Download Salivary Amylase and Pancreatic Enzymes in Sjagren`sSyndrome

however, there have been few reports of TRH tests with this
new assay (5).
In our study, new patient referrals with an initial value
for TSH by IRMA of >0.1 to <50 milli-int. unitsfL showed a
strong correlation of the increment in TSH 20 mm after
TEl! and the basal value of TSH by IRMA (r = 0.93). This
pattern of response was observed even when the basal
values for TSH by IRMA were <1 milli-int. unitiL. In these
patients, therefore, the basal value for TSH by nui gives as
much information as the TEN test concerning thyrotroph
function. In hypothalamic and pituitary disease the same
correlation may not hold true, but we did not have an
opportunity to study such patients.
Thyrotropin by IRMA was below the detection limit of the
assay in 124 hyperthyroid and 12 subclinically hyperthyroid
patients at presentation; 132 showed no increment in TSH
by IRMA 20 mm after TRH administration. The four patients
in whom an increment was detected had multinodular
goiters and were considered to be subclinically hyperthyroid. Values for free thyroxin and free triiodothyronine were
in general lower than in the other eight subclinically
hyperthyroid
patients, in whom no increment in TSH by
IRMA was detected. Probably, when there is no increment in
TSH by m,
the synthesis and secretion of TSH is completely suppressed (6). A small increment in TSH by m
from an undetectable value may indicate partial thyrotroph
suppression. We suggest that, in such cases, the thyroid
hormone values, although sometimes within the reference
range, have risen above the usual value for that patient and
have resulted in decreased
synthesis and secretion of TSH.
Under these circumstances
a TRH test with PSI! assayed by
IRMA gives more information than the initial value for PSI!
alone. We made a similar observation in three hyperthyroid
patients whose thyrotroph function returned
after treat-
ment with ‘‘i. Some patients taking thyroxin
for primary
hypothyroidism
might also show this pattern of response.
In the study of thyrotroph function in thyroid disease, an
initial value for TSH by IRMA above the detection limit of
the assay gives as much information as a full TEN test;
when the value is below the detection limit of the assay,
however, some thyrotroph function can be demonstrated
by
the TEN test in a few patients. Assays for TSH of even
higher sensitivity
may be able to distinguish
between
complete and partial suppression of thyrotrophs
without the
need for a TRH test (7).
References
1. Seth J, Kellett HA, Caldwell G, et al. A sensitive immunoradiometric assay for serum thyroid stimulating hormone: a replacement
for the thyrotrophin releasing hormone test? Br Med J
1984;ii:1334-6.
2. Ratcliffe WA, Challand GS, Ratcliffe JG. A critical evaluation of
separate methods in radioimmunoassays for total triiodothyronine
and thyroxine in unextracted human serum. Ann Clin Biochem
1974;11:224-9.
3. Irvine WJ, Toft AD, Hunter WM, Kirkham KE. An assessment
of plasma TSH radioimmunoassay
and of TSH stimulation test in
the diagnosis of 100 consecutive patients with suspected hypothyroidism. Clin Endocrinol 1973;2:135-9.
4. Caidwell G, Cow SM, Sweeting VM, et al. A new strategy for
thyroid function testing. Lancet 1985;i:1117-9.
5. Kerr DJ,..Alexander WD. Is the TEll test usually unnecessary?
Lancet 1984;ii:1161-2.
6. Bakke JL, Kaumer H, Lawrence N. Effect of thyroid hormone on
human pituitary
thyroid stimulating hormone content. J Clin
Endocrinol Metab 1964;24:281-4.
7. Weeks I, Sturgess M, Siddle K, Jones MK, Woodhead JS. A high
sensitivity iminunochemiluminometric assay for human thyrotrophin. Clin Endocrinol 1984;20:489-95.
CLIN. CHEM. 33/2, 305-307 (1987)
Salivary Amylase and Pancreatic Enzymes in Sjagren’sSyndrome
B. Pal, I. D. Grtfffths, A. Katralc,1 D. Junglee,1and P. Dandona1’2
Concentrations of immunoreactive trypsin (IRT) and pancreatic and salivary amylase activities were measured in 22
patients with primary SjOgren’s syndrome (SS) and in 13
patients with secondary SS.Nineteen of the 22 patients with
primary SS had above-normal IRT, and six had abovenormal pancreatic isoamylase activity. Six of the 13 patients
with secondary SS had above-normal IRT; none had abovenormal isoamylase activities. Serum IRT and pancreatic
isoamylase were correlated significantly (r
0.7; p
<0.0001). Above-normal values for IRT and pancreatic isoamylase were more frequent in patients who had SS for
longer than 10 years, but were not related to the presence of
salivary gland autoantibodies or to salivary isoamylase activity. We conclude that the concentration and activity of pancreatic enzymes are frequently abnormal in SS; that the abnor=
Department of Rheumatology, Royal Victoria Infirmary, Newcastle-Upon-Tyne, and ‘Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine,
London, NW3 2QG, U.K.
2Ad(fr
correspondence to this author.
Received September 12, 1986; accepted November 21, 1986.
mality is greater and more frequent in patients with primary
SS;and that it increases with the duration of the disease.
Additional Keyphrases: isoenzymes
trypsin
arthritis
systemiclupuserythematosus
rheumatoid
‘
Sjogren’s syndrome (55) is characterized
by progressive
destruction of the salivary and lacrimal glands by a chronic
inflammatory
pi-Ocess (1, 2). This leads to a decrease
in
salivary flow, dryness of the mouth and eyes, and sometimes
other exocrine disturbances.
55 is classically subdivided into
two groups: primary SS (or sicca syndrome), where exocrine
disturbances
occur in isolation, and secondary 55, where a
well-characterized
disorder of connective tissue is also present. This clinical subdivision is supported by clinical,
immunological, and immunogenetic differences between the
two groups.
Two previous studies suggested that concomitant abnor3Nonstandard abbreviations: SS, SjOgren’ssyndrome; RA, rheumatoid arthritis; SLE, systemic lupus ezythemathsus; IRT, immunoreactive trypsin.
CLINICALCHEMISTRY,Vol. 33, No. 2, 1987 305
malities in exocrine pancreatic function may occur in 55(3,
4). One study included a small number of patients with
primary
SS, the majority of the rest having concomitant
rheumatoid arthritis (RA) (3). The other did not relate the
abnormalities of pancreatic function to the duration of the
disease or to autoimmune
abnormalities
in the patients (4).
Both studies relied on traditional
pancreatic
function tests,
which are tedious and time consuming.
We have previously shown that the measurement
of
pancreatic enzymes trypsin, aniylase, and lipase in serum
provides a sensitive index of subclinical
abnormalities
in
pancreatic function, including diabetes mellitus (6), crstic
fibrosis (7), and iron overload (8). We therefore undertook a
comprehensive
study of changes in the pancreatic enzyme
concentrations/activity
in serum of subjects with primary or
secondary
SS, and the possible effect of (a) associated
autoimmune
abnormalities
and (b) the duration of disease.
1.2
1.0
0.8
i-i
E
Iix
0.6
0.4
Patients
#{149}1
-
and Methods
Patients
patients with SS were included in this study.
Nine had EA, four had systemic lupus erythematosus
(SLE),
and 22 had primary
SS according
to standard
criteria (9).
All patients had symptoms of xerophthalmia
and xerostomin. The diagnosis
of 55 was based on documentation
of
keratoconjunctivitis
sicca and evidence of salivary
gland
involvement (9); keratoconjunctivitis
sicca was judged present by (a) decreased tear flow rate by Schirmer’s test (less
than 10 mm wetting ofthe paper strip in5 mm) and (b)
abnormal staining of the cornea and conjunctiva with rose
bengal dye. Xerostomia was judged present by (a) lack of
pool of saliva under the tongue and (b) decreased stimulated
salivary flow rate. Exclusions
recently proposed by Fox et al.
(10),
e.g., pre-existing
lymphoma and sarcoidosis,
were
strictly adhered to.
The findings of a full clinical examination of each patient
were recorded, including presence or absence of salivary
gland swelling and evidence of any clearly definable connective-tissue disorder. Primary 55 was diagnosed only in the
absence of a recognizable connective-tissue
disorders such as
SLE, scieroderma, or mixed connective tissue disease. None
of’the patients included in this study had an impaired renal
function: the concentration
of urea in plasma was <6.5
mmol/L and creatinine was <120 .imol/L.
0.2
Thirty-five
Controls
The control group comprised 100 normal subjects (60 men,
40 women), ages 18-60 years.
Methods
Blood samples were obtained from all these patients; the
serum was separated and frozen at -20 #{176}C.
Rheumatoid
factor and antinuclear
factor were assayed in all sera. The
concentrations
of immunoreactive
trypsin (EC 3.4.21.4; ffi’l
and the activities of pancreatic
and salivary
amylase
(EC
3.2.1.1) isoenzymes in serum were also measured. IRT was
measured with a specific radioimmunoassay
kit (Hoechst,
Hounslow, U.K.), as previously described (6). Pancreatic
and
salivary isoamylases were measured by an enzymatic method based on a kit (Phadebas; Pharmacia,
Uppsala, Sweden),
as previously
described (11).
Statistical
comparisons
were by Student’s t-tests, linear
regression analysis, and
tests.
306 CLINICALCHEMISTRY, Vol. 33, No.2, 1987
-i
0-
I
S S
j.
controls
Fig. 1. Immunoreactive tiypsin (IRT) concentrations in 35 patients with
Sjogren’s syndrome (55) and 100 controls
The mean ± 50 indicatedfor each groupdiffer significantly
(p <0.0001)
Results
Twenty-five of the 35 patients investigated
had abovenormal IRT concentrations (see Figure 1). Of the 22 with
primary 55,19 had an increased concentration of IRT. Five
of nine patients with RA and SS had increased IRT, but only
one of four with SLE did. The mean (±SD) IRT concentration in 55 patients (0.55 ± 0.1 mg/L) was significantly
greater than that in controls (0.27 ± 0.07 mgfL, p <0.001).
Pancreatic amylase was increased in seven patients, six of
whom had primary 55, the seventh being one of the nine
patients with RA. The mean pancreatic amylase (148±68
U/L) in SS patients was not significantly different from that
in controls (130±45
U/L).
Salivary amylase activity was subnormal in six patients;
all except one had primary SS and one had RA. Five of these
six patients with low salivary amylase had increased
LET;
only two had above-normal
pancreatic
amylase activity.
Four of the six patients with subnormal salivary
amylase
had had SS longer than 10 years.
There was a highly significant correlation between LET
concentration and pancreatic isoamnylase activity (r = 0.70,
p <0.0001), but no correlation between salivary isoamylase
and JET or between salivary and pancreatic isoamylase. The
presence
of salivary
gland swelling
and salivary
gland
antibodies, rheumatoid factor, or antinuclear
antibody was
not related to increases in LET concentrations.
The mean
(± SD) lET in patients who had had SS longer than 10 years
was significantly
greater (0.65 ± 0.15 mg/L) than in patients with SS for less than 10 years (0.49 ± 0.12 mg/L, p
<0.01). Four of eight patients with SS longer than 10 years
had extremely high lET (0.7 mg/L) concentrations,
but only
five of 28 patients with SS for less than 10 years had
markedly increased LET.
Discussion
We found that a majority
of patients with SS-both
and secondary-had
increased
concentrations of
LET. Pancreatic
isoamylase
was also increased
in seven
patients. This study indicates variable pancreatic
damage in
SS, and confirms the abnormality
we have previously demonstrated in patients with primary biiary cirrhosis and SS
(5).
Lymphocytic
infiltrations
of the exocrine glands and
acinar tissue damage are often observed in patients with SS.
Exocrine pancreas may be similarly affected, which may
account for the frequent subclinical
pancreatic involvement
in this disorder. A recent report (17) showed the presence of
humoral
autoimmnunity
to pancreatic duct cells in 55,
indicating
the involvement of autoimmune
mechanisms
in
the pathogenesis of subclinical
exocrine insufficiency.
None of the patients who had an increase in the concentration of LET had clinical pancreatitis.
Eather, the increase
of LET in these patients is a marker of subclinical pancreatic
damage/abnormality,
which we have previously observed in
patients with cystic fibrosis (7) or thalassemia
major with
iron overload (8), in the elderly (13),
and after steroid
administration
in large doses (14). The fact that the frequency of above-normal
concentrations
of LET is greater than
that of above-normal pancreatic isoamylase activity is probably due to the fact that the radioimmunoassay
of LET
measures
both trypsinogen and trypsin, whereas the pancreatic isoaxnylase
assay measures
the enzyme activity only.
Damage to the acinar cells probably allows the proenzyme
to leak into blood in larger quantities
than the activated
enzyme. Nevertheless,
the highly significant
correlation
between LET and pancreatic isoamylase
in these patients is
interesting,
as is the observation that early damage of the
pancreas may result in hypersecretion
of pancreatic juice
into the duodenal lumen (15).
The frequency of above-normal values for LET and pancreatic amylase was greater in patients with primary SS than
in those with secondary
SS, probably because of the stage in
the natural history of the “exocrine pathology” at the time of
presentation. Patients with RA and primary biliary cirrhosis may be likely to present at earlier stages of “exocrine
pathology.”
We were surprised to see the low prevalence of subnormal
salivary isoamylase activity in a disease characterized clinically by salivary hyposecretion. We had anticipated a greater frequency of abnormal salivary isoamylase. Apparently a
low salivary isoamylase in serum occurs only late in the
disorder: four of the six patients with depressed activities of
salivary isoamylase
had had SS longer than 10 years.
Subnormal salivary isoamylase values were associated with
increased
lET in five patients. Salivary
amylase
was increased only in one patient, who also had an increase in
pancreatic isoamylase
and markedly increased LET. We also
primary
find it interesting that LET and pancreatic
and salivary
amylase were not related to any of the clinical features or
autoantibodies
studied, but there was a correlation between
the duration of the disease and pancreatic
and salivary
abnormalities.
In conclusion: SS is associated with frequent pancreatic
abnormality
that is independent of the extent of salivary
gland abnormality
but dependent upon the duration of the
disease.
We thank Drs. W. C. Dick and S. Blair for help and advice and
Mrs. P. Dale for preparing the manuscript.
References
Fox RI, Carstens
SA, Fong S, et al. Use of monoclonal antibodies
analyze peripheral blood and salivary gland lymphocyte subsets
in Sjogren’s syndrome. Arthritis Rheum 1982;25:419-26.
2. Manthorpe B, Frost-Larsen K, bayer H, Prowse JH. Sjogren’s
syndrome. A review with emphasis on immunological features.
Allergy 1981;36:139-53.
3. Gabelet C, Gerster JC, Eappoport G, Hiroz CA, Maeder E. A
controlled study of exocrune pancreatic function in Ogren’s syndrome and rheumatoid arthritis. Cliii Rheumatol 1983;2:139-43.
4. Dreilung DA, Soto JM. The pancreatic involvement in disseminated collagen disorders. Study of pancreatic secretion in patients
with scleroderma and Sjagren’s disease. Am J Gastroenterol
1974;61:546-53.
5. Fonseca V, Epstein 0, Katrak A, et al. Serum immunoreactive
trypsin and pancreatic lipase in primary biliary cirrhosis. J Clin
Pathol 1986;39:638-42.
6. Dandona P, Elias E, Beckett AG. Serum trypsin in diabetes
mellitus. Br Med J 1978;ii:1125-6.
7. Dandona P, Hodson ME, Ramdial L, Bell J, Batten JC. Serum
unununoreactive trypsin in cystic fibrosis. Thorax 1981;38:60-2.
8. Hussain M, Dandona P, Fedail M, Flynn D, Hofibrand AV.
Serum immunoreactive
trypsin in p-thalaasaemia
major. J Clin
Pathol 1981;34:963-4.
9. Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sj#{246}gren’s
syndrome: a clinical, pathological and serological study of 62 cases.
Medicine (Baltimore) 1965;44:187-231.
10. Fox RI, Robinson CA, Curd JG, et al. SjOgren’s syndrome:
proposed criteria for classification. Arthritis Rheum 1986;29:577-
1.
to
85.
11. Junglee D, Mohiuddun J, Katrak A, Prentice HG, Dandona P.
Serum salivary aunylase and pancreatic enzymes after total body
irradiation. Cliii Chem 1986;32:609-10.
12. Ludwig H, Schernthaner G. Humoral autoimmunity to pancreatic duct cells in Sjogren’s syndrome. Paper presented at the ut.
Congr. of Rheumatology, Sydney, Australia, May 1985 (Abstract
no.
255).
13. Mohiuddin
J, Katrak A, Jungles D, Green M, Dandona P.
enzymes in the elderly. Ann Clin Biochem
Serum pancreatic
1984;21:102-4.
14. Dandona P, Junglee D, Katrak A, Fonseca V, Havard CWH.
Serum pancreatic enzymes increase following methylprednisolone:
possible evidence of subclinical pancreatitis. Br Med J 1985;291:24.
15. Dreiling DA, Bardalo 0. Secretory patterns in minimal pancreatic pathologies. Am J Gastroenterol 1973;60:60-4.
CLINICALCHEMISTRY, Vol. 33, No. 2, 1987 307