Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: An Italian multicentre study

Accepted Manuscript Title: Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: an Italian multicentre study Author: Paolo Muratori Marco Carbone Giorgia Stangos Lisa Perini Claudine Lalanne Vincenzo Ronca Nora Cazzagon Giampaolo Bianchi Marco Lenzi Annarosa Floreani Pietro Invernizzi Luigi Muratori PII: DOI: Reference:

S1590-8658(18)30213-5 https://doi.org/doi:10.1016/j.dld.2018.02.015 YDLD 3679

To appear in:

Digestive and Liver Disease

Received date: Revised date: Accepted date:

19-10-2017 21-2-2018 23-2-2018

Please cite this article as: Muratori P, Carbone M, Stangos G, Perini L, Lalanne C, Ronca V, Cazzagon N, Bianchi G, Lenzi M, Floreani A, Invernizzi P, Muratori L, Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: an Italian multicentre study, Digestive and Liver Disease (2018), https://doi.org/10.1016/j.dld.2018.02.015 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 proof before it is published in its final 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.

Title: Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: an Italian multicentre study

cr

ip t

Running title: AIH and the acute onset

Authors: Paolo Muratori1,4 (corrisponding author), Marco Carbone2,

us

Giorgia Stangos1, Lisa Perini3, Claudine Lalanne1,4, Vincenzo Ronca2, Nora Cazzagon3, Giampaolo Bianchi1,4 Marco Lenzi1,4,

M

an

Annarosa Floreani3, Pietro Invernizzi2, Luigi Muratori1,4

1

Center for the Study and Treatment of Autoimmune Diseases of the

d

Liver and Biliary System, 4Centro  di  Ricerca  per  lo  Studio  delle 

Ac ce p

Italy.

te

Epatiti Policlinico di Sant'Orsola, University of Bologna, Bologna,

2

Division of Gastroenterology and Center for Autoimmune Liver

Diseases, Department of Medicine and Surgery, University of MIlanBicocca, Milan Italy 3

Department of Surgery, Oncology and Gastroenterology, University

of Padova, Padova, Italy.

Keywords: Liver, autoimmune disease

1

Page 1 of 23

Introduction Autoimmune hepatitis (AIH) represents a chronic inflammatory liver

ip t

disease of unknown etiology characterized by the presence of

cr

autoantibodies, hypergammaglobulinemia with specific IgG increase and interface hepatitis on liver histology (1).

presentation

expressions, to

ranging

pictures

of

from

totally

an

phenotypic

us

From the clinical standpoint, the onset of AIH can have different

hepatic

cirrhosis

asymptomatic with

relative

M

complications (2,3). Between these two extremes, there are

d

intermediate conditions, such as the chronic onset of disease (4,5),

te

disease flares linked to toxic/infective overlapping (6) or pictures of AIH subsequent to a liver transplant (7-9). In particular the acute

Ac ce p

presentation of AIH may contain two different clinical entities, one is the acute exacerbation of chronic AIH and the other is the genuine acute AIH without chronic histological changes. (10-12). other hand, autoimmune flares driven by

On the

immuno-modulatory

therapies such as interferon for hepatitis C (13-16), are no longer observed, thanks to the implementation of HCV-specific direct acting antiviral molecules (17). A very small number of AIH can present with a severe/fulminant onset, with early encephalopathy and

2

Page 2 of 23

coagulopathy, development of acute hepatic failure and the urgent need for liver transplantation (18-21). Under a diagnostic profile, numerical scores have been proposed by

ip t

a panel of experts of the International Autoimmune Hepatitis Group

cr

in order to reach a diagnosis of AIH (22, 23). They involve several parameters (autoantibodies, hypergammaglobulinemia, histology)

us

which, in the case of acute onset, can either be lacking

an

(hypergammaglobulinemia and autoantibodies) (24-27) or not applicable (hepatic biopsy due to coagulative problems) (20,21);

M

furthermore when the liver biopsy can be performed in the acute

d

cases the histological findings can be completely different from

te

those usually found in the chronic cases. It should also be pointed out that, since the scores have not been validated for these

Ac ce p

conditions (28-30), as frequently happens in medicine, evaluation and clinical judgment remain essential conditions in the diagnostic pathway.

Studies regarding the acute onset of AIH have often started from histological data (data which is therefore not objective) (8,31-39),

making the selection criteria uncoordinated and controversial, effectively impeding comparison between the different results (8,3139).

3

Page 3 of 23

The aim of our study was to analyze retrospectively the clinical features and the prognostic significance of acute onset AIH in a wide and well-characterized series of Italian patients, enrolled in

cr

ip t

three tertiary referral Centers.

Patients and Methods

us

This is a retrospective multicenter Italian study involving the

an

Universities of Bologna, Padua and Milan Bicocca with a total of 479 patients recruited in the last 17 years; all the patients had been

M

diagnosed with AIH on the basis of the diagnostic criteria of the

d

International Autoimmune Hepatitis Group; in particular, in all

te

patients, viral and other notable causes of liver disease (HCV, HBV, citomegalovirus, Ebstein Barr virus, abuse of alcohol, deficit of both

Ac ce p

ceruplasmin and alfa -1 antitripsin, high serum level of ferritin) were excluded. HEV was researched for only in up 30% of patients since many

patients

have

been

diagnosed

as

AIH

before

the

standardization of research kit and overall the low prevalence of the disease in this latitude. Furthermore, the pharmacological anamnesis was negative for all potential hepatotoxic drugs. 154 out of 324 patients from University of Bologna have been already included in our previous clinical study (2). 4

Page 4 of 23

Clinically, the presentation of AIH was arbitrarily defined as “acute” when there was evidence of acute hepatitis with jaundice and, under the laboratory profile, when transaminases 10 times the normal limit

ip t

(from now on called 10X) and/or a value of total bilirubin greater

cr

than 5 mg/dl were found. At the same time, the presentation was defined as “chronic” when non specific symptoms were present, and

us

were not directly and primarily attributable to chronic liver disease

an

(asthenia, weight loss, amenorrhea, fever, nausea, loss of appetite) and as “asymptomatic” when, during screening examinations, an

M

increase in transaminases or bilirubin was found in the absence of

d

other symptoms (2bis). In both these categories of patients the

<

5

te

transaminases were under 10X the normal limit and the bilirubin was mg/dl.

The

patients

were

monitored

with

Ac ce p

trimestral/semestral/annual office control visits/hospital admittance according to clinical necessity.

Histology

Two hundred and ninety-eight patients out of 479 (62%) had a liver biopsy at the time of diagnosis; in those patients, interface hepatitis with lymphomonocyte infiltration and the presence of plasma cells were found, thus fulfilling the criteria for a histological diagnosis compatible with AIH (21). 5

Page 5 of 23

A histological diagnosis of cirrhosis required the presence of F5-F6 fibrosis according to the Ishak’s score (40). 10 of 181 patients without a liver biopsy had a clinical cirrhosis evaluated on the basis

ip t

of reduced platelet count, portal hypertension at ultrasound

cr

evaluation and presence of esophageal varices at endescopy. Many patients lacked of liver biopsy because in part they refused it, in part

us

there were coagulative contraindications and in some cases the

an

therapy was started without liver biopsy for medical decision. However, all the 181 patients for whom liver histology was not

M

available, fulfilled the remaining criteria for AIH diagnosis (positive

liver

disorders

and

a

favourable

response

to

te

other

d

liver autoimmune serology, increased IgG, exclusion of viral and

immunosuppression).

Ac ce p

Serology

Sera were tested using indirect immunofluorescence on rat tissue,

as previously described, to search for the following reactivities: anti-

nuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), anti-liver-kidney microsomal antibodies, anti-liver cytosol (LC1)

antibodies and anti-mitochrondrial antibodies (AMA) (41-43). A titre over 1:40 was considered positive.

6

Page 6 of 23

Soluble liver antigen (SLA) antibodies were searched for with the ELISA test using commercial kits (Euroimmun, Lubecca Germany) (44).

ip t

Treatment

cr

All patients with AIH received conventional treatment with corticosteroids and azatioprine (2,45). In particular, once the was

established,

the

therapeutic

regimen

us

diagnosis

with

an

prednisolone or prednisone started at the dosage of 0.5-1 mg/kg/day for the first 4 weeks with a subsequent slow progressive

M

reduction of the steroid (reduction of 4-6 mg after every 4-6 weeks

d

of therapy in according with transaminases serum levels); after the

te

first four weeks of therapy, azathioprine was added. According to the IAIH guidelines (45,46) patients who normalized

Ac ce p

transaminases and IgG levels within the six months from the start of

therapy were considered “responders”, whereas patients who still maintained transaminase levels higher than the upper normal limit,

but less than 2X were considered to have an incomplete response and those having levels higher than 2X were considered to have non response (2,45).

Disease progression

7

Page 7 of 23

The clinical stage of the disease was evaluated at presentation, and the following steps of disease progression were considered during follow-up:

ip t

- biochemical remission and clinical stability (considered for each patient)

(reduced

platelet

count,

portal

cr

- biochemical, instrumental progression towards liver cirrhosis hypertension

at

ultrasound

us

evaluation, development of esophageal varices at endoscopy) considered only for non cirrhotic patients at presentation

an

- progression towards the clinical complications of cirrhosis (digestive hemorrhage, ascites, encephalopathy, development of

M

HCC) considered for each patient

- progression towards liver failure and need for liver transplant,

d

considered for each patient

Ac ce p

te

- death due to liver-related causes, considered for each patient

Statistical Analysis

Comparative analysis of the categorical values was carried out using the chi2 test and the Fisher’s exact test. The Mann-Whitney

test was used for evaluating the continuous variables. A p value < 0.05 was considered significant. Graph Pad InStat 3.0 for Macintosh was used for the statistical analysis. Logistic regression was carried out using SPSS version 10 for Windows, utilising acute onset as previously defined as a dependent variable.

8

Page 8 of 23

Results Among 479 patients (female gender 79%, median age at onset 42

ip t

years) 204 (43%) satisfied the definition of “acute“ onset AIH; the

cr

control group was represented by the other AIH patients with chronic/asymptomatic onset.

us

As expected considering the selection criteria of the populations, the

an

patients with “acute” onset of disease showed significantly higher serum levels of AST (22 X [2.5-90] vs. 4.9 [1-54] p<0.0001), ALT (26

M

X [3-92] vs. 7 [1-80] p<0.0001) and total bilirubin (7.9 X [0.4-62] vs.

d

1.06 [0.3-26] p<0.0001). Moreover, the group of patients having an

te

acute onset was characterized by significantly lower albumin levels (36 [18-62] vs. 40 [19-62] p=0.001) and significantly higher

Ac ce p

International Normalized Ratio (INR) (1.24 [1-3] vs. 1.1 [1-2.4] p<0.001). No significant differences were observed for sex, age at diagnosis, baseline values of alkaline phosphates, gamma GT,

gammaglobulin, immunoglobulin G (IgG) and frequency of HLA DRB1*03 and DRB1*04.

As far as liver histology is concerned, the grading of the disease observed in patients with acute onset was significantly higher (10 [318] vs. 8 [3-16] p=0.02) while the staging was analogous (3 [1-6] vs. 9

Page 9 of 23

3 [1-6] p=1). Histological cirrhosis was more likely in patients with chronic/asymptomatic onset without reaching statistical significance (20% vs. 13% p=0.056). Interestingly, 34% of the patients with acute

ip t

AIH onset showed an “acute on chronic” picture (stage of fibrosis

cr

not lower than F3).

us

After a similar follow up period (48 months [1-415] vs. 60 months [2-

an

438] p = NS) and despite a similar rate of complete response to treatment (66% vs. 57% p=NS) the patients with acute onset AIH

M

were less likely to develop experience any kind of progression of the

te

d

disease (13% vs. 22% p=0.02).

Taken as a whole” the extrahepatic autoimmune diseases were

Ac ce p

more frequently associated with chronic/asymptomatic onset (37% vs. 25% p=0.02); however, such an association is lost if the analysis is performed for each single extrahepatic autoimmune condition. All these results are summarized in Table 1.

With respect to the autoantibody profile, no differences were found in terms of frequency in the two groups considered; in particular, frequency of ANA, SMA, LKM1, LC1 and anti-SLA findings was

10

Page 10 of 23

analogous irrespective of the phenotypic presentation of AIH. All these results are summarized in Table 2.

ip t

Logistic regression was carried out using acute onset as a

cr

dependent variable and only with patients whose data are completed; starting from these assumptions we found that total

us

bilirubin and slow progression of the disease were independent

an

variables (p<0.001 and p=0.02, respectively) characterizing the acute onset of the disease.

M

When we focused on the histological setting differentiating the

d

“genuine” acute onset from the acute “on chronic” onset we

te

continued to find a trend of less progression of the disease in “genuine” acute patients than counterpart but without a statistical

Ac ce p

meaning (7 vs 12% p=NS); furthermore the genuine acute patients were distinguished by acute “on chronic” ones by higher serum levels of albumin (40 vs 36 p=0.02), less serum levels of INR (1.10 vs 1.26 p=0.02) and IgG (1.12 vs 1.4 p=0.03) respectively.

Discussion From the clinical standpoint at the time of diagnosis AIH is a very heterogeneous disease with an ample spectrum of manifestations 11

Page 11 of 23

which can be virtually absent (asymptomatic presentation with incidental finding of the disease), or those of an acute icteric hepatitis, even extremely severe and rapidly evolving into acute liver

ip t

failure (fulminant phenotype), passing through the manifestations of

cr

compensate or decompensate (encephalopathy, jaundice, ascites,

us

etc.) liver cirrhosis (2, 4, 28).

an

It is therefore often difficult to identify the actual onset of a disease which is so heterogeneous. Regarding the concept of acute onset,

M

the literature itself has different interpretations: the acute picture can

d

be of a clinical/biochemical type, but it can also be histological, and

te

the choice of the cut-off of the biochemical parameters is often

Ac ce p

arbitrary and not validated (8,31-39, 47-49).

Our choice of using 10X UNL (upper normal limit) of the value of the transaminases and/or the value of total bilirubin > 5 mg as inclusion criteria selected only those patients with a biochemically “acute” picture. This choice can justify, at least in part, the high frequency of

clinical “acute” onset of the disease we found in our experiences.

Previous studies offer heterogeneous interpretations of “acute” onset of AIH. Panayi et al. (47) analyzed the case studies of patients 12

Page 12 of 23

presenting to their clinical unit with jaundice and retrospectively identified 47 cases fulfilling the criteria for a diagnosis of AIH. Of these 47 cases, 50% already had histological cirrhosis, possibly due

ip t

to misdiagnosis and inappropriate treatment or lack thereof.

cr

A study very similar to ours in terms of patient selection criteria is that by Yamamoto et al. (48) in Japan which used the same

us

selection criteria to define the acute onset of disease. The Japanese

an

study, however, reached quite opposite conclusions: patients with higher INR at presentation were at higher risk of fatal outcome. It

development

of

the

coagulopathy

typical

of

acute

d

the

M

should be noted that the values of the INR were > 1.5 , suggesting

te

severe/fulminant liver failure (49).

Ac ce p

A British study reported on 32 patients with these characteristics (INR>1.5) were selected retrospectively; 60% required a liver transplant and 20% died from hepatic causes (49). In our patients with acute onset disease, the INR was significantly higher than in patients with chronic/asymptomatic onset, however, in none of your acute AIH patients met the criteria for a clinical diagnosis of severe/fulminant hepatitis.

13

Page 13 of 23

In another Japanese study (Abe et al.) (37) the selection criteria for establishing acute onset was linked to values of bilirubin > 2 mg/dl and to the fact that no signs of chronic liver disease was present at

ip t

the histological level; in these patients (23 cases), response to the

cr

therapy was worse in patients with elevated levels of bilirubin; in this regard in our study the acute onset did not obstacle a complete

us

response to immunosuppressive therapy, which was even slightly

an

more efficacious in acute than in chronic/asymptomatic patients.

M

Even if our study is partially limited by being retrospective and by

d

the low number of available liver biopsies, some aspects emerging

te

from our results would seem to have some relevance; in particular, in patients with clinical acute onset AIH the lower albumin levels and

Ac ce p

the prolonged INR in patients with acute onset reflects a transitory impairment of hepatocyte synthesis, following a phase of severe hepatocyte necrosis which is also reflected by a higher histological grading. The “clinical” acute onset taken as a whole appears to

progress less often to cirrhosis and/or terminal stages of liver disease, and at least in part this trend is true also for “genuine” acute onset. Possibly, It would seem that the acute onset of the disease in both its declinations , “genuine” acute onset and acute on chronic onset 14

Page 14 of 23

can facilitate the diagnosis resulting therefore in a greater rapidity in instituting immunosuppressive therapy and consequently on better controlling the disease with a better prognosis over a medium-long

ip t

period. To strengthen this hypothesis it would be of interest to know

cr

the so called “time to diagnosis”, but we have this information in too few patients to draw strong conclusions. Regarding the differences

us

with the analogous studies published in the literature on this subject

an

(31-39, 47-49), it is likely that both the patient selection and genetic background (various studies on acute onset were carried out by

M

Japanese researchers on a Japanese population) (26,30-32,36-39)

d

as well as the small size of some studies could have influenced and

te

affected the results, rendering them conflicting between themselves and those of our study. It is advisable in this respect, given the

Ac ce p

variability of the criteria used in the selection of patients, to establish common criteria and evaluate the possibility of a large scale multicentre study which could permit drawing strong definite conclusions on this subject.

References 1. Muratori P, Lenzi M, Cassani F et al. Diagnostic approach to autoimmune hepatitis Expert Rev Clin Immunol 2017; 13 :769-779. 2. Muratori P, Granito A, Quarneti C et al. Autoimmune hepatitis in Italy: the Bologna experience. J Hepatol. 2009;50 :1210-8.

15

Page 15 of 23

3. Muratori P, Lalanne C, Barbato E et al. Features and Progression of Asymptomatic Autoimmune Hepatitis in Italy. Clin Gastroenterol Hepatol. 2016;14:139-146.

ip t

4. Dyson JK, Webb G, Hirschfield GM, Lohse A, Beuers U, Lindor K, Jones DE. Unmet clinical need in autoimmune liver disease J Hepatol. 2015; 62: 208-18.

cr

5. Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, Dalekos GN, Muratori L. Review article: autoimmune hepatitis -- current management and challenges.Aliment Pharmacol Ther. 2013 Oct;38(8):887-913

us

6. Graziadei IW. The clinical challenges of acute on chronic liver failure. Liver Int 2011;31:24–26

an

7. Kerkar N, Hadzic N, Davies ET, et al. De novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409–413.

M

8. Miyagawa-Hayashino A, Haga H, Egawa H, et al. Outcome and risk factors of de novo autoimmune hepatitis in living-donor liver transplantation. Transplantation 2004;78:128–135.

d

9. Manns MP, Lohse AW, Vergani D. Autoimmune Hepatits Update 2015 J Hepatol. 2015 62:S100-11.

te

10 Burgart LJ, Batts KP, Ludwig J, Nikias GA, Czaja AJ. Recent onset autoimmune hepatitis. Biopsy findings and clinical correlations. Am J Surg Pathol 1995;19:699–708.

Ac ce p

11. Ferrari R, Pappas G, Agostinelli D, et al. Type 1 autoimmune hepatitis: patterns of clinical presentation and differential diagnosis of the ‘‘acute’’ type. QJM 2004;97:407–412. 12. Miyake Y, Iwasaki Y, Terada R, et al. Clinical features of Japanese type 1 autoimmune hepatitis patients with zone III necrosis. Hepatol Res 2007;37:801–805. 13. Shindo M, Di Bisceglie AM, Hoofnagle JH. Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C. Gastroenterology 1992;102:1406–1408. 14. Papo T, Marcellin P, Bernuau J, et al. Autoimmune chronic hepatitis exacerbated by alpha-interferon. Ann Intern Med 1992;116:51–53. 15. Garcia-Buey L, Garcia-Monzon C, Rodriguez S, et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 1995;108: 1770–1777. 16. Muratori L, Lenzi M, Cataleta M et al. Interferon therapy in liver kidney

16

Page 16 of 23

microsomal antibody type 1-positive patients with chronic hepatitis C. J of Hepatology 1994;21:199-203 17. EASL Reccomendations on treatment of Hepatitis C 2016. J Hepatol 2017 66 153-194.

ip t

18. Porta G, Gayotto LC, Alvarez F. Anti-liver-kidney microsome antibodypositive autoimmune hepatitis presenting as fulminantliver failure. J Pediatr Gastroenterol Nutr 1990;11:138–140.

cr

19. Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011;53:517– 526.

us

20. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179–1197.

an

21. Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology 2012;55:965–967

M

22. 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.

te

d

23. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–176.

Ac ce p

24. Fujiwara K, Fukuda Y, Yokosuka O. Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute-onset autoimmune hepatitis. J Gastroenterol 2008;43:951–958. 25. Iwai M, Jo M, Ishii M, Mori T, Harada Y. Comparison of clinical features and liver histology in acute and chronic autoimmune hepatitis. Hepatol Res 2008;38:784–789. 26. Miyake Y, Iwasaki Y, Kobashi H, et al. Autoimmune hepatitis with acute presentation in Japan. Dig Liver Dis. 2010;42:51–54. 27. Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci 2012;57:610–624. 28. Czaja AJ. Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis Sci 2013; 58: 897-914. 29. Yeoman AD, Westbrook RH, Zen Y, et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmunehepatitis. Hepatology 2011;53:926–934 30. Abe M, Hiasa Y, Masumoto T, et al. Clinical characteristics of autoimmune

17

Page 17 of 23

hepatitis with histological features of acute hepatitis. Hepatol Res 2001;21:213– 219. 31. Abe M, Onji M, Kawai-Ninomiya K, et al. Clinicopathologic features of the severe form of acute type 1 autoimmune hepatitis. Clin Gastroenterol Hepatol 2007;5:255–258.

ip t

32. Okano N, Yamamoto K, Sakaguchi K, et al. Clinicopathological features of acute-onset autoimmune hepatitis. Hepatol Res 2003; 25:263–270.

cr

33. Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobularure associated with acute clinical presentation. J Clin Pathol 2006;59:246–249.

us

34. Misdraji J, Thiim M, Graeme-Cook FM. Autoimmune hepatitis with centrilobular necrosis. Am J Surg Pathol 2004;28:471–478.

an

35. Singh R, Nair S, Farr G, Mason A, Perrillo R. Acute autoimmune hepatitis presenting with centrizonal liver disease: case report and review of the literature. Am J Gastroenterol 2002; 97:2670–2673

M

36. Fujiwara K, Nakano M, Yasui S, et al. Advanced histology and impaired liver regeneration are associated with disease severity in acute-onset autoimmune hepatitis. Histopathology 2011;58: 693–704.

te

d

37. Abe K, Kanno Y, Okai K, et al. Centrilobular necrosis in acute presentation of Japanese patients with type 1 autoimmune hepatitis World J Hepatol 2012;4:262.

Ac ce p

38. Sato Y, Tsuneyama K, Kage M et al. Intractable Liver and Biliary Diseases Study Group of Japan.: Acute presentation of autoimmune hepatitis: a multicentre study with detailed histological evaluation in a large cohort of patients. J Clin Pathol 2017 Apr 20. 39. Dohmen K, Tanaka H, Haruno M et al. Immunoserological and histological differences between autoimmune hepatitis with acute presentation and chronic autoimmune hepatitis. Hepatol Res 2017 Feb 20. 40 Ishak K, Baptista A, Bianchi l et al. Histological grading and staging of chronic hepatitis. J of Hepatology 1995;22:696-99. 41. Muratori P, Granito A, Pappas et al. The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome . Am J Gastroenterology 2009; 104: 1420-25 42. Muratori P, Muratori L, Agostinelli D, et al. Smooth Muscle Antibodies and Type 1 Autoimmune Hepatitis. Autoimmunity 2002;35:497-500 43. Muratori L, Cataleta M, Muratori P et al. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis. Gut 1998;42:721-726.

18

Page 18 of 23

44. Efe C, Ozaslan E, Wahlin S, et al. Antibodies to soluble liver antigen in patients with various liver diseases: A multicentre study. Liver Int 2013;33(2):190-196.

ip t

45. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51(6):2193-2213. 46 EASL Clinical Practice Guidelines: Autoimmune hepatitis J Hepatol 2015 63: 971–1004

us

cr

47 Panayi V, Froud OJ, Vine L, et al. The natural history of autoimmune hepatitis presenting with jaundice. Eur J Gastroenterol Hepatol 2014;26:640645.

an

48 Yamamoto K, Miyake Y, Ohira H, et al. Prognosis of autoimmune hepatitis showing acute presentation. Hepatol Res 2013;43:630-638.

te

d

M

49 Yeoman AD, Westbrook RH, Zen Y, et al. Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome. J Hepatol 2014;61:876-882

Ac ce p

Table 1. Clinical “Acute” vs “not acute” onset AIH Acute

Characters

onset (204 pts)

AIH Not acute

p

(275 pts)

Female gender

167 (82 %)

214 (77 %)

NS

Age - median (range) [yrs]

42 (2-83)

42 (2-89)

NS

AST - median (range) [X UNL]

22 (2.5-90)

4.9 (1-54)

< 0.0001

ALT - median (range) [X UNL]

26 (3-92)

7 (1-80)

< 0.0001

19

Page 19 of 23

1.5 (0.48.6)

1.1 (0.3-16)

NS

3.1 (0.1-22)

2.2 (0.2-23)

NS

ALP median (range) [X UNL] gGT median (range) [X UNL] Bilirubin - median (range) [mg/dl] Gamma-globulins median (range) [g/l]

24 (9-60)

22 (9-63)

Albumin median (range) (g/l)

36 (18-62)

40 (19-62)

0.0001

INR median (range)

1.24 (1-3)

1.1 (1-2.4)

< 0.0001

1.5 (0.5-4)

1.3 (0.5-7.4)

NS

an

ip t

7.9 (0.4-62) 1.06 (0.3-26) < 0.0001

36 (49%)”

37 (34%)£

NS

13 (18%)”

33 (31%)£

NS

10 (3-18)

8 (3-16)

0.02

3 (1-6)

3 (1-6)

NS

24 (13 %)*

52 (20 %)#

0.053

Disease Progression (%)°§

23 (13 %)°

53 (22%)§

0.02

Revised score 1999 (22)

15 (12-20)

16 (12-21)

NS

Simplified score 2007 (23)

6 (5-8)

6 (5-8)

NS

Follow-up median (range) [mesi]

48 (1-415)

60 (2-428)

NS

Complete response (%)^ç

114 (66 %)^

128 (57 %) ç

NS

Associated autoimmune diseases&

52 (25 %)

101 (37 %)

0.02

Treatment withdrawal (%)

24 (12 %)

25 (9 %)

NS

HLA DR4 (%)” £

M

HLA DR3 (%)” £

cr

us

IgG median (range) [X UNL]

d

Ishak’s grading median (range)

te

Ishak’s staging median (range)

Ac ce p

Cirrhosis at diagnosis (%)*#

20

NS

Page 20 of 23

Legend Table 1:

ip t

AIH: Autoimmune Hepatitis; NS: not significant; UNL: upper normal limit AST: aspartate aminotransferase; ALT: alanine aminotransferase *available on 185 patients; # available on 258 patients;

cr

“ available on 74 patients £ available on 104 patients ° available on 176 patients; § available on 238 patients;

us

^ available on 172 patients; ç available on 225 patients &

Autoimmune associated diseases: autoimmune thyroid disease, coeliac

an

disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus

d

M

erythematosus, Sjogren syndrome, vasculitis, vitiligo

te

Table 2: Serological characters in the study population AIH

AIH

Acute onset

Not acute onset

(204 pts)

(275 pts)

ANA

140 (69%)

191 (69 %)

NS

SLA

15 (7%)

26 (9%)

NS

SMA

120 (59 %)

141 (52 %)

NS

LKM

18 (8.6 %)

39 (14 %)

NS

LC1*°

9 (5.7 %)*

18 (8.2 %)°

NS

AMA

14 (7%)

19 (7%)

NS

Ac ce p

Reactivity

21

p

Page 21 of 23

Legend Table 2: NS: not significant; ANA – antinuclear antibodies; SLA: soluble liver antigen; SMA – smooth muscle antibody; LKM1 liver kidney microsome type 1; LC1;

an

us

cr

* available on 157 patients; ° available on 219 patients;

ip t

liver cytosol type 1; AMA – anti mitochondrial antibodies

Table 3. Parameters of AIH subdivided “genuine”acute” vs acute “on

M

chronic” onset

AIH AIH Histological

d

Characters

Histological

p

acute

te

acute onset “on chronic” (83 pts)

Ac ce p

(45 pts)

Female gender

17 (20 %)

15 (33 %)

NS

Age - median (range) [yrs]

42 (11-78)

42 (3-80)

NS

AST - median (range) [X UNL]

20 (2.5-70)

22 (4-76)

NS

ALT - median (range) [X UNL]

31 (4-92)

25 (5-67)

NS

Bilirubin - median (range) [mg/dl]

8.8 (0.2-49)

6.6 (0.1-23)

NS

Gamma-globulins median (range) [g/l]

19 (16-60)

24 (9-36)

0.005

Albumin median (range) (g/l)

40 (23-58)

36 (18-62)

0.02

22

Page 22 of 23

INR median (range)

1.26 (1-3)

0.02

1.12 (0.5-2)

1.4 (0.6-3.3)

0.003

Cirrhosis at diagnosis (%)

0

9 (20%)

<0.0001

Disease Progression (%)

6 (7 %)

6 (12%)

0.4

Follow-up median (range) [mesi]

42 (3-240)

48 (2-276)

NS

Complete response (%)

56 (67%)

32 (71 %)

NS

Prednisolone cessation (%)

13 (16%)

7 (15%)

NS

7 (8%)

4 (9%)

NS

23 (27 %)

11 (24 %)

NS

cr

Ac ce p

Legend Table 3:

te

d

M

Associated autoimmune diseases&

an

Complete treatment withdrawal (%)

us

IgG median (range) [X UNL]

ip t

1.1 (1-1.76)

AIH: Autoimmune Hepatitis; NS: not significant; UNL: upper normal limit AST: aspartate aminotransferase; ALT: alanine aminotransferase

&

Autoimmune associated diseases: autoimmune thyroid disease, coeliac

disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, vasculitis, vitiligo

23

Page 23 of 23