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We have read with great interest the review of gastrointestinal (GI)
complications after pelvic radiotherapy by Andreyev (1). Andreyev
emphasized importance of fibrosis as the underlying cause for most GI
symptoms after radiotherapy, and concluded that reversal or prevention of
fibrosis could be highly profitable in the treatment of this complication,
referring several anti-fibrotic agents such as lipo...
We have read with great interest the review of gastrointestinal (GI)
complications after pelvic radiotherapy by Andreyev (1). Andreyev
emphasized importance of fibrosis as the underlying cause for most GI
symptoms after radiotherapy, and concluded that reversal or prevention of
fibrosis could be highly profitable in the treatment of this complication,
referring several anti-fibrotic agents such as liposomal Cu/Zn superoxide
dismutase (2). However, there is another important target for the
treatment of this complication, that is, local ischemia.
Ischemia and fibrosis together play an important role in the
development of chronic GI complications after radiotherapy. Histological
examinations have revealed that radiation induces characteristic vascular
damage in the bowel, including marked fibrin thrombi and destruction of
the arterioles with subintimal thickening (3, 4). This vascular damage
deteriorates local blood supply, and persistent local ischemia leads to
diffuse fibrosis in lamina propria and submucosa of the bowel wall. Then,
fibrosis in turn accelerates vascular damage and further worsens local
ischemia (4). This malignant circle of local ischemia and fibrosis is the
key mechanism by which GI complications chronically progress and finally
lead to serious consequences such as massive bleeding or perforation.
Therefore, prevention or reversal of local ischemia is another important
approach for terminating this malignant cycle and suppressing the
progression of fibrosis. Indeed, Jones et al reported the efficacy of
hyperbaric oxygen for radiation proctitis refractory to conventional
therapies, and the European Committee for Hyperbaric Medicine and EORTC
consensus conference in 2001 recommended the use of hyperbaric oxygen in
the management of radiation proctitis and enteritis (5, 6).On the other
hand, deterioration of mucosal ischemia in the treatment of radiation
proctitis could result in unexpected acceleration of the disease as we
reported previously (3, 7 ).
We agree with Andreyev in that fibrosis is a promising target for the
treatment of GI complications after radiotherapy. However, we advocate
that local ischemia should be another important target as well as
fibrosis. With acceptance on this point, a therapeutic approach from the
both sides of this pathogenesis, namely, to suppress fibrosis and to
supply oxygen in the tissue, would provide more successful outcome in the
treatment of this disorder.
References
1.Andreyev J. Gastrointestinal complications of pelvic radiotherapy:
are they of any importance? Gut 2005;54(8):1051-4.
2.Delanian S, Porcher R, Balla-Mekias S, Lefaix JL. Randomized,
placebo-controlled trial of combined pentoxifylline and tocopherol for
regression of superficial radiation-induced fibrosis. J Clin Oncol
2003;21(13):2545-50.
3.Konishi T, Watanabe T, Kitayama J, Shibahara J, Nagawa H.
Endoscopic and histopathologic findings after formalin application for
hemorrhage caused by chronic radiation-induced proctitis. Gastrointest
Endosc 2005;61(1):161-4.
4.Haboubi NY, Schofield PF, Rowland PL. The light and electron
microscopic features of early and late phase radiation-induced proctitis.
Am J Gastroenterol 1988;83(10):1140-4.
5.Pasquier D, Hoelscher T, Schmutz J, Dische S, Mathieu D, Baumann M,
et al. Hyperbaric oxygen therapy in the treatment of radio-induced lesions
in normal tissues: a literature review. Radiother Oncol 2004;72(1):1-13.
6.Jones K, Evans AW, Bristow RG, Levin W. Treatment of radiation
proctitis with hyperbaric oxygen. Radiother Oncol 2005.
7.Konishi T, Watanabe T, Nagawa H. Formalin application in the
treatment of chronic radiation-induced hemorrhagic proctitis induces acute
deterioration of mucosal blood flow. Dis Colon Rectum 2006, in press.
Copyright: The Corresponding Author has the right to grant on behalf
of all authors and does grant on behalf of all authors, an exclusive
licence (or non exclusive for government employees) on a worldwide basis
to the BMJ Publishing Group Ltd to permit this article (if accepted) to be
published in GUT and any other BMJPGL products and sublicences such use
and exploit all subsidiary rights, as set out in our licence
Does Longitudinal Muscle Contraction of Esophagus Hold Important
Secrets?
Tutuian and colleagues [1] performed high resolution esophageal
manometry in a patient with achalasia and “chest pressure” following
swallowing. They observed a sustained increase in intraesophageal pressure
with maximum pressure at the time of maximal esophageal shortening. The
esophageal shortening is attributed t...
Does Longitudinal Muscle Contraction of Esophagus Hold Important
Secrets?
Tutuian and colleagues [1] performed high resolution esophageal
manometry in a patient with achalasia and “chest pressure” following
swallowing. They observed a sustained increase in intraesophageal pressure
with maximum pressure at the time of maximal esophageal shortening. The
esophageal shortening is attributed to longitudinal muscle contraction.
The mechanism that they propose for this pressure increase is “pump-gun”
(after the classic side-action firearm first patented in Britain by
Alexander Bain in 1854). They also suggest that reduction in esophageal
pressure during this episode is due to esophageal emptying that clears the
esophagus and results in resolution of the chest pain.
Although these observations are important, we propose an alternative
interpretation based on our recent description of a similar phenomenon in
association with gastro-esophageal reflux [2] where the so called “common
cavity pressure” (a simultaneous increase in esophageal pressure along the
length of the esophagus) was found to more closely relate to longitudinal
muscle contraction of the esophagus, rather than due to gastroesophageal
reflux (as commonly believed). We suggest that longitudinal muscle
contraction results in two things: 1, it renders esophagus stiff or non-
compliant and 2, it causes a reduction in esophageal length. Both of
these factors are critical and result in increase in intra-esophageal
pressure, based on the physical principle of Boyle’s law (pressure in a
non compliant cylinder increases as its volume decreases). Tutuian
suggests that the decrease in esophageal pressure is due to esophageal
emptying that clears the esophagus. We believe their explanation is
unlikely because LES pressure is fairly high (obstructive) during the
entire period of esophageal shortening. It is more likely that the
observed decrease in esophageal pressure is related to lengthening of the
esophagus and increase in esophageal compliance as the longitudinal muscle
contraction dissipates. Accordingly, the tracing provided by Tutuian
shows close temporal correlation between the decrease in esophageal
pressure and LES descent.
Tutian suggests that the increase in esophageal pressure due to
longitudinal muscle contraction is the cause of patient’s chest pain and
the latter is relieved as the esophageal pressure decreases. We described
long duration longitudinal muscle contraction (which we initially called a
sustained esophageal contraction, i.e., SEC) in association with
esophageal pain. [3] We suggest that this patient’s symptom of chest
pressure and pain is related to a long episode of longitudinal muscle
contraction and its relief related to dissipation of the longitudinal
muscle contraction.
In summary, this important event captured by Tutuian provides novel
insights into the mechanism by which longitudinal muscle contraction may
increase intra-esophageal pressure and at the same time cause symptoms.
Our explanation of the various events in this record may be slightly
different than described by Tutuian but we agree with him that this brief
episode holds an important secret as to what may cause spontaneous
esophageal pain.
Neelesh A. Tipnis, MD
Assistant Professor,
Medical College of Wisconsin
Ravinder K. Mittal, MD
Professor,
University of California—San Diego
References:
1 Tutuian R, Pohl D, Castell DO, et al. Clearance mechanisms of the
aperistaltic oesophagus: the "pump-gun" hypothesis. Gut Published Online
First: 14 December 2005. doi:10.1136/gut.2005.085423
2 Tipnis NA, Liu J, Puckett JL, et al. Common cavity pressure during
gastro-esophageal reflux: Reassessment using simultaneous pressure,
impedance and ultrasound imaging. Am J Physiol Gastrointest Liver Physiol
in Press.
3 Balaban DH, Yamamoto Y, Liu J, et al. Sustained esophageal
contraction: a marker of esophageal chest pain identified by intraluminal
ultrasonography. Gastroenterology. 1999 Jan;116(1):29-37.
In response to the comments of Duley et al. to our letter published
in GUT 2005 we would like to make some additional remarks.
First of all, Duley et al. conclude that our study had a retrospective
character, but this is not correct. This is a longitudinal cohort study in
which all patients with IBD visiting our out-patient department were
included. These patients were followed prospectively fo...
In response to the comments of Duley et al. to our letter published
in GUT 2005 we would like to make some additional remarks.
First of all, Duley et al. conclude that our study had a retrospective
character, but this is not correct. This is a longitudinal cohort study in
which all patients with IBD visiting our out-patient department were
included. These patients were followed prospectively for the development
of AZA-associated side effects. TPMT and ITPA genotypes were determined
during the follow-up period.
Next, Duley et al question the quality of our PCR sensitivity for the
detection of the A719G TPMT mutation. In contrast to what is implicated,
we performed our genotyping of the A719G mutation in three different ways.
First, we determined the digestion of the Acc1 site on the PCR product of
genomic DNA. In one case with an adequate positive control, we found a
homozygous G460A mutation, but no A719G mutation, thus representing a
homozygous TPMT*3B polymorphism. This result was corroborated by both DNA
sequencing and an INNO-LiPA assay in an independent laboratory.
In relation to TMPT we appreciate that a homozygous TPMT
polymorphism, leading to absence of enzymatic TPMT activity can lead to
severe leukopenia as was the case in our study. Analysis of TPMT
polymorphisms would therefore benefit the few (1/300) homozygote patients.
However, we and others noted that heterozygous TPMT is not a significant
predictor for AZA-related side effects. In addition, a high percentage of
patients using AZA develop side-effects (10-20%), irrespective of their
TPMT genotype. As a consequence determination of these genotypes has only
limited impact on the prescription policy of AZA and the recommended
follow-up of patients. Tests other than genotyping, such as measuring TPMT
activity or AZA metabolites, may be more useful in monitoring AZA
treatment. To gain consensus about this discussion a large cost-
effectiveness study should be performed.
In relation with ITPA, to our knowledge two studies have observed an
association between heterozygous ITPA 94C>A polymorphism and adverse
drug reactions.[1,2] The p-values presented in these studies were
described as statistically significant. However, they were in the range
that would require further studies before being generally accepted.[3]
In fact, there are now 4 studies (and one upcoming) that demonstrate no
significant correlation between and the ITPA 94C>A polymorphism and the
development of adverse drug reactions on AZA treatment.[4-7] As with TMPT
there might be an association with homozygous ITPA 94C-A patients and
thiopurine toxicity, but thus far insufficient numbers of homozygous
patients have been tested to allow a firm conclusion. Thus in our minds it
is to early to conclude that the ITPA 94C>A polymorphism is associated
with a higher risk at the development of side-effects on AZA treatment.
References
1. Marinaki AM, Ansari A, Duley JA, et al. Adverse drug reactions to
azathioprine therapy are associated with polymorphism in the gene encoding
inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics.
2004;14:181-187.
2. von Ahsen N, Armstrong VW, Behrens C, et al. Association of
Inosine Triphosphatase 94C>A and Thiopurine S-Methyltransferase
Deficiency with Adverse Events and Study Drop-Outs under Azathioprine
Therapy in a Prospective Crohn Disease Study. Clin Chem. 2005.
3. Lander E, Kruglyak L. Genetic dissection of complex traits:
guidelines for interpreting and reporting linkage results. Nat Genet.
1995;11:241-247.
4. Breen DP, Marinaki AM, Arenas M, et al. Pharmacogenetic
association with adverse drug reactions to azathioprine immunosuppressive
therapy following liver transplantation. Liver Transpl. 2005;11:826-833.
5. Gearry RB, Roberts RL, Barclay ML, et al. Lack of association
between the ITPA 94C>A polymorphism and adverse effects from
azathioprine. Pharmacogenetics. 2004;14:779-781.
6. Hindorf U, Lindqvist M, Strom M, et al. Lack of Association
Between the Inosine Triphosphate Pyrophosphatase (ITPA) 94c>a
Polymorphism, the Tpmt Genotype, the baseline Tpmt Activity and Adverse
Effects From Thiopurine Medication in Inflammatory Bowel Disease.
Digestive Disease Week. 2005.
7. van Dieren JM, van Vuuren AJ, Kusters JG, et al. ITPA genotyping
is not predictive for the development of side effects in AZA treated
inflammatory bowel disease patients. Gut. 2005;54:1664.
We appreciate the interest of Guidi et al. according our
review about the relevance of steatosis in chronic hepatitis C.[1] We
would like to outline three points according to their comments: the
prevalence of steatosis in regard to genotype; the role of
necroinflammation; the relationship between steatosis and treatment
outcome.
Firstly, several studies have observed a significant association...
We appreciate the interest of Guidi et al. according our
review about the relevance of steatosis in chronic hepatitis C.[1] We
would like to outline three points according to their comments: the
prevalence of steatosis in regard to genotype; the role of
necroinflammation; the relationship between steatosis and treatment
outcome.
Firstly, several studies have observed a significant association
between HCV genotype 3 infection and the presence of steatosis.[2,3]
Steatosis is present in 73% of HCV genotype 3 patients and in 50% of
patients infected with genotypes other than 3 (mainly genotype 1).[1] In
HCV genotype 1 patients, steatosis occurs more frequently than in the
general population of adults in the Western world (estimation of 20-30%).
So we do agree with the hypothesis of a potential direct pathogenic role
of the virus in the induction of liver steatosis, not limited to HCV
genotype 3.[1, 4-5] Furthermore, in a study from Abid et al., the HCV
core protein, from patients with severe (genotype 3a) or no (other
genotypes) liver steatosis, was expressed in Huh7 cells.[6]
Although
triglyceride accumulation occurred with genotypes 1b, 3a and 3h, the
genotype 3a core protein expression resulted in the highest level of
accumulation. In another recent study a positive correlation between
steatosis and the number of infected hepatocytes was observed only in
genotype 3 patients.[7] In most cases the number of cells with steatosis
greatly outnumbered that of HCV infected cells (HCV-antigens using
immunoperoxidase technique). The conclusion was that steatosis do not
appear to be directly related to the presence of HCV-antigens within
single hepatocytes, an indirect, possibly cytokine mediated, mechanism
might be operative.
Secondly, several studies have found a highly significant link
between steatosis and necroinflammation activity in one hand; and between
necroinflammation activity and fibrosis in another hand.[1, 2] Fatty
accumulation is not fibrogenic per se. Steatosis in presence of
necroinflammation could increase fibrosis progression rate. Furthermore,
we conducted a meta-analysis on individual patients' data of 3,068
patients with histologically confirmed chronic hepatitis C from several
centers.[8] Steatosis was independently associated with genotype 3, the
presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol
abuse, higher BMI and older age. Fibrosis was independently associated
with inflammatory activity, steatosis, male gender and older age, while
HCV genotype 2 was associated with reduced fibrosis. The association
between steatosis and fibrosis was invariably dependent on a simultaneous
association between steatosis and hepatic inflammation.
Thirdly, Guidi et al. reported in a selected population with chronic
hepatitis C, that the presence of steatosis was not associated with a
lower sustained virological response (SVR).[4] One main interest in their
study was that they rule out possible concomitant metabolic disorders,
namely alcoholic hepatitis and metabolic factors associated with non
alcoholic fatty liver disease. In a large study involving 1428 naïve
patients with chronic hepatitis C, the presence of steatosis was
associated with a lower SVR rate, even after taking into account other
factors (P <.001).[9] Absence of baseline steatosis, as well as end of
follow-up steatosis, was associated with higher SVR, except in patients
with genotype 3. In another retrospective analysis of 174 patients with
chronic hepatitis C, obesity (and not steatosis) was a negative predictor
of SVR.[10] It could be that obesity (with increased plasma free fatty
acid) higher causes steatosis, and then each independently diminishes
response to treatment. Obesity decreases interferon bioavailability and
impairs the immune response to HCV. The opposite was found in a study
involving nondiabetic European patients with HCV genotype 1 at low risk
for the metabolic syndrome, where the prevalence of steatosis was nearly
60%.[11] Insulin resistant was a risk factor for moderate/severe
steatosis, especially in men. Moderate/severe steatosis was found
associated with hyporesponsiveness to treatment.
We obviously agree on the need for larger works which could contribute to
explain the mechanisms that promote the occurrence of steatosis in chronic
hepatitis C, and the relationship with response to treatment.
References
1 - Asselah T, Rubbia-Brandt L, Marcellin P, et al. Steatosis in
chronic hepatitis C: why does it really matters? Gut 2006; 55 123-130.
2 - Asselah T, Boyer N, Guimont MC, et al. Liver fibrosis is not
associated with steatosis but with necroinflammation in French patients
with chronic hepatitis C. Gut. 2003;52(11):1638-43.
3 - Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects
chronic hepatitis C progression in a genotype specific way. Gut.
2004;53(3):406-12.
4 - Guidi M, Muratori P, Granito A, et al. Hepatic steatosis in
chronic hepatitis C: impact on response to anti-viral treatment with peg-
interferon and ribavirin. Aliment Pharmacol Ther 2005; 22:943-9.
6 - Abid K, Pazienza V, de Gottardi A, et al. An in vitro model of
hepatitis C virus genotype 3a-associated triglycerides accumulation. J
Hepatol. 2005;42(5):744-51.
7 - Grassi A, Ballardini G, Susca M, et al. HCV liver infection and
liver steatosis: evidence for indirect mechanisms in genotype 3? Aliment
Pharmacol Ther. 2005;22 S 2:79-82.
8 - Leandro G, Mangia A, Hui J, et al. Relationship Between
Steatosis, Inflammation and Fibrosis in Chronic Hepatitis C: a Meta-
Analysis of Individual Patient Data. Gastroenterology, in press.
9 - Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment
with peginterferon or interferon alfa-2b and ribavirin on steatosis in
patients infected with hepatitis C.Hepatology. 2003;38(1):75-85.
10 - Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass
index is an independent risk factor for nonresponse to antiviral treatment
in chronic hepatitis C. Hepatology. 2003; 38: 639-44.
11 - Cammà C, Bruno S, Di Marco V, et al. Insulin resistance is
associated with steatosis in nondiabetic patients with genotype 1 chronic
hepatitis C. Hepatology 2006;43:64-71.
T Asselah1, L Rubbia-Brandt2, P Marcellin1 and F Negro2 & 3
1 Service d’Hépatologie and INSERM CRB3, Hôpital Beaujon, Clichy,
University of Paris VII, France.
2 Service de Pathologie Clinique, Hô ;pital Universitaire, Genève,
Switzerland.
3 Services de Gastroentérologie et d’Hépatologie, Hôpital
Universitaire, Genève, Switzerland
Correspondence to:
Dr T Asselah, MD, PhD, VDSM
Service d’Hépatologie and INSERM CRB3, Hô ;pital Beaujon, Clichy 92
110, France. E-mail: tarikasselah@hotmail.com.
We read with interest the article by Mawdsley and Rampton on the
relationship between psychological stress, increased disease activity in
inflammatory bowel diseases (IBD), and the role of...
We read with interest the article by Mawdsley and Rampton on the
relationship between psychological stress, increased disease activity in
inflammatory bowel diseases (IBD), and the role of alterations in the
hypothalamic-pituitary-adrenal (HPA) axis function (Gut 2005; 54:
1481-91). In IBD patients, chronic colonic inflammation induces a
downregulation of HPA axis responses, and animal studies have shown that
altered function of the HPA axis renders rodents susceptible to stress-induced
increases in gastrointestinal inflammation. Central receptors located in the
medial prefrontal cortex and hippocampus play a crucial role in glucocorticoid
(GC) mediatedcounterregulation of
stress-induced HPA axis activation [1].
Polymorphisms of the GC receptor (GR) gene may contribute
to the large interindividual variations in sensitivity to GCs and HPA axis
activity, that are frequently observed in healthy individuals. Several
polymorphisms of the GR gene have been described, and three of these are
relatively frequent; however, knowledge on the influence of these polymorphisms
on HPA axis response is very limited.
A genetic study was carried out in our laboratory to
evaluate the incidence of these polymorphisms in 57 young patients with IBD (34
with Crohn’s disease, CD and 23 with ulcerative colitis, UC, mean age 13.8
years, range 1-45 years, 41.4% males, 58.6% females). The study was approved by
the local ethics committee and written informed consent was obtained from all
patients or their relatives or guardians. The studied polymorphisms have been
the BclI, in intron 2, and the N363S polymorphism in exon 2, that have been
associated with an increased sensitivity to GCs in vivo [2][3] and the ER22/23EK polymorphism, in exon
2, associated with a partial form of GC resistance [4]. Genomic DNA was extracted from
peripheral leukocytes, amplified with specific primers and subsequently
digested with MnlI (ER22/23EK), Tsp509I (N363S) or BclI restriction enzymes
[5][6].
The results of the analysis are presented in table I;
we found a significantly higher frequency of the BclI mutated
genotype in patients with CD in comparison with healthy controls (p= 0.03,
Fisher test, OR 3.84; 95%CI 1.23-11.91), no difference was on the contrary
observed between UC patients and controls.
BclI
GENOTYPEn (%)
OR (95% CI)
p value
Wild type
Heterozygous
Mutated
Mutated vs not mutated
Controls
(n= 70)
30 (42.9%)
34 (48.5%)
6 (8.6%)
-
-
CD
(n=34)
9 (26.5%)
16 (47%)
9 (26.5%)
3.84
(1.23-11.91)
0.03
UC
(n=23)
10 (43.5%)
12 (52.2%)
1 (4.3%)
1.03 (0.39-
2.65)
1
ER22/23EK
Wild type
Heterozygous
Mutated
Heterozygous vs wild type
Controls
(n= 70)
67 (95.7%)
3 (4.3%)
0 (0%)
-
-
CD
(n=34)
32 (94.1%)
2 (5.9%)
0 (0%)
1.39
(0.22- 8.78)
0.6
UC
(n=23)
22 (95.7%)
1 (4.3%)
0 (0%)
1.01
(0.10- 10.27)
1
N363S
Wild type
Heterozygous
Mutated
Heterozygous vs wild type
Controls
(n= 70)
67 (95.7%)
3 (4.3%)
0 (0%)
-
-
CD
(n=34)
33 (97.1%)
1 (2.9%)
0 (0%)
0.68
(0.07- 6.76)
1
UC
(n=23)
21 (91.3%)
2 (8.7%)
0 (0%)
2.13(0.33-13.60)
0.6
Table I: BclI, ER22/23EK and N363S
genotype in patients with CD, UC and controls.
The BclI polymorphism has been associated
with high systolic pressure, insulin sensitivity, body mass index and abdominal
fat distribution [2][7]; carriers of the mutated
allele have increased GC sensitivity, and higher cortisol suppression after low
dose dexamethasone [8]. A higher frequency of the mutated genotype has been observed in this
study in patients with CD; this mutation could lead to an increased sensitivity
in peripheral and central GRs, determining a raised susceptibility to feedback
inhibition of GCs on the HPA axis. It is of interest that previous studies have
demonstrated [9], in a subgroup of patients
with Crohn’s disease, alterations of the HPA axis resulting in relative
hypocortisolism.
No difference was on the contrary observed for the
N363S polymorphism,associated with an
increased sensitivity to GCs [3][10], or the ER22/23EK polymorphism, that is,
on the contrary, associated with a partial form of GC resistance [4] (table I).
This is the first study examining the possibility that IBD may be
associated withGR polymorphisms; our
results support the hypothesis that common polymorphisms in the GR gene may
have modulating effects on the relation between psychological factors and HPA
axis regulation in patients with CD. These data however need to be confirmed in
a larger group of patients.
The Authors declare no competing interest.
Acknowledgements
This research was supported by grants from the
Italian Ministry of University and Scientific Research (PRIN projects 2004065777
and 2003053403) and the Italian Ministry
of Health. Dr. Sara De Iudicibus, Dr. Gabriele Stocco and Dr. Ilenia Drigo are
recipients of research felloships from IRCCS Burlo Garofolo, Trieste.
References
1.Sternberg
EM, Chrousos GP, Wilder RL, et al. The stress response and the regulation of
inflammatory disease. Ann Intern Med 1992;117:854-66.
2.Buemann B, Vohl MC,
Chagnon M, et al. Abdominal visceral fat is associated with a BclI
restriction fragment length polymorphism at the glucocorticoid receptor gene
locus. Obes Res 1997;5:186-92.
3.Lin
RC, Wang WY, Morris BJ. High penetrance, overweight, and glucocorticoid
receptor variant: case-control study. Bmj
1999;319:1337-8.
4.van
Rossum EF, Koper JW, Huizenga NA, et al. A polymorphism in the glucocorticoid
receptor gene, which decreases sensitivity to glucocorticoids in vivo, is
associated with low insulin and cholesterol levels. Diabetes 2002;51:3128-34.
5.Koper
JW, Stolk RP, de Lange P, et al. Lack of association between five polymorphisms
in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 1997;99:663-8.
6.Bachmann
AW, Sedgley TL, Jackson RV, et al. Glucocorticoid receptor polymorphisms and
post-traumatic stress disorder. Psychoneuroendocrinology
2005;30:297-306.
7.Weaver
JU, Hitman GA, Kopelman PG. An association between a Bc1I restriction fragment
length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia
in obese women. J Mol Endocrinol 1992;9:295-300.
8.van Rossum EF, Koper JW,
van den Beld AW, et al. Identification of the BclI polymorphism in the
glucocorticoid receptor gene: association with sensitivity to glucocorticoids
in vivo and body mass index. Clin
Endocrinol 2003;59:585-92.
9.Reinshagen
M, Haefele T, Holicki S, et al. The ultra low dose ACTH-test identifies a
subgroup of patients with Crohns disease and an impaired hypothalamo-pituitary-adrenal
(HPA) axis. Gastroenterology 2002;122:S1384.
10.Huizenga NA, Koper JW, De
Lange P, et al. A polymorphism in the glucocorticoid receptor gene
may be associated with and increased sensitivity to glucocorticoids in vivo. J
Clin Endocrinol Metab 1998;83:144-51.
We read this article with great interest. Thanks to author for
submitting an interesting article. If the patients were on prednisolone
or other immunosuppressive drugs then possible effects on CRC risk may be
influenced by use of glucocorticoids or immunosuppressant. Question is
which drugs really reduce the risk of colorectal cancer risk? As any
effect of 5-ASA therapy on the risk of CRC could be me...
We read this article with great interest. Thanks to author for
submitting an interesting article. If the patients were on prednisolone
or other immunosuppressive drugs then possible effects on CRC risk may be
influenced by use of glucocorticoids or immunosuppressant. Question is
which drugs really reduce the risk of colorectal cancer risk? As any
effect of 5-ASA therapy on the risk of CRC could be mediated by the
reduction in mucosal inflammation. If the patients were on multiple drugs,
than evaluation of 5-ASA effects on IBD patients comparing those with non-
IBD person taking 5-ASA is questionable! Was 5-ASA use for IBD was
compared to controlled or quiescent IBD?
In this study IBD reference group was selected consisting of patients
without a history of IBD or prescription for 5-ASA. If this group of
patients were taking any other NSAIDs or any other drugs, what is the
chance that those drugs may influence the results?
Here the author mentioned that two 5-ASA groups was matched to a
reference patient by age (within five years), sex, and medical practice.
They were also matched by calendar time (that is, they had to be
registered at the practice at the date of the first record of a 5-ASA
prescription of their matched patient). In the event of no eligible
control patient within five years of age, an age and sex matched control
patient was selected from another practice. Our question is if patients
were selected from another practice suddenly there is chance of selection
biases. So these patients were under threats to various biases.
Positive family history of colon/rectum polyps can be a cause of
colorectal cancer development. How was the group of patients evaluated
while calculating the risk of CRC development association with 5-ASA?
Environmental factor plays an important role in IBD; smoking is one
of the important factors. Our question is was smoking countered as an
important factor causing IBD and colorectal cancer. Number of patients who
were smoking was not clearly identified in this study. Only smoking is
enough to cause colorectal cancer.
In a recent article [2] we found that there are genetic materials
involved in inflammatory bowel disease. Mutations in the nod2 gene are
present in as many as one third of individuals with Crohn disease. We
would aspect that spectrum of genes causing inflammatory bowel disease
will be identified, attention will be focused on the mechanisms through
which they lead to ulcerative colitis and Crohn's disease.
References
1. T P van Staa, T Card, R F Logan, and H G M Leufkens
5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel
disease: a large epidemiological study
Gut, Nov 2005; 54: 1573 - 1578.
2. Giorgos Bamias, Mark R. Nyce, Sarah A. De La Rue, and Fabio
Cominelli
New Concepts in the Pathophysiology of Inflammatory Bowel Disease
Ann Intern Med, Dec 2005; 143: 895 - 904.
We note Dr Browning's interest in our work. Unfortunately, we find
his letter
to be factually incorrect, and therefore scientifically misleading.
In attempting to analyse further our own data, he has made invalid
assumptions regarding our data set, which render his calculations
inaccurate,
and his conclusions inappropriate. Moreover, the selected literature
references which he quotes omit c...
We note Dr Browning's interest in our work. Unfortunately, we find
his letter
to be factually incorrect, and therefore scientifically misleading.
In attempting to analyse further our own data, he has made invalid
assumptions regarding our data set, which render his calculations
inaccurate,
and his conclusions inappropriate. Moreover, the selected literature
references which he quotes omit critical recent data and reviews of this
area,
and are not representative of the current state of knowledge.
In response to requests from the scientific referees of our paper, we
included
data on 294 controls, who had been typed for either the DLG variants, the
OCTN1/2 variants, or both OCTN1/2 and DLG5 variants. The OCTN1/2 data
(not the focus of this paper) were added, as a marker independent of the
DLG5 gene, in order to show that the two sets of controls were
homogeneous. Of these 294 controls, DLG5 genotyping was undertaken in
269 samples, and successful genotypes obtained in 256 (95.2%). Thus the
failure rate in controls (4.8%) was similar to that in IBD patients (4.4%,
p=0.78
by Chi squared analysis). The Hardy-Weinberg data which Dr Browning
derives are not attributable to genotyping failure.
The contribution of the DLG5 gene is clearly complex. Dr Browning
fails to
quote a series of large studies in adult European populations which are
directly pertinent to our work. In the same volume of Gut as our paper,
Torok
et al.[1] show no association of the DLG5 113A variant in the German
population, with a non-significant reduction in 113A allelic frequency in
Crohn's disease (625 CD patients, 1012 controls). Vermeire et al. performed
studies in 2032 Belgian individuals, using strategies of case-control
analysis,
as well as transmission disequilibrium testing, and noted significant
undertransmission of the DLG5 113A allele towards affected offspring
(p=0.01, by Chi squared analysis.[2] Data presented in abstract from
Cambridge[3], and Oxford[4] show no significant association - in the full
paper in press, the final analysis of the Cambridge data again
demonstrates
non-significant reduction in 113A allelic frequency in Crohn's disease
(personal communication, Miles Parkes).
It is noteworthy that unpublished data from our own Unit suggest
that in
childhood onset disease, the penetrance of the DLG5 113A allele may be
critically influenced by gender, and environmental influences (Russell et
al.,
submitted).
These issues have recently been the subject of thoughtful editorials,
and
correspondence both in Gastroenterology[5], and most recently in the
European Journal of Human Genetics[6,7] - again unfortunately these
manuscripts are not considered by Dr Browning. We of course feel strongly
that this area is clearly of great interest, but we regretfully find the
deficiencies in Dr Browning's letter to be potentially counter-productive.
References
1. Torok H, Glas J, Tonenchi L et al. Polymorphisms in the DLG5 and
OCTN
cation transporter genes in Crohn's disease. Gut 2005:54:1421-7.
2. Vermeire S, Pierik M, Hlavaty T et al. Association of Organic
Cation
Transporter Risk Haplotype with Perianal Penetrating Crohn's disease, but
not
with Susceptibility to IBD. Gastroenterology 2005:129:1845-53.
3. Waller S, Tremelling M, Bredin F, Greenfield S, Parkes M.
Replication of
association between IBD and TNF-857, but not DLG5,NFKB, Keratin 8, or
TUCAN/CARD8 Gut 2005:54;suppl2 A95.
4. Cummings JRF, Herrlinger KR, Ahmad T, Jewell DP. Genotype-
phenotype
analyses of the IBD susceptibility gene DLG5. Gut 2005:54: suppl 2 A95.
5. Trinh TT, Rioux JD. Understanding Association and Causality in the
Genetic
Studies of Inflammatory Bowel Disease. Gastroenterology 2005;129: 2106
-2109.
6. Tenesa A, Noble C, Satsangi J, Dunlop M. Association of DLG5 and
inflammatory bowel disease across populations. Eur Journal Hum Genet 2006
Jan 4 e-pub.
7. Daly MJ, Rioux JD. Reply to Tenesa et al Association of DLG5 and
inflammatory bowel disease across populations. Eur Journal Hum Genet 2006
Jan 4 e-pub.
We read this article with great interest. Treatment of anal fissure is
really troublesome. Here the author puts emphasis on the Neuromyogenic properties of anal sphincter and treatment by topical glyceryl trinitrate,
a nitric oxide donor, which decreases anal sphincter tone and improves
anal mucosal blood flow and promotes the healing of anal fissures. Because
of the easy application process glyceryl tri...
We read this article with great interest. Treatment of anal fissure is
really troublesome. Here the author puts emphasis on the Neuromyogenic properties of anal sphincter and treatment by topical glyceryl trinitrate,
a nitric oxide donor, which decreases anal sphincter tone and improves
anal mucosal blood flow and promotes the healing of anal fissures. Because
of the easy application process glyceryl trinitrate becomes popular.
In a study[1] published in NEJM showe that treatment with either topical nitroglycerin or botulinum toxin is as effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the
more effective nonsurgical treatment. Botulism toxin has proved its superiority than nitrates in many clinical trials.Despite the reported success[2] of botulinum toxin, its use has not been widely adopted, possibly due to the need for injection into the sphincter complex and
because it is expensive. The optimal dose and method of administration require validation.
Patients on nitroglycerin at some time in the course of treatment, reported moderate-to-severe headaches after application of the ointment. These headaches were transient (30 to 40 minutes) and were relieved with oral analgesia. some patients may stop applying the ointment because of
severe headache. Some patients in the nitroglycerin group reported moderate anal burning. A second potential difficulty is the development of drug tolerance, a problem well documented with nitrate therapy for cardiovascular disease and now also reported during treatment for anal
fissure.[3]
Yet a number of practical and theoretical questions remain unanswered about therapy with nitrates or botulinum toxin. For nitrates: Which preparation should be used, at what concentration, and how often should it be applied? For botulinum toxin: What dose should be used, and where
should it be injected — the internal or external sphincter? For both agents: Which works faster and with fewer adverse effects? How substantial is the problem of incontinence, and is it ever more than temporary? What are the relative costs? Finally, what are the long-term relapse rates? If
the beauty of chemical sphincterotomy lies in its transience, how often
will elevated sphincter pressures lead to recurrence months or years down
the road?
References
1.A Comparison of Injections of Botulinum Toxin and Topical Nitroglycerin
Ointment for the Treatment of Chronic Anal Fissure.Brisinda G., Maria G.,
Bentivoglio A. R., Cassetta E., Gui D., Albanese A.N Engl J Med 1999;
341:65-69, Jul 8, 1999.
2. A Comparison of Botulinum Toxin and Saline for the Treatment of Chronic
Anal Fissure.Maria G., Cassetta E., Gui D., Brisinda G., Bentivoglio A.
R., Albanese A.
N Engl J Med 1998; 338:217-220, Jan 22, 1998.
3.Watson SJ, Kamm MA, Nicholls RJ, Phillips RK. Topical glyceryl
trinitrate in the treatment of chronic anal fissure. Br J Surg 1996;83:771
-775.
we read with great interest the review by Asselah et al. (1), about
the relevance of steatosis in chronic hepatitis C. They properly report
that steatosis occurs more frequently in patients with chronic hepatitis C
(55%) than in the general population (20-30%) of adults in the Western
world (2), and that it is associated with various factors, including
obesity, high alcohol consumption, diabetes melli...
we read with great interest the review by Asselah et al. (1), about
the relevance of steatosis in chronic hepatitis C. They properly report
that steatosis occurs more frequently in patients with chronic hepatitis C
(55%) than in the general population (20-30%) of adults in the Western
world (2), and that it is associated with various factors, including
obesity, high alcohol consumption, diabetes mellitus, and hyperlipidaemia.
They also discuss experimental models demonstrating that hepatitis C virus
(HCV) proteins derived from genotype 1 isolates can induce steatosis (3-6). Among the conclusions, they claim the need for larger studies which
take into account confounding factors for steatosis.
We have recently published our experience in assessing the impact of
steatosis on antiviral treatment in a group of 102 naive patients with
chronic hepatitis C of different genotypes (7). We excluded subjects with
at least one of these features: present or past alcohol consumption, body
mass index of 30 or more (indicating obesity), hyperglicaemia,
hypercholesterolaemia and hypertriglyceridaemia. This was done to rule out
possible concomitant metabolic disorders, namely alcoholic hepatitis and
non alcoholic fatty liver disease. However, we observed that hepatic
steatosis was present histologically in 51% of cases; we then hypothesized
a potential direct pathogenic role of the virus in the induction of liver
steatosis, not limited to HCV genotype 3.
We also observed a significantly higher necroinflammatory activity
and a greater prevalence of an advanced stage of fibrosis in HCV patients
with steatosis.
Interestingly, the presence of steatosis was not associated with a
lower sustained virological response. To our knowledge, no previous work
reported a selected population like ours, and we obviously agree on the
need for larger works which could contribute to explain the mechanisms
that promote the occurrence of steatosis in chronic hepatitis C.
References
1 Asselah T, Rubbia-Brandt L, Marcellin P, et al. Steatosis in
chronic hepatitis C: why does it really matters? Gut 2006; 55 123-130.
3 Barba G, Harper F, Harada T, et al. Hepatitis C virus core protein
shows a cytoplasmic localization and associates to cellular lipid storage
droplets. Proc Natl Acad Sci USA 1997;94:1200–5.
4 Shi ST, Polyak SJ, Tu H, et al. Hepatitis C virus NS5A colocalizes
with the core protein on lipid droplets and interacts with
apolipoproteins. Virology 2002;292:198–210.
5 Perlemuter G, Sabile A, Letteron P, et al. Hepatitis C virus core
protein inhibits microsomal triglyceride transfer protein activity and
very low density lipoprotein secretion: a model of viral-related
steatosis. FASEB J 2002;16:185–94.
6 Okuda M, Li K, Beard MR, et al. Mitochondrial injury, oxidative
stress, and antioxidant gene expression are induced by hepatitis C virus
core protein. Gastroenterology 2002;122:366–75.
7 Guidi M, Muratori P, Granito A, et al. Hepatic steatosis in
chronic hepatitis C: impact on response to anti-viral treatment with peg-
interferon and ribavirin. Aliment Pharmacol Ther 2005; 22:943-9.
The recent study by Noble and colleagues[1] did not find an
association of the DLG5 G113A polymorphism with either inflammatory bowel
disease (IBD) or Crohn’s disease (CD). Previous studies in other European
populations had reported an increase in 113A allele frequency in IBD and
CD patients [2,3], but, in striking contrast, Noble et al.[1] reported a
trend toward decreased carrier frequency for the 1...
The recent study by Noble and colleagues[1] did not find an
association of the DLG5 G113A polymorphism with either inflammatory bowel
disease (IBD) or Crohn’s disease (CD). Previous studies in other European
populations had reported an increase in 113A allele frequency in IBD and
CD patients [2,3], but, in striking contrast, Noble et al.[1] reported a
trend toward decreased carrier frequency for the 113A allele in the IBD
patients (p=0.069) and in the CD patients (p=0.057).
We believe there is reason to re-examine the genotype data used in
the Noble et al. report.
First, there are significant differences in the proportion of missing
genotypes between the IBD patients and the controls (p<0.00001,
Fisher’s exact test). Using the data in Table 1 and Table 3[1], the missing
genotype rate is 13% in controls and 4% in IBD patients. This difference
strongly suggests differences in DNA quality or genotyping process between
the IBD and control samples.
Second, using the data in Table 3[1], the G113A polymorphism is not
in Hardy-Weinberg equilibrium (HWE) in the IBD patients (HWE p-value=0.0056, likelihood ratio test). Hardy-Weinberg equilibrium describes the
relationship of allele and genotype frequencies in a randomly mating
population, and departure from HWE in controls is commonly used to test
for genotyping error.[4] If the G113A polymorphism is independent of
IBD disease status, then we expect the G113A polymorphism to be in HWE in
IBD patients. There are fewer heterozygote IBD patients than expected
under Hardy-Weinberg equilibrium, and this may be related to the
differences in heterozygote frequencies between IBD patients and controls
(p=0.033) and between CD patients and controls (p=0.029) reported by
Noble et al.[1] One possible explanation for this difference in
heterozygote frequencies is genotyping error in IBD patients caused by
allelic dropout of the 113A allele.
The differences in missing genotype rates and the departure from HWE
in IBD patients suggest that the quality of the genotype data that
underlie the conclusions of this study should be investigated.
References
1. Noble CL, Nimmo ER, Drummond H, et al. (2005) DLG5 variants do not
influence susceptibility to inflammatory bowel disease in the Scottish
population. Gut 2005;54:1416-20.
2. Stoll M, Corneliussen B, Costello CM, et al.(2004) Genetic
variation in DLG5 is associated with inflammatory bowel disease. Nat Genet
2005;36:476-80.
3. Daly MJ, Pearce AV, Farwell L, et al. (2005) Association of DLG5
R30Q variant with inflammatory bowel disease. Eur J Hum Genet 2005;13:835-
9.
4. Leal SM. Detection of genotyping errors and pseudo-SNPs via
deviations from Hardy-Weinberg equilibrium. Genet Epi 2005;29:204-14.
Dear Sir:
We have read with great interest the review of gastrointestinal (GI) complications after pelvic radiotherapy by Andreyev (1). Andreyev emphasized importance of fibrosis as the underlying cause for most GI symptoms after radiotherapy, and concluded that reversal or prevention of fibrosis could be highly profitable in the treatment of this complication, referring several anti-fibrotic agents such as lipo...
Dear Editor:
Does Longitudinal Muscle Contraction of Esophagus Hold Important Secrets?
Tutuian and colleagues [1] performed high resolution esophageal manometry in a patient with achalasia and “chest pressure” following swallowing. They observed a sustained increase in intraesophageal pressure with maximum pressure at the time of maximal esophageal shortening. The esophageal shortening is attributed t...
Dear Editor,
In response to the comments of Duley et al. to our letter published in GUT 2005 we would like to make some additional remarks.
First of all, Duley et al. conclude that our study had a retrospective character, but this is not correct. This is a longitudinal cohort study in which all patients with IBD visiting our out-patient department were included. These patients were followed prospectively fo...
Dear Editor,
We appreciate the interest of Guidi et al. according our review about the relevance of steatosis in chronic hepatitis C.[1] We would like to outline three points according to their comments: the prevalence of steatosis in regard to genotype; the role of necroinflammation; the relationship between steatosis and treatment outcome.
Firstly, several studies have observed a significant association...
Dear Editor.
We read with interest the article by Mawdsley and Rampton on the relationship between psychological stress, increased disease activity in inflammatory bowel diseases (IBD), and the role of...
Dear Editor,
We read this article with great interest. Thanks to author for submitting an interesting article. If the patients were on prednisolone or other immunosuppressive drugs then possible effects on CRC risk may be influenced by use of glucocorticoids or immunosuppressant. Question is which drugs really reduce the risk of colorectal cancer risk? As any effect of 5-ASA therapy on the risk of CRC could be me...
Dear Editor,
We note Dr Browning's interest in our work. Unfortunately, we find his letter to be factually incorrect, and therefore scientifically misleading.
In attempting to analyse further our own data, he has made invalid assumptions regarding our data set, which render his calculations inaccurate, and his conclusions inappropriate. Moreover, the selected literature references which he quotes omit c...
Dear Editor,
We read this article with great interest. Treatment of anal fissure is really troublesome. Here the author puts emphasis on the Neuromyogenic properties of anal sphincter and treatment by topical glyceryl trinitrate, a nitric oxide donor, which decreases anal sphincter tone and improves anal mucosal blood flow and promotes the healing of anal fissures. Because of the easy application process glyceryl tri...
Dear Editor,
we read with great interest the review by Asselah et al. (1), about the relevance of steatosis in chronic hepatitis C. They properly report that steatosis occurs more frequently in patients with chronic hepatitis C (55%) than in the general population (20-30%) of adults in the Western world (2), and that it is associated with various factors, including obesity, high alcohol consumption, diabetes melli...
Dear Editor,
The recent study by Noble and colleagues[1] did not find an association of the DLG5 G113A polymorphism with either inflammatory bowel disease (IBD) or Crohn’s disease (CD). Previous studies in other European populations had reported an increase in 113A allele frequency in IBD and CD patients [2,3], but, in striking contrast, Noble et al.[1] reported a trend toward decreased carrier frequency for the 1...
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