Dear Editor,

We read with interest the paper by Foucher et al.[1] where the authors assess the accuracy of transient elastography for the detection of cirrhosis. Its use to assessing the severity of chronic liver disease in other clinical scenarios warrant further evaluations. According to large population studies, the prevalence of chronically hepatitis C virus (HCV) infected patients who have persistently normal serum aminotransferase (PN-ALT) levels is most likely around 30-50%.[2] A major problem is to define whether these patients may suffer a progressive disease; additionally, although no consensus exists regarding who must be treated and when antiviral therapy must be initiated, positive decisions have been reinforced by the recent results of a large clinical trial indicating that pegylated interferon plus ribavirin combination therapy is effective and safe in these patients with PN-ALT.[3] In a recent review the schedule of antiviral combination treatment of patients with chronic hepatitis C and normal aminotransferases is described and indication of antiviral therapy in some cases might be decided on the basis of histological findings[2]; hence, liver biopsy seems to be a key in this decision and a patient must be treated if there is significant fibrosis (>OR= F2). However, meanwhile liver biopsy remains the “gold standard” for the assessment of hepatic fibrosis, it represents an invasive procedure with some risks and limitations[1], and is not well accepted by all patients. Non-invasive methods such as Fibrotest, Forns’ index (FI) and APRI have been designed to assess liver fibrosis.[4] Fibroscan® (FS), a new transient elastography technique to measure liver stiffness or elasticity[5,6], have rised great expectancy as an alternative method for staging liver disease. Stiffness insignificantly correlates to fibrosis stage and is a promising, reproducible and independent of the operator, method for the detection of cirrhosis.[1,6] Our aim was the assessment by FS of hepatic fibrosis in patients infected by HCV and PN-ALT, comparing the accuracy of FS to that previously described for biomarkers.

We analysed prospectively 28 chronically HCV infected patients (18 females) with PN-ALT (at least three determinations yearly), assessing hepatic fibrosis by FS. Concordances and correlations between FS and FI and APRI were also evaluated. Almost all consecutive patients were asymptomatic and none of them have had the well known complications of advanced liver disease or cirrhosis.[7] Patients’ characteristics (mean ± SD) were as follow: age 44.3 ± 10 years, BMI 24.1± 2.8 Kg/m2, platelets count 249.6 ± 58 /mm3, serum cholesterol levels 190.5 ± 26 mg/dL, serum AST levels 25 ± 5 IU/L, serum ALT levels 27.7 ± 6.7 IU/L and serum GGT levels 23.2 ± 21 IU/L. Results of the study were as follow: 26 (92.8%) patients had HCV-genotype 1. Mean value of FS was 6.35 ± 3.3 KPa, indicating absence or mild stage of fibrosis (<8.5 KPa); as expected, mean values of FI (3.35 ± 1.4) and APRI (0.27 ± 0.09) also reflects minimal or no fibrosis (<4.5 and <0.5, respectively). These provocative findings show that this cohort of PN-ALT chronically HCV infected patients have a low stage of fibrosis according to three non- invasive methods. A previous study has compared and validated these methods in chronic hepatitis C patients with elevated ALT.[8]

Liver biopsy has been used as the “gold standard” for the assessment of hepatic fibrosis. It has been used for staging the liver damage in chronic viral hepatitis and for decision analysis as to the need of treatment in patients with chronic hepatitis C. The limitations of biopsy such as patient acceptability, sampling error or diagnostic inaccuracy, and the remote risk of complications, have led clinical investigators to study alternative methods to stage chronic viral hepatitis.[1,4,9] Serum biological markers determination is the most widely used procedure for stimation of liver fibrosis[9]; combining serum biomarkers with FS may increase the accuracy of these non-invasive methods, suggesting that it may be valid to circumvent the limitations of hepatic histology.[8,9] FS is an objective and safe technique, enthusiastically accepted by patients. Hence, periodical examinations can be performed as a follow-up protocol for assessment of hepatic fibrosis progression or improvement. Moreover, it is a precise method for the detection of cirrhosis and promising in order to predict complications of cirrhosis.[1] Accordingly, our data may suggest that therapeutic management of PN-ALT patients could be established according to fibrosis stage detected along successive FS examinations. Those PN-ALT patients with evidence of fibrosis by FS would need to start an early antiviral treatment. Although with the inconvenience of less effectivity in obese subjects, transient elastography may be very helpful in a better diagnostic and therapeutic management of PN-ALT chronically HCV infected patients, questioning the leading role of biopsy.[8,9] Further studies on this topic may be warranted in order to evaluate the diagnostic accuracy for staging hepatic fibrosis, the natural history of disease and the optimised response to combination antiviral therapy. Additionally, it has been demonstrated that combining a FS measurement with biomarkers may increase the diagnostic accuracy of both tests.[8,9] In conclusion, repeated stiffness assessment appears to be a good and safe alternative method to indicate antiviral combination therapy in PN-ALT patients reluctant to liver biopsy. (Grant ISC III 03/02).

References

1. Foucher J, Chanteloup E, Vergniol J, et al. Diagnosis of cirrhosis by transient elastography (Fibroscan®): a prospective study. Gut online 14 Jul 2005.

2. Alberti A. Towards more individualised management of hepatitis C virus patients with initially or persistently normal alanineaminotransferase levels. J Hepatol 2005;42:266-74.

3. Zeuzem S, Diago M, Gane E, et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004;127:1724-32.

4. Wai CT, Greenson JK, Fontana RJ, et al. A simple non-invasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38:518-26.

5. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography : a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29:1705-13.

6. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41:48-54.

7. Benvegnù L, Gios M, Bocato S et al. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004; 53:744-9.

8. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128: 343-50.

9. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004;99:1160-74.

Maria Trapero-Marugan, Jorge Mendoza and Ricardo Moreno-Otero.

Gastroenterology and Hepatology Service (ISC III 03/02)
Hospital Universitario de La Princesa
Autonomous University of Madrid
Spain

Dear Editor,

I enjoyed the article by Albert et al. comparing newly emerging imaging modalities for the assessment and detection of small bowel Crohn’s disease, an area of the gastro-intestinal tract that is often difficult to adequately image, assess and biopsy.[1]

However, their article failed to mention 99mTc HMPAO labelled white cell scanning at all as a method of imaging the small (and large) bowel. Planar white-cell scintigraphy is a well-established, non-invasive method of assessing intestinal inflammation.[2] While histological assessment is considered to be the gold standard method of detecting intestinal inflammation planar white-cell scintigraphy accurately reflects disease extent and histological activity.[3] The new imaging methods discussed by Albert et al. also suffer from this disadvantage of not allowing histological assessment.

In addition to planar white cell scanning single photon emission computerised tomography (SPECT) white cell scanning has been shown to correlate very well with histology (r=0.8 p<0.0001) in subjects with active IBD.[4]

We have previously shown that both white cell scanning techniques are valuable not only in assessing extent and severity of inflammation but in following up response to treatment in subjects with ulcerative colitis and Crohn’s disease.[5,6]

When evaluating newly emerging imaging techniques it is vital not to forget previously established techniques.

References

1. Albert JG, Martiny F, Krummenerl A et al.Diagnosis of small bowel Crohn’s disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and fluoroscopic enteroclysis. Gut 2005;52(12):1721-1727.

2. Danpure HJ. Osman S. Carroll MJ. The development of a clinical protocol for the radiolabelling of mixed leucocytes with 99Tcm- hexamethylpropyleneamine oxime. Nuclear Medicine Communications 1988;9(6):465-75.

3. Lantto E, Jarvi K, Krekla I, et al. Technetium-99m hexamethyl propylene anime oxine leucocytes in the assessment of disease activity in inflammatory bowel disease. Eur J Nucl Med 1992;19(1):14-18.

4. Weldon MJ, Masoomi AM, Britten AJ et al. Quantification of inflammatory bowel disease activity using technetium-99m HMPAO labelled leucocyte single photon emission computerised tomography (SPECT). Gut 1995; 36(2)243-50.

5. Poullis A, Irwin AG, Dearing M, et al. Methodological study to assess repeat planar white cell scanning in monitoring the efficacy of treatment in inflammatory bowel disease. Gut 2003;52 (Suppl I):A87.

6. Poullis A, Irwin AG, Dearing M, et al. Methodological study to assess repeat SPECT white cell scanning in monitoring the efficacy of treatment in inflammatory bowel disease. Gastroenterology 2003:Suppl (1):A267.

Dear Editor,

We read with great interest the guideline for gastroenteropancreatic neuroendocrine (including carcinoid) tumors by Ramage et al.[1] In this excellent guideline, they reported that appendix is the most frequent site of gastrointestinal primary endocrine tumors, consisting 35% of the total tumors, while colon and rectal carcinoids consisted only 7% and 10%, respectively. One important aspect not mentioned, however, is the fact that the site distribution of gastrointestical carcinoids differs among races.

Modlin et al previously reported a marked predominance of white Caucasians population in carcinoids of the colon and appendix based upon the nationwide surveillance in the United States.[2] In contrast, the incidence of rectal carcinoids was 3- to 4-fold higher in African- Americans than in white Caucasians. Accordingly, the site distribution of colorectal carcinoids markedly differs among these two races.

Regarding carcinoids in Asian population, there have been few reports based upon a large database. In order to provide such evidence, we analyzed colorectal carcinoids in the Japanese population using the Multi-Institutional Registry of Large Bowel Cancers in Japanh, a nationwide database which covers approximately 10% of the Japanese population, from 1984 to 1998.[3] Among 90,057 cases of colorectal tumors registered during this period, a total of 345 cases of colorectal carciniods were identified. All cases were from the Asian population. The site distribution consisted of the ileum 3 (0.9%), appendix 8 (2.3%), colon 28 (8.2%) and rectum 304 (88.6%). Thus, carcinoids in the Japanese population exhibited much higher distribution in the rectum than in the colon and appendix. This over-representation of rectal carcinoids is compatible with a previous report from Taiwan in which 33 cases (89.2%) out of 37 colorectal carcinoids originated from the rectum.[4]

The difference in the distribution of colorectal carcinoids among races suggests that race-related genetic factors play an important role in the development of gastrointestinal carcinoids. With acceptance on this point, racial disparity could be a point to consider in the diagnosis of carcinoids, and further investigation using a larger database is needed to clarify these points.

References

1. Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005;54 Suppl 4:iv1-16.

2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97(4):934-59.

3. Kotake K, Honjo S, Sugihara K, et al. Changes in colorectal cancer during a 20-year period: an extended report from the multi-institutional registry of large bowel cancer, Japan. Dis Colon Rectum 2003;46(10 Suppl):S32-43.

4. Weng YJ, Wang SS, Yang WG, et al. Carcinoid tumors of the gastrointestinal tract in Chinese of Taiwan: an analysis of fifty cases. Zhonghua Yi Xue Za Zhi (Taipei) 1996;58(4):254-8.

Institutions of the authors:
T. Konishi, T. Watanabe and H. Nagawa, Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
T. Muto, Department of Surgery, Cancer Institute Hospital, Tokyo, Japan
K. Kotake,Department of Surgery, Tochigi Cancer Center, Tochigi, Japan

All Correspondence to:
Dr. Toshiaki Watanabe
Department of Surgical Oncology
University of Tokyo
7-3-1 Hongo Bunkyo-ku
Tokyo 113-8655
Japan
TEL: +81-3-5800-8653
FAX: +81-3-3811-6822
E-mail: toshwatanabe@yahoo.co.jp

Conflict of interest: none

Dear Editor,

Re: Stratification by gender and subgroup is necessary for RCT on IBS by Prof. Bian

Thank you for the communication of your interesting study results. Your findings highlight a problem especially for acupuncture research. Many experimental trials are pointing out the efficacy of acupuncture, also regarding problems of the gastrointestinal tract.[1-4] However, many of these trials are not always controlled by appropriate placebo. Thus it is difficult to explain the positive result with specific effects.

Acupuncture and placebo-acupuncture seem to have the same positive effect in many RCTs.[5-8] That does not mean that an acupuncture effect is always a placebo effect. Especially in musculoskeletal diseases acupuncture seem to be stronger than placebo.[9-12] Indeed, in functional diseases the efficacy of acupuncture seems to rely on placebo effects. In our study, we placed the “Streitberger-needle”[13] 2 cm apart the real points to avoid acupressure effects. Nevertheless, we had definitive effects of the placebo acupuncture.[14] Thus, it seems that the identified physiological effects seem to play an ancillary role. Our results are supported by another recently published trial.[15] They used a sham acupuncture on non-acupuncture-points. As a consequence, it was not sure if the effects are due to some unspecific effects. The sham acupuncture trials have the disadvantage that the unspecific effect could always be due to some hypothesized unspecific needling effects. It will be always questioned: “Was that really a non-acupuncture point? How do you know that a sham acupuncture will not cause any effect?”. This is excluded with our study design.

The question arises why placebo-acupuncture and placebo in general[16] are so effective in irritable bowel syndrome. And the second question is whether the results of experimental trials are really due to specific effects. And if they are: why is this not reflected in clinical trials? What role does the cognitive processing play in this context? Further research is required to shed light on this phenomenon. It was not possible to do a subgroup analysis from a statistical point of view as we had only 9 males in our study. This is the same for the clinical subgroups. However, the placebo-effect was so strong that almost 526 patients would be necessary to prove some effect. Such an effect could be interesting, but it must be questioned if it is clinically relevant.

References:

(1) Cui KM, Li WM, Gao X et al. Electro-acupuncture relieves chronic visceral hyperalgesia in rats. Neurosci Lett 2005;376(1):20-3.

(2) Jin HO, Zhou L, Lee KY et al. Inhibition of acid secretion by electrical acupuncture is mediated via beta-endorphin and somatostatin. Am J Physiol 1996;271(3 Pt 1):G524-G530.

(3) Li P, Rowshan K, Crisostomo M et al. Effect of electroacupuncture on pressor reflex during gastric distension. Am J Physiol Regul Integr Comp Physiol 2002;283(6):R1335-R1345.

(4) Li Y, Tougas G, Chiverton SG et al. The effect of acupuncture on gastrointestinal function and disorders. Am J Gastroenterol 1992;87(10):1372-81.

(5) Linde K, Jobst K, Panton J. Acupuncture for chronic asthma. Cochrane Database Syst Rev 2000;(2):CD000008.

(6) Linde K, Streng A, Jürgens S et al. Acupuncture for Patients with Migraine. JAMA 2005;293:2118-25.

(7) Melchart D, Streng A, Hoppe A et al. Acupuncture in patients with tension-type headache: randomised controlled trial. BMJ 2005;331(7513):376 -82.

(8) White AR, Rampes H, Ernst E. Acupuncture for smoking cessation. Cochrane Database Syst Rev 2002;(2):CD000009.

(9) Kleinhenz J, Streitberger K, Windeler J et al. Randomised clinical trial comparing the effects of acupuncture and a newly designed placebo needle in rotator cuff tendinitis. Pain 1999;83(2):235-41.

(10) Manheimer E, White A, Berman B et al. Meta-analysis: acupuncture for low back pain. Ann Intern Med 2005;142(8):651-63.

(11) White P, Lewith G, Prescott P et al. Acupuncture versus placebo for the treatment of chronic mechanical neck pain: a randomized, controlled trial. Ann Intern Med 2004;141(12):911-9.

(12) Witt C, Brinkhaus B, Jena S et al. Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet 2005;366(9480):136- 43.

(13) Streitberger K, Kleinhenz J. Introducing a placebo needle into acupuncture research. Lancet 1998;352(9125):364-5.

(14) Schneider A, Enck P, Streitberger K et al. Acupuncture treatment in irritable bowel syndrome. Gut 2005. Epub ahead of print.

(15) Forbes A, Jackson S, Walter C et al. Acupuncture for irritable bowel syndrome: a blinded placebo-controlled trial. World J Gastroenterol 2005;11(26):4040-4.

(16) Enck P, Klosterhalfen S. The placebo response in functional bowel disorders: perspectives and putative mechanisms. Neurogastroenterol Motil 2005;17(3):325-31.