Letters to the editor
Polycythaemia and hyperparathyroidism: A fortuitous association? To the editor: In recent decades it has been shown that parathyroid hormone could influence haematopoiesis through a direct action on haematopoietic precursors: at low concentration, parathormone could stimulate haematopoiesis and, in contrast, would be inhibitory at high concentration. Furthermore, about 10 cases of polycythaemia associated with hyperparathyroidism have been reported (1-8). We briefly describe 3 new cases which bring into question the real frequency of the association and the pathophysiological relationship between these two diseases. Case No 1
D., a man born in 1908, was admitted to the hospital in April 1979 because of a polycythaemia revealed when he was examined for a recurrent superficial phlebitis of the inferior limbs of 6 months duration. The red blood cells (RBC) count was in the range of 5.5 to 5.7 x 101*/1, white blood cells from 11 to 16 x 10”l with 68 to 72% neutrophils and a thrombocytosis of 700 to 800 x 109/l. Conjunctival and facial erythrosis was severe. There was no clinical or radiological splenomegaly. The diagnosis of polycythaemia Vera was confirmed by the measure of the red blood cell mass with a total blood volume of 5.45 1 (normal: 4.35 l), a total red cell mass of 2.41 1 (normal: 1.98 1). No aetiology was found. This apparently primary global myeloproliferative syndrome was associated with hyperparathyroidism: hypercalcaemia: 2.80 mmol/l, phosphoraemia: 0.58 mmol/l, calciuria: 15.2 mmol/day (N:4 2 l), phosphaturia: 47.4 mmol/day (N:28 7). Renal function was normal. The association between the myeloproliferative syndrome and the hypercalcaemia was considered as fortuitous. It was decided first to treat the myeloproliferative syndrome with Pipobromam (50 mg/d). A remission was obtained within 3 months; a maintenance treatment with pipobroman (25 mg/d) was given and remission persisted. The hypercalcaemia remained unchanged. An exploratory surgery was performed on 01/07/82: there was a small tumour in the right inferior gland, composed of a dense proliferation of small cells facing rows of large cells. The post-surgical period was unremarkable; however, the
calcaemia remained elevated, suggesting the presence of an ectopic parathyroid gland, revealed by CT scan of the left side between the inferior cervical part of the oesophagus and the left proximal intsrnal carotid. Thereafter, the patient who lived outside Paris refused a new surgical exploration, refused to attend the outpatient clinic and was lost to follow-up. Case no 2
Mr. Robert G., born in 1924, sought medical advice in March 1982 for bouts of dizziness. There was no other sign of polycythaemia Vera. A blood count showed: RBC: 6.07 x 10l2/1,Hb: 181 g/l, Ht: 53.2%, MCV: 88 y3, WBC: 11.6 x 109/1(neutrophils: 71 %, lymphocytes: 19%, monocytes; lo%, platelets: 369 x 109/l).The sedimentation rate was 1 mm at the 1st hour. There was no argument in favour of a secondary polycythaemia. The calcaemia was 2.6 mmol/l, phosphoraemia: 0.48 rnmol/l. A diagnosis of polycythaemia Vera was made and a treatment with pipobroman: 50 mg/d, was begun. Remission was obtained within 6 months and the maintenance treatment was pipobroman: 25 mg/d. Under these conditions the RBC level remained normal. The patient was seen every 3 months by his family physician and every 6 months at the haematology outpatients clinic. In August 1987, he was admitted in emergency in a hyperalgic state with such a severe asthenia as to make him bedridden. An emergency electrolytes measurement showed: Na: 129 mEq/l, K: 3.1 mEq/l, CI: 85 mEq/l, creatinine: 385 mmol/l, BUN: 29.4 mmol/l, uricaemia: 658 mmol/l and calcaemia: 4.5 mmol/l. After a treatment by hyperdiuresis with furosemide and the administration of 1250 mg of mithramycin, despite the prescription of Calsyn (660 UL/24 h) the patient deteriorated and died on the 2nd d after admission in a state of intractable pulmonary oedema. The autopsy revealed a 2.5 x 1.5 cm tumour of the right parathyroid with a paratrabecular structure and the morphological aspect of a large cell adenoma. In summary, the patient with an apparently primary polycythaemia, well controlled for 5 years with a pipobroman maintenance treatment, died from a complex syndrome with hypercalcaemia secondary to hyperparathyroidism from a parathyroid adenonia. 153
Letters to the editor Case no 3
Mr. Jean R., born in 1908, was referred to the haematology department of the Beaujon Hospital in February 1989 after a venous thrombosis of the right inferior limb to explore the association to polycythaemia with hypercalcaemia. The blood count showed: Hb: 190 g/l, Ht: 57%, hyperleukocytosis of 12 x 109/1, neutrophils; 78 ”/, , platelets: 3 13 x 109/1, and a sedimentation rate of 3 mm at the 1st hour. The red cell volume was high at 3.14 1 (Normal: 2 I). In addition there was a hypercalcaemia of 2.9 mmol/l with a phosphoraemia of 0.85 mmol/l; this had been known since February 1986 and was asymptomatic. Renal function was normal. No aetiology was found for the polycythaemia. The results of parathyroid function tests were typical of primary hyperparathyroidism with a plasmatic parathromone level of 214 micromoles/ml (10 < N < 58). However, no parathyroid adenoma could be found on a CT scan of the neck and superior mediastinum. The serum erythropoietin level was 19.5 mU/ml (control: 14 m u ) and its urinary excretion rate: 2800 mU/24 h (500 < N < 1800). Thus there was a hypererythropoietinaemia unusual in myeloproliferative syndromes. The patient refused a surgical exploration of the parathyroid glands and was lost to follow-up. In the absence of any systematic study, the incidence of hypercalcaemia in polycythaemia is unknown and the association of a primary hyperparathyroidism with polycythaemia Vera has only very rarely been reported. Twelve cases have been reported, including our own 3. In all but 2 cases, diagnosis of hyperparathyroidism was claimed either on histological characterization of a parathyroid adenoma obtained by surgical procedure or autopsy or on the classical biological signs of hyperparathyroidism (hypercalcaemia, hypophosphoraemia, increased level of parathormone in blood, increased CAMP urinary elimination). This association brings up essentially two questions: what is its real frequency and is there any causal relationship between its two elements. Is one to think that the association of polycythaemia and primary hyperparathyroidism is fortuitous and only results from the coexistence of two unexceptional diseases? Some arguments favour this concept: in some cases, both diseases seem to follow an independent course. In the case of Hayne et al. (5), and in our case no 2, the myeloproliferative syndrome preceded the discovery of the hyperparathyroidism by several years; the reverse was seen in our case no 1 and the diagnosis was simultaneous in the case of Godeau et al. (3), and in our case no 3, owing to a systematic measure of the calcaemia. Above all, in 8 cases out of 10, the haematologic aspect was that of a primary myeloproliferative syndrome in154
volving 2 or 3 myeloid cell lines as in polycythaemia Vera and not that of a pure erythrocytosis usual in secondary polycyth aemia. However, there are strong arguments in favour of a causal relationship between the primary hyperparathyroidism and the polycythaemia: 1. In 4 cases out of 5 where it was performed, the removal of the parathyroid adenoma was followed by a complete and stable remission even in the absence of any other treatment (3, 6, 7, 8). 2. In the case no 1 of Glovinski et al., cultured erythroblasts did not grow in the absence of erythropoietin and grew normally in its presence. Such a result spoke in favour of a secondary polycythaemia. Furthermore, on our case No 3 erythropoietin blood level and urinary elimination were increased, which is not usually observed in polycythaemia Vera. 3. The haemopoletic activity of parathyroid hormone (PTH) was demonstrated for more than twenty years (9), mainly for erythropoiesis (10). But if hyperparathyroidism had a physiopathogenic role in cases associated with polycythaemia, the impact would be on haemopoietic precursors at the stem cell level since several cell lines are proliferating; that is probably the case (1 1). It is presently impossible to give a definitive answer to either of the questions we asked: however, our goal in presenting these 3 cases was to bring into focus the possibility of an association, maybe not as exceptional as it may seen, which deserves to be looked for systematically.
References 1. BERLINR. Primary hyperplasia of the parathyroid glands associated with ulcers in the oesophagus and duodenum and polycythaemia of the splenomegalic type. Acta Med Scand . 1949: 135: 18-24. TG, PROCTOR J, BROWNS, WRONGOM. Nepho2. FEEST calcinosis: another cause of renal erythrocytosis. Br Med J 1979: 2: 605. 0, HUSSONOIS C. 3 . GODEAUP, BLETRY0, BROCHARD Polycythemia Vera and primary hyperparathyroidism. Arch Intern Med 1981: 141: 951-953. F, UNGERJ, STISCKMANS P, MONSIEUR R, 4. DELWICHE BELLENSR. Polycythaemia Vera. Arch Intern Med 1982: 142: 642. MS, JOHNSON EA, BRAUND 5. HAYNEST, DIESTELMEIER RR. Polycythaemia Vera, primary hyperparathyroidism and dysplastic nevus syndrome: report of a case. Am J Clin Pathol 1985: 83: 512-515. K, RAPOPORT D, DINTSMAN 6. ZIVY ,RUBINM, LOMBROSO M. Primary hyperparathyroidism associated with pancytosis. N Engl J Med 1985: 313: 187. J, BLETRY0, DUBEAUX P, etal. Hyperpar7. GLOVINSKI athyroldie primitive et polyglobulie secondaire. Rev du Rhumatisme 1988: 55: 529-532. P, FRAIROT A, BERAUDG. 8. VOLLEL, ROCHEJ, REVELIN Association d’une hyperparathyroi’die primitive et d’une polyglobulie secondaire. Presse Med 1988: 17: 1861-1862. JP, WHITFIELD JF, WEISSCA. 9. PERRISAD, MACMANUS
Letters to the editor Parathyroid glands and mitotic stimulation in rat bone marrow after hemorrhage. Am J Physiol 1971: 220: 773-778. 10. DUNNCDR, TRENTD. The effect of parathyroid hormone on erythropoiesis in serum free cultures of fetal mouse liver cells. Proc SOCExp Biol Med 1981: 166: 556-561. 11. GALLIEN-LARTIGUE 0, CARREZ D. Induction de la phae S dans les cehles souches multipotentes de la moelle osseuse par I’hormone parathyroidienne. CR Acad Sci (Paris) 1974: 238: 1765.
Correspondence: P. Boivin, J.F. Bernard Haematology department Beaujon Hospital 92 118 Clichy Cedex France
155
Polycythaemia and hyperparathyroidism: A fortuitous association? To the editor: In recent decades it has been shown that parathyroid hormone could influence haematopoiesis through a direct action on haematopoietic precursors: at low concentration, parathormone could stimulate haematopoiesis and, in contrast, would be inhibitory at high concentration. Furthermore, about 10 cases of polycythaemia associated with hyperparathyroidism have been reported (1-8). We briefly describe 3 new cases which bring into question the real frequency of the association and the pathophysiological relationship between these two diseases. Case No 1
D., a man born in 1908, was admitted to the hospital in April 1979 because of a polycythaemia revealed when he was examined for a recurrent superficial phlebitis of the inferior limbs of 6 months duration. The red blood cells (RBC) count was in the range of 5.5 to 5.7 x 101*/1, white blood cells from 11 to 16 x 10”l with 68 to 72% neutrophils and a thrombocytosis of 700 to 800 x 109/l. Conjunctival and facial erythrosis was severe. There was no clinical or radiological splenomegaly. The diagnosis of polycythaemia Vera was confirmed by the measure of the red blood cell mass with a total blood volume of 5.45 1 (normal: 4.35 l), a total red cell mass of 2.41 1 (normal: 1.98 1). No aetiology was found. This apparently primary global myeloproliferative syndrome was associated with hyperparathyroidism: hypercalcaemia: 2.80 mmol/l, phosphoraemia: 0.58 mmol/l, calciuria: 15.2 mmol/day (N:4 2 l), phosphaturia: 47.4 mmol/day (N:28 7). Renal function was normal. The association between the myeloproliferative syndrome and the hypercalcaemia was considered as fortuitous. It was decided first to treat the myeloproliferative syndrome with Pipobromam (50 mg/d). A remission was obtained within 3 months; a maintenance treatment with pipobroman (25 mg/d) was given and remission persisted. The hypercalcaemia remained unchanged. An exploratory surgery was performed on 01/07/82: there was a small tumour in the right inferior gland, composed of a dense proliferation of small cells facing rows of large cells. The post-surgical period was unremarkable; however, the
calcaemia remained elevated, suggesting the presence of an ectopic parathyroid gland, revealed by CT scan of the left side between the inferior cervical part of the oesophagus and the left proximal intsrnal carotid. Thereafter, the patient who lived outside Paris refused a new surgical exploration, refused to attend the outpatient clinic and was lost to follow-up. Case no 2
Mr. Robert G., born in 1924, sought medical advice in March 1982 for bouts of dizziness. There was no other sign of polycythaemia Vera. A blood count showed: RBC: 6.07 x 10l2/1,Hb: 181 g/l, Ht: 53.2%, MCV: 88 y3, WBC: 11.6 x 109/1(neutrophils: 71 %, lymphocytes: 19%, monocytes; lo%, platelets: 369 x 109/l).The sedimentation rate was 1 mm at the 1st hour. There was no argument in favour of a secondary polycythaemia. The calcaemia was 2.6 mmol/l, phosphoraemia: 0.48 rnmol/l. A diagnosis of polycythaemia Vera was made and a treatment with pipobroman: 50 mg/d, was begun. Remission was obtained within 6 months and the maintenance treatment was pipobroman: 25 mg/d. Under these conditions the RBC level remained normal. The patient was seen every 3 months by his family physician and every 6 months at the haematology outpatients clinic. In August 1987, he was admitted in emergency in a hyperalgic state with such a severe asthenia as to make him bedridden. An emergency electrolytes measurement showed: Na: 129 mEq/l, K: 3.1 mEq/l, CI: 85 mEq/l, creatinine: 385 mmol/l, BUN: 29.4 mmol/l, uricaemia: 658 mmol/l and calcaemia: 4.5 mmol/l. After a treatment by hyperdiuresis with furosemide and the administration of 1250 mg of mithramycin, despite the prescription of Calsyn (660 UL/24 h) the patient deteriorated and died on the 2nd d after admission in a state of intractable pulmonary oedema. The autopsy revealed a 2.5 x 1.5 cm tumour of the right parathyroid with a paratrabecular structure and the morphological aspect of a large cell adenoma. In summary, the patient with an apparently primary polycythaemia, well controlled for 5 years with a pipobroman maintenance treatment, died from a complex syndrome with hypercalcaemia secondary to hyperparathyroidism from a parathyroid adenonia. 153
Letters to the editor Case no 3
Mr. Jean R., born in 1908, was referred to the haematology department of the Beaujon Hospital in February 1989 after a venous thrombosis of the right inferior limb to explore the association to polycythaemia with hypercalcaemia. The blood count showed: Hb: 190 g/l, Ht: 57%, hyperleukocytosis of 12 x 109/1, neutrophils; 78 ”/, , platelets: 3 13 x 109/1, and a sedimentation rate of 3 mm at the 1st hour. The red cell volume was high at 3.14 1 (Normal: 2 I). In addition there was a hypercalcaemia of 2.9 mmol/l with a phosphoraemia of 0.85 mmol/l; this had been known since February 1986 and was asymptomatic. Renal function was normal. No aetiology was found for the polycythaemia. The results of parathyroid function tests were typical of primary hyperparathyroidism with a plasmatic parathromone level of 214 micromoles/ml (10 < N < 58). However, no parathyroid adenoma could be found on a CT scan of the neck and superior mediastinum. The serum erythropoietin level was 19.5 mU/ml (control: 14 m u ) and its urinary excretion rate: 2800 mU/24 h (500 < N < 1800). Thus there was a hypererythropoietinaemia unusual in myeloproliferative syndromes. The patient refused a surgical exploration of the parathyroid glands and was lost to follow-up. In the absence of any systematic study, the incidence of hypercalcaemia in polycythaemia is unknown and the association of a primary hyperparathyroidism with polycythaemia Vera has only very rarely been reported. Twelve cases have been reported, including our own 3. In all but 2 cases, diagnosis of hyperparathyroidism was claimed either on histological characterization of a parathyroid adenoma obtained by surgical procedure or autopsy or on the classical biological signs of hyperparathyroidism (hypercalcaemia, hypophosphoraemia, increased level of parathormone in blood, increased CAMP urinary elimination). This association brings up essentially two questions: what is its real frequency and is there any causal relationship between its two elements. Is one to think that the association of polycythaemia and primary hyperparathyroidism is fortuitous and only results from the coexistence of two unexceptional diseases? Some arguments favour this concept: in some cases, both diseases seem to follow an independent course. In the case of Hayne et al. (5), and in our case no 2, the myeloproliferative syndrome preceded the discovery of the hyperparathyroidism by several years; the reverse was seen in our case no 1 and the diagnosis was simultaneous in the case of Godeau et al. (3), and in our case no 3, owing to a systematic measure of the calcaemia. Above all, in 8 cases out of 10, the haematologic aspect was that of a primary myeloproliferative syndrome in154
volving 2 or 3 myeloid cell lines as in polycythaemia Vera and not that of a pure erythrocytosis usual in secondary polycyth aemia. However, there are strong arguments in favour of a causal relationship between the primary hyperparathyroidism and the polycythaemia: 1. In 4 cases out of 5 where it was performed, the removal of the parathyroid adenoma was followed by a complete and stable remission even in the absence of any other treatment (3, 6, 7, 8). 2. In the case no 1 of Glovinski et al., cultured erythroblasts did not grow in the absence of erythropoietin and grew normally in its presence. Such a result spoke in favour of a secondary polycythaemia. Furthermore, on our case No 3 erythropoietin blood level and urinary elimination were increased, which is not usually observed in polycythaemia Vera. 3. The haemopoletic activity of parathyroid hormone (PTH) was demonstrated for more than twenty years (9), mainly for erythropoiesis (10). But if hyperparathyroidism had a physiopathogenic role in cases associated with polycythaemia, the impact would be on haemopoietic precursors at the stem cell level since several cell lines are proliferating; that is probably the case (1 1). It is presently impossible to give a definitive answer to either of the questions we asked: however, our goal in presenting these 3 cases was to bring into focus the possibility of an association, maybe not as exceptional as it may seen, which deserves to be looked for systematically.
References 1. BERLINR. Primary hyperplasia of the parathyroid glands associated with ulcers in the oesophagus and duodenum and polycythaemia of the splenomegalic type. Acta Med Scand . 1949: 135: 18-24. TG, PROCTOR J, BROWNS, WRONGOM. Nepho2. FEEST calcinosis: another cause of renal erythrocytosis. Br Med J 1979: 2: 605. 0, HUSSONOIS C. 3 . GODEAUP, BLETRY0, BROCHARD Polycythemia Vera and primary hyperparathyroidism. Arch Intern Med 1981: 141: 951-953. F, UNGERJ, STISCKMANS P, MONSIEUR R, 4. DELWICHE BELLENSR. Polycythaemia Vera. Arch Intern Med 1982: 142: 642. MS, JOHNSON EA, BRAUND 5. HAYNEST, DIESTELMEIER RR. Polycythaemia Vera, primary hyperparathyroidism and dysplastic nevus syndrome: report of a case. Am J Clin Pathol 1985: 83: 512-515. K, RAPOPORT D, DINTSMAN 6. ZIVY ,RUBINM, LOMBROSO M. Primary hyperparathyroidism associated with pancytosis. N Engl J Med 1985: 313: 187. J, BLETRY0, DUBEAUX P, etal. Hyperpar7. GLOVINSKI athyroldie primitive et polyglobulie secondaire. Rev du Rhumatisme 1988: 55: 529-532. P, FRAIROT A, BERAUDG. 8. VOLLEL, ROCHEJ, REVELIN Association d’une hyperparathyroi’die primitive et d’une polyglobulie secondaire. Presse Med 1988: 17: 1861-1862. JP, WHITFIELD JF, WEISSCA. 9. PERRISAD, MACMANUS
Letters to the editor Parathyroid glands and mitotic stimulation in rat bone marrow after hemorrhage. Am J Physiol 1971: 220: 773-778. 10. DUNNCDR, TRENTD. The effect of parathyroid hormone on erythropoiesis in serum free cultures of fetal mouse liver cells. Proc SOCExp Biol Med 1981: 166: 556-561. 11. GALLIEN-LARTIGUE 0, CARREZ D. Induction de la phae S dans les cehles souches multipotentes de la moelle osseuse par I’hormone parathyroidienne. CR Acad Sci (Paris) 1974: 238: 1765.
Correspondence: P. Boivin, J.F. Bernard Haematology department Beaujon Hospital 92 118 Clichy Cedex France
155
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