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EFFECTS OF MAGNESIUM ON PARATHYROID HORMONE SECRETION DURING CHRONIC HÆMODIALYSIS
462
EFFECTS OF MAGNESIUM ON PARATHYROID HORMONE SECRETION DURING CHRONIC HÆMODIALYSIS PETER PLETKA DANIEL S. BERNSTEIN CONSTANTINE L. HAMPERS JOHN P. MERRILL LOUIS M. SHERWOOD
Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School; Department of Nutrition, Harvard School of Public Health; and Endocrine Unit, Department of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.
In sixteen patients with chronic renal failure treated by hæmodialysis, dialysisbath magnesium concentration was increased from 1·5 to 2·5 meq. per litre, and in twelve patients it was reduced from 1·5 to 0·5 meq. per litre. Serumparathyroid hormone (P.T.H.) fell in patients on highmagnesium dialysis from 2·41 to 1·93 ng. per ml. after a period of 2 months, the greatest decrease occurring in patients who had been on dialysis for less than 6 months. In the low-magnesium dialysis group serumP.T.H. rose from 0·84 to 1·84 ng. per ml. after 2 months. It is suggested that high-magnesium dialysis may reduce the incidence of secondary hyperparathyroidism while low-magnesium dialysis increases it.
Sum ary
Introduction
hyperparathyroidism leading to renal osteodystrophy and ectopic calcification is one of the major complications of chronic renal failure in patients Other features of urxmia on chronic haemodialysis. tend to improve on hmmodialysis, but bone disease often gets worse, and its incidence and severity are proportional to the duration of dialysis. 1,2 Concentrations of immunoreactive parathyroid hormone (P.T.H.) SECONDARY
in serum are generally raised in chronic renal failure 3-66 and reflect the severity of the bone disease.5 Attempts have been made to reduce the incidence of these complications by administration of vitamin D 1,7 and by using high-calcium dialysis,8 but both may be associated with ectopic calcification.9,Io
Stinson, E. B., Dong, E., Jr., Iben, A. B., Shumway, N. E. Am. J. Surg. 1969, 118, 182. 4. Stinson, E. B., Dong, E., Jr., Bieber, C. P., Popp, R. L., Shumway, N. E. J. thorac. cardiovasc. Surg. 1969, 58, 326. 5. Griepp, R. B., Stinson, E. B., Dong, E., Jr., Clark, D. A., Shumway, N. E. Ann. thorac. Surg. (in the press). 6. Starzl, T. E., Porter, K. A., Isasaki, Y., Marchioro, T. L., Kashiwagi, N. in Study Group on Antilymphocytic Serum (edited by G. E. W. Wolstenholme and M. O’Connor); p. 5. London, 3.
1967.
Stinson, E. B., Dong, E., Jr., Bieber, C. P., Schroeder, J. S., Shumway, N. E. J. Am. med. Ass. 1969, 207, 2233. 8. Bodmer, W., Tripp, M., Bodmer, J. in Histocompatibility Testing (edited by E. S. Curtoni, P. L. Mattiuz, R. M. Tosi); p. 341. Copenhagen, 1967. 9. Lower, R. R., Dong, E., Jr., Glazener, F. S. Circulation, 1966, 33, 7.
455.
Schroeder, J. S., Popp, R. L., Stinson, E. B., Dong, E., Jr., Shumway, N. E., Harrison, D. C. ibid. 1969, 40, 155. 11. Butler, W. T., Rossen, R. D., Hersh, E. M., Beall, A. C., Jr., Morgan, R. O., Diethrich, E. B., DeBakey, M. E. Laval méd. 1970, 41, 155. 12. Botha, M. C. Lancet, 1969, ii, 508. 13. Fernbach, D. J., Nora, J. J., Cooley, D. A. ibid. 1969, i, 425. 10.
P.T.H. secretion Since magnesium is dialysis bath used for
Magnesium, like calcium, influences in vivo
and in vitro.15 component of the
11-14
normally a patients on long-term hxmodialysis, we investigated the effects of magnesium concentration on P.T.H. secretion. Patients and Methods
Twenty-eight patients with chronic renal failure of aetiologies who had been maintained on thriceweekly hxmodialysis from 1 to 12 months were randomly various
In one group, selected and divided into two groups. comprising sixteen patients, magnesium concentration in the dialysis bath was increased from the usual 1-5 meq. per litre to 2-5 meq. per litre; in another group, of twelve patients, magnesium concentration was reduced from 1-5 Calcium concentration was kept to 0-5 meq. per litre. constant at 2-6 meq. per litre. Blood was taken from all patients before the investigation and after 1 and 2 months of either low or high magnesium dialysis. All bloodsamples were obtained before dialysis and serum-P.T.H. concentrations were measured in duplicate by radioimmunoassay. 16, 17 The results were expressed in terms of bovine equivalent using purified bovine P.T.H. Serummagnesium concentrations were monitored frequently, and special attention was paid to the possible development of symptoms which might be attributable to hypermagnesaemia.18 Magnesium was measured by the method of Orange and Rhein.193
Results P.T.H. concentrations before the start of high or low magnesium dialysis are shown in table i. The results are derived from an average of two blood collections taken 3 days apart and done in duplicate. Serum-P.T.H. concentrations were higher in patients who had been on hxmodialysis for a longer period of time, the sharpest increase being noted after 3 months of dialysis. Patients who had been on dialysis for between 6 and 12 months showed a further increase in P.T.H. secretion. Table 11 shows results in sixteen patients on highmagnesium and twelve patients on low-magnesium dialysis. Serum-magnesium concentrations in the two groups were high to start with and not significantly different from one another. Control P.T.H. levels were different only because five patients in the highmagnesium group had extremely high values; however, all patients had very high serum-levels of P.T.H. compared with the normal level. In the high-magnesium group, serum-P.T.H. fell from 2-41 to 1-55 ng. per ml. after 1 month, while serum-magnesium rose from 3-17 to 3-29 meq. per litre. After 2 months, however, the serum-magnesium was slightly lower and serum-P.T.H. concentration was 1-93 ng. per ml. At 1 and 2 months neither the changes in hormone concentration nor the changes in serummagnesium were significantly different (P>0-05). The TABLE I-SERUM-P.T.H. IN RELATION TO DURATION OF H1F.MODIALYSIS
463 TABLE II-SERUM P.T.H. AND MAGNESIUM LEVELS DURING HIGH AND LOW MAGNESIUM DIALYSIS
*
mean
Normal serum-p.T.H. < 0-2 ng. per ml. bovine equivalents. from control (p < 0-05). t Significantly different from control (p
Significantly different
decrease in the
serum-P.T.H. was
16-5%
after
2 months.
After low-magnesium dialysis, serum-P.T.H. levels from 0-84 to 1-40 ng. per ml. after 1 month and 1-84 ng. per ml. after 2 months. The increase in serum-P.T.H. at 2 months was significant (P<0-05). Serum-magnesium concentration fell from 3-36 to 2’13 meq. per litre after 1 month and 1-90 meq. per litre thereafter. When the effect of high-magnesium dialysis was in relation to the duration of dialysis, the analysed " suppressibility " of P.T.H. secretion was related primarily to duration of dialysis (table in). In two patients who had been on haemodialysis for less than 3 months, serum-P.T.H. fell from 0-65 to 0-40 ng. per ml. Although this finding is possibly significant it could not be analysed statistically. In patients who had been on dialysis for 3-6 months serum-P.T.H. fell from 2-75 to 1-57 ng. per ml. In patients who had been dialysed for 6-12 months, it remained unchanged
rose
despite high-magnesium dialysis.
Service.
Requests for reprints should be addressed
III-SUPPRESSIBILITY
OF
SERUM-P.T.H.
DURING
HIGH-
MAGNESIUM DIALYSIS IN RELATION TO DURATION OF DIALYSIS
to
P. P.
REFERENCES 1. Pendras, J. P. Archs intern. Med. 1969, 124, 312. 2. Katz, A. I., Hampers, C. L., Merrill, J. P. Medicine, Baltimore, 1969, 48, 333. 3. Berson, S. A., Yalow, R. S. Science, 1966, 154, 907. 4. Reiss, E., Canterbury, J. M., Kanter, A. Archs intern. Med. 1969,
5. 6.
TABLE
0 001).
did increase the serum-magnesium level. The reduction of magnesium in the dialysis bath to 0-5 meq. per litre, which lowered serum-magnesium to normal levels, is clearly associated with increased P.T.H. secretion and might, in long-term dialysis, result in an increased incidence and severity of secondary hyperparathyroidism and its attendant complications. This work was supported by grants from the U.S. Public Health Service, the John A. Hartford Foundation, Inc., and the Fund for Research and Teaching, Department of Nutrition, Harvard School of Public Health. L. M. S. is the recipient of a research career development award from the U.S. Public Health
Discussion
While the danger of administering magnesiumcontaining medications to patients with renal failure has been stressed,18 no adverse clinical effects were noted in the patients dialysed against 2-5 meq. per litre of magnesium, and serum-magnesium concentrations did not increase. High-magnesium dialysis resulted in P.T.H. suppression in patients who had been on dialysis for less than 6 months, while in the remainder serum-P.T.H. was unchanged. Since changes in serummagnesium affect P.T.H. secretion, 11, 15 the maintenance of a constant serum-magnesium by dialysis against a magnesium concentration close to the existing serumlevel may be beneficial. Increased retention of magnesium under these circumstances should theoretically be associated with increasing serum-magnesium. Since intracellular depletion of magnesium has been reported in chronic renal failure, 20however, retained magnesium may partially correct this deficiency and not result in an increased serum concentration. We do not know if gastrointestinal excretion of magnesium is increased in uraemia, as it is for calcium, but if it were we could explain, in part at least, why high-magnesium dialysis
<
7. 8.
9.
10. 11. 12. 13. 14.
124, 417. Genuth, S. M., Sherwood, L. M., Ventes, V., Leonards, J. J. clin. Endocr. Metab. 1970, 30, 15. Potts, J. T., Jr., Reitz, R. E., Deftos, L. J., Kaye, M. D., Richardson, F. A., Buckle, R. M., Aurbach, G. D. Archs intern. Med. 1969, 124, 408. Dent, C. E., Harper, C. M., Philpot, G. R. Q.Jl Med. 1961, 30, 1. Furszyfer, J., Goldsmith, R. S., Johnson, W. J., Arnaud, C. D.; Fourth Annual Meeting of the American Society for Nephrology; 1970; abstracts, p. 27. Felts, J. H., Whitley, J. E., Anderson, D. D., Carpenter, H. M., Bradshaw, H. H. Ann. intern. Med. 1965, 62, 1272. Johnson, J. W., Hattner, R. S., Hampers, C. L., Bernstein, D. S., Merrill, J. P., Sherwood, L. M. Metabolism (in the press). MacIntyre, I., Davidson, D. Biochem. J. 1958, 70, 456. Heaton, F. W. Clin. Sci. 1965, 28, 543. Care, A. D., Sherwood, L. M., Potts, J. T., Jr., Aurbach, G. D. Nature, 1966, 209, 55. Buckle, R. M., Care, A. D., Cooper, C. W., Gitelman, H. J. J.
Endocr. 1968, 42, 529. 15. Sherwood, L. M., Herrmann, I., Bassett, C. A. Nature, 1970, 225, 1056. 16. Berson, S. A., Yalow, R. S., Aurbach, G. D., Potts, J. T. Proc. natn. Acad. Sci., U.S.A. 1963, 49, 613. 17. Sherwood, L. M., Potts, J. T., Jr., Care, A. D., Mayer, G. P., Aurbach, G. D. Nature, 1966, 209, 52. 18. Randall, R. E., Jr., Cohen, M. D., Spray, C. E., Jr., Rossmeisl, E. C. Ann. intern. Med. 1964, 61, 73. 19. Orange, M., Rhein, H. C. J. biol. Chem. 1951, 189, 379. 20. Lim, P., Dong, S., Khoo, O. T. New Engl. J. Med. 1969, 280, 981. "
Let us hope, then, that this great society will henceforth be known by some such designation as theBritish Medical Association’.... There will arise, we expect, immense advantages from the establishment of this association of medical practitioners; for it has been alleged against us, and it must be acknowledged with truth, that the members of the profession might be likened to a rope of sand, no two portions acting in harmony, propelled by the same impulse, or actuated by similar objects ... as individuals, the members of the profession are beloved and respected; but ... as a body in the state, from the absence of proper government, and from the monstrous division of the members into classes, their voice is not acknowledged as an authoritative voice, and both their intelligence and utility are even questioned and denied."
-Lancet, 1832-33, ii, 574.
EFFECTS OF MAGNESIUM ON PARATHYROID HORMONE SECRETION DURING CHRONIC HÆMODIALYSIS PETER PLETKA DANIEL S. BERNSTEIN CONSTANTINE L. HAMPERS JOHN P. MERRILL LOUIS M. SHERWOOD
Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School; Department of Nutrition, Harvard School of Public Health; and Endocrine Unit, Department of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.
In sixteen patients with chronic renal failure treated by hæmodialysis, dialysisbath magnesium concentration was increased from 1·5 to 2·5 meq. per litre, and in twelve patients it was reduced from 1·5 to 0·5 meq. per litre. Serumparathyroid hormone (P.T.H.) fell in patients on highmagnesium dialysis from 2·41 to 1·93 ng. per ml. after a period of 2 months, the greatest decrease occurring in patients who had been on dialysis for less than 6 months. In the low-magnesium dialysis group serumP.T.H. rose from 0·84 to 1·84 ng. per ml. after 2 months. It is suggested that high-magnesium dialysis may reduce the incidence of secondary hyperparathyroidism while low-magnesium dialysis increases it.
Sum ary
Introduction
hyperparathyroidism leading to renal osteodystrophy and ectopic calcification is one of the major complications of chronic renal failure in patients Other features of urxmia on chronic haemodialysis. tend to improve on hmmodialysis, but bone disease often gets worse, and its incidence and severity are proportional to the duration of dialysis. 1,2 Concentrations of immunoreactive parathyroid hormone (P.T.H.) SECONDARY
in serum are generally raised in chronic renal failure 3-66 and reflect the severity of the bone disease.5 Attempts have been made to reduce the incidence of these complications by administration of vitamin D 1,7 and by using high-calcium dialysis,8 but both may be associated with ectopic calcification.9,Io
Stinson, E. B., Dong, E., Jr., Iben, A. B., Shumway, N. E. Am. J. Surg. 1969, 118, 182. 4. Stinson, E. B., Dong, E., Jr., Bieber, C. P., Popp, R. L., Shumway, N. E. J. thorac. cardiovasc. Surg. 1969, 58, 326. 5. Griepp, R. B., Stinson, E. B., Dong, E., Jr., Clark, D. A., Shumway, N. E. Ann. thorac. Surg. (in the press). 6. Starzl, T. E., Porter, K. A., Isasaki, Y., Marchioro, T. L., Kashiwagi, N. in Study Group on Antilymphocytic Serum (edited by G. E. W. Wolstenholme and M. O’Connor); p. 5. London, 3.
1967.
Stinson, E. B., Dong, E., Jr., Bieber, C. P., Schroeder, J. S., Shumway, N. E. J. Am. med. Ass. 1969, 207, 2233. 8. Bodmer, W., Tripp, M., Bodmer, J. in Histocompatibility Testing (edited by E. S. Curtoni, P. L. Mattiuz, R. M. Tosi); p. 341. Copenhagen, 1967. 9. Lower, R. R., Dong, E., Jr., Glazener, F. S. Circulation, 1966, 33, 7.
455.
Schroeder, J. S., Popp, R. L., Stinson, E. B., Dong, E., Jr., Shumway, N. E., Harrison, D. C. ibid. 1969, 40, 155. 11. Butler, W. T., Rossen, R. D., Hersh, E. M., Beall, A. C., Jr., Morgan, R. O., Diethrich, E. B., DeBakey, M. E. Laval méd. 1970, 41, 155. 12. Botha, M. C. Lancet, 1969, ii, 508. 13. Fernbach, D. J., Nora, J. J., Cooley, D. A. ibid. 1969, i, 425. 10.
P.T.H. secretion Since magnesium is dialysis bath used for
Magnesium, like calcium, influences in vivo
and in vitro.15 component of the
11-14
normally a patients on long-term hxmodialysis, we investigated the effects of magnesium concentration on P.T.H. secretion. Patients and Methods
Twenty-eight patients with chronic renal failure of aetiologies who had been maintained on thriceweekly hxmodialysis from 1 to 12 months were randomly various
In one group, selected and divided into two groups. comprising sixteen patients, magnesium concentration in the dialysis bath was increased from the usual 1-5 meq. per litre to 2-5 meq. per litre; in another group, of twelve patients, magnesium concentration was reduced from 1-5 Calcium concentration was kept to 0-5 meq. per litre. constant at 2-6 meq. per litre. Blood was taken from all patients before the investigation and after 1 and 2 months of either low or high magnesium dialysis. All bloodsamples were obtained before dialysis and serum-P.T.H. concentrations were measured in duplicate by radioimmunoassay. 16, 17 The results were expressed in terms of bovine equivalent using purified bovine P.T.H. Serummagnesium concentrations were monitored frequently, and special attention was paid to the possible development of symptoms which might be attributable to hypermagnesaemia.18 Magnesium was measured by the method of Orange and Rhein.193
Results P.T.H. concentrations before the start of high or low magnesium dialysis are shown in table i. The results are derived from an average of two blood collections taken 3 days apart and done in duplicate. Serum-P.T.H. concentrations were higher in patients who had been on hxmodialysis for a longer period of time, the sharpest increase being noted after 3 months of dialysis. Patients who had been on dialysis for between 6 and 12 months showed a further increase in P.T.H. secretion. Table 11 shows results in sixteen patients on highmagnesium and twelve patients on low-magnesium dialysis. Serum-magnesium concentrations in the two groups were high to start with and not significantly different from one another. Control P.T.H. levels were different only because five patients in the highmagnesium group had extremely high values; however, all patients had very high serum-levels of P.T.H. compared with the normal level. In the high-magnesium group, serum-P.T.H. fell from 2-41 to 1-55 ng. per ml. after 1 month, while serum-magnesium rose from 3-17 to 3-29 meq. per litre. After 2 months, however, the serum-magnesium was slightly lower and serum-P.T.H. concentration was 1-93 ng. per ml. At 1 and 2 months neither the changes in hormone concentration nor the changes in serummagnesium were significantly different (P>0-05). The TABLE I-SERUM-P.T.H. IN RELATION TO DURATION OF H1F.MODIALYSIS
463 TABLE II-SERUM P.T.H. AND MAGNESIUM LEVELS DURING HIGH AND LOW MAGNESIUM DIALYSIS
*
mean
Normal serum-p.T.H. < 0-2 ng. per ml. bovine equivalents. from control (p < 0-05). t Significantly different from control (p
Significantly different
decrease in the
serum-P.T.H. was
16-5%
after
2 months.
After low-magnesium dialysis, serum-P.T.H. levels from 0-84 to 1-40 ng. per ml. after 1 month and 1-84 ng. per ml. after 2 months. The increase in serum-P.T.H. at 2 months was significant (P<0-05). Serum-magnesium concentration fell from 3-36 to 2’13 meq. per litre after 1 month and 1-90 meq. per litre thereafter. When the effect of high-magnesium dialysis was in relation to the duration of dialysis, the analysed " suppressibility " of P.T.H. secretion was related primarily to duration of dialysis (table in). In two patients who had been on haemodialysis for less than 3 months, serum-P.T.H. fell from 0-65 to 0-40 ng. per ml. Although this finding is possibly significant it could not be analysed statistically. In patients who had been on dialysis for 3-6 months serum-P.T.H. fell from 2-75 to 1-57 ng. per ml. In patients who had been dialysed for 6-12 months, it remained unchanged
rose
despite high-magnesium dialysis.
Service.
Requests for reprints should be addressed
III-SUPPRESSIBILITY
OF
SERUM-P.T.H.
DURING
HIGH-
MAGNESIUM DIALYSIS IN RELATION TO DURATION OF DIALYSIS
to
P. P.
REFERENCES 1. Pendras, J. P. Archs intern. Med. 1969, 124, 312. 2. Katz, A. I., Hampers, C. L., Merrill, J. P. Medicine, Baltimore, 1969, 48, 333. 3. Berson, S. A., Yalow, R. S. Science, 1966, 154, 907. 4. Reiss, E., Canterbury, J. M., Kanter, A. Archs intern. Med. 1969,
5. 6.
TABLE
0 001).
did increase the serum-magnesium level. The reduction of magnesium in the dialysis bath to 0-5 meq. per litre, which lowered serum-magnesium to normal levels, is clearly associated with increased P.T.H. secretion and might, in long-term dialysis, result in an increased incidence and severity of secondary hyperparathyroidism and its attendant complications. This work was supported by grants from the U.S. Public Health Service, the John A. Hartford Foundation, Inc., and the Fund for Research and Teaching, Department of Nutrition, Harvard School of Public Health. L. M. S. is the recipient of a research career development award from the U.S. Public Health
Discussion
While the danger of administering magnesiumcontaining medications to patients with renal failure has been stressed,18 no adverse clinical effects were noted in the patients dialysed against 2-5 meq. per litre of magnesium, and serum-magnesium concentrations did not increase. High-magnesium dialysis resulted in P.T.H. suppression in patients who had been on dialysis for less than 6 months, while in the remainder serum-P.T.H. was unchanged. Since changes in serummagnesium affect P.T.H. secretion, 11, 15 the maintenance of a constant serum-magnesium by dialysis against a magnesium concentration close to the existing serumlevel may be beneficial. Increased retention of magnesium under these circumstances should theoretically be associated with increasing serum-magnesium. Since intracellular depletion of magnesium has been reported in chronic renal failure, 20however, retained magnesium may partially correct this deficiency and not result in an increased serum concentration. We do not know if gastrointestinal excretion of magnesium is increased in uraemia, as it is for calcium, but if it were we could explain, in part at least, why high-magnesium dialysis
<
7. 8.
9.
10. 11. 12. 13. 14.
124, 417. Genuth, S. M., Sherwood, L. M., Ventes, V., Leonards, J. J. clin. Endocr. Metab. 1970, 30, 15. Potts, J. T., Jr., Reitz, R. E., Deftos, L. J., Kaye, M. D., Richardson, F. A., Buckle, R. M., Aurbach, G. D. Archs intern. Med. 1969, 124, 408. Dent, C. E., Harper, C. M., Philpot, G. R. Q.Jl Med. 1961, 30, 1. Furszyfer, J., Goldsmith, R. S., Johnson, W. J., Arnaud, C. D.; Fourth Annual Meeting of the American Society for Nephrology; 1970; abstracts, p. 27. Felts, J. H., Whitley, J. E., Anderson, D. D., Carpenter, H. M., Bradshaw, H. H. Ann. intern. Med. 1965, 62, 1272. Johnson, J. W., Hattner, R. S., Hampers, C. L., Bernstein, D. S., Merrill, J. P., Sherwood, L. M. Metabolism (in the press). MacIntyre, I., Davidson, D. Biochem. J. 1958, 70, 456. Heaton, F. W. Clin. Sci. 1965, 28, 543. Care, A. D., Sherwood, L. M., Potts, J. T., Jr., Aurbach, G. D. Nature, 1966, 209, 55. Buckle, R. M., Care, A. D., Cooper, C. W., Gitelman, H. J. J.
Endocr. 1968, 42, 529. 15. Sherwood, L. M., Herrmann, I., Bassett, C. A. Nature, 1970, 225, 1056. 16. Berson, S. A., Yalow, R. S., Aurbach, G. D., Potts, J. T. Proc. natn. Acad. Sci., U.S.A. 1963, 49, 613. 17. Sherwood, L. M., Potts, J. T., Jr., Care, A. D., Mayer, G. P., Aurbach, G. D. Nature, 1966, 209, 52. 18. Randall, R. E., Jr., Cohen, M. D., Spray, C. E., Jr., Rossmeisl, E. C. Ann. intern. Med. 1964, 61, 73. 19. Orange, M., Rhein, H. C. J. biol. Chem. 1951, 189, 379. 20. Lim, P., Dong, S., Khoo, O. T. New Engl. J. Med. 1969, 280, 981. "
Let us hope, then, that this great society will henceforth be known by some such designation as theBritish Medical Association’.... There will arise, we expect, immense advantages from the establishment of this association of medical practitioners; for it has been alleged against us, and it must be acknowledged with truth, that the members of the profession might be likened to a rope of sand, no two portions acting in harmony, propelled by the same impulse, or actuated by similar objects ... as individuals, the members of the profession are beloved and respected; but ... as a body in the state, from the absence of proper government, and from the monstrous division of the members into classes, their voice is not acknowledged as an authoritative voice, and both their intelligence and utility are even questioned and denied."
-Lancet, 1832-33, ii, 574.