Burst of autoimmunity with the emergence of Primary Sjogren syndrome, cholestatic autoimmune hepatitis and latent autoimmune diabetes of adults (LADA).

To the Editor: Primary Sjogren syndrome (pSS) is a systemic autoimmune disorder characterized by the simultaneous presence of keratoconjunctivitis sicca and xerostomia in the absence of other connective tissue diseases. Although pSS is an autoimmune exocri-nopathy, the involvement of nonexo-crine organs, such as the liver, kidneys and lungs, has been reported. Autoimmune hepatitis (AIH) and primary biliary cirrhosis are the most common liver diseases coinciding with pSS. (1) Cholestasis is a rare finding in AIH. Latent autoimmune diabetes in adults (LADA) is the type of diabetes in adults which is initially noninsulin requiring but with immune markers of Type 1 diabetes that often progress to insulin dependence. (2) We report a patient who presented with the symptoms and findings of pSS, cholestatic AIH and LADA at the same time.

A 43-year-old woman was admitted to our hospital with the complaints of abdominal pain, polyuria, dry mouth and dry eyes for six months. She had not taken any medications nor alcohol. She had no remarkable history. Physical examination revealed icteric sclera and hepatosplenomegaly. Her body mass index was 29.6 kg/[m.sup.2]. Abnormal laboratory findings were as follows: sedimentation rate 46 mm/h, C-reactive protein 10.2 mg/dL, fasting glucose 134 mg/dL, aspartate aminotransferase 434 IU/L, alanine aminotransferase 623 IU/L, alkaline phosphatase 437 U/L, GGT 345 U/L, total bilirubin 2.9 mg/dL, conjugated bilirubin 2.14 mg/dL. Thyroid hormone profile was normal. Hemoglobin Alc was 8.2%. Oral glucose tolerance test level at 120 minutes was 246 mg/dL. C-peptide level was 0.38 nmol/L at 0 minutes and 0.42 nmol/L at 6 minutes after glucagon stimulation, which showed impaired insulin secretion. She had two positive anti-glutamic acid decarboxylase tests within two months. She was diagnosed as having LADA. The concentration of IgG was 2310 mg/dL. Serum electrophoresis showed polyclonal gammopathy. A test for anti-nuclear antibody was positive, at a titer of 1:320. Tests for rheumatoid factor and anti-SSA were positive. Imaging studies revealed normal biliary tract and hepatosplenomegaly. Liver biopsy revealed prominent portal lymphoplasmocytic infiltration with interface hepatitis, confirming the presence of AIH and moderate cholestasis in the hepatocytes. Labial salivary gland biopsy showed focal lymphocytic infiltration in accordance with the diagnosis of pSS. Diagnosis of pSS and AIH were made on the basis of the criteria proposed by the American-European Consensus Group (3) and International Autoimmune Hepatitis Group, (4) respectively. The patient was given insulin, rosiglitazone (added to the insulin treatment after the normalization of liver enzymes), methylprednisolone (60 mg/d) and azathioprine (100 mg/d). One month later, the patient's symptoms were relieved, and sedimentation rate and liver enzymes were normal. Six months after the start of treatment, liver biopsy revealed improved histologic findings with no lymphoplasmocytic infiltration in the portal area in the liver.

Patients with any autoimmune disease are prone to develop other autoimmune diseases. Association of LADA and AIH with cholestatic pattern can be seen in patients with pSS. Liver biopsy has a fundamental role in the diagnosis of AIH in pSS. The assessment of liver histology is not only necessary for diagnosis but also for evaluating prognosis of the patient with AIH. It was shown that the AIH patients with more severe interface hepatitis in pSS group had better response to corticosteroid therapy. (1) Corticosteroid therapy is the mainstay of therapy for AIH. If there is severe interface hepatitis, for the achievement of remission in as short a time as possible, at the beginning, the patient should be offered high dose corticosteroid therapy (prednisolone with a dose of 1 mg per kg).

In this case, LADA represented the diabetes part of an autoimmune iceberg. As the goals of treatment for LADA patients are suppression of autoimmune [beta] cell destruction and preservation of islet [beta] cell function, true diagnosis and treatment are crucial. Rosiglitazone combined with insulin preserves [beta] cell function; but sulfonylureas may play a detrimental role with its [beta] cell stimulatory effect. (5) Therefore, we treated the patient initially with insulin for an antagonizing glucose increasing effect of steroid and for [beta] cell preservation. After the normalization of liver enzymes, we added rosiglitazone to the insulin therapy. It is important to study in detail the clinical and laboratory manifestations of autoimmune diabetes in the presence of associated autoimmune diseases to treat and, moreover, to slow down the progress of LADA.

In conclusion, physicians should be alert for the possibility of associating autoimmune diseases in suitable clinical conditions in a patient diagnosed with an autoimmune disease. To our knowledge, this is the first case report for the coexistence of pSS, AIH and LADA in one patient.

Orhan Kocaman, MD

Cem Aygun, MD

Yesim Gurbuz, MD

Ayse Cefle, MD

Tolga Konduk, MD

Omer Senturk, MD

Altay Celebi, MD

Sadettin Hulagu, MD

Gastroenterology Division

Kocaeli University Medical Faculty Hospital

Kocaeli, Turkey

References

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2. Tuomi T, Groop LC, Zimmet PZ, et al. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 1993;42:359-362.

3. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-558.

4. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929-938.

5. Zhou Z, Li X, Huang G, et al. Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA). Diabetes Metab Res Rev 2005;21:203-208.