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Serum Ceruloplasmin-Bound Copper and Non-Cerulo-Plasmin Copper in Uncomplicated Psoriasis*
Vol. 47, No. 2
THE JOURNAL OF INVESTIOATIVE DERMATOLOOY
Copyright
Printed in U.S.A.
1966 by The Williams & Wilkins Co.
Preliminary and Short Report SERUM CERULOPLASMIN-BOUND COPPER AND NON-CERULOPLASMIN COPPER IN UNCOMPLICATED PSORIASIS* MATTI KEKKI, M.D.t, PENTTI KOSKELO, M.D.t AND ALLAN LASSUS, M.D4
It has been demonstrated by Lipkin et al. (1) RESULTS that the copper content of blood serum of paThe results are given in Table I and in the diatients with psoriasis is on an average signifi- gram Figure 1. No difference was seen in the cantly higher than that of control subjects. A mean serum ceruloplasmin content of the control considerable overlap, however, is apparent in the subjects and the psoriasis patients. The mean serum copper levels in normal subjects and psori- total copper content was higher in the psoriasis atics. The elevated serum copper levels found in
group than in the control group. In spite of considerable overlapping the difference is statistically significant (p < 0.001). A very clear difference was seen in the non-ceruloplasmin copper content between the psoriasis patients and control subwith Wilson's disease—so that the copper and jects. The non-ceruloplasmin copper content in ceruloplasmin almost always vary in the same the psoriasis patients was on an average more direction and either one is a good index of the than twofold that of the controls, the difference other (3). We found serum ceruloplasmin to be being statistically highly significant (p < 0.001). normal in patients with uncomplicated psoriasis No correlation was found between the increased (4), differing with the reports mentioned above. copper contents and routine laboratory tests and 'We therefore sought to determine whether the clinical condition. elevation of copper observed is due to the elevation of a copper fraction in serum which is not COMMENTS bound to ceruloplasmin. psoriasis appear to be unaccompanied by quantitative tissue copper alterations (2). It is known that copper bound to ceruloplasmia accounts for almost all the serum copper—except in patients
It is evident that the elevation of the serum
copper level in patients with uncomplicated psoriasis is due to an increase in a non-eeruloplasmin bound copper fraction. The methodological error
MATERIAL AND METHODS
The material consisted of 58 healthy ambulatory subjects and 65 patients with uncomplicated psoriasis. The controls consisted of 27 men and 31 women, from 20 to 59 years, the mean age being 43 years. In the psoriasis group there were 29 men and 36 women. The mean age was 34 years and the range from 7 to 78 years.
due to the indirect fractional determination of
the copper content may be relatively large in the small non-ceruloplasmia copper fraction. How-
ever, this does not affect the results since the
Serum copper was determined spectrophoto-
methodological error is of the same magnitude in both the control and the experimental series.
metrically with bicyclohexaaoaeoxalyldihydraxone
according to Peterson and Bollier (5). All pre-
TABLE I
cautions were taken to minimize the risk of chem-
Serum ceruloplasmin copper and non-ceruloplasmin
ical contamination. Serum ceruloplasmin determinations were carried out by the colorimetric enzymatic method of Ravin (6). Double determinations were made in every instance in both the copper and the ceruloplasmin analyses. The ceruloplasmin-bound copper was calculated from the serum ceruloplasmin values obtained by taking into consideration that one ceruloplasmin molecule contains eight copper atoms and that its molecular weight is 160,000 (7). The serum content of the non-ceruloplasmin copper was obtained simply by subtracting the ceruloplasmin copper from the total copper.
cop per in 58 healthy subjects and 65 patients with uncomplicated psOriasis
Results are stated in pg. per 100 ml. Total Copper
Ceroloplasmio Copper
Non-Ceroloplasmin Copper
Healthy subjects Mean Range S.D.
137
118
19
89-197
77—158
0—45
51
17
12
This investigation was supported by a grant
Patients with pso-
from the Finnish Medical Research Council. Received for publication April 5, 1966.
* From the Third Department of Medicinet
and the Department of Dermatology, University of Helsinki, Helsinki 29, Finland.
159
riasis Mean Range S.D.
165
119
45
117—239
75—211
4—90
31
24
22
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
160
250
200 I. U
'I.
E
0
I. I.
0
150
r I.
•1'
I.
r
4.
II
p p
.1.
I.
p I.
I.
—T4
1-
•1•
'F
100
I. I.
I 50
—LI.
r+i
TOTAL SERUM COPPER
CERULOPLASMIN COPPER
HEALTHY
HEALTHY PERSONS
PERSONS
PSORIASIS
NON-CERULOPLASMIN COPPER HEALTHY PERSONS
PSORIASIS
PSORIASIS
Fie. 1. Total semm copper, ceruloplasmin copper and non-ceruloplasmin copper in healthy persons and patients with uncomplicated psorlasis.
It is known that copper plays a role in the ries. The serum non-ceruloplasmin copper was keratinization process of the skin of certain ani- significantly elevated in patients with psoriasis. mals and that copper causes a defect in keratin formation (8). The role of copper in the incomREFERENCES plete keratinization process of psoriatic skin is not known. It could be thought that the psoriatic skin is not able to utilize copper in the keratinization 1. Lipkin, G., Herrmann, F. and Mandol, L.: Studies on serum copper. I. The copper conprocess and causes a change in the distribution of tent of blood serum in patients with psorianon-ceruloplasmin copper between the intravassis. J. Invest. Derm., 89: 1062. cular and extravascular compartments of the 2. Lipkin, G., Gowdey, J. and543, Wheatley, V. R.: Skin copper levels in psoriasis. J. Invest.
body.
SUMMARY
Derm., 42:
205, 1964.
3. Scheinberg, H. and Sternlieb, I.: Copper me-
tabolism. Pharmacol. Rev., 12: 355, 1960. Serum total copper, ceruloplasmin-bound copP., Kekki, M., Virkkunen, M., Lasper and non-ceruloplasmin copper were studied in 4. Koskelo, sus, A. and Somer, T.: Serum ceruloplasmin
58 healthy persons and 65 patients with uncomplicated psoriasis. No difference was seen in the ceruloplasmin-bound copper between the two Se-
concentration in rheumatoid arthritis, ankylosing spondylitis, psoriasis, and sarcoidosis.
To be published.
SERUM COPPER IN PSORIASIS
161
5. Peterson, R. E. and Bollier, M. E.: Spectro- 7. Rasper, C. B. and Deutsch, H. F.: Physicophotometric determination of serum copper chemical studies of human ceruloplasmin. J. with bieyclohexanoneoxalyldihydrazone. Anal. Chem., 27: 1195, 1955.
6. Ravin, H. A.: An improved colorimetric enzymatic assay of ceruloplasmin. J. Lab. Clin. Med., 58:
161,
1961.
Biol. Chem., 238: 2325, 1963.
8. Burley, R. W. and De Rock, W. J.: N-terminal amino acid residues in wool from normal and copper-deficient sheep. Arch. Biochem., 68: 21, 1957.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.
THE JOURNAL OF INVESTIOATIVE DERMATOLOOY
Copyright
Printed in U.S.A.
1966 by The Williams & Wilkins Co.
Preliminary and Short Report SERUM CERULOPLASMIN-BOUND COPPER AND NON-CERULOPLASMIN COPPER IN UNCOMPLICATED PSORIASIS* MATTI KEKKI, M.D.t, PENTTI KOSKELO, M.D.t AND ALLAN LASSUS, M.D4
It has been demonstrated by Lipkin et al. (1) RESULTS that the copper content of blood serum of paThe results are given in Table I and in the diatients with psoriasis is on an average signifi- gram Figure 1. No difference was seen in the cantly higher than that of control subjects. A mean serum ceruloplasmin content of the control considerable overlap, however, is apparent in the subjects and the psoriasis patients. The mean serum copper levels in normal subjects and psori- total copper content was higher in the psoriasis atics. The elevated serum copper levels found in
group than in the control group. In spite of considerable overlapping the difference is statistically significant (p < 0.001). A very clear difference was seen in the non-ceruloplasmin copper content between the psoriasis patients and control subwith Wilson's disease—so that the copper and jects. The non-ceruloplasmin copper content in ceruloplasmin almost always vary in the same the psoriasis patients was on an average more direction and either one is a good index of the than twofold that of the controls, the difference other (3). We found serum ceruloplasmin to be being statistically highly significant (p < 0.001). normal in patients with uncomplicated psoriasis No correlation was found between the increased (4), differing with the reports mentioned above. copper contents and routine laboratory tests and 'We therefore sought to determine whether the clinical condition. elevation of copper observed is due to the elevation of a copper fraction in serum which is not COMMENTS bound to ceruloplasmin. psoriasis appear to be unaccompanied by quantitative tissue copper alterations (2). It is known that copper bound to ceruloplasmia accounts for almost all the serum copper—except in patients
It is evident that the elevation of the serum
copper level in patients with uncomplicated psoriasis is due to an increase in a non-eeruloplasmin bound copper fraction. The methodological error
MATERIAL AND METHODS
The material consisted of 58 healthy ambulatory subjects and 65 patients with uncomplicated psoriasis. The controls consisted of 27 men and 31 women, from 20 to 59 years, the mean age being 43 years. In the psoriasis group there were 29 men and 36 women. The mean age was 34 years and the range from 7 to 78 years.
due to the indirect fractional determination of
the copper content may be relatively large in the small non-ceruloplasmia copper fraction. How-
ever, this does not affect the results since the
Serum copper was determined spectrophoto-
methodological error is of the same magnitude in both the control and the experimental series.
metrically with bicyclohexaaoaeoxalyldihydraxone
according to Peterson and Bollier (5). All pre-
TABLE I
cautions were taken to minimize the risk of chem-
Serum ceruloplasmin copper and non-ceruloplasmin
ical contamination. Serum ceruloplasmin determinations were carried out by the colorimetric enzymatic method of Ravin (6). Double determinations were made in every instance in both the copper and the ceruloplasmin analyses. The ceruloplasmin-bound copper was calculated from the serum ceruloplasmin values obtained by taking into consideration that one ceruloplasmin molecule contains eight copper atoms and that its molecular weight is 160,000 (7). The serum content of the non-ceruloplasmin copper was obtained simply by subtracting the ceruloplasmin copper from the total copper.
cop per in 58 healthy subjects and 65 patients with uncomplicated psOriasis
Results are stated in pg. per 100 ml. Total Copper
Ceroloplasmio Copper
Non-Ceroloplasmin Copper
Healthy subjects Mean Range S.D.
137
118
19
89-197
77—158
0—45
51
17
12
This investigation was supported by a grant
Patients with pso-
from the Finnish Medical Research Council. Received for publication April 5, 1966.
* From the Third Department of Medicinet
and the Department of Dermatology, University of Helsinki, Helsinki 29, Finland.
159
riasis Mean Range S.D.
165
119
45
117—239
75—211
4—90
31
24
22
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
160
250
200 I. U
'I.
E
0
I. I.
0
150
r I.
•1'
I.
r
4.
II
p p
.1.
I.
p I.
I.
—T4
1-
•1•
'F
100
I. I.
I 50
—LI.
r+i
TOTAL SERUM COPPER
CERULOPLASMIN COPPER
HEALTHY
HEALTHY PERSONS
PERSONS
PSORIASIS
NON-CERULOPLASMIN COPPER HEALTHY PERSONS
PSORIASIS
PSORIASIS
Fie. 1. Total semm copper, ceruloplasmin copper and non-ceruloplasmin copper in healthy persons and patients with uncomplicated psorlasis.
It is known that copper plays a role in the ries. The serum non-ceruloplasmin copper was keratinization process of the skin of certain ani- significantly elevated in patients with psoriasis. mals and that copper causes a defect in keratin formation (8). The role of copper in the incomREFERENCES plete keratinization process of psoriatic skin is not known. It could be thought that the psoriatic skin is not able to utilize copper in the keratinization 1. Lipkin, G., Herrmann, F. and Mandol, L.: Studies on serum copper. I. The copper conprocess and causes a change in the distribution of tent of blood serum in patients with psorianon-ceruloplasmin copper between the intravassis. J. Invest. Derm., 89: 1062. cular and extravascular compartments of the 2. Lipkin, G., Gowdey, J. and543, Wheatley, V. R.: Skin copper levels in psoriasis. J. Invest.
body.
SUMMARY
Derm., 42:
205, 1964.
3. Scheinberg, H. and Sternlieb, I.: Copper me-
tabolism. Pharmacol. Rev., 12: 355, 1960. Serum total copper, ceruloplasmin-bound copP., Kekki, M., Virkkunen, M., Lasper and non-ceruloplasmin copper were studied in 4. Koskelo, sus, A. and Somer, T.: Serum ceruloplasmin
58 healthy persons and 65 patients with uncomplicated psoriasis. No difference was seen in the ceruloplasmin-bound copper between the two Se-
concentration in rheumatoid arthritis, ankylosing spondylitis, psoriasis, and sarcoidosis.
To be published.
SERUM COPPER IN PSORIASIS
161
5. Peterson, R. E. and Bollier, M. E.: Spectro- 7. Rasper, C. B. and Deutsch, H. F.: Physicophotometric determination of serum copper chemical studies of human ceruloplasmin. J. with bieyclohexanoneoxalyldihydrazone. Anal. Chem., 27: 1195, 1955.
6. Ravin, H. A.: An improved colorimetric enzymatic assay of ceruloplasmin. J. Lab. Clin. Med., 58:
161,
1961.
Biol. Chem., 238: 2325, 1963.
8. Burley, R. W. and De Rock, W. J.: N-terminal amino acid residues in wool from normal and copper-deficient sheep. Arch. Biochem., 68: 21, 1957.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.