Another Cause of Autoimmune Hepatitis
42-year-old man was admitted to our hospital
because of elevated liver enzymes (aspartate
aminotransferase, 642 IU/L [normal range:
12-37]; alanine aminotransferase, 788 IU/L [normal
range: 7-45]; alkaline phosphatase, 605 IU/L [normal
range: 124-367]; c-glutamyl transpeptidase, 180 IU/L
[normal range: 6-30]; and total bilirubin, 8.6 mg/dL
[normal range: 0.3-1.2]). His serum immunoglobulin
G (IgG) concentration was 5622 mg/dL (normal
range: 870-1700), and anti-nuclear antibody titer
(1:20480), anti-double-stranded DNA (>400 IU/mL),
and smooth muscle antibody titer (1:40) were all
abnormal. Infection with hepatitis A, B, and C; cyto-
megalovirus; and Epstein-Barr virus were excluded,
and no drug use was noted. Ultrasonography, abdomi-
nal computed tomography, and magnetic resonance
imaging showed no abnormalities of the extrahepatic
Abbreviations: AIH, autoimmune hepatitis; HE, hematoxylin and eosin;
IgG, immunoglobulin G.
This study was supported in part by a research grant from the Japanese
Ministry of Health, Labour, and Welfare and a Shinshu University Grant-in-
Aid for Young Scientists of Exploratory Research.
Address reprint requests to: Takeji Umemura, M.D., Ph.D., Department of
Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi,
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conflict of interest: Nothing to report.
C 2010 by the American Association for the Study of Liver Diseases.
bile ducts or pancreas. The first liver biopsy showed
changes associated with typical autoimmune hepatitis
(AIH); liver parenchyma was collapsed with broad fi-
brous septa containing entrapped hepatocytes, and
lymphoplasmacytic infiltration with interface activity
was seen (Fig. 1A; hematoxylin and eosin [H&E]
staining, magnification ?200). Hepatocytes showed
rosetting in numerous places (Fig. 1B; H&E staining,
magnification ?400). Lobular inflammation was evi-
dent with giant cell change of hepatocytes (Fig. 1C;
H&E staining, magnification ?400), but no biliary
epithelial changes were found. The patient fulfilled the
criteria for definite AIH by the International Autoim-
mune Hepatitis Group and was administered cortico-
steroids at 60 mg/day, which led to improvement of
laboratory findings. Prior to treatment, however, the
patient’s serum IgG4 concentration was 642 mg/dL
(normal: ? 135) in a stored serum sample, and immu-
nostaining of liver tissue showed abundant plasma cells
with strong immunohistochemical reactivity to IgG4
in a portal tract (Fig. 1D; IgG4 immunostaining, mag-
nification ?400). A second liver biopsy performed 7
months afterward showed remaining portal sclerosis,
but lobular distortion and portal inflammation were
ameliorated, and serum alanine aminotransferase and
IgG4 concentrations were normalized. IgG4-positive
plasma cells were scarce in portal tracts (data not
In an earlier report, a strong and unexpected associ-
ation was seen between serum IgG4 concentration and
IgG4-bearing plasma cell infiltration in the liver of a
case with type 1 AIH, raising the possibility of a new
disease entity termed IgG4-associated AIH.1Raised se-
rum IgG4 concentration and IgG4-bearing plasma cell
infiltration have a high sensitivity and specificity for
the diagnosis of IgG4-related diseases.2-4Similar to the
present case, histological findings in the liver of
patients with IgG4-associated AIH showed bridging fi-
brosis, portal inflammation with abundant plasma cell
infiltration, interface hepatitis, and lobular hepatitis.
More interestingly, giant cell change and rosette forma-
tion were obvious as well. These two cases imply that
IgG4-related inflammatory processes can occur in the
hepatic parenchyma similarly to those in the pancrea-
tobiliary system, and such cases may resemble AIH
both clinically and pathologically. On the contrary,
Chung et al. described IgG4-associated AIH as
patients with AIH who had IgG4-positive plasma cells
in the liver.5Because no cases showed high serum
IgG4 in their cohort, we believe they are different
from our two representative patients and thus should
not be classified as an IgG4-related disease. Koyabu
et al. recently reported that an IgG4/IgG1-bearing
plasma cell ratio of >1 in the liver is specific for
IgG4-related diseases.6In our patient, the IgG4/IgG1
ratio was >1 (data not shown) and consistent with
their findings, which provides further evidence of our
case as an IgG4-related disorder. Because IgG4-associ-
ated AIH is clearly an IgG4 hepatopathy, this disease
should be differentiated from classical AIH. Detection
of IgG4 and assessment of liver histology using IgG4
immunostaining may be useful for distinguishing
IgG4-related diseases from classical AIH.
TAKEJI UMEMURA, M.D., PH.D.1
YOH ZEN, M.D., PH.D.2,3
YASUNI NAKANUMA, M.D., PH.D.3
KENDO KIYOSAWA, M.D., PH.D.1
1Department of Internal Medicine,
Division of Hepatology and Gastroenterology,
Shinshu University School of Medicine,
2Division of Pathology,
Kanazawa University Hospital,
3Department of Human Pathology,
Kanazawa University Graduate School of Medicine,
1. Umemura T, Zen Y, Hamano H, Ichijo T, Kawa S, Nakanuma Y, et al.
IgG4 associated autoimmune hepatitis: a differential diagnosis for classi-
cal autoimmune hepatitis. Gut 2007;56:1471-1472.
2. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T,
et al. High serum IgG4 concentrations in patients with sclerosing pan-
creatitis. N Engl J Med 2001;344:732-738.
3. Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al.
IgG4-related sclerosing cholangitis with and without hepatic inflamma-
tory pseudotumor, and sclerosing pancreatitis-associated sclerosing chol-
angitis: do they belong to a spectrum of sclerosing pancreatitis? Am J
Surg Pathol 2004;28:1193-1203.
5. Chung H, Watanabe T, Kudo M, Maenishi O, Wakatsuki Y, Chiba T.
Identification and characterization of IgG4-associated autoimmune hepa-
titis. Liver Int 2010;30:222-231.
6. Koyabu M, Uchida K, Miyoshi H, Sakaguchi Y, Fukui T, Ikeda H,
et al. Analysis of regulatory T cells and IgG4-positive plasma cells
among patients of IgG4-related sclerosing cholangitis and autoimmune
liver diseases. J Gastroenterol 2010; doi:10.1007/s00535- 010-0199-3.
390 UMEMURA ET AL.HEPATOLOGY, July 2010