1157
intolerance is of great interest today in population
Although much surveys and paediatric medicine. research in many parts from been has work published 16-22 in remain world of the any map showlarge gaps of lactose tolerance and intoleradult ing the incidence ance 23
Clearly,
any test which eliminates
venepunctures would
simplify
multiple
the work in these
considerably. In all cases end-expiratory sampling has given a similar result to blood-glucose rise in the estimation of hypolactasia, and it could therefore be simply applied as a diagnostic test in gastrointestinal dissurveys
orders or in field surveys where the incidence of lactose intolerance is to be determined in a general
population. We thank Dr E. N. Rowlands, Dr J. J. Misiewicz, and Dr T. D. Kellock for their helpful advice and criticism. G. M. is in receipt of the T. K. Stubbins fellowship of the Royal College of Physicians. Requests for reprints should be addressed to L. M. B., Department of Gastroenterology, Central Middlesex Hospital,
London NWIO 7NS. REFERENCES
Cuatrecasas, P., Lockwood, D. H., Caldwell, J. R. Lancet, 1965, i, 14. 2. Bayless, T. M., Rosensweig, N. S., Christopher, N., Huang, S. S. Gastroenterology, 1968, 54, 475. 3. Newcomer, A. D., McGill, D. B. ibid. 1966, 50, 340. 4. Galloway, D. H., Mathews, R. D., Colasito, D. J. Nature, 1966, 1.
212, 1238. 5. Levitt, M. D. New Engl. J. Med. 1969, 281, 122. 6. Levitt, M. D., Ingelfinger, F. J. Ann. N.Y. Acad. Sci. 1968, 150, 75. 7. Calloway, D. H., Murphy, E. L., Bauer, D. Am. J. dig. Dis. 1969, 14, 811. 8. Levitt, M. D., Donaldson, R. M. J. Lab. clin. Med. 1970, 75, 937. 9. Metz, G. L., Gassull, M. A., Leeds, A. R., Blendis, L. M., Jenkins, D. J. A. Spring, 1975, meeting of British Society of Gastroenterology, abstracts. 10. Bond, J. H., Levitt, M. D. J. clin. Invest. 1972, 51, 1219. 11. Guilbault, G. G. Analyt. Chem. 1966, 38, 527. 12. Dahlqvist, A. Enzym. biol. clin. 1970, 2, 52. 13. Hiraoka, T., Glick, D. Analyt. Biochem. 1963, 5, 497. 14. Chenoweth, W. L. PH.D. dissertation, University of California,
Berkeley. 15. Isoski, M., Jussila, J., Sarna, S. Gastroenterology, 1972, 62, 28. 16. Kretchmer, N., Ransome-Kuti, O. Proc. Inst. Med. Chic. 1970,
28, 213. 17. Olatunbosun, D. A., Adadevoh, B. K. Am. J. dig. Dis. 1971, 16, 909. 18. Alzate, H., Gonzalez, H., Guzman, J. Am. J. clin. Nutr. 1969, 22, 122. 19. Gudmand-Hoyer, E., Jarnum, S. Acta med. scand. 1969, 186, 235. 20. Spanidou, E. P., Petrakis, N. L. Lancet, 1972, ii, 872. 21. Chung, M. H., McGill, D. B. Gastroenterology, 1968, 54, 225. 22. Bolin, T. D., Morrison, R. M., Steel, J., Davis, A. E. Med. J. Aust. 1970, i, 1289. 23. Simoons, F. J. Am. J. dig. Dis. 1973, 18, 595.
"
The process by which final demands upon the service determined is complex and certainly involves many non-medical considerations which remain only poorly understood. What emerges as certain is that demand tends
are
outstrip supply. Rationing, however, has never been explicitly organised but has hidden behind each doctor’s clinical freedom to act solely in the interests of his patient. Any conflict of interest between patients has been implicitly resolved by the doctor’s judgments as to their relative need
to
for care and attention. The clinical freedom to differ widely as to their conception of need has led to inconsistencies of treatment between patients and to the allocation, without challenge, of scarce resources to medical practices of no proven value."—MICHAEL H. CoopER, Rationing Health
Care;
p. 107.
London, 1975.
RUBELLA-VIRUS INFECTION IN JUVENILE RHEUMATOID ARTHRITIS Y. CHIBA J. L. DZIERBA
P. L. OGRA S. S. OGRA
J. K. HERD Departments of Pediatrics and Microbiology, School of Medicine, State University of New York at Buffalo, and Division of Virology, Children’s Hospital, Buffalo, N.Y.
Summary
14222, U.S.A.
Antibody
activity
against
mumps,
measles, polio, and rubella viruses was
determined in patients with juvenile rheumatoid arthritis (J.R.A.), rubella-vaccine associated arthritis, adult rheumatoid arthritis, other chronic systemic disorders (e.g., systemic lupus and dermatomyositis), and in a matched population of normal, non-rheumatoid (control) children. The antibody levels against mumps, measles, and poliovirus were similar in all patients. Rubella-antibody levels in rheumatoid arthritis and other systemic disorders were similar to those observed in controls. The mean rubella-antibody levels in rubella-vaccine arthritis were 4 times higher than in controls. The IgM and IgG rubellaantibody levels in J.R.A. were found to be 4-6 times higher when compared to titres observed in the controls. Highest antibody levels were seen in younger children with J.R.A. Detection of rubella-virus antigen was attempted by immunofluorescence in the sediment smears of synovial fluid of patients with J.R.A., adult rheumatoid arthritis, and other nonrheumatoid joint diseases. Specific staining for rubella virus antigen was observed in the synovial fluid of 33 % of patients with J.R.A. No antigen was detected in the synovial fluid from other patients. These observations suggest a possible role of rubella-virus infection in J.R.A.
Introduction AN association between acute arthritis and natural or vaccine-induced rubella virus infection has been amply demonstrated.1-6 Polyarthritis and polyarthralgia are frequent presenting manifestations of natural rubella in adult women.6 With the introduction of live attenuated vaccines, several investigators have defined the clinical and epidemiological features of arthritis associated with rubella-virus vaccines. In general, the joint manifestations of rubella-associated arthritis are transient: only rarely do joint symptoms persist for months after immunisation.8.7 The mechanism for the joint disease in rubella is poorly understood. The manifestations of arthritis have been related to the presence of infectious rubella virus in affected joints.7-9 There may be a positive relation between the development of arthritis, the appearance of rubella antibody in serum and joint fluid, and the presence of rubella virus in the affected joints Although rubella arthritis bears many clinical similarities to juvenile rheumatoid arthritis (j.R.A.), there is no evidence of a direct role of rubella infection in the aetiology or pathogenesis of chronic arthritis of childhood. We have investigated the serum-antibody response to naturally acquired or vaccine-induced viral infec-
1158
tions in patients with J.R.A. and other chronic systemic disorders and looked for serological or immunohistological relations between rubella-virus infection and J.R.A. Materials and Methods
Population Groups Three groups of age and
sex
matched individuals
Immunofluorescence.-All synovial-fluid were
investigated: Group 1.-46 children with or without clinical and serological evidence of prior natural rubella infection. Group 2.-A heterogenous population of 111 children and It young adults with different chronic systemic disorders. included 10 children who had had one or more episodes of arthritis after parenteral immunisation with HPV-77 DK/12 live attenuated rubella-virus vaccine; 42 children with J.R.A.; 15 children with systemic lupus erythematosus (S.L.E.), scleroderma dermatomyositis, or polymyositis; 15 children with ulcerative colitis, nephrotic syndrome, and rheumatic fever; and 29 adults with late-onset rheumatoid arthritis (R.A.). Group 3.-12 J.R.A. patients initially seronegative for rubella antibody who later had naturally acquired rubella-virus infection. These patients and 12 other age and sex matched controls with natural rubella infection were followed up to permit a prospective comparative evaluation of rubella-antibody response in the serum.
The patients in groups 1 and 3 ranged in age from 3 15 years. The adult R.A. patients in group 2 ranged in age from 20 to 40 years. Group 1 was selected from a population of children being followed up to investigate long-term immunity to natural or vaccine-induced infecIt included 14 children serotion with rubella virus. for rubella antibody, and 32 who had acquired negative natural rubella infection before this study began. The patients in group 2 with rubella arthritis had been immunised with HPV-77 DK/12 vaccine during the previous 1-3 years and had had repeated episodes of arthralgia or arthritis for at least 4-6 months after immunisation. The J.R.A. patients were recruited from the arthritis clinics of the Children’s Hospital, Buffalo: 11 had no evidence of rubella infection and 31 patients had serological evidence of rubella infection. Patients with other disorders were selected from the inpatient and clinic populations of the Children’s Hospital, Buffalo, and adults with R.A. were recruited from the arthritis clinics of the E. J. Meyer Memorial Hospital, Buffalo. The diagnosis of rheumatoid arthritis was based on the criteria of the American Rheumatism Association lo All those included in this study had been immunised with poliovirus vaccine and had acquired natural or vaccine-induced infections with mumps or measles virus. to
Specimens Sera were tested for antibody against mumps, measles, polio, and rubella viruses. In addition, sediment smears of the synovial fluid obtained from 25 J.R.A. patients, 9 adults with R.A., 4 children with non-rheumatoid septic arthritis, and 2 adults with osteoarthritis were available for immunohistological studies. The synovial-fluid smears from patients with J.R.A. and R.A. were obtained 2-3 years after the onset of arthritis. Immediately after collection all smears were fixed in acetone and stored frozen at - 70°C for further testing.
Methods
.
Mumps, measles, and poliovirus antibody activities were determined by hsemagglutination inhibition 11 Poliovirus antibody assays were done by tissue-culture neutralisation technique using primary rhesus-monkey kidney-cell cultures.12 Rubella antibody activity in whole samples of serum determined by haemagglutination inhibition, and the activity in serum IgG, IgA, and IgM fractions was determined by radioimmunodiffusion and autoradiography using 32P-labelled rubella virus as antigen.13 was
Antisera to immunoglobulins.-Monospecific antisera to human IgG, IgA, and IgM were obtained from Melpar Laboratories, Falls Church, Virginia. The antisera were tested for specificity and cross-reactivity.12 Only antisera found to be monospecific and free of antibody activity against rubella virus were used in this study. smears
were
tested for rubella-virus antigen by indirect immunofluorescence using high-titre convalescent human rubella serum. Control studies were run in parallel using human serum containing no detectable rubella-antibody activity. The fluorescein isothiocynate (F.l.T.C.) labelled antisera to human IgG have been described previously,15.16 The specificity of the F.l.T.c.-labelled antisera to human IgG was tested by immunoelectrophoresis and Ouchterlony analysis. The labelled antisera had a molar fluoresceinprotein ratio of 3-4, and were used at a dilution which provided 1/2 unit of activity according to the techniques of Beutner et a}.l6 All fluorescein-labelled antisera were absorbed with rabbit-liver powder and ABO red bloodcells before use. As an additional control, the specificity of immunofluorescence for rubella antigen was tested by specific blocking experiments. The staining for rubella virus was blocked by the treatment of synovial-fluid smears with guineapig antibody to rubella virus before the smears were stained with F.I.T.c.-labelled antisera to human IgG.
Results
Mumps, Measles, and Poliovirus Antibodies The geometric mean titres of antibody to and measles viruses and poliovirus in groups
mumps 1 and 2 The individual and mean antiare shown in table I. body titres in the normal children in group 1 appeared to be similar to the titres in group-2 patients with rubella arthritis, J.R.A., and other chronic systemic disorders. The minor variations seen in the mean titres between the controls and test patients are not
statistically significant (P>005). Many children with J.R.A. had appreciable levels of antibody against mumps, measles, and poliovirus when the study began and when arthritis had first been diagnosed. However, several patients developed serological evidence of natural mumps and measlesvirus infection or were immunised with poliovaccine 1-2 years after the onset of arthritis. The individual and mean titres of mumps, measles, and poliovirus antibody in these patients were similar to the titres observed in J.R.A. patients who had acquired such infections previously.
Rubella-virus Antibodies A retrospective screening for rubella-antibody activity in groups 1 and 2 revealed that the activity TABLE I-RECIPROCAL G.M.T.S TO MUMPS, MEASLES, AND POLIOVIRUS IN J.R.A., ADULT R.A., AND OTHER NON-RHEUMATOID CHRONIC SYSTEMIC DISEASES
1159
in a predictable sequence. The responses at 1 and 3 months after infection in J.R.A. patients and
globulins
controls were similar (table in), although higher IgM levels were noted in J.R.A. The IgM response in J.R.A. patients persisted, and IgM activity was detectable for up to 20 months after infection; in the controls IgM rubella antibodies were undetectable 3-4 months after infection. The results of serial rubella-antibody testing are summarised in fig. 2.
Localisation of Rubella-virus Antigen Staining for rubella-virus antigen was seen in the smears of synovial fluid of 9 of the 25 patients with J.R.A. These 9 patients had moderately severe disease of at least 3-4 years’ duration, and the individual rubella antibody titres in these patients were 2-4 times higher than in normal controls. The immunofluorescence for rubella-virus antigen was largely Fig. 1-Distribution of serum IgG rubella-antibody levels in patients with J.R.A., rubella arthritis, adult R.A., and other, non-rheumatoid chronic systemic diseases.
TABLE II-RUBELLA-ANTIBODY TITRES IN DIFFERENT AGE-GROUPS OF PATIENTS WITH J.R.A. COMPARED WITH LEVELS OBSERVED IN HEALTHY CHILDREN WITHOUT ARTHRITIS
The antibody levels in normal non-rheumatoid subjects are included for comparison. Individual (W) and geometric mean (-) titres are shown.
was predominantly found in the IgG class of immunoglobulin. Frequently, however, many patients also had appreciable levels of IgA and IgM antibody. The individual and geometric mean IgG titres in J.R.A. and other population groups studied are presented in fig. 1. In general, the antibody levels in adults with rheumatoid arthritis and in patients with other disorders (group 2) were similar to the levels observed in controls (group 1). The mean antibody titres in R.A. and other systemic disorders ranged
TABLE III-SERUM IgG, IgM,AND IgARUBELLA-ANTIBODYRESPONSES IN PATIENTS WITH J.R.A. AND IN NORMAL (HEALTHY) CONTROLS AFTER NATURALLY ACQUIRED RUBELLA-VIRUS INFECTION
390, and the mean titre in controls about 203. These differences did not On the seem to be statistically significant (p>0’05). other hand, the antibody titres in arthritis associated from 180
to
(group 1)
was
with rubella vaccination were 4 times higher than those observed in controls (fig. 1). The mean rubella-antibody titre in patients with J.R.A. was 830. The antibody levels were 4-6 times higher than the titres observed in controls. These differences appeared to be statistically significant (P< 0-01 (table n). Comparative analysis of antibody levels in normal children (group 1) and in, patients with J.R.A., according to the age, revealed highest rubella antibody levels in J.R.A. patients in age groups 0-5 and 6-10 years. The antibody titres were 4-8 times higher in comparison to the healthy children of similar ages (table 11). However, the antibody levels in 11-16-yearold patients with J.R.A. and in matched controls were similar.
Follow-up after Natural Rubella 12 J.R.A. patients (group 3) who were seronegative for rubella antibody developed natural rubella infection during the study. The rubella-antibody response in these patients and in 12 normal age and sex matched controls (infected similarly) _ was measured every 2 months for about 2 years. The representative data of 5 J.R.A. patients and 5 controls are shown in table III. After the onset of rash, the antibody response appeared in IgM, IgG, and infrequently in IgA immuno-
*
Each J.R.A. patient was age matched to within 2 years with a healthy control. t Determined by radioimmunodiffusion and autoradiography and expressed as reciprocal of serum dilution.
1160
The chronic carrier state with rubella virus, especially after gestational infection, is well known. Infants congenitally infected with rubella excrete the virus for a long time after birth,17,18 and persistent infection is a characteristic of cell cultures obtained from such infants 1’.ls Chronic rubella infection also seems to occur in cell cultures derived from tissue explants obtained from individuals, with postnatal rubella infection.2° Recently, a prolonged IgM rubella-antibody response has been observed after naturally acquired postnatal rubella-virus infection in certain children and adults.21,22 Although it remains to be seen if such infections with prolonged IgM response are associated with subsequent development of chronic joint disease, these studies and our findings support the possible development of chronic persistent infection with rubella virus when acquired after birth. Fig. 2-IgM and IgG rubella-antibody titres in the serum of patients with J.R.A. and in controls after naturally acquired infection with wild rubella virus. Each point represents the geometric mean values of individual levels observed in 12 patients in each group.
associated with mononuclear cells in the synovial-fluid smears. Occasionally, however, discrete specific for the antigen which was not associated with staining any identifiable cellular elements was also observed. No rubella-virus antigen staining was found in the remaining J.R.A. synovial smears, although many of these patients exhibited similar serological features of rubella-virus infection and clinical activity of J.R.A. No rubella virus antigen was demonstrated in the smears of adults with rheumatoid arthritis, osteoarthritis, and non-rheumatoid septic arthritis. No immunofluorescence for mumps, measles, and poliovirus antigens was observed in any of the synovial-fluid smears tested. These patients had appreciable levels of antibody activity against mumps, measles, and poliovirus at the time the synovial fluid was
collected.
Discussion The important findings here are the persistent raised IgM rubella-antibody response and the detection of rubella-virus antigen in the synovial tissues of several patients with J.R.A. Also of interest is the heightened IgG rubella-antibody activity in arthritis associated with rubella immunisation and in J.R.A. patients screened retrospectively. However, many patients had no serological evidence of rubella infection when the diagnosis of J.R.A. was first made. The raised rubella-antibody response in J.R.A. may represent a broad-scale, non-specific alteration in the immunological responsiveness in this syndrome, resulting in an exaggerated immune response to a variety of antigens including rubella virus. Alternatively, these findings may represent evidence for a prolonged infection and continued presence of rubella-virus antigen in the synovial tissues of J.R.A. patients. However, a prolonged IgM and a raised IgG antibody response were restricted to J.R.A. patients, and mumps, measles, and poliovirus antibody titres were no different from those found in controls and in patients with other connective-tissue disorders. These data would seem to support the second explanation.
Childhood immunisation programmes have revealed a definite association between the development of arthralgia and arthritis and rubella vaccination 1 In a few cases, infectious rubella virus has been isolated from the affected joints months after immunisation. Furthermore, in induced infection in laboratory animals, rubella virus seems to localise in highest concentrations in cartilage and chondrocytes 23 These data suggest that wild strains and certain vaccine strains of rubella virus may have a predilection for synovial tissue after a systemic infection. The viral aetiology of rheumatoid arthritis has long been a matter for speculation. Several well-controlled clinical and epidemiological studies have failed to provide any conclusive evidence implicating a specific virus in the aetiology or pathogenesis of chronic arthritis a4 Two groups have attempted, with conflicting results, to correlate the serological evidence of prior rubella infection and the development of rheumatoid arthritis.25,21 Unfortunately, however, these studies lack immunohistological evidence of chronic infection and immunoglobulin specificity of rubella-antibody response. We detected rubella-virus-specific antigen in the synovial tissues in about a third of J.R.A. patients tested. In addition, raised IgG rubella-antibody levels were observed in most J.R.A. patients when screened retrospectively. A more careful sequential prospective follow-up revealed prolonged IgM and raised IgG rubella-antibody responses in J.R.A. patients after naturally acquired rubella. We suggest that, at least in a certain proportion of patients with J.R.A., chronic synovial infection with rubella virus may be closely related to the pathogenesis and clinical course of the arthritis. The persistence of viral antigen and its contribution to the pathogenesis of joint disease may be determined by genetic and immunological factors of host defence. No significant increase in rubella-antibody titre was observed in adults with late-onset R.A. Further, no viral antigen was demonstrable in these joint tissues. More detailed examination of the joint tissues in lateonset R.A. is required before any firm conclusions can be drawn from these observations. High antibody levels and the presence of rubella virus in the joint fluid were observed in arthritis associated with natural or induced rubella infection. It remains to be seen whether such individuals subse-
1161
J.R.A. To date, 1 patient has manirheumatoid disease after rubella-related
quently develop fested
.
arthritis 2’ This work was supported by grants and contracts from U.S. Public Health Service, National Institute of Arthritis, Metabolism and Digestive Diseases (AM-17050), National Institute of Child Health and Human Development (HD06321), National Institute of Allergy and Infectious Disease (AI-09769) (AI-32522), and Clinical Research Center Program
In both
patients parathyroid tumours were found at operation. It is suggested that both patients had tertiary hyperparathyroidism in which the normally tell-tale hypercalcæmia was at first masked by the other abnormalities, and that this masking may account for some cases reported as having normocalcæmic primary (or tertiary) hyperparathyroidism. Interpretation of total plasma-calcium is likely to be
(RR-628).
unreliable unless the
Requests for reprints should be addressed to P. L. 0., Children’s Hospital, 219 Bryant Street, Buffalo, New York 14222,
be shown
or
25-hydroxyvitamin-D
assumed
to
levels
can
be normal.
U.S.A.
Introduction REFERENCES
THERE
Lerman, S. J., Nankervis, G. A., Heggie, A. D. Ann. intern. Med. 1971, 74, 67. 2. Spruance, S. L., Smith, C. B. Am. J. Dis. Child. 1971, 122, 105. 3. Spruance, S. L., Klock, L. E., Jr., Bailey, A. J. Pediat. 1972, 1.
80, 413. Kantor, T. G., Tanner, M. Arthritis Rheum. 1962, 5, 378. Cooper, L. Z., Ziring, P. R., Weiss, H. J. Am. J. Dis. Child. 1969, 118, 218. 6. Yanez, J. E., Thompson, G. R., Mikkelsen, W. M. Ann. intern. Med. 1966, 64, 772. 7. Ogra, P. L., Herd, J. K. J. Immun. 1971, 107, 810. 8. Hildebrandt, H. M., Massab, H. F. New Engl. J. Med. 1966, 274,
4. 5.
1428.
9. 10. 11.
12.
13. 14.
15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
25. 26. 27.
Stokes, J., Jr., Weibel, R. E., Bunyak, E. B. Symp. immunobiol. Standard. 1969, 2, 415. Ropes, M. W., Bennett, G. A., Cobb, S. Arthritis Rheum. 1959, 2, 16. Lennette, E. H., Schmidt, N. J. in Diagnostic Procedures for Viral and Rickettsial Diseases; p. 528. New York, 1964. Ogra, P. L., Karzon, D. T., Righthand, F., MacGillivray, M. New Engl. J. Med. 1968, 279, 893. Ogra, P. L., Kerr-Grant, D., Umana, G., Dzierba, J., Weintraub, D. ibid. 1971, 285, 1333. Vaheri, A., Vesikari, T. Arch. ges. Virusforsch. 1971, 35, 10. Ogra, S. S., Ogra, P. L., Lippes, J., Tomasi, T. B., Jr. Proc. Soc. exp. Biol. Med. 1972, 139, 570. Beutner, E. H., Sepelvedu, M. R., Barnett, E. V. Bull. Wld Hlth Org. 1968, 39, 587. Rawls, W. E. Progr. med. Virol. 1968, 10, 238. Menser, M. A., Forrest, J. M., Slinn, R. F. Lancet, 1971, ii, 797. Rawls, W. E., Melnick, J. L. J. exp. Med. 1966, 123, 795. Heggie, A. D. New Engl. J. Med. 1971, 285, 664. Al-Nakib, W., Best, J. M., Banatvala, J. E. Lancet, 1975, i, 182. Pattison, J. R., Dane, D. S., Mace, J. E. ibid. p. 185. London, W. T., Fuccillo, D. A., Anderson, B. Nature, 1970, 226, 1972. Phillips, P. E. J. exp. Med. 1971, 134, 313. Deinard, A. S., Venters, H. D., Bilka, P. J., Herrmann, K. L., Page, A. R. Lancet, 1974, i, 526. Cassidy, J. T., Shillis, J. L., Brandon, F. B., Sullivan, D. B., Brackett, R. G. Pediatrics, 1974, 54, 239. Martinis, T. W., Bland, J. W., Philips, C. A. Arthritis Rheum. 1968, 11, 683.
are now
several reports of normocalcaemic
primary hyperparathyroidism.1 In some reports the plasma-calcium levels were not corrected for protein content 5,6 and in others the "normal" levels cited are in the range (10-2-10-6 mg. per 100 ml.) which would be considered abnormal in our laboratory. Nevertheless we also have, very rarely, encountered
ambiguously raised plasma-calcium in patients later shown to have small parathyroid adenomas. This is to be expected in an early phase in the life-cycle of an adenoma and it does not usually constitute a clinical problem because such patients are seldom very ill.
The situation is different in the two patients here who both had severe symptoms of bone disease and convincingly normal total (in one patient ionised also) plasma-calcium levels and who at operation had large parathyroid adenomas. Both patients were at first thought to have osteomalacia of different causes, but on appropriate treatment for this their plasma-calciums rose, and in one case this was hydrocortisone resistant. We will later discuss the relevance of these two patients to the problem of diagnosis in this group of diseases.
reported
Methods Serum immunoreactive parathyroid hormone was determined by the method of Berson et al.7 Plasma 25hydroxyvitamin-D (25-H.c.c.) levels was measured by the competitive protein-binding method.s The fsecal fat determinations were calculated to 24-hour outputs by continuous fsecal marking with cuprous thiocyanate.9
Case-histories MASKED PRIMARY (OR TERTIARY) HYPERPARATHYROIDISM C. E. DENT
P. E. D. P. MULLAN
JONES
Metabolic Ward, University College Hospital, London, and
Salisbury
General Infirmary
described in whom clinical and laboratory preliminary of a osteomalacia, investigations suggested diagnosis from gluten-sensitive enteropathy in one and from anticonvulsant therapy in the other. However, when the primary disease was corrected by diet and extra vitamin D, respectively, both patients developed hypercalcæmia. A standard hydrocortisone test in the second patient failed to reduce the hypercalcæmia.
Summary
Two
the
patients
are
FIRST
Housewife born in 1924.
CASE
As
a
child she grew
more
slowly than her identical twin sister and remained shorter than her. Her long history is summarised as follows. In 1949, blood-transfusion for severe anaemia, in 1950, diarrhoea with pale offensive stools; in 1953, spontaneous tetany, recurring during lactation after the birth of twins in 1955 when the plasma-calcium was 5-8 mg. per 100 ml. and she was treated with intravenous calcium. In 1956, diarrhoea recurred and a gluten-free diet was given with notable symptomatic improvement and weight gain; oral calciferol was started and continued until 1961 (fig. 1). In 1962, hysterectomy for menorrhagia; in 1963, an intravenous pyelogram for bilateral loin pain showed bilateral radiopaque calculi with hydronephrosis; in 1964, left nephrectomy was done for non-functioning kidney, histology showed calculous pyelonephritis. In retrospect we wonder if the stones could have resulted from an overdose
intolerance is of great interest today in population
Although much surveys and paediatric medicine. research in many parts from been has work published 16-22 in remain world of the any map showlarge gaps of lactose tolerance and intoleradult ing the incidence ance 23
Clearly,
any test which eliminates
venepunctures would
simplify
multiple
the work in these
considerably. In all cases end-expiratory sampling has given a similar result to blood-glucose rise in the estimation of hypolactasia, and it could therefore be simply applied as a diagnostic test in gastrointestinal dissurveys
orders or in field surveys where the incidence of lactose intolerance is to be determined in a general
population. We thank Dr E. N. Rowlands, Dr J. J. Misiewicz, and Dr T. D. Kellock for their helpful advice and criticism. G. M. is in receipt of the T. K. Stubbins fellowship of the Royal College of Physicians. Requests for reprints should be addressed to L. M. B., Department of Gastroenterology, Central Middlesex Hospital,
London NWIO 7NS. REFERENCES
Cuatrecasas, P., Lockwood, D. H., Caldwell, J. R. Lancet, 1965, i, 14. 2. Bayless, T. M., Rosensweig, N. S., Christopher, N., Huang, S. S. Gastroenterology, 1968, 54, 475. 3. Newcomer, A. D., McGill, D. B. ibid. 1966, 50, 340. 4. Galloway, D. H., Mathews, R. D., Colasito, D. J. Nature, 1966, 1.
212, 1238. 5. Levitt, M. D. New Engl. J. Med. 1969, 281, 122. 6. Levitt, M. D., Ingelfinger, F. J. Ann. N.Y. Acad. Sci. 1968, 150, 75. 7. Calloway, D. H., Murphy, E. L., Bauer, D. Am. J. dig. Dis. 1969, 14, 811. 8. Levitt, M. D., Donaldson, R. M. J. Lab. clin. Med. 1970, 75, 937. 9. Metz, G. L., Gassull, M. A., Leeds, A. R., Blendis, L. M., Jenkins, D. J. A. Spring, 1975, meeting of British Society of Gastroenterology, abstracts. 10. Bond, J. H., Levitt, M. D. J. clin. Invest. 1972, 51, 1219. 11. Guilbault, G. G. Analyt. Chem. 1966, 38, 527. 12. Dahlqvist, A. Enzym. biol. clin. 1970, 2, 52. 13. Hiraoka, T., Glick, D. Analyt. Biochem. 1963, 5, 497. 14. Chenoweth, W. L. PH.D. dissertation, University of California,
Berkeley. 15. Isoski, M., Jussila, J., Sarna, S. Gastroenterology, 1972, 62, 28. 16. Kretchmer, N., Ransome-Kuti, O. Proc. Inst. Med. Chic. 1970,
28, 213. 17. Olatunbosun, D. A., Adadevoh, B. K. Am. J. dig. Dis. 1971, 16, 909. 18. Alzate, H., Gonzalez, H., Guzman, J. Am. J. clin. Nutr. 1969, 22, 122. 19. Gudmand-Hoyer, E., Jarnum, S. Acta med. scand. 1969, 186, 235. 20. Spanidou, E. P., Petrakis, N. L. Lancet, 1972, ii, 872. 21. Chung, M. H., McGill, D. B. Gastroenterology, 1968, 54, 225. 22. Bolin, T. D., Morrison, R. M., Steel, J., Davis, A. E. Med. J. Aust. 1970, i, 1289. 23. Simoons, F. J. Am. J. dig. Dis. 1973, 18, 595.
"
The process by which final demands upon the service determined is complex and certainly involves many non-medical considerations which remain only poorly understood. What emerges as certain is that demand tends
are
outstrip supply. Rationing, however, has never been explicitly organised but has hidden behind each doctor’s clinical freedom to act solely in the interests of his patient. Any conflict of interest between patients has been implicitly resolved by the doctor’s judgments as to their relative need
to
for care and attention. The clinical freedom to differ widely as to their conception of need has led to inconsistencies of treatment between patients and to the allocation, without challenge, of scarce resources to medical practices of no proven value."—MICHAEL H. CoopER, Rationing Health
Care;
p. 107.
London, 1975.
RUBELLA-VIRUS INFECTION IN JUVENILE RHEUMATOID ARTHRITIS Y. CHIBA J. L. DZIERBA
P. L. OGRA S. S. OGRA
J. K. HERD Departments of Pediatrics and Microbiology, School of Medicine, State University of New York at Buffalo, and Division of Virology, Children’s Hospital, Buffalo, N.Y.
Summary
14222, U.S.A.
Antibody
activity
against
mumps,
measles, polio, and rubella viruses was
determined in patients with juvenile rheumatoid arthritis (J.R.A.), rubella-vaccine associated arthritis, adult rheumatoid arthritis, other chronic systemic disorders (e.g., systemic lupus and dermatomyositis), and in a matched population of normal, non-rheumatoid (control) children. The antibody levels against mumps, measles, and poliovirus were similar in all patients. Rubella-antibody levels in rheumatoid arthritis and other systemic disorders were similar to those observed in controls. The mean rubella-antibody levels in rubella-vaccine arthritis were 4 times higher than in controls. The IgM and IgG rubellaantibody levels in J.R.A. were found to be 4-6 times higher when compared to titres observed in the controls. Highest antibody levels were seen in younger children with J.R.A. Detection of rubella-virus antigen was attempted by immunofluorescence in the sediment smears of synovial fluid of patients with J.R.A., adult rheumatoid arthritis, and other nonrheumatoid joint diseases. Specific staining for rubella virus antigen was observed in the synovial fluid of 33 % of patients with J.R.A. No antigen was detected in the synovial fluid from other patients. These observations suggest a possible role of rubella-virus infection in J.R.A.
Introduction AN association between acute arthritis and natural or vaccine-induced rubella virus infection has been amply demonstrated.1-6 Polyarthritis and polyarthralgia are frequent presenting manifestations of natural rubella in adult women.6 With the introduction of live attenuated vaccines, several investigators have defined the clinical and epidemiological features of arthritis associated with rubella-virus vaccines. In general, the joint manifestations of rubella-associated arthritis are transient: only rarely do joint symptoms persist for months after immunisation.8.7 The mechanism for the joint disease in rubella is poorly understood. The manifestations of arthritis have been related to the presence of infectious rubella virus in affected joints.7-9 There may be a positive relation between the development of arthritis, the appearance of rubella antibody in serum and joint fluid, and the presence of rubella virus in the affected joints Although rubella arthritis bears many clinical similarities to juvenile rheumatoid arthritis (j.R.A.), there is no evidence of a direct role of rubella infection in the aetiology or pathogenesis of chronic arthritis of childhood. We have investigated the serum-antibody response to naturally acquired or vaccine-induced viral infec-
1158
tions in patients with J.R.A. and other chronic systemic disorders and looked for serological or immunohistological relations between rubella-virus infection and J.R.A. Materials and Methods
Population Groups Three groups of age and
sex
matched individuals
Immunofluorescence.-All synovial-fluid were
investigated: Group 1.-46 children with or without clinical and serological evidence of prior natural rubella infection. Group 2.-A heterogenous population of 111 children and It young adults with different chronic systemic disorders. included 10 children who had had one or more episodes of arthritis after parenteral immunisation with HPV-77 DK/12 live attenuated rubella-virus vaccine; 42 children with J.R.A.; 15 children with systemic lupus erythematosus (S.L.E.), scleroderma dermatomyositis, or polymyositis; 15 children with ulcerative colitis, nephrotic syndrome, and rheumatic fever; and 29 adults with late-onset rheumatoid arthritis (R.A.). Group 3.-12 J.R.A. patients initially seronegative for rubella antibody who later had naturally acquired rubella-virus infection. These patients and 12 other age and sex matched controls with natural rubella infection were followed up to permit a prospective comparative evaluation of rubella-antibody response in the serum.
The patients in groups 1 and 3 ranged in age from 3 15 years. The adult R.A. patients in group 2 ranged in age from 20 to 40 years. Group 1 was selected from a population of children being followed up to investigate long-term immunity to natural or vaccine-induced infecIt included 14 children serotion with rubella virus. for rubella antibody, and 32 who had acquired negative natural rubella infection before this study began. The patients in group 2 with rubella arthritis had been immunised with HPV-77 DK/12 vaccine during the previous 1-3 years and had had repeated episodes of arthralgia or arthritis for at least 4-6 months after immunisation. The J.R.A. patients were recruited from the arthritis clinics of the Children’s Hospital, Buffalo: 11 had no evidence of rubella infection and 31 patients had serological evidence of rubella infection. Patients with other disorders were selected from the inpatient and clinic populations of the Children’s Hospital, Buffalo, and adults with R.A. were recruited from the arthritis clinics of the E. J. Meyer Memorial Hospital, Buffalo. The diagnosis of rheumatoid arthritis was based on the criteria of the American Rheumatism Association lo All those included in this study had been immunised with poliovirus vaccine and had acquired natural or vaccine-induced infections with mumps or measles virus. to
Specimens Sera were tested for antibody against mumps, measles, polio, and rubella viruses. In addition, sediment smears of the synovial fluid obtained from 25 J.R.A. patients, 9 adults with R.A., 4 children with non-rheumatoid septic arthritis, and 2 adults with osteoarthritis were available for immunohistological studies. The synovial-fluid smears from patients with J.R.A. and R.A. were obtained 2-3 years after the onset of arthritis. Immediately after collection all smears were fixed in acetone and stored frozen at - 70°C for further testing.
Methods
.
Mumps, measles, and poliovirus antibody activities were determined by hsemagglutination inhibition 11 Poliovirus antibody assays were done by tissue-culture neutralisation technique using primary rhesus-monkey kidney-cell cultures.12 Rubella antibody activity in whole samples of serum determined by haemagglutination inhibition, and the activity in serum IgG, IgA, and IgM fractions was determined by radioimmunodiffusion and autoradiography using 32P-labelled rubella virus as antigen.13 was
Antisera to immunoglobulins.-Monospecific antisera to human IgG, IgA, and IgM were obtained from Melpar Laboratories, Falls Church, Virginia. The antisera were tested for specificity and cross-reactivity.12 Only antisera found to be monospecific and free of antibody activity against rubella virus were used in this study. smears
were
tested for rubella-virus antigen by indirect immunofluorescence using high-titre convalescent human rubella serum. Control studies were run in parallel using human serum containing no detectable rubella-antibody activity. The fluorescein isothiocynate (F.l.T.C.) labelled antisera to human IgG have been described previously,15.16 The specificity of the F.l.T.c.-labelled antisera to human IgG was tested by immunoelectrophoresis and Ouchterlony analysis. The labelled antisera had a molar fluoresceinprotein ratio of 3-4, and were used at a dilution which provided 1/2 unit of activity according to the techniques of Beutner et a}.l6 All fluorescein-labelled antisera were absorbed with rabbit-liver powder and ABO red bloodcells before use. As an additional control, the specificity of immunofluorescence for rubella antigen was tested by specific blocking experiments. The staining for rubella virus was blocked by the treatment of synovial-fluid smears with guineapig antibody to rubella virus before the smears were stained with F.I.T.c.-labelled antisera to human IgG.
Results
Mumps, Measles, and Poliovirus Antibodies The geometric mean titres of antibody to and measles viruses and poliovirus in groups
mumps 1 and 2 The individual and mean antiare shown in table I. body titres in the normal children in group 1 appeared to be similar to the titres in group-2 patients with rubella arthritis, J.R.A., and other chronic systemic disorders. The minor variations seen in the mean titres between the controls and test patients are not
statistically significant (P>005). Many children with J.R.A. had appreciable levels of antibody against mumps, measles, and poliovirus when the study began and when arthritis had first been diagnosed. However, several patients developed serological evidence of natural mumps and measlesvirus infection or were immunised with poliovaccine 1-2 years after the onset of arthritis. The individual and mean titres of mumps, measles, and poliovirus antibody in these patients were similar to the titres observed in J.R.A. patients who had acquired such infections previously.
Rubella-virus Antibodies A retrospective screening for rubella-antibody activity in groups 1 and 2 revealed that the activity TABLE I-RECIPROCAL G.M.T.S TO MUMPS, MEASLES, AND POLIOVIRUS IN J.R.A., ADULT R.A., AND OTHER NON-RHEUMATOID CHRONIC SYSTEMIC DISEASES
1159
in a predictable sequence. The responses at 1 and 3 months after infection in J.R.A. patients and
globulins
controls were similar (table in), although higher IgM levels were noted in J.R.A. The IgM response in J.R.A. patients persisted, and IgM activity was detectable for up to 20 months after infection; in the controls IgM rubella antibodies were undetectable 3-4 months after infection. The results of serial rubella-antibody testing are summarised in fig. 2.
Localisation of Rubella-virus Antigen Staining for rubella-virus antigen was seen in the smears of synovial fluid of 9 of the 25 patients with J.R.A. These 9 patients had moderately severe disease of at least 3-4 years’ duration, and the individual rubella antibody titres in these patients were 2-4 times higher than in normal controls. The immunofluorescence for rubella-virus antigen was largely Fig. 1-Distribution of serum IgG rubella-antibody levels in patients with J.R.A., rubella arthritis, adult R.A., and other, non-rheumatoid chronic systemic diseases.
TABLE II-RUBELLA-ANTIBODY TITRES IN DIFFERENT AGE-GROUPS OF PATIENTS WITH J.R.A. COMPARED WITH LEVELS OBSERVED IN HEALTHY CHILDREN WITHOUT ARTHRITIS
The antibody levels in normal non-rheumatoid subjects are included for comparison. Individual (W) and geometric mean (-) titres are shown.
was predominantly found in the IgG class of immunoglobulin. Frequently, however, many patients also had appreciable levels of IgA and IgM antibody. The individual and geometric mean IgG titres in J.R.A. and other population groups studied are presented in fig. 1. In general, the antibody levels in adults with rheumatoid arthritis and in patients with other disorders (group 2) were similar to the levels observed in controls (group 1). The mean antibody titres in R.A. and other systemic disorders ranged
TABLE III-SERUM IgG, IgM,AND IgARUBELLA-ANTIBODYRESPONSES IN PATIENTS WITH J.R.A. AND IN NORMAL (HEALTHY) CONTROLS AFTER NATURALLY ACQUIRED RUBELLA-VIRUS INFECTION
390, and the mean titre in controls about 203. These differences did not On the seem to be statistically significant (p>0’05). other hand, the antibody titres in arthritis associated from 180
to
(group 1)
was
with rubella vaccination were 4 times higher than those observed in controls (fig. 1). The mean rubella-antibody titre in patients with J.R.A. was 830. The antibody levels were 4-6 times higher than the titres observed in controls. These differences appeared to be statistically significant (P< 0-01 (table n). Comparative analysis of antibody levels in normal children (group 1) and in, patients with J.R.A., according to the age, revealed highest rubella antibody levels in J.R.A. patients in age groups 0-5 and 6-10 years. The antibody titres were 4-8 times higher in comparison to the healthy children of similar ages (table 11). However, the antibody levels in 11-16-yearold patients with J.R.A. and in matched controls were similar.
Follow-up after Natural Rubella 12 J.R.A. patients (group 3) who were seronegative for rubella antibody developed natural rubella infection during the study. The rubella-antibody response in these patients and in 12 normal age and sex matched controls (infected similarly) _ was measured every 2 months for about 2 years. The representative data of 5 J.R.A. patients and 5 controls are shown in table III. After the onset of rash, the antibody response appeared in IgM, IgG, and infrequently in IgA immuno-
*
Each J.R.A. patient was age matched to within 2 years with a healthy control. t Determined by radioimmunodiffusion and autoradiography and expressed as reciprocal of serum dilution.
1160
The chronic carrier state with rubella virus, especially after gestational infection, is well known. Infants congenitally infected with rubella excrete the virus for a long time after birth,17,18 and persistent infection is a characteristic of cell cultures obtained from such infants 1’.ls Chronic rubella infection also seems to occur in cell cultures derived from tissue explants obtained from individuals, with postnatal rubella infection.2° Recently, a prolonged IgM rubella-antibody response has been observed after naturally acquired postnatal rubella-virus infection in certain children and adults.21,22 Although it remains to be seen if such infections with prolonged IgM response are associated with subsequent development of chronic joint disease, these studies and our findings support the possible development of chronic persistent infection with rubella virus when acquired after birth. Fig. 2-IgM and IgG rubella-antibody titres in the serum of patients with J.R.A. and in controls after naturally acquired infection with wild rubella virus. Each point represents the geometric mean values of individual levels observed in 12 patients in each group.
associated with mononuclear cells in the synovial-fluid smears. Occasionally, however, discrete specific for the antigen which was not associated with staining any identifiable cellular elements was also observed. No rubella-virus antigen staining was found in the remaining J.R.A. synovial smears, although many of these patients exhibited similar serological features of rubella-virus infection and clinical activity of J.R.A. No rubella virus antigen was demonstrated in the smears of adults with rheumatoid arthritis, osteoarthritis, and non-rheumatoid septic arthritis. No immunofluorescence for mumps, measles, and poliovirus antigens was observed in any of the synovial-fluid smears tested. These patients had appreciable levels of antibody activity against mumps, measles, and poliovirus at the time the synovial fluid was
collected.
Discussion The important findings here are the persistent raised IgM rubella-antibody response and the detection of rubella-virus antigen in the synovial tissues of several patients with J.R.A. Also of interest is the heightened IgG rubella-antibody activity in arthritis associated with rubella immunisation and in J.R.A. patients screened retrospectively. However, many patients had no serological evidence of rubella infection when the diagnosis of J.R.A. was first made. The raised rubella-antibody response in J.R.A. may represent a broad-scale, non-specific alteration in the immunological responsiveness in this syndrome, resulting in an exaggerated immune response to a variety of antigens including rubella virus. Alternatively, these findings may represent evidence for a prolonged infection and continued presence of rubella-virus antigen in the synovial tissues of J.R.A. patients. However, a prolonged IgM and a raised IgG antibody response were restricted to J.R.A. patients, and mumps, measles, and poliovirus antibody titres were no different from those found in controls and in patients with other connective-tissue disorders. These data would seem to support the second explanation.
Childhood immunisation programmes have revealed a definite association between the development of arthralgia and arthritis and rubella vaccination 1 In a few cases, infectious rubella virus has been isolated from the affected joints months after immunisation. Furthermore, in induced infection in laboratory animals, rubella virus seems to localise in highest concentrations in cartilage and chondrocytes 23 These data suggest that wild strains and certain vaccine strains of rubella virus may have a predilection for synovial tissue after a systemic infection. The viral aetiology of rheumatoid arthritis has long been a matter for speculation. Several well-controlled clinical and epidemiological studies have failed to provide any conclusive evidence implicating a specific virus in the aetiology or pathogenesis of chronic arthritis a4 Two groups have attempted, with conflicting results, to correlate the serological evidence of prior rubella infection and the development of rheumatoid arthritis.25,21 Unfortunately, however, these studies lack immunohistological evidence of chronic infection and immunoglobulin specificity of rubella-antibody response. We detected rubella-virus-specific antigen in the synovial tissues in about a third of J.R.A. patients tested. In addition, raised IgG rubella-antibody levels were observed in most J.R.A. patients when screened retrospectively. A more careful sequential prospective follow-up revealed prolonged IgM and raised IgG rubella-antibody responses in J.R.A. patients after naturally acquired rubella. We suggest that, at least in a certain proportion of patients with J.R.A., chronic synovial infection with rubella virus may be closely related to the pathogenesis and clinical course of the arthritis. The persistence of viral antigen and its contribution to the pathogenesis of joint disease may be determined by genetic and immunological factors of host defence. No significant increase in rubella-antibody titre was observed in adults with late-onset R.A. Further, no viral antigen was demonstrable in these joint tissues. More detailed examination of the joint tissues in lateonset R.A. is required before any firm conclusions can be drawn from these observations. High antibody levels and the presence of rubella virus in the joint fluid were observed in arthritis associated with natural or induced rubella infection. It remains to be seen whether such individuals subse-
1161
J.R.A. To date, 1 patient has manirheumatoid disease after rubella-related
quently develop fested
.
arthritis 2’ This work was supported by grants and contracts from U.S. Public Health Service, National Institute of Arthritis, Metabolism and Digestive Diseases (AM-17050), National Institute of Child Health and Human Development (HD06321), National Institute of Allergy and Infectious Disease (AI-09769) (AI-32522), and Clinical Research Center Program
In both
patients parathyroid tumours were found at operation. It is suggested that both patients had tertiary hyperparathyroidism in which the normally tell-tale hypercalcæmia was at first masked by the other abnormalities, and that this masking may account for some cases reported as having normocalcæmic primary (or tertiary) hyperparathyroidism. Interpretation of total plasma-calcium is likely to be
(RR-628).
unreliable unless the
Requests for reprints should be addressed to P. L. 0., Children’s Hospital, 219 Bryant Street, Buffalo, New York 14222,
be shown
or
25-hydroxyvitamin-D
assumed
to
levels
can
be normal.
U.S.A.
Introduction REFERENCES
THERE
Lerman, S. J., Nankervis, G. A., Heggie, A. D. Ann. intern. Med. 1971, 74, 67. 2. Spruance, S. L., Smith, C. B. Am. J. Dis. Child. 1971, 122, 105. 3. Spruance, S. L., Klock, L. E., Jr., Bailey, A. J. Pediat. 1972, 1.
80, 413. Kantor, T. G., Tanner, M. Arthritis Rheum. 1962, 5, 378. Cooper, L. Z., Ziring, P. R., Weiss, H. J. Am. J. Dis. Child. 1969, 118, 218. 6. Yanez, J. E., Thompson, G. R., Mikkelsen, W. M. Ann. intern. Med. 1966, 64, 772. 7. Ogra, P. L., Herd, J. K. J. Immun. 1971, 107, 810. 8. Hildebrandt, H. M., Massab, H. F. New Engl. J. Med. 1966, 274,
4. 5.
1428.
9. 10. 11.
12.
13. 14.
15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
25. 26. 27.
Stokes, J., Jr., Weibel, R. E., Bunyak, E. B. Symp. immunobiol. Standard. 1969, 2, 415. Ropes, M. W., Bennett, G. A., Cobb, S. Arthritis Rheum. 1959, 2, 16. Lennette, E. H., Schmidt, N. J. in Diagnostic Procedures for Viral and Rickettsial Diseases; p. 528. New York, 1964. Ogra, P. L., Karzon, D. T., Righthand, F., MacGillivray, M. New Engl. J. Med. 1968, 279, 893. Ogra, P. L., Kerr-Grant, D., Umana, G., Dzierba, J., Weintraub, D. ibid. 1971, 285, 1333. Vaheri, A., Vesikari, T. Arch. ges. Virusforsch. 1971, 35, 10. Ogra, S. S., Ogra, P. L., Lippes, J., Tomasi, T. B., Jr. Proc. Soc. exp. Biol. Med. 1972, 139, 570. Beutner, E. H., Sepelvedu, M. R., Barnett, E. V. Bull. Wld Hlth Org. 1968, 39, 587. Rawls, W. E. Progr. med. Virol. 1968, 10, 238. Menser, M. A., Forrest, J. M., Slinn, R. F. Lancet, 1971, ii, 797. Rawls, W. E., Melnick, J. L. J. exp. Med. 1966, 123, 795. Heggie, A. D. New Engl. J. Med. 1971, 285, 664. Al-Nakib, W., Best, J. M., Banatvala, J. E. Lancet, 1975, i, 182. Pattison, J. R., Dane, D. S., Mace, J. E. ibid. p. 185. London, W. T., Fuccillo, D. A., Anderson, B. Nature, 1970, 226, 1972. Phillips, P. E. J. exp. Med. 1971, 134, 313. Deinard, A. S., Venters, H. D., Bilka, P. J., Herrmann, K. L., Page, A. R. Lancet, 1974, i, 526. Cassidy, J. T., Shillis, J. L., Brandon, F. B., Sullivan, D. B., Brackett, R. G. Pediatrics, 1974, 54, 239. Martinis, T. W., Bland, J. W., Philips, C. A. Arthritis Rheum. 1968, 11, 683.
are now
several reports of normocalcaemic
primary hyperparathyroidism.1 In some reports the plasma-calcium levels were not corrected for protein content 5,6 and in others the "normal" levels cited are in the range (10-2-10-6 mg. per 100 ml.) which would be considered abnormal in our laboratory. Nevertheless we also have, very rarely, encountered
ambiguously raised plasma-calcium in patients later shown to have small parathyroid adenomas. This is to be expected in an early phase in the life-cycle of an adenoma and it does not usually constitute a clinical problem because such patients are seldom very ill.
The situation is different in the two patients here who both had severe symptoms of bone disease and convincingly normal total (in one patient ionised also) plasma-calcium levels and who at operation had large parathyroid adenomas. Both patients were at first thought to have osteomalacia of different causes, but on appropriate treatment for this their plasma-calciums rose, and in one case this was hydrocortisone resistant. We will later discuss the relevance of these two patients to the problem of diagnosis in this group of diseases.
reported
Methods Serum immunoreactive parathyroid hormone was determined by the method of Berson et al.7 Plasma 25hydroxyvitamin-D (25-H.c.c.) levels was measured by the competitive protein-binding method.s The fsecal fat determinations were calculated to 24-hour outputs by continuous fsecal marking with cuprous thiocyanate.9
Case-histories MASKED PRIMARY (OR TERTIARY) HYPERPARATHYROIDISM C. E. DENT
P. E. D. P. MULLAN
JONES
Metabolic Ward, University College Hospital, London, and
Salisbury
General Infirmary
described in whom clinical and laboratory preliminary of a osteomalacia, investigations suggested diagnosis from gluten-sensitive enteropathy in one and from anticonvulsant therapy in the other. However, when the primary disease was corrected by diet and extra vitamin D, respectively, both patients developed hypercalcæmia. A standard hydrocortisone test in the second patient failed to reduce the hypercalcæmia.
Summary
Two
the
patients
are
FIRST
Housewife born in 1924.
CASE
As
a
child she grew
more
slowly than her identical twin sister and remained shorter than her. Her long history is summarised as follows. In 1949, blood-transfusion for severe anaemia, in 1950, diarrhoea with pale offensive stools; in 1953, spontaneous tetany, recurring during lactation after the birth of twins in 1955 when the plasma-calcium was 5-8 mg. per 100 ml. and she was treated with intravenous calcium. In 1956, diarrhoea recurred and a gluten-free diet was given with notable symptomatic improvement and weight gain; oral calciferol was started and continued until 1961 (fig. 1). In 1962, hysterectomy for menorrhagia; in 1963, an intravenous pyelogram for bilateral loin pain showed bilateral radiopaque calculi with hydronephrosis; in 1964, left nephrectomy was done for non-functioning kidney, histology showed calculous pyelonephritis. In retrospect we wonder if the stones could have resulted from an overdose
