Autoimmune hepatitis in childhood

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Abbreviations

AIH

autoimmune hepatitis

ANA

anti‐nuclear antibody

anti‐LC1

antibody to liver cytosol type 1

anti‐LKM1

antibody to liver kidney microsomal type 1

anti‐SLA

antibody to soluble liver antigen

ASC

autoimmune sclerosing cholangitis

ERCP

endoscopic retrograde cholangiopancreatography

IBD

inflammatory bowel disease

IF

immunofluorescence on rodent tissue

IgA

immunoglobulin A

IgG

immunoglobulin G

LT

liver transplantation

MRCP

magnetic resonance cholangiopancreatography

pANNA

peripheral anti–nuclear neutrophil antibody

SMA

smooth muscle antibody.

Autoimmune hepatitis (AIH) is characterized histologically by interface hepatitis, biochemically by increased transaminase levels, and serologically by circulating autoantibodies and high immunoglobulin G (IgG) levels.

Clinical Features (Table 1)

Table 1.

Clinical, Immunological, and Histological Features at the Presentation of AIH1, AIH2, and ASC2, 4

	AIH1	AIH2	ASC
Median age (years)	11	7	12
Females (%)	75	75	55
Mode of presentation (%)
Acute hepatitis	47	40	37
Fulminant hepatic failure	3	25	0
Insidious onset	38	25	37
Complication of chronic liver disease	12	10	26
Associated immune diseases (%)	22	20	48
IBD (%)	20	12	44
Family history of autoimmune disease (%)	43	40	37
Bile duct changes on cholangiography (%)	0	0	100
ANA/SMA (%)	100	25	96
Anti‐LKM1 (%)	0	100	4
pANNA (%)	45	11	74
Anti‐SLA (%)a	58	58	41
Increased IgG level (%)	84	75	89
Partial IgA deficiency (%)	9	45	5
Histology (%)
Interface hepatitis	92	94	60
Biliary features	28	6	35

^aMeasured with a radioligand assay.

There are two forms of juvenile AIH: type 1 (AIH1), which is positive for smooth muscle antibodies (SMAs) and/or anti‐nuclear antibodies (ANAs), and type 2 (AIH2), which is positive for antibody to liver kidney microsomal type 1 (anti‐LKM1) and/or antibody to liver cytosol type 1 (anti‐LC1). In both forms, approximately 80% of the patients are girls.1

In children/adolescents, a form of sclerosing cholangitis characterized by ANA and SMA positivity, high levels of IgG, and interface hepatitis [autoimmune sclerosing cholangitis (ASC)] is as prevalent as AIH1.2 In the absence of bile duct imaging, these patients are diagnosed with AIH1. ASC is often associated with inflammatory bowel disease (IBD) and affects boys and girls equally.

Other autoantibodies of diagnostic importance are peripheral anti–nuclear neutrophil antibodies (atypical peripheral anti–nuclear cytoplasmic antibodies or pANNAs) and antibody to soluble liver antigen (anti‐SLA). pANNAs are frequent in AIH1 and ASC. Anti‐SLA is found in 40% to 60% of AIH1, AIH2, and ASC patients and indicates a more severe course.3

AIH1 accounts for two‐thirds of cases and often presents around puberty, whereas AIH2 affects younger children, including infants. IgG levels are usually raised, but 16% of AIH1 patients and 25% of AIH2 patients have normal levels. Immunoglobulin A (IgA) deficiency is common in AIH2 patients.4

There are three clinical patterns of AIH presentation: an acute pattern (rarely fulminant, particularly in AIH2) in approximately 50%, an insidious pattern (progressive fatigue, relapsing jaundice, headache, anorexia, and amenorrhea) in approximately 50%, and complications of portal hypertension (splenomegaly and bleeding varices) in approximately 10%.4 Hence, autoimmune liver disease should be excluded for all children with symptoms/signs of liver disease not ascribable to known pathologies.

AIH2 can be part of the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome: the liver disease is present in approximately 20% of cases.1

Diagnosis

The diagnosis of AIH is based on inclusion and exclusion criteria established by the International Autoimmune Hepatitis Group for adult patients.5, 6 The International Autoimmune Hepatitis Group scoring system is not suitable for juvenile AIH because diagnostically relevant autoantibodies often have titers lower than those considered positive in adults1 and because it does not allow a distinction to be made between AIH and ASC; this distinction can be made only with cholangiography (Table 2).

Table 2.

Diagnostic Criteria for Juvenile Autoimmune Liver Disease

Criteria	Disease
Elevated transaminase levels
Exclusion of viral hepatitis, Wilson's disease, and nonalcoholic steatohepatitis
Positive for autoantibodies
ANA/SMA (IF titer ≥ 1:20)	AIH1 or ASC
Anti‐LKM1 (IF titer ≥ 1:10) and/or anti‐LC1	AIH2
Anti‐SLA (enzyme‐linked immunosorbent assay)	AIH1, AIH2, ASC
Elevated IgG levels
Liver biopsy
Interface hepatitis
Multilobular collapse
Cholangiogram (MRCP or ERCP)
Normal	AIH
Abnormal	ASC

Treatment

AIH responds well to immunosuppression, even in the presence of poor synthetic function and/or established cirrhosis. Prednisolone is started at 2 mg/g/day (maximum = 60 mg/day) and is gradually decreased over the course of 4 to 8 weeks in parallel with progressive normalization of transaminase levels to reach the minimal maintenance dose (usually 5 mg/day) able to sustain normal transaminase levels. During the first 6 to 8 weeks, liver function tests are checked weekly to fine‐tune the treatment and avoid severe side effects. The initial goal is to obtain an 80% reduction of the baseline transaminase levels within 8 weeks of treatment. If progressive normalization of transaminases is not observed, azathioprine is added at a starting dose of 0.5 mg/kg/day; in the absence of toxicity, this is increased up to a maximum of 2 to 2.5 mg/kg/day until remission (i.e., normal transaminase levels). Azathioprine is not recommended as a first‐line treatment because of its potential hepatotoxicity, particularly in severely jaundiced patients. Transaminase normalization may take several months.4

Relapse on treatment affects approximately 40% and requires a temporary increase in the steroid dose. Often, relapse is due to nonadherence, particularly in adolescents.1 The risk of relapse is higher if steroids are administered on alternate days. Small daily doses are more effective at maintaining disease control and preventing the need for high‐dose steroid pulses during relapses, and they do not ultimately affect growth.7

Treatment is recommended for at least 3 years before cessation is considered. Treatment withdrawal can then be attempted if liver function tests and IgG levels have been persistently normal, autoantibodies have been either undetectable or detectable at very low titers (ANA/SMA < 1:10; negative findings for anti‐LKM1) for at least 12 months, and a liver biopsy sample shows no inflammatory changes. Treatment withdrawal is successful in approximately 20% of AIH1 patients, but this is rare for AIH2 patients.4 Autoantibody titers and IgG levels correlate with disease activity. The prognosis for juvenile AIH is good; most patients survive a long time with excellent quality of life on low‐dose medication. End‐stage liver disease requiring liver transplantation (LT) despite treatment, however, develops in approximately 9% of patients within 15 years of the diagnosis.4

The induction of remission has been reported with cyclosporine A alone for 6 months followed by maintenance with low‐dose prednisone and azathioprine,8 but whether this is better than the standard treatment awaits an evaluation in controlled studies.

The induction of remission with the doses of budesonide used in adults has been disappointing in juvenile AIH, with a low remission rate after 12 months of treatment.9 Large controlled studies are needed to establish appropriate doses for children.

In the 10% of patients who do not respond to standard immunosuppression or are intolerant of azathioprine, mycophenolate mofetil (20 mg/kg twice daily) has been successfully used.1 In cases of persistent nonresponse, a calcineurin inhibitor (cyclosporine A or tacrolimus) should be considered.

In ASC, with early treatment, parenchymal liver damage responds well to the same immunosuppressive schedule used for AIH; ursodeoxycholic acid (15‐20 mg/kg/day) is usually added, and there is good medium‐/long‐term survival. However, the bile duct disease progresses in approximately 50% of patients, and this leads to LT in approximately 20%.2 The progression of liver disease is associated with poorly controlled IBD.

LT is indicated for AIH patients with fulminant hepatic failure (with encephalopathy) and for AIH patients (approximately 10%) and ASC patients (approximately 23%) who develop end‐stage liver disease despite treatment (Table 3). After LT, the reported recurrence rates are approximately 20% for AIH and 27% to 67% for ASC.10 AIH recurrence does not affect post‐LT outcomes, whereas ASC recurrence, which is often associated with uncontrolled IBD, leads to retransplantation in a high proportion of patients.10

Table 3.

Responses to Treatment and Outcomes for Children With AIH1, AIH2, and ASC2, 4

	AIH1	AIH2	ASC
Remission rate (%)	97	87	89
Median time to remission (months)	6	9	2
Relapse rate (%)	42	46	45
Cessation of treatment (%)	19	0	5
LT rate (%)	6a	13a	23
Disease recurrence after transplantation (%)	0	0	67

*Including patients with fulminant hepatic failure.

This table has been adapted with permission from Mieli‐Vergani and Vergani.11

De Novo AIH After LT

AIH can arise de novo after LT in children not undergoing transplantation for autoimmune disease, and it is characterized by interface hepatitis (Fig. 1), high IgG levels, and positive findings for autoantibodies (ANAs, SMAs, and classic and atypical anti‐LKM1).10 The same schedule of prednisolone and azathioprine used for classic AIH is highly effective and leads to excellent graft/patient survival, whereas the standard antirejection treatment fails; this makes an early diagnosis essential for preventing graft loss. Rapamycin is reportedly effective in difficult‐to‐treat patients.10

Figure 1.

De novo AIH after LT: a dense portal tract infiltrate with numerous plasma cells invading the surrounding parenchyma (interface hepatitis; hematoxylin and eosin, original magnification ×100).