hepatitis autoinmune experiencia en japon

7/30/2019 Hepatitis Autoinmune Experiencia en Japon

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Original Article

Autoimmune fulminant liver failure in adults: Experience ina Japanese centerhepr_755 133..141

Keiichi Fujiwara,1 Shin Yasui,1 Akinobu Tawada,1 Koichiro Okitsu,1 Yutaka Yonemitsu,1

Tetsuhiro Chiba,1 Makoto Arai,1 Tatsuo Kanda,1 Fumio Imazeki,1 Masayuki Nakano,2

Shigeto Oda3 and Osamu Yokosuka1

Departments of 1Medicine and Clinical Oncology and 3Emergency and Critical Care Medicine, Graduate School ofMedicine, Chiba University, and 2Department of Pathology, Tokyo Womens Medical University Yachiyo MedicalCenter, Chiba, Japan

Aim: After the establishment of the international criteria ofautoimmune hepatitis (AIH) in 1999 and the recognition ofacute onset AIH, the diagnosis of patients with fulminant typeof AIH came to be made. We diagnosed autoimmune fulmi-nant liver failure based on the criteria, and discussed theetiology of fulminant hepatitis (FH) and late onset hepaticfailure (LOHF), and the characteristics of autoimmune fulmi-nant liver failure.

Methods: We investigated the etiology of 95 consecutiveadult patients with FH or LOHF admitted to our liver unitbetween 1990 and 2009. Clinical and biochemical features,therapies and outcomes were examined in patients with AIHafter 2000.

Results: Of 95 patients, 85 were FH and 10 LOHF. The etiol-ogy was due to viral infections in 51.6% (hepatitis A virus in

7.4%, hepatitis B virus in 43.2% and hepatitis E virus in 1.1%),AIH in 15.8%, drug allergy-induced in 12.6%, and unknowncauses in 20.0%. The rate of patients with AIH increased sig-nificantly between 2000 and 2009 compared to the ratebetween 1990 and 1999 (P = 0.002). In recovered patientswith AIH without transplantation after 2000, coma grade waslower, alanine aminotransferase level, prothrombin time activ-ity and alfa-fetoprotein level were higher than in the otherswith statistical significance.

Conclusion: AIH is not a rare cause of FH and LOHF, andthe number of patients with unknown causes would surelydecrease in concert with the precise diagnosis of AIH.

Key words: acute onset autoimmune hepatitis, etiology,fulminant hepatitis, late onset hepatic failure.

INTRODUCTION

ACUTE LIVER FAILURE (ALF) is a rare but challeng-ing clinical syndrome with multiple causes, charac-terized by the sudden loss of hepatic function in a

person without preceding chronic liver disease. In

Japan, ALF is classified into two groups based on the

presence of histological hepatitis showing lymphocyte

infiltration.1,2 One is fulminant hepatitis (FH) or its

related diseases, acute hepatitis severe type (AHs) and

late onset hepatic failure (LOHF), which can present in

patients with ALF due to viral infection, autoimmune

hepatitis, drug allergy-induced liver injury and

unknown hepatitis. The other is ALF without histologi-

cal hepatitis, which can present in patients with drug

toxicity, ischemia, metabolic errors and miscellaneous

rare causes.

In a Japanese nationwide survey in patients with FH

and LOHF between 1998 and 2003, the etiology was

viral infections in 48.0% (hepatitis A virus (HAV) in

6.4%, hepatitis B virus (HBV) in 38.8% and other

viruses in 2.7%), drug allergy-induced in 9.3%, autoim-

mune hepatitis (AIH) in 6.9%, unknown causes in

32.8% and indeterminate causes in 3.0%.1 A specificetiology could not be identified in 3040% of

adult patients in past Japanese surveys. The survival rate

of patients with FH and LOHF without liver transplan-

tation was 78.6% in HAV, 36.2% in HBV (48.2% in

acquired infection and 20.3% in carrier), 39.2% in drug

allergy-induced, 17.1% in AIH, and 32.3% in unknown

causes.1

Correspondence: Dr Keiichi Fujiwara, Department of Medicine and

Clinical Oncology, Graduate School of Medicine, Chiba University,

1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Email:

[email protected]

Received 27 October 2010; revision 15 November 2010; accepted 16

November 2010.

Hepatology Research 2011; 41: 133141 doi: 10.1111/j.1872-034X.2010.00755.x

2011 The Japan Society of Hepatology 133


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There are no specific therapies of proven benefit

except for emergency liver transplantation. FH is a

national problem despite its rare incidence because of

its extremely high mortality. Especially, many patients

with HBV carrier, AIH and unknown cause presented

subacute type of FH or LOHF, and their survival rates

without liver transplantation were especially low, at

12.5%, 16.7% and 22.9%, respectively.1 Thus, the

outcome of FH is influenced by its etiology, making

etiological consideration of FH particularly important.

After establishment of the criteria by the International

Autoimmune Hepatitis Group3 and the recognition of

acute onset AIH,4 the diagnosis of patients with autoim-

mune acute liver failure came to be made.5,6 But they

often demonstrate an atypical histological pattern for

AIH, consisting of centrilobular necrosis with or without

portal change, at their early stage of illness.7,8 Failure to

recognize this pattern of acute onset AIH may lead to

delay in diagnosis. A major problem is that there is nogold standard for making the diagnosis of acute onset

AIH.

In the present study, we diagnosed autoimmune ful-

minant liver failure while considering the international

criteria as well as this unusual histological pattern, and

discussed the etiology of FH with the aim of arriving at

a more precise diagnosis and treatment.

PATIENTS AND METHODS

Patients

NINETY-FIVE CONSECUTIVE adult patients withfulminant hepatitis (FH) or late onset hepaticfailure (LOHF) admitted to Chiba University Hospital

between 1990 and 2009 were included in this study.

The work described in this manuscript have been carried

out in accordance with The Code of Ethics of the

World Medical Association (Declaration of Helsinki).

Informed consent was obtained from all patients or

appropriate family members.

Diagnosis of fulminant hepatitis

Patients with prothrombin time activity less than 40%of control and hepatic encephalopathy of a coma grade

greater than II9 within 8 weeks of the initial symptoms

of illness were defined as FH.2 Patients in whom

encephalopathy developed between 8 and 24 weeks

after disease onset with prothrombin time activity less

than 40% of control were diagnosed as LOHF. Patients

with FH were further classified into two subtypes: acute

type and subacute type in whom encephalopathy

developed within 10 days and later than 11 days,

respectively.

Patients with chronic liver diseases except asymptom-

atic HBV carriers showing acute exacerbation, those with

alcoholic hepatitis, those with ALF having no histologi-

cal features of hepatitis, such as liver damage due to

drug or chemical intoxication and microcirculatory dis-

turbance, infiltration of malignant cells, post-surgical

operation, Wilsons disease, acute fatty liver of preg-

nancy or Reyes syndrome, were excluded according to

the Japanese criteria.1

Etiology

The etiology of FH was classified into five categories:

viral infection, autoimmune hepatitis (AIH), drug

allergy-induced liver injury, unknown (etiology

unknown despite sufficient examinations available) and

indeterminate (etiology undetermined because of insuf-

ficient examinations) by the Japanese criteria according

to the Intractable Liver Diseases Study Group of Japan,

the Ministry of Health, Welfare and Labor (2003).1

Patients with HBV infection were further classified into

two subgroups: acquired HBV infection and acute exac-

erbation of HBV carriers.

A diagnosis of hepatitis A, B C and E was made based

on the positivity for IgM anti-HAV antibody (IgM-HA),

on the positivity for hepatitis B surface antigen (HBs

Ag), IgM anti-hepatitis B core antibody (IgM-HBc) or

HBV DNA, on the positivity for hepatitis C virus (HCV)

RNA and the low titer positivity for anti-HCV antibody(HCV Ab), and on the positivity for hepatitis E virus

(HEV) RNA, respectively. A diagnosis of AIH was made

based on the presence of anti-nuclear antibody (ANA)

and/or anti-smooth muscle antibody (ASMA), as well as

on the definite or probable diagnosis defined by the

International Autoimmune Hepatitis Group.3 A definite

diagnosis was made based on the pretreatment score

>15, and a probable diagnosis on the score 1015. A

diagnosis of drug allergy-induced liver injury was made

based on the distinctive clinical course.

Clinical, biochemical andimmunoserologic analysis

Data obtained from patients were as follows: sex; age at

diagnosis; time of onset; duration from onset to coma;

coma grade; presence of liver atrophy; complications;

serum levels of alanine aminotransferase (ALT), total

bilirubin (T-Bil), prothrombin time (PT) activity,

immunoglobulin G (IgG), anti-nuclear antibody

134 K. Fujiwara et al. Hepatology Research 2011; 41: 133141

2011 The Japan Society of Hepatology


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(ANA), anti-smooth muscle antibody (ASMA), liver

kidney microsomal antibody-1 (LKM-1) and anti-

mitochondrial antibody (AMA), alfa-fetoprotein, hepa-

tocyte growth factor; human leukocyte antigen (HLA);

pretreatment AIH score; types of therapy, duration from

onset to corticosteroid therapy and outcome. They were

also examined for any histories of recent exposure to

drugs and chemical agents as well as heavy alcohol con-

sumption (>50 g/day). ANA and ASMA were examined

by a fluorescent antibody method, and AMA was exam-

ined by a fluorescent antibody method or an enzyme

linked immunosorbent assay (ELISA), and LKM-1 was

examined by ELISA.

In acute onset AIH, early symptoms including fever,

general malaise, fatigue, nausea, vomiting and right

upper quadrant discomfort are frequently observed, so

we defined the beginning of these symptoms or the time

of first detection of liver dysfunction as clinical onset.

Virological analysis

Patients were examined for viral markers such as IgM-

HA, IgM-HBc, HBs Ag, HCV Ab, HCV RNA, HEV RNA,

IgM anti-Epstein-Barr virus (EBV) antibody (IgM-EBV),

IgM anti-herpes simplex virus (HSV) antibody (IgM-

HSV) and IgM anti-cytomegalovirus (CMV) antibody

(IgM-CMV).

Volumetric analysis of the liver

The whole liver volume was measured using CT films

according to the method of Heymsfield et al. (CT-

derived liver volume)10 and the standard liver volumewas calculated from the body surface area using the

formula of Urata et al.11 In this study, liver atrophy was

defined as the CT-derived liver volume/standard liver

volume ratio


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numbers of HAV, HBV acquired, HBV carrier, and drugallergy-induced were not significant between the two

periods. The number of unknown causes showed a

decreasing trend, but the difference was not significant

(P= 0.08).

Outcome of FH and LOHF in our unit

In 91 patients without liver transplantation, the survival

rate of those with 81 FH was 23.5% (42.9% of HAV,

33.3% of acquired HBV infection, 8.3% of HBV carrier,

0% of HEV, 22.2% of AIH, 20.0% of drug allergy-

induced, 20.0% of unknown causes). In 33 acute FH,the survival rate was 48.5% (60.0% of HAV, 40.0% of

HBV acquired infection, 0% of HEV, 66.7% of drug

allergy-induced, 75.0% of unknown). In 48 subacute

FH, the survival rate was 8.3% (0% of HAV, 14.3% of

HBV acquired infection, 8.3% of HBV carrier, 22.2% of

AIH, 0% of drug allergy-induced, 0% of unknown). In

10 LOHF, the survival rate was 10.0% (0% of HBV

acquired infection, 25.0% of AIH, 0% of drug allergy-

induced, 0% of unknown).

Four patients received living donor liver transplanta-

tions and 3 (one of 2 with AIH, one with drug allergy-

induced and one with unknown cause) recovered.

Clinical and biochemical features of patientswith autoimmune fulminant liver failureafter 2000

After the establishment of the international criteria of

AIH in 1999, the etiology of twelve patients, 4 men and

8 women, were AIH. Eight were FH and 4 LOHF. The

clinical and biochemical features of all patients at thetime of diagnosis are provided in Tables 1 and 2. Mean

age at the time of diagnosis was 54.8 1 15.8 years. The

duration from onset to hepatic encephalopathy was

40.8 1 38.1 day. Coma grade was II in 8 and III in 4.

Liver atrophy was found in all patients. Five patients

(42%) had primary complications described in

Table 1.

Mean ALT was 597 1 625 IU/L, mean T-Bil

20.8 1 8.1 mg/dL, and mean PT activity 25 1 8%.

Mean IgG was 2661 1 885 mg/dL. The IgG level

was normal (2.0 x UNV in 2 (17%). ANA was positive

(31:40) in all patients, 1: 40 in 1 (8%), 1: 80 in 3

(25%), and >1: 80 in 8 (67%). ASMA was positive

(31:40) in 3 (25%). One patient (#3) was positive for

LKM-1.

No patients were positive for HBs Ag and one was

positive for HCV Ab. Although 42% of the patients had

primary complications and histories of medications as

described above, suspected hepatotoxic drugs were

excluded according to the drug-induced liver injury

diagnostic scale of Maria and Victorino12 in this study.

Mean alfa-fetoprotein was 152.7 1 325.8 ng/dL and

mean hepatocyte growth factor was 4.41 1 5.32 ng/dL.Although we could examine HLA-DR in only 6 of the

patients because this procedure is not covered by the

Japanese national health insurance plan, none had

HLA-DR 3, but 3 had HLA-DR 4.

Pretreatment AIH score on admission to our unit was

probable diagnosis in 6 and definite in 6. The duration

from onset to admission was 37.9 1 36.4 days.

Figure 2 Etiology of fulminant hepati-

tis and late onset hepatic failure in our

unit between 1990 and 1999 (n = 54)

and between 2000 and 2009 (n = 41).

Etiology of fulminant hepatitis and late onset hepatic failure

HAV

9%

(19901999, n = 54) (20002009, n = 41)

HAV5%

Unknown

26%

Unknown

12%

HBV acquired

32%

HBV acquired

30%

Drug13%

Drug12%

AIH6%

AIH

29%HBVcarrier

13%

HBV carrier

12%

HEV

2%

136 K. Fujiwara et al. Hepatology Research 2011; 41: 133141

2011 The Japan Society of Hepatology


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Table

1

Clinicalfeatures

ofpatientswithautoimmunefulminan

tliverfailureatthetimeofdiagnosis

Patient

Age/sex

Onset

Diagnosis

D

urationfrom

o

nsettocoma

(days)

Coma

grade

Live

ratrophy

(CTLV/SLV)

Complication

1

17/F

2002

FH

22

III

+(0.44)

2

55/M

2003

LOHF

62

II

+(0.75)

3

61/M

2004

LOHF

1

34

II

+(0.46)

PostoperationforGastric/tonguecancer

4

58/M

2007

FH

24

II

+(0.64)

5

56/M

2007

LOHF

1

34

II

+(0.73)

Hypertension,mediastinaltumor

6

52/M

2007

FH

24

II

+(0.42)

Hypertension,

hyperuremia

7

70/F

2007

FH

19

II

+(0.52)

8

71/F

2008

FH

19

II

+(0.65)

Hashimotodisease

9

55/F

2008

LOHF

89

III

+(0.79)

10

76/F

2008

FH

13

III

+(0.78)

11

49/F

2009

FH

42

II

+(0.70)

12

38/F

2009

FH

46

III

+(0.61)

ChronichepatitisC,H

ashimotodisease

CTLV,CT-derivedlivervolume;FH,

fulminanthepatitis;LOHF,

lateonsethepaticfailure;SLV,standardlivervo

lume.

Table

2

Biochemicalfeaturesofpatientswithautoimmunefulm

inantliverfailureatthetimeofdiagnos

is

Patient

ALT

(IU/L)

T-B

il

(m

g/dL)

PT(%)

ANA

(fold)

ASMA

(fold)

IgG

(mg/dL)

HLA-DR

a-fetoprotein

(ng/dL)

Hepatocytegrowth

factor(ng/dL)

AIHscorein

admission

Daysfrom

onset

toadmission

1

496

14.8

29

320

1280

80

3

053

ND

10.1

5.41

15

30

3

1998

9.4

40

640

hepatitis autoinmune experiencia en japon

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