# Letter to the editor: Regression of liver fibrosis after bariatric surgery: a glass two-third full rather than half empty.

François Pattou, Guillaume Lasailly, Violeta Raverdy, Robert Caiazzo,
Philippe Mathurin

<figure><img src="image_1.png" /></figure>

## To cite this version:

François Pattou, Guillaume Lasailly, Violeta Raverdy, Robert Caiazzo, Philippe Mathurin. Letter to the editor: Regression of liver fibrosis after bariatric surgery: a glass two-third full rather than half empty.. Hepatology, 2022, Hepatology, 76 (2), pp.E51-E52. 10.1002/hep.32516. hal-04426354

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# Letter to the editor: Regression of liver fibrosis after bariatric surgery: a glass two-third full rather than half empty.

François Pattou, Guillaume Lasailly, Violeta Raverdy, Robert Caiazzo,
Philippe Mathurin

► To cite this version:

François Pattou, Guillaume Lasailly, Violeta Raverdy, Robert Caiazzo, Philippe Mathurin. Letter to the editor: Regression of liver fibrosis after bariatric surgery: a glass two-third full rather than half empty.. Hepatology, 2022, Hepatology, 76 (2), pp.E51-E52. 10.1002/hep.32516. hal-04426354

HAL Id: hal-04426354

https://lilloa.hal.science/hal-04426354v1

Submitted on 14 Feb 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

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Distributed under a Creative Commons Attribution 4.0 International License
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# Letter to the editor: Regression of liver fibrosis after bariatric operations: A glass two-third full rather than half empty

To the editor,

We read with interest the report by Pais et al.[1] of a series of 66 patients with severe obesity and advanced fatty liver disease proven by liver biopsy during bariatric operations, who subsequently underwent a second biopsy, one to eleven years later. The authors conclude that an operation is highly efficient in improving steatohepatitis, but not to reverse advanced fibrosis, a validated endpoint for evaluating NASH treatment.

In Lassailly et al.[2], we previously reported the improvement of liver fibrosis associated with NASH following bariatric operations.[2] In that prospective study, 58 out of 180 participants (32.2% [95% CI, 25.4–39.0]) also had advanced liver fibrosis (≥F3, bridging fibrosis) at baseline, as compared with 71 out of 196 participants in the Pais et al. study (36.2% [95% CI, 29.5–42.9]). Postoperative biopsies were planned after one and five years and completed by more than two-thirds of eligible participants: 125 out of 169 (74% [95% CI, 67.6–80.6]) at one year, and 64 of 94 patients (68% [95% CI, 58.6–77.4]) at five years. Furthermore, there was no significant difference between the characteristics of patients who underwent repeated liver biopsies and those who did not. Five years after operation, fibrosis decreased in 40 of 57 patients (70.2% [95% CI, 81.6–56.6]), with a resolution of bridging fibrosis in 15 out of 22 patients (68.2% [95% CI, 49.4–88.2]) (Figure 1), and remained stable in 17 patients (26.6% [95% CI, 15.8–37.4]). Thus, fibrosis progressed in only six patients (9.8% [95% CI, 2.5–17.1]), all with persisting NASH. Overall, our findings unveiled the added value of getting rid of NASH, providing direct evidence that advanced fibrosis could be gradually reversed after removing the causal injury.

In contrast, Pais et al.[1] obtained a single postoperative biopsy at variable time points in each patient. Because the length of follow-up was a major independent predictor of fibrotic response, the authors' conclusion could have been impacted if the results had been analyzed separately before and after five years. In addition, only one-third of eligible study participants (66 of 196 patients; 33.8% [95% CI, 27.2–40.4]) underwent

repeated biopsy. These individuals were five years older and had more frequent bridging fibrosis and higher plasma aspartate aminotransferase at baseline, suggesting a selection bias favoring patients with more advanced liver disease. However, when the difference in postoperative time is taken into account, data from Pais et al.[1] appear to be globally consistent with our prospective results[2] (Figure 1).

Altogether, this suggests that the resolution of NASH with operations yields a two-thirds improvement of liver fibrosis, including bridging fibrosis, over five years or more, and thus outperforms the outcome of pharmaceutical[3] or lifestyle[4] interventions. Noteworthy, a recent study[5] showed that this remarkable outcome through operations could reduce the major liver and adverse cardiovascular outcomes. The rigorous evaluation of surgical interventions for the treatment of advanced NASH in randomized controlled trials is underway (ClinicalTrials.gov Identifier: NCT03472157).

## CONFLICT OF INTEREST

FP is the recipient of a grant from Agence National de la Recherche (Precinash ANR-16-RHUS-006).

François Pattou<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,<fnref n="5" /> ID
Guillaume Lasailly<fnref n="6" />

Violeta Raverdy<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,<fnref n="5" /> ID

Robert Caiazzo<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,<fnref n="5" />

Philippe Mathurin<fnref n="6" />

<footnote n="1">¹University of Lille, European Genomic Institute
for Diabetes, Lille, France</footnote>

<footnote n="2">²Institut Pasteur Lille, Lille, France</footnote>

<footnote n="3">³INSERM, UMR 1190, Translational Research
for Diabetes, Lille, France</footnote>

<footnote n="4">⁴CHU Lille, Integrated Center for Obesity, Lille,
France</footnote>

<footnote n="5">⁵CHU Lille, General and Endocrine Surgery,
Lille, France</footnote>

<footnote n="6">⁶Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE -
Institute for Translational Research in
Inflammation, Lille, France</footnote>
<figure><img src="image_2.png" /></figure>

AASLD
AMERICAN ASSOCIATION FOR
THE STUDY OF LIVER DISEASES

# Letter to the editor: Regression of liver fibrosis after bariatric operations: A glass two-third full rather than half empty

To the editor,

We read with interest the report by Pais et al.[1] of a series of 66 patients with severe obesity and advanced fatty liver disease proven by liver biopsy during bariatric operations, who subsequently underwent a second biopsy, one to eleven years later. The authors conclude that an operation is highly efficient in improving steatohepatitis, but not to reverse advanced fibrosis, a validated endpoint for evaluating NASH treatment.

In Lassailly et al.[2], we previously reported the improvement of liver fibrosis associated with NASH following bariatric operations.[2] In that prospective study, 58 out of 180 participants (32.2% [95% CI, 25.4–39.0]) also had advanced liver fibrosis (≥F3, bridging fibrosis) at baseline, as compared with 71 out of 196 participants in the Pais et al. study (36.2% [95% CI, 29.5–42.9]). Postoperative biopsies were planned after one and five years and completed by more than two-thirds of eligible participants: 125 out of 169 (74% [95% CI, 67.6–80.6]) at one year, and 64 of 94 patients (68% [95% CI, 58.6–77.4]) at five years. Furthermore, there was no significant difference between the characteristics of patients who underwent repeated liver biopsies and those who did not. Five years after operation, fibrosis decreased in 40 of 57 patients (70.2% [95% CI, 81.6–56.6]), with a resolution of bridging fibrosis in 15 out of 22 patients (68.2% [95% CI, 49.4–88.2]) (Figure 1), and remained stable in 17 patients (26.6% [95% CI, 15.8–37.4]). Thus, fibrosis progressed in only six patients (9.8% [95% CI, 2.5–17.1]), all with persisting NASH. Overall, our findings unveiled the added value of getting rid of NASH, providing direct evidence that advanced fibrosis could be gradually reversed after removing the causal injury.

In contrast, Pais et al.[1] obtained a single postoperative biopsy at variable time points in each patient. Because the length of follow-up was a major independent predictor of fibrotic response, the authors' conclusion could have been impacted if the results had been analyzed separately before and after five years. In addition, only one-third of eligible study participants (66 of 196 patients; 33.8% [95% CI, 27.2–40.4]) underwent

repeated biopsy. These individuals were five years older and had more frequent bridging fibrosis and higher plasma aspartate aminotransferase at baseline, suggesting a selection bias favoring patients with more advanced liver disease. However, when the difference in postoperative time is taken into account, data from Pais et al.[1] appear to be globally consistent with our prospective results[2] (Figure 1).

Altogether, this suggests that the resolution of NASH with operations yields a two-thirds improvement of liver fibrosis, including bridging fibrosis, over five years or more, and thus outperforms the outcome of pharmaceutical[3] or lifestyle[4] interventions. Noteworthy, a recent study[5] showed that this remarkable outcome through operations could reduce the major liver and adverse cardiovascular outcomes. The rigorous evaluation of surgical interventions for the treatment of advanced NASH in randomized controlled trials is underway (ClinicalTrials.gov Identifier: NCT03472157).

## CONFLICT OF INTEREST

FP is the recipient of a grant from Agence National de la Recherche (Precinash ANR-16-RHUS-006).

François Pattou<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,<fnref n="5" /> ID

Guillaume Lasailly<fnref n="6" />

Violeta Raverdy<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,<fnref n="5" /> ID

Robert Caiazzo<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,<fnref n="5" />

Philippe Mathurin<fnref n="6" />

<footnote n="1">¹University of Lille, European Genomic Institute
for Diabetes, Lille, France</footnote>

<footnote n="2">²Institut Pasteur Lille, Lille, France</footnote>

<footnote n="3">³INSERM, UMR 1190, Translational Research
for Diabetes, Lille, France</footnote>

<footnote n="4">⁴CHU Lille, Integrated Center for Obesity, Lille,
France</footnote>

<footnote n="5">⁵CHU Lille, General and Endocrine Surgery,
Lille, France</footnote>

<footnote n="6">⁶Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE -
Institute for Translational Research in
Inflammation, Lille, France</footnote>
Correspondence

François Pattou, University of Lille, 59000 Lille,
France.

Email: francois.pattou@univ-lille.fr

ORCID

François Pattou https://orcid.
org/0000-0001-8388-3766

Violeta Raverdy https://orcid.
org/0000-0001-5754-2028

REFERENCES

1. Pais R, Aron-Wisnewsky J, Bedossa P, Ponnaiah M, Oppert J-M, Siksik J-M, et al. Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Hepatology. 2022;76:456-68.

2. Lassailly G, Caiazzo R, Ntandja-Wandji L-C, Gnemmi V, Baud G, Verkindt H, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. 2020;159(4):1290-301:e1295.

3. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multi-centre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184-96.

4. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367-78.e5; quiz e14-5.

5. Aminian A, Al-Kurd A, Wilson R, Bena J, Fayazzadeh H, Singh T et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA. 2021;326(20):2031-42.

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

**FIGURE 1** Estimates with 95% confidence intervals (error bars) of the proportions of participants with advanced fatty liver disease who experienced (A) NASH resolution, (B) improvement of liver fibrosis, and (C) resolution of advanced (bridging) fibrosis after bariatric operations at 1 and 5 years in Lassailly et al.[2] and between 1 and 11 years in Pais et al.[1]
Correspondence

François Pattou, University of Lille, 59000 Lille,
France.

Email: francois.pattou@univ-lille.fr

ORCID

François Pattou https://orcid.
org/0000-0001-8388-3766

Violeta Raverdy https://orcid.
org/0000-0001-5754-2028

REFERENCES

1. Pais R, Aron-Wisnewsky J, Bedossa P, Ponnaiah M, Oppert J-M, Siksik J-M, et al. Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Hepatology. 2022;76:456-68.

2. Lassailly G, Caiazzo R, Ntandja-Wandji L-C, Gnemmi V, Baud G, Verkindt H, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. 2020;159(4):1290-301:e1295.

3. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multi-centre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184-96.

4. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367-78.e5; quiz e14-5.

5. Aminian A, Al-Kurd A, Wilson R, Bena J, Fayazzadeh H, Singh T et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA. 2021;326(20):2031-42.

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

**FIGURE 1** Estimates with 95% confidence intervals (error bars) of the proportions of participants with advanced fatty liver disease who experienced (A) NASH resolution, (B) improvement of liver fibrosis, and (C) resolution of advanced (bridging) fibrosis after bariatric operations at 1 and 5 years in Lassailly et al.[2] and between 1 and 11 years in Pais et al.[1]