As therapy of HIV patients with HAART has resulted in long-term
survival, the major burden of "disease" is becoming end-stage liver disease
secondary to HCV infection with rapidly progressive fibrosis and
cirrhosis. We are increasingly being asked to advise on this group of
patients, however, the literature is cautious about treatment and response
rates. Who do we treat? What is the response rate to ac...
As therapy of HIV patients with HAART has resulted in long-term
survival, the major burden of "disease" is becoming end-stage liver disease
secondary to HCV infection with rapidly progressive fibrosis and
cirrhosis. We are increasingly being asked to advise on this group of
patients, however, the literature is cautious about treatment and response
rates. Who do we treat? What is the response rate to achieve HCV
clearance? What are the risks of potential HIV decompensation? Interferon
monotherapy (incl PEG-Inf) or combination therapy?
Should the guidelines include special interest groups such as HCV/HIV
and HCV/HBV co-infections?
Dr Frank Weilert
Gastroenterolist
Waikato Hospital
Hamilton
New Zealand
Mawdsley et al raises the important question as to whether patients
with irritable bowel syndrome (IBS) would gain as much symptomatic
improvement if recommended to exclude the top four foods (yeast, milk,
whole egg and wheat) compared to an IgG antibody test-based diet.[1] In other
words, does the test add specificity? This requires a trial which compares
patients receiving an IgG antibody tes...
Mawdsley et al raises the important question as to whether patients
with irritable bowel syndrome (IBS) would gain as much symptomatic
improvement if recommended to exclude the top four foods (yeast, milk,
whole egg and wheat) compared to an IgG antibody test-based diet.[1] In other
words, does the test add specificity? This requires a trial which compares
patients receiving an IgG antibody test-based diet to those advised to
eliminate some or all of the top four foods. We are currently seeking
funding for such a trial.
There is some evidence however, from our trial that the IgG antibody
test-based diet may provide a better response than simply eliminating a
standard set of foods. When the change in IBS symptom severity score is
compared for fully adherent true and sham diet patients who were advised
to eliminate one or more of the top four foods, it is found that the true
diet patients experienced a significantly greater reduction than the sham
diet patients (difference=94; 95% CI: 18, 170; p=0.017).
We agree with Carrock Sewell's comment that the food elimination
diets in the true and sham groups were not similar in terms of content,[2]
although they were for numbers of food types excluded. This was to some
extent inevitable given the high prevalence of IgG antibodies to certain
foods, such as yeast (86.7%) and milk (84.3%). However, the exclusion
was not quite as unbalanced as implied since the so-called sugar foods
were allowed in the "yeast positive" patients. Whilst we accept that a
more balanced comparison would have been desirable, the principal point of
the sham diet was to control for placebo effect. In future more care needs
to be taken to match diets not just for number of food types excluded but
also for types of food. We are still confident, however, that the
difference in symptom improvement observed in our study for the true and
sham diet groups is a real one. This is evidenced by the highly
significant difference in worsening of symptoms between true and sham
groups when patients reintroduced foods they had been asked to exclude
(p=0.003).
References
1. Mawdsley JE, Irving PM, Makins RJ. IgG antibodies to foods in IBS [electronic response to Atkinson et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl.com 2004URL direct link to eLetter
2. Carrock Sewell WA. IgG food antibodies should be studied in similarly treated groups [electronic response to Atkinson et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl.com 2004URL direct link to eLetter
We read with great interest the article by Bettschart et al,[1] discussing an increase of cholangiocarcinoma incidence
after biliary-enteric drainage for benign disease.
In their hypothesis,
changes in the biliary epithelium were induced by toxic carcinogenesis due
to reflux of intestinal contents and bile stasis. However, this chronic
irritation and carcinogenesis of the biliary mucosa a...
We read with great interest the article by Bettschart et al,[1] discussing an increase of cholangiocarcinoma incidence
after biliary-enteric drainage for benign disease.
In their hypothesis,
changes in the biliary epithelium were induced by toxic carcinogenesis due
to reflux of intestinal contents and bile stasis. However, this chronic
irritation and carcinogenesis of the biliary mucosa after biliary-enteric
anastomosis has not been reported after surgery for malignant disease.
We present a case of a 65-year-old woman who developed a
cholangiocarcinoma eight years after duodenopancreatectomy for an
ampullary carcinoma, stage I. The patient was referred to our department
because of obstructive jaundice and cholangitis. CT scan showed that the
patient was disease-free. Percutaneous transhepatic cholangiography showed
biliary-enteric anastomosis stricture and a diffuse biliary stenosis.
Figure 1 Anastomosis stricture and a diffuse biliary stenosis. Cholangiocarcinoma (arrow) on
the right hepatic duct.
A percutaneous transhepatic anastomosis dilatation was performed
but it was ineffective. The patient was operated upon and an extensive
fibrosis and inflammation of the biliary-enteric anastomosis and biliary
duct was detected. A resection of the stricture and a hepatojejunostomy
were performed. In addition to fibrotic and inflammatory tissue,
histological examination showed a poorly differenced cholangiocarcinoma
with invasion of all the levels of the right hepatic duct wall. Surgical
margins were free of disease. The patient was discharged on the tenth
postoperative day. She died ten months after surgery.
As the authors we support the hypothesis that the reflux of intestinal
contents, bacterial translocation and pancreatic juice can trigger biliary
mucosa changes and the carcinogenesis process.1-4 We think that besides
those predisposing factors causing chronic cholangitis, there must be
susceptibility in these patients due to genetically altered enzymes that
are involved in detoxifying carcinogenic products.5 This is the first case
reported of malignant transformation in the biliary epithelium after
biliary-enteric anastomosis for malignant disease and as there are no
markers to identify patients in the early stage of development of
malignant transformation we agree with the authors,1-2 about monitoring
all patients who develop cholangitis after biliary-enteric anastomosis for
benign disease and also patients with malignant disease who are in
remission.
References
(1) Bettschart V, Clayton RAE, Parks RW, et al. Cholangiocarcinoma arising
after biliary-enteric drainage procedures for benign disease. Gut 2002;50;128-9.
(2) Tocchi A, Mazzoni G, Liotta G, et al. Late development of bile duct
cancer in patients who had biliary-enteric drainage for benign disease: A
follow-up study of more than 1000 patients. Ann Surg 2001; 234: 210-214.
(3) Perez RL, Gabarrel OA, Vinas SJ, et al. Biliary tract cancer following
bilioenteric anastomosis. Rev Esp Enferm Dig 1994; 86:853-5.
(4) Maeda A, Shumpei Y, Kunou T, et al. Bile duct cancer developing 21 years
after choledochoduodenostomy. Dig Surg 2003;20:331-334.
(5) Strog RW. Late bile duct cancer complicating biliary-enteric anastomosis
for benign disease. Am J Surg 1999;177:472-4.
In a case-control study on the associations between functional
genetic polymorphisms in biotransformation enzymes and Crohn’s disease, we
found a strong association of the Tyr113His (348T>C) polymorphism in
exon 3 of the microsomal epoxide hydrolase (EPHX1) gene and Crohn’s
disease.[1] The three referees all agreed that the study was interesting
and should be published so that other groups can attempt to...
In a case-control study on the associations between functional
genetic polymorphisms in biotransformation enzymes and Crohn’s disease, we
found a strong association of the Tyr113His (348T>C) polymorphism in
exon 3 of the microsomal epoxide hydrolase (EPHX1) gene and Crohn’s
disease.[1] The three referees all agreed that the study was interesting
and should be published so that other groups can attempt to replicate the
results in independent study cohorts. This was done recently by Cuthbert
et al,[2] who investigated 344 controls and 307 patients with Crohn’s
disease, and who were unable to reproduce our results. In addition, they
reported that our data for the EPHX1 exon 3 polymorphism in the control
group were not in Hardy-Weinberg equilibrium (HWE), as also noticed
earlier by Györffy et al.[3] Our data on EPHX1 exon 3 genotyping were obtained by restricted fragment
length polymorphism (RFLP) analyses by applying the method as described by
Lancaster et al.[4]
However, recently it was reported that a silent substitution polymorphism
(G to A) at codon 119 of the EPHX1 gene may exist, which may flaw the PCR-
RFLP method applied by us, since the presence of this polymorphism may
disturb the proper binding of the reverse primer, covering the 119 G>A
area, resulting in an over-classification of His113 alleles.[5,6] Therefore, we developed a dual-colour allele-specific discrimination assay
for genotyping the polymorphism at codon 113 of the EPHX1 gene. EPHX1
genotypes were detected using the iCycler iQ Multicolour Real-Time
Detection System (Bio-Rad Laboratories) using molecular beacons. PCR was
performed with the forward primer 5’-CAA CTC CAA CTA CCT GAA G-3’ and the
reverse primer 5’-TGA CAT ACA TCC CTC TCT G-3’ in the presence of the FAM-
labeled wild-type beacon (5’-CGC GAT GAT TCT CAA CAG ATA CCC TCA CTT CAA
TCG CG-3’) and the HEX-labeled mutant beacon (5’-CGC GAT ATT CTC AAC AGA
CAC CCT CAC TTC AAT CGC G-3’). The 25 microliter reaction mixture
contained 200 ng of genomic DNA, 10 mM Tris/HCl (pH 9.0), 50 mM KCl, 0.1%
Triton X-100, 4 mM MgCl2, 0.25 mM dNTPs, 50 ng of each primer, 200 nM of
each beacon and 2.5 U Taq-DNA-polymerase. The PCR conditions were 3 min at
95°C, then 40 cycles of 30 s at 95°C, 30 s at 59°C and 30 s at 72°C.
Fluorescent signals were measured at 59°C. Genotypes were assigned using
the iCycler iQ Optical System Software version 3.1. At each PCR run (in 96
wells plates) in several wells sterile H2O instead of genomic DNA was
added as negative controls for amplification.
Since the PCR-RFLP analyses were performed in the first half of 1999, only
part of the samples was still available (125 of 149 controls and 149 of
151 cases) and these were re-evaluated by the i-Cycler method.
Genotype
distribution of the EPHX1 Tyr113His polymorphism in patients with Crohn’s
disease and controls was now in Hardy-Weinberg equilibrium (chi2 = 2.47, p
= 0.12 and chi2 = 0.82, p = 0.37, respectively) and genotype distribution
was not significantly different between cases and controls (chi2 = 3.5, p
= 0.17). The Tyr allele frequencies of 0.70 and 0.68 obtained for cases
and controls, respectively, are very similar to the corresponding values of
0.71 and 0.70, as reported by Cuthbert et al.[2]
Thus, in answer to the
question as posed by Cuthbert et al: “Genetic association between EPHX1
and Crohn’s disease: population stratification, genotyping error, or
random chance?”, we can conclude that a genotyping error was responsible
for our earlier published association between the EPHX1 Tyr113His
polymorphism and Crohn’s disease.[1] We now clearly state, that our revised
data do not support an association between this EPHX1 polymorphism and
Crohn’s disease.
Similar genotyping errors may also be present in several other studies on
the EPHX1 exon 3 polymorphism in association with a variety of diseases,
since many studies are based on methods using a reverse primer covering
the “119 silent mutation area” of the EPHX1 gene.[4,7-10] This may also
have consequences for interpretation of results in the cited papers.
However, a rapid literature search by Pubmed reveals more than 100 papers
on EPHX1 polymorphisms during the last 10 years, suggesting that many
more papers may deal with genotyping problems as outlined above.
In addition, Cuthbert et al also reported that another
polymorphism tested in our study 1, the CYP1A1 exon 7 Ile/Val
polymorphism, was not in HWE in the control group.[2] This is correct,
however this deviation from HWE may be attributed to random chance, due to
rarity of the Val allele in our population, which makes the chi2 test
inappropriate under such conditions. For instance genotype distribution is
according to the HWE, when only two individuals less would have been
classified as Val/Val homozygotes.
We thank Cuthbert and co-workers[2] and Györffy and co-workers[3] for their
interest in our work. In addition, we conclude that (interpretation of)
data in many other published studies on EPHX1 Tyr113His (exon 3)
polymorphism should be critically re-evaluated.
References
1. De Jong DJ, van der Logt EMJ, van Schaik A, Roelofs HMJ, Peters
WHM, Naber THJ. Genetic polymorphisms in biotransformation enzymes in
Crohn’s disease: association with microsomal epoxide hydrolase. Gut
2003;52:547-51.
2. Cuthbert AP, Fisher SA, Lewis CM, Mathew CG, Sanderson J, Forbes A.
Genetic association between EPHX1 and Crohn’s disease: Population
stratification, genotyping error, or random chance? Gut 2004;53:1386.
3. Györffy B, Kocsis I, Vásárhelyi B. Biallelic genotype distributions in
papers published in Gut between 1998 and 2003: altered conclusions after
recalculating the Hardy-Weinberg equilibrium. Gut 2004;53:614-5.
4. Lancaster JM, Brownlee HA, Bell DA, Futreal PA, Marks JR, Berchuck A,
Wiseman RW, Taylor JA. Mol Carcinogen 1996;17:160-2.
5. Baxter SW, Choong DYH, Campbell IG. Microsomal epoxide hydrolase
polymorphism and susceptibility to ovarian cancer. Cancer Lett 2002;177:75
-81.
6. Gsur A, Zidek T, Schnattinger K, Feik E, Haidinger G, Hollaus P, Mohn-
Staudner A, Armbruster C, Madersbacher S, Schatzl G, Trieb K, Vutuc C,
Micksche M. Association of microsomal epoxide hydrolase polymorphisms and
lung cancer risk. Br J Cancer 2003;89:702-6.
7. Harrison DJ, Hubbard AL, MacMillan J, Wyllie AH, and Smith CA.
Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon
cancer. Br J Cancer 1999;79:168-71.
8. Sachse C, Smith G, Wilkie MJ, Barrett JH, Waxman R, Sullivan F, Forman
D, Bishop DT, Wolf CR. A pharmacogenetic study to investigate the role of
dietary carcinogens in the etiology of colorectal cancer. Carcinogenesis
2002;23:1839-49.
9. Cortessis V, Siegmund K, Chen Q, Zhou N, Diep A, Frankl H, Lee E, Zhu
QS, Haile R, Levy D. A case-control study of microsomal epoxide hydrolase,
smoking, meat consumption, glutathione S-transferase M3, and risk of
colorectal adenomas. Cancer Res 2001;61:2381-5.
10. Tranah GJ, Giovannucci E, Ma J, Fuchs C, Hankinson SE, Hunter DJ.
Epoxide hydrolase polymorphisms, cigarette smoking and risk of colorectal
adenoma in the Nurses' Health Study and the Health Professionals Follow-up
Study. Carcinogenesis 2004;25:1211-8.
We read with interest the recent article by de Jong et al.[1] reporting studies of genetic associations between DNA polymorphisms in xenobiotic metabolising genes and Crohn’s disease (CD). The authors employed a case control study design to test 7 polymorphisms in 5 candidate genes for disease association. Evidence was found for a significant association of a single nucleotide polymorphism (SNP), Tyr...
We read with interest the recent article by de Jong et al.[1] reporting studies of genetic associations between DNA polymorphisms in xenobiotic metabolising genes and Crohn’s disease (CD). The authors employed a case control study design to test 7 polymorphisms in 5 candidate genes for disease association. Evidence was found for a significant association of a single nucleotide polymorphism (SNP), Tyr113His (348T>C), in the microsomal epoxide hydrolase 1 gene, EPHX1, with CD. Homozygosity for the T (Tyr 113) allele was significantly higher in cases than in healthy controls (χ2 = 23.7, p <_0.0001 odds="odds" ratio="2.9)." the="the" observed="observed" frequency="frequency" of="of" t="t" allele="allele" in="in" controls="controls" was="was" _41="_41" which="which" is="is" outside="outside" range="range" frequencies="frequencies" _58-94="_58-94" reported="reported" other="other" control="control" populations="populations" reviewed="reviewed" de="de" jong="jong" i="i"/>et al). Its frequency in CD cases was 67%. In view of the strength of reported association, we sought to replicate this observation. We genotyped the Tyr113His SNP (ref SNP ID rs1051740) in 307 independent, sporadically-ascertained cases of CD and 344 ethnically matched healthy control subjects.[2] This compared with 151 cases and 149 controls typed by de Jong et al. Our study design provided 80% power to detect a significant difference (p <_0.05 in="in" allele="allele" frequency="frequency" of="of" _88047.5="_88047.5" between="between" cases="cases" and="and" controls="controls" compared="compared" to="to" the="the" difference="difference" _26="_26" observed="observed" published="published" study.="study." our="our" power="power" calculations="calculations" were="were" based="based" on="on" an="an" minor="minor" c="c" _30.2="_30.2" control="control" cohort="cohort" common="common" t="t" being="being" _69.8.="_69.8." p="p"/>
We used TaqMan™ chemistry (Applied Biosystems) to genotype DNA from cases and controls with an Applied Biosystems 7700 Sequence Detection System. Pre-optimised primers and fluorescent probes were obtained from Applied Biosystems (SNP assay ID C_14938_1). All cases and controls were previously genotyped for three confirmed disease susceptibility alleles (DSAs) for CD (R702W, G908R, L1007fs) in CARD15,[3-5] permitting stratification of data by CARD15 mutational status to identify potential gene-gene interactions.[6] Allele and genotype frequencies were compared between cases and controls using a Chi-squared test for difference in proportions. Likewise, a Chi-squared test was used to assess Hardy Weinberg equilibrium (HWE) across genotypes.
We found no significant differences in allele or genotype frequencies between cases and controls (Table 1).
Table 1
Tyr113His Genotype
Phenotype
N
T/T
Tyr/Tyr
T/C
Tyr/His
C/C
His/His
Tyr allele frequency
(T) (%)
Controls
344
167
146
31
69.8
Crohn’s
ALL
307
155
127
25
71.2
Crohn’s
0 CARD15 DSAsa
202
99
83
20
69.6
Crohn’s
1 CARD15 DSA
69
33
33
3
71.7
Crohn’s
2 CARD15 DSAs
20
12
7
1
77.5
a Disease susceptibility alleles.
Stratification of the data by CARD15 mutation status showed no significant differences in Tyr113His allele frequencies in CD cases with 0, 1 or 2 CARD15 mutations. Genotypes in our cases and controls were in HWE (p >0.5).
Case control-based studies of genetic association assume that differences in allele frequencies relate directly to the phenotype under investigation, and that no unobserved confounding factors exist which may be attributable to the associated allele. While having greater power than family-based studies to detect associations through linkage disequilibrium mapping, case control analysis is susceptible to type I errors (false positives).[7] One of the most commonly cited explanations for non-replication of genetic associations is stratification, through population admixture, and variability in disease frequencies between and within component subpopulations. However, relatively few instances of this have been clearly established. Stratification may be identified and potentially controlled for by incorporating anonymous genetic markers into the study design.[8,9] However, the efficacy of this approach depends on the level of stratification present, and the difference in SNP frequency and disease prevalence in the normal and affected populations. We noted that in de Jong et al the distribution of genotypes in controls for SNP Tyr113His was not in Hardy Weinberg equilibrium [(χ2 = 5.67, p = 0.017]. It is possible that this may have generated a type I error in their analysis. A degree of population admixture in their control cohort could account for the deviation from HWE and give rise to the observed association between the normally common T allele (as we observed) and Crohn’s disease. Alternative explanations are genotyping error and random chance. We examined the genotype distribution for the 7 SNPs tested by de Jong et al and found that in addition to Tyr113His, the Ile462Val (1506A/G) SNP in CYP1A1 was not in HWE [[(χ2 = 7.87, p = 0.005]). A recent review of published association studies by Xu et al.[9] found that 12% of SNPs tested were inconsistent with HWE in control subjects.
Our findings highlight the value of testing genetic association data for normal genotype distribution, and for rigorous replication of genetic associations with adequate statistical power.
References
(1) DJ de Jong, EMJ van der Logt, A van Schaik, HMJ Roelofs, WHM Peters, THJ Naber. Genetic polymorphisms in biotransformation enzymes in Crohn’s disease: association with microsomal epoxide hydrolase. Gut 2003;52:547-551.
(2) Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, Mascheretti S, Sanderson J, Forbes A, Mansfield J, Schreiber S, Lewis CM, Mathew CG. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.
Gastroenterology 2002 Apr;122(4):867-74.
(3) Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001 May 31;411(6837):603-6.
(4) Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001 May 31;411(6837):599-603.
(5) Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 2001 Jun 16;357(9272):1925-8. [Erratum in: Lancet 2002 Sep 7;360(9335):806.]
(6) Mirza MM, Fisher SA, King K, Cuthbert AP, Hampe J, Sanderson J, Mansfield J, Donaldson P, Macpherson AJ, Forbes A, Schreiber S, Lewis CM, Mathew CG. Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease. Am J Hum Genet 2003 Apr;72(4):1018-22.
(7) Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 2003 Feb 15;361(9357):598-604.
(8) Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 1999 Jul;65(1):220-8.
(9) Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM. Control of confounding of genetic associations in stratified populations. Am J Hum Genet 2003 Jun;72(6):1492-1504.
(10) Xu J, Turner A, Little J, Bleecker ER, Meyers DA. Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: hint for genotyping error? Hum Genet 2002 Dec;111(6):573-4.
We read the article by Allen et al[1] with interest and would like to report a case of probable cannabinoid hyperemesis
seen in a district general hospital in the UK.
A 21-year-old chef was admitted to our hospital on seven occasions
during a two year period (April 2001 to December 2002) with profuse
vomiting. Apart from a history of migraine as a child he was fit and well.
He smoked cannabi...
We read the article by Allen et al[1] with interest and would like to report a case of probable cannabinoid hyperemesis
seen in a district general hospital in the UK.
A 21-year-old chef was admitted to our hospital on seven occasions
during a two year period (April 2001 to December 2002) with profuse
vomiting. Apart from a history of migraine as a child he was fit and well.
He smoked cannabis. Physical examination was unremarkable. The observation
that the patient wanted to take regular baths because he had found that
bathing eased the sickness was documented in the nursing notes but its
significance was not appreciated. Investigations during attacks disclosed
neutrophilia but blood urea, electrolytes, liver biochemistry and serum
amylase were normal. Abdominal X-ray was also normal. Upper GI endoscopy
showed grade I oesophagitis and gastritis. Gastric biopsies were
histologically normal. An abdominal ultrasound scan and small bowel barium
follow through examination were normal. Additional normal or negative
investigations included: autoantibodies and immunoglobulins, C-reactive
protein and urinary porphyrin screen. A CT scan of the brain was also
normal.
During his last admission, the patient’s girlfriend showed us an
article published in an Australian newsletter, which she had obtained via
the internet, in which Dr JH Allen had raised the possibility of a link
between recurrent vomiting and cannabis abuse. With the aid of the
internet we traced and contacted Dr Allen who shared his experience of
this condition with us.
Reviewing the patient’s history, he freely admitted to smoking
cannabis and experiencing the compulsive desire to bathe during the bouts
of vomiting. Following his last admission in December 2002 our patient
stopped smoking cannabis and has remained free of symptoms. The clinical
presentation which is almost identical to the cases described by Allen et
al together with the response to cessation of smoking cannabis supports
the view that our patient was suffering from cannabinoid hyperemesis and
that this condition is international.
Reference
1. Allen JH, de Moore, GM Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in
association with chronic cannabis abuse. Gut 2004; 53: 1566-1570
We read with interest the article by Kamisawa and colleagues reporting IgG4-positive plasma cells in the peripancreatic
tissue, extraphepatic bile duct, gall bladder, and salivary gland.[1] The
association of retroperitoneal fibrosis and sclerosing pancreatitis with
IgG4 -bearing plasma cells in the tissues of both lesions has been also
reported.[2]
We read with interest the article by Kamisawa and colleagues reporting IgG4-positive plasma cells in the peripancreatic
tissue, extraphepatic bile duct, gall bladder, and salivary gland.[1] The
association of retroperitoneal fibrosis and sclerosing pancreatitis with
IgG4 -bearing plasma cells in the tissues of both lesions has been also
reported.[2]
We would like to report the first case of interstitial pneumonia
associated with autoimmune pancreatitis with IgG4-positive plasma cells in
the intersitium.
Hyperamylasemia was detected in a routine blood examination in a 63
year-old man who had been treated for duodenal ulcer at a clinic. He was
admitted to our hospital for further examination. He did not complain of
epigastralgia or back pain. Serum amylase was 323 (39-130 IU/L), IgG was
elevated to 2350 (800~1600mg/dl), and IgG4 was 1690 (<_80 mg="mg" dl.="dl." antinuclear="antinuclear" antibody="antibody" anti-ss-a="anti-ss-a" anti-ss-b="anti-ss-b" rheumatoid="rheumatoid" factor="factor" and="and" anti-smooth="anti-smooth" muscle="muscle" were="were" all="all" negative.="negative." abdominal="abdominal" ultrasonography="ultrasonography" computed="computed" tomography="tomography" ct="ct" showed="showed" swelling="swelling" of="of" the="the" head="head" tail="tail" pancreas.="pancreas." endoscopic="endoscopic" retrograde="retrograde" pancreatography="pancreatography" irregular="irregular" narrowing="narrowing" main="main" pancreatic="pancreatic" duct="duct" in="in" tail.="tail." magnetic="magnetic" resonance="resonance" cholangiography="cholangiography" extrinsic="extrinsic" stenosis="stenosis" lower="lower" common="common" bile="bile" duct.="duct." patient="patient" was="was" diagnosed="diagnosed" with="with" autoimmune="autoimmune" pancreatitis="pancreatitis" but="but" he="he" refused="refused" steroid="steroid" therapy="therapy" followed="followed" as="as" an="an" outpatient.="outpatient." p="p"/> Three months later, honeycombing of the bilateral lower lung field
was detected in a follow-up abdominal CT. Chest CT revealed ground glass
attenuation in the middle and lower lobe, and honeycombing predominantly
at the back of the lower lobe, bilaterally (Fig 1A).
Figure 1A chest CT showing ground glass attenuation in the middle and lower lobe, and honeycombing predominantly at the back of the lower lobe bilaterally
Retrospectively, a
slight reticular shadow in the lower lung field was detected in the chest
roentogenogram taken at the first admission, but the lesion had progressed
over 3 months. He was readmitted for further examination. He had a history
of smoking 30 to 40 cigaretts a day for approximately 40 years. IgG was
3934 mg/dl, IgG4 was 2690 mg/dl, KL-6 was 1440 ( With Gallium scintigraphy, uptake was observed bilaterally at the
back of the lower lobe, suggesting active pneumonia. Histology obtained by
transbronchial lung biopsy from segment 8a of the right lobe showed marked
thickening of the alveolar septum with marked infiltration of plasma cells
and lymphocytes (Fig 1B).
Figure 1B histology of the biopsy specimen from the lung (H.E)
Immunostaining with IgG4 was performed using the
imunoperoxidase method. (Mouse Anti-Human IgG4, ICN Biomedicals, Inc,
Ohio, Canada). Infiltration of IgG4-positive plasma cells was detected in
the alveolar septum (Fig 1C).
Figure 1C IgG4 staining of the biopsy specimen from the lung
Macrophages in the alveoli are considered
due to smoking, which often co-exists with interstitial pneumonia in
smokers.[3]
Because interstitial pneumonia associated with autoimmune
pancreatitis was strongly suggested, prednisolone (40 mg/day) was
administered for 2 weeks and then the dose was tapered. Chest CT taken 2
weeks ater treatment showed that the ground glass attenuation in the
middle and lower lobe had disapeared, whereas the honeycombing remained
(Fig 1D).
Figure 1D chest CT ater treatment
Abdominal ultrasonography performed 2 weeks after treatment
showed a marked decrease in the swelling the pancreas.
In the present case, infiltration of IgG4-positive plasma cells in
the interstitium strongly suggests that the interstitial lung disease was
associated with autoimmune pancreatitis. Interstitial pneumonia asoociated
with Sjogren's syndrome is unlikely in this case, although there was
decreased lacrimal secretion. Sicca syndrome observed in autoimmune
pancreatitis is distinctive from classical Sjogren's syndrome in that it
is negative for anti-SS-A or anti-SS-B antibodies, serum IgG4 is elevated
and infiltration of IgG4-positive plasma cells in the salivary glands is
observed.[1,4]
Autoimmune pancreatitis, in some cases, might be part of a systemic
disease associated with IgG4.
References
(1) Kamisawa T, Funata N, Hayashi Y et al. Close relationship between
autoimmune pancreatitis and multifocal fibrosclerosis. Gut 2003;52:683-7.
(2) Hamano H, Kawa S, Ochi Y et al. Hydronephrosis associated with
retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 2002; 359:1403-04.
(3) American Thoracic Society: American Thoracic Society/European
Respiratory Society International Multidisciplinary Concensus
Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit
Care Med 2002;165:277-304.
(4) Hamano H, Kawa S, Horiuchi A et al. High serum concentration in
patients with sclerosing pancreatitis. N Engl J Med 2001;344:732-738.
We read with great interest the article by Rad and coworkers[1] on the influence of cytokine gene polymorphisms on mucosal cytokine expression, gastric inflammation and host specific colonisation in Helicobacter pylori infection. The authors reported an association of the contrainflammatory IL-10 promotor haplotype (GCC) with higher mucosal mRNA levels and colonisation with more virulent cagA+,vacAs1+ and...
We read with great interest the article by Rad and coworkers[1] on the influence of cytokine gene polymorphisms on mucosal cytokine expression, gastric inflammation and host specific colonisation in Helicobacter pylori infection. The authors reported an association of the contrainflammatory IL-10 promotor haplotype (GCC) with higher mucosal mRNA levels and colonisation with more virulent cagA+,vacAs1+ and babA2+ strains in 207 patients with H.pylori induced chronic gastritis. Rad and coworkers identified pathogenicity genes of H.pylori isolates by PCR based techniques from gastric biopsies. However, the human stomach is colonized not only by a single strain of H.pylori which obscures the investigation of germline mutations and host specific colonisation.[2] Moreover, within an apparently homogeneous population remarkable genetic differences exist among single-colony isolates. The capacity of H.pylori to lose and possibly acquire exogenous DNA is consistent with a model of continuous microevolution within its cognate host.[3] Thus, the identification of bacterial virulence factors is directly dependent on the localisation of the biopsy. That means, if cagA+,vacAs1+ and babA2 were not detected in biopsy specimen the cocolonisation with strains harbouring these genes at another localisation cannot be excluded. Interestingly, the degree of inflammation and frequency of gastric atrophy and intestinal metaplasia was not different in patients carrying pro- or contrainflammatory haplotypes. The significance of genetic association studies is highly dependent on a well-defined phenotype. In contrast to the degree of granulocytic and lymphocytic infiltration in chronic gastritis, which may again vary regionally, the development of gastric ulcer is an unambiguous hallmark for the severity of H.pylori induced mucosal damage.
We recruited 614 consecutive Caucasian patients from Northern Germany who underwent gastroscopy with confirmed H.pylori infection by rapid urease test or histology. Endoscopic findings and the results of histopathological examination of biopsies, classified according to the Sydney classification, were recorded. In total 316 patients presented with chronic gastritis and served as controls and 124 patients suffered from gastric ulcer. DNA was extracted by standard techniques from 5 ml of EDTA blood. All patients were genotyped for IL-10 –1082, -819 and -592 by TaqMan technology. Samples were recoded and genotypes were assigned without knowledge of clinical status. Single marker and haplotype analysis was conducted to assess associations with development of gastric ulcer.
There were no associations found between any of the SNPs tested and H.pylori related pathologic findings (data not shown). The proinflammatory low secreting haplotype ATA did not confer a risk factor for the development of an ulcer as well as the contrainflammtory haplotype GCC did not protect the patients from gastric ulcer (Table I).
IL-10 promotor
-1082-819-592
chronic
gastritis
(n=316)
gastric
ulcer
(n=124)
OR
p(chi2)
GCC
ATA
ACC
48.0%
23.6%
28.2%
48.3%
24.2%
27.5%
1.01
1.03
0.97
0.939
0.862
0.842
Table
1: Haplotype
analysis of the IL-10 promotor in 427 patients with
chronic gastritis and gastric ulcer disease (OR=odds ratio)
Our results are in agreement with the study of Hida and coworkers who reported higher IL-10 mRNA expression in cagA+ H.pylori gastritis without relation to endoscopic diagnosis.[4] Therefore, we conclude that genetic variations in the IL-10 promotor may influence mucosal cytokine expression but pro- and contrainflammatory haplotypes do not influence the clinical course of gastric inflammation at least in Northern Germany. Furthermore we suggest that association studies of germline polymorphisms with the outcome of chronic H.pylori infection should focus on clearly defined phenotypes like ulcer disease, gastric carcinoma or primary gastric B-cell lymphoma.
References
1. Rad R, Dossumbekova A, Neu B et al. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut 2004;53: 1082-9.
2. Camorlinga-Ponce M, Romo C, Gonzalez-Valencia G et al. Topographical localisation of cagA positive and cagA negative Helicobacter pylori strains in the gastric mucosa; an in situ hybridisation study. J Clin Pathol 2004;57: 822-8.
3. Israel DA, Salama N, Krishna U et al. Helicobacter pylori genetic diversity within the gastric niche of a single human host. Proc Natl Acad Sci U S A 2001;98: 14625-30.
4. Hida N, Shimoyama T, Jr., Neville P et al. Increased expression of IL-10 and IL-12 (p40) mRNA in Helicobacter pylori infected gastric mucosa: relation to bacterial cag status and peptic ulceration. J Clin Pathol 1999;52: 658-64.
In response to the letter addressed by Dr Harlozinska-Szmyrka we agree
with the remarks made in relation to the difficulties in discrimination
between chronic pancreatitis and adenocarcinoma using currently employed
diagnostic imaging and tumour marker analysis. Our study aimed at
determining risk of cancer development in patients with proven chronic
pancreatitis,[1] examining age and sex standardised i...
In response to the letter addressed by Dr Harlozinska-Szmyrka we agree
with the remarks made in relation to the difficulties in discrimination
between chronic pancreatitis and adenocarcinoma using currently employed
diagnostic imaging and tumour marker analysis. Our study aimed at
determining risk of cancer development in patients with proven chronic
pancreatitis,[1] examining age and sex standardised incidence ratios
calculated from the number of observed cases of pancreatic cancer in our
cohort of 373 patients with predominantly alcohol-related chronic
pancreatitis to the number of cases expected in the National Cancer
Registry. Our study design did not take into consideration diagnostic
dilemmas and focused purely on cancer risk in our cohort or patients using
the defined stringent criteria. Indeed, we previously underlined the
interest of biological markers in this situation e.g. CA19-9 and
circulating K-ras;[2,3] however these markers have problems with both
sensitivity and specificity. We acknowledge that given the difficulties in
diagnosing cancer in this situation, the establishment of new tumor
markers such as tissue polypeptide specific antigen (TPS) [4] with proven
good sensitivity and specificity should provide for progress in the
future. Is has to be stressed however, that TPS, a marker of proliferation
activity, is not specific to pancreatic cancer and other digestive and non
-digestive cancers as well as benign chronic disorders may have high
levels of this marker.[5-7] Thus, validated data concerning tumour markers,
either alone or in combination, in distinguishing pancreatic cancer from
chronic pancreatitis should prove important in diagnostic situations.
References
(1) Malka D, Hammel P, Maire F, et al. Risk of pancreatic
adenocarcinoma in chronic pancreatitis. Gut 2002;51:849-52.
(2) Nouts A, Levy P, Voitot H, et al. Diagnostic value of serum Ca 19-9
antigen in chronic pancreatitis and pancreatic adenocarcinoma.
Gastroenterol Clin Biol 1998;22:152-9.
(3) Maire F, Micard S, Hammel P, et al. Differential diagnosis between
chronic pancreatitis and pancreatic cancer: value of the detection of
KRAS2 mutations in circulating DNA. Br J Cancer 2002 27;87:551-4.
(4) Slesak B, Harlozinska-Szmyrka A, Knast W et al. Tissue polypeptide
specific antigen (TPS), a marker for differentiation between pancreatic
carcinoma and chronic pancreatitis. A comparative study with CA 19-9. Cancer 2000;89:83-8.
(5) Malamitsi-Puchner A, Vazeou-Gerasimidi A, Sarandakou A et al. Tissue
polypeptide-specific antigen serum concentrations in children,
adolescents, and young adults with type 1 diabetes. Diabetes Care 2002;25:240-1.
(6) Hrycek A, Kokocinska D, Kosmider J, et al. Tissue-polypeptide-specific
antigen in SLE patients treated with low doses of quinagolide. Lupus 2003;12:149-52.
(7) Valik D, Nekulova M. Serum tissue polypeptide-specific antigen (TPS):
what is its diagnostic value? Br J Cancer 2000;82:1756-8.
I have read with interest the study of a diet for IBS based on serum
IgG levels to foods.[1]
In rigorous elimination diet studies, about one third of IBS patients
turn out not to have food intolerance.[2-4] Yet everyone tested for
food-specific IgG in this study had some positive reactions and was
therefore subject to dietary recommendations. This does not suggest that
serum IgG is a particul...
I have read with interest the study of a diet for IBS based on serum
IgG levels to foods.[1]
In rigorous elimination diet studies, about one third of IBS patients
turn out not to have food intolerance.[2-4] Yet everyone tested for
food-specific IgG in this study had some positive reactions and was
therefore subject to dietary recommendations. This does not suggest that
serum IgG is a particularly useful test.
One notable finding of this study is that 87% of patients gave a high
level of IgG to yeast. In two large-scale studies of IBS using diagnostic
elimination diets, the percentages who had a symptomatic reaction to yeast
when challenged, were 5.5% (out of 73 unselected IBS patients)[2] and 12%
(out of 122 unselected IBS patients).[3] It seems implausible that yeast
causes IBS symptoms in 87% of patients in Manchester but only 5-12% of
patients in Oxfordshire and Cambridgeshire. The logical implication is
that high levels of IgG against yeast do not reveal anything significant
in relation to IBS symptoms.
The same must be concluded about several other foods. The numbers of
patients with positive responses to eggs, cow's milk and cashew nuts, as
judged by IgG levels, are much higher than one would expect from empirical
dietary studies,[2,3] while the numbers testing positive to chocolate and
oranges are far too low. Again, it seems doubtful that IgG can reveal
sensitivities accurately in IBS.
The percentage of patients showing substantial benefit from this diet
is disappointing. In studies using a well-conducted and rigorous
elimination diet, the "number needed to treat" is between 1.5 and 2.2.[2-5] The "number needed to treat" in this study diets is 9. (The
figure of 2.5, calculated on the basis of those who fully complied with
the diet, abrogates the intention-to-treat principle.)
This poor response to an IgG-based diet confirms the widely held view
that IgG testing for food intolerance is not of value.[6-8] These
results suggest that if IgG testing identifies food intolerances at all,
it does so fortuitously and with a low degree of accuracy.
The difference in outcome between the "true diet" and the "sham diet"
group can largely be explained, not by specific identification of food
reactions, but by the gross differences between the two diets. The "true
diet" excluded milk products for 84% of patients and wheat for 49% (both
foods are known to be common offenders in IBS) while the total number of
foods avoided by the group was 498 (figure calculated from Table 2). For
the "sham diet" group, 1.3% avoided milk, 8% avoided wheat, and the total
number of foods avoided was only 453. These overall differences between
the diets can easily explain the modest difference in outcome between the
two diet groups. The same diet sheets, distributed randomly to the
patients in each group regardless of IgG levels, would probably have
produced the same overall result.
The effectiveness of the blinding in this trial is questionable. The
"nutritional advisor" giving support by telephone may have become aware of
which patients were receiving the "sham diet" since this regularly
excluded potatoes and rice, while the "true diet" rarely did so ? the
reverse being true for wheat, milk and yeast. The views of the nutritional
advisor on the likely effectiveness of the diets could inadvertently have
been communicated to the patients, and influenced their assessment of the
outcome.
Before this trial was begun, it would have made sense to try to
answer the more basic research question: do high levels of IgG against a
food predict an adverse reaction to that food? Only one very small trial
has so far done this.[9] It measured food-specific serum IgG in
individual IBS patients and compared the results with those from food
challenges (following a period of avoidance): there was no correspondence
between the foods identified. Such work needs to be repeated with larger
sample sizes.
References
1. Atkinson W, Sheldon T A, Shaath N, Whorwell P J. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53: 1459-1464.
2. Nanda R, James R, Smith Itch, Dudley CR, Jewell DP. Food
intolerance and the irritable bowel syndrome. Gut 1989; 30:1099-1104.
3. Hunter J 0, Workman E, Alun Jones V. The role of diet in the
management of Irritable Bowel Syndrome. In Gibson P R & Jewell D P
(eds) Topics in Gastroenterology 1985; Vol. 12 Oxford:Blackwell
Scientific.
4. Stefanini GF, Saggioro A, Alvisi V, et al. Oral cromolyn sodium in
comparison with elimination diet in the irritable bowel syndrome.
diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol
1995; 30:535-41.
5. Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and
hypersensitivity to food. Ann Allergy 1985; 54:538-40.
6. Barnes RM. IgG and IgA antibodies to dietary antigens in food allergy
and intolerance. Clin Exp Allergy 1995; 25 Suppl 1:7-9.
7. Zar S, Kumar D, Benson MJ. Food hypersensitivity and irritable
bowel syndrome. Aliment Pharmacol Ther 2001; 15:439-49.
8. Teuber SS, Porch-Curren C. Unproved diagnostic and therapeutic
approaches to food allergy and intolerance. Curr Opin Allergy Clin Imunol
2003; 3:217-221.
9. Zwetchkenbaum J, Burakoff R. The irritable bowel syndrome and food
hypersensitivity. Annals of Allergy 1988; 61:47-9.
Dear Editor,
As therapy of HIV patients with HAART has resulted in long-term survival, the major burden of "disease" is becoming end-stage liver disease secondary to HCV infection with rapidly progressive fibrosis and cirrhosis. We are increasingly being asked to advise on this group of patients, however, the literature is cautious about treatment and response rates. Who do we treat? What is the response rate to ac...
Dear Editor
Mawdsley et al raises the important question as to whether patients with irritable bowel syndrome (IBS) would gain as much symptomatic improvement if recommended to exclude the top four foods (yeast, milk, whole egg and wheat) compared to an IgG antibody test-based diet.[1] In other words, does the test add specificity? This requires a trial which compares patients receiving an IgG antibody tes...
Dear Editor
We read with great interest the article by Bettschart et al,[1] discussing an increase of cholangiocarcinoma incidence after biliary-enteric drainage for benign disease.
In their hypothesis, changes in the biliary epithelium were induced by toxic carcinogenesis due to reflux of intestinal contents and bile stasis. However, this chronic irritation and carcinogenesis of the biliary mucosa a...
In a case-control study on the associations between functional genetic polymorphisms in biotransformation enzymes and Crohn’s disease, we found a strong association of the Tyr113His (348T>C) polymorphism in exon 3 of the microsomal epoxide hydrolase (EPHX1) gene and Crohn’s disease.[1] The three referees all agreed that the study was interesting and should be published so that other groups can attempt to...
Dear Editor
We read with interest the recent article by de Jong et al.[1] reporting studies of genetic associations between DNA polymorphisms in xenobiotic metabolising genes and Crohn’s disease (CD). The authors employed a case control study design to test 7 polymorphisms in 5 candidate genes for disease association. Evidence was found for a significant association of a single nucleotide polymorphism (SNP), Tyr...
We read the article by Allen et al[1] with interest and would like to report a case of probable cannabinoid hyperemesis seen in a district general hospital in the UK.
A 21-year-old chef was admitted to our hospital on seven occasions during a two year period (April 2001 to December 2002) with profuse vomiting. Apart from a history of migraine as a child he was fit and well. He smoked cannabi...
Dear Editor
We read with interest the article by Kamisawa and colleagues reporting IgG4-positive plasma cells in the peripancreatic tissue, extraphepatic bile duct, gall bladder, and salivary gland.[1] The association of retroperitoneal fibrosis and sclerosing pancreatitis with IgG4 -bearing plasma cells in the tissues of both lesions has been also reported.[2]
We would like to report the first case of...
We read with great interest the article by Rad and coworkers[1] on the influence of cytokine gene polymorphisms on mucosal cytokine expression, gastric inflammation and host specific colonisation in Helicobacter pylori infection. The authors reported an association of the contrainflammatory IL-10 promotor haplotype (GCC) with higher mucosal mRNA levels and colonisation with more virulent cagA+,vacAs1+ and...
Dear Editor
In response to the letter addressed by Dr Harlozinska-Szmyrka we agree with the remarks made in relation to the difficulties in discrimination between chronic pancreatitis and adenocarcinoma using currently employed diagnostic imaging and tumour marker analysis. Our study aimed at determining risk of cancer development in patients with proven chronic pancreatitis,[1] examining age and sex standardised i...
Dear Editor
I have read with interest the study of a diet for IBS based on serum IgG levels to foods.[1]
In rigorous elimination diet studies, about one third of IBS patients turn out not to have food intolerance.[2-4] Yet everyone tested for food-specific IgG in this study had some positive reactions and was therefore subject to dietary recommendations. This does not suggest that serum IgG is a particul...
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