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contribute to this impression [52]. Patients can be asymptomatic, referred to a phy-

sician because of incidental identication of an abnormal liver prole or they can

present with fatigue, joint pains, and some signs of liver disease in association

withan abnormal liver prole suggestive of hepatocellular injury. A history of inter-

mittently abnormal liver prole can be identied sometimes. Hypergammaglobulinemia

is a characteristic laboratory nding in AIH.In approximately a third of patients,

AIH can present as fulminant hepatitis and laboratory ndings not suggestive of that

disease, including normal IgG and total serum gammaglobulin concentrations and

negative or low titers of ANA.In these patients, liver histology is useful; however,

expertise in obtaining a liver biopsy, usually transjugularly, is necessary to get liver

tissue in this type of patient. Liver histology tends to show centrilobular massive

and submassive necrosis [53].

As hepatitis, including AIH, can be triggered by some medications, information

on drug intake or herbal preparations must be sought, and the suspected triggering

agent stopped. Drug-induced hepatitis can have features of AIH; a diagnosis of AIH

has to be considered in all cases, and also, the suspected agent has to be stopped

immediately. In general, drug-induced hepatitis tends to resolve in association with

the discontinuation of the medication; however, treatment with corticosteroids is

indicated in patients who present with orid features of both diseases as, indeed,

AIH may be part of the pathogenetic process in some patients. Histologically, AIH

and drug-induced hepatitis have similar features. At presentation, cirrhosis was not

found in any of the patients with drug-induced AIH in a retrospective study that

included 261 patients, with a prevalence of nine percent [54]. However, it was pres-

ent in twenty percent of the patients with AIH proper [54]. Minocycline and nitro-

furantoin were identied as the most common causes of drug-induced AIH in this

study [54]. Only two patients were not treated with corticosteroids, and of those

treated, only one patient with drug-induced AIH did not have a complete response

to treatment. In patients in whom corticosteroids were discontinued, hepatitis had

not recurred during a median follow up of 36 months; however, it did recur in

patients with AIH proper [54]. This natural history was interpreted to suggest that

the drug-induced AIH was indeed induced by the drug and not by an underlying

process of immune-mediated inammation [54].

Physical Examination

On physical examination, patients may or may not exhibit signs suggestive of liver

disease, including spider angiomata, jaundice, and ascites. Patients with AIH pre-

senting with fulminant liver failure display signs of hepatic encephalopathy.

The common laboratory ndings are increased serum activity of transaminases

(alanine and aspartate), normal or increased serum concentration of bilirubin, and

modestly increased activity of AP and GGTP. The presence of autoantibodies, as

discussed below, is characteristic of autoimmune hepatitis. ANA and ASMA are the

most prevalent antibodies identied in the serum of patients with this disease.

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Hypergammaglobulinemia is also typical of AIH; serum protein electrophoresis dis-

plays a peak in the gamma globulin region, consistent with a high serum concentra-

tion of immunoglobulin gamma.

Autoantibodies

AIH is associated with autoantibodies in most cases, although their absence does

not exclude the diagnosis in patients with other features characteristics of the dis-

ease. AIH type 1 refers to the disease in adults, associated, in general, with antinu-

clear antibodies (ANA) directed to centromere, ribonucleoproteins, and

ribonucleoprotein complexes [55–57] and anti-smooth muscle antibodies (ASMA),

directed to actin and other nonactin cellular components [58]. AIH type 2 is charac-

terized by the presence of anti-LKM antibodies, predominantly in children [56].

The occurrence of anti-LKM, together with ANA and anti-SMA, is reported as less

than 4% of patients with AIH. Other autoantibodies can be found in the serum of

patients with AIH and, when present, help to conrm the diagnosis in atypical cases,

including antibodies to soluble liver antigen (anti-SLA) [59] and antibodies to liver

cytosol type 1 (anti-LC1) (Table4.1).

Table 4.1 Autoantibodies in autoimmune hepatitis

Type of

antibody Antigen

Indirect

immunouorescence

characteristics

Reported clinical

relevance References

Antinuclear Centromere,

ribonucleoproteins,

and ribonucleoprotein

complexes

Homogenous or

speckled nuclear

staining of hepatocytes

Characterizes AIH

1, long-term

prognosis is better

than in

seronegative,

associated with

HLA-DR4

[

55]

Anti-double

stranded

DNA

Double

stranded-DNA

Stain of kinetoplast

Crithidia luciliae, used

as substrate

Common in ANA

positive AIH 1,

associated with

HLA DR4, may

portend inferior

immediate

response to

steroids

[

57]

Anti-

smooth

muscle

Actin and nonactin

cellular components

including vimentin,

skeletin, tubulin,

desmin

Smooth muscle bers

within blood vessels and

muscularis usually

sought on mucosa of

murine stomach and

kidney

AIH 1 [58]

(continued)

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Histology

The histological hallmark of AIH is interface hepatitis (Fig.4.1) associated with

conuent hepatic necrosis and bridging brosis[65].The inammatory inltrate of

autoimmune hepatitis is comprised of lymphocytes (Fig. 4.2) and plasma cells

Table 4.1 (continued)

Type of

antibody Antigen

Indirect

immunouorescence

characteristics

Reported clinical

relevance References

Anti-

LKM 1

Anti-

LKM 2

Anti-

LKM 3

Anti-LKM

CYP2D6

CYP2C9

UGT

CYP1A2

Cytoplasm of

hepatocytes and

proximal renal tubules

AIH 2, genetic

predisposition to

HLA-B14, DR3,

and C4A-QO, and

AIH in

association with

APECED

[

56]

SLA Sec synthase N/A Specic for AIH

1, portends

relapse and severe

disease, and

associated with

HLA-DR3 and

DR4

[

59]

LCI 1 FTCD Cytoplasm of

hepatocytes sparing

those surrounding the

central vein

AIH type 2 [

60]

ASGPR Type 2

transmembrane

glycoprotein

expressed on the

hepatocyte membrane

N/A Correlates with

histological

severity

[61]

ANA antinuclear antibodies; Anti-LKM anti-liver kidney microsomes antibodies; SLA soluble liver

antigen; Anti-LC1 anti-liver cytosol antibody; ASGPR anti-asialoglycoprotein receptor antibodies;

CYP cytochrome P 450; UGT Uridine diphosphate glucuronosyltransferase, family of enzymes

that catalyze the covalent addition of glucuronic acid to several lipophilic chemicals; their function

concerns the detoxication of numerous exogenous and endogenous substances by increasing their

polarity, improving their suitability to be excreted in bile or urine[62]; FTCD formiminotransfer-

ase cyclodeaminase enzyme that catalyzes the conversion of histidine to glutamic acid[63]; Anti-

SLA anti-soluble liver antigen antibodies, identied as being the same as anti-liver pancreas

antibodies; Sec synthase a pyridoxal phosphate (PLP)-dependent protein that converts the serine

attached to tRNA [Ser] Sec to Sec to an aminoacrylyl intermediate that serves as the acceptor for

activated selenium; when selenium is donated, selenocysteyl-tRNA[Ser]Sec is formed [64].

Selenocysteyl-tRNA[Ser]Sec is a carrier molecule upon which selenocysteine is biosynthesized

and also, donates selenocysteine, the 21st naturally occurring amino acid of protein, to the forming

polypeptide chain in response to specic UGA codons [

64]; AIH 1 and 2 Autoimmune hepatitis

type 1 and type 2; APECED autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

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(Fig.4.3) of the CD8 population [65].Lobular inammatory inltrates may be iden-

tied, as well as rosette formation, and even in acute presentation, nodular forma-

tion can be present [52, 65]. The predictive value of periportal plasma cells for

relapse in patients with autoimmune hepatitis is important. Liver histology from

patients who had achieved remission and had been taken off steroids, and subse-

quently had relapsed had, characteristically, plasma cell inltration in the portal

tracts, in contrast to patients who had not relapsed. These results tend to suggest that

liver histology should be reviewed prior to drug discontinuation in patients with

AIH.In addition, a pathogenetic mechanism mediated by plasma cells in patients

who relapsed is suggested[66]. One of the possible mechanisms of disease perpetu-

ation by plasma cells may be their relationship with activated stellate cells, which

Fig. 4.2 Lymphocytes

(arrow) inltrating between

surviving hepatocytes

within the inammatory

inltrate in a case of

autoimmune hepatitis.

Hematoxylin and Eosin,

original magnication 40X

Fig. 4.3 Plasma cells

(arrows) within

inammatory inltrate in a

case of autoimmune

hepatitis. Hematoxylin and

Eosin, original

magnication 40X

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are pivotal in the generation of brosis, and with which they colocalized in an

immunohistochemical study[67]; the number of plasma cells was reported to cor-

relate with stellate cells and brosis scores. After treatment, patients in remission

had a decreased number of plasma cells, hepatic stellate cells, and degree of bro-

sis[66]. Indeed, an immunohistological study of paired biopsies before and after

clinical remission from children with AIH was reported to reveal a decrease in

hepatic stellate cells activation, as evidenced by attenuation of anti-alpha smooth

muscle immunoreactivity, in association with a reduction in inammation score,

although no changes in brosis were documented [68]; these results suggest that a

decrease in hepatic stellate deactivation, in association with treatment, may be asso-

ciated with the halting of brogenic mechanisms.

Emperipolesis is the penetration of a cell by another of a different lineage that

remains intact [65]. It was reported in 65.3% of patients with AIH, from a group of

101, a nding signicantly higher than in disease control liver biopsies, and associ-

ated with higher serum activity of aminotransferases, inammatory activity, and

degree of brosis than in disease control biopsies. CD8 T cells were the majority of

lymphocytes identied in emperipolesis, which was associated with induction of

cleaved caspase-3 expression, and notable in areas of apoptosis, which has sug-

gested that emperipolesis may induce apoptosis, which then may contribute to the

liver injury in AIH [69].

Drug-induced hepatitis and AIH have similar histological features, hence the

importance of a detailed history of medications and over the counter preparations

taken in relationship with the onset of hepatitis. Prominent intra-acinar lymphocyte

inltrate or canalicular cholestasis without portal inammation, rosette formation,

rich portal plasma inltrates, and intra-acinar eosinophils has been identied as

common features in AIH, whereas a combination of prominent intra-acinar lympho-

cyte inltrates, canalicular cholestasis, andfewerthan two of the features that were

highly exhibited by the livers affected by AIH support a diagnosis of drug-induced

hepatitis. Interestingly, eosinophils were more prevalent in AIH than in drug-

induced hepatitis [70].

Diagnostic Scores forAIH

Diagnostic criteria for autoimmune hepatitis have been published and presented as

scoring systems to diagnose this disease[52, 71, 72]. The revised scoring system

most frequently used during the decade that followed its publication [52] is adapted

in Tables 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, and 4.8 and presented from the perspective of

approaching a patient in whom AIH is suspected. A simplied score system, the

variables of which are titers of autoantibodies, the serum concentration of IgG, liver

histological features, and exclusion of viral hepatitis, has been published[71] and

summarized in Tables 4.9, 4.10, and 4.11.

Comparative analyses of the two scoring systems have been reported. In a study

that comprised 153 patients in whom a diagnosis of denitive AIH had been made

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Table 4.2

Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor [52]—History

Yes (score) No (score)

Use of potential hepatotoxins (e.g., medications, herbal substances)

temporally related to the hepatitis

−4 +1

History of autoimmune diseases in patient or rst-degree relatives +2 No score

Alcohol intake

<25g/day +2 No score

>60g/day −2 No score

Table 4.3 Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor—Physical exam

Score

Female gender +2

Table 4.4

Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor—Laboratory ndings

Ratio Score

ALP:AST (or ALT) ratio <1.5 +2

1.5–3.0 0

>3.0 −2

>2.0 +3

1.5–2.0 +2

1.0–1.5 +1

<1.0 0

Titer

ANA, SMA, or LKM-1 >1:80 +3

1:80 +2

1:40 +1

<1:40 0

AMA Positive −4

Hepatitis serology Positive Negative

−3 +3

AP alkaline phosphatase; AST aspartate aminotransferase; ALT alanine aminotransferase

Hepatitis serology: IgM anti-HAV, HBsAg, IgM anti-HBc, anti-HCV, and HCV-RNA.If a viral

etiology is considered in spite of negative viral hepatitis serology as listed here, serology for cyto-

megalovirus,Epstein Barr virusand hepatitis Emust be obtained as these viral infections may be

thecause of the hepatitis

Ratio calculated as units above the upper limit of normal (ULN) (i.e., (AP IU/L ÷ (ULN) AP ÷

(IU/L AST÷ ULN AST)

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Table 4.5

Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor—Histology

Score

Interface hepatitis +3

Predominance of lymphocytes and plasma cells in inammatory inltrate +1

Rosettes formation of hepatocytes +1

Absence of the three ndings cited above –5

Biliary epithelial cell changes suggestive of PBC (e.g., ductopenia, granulomata, bile

ductular proliferation, concentric brosis of bile ducts) or PSC (e.g., concentric brosis

of bile ducts)

–3

Findings suggestive of other etiologies –3

Table 4.6 Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor—Items characterized as optional

Score

Presence of autoantibodies identied in AIH including pANCA, anti-LC1, anti-SLA, and

anti-ASGPR in the absence of typical autoantibodies (see above)

HLA DR3 or DR4in Caucasian and Japanese subjects

Any other HLA class II antigen

Table 4.7

Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor—Follow-up period under therapy with immunosuppressants

Denition 1 and score Denition 2 and score

Complete

response as

described

under

denitions 1

or 2

Notable improvement of symptoms and

normalization of serum liver associated

enzyme activity, serum bilirubin and IgG

concentrations within 1year and sustained

followed by a 6month period on

maintenance therapy or liver histology at any

point during the period described above

displaying not more than minimal

inammatory activity, or denition 2

Substantial improvement of

symptoms in association with a

decreaseby 50% of the serum

abnormalities of the liver tests

from baseline, during the rst

month of treatment, followed by

a continuous decrease in the

activity of AST and ALT to less

than twice the ULN within

6months during any reduction

toward maintenance therapy, or

liver histology within 1year

displaying minimal inammatory

activity

+2 +2

Relapse as

described

under

denitions 1

or 2

Increased activity of AST and ALT activities

to higher than twice the ULN, or ndings on

liver histology consistent with active disease,

either in association or not with symptoms,

after a complete remission, as dened above,

or denition 2

Return of symptoms requiring

administration of therapy, or

increase of dose, if the patient is

on medications for AIH, after a

complete response as dened

above

+3 +3

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based on the revised original scoring system [52], 11 (7.1%) were classied as

probable AIH by the use of the simplied scoring system [71], and two (1.3%) were

identied as not having AIH.With the use of the simplied scoring system[71],

ve patients were classied as having denitive and ve as not having AIH, of the

13 who had been classied as probable AIH.Discordance in the diagnosis between

the two scoring systems was 15%, comprising 23 patients, whereas concordance

was exhibited in 127 patients (97.7%) for denite and for probable diagnosis in 3

Table 4.9 Simplied autoimmune hepatitis scoring system[71]—Laboratory variables

Titer Score

Autoantibodies

ANA or ASMA

≥1:40 1

ANA or ASMA ≥1:80

Anti-LKM or ≥1:40 2

Anti-SLA Positive

Change

Serum concentration of IgG >ULN limit 1

>1.10 times upper 2

Within normal limits

Absence of viral hepatitis 2

Table 4.10 Simplied autoimmune hepatitis scoring system—Histology

Features Score

Typical of AIH: interface hepatitis, lymphocytic or lymphoplasmacytic inltration of

portal tracts and lobules, emperipolesis, and hepatic rosette formation

Compatible with AIH: lymphocytic inltration of portal tracts and lobular activity

without all the features considered typical

Atypical: ndings of other diseases

Table 4.11 Simplied autoimmune hepatitis scoring system—Interpretation of the summation

of scores

Total score

≥6 Probable AIH

≥7 Denite AIH

Table 4.8 Systematic application of the revised scoring system for the diagnosis of autoimmune

hepatitis in the evaluation of a patient with suspected disease and scores associated with presence

or absence of the factor—Interpretation of scores

Denite AIH Probable AIH

Pre treatment >15 10–15

Post treatment >17 12–17

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100

(2.4%) [72]. Remission with treatment in patients diagnosed as having denite or

probable AIH by the use of the revised original scoring criteria was 68% and 75%,

respectively, and the failure of therapy was 16 and 0%, respectively. Seventy and 50

percent of patients classied by the simplied scoring criteria as having denite

and probable AIH, respectively, achieved remission in association with therapy, and

15 and 25% of patients, respectively, failed treatment. These responses were not

different in relation to the score used. In this study, ve patients had non diagnostic

scores as per the simplied scoring criteria, four of whom responded to treatment

with remission, and one was still on therapy at the time of the study completion

[72]. Neither of the two scoring systems compared classied patients with chronic

liver disease from alcohol, viral hepatitis, or primary biliary cholangitis (PBC) with

those who had denite AIH; two patients with primary sclerosing cholangitis (PSC)

were classied as AIH by both systems [72]. The comparison of sensitivity, speci-

city, and positive predictability and negative predictability of the original scoring

system with the simplied scoring system was 100 and 95%, 73 and 90%, 82 and

92%, 67 and 83%, and 100 and 97%, respectively [72], in this study from a center

in the United States. The simplied scoring system has been considered to be sim-

pler in its application than the revised system, of being able to exclude more fre-

quently other liver diseases, and of carrying a higher specicity than that of the

latter, with the revised scoring system being reported as 95% specic and 90%

sensitive, but a sensitivity of 65% and a specicity of 100% for the simplied scor-

ing system [73]. A study that included patients with overlap syndrome, AIH, and

other liver diseases in association with AIH, documented that the simplied and the

revised scoring systems werespecic at97.9 and 97%, respectively[74]. However,

it was noted that the ability to identify AIH in patients with other liver diseases was

signicantly lower withthe use of the simplied scoring system thanwiththe use

of the revised scoring system, liver histology being the only factor able to reveal

that information [74]. In this regard, from in a series that included 25 patients from

Asia, Europe, and the United States, 20 of whom had chronic hepatitis C and ve

chronic hepatitis B, it was reported that, according to the revised scoring system,

72% met the criteria for the diagnosis of probable AIH, and 48% met these criteria

as per the simplied scoring system [75]; however, none of the patients were diag-

nosed with denite AIH by either score [73]. These ndings underscore the impor-

tance of the differential diagnosis in evaluating patients with liver disease.

Specically, the existence of a viral disease, i.e., hepatitis, does not exclude the

presence of another liver disease, including metabolic and autoimmune disease.

Accordingly, a full liver disease workup is required in the approach to a patient

with suspected liver disease. This study [75] tends to support those of the prior

report that documented that liver biopsy was necessary to conrm the coexistence

of additional liver pathology [73]. It is also emphasized that the use of the scoring

systems is complementary to clinical judgment. Autoimmune markers by ELISA

methodology have not been used to validate the scoring system [72]; this is neces-

sary as clinical laboratories have moved to this type of assay as the methodology

for these tests.

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101

Overlap Syndromes

There are clinical, histological, and biochemical features of AIH, PBC, and PSC

[76] that coexist in a minority of patients with any of these diseases. These entities

have been named overlap syndromes, mostly comprising AIH and PBC cases, and

have been the subject of some controversy regarding their existence as separate enti-

ties, as part of the same disease, as one disease changing to another, or some char-

acteristics of each. The diagnostic criteria for the overlap syndrome of AIH with

PBC have been named the Paris criteria[77] and include at least two of the three

accepted criteria for the diagnosis of each of those individual diseases, and has a

sensitivity and specicity of 92% and 97%, respectively. For PBC, the diagnostic

criteria are: (1) serum AP activity at least two times the upper limit of normal or

serum GGTP ve times the upper limit of normal, (2) positive antimitochondrial

antibody (AMA), and (3) liver biopsy exhibiting the lesion of chronic nonsuppura-

tive destructive cholangitis (i.e., orid bile duct lesion). For AIH, the diagnostic

criteria are: (1) serum activity of ALT at least ve times the upper limit of normal,

(2) serum IgG concentrations at least twice the upper limit of normal or positive

ASMA, and (3) interface hepatitis on liver histology [77]. The diagnosis of AIH

overlapping PSC is the absence of AMA and typical cholangiogram (e.g., strictures)

by MRI or ERCP [78, 79].

AIH with overlap to PBC has been reported to occur in approximately 7–10% of

patients and AIH with PSC 8–17%. AMA negative PBC, small duct PSC, autoim-

mune PSC, and immunoglobulin G4-associated cholangitis are considered variants

of the overlap syndromes[76]. The difculty in diagnosing overlap syndromes with

a high level of certainty seems to have encouraged scoring systems to classify

patients with an overlap of AIH on PBC and PSC. Features of AIH overlap were

identied in 137 cases of histologically diagnosed PBC by the use of the revised

scoring system, with 2% being found to meet criteria for denite AIH and 62% for

probable AIH; no cases of denite AIH overlap were identied, with 19% meeting

criteria for probable AIH overlap [80]. The main contribution to identifying overlap

AIH in PBC was the presence of ANA, associated autoimmune disorders, and his-

tological ndings [80]. In this regard, the serological prole of patients with PBC

with an overlap to AIH has been documented to consist of a predominance of anti-

dsDNA antibodies, found in 60% of patients with overlap syndrome of AIH and

PBC, in contrast to a 4% prevalence in patients with PBC, and 26% of patients with

AIH.The dual presence of anti-dsDNA antibodies and AMA was only reported in

2% of patients with PBC or AIH, in contrast to 47% of samples from patients with

overlap syndrome, a nding that could help identify this not so distinct entity [81].

Analyses of data from patients with PSC have documented a prevalence of AIH

overlap of 6 and 11%, in contrast to what ranged from 30 to 50% by the use of the

original scoring system [82]. However, others have documented a prevalence of

19% of overlap of AIH in PSC with the use of the revised system[83]. With the

advent of the simplied scoring system, several published retrospective studies have

reported the ability of the revised and the simplied scoring system for the

4 Autoimmune Hepatitis

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