Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1267_Библиотеки_им_академика_М_И_Перельмана.pdf
166
Fig. 11.8 Submucosal brosis in ulcerative colitis. Extensive ulceration (black star) is associated with
brosis (blue) as part of the wound healing process (Masson Trichrome, original magnication 4×)
I. O. Gordon
Fig. 11.9 Submucosal brosis in ulcerative colitis. Fibrous bands in the submucosa of nonulcerated areas of ulcerative colitis typically form adjacent to the muscularis mucosae and muscularis propria and are otherwise perpendicular to the luminal ow (Masson Trichrome, original
magnication 4×)
11 Histopathology ofIntestinal Fibrosis
Table 11.1 Criteria for histologic brosis score of intestine
Score Description
Fibrosis 0 No increased collagen deposition
1 Increased collagen deposition in submucosa
2 Increased collagen deposition in submucosa and mucosa
3 Increased collagen deposition in muscularis mucosa, submucosa, and
mucosa; thickening, disorganization of the muscularis mucosa
4 Increased collagen deposition in muscularis propria, muscularis
mucosa, submucosa, and mucosa
5 Increased collagen deposition throughout all layers including serosa
Percent
involvement
Note: used in rat model; based on Masson trichrome and Sirius Red stained sections
Reprinted from Theiss etal. [24], with permission
Table 11.2 Criteria for histologic brosis score
Score Description
0 No brosis
1 Mild brosis (focal mucosal/submucosal collagen deposition without architectural
distortion)
2 Moderate brosis (signicant mucosal/submucosal collagen deposition with modest
distortion of mucosal/submucosal architecture but without obscuring of the mucosal/
submucosal border)
3 Severe brosis (extensive mucosal/submucosal collagen deposition with marked
architectural distortion obscuring the mucosal/submucosal border)
Note: used in mouse model; based on Masson trichrome stained sections
Adapted from Higgins etal. [25], with permission
1 0–25% of section
2 25–50% of section
3 50–75% of section
4 75–100% of section
167
deposition (score 4), and nally all layers including serosa (score 5). Interestingly,
there is also consideration of the percent of the section involved by brosis
(Table11.1), an important consideration given the segmental, and microscopically
patchy, nature of Crohn’s disease. The more recent mouse scoring system by
Higgins et al. (Table 11.2) utilizes a progressive score considering only brosis
(collagen deposition) affecting the mucosa and submucosa on Masson trichrome
stained sections, with four tiers, from no brosis (score 0) to severe brosis (score 3).
This scoring system is much less detailed than the earlier one, and has also been
used on human tissue comparing brosis on pathology to exvivo ultrasound evaluation in patients with inammatory bowel disease [29].
Histologic scoring of brosis in studies comparing to radiographic ndings are
also somewhat less detailed, and do not include the percent section involvement,
presumably due to examining only strictured segments. These studies use human
tissue with Hematoxylin & Eosin stained sections. Adler etal. [26] separates brosis grade from muscle thickness, specically thickening of the muscularis propria
(Table11.3). Unlike the earlier rodent scoring systems described above, this scoring
168
I. O. Gordon
Table 11.3 Histologic
evaluation scoring
Table 11.4 Scoring system for inammatory and brostenotic features of Crohn’s disease lesions
Fibrostenosis
(score) Pathology
None (0) No or minimal brosis limited to submucosa (<25% thickness)
Mild/moderate (1) Mild stricture (>15mm) with nondilated lumen
Submucosal brosis and muscular hyperplasia >25% with preserved
layers
Severe (2) Massive transmural brosis; effacement of normal layers; severe stricture
Note: used in human tissue; based on H&E stained sections
Adapted from Chiorean etal. [28], with permission
Fibrosis grades
0 No brosis
1 Minimal brosis in submucosa or subserosa
2 Increased submucosal brosis, septa into
muscularis propria
3 Septa through muscularis propria, increase
in subserosal collagen
4 Signicant transmural scar, marked
subserosal collagen
Muscle
0 Normal thickness
1 Increased thickness of muscularis propria
layer
Note: used in human tissue; based on H&E stained sections
Adapted from Adler etal. [26], with permission
does not recognize mucosal brosis, or muscularis mucosae brosis or hyperplasia.
Fibrosis is scored progressively, but considers submucosa, muscularis propria, and
subserosa in each grade (Table11.3). Chiorean etal. [28] takes a simplied approach
with fewer score options in a three-tiered system (Table 11.4). Focus is again on
submucosal brosis and on muscularis hyperplasia, though it is not specied
whether this is referring to muscularis mucosae or muscularis propria.
Scoring schema from studies looking at resection specimen margins are probably the most generally applicable, as they consider pathologic features of Crohn’s
disease generally, not just ndings from a stricture. Fibrosis of muscularis mucosae
and submucosa are the focus, without specic mention of mucosa, muscularis propria, or subserosa, and a three-tiered progressive intensity grade was used [30, 31].
Interestingly, Maconi etal. [27] applied this scoring system, slightly modied to
include four-tiers, to a group of Crohn’s patients resected for ileal stenosis
(stricture), where representative sections along the entire resected segment length
were analyzed, and correlated the histologic ndings with ultrasound echo
patterns.
Neither the mouse nor the human scoring systems described here have been
validated. As brosis in Crohn’s disease is not generally thought to progress from
11 Histopathology ofIntestinal Fibrosis
169
lumen to serosa, a scoring system that accounts for all layers of the bowel wall
simultaneously is preferred. A similar scoring system should be applicable to both
mice and human studies. The ideal Crohn’s brosis scoring system would account
for changes in the muscularis mucosae, including both hyperplasia and brosis,
submucosal brosis and muscularization, muscularis propria hyperplasia and brosis, and subserosal brosis. A four-tiered scoring system (e.g. none, mild, moderate,
severe) applied to each site (i.e. mucosa, muscularis mucosae, submucosa, muscularis propria, and subserosa) would be ideal, at least in early studies until clinical
correlation could be established, and then perhaps the score could be contracted into
three tiers. As Crohn’s disease is patchy, multiple sections per specimen should be
assessed, and a unied “per specimen” score could also be generated. Again, clinical correlation studies would be needed to best understand whether the unied score
would reect the highest overall score, or a combination of the scores from each
section examined.
As the recognition and understanding of brosis in ulcerative colitis lags behind
that of Crohn’s disease, so does the concept of brosis scoring schema for ulcerative
colitis. Measurement of the bowel wall layers has revealed muscularis mucosae
thickening in ulcerative colitis [22], as well as increased bronectin and collagen I
in the mucosa, increased collagen I in the muscularis mucosae, and increased collagen I and III in the muscularis propria [32].
We developed a histologic brosis burden score for ulcerative colitis with a
three-tiered approach focusing on the percent of submucosal brosis, and found
moderate interobserver agreement on Hematoxylin & Eosin stained sections, and
signicant correlation when compared to Masson trichrome stain and Sirius red
stain [22]. Bowel wall layer measurements revealed thickening of the muscularis
mucosae, and this correlated with the presence of chronic mucosal injury [22].
11.4 Conclusion
In summary, fibrosis is a defining histopathologic feature of Crohn’s disease. A
variety of histologic scoring systems have been developed to evaluate fibrosis
of inflammatory bowel disease, with a focus on Crohn’s disease. In ulcerative
colitis, recognition of histologic fibrosis has not been part of the diagnostic
cadre, but has certainly been recognized and described in the literature. More
studies evaluating the clinicopathologic correlation of fibrosis in ulcerative
colitis are needed. Current histologic scoring systems reveal a variety of definitions of fibrosis and are incongruent as to the importance of fibrosis and mesenchymal cell hyperplasia in each of the bowel wall layers. Perhaps a unified
histologic fibrosis scoring system, which can account for Crohn’s disease,
ulcerative colitis, strictured and non-strictured areas, and which incorporates
the current understanding of the pathophysiology of fibrosis in inflammatory
bowel disease, would be needed before widespread use could be established for
clinical trials.
170
I. O. Gordon
References
1. Koukoulis G, Ke Y, Henley JD, Cummings OW. Obliterative muscularization of the small
bowel submucosa in Crohn disease: a possible mechanism of small bowel obstruction. Arch
Pathol Lab Med. 2001;125(10):1331–4.
2. Zhang X, Ko H-BM, Cai Z, Zhu H, Polydorides AD, Torres J, etal. Fibromuscular strictures
in Ileal Crohn’s disease: a detailed morphometric and Histopathologic analysis. Mod Pathol.
2017;30(S2):209A–10A.
3. Burke JP, Mulsow JJ, O’Keane C, Docherty NG, Watson RW, O’Connell PR.Fibrogenesis in
Crohn’s disease. Am J Gastroenterol. 2007;102(2):439–48.
4. Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G.Wound healing and brosis in intes-
tinal disease. Gut. 2007;56(1):130–9.
5. Rieder F, Fiocchi C.Intestinal brosis in IBD—a dynamic, multifactorial process. Nature Rev.
2009;6(4):228–35.
6. Scales BS, Huffnagle GB. The microbiome in wound repair and tissue brosis. J Pathol.
2013;229(2):323–31.
7. Burke JP, Cunningham MF, Watson RW, Docherty NG, Coffey JC, O’Connell PR.Bacterial
lipopolysaccharide promotes probrotic activation of intestinal broblasts. Br J Surg.
2010;97(7):1126–34.
8. Gumaste V, Sachar DB, Greenstein AJ.Benign and malignant colorectal strictures in ulcerative
colitis. Gut. 1992;33(7):938–41.
9. De Dombal FT, Watts JM, Watkinson G, Goligher JC. Local complications of ulcer-
ative colitis: stricture, pseudopolyposis, and carcinoma of colon and rectum. Br Med J.
1966;1(5501):1442–7.
10. Hunt RH, Teague RH, Swarbrick ET, Williams CB.Colonoscopy in management of colonic
strictures. Br Med J. 1975;3(5979):360–1.
11. Goulston SJ, McGovern VJ.The nature of benign strictures in ulcerative colitis. N Engl J Med.
1969;281(6):290–5.
12. Edwards FC, Truelove SC.The course and prognosis of ulcerative colitis. Gut. 1964;5:1–22.
13. Gore RM.Colonic contour changes in chronic ulcerative colitis: reappraisal of some old con-
cepts. AJR Am J Roentgenol. 1992;158(1):59–61.
14. Gordon IO, Agrawal N, Goldblum JR, Fiocchi C, Rieder F. Fibrosis in ulcerative coli-
tis: mechanisms, features, and consequences of a neglected problem. Inamm Bowel Dis.
2014;20(11):2198–206.
15. Mitomi H, Okayasu I, Bronner MP, Kanazawa H, Nishiyama Y, Otani Y, et al. Comparative
histologic assessment of proctocolectomy specimens from Japanese and American patients
with ulcerative colitis with or without dysplasia. Int J Surg Pathol. 2005;13(3):259–65.
16. Warren S, Sommers SC.Pathogenesis of ulcerative colitis. Am J Pathol. 1949;25(4):657–79.
17. Lumb G.Pathology of ulcerative colitis. Gastroenterology. 1961;40:290–8.
18. Lumb G, Protheroe RH. Ulcerative colitis; a pathologic study of 152 surgical specimens.
Gastroenterology. 1958;34(3):381–407.
19. Jones MK, Tomikawa M, Mohajer B, Tarnawski AS.Gastrointestinal mucosal regeneration:
role of growth factors. Front Biosci. 1999;4:D303–9.
20. Dammeier J, Brauchle M, Falk W, Grotendorst GR, Werner S.Connective tissue growth factor:
a novel regulator of mucosal repair and brosis in inammatory bowel disease? Int J Biochem
Cell Biol. 1998;30(8):909–22.
21. Willis E, Lopez R, Agrawal N, Rieder F, Gordon I.Alterations in lamina propria and muscu-
laris mucosa in ulcerative colitis are associated with prior medication and degree of histologic
inammatory activity. Mod Pathol. 2017;30(S2):206A.
22. Gordon IO, Agrawal N, Willis E, Goldblum JR, Lopez R, Allende D, Liu X, Patil DY, Yerian
L, El-Khider F, Fiocchi C, Rieder F.Fibrosis in ulcerative colitis is directly linked to severity
and chronicity of mucosal inammation. Aliment Pharmacol Ther. 2018;47(7):922–39.
11 Histopathology ofIntestinal Fibrosis
23. Higgins PD. Measurement of brosis in Crohn’s disease strictures with imaging and blood
biomarkers to inform clinical decisions. Dig Dis. 2017;35(1–2):32–7.
24. Theiss AL, Fuller CR, Simmons JG, Liu B, Sartor RB, Lund PK.Growth hormone reduces
the severity of brosis associated with chronic intestinal inammation. Gastroenterology.
2005;129(1):204–19.
25. Higgins PD, Johnson LA, Sauder K, Moons D, Blanco L, Taube S, etal. Transient or persistent
norovirus infection does not alter the pathology of salmonella typhimurium induced intestinal
inammation and brosis in mice. Comp Immunol Microbiol Infect Dis. 2011;34(3):247–57.
26. Adler J, Punglia DR, Dillman JR, Polydorides AD, Dave M, Al-Hawary MM, etal. Computed
tomography enterography ndings correlate with tissue inammation, not brosis in resected
small bowel Crohn’s disease. Inamm Bowel Dis. 2012;18(5):849–56.
27. Maconi G, Carsana L, Fociani P, Sampietro GM, Ardizzone S, Cristaldi M, etal. Small bowel
stenosis in Crohn’s disease: clinical, biochemical and ultrasonographic evaluation of histological features. Aliment Pharmacol Ther. 2003;18(7):749–56.
28. Chiorean MV, Sandrasegaran K, Saxena R, Maglinte DD, Nakeeb A, Johnson CS.Correlation
of CT enteroclysis with surgical pathology in Crohn’s disease. Am J Gastroenterol.
2007;102(11):2541–50.
29. Dillman JR, Stidham RW, Higgins PD, Moons DS, Johnson LA, Keshavarzi NR, et al.
Ultrasound shear wave elastography helps discriminate low-grade from high-grade bowel wall
brosis in exvivo human intestinal specimens. J Ultrasound Med. 2014;33(12):2115–23.
30. Fazio VW, Marchetti F, Church M, Goldblum JR, Lavery C, Hull TL, etal. Effect of resection
margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled
trial. Ann Surg. 1996;224(4):563–71. Discussion 71–3.
31. Kotanagi H, Kramer K, Fazio VW, Petras RE.Do microscopic abnormalities at resection mar-
gins correlate with increased anastomotic recurrence in Crohn’s disease? Retrospective analysis of 100 cases. Dis Colon Rectum. 1991;34(10):909–16.
32. de Bruyn JR, Meijer SL, Wildenberg ME, Bemelman WA, van den Brink GR, D’Haens
GR.Development of brosis in acute and longstanding ulcerative colitis. J Crohns Colitis.
2015;9(11):966–72.
171
Chapter 12
Clinical, Cellular andSerologic Biomarkers
ofIntestinal Fibrosis
AntonioDi Sabatino andPaoloGiuffrida
Abstract Intestinal brosis, which is due to an exaggerated accumulation of
extracellular matrix, is a frequent complication of inammatory bowel disease
(IBD) leading to intestinal obstruction and need for surgery. Currently, there are no
biomarkers able to predict the development of intestinal brosis in patients with
inammatory bowel disease. Most of the candidate biomarkers, including clinical
factors (i.e. smoking, ileal location, early use of steroids), circulating cells (i.e.
brocytes), serum extracellular matrix components (i.e. collagen, bronectin) or
enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors
(i.e. basic broblast growth factor, YKL-40) and serum antimicrobial antibodies
(i.e. anti-Saccharomyces cerevisiae antibodies ASCA), have been shown to predict
a disabling disease course rather than a brostenosing phenotype. In this chapter we
critically review clinical, cellular and serological biomarkers of intestinal brosis in
inammatory bowel disease.
Keywords Anti-microbial antibody · Extracellular matrix · Fibrocyte · Growth
factor · Ileal location
Abbreviations
ACCA Anti-chitobioside carbohydrate antibody
ALCA Anti-laminaribioside IgG antibody
AMCA Anti-mannobioside carbohydrate antibody
anti-C Anti-chitin carbohydrate antibody
anti-CBir1 Anti-bacterial agellin CBir1 antibody
anti-I2 Anti-Pseudomonas-associated sequence I2 antibody
A. Di Sabatino (*) · P. Giuffrida
Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia,
Pavia, Italy
e-mail: a.disabatino@smatteo.pv.it
F. Rieder (ed.), Fibrostenotic Inammatory Bowel Disease,
https://doi.org/10.1007/978-3-319-90578-5_12
173© Springer International Publishing AG, part of Springer Nature 2018
174
anti-L Anti-laminarin carbohydrate antibody
anti-OmpC Anti-Escherichia coli outer membrane protein C antibody
ASCA Anti-Saccharomyces cerevisiae antibody
bFGF Basic broblast growth factor
CD Crohn’s disease
ECM Extracellular matrix
ELF Enhanced liver brosis
FAP Fibroblast activation protein
IBD Inammatory bowel disease
MMP Matrix metalloproteinase
PDGF Platelet-derived growth factor
PIIINP N-terminal propeptide of type III collagen
TGF Transforming growth factor
TIMP Tissue inhibitor of matrix metalloproteinases
TNF Tumor necrosis factor
UC Ulcerative colitis
VEGF Vascular endothelial growth factor
A. Di Sabatino and P. Giuffrida
12.1 Introduction
Currently, there are no reliable biomarkers useful in clinical practice in predicting
the risk of developing intestinal brosis with subsequent stricture formation in
inammatory bowel disease (IBD) [1]. Proposed biomarkers, such as clinical factors (i.e. smoking, ileal location, early use of steroids), circulating cells (i.e. brocytes), serum extracellular matrix (ECM) components (i.e. collagen, bronectin) or
enzymes [i.e. tissue inhibitor of matrix metalloproteinase (TIMP)-1], serum growth
factors [i.e. basic broblast growth factor (bFGF), YKL-40] and serum antimicrobial antibodies [i.e. anti-Saccharomyces cerevisiae antibodies (ASCA)], have shown
contradictory results mostly derived from retrospective studies on relatively heterogeneous patients’ cohorts. Moreover, most of the above mentioned factors were
reported to be predictive of a disabling disease course rather than of a stricturing
phenotype (Fig.12.1). Biomarkers of intestinal brosis are needed as they would be
useful for the management of IBD patients at risk of brostenotic complications,
and for the identication of early phases of the brogenic process in order to prevent
stricture development [2]. In this chapter we critically revise the diagnostic and
prognostic power of brogenic biomarkers in IBD.
12.2 Clinical Biomarkers
A number of clinical factors, such as diagnosis before 40years of age, early need
for steroids, thiopurines or anti-tumor necrosis factor (TNF)-α agents, perianal disease, smoking habitus, ileal location, disease activity and deep mucosal ulceration,
12 Clinical, Cellular andSerologic Biomarkers ofIntestinal Fibrosis
175
Disease activity
Ileal location
Deep mucosal ulceration
Use of
steroids
PIIINP
bFGF
YKL-40
Fibronectin
Fig. 12.1 Candidate clinical (upper quadrants) and serologic (lower quadrants) biomarkers of
brostenosing (blue), disabling (green) and penetrating (yellow) disease. ACCA anti-chitobioside
carbohydrate antibody, AMCA anti-mannobioside carbohydrate antibody, anti-CBir1 anti-bacterial
agellin CBir1 antibody, anti-I2 anti-Pseudomonas-associated sequence I2 antibody, anti-L antilaminarin carbohydrate antibody, anti-OmpC anti-Escherichia coli outer membrane protein C anti-
body, ASCA anti-Saccharomyces cerevisiae antibody, bFGF basic broblast growth factor, PIIINP
N-terminal propeptide of type III collagen, TIMP tissue inhibitor of matrix metalloproteinases,
TNF tumor necrosis factor
ASCA
ACCA
Age < 40 years at diagnosis
Use of thiopurines or anti-TNF-a agents
Smoking
Perianal disease
Anti-I2
Colonic location
Anal
stricture
AMCA
Anti-L
Anti-CBir1 Anti-OmpC
have been demonstrated to be predictors of either disabling disease or post-surgical
recurrence in IBD patients [3, 4]. However, only ileal location, disease activity and
use of steroids were found to be specically associated with stricture development
according to observational data derived from TREAT Registry [5]. Currently, the
predictive power of all the above mentioned candidate clinical factors has not been
tested in large prospective ad-hoc studies, thus their value in clinical practice as
brogenic predictors is still under debate.
12.3 Cellular Biomarkers
Circulating brocytes are mesenchymal progenitor cells derived from bone marrow
and considered as marker of brosis in idiopathic pulmonary brosis [6].
Conversely, no data have been obtained so far on circulating brocytes in patients
with stricturing CD. However, an increased percentage of brocytes has been
reported either in the peripheral blood or in the inamed gut mucosa from CD
patients [7]. Of note, brocytes isolated from peripheral blood of CD patients
produce high amount of collagen type I after in vitro stimulation with
lipopolysaccharide [7].
176
A. Di Sabatino and P. Giuffrida
12.4 Serologic Biomarkers
Serologic biomarkers include ECM proteins, growth factors and anti-microbial
antibodies. As regards ECM components, serum N-terminal propeptide of collagen
type III (PIIINP) is increased in stricturing CD prior to intestinal resection in comparison to control subjects, and it decreases 6months after effective surgery [8]. On
the other hand, a previous study reported no signicant difference of serum PIIINP
between CD patients, whose phenotype was not specied, and controls [9].
Additionally, the same study [9] showed that serum C-terminal propeptide of collagen type I and C-terminal telopeptide of collagen type I were signicantly lower
and higher, respectively, in CD patients than in controls. Although TIMP-1 was
found to be up-regulated in CD intestinal mucosa overlying strictures [10], serum
TIMP-1 levels were not increased in stricturing CD patients [11]. The enhanced
liver brosis (ELF) test, a panel comprising three circulating biomarkers, such as
hyaluronic acid, TIMP-1 and PIIINP, and predicting liver brosis [12], was shown
to be a prognostic marker of liver transplantation-free survival in patients with primary sclerosing cholangitis, most of whom had a concomitant diagnosis of IBD
[13]. In our hands, ELF test was able to discriminate patients with stricturing CD
from those with other phenotypes [unpublished data]. Serum laminin, a component
of basement membrane, is increased in CD patients in comparison to control subjects, and correlates with disease activity but not with the stricturing phenotype
[14]. Plasma bronectin, which is a high-molecular weight ECM glycoprotein, is
up-regulated in CD patients with stricturing phenotype [15] and it signicantly
decreases soon after intestinal resection [16]. Conversely, plasma bronectin did not
predict the development of a post-surgical stricture over 1-year follow-up [16]. A
number of serum ECM fragments derived from the cleavage by proteases implicated in tissue remodeling in chronic intestinal inammation [17], have been associated with liver or skin brosis [18–20]. Some of these ECM fragments, such as
matrix metalloproteinase (MMP)-2/MMP-8-degraded and citrullinated vimentin,
MMP-9-degraded collagen type III and MMP-9-degraded collagen type IV, were
found to be abnormally expressed in the serum of IBD patients, however, the results
were not stratied according to different CD phenotypes [21, 22].
Growth factors, which have been tested in the serum of CD patients as brogenic biomarkers, encompass bFGF, human chitinase 3-like 1 (also known as
YKL-40), vascular endothelial growth factor (VEGF) and platelet-derived growth
factor (PDGF). Serum levels of bFGF, which promotes wound healing by acting
on myobroblast proliferation, are up-regulated in CD patients [23–25], and are
associated with the stricturing behavior and with the increased bowel wall thickness [25]. Serum YKL-40, which is produced by activated macrophages and neutrophils and induces collagen secretion by intestinal myobroblasts, is increased
in patients with CD in comparison to controls [26, 27]. As VEGF has been demonstrated to play a pro-brogenic and pro-angiogenic role in liver brosis [28], it
has been also investigated in CD.In particular, VEGF is not only up-regulated in
the serum of patients with CD [24, 25], but also correlates with color Doppler
signaling, suggesting that VEGF might be considered a biomarker of angiogenesis