Review for 10.1186/s12876-022-02588-0 (2022)

Reviewer’s report
Title: 
No association of serum ferritin levels with advanced liver fibrosis in
untreated German patients with autoimmune hepatitis
Version: 
0 
Date: 
07 Jul 2022
Reviewer's report:
In their letter, Engel et al. reported that they could not validate the findings of
Chen et al. that was published in the January 2022 issue of BMC
Gastroenterology. The letter includes some important points that could be of
value for the scientific conversation, however a few modifications might be
advisable.
It is absolutely a fair point that an odd ratio of 1.002 has a questionable practical
relevance. However, it can still have value from a scientific point of view.
Importantly, small effects like this are hard to validate (and probably would
require bigger cohorts). But the main concern is that the authors did not repeat
the analysis as it was performed in the paper from Chen et al. If the aim of a
paper is to validate (or disprove) a previous finding, then the authors should try
to reproduce the original analysis as much as possible as a first step. Only after
that should they do any corrections if they have concerns about the used
methods, and report both results. 
However, Engel et al. did not evaluate absolute ferritin levels as Chen et al. but
they normalized ferritin concentrations to the ULN "to avoid bias by different
reference values for different age groups and gender". Patients' age and sex can
indeed influence their ferritin levels (but so can inflammation and bleeding),
however normalization is not necessarily the best way to deal with this effect. In
fact, these factors were considered in the uni and multivariate regression analysis
of the original paper: sex was not associated with fibrosis, and age lost
significance in the multivariate model against other factors including ferritin
level. On the other hand, normalization can cover the possible subtle effect of
ferritin level. Furthermore, it is possible that ferritin above a certain level induces
fibrotic pathways in a particular cell type (for example stellate cells) regardless
of the accepted ULN of the age and sex category where the investigated patients
belong to. In fact, iron independent fibrosis facilitating effect of the ferritin
molecule has been reported in rats (Ruddell RG, et al. Ferritin functions as a
proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear
factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009).
Therefore, it is hard to decide which is the right way to analyze and both
approaches have their pros and cons. Consequently, the authors should present
the results of both.
Additionally, after logarithmic transformation of the ferritin levels, the
regression analysis might result in higher odds ratio.
Finally, the suggestion for Chen et al. to validate the treatment response score of
Taubert et al. is reasonable and potentially beneficial for the medical community.
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