . I n t h e p r e s e n t s t u d y o f p a t i e n t s w i t h h y p e r g a s t r i n a e m i a and p e r n i c i o u s anaemia t h e r e was no p a t t e r n o f g e n e r a l p a r a t h y r o i d h y p e r f u n c t i o n . N a t u r a l l y we have no i n f o r m a t i o n as t o t h e h i s t o l o g i c a l appearance o f t h e p a r a t h y r o i d g l a n d s i n t h e s e cases. Thus we do n o t know i f t h e r e m i g h t have been h y p e r p l a s i a o f t h e g l a n d s w i t h o u t h y p e r c a l c a e m i a as i n t h e work by G r i m e l i u s e t a l . ( 7 ) . I n t h a t s t u d y , however, t h e r a t s were exposed t o h y p e r g a s t r i n a e m i a f o r 1 4 weeks o n l y , w h i l e i n r h e p r e s e n t work t h e p a t i e n t s had a d u r a t i o n o f d i s e a s e f r o m 1 t o 2 1 y e a r s . I n a work by V a n t i n i e t a l . ( 1 9 ) an i n t r a v e n o u s i n f u s i o n o f p e n t a g a s t r i n i n d u c e d a s i g n i f i c a n t i n c r e a s e o f b o t h c a l c i t o n i n and PTH l e v e l s , and a d e c r e a s e i n serum c a l c i u m l e v e l s was c o n c o m i t a n t l y seen. D e m o n s t r a t i o n o f h y p e r c a l c a e m i a i s a r e q u i s i t e f o r t h e d i a g n o s i s o f p r i m a r y HPT. I n a d d i t i o n , s e v e r a l methods can be used f o r e v a l u a t i o n o f p a r a t h y r o i d f u n c t i o n i n c l u d i n g d e t e r m i n a t i o n s o f t h e serum c o n c e n t r a t i o n s o f PTH o r o f t h e u r i n a r y e x c r e t i o n s o f CAMP. F u r t h e r m o r e v a r i o u s i n d i r e c t e v i d e n c e o f p a r a t h y r o i d hormone a c t i v i t y based on t h e r e n a l h a n d l i n g o f c a l c i u m and phosphate has been r e p o r t e d t o be o f c l i n i c a l v a l u e ( 3 , 1 7 ) . The l a r g e number o f t e s t s t h a t have been d e v e l o p e d t o assess p a r a t h y r o i d f u n c t i o n i n d i c a t e s t h a t none o f them i s e n t i r e l y s a t i s f a c t o r y f o r c l i n i c a l purposes. 219 We have previously found t h a t determinations of b o t h t o t a l urinary cAblP ( 2 3 ) - and serum concentrations of PTH (20) will separate most patients with hyper- calcaemia and primary HPT from patients w i t h normal parathyroid function. A common picture i n primary HPT i s also a h i g h fasting urinary calcium (11, 141, due t o actions of PTH o n bone. F o r a l l these parameters, which more o r l e s s closely r e f l e c t parathyroid function, the p a t i e n t s with pernicious anaemia and hyperaastrinaemia as a g r o u p presented values t h a t were closely compatible with those found i n apparently heal thy subjects. Furthermore, there was no suggestion of any correlation between the individual serum l e v e l s of gastrin on one h a n d a n d serum PTH o r calcium concentrations on the other. Thus i t seems unlikely t h a t there i s any consistent relationship between the raised gastrin values i n pernicious anaemia, a n d parathyroid function. One patient displayed a pattern which was compatible w i t h mild primary HPT ( s l i g h t hypercalcaemia and elevated urinary C A M P ) . This was presumably a chance finding since the prevalence of HPT in the apparently heal thy elderly population seems t o be a t l e a s t one per cent ( 4 ) . In 3 other normocalcaemic cases e i t h e r PTH o r urinary CAMP was elevated. These p a t i e n t s presented no other signs of HPT nor were they known t o s u f f e r from any other disease of possible importance. I t seems most l i k e l y t h a t the laboratory data i n these cases r e f l e c t the ineffec- tiveness of any s i n g l e t e s t t o f u l l y discriminate normal i n d i v i d u a l s from those wi t h para thyroid hyperfunc ti on. operated f o r HPT w i t h regard t o the prevalence of pernicious anaemia, which was s i g n i f i c a n t l y higher i n those patients w i t h primary HPT than i n the unselected population. I t is, however, doubtful i f t h i s r e a l l y means an increased risk f o r a p a t i e n t w i t h pernicious anaemia t o develop HPT. Pernicious anaemia, or any other disease one looks f o r , i s l i k e l y to be diagnosed i n an increased frequency i n any thoroughly investigated p a t i e n t material such as ours ( 2 ) . I t i s also reasonable t o assume t h a t pernicious anaemia was under-diagnosed i n the unselected population material i n the study by Tyrberg 8 Smedby ( 1 8 ) . Some complex relationship between the two diseases cannot be excluded however. On the other h a n d , i f pernicious anaemia r e a l l y means an increased risk f o r developing HPT t h i s must be a weak factor as only 8 out of 441 patients developed b o t h diseases during an observation time of up t o 29 years. aemia, i n pernicious anaemia, i s n o t of p a r t i c u l a r importance f o r the develop- m e n t of primary hyperparathyroidism. We a l s o carried out a retrospective analysis of our material of patients Taken together the information i n t h i s study indicates t h a t hypergastrin- Financial assistance was given by the Swedish Medical Research Council ( p r o j e c t Nos. 882-17X-04787-078, 102 and 4534). 220 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Adami, H-O., Bergstrom, R. 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