Concurrent Autoimmune Diseases in Patients With Autoimmune ...

ORIGINAL ARTICLE

Concurrent Autoimmune Diseases in Patients With Autoimmune Hepatitis

Andreas Teufel, MD, PhD,* Arndt Weinmann, MD,* George J. Kahaly, MD,* Catherine Centner, MD,* Anja Piendl, MD,* Marcus Wo?rns, MD,* Ansgar W. Lohse, MD,w

Peter R. Galle, MD,* and Stephan Kanzler, MD*z

Background: Although the pathomechanisms of autoimmune diseases in various organs remain unresolved, an accumulation of autoimmune diseases in individual patients has been observed. An overlap of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or primary sclerosing cirrhosis has been well documented. However, the overlap of autoimmune diseases other than PBC or PSC has not yet been investigated in a large cohort.

Goal: The goal of our analysis was to investigate the incidence of concurrent autoimmune diseases in patients with AIH.

Study: We analyzed our cohort of 278 patients with AIH for concurrent autoimmune diseases.

Results: A total of 111 patients (40%) were diagnosed with additional autoimmune diseases. Besides overlap syndromes for PBC and PSC, autoimmune thyroiditis was the most common concurrent disease (28 patients, 10%). Other concurrent autoimmune diseases comprised vitiligo (5 patients), rheumatoid arthritis (5 patients), Sjogren syndrome (4 patients), ulcerative colitis (4 patients), conjunctivitis (4 patients), celiac disease (3 patients), systemic lupus erythematodes (2 patients), type I diabetes (2 patients), multiple sclerosis (2 patients), polymyalgia rheumatica (2 patients), and urticaria (2 patients). One patient each was diagnosed with Crohn's disease, autoimmune gastritis, collagenous colitis, hypophysitis, and sarcoidosis. Investigating 100 patients with polyglandular syndrome and autoimmune thyroid disease for the occurrence of autoantibodies associated with AIH, we identified AIH-associated antibodies only in 1 patient.

Conclusions: Concurrent autoimmune diseases are common in patients with AIH and mirror the full range of known autoimmune diseases. Therefore, an extended diagnostic screening for accumulating autoimmune diseases, especially autoimmune thyroiditis, seems reasonable in patients with AIH.

Key Words: AIH, overlap, thyroiditis, autoimmune disease

(J Clin Gastroenterol 2010;44:208?213)

The observation of a concurrence of diverse autoimmune diseases has been frequently reported. Acknowledging these concurrencies, a concept or hypothesis of shared autoimmunity has been proposed, although molecular or genetic proof is still lacking. In the context of this

Received for publication February 8, 2009; accepted October 21, 2009. From the *Department of Medicine I, Johannes Gutenberg University,

Mainz; wDepartment of Medicine I, University of Hamburg, Hamburg; and zDepartment of Medicine II, Leopoldina Hospital, Schweinfurt, Germany. This study has not been supported by any grants. None of the authors has any conflicts of interest. Reprints: Stephan Kanzler, MD, Department of Medicine II, Leopoldina Hospital, Gustav-Adolf-Str. 8, 97422 Schweinfurt, Germany (e-mail: skanzler@leopoldina.de). Copyright r 2010 by Lippincott Williams & Wilkins

concept, diverse forms of occurrence of autoimmune diseases have been discussed for developing because of a shared autoimmune mechanism. This idea was substantiated on the one hand, by the occurrence of not only a single autoimmune disease in several members of the same family, which have also been referred to as multiplex families,1,2 but rather the concurrence of diverse autoimmune diseases in several family members. In contrast, the manifestation of different autoimmune diseases in the same patient, classified as overlap syndromes, further supported this hypothesis.3 These overlap syndromes may even be composed of multiple individual autoimmune diseases. Individual cases of overlap were reported in individual patients simultaneously suffering from up to 4 organ-specific autoimmune diseases.4 These observations of frequent concurrent autoimmune diseases in patients with autoimmune hepatitis (AIH) were finally incorporated in the diagnostic score of the International Autoimmune Hepatitis Group.5

We and other investigators have earlier reported on overlap syndromes of AIH with primary biliary cirrhosis (PBC) or primary sclerosing cirrhosis (PSC) and the epidemiologic details on these overlap syndromes as well as their clinical course.6?9 These AIH/PBC and AIH/PSC overlap syndromes are frequent and it was estimated that AIH/PBC overlap diseases may occur in their full manifestations in about 10% to 20% of cases and AIH/PSC overlap with a frequency of 2% to 8% of patients.6

In contrast, only very limited data exist on the frequency of concurrent autoimmune diseases other than PBC or PSC in larger collectives. The largest reported collective to be investigated for the wide variety of associated autoimmune diseases so far contained 38 patients.10 Furthermore, most reports on simultaneously occurring autoimmune diseases in patients with AIH have mainly been focussing on individual diseases simultaneously occurring with AIH, mostly as single case reports (Table 1).

At present, an analysis of a large cohort of patients with AIH has not yet been reported. Thus, the aim of our study was to investigate our large collective of 278 patients with AIH (including patients with overlap syndromes of PBC and PSC) to further elucidate the incidence of diverse individual autoimmune diseases in patients with AIH. Results of this study may be of significant value with respect to the diagnosis of associated autoimmune diseases as frequently associated autoimmune diseases may become part of the initial screening in patients with newly diagnosed AIH.

MATERIALS AND METHODS

Study Cohort Two hundred and seventy-eight patients satisfied the

international criteria for the diagnosis of AIH.78 All patients

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Concurrent Autoimmune Diseases in ATH

TABLE 1. Summary on Concurrent Disease in Patients With Autoimmune Hepatitis Reported in Individual Case Reports

Disease

References

Addison disease Anticardiolipin antibody syndrome Antiphospholipid antibody syndrome

Atrophic gastritis Autoimmune hemolytic anemia Autoimmune hyperlipidemia Autoimmune pancreatitis Celiac disease

Colitis ulcerosa Cryoglobulinemia Erythema annulare Felty syndrome Glomerulonephritis Grave disease Inflammatory bowel disease Lupus erythematodes

Mixed connective tissue disease Mononeuritis multiplex Multiple sclerosis Myasthenia gravis Panniculitis Polyglandular autoimmune syndrome Rheumatic diseases Sjogren syndrome

Systemic sclerosis Thrombotic thrombocytopenic purpura Thymoma Thyroiditis Thyrotoxicosis Uveitis

Bergwitz et al11; Tauchmanova et al12 Gurudu et al13 Dourakis et al14; Hadjigogos and Marinaki15; Hueber et al16;

Linares et al17; Pathmakanthan et al18; Sema et al19 Bergwitz et al11 Gurudu et al13 Rumbo et al20 Gaburri et al21 Arvola22; Biecker et al23; Bridoux-Henno et al24; Caiulo et al25;

Csak et al26; Maggiore and Caprai27 Cronin et al28; Linares et al17 Biecker et al23 Gulati et al29 Inaba et al30; Sema et al19 Takahashi et al31 Cui et al32; Inoue et al33; Nagai et al34 Seibold et al35 Angulo et al36; Fujiwara et al37; Iwai et al38; Kaw et al39;

Kooy et al40; Moriwaki et al41; Satoh et al42; Shoenfeld et al1; Suzuki et al43; Takahashi et al44; Tojo et al45; Usta et al46; Yamasaki et al47 Maeda et al48 Luth et al49 de Seze et al50 Han et al51 Allen-Mersh52 Oki et al53; Smith et al54 Czaja et al55; Nobili et al56 Biasi et al57; Hoshino et al58; Katayama et al59; Lee et al60; Matsumoto et al61; Ramos-Casals et al62; Wada et al63; Wanchu et al64 Marie et al65; Lis-Swiety et al66; Ishikawa et al67 Shibuya et al68; Yamaike et al69 Asakawa et al4; Han et al51 Bergwitz et al11; Nagai et al70; Nobili et al71; Salvi et al72; Tomsic et al73; Soy et al74 Arvola et al22 Bloom et al75; Kamal et al76; Romanelli et al77

that matched these criteria were included. All patient records were manually searched for indications of concurrent autoimmune diseases. Primary care physicians were not contacted. Of these 278 patients, 229 (82%) were women and 49 (18%) were men. Median age at diagnosis was 46 years, ranging between 10 and 82 years. Most of these patients were white. Further demographic data were not available for all patients. They had been enrolled in our chronic liver disease program from 1970 until present. All patients had been followed in a uniform manner up to 34 years. On the basis of immunoserologic assessment for autoantibodies, 206 patients were assessable for a subtype of AIH. Of these, 194 patients (94%) were classified as type-1 AIH because of positive anti nuclear antibodies (ANA), or anti-SLA/LP autoantibodies.55,79 Twelve (6%) patients had elevated liver kidney microsome (LKM) autoantibodies, characteristic of type-2 AIH.80 Seventy-two patients had no detectable autoantibodies, but nevertheless fulfilled the AIH criteria.

Diagnosis of overlap syndrome was made according to the diagnostic criteria of the involved diseases. For PBC, these criteria were generally AMA (AMA-M2) titer higher than 1:80, elevated IgM, and histology. For PSC, these criteria generally were also histology and typical findings in endoscopic retrograde cholangio pancreatography. Followup was usually maintained at 3-month or 6-month intervals during treatment discontinuation and for at least 1 year after treatment. Thereafter, follow-up assessments were made at annual intervals, if the clinical condition was stable.

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Immunoserologic Assessments SMA, ANA, and LKM were analyzed by indirect

immunofluorescence on murine tissue sections as described earlier. Anti-SLA/LP was analyzed by inhibition enzymelinked immunosorbent assay.79 A serum titer of 1:80 or higher was considered positive for ANA.55 A titer of 1:40 or higher was considered positive for SMA and anti-LKM-1. All patients were tested for SMA and ANA and 193 patients (91%) were tested for anti-LKM-1. Patients with SMA and/or ANA in the absence of anti-LKM-1 were classified as type-1 AIH. Patients with anti-LKM1 were classified as type-2 AIH. These immunologic assessments for the above antibodies associated with AIH were made the same way in patients with autoimmune thyroid disease as a screening test for AIH in these patients.

Screen for Concurrent Autoimmune Diseases in Patients With AIH

All available medical records from the archive of the Department of Medicine I of the University of Mainz have been manually searched for evidence/notes of concurrent diseases.

Screening for AIH in Patients With Autoimmune Thyroiditis

Since 1988, more than 15,000 patients with endocrine diseases have been screened for polyglandular autoimmune syndromes (PAS) at our institution. A total of 360 patients

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were positive for PAS II and have been followed regularly since 1990. In these patients, quantitative enzyme immunoassay (Immunoradiometric assay method; Brahms, Berlin, Germany) was used to test for the presence of autoantibodies against thyroid-stimulating hormone receptor. Enzymelinked immunosorbent assay (Pharmacia/Upjohn GmbH, Freiburg, Germany) was applied for autoantibodies against thyroid peroxidase, thyroglobulin (positive, >100 IU/mL), and glutamic acid decarboxylase (positive, >1500 U/mL). Analysis of clinical data showed that, taken together, both autoimmune thyroid diseases had the highest prevalence (n = 99; 65.6%), with equal numbers of Graves disease (n = 50; 33.1%) and autoimmune thyroiditis (n = 49; 32.5%).81,82 Sera of these patients were chosen for further evaluation of antibodies associated with AIH. Antibody screening was done as described above.

RESULTS In our cohort of 278 patients with AIH, a total of 111 patients (40%) were diagnosed with additional autoimmune diseases. Besides overlap syndromes for PBC and PSC, autoimmune thyroiditis was the most common concurrent disease, diagnosed in 28 patients (10%). Other concurrent autoimmune diseases comprised vitiligo (5 patients, 1.8%), rheumatoid arthritis (5 patients, 1.8%), Sjogren syndrome (4 patients, 1.4%), ulcerative colitis (4 patients, 1.4%), conjunctivitis (4 patients, 1.4%), celiac disease (3 patients, 1.1%), systemic lupus erythematodes (2 patients, 0.7%), type I diabetes (2 patients, 0.7%), multiple sclerosis (2 patients, 0.7%), polymyalgia rheumatica (2 patients, 0.7%), and urticaria (2 patients, 0.7%). One patient each was diagnosed with Crohn's disease, autoimmune gastritis, collagenous colitis, hypophysitis, and sarcoidosis (0.4% each) (Table 2). Besides the incidence of concurrent autoimmune diseases in patients with AIH, we further investigated whether simultaneous occurrence of other autoimmune diseases in these patients was correlated with a more aggressive course of the disease. Thus, as a measure of aggressiveness of the disease we examined the rates of relapses of AIH in these patients and compared the group of patients with concurrent other autoimmune diseases with those not showing any concurring autoimmune diseases. However, no significant differences in the number of relapses were observed between these 2 groups. Of the 167 patients suffering from AIH but not from other autoimmune diseases, 62 (35%) suffered at least 1 relapse of the disease. Of the 111 AIH patients with additional autoimmune diseases, 52 (47%) suffered at least 1 relapse (P = 0.25, 2-tailed Fisher test). Furthermore, recurrences in patients with AIH/PBC or AIH/PSC overlap syndromes were also shown not to differ significantly, depending on additional autoimmune diseases. In 56 patients with AIH/PBC or AIH/PSC overlap syndromes without further autoimmune diseases, 25 (44%) showed at least 1 recurrence of the disease. Similarly, 11 (61%) of 18 patients with AIH/PBC or AIH/PSC overlap syndromes and additional autoimmune diseases suffered from recurrent AIH (P = 0.5, 2-tailed Fisher's test, Table 3). However, our data showed a trend toward higher recurrence in patients with additional autoimmune diseases, which may need to be further addressed in the future (47% vs. 35% for AIH and 61% vs. 44% for overlap syndromes AIH/PBC or AIH/PSC only). Also comparing the rate of cirrhosis in patients with or without concurrent auto-

TABLE 2. Concurrent Autoimmune Diseases in Our Cohort of 278 Patients With Autoimmune Hepatitis

Concurrent Autoimmune Diseases

No. Patients Percentage

Total no. concurrent autoimmune diseases 140

Total patients with concurrent autoimmune 111*

40*

diseases

AIH/PBC or AIH/PSC overlap

72

26

Autoimmune thyroid diseases

Hashimoto thyroiditis

20

7.2

Grave disease

5

1.8

Unspecified autoimmune thyroiditis

3

1.1

Vitiligo

5

1.8

Rheumatoid arthritis

5

1.8

Sjogren syndrome

4

1.4

Ulcerative colitis

4

1.4

Conjunctivitis

4

1.4

Celiac disease

3

1.1

Systemic lupus erythematodes

2

0.7

Type I diabetes

2

0.7

Multiple sclerosis

2

0.7

Polymyalgia rheumatica

2

0.7

Urticaria

2

0.7

Crohn's disease

1

0.4

Autoimmune gastritis

1

0.4

Collagenous colitis

1

0.4

Hypophysitis

1

0.4

Sarcoidosis

1

0.4

Overlap to PBC and PSC included 29 patients presented with more than 1 concurrent autoimmune disease.

*29 patients presented with more than 1 concurrent autoimmune disease. AIH indicates autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

immune diseases did not reveal any significant differences (Fisher test, P = 0.1).

As autoimmune thyroiditis was found to be by far the most prevalent concurrent autoimmune disease other than PBC or PSC in patients with AIH, we investigated the prevalence of AIH in patients with autoimmune thyroiditis. To assess the prevalence of autoimmune liver infection in patients with immunothyroiditis, autoantibodies associated with autoimmune liver disease (ANA, SMA, LKM, antiSLA/LP) were investigated in 100 patients with PAS and autoimmune thyroiditis. Some of these patients suffered from additional endocrine diseases. However, of these only in 1 patient were ANA autoantibodies shown to be elevated in the serum. Thus, in contrast to our patients with AIH, in patients with PAS and autoimmune thyroiditis no significant concurrent liver infection, and therefore no correlation to AIH, was observed.

DISCUSSION Accumulation of autoimmune diseases in individual patients has been observed earlier and the association of AIH with PBC or PSC repeatedly has been well documented.6?9 However, the association of AIH with autoimmune diseases other than PBS or PSC has only rarely been described, mostly as single case reports. Summarizing these case reports, AIH may be observed to overlap with the full variety of known autoimmune diseases from localized autoimmune diseases, such as uveitis, to systemic autoimmune disorders such as lupus erythematodes or systemic

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TABLE 3. Recurrence of Autoimmune Hepatitis in Patients With Concurrent Autoimmune Disease Versus Patients Not Demonstrating Symptoms of Concurrent Autoimmune Disease

Recurrence With Concurrent Disease

Recurrence Without Concurrent Disease

AIH AIH/PBC,

AIH/PSC

47% (52/111) 61% (11/18)

35% (60/167) 46% (25/54)

AIH indicates autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

sclerosis. Thus, we investigated the incidence of concurrent autoimmune diseases in our large cohort of 278 patients with AIH. In our cohort of 278 patients with AIH a total of 111 patients (40%) were diagnosed with additional autoimmune diseases. This frequency of associated autoimmune diseases was approximately in range with the frequency observed by Choudhuri et al10 who had reported on associated autoimmune diseases in 39% from a much smaller cohort. From these analyses it became clear that, in general, association of AIH with other autoimmune diseases is common. It must be acknowledged, however, that many diagnoses were made by general practitioners regularly treating these patients, as we see most of them on a consultant basis. Thus, many of the concurrent autoimmune diseases were reported to us on subsequent visits through documents from other hospitals. As these patients did not undergo a systematic search for concurrent autoimmune diseases, there may be an additional number of undetected cases and thus the real number of concurrent autoimmune diseases may even be higher.

Extracting overlap syndromes of AIH to PBC or PSC from the analysis, we still observed 68 additional autoimmune diseases in these patients. By far the most common of these autoimmune diseases other than PBC or PSC in patients with AIH was autoimmune thyroiditis. This finding was again shared by Choudhuri et al10 who found thyroiditis in approximately 8% of patients with respect to a smaller number of their cohort. The higher incidence of associated type I diabetes (4 patients, 11%) was not met by our patient cohort, which may be attributed to the low overall number and resulting sampling error of patients in the study by Choudhuri et al.10 As approximately 10% of the patients with AIH exhibit autoimmune thyroid disease it seems reasonable to recommend routine screening for autoimmune thyroid disease in patients with AIH. Interestingly, all patients suffering from AIH and autoimmune thryoiditis were women. It remains to be investigated further whether this condition of both autoimmune diseases develops in women only. The pathophysiologic reasons for this high rate of patients showing an overlap to immunothyroiditis remain to be investigated further. As one may speculate on a potential cross reactivity of the respective antibodies to cause other autoimmune diseases, and especially immunothyroiditis, we investigated the occurrence of these antibodies in patients suffering from PAS and immunothyroiditis. However, despite the high association of autoimmune thyroid disease in patients with AIH screening did not reveal any commonly associated liver disease in these patients.

However, the most common overlap syndromes with other autoimmune diseases were overlap of PBC or PSC,

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with a total of 72 (26%) patients suffering from overlapping autoimmune liver disease. These figures were absolutely in the range reported earlier by Dienes et al,6 who had estimated that AIH/PBC overlap diseases may occur simultaneously in their full manifestations in about 10% to 20% of cases and AIH/PSC overlap, with a frequency of 2% to 8% in patients with PSC.

Besides autoimmune thyroid diseases, concurrent autoimmune diseases in these patients exhibited the full range of diversity of autoimmunity from localized autoimmune diseases such as Sjogren syndrome to generalized autoimmune diseases such as systemic lupus erythematodes. These findings again mirror the reported assembly of individual case reports describing the association of individual autoimmune diseases with AIH.

With autoimmune diseases affecting more than a single organ, the liver in particular, one may think of a more aggressive susceptibility toward autoimmune diseases. Such a rather aggressive clinical course of (some) overlap syndromes, despite a response of clinical manifestations to standard treatment, had been suggested earlier in the context of autoimmune rheumatic disease.3 Thus, we further investigated whether concurrence of additional autoimmune diseases in these patients was correlated with a more aggressive course of the disease. As a measure of aggressiveness of the disease, we examined the rates of relapse of AIH in these patients. However, compared with patients without other associated autoimmune diseases, we were not able to show a significantly higher rate of recurrence. Therefore, it must be concluded from our present data that the concurrence of additional autoimmune diseases in patients with AIH does not alter the clinical course or severity of AIH. However, in all subsets a trend toward a higher recurrence in patients with additional autoimmune diseases was observed. Thus, this issue may need further evaluation in larger multicenter studies.

CONCLUSIONS We conclude that association of additional autoimmune diseases other than PBC or PSC in patients with AIH is common. Association of further autoimmune disease was not significantly correlated with a more severe course or increased recurrence of disease. However, as a trend toward higher recurrence was observed, this may need further investigation. The most commonly associated disease besides PBC or PSC was immunothyroiditis. Thus, it must be regarded mandatory to recommend routine screening for immunothyroiditis in patients with AIH.

REFERENCES

1. Shoenfeld Y, Slor H, Shafrir S, et al. Diversity and pattern of inheritance of autoantibodies in families with multiple cases of systemic lupus erythematosus. Ann Rheum Dis. 1992;51: 611?618.

2. Slor H, Shafrir S, Isenberg DA, et al. The genetics of autoimmunity: the familial tendency of systemic lupus erythematosus. Isr J Med Sci. 1989;25:678?682.

3. Rodriguez-Reyna TS, Alarcon-Segovia D. Overlap syndromes in the context of shared autoimmunity. Autoimmunity. 2005;38: 219?223.

4. Asakawa H, Kashihara T, Fukuda H, et al. A patient with thymoma and four different organ-specific autoimmune diseases. Neth J Med. 2002;60:292?295.

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Teufel et al

J Clin Gastroenterol Volume 44, Number 3, March 2010

5. 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.

6. Dienes HP, Erberich H, Dries V, et al. Autoimmune hepatitis and overlap syndromes. Clin Liver Dis. 2002;6:349?362, vi.

7. Silveira MG, Lindor KD. Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases. Expert Rev Gastroenterol Hepatol. 2007;1:329?340.

8. Rust C, Beuers U. Overlap syndromes among autoimmune liver diseases. World J Gastroenterol. 2008;14:3368?3373.

9. Beuers U, Rust C. Overlap syndromes. Semin Liver Dis. 2005; 25:311?320.

10. Choudhuri G, Somani SK, Baba CS, et al. Autoimmune hepatitis in India: profile of an uncommon disease. BMC Gastroenterol. 2005;5:27.

11. Bergwitz C, Brabant G, Trautwein C, et al. A patient with autoimmune hepatitis type I, Addison's disease, atrophic thyroiditis, atrophic gastritis, exocrine pancreatic insufficiency, and heterozygous alpha1-antitrypsin deficiency. Am J Gastroenterol. 2002;97:1050?1052.

12. Tauchmanova L, Rossi R, Coppola A, et al. Antiphospholipid syndrome, adrenal failure, dilated cardiomyopathy and chronic hepatitis: an unusual manifestation of multiorgan autoimmune injury? Eur J Endocrinol. 1998;139:641?645.

13. Gurudu SR, Mittal SK, Shaber M, et al. Autoimmune hepatitis associated with autoimmune hemolytic anemia and anticardiolipin antibody syndrome. Dig Dis Sci. 2000;45: 1878?1880.

14. Dourakis SP, Michael AE, Papanikolaou IS, et al. Autoimmune hepatitis associated with the antiphospholipid syndrome. Eur J Gastroenterol Hepatol. 2001;13:591?593.

15. Hadjigogos K, Marinaki P. Autoimmune hepatitis and the antiphospholipid antibody syndrome. A case report. Panminerva Med. 2003;45:223?224.

16. Hueber AJ, Boxberger F, Ganslmayer M, et al. Antiphospholipid syndrome in combination with autoimmune hepatitis. Eur J Gastroenterol Hepatol. 2005;17:241?243.

17. Linares P, Vivas S, Olcoz JL. Autoimmune hepatitis associated with the antiphospholipid syndrome and ulcerative colitis. Eur J Intern Med. 2005;16:376.

18. Pathmakanthan S, Kay EW, Murray FE. Autoimmune chronic active hepatitis associated with the presence of antiphospholipid antibodies. Eur J Gastroenterol Hepatol. 1998;10:155?157.

19. Sema K, Takei M, Uenogawa K, et al. Felty's syndrome with chronic hepatitis and compatible autoimmune hepatitis: a case presentation. Intern Med. 2005;44:335?341.

20. Rumbo C, Betzhold J, Merati S, et al. Autoimmune hyperlipidemia in a child with autoimmune hepatitis. J Clin Gastroenterol. 2002;35:196?199.

21. Gaburri PD, Chebli JM, Quinet de Andrade Perez LV, et al. Autoimmune pancreatitis and hepatitis: an uncommon association. Am J Gastroenterol. 2000;95:2391?2394.

22. Arvola T, Mustalahti K, Saha MT, et al. Celiac disease, thyrotoxicosis, and autoimmune hepatitis in a child. J Pediatr Gastroenterol Nutr. 2002;35:90?92.

23. Biecker E, Stieger M, Zimmermann A, et al. Autoimmune hepatitis, cryoglobulinaemia and untreated coeliac disease: a case report. Eur J Gastroenterol Hepatol. 2003;15:423?427.

24. Bridoux-Henno L, Dabadie A, Briard D, et al. A case of celiac disease presenting with autoimmune hepatitis and erythroblastopenia. J Pediatr Gastroenterol Nutr. 2001;33:616?619.

25. Caiulo VA, Averbene C, Olmi S, et al. Celiac disease associated with chronic autoimmune hepatitis. Description of a case. Minerva Pediatr. 1993;45:511?513.

26. Csak T, Folhoffer A, Horvath A, et al. Holmes-Adie syndrome, autoimmune hepatitis and celiac disease: a case report. World J Gastroenterol. 2006;12:1485?1487.

27. Maggiore G, Caprai S. Liver involvement in celiac disease. Indian J Pediatr. 2006;73:809?811.

28. Cronin EM, Sibartie V, Crosbie OM, et al. Autoimmune hepatitis in association with lymphocytic colitis. J Clin Gastroenterol. 2006;40:648?650.

29. Gulati S, Mathur P, Saini D, et al. Erythema annulare centrifugum with autoimmune hepatitis. Indian J Pediatr. 2004;71: 541?542.

30. Inaba H, Komatsu T, Shimizu K, et al. A case report of autoimmune hepatitis with Felty's syndrome. Nippon Shokakibyo Gakkai Zasshi. 1995;92:1876?1881.

31. Takahashi K, Takasaki S, Morita C, et al. Autoimmune hepatitis with membranous glomerulonephritis. J Gastroenterol Hepatol. 2001;16:356?359.

32. Cui B, Abe M, Hidata S, et al. Autoimmune hepatitis associated with Graves' disease. Intern Med. 2003;42:331?335.

33. Inoue K, Okajima T, Tanaka E, et al. A case of Graves' disease associated with autoimmune hepatitis and mixed connective tissue disease. Endocr J. 1999;46:173?177.

34. Nagai T, Imamura M, Kamiya Y, et al. Graves' disease accompanied by anti-myeloperoxidase antibody-related nephropathy and autoimmune hepatitis. Intern Med. 2004;43:516?520.

35. Seibold F, Weber P, Jenss H, et al. Autoimmune hepatitis in inflammatory bowel disease: report of two unusual cases. Z Gastroenterol. 1997;35:29?32.

36. Angulo JM, Sigal LH, Espinoza LR. Coexistent minocyclineinduced systemic lupus erythematosus and autoimmune hepatitis. Semin Arthritis Rheum. 1998;28:187?192.

37. Fujiwara K, Kono T, Ishii M, et al. Lupus erythematosus panniculitis in a patient with autoimmune hepatitis. Acta Derm Venereol. 2000;80:373?375.

38. Iwai M, Harada Y, Ishii M, et al. Autoimmune hepatitis in a patient with systemic lupus erythematosus. Clin Rheumatol. 2003;22:234?236.

39. Kaw R, Gota C, Bennett A, et al. Lupus-related hepatitis: complication of lupus or autoimmune association? Case report and review of the literature. Dig Dis Sci. 2006;51:813?818.

40. Kooy A, de Heide LJ, Engelkens HJ, et al. Hepatitis in a patient with SLE: is it autoimmune hepatitis? Neth J Med. 1996;48:128?132.

41. Moriwaki Y, Maebo A, Yamade W, et al. Autoimmune hepatitis or hepatic involvement in SLE??A case report. Gastroenterol Jpn. 1987;22:222?227.

42. Satoh T, Hirakata M, Yoshida T, et al. Systemic lupus erythmatosus associated with autoimmune hepatitis two cases with novel autoantibodies to transfer RNA-related antigens. Clin Rheumatol. 1997;16:305?309.

43. Suzuki K, Matsuki Y, Hidaka T, et al. Double filtration plasmapheresis in a patient with autoimmune hepatitis-systemic lupus erythematosus overlap. Intern Med. 1993;32:725?729.

44. Takahashi A, Rai T, Onizawa M, et al. Autoimmune hepatitis complicated by late-onset systemic lupus erythematosus. Hepatol Res. 2007;37:771?774.

45. Tojo J, Ohira H, Abe K, et al. Autoimmune hepatitis accompanied by systemic lupus erythematosus. Intern Med. 2004;43: 258?262.

46. Usta Y, Gurakan F, Akcoren Z, et al. An overlap syndrome involving autoimmune hepatitis and systemic lupus erythematosus in childhood. World J Gastroenterol. 2007;13: 2764?2767.

47. Yamasaki S, Origuchi T, Nakata K, et al. Autoimmune hepatitis in a patient with systemic lupus erythematosus: a case report. Mod Rheumatol. 2004;14:169?173.

48. Maeda M, Kanayama M, Hasumura Y, et al. Case of mixed connective tissue disease associated with autoimmune hepatitis. Dig Dis Sci. 1988;33:1487?1490.

49. Luth S, Birklein F, Schramm C, et al. Multiplex neuritis in a patient with autoimmune hepatitis: a case report. World J Gastroenterol. 2006;12:5396?5398.

50. de Seze J, Canva-Delcambre V, Fajardy I, et al. Autoimmune hepatitis and multiple sclerosis: a coincidental association? Mult Scler. 2005;11:691?693.

51. Han YS, Kim BH, Kim TH, et al. Autoimmune hepatitis in a patient with myasthenia gravis and thymoma?a report on the first case in Korea. Korean J Intern Med. 2000;15:151?155.

52. Allen-Mersh TG. Weber-Christian panniculitis and autoimmune disease: a case report. J Clin Pathol. 1976;29:144?149.

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