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We read with interest the paper by Mera et al1 on the effect of
eradicating H. pylori infection on precancerous gastric lesions. However,
we have concern regarding the extent to which the limited data provided in
the paper support the authors’ conclusions of regression of atrophy and
intestinal metaplasia following H. pylori eradication.
The main outcome reported was the average histological...
We read with interest the paper by Mera et al1 on the effect of
eradicating H. pylori infection on precancerous gastric lesions. However,
we have concern regarding the extent to which the limited data provided in
the paper support the authors’ conclusions of regression of atrophy and
intestinal metaplasia following H. pylori eradication.
The main outcome reported was the average histological score. This is
an arbitrary ordinal scale, which is based upon the presence of
superficial gastritis, atrophic gastritis, intestinal metaplasia,
dysplasia or cancer as the most advanced lesion found in the four gastric
biopsies performed at each time-point. The average score was 3.77 at
baseline and following eradication of the infection fell to 3.18 after
twelve years. The extent to which resolution of the different components
of the average histological score contributed to the fall in the score is
not made clear in the paper. However, the authors do present data showing
that the acute polymorphonuclear cell infiltration fully resolved and the
chronic mononuclear cell infiltration partially resolved. The magnitude
of the resolution of the inflammatory infiltrate would appear to be
adequate to explain the fall in the average histological score without any
associated resolution of the intestinal metaplasia or atrophy. The
Results section does not give information on the score for atrophy or
intestinal metaplasia at baseline versus twelve years.
In the Discussion section comment is made to changes in atrophy and
intestinal metaplasia. However, insufficient data to draw any meaningful
conclusions or perform statistical analysis. In addition, there is
clearly an error in the data provided is the Discussion section as 70/182
is called 20%.
We would be grateful if the authors would provide the individual
metaplasia and atrophy scores at baseline and at twelve years in the two
groups in order to allow independent analysis and interpretation of this
important study. This is important as these are the lesions most strongly
associated with cancer risk.
Our interpretation of the limited data made available in the current
version of the paper is that there is evidence of early complete
resolution of the acute polymorphonuclear infiltration and partial
resolution of the chronic mononuclear cell infiltration but no convincing
evidence presented of resolution of the intestinal metaplasia or atrophy.
The findings are therefore consistent with a number of previous studies
showing no evidence of reversal of the important precancerous lesions. We
also note that during the twelve years of follow-up five cancers occurred
in the H. pylori treatment group and four in the non-treatment group.
Contrary to the conclusions of the authors, the benefits of eradicating H.
pylori infection in patients with advanced gastritis as a means of
preventing cancer remains far from clear.
References
1. Mera R, Fontham E T H, Bravo L E et al. Long-term follow up of
patients treated for Helicobacter pylori infection. Gut, 2005; 54: 1536-
1540.
2. Correa P, Fontham E T H, Bravo J C et al. Chemoprevention of
gastric dysplasia: Randomised trial of antioxidant supplements and anti-
Helicobacter therapy. JNCL, 2000; 92: 1881-1888.
In a retrospective study of patients with inflammatory bowel disease,
van Dieren et al recently reported the absence of correlation between
genotypes for both inosine triphosphate pyrophosphatase (ITPA) thiopurine
methyltransferase (TPMT) with any side effects to azathioprine (AZA) (Gut
2005;54:1664). This contrasts with two other studies. A rigorous
prospective study recently published has demonstrat...
In a retrospective study of patients with inflammatory bowel disease,
van Dieren et al recently reported the absence of correlation between
genotypes for both inosine triphosphate pyrophosphatase (ITPA) thiopurine
methyltransferase (TPMT) with any side effects to azathioprine (AZA) (Gut
2005;54:1664). This contrasts with two other studies. A rigorous
prospective study recently published has demonstrated significant
association between ITPA genotype and early drop-out from AZA therapy.(1)
Our original publication implicated ITPA in a number of adverse effects,
which were independent of myelosuppression.(2) One letter has reported non
-association of ITPA specifically with myelosuppression,(3) but we have
previously pointed out that thiopurine induced myelosuppression is well
documented over the past 25 years to be associated with TPMT, not ITPA
status.(4)
However, we draw attention to a curious feature of the TPMT results
of van Dieren et al, that one patient - who suffered severe
myelosuppression - was reported as a TPMT*3B/*3B genotype. We previously
published a meta-analysis of the incidence of the TPMT*3B mutant
allele,(5) discovering that it is extremely rare, and this has been
confirmed by a recent large study, making the chance of *3B homozygosity
negligible.(6) Indeed, our evidence suggested that even the few cases of
TPMT*3B may be over-reported, as a result of a technical problem in TPMT
genotyping by PCR-RFLP. The A719G TPMT*3C mutation is usually identified
by restriction endonuclease digestion that relies on creation of an Acc1
recognition site, and we have shown that this method is prone to
failure.(5) The TPMT*3A allele, the most common mutant polymorphism among
Caucasians, is a double mutant combining the TPMT*3C mutation and the
G460A TPMT*3B mutation. A failure of A719G recognition will thus result in
misreading the TPMT*3A allele as TPMT*3B (and TPMT*3C as wild-type
TPMT*1).
Curiously, van Dieren et al state that pre-therapy TPMT genotyping is
“of limited clinical value” but their results show that the two cases of
severe and potentially life threatening myelosuppression in their patient
group were predicted by TPMT genotyping. In the absence of sequencing
evidence, a cloud of doubt remains over the other TPMT genotype results
presented. But until extensive and preferably prospective studies are
accumulated in the literature it seems too early to dismiss the full
pharmacogenetic value of ITPA and TPMT. In large scale clinical practices
TPMT requesting is proving popular and useful, particularly in combination
with thioguanine nucleotide monitoring.(6-8) We keenly await further
publications elucidating genetic regulation of thiopurine metabolism as a
valuable pharmacogenetic model.
Conflict of interest
None declared.
References
1. 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;51:2074-84
2. 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;14:181-7
3. Allorge D, Hamdan R, Broly F, et al. ITPA genotyping test does not
improve detection of Crohn's disease patients at risk of azathioprine/6-
mercaptopurine induced myelosuppression. Gut 2005;54:565
4. Sanderson J, Ansari A, Marinaki T, et al. Thiopurine
methyltransferase: should it be measured before commencing thiopurine drug
therapy? Annals of Clinical Biochemistry 2004;41:294-302
5. Brouwer C, Marinaki AM, Lambooy LH, et al. Pitfalls in the
determination of mutant alleles of the thiopurine methyltransferase gene.
Leukemia 2001;15:1792-3
6. Dervieux T, Meyer G, Barham R, et al. Liquid chromatography-tandem
mass spectrometry analysis of erythrocyte thiopurine nucleotides and
effect of thiopurine methyltransferase gene variants on these metabolites
in patients receiving azathioprine/6-mercaptopurine therapy. Clin Chem
2005;51:2074-84.
7. Gearry RB, Barclay ML, Roberts RL, et al. Thiopurine
methyltransferase and 6-thioguanine nucleotide measurement: early
experience of use in clinical practice. Intern Med J 2005;35:580-5.
8. Holme SA, Duley JA, Sanderson J, et al. Erythrocyte thiopurine
methyl transferase assessment prior to azathioprine use in the UK. Qjm
2002;95(7):439-44.
The introduction of newer TNF blockers (etanercept, infliximab, adalimumab) has greatly improved the treatment of chronic inflammatory disorders such as Crohn’s disease, rheumatoid arthritis and ankylosing spondylitis. As the main side effect however many patients are rendered susceptible to infections.(1) Especially the activation of latent tuberculosis infection (LTBI) is a common and dangerous problem....
The introduction of newer TNF blockers (etanercept, infliximab, adalimumab) has greatly improved the treatment of chronic inflammatory disorders such as Crohn’s disease, rheumatoid arthritis and ankylosing spondylitis. As the main side effect however many patients are rendered susceptible to infections.(1) Especially the activation of latent tuberculosis infection (LTBI) is a common and dangerous problem. A national three and half year survey in France found 56 cases of activated LTBI due to infliximab.(2)
Physicians are therefore advised to screen for LTBI before commencing any TNF blocker. All recommendations include careful history, and chest radiograph.(1,3) The need for tuberculin skin testing has been questioned as a high incidence of anergy in Crohn’s patients on immunosuppressive therapy has been reported.(4) It now seems to be consensus not to skin test these patients and to give chemoprophylaxis for certain ethnic groups.(5) Careful monitoring for activation of LTBI is required for patients not receiving chemoprophylaxis.
We initiated Infliximab therapy in an anxious 28 year old female with refractory Crohn’s disease. Screening for LTBI showed a normal chest x-ray and tuberculin skin test, but at that stage the patient was receiving high dose steroids. Two months later she presented to her general practitioner with a productive cough. Sputum cultures were obtained and a preliminary report revealed mycobacteria growth. However as the patient did not develop any constitutional symptoms and final culture results showed an atypical mycobacterium it was opined that this rather represents a contaminant.
Not only false negative tuberculin skin tests but also false positive cultures for mycobacteria can cause a diagnostic dilemma in Crohn’s patients. Furthermore this can cause additional distress in already anxious patients.
References
1. Keane J. TNF-blocking agents and tuberculosis; new drugs illuminate an old problem. Rheumatology 2005 March 1
2. Baldin B, Dozol A, Spreux A, Chichmanian RM. Tuberculosis and infliximab treatment. National surveillance from January 1, 2000 through June 30, 2003. Presse Med 2005 Mar 12; 34 (5):353-7
3. Salmon D. Recommendations about the prevention and management of tuberculosis in patients taking infliximab. Joint Bone Spine 2002;69:170-2
4. British Thoracic Society with Ormerod LP, Milburn H, Gillespie S, Ledingham JM, Rampton DS. Recommendations for assessing risk, and managing tuberculosis infection and disease in patients due to start anti-TNF alpha treatment. Thorax, in press 2005. (Also online at http://thorax.bmjjournals.com/cgi/rapidpdf/thx.2005.046797v1)
5. Rampton DS. Preventing TB in patients with Crohn’s disease needing Infliximab or other anit-NTF therapy. Gut, 2005; 54: 1360 - 1362.
Dear Editor
We would like to thank Dr Huo and his colleagues for their comments. The
followings are point-by-point responses to their comments.
1) The serum ALT levels were not considered in our analysis of prognostic
factors because the stratification into 5 groups rendered it too
complicated for statistical calculation of multivariate analysis. In
addition, we aimed to examine independently the differences...
Dear Editor
We would like to thank Dr Huo and his colleagues for their comments. The
followings are point-by-point responses to their comments.
1) The serum ALT levels were not considered in our analysis of prognostic
factors because the stratification into 5 groups rendered it too
complicated for statistical calculation of multivariate analysis. In
addition, we aimed to examine independently the differences of the outcome
in patients with different ALT since elevated ALT level is the most
commonly used criterion for initiation of treatment [1]. As for HBV DNA
levels, our conclusion was that development of cirrhosis complication was
related to prolonged low level viremia up to the time of development of
complications. Baseline HBV DNA levels would be of little help in
determining whether HBV DNA levels were of importance. A good example
would be the high HBV DNA levels in children; that does not mean they are
at risk for cirrhotic complication when they are young.
2) We are not sure what Dr. Huo means. As is clearly shown in the
table under Figure 2, for patients with ALT > 2 – 6 times upper limit
of normal (ULN), the risk for development of complications was
significantly different from those with ALT 0.5 – 1 X ULN. Also the risk
for development of complications was significant LOWER than patients with
ALT > 1 -2 X ULN and ALT > 2 – 6 X ULN. Clearly ALT levels of >
1-2 X ULN are at the highest risk for complications.
We would like to stress “baseline HBV DNA levels” of the study of Yu et al
were arbitrary [2], taken at the particularly time point the subjects were
recruited on a completely random basis.
As for the study of Yang et al. [3], the HBeAg status was only checked on
recruitment. It is unknown what proportion of these patients had HBeAg
seroconversion during subsequent follow-up of 92,359 patient-years, i.e.,
the HBeAg/ anti-HBe status was unknown at the time of development of
hepatocellular carcinoma.
3) As for our specifically studying the late complications of
cirrhosis, not only is this not a flaw, we consider this as one of the
important and innovative aspect of our study. Dr. Huo is WRONG to say that
only the formation of cirrhosis or hepatocellular carcinoma is directly
linked with chronic HBV infection. As the study of Liaw et al has
elegantly shown, lowering viral replication can suppress the DEVOLOPMENT
of late complications of cirrhosis [4]. In fact, this exactly confirms the
proposal of our study.
Man-Fung Yuen, MD, PhD
Ching-Lung Lai, MD
Department of Medicine, The University of Hong Kong, Queen Mary Hospital,
Hong Kong.
Tel: 852 28554252
Fax: 852 28162863
Email: mfyuen@hkucc.hku.hk; hrmelcl@hkucc.hku.hk
References
1. Yuen MF, Yuan HJ, Wong DKH, et al. Prognostic determinants for chronic
hepatitis B in Asians: therapeutic implications. Gut 2005;54:1610- 4.
2. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level
and hepatocellular carcinoma: a prospective study in men. J Natl Cancer
Inst 2005;97:265-72.
3. Yang HI, Lu SN, Liaw YF, et al; the Taiwan Community-Based Cancer
Screening Project Group. Hepatitis B e antigen and the risk of
hepatocellular carcinoma. New Engl J Med 2002;347:168-74.
4. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic
hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521-31.
Arguably, the two most powerful endogenous appetite stimulants are
ghrelin[1] and the cannabinoids.[2] What is not known is whether or not
they interact, and whether there is mutual reinforcement of their
individual actions. If it were the case that cannabinoids and ghrelin are
synergistic, coprescription of the two agents (delta 9-tetrahydrocannabinol
being the approved appetite enhancing pharmacologic...
Arguably, the two most powerful endogenous appetite stimulants are
ghrelin[1] and the cannabinoids.[2] What is not known is whether or not
they interact, and whether there is mutual reinforcement of their
individual actions. If it were the case that cannabinoids and ghrelin are
synergistic, coprescription of the two agents (delta 9-tetrahydrocannabinol
being the approved appetite enhancing pharmacological derivative of the
cannabinoids) would enable smaller doses of ghrelin to be utilised to
stimulate appetite and acheive weight gain than is currently the case in
conditions such as cachexia of chronic obstructive pulmonary disease[3]
where, even though the target organ of the disorder (the lung in this
instance) is only sparsely populated with ghrelin producing
cells,[4] exogenous ghrelin may be impressively beneficial.[3] The
situation in cardiac disorders is different in that, instead of ghrelin-
producing cells, what has been identified in the target organ, namely, the
myocardium, is mRNA expression of type 1a ghrelin receptors[5], and, in
retrospect, this might have been the basis of the succesful use of
exogenous ghrelin for treatment of cardiac cachexia in laboratory
animals.[6] Here, again, there is potential for a benefit from
coprescription with cannabinoids.
Yours sincerely
OMP Jolobe MRCP(UK)
References:
(1) Peeters TL Ghrelin: a new player in the control of gastrointestinal functions
GUT 2005:54:1638-49.
(2) Berry EM., Mechoulam R Tetrahydrocannabinol and endocannabinoids in feeding and appetite
Pharmacology and Therapeutics 2002:95:185-90.
(3) Nagaya N., Itoh T., Murakami S., et al. Treatment of cachexia with ghrelin in patients with COPD
CHEST 2005:128:1187-93.
(4) Volante M., Fulcheri E., Allia E., et al. Ghrelin expression in fetal, infant, and adult human lung
Journal of Histochemistry and Cytochemistry 2002:50:1013-21.
(5) Gnanapavan S., Kola B., Bustin SA., et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor GHS-R in humans. Journal of Clinical Endocrinology and Metabolism 2002:87:2988-91.
(6) Nagaya N., Uematsu M., Kojima M., et al. Chronic administartion of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001:104:1430-5.
We read with interest the paper by Yuen et al. published in a recent
issue of Gut.[1] This study included a large patient cohort with chronic
hepatitis B and analyzed the determinants predicting the outcome. Authors
concluded that low level viremia and mildly elevated serum ALT levels more
commonly lead to the development of complications. This conclusion,
however, is not supported by their findings...
We read with interest the paper by Yuen et al. published in a recent
issue of Gut.[1] This study included a large patient cohort with chronic
hepatitis B and analyzed the determinants predicting the outcome. Authors
concluded that low level viremia and mildly elevated serum ALT levels more
commonly lead to the development of complications. This conclusion,
however, is not supported by their findings as the independent predictive
factors are male gender, age, stigmata of chronic liver disease and
others, whereas serum ALT and hepatitis B virus (HBV) DNA levels are not.
It is questionable if patients with mildly elevated baseline ALT
levels are truly associated with a higher risk of complication. As shown
in Fig. 2 in the paper,[1] the incidence of complication in group with ALT>2-6 x ULN and group with ALT>6 x ULN was still significantly
higher compared to the group with ALT<0.5x ULN that had the lowest
risk of complication. More importantly, serum ALT level was not an
independent risk factor predicting a poor outcome in the Cox multivariate
analysis, suggesting lower serum ALT and/or HBV DNA levels were only
associated but not independent factors. Although HBV DNA levels were
tested to correlate with the clinical course, it should be noted that DNA
levels were measured at different time points (21 patients before, 9 at,
and 80 after the complication developed) and this inhomogeneous
information makes the analysis of the impact of HBV DNA level on disease
course less useful. Interestingly, entirely different conclusions were
reported from a recent study that prospectively investigated 4,841
Taiwanese men who were HBV carriers.[2] A higher baseline HBV DNA level
was associated with an increased risk of the development of hepatocellular
carcinoma (HCC) with a risk ratio up to 7.3-fold.[2] In addition, a
positive baseline hepatitis B e antigen consistently predicted a higher
risk of HCC.[2,3] The contrast between these studies can be best
explained that patient data were collected at different time points in the
natural history of chronic hepatitis B. In this regard, the necessity of
serial multiple measurements of clinical parameters in patients with
chronic hepatitis B has been emphasized to reveal important information
associated long-term outcome.[4]
Another potential flaw in this study is that authors have defined
ascites, spontaneous bacterial peritonitis and encephalopathy as
complications of chronic hepatitis B. It should be noted these are rather
late complications of cirrhosis and may not be directly related to HBV
infection. Since the time interval from silent cirrhosis to the
development of complication may vary widely and many cirrhotic patients
never develop significant cirrhosis-related complications in the natural
history, the complication should be defined as formation of cirrhosis or
HCC which is directly linked with chronic HBV infection.
In summary, the evaluation of end point should be cirrhosis or HCC
rather than cirrhosis-related complication which is not directly related
to HBV infection. Lower serum ALT and HBV DNA levels more likely reflect a
later stage of chronic hepatitis B and are possibly associated with
increasing age of these patients who may already have severe fibrosis or
sub-clinical cirrhosis.
Teh-Ia Huo, MD
Taipei Veterans General Hospital and National Yang-Ming University,
School of Medicine, Taipei, Taiwan
Correspondence to:
Teh-Ia Huo, MD
Division of Gastroenterology
Department of Medicine
Taipei Veterans General Hospital
Taipei, Taiwan
Tel: + 886 2 2871 2121 Ext.: 3352
Fax: + 886 2 2873 9318
Email: tihuo@vghtpe.gov.tw
Competing Interest: None declared.
References
1. Yuen MF, Yuan HJ, Wong DKH, et al. Prognostic determinants for
chronic hepatitis B in Asians: therapeutic implications. Gut 2005;54:1610-
4.
2. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA
level and hepatocellular carcinoma: a prospective study in men. J Natl
Cancer Inst 2005;97:265-72.
3. Yang HI, Lu SN, Liaw YF, et al; the Taiwan Community-Based Cancer
Screening Project Group. Hepatitis B e antigen and the risk of
hepatocellular carcinoma. New Engl J Med 2002;347:168-74.
4. Chen CJ. Time-dependent events in natural history of occult
hepatitis B virus infection: the importance of population-based long-term
follow-up study with repeated measurements. J Hepatol 2005;42:438-40.
We read with great interest the paper by Antonius Schneider et al.
assessing acupuncture treatment in irritable bowel syndrome (IBS).[1]
They successfully recruited 43 patients with IBS according to Rome II
criteria, and randomly assigned them to receive either acupuncture (n=22)
(AC) or sham acupuncture (n=21) (SAC) using the so-called "Streitberger
needle". Treatment duration was 10 sessions with an...
We read with great interest the paper by Antonius Schneider et al.
assessing acupuncture treatment in irritable bowel syndrome (IBS).[1]
They successfully recruited 43 patients with IBS according to Rome II
criteria, and randomly assigned them to receive either acupuncture (n=22)
(AC) or sham acupuncture (n=21) (SAC) using the so-called "Streitberger
needle". Treatment duration was 10 sessions with an average of two
acupuncture sessions per week, and primary endpoint was improvement of
quality of life (QOL) using the Functional Digestive Diseases Quality of
Life Questionnaire (FDDQL) and a general Quality of Life Questionnaire (SF
-36),compared to baseline assessment. They found that both the AC as well
as the SAC group improved significantly in global QOL by the FDDQL at the
end of treatment (p=0.022), with no differences between both groups. This
observation led authors to conclude that acupuncture in IBS is primarily a
placebo response.
This result supported the conclusion of studies by Fireman et al.[2] and
Forbes A et al.[3] Interestingly, we have recently finished one study
with conclusion that acupuncture can attenuate chronic visceral
hypersensitivity in rats.[4] Results showed that acupuncture has
immediate and cumulative effects on chronic visceral pain induced by
colorectal distention stimuli in rats with chronic visceral
hypersensitivity. This result supported the findings in previous report[5], and really matched the phenomena of our clinical practice that IBS
sufferers did get benefits from acupuncture treatment. We also found
acupuncture can modulate the expression of corticotropin-releasing factor
in the limbic system and concentration of serotonin in the colon[4], not
just modulate the endorphin system via central processing of pain.[6,7]
In evidence, placebo effect cannot explain the efficacy of acupuncture on
the rats with chronic visceral hypersensitivity. Furthermore, some trials
did provide evidences that acupuncture have treatment effect on patients
with IBS. In one open-design pilot study [8], after a 4-week course of
acupuncture treatment, seven patients with IBS showed an improvement in
overall well-being and bloating but not abdominal discomfort or defecation
frequency. One study of seven patients with diarrhoea-predominant IBS showed
that transcutaneous electrical acustimulation (TEAS) at acupoints PC6 and
ST36 significantly increased the threshold of rectal sensation of gas,
desire to defecate, and pain, but had no effects on rectal tone or
compliance.[9]
Why evidences from clinical trials are so confusing? How to unfasten
this sticking point? One study showed that gender is one factor to affect
the manifestations of IBS. Male IBS patients have more significant
decreased parasympathetic tone and increased sympathetic activity with
altered autonomic nervous system responsiveness to a visceral stimulus
than that of IBS female patients[11], and these differences may be due to
gender difference in cortico-limbic processing of visceral stimuli. In
another study with treatment scheme of twice per week for 2 months,
transcutaneous electrical acustimulation( TEAS ) at LI 4 and ST36 improved
the abnormal rectal sensation and related symptoms in patients with
diarrhea-predominant IBS (n=24), but not in those with constipation-
predominant IBS (n=20) and functional constipation (n=30).[10] This
result indicates that there are characteristic differences between
diarrhea- and constipation-predominant IBS patients.
Because of different characteristics of male and female patients with
IBS, and diarrhea- and constipation-predominant IBS, we think it is not
appropriate to mix the gender[1, 2,3,8,9,10,11] and subgroup of IBS[1,2,3,
8,9,11] for assessing the therapeutic effect of acupuncture on IBS. In
fact, it threatened the internal validity of clinical trial results.
Future randomized, double blind and placebo-controlled study with
acupuncture on IBS should stratify patients by gender and subgroups in
randomization and assessment, and we believe it is essential too for
studies on IBS with drug therapy.
References
1. Schneider A, Enck P, Streitberger K, Weiland C, Bagheri S, Witte
S, Friederich HC, Herzog W, Zipfel S. Acupuncture treatment in irritable
bowel syndrome. Gut. 2005, September 22, in press.
2. Fireman Z, Segal A, Kopelman Y, Sternberg A, Carasso R.
Acupuncture treatment for irritable bowel syndrome. A double-blind
controlled study. Digestion. 2001; 64: 100-3.
3. Forbes A, Jackson S, Walter C, Quraishi S, Jacyna M, Pitcher M.
Acupuncture for irritable bowel syndrome: a blinded placebo-controlled
trial. World J Gastroenterol. 2005; 11: 4040-4.
4. Z.-X.Bian, X-G. Hu, R-A.Qin, X.-J. Zhang, L. Liu. Electro-
acupuncture attenuates behavioral hyperalgesia and relieves stress-induced
defecation in rats with chronic visceral hypersensitivity. unpublished
data 2005.
5. Cui KM, Li WM, Gao X, Chung K, Chung JM, Wu GC. Electro-
acupuncture relieves chronic visceral hyperalgesia in rats. Neurosci Lett.
2005 Mar 7; 376(1): 20-3.
6. Han JS. Acupuncture and endorphins. Neurosci.Lett. 2004; 361: 258-
61.
7. Hui KK, Liu J, Makris N, Gollub RL, Chen AJ, Moore CI et al.
Acupuncture modulates the limbic system and subcortical gray structures of
the human brain: evidence from fMRI studies in normal subjects.Hum.Brain
Mapp. 2000; 9: 13-25.
8. Diehl DL. Chan J, Carr I, Mayberry JF. The role of acupuncture in
the treatment of irritable bowel syndrome: a pilot study.
Hepatogastroenterology. 1997; 44: 1328-30.
9. Xing J, Larive B, Mekhail N, Soffer E. Transcutaneous electrical
acustimulation can reduce visceral perception in patients with the
irritable bowel syndrome: a pilot study. Altern Ther Health Med. 2004; 10:
38-42.
10. Xiao WB, Liu YL. Rectal hypersensitivity reduced by acupoint TENS
in patients with diarrhea-predominant irritable bowel syndrome: a pilot
study. Dig Dis Sci. 2004; 49: 312-9.
11. Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD.
Sex specific alterations in autonomic function among patients with
irritable bowel syndrome. Gut. 2005; 54: 1396-1401.
12. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of
bias. Dimensions of methodological quality associated with estimates of
treatment effects in controlled trials. JAMA. 1995; 273: 408-12.
This systematic, original large study from the Leuven group proves
what experienced physicians have appreciated for many years: that
heartburn is a specific symptom that is easily identifiable by careful
history or validated questionnaire, that heartburn is predictive of
abnormal esophageal acid exposure in about 75% of people with the symptom,
and that it occurs in a minority of patients with typical...
This systematic, original large study from the Leuven group proves
what experienced physicians have appreciated for many years: that
heartburn is a specific symptom that is easily identifiable by careful
history or validated questionnaire, that heartburn is predictive of
abnormal esophageal acid exposure in about 75% of people with the symptom,
and that it occurs in a minority of patients with typical or "true"
dyspepsia especially when the latter represents symptoms other than pain
or burning occurring after meal ingestion.
The prevalence of <20% in the typical dyspepsia group of Tack et al is
consistent with the high rate of somatic symptoms in these patients and it
is likely that it represents "background noise". In a community based
study of uninvestigated dyspepsia, the prevalence of heartburn was
similar, and somatization scores (SCL-90) and somatic symptom checklist
scores were higher than in community controls.[1]
Data from this important study suggest that the subgroup of reflux-like
dyspepsia (e.g. in Rome I criteria) should be discarded, that studies
demonstrating efficacy of acid reduction in dyspepsia are generally
uninformative in the context of true dyspepsia, and that inclusion
criteria for true dyspepsia studies can be tightened by using a
questionnaire to exclude heartburn rather than requiring laborious and
costly 24 hour pH monitroing or upper gastrointestinal endoscopy.
The implications of this study are very significant and they should be
embraced by practising physicians, regulatory agencies and those who write
consensus documents on symptom-based criteria for functional
gastrointestinal disorders.
Well done and best wishes.
Sincerely,
Michael
References
1. Castillo et al. 2004. Clinical Gastroenterology and Hrepatology 2:9850-996.
According to a recently published study[1], insulin resistance is a
worsening factor in HCV-related chronic hepatitis. There is much debating
as to whether insulin resistance depends on hepatitis C virus or, vice
versa, it is an independent syndrome.
Likely, being insulin resistance the link between obesity, metabolic
alterations and endothelial damage, it is a characteristic feature of the
met...
According to a recently published study[1], insulin resistance is a
worsening factor in HCV-related chronic hepatitis. There is much debating
as to whether insulin resistance depends on hepatitis C virus or, vice
versa, it is an independent syndrome.
Likely, being insulin resistance the link between obesity, metabolic
alterations and endothelial damage, it is a characteristic feature of the
metabolic syndrome. Non alcoholic steato-hepatitis is a recently
recognized entity associated with the metabolic syndrome. It frequently
overlaps with HCV-related chronic hepatitis, sharing some histological
features (mainly steatosis).
Our aim was to verify the possibility of improving the rate of
antiviral treatment response by ameliorating the metabolic syndrome.[2]
Thirty-two naïve patients with HCV-related chronic hepatitis and
metabolic syndrome (assessed with ATP III criteria), genotype 1, aged 44-68 years, 16 males, were consecutively enrolled. The whole population was
divided into two groups: 15 patients (Group A) were on a strict low
calorie diet for three months to achieve a 10% reduction of BMI before
starting treatment, whereas 17 were on a free diet for a same period
(Group B).
All patients were offered standard combined antiviral therapy: (Peg-
IFN alpha 2b= 1.5 mcg/kg body weight/weekly and Ribavirin 1000-1200
mg/daily) for at least three months for non responders (same virological
load before and after), and 12 months if responders or partially
responders (decrease of HCV-RNA > or = 2 log 10). The results were:
HOMA in Group A was different before and after weight reduction (4.86+/-
0.96 versus 3.45+/-0.66; p=0.0018; paired t test), with 60% and 17.6% of
response in Group A and B, respectively (p=0.035; chi square). The flu-
like-syndrome was present in 8 patients in Group A and in 13 patients in
Group B.
The low calorie diet was the only parameter differentiating the response
rate to antiviral therapy. Our speculation is that, by improving the
metabolic syndrome, the decrease in BMI plays a key role in reducing the
metabolic co-factor and creating a better substratum to a good antiviral
response. The lower dosages encourage better patient compliance to
treatment.
Reference
1. Fartoux L, Poujol-Robert A, Guechot J, Wendum D, Poupon R, Serfaty
L. Insulin resistance is a cause of steatosis and fibrosis progression in
chronic hepatitis C.
Gut. 2005;54:1003-8.
2. Park HS, Lee K. Greater beneficial effects of visceral fat
reduction compared with subcutaneous fat reduction on parameters of the
metabolic syndrome: a study of weight reduction programmes in subjects
with visceral and subcutaneous obesity.
Diabet Med 2005;22:266-72.
Pandolfino et al. and Bruley des Varannes et al. present data from
simultaneous pH monitoring by wireless Bravo™ and catheter mounted
antimony electrode systems.[1,2] Both studies demonstrate that the
wireless system records significantly fewer reflux events; the effect on
overall acid exposure was more limited. Further analysis revealed that
events ‘missed’ by the Bravo™ system were shorter and less...
Pandolfino et al. and Bruley des Varannes et al. present data from
simultaneous pH monitoring by wireless Bravo™ and catheter mounted
antimony electrode systems.[1,2] Both studies demonstrate that the
wireless system records significantly fewer reflux events; the effect on
overall acid exposure was more limited. Further analysis revealed that
events ‘missed’ by the Bravo™ system were shorter and less acidic than
those detected by both systems. The authors suggest that the different
recording characteristics of the two systems explain the apparent 'higher
sensitivity' of the catheter pH system, including the lesser sampling rate
of the Bravo™ system,[1,2] and systematic inaccuracy in catheter
electrode calibration.[1] (Calibration in vivo was not checked by Bruley
des Varannes et al; this group also used Medtronic equipment and the same
systematic error could also have explained some of the discrepancy between
the systems).
Beyond these technical concerns, the significance of short ‘reflux
events’ is questionable because short drops to pH<4 can be caused by
factors unrelated to gastro-oesophageal reflux. First, ingestion of mildly
acidic fluids (despite instruction). Second, movement of the catheter
relative to the mucosa;[1] i.e. ‘drying’ or ‘loss of contact’ of the
catheter electrode (the internal reference of Bravo™ reduces this source
of error). Third, movement of the catheter relative to the gastro-
oesophageal junction (GOJ) during swallowing. The last point requires
explanation: on swallowing the oesophagus shortens by several centimetres
due to longitudinal muscle contraction,[3,4] an event that stabilizes the
oesophageal wall and increases the effectiveness of peristaltic
contraction and bolus transport.[5] Even greater shortening can occur
during oesophageal spasm (6) and transient lower oesophageal sphincter
relaxation (with or without acid reflux). As the oesophagus shortens the
catheter electrode moves distally towards the GOJ and may pass into the
proximal stomach, a region in which highly acidic conditions may be
present.[7,8] Thus the catheter electrode may dip into the ‘acid
pocket’[8] at the GOJ before relaxation of the oesophagus returns the
catheter into its original position. This cannot occur with Bravo™ because
it is fixed to the oesophageal wall. As a result a short drop in pH is
recorded by the catheter electrode but not the Bravo™ system.
As stated by the authors, pH studies alone cannot explain the
discrepancies between the catheter and Bravo™ systems. Studies that
combine pH monitoring (chemical reflux and clearance) and multichannel
intraluminal impedance (volume reflux and clearance) with manometry are
required to define the physiology of these events and help determine their
relevance (if any) in eliciting symptoms. Studies using polymodal
measurements have shown that oesophageal volume clearance is considerably
faster than chemical clearance.[9] Chemical clearance usually progresses
by stepwise increases in pH as swallowing activity brings bicarbonate
containing saliva into contact with acid reflux. However short pH drops
(often <20s) can occur with peristaltic contractions and resolve
without further swallowing activity. Short pH drops can also be seen
during transient LOS relaxation, again resolving without swallowing
activity. These observations strongly suggest that many short ‘reflux
events’ recorded by catheter systems may be artefacts, related to
oesophageal shortening rather than gastro-oesophageal reflux.
The Bravo™ system is a well tolerated alternative to catheter-based
pH measurement, experience with the technique is increasing and normal
values are being established. If the accuracy (specificity) of catheter
based detection of reflux events is shown to be limited, the Bravo™ system
may establish itself as the new standard for pH measurement in the
investigation and diagnosis of gastro-oesophageal reflux disease.
Figure 1. Concurrent high resolution manometry (HRM) and pH recording during a transient lower oesophageal sphincter relaxation (TLOSR) in a normal volunteer. The positions of the Bravo™ capsule, catheter electrode and (LOS) are indicated on the schematic diagram and the HRM plot. The TLOSR is associated with a brief oesophageal contraction with ~5cm shortening. The position of the Bravo™ capsule remains constant relative to the LOS and the Bravo™ pH recording remains at ~pH6; however the catheter electrode approaches the LOS and records a short pH drop to <pH4 as it enters the ‘acid pocket’. Relaxation of the oesophagus restores the position of the LOS and the catheter pH recording normalizes without swallowing activity. This ‘reflux event’ is an artifact, related to oesophageal shortening rather than gastro-oesophageal reflux.
References
1. Pandolfino J, Zhang Q, Schreiner M, Ghosh S, Roth M, Kahrilas PJ.
Acid reflux event detection using the Bravo™ wireless vs the Slimline™
catheter pH systems: why are the numbers so different? Gut 2005.
2. Bruley des Varannes S, Mion F, Ducrotte P, Zerbib F, Denis P, Ponchon
T, Thibault R, Galmiche JP. Simultaneous recordings of oesophageal acid
exposure with conventional pH monitoring and a wireless system (Bravo(R)).
Gut 2005.
3. Pouderoux P, Lin S, Kahrilas PJ. Timing, propagation, coordination, and
effect of esophageal shortening during peristalsis. Gastroenterology
1997;112:1147-54.
4. Kahrilas PJ, Wu S, Lin S, Pouderoux P. Attenuation of esophageal
shortening during peristalsis with hiatus hernia. Gastroenterology
1995;109:1818-25.
5. Pal A, Brasseur JG. The mechanical advantage of local longitudinal
shortening on peristaltic transport. J Biomech Eng 2002;124:94-100.
6. Fox M, Hebbard G, Janiak P, Brasseur JG, Ghosh S, Thumshirn M, Fried M,
Schwizer W. High-resolution manometry predicts the success of oesophageal
bolus transport and identifies clinically important abnormalities not
detected by conventional manometry. Neurogastroenterol Motil 2004;16:533-
42.
7. Fletcher J, Wirz A, Henry E, McColl KE. Studies of acid exposure
immediately above the gastro-oesophageal squamocolumnar junction: evidence
of short segment reflux. Gut 2004;53:168-73.
8. Fletcher J, Wirz A, Young J, Vallance R, McColl KE. Unbuffered highly
acidic gastric juice exists at the gastroesophageal junction after a meal.
Gastroenterology 2001;121:775-83.
9. Koek GH, Vos R, Flamen P, Sifrim D, Lammert F, Vanbilloen B, Janssens
J, Tack J. Oesophageal clearance of acid and bile: a combined
radionuclide, pH, and Bilitec study. Gut 2004;53:21-6.
10. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux
monitoring: review and consensus report on detection and definitions of
acid, non-acid, and gas reflux. Gut 2004;53:1024-31.
Dear Editor
We read with interest the paper by Mera et al1 on the effect of eradicating H. pylori infection on precancerous gastric lesions. However, we have concern regarding the extent to which the limited data provided in the paper support the authors’ conclusions of regression of atrophy and intestinal metaplasia following H. pylori eradication.
The main outcome reported was the average histological...
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We read with great interest the paper by Antonius Schneider et al. assessing acupuncture treatment in irritable bowel syndrome (IBS).[1] They successfully recruited 43 patients with IBS according to Rome II criteria, and randomly assigned them to receive either acupuncture (n=22) (AC) or sham acupuncture (n=21) (SAC) using the so-called "Streitberger needle". Treatment duration was 10 sessions with an...
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Dear Editor,
According to a recently published study[1], insulin resistance is a worsening factor in HCV-related chronic hepatitis. There is much debating as to whether insulin resistance depends on hepatitis C virus or, vice versa, it is an independent syndrome.
Likely, being insulin resistance the link between obesity, metabolic alterations and endothelial damage, it is a characteristic feature of the met...
Dear Editor,
Pandolfino et al. and Bruley des Varannes et al. present data from simultaneous pH monitoring by wireless Bravo™ and catheter mounted antimony electrode systems.[1,2] Both studies demonstrate that the wireless system records significantly fewer reflux events; the effect on overall acid exposure was more limited. Further analysis revealed that events ‘missed’ by the Bravo™ system were shorter and less...
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