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Clinical significance of concomitant extrahepatic autoimmune disease in patients with autoimmune liver disease

Background and Aim: This study aimed to determine the presence of concomitant extrahepatic autoimmune disease (EAD) in patients with autoimmune liver disease (ALD) and the efficacy of the treatment response of ALD with the presence of any EAD. Materials and Methods: Between January 2001 and November 2017, 241 patients with ALD were included in the study. Results: Of the 241 patients, 88, 134, and 19 had autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and overlap syndrome (OS), respectively. Thirty-one patients had cirrhosis: 77% and 23% had compensated and decompensated disease, respectively. The presence of at least one EAD was defined in 38.6% of the patients with ALD (n=93), and 12% of them had ≥1 EAD. EAD was most commonly seen in patients with OS and PBC compared with those with AIH (p=0.036). Autoimmune thyroid disease was the most common association (20%), followed by Sjogren syndrome (12.0%). At the end of the follow-up period, 165 patients (72%) had biochemical response. The presence of EAD did not affect the biochemical response. Conclusion: EAD is most frequently seen in patients with ALD. The presence of EAD is not associated with the treatment response.


Introduction
Autoimmune liver disease (ALD) consists of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). [1] ALD may be associated with more than one subgroup as an overlap syndrome (OS). The term of OS is used to define the co-anti-nuclear antibody, anti-smooth muscle antibody, anti-liver kidney membrane-1, and anti-mitochondrial antibodies were performed. All patients underwent abdominal sonography confirming the presence of cirrhosis, its complications, and HCC. Laboratory tests were performed at diagnosis and during the follow-up period.
Definitions: EAD was defined as patients with at least one or more of the following conditions including autoimmune thyroid disease (autoimmune thyroiditis, Hashimoto's disease, Graves' disease), Sjogren's syndrome, diabetes mellitus type 1, autoimmune skin disease (alopecia, vitiligo, psoriasis, dermatitis herpetiformis), systemic lupus erythematous, celiac disease, vasculitis, rheumatoid arthritis (RA), connective tissue disease, inflammatory bowel disease, polymyositis, uveitis, systemic sclerosis, PSC, Churg-Strauss syndrome, autoimmune thrombocytopenia and autoimmune hemolytic anemia. [5][6][7][8] Biochemical response in patients with AIH was defined as a complete normalization of serum aminotransferases and immunoglobulin G levels. [9] In patients with PBC, the response criteria are based on the improvement of serum ALP, AST, and bilirubin levels after 12 months of UDCA treatment based on Paris-II criteria (ALP <1.5 × upper limit of normal [ULN], AST <1.5 × ULN, normal bilirubin). [10] Follow-up: Patients were seen at regular intervals in an outpatient clinic during the follow-up period. Cirrhosis and its complications were evaluated. Further investigations included surveillance for HCC with radiological imaging and alpha-fetoprotein determinations every 6 months. If necessary, dynamic computed tomography or magnetic resonance imaging was performed.

Statistical Analysis
Mean, standard deviation, median, minimum, maximum, frequency, and percent were used for descriptive statistics. Categorical variables were assessed using the chi-squared test. Comparison between two groups was assessed using the Mann-Whitney U test for non-normally distributed variables. A p<0.05 was considered significant.

Discussion
The present study investigated the frequency, type, and clinical significance of concomitant EAD in patients with ALD in a single tertiary center. The presence of at least one EAD was found in 39% of the pa-tients with ALD, and ≥1 EAD was observed in 12% of the patients. Female sex was predominant (96%). EAD was most commonly seen in patients with OS and PBC compared with those with AIH (p=0.036). Among the EAD, autoimmune thyroid disease was most commonly encountered (20%), followed by Sjogren syndrome (12%). This finding is compatible with previous studies, [5,7,8,[11][12][13] which reported a close association between EAD and ALD, and autoimmune thyroid disease was most frequently encountered. Because the association between AIH and EAD is well known, these results indicate that high frequency of concomitant EAD was also seen in patients with OS and PBC.
The prevalence and pattern of concomitant EAD in patients with ALD vary due to different geographical areas, genetic background, and study populations. Floreani et al. [5] reported a high prevalence of EAD (61%) in Italian patients with PBC. Several investigators previously reported the prevalence of EAD in patients with ALD between 28.3% and 43.6%. [8,11,13] In the present study, the overall prevalence of EAD in patients with ALD was 38.6%, whereas it was 43.3% in patients with PBC. These results were compatible with previous reports [8,11,13] but lower than those of the Italian group. Autoimmune thyroid disease was the most frequently observed, with a prevalence of 10% and 15%, [5,8,[11][12][13] which was similar to our results (20%). The differences mostly seen  in the pattern of the EAD. Some centers reported a high prevalence of Sjogren syndrome with/without Raynaud phenomenon and autoimmune skin disease, [5,11] the other centers did not. [8,13] The prevalence of Sjogren syndrome, Raynaud phenomenon, and autoimmune skin disease was 34%, 18%, and 5% in Italian patients with PBC, respectively. In the present study, the prevalence of Sjogren syndrome in patients with PBC was 16.4%, which was lower than that of their Italian counterparts, whereas autoimmune skin disease was not observed in patients with PBC. Unfortunately, Raynaud phenomena was not evaluated. This discrepancy may be explained by the heterogenous study population and different geographical distributions. Of note, 2.2% frequency of celiac disease was observed in patients with PBC, similar to the Italian study, which reported 1.4%. [5] Several investigators reported that the presence of EAD was not associated with treatment response, did not affect disease outcome, and were not related with the onset of major events during the follow-up period. [5,[11][12][13][14] Teufel et al. [12] reported that the presence of EAD in patients with AIH did not affect treatment response and relapse rate. In the present study, no statically significant differences among the patient groups in the treatment response based on biochemical response. The presence of EAD in patients with AIH, PBC, and OS did not affect biochemical response, disease progression, and patient survival. This finding confirms that of previous studies. [11][12][13][14] In conclusion, EAD was most frequently seen in patients with ALD. The presence of EAD was not associated with treatment response and disease progression. Asymptomatic patients with ALD may be identified as a result of the presence the EAD.