Predicting Relapse in Patients with Inflammatory Bowel Disease

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Inflammatory bowel disease increase specificity rather than decrease ...... it. The definition of remission and Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from relapse were similar in the two studies, and both used an ELISA assay Predicting relapse in patients with (although the assays were probably at least slightly different). In the previous inflammatory bowel disease: what is study, patients were in remission for 1– 4 months while in the Costa study they the role of biomarkers? were in remission for 1–12 months. Perhaps the value of calprotectin for D S Pardi, W J Sandborn predicting relapse in Crohn’s disease decreases the longer a patient is in ...... remission. Several other clinical indices and Faecal calprotectin seems to be a relatively sensitive and specific biological markers have been studied marker of the risk of relapse in ulcerative colitis, but not in Crohn’s in IBD. These can be divided into clinical disease disease activity indices, endoscopic indices, serum markers, faecal markers, and miscellaneous tests. Clinical indices, including the Crohn’s disease activity arious laboratory biomarkers have multivariate analysis, patients with index (CDAI) and other disease activity been studied in inflammatory Crohn’s disease with a baseline faecal indices for Crohn’s disease and ulcera- Vbowel disease (IBD) as diagnostic calprotectin greater than 150 mg/g had a tive colitis, are largely subjective and aids, indicators of disease activity or non-significant twofold increased like- typically cumbersome and have signifi- severity, and to predict the risk of lihood of relapse whereas those with cant interobserver variability. Further- relapse in those patients in remission. ulcerative colitis and an elevated faecal more, they are not valid in patients with These biomarkers have enormous calprotectin had a significant 14-fold fistulas, stomas, and non-inflammatory potential implications for patient increase risk. C reactive protein (CRP) causes of symptoms (for example, ste- management. For example, therapeutic and erythrocyte sedimentation rate nosis, post surgical anatomy). There are decisions could be directed more (ESR), either as single tests or combined also several endoscopic indices of sever- appropriately if a marker could reliably with calprotectin, were not useful for ity. The Crohn’s disease endoscopic distinguish active IBD from other predicting relapse. index of severity7 has a poor correlation inflammatory or non-inflammatory The results of this study add to the with clinical activity and treatment causes of symptoms, or if one could growing body of literature on biomar- induced remission, although complete distinguish Crohn’s disease from ulcera- kers in IBD in general and faecal mucosal healing may predict a favour- tive colitis. In addition, a simple, inex- calprotectin in particular. In previous able course. However, this index is pensive, sensitive, specific marker could studies, faecal calprotectin has been complex and not suitable for routine help monitor response in the clinic and shown to be a sensitive marker of clinical practice.8 The most well known http://gut.bmj.com/ in clinical trials. Finally, the ability to activity in Crohn’s disease and to endoscopic index of severity is the reliably predict the risk of recurrence correlate well with endoscopic and Rutgeerts score which is simple and would help direct appropriate therapy to histological disease activity in ulcerative accurately predicts the risk of recurrence those who would most likely benefit colitis.34 Faecal calprotectin also nor- after surgical resection.9 from it and avoid the expense and malises along with endoscopic healing A multitude of serum markers have potential toxicity of chronic mainte- in Crohn’s disease5 and is a very been studied in IBD. Many of these are nance therapy in those who have a low sensitive and specific marker for distin- acute phase reactants (acid a1 glycopro- on September 30, 2021 by guest. Protected copyright. risk of recurrence. In the current issue of guishing IBD from irritable bowel syn- tein (orosomucoid)), CRP, fibrinogen, 1 3 Gut, Costa and colleagues addressed the drome (IBS). The Costa study suggests lactoferrin, serum amyloid A, and a1 latter issue by studying the role of faecal that calprotectin is a good marker of antitrypsin.10 In an early study, Brignola calprotectin as a marker of risk of relapse risk in ulcerative colitis, but not and colleagues found that combining relapse in ulcerative colitis and Crohn’s in Crohn’s disease, related primarily to acid a1 glycoprotein, a2 globulin, and disease (see page 364). Calprotectin poor specificity, and therefore poor ESR into an index resulted in 88% represents 50–60% of neutrophilic cyto- positive predictive value. However, a accuracy in predicting relapse over solic protein, is stable in faeces for previous study of faecal calprotectin as 18 months in patients with Crohn’s several days after excretion, and has a a marker of relapse risk in IBD found a disease in remission.11 They found no relatively easy to perform assay which is faecal calprotectin level of 50 mg/g to be value in baseline levels of haemoglobin, available commercially and correlates a sensitive and specific marker of white blood cell count, albumin, iron, or well with the more difficult and more recurrence risk in both ulcerative colitis CRP. Other studies have also found expensive indium 111-labelled leucocyte and Crohn’s disease.6 In this study, limited value for CRP in predicting excretion2 patients with a faecal calprotectin level relapse.1612Data on other markers such Costa and colleagues1 studied 38 greater than 50 mg/g had a 13-fold as serum and urinary neopterin levels, patients with Crohn’s disease and 41 increased risk of relapse, and the speci- serum tumour necrosis factor (TNF) a with ulcerative colitis in remission for a ficity for predicting relapse in Crohn’s levels, TNF-a receptor levels, and var- mean of five months. A baseline faecal disease was 83%, compared with 43% in ious interleukins (IL-1, IL-6, IL-8), calprotectin level greater than 150 mg/g the Costa study.6 interleukin receptors (IL-2R, IL-6R), had a sensitivity for predicting relapse The reason(s) for the poorer specifi- or interleukin receptor antagonists within the next year of 89% in ulcerative city of calprotectin in the current study (IL-1ra) are limited or contradictory.913 colitis and 87% in Crohn’s disease. The are not clear. A different cut off value As serum markers of inflammation specificity in ulcerative colitis was 82% was used, but the higher cut off in the can be elevated in a variety of condi- but only 43% in Crohn’s disease. After Costa study would be expected to tions, it seems likely that faecal markers

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...... of inflammation, in the absence of of 84–89% and a specificity of 61–76% Authors’ affiliations enteric infection, would be more specific for predicting relapse within one year D S Pardi, W J Sandborn, Inflammatory Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from for IBD. Faecal markers can be divided but only 53% and 85%, respectively, at Bowel Disease Clinic, Division of into faecal excretion of leucocytes, four months.8 Furthermore, these tests Gastroenterology and Hepatology, Mayo serum proteins, or leucocyte products. are somewhat time consuming and Clinic College of Medicine, Rochester, Faecal excretion of indium 111-labelled difficult, with limited availability and Minnesota, USA white blood cells has a good correlation therefore are of questionable clinical with colitis but not ileitis and has value. Correspondence to: Dr D S Pardi, Mayo Clinic no correlation with CDAI.14 These Other tests that have been used to College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; issues, together with the cost, radiation measure disease activity or to predict [email protected] exposure, and limited availability of relapse include assaying whole gut this technology makes measurement lavage fluid for immunoglobulin G, of faecal excretion of indium-labelled IL-1B, and IL-8.13 However, data on REFERENCES white blood cells of limited value these markers are limited and patient 1 Costa F, Mumolo MG, Ceccarelli L, et al. clinically. Calprotectin is a stronger predictive marker of acceptability would likely be low for relapse in ulcerative collitis than in Crohn’s Faecal excretion of various serum repeated testing. Others have measured disease. Gut 2005;54:364–8. proteins has also been studied in IBD. various inflammatory markers, includ- 2 Roseth AG, Schmidt TN, Fagerhol MK. Perhaps the best studied is faecal a Correlation between faecel excretion of indium 1 ing TNF-a and IL-1B production from 111-labeled granulocytes and calprotectin, a antitrypsin excretion. However, the data stimulated cultured lamina propria granulocyte marker protein in patients with on this protein and its correlation with mononuclear cells and showed that the inflammatory bowel disease. Scand J Gastroenterol 1999;34:50–4. disease activity and response to therapy degree of production is predictive of 14 3 Tibble JA, Teahon K, Thjodleifsson B, et al. A simple are mixed. More promising is faecal relapse over one year.18 However, method for assessing intestinal inflammation in excretion of various leucocyte products. this technology requires mucosal bio- Crohn’s disease Gut 2000;47:506–13. Faecal lysozyme excretion correlates 4 Roseth AG, Aadland E, Jahnsen J, et al. psies and therefore application to Assessment of disease activity in ulcerative colitis with disease activity and indium 111 small bowel disease would be limited. by faecal calprotectin, a novel granulocyte marker white blood cell excretion in colitis but Furthermore, this technique is relatively protein. Digestion 1997;58:176–80. not in ileitis, and it is also elevated in 5 Roseth AG. Determination of faecal calprotectin, difficult requiring cell culture and a novel marker of organic gastrointestinal other gastrointestinal inflammatory dis- stimulation. disorders. Dig Liver Dis 2003;35:607–9. 14 orders, limiting its specificity for IBD. In summary, the current clinical 6 Tibble JA, Sigthorsson G, Bridger S, et al. Surro- Faecal lactoferrin concentration is gate markers of intestinal inflammation are predic- indices or biological markers of disease tive of relapse in patients with inflammatory bowel increased in active IBD compared with activity are for the most part too disease. Gastroenterology 2000;119:15–22. inactive IBD, IBS, and healthy con- invasive, too difficult, too expensive, or 7 Mary JY, Modigliani R. Development and trols.14 15 In addition, in patients taper- validation of an endoscopic index of severity for require radiation exposure. Two possible Crohn’s disease: a prospective multicenre study. ing off steroids, persistent elevations in exceptions are faecal calprotectin and Gut 1989;30:983–9. faecal lactoferrin may predict an faecal lactoferrin excretion, which are 8 Sostegni R, Daperno M, Scaglione N, et al. increased risk of early relapse and Review article: Crohn’s disease: Monitoring relatively simple and inexpensive. Based disease activity. Aliment Pharmacol Ther therefore may help guide the rapidity on two studies to date16 faecal calpro- 2003;17(suppl 2):11–17.

15 http://gut.bmj.com/ of the steroid taper. Finally, faecal tectin seems to be a relatively sensitive 9 Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s lactoferrin levels may rise significantly and specific marker of the risk of relapse prior to a clinically evident relapse and disease. Gastroenterology 1990;99:956–63. in ulcerative colitis. It also appears to be 10 Nielsen OH, Vainer B, Madsen SM, et al. thus may be a good marker to predict a sensitive marker of relapse risk in Established and emerging biologic activity subsequent IBD flares.15 Other faecal markers of inflammatory bowel disease. Crohn’s disease but the data on specifi- markers, such as elastase, myeloperox- Am J Gastroenterol 2000;95:359–67. city are conflicting at this point. 11 Brignola C, Campieri M, Bazzocchi G, et al. A idase, leucocyte esterase, and TNF-a, However, these data need to be inter- laboratory index for predicting relapse in 14 asymptomatic patients with Crohn’s disease.

have less promising data. on September 30, 2021 by guest. Protected copyright. preted cautiously. The number of Several miscellaneous tests have also Gastroenterology 1986;91:1490–4. studies is small, and in both studies 12 Boirivant M, Leoni M, Taricotti D, et al. The been studied in IBD. Indium 111 white using calprotectin to predict relapse clinical significance of serum C-reactive protein blood cell scanning can identify and levels in Crohn’s disease. J Clin Gastroenterol risk, most patients were on medical localise active disease and distinguish 1988;10:401–5. therapy. Calprotectin may behave 13 Arnott IDR, Watts D, Ghosh S. Review article: is IBD from IBS and fibrotic from inflam- differently in patients who are on no clinical remission the optimum therapeutic goal in matory strictures. However, labelled the treatment of Crohn’s disease? Aliment therapy. Therefore, before faecal calpro- leucocyte scans cannot distinguish IBD Pharmacol Ther 2002;16:857–67. tectin or any other biological marker 14 van der Sluys Veer A, Biemond I, Verspaget HW, from other causes of intestinal inflam- of activity can be incorporated into et al. Faecal parameters in the assessment of mation and are expensive and involve activity in inflammatory bowel disease. routine clinical practice, other studies radiation exposure.16 Scand J Gastroenterol 1999;(suppl 230):106–10. in larger and diverse groups of patients 15 Walker TR, Land ML, Cook TM, et al. Serial fecal Intestinal permeability can be mea- will be necessary to clarify its role lactoferrin measurements are useful in the interval sured by a variety of methods. Measures assessment of patients with active and inactive further. of intestinal permeability have 95% inflammatory bowel disease. Gastroenterology 2004;126:A215. sensitivity for identifying active Gut 2005;54:321–322. 16 Tibble JA, Bjarnason I. Noninvasive investigation Crohn’s enteritis but only 50% for doi: 10.1136/gut.2004.048850 of inflammatory bowel disease. colitis.17 Intestinal permeability is World J Gastroenterol 2001;7:460–5. 17 Bjarnason I, MacPherson A, Hollander D. thought to be a potentially useful Intestinal permeability: An overview. measure of response to therapy in Conflict of interest: declared Gastroenterology 1995;108:1566–81. Crohn’s disease, particularly in the small (the declaration can be 18 Schreiber S, Nikolaus S, Hampe J, et al. Tumor 16 viewed on the Gut website at necrosis factor alpha and interleukin 1 beta in bowel. In Crohn’s disease, tests of http://www.gutjnl.com/ relapse of Crohn’s disease. Lancet intestinal permeability have a sensitivity supplemental). 1999;353:459–61.

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Crohn’s disease underwent both CT enteroclysis and ...... wireless capsule enteroscopy examina- Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from tions, conducted by two independent blinded investigators. The results of the Wireless capsule endoscopy and two investigations (diagnoses and number, extent, and location of lesions Crohn’s disease detected) were compared by a third investigator. Patients included in the P Swain study had obscure gastrointestinal bleeding (n = 8), Crohn’s disease (n ...... = 8), unexplained diarrhoea (n = 5), or suspected carcinoid tumour (n = 1). Wireless capsule endoscopy appears to be superior to all current Pathological lesions were detected using forms of radiological investigation of the small intestine in capsule enteroscopy in 13 patients (59 detecting the mucosal abnormalities of Crohn’s disease %) and using CT enteroclysis in eight (36%; p = 0.12). In seven patients (one case each of colonic Crohn’s disease, hen the wireless capsule endo- comparing capsule endoscopy with radi- diverticulitis, Meckel’s diverticulum, scope (WCE) was introduced,1 ology in the form of a small bowel meal carcinoid tumour, mesothelioma, colon- fears that the capsule might caused controversy because some felt W ic polyps, and irritable bowel syn- become impacted caused early clinical that WCE was being compared with an drome), no pathological changes were protocols to exclude any patients with a inferior radiological investigation. In found in the small intestine using either hint of previous subacute obstruction or this study, barium follow through was method. The diagnosis was established symptoms suggestive of Crohn’s dis- normal in 17 patients and showed ileal 2–6 by wireless capsule enteroscopy in four ease. In fact a few patients with nodularity in three patients. Capsule patients with obscure bleeding whereas Crohn’s disease were inadvertently endoscopy was normal in three patients 3–6 CT enteroclysis was positive in only one included in these early studies as the and showed positive findings in the patient (p = 0.1). Crohn’s disease was symptoms of this disease are often remaining 17 patients. The barium found in two patients with unexplained subtle and other investigations are study was considered diagnostic in four diarrhoea. Small bowel lesions were sometimes inconclusive. WCE in a short (20%) patients. Capsule endoscopy was identified in six patients with known time has acquired a well established role considered diagnostic in nine (45%) Crohn’s disease using capsule entero- in the investigation of patients with patients, suspicious in eight (40%) scopy or CT enteroclysis. Wireless cap- recurrent gastrointestinal bleeding of patients, and failed in three (15%) sule enteroscopy detected more small obscure origin when gastroscopy and patients. For obscure gastrointestinal bowel lesions than CT enteroclysis in 2–6 colonoscopy fail to reveal the source. bleeding, the diagnostic potential of patients with obscure gastrointestinal Occult Crohn’s disease was found to be barium follow through was much worse bleeding and Crohn’s disease. a cause of bleeding or anaemia in compared with capsule endoscopy (5% v Enteroclysis with or without CT or several of these series. Capsule endo- 31%; p ,0.05). Capsule endoscopy was magnetic resonance may produce super- http://gut.bmj.com/ scopy has been used in more than well tolerated and better accepted by ior images compared with barium fol- 100 000 patients worldwide. patients compared with the most low through but is hated by many Several comparative studies have recently performed endoscopic proce- patients who find the trans-nasal intu- shown that WCE could outperform push dure. bation of the duodenum uncomfortable. enteroscopy in finding clinical causes of Subsequent studies have shown that Technical improvements in MR have bleeding. Although the image quality of wireless capsule was also superior to allowed this technology to provide good push enteroscopy is superior in the area state of the art enteroclysis (small bowel

quality small bowel images using MR on September 30, 2021 by guest. Protected copyright. it reached, WCE did not miss much that enema) and computed tomography (CT) enteroclysis, and contrast swallowed by push enteroscopy saw and provided enteroclysis, which currently constitute mouth may provide nearly as good images from the large percentage of the best available radiological investiga- images as those acquired when contrast the small intestine that could not be tions for imaging the small bowel. is administered by nasoduodenal tube.12 reached by push enteroscopy. In five Liangpunsakul and colleagues10 com- The surprise to many endoscopists comparisons the capsule found more pared state of the art enteroclysis with using capsule endoscopy was how some small intestinal pathology than push WCE for its capacity to demonstrate apparently very severe mucosal abnorm- enteroscopy (66%, 68%, 69%, 55%, 66% v ulcers in the small intestine. There were alities could be missed on good quality 19%, 32%, 36%, 38%, 28%)3–5 7 8 and four 40 patients during this study period radiological studies. of these studies showed statistically with negative upper and lower endos- There are now several fully published significant differences in favour of copies and small bowel series. Three peer reviewed studies suggesting that capsule endoscopy.4578 patients had multiple small bowel ulcers Crohn’s disease can be diagnosed with WCE has also performed well in com- detected by WCE. The radiologists were capsule endoscopy in patients who have parisons with small bowel radiology. told in advance of the WCE findings. had a negative colonoscopy, gastro- Just as the numbers of barium meal and Despite this, the enteroclysis studies scopy, and small bowel barium stud- barium enemas have atrophied with the were negative. All three patients ies.13–17 It may be true that a higher rate widespread availability of gastroscopy improved after therapy for Crohn’s of ileoscopy might have increased the and colonoscopy, radiological investiga- disease. In this study, WCE was more rate of diagnosis of Crohn’s disease in tions of small intestinal disease may sensitive for small bowel ulcers than the some of these series. Rates of ileoscopy also wither with the advent of painless best enteroclysis available. in large published series of colonoscopy less invasive enteroscopy offered by the Voderholzer and colleagues11 com- are surprisingly low (for example, 11% wireless capsule endoscope. pared the diagnostic yield of WCE with in 9000 patients18) and it can be difficult The first published study on this topic CT enteroclysis. Twenty two patients to get through the ileocaecal valve, by Costamagna et al in Gastroenterology9 with suspected small bowel pathology especially if Crohn’s disease has altered

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against a stricture. The costs and man- power implications of changing from Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from small bowel radiology to WCE will slow the rate of uptake. WCE will probably be less good than radiology at detecting fistulae and this might be a reason for occasionally choosing radiological investigations in preference to capsule examinations. Addressing the stricture issue, capsule impaction does occur and the reported incidence was 2% in one large pooled series.25 Perhaps unexpectedly, most Figure 1 Notching on folds and notching with an inflammatory penumbra. capsule impactions are asymptomatic and rarely produce obstructive symp- the anatomy of the valve. WCE on the WCE in a consecutive series of patients toms of colicky abdominal pain, failure other hand does not always reach the with Crohn’s was double that detected to pass gas, or vomiting. If the capsule is ileocaecal valve because of delayed by CT enteroclysis (25 v 12/41; p,0.005) pointing forwards it may provide good transit. and these findings led to alteration of images of the stricture. It is usually It is clear from these and other studies management in 10 patients with clinical possible to tell if the capsule is pointing that patients with normal ileoscopy at improvement in all (see page 369). They forwards as it passes through the colonoscopy have been found to have suggest that the logic of designing slow pylorus and does not usually ‘‘tumble’’ small bowel abnormalities which are release treatments that are only effective once in the small intestine. For many thought to be Crohn’s disease at capsule in the colon and terminal ileum for patients, capsule impaction can be a endoscopy and appeared to respond to Crohn’s disease may be flawed. Their good outcome as it can lead to surgery which can cure symptoms and also treatment for this condition. Mow and results also demonstrate that a normal provide histological diagnoses, which colleagues,16 Hume and colleagues,19 and terminal ileoscopy at colonoscopy does are sometimes unexpected. Most recom- Lo20 suggested that capsule enteroscopy not exclude active small bowel Crohn’s mend that if the capsule examination may be especially helpful in distinguish- disease higher up and also that a normal does not show images of the colon, and ing Crohn’s disease from ulcerative wireless capsule examination does not the patient does not notice the passage colitis in patients with indeterminate rule out the diagnosis of Crohn’s disease of the capsule in the stool, a plain colitis, perhaps especially in those in (lesions can be missed or not reached). abdominal x ray should be performed whom ileal pouch formation is being Because WCE appears superior to all approximately seven days after the considered. WCE has also been used in current forms of radiological investiga- examination to check for capsule reten- children with gastrointestinal blood tion of the small intestine in detecting tion. loss, anaemia, or abdominal pain, and the mucosal abnormalities of Crohn’s It would dampen enthusiasm for the cases of Crohn’s disease are a moder- disease, one might imagine that there use of wireless capsule examination in http://gut.bmj.com/ ately common finding in this group.21 22 would be rapid adoption of this techni- Crohn’s disease if a radiological study In India, WCE was able to provide que which does not expose patients to such as a CT enteroclysis had to precede images of small intestinal tuberculosis the hazards of repeated high dose x ray every wireless capsule examination. which can be difficult to distinguish examinations and that radiological 23 Alternative options might include the from Crohn’s disease. methods might be abandoned. There use of a ‘‘patency capsule’’, careful In Voderholzer’s paper published in will be some hesitancy to do this for patient selection to avoid patients with this issue of Gut,24 the frequency of small three reasons. There is anxiety that a

symptoms suggestive of subacute on September 30, 2021 by guest. Protected copyright. intestinal Crohn’s disease found by capsule might become stuck or impacted obstruction, using capsules on a thread so that the capsule could be retrieved if it got stuck at a stricture, making a smaller diameter capsule, which might also be valuable in small children, and developing better retrieval methods. A ‘‘patency’’ capsule has been developed (M2A patency; Given, Yoqneam, Israel) to detect possible strictures non- invasively which might lead to capsule retention. This device has identical dimensions to the M2A wireless capsule endoscope. It contains a small trans- ponder in the form of a passive radiofrequency identification tag (RFID) and a dissolving body. Patency is verified if the capsule is excreted intact from the patient’s body. Excretion is tested before disintegration with a patency scanner, which emits a radiofrequency signal and detects the presence of the RFID tag in the patient’s body. If the capsule is retained in the gastrointestinal tract, it Figure 2 Aphthous and larger ulcers. disintegrates into small, mostly soft,

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It may be possible to categorise early

endoscopic appearances of small bowel Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from Crohn’s disease from wireless capsule images as follows: notching of folds, a few small aphthous ulcers, larger ulcers, linear ulcers, circumferential involvement, abnormal vascularity, vasculitis, and even cobblestone appearances before radiological involvement can be demonstrated. The images in figs 1–4 were all taken from patients with normal small bowel radiology who improved clinically when treated for Crohn’s disease. Location, length of Figure 3 Crohn’s vasculitis. segment involvement, and small bowel transit information can be derived from fragments which can easily pass disease. It seems likely that a few the capsule images, localisation imager, through strictures patients with one or two aphthous and timer, although the capsule often Clinical studies with the patency ulcers may be found to have Crohn’s does not move at a steady rate and capsule are available at present in disease if they are followed up, but most frequently moves in a retrograde fash- abstract form only. In one study, 61 will not. It is also apparent that a ion. patients ingested 63 patency capsules: normal wireless capsule examination WCE does not yet feature a biopsy 36 capsules were excreted intact (29/36 does not exclude Crohn’s disease as capacity. Such a function would be very in less than 40 hours) and 27 disinte- lesions are missed by this examination, valuable for management and diagnosis grated in the gastrointestinal tract. Of as with any other, and because macro- of small intestinal Crohn’s. The advent 54 patients who had radiographically scopic mucosal abnormalities can heal in Japan of a practical but demanding indicated strictures, 31/54 passed the completely and relapse later in the colon form of push enteroscopy with a double capsules intact. Fifteen patients who and are likely to do the same in the balloon system has allowed for the first tested positively for patency were given small intestine. The ultimate diagnosis time the possibility of taking directed the M2A video capsule, all of which of patients with a few aphthous ulcers biopsies under endoscopic visual control 26 passed naturally. These results suggest in the small intestine on WCE, assum- from the mid jejunum and upper ileum27 that this method might be used in ing such patients are not taking non- without surgery. patients with suspected Crohn’s disease steroidal anti-inflammatory drugs, will There is currently a problem with how strictures to allow safe use of the require prospective studies. best to use capsule endoscopy in wireless capsule endoscope without Capsule endoscopy appears to be most patients with abdominal pain or irrita- prior radiological investigation, even in valuable in its ability to diagnose early ble bowel-like syndrome symptoms. patients with strictures. Crohn’s disease, and several studies Some of these patients may have

The absence of a ‘‘definition’’ of have demonstrated its value in patients Crohn’s disease or perhaps coeliac dis- http://gut.bmj.com/ Crohn’s disease causes difficulties. with suggestive symptoms but negative ease but most will not have small 24 Voderholzer and colleagues has sug- colonoscopy and radiology. It also has intestinal pathology. The finding of one gested that the finding of more than 10 proved valuable in investigating chil- or two aphthous ulcers or erosions in aphthous ulcers on a capsule examina- dren with symptoms suggestive of patients during capsule endoscopy is 20 21 tion is strongly suggestive of Crohn’s Crohn’s disease. common and it is likely that many of these do not have Crohn’s disease. It

may be clinically expedient at present to on September 30, 2021 by guest. Protected copyright. avoid using WCE in patients with chronic abdominal pain unless they also have abnormal blood tests or other symptoms such as weight loss, as the incidence of clinically relevant small intestinal pathology is very low while minor clinically irrelevant abnormalities are common.28 It seems probable that the wireless capsule will have an increasing role in the investigation and management of Crohn’s disease and will be used in preference to radiological investigations using x rays. It is likely to be of most assistance in the early diagnosis, in determining the extent and sites of small intestinal involvement, and in examining patients with indeterminate colitis. It may also be valuable in differentiating Crohn’s from other causes of small intestinal disease, find a role as a radiation free method of follow up, and provide evidence about Figure 4 Cobblestone appearances: nodularity with and without ulceration. the cause of specific symptoms which

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might in turn lead to more logical and colonoscopy negative gastrointestinal bowel disease. Clin Gastroenterol Hepatol bleeding. Gut 2003;52:1122–6. 2004;2:31–40.

therapy. The study published in this Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from 6 Pennazio M, Santucci R, Rondonotti, et al. 17 Ge ZZ, Hu YB, Xiao SD. Capsule endoscopy in issue of Gut suggests that WCE is Outcome of patients with obscure gastrointestinal diagnosis of small bowel Crohn’s disease. emerging from an early descriptive bleeding after capsule endoscopy: Report of 100 World J Gastroenterol 2004;10:1349–52. phase of astonishment that excellent consecutive cases. Gastroenterology 18 Bowles CJ, Leicester, R, Romaya C, et al. A 2004;216:643–53. prospective study of colonoscopy practice in the images of small intestinal Crohn’s can 7 Mata A, Llach J, Bordas JM, et al. Role of capsule UK today: are we adequately prepared for be so easily acquired when radiological endoscopy in patients with obscure digestive national colorectal cancer screening tomorrow? studies are normal and is beginning to bleeding. Gastroenterol Hepatol Gut 2004;53:277–83. learn how best to take advantage of the 2003;26:619–23. 19 Hume G, Whittaker D, Radford-Smith G, et al. 8 Saurin JC, Delvaux M, Gaudin JL, et al. Can capsule endoscopy (CE) help differentiate the information which can be acquired from Diagnostic value of endoscopic capsule in patients aetiolgy of indeterminate colitis? Conference this technological advance. with obscure digestive bleeding: Blinded proceedings of 3rd International Conference on comparison with push enteroscopy. Endoscopy Capsule Endoscopy, Miami, Florida, 2004;38A. Gut 2005;54:323–326. 2003;35:576–84. 20 Lo SK. Capsule endoscopy in the diagnosis and doi: 10.1136/gut.2004.047282 9 Costamagna G, Shah SK, Riccioni ME, et al. A management of inflammatory bowel disease. prospective trial comparing small bowel Gastrointest Endosc Clin N Am 2004;14:179–93. radiographs and video capsule endoscopy for 21 Seidman EG, Sant’Anna AM, Dirks MH. Potential Conflict of interest: declared suspected small bowel disease. Gastroenterology applications of wireless capsule endoscopy in the (the declaration can be 2002;123:999–1005. pediatric age group. Gastrointest Endosc viewed on the Gut website at 10 Liangpunsakul S, Chadalawada V, Rex DK, et al. Clin N Am 2004;14:207–17. Wirelewss capsule endoscopy detects small bowel 22 Arguelles AF, Arguelles MF, Caunedo AA, et al. http://www.gutjnl.com/ Utility of capsule endoscopy in pediatric supplemental). ulcers in patients with normal results from state of the art enteroclysis. Am J Gastroenterol gastroenterology. An Pediatr (Barc) 2003;98:1295–8. 2003;59:586–9. 11 Voderholzer WA, Ortner M, Rogalla P, et al. 23 Reddy DN, Sriram PV, Rao GV, et al. Capsule Correspondence to: Dr P Swain, Department of Diagnostic yield of wireless capsule enteroscopy endoscopy appearances of small-bowel Surgical Oncology and Technology, Imperial in comparison with computed tomographic tuberculosis. Endoscopy 2003;35:99. 24 Voderholzer WA, Beinhoelzl J, Rogalla P, et al. College London, St Mary’s Hospital, London enteroclysis. Endoscopy 2003;35:1009–14. Small bowel involvement in Crohn’s disease: a W2 1NY, UK; [email protected] 12 Schreyer AG, Geissler A, Albrich H, et al. prospective comparison of wireless capsule Abdominal MRI after enteroclysis or with oral endoscopy and computed tomography contrast in patients with suspedted or proven enteroclysis. Gut 2005;54:369–73. Crohn’s disease. Clin Gastroenterol Hepatol REFERENCES 25 Enns R, Mergender K, Brandabur J, et al. Capsule 2004;6:491–7. 1 Iddan G, Meron G, Glukhovsky A, et al. Wireless endoscopy CE: A multicentre, international review capsule endoscopy. Nature 2000;405:417. 13 Scapa E, Jacob H, Lewkowicz S, et al. Initial and comparison of capsule studies done in three 2 Appleyard M, Glukhovsky A, Swain P. Wireless- experience of wireless-capsule endoscopy for different tertiary-care centres. Gastrointest Endosc capsule diagnostic endoscopy for recurrent small- evaluating occult gastrointestinal bleeding and 2003;57:AB101. bowel bleeding. N Engl J Med 2001;344:232–3. suspected small bowel pathology. 26 Bolvin M, Lochs H, Voderholzer W, et al. 3 Lewis BS, Swain P. Capsule endoscopy in the Am J Gastroenterol 2002;97:2776–9. Evaluation of the Given patency system in the GI evaluation of patients with suspected small 14 Fireman Z, Mahajna E, Broide E, et al. tract—results of a multicentre study. Conference intestinal bleeding: Results of a pilot study. Diagnosing small bowel Crohn’s disease with proceedings of 3rd International Conference on Gastrointest Endosc 2002;56:349–53. wireless capsule endoscopy. Gut Capsule Endoscopy, Miami, Florida, 2004;37A. 4 Ell C, Remke S, May A, et al. The first prospective 2003;52:390–2. 27 Yamamoto H, Sekine Y, Sato Y, et al. Total controlled trial comparing wireless capsule 15 Herrerias JM, Caunedo A, Rodriguez-Tellez M, et enteroscopy with a nonsurgical steerable double endoscopy with push enteroscopy in chronic al. Capsule endoscopy in patients with suspected balloon method. Gastrointest Endosc gastrointestinal bleeding. Endoscopy Crohn’s disease and negative endoscopy. 2001;53:216–20. 2002;34:685–9. Endoscopy 2003;35:564–8. 28 Bardan E, Nadler M, Chowers Y, et al. Capsule 5 Mylonaki M, Fritscher-Ravens A, Swain P. 16 Mow WS, Lo SK, Targan SR, et al. Initial endoscopy for the evaluation of patients with http://gut.bmj.com/ Wireless capsule endoscopy: a comparison with experience with wireless capsule enteroscopy in chronic abdominal pain. Endoscopy push enteroscopy in patients with gastroscopy the diagnosis and management of inflammatory 2003;35:688–9. on September 30, 2021 by guest. Protected copyright. Pancreaticobiliary biofilm black pigment and mixed gall stones, by ...... virtue of mucus production, and the elaboration of B-glucuronidase that deconjugates bilirubin leading to its Pancreaticobiliary biofilm: is precipitation with calcium and palmitate.3–7 Moreover, in the form of a cholesterol the answer? biofilm in which bacteria deposit them- selves in complex patterns within a R A Kozarek mucopolysaccharide or glycocalyx infra- structure, their presence has been asso- ...... ciated with progressive occlusion of implanted medical devices which have Cholesterol stone formation may be a physiological response to a lumen and infections resistant to limit bacterial biofilm development in bile. Its incorporation into conventional courses of antibiotics.8 plastic polymers may be a novel way to prevent biofilm Plastic biliary stents, most often placed development and subsequent stent occlusion in patients with for malignant obstructive jaundice, have also been noted to occlude by virtue of biliary prostheses biofilm development.910 This biofilm appears to be multidimensional and acteria in the biliary tree have been as do 75% of patients with acute consists of slime, immunoglobulins, the bane of surgeons and gastro- cholecystitis, and virtually 100% of and other proteins in conjunction with Benterologists alike. On the one individuals with cholangitis.12 On the multiple bacteria species in the setting hand, up to 50% of patients with chronic other hand, gut flora are thought to play of incomplete stent occlusion, and cholecystitis have positive bile cultures, a key role in the formation of at least calcium bicarbonate and palmitate

www.gutjnl.com COMMENTARIES 327 interlaced within a bacterial matrix with viability of bacteria within a biofilm manipulation of biliary excretion of complete stent occlusion.4911–13In either with progressive biliary stent occlusion. cholesterol would not preclude mucin Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from setting, the cholesterol concentration Our group has previously noted negative or protein deposition onto the inner within the stent is relatively low. bacterial cultures in patients with stent surface, findings noted by most Attempts to improve prosthesis chronic calcific pancreatitis at the time authors, prior to bacterial adherence.10–13 patency by use of prophylactic antibio- of initial manipulation but an average of Nevertheless, Swidsinski et al have tics, antimucin drugs, ursodeoxycholic 3.4 enteric bacteria in aspirated juice added further fuel to the importance of acid, and changes in stent polymer have once a stent has been placed.18 bacterial biofilms and the need to invariably been disappointing.14–16 Clini- Moreover, we have noted that pancrea- delineate novel therapies to prevent cal stent occlusion leads to jaundice and tic sepsis can occur uncommonly and their initiation or preclude their propa- bacterial cholangitis, with polymicrobial that prosthesis occlusion is necessary gation. infections in up to 90% of patients in but not a sufficient explanation for why Gut 2005;54:326–328. 21117 several studies. Recently, similar the patient develops infectious compli- doi: 10.1136/gut.2004.048900 changes to include polymicrobial bac- cations of pancreatic endotherapy. The terial contamination and pancreatic findings by Swidsinski et al, that indivi- Correspondence to: Professor R A Kozarek, sepsis have been noted in patients with duals with chronic calcific pancreatitis Section of Gastroenterology, Virginia Mason 18 19 Medical Center, 1100 Ninth Ave, Seattle, WA indwelling pancreatic prostheses. who have undergone endoscopic ther- 98101, USA; [email protected] In this issue of Gut, Swidsinski and apy develop complex biofilms within the colleagues20 present elegant insights into duct epithelium may mean nothing Conflict of interest: None declared. the presence of bacterial biofilm and the more than exposure of the pancreatic viability of those bacteria in duodenal, duct to duodenal flora by virtue of stent REFERENCES bile duct, and pancreatic duct mucosa as placement or pancreatic sphincterot- 1 Merchant SS, Falsey AR. Staphylococcus aureus well as in gall stones, common bile duct omy.20 If so, further work should cholecystitis: a report of three cases with review of stones, and biliary stents (see page 388). demonstrate that distal bile duct walls the literature. Yale J Biol Med 2002;75:285–91. 2 Rerknimitr R, Fogel EL, Kalayci C, et al. Using oligonucleotide probes, fluores- have comparable bacterial biofilm in Microbiology of bile in patients with cholangitis or cence in situ hybridisation (FISH) stu- individuals who have undergone biliary cholestasis with and without plastic biliary dies were used to characterise bacterial sphincterotomy. The latter may or may endoprosthesis. Gastrointest Endosc not play a role in the subsequent 2002;56:885–9. species within a biofilm and three 3 Swidsinski A, Lee SP. The role of bacteria in different parameters used to define development of common bile duct gallstone pathogenesis. Front Biosci presumptive bacterial viability: (1) stones seen in a subset of patients, even 2001;6:E93–103. amenability of cells to FISH versus ratio those with widely patent sphincterot- 4 Stewart L, Ponce R, Oesterle AL, et al. Pigment gallstone pathogenesis: slime production by of EUS 338 Cy3 positive and Gram omies. Alternatively, the development of biliary bacteria is more important than beta- positive cells (DNA staining); (2) hybri- biofilm in patients with chronic calcific glucuronidase production. J Gastrointest Surg disation time required to achieve fluor- pancreatitis may be onerous and asso- 2000;4:547–53. 5 Vitetta L, Best SP, Sali A. Single and multiple escence signal; and (3) time associated ciated with increased stone formation, cholesterol gallstones and the influence of with complete exhaustion of fluores- paralleling recent studies demonstrating bacteria. Med Hypotheses 2000;55:502–6. cence. Decreased bacterial viability was pancreatic stone protein within biliary 6 Lu Y, Xiang TH, Shi JS, Zhang BY. Bile anaerobic 11 bacteria detection and antibiotic susceptibility in stents prior to complete occlusion. http://gut.bmj.com/ assumed in the presence of decreased patients with gallstone. Hepatobiliary Pancreat DNA staining, prolonged time to achieve Perhaps the most interesting aspect of Dis Int 2003;2:431–4. autofluorescence, and rapid exhaustion the manuscript from a personal stand- 7 Konikoff FM, Lechene de la Porte P, Laufer H, et of fluorescence staining. point was the finding that bacteria were al. Calcium and the anionic polypeptide fraction (APF) have opposing effects on cholesterol Results included the presence of a always above, and not below, the sludge crystallization in model bile. J Hepatol bacterial biofilm in brown/mixed gall matrix in patients with variably 1997;27:707–15. stones, findings supported by Stewart, et occluded biliary stents, and that bacter- 8 Costerton JW, Cheng KJ, Geesey GG, et al. Bacterial biofilms in nature and disease. Annu Rev al, who noted that 73% of pigmented ial concentrations in patent, but nar- Microbiol 1987;41:435–64. on September 30, 2021 by guest. Protected copyright. gall stones/bile duct stones contained rowed, stents were higher at the liver, as 9 Leung JW, Liu Y, Chan RC, et al. Early attachment bacteria,4 data comparable with those opposed to the duodenal, end of the of anaerobic bacteria may play an important role in biliary stent blockage. Gastrointest Endosc previously noted with black pigment prosthesis. In contrast, occluded stents, 2000;52:725–9. stones. In contrast, no biofilm was as well as brown pigment and mixed 10 Weickert U, Venzke T, Konig J, et al. Why do noted within the mucosa of 20 gall cholesterol gall stones, were associated bilioduodenal plastic stents become occluded? A bladder or five bile duct walls or in the with decreased viable bacteria as detect- clinical and pathological investigation on 100 consecutive patients. Endoscopy elutes of 132 cholesterol gall stones that able by FISH, and less than 10% of the 2001;33:786–90. were tested. bacteria seen by Gram stain or auto- 11 Prat F, Cosson C, Domingo N, et al. Study of the The latter data can be construed as a fluorescence were amenable to FISH. mechanisms of biliary stent occlusion: an analysis of occluded and nonoccluded stents, with different pathogenesis of cholesterol gall Had the authors simply cultured the bile emphasis on the role of antinucleating biliary stone formation (mucin eliciting choles- proximal to the stent, however, our anionic peptide factor. Endoscopy terol crystal nucleation in supersatu- group as well as others would have 2004;36:322–8. 21 12 Zhang H, Tsang TK, Jack CA, et al. Role of bile rated bile). Alternatively, as the shown polymicrobial bacterial contam- mucin in bacterial adherence to biliary stents. authors suggest, it is possible that ination that may ultimately result in J Lab Clin Med 2002;139:28–34. cholesterol has the potential to inhibit ‘‘stent flu’’ or frank cholangitis.21718 13 Chan FK, Suen M, Li JY, et al. Bile bacterial growth and may actually be a immunoglobulins and blockage of biliary The implied conclusion that choles- endoprosthesis: an immunohistochemical study. novel mechanism to inhibit bacterial terol stone formation may be a physio- Biomed Pharmacother 1998;52:403–7. growth within biofilms. logical response to limit bacterial 14 Leung JW, Liu YL, Desta TD, et al. In vitro Perhaps the most intriguing findings biofilm development in bile and there- evaluation of antibiotic prophylaxis in the prevention of biliary stent blockage. Gastrointest in the study were the presence of fore useful to prevent biofilm develop- Endosc 2000;51:296–303. bacterial attachment to pancreatic duct ment and subsequent stent occlusion in 15 Halm U, Schiefke I, Fleig WE, et al. Ofloxacin and epithelium in seven of nine patients patients with biliary prostheses holds ursodeoxycholic acid versus ursodeoxycholic acid alone to prevent occlusion of biliary stents: a with chronic calcific pancreatitis as well some merit. More likely, however, chol- prospective, randomized trial. Endoscopy as the dramatic diminution in bacterial esterol coated stents or pharmacological 2001;33:491–4.

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16 Faigel DO. Preventing biliary stent occlusion. 18 Kozarek R, Hovde O, Attia F, et al. Do pancreatic 20 Swidsinski A, Schlien P, Pernthaler A, et al. Gastrointest Endosc 2000;51:104–7. duct stents cause or prevent pancreatic sepsis? Bacterial biofilm within diseased pancreatic and 17 Leung JW, Liu YL, Lau GC, et al. Gastrointest Endosc 2003;58:505–9. biliary tracts. Gut 2005;54:388–95. Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from Bacteriologic analyses of bile and brown 19 Provansal-Cheylan M, Bernard JP, Mariani A, 21 Smith BF. Human gallbladder mucin binds pigment stones in patients with acute et al. Occluded pancreatic endoprostheses— biliary lipids and promotes cholesterol crystal cholangitis. Gastrointest Endosc analysis of the clogging material. Endoscopy nucleation in model bile. J Lipid Res 2001;54:340–5. 1989;21:63–9. 1987;28:1088–97.

Hepatocellular carcinoma requires measurement of portal pressure ...... whereas the CLIP system is simple, uses clinical parameters, and can be used at the bedside. The accuracy of the CLIP Predicting survival in early model is interesting as many of the same parameters as Okuda (Child-Pugh hepatocellular carcinoma score and tumour extent) are used, yet simple changes such as the classification S Ryder of tumours as uni or multifocal drama- tically improves its predictive value over ...... Okuda. The Barcelona Clinic Model Are prognostic models for hepatocellular carcinoma useful in (BCLC) presents features in more detail with more categories, and uniquely predicting survival? includes performance status, a factor which has been key in predicting ver the past decade, non-surgical models have established two key factors response to treatment in most other therapies for hepatocellular car- influencing outcome: how good is the oncology settings. In large clinical trials Ocinoma (HCC) occurring on a underlying liver function and how of therapy for HCC, the BCLC system background of cirrhosis have been extensive is the tumour. would seem to have significant advan- established as effective. Hepatic arterial In this issue of Gut, two articles tages in the level of detail of stratifica- chemoembolisation has a proven survi- address this issue: one comparing cur- tion which is possible. From a clinical val advantage in selected patient rent prognostic models—Cancer of the perspective, the CLIP score will give groups,12 and there is now strong Liver in Italy (CLIP),7 Barcelona Clinic patients and clinicians an almost evidence that ablative therapies, both Liver Cancer (BCLC),8 and the Okuda equally reliable guide as to outlook. percutaneous alcohol injection3 and system6—in a single Italian centre,9 and The Japanese model was developed radiofrequency ablation,4 have survival the other by Tateishi and colleagues10 entirely in patients treated by ablative benefit. In addition, HCC incidence is assessing a new model developed in a therapy, which meant that 93% of increasing in the Western world, mainly large cohort of Japanese patients (see patients had tumours smaller than 10 due to the hepatitis C epidemic and this pages 411 and 419). It should be 5 cm in diameter. Again, the analysis http://gut.bmj.com/ cancer now has an increasing impact on emphasised that these are not natural produced a simple clinical algorithm health services. history based models; almost all based on parameters known to reflect A further change in the clinical patients had therapy and some patients liver function (bilirubin and albumin) setting in which we encounter HCC had more than one treatment modality. and tumour extent (size and number). has occurred. The advent of ablative This form of modelling of survival In this system, the ability of these therapy for HCC, which can destroy therefore reflects the outcome likely to simple parameters to predict survival tumour nodules up to approximately be seen in a real clinic setting but is was high. The overall five year survival on September 30, 2021 by guest. Protected copyright. 5 cm in diameter, has focused the need subject to the impact of many treatment rates varied from almost 80% in patients for detection of tumours at an early related effects on survival which may with good liver function and small stage in cirrhotic patients and has led to not be reproducible in standard clinical tumours to 15% in those with poor liver the widespread use of screening in most practice. It is also important to recognise and large or multiple tumours. This of the world. There is no doubt that that these studies were aimed at prog- model will require further validation; screening using ultrasound and a feto- nosis in patients with ‘‘early’’ HCC, perhaps its major drawback was its protein will detect HCC at a smaller essentially presymptomatic patients validation in a cohort undergoing size.5 This has produced the need for detected primarily by screening, and another form of therapy (surgical resec- new prognostic models given that the therefore represent a subgroup of the tion). However, it was interesting that it initial Okuda system6 was developed patient population. still predicted survival in a group being some 30 years ago when the size of The comparative study, in which 87% treated with an alternative strategy, HCCs at presentation was substantially of patients had screening detected HCC,9 suggesting that the parameters used larger than today. showed that the long established Okuda will hold true for most situations where Thus prognostic models are important system is no longer useful in patients early HCC is being treated. The simpli- from both a clinical perspective, of being with relatively early HCC; not surprising city of this score is attractive; it only able to give patients and their relatives given that Okuda I (early) is defined as takes into account tumour size and accurate information on survival, and less than 50% of liver volume replaced number, albumin, and bilirubin, para- from a research perspective, to assess by tumour, which can still include meters which will be available for all outcome of new therapies to help define massive tumours which would be far patients early on in the clinical assess- prognosis as accurately as possible. A too large to treat with ablative therapy. ment. It differs from the CLIP score in number of prognostic models for HCC The other systems performed well, with not using a fetoprotein and portal vein have been developed. All models have the best predictor being the BCLC invasion and excludes the other compo- been established in patient cohorts and system. This has the disadvantage of nents of the Child Pugh score. Further validated in other cohorts. All available complexity; if strictly followed it validation of this system is required to

www.gutjnl.com COMMENTARIES 329 see if it performs as well as CLIP and decompensated liver disease is limited REFERENCES BCLC in other parts of the world, where to liver transplantation and there is no 1 Llovet JM, Real MI, Montana X, et al. Arterial Gut: first published as 10.1136/gut.2004.048850 on 11 February 2005. Downloaded from the aetiology of liver disease may be possible therapy for those with both a embolisation or chemoembolisation versus different, and with treatment modalities poorly functioning liver and a large HCC symptomatic treatment in patients with unresectable hepatocellular carcinoma: a such as arterial chemoembolisation. because of the high tumour recurrence randomised controlled trial. Lancet The overriding importance of tumour rates post transplantation. In most parts 2002;359:1734–9. size and liver function comes across in of the world, the typical patient with 2 Lo CM, Ngan H, Tso WK, et al. 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Natural outlook may be much more determined survival, and if the costs, both finan- history of hepatocellular carcinoma and by tumour extension. In this latter cially and psychologically, are worth- prognosis in relation to treatment. study of 850 group, second tumour development while. The main problems with patients. Cancer 1985;56:918–28. 7 The cancer of the liver Italian programme (CLIP) and the potential to treat the underlying screening are that a significant minority investigators. A new prognostic system for liver disease are also likely to affect of HCC patients present with their hepatocellular carcinoma: a retrospective study of outcome; there is compelling evidence tumour at the same time as the present 435 patients. Hepatology 1998;28:751–5. 8 Llovet JM, Bru C, Bruix J. Prognosis of that therapy for hepatitis C will reduce with their underlying liver disease, and hepatocellular carcinoma: the BCLC staging 11 cancer incidence. that the screening tests (a fetoprotein classification. Semin Liver Dis 1999;19:329–38. Perhaps the most important point and ultrasound) are either relatively 9 Grieco A, Pompili M, Caminiti G, et al. Prognostic from both the comparative studies and factors for survival in patients with early- insensitive for small HCC or very opera- intermediate hepatocellular carcinoma this new algorithm is that in using a tor dependant. The risk of HCC varies undergoing non-surgical therapy: comparison of combination of ablative therapy and according to sex and the cause of Okuda, CLIP, and BCLC staging systems in a chemoembolisation survival rates are single Italian centre. Gut 2005;54:411–8. cirrhosis, adding further complexity to 10 Tateishi R, Yoshida H, Shiina S, et al. Proposal of very high. The best comparator studies the debate. There is a need for studies a new prognostic model for hepatocellular were two natural history series in which better identify patients at risk carcinoma: an analysis in 403 patients. Gut untreated patients with small HCC and 2005;54:419–25. and examine new modalities of screen- 11 Kowdley KV. Does interferon therapy prevent good liver function at presentation ing, such as magnetic resonance ima- hepatocellular carcinoma in patients with which showed an approximate three ging. However, there is no doubt that if chronic hepatitis C? Gastroenterology http://gut.bmj.com/ year survival rate of 25%.12 13 The three 1999;117:738–9. small HCC are detected they can be 12 Barbara L, Benzi G, Galani S. Natural history of year survival in the Grieco study was treated. We also have prognostic models small untreated hepatocellular carcinoma in 40% with a comparable aetiology of liver which allow both clinical prediction of cirrhosis; a multivariate analysis of prognostic disease. This is in contrast with overall factors of tumour growth rate and patient survival. outcome and clinical trials of therapy to Hepatology 1992;16:132–7. survival values which remain poor be undertaken. 13 Columbo M, Sangiovanni A. The natural history worldwide, with only 5–8% five year of hepatocellular carcinoma. Ital J Gastroenterol survival rates in the USA and Europe. Gut 2005;54:328–329. 1992;24:95–9. These values emphasise that good doi: 10.1136/gut.2004.052092 14 Oka H, Kuriola N, Kim K. Prospective study of on September 30, 2021 by guest. Protected copyright. early detection of hepatocellular carcinoma in results with a change in outcome can Correspondence to: Dr S Ryder, Queen’s patients with cirrhosis. Hepatology be achieved but only if tumours are Medical Centre, Nottingham, UK; 1990;12:680–7. diagnosed at an early stage on a back- stephen.ryder@ 15 Mima S, Sekiya C, Kanagawa H. Mass screening mail.qmcuh-tr.trent.nhs.uk for hepatocellular carcinoma: experience in ground of good liver function. The Hokkaido, Japan. J Gastroenterol Hepatol treatment option in patients with Conflict of interest: None declared. 1994;9:361–5.