Review for 10.1186/s12876-021-01720-w (2021)

Title: Economic Burden of Non-Alcoholic Steatohepatitis with Significant Fibrosis in Thailand
Version: 1 Date: 14 Jan 2021
Reviewer's report:
Notes for authors:
1. This analysis demonstrates the substantial cost burden of NASH in Thailand based on Markov
modeling of disease burden and direct costs. The article effectively communicates the methods
used to estimate cost burden, and demonstrates a growing need to address NASH in low and
middle income countries. An important outcome of this analysis is the relatively larger burden
of disease among younger age groups as compared to high-income countries. However, certain
details are missing that make it difficult to assess the data sources used for analysis, and to
compare outputs against overall liver disease burden. Authors should further describe how
fibrosis progression / regression rates were derived, and provide overall population size and cost
estimates by disease stage, especially for advanced disease.
2. Introduction:
a. “and other liver-related mortalities[3–6].
i. Should also note that NASH is associated with greater risk of mortality due to non-liver causes
(diabetes, colorectal cancer, etc.)
3. Methods:
a. “The transitional probabilities for all fibrosis stages were obtained from a systematic review
and meta-analysis estimating the rates of fibrosis progression[26].
i. Please discuss in detail how fibrosis progression rates were derived from Singh 2015 article.
Given that the results of this meta-analysis have a large uncertainty range, and some transitions
are reported as overall reversed (e.g. rate of regression exceeds rates of progression in Singh
2015 Table 3)
b. Table 1. Why is cost shown for NAFLD if results are only presented for NASH with significant
fibrosis? Suggest removing if this wasn’t used to estimate lifetime cost. Also, need to discuss
as a limitation whether the costs truly apply to all cases, or only those cases who are diagnosed
and under care, as F2/F3 patients may be asymptomatic.
4.    Results: Tables 3 & 4. Can you show the proportion of total costs by disease stage? This
could better show potential cost-effectiveness of preventing progression to advanced disease.
5. Discussion:
a. Because results are different from high-income countries, there should be further discussion
around the reasons why, including:
i. Relative increase in obesity: The growth rate of overweight and obesity has been much higher
in recent decades in Thailand as compared to Western countries (https://ncdrisc.org/country-
profile.html). It follows that younger people today will face a higher burden of metabolic
syndrome as compared to earlier generations
b. Should discuss limitations of studies based on liver biopsy: Uncertainty around NASH
diagnosis with significant variation in cases classified as not, probable or definite NASH
i. Suggest citing Ratziu 2005 article to discuss substantial biopsy sampling variability and the
resulting uncertainty around all studies based on liver biopsy series (including Singh meta-
analysis) https://pubmed.ncbi.nlm.nih.gov/15940625/
6. Supplement: The estimated size of the population in each disease stage should be provided
(total cases if breakdown by age group is not available). This is necessary to better understand
and validate the disease burden. For example, what is the estimated number of HCC cases among
NASH in Thailand? The IARC database estimates 27,394 incident liver cancers in 2020. How do
the model outputs compare? What proportion of liver cancers in Thailand might be attributable
to NASH based on this estimate? See: https://gco.iarc.fr/today/data/factsheets/populations/764-
thailand-fact-sheets.pdf. Likewise, how many NASH-related liver transplants are estimated each
year? How does this compare to the total number of liver transplants performed in Thailand?
Are there many patients who transition to this disease state, but do not incur full costs due to
lack of available organs, or presence of co-morbidities that prevent transplant?