Chronic Sialadenitis revealing hepatitis C: a case report

MADRID C, COURTOIS B, DURAN D. CHRONIC SIALADENITIS REVEALING HEPATITIS C: A CASE REPORT. MED ORAL 2004;9:328-32.

SUMMARY

One 53-year-old male was referred with a history of sensitive peripheral neuropathy and Raynaud disease leading to suspect a Sjögren’s syndrome (SS). Labial salivary gland biopsy shown the classical features of chronic lymphocytic sialadenitis. As clinical and immunologic tests were positive, we conclude to a chronic lymphocytic sialadenitis simulating SS. Enzyme immunoassay and recombinant immunoblot were positive to HCV. Circulating HCV-RNA was detected by PCR. Liver biopsy revealed chronic persistent hepatitis. In one second biopsy, RNA was extracted. PCR amplification and southern blot hybridization for HCV-RNA were performed. After a 8-month-treatment by interferon alpha, HCV-RNA was no longer detected in the serum. There was an objective improvement of the Schirmer's test. The detection of HCV-RNA in the salivary glands of a Sjögren's like syndrome-patient suggests that a direct infection of the salivary glands by HCV could play an important role in the pathogenesis of HCV related sialadenitis.

Key Words: Sjögren's syndrome, chronic sialadenitis, hepatitis C.

INTRODUCTION

There are accumulating documentation of autoimmune mediated extrahepatic manifestations of hepatitis C virus (HCV) infection (1). 38% of patients with HCV will manifest symptoms of at least one extrahepatic manifestation during the illness (2). For some (eg, cryoglobulinemia), the association is well established. For others, such as sialadenitis, the association is probable but not completely documented. Salivary gland lesions have been found in 49% of patients with chronic virus C hepatitis (3) : all had lymphocytic capillaritis sometimes associated with lymphocytic sialadenitis incompletely resembling that of a Sjögren's syndrome (SS). The histological features of the lesions looked like those of primary SS but duct walls were intact and alterations were pericapillary rather than periductal, without destruction of the salivary gland ducts. In order to differentiate primary SS without C virus hepatitis and HCV-related Sjögren's like sialadenitis, Coll (4) tried to determine whether the observed focal lymphocyte infiltration of salivary glands in HCV-infected patients is phenotypically different from the lymphocytes that infiltrate the salivary glands in primary SS patients without HCV infection. The results show that, both in histological and immunohistochemical terms, primary SS and HCV related chronic sialadenitis only differ by minor histological (already exposed) and phenotypical features (predominance of CD 20 lymphocytes in HCV-related sialadenitis versus predominance of CD 25 and epithelial cells in primary SS).

CLINICAL CASE

We report the case of a 53-years-old male that consulted the Unit of Oral Medicine of the Hôtel Dieu (Toulouse, France) with a history of peripheral sensitive neuropathy affecting upper and lower limbs and a long lasting Raynaud disease.

He was referred for labial salivary gland biopsy by his neurologist who suspected a Sjögren Syndrome although there was no spontaneous complaint of mouth or eye dryness.

There was no clinical evidence of keratoconjunctivitis sicca: a Schirmer's test (Clement Clarke^®, Edinburgh, UK) was performed detecting a subnormal wetting (about 5mm/5') but a shortened tear break-up time (inferior to 10s). The Rose-Bengal test was negative.

Oral examination did not demonstrate a reduction of salivary secretion and the assessment of the salivary flow by the Saxon's test was negative (more than 3g in 5 minutes). We proposed a salivary gland scintigraphy in order to assess the salivary secretion but the patient, who did not experience xerostomia, refused.

A labial salivary gland biopsy was performed on the left lower lip recollecting 5 minor salivary glands (figure 1). Classical features of chronic lymphocytic sialadenitis were found: a nodular periductal infiltrate mainly composed of lymphoid and plasma cells, enlarged ducts and acinar atrophy were found. The conclusion of the histopathology was a focus score of 2 and a Chisholm's scale of 4. The results of laboratory studies were as follows: WBC count: 7000/mm³; RBC count: 481x 104/ mm3; haemoglobin: 13g/dl; platelets: 255 000; ESR: 72mm/hr; total protein: 8g/dl with 25.6% of gamma-globulin (normal range: 10.5 to 19.9); SGOT/AST: 48 IU/l; SGPT/ALT: 47 IU/l; alkaline phosphatase: 182 IU/l; GammaGTP: 9 IU/l.

Several immunologic tests disclosed positive values. The rheumatoid factor was found at 85 UI/l; antinuclear antibodies (1:2000, homogeneous pattern) and Anti SS-A -Ro antibodies were positive. A mixed cryoglobulinaemia was evidenced (polyclonal IgG and kappa polyclonal IgM _).

Even if the mild elevation of transaminase levels could be related to SS, we decided in March of 2001 testing for anti-HCV antibodies by enzyme-linked immunoabsorbent assay (Innotest HCV ab III; Innogenetics^®, Heiden, Germany) and recombinant immunoblot assay (Inno-Lia HCV ab III; Innogenetics^®, Heiden, Germany) that gave positive results on both tests.

Circulating HCV-RNA presence and titres in the serum were determined by using a reverse transcriptase-polymerase chain reaction for HCV-RNA carried out by a microwell plate-based detection test (Amplicor HCV 2.0, Roche^®, Branchburg, NJ).

Results of tests using commercial enzyme immunoassay (Roche Diagnostic System, Basel, Switzerland) for hepatitis B infection (anti-hepatitis B core and surface antigens) and human immunodeficiency virus antibodies were negative.

A liver biopsy was performed. The histopathologic analysis demonstrated a chronic persistent hepatitis of mild grade without fibrosis (figure 2).

We performed a second labial salivary gland biopsy and the RNA extraction was carried out as previously described (5) PCR amplification for HCV-RNA was done by nested PCR from the 5' non-coding highly conserved region of the genome. The specificity was confirmed by a commercial strip hybridization assay (Inno-Lipa II, Innogenetics^®, Zwijndrecht, Belgium) and showed HCV genotype 1b, which is the most prevalent genotype in France and also often encountered in persons with unknown risk factors.

Despite the absence of fibrosis and due to the presence of neuropathic extrahepatic manifestations of HCV infection, the patient was treated during 8 months with interferon alpha 2b (Viraferon^®, 3x10⁶ IU, 3 times a week).

HCV-RNA was no longer detectable in the serum at the end of the treatment and there was an objective improvement of the Schirmer's test: 9 mm for 5 minutes. Before beginning the treatment, the patient had neither subjective complain about a salivary deficiency nor any objective reduction in salivary outflow, that is why he did not report any change in his oral condition after the interferon therapy.

DISCUSSION

Although the patient had been referred for assessment of a suspected Sjögren's syndrome mainly suggested by extra glandular manifestations such as Raynaud disease and peripheral sensitive neuropathy, we finally were unable to confirm absolutely this diagnosis neither according to San Diego (or Fox) criteria nor according European one's. While xerostomia is an essential criterion for Fox, the absence of unequivocal ocular signs prevented to fill the European conditions. Despite the positivity of numerous immunologic values that could lead to a secondary SS, we could only propose the diagnosis of chronic lymphocytic sialadenitis simulating a Sjögren's syndrome. Actually, this proposal is not completely satisfactory in the reported case since classically the histological infiltrate is less definite (Chisholm 1 to 2 in HCV sialadenitis versus 3 to 4 in primary SS (6)) and there is usually no detection of serum autoimmunity markers (while they are specifically positive for anti-Ro nuclear autoantibodies in the reported case). As anti-La autoantibodies are rather specific to primary SS being positive in 30 to 70% of them(7), the fact that these autoantibodies are not detected in the reported case is in favour of a Sjögren's like syndrome.

The peripheral sensitive neuropathy that motivated the consultation being then related to a polyclonal cryoglobulinemia.

The cause of SS is unknown but a viral etiology has been suggested (8). Early studies indicated that the prevalence of HCV antibodies might be higher among patients with primary SS than in general population. But it appears in further studies that part of this is due to misdiagnosis and misclassification and the frequency changed with geographical region and inclusion criteria. Nevertheless salivary dysfunction has also been reported in HCV seropositive individuals. Actually, HCV might be associated with salivary gland abnormalities in two separate ways:

A severe sialadenitis associated with SS: a result of secondary autoimmune phenomena triggered by HCV occurring in genetically predisposed individuals (particular autoimmune markers as HLA haplotypes).

This could explain a particular geographical distribution. HLA DR3 is frequently associated with SS and HCV cryoglobuline-mia has also been related to the same haplotype.

The second way relates to the fact that patients with HCV infections commonly have a mild form of lymphocytic sialadenitis that, like in the reported case, morphologically closely resembles that of SS but is not identical: no clinical features, difference of patient gender, expression of autoimmune markers that would suggest a SS diagnosis. We could call it as suggested by Roy and Bagg (8), a HCV related sialadenitis or a Sjögren like syndrome. The detection HCV-RNA in salivary glands could advocate the way of direct infection of the salivary tissue for the pathogenesis of both SS and non-SS chronic lymphocytic sialadenitis. Nevertheless Arietta and col. (5) clearly point out that the HCV infected-cells did not show any difference with respect to the uninfected cells. Most published reports of HCV-RNA detection in salivary glands concerned patients already known as HCV-positive (9-11). In the group of 19 xerostomia-affected patients studied by Arietta and col(5), 8 patients were anti-HCV-positives (7 with chronic sialadenitis, 1 with SS) when the salivary gland samples were obtained. The remaining 11 patients had no serum markers of HCV infection. Finally, positive hybridization signals were observed in the salivary gland biopsies from the 8 patients with HCV-RNA in serum but in none of the biopsies from the 11 HCV -negative patients.

In the present case report, the discovery of a sub clinical HCV infection followed on the diagnosis of non-syndromic lymphocytic chronic sialadenitis. This case suggests that it could be of interest to check in a group of non-SS chronic lymphocytic sialadenitis if the prevalence of sub clinical circulating HCV-RNA is higher than among the general population.

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