Review for 10.1186/s12876-022-02404-9 (2022)

Title: The Impact of Treatment with Bile Acid Sequestrants on Quality of Life in Patients with
Bile Acid Diarrhoea
Version: 1 Date: 31 Jan 2022
Reviewer:  Ginevra Berti
Reviewer's report:
The manuscript I reviewed aims to value the quality of life in patients with BAD before and
after treatment with bile acid sequestrants for 8 weeks. Patients with ongoing symptoms of
diarrhoea that had a SeHCAT scan requested, were screened for eligibility. According to their
hospital guidelines, SeHCAT results were considered negative if >19.9%, positive if <11.9%
and indeterminate if 12%-19.9%. Eligible patients were divided into four groups: SeHCAT
negative control group (CG); SeHCAT positive patients were subdivided into idiopathic BAD,
post-cholecystectomy (PC) and terminal ileal Crohn’s disease (CD). Patients with a positive or
indeterminate SeHCAT result received as first-line treatment colesevelam 625mg once or twice
daily, depending on symptoms. If not available, cholestyramine 4-8 g sachets/day was offered
instead. Before treatment, at 4 and at 8 weeks of treatment, SeHCAT positive patients completed
a 7-day stool chart to access daily stool frequency and consistency (Bristol Stool Form Scale),
EQ-5D-3L, SF-36 and IBDQ-32 (where relevant) questionnaires. SeHCAT negative patients
completed questionnaires only at baseline. Clinical response was defined as improved bowel
frequency by >50% from baseline or less than 3 bowel movements per day.
Data were compared using Student’s paired t-tests for paired data and Student’s t-tests for
unpaired ones. The statistical level of significance was defined as p # 0.05. Cohen’s d effect size
was calculated to assess the magnitude of clinical effects for changes in QoL scores within each
patient cohort before and after treatment. Considering an effect size of 0.2 the minimal clinical
difference (MCD), an effect size greater than 0.2 was considered clinically significant.
In the CD group, the IBDQ32 showed a significant improvement (P=0.007) and a moderate
effect size, which was statistically significant (p = 0.03), before and after treatment.
In the SF-36 test, the BAD and CD groups had a non-significant improvement post-treatment
in all components, except for role limitation due to physical health that had a significant
improvement post-treatment in the BAD group (P=0.02). In the PC cohort mean scores were
reduced in all components after treatment, apart from general health and emotional well-being.
In all components, the CG cohort generally scored higher in their baseline scores than the
other three groups. The physical component summary showed small improvements in the BAD
and CD groups. There was a moderate effect size in the mental component summary that was
clinically significant in the CD group and clinically and statistically significant in the BAD group
(P=0.03). Instead, they both decreased in the PC group.
In the EQ-5D-3L for the mobility item there was no change in the BAD group before and
after treatment, while in the PC group there was a decline and in the CD an improvement,
both clinically but not statistically significant. On the self-care dimension, there was a clinically
significant improvement in the BAD and CD groups but a clinically significant decline in the
PC group, before and after treatment. The activity aim showed a statistically and clinically
significant post-treatment improvement in the BAD group, a clinically significant decline in
the PC group and no change in the CD group. Pain and discomfort improved clinically post-
treatment in the BAD and in the CD group. There was no change in the PC group. Anxiety and
depression dimension showed clinically significant improvement in both the BAD and the CD
group, but with a clinically significant worsening in the PC group. The VAS demonstrated a
clinically significant improvement in both the PC group and the CD group, but no change in
the BAD group.
26 out of 47 (55%) patients clinically responded to treatment, with a direct proportionality
between the percentage of responders and gravity of BAM. In summary, in SF-36 role limitation
due to physical health improved significatively in the BAD group, also MCS size effect
improvement was clinically significant in the CD group and statistically significant in the BAD
group. In EQ-5D-3L, the aims pain and disability and activity had respectively a clinically and
a significant improvement. Also, the CD group in IBDQ-32 showed a significant improvement.
There are few statistically significant findings, probably due to the small numbers of the groups
and that Colesevelam acts more on stool consistency than frequency. Indeed, is interesting how
from this study emerges the fact that even if the PC group is the one with the higher number of
clinical responders, it has less improvement of QoL with treatment, highlighting the possibility
of other aspects that influence this. Secondly, this study shows that the CD group is the one with
the better response in quality of life to treatment, so in these patients, an adequate treatment of
BAD can improve the QoL.
I found this manuscript interesting, because the effects of therapy on BAM patients’ quality of
life is not often analysed and because it has a good project and development. This study has
indeed some limits like the few statistically significant findings due to the small number of
participants and the use of two different therapies. I think also that there are some points that
would be better for the authors to review before publication.
Major issues
Page 3 lines 80-88 the authors should describe the statistically significant results also in the
abstract
Page 6 lines 165-167 It would be clearer to specify if other tests were conducted to exclude other
causes of chronic diarrhoea before performing the SeHCAT test
Page 6 lines 336-338 “8 patients had an indeterminate SeHCAT score (15-20%) where a trial of
treatment was given, of which no patients had a clinical response” assuming the fact that usually
the cut off for a positive SeHCAT is a score <15, the inclusion of these patients in the SeHCAT
positive groups might have negatively influenced the results. The authors should briefly discuss
this issue
Page 7 lines 189-190 The authors should clarify if the results reported are only those at week
8. It could be important to evaluate the effects of the therapy at different times to assess if the
improvement with treatment changes with time
Page 9 line 236 Specify please if the Student’s T-test was at one or two tails
Page 10 lines 246-247, page 13 line 330 and figure 1: it seems that 76 patients completed the
questionnaires and 46 were treated with BAS, are there two patients that completed only the SF
36 or the EQ-5D-3L? Could the authors clarify it?
Page 10 lines 264-265 From Table 2 it seems that in the PC cohort not only general health but
also emotional well-being improved. Could the authors check it?
Page 11 line 277 I suggest specifying when an improvement is clinically significant
Page 11 line 291 The P value reported is 0.00, it is not reported to be statistically significant,
could you check it?
Page 11 lines 272,292 and page 12 lines 305,306,307 and 321 in the same test for the different
dimensions, the degrees of freedom reported for each group change, could you verify if it?
Page 12 line 311 the d value is 30, could you check it?
Page 13 line 340 for SF-36 MCS could you check if the values of P and N are correct?
Page 13 lines 339-341 The phrase is a bit confused. It would be useful to separate clinically and
statistically significant findings.
Page 14 lines 358-359 is the statistically significant worse outcome in the PC group post-
treatment in the mobility and self-care dimensions of the EQ-5D-3L as compared to the BAD and
CD cohort described in table 3 by the P value on the right column? Could the authors clarify it in
the tables? Were the three groups’ scores (PC; BAD and CD) compared pre and post treatment
using the Student’s t-tests?
Page 15 lines 406-413 This paragraph is quite unclear about what scores are worse at baseline
in the CG group, could the authors make it clearer?
Minor issues
Page 3 line 77 I suggest using “was evaluated” referring to QoL
Page 3 line 81 I suggest specifying that the questionnaires completed by the CG group at baseline
were the same because it is not so clear
Page 6 line 144 I advise using “has” instead of “have”
Page 7 lines 181-187 I suggest a table or an image to report the change in stool frequency
and consistent of patients. Also, could you explain what is the definition of a partial response?
Patients that did not have a response at 4 weeks had also an increase of their BAS dose?
Page 13 lines 345-346 I suggest reporting the proportion of patients that used colesevelam or
cholestyramine and their dosage in the different groups, it would be interesting to value if they
correlate with the different results obtained in the groups
Page 10 lines 269-270 and lines 275-276 When a statistically significant difference is reported
I suggest reporting the P value
Page 12 line 310 It is clearer specifying that the improvement is clinically significative
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