The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

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Toward an Integrated Clinical, Molecular and Serological Classification of Inflammatory Bowel Disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60750-8.pdf

Inflammatory bowel disease: cause and immunobiology

There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.

The role of short-chain fatty acids in health and disease.

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge—conventional TACE. Recently, a drug-eluting bead (DC Bead®) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.

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Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study

Background:
Crohn's disease and ulcerative colitis are complex disorders with some shared and many unique predisposing genes. Accurate phenotype classification is essential in determining the utility of genotype–phenotype correlation. The Montreal Classification of IBD has several weaknesses with respect to classification of children. The dynamic features of pediatric disease phenotype (change in disease location and behavior over time, growth failure) are not sufficiently captured by the current Montreal Classification.

Methods:
Focusing on facilitating research in pediatric inflammatory bowel disease (IBD), and creating uniform standards for defining IBD phenotypes, an international group of pediatric IBD experts met in Paris, France to develop evidence-based consensus recommendations for a pediatric modification of the Montreal criteria.

Results:
Important modifications developed include classifying age at diagnosis as A1a (0 to 40 years), distinguishing disease above the distal ileum as L4a (proximal to ligament of Treitz) and L4b (ligament of Treitz to above distal ileum), allowing both stenosing and penetrating disease to be classified in the same patient (B2B3), denoting the presence of growth failure in the patient at any time as G1 versus G0 (never growth failure), adding E4 to denote extent of ulcerative colitis that is proximal to the hepatic flexure, and denoting ever severe ulcerative colitis during disease course by S1.

Conclusions:
These modifications are termed the Paris Classification. By adhering to the Montreal framework, we have not jeopardized or altered the ability to use this classification for adult onset disease or by adult gastroenterologists. (Inflamm Bowel Dis 2011)

/pdf/pediatric-modification-of-the-montreal-classification-for-5giskky106.pdf

Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.

Background. This study evaluated the effects of an association of ethiodized oil (Lipiodol Ultra Fluide, Laboratoires Guerbet, Aulnay-sous-Bois, France), with or without gelatin sponge, with doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) on the biodistribution and kinetics of doxorubicin during intraarterial injection.



Methods. Eighteen patients with hepatocellular carcinoma on cirrhotic liver received a therapeutic injection into the hepatic artery of 50 mg of doxorubicin alone (Group 1; n = 4), or emulsified in 10 ml of ethiodized oil and 2.5 ml of ioxaglate (Hexabrix, Laboratoires Guerbet) with (Group 2; n = 7) or without (Group 3; n = 7) gelatin sponge embolization. Before treatment, the absence of intrahepatic shunts was verified by an injection of technetium-labeled albumin macroaggregates. The biodistribution of doxorubicin was studied on two fronts: (1) pharmacokinetic–by measurement of the doxorubicin blood level during the 48 hours after injection; and (2) scintigraphic (2 mg of doxorubicin were labeled with 2 mg of iodine 131)–by examination of the scintigrams and calculation of the following parameters: tumorous liver/ nontumorous liver binding ratio (T/NT ratio), liver/liver + lungs + abdomen binding ratio, and doxorubicin half-life in tumorous tissue.



Results. Pharmacokinetics results showed the following: the peak plasma concentration was significantly higher in Group 1 as compared with Groups 2 or 3 (Group 1: 2.1 ± 0.9 mg/ml; Group 2: 0.9 ± 0.3 mg/ml; Group 3:0.5 ± 0.2 mg/ml); the area under curve calculated from time zero to 1 hour was lower in Groups 2 and 3 compared with Group 1. Examination of the scintigrams showed the following: diffuse activity throughout the organism (Group 1), diffuse activity with strong hepatic and tumorous binding (Group 2), and mostly hepatic and tumoral binding (Group 3). The liver/liver + lungs + abdomen binding ratio was 28% ± 1% in Group 1, 36% ± 5% in Group 2, and 63% ± 7% in Group 3. The T/NT ratios were 1.0 f 0 (Group I), 1.5 ± 0.1 (Group 2), and 4.7 ± 0.5 (Group 3). The doxorubicin half-lives in tumorous tissue were 0.7 f 0.1 days (Group I), 1.8 ± 0.2 days (Group 2), and 2.6 days (n = 1; Group 3).



Conclusions. This study shows (1) that the association of ethiodized oil with doxorubicin lowers the peak concentration of doxorubicin and increases the intratumoral concentration and half-life of doxorubicin, and (2) that these kinetic ameliorations are even more pronounced after embolization. Therefore, from a kinetic standpoint, the doxorubicin-ethiodized oil-gelatin sponge association is the best. Cancer 1992; 70:585–590.

Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin.

Background and aims: Epithelioid granulomas is one of the best histological criterion for distinguishing Crohn’s disease (CD) from other inflammatory bowel diseases. Few data are available on the time of occurrence of epithelioid granulomas, and the value of epithelioid granulomas in predicting outcome has been determined only in cohorts of prevalent CD cases. Our objective was to evaluate epithelioid granuloma occurrence in incident CD cases and to examine the associations between epithelioid granulomas and outcome.

Patients and methods: We reviewed the histological reports of endoscopic and surgical specimens in a cohort of 188 consecutive incident CD cases seen in 1994 and 1995, and recorded the occurrence of epithelioid granulomas, isolated giant cells, and microgranulomas. Kaplan-Meier curves were plotted for time from CD diagnosis to immunosuppressive treatment or surgery, and associations between epithelioid granulomas and outcome were evaluated in a multivariate analysis. Follow up was at least five years.

Results: Granulomas were found in 69 (37%) patients, including 46 (25%) at presentation. Median time from CD diagnosis to epithelioid granuloma detection was 0.16 (0–63) months overall, and 9.59 (0.1–63) months in 23 patients who became epithelioid granuloma positive during follow up. Isolated giant cells were found in 6% of patients and microgranulomas in 12%. Epithelioid granuloma detection increased with the number of endoscopic sampling procedures; sampling site had no influence. By multivariate analysis, epithelioid granulomas were associated with surgical resection but not immunosuppressive therapy.

Conclusions: Epithelioid granulomas may separate CD into two pathological subsets and may indicate aggressive disease.

https://gut.bmj.com/content/gutjnl/54/2/215.full.pdf

Frequency and significance of granulomas in a cohort of incident cases of Crohn’s disease

AIMS--To assess the value of histology in diagnosing inflammatory bowel disease (IBD) in colorectal biopsy specimens. METHODS--Retrospective, double blind evaluation of colorectal biopsy specimens from 41 patients with colitis (28 with ischaemic colitis and 13 with acute self-limited colitis) and 84 patients with IBD (42 with Crohn's disease and 42 with ulcerative colitis). RESULTS--The features distinguishing IBD from other forms of colitis included distorted architecture, lymphocyte and plasma cell infiltrate, excess of polymorphonuclear leucocytes, polymorphonuclear cryptitis, crypt abscesses, and basal lymphoid aggregates. The features discriminating between Crohn's disease and ulcerative colitis included an irregular or villous surface, distorted architecture, decrease in mucus content, and polymorphonuclear cryptitis. Using multivariate analysis, 90% of patients with Crohn's disease and 71% of those with ulcerative colitis were correctly classified, the former being strongly defined by epithelioid granulomas, microgranulomas and isolated giant cells, and the latter best defined by an irregular or villous surface, decrease in mucus content and crypt atrophy. CONCLUSIONS--Examination of colorectal biopsy specimens is a reliable method for diagnosing IBD. In the absence of epithelioid granulomas, microgranulomas and isolated giant cells a diagnosis of Crohn's disease is based on the absence of histological criteria favouring ulcerative colitis. The histological spectrum of indeterminate colitis remains to be clarified.

https://jcp.bmj.com/content/jclinpath/48/8/749.full.pdf

Histological discrimination of idiopathic inflammatory bowel disease from other types of colitis.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) can have severe gastrointestinal effects and cause peptic ulcers to bleed. Acute bleeding from oesophageal varices is a major complication of cirrhosis of the liver. Aims To investigate the role, using a case-control study, of NSAIDs in first bleeding episodes associated with oesophageal or cardial varices in cirrhotic patients. Patients/Methods A structured interview was conducted of 125 cirrhotic patients with bleeding mainly related to oesophageal varices and 75 cirrhotic controls with oesophageal varices who had never bled. Results Cirrhotic patients who were admitted for bleeding related to portal hypertension were more likely to have used NSAIDs during the week before the index day (31 of 125 (25%)) than the cirrhotic controls (eight of 75 (11%); odds ratio = 2.8, p = 0.016). Use of aspirin alone or combined with other NSAIDs was also more prevalent in the cases (21 of 125 (17%)) than in the controls (three of 75 (4%); odds ratio = 4.9, p = 0.007). Logistic regression analysis showed that NSAID use (p = 0.022, odds ratio = 2.9, 95% confidence interval = 1.8 to 4.7) and variceal size (p Conclusions Aspirin, used alone or combined with other NSAIDs, was associated with a first variceal bleeding episode in patients with cirrhosis. Given the life threatening nature of this complication, the possible benefit of this treatment should be weighed against the risk shown here. No firm conclusions could be drawn on non-aspirin NSAIDs used alone.

https://gut.bmj.com/content/gutjnl/44/2/270.full.pdf

Denis Heresbach

Papers

Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin.

Frequency and significance of granulomas in a cohort of incident cases of Crohn’s disease

Histological discrimination of idiopathic inflammatory bowel disease from other types of colitis.

Anti-inflammatory drugs and variceal bleeding: a case-control study

Significance of interleukin-1beta and interleukin-1 receptor antagonist genetic polymorphism in inflammatory bowel diseases.