A study about AIH in Infants by an hepatologist

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Autoimmune hepatitis

Hepatite auto-imune

Gilda Porta

J Pediatr (Rio J) 2000; 76 (Supl.2): S181-6

Introduction

Autoimmune hepatitis is a continuous inflammatory disease of the

liver, with variable beginning and duration, caused by unknown

factors. It constitutes a syndrome characterized by the presence of

clinical, biochemical, serologic, and histological elements, which

suggest immunologic reaction against antigens of the host, and lead

to irreversible cellular damage. It usually affects young, female

patients, and it is characterized by the presence of

hypergammaglobulinemia, organ nonspecific circling autoantibodies,

and histological alterations, with lymphoplasmocytic inflammatory

infiltrate, interface hepatitis, and presence, most of the times, of

rosette-forming hepatocytes. The therapeutic response to

corticosteroids occurs in 80% of the cases, and then clinical,

laboratory, and therapeutic remission takes place. An association

with other extrahepatic autoimmune diseases may occur (autoimmune

thyroiditis, arthritis, hemolytic anemia, and glomerulopathies) (1).

In childhood, it is considered a rare entity, corresponding to about

10% of the patients with chronic liver disease (2-6). In Brazil, it

is also considered a rare disease, and affects approximately 5 to 10%

of the hepatic diseases in the main gastroenterology services in the

country (7). According to data from the Liver Unit and the Children's

Institute of Hospital de Clínicas, School of Medicine, Universidade

de São o, autoimmune hepatitis corresponds to less than 5% and

less than 2% of the adult and pediatric patients, respectively, in

the wait for hepatic transplantation (personal communication) (7).

The classification of autoimmune hepatitis can be based on clinical,

laboratory, histological, genetic, and pathogenetic findings.

However, the classification most commonly accepted by authors (8) is

based on the presence of organ-nonspecific autoantibodies, according

to the description that follows.

Type 1 - This type of autoimmune hepatitis is present when there is

positivity to the antimuscle antibody, particularly to the anti-actin

antibody, associated or not with antinuclear antibodies. Other

antibodies may be found, such as those directed against soluble liver

antigens (against cytokeratin 8 and 18), which may be present in

approximately 30% of the cases (9). Besides these antibodies against

liver and pancreas antigens, there may be nuclear envelope proteins

(laminins A and C) (9) against antineutrophil cytoplasmic antibodies,

and anticytoplasmic antibodies against cytoplasmic components of

neutrophils (10,11).

Type 2 - This type presents positivity to anti-liver-kidney

microsomal antibodies type 1. This type usually starts in childhood,

and the antibodies are directed against an IID6 antigen of cytochrome

P450 isoform (CYP2D6). Indirect immunofluorescence stains hepatocytes

and renal proximal tubules; because of this, this type of hepatitis

is also denominated anti-liver-kidney microsome antibodies type 1.

Anti-CYP2D6 are found in 95 to 100% of the patients with autoimmune

hepatitis type 2 (12,13). Anti-liver cytosol antibodies may also be

found, and, occasionally, this may be the only antibody present in

this type of autoimmune hepatitis (14). Through the indirect

immunofluorescence technique, this antibody is characterized by

fluorescence of hepatocytes in the periportal region, and not in the

centrolobular perivein (14,15).

These two types of autoimmune hepatitis are also different concerning

the genetic susceptibility related to autoimmune hepatitis. So, in

Europe and in the United States, studies showed association with the

HLA-A1-B8-DR3 molecule, and, secondarily, with DR4 in autoimmune

hepatitis type 1 (16). In Japan, it was associated with the HLA-DR4

molecule (17).17 In Argentina, Faimboin et al. (18), studying

children with autoimmune hepatitis, observed association of the

disease with the antigens HLA-DR13 and DQ6. In Brazil, Bittencourt et

al. (19) observed association, particularly in children, of

autoimmune hepatitis type 1 with HLA-DR13 and DQ6, and, secondarily,

with HLA-DR3, similarly to the findings in Argentina. On the other

hand, the same authors found association of autoimmune hepatitis with

HLA-DR7 and DQ2, and, secondarily, with DR3 in patients with

autoimmune hepatitis type 2, which is a new fact in the literature

(19).

In a survey performed together with the Gastroenterology Department

and the Pediatric Hepatology Unit, at Instituto da Criança, Hospital

de Clínicas, Medical School, Universidade de São o, 225 patients,

including children, adolescents and adults with diagnosis of

autoimmune hepatitis were classified according to the presence of

types of organ-nonspecific autoantibodies:

Types

Type 1 autoimmune hepatitis - 177 - 78.6

Type 2 autoimmune hepatitis - 32 - 12.5

(anti-liver-kidney microsome antibodies type 1)

Absence of markers - 18 - 8.0

Clinical status and laboratory exams

Most times, autoimmune hepatitis presents symptoms compatible with

acute hepatitis. A study carried out in 111 children and teenagers

with autoimmune hepatitis at Instituto da Criança Prof. Pedro de

Alcântara showed an abrupt beginning of the disease in 89% of cases,

an insidious beginning in 19%, associated jaundice, choluria, fever,

asthenia, anorexia, emaciation, and increased abdominal volume. In

some cases, the presentation form is fulminant; this usually occurs

in type 2 autoimmune hepatitis (20). The course of the disease may be

persistent or recurrent. There are no differences regarding symptoms

in the different types of autoimmune hepatitis. However, type 2 is

more frequent in earlier ages than type 1. Some cases may manifest

sings of hepatic decompensation (already advanced) since the

beginning, such as ascites, gastrointestinal bleeding, hepatic

encephalopathy, and even coma. Variable degrees of portal

hypertension and history of upper gastrointestinal bleeding may also

occur since the beginning, and they depend on the duration of the

disease. Asymptomatic patients, diagnosed accidentally due to

alterations in biochemical exams of the hepatic function, are rare.

Hepatomegaly is present in 90% of the cases, and splenomegaly, in

60%. Associated extrahepatic manifestations may be present, such as

acne, inflammatory papules, pregnancy striae, Weber paniculitis,

arthritis, arthralgia, albuminuria, hematuria, glomerulonephritis,

renal tubular acidosis, intestinal inflammatory disease, pleural

effusions, pleurisy, pulmonary arteriovenous anastomoses, fibrosing

alveolitis, polyarteritis nodosa, Cushingoid facies, gynecomastia in

boys, amenorrhea, thyroiditis, diabetes mellitus type 1, autoimmune

hemolytic anemia, iridocyclitis (21). The appearance of

hepatocellular carcinoma constitutes a rare complication (22).

The most characteristic laboratory findings are increase in the

transaminases, which may reach levels compatible with an acute

hepatitis (>1,000 U/L), and hypergammaglobulinemia. The levels of

gammaglutamyltranspeptidase and alkaline phosphatase may be also

high, but they are lower than transaminases. Bilirubin levels, due to

direct fraction, are usually increased, except for the insidious and

prolonged forms, in which they may be normal. Albumin levels are

usually decreased, and prothrombin time is prolonged.

Gammaglobulinemia is increased in most patients, with levels superior

to 2 g/dL, and much higher values are observed in type 1 when

compared to type 2 autoimmune hepatitis. IgG values are almost always

elevated, and they are much higher in type 1 autoimmune hepatitis;

low levels of IgA are found particularly in type 2 autoimmune

hepatitis, and these values are much higher than the level of IgM in

type 1 autoimmune hepatitis. Complement concentrations, particularly

C4, may be low, with levels much lower in type 2 when compared to

type 1 autoimmune hepatitis; C3 may be low in both types. Anemia may

be discrete, in general microcytic-hypochromic, except when it is

associated with hemolytic process. Leukopenia and thrombocytopenia

may occur, usually associated with hyperslenism. The patterns of

organ-nonspecific autoantibodies directed against internal cellular

components show the two types, and also define them, which are

mutually exclusive. Autoantibodies may disappear, in general, during

treatment with corticosteroids and/or azathioprine, or new ones may

still arise during the course of the disease in both types of

autoimmune hepatitis.

Histological findings show: chronic inflammatory infiltrate,

predominantly in the portal, periportal and intralobular spaces

(composed by lymphocytes, plasmocytes, and sometimes

polymorphonuclear neutrophils and eosinophils), interface hepatitis,

rosettes, enlargement of portal spaces due to fibrosis,

disarrangement of lobular architecture, with important lesions in the

hepatocytes, such as ballooning degeneration, retraction,

fragmentation, desintegration, and necrosis (23), which leads to the

formation of cirrhosis.

There is no criterion totally established for the diagnosis of

autoimmune hepatitis yet. It is based on the presence of a clinical

status compatible with hepatitis, variable evolution, with or without

other extrahepatic manifestations, absence of infection markers (such

as hepatitis A, B, or C viruses), increase in transaminases,

hypergammaglobulinemia, increased levels of immunoglobulins, and

presence of organ-nonspecific autoantibodies. Variable patterns of

autoantibodies and clinical manifestations lead to the hypothesis

that this disease is a heterogeneous syndrome, with several possible

etiologies. In some cases, autoimmune hepatitis is suspected even

when no immunologic markers or hypergammaglobulinemia are found, and

when there is a good response to corticosteroids. In 1993, an

international group led by (24) elaborated criteria for an

improved systematization and characterization of the disease in order

to make its diagnosis become easier. These criteria, though, were

revised by this group in 1999 (25). A score system was proposed

aiming at creating a set of descriptive criteria for difficult cases

or when there was the need for a more objective evaluation. The

diagnosis of autoimmune hepatitis should be considered in spite of

the score proposed to any patients, independently on the gender,

presenting either acute or chronic liver disease, and abnormal

hepatic biochemical test in the absence of signs and symptoms of any

other hepatic disease already studied, especially if there is history

of autoimmune diseases in the patient or in his/her first relatives.

The score system was proposed aiming at creating a set of descriptive

criteria for difficult cases, or when there was the need for a more

objective evaluation.

Tabela 1 -

Score system for the diagnosis of autoimmune hepatitis - minimal

parameters (revised)

Differential diagnosis

1. Acute hepatitis - This diagnosis is excluded when there is

negativity to IgM-HAV (hepatitis A virus) and anti-HBc IgM (type ,

PCR-HCV (type C), IgM (cytomegalovirus), VCA-IgM-VEB (Epstein Barr

virus).

2. disease - This disease should be considered in all cases of

hepatic disease with acute or chronic onset and negative serological

markers. In childhood, neurological symptoms are not frequent, and

liver disease is preponderant; Kayser-Fleischer ring is almost always

absent.

3. Alpha-1 antitrypsin deficiency - This protein should be assessed

in any case of chronic liver disease. Low levels suggest alpha-1

antitrypsin deficiency, but the golden standard for the diagnosis is

the performance of phenotype through isoelectric focalization or

polymerase chain reaction. PiZZ phenotype defines the deficiency, and

this may lead or not to hepatic cirrhosis.

4. Primary sclerosing cholangitis - This disease may start still in

the neonatal period (31). In childhood, few patients present symptoms

of itching, arthralgia, or complications of the disease. The

suspicion is present when there is hepatosplenomegaly or

hepatomegaly, with canalicular enzymes usually significantly elevated

(gammaglutamyltranspeptidase and alkaline phosphatase); it may be

associated with inflammatory bowel disease. The definitive diagnosis

is carried out with cholangiography showing intra and/or extrahepatic

alterations in the biliary tree. There are also mixed forms of

autoimmune and primary sclerosing cholangitis, whose diagnosis is

frequently difficult. In patients presenting autoimmune hepatitis,

positive FAN, and positive anti-actin antibody, the performance of

retrograde cholangiography is sometimes of paramount importance,

particularly in cases with symptoms suggestive of autoimmune

hepatitis and that do no respond well to associated corticotherapy or

to azathioprine, even with canalicular enzymes not significantly

altered.

5. Chronic hepatitis type C - The etiologic relationship between

hepatitis C virus and autoimmune hepatitis, particularly of type 2

(anti-liver-kidney microsome antibodies type 1) has been intensely

studied (26). About one-third of patients infected with hepatitis C

virus present several immunologic alterations, with the presence of

autoantibodies, particularly anti-liver-kidney microsome antibodies

type 1, but also antimuscle antibodies and FAN. It seems that the

analogy between autoimmune hepatitis and type C chronic hepatitis is

related only to the autoreactivity profile, with the presence of

autoantibodies. Data suggest that cases with FAN and/or antimuscle

autoantibodies present more activity of the disease.

Treatment

The efficacy of the treatment with immunosuppressants is assessed by

the patient's ability to induce complete remission, as well as to

maintain it after the suspension of the drug; the main objective is

the definitive control of the disease.

In 1993, the International Autoimmune Hepatitis Group (24)

established a set of criteria to uniformly define the therapeutic

response, considering that several schemes were efficacious; these

schemes were reviewed in 1999 (25), only in order to get simplified.

They would serve to evaluate any therapeutic regimen used.

Complete response

The complete response consists of one or both of the following items:

- Accentuated improvement of symptoms and normalization of all the

hepatic function tests (aspartate and alanine aminotransferases),

bilirubins, and immunoglobulins) in the 1st year counting from the

beginning of the treatment and being maintained by at least 6 months

during therapy, or minimal inflammatory activity showed by hepatic

biopsy at any moment of the treatment.

- Accentuated improvement of the symptoms and decrease of at least

50% in all hepatic function tests in the 1st month of treatment, with

aspartate and alanine aminotransferase levels decreasing until

reaching less than two times the superior limit of normality within 6

months, and during any reductions, until reaching the ideal

therapeutics, or minimal inflammatory activity showed by hepatic

biopsy within 1 year.

Relapse

It consists of one or both of the following items:

- Increase in the levels of serum aspartate and alanine

aminotransferases higher than two times the superior limit of

normality, or inflammatory activity showed by hepatic biopsy, with or

without the reappearance of symptoms and after the complete response,

as defined previously.

- Reappearance of the symptoms, requiring increase (or

reintroduction) of immunosuppressants, accompanied by any increase in

aspartate and alanine aminotransferases after previous complete

response.

Currently, the survival rate in treated pediatric patients is over

90% 10 years after the diagnosis, and the rate of remission induced

by therapy with immunosuppressants is approximately 80%. About 50% of

the patients remain in remission or present only a mild form of the

disease when the medication is withdrawn (27). The monitoring of the

therapeutic response is important to assess the patient's and his/her

relatives' adhesion to drugs and procedures prescribed along the

treatment. Treatment consists of giving prednisone alone or

associated with azathioprine.

In childhood, two schemes may be used (27):

1. Initial:

a) Sole drug: prednisone at 1-2 mg/kg/day (maximal dose 60 mg/day).

Associated therapy: prednisone at 1-2 mg/kg/day, and azathioprine

at 1.5-2 mg/kg/day.

2. Maintenance:

a) Sole drug: prednisone at 1 mg/kg/day, or azathioprine at 1.5-2

mg/kg/day.

Associated therapy: prednisone at 0.1-0.25 mg/kg/day, and

azathioprine at 1.5-2 mg/kg/day.

The monitoring should be performed every 6-8 weeks during the first 6

months of treatment; posteriorly, it should happen every 3-6 months,

until 2 years have passed since the beginning of treatment. The

reduction in corticosteroid is carried out at each medical

appointment, until the maintenance dose is achieved. At each visit,

clinical evaluation is performed, as well as the following laboratory

exams: complete hemogram, platelet count, coagulogram (with dosages

of prothrombin time, activated partial thromboplastin time, and

thromboplastin time), serum determination of aminotransferases

(aspartate and alanine), gammaglutamyltranspeptidase, alkaline

phosphatase, total and fraction protein, and bilirubin

electrophoresis. Hepatic biopsies are performed whenever possible

(depending on the coagulogram values) before the beginning and 2

years after the treatment, provided that the patient has responded to

the treatment. Patients that do not respond adequately to the

treatment should undergo percutaneous or endoscopic retrograde

cholangiography, and the performance of another biopsy is not

recommended, since it does not help in the treatment. The suspension

of drugs rarely occurs, and when it does, it is usually in type 2.

Some patients remain in remission for months and years; however, they

should be monitored every 6 months. The first sign of relapse is

usually loss of appetite, anorexia, myalgia, tiredness, and/or

alterations in the hepatic function tests. Most children are

asymptomatic when they relapse. The handling of relapses depends on

the severity of the case. Sometimes, initial doses are given, but

usually corticosteroid levels are low. Patients that relapse should

receive drugs during the whole life, usually associated. All patients

with type 3 autoimmune hepatitis relapse after drug withdrawal. In

the literature, the relapse rate after the suspension of drugs in

adults ranges from 50 to 87% of the cases (27-29); This confirms the

impossibility of interrupting the treatment. Studies carried out at

the Clínica Mayo show a histological aggravation in relation to the

number of relapses (29).

In cases of therapeutic failure, with evolution to hepatic

insufficiency, the hepatic transplantation should be considered. The

recurrence of the disease after surgery is extremely rare, and

autoantibodies disappear completely (30).

Gilda Porta - Professor of Pediatrics, Universidade de São o

(USP) School of Medicine. Physician, Liver Transplantation Group,

Hospital Sírio Libanês.

Correspondence:

Gilda Porta

Rua João Moura, 647 cj 71

CEP 05412-911 São o, SP - Brazil

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