Title: Aberrant cytokeratin 7 expression by hepatocytes can predict the ductopenia grade in
primary biliary cholangitis
Version: 2 Date: 18 Sep 2022
Reviewer's report:
In this interesting study, the authors aimed to assess aberrant cytokeratin 7 (CK7) expression by
hepatocytes in PBC patients by analyzing clinicopathological data of patients diagnosed with
PBC. Overall, 89 PBC patients who underwent liver biopsy were enrolled in the study, and
15, 29, and 45 patients had aberrant CK7 expression by hepatocytes (CK7+Hs (2+), CK7+Hs
(1+), and CK7-Hs, respectively). Significant differences in TB, DB, ALP, TA, IgM, interface
activity, and ductopenia grade between patients with CK7-Hs and CK7+Hs (2+) were found.
Interestingly, they also found significant differences in AMA, AMA-M2, anti-gp210, TB, DB,
ALP, TA, IgM, fibrosis, and ductopenia grade between CK7+Hs and CK7-Hs (P<0.05). The
odds ratios of CK7+Hs according to anti-gp210, ductopenia grade, and interface activity were
6.413, 4.145, and 3.247, respectively. They concluded that CK7+Hs represent the cholestasis
index of PBC and are associated with the ductopenia grade and interface activity. Aberrant
cytokeratin 7 expressions by hepatocytes can predict the ductopenia grade in PBC.
The study is of interest and would provide findings of potential clinical/prognostic significance.
However, some points should be addressed.
-Study population: forty-nine patients had overlapping AIH. This is a crucial issue as the
diagnosis of overlap syndrome may be difficult as specific diagnostic tools are lacking, as
described in a comprehensive review (Diagnosis and therapy of autoimmune hepatitis. Mini Rev
Med Chem. 2009 Jun;9(7):847-60. doi: 10.2174/138955709788452676).
-The authors report the detection of anti-gp210 and anti-sp100 antibodies. Since they are
both antinuclear antibodies (ANA), they should recall in the introduction the importance of
those two antinuclear antibodies that are regarded as PBC-specific ANA because their very
high PBC-specificity was demonstrated in a large study assessing their specificity in more
than 4000 sera (Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/
membranous' patterns: diagnostic accuracy for primary biliary cirrhosis. Aliment Pharmacol
Ther. 2006 Dec;24(11-12):1575-83;  Autoantibodies to speckled protein family in primary
biliary cholangitis. Allergy Asthma Clin Immunol. 2021 Mar 31;17(1):35. ). They also should
describe how were detected (immunoblotting? ELISA?).
-I have the last suggestion. The authors stated in the Discussion that "There are some limitations
to this study. The total number of PBC patients was too small to use ordinal regression to
investigate the relationships among the degree of CK7+Hs in PBC.". However, in my opinion,
they could also recall that according to current guidelines on the diagnosis of PBC, the presence
of two (cholestasis + AMA/PBC-specific ANA positivity) of the three diagnostic criteria
(cholestasis, AMA/PBC-specific ANA positivity, Typical histology) are sufficient to make a
definite diagnosis of PBC. Thus, it could be questionable to perform a liver biopsy when there
are already sufficient diagnostic criteria.
Title: Aberrant cytokeratin 7 expression by hepatocytes can predict the ductopenia grade in
primary biliary cholangitis
Version: 2 Date: 18 Sep 2022
Reviewer's report:
In this interesting study, the authors aimed to assess aberrant cytokeratin 7 (CK7) expression by
hepatocytes in PBC patients by analyzing clinicopathological data of patients diagnosed with
PBC. Overall, 89 PBC patients who underwent liver biopsy were enrolled in the study, and
15, 29, and 45 patients had aberrant CK7 expression by hepatocytes (CK7+Hs (2+), CK7+Hs
(1+), and CK7-Hs, respectively). Significant differences in TB, DB, ALP, TA, IgM, interface
activity, and ductopenia grade between patients with CK7-Hs and CK7+Hs (2+) were found.
Interestingly, they also found significant differences in AMA, AMA-M2, anti-gp210, TB, DB,
ALP, TA, IgM, fibrosis, and ductopenia grade between CK7+Hs and CK7-Hs (P<0.05). The
odds ratios of CK7+Hs according to anti-gp210, ductopenia grade, and interface activity were
6.413, 4.145, and 3.247, respectively. They concluded that CK7+Hs represent the cholestasis
index of PBC and are associated with the ductopenia grade and interface activity. Aberrant
cytokeratin 7 expressions by hepatocytes can predict the ductopenia grade in PBC.
The study is of interest and would provide findings of potential clinical/prognostic significance.
However, some points should be addressed.
-Study population: forty-nine patients had overlapping AIH. This is a crucial issue as the
diagnosis of overlap syndrome may be difficult as specific diagnostic tools are lacking, as
described in a comprehensive review (Diagnosis and therapy of autoimmune hepatitis. Mini Rev
Med Chem. 2009 Jun;9(7):847-60. doi: 10.2174/138955709788452676).
-The authors report the detection of anti-gp210 and anti-sp100 antibodies. Since they are
both antinuclear antibodies (ANA), they should recall in the introduction the importance of
those two antinuclear antibodies that are regarded as PBC-specific ANA because their very
high PBC-specificity was demonstrated in a large study assessing their specificity in more
than 4000 sera (Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/
membranous' patterns: diagnostic accuracy for primary biliary cirrhosis. Aliment Pharmacol
Ther. 2006 Dec;24(11-12):1575-83;  Autoantibodies to speckled protein family in primary
biliary cholangitis. Allergy Asthma Clin Immunol. 2021 Mar 31;17(1):35. ). They also should
describe how were detected (immunoblotting? ELISA?).
-I have the last suggestion. The authors stated in the Discussion that "There are some limitations
to this study. The total number of PBC patients was too small to use ordinal regression to
investigate the relationships among the degree of CK7+Hs in PBC.". However, in my opinion,
they could also recall that according to current guidelines on the diagnosis of PBC, the presence
of two (cholestasis + AMA/PBC-specific ANA positivity) of the three diagnostic criteria
(cholestasis, AMA/PBC-specific ANA positivity, Typical histology) are sufficient to make a
definite diagnosis of PBC. Thus, it could be questionable to perform a liver biopsy when there
are already sufficient diagnostic criteria.
Please review this paper.
user
Title: Aberrant cytokeratin 7 expression by hepatocytes can predict the ductopenia grade in
primary biliary cholangitis
Version: 2 Date: 18 Sep 2022
Reviewer's report:
In this interesting study, the authors aimed to assess aberrant cytokeratin 7 (CK7) expression by
hepatocytes in PBC patients by analyzing clinicopathological data of patients diagnosed with
PBC. Overall, 89 PBC patients who underwent liver biopsy were enrolled in the study, and
15, 29, and 45 patients had aberrant CK7 expression by hepatocytes (CK7+Hs (2+), CK7+Hs
(1+), and CK7-Hs, respectively). Significant differences in TB, DB, ALP, TA, IgM, interface
activity, and ductopenia grade between patients with CK7-Hs and CK7+Hs (2+) were found.
Interestingly, they also found significant differences in AMA, AMA-M2, anti-gp210, TB, DB,
ALP, TA, IgM, fibrosis, and ductopenia grade between CK7+Hs and CK7-Hs (P<0.05). The
odds ratios of CK7+Hs according to anti-gp210, ductopenia grade, and interface activity were
6.413, 4.145, and 3.247, respectively. They concluded that CK7+Hs represent the cholestasis
index of PBC and are associated with the ductopenia grade and interface activity. Aberrant
cytokeratin 7 expressions by hepatocytes can predict the ductopenia grade in PBC.
The study is of interest and would provide findings of potential clinical/prognostic significance.
However, some points should be addressed.
-Study population: forty-nine patients had overlapping AIH. This is a crucial issue as the
diagnosis of overlap syndrome may be difficult as specific diagnostic tools are lacking, as
described in a comprehensive review (Diagnosis and therapy of autoimmune hepatitis. Mini Rev
Med Chem. 2009 Jun;9(7):847-60. doi: 10.2174/138955709788452676).
-The authors report the detection of anti-gp210 and anti-sp100 antibodies. Since they are
both antinuclear antibodies (ANA), they should recall in the introduction the importance of
those two antinuclear antibodies that are regarded as PBC-specific ANA because their very
high PBC-specificity was demonstrated in a large study assessing their specificity in more
than 4000 sera (Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/
membranous' patterns: diagnostic accuracy for primary biliary cirrhosis. Aliment Pharmacol
Ther. 2006 Dec;24(11-12):1575-83;  Autoantibodies to speckled protein family in primary
biliary cholangitis. Allergy Asthma Clin Immunol. 2021 Mar 31;17(1):35. ). They also should
describe how were detected (immunoblotting? ELISA?).
-I have the last suggestion. The authors stated in the Discussion that "There are some limitations
to this study. The total number of PBC patients was too small to use ordinal regression to
investigate the relationships among the degree of CK7+Hs in PBC.". However, in my opinion,
they could also recall that according to current guidelines on the diagnosis of PBC, the presence
of two (cholestasis + AMA/PBC-specific ANA positivity) of the three diagnostic criteria
(cholestasis, AMA/PBC-specific ANA positivity, Typical histology) are sufficient to make a
definite diagnosis of PBC. Thus, it could be questionable to perform a liver biopsy when there
are already sufficient diagnostic criteria.
assistant