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Criterios HAI hepatology 2008 48 (5) 1540-1548[1]

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AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE
Performance Parameters of the Diagnostic Scoring
Systems for Autoimmune Hepatitis
Albert J. Czaja
The diagnostic criteria for autoimmune hepatitis (AIH) have been codified by an international panel, and a revision of the original scoring system based on 12 clinical components
has been promulgated. A simplified scoring system has been proposed recently that is based
on four clinical components. The goals of this study were to compare the performance
parameters of the revised original and the simplified scoring systems and to determine the
prowess of each as a diagnostic instrument. Diagnostic scores were determined using each
scoring system in 435 patients with diverse chronic liver diseases, including 153 individuals
with AIH by codified clinical criteria. The sensitivity, specificity, and predictability of each
scoring system for the pretreatment diagnosis of AIH were determined. The revised original
scoring system had greater sensitivity for the diagnosis than the simplified scoring system
(100% versus 95%), and seven patients diagnosed as AIH using the revised original system
were nondiagnostic by the simplified system (5%). The revised original scoring system also
ascribed a diagnosis of AIH to 20 of 21 patients with cryptogenic chronic hepatitis, whereas
only five patients were similarly classified by the simplified system (95% versus 24%). The
simplified system had greater specificity (90% versus 73%) and predictability (92% versus
82%) for AIH than the revised original system, and it more commonly excluded the diagnosis in other diseases with concurrent immune features (83% versus 64%). Conclusion: The
revised original scoring system performs better in patients with few or atypical features of
AIH, and the simplified system is better at excluding the diagnosis in diseases with concurrent immune manifestations. Each system has attributes that can be exploited. (HEPATOLOGY
2008;48:1540-1548.)
T
he diagnostic criteria for autoimmune hepatitis
(AIH) were codified by an international panel in
1993,1 and these recommendations were updated
in 1999.2 They provided clinical guidelines for the definite and probable diagnosis of AIH and a scoring system
that allowed assessment of the strength of the diagnosis.
The revised original scoring system could be applied before or after corticosteroid treatment, and it was intended
as a research tool to allow characterization of study populations within and between clinical studies.2
Abbreviations: AIH, autoimmune hepatitis; ELISA, enzyme-linked immunosorbent assay; HLA, human leukocyte antigen; IgG, immunoglobulin G; ROC, receiver operating characteristic.
From the Division of Gastroenterology and Hepatology, Mayo Clinic College of
Medicine, Rochester, MN.
Received May 9, 2008; accepted June 26, 2008.
Address reprint requests to: Albert J. Czaja, M.D., Mayo Clinic College
of Medicine, 200 First Street S.W., Rochester, MN 55905. E-mail:
czaja.albert@mayo.edu; fax: 507-284-0538.
Copyright © 2008 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22513
Potential conflict of interest: Nothing to report.
1540
The virtues of the revised original scoring system
were that it facilitated objective comparisons between
patient populations and accommodated individuals
with atypical manifestations. By grading phenotypic,
biochemical, serological, epidemiological, genetic, and
histological features, the scoring system had a high sensitivity (97% to 100%) for AIH,2 and it could render
the diagnosis in individuals who lacked certain classical
features (hypergammaglobulinemia or autoantibodies)
or who manifested atypical components (antimitochondrial antibodies, cholestasis, or atypical histological features).3,4 The scoring downgrades associated
with absent or inconsistent features could be overridden by the strength of other manifestations.
The major limitation of the scoring system was its
complexity (13 components and 29 possible grades), and
its awkwardness as an easily applicable clinical tool.2,3 To
resolve these difficulties, the International Autoimmune
Hepatitis Group developed a simplified scoring system
based on four components and twelve possible grades.5
Unlike the original scoring system, the simplified system
was tested in patients from Germany, Japan, Spain,
HEPATOLOGY, Vol. 48, No. 5, 2008
Greece, Norway, Brazil, Austria, the United Kingdom,
and the United States, and it was also validated in diverse
control populations that included cholestatic, viral, metabolic, toxic, and genetic hepatic disorders.5 In this fashion, the universality of the simplified scoring system was
established, and its high sensitivity (88%) and specificity
(97%) for AIH were demonstrated.
The simplified scoring system has not been compared
with the revised original scoring system, and its ability to
replace this more comprehensive assessment has not been
established. Each system was developed with different intentions (research use versus clinical use), and their applications may have different consequences. The
comprehensive nature of the revised original scoring system may identify individuals with AIH that would not be
detected with the simplified system. Alternatively, the
simplified system may include in the diagnosis individuals
with atypical features that would have otherwise been excluded by the revised original scoring method. Each system may have different and even complementary roles,
and the simplified system may be an expansion rather
than a revision of the current diagnostic armamentarium.
In this retrospective study, we compare the performance parameters of the revised original2 and simplified5
scoring systems of the International Autoimmune Hepatitis Group in patients satisfying conventional pretreatment clinical criteria for the diagnoses of autoimmune,
viral, cholestatic, alcoholic, and metabolic chronic liver
diseases, and we determine the concordance and discrepancies between these systems in the same patient populations. In this fashion, we determine the diagnostic
prowess of these systems and the complementarity or redundancy of the information they provide.
Patients and Methods
Study Population
Four hundred thirty-five patients who had been evaluated in a uniform fashion by the author were selected for
study because they each satisfied conventional clinical criteria for their particular diagnosis at presentation, and
they had each been assessed for the features common to
both scoring systems, including serum immunoglobulin
G (IgG) levels, conventional autoantibodies by indirect
immunofluorescence, serological markers for hepatitis B
and hepatitis C viruses, and histological examination.2,5
One hundred fifty-three patients (35%) were diagnosed as having definite or probable AIH according to the
codified clinical criteria promulgated by the International
Autoimmune Hepatitis Group in 19992 and reflected in
the practice guidelines of the American Association for
the Study of Liver Diseases in 2002.6 These patients were
assessed at presentation, and their diagnosis was based on
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the codified clinical (not scoring) criteria espoused in
1999.2 One hundred thirty-nine patients (91%) received
conventional corticosteroid regimens according to protocols published previously,6 including prednisone alone
(51 patients) or a lower dose of prednisone in conjunction
with azathioprine (88 patients). Four patients had received investigational therapies, and 10 patients had not
been treated at the time of diagnosis. The treatment outcomes of remission or treatment failure were assessed by
applying the definitions reported.6
One hundred twenty patients (28%) were diagnosed
with conventional clinical criteria as having chronic hepatitis C7; 18 patients (4%) were diagnosed as having
chronic hepatitis B7,8; 46 patients (10%) were diagnosed
as having nonalcoholic fatty liver disease9,10; 42 patients
(10%) were diagnosed as having primary biliary cirrhosis11; 24 patients (6%) were diagnosed as having primary
sclerosing cholangitis12; 21 patients (5%) were diagnosed
as having cryptogenic chronic hepatitis13-16; and 11 patients (2%) were diagnosed as having chronic alcoholic
liver disease.17 These 435 patients were further classified
into the categories of autoimmune (n ⫽ 153), viral (n ⫽
138), metabolic (n ⫽ 46), cholestatic (n ⫽ 66), cryptogenic (n ⫽ 21), and alcoholic (n ⫽ 11) liver disease. The
study was approved by the Institutional Review Board of
the Mayo Clinic.
Clinical and Laboratory Assessments
Clinical examinations and conventional laboratory
tests of liver inflammation and function had been performed at presentation and before the institution of specific therapy in all patients in accordance with a published
protocol.6 Concurrent extrahepatic disorders of an immune nature had been sought in a systematic fashion as
described.6 Serum protein electrophoresis had been assessed via immunonephelometry in 431 patients (99%),
and serum IgG concentrations had been determined via a
similar method in all patients.
Smooth muscle antibodies18 and antinuclear antibod19
ies had been assessed via indirect immunofluorescence
on murine tissue sections in all patients. Antibodies to
liver kidney microsome type 1 had been evaluated via
indirect immunofluorescence on murine tissue sections in
402 patients (92%),20 and antimitochondrial antibodies
had been assessed in all but one patient (99%) via indirect
immunofluorescence (n ⫽ 428)21 or via enzyme-linked
immunosorbent assay (ELISA) (n ⫽ 6).22 All patients had
undergone at least three of the conventional serological
tests for autoantibodies, and 403 patients (93%) had been
evaluated using all four tests.
Hepatitis B surface antigen (Ortho Diagnostic Systems, Inc., Raritan, NJ) and antibodies to hepatitis C
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HEPATOLOGY, November 2008
Table 1. Revised Original Pretreatment Scoring System of the International Autoimmune Hepatitis Group*
Component
Sex
AP:AST (or ALT) ratio
␥-globulin or IgG level above normal
ANA, SMA, or anti-LKM1 titers
AMA
Viral markers
Drugs
Alcohol
Result
Points
Component
Result
Points
Female
⬎3
⬍1.5
⬎2.0
1.5–2.0
1.0–1.5
⬍1.0
⬎1:80
1:80
1:40
⬍1:40
⫹2
⫺2
⫹2
⫹3
⫹2
⫹1
0
⫹3
⫹2
⫹1
0
HLA
Immune disease
DR3 or DR4
Thyroiditis, colitis, others
⫹1
⫹2
Other markers
Anti-SLA, actin, LC1, pANCA
⫹2
Histological features
Positive
Positive
Negative
Yes
No
⬍25g/day
⬎60g/day
⫺4
⫺3
⫹3
⫺4
⫹1
⫹2
⫺2
Treatment response
Interface hepatitis
Plasmacytic
Rosettes
None of above
Biliary changes
Other features
Complete
Relapse
⫹3
⫹1
⫹1
⫺5
⫺3
⫺3
⫹2
⫹3
Pretreatment aggregate score:
Definite diagnosis >15
Probable diagnosis 10 –15
Abbreviations: AP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; anti-LC1, antibody to liver
cytosol type 1; anti-LKM1, antibodies to liver/kidney microsome type 1; anti-SLA, antibody to soluble liver antigen; AST, aspartate aminotransferase; HLA, human
leukocyte antigen; IgG, immunoglobulin G; pANCA, perinuclear anti-neutrophil cytoplasmic antibodies; SMA, smooth muscle antibody.
*Adapted from Alvarez et al.2
virus (Abbott Laboratories, North Chicago, IL) had been
assessed in all patients via second-generation ELISA.
Histological Assessments
Liver tissue examinations had been performed at accession in all patients, and the liver specimens have been
examined by members of the liver pathology working
group at the Mayo Clinic. The pathological diagnoses
were rendered in accordance with pre-established criteria.23,24 Our previous validation studies have indicated
that the reproducibility of the histological interpretation
was 94%.23,25
Human Leukocyte Antigen Determinations
Four hundred ten patients (94%) had been evaluated
for the class II (DR locus) human leukocyte antigens
(HLA) by polymerase chain reaction with sequence-specific oligonucleotide probes (n ⫽ 187),26 restriction
fragment length polymorphism (n ⫽ 217),27 or microlymphocytotoxicity (n ⫽ 6).28
Scoring Systems
The revised original scoring system of the International
Autoimmune Hepatitis Group and the simplified system
were applied to all patients.2,5 The 12 components of the
revised original scoring system that were applicable to the
pretreatment evaluation (Table 1) were graded in the 410
patients who had undergone HLA testing. The 25 pa-
tients untested for HLA were graded for the other 11
components that were applicable to the pretreatment
evaluation (Table 1). Only the pretreatment criteria for
the diagnosis of AIH were applied, and a score of 10 to 15
points supported a probable diagnosis and a score of ⬍15
points supported a definite diagnosis by this revised original method (Table 1).2
The four components of the simplified scoring system
were graded in all patients (Table 2). A score of 6 points
constituted a probable diagnosis of AIH using the simplified system, and a score of ⱖ7 points constituted a definite diagnosis (Table 2).5
Statistical Analyses
Sensitivity, specificity, and predictability were the performance parameters for diagnosis that were assessed for
each scoring system. The clinical diagnoses based on codified criteria for AIH pretreatment2 and on conventional
clinical criteria for the other chronic liver diseases7-17 were
the gold standards of diagnosis.
Sensitivity. Sensitivity reflected the number of patients with definite or probable AIH by the codified clinical criteria who were diagnosed similarly by the scoring
system under study (true positives) divided by the sum of
true positives plus the number of patients with the disease
by the codified clinical criteria who were undiagnosed by
the scoring system under study (false negatives).
Specificity. Specificity reflected the number of pa-
HEPATOLOGY, Vol. 48, No. 5, 2008
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Table 2. Simplified Scoring System of the International
Autoimmune Hepatitis Group*
Component
Autoantibodies
ANA or SMA
ANA or SMA
Antibodies to liver kidney microsome type 1
Antibodies to soluble liver antigen
Absent autoantibodies
Immunoglobulin level
Immunoglobulin G
Histological Findings
Morphological features of AIH
Viral Disease
Absence of viral hepatitis
Result
Points
ⱖ1:40
ⱖ1:80
ⱖ1:40
Positive
None
⫹1
⫹2
⫹2
⫹2
0
⬎UNL
⬎1.1 ULN
Normal
⫹1
⫹2
0
Compatible
Typical
Incompatible
⫹1
⫹2
0
No viral markers
Viral markers prsent
⫹2
0
ⱖ7
6
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nal scoring system and the simplified scoring system
(Analyze-it Software, Ltd., Leeds, United Kingdom).
Results
Pretreatment Aggregate Score: Definite diagnosis
Probable diagnosis
Abbreviations: ANA, antinuclear antibodies; SMA, smooth muscle antibodies;
ULN, upper limit of normal range. *Adapted from Hennes et al.5
tients without AIH by the codified clinical criteria who
were also discounted by the scoring system under study
(true negatives) divided by the sum of true negatives plus
the number of patients without AIH by the codified clinical criteria who were diagnosed with the disease by the
scoring system under study (false positives).
Predictability. Predictability reflected the number of
true positives and true negatives divided by the entire
study population. Positive predictability reflected the
number of true positives divided by the sum of true positives and false positives. Negative predictability reflected
the number of true negatives divided by the sum of true
negatives and false negatives.
Receiver Operating Characteristic Curves. Receiver
operating characteristic (ROC) curves were plotted to illustrate the sensitivity and specificity of the revised origi-
Comparison of Scoring Systems for Autoimmune
Hepatitis. The revised original scoring system of the International Autoimmune Hepatitis Group graded all patients who satisfied the codified clinical criteria for AIH as
having either definite (n ⫽ 140) or probable (n ⫽ 13)
AIH. In contrast, the simplified scoring system made the
diagnosis of definite (n ⫽ 132) and probable (n ⫽ 14)
AIH less frequently (95% versus 100%) (Table 3). The
frequency of a definite diagnosis was greater by the revised
original scoring system than by the simplified scoring system (92% versus 86%), and seven patients (5%) who had
been graded as definite (n ⫽ 2) or probable (n ⫽ 5) AIH
according to the revised original scoring system had nondiagnostic scores using the simplified scoring system (Table 3).
Of the 140 patients graded as definite AIH using the
revised original scoring system, 13 patients (9%) were
classified as probable (n ⫽ 11) or no AIH (n ⫽ 2) using
the simplified system. Of the 13 patients with probable
AIH using the revised original scoring system, 10 patients
were classified as definite (n ⫽5) or no AIH (n ⫽ 5) using
the simplified system. The scoring systems rendered concordant diagnoses of definite (n ⫽ 127) or probable AIH
(n ⫽ 3) in 130 patients (85%). Discordant diagnoses of
AIH were rendered in 23 patients (15%).
Scoring Discrepancies for Autoimmune Hepatitis.
Sixteen of the 23 patients with discrepant diagnoses for
AIH had either been scored as definite AIH using the
revised original scoring system and probable AIH using
the simplified scoring system (n ⫽ 11) or definite AIH
using the simplified system and probable AIH using the
revised original scoring system (n ⫽ 5). These differences
related to the points awarded or subtracted for features
Table 3. Comparison of Clinical Diagnoses and Scoring Diagnoses Using Each System
Diagnosis by Scoring System, n (%)
Definite AIH
Probable AIH
Nondiagnostic
Clinical Diagnosis
Original*
Simplified
Original*
Simplified
Original*
Simplified
AIH (n ⫽ 153)
Cryptogenic hepatitis (n ⫽ 21)
Chronic alcoholic liver disease (n ⫽ 11)
Chronic hepatitis B (n ⫽ 18)
Chronic hepatitis C (n ⫽ 120)
Primary biliary cirrhosis (n ⫽ 42)
Primary sclerosing cholangitis (n ⫽ 24)
Nonalcoholic fatty liver disease (n ⫽ 46)
140 (92)
1 (5)
0 (0)
0 (0)
0 (0)
0 (0)
2 (8)
1 (2)
132 (86)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (8)
0 (0)
13 (8)
19 (90)
4 (36)
6 (33)
32 (27)
2 (5)
7 (29)
3 (7)
14 (9)
5 (24)
0 (0)
2 (11)
10 (8)
6 (14)
3 (13)
1 (2)
0
1 (5)
7 (64)
12 (67)
88 (73)
40 (95)
15 (63)
42 (91)
7 (5)
16 (76)
11 (100)
16 (89)
110 (92)
36 (86)
19 (79)
45 (98)
*Original ⫽ revised original scoring system (Table 1).
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HEPATOLOGY, November 2008
Table 4. Features Associated with Diagnostic Discrepancies
Between Scoring Systems for Autoimmune Hepatitis
Number of Scoring Adjustments
Accounting for Discrepant Diagnoses
in 23 Patients
Features Unrecognized or
Scored Less via Simplified
Scoring System
Female sex
Concurrent immune diseases
AP/AST ratio ⬎1.5 and ⬍3
AP/AST ratio ⬍1.5
Abnormal serum ␥-globulin
and normal serum IgG levels
High-titer autoantibodies
AMA present
Exposure to possible
hepatotoxic medication
HLA DRB1*03, DRB1*04, or
both
Atypical histological features
Original
Scoring
System*
Upgrades
Original
Scoring
System*
Downgrades
16
6
—
21
—
—
2
—
8
14
—
—
—
3
—
1
13
—
—
1
Abbreviations: AP, alkaline phosphatase; AMA, antimitochondrial antibodies;
AST, aspartate aminotransferase; IgG, immunoglobulin G.
*Original scoring system ⫽ revised original scoring system (Table 1).
graded in the revised original scoring system but not in the
simplified scoring system (Table 4).
Points awarded by the revised original scoring system
for female sex (n ⫽ 9), abnormal serum ␥-globulin level
despite normal serum IgG level (n ⫽ 6), high-titer autoantibodies (n ⫽ 10), ratio of serum alkaline phosphatase
to aspartate aminotransferase levels less than 1.5 (n ⫽ 11),
concurrent immune diseases (n ⫽ 3), and presence of
HLA DRB1*03, DRB1*04 or both (n ⫽ 5) were the bases
for ascribing a definite diagnosis to the 11 patients graded
as having a probable diagnosis using the simplified scoring
system.
Points subtracted or not awarded by the revised original scoring system for male sex (n ⫽ 3), atypical histological features (n ⫽ 1), antimitochondrial antibodies (n ⫽
3), ratio of serum alkaline phosphatase to aspartate aminotransferase levels greater than 1.5 and less than 3.0 (n ⫽
2), lack of concurrent immune diseases (n ⫽ 5), exposure
to possible hepatotoxic medication (n ⫽ 1), and lack of
classical HLA markers (n ⫽ 2) were the bases for ascribing
a probable diagnosis to the five patients graded as having
a definite diagnosis using the simplified scoring system.
Similarly, the discrepant diagnoses in the seven patients graded definite or probable AIH using the revised
original system and nondiagnostic for AIH using the simplified system related to features not counted or graded as
strongly using the simplified system, including female sex
(n ⫽ 5), concurrent immune diseases (n ⫽ 3), abnormal
serum ␥-globulin levels despite normal serum IgG levels
(n ⫽ 2), high-titer autoantibodies (n ⫽ 1), ratio of serum
alkaline phosphatase to aspartate aminotransferase levels
less than 1.5 (n ⫽ 7), and the presence of HLA
DRB1*0301, DRB1*0401, or both (n ⫽ 5).
The nature and frequency of the features that resulted
in diagnostic upgrades or downgrades in the revised original scoring system and that contributed to the diagnostic
discrepancies with the simplified scoring system are detailed in Table 4.
Treatment Outcomes of Probable and Definite Autoimmune Hepatitis. In the 139 treated patients with
definite (n ⫽ 131) or probable (n ⫽ 8) AIH using the
revised original scoring criteria, remission (68% versus
75%, P ⬍ 0.9) and treatment failure (16% versus 0%,
P ⫽ 0.6) occurred with similar frequencies. In the 134
treated patients with definite (n ⫽ 122) or probable (n ⫽
12) AIH using the simplified scoring criteria, the frequencies of remission (70% versus 50%, P ⫽ 0.2) and treatment failure (15% versus 25%, P ⫽ 0.4) were also similar.
Of the five treated patients who had nondiagnostic scores
for AIH using the simplified scoring system, four entered
remission, and one continues on therapy.
Comparison of Scoring Systems for Excluding
Other Diagnoses. Neither the revised original nor the
simplified scoring system graded patients with chronic
alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, or primary biliary cirrhosis as having definite AIH
(Table 3). Both systems graded two patients with primary
sclerosing cholangitis as definite AIH, and the original
scoring system made the same designation in one patient
with cryptogenic chronic hepatitis and one patient with
nonalcoholic fatty liver disease.
Probable diagnoses of AIH were rendered more commonly using the revised original scoring system in all diagnostic categories except for primary biliary cirrhosis.
The revised original scoring system graded 20 of 21 patients with cryptogenic chronic hepatitis (95%) as having
definite (n ⫽ 1) or probable (n ⫽ 19) AIH, whereas the
simplified scoring system designated only five patients in
the probable category (24%) (Table 3). Of 282 patients
with diagnoses other than AIH using clinical criteria, 166
(59%) had concurrent immune features, including autoantibodies (n ⫽ 50), abnormally increased serum IgG
level (n ⫽ 71), or both (n ⫽ 45). The revised original
scoring system graded 60 of these patients (36%) as having either definite (n ⫽ 3) or probable (n ⫽ 57) AIH,
whereas the simplified system designated only 29 patients
(17%) in this fashion. The simplified scoring system more
commonly excluded the diagnosis of AIH in patients with
other diagnoses and concurrent immune manifestations
than the revised original scoring system (83% versus
64%).
HEPATOLOGY, Vol. 48, No. 5, 2008
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Table 5. Diagnosis of Autoimmune Hepatitis in Other Disease Categories by Original and Simplified Scoring Systems
Diagnosis by Scoring System, n (%)
Definite AIH
Probable AIH
Nondiagnostic
Clinical Diagnostic Category
Original*
Simplified
Original*
Simplified
Original*
Simplified
Non-AIH (n ⫽ 282)
Chronic viral hepatitis (n ⫽ 138)
Chronic nonviral liver disease (n ⫽ 144)
Chronic cholestatic liver disease (n ⫽ 66)
Chronic metabolic liver disease (n ⫽ 46)
4 (1)
0 (0)
4 (3)
2 (3)
1 (2)
2 (1)
0 (0)
2 (1)
2 (3)
0 (0)
73 (26)
38 (28)
35 (24)
9 (14)
3 (7)
27 (10)
12 (9)
15 (11)
9 (14)
1 (2)
205 (73)
100 (72)
105 (73)
55 (83)
42 (92)
253 (89)
126 (91)
127 (88)
55 (83)
45 (98)
*Original ⫽ revised original scoring system (Table 1).
Definite diagnoses of AIH were unusual with each
scoring system when clinical categories of chronic liver
disease rather than individual clinical diagnoses were assessed (Table 5). In contrast, probable diagnoses were
more common when using the revised original scoring
system versus the simplified scoring system in patients
with different categories of chronic liver disease, especially
in the patients with chronic viral hepatitis. The only exception was in the patients with chronic cholestatic liver
disease in whom the performance parameters of each scoring system were identical.
Performance Parameters for Diagnosing Autoimmune Hepatitis. Both scoring systems had high sensitivity, specificity, and predictability for diagnosing definite
or probable AIH when compared with the codified clinical criteria for diagnosis (Table 6). The revised original
scoring system had complete sensitivity and negative predictability for AIH, but it was less specific for the diagnosis than the simplified scoring system and it had a lower
positive predictability (Table 6). The advantages of the
simplified scoring system reflected its better performance
in patients with diagnoses other than AIH (Table 3).
Scores higher than 10 in the revised original scoring system (Fig. 1A, right to left on the ROC curve) and higher
than 6 in the simplified scoring system (Fig. 1B, right to
left on the ROC curve) increased the specificity of the
scoring system but decreased its sensitivity.
Table 6. Performance Parameters of Scoring Systems for
Diagnosis of Autoimmune Hepatitis
Performance
Parameters
Original
Scoring
System,* n
(%)
Simplified
Scoring
System, n (%)
Sensitivity
Specificity
Predictability
Positive predictability
Negative predictability
153/153 (100)
205/282 (73)
358/435 (82)
153/230 (67)
205/205 (100)
146/153 (95)
253/282 (90)
399/435 (92)
146/175 (83)
253/260 (97)
*Original scoring system ⫽ revised original scoring system (Table 1).
Fig. 1. ROC curves for (A) the revised original scoring system and (B)
the simplified scoring system in the 435 patients. The point on the ROC
curve that has been proposed as the minimum pretreatment diagnostic
score for probable AIH is shown for each system. Left to right movement
along the ROC curve decreases the diagnostic score, thereby increasing
the sensitivity and decreasing the specificity of the score.
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Discussion
This study indicates that each scoring system proposed
by the International Autoimmune Hepatitis Group has
high sensitivity and specificity for the diagnosis of definite
or probable AIH and that the simplified scoring system
has superior specificity and predictability for the disease
(Table 6). The scoring systems, however, are not fully
interchangeable, and in certain clinical circumstances,
one system may be more valuable than the other.
Autoimmune hepatitis does not have pathognomonic
clinical, laboratory, or histological features, and other
chronic liver diseases—including alcoholic, viral, cholestatic, drug-induced, and metabolic disorders—may have
similar findings (Table 3).29-33 The higher specificity and
predictability of the simplified scoring system for AIH
may reduce the diagnostic confusion that can be associated with the trappings of hypergammaglobulinemia and
autoantibody positivity.7
Furthermore, scores for the ratio of the serum alkaline
phosphatase level to the aspartate aminotransferase level,
serum ␥-globulin concentration, serum IgG level, autoantibody titer, and individual histological features may be
more reflective of the severity than the nature of the liver
disease (Table 1). These features are intrinsic to the revised original scoring system,2 and they may render a
greater number of probable diagnoses of AIH in diseases
that are etiologically distinct than the simplified system.34
Mild forms of AIH may not be as well recognized via the
revised original scoring system, whereas its application to
all patients with chronic liver disease may promote designations of an overlap syndrome. In the former circumstance, the clinical diagnosis may not be supported by the
scoring method,35 and in the latter circumstance, a diagnosis may be rendered that lacks a codified definition or
treatment strategy.29,33,34
Alternatively, the simplified scoring system may underestimate the diagnosis of AIH in patients who have few
or atypical features of the disease. Seven of the 153 patients (5%) designated as having AIH using the revised
original scoring system were not graded as AIH via the
simplified scoring system (Table 3). Furthermore, 20 of
21 patients who had been designated as cryptogenic
chronic hepatitis were recognized as AIH using the revised original scoring system in contrast to only 5 patients
(24%) graded using the simplified scoring system (Table
3). The revised original scoring system ensures the application of a comprehensive diagnostic template, and in this
fashion, it may render the diagnosis of AIH in patients
unrecognized via the simplified scoring system or designated as cryptogenic chronic hepatitis using conventional
clinical criteria (Table 3).
HEPATOLOGY, November 2008
Discrepancies in diagnosis have clinical relevance only
if they mask the outcome of the disease or affect therapeutic actions. Not all patients with AIH have immediately
life-threatening disease or require corticosteroid treatment, and the underestimation of the diagnosis of AIH in
a patient with few or atypical features may have no clinical
consequence.36 The seven patients who were not diagnosed with AIH via the simplified scoring system may not
have suffered from the misclassification. Similarly, the
consequences of misclassifying a patient as definite or
probable AIH is unlikely to affect prognosis or treatment
since the therapeutic decision is based on the clinical manifestations of disease severity.6 Furthermore, the response
to corticosteroid therapy provides reassurance about the
accuracy of the original diagnosis, and a treatment trial is
encouraged by the revised original scoring system.2
The threshold of tolerance for a misclassification by the
scoring systems is unknown, and until the natural history
of nonclassical AIH and the prognostic distinctions between definite and probable AIH are fully clarified, an
error in diagnosis via any scoring system cannot be rationalized. In this study, the patients with probable or definite diagnoses of AIH via each scoring system responded
as well to corticosteroid therapy, and this finding supported the accuracy of the codified clinical criteria of the
International Autoimmune Hepatitis Group for identifying patients with the diagnosis of AIH, strengthened the
gold standard against which each scoring system was
tested in this study, and suggested that distinctions between probable and definite diagnoses of AIH did not
impact on treatment outcome. Four of the five treated
patients with nondiagnostic scores for AIH via the simplified scoring system responded well to corticosteroid
treatment, and this finding supported the value of applying the revised original scoring system to patients with few
or atypical findings at presentation.
Another discrepancy between the scoring systems was
in the reclassification of cryptogenic chronic hepatitis as
AIH (Table 3). Many patients with seronegative chronic
hepatitis respond as well to corticosteroid therapy as patients with classical AIH,15,16 and any denial or delay in
the institution of effective treatment in such patients may
affect their outcome. The ability of the revised original
scoring system to support the diagnosis of AIH in patients
who lack the conventional serological markers of the disease may encourage treatment and impact on outcome.
No scoring system can supplant clinical judgment in
making a diagnosis or in instituting proper therapy, but a
scoring system that sharpens clinical judgment— especially in difficult cases—must benefit the patient, and the
revised original scoring system may have this advantage.
HEPATOLOGY, Vol. 48, No. 5, 2008
Each scoring system was developed for different reasons, and our study indicates that they each contribute in
different ways to the diagnosis of AIH. The revised original scoring system was developed to ensure comparable
study populations in clinical trials, and it renders an aggregate score that reflects all aspects of the clinical syndrome. Its capacity in this regard remains unchallenged,
and it agrees most closely with the codified clinical criteria
for the diagnosis of AIH (Table 3). Our findings indicate
that the revised original scoring system is most useful in
the evaluation of patients with few or no features of AIH
but in whom other diagnostic considerations have been
excluded. In this fashion, it can support the clinical diagnosis in patients who lack classical features or who have
atypical manifestations.
The simplified scoring system was developed to provide a convenient tool that can be easily applied to support the clinical diagnosis, and it performs well against the
revised original scoring system in this regard (Table 6). Its
major values are its diagnostic specificity, especially in
excluding patients with etiologically distinctive disease
who have concurrent immune trappings, and the ease of
its application in the clinical setting. Until the diagnostic
relevance of overlap or variant syndromes of AIH is codified, the simplified system will minimize diagnostic confusion and focus the treatment decision. Its simplicity and
accuracy make it a feasible adjunct to everyday clinical
practice.
Both scoring systems exist to support, not supersede,
the clinical diagnosis, and their existence can be justified
only by this capacity. Their clinical relevance relates to
their ability to strengthen diagnostic confidence— especially in individuals with confusing clinical phenotypes—
and this ability relates to the scoring attributes particular
to each system. Future studies must compare the performance parameters in patients with different levels of disease severity and with autoantibodies detected via ELISA
instead of indirect immunofluorescence. As serological
assays based on ELISA replace those based on indirect
immunofluorescence in many centers, each scoring system must continue to be updated and revised.
In conclusion, both scoring systems of the International Autoimmune Hepatitis Group have high sensitivity and specificity for the diagnosis of AIH, and the
simplified scoring system has superior specificity and predictability. The systems are not interchangeable, and each
may have value in certain clinical situations. The revised
original scoring system has greater value in diagnosing
patients with few or atypical features of AIH, especially in
patients with cryptogenic or autoantibody-negative
chronic hepatitis, and the simplified scoring system can
exclude the diagnosis more frequently in patients with
CZAJA
1547
etiologically distinctive disease who have concurrent immune manifestations. Each system has been validated
against codified clinical criteria for the diagnosis, and each
can support but not supersede the clinical diagnosis.
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