Journal of lnternal Medicine 1991 : 2 3 0 : 443-448

Features of Sjogren’s syndrome in patients with primary biliary cirrhosis P. UDDENFELDT, & Y . OSTBERGS





From the Department of Internal Medicine. the *Department of Diagnostic Radiology. the tDepartrnent o/ Ophtlialmology arid the *Department of Otorhinolaryngology. University of Umed. Urned. Sweden

Abstract. Uddenfeldt P, Danielsson A. Forssell A, Holm M. Ostberg lnternal Medicine, Department of Diagnostic Radiology, Department and Department of Otorhinolaryngology, University of Umei, Umel. of Sjogren’s syndrome in patients with primary biliary cirrhosis. Medicine 1991 : 2 3 0 : 443-448.

Y (Department of of Ophthalmology Sweden). Features Journal of Internal

Twenty-six consecutive patients with primary biliary cirrhosis (PBC) from northern Sweden were studied regarding the occurrence and features of Sjogren’s syndrome (SS). In more than 50% of the patients the rose bengal dye test showed conjunctival and/or corneal staining. In six patients keratoconjunctivitis sicca (KCS) was present with positive rose bengal and Schirmer tests. In a further three patients only the results of the Schirmer tests were abnormal. Radiological findings of sialectasia were demonstrated in six patients, five of whom had KCS. Two of the seven patients who fulfilled our criteria for Sjogren’s syndrome were HLA-B8 positive. A high prevalence of increased immune globulins and rheumatic factor was found, but this did not correlate with the presence of Sjogren’s syndrome. Some features of Sjogren’s syndrome were found in 73% of PBC patients, and keratoconjunctivitis sicca and/or sialectasia were found in 27% of PBC patients. This constitutes a high frequency of secondary manifestations of the liver disease.

Keywords : primary biliary cirrhosis, Sjogren’s syndrome.

Introduction In 1933 Sjogren described an ocular disorder, ‘ keratoconjunctivitis sicca ’, as one local phenomenon of a more generalized symptom complex with decreased lacrimal and salivary gland secretion and chronic arthritis, occurring mainly in menopausal women [l]. Von Grosz, in 1936, first honoured Sjogren by referring to this disease as Sjogren’s syndrome [2]. Subsequently, Sjogren’s syndrome (SS) was defined by the presence of at least two of the following : keratoconjunctivitis sicca (KCS), xerostomia, and a well-defined chronic inflammatory connective tissue disease [3]. The terms ‘sicca complex ’ or ‘ sicca syndrome ’ have been used in the past to describe the combination of KCS and/or xerostomia, but these have now been replaced by the term primary SS [4]. The definition of secondary SS

refers to a combination of KCS and xerostomia, with primarily rheumatoid arthritis and SLE [S]. It is now well known that many autoimmune diseases can be associated with this syndrome [6-81. PBC is believed to be an autoimmune liver disease characterized by a chronic granulomatous inflammation that affects the intrahepatic bile ducts. The disease is mostly seen in middle-aged women, and it has a variable prognosis, eventually progressing to cirrhosis and death from liver failure or variceal haemorrhage. Multiorgan involvement is frequently observed in PBC [9, 101, and sometimes extrahepatic manifestations may dominate the clinical picture. Arthropathy and rheumatoid arthritis appear to be common in patients with PBC [lI.]. The aim of the present investigation was to study the features of Sjogren’s syndrome in a consecutive series of patients with PBC. 443



Table 1. Clinical characteristics of 26 patients with primary biliary cirrhosis

Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

22 23 24 25 26

Sex and age (years)

Disease duration (years)

M. 60 F. 42 F, 51 F, 44 F, 60 F. 50 F. 77 F, 49 F. 68 F. 43 F, 64 F, 74 F. 57 F. 64 F, 55 F. 63 F, 50 F, 39 F, 50 F. 51 F, 71 M. 54 F. 57 F, 62 F, 43 F, 44

8 15 10 6 7 8 20 8 11 12 20 6 13 I5 17 1 4 8 1 12 4 17 1 5 7 1


S-Bil (Bmol I-')

s-ALP (pkat I-')

P-IgM (g I-')

AMA (titre)

Liver biopsy stage

Clinical stage

15 45 10 18 8 43 19 11 27 23 16 225 22

12 23 21 40 7 27 19 15 7 32 5 60 16 74 16 3 32 8 14 3 19 21 8 7 14 12

3.3 18.3 19.3 4.6 9.4 4.4 8.8 4.0 2.7 2.0 1.7 3.8 3.3 15.5 3.2 11.2 8.0 1.6 6.9 2.6 1.3 4.1 7.9 2.8 2.7 6.2

1/100 1/400 11400 1/100 Neg 1/25 If400 1/25 1/100 1/25 1/100 1/25 11400 1/800 1/100 1/800 11400 Neg 1/25 11400 1/400 1/100 If400 1/400 1/100 1/800

ND 2 3 3 2 2 4 3 ND 2 4 2 2 3 4 3 2 2 2 2 NU 3 2 3 3 3

Asymptomatic Symptomatic Asymptomatic Symptomatic Asymptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic Asymptomatic Symptomatic Asymptomatic Asymptomatic Symptomatic Symptomatic Asymptomatic Symptomatic Symptomatic Symptomatic




9 13 14 12 35 8 6 11 39 11 8

7 57 3.5-21

M = male, F = female, S-bil = S-bilirubin, S-ALP = S-alkaline phosphatase. AMA

Patients and methods Over a 2-year period, 26 consecutive patients (24 women and two men) with PBC were studied. The diagnosis was established by clinical presentation, laboratory data (increased s-alkaline phosphatase activity, presence of antimitochondrial antibodies) and a liver biopsy diagnostic of or compatible with PBC [12]. Liver biopsies were not available for three patients (in one case for technical reasons and in the other two because of contraindications). In these cases a n increase in ALP and the presence of antimitochondrial antibodies were mandatory. At the time of the investigation, the mean age of the patients was 56 years (range 39-77 years), and the estimated mean duration of the liver disease was 9 years (range 1-20 years). Fifty-three per cent of the patients were in a n early stage of the disease, whereas 4 7 % were in a more advanced stage (stages I11 or IV) as assessed by liver biopsy [12]. The clinical and laboratory data are presented in Table 1. The diagnosis of Sjogren's syndrome was based on

= antimitochondrial

antibodies, ND = not done.

the presence of a Schirmer test of less than 5 mm, and corneal staining with rose bengal and/or radiological findings of sialectasia. All patients were examined for ocular and salivary gland symptoms. Subjective symptoms of xerostomia were elicited with particular regard to the need for increased fluid intake during meals and/or during the night. The parotid glands were examined for the presence of enlargement or atrophy, and the oral cavity was inspected for signs of xerostomia and/or atrophy of the mucous membranes. Subjective xerophthalmia was elicited by asking, for example, about ' foreign-body sensation ', burning, tiredness with or without difficulty in opening the eyes, dryness, redness or soreness. Schirmer test A sterile standardized strip of blotting paper (5 x 3 5 mm) was folded 5 mm from the end and inserted into the lower conjunctival fornix. After 5 min with the head in a supine position and the eyes



Table 2. Various features of Sjogren's syndrome in 26 patients with primary biliary cirrhosis (PBC)

Patient no.

* Asymptomatic I* 2

31 4 5* 6 7 8 9 10

Parotid gland symptoms






SD S-a S-a N S-a. N SD S-a. ND S-a. S-a. A ND N N N N N N N N GD GD GD N GD




+ + -


+ + + +



Abnormal (%)

Rose bengal test Sialogram

12 13 14 15 16 17' 18 19' 20'

21 22 23* 24 25 26

Lacrimal gland symptoms

+ + -




+ + + -






111 I N N N I11 I1

N I1 I N 111

I1 I1 I1





N I11 N N N N

N 111 N N N


N N N I11 N


N N 111 N N

N 54

Schirmer test - __ Dx Sin 24 18 0 20 0 17 13 1 7 0 0 13 1 35 22 6 18 35 12 29 35 35 3 10 10 14



35 9 0 15 1 7 0 I 15 0 0 7 12 12 6 29 18 28 9 12 27 33 1 4

20 13


Sialogram: SD = segmented ducts. S-a = sialectasia. A = atrophy, GD = gracile ducts, N = normal, ND = not done. Rose bengal: I = staining of conjunctiva, I1 = staining of conjunctiva and cornea, 111 = as in I1 but marked staining.

looking upwards, the strip was removed and the length of the wetted paper was measured from the fold. The test was performed with the patient adequately hydrated and not taking drugs that could affect the results obtained. Rose bengal test

The day after the Schirmer test, one drop of 1% rose bengal was instilled into each conjunctival sac. After several blinks (over a period of 10 to 15 s) irrigation with physiological saline was performed, and the conjunctiva and cornea were photographed. Sialography

The orifice of the duct was cannulated with a small polyethylene catheter which was adjusted with a tapered tip until the duct was more or less occluded, to prevent leakage of contrast medium into the oral cavity. The contrast medium (Isopaque Cerebral

6 0 % - 280 mg I ml-l) was injected slowly until the patient felt moderate pain over the parotid region, usually after the injection of 0.6-1.2 ml. Lateral projection pictures were then taken with the patient in the supine position. Since the aim of the examination was merely to visualize the ductal system, and not to evaluate the size of the gland, further projections were considered to be of minor value. Classification of the sialograms was based on the presence of atrophy and sialectasias. Glands with sparse ductal ramifications and contrast filling primarily of intraglandular ducts of the first orders were considered to be atrophic. Sialectasias were recorded according to Blatt et al. [ 131. Surgery

In three patients an open biopsy from the parotid gland was performed from the superficial, inferior and posterior parts of the gland. The biopsy was



Psymptomotic ( 7 )

ss ( 7 )

Arthritis ( 7 )

Fig. I . Relationship between Sjogren’s syndrome (SS) and arthritis in asymptomatic and symptomatic PBC patients.

performed under local anaesthesia during the initial 3 d and the last 3 months after the sialography. Informed consent was obtained from all patients, and the study protocol was approved by the Medical Ethics Committee of UmeA University.

Results The results for each patient are shown in Table 2. Sialograms were not obtained in two cases, as the orifice of the parotid duct could not be identified. For the same reason, sialography was only unilateral in 3 patients (nos 5, 1 7 and 18). Sialectasia was found in 25% (6/24) of the patients-it was bilateral (except for the patient with only a unilateral sialogram) and of the punctuate type in all but one case, who also had globular sialectasias. Only one patient exhibited parotid gland enlargement. Four patients had segmented ducts ; three intraglandularly and one of the main duct. Sialectasias were present in three of these patients. Glandular atrophy was considered to be present in three patients, and in the only subject who did not have sialectasias as well, the diagnosis was verified by an open parotid gland biopsy, which revealed replacement of the parenchyma by fat tissue. Gracile ducts without any other sign of atrophy were found in four patients, two of whom had symptoms of xerostomia. Two of these patients were subjected to parotid biopsies, which showed fatty degeneration, indicating atrophy. Almost 50% of the 26 PBC patients had symptoms of xerostomia; four of the six patients with sialectasias had symptoms of xerostomia. The rose bengal test showed epithelial damage in 1 4 patients, and the Schirmer test was less than

5 mm in 9 out of 26 patients. Six patients exhibited a combination of abnormal rose bengal dye and Schirmer tests, and they were diagnosed as having KCS. Four of them also had parotid gland symptoms, and five patients with sialectasias also had KCS. The remaining patients with sialectasias had signs and symptoms of xerostomia. Thus 2 7 % of our PBC patients had SS. Seven patients had arthritis and, according to the criteria of the American Rheumatism Association, five patients had rheumatoid arthritis (Fig. 1) [14]. Three of these seven patients had KCS and/or sialectasias, while two were HLA-B8 positive (Table 2). Two patients had antibodies to nuclear antigens ; one with a homogenous pattern with sclerodactyli, and one with a speckled pattern with no evidence of connective tissue disease. There was no correlation between SS and the symptoms, duration or stage of the liver disease, serum bilirubin, serum aminotransferases, serum alkaline phosphatase, bile acids, serum immune globulins M. G or A, titre of WaalerRose, titre of mitochondria1 antibodies, or Clq binding capacity.

Discussion The present study suggests that Sjogren’s syndrome (SS) is fairly common among patients with PBC. The population studied consisted of about one-third of all patients with PBC within the health region [15], and thus seems to be representative of patients with PBC in northern Sweden. One or more signs of SS were found in 73% of patients with PBC; 54% (14) showed an abnormal rose bengal stain, 35% (9) exhibited a Schirmer test result of less than 5 mm, and in 2 5 % (6/24) sialectasias were revealed by sialogram. In the earlier literature, the reported frequency of SS in PBC varies from 26-72% 19, 16. 171. Other liver diseases, including autoimmune chronic active hepatitis, have also been shown to be associated with KCS and/or xerostomia, but these are not as widely recognized as in the case of PBC [91. However, direct comparison between different studies is difficult because of the lack of international agreement on the diagnostic criteria for both KCS and xerostomia [6]. In the present study, 2 7 % (7) of the patients fulfilled our criteria for SS. Using only a rose bengal test with corneal staining to establish the diagnosis of KCS [lo]. it has been found that 6 6 % of patients in


a sample of 113 PBC patients had SS. If this single method is applied to the present material, the frequency of SS would increase from 2 7 % to 46%. The rose bengal test is sensitive to epithelial damage, but its specificity is quite low and therefore, in our opinion, this test should always be combined with a Schirmer test when diagnosing KCS. The Schirmer test alone is unreliable [18]. The correlation between KCS and sialectasia was high-only one patient out of the six subjects with sialectasias did not fulfil the criteria for KCS. The presence of sialectasia in SS varies with the severity of symptoms from 50% to almost 100% [3, 191. Sialectasia is caused not only by autoimmune processes, but also by infections. Moreover, congenital sialectasia has been reported, although it is very rare [20]. None of our patients had a history of salivary gland infections. In addition to the sialectasia, there was also a higher prevalence of segmentation and atrophy than would be expected in healthy people 1201. In general, these abnormalities were found together with sialectasia. In addition, gracile ducts were found in four (17%) patients and, although such a finding could be regarded as normal, two of these patients had symptoms of xerostomia. Parotid biopsies from these two patients revealed fatty degeneration of the glandular tissue. This may indicate the existence of another type of glandular atrophy, which differs from that seen with sialectasia. Previous investigations have demonstrated a correlation between SS and the presence of HLA-B8 12 11. Subsequently, when differentiated into primary and secondary SS, there was no HLA-association when KCS and/or xerostomia were present in combination with rheumatoid arthritis [5] or PBC [15], i.e. secondary SS. Of the seven patients with SS (six cases of KCS and one of sialectasia) only two had €€LA-B8antigen, which is considered to be a marker of the primary form of SS [22]. Rheumatoid factor was present in 10 cases (titre of 3 1/40), five of whom had SS. This result is in agreement with previous data which suggest that rheumatoid factor is common to both SS [3] and PBC 1231, irrespective of concomitant arthritis. Several patients had increased serum levels of immune globulins, not only IgM, but also IgG and IgA. However, there was no correlation with the presence or degree of SS, which is consistent with the data reported by AlarconSegovia et al. [24]. Only two of the six patients with KCS had asymptomatic PBC (Fig. I ) , and more symptomatic


patients exhibit joint symptoms [111 and pulmonary dysfunction [25], which may indicate that symptomatic PBC is a more generalized form of the disease, with involvement of other tissues or organs. In contrast to other authors [26], we found no correlation between the degree of impairment in the Schirmer test or staining with rose bengal, and the duration and/or histological progression of the liver disease. The present investigation shows that SS is fairly common in PBC, whether or not arthritis is present. Only two of the patients with SS were HLA-B8 positive, suggesting the presence of secondary SS. Of the entire group of PBC patients, 2 7 % had HLA-B8 antigen, i.e. approximately the same proportion as in the background population, which confirms the lack of association between HLA-B8 and PBC.

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JP, Tala1 N. Association of Sjogren's syndrome with HLA-B8. Arthritis Rheum 1976: 19: 883-6. Moutsopoulos HM, Mann DL.Johnson H. Chused TM. Genetic differences between primary and secondary sicca syndrome. N Engl/ Med 1 9 7 9 : 301 : 761-3. Crowe JP. Christensen E. Butler J et al. Primary biliary cirrhosis : the prevalence of hypothyroidism and its relationship to thyroid autoantibodies and sicca syndrome. Gastroenterology 1980: 78: 1437-41. Alarcon-Segovia D. Diaz-Jouanen E. Fishbein E. Features of Sjogren's syndrome in primary biliary cirrhosis. Ann Interrr Med 1973: 79: 31-6. Uddenfeldt P. Bjerle P. Danielsson A. Nystrom L. Stjernberg N. Lung function abnormalities in patients with primary biliary cirrhosis. Acta Med Scand 1 9 8 8 : 223: 549-55. Giovannini A, Ballardin C. Amatetti S. Bonazzoli P. Hianchi FB. Patterns of lacrimal dysfunction in primary biliary cirrhosis. Hr / Ophthalrnol 1 9 8 5 : 6 9 : 832-835.

Received 8 January 1991, accepted 7 May 199 1. Correspondence: Ake Danielsson. MD PhD. Department of Internal Medicine. Section for Gastroenterology, University Hospital, S-901 85 Ume5. Sweden.

Features of Sjögren's syndrome in patients with primary biliary cirrhosis.

Twenty-six consecutive patients with primary biliary cirrhosis (PBC) from northern Sweden were studied regarding the occurrence and features of Sjögre...
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