Lupus Hepatitis and Autoimmune Hepatitis (Lupoid Hepatitis)

Author’s Accepted Manuscript Lupus Hepatitis and Autoimmune Hepatitis (Lupoid hepatitis): Why do we need to Differentiate Between these two types of Hepatitis? Avinash Adiga, Kenneth Nugent www.elsevier.com

PII: DOI: Reference:

S0002-9629(16)30600-0 http://dx.doi.org/10.1016/j.amjms.2016.10.014 AMJMS316

To appear in: The American Journal of the Medical Sciences Received date: 18 July 2016 Revised date: 23 September 2016 Accepted date: 31 October 2016 Cite this article as: Avinash Adiga and Kenneth Nugent, Lupus Hepatitis and Autoimmune Hepatitis (Lupoid hepatitis): Why do we need to Differentiate Between these two types of Hepatitis?, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2016.10.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title page

Lupus hepatitis and autoimmune hepatitis (lupoid hepatitis): why do we need to differentiate between these two types of hepatitis?

Avinash Adiga MD, Kenneth Nugent MD Department of Internal Medicine, Texas tech University health Sciences Center, Lubbock, TX Corresponding author-Kenneth Nugent, 3601 4th Street, Lubbock, TX 79430; telephone-806743-6847; [email protected]

Running title- Lupus hepatitis and autoimmune hepatitis Key words- autoimmune hepatitis, system lupus erythematosus, hepatitis

Conflicts- none

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Abstract Liver dysfunction occurs in about 50% of patients with systemic lupus erythematosus (SLE), and patients with SLE and elevated liver enzymes can present a complicated and difficult differential diagnosis. Lupus hepatitis and autoimmune hepatitis are two immunological conditions involving the liver which can have similar clinical, laboratory, and systemic presentations leading to difficulties in diagnosis. Physicians need to be aware of these two hepatic diseases since diagnosis and appropriate therapy need to occur early in the disease course to prevent progression to advanced liver disease. We review the liver diseases associated with systemic lupus erythematosus and discuss the approach to the diagnostic evaluation of these patients. In particular, differentiation between lupus hepatitis and autoimmune hepatitis requires careful clinical and often histologic evaluation.

Key words-autoimmune hepatitis, system lupus erythematosus, hepatitis

Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder involving various organs, including the skin, joints, kidneys, and central nervous system. Liver involvement occurs in 50-60% patients at some point during the course of their disease.1 Thirty to fifty percent of patients have hepatomegaly, and 23.5% of patients have elevated liver enzymes.2,3,4 In many cases these elevated transaminases are due to hepatotoxic drugs, viral hepatitis, or fatty liver.5 When these causes of elevated transaminases are ruled out, primary liver diseases, such as autoimmune hepatitis (AIH) or lupus related liver disease, need to be considered.1,6 This evaluation requires careful consideration of liver diseases associated with SLE, including lupus hepatitis and SLE-overlap syndromes, and requires a thorough clinical evaluation, serology tests, and often liver biopsy.

Lupus hepatitis Hepatic dysfunction occurs frequently in SLE patients. This can reflect liver disease as a component of SLE, a liver disorder associated with another immune disease such as primary biliary cirrhosis, drug toxicity, or another unrelated diagnosis, such as viral infection (Figure 1). Transaminitis occurs in 25-59% of SLE patients during their lifetime.5,7,8,9 Since studies in the

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medical literature have often used different transaminases values to diagnose hepatic dysfunction, a wide incidence range has been noted. Drug induced hepatic dysfunction was seen in 21-31% of cases in several studies.5,8,10 One study identified aspirin as the most common drug causing toxicity.8 Increased use of immunosuppressive medications, including azathioprine, methotrexate, and antimalarial drugs, has been associated with an increased risk for liver dysfunction.10 Non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis were identified in 18-26% of patients.8,10 Viral hepatitis was found in 0.8-14% of patients.7,8 In 28 to 42% of patients, no obvious causes of liver dysfunction was found, and it was thought to be due to lupus itself. The other causes of liver dysfunction in lupus included alcohol, autoimmune hepatitis, and congestion. Liver biopsy in SLE patients with hepatic dysfunction showed fatty liver in 72.6%, nodular regenerative hyperplasia in 6.8%, viral hepatitis in 4.1%, primary biliary cirrhosis in 2.7%, and autoimmune hepatitis in 2.7% of cases.11 Matsumoto et al studied 52 autopsy liver specimens from patients with a history of lupus and found hepatic congestion (40 patients), fatty liver (38 patients), arteritis (11 patients), cholestasis (9 patients), peliosis hepatitis (6 patients), chronic persistent hepatitis (6 patients), non-specific reactive hepatitis (5 patients), and cholangiolitis(4 patients).12 Common histopathological findings in lupus hepatitis include mild portal infiltration with lymphocytes, neutrophils, and plasma cells and hydropic degeneration of liver cells; steatosis, mild cholestasis, focal necrosis, and nodular cirrhosis can also be seen.13 Strongly positive deposits of complement 1q seen with liver immunohistochemistry strongly suggest lupus hepatitis.13

Autoimmune hepatitis Autoimmune hepatitis is a chronic hepatitis of unknown etiology characterized by hepatocellular necrosis and inflammation; it affects 100,000 to 200,000 persons in the United States.14 Autoimmune hepatitis was initially called “lupoid hepatitis” by MacKay in 1959 and was originally described in Caucasians. However, it also occurs in black, Hispanic, Arab, and Japanese populations and has a worldwide distribution.15,16 It occurs more commonly in females, peaks in early adulthood, but affects all ages.14 These patients can present without symptoms and have only incidentally obtained abnormal laboratory tests or can present with acute, sometimes fulminant hepatitis. The usual presentation includes non-specific symptoms, such as nausea,

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anorexia, abdominal discomfort, and jaundice. These patients can have other concurrent immunologic diseases, such as autoimmune thrombocytopenia, autoimmune thyroiditis, synovitis, and ulcerative colitis.17 In addition, systemic connective tissue diseases, such as SLE, undifferentiated connective tissue disease, mixed connective tissue disease, and limited systemic scleroderma, have occasionally been reported in association with autoimmune hepatitis. Millian et al studied 46 patients with autoimmune hepatitis; 16 (34.8%) were also diagnosed with autoimmune connective tissue disease, including 7 with Sjogren’s disease, 6 with SLE, and 3 with rheumatoid arthritis.18 Type I autoimmune hepatitis is the classic syndrome seen in young women and is associated with marked hypergammaglobulinemia, lupoid features, and positive ANAs. Type II autoimmune hepatitis is usually seen in children and in Mediterranean populations and is associated with anti-liver and kidney microsomal antibodies and a negative ANA.19 Type III autoimmune hepatitis is associated with positive ANA, SMA, and antibodies to soluble liver antigen/liver pancreas (anti-SLA/LP). The diagnostic criteria for autoimmune hepatitis were established by the International Autoimmune Hepatitis Group (IAHG) in 1993; these criteria were revised in 1999 and in 2010 (Table 1). This system uses numerical scoring based on biochemical, serologic, and histological findings. Autoimmune hepatitis is diagnosed when typical immunological (serum autoantibodies), histological (interface hepatitis), clinical (associated autoimmune disorders), and biochemical (hypergammaglobulinemia with high IgG) features are present, and all other causes of liver disease are ruled out.20

Lupus hepatitis and lupoid hepatitis Systemic lupus erythematosus associated hepatitis (“lupus hepatitis”) and autoimmune hepatitis (“lupoid hepatitis”) are two different diseases, even though both are autoimmune disorders with polyarthralgias, hypergammaglobulinemia, and positive ANAs.21 Differentiation between lupus hepatitis and autoimmune hepatitis with extrahepatic manifestations is not easy (Figure 2). In addition, autoimmune hepatitis-SLE overlap presentations occasionally occur. Oka et al reported that 5 (3%) of 162 patients with autoimmune hepatitis met American College of Rheumatology (ACR) criteria for SLE.22 Tamai et al identified 2 patients out of 21 with autoimmune hepatitis who met these criteria.23 Runyon et al reported that 1.7% of 238 patients with SLE had chronic active hepatitis or liver cirrhosis.1 Cumali et al the determined that the

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prevalence of autoimmune hepatitis was 4.7% in SLE patients, and it increased to 19.4% in SLE patients with liver enzyme abnormalities.24 Chowdhary et al diagnosed autoimmune hepatitis in 9 SLE patients (40 total) with liver enzyme abnormalities.25 There are also case reports of minocycline-induced SLE and autoimmune hepatitis, of late onset (age 69) SLE in a patient with autoimmune hepatitis, and of myocarditis and thrombotic thrombocytopenic purpura as complications in SLE and autoimmune hepatitis overlap.26,27,28,29

Diagnostic difficulties Autoimmune hepatitis is associated with an increased risk of developing systemic connective tissue diseases. Conversely, the presence of systemic connective tissue diseases increases the risk of autoimmune hepatitis.30 Therefore, it is important to distinguish between autoimmune hepatitis and lupus hepatitis, since complications, prognosis, and therapy are different. Autoimmune hepatitis more commonly leads to end stage liver disease; SLE often leads to end stage renal disease. Patients with lupus and active hepatitis can have high scores on the AIHG diagnostic criteria, but the histology may not support this diagnosis. Consequently, autoimmune hepatitis scoring may not be accurate in SLE patients. Boberg et al reported that 88% of patients in a study fulfilled IAHG criteria for autoimmune hepatitis, but only 8% had biopsy proven autoimmune hepatitis.31 Cumali et al found that 70% of patients with SLE with liver enzyme abnormalities met IAHG criteria, but only 13.8% of the patients had autoimmune hepatitis on biopsy.24 These discrepancies indicate that liver biopsy is essential in this diagnosis and that relying on the IAHG score may lead to diagnostic errors.

Histology Several histological and clinical features differentiate autoimmune hepatitis from SLE. Liver biopsy in lupus hepatitis usually shows lobular infiltrates or occasionally periportal infiltrates with only a few lymphoid cells.32 Autoimmune hepatitis is characterized by portal mononuclear infiltrates which can invade the limiting plate, infiltrate into the surrounding lobule causing periportal piecemeal necrosis, and form rosettes of hepatocytes. With progression of disease, bridging necrosis, panlobular and multilobular necrosis, and finally cirrhosis can develop.33 Bile duct changes, such as destructive and non-destructive cholangitis and ductopenia,

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occur in 25% of patients. An extensive plasma cell infiltrate can occur, and fibrosis is present in all but mild forms of autoimmune hepatitis.34

Laboratory tests Elevated IgG and anti-nuclear antibodies levels occur in both autoimmune hepatitis and SLE.14 Anti-ribosomal P antibody is a useful serological marker to differentiate between lupus hepatitis and autoimmune hepatitis; it is positive in 44% of patients with lupus hepatitis but is absent in autoimmune hepatitis patients.35 This antibody is seen only in 10% of SLE patients without liver disease, and its positivity is associated with more severe forms of hepatitis.36 In patients with fatty liver, drug-induced hepatitis, and SLE-autoimmune hepatitis overlap syndrome, anti-ribosomal P antibodies were present only in patients with renal dysfunction or CNS lupus.35 Anti-Smith antibodies are another useful marker for lupus hepatitis. Approximately 99% of patients with positive anti-SM meet the diagnostic criteria for SLE37, but this test is limited by low sensitivity (20-30%). Positive anti-DsDNA antibodies also support the diagnosis of lupus but can be transiently elevated in autoimmune hepatitis.9 Soluble liver antigen (SLA), liver-pancreas, smooth-muscle antibody (SMA) with specificity for F-actin and microsomal autoantigens, and anti-liver kidney antibodies (anti-LKM antibody) are specific for autoimmune hepatitis and are not seen in lupus hepatitis.14

Differential diagnosis Wilson’s disease, α-1 antitrypsin deficiency, and hemochromatosis, infections (hepatitis A, B, C and CMV, EBV), and drug-induced liver injury can have autoimmune features38 and need to be considered before making a final diagnosis. Hepatitis C virus infection can present with secondary rheumatologic manifestations similar to SLE.39 ANA (10%–30%), rheumatoid factor (71%), and ASMA (66%) autoantibodies can be positive in these cases.40

Drug-induced hepatotoxicity Drug-induced hepatotoxicity is reported in 2.3% of SLE patients10 and 31% of SLE patients with overt liver dysfunction.8 Due to elevated levels of oxidative stress, patients with lupus have more frequent NSAID-induced hepatitis than normal subjects.41 Ibuprofen has the best liver safety profile among all the NSAIDs and has not caused severe liver injury in larger

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studies. Although severe liver reactions and hospitalization are uncommon with diclofenac, transaminitis occurs in about 3% of cases.42 Sulindac, nimesulide (not available in the United States), and some oxicams are associated with high rates of hepatotoxicity. Liver damage associated with COX-2 inhibitors is rare. Hepatotoxicity occurs in about 1.3% of patients on azathioprine or mercaptopurine and is usually associated with transaminitis; severe complications are rare.43 Methotrexate-induced liver toxicity is well known and has a frequency of 0.6% to 13%.42 Anti-tumor necrosis factor agents are associated with minor liver function abnormalities, and severe liver dysfunction is infrequent.

Viral hepatitis Viral infections are possible triggering events in autoimmune disorders. Chronic hepatitis C virus infection can present with systemic manifestations and can mimic SLE.44 Patients with SLE have a higher risk for viral and bacterial infections due to chronic use of corticosteroids and immunosuppressive drugs. Higher EBV viral loads are noted in lupus patients.45 Infections with hepatitis A virus, CMV virus, and herpes virus can cause hepatic dysfunction in these patients, and routine viral serology should be considered when evaluating these patients.46

Treatment The American Association for the Study of Liver Disease guidelines for treatment of autoimmune hepatitis recommend treatment only for patients with gamma globulin levels greater than twice the upper limit of normal if the aminotransferases are at least fivefold higher than the upper limit of normal and does not recommend treatment for patients with gamma globulin levels less than twice the upper limit of normal unless the aminotransferases are greater than 10fold higher than the upper limit of normal.47 The British Society of Gastroenterology guideline recommends treating autoimmune hepatitis if the serum aminotransferase levels are greater than fivefold higher than the upper limit of normal. The treatment protocol needs to be individualized based on histology, age of the patient, and the risk for progression. It is recommended to start therapy with prednisone monotherapy 60mg/day tapered to a maintenance dose. A combination of lower dose of prednisone 30mg plus azathioprine can be used in patients at risk for developing side effects with corticosteroid therapy. Systemic lupus erythematosus-autoimmune hepatitis

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overlap responds rapidly to corticosteroids, and the hepatic dysfunction improves in parallel with systemic manifestations of SLE.48

Prognosis It is important to differentiate lupus hepatitis from autoimmune hepatitis due to differences in their prognoses. Autoimmune hepatitis has a more aggressive histology pattern when compared to lupus hepatitis, and untreated symptomatic autoimmune hepatitis has a poor prognosis with a five-year survival rate below 25% in untreated patients versus 80% in those treated with corticosteroids.49 Complete remission in these patients is crucial for long term survival and quality of life. Lupus hepatitis usually responds to corticosteroids and has a benign course with no complications. Lim et al reported that overall progression of disease in autoimmune hepatitis and SLE-autoimmune hepatitis overlap was not different, but severe progression, such as hepatocellular carcinoma, liver transplant, or death, occurs only in autoimmune hepatitis patients.50

Conclusion Hepatic dysfunction is common in lupus and needs to be differentiated from drug, toxin, viral, autoimmune, and other causes of hepatitis. The immunological mechanisms associated with lupus hepatitis and autoimmune hepatitis are similar and include female predominance, genetic susceptibility, hypergammaglobulinemia, autoantibody positivity, and a response to immunosuppressive therapy (Table 2).23 Twenty-five percent of patients with autoimmune hepatitis fulfill the revised ACR criteria for SLE.51,52 The scoring system created by AIHG should be used with caution due to its high false positive rates. The presence of malar rash, pleural fluid, oral ulcers, leucopenia, proteinuria, and hypocomplementemia suggest SLE. Serology, including ribosomal P antibodies, anti-SLA, anti-SMA, and anti-LKM antibodies, help establish the diagnosis. Liver biopsies need careful review by experts when possible; lupus hepatitis has lobular infiltrates with few lymphocytes and autoimmune hepatitis has portal infiltrates with periportal piecemeal necrosis and hepatocyte rosette formation, depending on the severity of the inflammation. Bridging fibrosis, panlobular/ multilobular necrosis, and cirrhosis suggest autoimmune hepatitis. Intense deposits of complement 1q in the liver strongly suggest lupus hepatitis.12 Because of these serologic and biochemical similarities, treatment of SLE may

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disguise an underlying autoimmune hepatitis, which can lead to confusion and a delayed diagnosis. An accurate diagnosis is critical since lupus hepatitis is a benign condition, and autoimmune hepatitis is associated with a poor prognosis, higher rates of progression, and the need for aggressive therapy.

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45. Moon UY, Park SJ, Oh ST, Kim WU, Park SH, Lee SH, Cho CS, Kim HY, Lee WK, Lee SK. Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood. Arthritis Res Ther. 2004; 6:R295-302. 46. Ramos-Casals M1, Cuadrado MJ, Alba P, Sanna G, Brito-Zerón P, Bertolaccini L, Babini A, Moreno A, D'Cruz D, Khamashta MA. Acute viral infections in patients with systemic lupus erythematosus: description of 23 cases and review of the literature. Medicine (Baltimore). 2008 Nov; 87(6):311-8. 47. Czaja AJ, Freese DK. American Association for the Study of Liver Disease. Diagnosis and treatment of autoimmune hepatitis. Hepatology. 2002 Aug; 36(2):479-97. 48. Alvarez F, Berg PA, Bianchi FB, Bianchi L, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999 Nov; 31(5):929-38. 49. Kirk AP, Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut. 1980 Jan; 21(1):78-83. 50. Doo-Ho L, Seung-Hyeon B, Soo MA, Seokchan H, Yong-Gil K, Chang-Keun L and Bin Y. Autoimmune Hepatitis in Systemic Lupus Erythematosus. Meeting: 2014 ACR/ARHP Annual Meeting 51. Fries JF Siegel RC: Testing the preliminary criteria for the classification of SLE. Ann Rheum Dis. 1973 Mar; 32(2):171-7. 52. Chwalinska-Sadowska H, Mileswki B, Maldyk H. Diagnostic troubles with differentiation of systemic lupus erythematosus against chronic active hepatitis. Mater Med Pol. 1977 Jan-Mar; 9(1):60-4.

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Figure legends Figure 1. This figure provides an overview of potential diagnoses in a patient with systemic lupus who has either acute or chronic liver disease. Figure 2. This figure provides a diagnostic strategy for the evaluation of patients with hepatic disease and possible lupus hepatitis or autoimmune hepatitis.

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Table 1: Comparison of lupus hepatitis and autoimmune hepatitis ANA positivity

Lupus hepatitis Most of the patients

Autoimmune hepatitis 80% in type 1 autoimmune hepatitis Normal

Complement

Low

Anti SMA antibody

May be positive

Usually positive in type 1 autoimmune hepatitis

Anti LKM antibody

Negative

Positive in type 2 autoimmune hepatitis

Anti- liver pancreas antigen

Negative

Positive in type 3 autoimmune hepatitis

Anti- ribosomal P antibody

Positive

Negative

Histology

Lobular infiltrates with Periportal piecemeal necrosis paucity of lymphocytes. Mild and hepatocyte rosette formation. chronic inflammation. Abundant plasma cell and lymphocyte infiltrate

Progression

Benign

Progresses to cirrhosis

Prognosis

Good

5 year survival 80% in treated patients and 25% in untreated patients.

ANA, antinuclear antibody; anti- SMA, smooth muscle antibody; anti LKM, antibody to liver/kidney microsomes; AMA, antimitochondrial antibody

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Table 2: Revised Scoring system of the International Autoimmune Hepatitis Group Sex AP : (AST or ALT) ratio ϒ globulin or IgG level above normal

ANA, SMA or anti- LKM-1 titre

AMA Viral markers Drugs Alcohol HLA Immune disorders Other markers Histologic features

Treatment response

Female >3 <1.5 >2.0 1.5- 2.0 1.0- 1.5 <1.0 > 1: 80 1:80 1:40 < 1:40 Positive Positive Negative Yes No <25g/day >60g/day DR 3 or DR 4 thyroiditis, colitis anti LC-1, pANCA Anti SLA, anti actin, Interface hepatitis Plasmacytes Rosette None of the above Biliary changes Other changes Complete Relapse >15

+2 -2 +2 +3 +2 +1 0 +3 +2 +1 0 -4 -3 +3 -4 +1 +2 -2 +1 +2 +2 +3 +1 +1 -5 -3 +2 +2 +3

Pre-treatment aggregate score: definite diagnosis Probable diagnosis 10-15 Post treatment aggregate score : definite >17 diagnosis Probable diagnosis 12-17 AP: (AST or ALT) ratio, ratio of alkaline phosphatase level to aspartate or alanine aminotransferase level; IgG, immunoglobulin G; ANA, antinuclear antibody, SMA, smooth muscle antibody, anti LKM1, antibody to liver/kidney microsomes type 1; AMA, antimitochondrial antibody; HLA, human leukocyte antigen; anti LC1, antibody to liver cytosol type 1; pANCA, perinuclear anti neutrophil cytoplasmic antibody; anti SLA, antibody to soluble liver antigen.

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