Diagnostic Value and Utility of the Simplified
International Autoimmune Hepatitis Group (IAIHG)
Criteria in Acute and Chronic Liver Disease
Andrew D. Yeoman, Rachel H. Westbrook, Thawab Al-Chalabi, Ivana Carey, Nigel D. Heaton, Bernard C. Portmann, and
Michael A. Heneghan
Diagnostic criteria for autoimmune hepatitis (AIH) have been created and revised by the
International Autoimmune Hepatitis Group (IAIHG). Simplified criteria have been created,
but remain independently unvalidated. We report on the diagnostic accuracy of the simplified criteria in patients across a range of diagnoses, including a subset of patients presenting
with fulminant liver failure who required liver transplant. Patients with AIH and non-AIH
etiologies of liver disease were identified from dedicated patient databases. Parameters relevant to the simplified and 1999 IAIHG criteria were recorded, and sensitivity, specificity,
and positive and negative predictive values for scores of >6 (probable AIH) and >7 (definite
AIH) were calculated. A total of 549 patients with chronic liver disease were evaluated, (221
with AIH, 26 with variant syndromes, and 302 with non-AIH). For scores >6, sensitivity was
90%, and specificity was 98% with positive and negative predictive values of 97% and 92%,
respectively. For scores >7; sensitivity was 70%, and specificity was 100% with positive and
negative predictive values of 100% and 74%, respectively. Seven false positive diagnoses of
AIH occurred, all with simplified scores of 6. Concordance with 1999 criteria was 90% for
probable and 61% for definite AIH. The frequency of an overall diagnosis of AIH (probable
or definite AIH) among the 70 patients with fulminant liver failure was 24% for simplified
criteria and 40% for 1999 criteria, respectively. Conclusion: The simplified criteria retain
high specificity but exhibit lower sensitivity for scores of >7. The explanations for this are
unclear but may relate to loss of such discriminating information as response to corticosteroids. Prospective evaluation of these criteria is required to corroborate these observations.
(HEPATOLOGY 2009;50:538-545.)
T
he International Autoimmune Hepatitis Group
(IAIHG) was conceived in 1993, consisting of
experts in the field of autoimmune liver disease.
Convened originally to develop criteria to aid in the diagnosis of autoimmune hepatitis (AIH) that would be useful
Abbreviations: AIH, autoimmune hepatitis; ALD, alcoholic liver disease; AUC,
area under the curve; FHF, fulminant hepatic failure; HBV, hepatitis B virus;
HCV, hepatitis C virus; IAIHG, International Autoimmune Hepatitis Group;
IgG, immunoglobulin G; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ROC, receiver operating characteristic.
From the Institute of Liver Studies, King’s College Hospital NHS Foundation
Trust, London, UK.
Received January 23, 2009; accepted April 14, 2009.
Address reprint requests to: Dr. Michael A. Heneghan, Institute of Liver Studies,
King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS,
UK. E-mail: [email protected]; fax: ⫹44-20-3299 3167.
Copyright © 2009 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.23042
Potential conflict of interest: Nothing to report.
538
in clinical practice (distinguishing chronic active hepatitis
related to hepatitis C virus [HCV] infection from that of
a true autoimmune etiology) and to allow comparison
between patients in trials of AIH, these criteria were
widely accepted and incorporated into clinical practice in
both nontransplant1-5 and transplant settings.6,7
The initial deliberations led to diagnostic criteria that
defined individuals into one of three categories: not AIH,
probable AIH, and definite AIH.1 Although cumbersome, when applied, these criteria could be used to diagnose AIH with a high degree of sensitivity, albeit with a
lower specificity. Prospective validation of these cohorts
suggested a sensitivity for the diagnosis of AIH of between
97% and 100%.2-4 Over time, it became evident that
patients with other autoimmune liver conditions such as
primary sclerosing cholangitis (PSC) and primary biliary
cirrhosis (PBC) could be ascribed a false positive diagnosis
of AIH. Therefore, a desire arose, not just to give the
criteria greater specificity, but also to allow easier imple-
HEPATOLOGY, Vol. 50, No. 2, 2009
YEOMAN ET AL.
Table 1. Original Revised (1999) Criteria for the Diagnosis
of AIH
Parameter/Discriminator
Score
Female sex
ALP:AST (or ALT) ratio
⬍1.5
1.5–3.0
⬎3.0
Serum globulins or IgG above normal
⬎2.0
1.5–2.0
1.0–1.5
⬍1.0
ANA, SMA, or LKM-1
⬎1:80
1:80
1:40
⬍1:40
AMA-positive
Hepatitis viral markers
Positive
Negative
Drug history
Positive
Negative
Average alcohol intake
⬍25 g/day
⬎60 g/day
Liver histology
Interface hepatitis
Predominantly lymphoplasmacytic infiltrate
Rosetting of liver cells
None of the above
Biliary changes
Atypical features
Other autoimmune disease(s) in either patient or first-degree relative
Optional additional parameters
Seropositivity for other defined antibodies
HLA DR3 or DR4
Response to therapy
Remission alone
Remission with relapse
Interpretation of aggregate scores
Pretreatment:
Definite AIH
Probable AIH
Posttreatment:
Definite AIH
Probable AIH
⫹2
⫹2
0
⫺2
⫹3
⫹2
⫹1
0
⫹3
⫹2
⫹1
0
⫺4
⫺3
⫹3
⫺4
⫹1
⫹2
⫺2
⫹3
⫹2
⫹1
⫺5
⫺3
⫺3
⫹2
⫹2
⫹1
⫹2
⫹3
⬎15
10–15
⬎17
12–17
Adapted from Alvarez et al.5
(n ⫽ 12) analyzed, which led to criticism of its application. Furthermore, the diagnosis of AIH continued to be
challenging, especially in patients with atypical histological, biochemical, and immunological features.
Consequently, the IAIHG group have recently streamlined the diagnostic criteria, with a sharp focus on the
clinical diagnosis of AIH, and the aim of making them
readily usable “at the bedside”.8 As a result, the new, simplified criteria incorporates only four parameters: presence of associated autoantibodies, immunoglobulin G
(IgG) level, liver histology, and the absence of viral hepatitis. The reduction in number of parameters analyzed was
based on the outcomes of stepwise logistic regression
which identified the above features, when combined, as
having the greatest predictive value for the diagnosis of
AIH with an area under the curve (AUC) on receiver
operating characteristic (ROC) of 0.99. The simplified
IAIHG criteria for the diagnosis of AIH are summarized
in Table 2.
Currently, in this new system, a score of ⱖ6 (8 being
maximum) equates to “probable AIH” whereas a score of
ⱖ7 or above denotes “definite AIH”. The specificity of
this score in the training and validation sets obtained from
retrospective analysis of a multinational cohort is 97% for
a probable diagnosis and 99% for a definite diagnosis of
AIH. Meanwhile, sensitivity was reported as 88% for
probable and 81% for a definite diagnosis of AIH using
these criteria.
What remains uncertain, however, is whether these
criteria remain reproducible outside of the IAIHG multinational patient cohort, although a recent publication has
described performance characteristics of the score in a
series which contributed to the cohort used in the development of the simplified criteria.9 We therefore set out to
examine the validity and utility of the new simplified
IAIHG diagnostic criteria and make an assessment of its
Table 2. Simplified Diagnostic Criteria for the Diagnosis
of AIH
Parameter
mentation in clinical, rather than research, practice. This
led to a revision of the original criteria in 1999.5 These
revised criteria proposed modification of the scores allocated to the presence, or otherwise, of cholestatic liver
function tests, drug history, liver histology, and response
to treatment. The original revised, and widely applied,
IAIHG criteria for the diagnosis of AIH are summarized
in Table 1. The revised score, although a useful adjunct to
the diagnosis of AIH in cases with atypical features, remained cumbersome due to the sheer number of variables
539
ANA or SMA ⫹
ANA or SMA ⫹
LKM ⫹
SLA
IgG Level
Liver Histology
Absence of Viral Hepatitis
Adapted from Hennes et al.8
ⱖ6 points: Probable AIH
ⱖ7 points: Definite AIH
Discriminator
Score
ⱖ1:40
ⱖ1:80 or
ⱖ1:40 or
Positive
⬎Upper limit of normal
⬎1.1⫻ Upper limit of normal
Compatible with AIH
Typical of AIH
No
Yes
⫹1
⫹2
⫹2
⫹2
⫹1
⫹2
⫹1
⫹2
0
⫹2
540
YEOMAN ET AL.
sensitivity and specificity in the diagnosis of AIH both in
comparison to the IAIHG simplified criteria and also to
the original, revised criteria published in 1999.
In addition, it is not known how many patients (if any)
in the simplified IAIHG criteria presented with fulminant
hepatic failure (FHF) and, although this group represents
a relatively infrequent presentation of AIH, these patients
present difficult challenges diagnostically. Therefore, it is
of interest to assess the utility of the simplified criteria in
this patient group. Indeed, work from our own institution, among others, suggests that features of autoimmunity (such as autoantibodies) are a frequent finding in
patients with FHF despite the absence of classical clinical
features of AIH.10-13
Consequently, the utility of the simplified diagnostic
criteria in this setting has not been established. Moreover,
if it was possible to aid the early identification of an autoimmune etiology of FHF, prompt treatment might improve clinical outcome and prevent the need for liver
transplantation.
Patients and Methods
Patients with AIH were identified from a dedicated
database, collected prospectively since 1971, and continuously updated. Patients with other liver diagnoses (hepatitis B virus [HBV] and HCV infection, PSC, PBC,
hemochromatosis, Wilson’s disease, drug-induced liver
injury, nonalcoholic steatohepatitis [NASH], alcoholic
liver disease [ALD], PBC/AIH overlap [variant], and
PSC/AIH overlap [variant] syndromes) were also retrospectively identified from the Institute of Liver Studies,
Liver Database. All diagnoses were made via standard
clinical criteria and, for drug-induced liver injury, by exclusion of all other causes in patients exposed to known
hepatotoxic agents.
For the cohort with non–acetaminophen induced liver
failure, individuals were retrospectively identified from a
dedicated database of patients who underwent transplantation at King’s College Hospital, National Health Service Foundation Trust, London, UK. Individuals who
underwent transplantation were chosen because the majority with this mode of presentation do not have a liver
biopsy before transplant due to the risk of hemorrhage.
Moreover, because the simplified criteria mandate biopsy
material, patients who underwent transplantation for
FHF have explant histological material available for analysis in all instances.
Only patients with complete demographic, laboratory,
and clinical data pertinent to both the simplified and original revised criteria, at the time of their initial diagnosis,
were included in this study. In addition, histology was
available in every patient. Viral hepatitis was excluded via
HEPATOLOGY, August 2009
second-generation and third-generation microparticle enzyme immunoassays for HBV and HCV. For the purposes of this study, overlap syndromes were considered as
AIH, as recently reported by Hennes et al. in their description of the simplified criteria for the diagnosis of
AIH.8 Scores derived from the new, simplified criteria and
the 1999 IAIHG criteria scores were then calculated. The
sensitivity and specificity of these scores for a probable or
definite diagnosis of AIH were then calculated, and the
positive and negative predictive values were recorded.
For patients with FHF, only the relative frequency
with which a probable or definite diagnosis of AIH was
determined by each score was recorded. It is not possible
to calculate the relative sensitivity or specificity for either
the 1999 or simplified diagnostic criteria in this clinical
context, because it is frequently impossible to ascribe a
firm diagnosis in these patients. Diagnosis in these situations is rendered difficult both due to the severity of hepatic insult at presentation (rendering histological
evaluation extremely difficult), as well as the immunoparesis commonly seen in the critically ill patient in whom
both autoantibodies and/or elevated IgG concentrations
may be absent.14 It is, however, of interest to compare the
simplified criteria scores for this patient cohort with the
original revised criteria (as the “gold standard”) scores in
order to document the relative frequencies with which
these criteria identify individuals with either a probable or
definite diagnosis of AIH.
Statistical Analysis. All results are displayed as percentages, or, for continuous variables, median and range.
Comparisons of proportions were analyzed by chisquared test or Fisher’s exact test if any of the variables
equaled less than 5. ROC curves were generated to analyze and compare the accuracy of the simplified and original revised criteria in the diagnosis of AIH. All statistical
analysis was performed using the SPSS statistical software
package version 14 (SPSS Inc., Chicago, IL).
Results
A total of 549 patients, comprising 348 females (63%)
and 201 males (37%), were identified who had the relevant clinical, laboratory, and histological information
available at the time of diagnosis in order to calculate both
the 1999 and the simplified IAIHG criteria scores. Of
these, 221 patients held a diagnosis of AIH (79% female)
with the remaining 328 (53% female) patients having
diagnoses of HBV, HCV, PBC, PSC, NASH, AIH/PBC
overlap, AIH/PSC overlap, ALD, Wilson’s disease, alcohol-related liver disease, hemochromatosis, and drug-induced liver injury. Drug-induced liver injury was related
to statins in two patients, nandrolone in two, amoxicillin/
clavulanic acid in two, methylene-dioxy-N-methamphet-
HEPATOLOGY, Vol. 50, No. 2, 2009
YEOMAN ET AL.
541
Table 3. Demographic and Laboratory Features with 1999 and Simplified Criteria Scores Across Diagnoses
in the Validation Cohort
Liver Diagnosis (n)
AIH (221)
HBV (51)
HCV (53)
NASH (49)
PBC (57)
PSC (49)
PBC/AIH variant (9)
PSC/AIH variant (17)
Alcohol-related (20)
Hemochromatosis (7)
Drug-induced (9)
Wilson’s Disease (7)
FHF (70)
F:M
(%)
AST Median
(range)
AST/Alp Ratio
Median (range)
Autoantibodies†
(%)
79:21
27:73
36:64
57:43
96:4
47:53
100:0
35:65
55:45
14:86
44:56
43:57
74:26
617 (23–4603)
44 (19–1507)
56 (23–210)
46 (21–937)
94 (28–537)
82 (31–883)
131 (44–1200)
202 (63–1750)
62 (27–217)
51 (26–180)
111 (24–13078)
80 (32–347)
958 (66–13874)
0.13 (0.01–3.9)
0.54 (0.03–3.4)
0.53 (0.10–2.6)
0.77 (0.17–4.2)
1.60 (0.60–6.7)
1.60 (0.33–4.8)
0.35 (0.04–2.6)
0.86 (0.10–3.5)
0.80 (0.2–2.4)
0.72 (0.2–1.6)
0.56 (0.01–2.1)
1.00 (0.06–4.9)
0.06 (0.001–0.9)
84
10
26
14
19
20
89
94
20
0
11
0
37
IgG Median
(range)
24.8 (4.7–70.7)
16.3 (13–23.6)
13.8 (9.4–25.4)
11.4 (7.6–29.4)
15.3 (6.9–28.7)
18.8 (7.4–38.0)
18.1 (9.6–26.9)
21.8 (14.0–50.4)
17.8 (11.4–32.8)
15.9 (12–25)
14 (8.0–22.4)
20.2 (7.6–23.0)
11.8 (1.9–63.9)
1999
Score
Simplified
Score
22 (10–28)
0 (0–3)
0 (0–8)
5 (1–13)
1 (0–13)
4 (0–10)
14 (7–17)
13 (9–21)
1 (0–9)
0 (0–3)
1 (0–7)
5 (1–7)
7 (0–18)
7 (3–8)
0 (0–4)
1 (0–4)
2 (2–5)
2 (1–6)
3 (2–6)
5 (4–8)
6 (0–8)
3 (2–6)
2 (2–4)
2 (2–5)
3 (2–4)
3 (2–8)
†Antinuclear antibody, anti–smooth muscle, or anti–liver-kidney microsomal antibody titers ⱖ1:40.
AIH, autoimmune hepatitis; ALP, alkaline phosphatase; AST, aspartate aminotransferase; F, female; FHF, fulminant hepatic failure; HBV, hepatitis B virus; HCV,
hepatitis C virus; IgG, immunoglobulin G; M, male; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
amine (MDMA) in one, synthetic estrogens in one, and
enalapril in another. The laboratory and demographic
features, in addition to the median simplified and 1999
IAIHG scores by underlying liver diagnosis, are summarized in Table 3.
Patients with AIH. The median age at diagnosis of
patients with AIH was 46 years (range 5-80).
The simplified criteria identified 132 (60%) patients as
definite AIH, 73 (33%) patients as probable AIH, and 16
(7%) as not having AIH, in contrast with the 1999 criteria, which for this cohort, identified 220 of 221 (99.5%)
patients with definite AIH and only one as probable AIH
(1 of 221 ⫽ 0.5%). The sensitivity of the simplified criteria in this cohort was 90% for a probable diagnosis of
AIH and 70% for a definite diagnosis. Meanwhile, the
specificity was 98% and 100% for probable and definite
AIH, respectively. The positive and negative predictive
values were 97% and 92% for a probable diagnosis and
100% and 74%, respectively, for a definite diagnosis of
AIH.
In comparison, evaluation of the 1999 IAIHG criteria demonstrated sensitivities and specificities of
100% and 97% for probable AIH and 99.5% and 98%
for definite AIH, respectively. These results are summarized in Table 4.
Concordance between the original revised and the simplified scores for a probable or definite diagnosis of AIH
was 90% and 61%, respectively. An overall diagnosis of
AIH (probable or definite) was recorded in 100% of patients using the 1999 criteria but only in 90% using the
simplified criteria. In addition, ROC curves for an overall
diagnosis of AIH demonstrated an AUC of 0.934 (95%
confidence interval, 9.09-9.59) for the simplified criteria
whereas the 1999 criteria had a greater AUC of 0.979
(95% confidence interval, 0.966-0.993) (Fig. 1).
Variant Syndromes. Of the 26 patients with a variant
syndrome, nine had PBC/AIH and 17 had PSC/AIH. All
26 were treated with prednisolone ⫾ azathioprine following their diagnosis. Fifteen (58%) were ascribed a diagnosis of AIH (seven probable, eight definite) by the
simplified criteria as compared to 24 (92%) patients (15
probable and nine definite) by the 1999 criteria, but this
did not reach statistical significance (P ⫽ 0.17). Patients
with the PSC/AIH variant were more likely to be ascribed
a probable or definite diagnosis of AIH on the simplified
criteria than those with the PBC/AIH variant, although
this again did not reach statistical significance (65% versus 44% P ⫽ 0.42). However, comparison of patients
with pure AIH in contrast to those with variant AIH
revealed that individuals with pure AIH were significantly
more likely to be female (79% versus 58%; P ⫽ 0.013),
icteric at presentation (69% versus 23%; P ⫽ ⬍0.0001),
with a higher bilirubin (59 ␮mol/L versus 17 ␮mol/L;
Table 4. Sensitivity, Specificity, Positive Predictive Value
(PPV), and Negative Predictive Value (NPV) of the Simplified
and 1999 IAIHG Criteria for the Diagnosis of AIH
Criteria
Simplified Criteria
Probable diagnosis AIH (6–7)
Definite diagnosis AIH (ⱖ7)
Overall Diagnosis AIH (ⱖ6)
1999 Criteria
Probable diagnosis AIH (10–15)
Definite diagnosis AIH (ⱖ15)
Overall Diagnosis AIH (ⱖ10)
Sensitivity
Specificity
PPV
NPV
90%
70%
90%
98%
100%
98%
97%
100%
97%
92%
74%
92%
100%
99%
100%
97%
98%
97%
96%
97%
97%
100%
99%
99%
542
YEOMAN ET AL.
Fig. 1. Receiver operating characteristic (ROC) curves for the simplified and 1999 criteria in the diagnosis of AIH.
P ⫽ ⬍0.0001), aspartate aminotransferase (AST) (617.5
IU/L versus 127.5 IU/L; P ⫽ ⬍0.0001) and international
normalized ratio (1.21 versus 0.98; P ⫽ ⬍0.0001) at
diagnosis. Patients with pure AIH also had higher median
simplified criteria biopsy scores (2 versus 1 ⬍ 0.0001) and
were more likely to respond to corticosteroids (95% versus 73% P ⫽ 0.002). Median IgG concentrations trended
toward being higher in patients with pure AIH (24.8 g/L
versus 19.7 g/L) but did not reach significance (P ⫽ 0.16),
whereas the proportion of patients with positive autoantibodies in titers of either ⱖ1:40 or ⱖ1:80 did not significantly differ between the two groups. These results are
summarized in Table 5.
Patients with a False Negative Diagnosis of AIH.
Twenty-seven patients (11%) with a clinical diagnosis of
AIH or variant AIH were not ascribed a diagnosis of AIH
via utilization of the simplified criteria. Having identified
significant clinical differences between patients with pure
and variant AIH, analysis focused on the majority of patients who have pure AIH. Sixteen patients (7.2%) with
HEPATOLOGY, August 2009
pure AIH were not ascribed a diagnosis of AIH on the simplified criteria, whereas the 1999 criteria identified all these
as having either probable or definite AIH. When comparing
patients ascribed a false negative or a true positive diagnosis
of pure AIH, there was no statistical difference between the
ratio of females to males, frequency of an icteric presentation,
bilirubin, AST, and alkaline phosphatase/AST ratio at presentation. The major differences therefore related to lower
concentrations of IgG (median 12.5 versus 25.5 g/dL; P ⫽
⬍0.0001) and proportion of autoantibody titers of ⱖ1:40
(38% versus 84%; P ⫽ ⬍0.0001) or ⱖ1:80 (6% versus
72%; P ⫽ ⬍0.0001) among false negative cases. The demographic, laboratory, and clinical characteristics of patients
with a false negative or true positive diagnosis of AIH is
summarized in Table 6.
In view of the reduction in sensitivity for a diagnosis of
AIH recorded via the utilization of the simplified criteria,
we hypothesized that the addition of responsiveness to
corticosteroids might alter the test performance characteristics. We nominally awarded a score of ⫹2 points for a
complete response and 0 for no response, and used revised
cutoffs of ⱖ7 for probable and ⱖ8 for a definite diagnosis
of AIH. This resulted in improved sensitivity for this cohort from 90% to 96% for a probable diagnosis, and from
70% to 92% for a definite diagnosis of AIH. Subsequently, the sensitivity for an overall diagnosis of AIH
increased from 90% to 96% (P ⫽ ⬍0.0001).
Patients with a False Positive Diagnosis of AIH.
Utilizing the simplified criteria, there were seven false positives out of 328 (2.1%) non-AIH patients ascribed a
Table 5. Comparison of Demographic, Laboratory, and
Clinical Variables at Presentation Between Patients
Clinically Diagnosed with Either Pure or Variant AIH in the
Study Cohort
Variable
F:M
Icteric
Bilirubin
AST
ALP:AST ratio
INR
Cirrhotic
Exclusion of viral
hepatitis
Simplified criteria biopsy
score
Responders to treatment
IgG (g/dL)
Autoantibodies
ⱖ1:40
ⱖ1:80
Pure AIH
n ⴝ 221
Variant AIH
n ⴝ 26
P Value
79:21
69%
59 (7–1096)
617.5 (23–4603)
0.14 (0.01–3.80)
1.21 (0.87–2.80)
49%
58:42
23%
17 (4–246)
156.5 (44–1750)
0.794 (0.03–3.5)
0.98 (0.86–1.60)
38%
0.013
⬍0.0001
⬍0.0001
0.0001
⬍0.0001
⬍0.0001
0.31
100%
100%
0.99
2 (0–2)
95%
24.8 (4.7–70.7)
1 (0–2)
73%
19.7 (9.6–50.4)
⬍0.0001
0.002
0.163
81%
67%
92%
73%
0.14
0.56
ALP, alkaline phosphatase; AST, aspartate aminotransferase; F, female; IgG,
immunoglobulin G; INR, international normalized ratio; M, male.
HEPATOLOGY, Vol. 50, No. 2, 2009
YEOMAN ET AL.
Table 6. Comparison of Demographic, Laboratory, and
Clinical Variables at Presentation Between False Negative
and True Positive Cases of Pure AIH as Ascribed by the
Simplified Diagnostic Criteria
Variable
F:M
Icteric
Bilirubin
AST
ALP:AST ratio
INR
Cirrhotic
Exclusion of viral
hepatitis
Simplified criteria biopsy
score
Responders to treatment
IgG (g/dL)
Autoantibodies
ⱖ1:40
ⱖ1:80
False Negatives
n ⴝ 16
True Positives
n ⴝ 205
P Value
81:19
81%
97 (11–487)
612 (41–2060)
0.11 (0.04–0.75)
1.3 (0.94–2.80)
38%
79:21
68%
58 (7–1096)
619 (23–4603)
0.16 (0.01–3.80)
1.2 (0.87–2.80)
50%
0.99
0.40
0.60
0.59
0.84
0.53
0.34
100%
100%
0.99
543
“seronegative” liver failure. In those diagnosed with AIH
by clinical perception, 50% were identified as such by the
simplified criteria versus 60% for the 1999 criteria. Concordance between the 1999 and simplified criteria for an
overall diagnosis of AIH was 13 of 28 (46%) patients. In
four patients, the simplified criteria suggested a definite
diagnosis of AIH in whom the 1999 criteria would have
graded them as only probable. Additionally, there were 11
instances (16%) in which the 1999 criteria attributed a
probable diagnosis of AIH, but the simplified score categorized these individuals as not having AIH. In the nonFHF cohort, this occurred in only 7% of patients.
Discussion
2 (0–2)
2 (0–2)
0.28
100%
94%
0.99
12.5 (8.00–20.00) 25.5 (4.72–70.70) ⬍0.0001
38%
6%
84%
72%
⬍0.0001
⬍0.0001
ALP, alkaline phosphatase; AST, aspartate aminotransferase; F, female; IgG,
immunoglobulin G; INR, international normalized ratio; M, male.
probable diagnosis, and none with a definite diagnosis of
AIH. In comparison, the original revised IAIHG criteria
ascribed 10 of 328 (3.0%) patients as having probable
AIH, and none as having definite AIH. Using the simplified criteria, the seven false positive cases defined as probable AIH comprised four patients with PSC, two with
PBC, and one with ALD. The false positive, probable
AIH cases, identified by utilization of the original, revised
criteria carried diagnoses of NASH in six patients, lone
PBC in two patients, and lone PSC in two patients.
Patients with Fulminant Hepatic Failure. Seventy
patients comprising 52 females (74%) and 18 males
(26%) with non–acetaminophen induced FHF had the
relevant clinical, laboratory, and histological data available to calculate the original revised and simplified criteria
scores. In this cohort, the frequency of a diagnosis of AIH,
based on the simplified criteria, was 10% for probable
(seven patients) and 14% (10 patients) for definite AIH,
whereas on the 1999 criteria this equated to 31% (22
patients) and 9% (six patients), respectively. The frequency of an overall diagnosis of AIH was therefore 24%
on the simplified criteria and 40% on the 1999 criteria.
Only one patient in the seronegative group met criteria
for probable AIH, and none met the criteria for definite
AIH, via the simplified criteria whereas nine patients met
the criteria for probable AIH and none for definite AIH
via the 1999 criteria.
Prior to the application of either of the 1999 or simplified criteria, 28 of 70 (40%) patients were diagnosed
with AIH on clinical grounds, and 42 (60%) were deemed
In this retrospective review of cases from a single, tertiary referral center, the simplified IAIHG criteria clearly
demonstrate high specificity for the probable and definite
diagnosis of AIH in patients with a nonfulminant course.
However, despite sensitivity remaining high for a probable diagnosis it diminishes to only 70% for a definite
diagnosis of AIH. Additionally, the concordance between
the 1999 and simplified criteria was poor for both probable and definite AIH with the 1999 criteria producing a
greater area under the ROC curve, consistent with greater
diagnostic accuracy. Of further concern is the lack of sensitivity evident on the simplified criteria for a definite
diagnosis of AIH, when it is clearly demonstrated that
virtually all patients with AIH (99.5%) in this cohort were
classified as definite AIH by the 1999 criteria.
A recent, single-center study corroborates the high sensitivity of the simplified criteria for an overall diagnosis of AIH
(95%) but notes it to be inferior to the 1999 criteria (100%).
Specificity remained high in this retrospective series.9 In addition, this report suggests that the simplified criteria perform less well in patients with atypical features, a statement
with which we concur, based on our own findings. This
study, however, appears intended to compare the performance of the 1999 and simplified criteria and, furthermore,
does not represent a true validation of the simplified criteria,
because an unspecified number of patients in this study were
included in the IAIHG simplified criteria cohort reported by
Hennes et al.8 Consequently, the close similarity in sensitivity and specificity between the two reports is entirely to be
expected and therefore it is reasonable to conclude that the
simplified criteria have not, until now, been independently
validated.
In the published iteration of the simplified IAIHG criteria, the authors included variant or overlap syndromes as
representing AIH for the purposes of their study, because it
was deemed important to detect the AIH component in
these syndromes. This, however, is a moot point, and open
to debate, since variant syndromes may behave differently
544
YEOMAN ET AL.
over time from classical AIH.15 In keeping with the simplified IAIHG group report guidelines,8 we also included variant syndromes as representing AIH, so that a true
comparison could be undertaken. Although the sensitivity
(100% for 1999 criteria, 93% by simplified criteria) and
specificity (97% by 1999 criteria, 98% on simplified criteria)
for an overall diagnosis of AIH did not change significantly
when variants were excluded, this may be due to a type II
error. Possible explanations for the loss of sensitivity evident
upon the simplified criteria can be evaluated by comparing
the different characteristics of patients with pure AIH or
variant AIH. Such analysis reveals that patients with pure
AIH were more likely to be icteric, have a higher bilirubin,
AST, and international normalized ratio at presentation and
a greater likelihood of response to corticosteroids than variant syndrome patients. In view of their different clinical behaviors, this brings into further question whether these
individuals should be specifically regarded as having AIH or
not for the purposes of assessment by the simplified criteria.
If variant syndromes are thus considered as not representing AIH, our experience suggests that the main discriminators between a false negative and true positive diagnosis of
AIH via application of the simplified criteria are significantly
lower IgG concentrations and frequencies of positive autoantibodies, both at titers of ⱖ1:40 and ⱖ1:80. That there
should be such widespread discrepancies between false negative and false positive cases for two of the four simplified
diagnostic criteria is a cause for concern.
Furthermore, that the simplified criteria appear less likely
to ascribe a diagnosis of AIH than the 1999 criteria, in fulminant and nonfulminant presentations, must also be interpreted in the context of exclusion of other discriminating
information such as sex, alcohol and drug history, the presence of cholestatic liver tests, and perhaps most importantly,
response to corticosteroids. Such a response to therapy remains a characteristic feature of AIH in clinical practice and,
indeed, this finding has been strongly supported in previous
incarnations of the diagnostic criteria.1,5
It is somewhat surprising then, that responsiveness to
corticosteroids was omitted from the simplified criteria.
Indeed, in this cohort, the application of the simplified
criteria was less likely to ascribe a definite diagnosis of
AIH than would the 1999 criteria. In such a situation, a
trial of corticosteroid therapy would likely be undertaken.
Furthermore, the putative addition of responsiveness to
corticosteroids significantly increased the sensitivity of a
diagnosis of AIH. Importantly, among the non-AIH cohort, no additional patient was up-scored to probable or
definite AIH via this modification.
The utility of the IAIHG scoring systems for diagnosis
of AIH have not been specifically studied in patients with
FHF, largely due to its low incidence but also as a conse-
HEPATOLOGY, August 2009
quence of the difficulties in ascribing a firm diagnosis to
patients with this disorder. However, data published from
the United States Acute Liver Failure Study Group, reports that almost 49 of 125 patients (39%) with non–
acetaminophen induced acute, or subacute liver failure,
were due to either AIH (10%) or an indeterminate etiology (29%), with a proportion of these patients likely to
have undiagnosed AIH.16
In support of this statement, and as previously discussed, autoantibodies may be identified in patients with
FHF. In the study by Bernal et al., autoantibodies were
not identified in any patient with acetaminophen-induced FHF but were present in 43% of non–acetaminophen induced etiologies.10 Moreover, the more specific
soluble liver antigen was the most frequent antibody identified in this series.10 The presence of these AIH-associated autoantibodies in patients with FHF does not,
however, prove causation, and indeed may be present in
patients with hepatotropic viral infections.17,18 Nonetheless, the presence of autoantibodies in patients with FHF
remains of clinical interest, because many of these patients
demonstrate features associated with autoimmunity such
as female sex and the presence of human leukocyte antigen DR3 allotype.19,20
Although there is indeed some overlap between our
FHF cohort and that evaluated by Bernal et al., this
equated to only nine cases or 13% of the total (W. Bernal,
personal communication). Importantly, in our series, the
simplified IAIHG criteria appear less sensitive than the
“gold standard” of the 1999 criteria, in ascribing an overall (probable or definite) diagnosis of AIH (24% versus
40%). This was entirely due to 11 patients (16% of this
cohort) who were coded as probable AIH via the 1999
criteria but on the simplified criteria were classified as not
having AIH. Implicit in this statement, is the observation
that no patient who met the simplified criteria for probable AIH was classified as not having AIH on the 1999
criteria. In this clinical context, however, a greater proportion of patients were classified as definite AIH by the
simplified criteria than by the 1999 criteria, implying that
the newer system has greater specificity but, overall, inferior sensitivity. In clinical practice, this could lead to the
diagnosis of AIH not being considered and therefore corticosteroid therapy not being instituted. This has clinical
relevance, because the early use of corticosteroids in this
setting may improve outcome.21-28 The application of the
simplified and 1999 criteria to patients with FHF should,
however, be interpreted with caution, because these criteria were not developed with this clinical presentation in
mind, and their utility in this setting is studied for the first
time in this report. Nonetheless, because the simplified
criteria reported by the IAIHG aims to improve the diag-
HEPATOLOGY, Vol. 50, No. 2, 2009
nosis of AIH at its initial presentation, it remains important not to ignore the small, but highly significant,
proportion of patients with a fulminant course.
A further consideration for testing of these criteria relate
to a unique population of individuals who have viral liver
disease and overlapping features of autoimmunity, either
present at disease presentation or precipitated by the use of
interferon therapy. We attempted to utilize these criteria in a
cohort of 17 patients (12 with chronic HCV and five with
chronic HBV) with features of autoimmunity. Among this
cohort, 13 had autoimmune features (autoantibodies and/or
elevated IgG) prior to antiviral therapy, without features of
autoimmune liver disease on biopsy with the remaining four
patients developing autoimmune features after therapy. Four
patients in this cohort were ascribed a diagnosis of AIH (two
being interferon-induced) by clinical perception. Interestingly, the simplified criteria only identified two of these individuals as having AIH superimposed on viral hepatitis,
whereas the 1999 criteria identified all four patients, thus
corroborating its superiority as a diagnostic tool in challenging cases.
In conclusion, in this study we have demonstrated that
the simplified IAIHG score identifies the presence of AIH
with an extremely high degree of specificity but that sensitivity is lacking, particularly for a definite diagnosis of
AIH. This is important because, in a prospectively obtained cohort of patients attending our institution, 99.5%
were classified as definite AIH by the 1999 criteria. Additionally, among a separate cohort of patients with FHF, a
smaller proportion of patients would be ascribed a diagnosis of AIH on the simplified criteria than on the 1999
criteria, or as attributed by clinical perception. Prospective evaluation of these criteria is required to corroborate
these observations.
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