Title: Management of hepatocellular carcinoma, an important cause of death in Japanese
autoimmune hepatitis patients
Version: 3 Date: 13 Feb 2024
Reviewer's report:
In this retrospective study, Dr. Tadokoro and colleagues investigated the risk factors and
prognosis of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH).
Overall, they studied 131 patients, of whom 87 AIH and 44 AIH-PBC overlap cases.
They reported HCC occurrence in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis
at onset, 11; median time to carcinogenesis, 7 years).
Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate
analysis (odds ratio, 41.36; p< 0.0001). Multidisciplinary therapy was administered as treatment
for HCC but no patient received immune checkpoint inhibitors. Two of the three patients who
used molecular-targeted drugs discontinued the therapy due to  adverse events occurrence. The
authors concluded that HCC is an important cause of death in AIH patients. Currently available
drug therapies are limited and early detection is desirable.
The study is of clinical interest as HCC occurrence and management in AIH patients is still
a topic poorly addressed. However, some issue require additional informations and should be
addressed.
-overall, the study population included 19 male patients, of whom 4 (21%) developed HCC.
However, at multivariate analysis male sex was not associated with HCC risk. This deserve to be
discussed since male sex in general, is a well-known risk factor for HCC developmet according
to literature studies. Could the author specify whether the four male patients who developed
HCC were cirrhotic?
- AIH and AIH/PBC diagnosis: the authors reported that diagnosis of AIH was made using the
revised IAIHG score (1999). However, it would be of clinical relevance to describe also how
performed the simplified AIH score (2008) since it has been demonstrated that the simplified
score is more specific for AIH diagnosis and, most importantly, recalling a study that validated
the simplified score in clinical practice /real world patients, including those with  overlap
syndrome AIH/PBC, as previously reported (Validation of simplified diagnostic criteria for
autoimmune hepatitis in Italian patients. Hepatology. 2009 May;49(5):1782-3; author reply
1783. doi: 10.1002/hep.22825.).
-as reported, 34 patients (26%) did not normalize ALT levels after 1 year and 25 patients
(19%) whose immunoglobulin levels did not normalize after 1 year. This is an important finding
suggesting that chronic inflammation could be associated with higher risk of HCC development
in AIH patients as demonstrated for viral (HBV and HCV) chronic liver diseases (DOI: 10.3748/
wjg.v27.i22.2994). Were they under standard therapy?  unresponsive?
- history of frequent relapse is a well-known risk factor for AIH complications including HCC.
Could the authors describe the prevalence of relapse in the 12 HCC patients?
-during the observation 21 patients with AIH died, nine from liver failure. Why these patients
were not listed for OLT?
- There were 9 patients with history of viral hepatitis. Although the author reported that there
were no patients with active hepatitis, it would be important to specify whether there were HBV
patients under anti-viral treatment.
- The authors considered and analyzed the "risk factors for carcinogenesis". Could they clearly
describe which factors were considered and why (corresponding references) those factors were
selected and analysed?
- In the introduction the authors should recall a recent important Japanese study investigating
the risk of HCC in different chronic liver disease and assessing the risk in non-cirrhotic
and cirrhotic patients, thus addressing the real impact of cirrhosis in HCC development (doi:
10.1002/cam4.1998. ). According to this meta-analytic approach,  the annual incidence of
HCC in chronic liver diseases and the ratio of HCC incidence in non-cirrhotic/cirrhotic stages
showed an etiological hierarchy with HCV and HBV showing a higher risk of HCC compared
to AIH (0.19% to 0.53% (2.79-fold, P = 0.03), that resulted less frequently complicated by
HCC development. This different HCC development risk between viral (HCV and HBV) and
autoimmune liver diseases has been linked with the different immunological profile of regulatory
T cells (World J Gastroenterol 2021; 27: 2994-3009 [DOI: 10.3748/wjg.v27.i22.2994]
-As the primary endpoint addressed in the study was the identification of risk factor in a
Japanese cohort AIH patients, and geographical difference have been reported in AIH clinical
features (clinical presentation, response to treatment, autoantibody profile etc) worldwide, in
my opinion the manuscript title should more specifically recall the study objective (Risk factors
of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis
patients).
-As additional limit of the study, the authors should also recognized the mixed population
including both AIH and AIH/PBC patients thus making less firm the regarding the real risk of
HCC development in AIH pure patients.
Title: Management of hepatocellular carcinoma, an important cause of death in Japanese
autoimmune hepatitis patients
Version: 3 Date: 13 Feb 2024
Reviewer's report:
In this retrospective study, Dr. Tadokoro and colleagues investigated the risk factors and
prognosis of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH).
Overall, they studied 131 patients, of whom 87 AIH and 44 AIH-PBC overlap cases.
They reported HCC occurrence in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis
at onset, 11; median time to carcinogenesis, 7 years).
Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate
analysis (odds ratio, 41.36; p< 0.0001). Multidisciplinary therapy was administered as treatment
for HCC but no patient received immune checkpoint inhibitors. Two of the three patients who
used molecular-targeted drugs discontinued the therapy due to  adverse events occurrence. The
authors concluded that HCC is an important cause of death in AIH patients. Currently available
drug therapies are limited and early detection is desirable.
The study is of clinical interest as HCC occurrence and management in AIH patients is still
a topic poorly addressed. However, some issue require additional informations and should be
addressed.
-overall, the study population included 19 male patients, of whom 4 (21%) developed HCC.
However, at multivariate analysis male sex was not associated with HCC risk. This deserve to be
discussed since male sex in general, is a well-known risk factor for HCC developmet according
to literature studies. Could the author specify whether the four male patients who developed
HCC were cirrhotic?
- AIH and AIH/PBC diagnosis: the authors reported that diagnosis of AIH was made using the
revised IAIHG score (1999). However, it would be of clinical relevance to describe also how
performed the simplified AIH score (2008) since it has been demonstrated that the simplified
score is more specific for AIH diagnosis and, most importantly, recalling a study that validated
the simplified score in clinical practice /real world patients, including those with  overlap
syndrome AIH/PBC, as previously reported (Validation of simplified diagnostic criteria for
autoimmune hepatitis in Italian patients. Hepatology. 2009 May;49(5):1782-3; author reply
1783. doi: 10.1002/hep.22825.).
-as reported, 34 patients (26%) did not normalize ALT levels after 1 year and 25 patients
(19%) whose immunoglobulin levels did not normalize after 1 year. This is an important finding
suggesting that chronic inflammation could be associated with higher risk of HCC development
in AIH patients as demonstrated for viral (HBV and HCV) chronic liver diseases (DOI: 10.3748/
wjg.v27.i22.2994). Were they under standard therapy?  unresponsive?
- history of frequent relapse is a well-known risk factor for AIH complications including HCC.
Could the authors describe the prevalence of relapse in the 12 HCC patients?
-during the observation 21 patients with AIH died, nine from liver failure. Why these patients
were not listed for OLT?
- There were 9 patients with history of viral hepatitis. Although the author reported that there
were no patients with active hepatitis, it would be important to specify whether there were HBV
patients under anti-viral treatment.
- The authors considered and analyzed the "risk factors for carcinogenesis". Could they clearly
describe which factors were considered and why (corresponding references) those factors were
selected and analysed?
- In the introduction the authors should recall a recent important Japanese study investigating
the risk of HCC in different chronic liver disease and assessing the risk in non-cirrhotic
and cirrhotic patients, thus addressing the real impact of cirrhosis in HCC development (doi:
10.1002/cam4.1998. ). According to this meta-analytic approach,  the annual incidence of
HCC in chronic liver diseases and the ratio of HCC incidence in non-cirrhotic/cirrhotic stages
showed an etiological hierarchy with HCV and HBV showing a higher risk of HCC compared
to AIH (0.19% to 0.53% (2.79-fold, P = 0.03), that resulted less frequently complicated by
HCC development. This different HCC development risk between viral (HCV and HBV) and
autoimmune liver diseases has been linked with the different immunological profile of regulatory
T cells (World J Gastroenterol 2021; 27: 2994-3009 [DOI: 10.3748/wjg.v27.i22.2994]
-As the primary endpoint addressed in the study was the identification of risk factor in a
Japanese cohort AIH patients, and geographical difference have been reported in AIH clinical
features (clinical presentation, response to treatment, autoantibody profile etc) worldwide, in
my opinion the manuscript title should more specifically recall the study objective (Risk factors
of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis
patients).
-As additional limit of the study, the authors should also recognized the mixed population
including both AIH and AIH/PBC patients thus making less firm the regarding the real risk of
HCC development in AIH pure patients.
Please review this paper.
user
Title: Management of hepatocellular carcinoma, an important cause of death in Japanese
autoimmune hepatitis patients
Version: 3 Date: 13 Feb 2024
Reviewer's report:
In this retrospective study, Dr. Tadokoro and colleagues investigated the risk factors and
prognosis of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH).
Overall, they studied 131 patients, of whom 87 AIH and 44 AIH-PBC overlap cases.
They reported HCC occurrence in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis
at onset, 11; median time to carcinogenesis, 7 years).
Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate
analysis (odds ratio, 41.36; p< 0.0001). Multidisciplinary therapy was administered as treatment
for HCC but no patient received immune checkpoint inhibitors. Two of the three patients who
used molecular-targeted drugs discontinued the therapy due to  adverse events occurrence. The
authors concluded that HCC is an important cause of death in AIH patients. Currently available
drug therapies are limited and early detection is desirable.
The study is of clinical interest as HCC occurrence and management in AIH patients is still
a topic poorly addressed. However, some issue require additional informations and should be
addressed.
-overall, the study population included 19 male patients, of whom 4 (21%) developed HCC.
However, at multivariate analysis male sex was not associated with HCC risk. This deserve to be
discussed since male sex in general, is a well-known risk factor for HCC developmet according
to literature studies. Could the author specify whether the four male patients who developed
HCC were cirrhotic?
- AIH and AIH/PBC diagnosis: the authors reported that diagnosis of AIH was made using the
revised IAIHG score (1999). However, it would be of clinical relevance to describe also how
performed the simplified AIH score (2008) since it has been demonstrated that the simplified
score is more specific for AIH diagnosis and, most importantly, recalling a study that validated
the simplified score in clinical practice /real world patients, including those with  overlap
syndrome AIH/PBC, as previously reported (Validation of simplified diagnostic criteria for
autoimmune hepatitis in Italian patients. Hepatology. 2009 May;49(5):1782-3; author reply
1783. doi: 10.1002/hep.22825.).
-as reported, 34 patients (26%) did not normalize ALT levels after 1 year and 25 patients
(19%) whose immunoglobulin levels did not normalize after 1 year. This is an important finding
suggesting that chronic inflammation could be associated with higher risk of HCC development
in AIH patients as demonstrated for viral (HBV and HCV) chronic liver diseases (DOI: 10.3748/
wjg.v27.i22.2994). Were they under standard therapy?  unresponsive?
- history of frequent relapse is a well-known risk factor for AIH complications including HCC.
Could the authors describe the prevalence of relapse in the 12 HCC patients?
-during the observation 21 patients with AIH died, nine from liver failure. Why these patients
were not listed for OLT?
- There were 9 patients with history of viral hepatitis. Although the author reported that there
were no patients with active hepatitis, it would be important to specify whether there were HBV
patients under anti-viral treatment.
- The authors considered and analyzed the "risk factors for carcinogenesis". Could they clearly
describe which factors were considered and why (corresponding references) those factors were
selected and analysed?
- In the introduction the authors should recall a recent important Japanese study investigating
the risk of HCC in different chronic liver disease and assessing the risk in non-cirrhotic
and cirrhotic patients, thus addressing the real impact of cirrhosis in HCC development (doi:
10.1002/cam4.1998. ). According to this meta-analytic approach,  the annual incidence of
HCC in chronic liver diseases and the ratio of HCC incidence in non-cirrhotic/cirrhotic stages
showed an etiological hierarchy with HCV and HBV showing a higher risk of HCC compared
to AIH (0.19% to 0.53% (2.79-fold, P = 0.03), that resulted less frequently complicated by
HCC development. This different HCC development risk between viral (HCV and HBV) and
autoimmune liver diseases has been linked with the different immunological profile of regulatory
T cells (World J Gastroenterol 2021; 27: 2994-3009 [DOI: 10.3748/wjg.v27.i22.2994]
-As the primary endpoint addressed in the study was the identification of risk factor in a
Japanese cohort AIH patients, and geographical difference have been reported in AIH clinical
features (clinical presentation, response to treatment, autoantibody profile etc) worldwide, in
my opinion the manuscript title should more specifically recall the study objective (Risk factors
of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis
patients).
-As additional limit of the study, the authors should also recognized the mixed population
including both AIH and AIH/PBC patients thus making less firm the regarding the real risk of
HCC development in AIH pure patients.
assistant