CoChat
Sign Up
Cited by 49Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes

Open access
Steinman, Jonathan B., Salomao, Marcela A., Pajvani, Utpal B.·2021·Liver International
DOI 10.1111/liv.15025
Open this paper in CoChat — free accountOpen PDF

Abstract

Non‐alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β‐Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient‐specific activation of these pathways may explain the variability in clinical presentation, and the zone‐specific response observed in clinical trials.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/liv.15025

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In zone 3, there is a well-known histologic pattern of liver damage in diseases that culminate in HCC, and zone 3 is frequently associated with oxidative stress.

    “In zone 3, there is a well-known histologic pattern of liver damage in diseases that culminate in HCC (61, 62), and zone 3 is frequently associated with oxidative stress (63, 64).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [61]

    The Figure 2 caption shows a pericentral histologic pattern of NASH, but the copy does not link that pattern to HCC. More decisively, §4.2.1 (Vitamin E) places the highest oxidative stress in the periportal region, not zone 3; §4.3 likewise describes greater oxidative stress in the periportal area. Page numbers were not available in our copy. (LLM, conf=0.83)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Liver zonation is perturbed in CLD, including MASLD.

    “Accordingly, liver zonation is perturbed in CLD, including MASLD54,55.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [54]

    Section 1.2.1 (Immune response) says NAFLD exaggerates the liver’s periportal immune-cell pattern, supporting perturbed zonation in the disease the paper calls NAFLD. Section 2 (Developmental pathways as determinants of NAFLD zonation) also describes altered zonal distribution of signals in NAFLD/NASH. The paper does not establish the broader claim for chronic liver disease generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 93

  1. 10.1016/S2468-1253(20)30077-7 · DOI · Paper page
  2. 10.1016/S2468-1253(20)30090-X · DOI
  3. 10.1053/j.gastro.2019.11.312 · DOI · Paper page
  4. 10.4254/wjh.v9.i16.715 · DOI
  5. 10.1016/S0973-6883(12)60102-9 · DOI
  6. 10.1002/cld.579 · DOI
  7. 10.1016/j.cld.2017.08.003 · DOI
  8. 10.1053/j.gastro.2015.04.043 · DOI · Paper page
  9. 10.1002/hep.24268 · DOI
  10. 10.1002/hep.21327 · DOI · Paper page
  11. 10.1002/lt.25003 · DOI
  12. 10.1002/lt.25387 · DOI
  13. 10.1053/j.gastro.2020.01.051 · DOI
  14. 10.1002/hep.29724 · DOI
  15. 10.1016/j.jhep.2018.01.005 · DOI
  16. 10.1146/annurev.nu.16.070196.001143 · DOI · Paper page
  17. 10.1038/s41575-019-0134-x · DOI · Paper page
  18. 10.1126/science.abc4346 · DOI · Paper page
  19. 10.1002/hep.31149 · DOI
  20. 10.3390/cells6040048 · DOI · Paper page
  21. 10.1038/cmi.2016.3 · DOI · Paper page
  22. 10.1038/s41586-020-2977-2 · DOI
  23. 10.1002/hep.26937 · DOI · Paper page
  24. 10.1016/j.immuni.2020.08.004 · DOI · Paper page
  25. 10.1038/s41586-019-1631-3 · DOI · Paper page
  26. 10.1053/j.gastro.2007.05.012 · DOI · Paper page
  27. 10.1111/liv.12100 · DOI
  28. 10.1002/hep.20842 · DOI
  29. 10.1002/hep.23133 · DOI
  30. 10.1111/j.1872-034X.2011.00855.x · DOI
  31. 10.1038/ajg.2010.152 · DOI
  32. 10.1002/hep.28374 · DOI
  33. 10.1002/hep.22724 · DOI
  34. 10.1016/j.cgh.2017.02.030 · DOI
  35. 10.1016/j.dld.2010.05.007 · DOI
  36. 10.1002/hep.23823 · DOI
  37. 10.1053/j.gastro.2020.07.034 · DOI
  38. 10.1016/j.jhep.2021.06.034 · DOI
  39. 10.1007/s10620-016-4062-0 · DOI
  40. 10.1002/hep.20701 · DOI · Paper page
  41. 10.1136/jcp.2010.079145 · DOI
  42. 10.1136/bmjgast-2016-000114 · DOI
  43. 10.1016/j.jdiacomp.2014.01.013 · DOI
  44. 10.1002/dvdy.24222 · DOI
  45. 10.1016/bs.ctdb.2018.12.003 · DOI
  46. 10.1152/physrev.1989.69.3.708 · DOI
  47. 10.1016/j.jhep.2017.10.017 · DOI
  48. 10.1038/ejhg.2011.181 · DOI
  49. 10.1038/nature21065 · DOI · Paper page
  50. 10.1016/j.ajpath.2014.08.022 · DOI · Paper page
  51. 10.1126/scisignal.2001249 · DOI
  52. 10.1177/1535370217707731 · DOI
  53. 10.1002/hep.28601 · DOI
  54. 10.1002/hep.28638 · DOI
  55. 10.1016/j.jhep.2020.09.032 · DOI
  56. 10.1080/10409238.2018.1448752 · DOI
  57. 10.1002/hep.25559 · DOI
  58. 10.1002/hep.24156 · DOI
  59. 10.1002/hep.26230 · DOI
  60. 10.1016/j.celrep.2013.10.030 · DOI · Paper page
  61. 10.1002/hep.30928 · DOI · Paper page
  62. 10.1016/j.cmet.2020.03.010 · DOI · Paper page
  63. 10.1002/hep.30150 · DOI · Paper page
  64. 10.1016/j.tem.2015.02.006 · DOI
  65. 10.2337/db13-0769 · DOI
  66. 10.1038/nm.2667 · DOI · Paper page
  67. 10.1016/j.molmet.2014.03.004 · DOI
  68. 10.1038/nrendo.2016.135 · DOI · Paper page
  69. 10.1016/j.pharmthera.2017.05.011 · DOI
  70. 10.3389/fendo.2018.00382 · DOI
  71. 10.1155/2013/601361 · DOI
  72. 10.1152/ajpendo.00391.2020 · DOI
  73. 10.1016/j.cell.2014.03.012 · DOI · Paper page
  74. 10.1038/s41467-018-06611-5 · DOI · Paper page
  75. 10.1016/S0140-6736(14)61933-4 · DOI · Paper page
  76. 10.18632/oncotarget.2899 · DOI
  77. 10.1002/hep.29371 · DOI
  78. 10.1056/NEJMoa0907929 · DOI · Paper page
  79. 10.1002/hep.27235 · DOI · Paper page
  80. 10.1007/s12072-019-10001-4 · DOI
  81. 10.1002/hep.1840380427 · DOI
  82. 10.1038/nrgastro.2013.193 · DOI
  83. 10.3389/fimmu.2018.00745 · DOI
  84. 10.1042/BJ20030426 · DOI
  85. 10.1074/jbc.M403143200 · DOI
  86. 10.1053/j.gastro.2016.08.027 · DOI
  87. 10.1002/hep4.1354 · DOI
  88. 10.1136/gutjnl-2020-320622 · DOI
  89. 10.1016/j.tem.2019.05.007 · DOI
  90. 10.1016/S0140-6736(19)32517-6 · DOI · Paper page
  91. 10.1002/hep.23759 · DOI
  92. 10.1016/j.jhep.2016.06.005 · DOI
  93. 10.1002/hep4.1449 · DOI

Cited by

Sorted by citations

Authors
Steinman, J. B., Salomao, M. A., & Pajvani, U. B.
Affiliations
  • Columbia University (US)
  • Mayo Clinic (US)
Corresponding author
Pajvani, Utpal B.
ORCID
Venue
Liver International
Publisher
Wiley
Published
2021-08-18
Volume
41
Issue
11
Pages
2534-2546
ISSN
  • 0106-9543 (ISSN-L)
  • 1478-3223
  • 1478-3231
DOI
10.1111/liv.15025
OpenAlex
W3186275497
Cited by
49
References
15
Citations by year
2026: 10 · 2025: 12 · 2024: 15 · 2023: 5 · 2022: 4 · 2021: 3
FWCI
1.03
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Liver International (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
nonalcoholic steatohepatitis, hepatic zonation, liver fibrosis, Wnt/β-catenin signaling, Hedgehog signaling, Notch signaling, nuclear receptors, cysteamine, obeticholic acid, pioglitazone, treatment response variability, steatosis
MeSH terms
Pioglitazone, Humans, Liver, Liver Cirrhosis, Hepatocytes, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review