Reversal of cirrhosis: evidence-based medicine?
In the May issue 2002 of Gastroenterology, Poynard et al.¹ report on the impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic viral hepatitis C. Our main issues are the following:

The term “reversal” (like “regression”) is intrinsically ambiguous. Reversal (and regression) can be minimal, partial, substantial, or complete; all variants are covered by the term reversal (or regression).

Poynard et al.¹ define reversal of cirrhosis as “a change in fibrosis score based on the biopsy sample” (pg. 1304 and 1312). This is a questionable definition of reversal of cirrhosis. Cirrhosis implies more than just fibrosis, but in addition nodular parenchymal regeneration and development of intrahepatic porto-hepatic and arteriovenous vascular shunts in fibrous septa.² Furthermore, cirrhosis appears in a broad spectrum of variants: early cirrhosis, fully developed cirrhosis, active and inactive cirrhosis, and as morphological types: micronodular, macronodular, mixed micro-macronudular, and incomplete septal cirrhosis.^3,4

It thus is clear that the study by Poynard et al.¹ does not concern reversal of cirrhosis (i.e., reversal of all key features of cirrhosis), but concerns reversal of fibrosis in cirrhosis. Such interchangeable use of the terms fibrosis and cirrhosis catapults this topic back into the early previous century when confusion between fibrosis and cirrhosis necessitated consensus meetings, the best known being held in Havana in 1956,⁵ stating explicitly (pg. 216, lines 1-2) : “Fibrosis should not be used synonymously for cirrhosis.” This is very old stuff, but remains important!

Concern is raised by the fact that Poynard et al.¹ warn the reader only once about their special definition of “reversal” by using inverted commas (pg. 1309, last paragraph). In the remaining text, they even use reversal interchangeably with disappearance of cirrhosis (pg. 1311). They omit to warn the reader about their special definition of the term “reversal” in the abstract. Any reader scanning the literature by reading abstracts gets incorrect information.

“Half of the patients with baseline cirrhosis treated with the reinforced regimen had a disappearance of cirrhosis at the time of the subsequent follow-up biopsy” (pg. 1311). This conclusion represents inadequate interpretation of results, obtained in histological semiquantitative scoring of liver fibrosis in needle biopsies. The Metavir⁶ scores F3, F2, F1, and even F0 do not exclude cirrhosis; they do not prove a disappearance or absence of cirrhosis!

More than one study has documented the conversion of micronodular into macronodular cirrhosis, especially if the causative agent could be eliminated and the necro-inflammatory parenchymal damage reduced.^7,8 The repair process of cirrhosis may possibly even evolve into the stage of incomplete septal cirrhosis,^9,10 the variant of macronodular cirrhosis which is particularly difficult to diagnose on liver needle specimens.³

Although we fully agree that cirrhosis is not totally irreversible, we also maintain with others^9,10 that complete regression of cirrhosis has never been clearly demonstrated.

It is our contention that the reinforced regimen used by Poynard et al.¹ has converted an originally readily recognizable cirrhosis (Metavir stage F4) into less active macronodular forms of cirrhosis, less easily identifiable in even adequate needle biopsy specimens and correctly staged in the Metavir scoring system as F3, F2, F1, and even F0. Poynard et al.¹ might perhaps invoke the definition of the Metavir score F3, which reads: “numerous septa without cirrhosis.”⁶ Regrettably this definition is somewhat unfortunate; it obviously intends to mean numerous septa without ‘obvious’ cirrhosis.” It cannot be that 10 distinguished French hepatopathologists (the Metavir group) would agree that clinicians, statisticians, or other nonpathologists conclude from a F4-to-F3 conversion that cirrhosis has disappeared! Semiquantitative scoring of liver biopsies and interpretation of the results requires collaboration between pathologists and preferably informed clinicians.^11,12

On page 1312, Poynard et al.¹ consider the limitations of their study, and mention the “possibility of sampling error especially between stage 3 (extensive fibrosis) and stage 4 (cirrhosis), particularly with biopsies of small size.” This is correct. They then go on apparently minimizing the possibility of sampling error in their study by mentioning three considerations about mean biopsy size, activity improvement, and virologic response. However, none of these remarks excludes the possibility of a micro-to-macronodular conversion of those patients’ cirrhosis, and hence does not justify to conclude to disappearance of cirrhosis.

Since patients with cirrhosis reversal were younger, Poynard et al.¹ consider the possibility that early cirrhosis is easier to reverse than more established cirrhosis, and conclude: “These large prospective studies with repeated biopsies have finally identified a new category of extensive fibrosis that could be named a “reversible cirrhotic stage.” This allegedly new category is relatively old! Other workers deserve the credit for this concept. It is known since 1936 from experimental work,¹³ and has been indicated as precirrhotic liver,^13,14 as the stage preceding the comitted precursor stage¹⁵ and as early minimal cirrhosis by Galambos who insisted on staging of cirrhosis.¹⁶

The Ishak scoring system,¹⁷ although imperfect like any scoring system, may be more appropriate in this respect than the Metavir system used by Poynard et al.¹ The highest score F6 is defined as: “Cirrhosis, probable or definite.” In this way, this scoring system at least recognizes that there is problematic grey zone between cirrhosis and something-that-looks-like-cirrhosis-but-is-not-yet-definite cirrhosis. Admittedly, the Ishak score does not solve the basic problem that indeed today the need persists of defining the borderline between authentic cirrhosis and its more readily reversible precursor stages.¹⁸ We insist that our disappointment with the paper by Poynard et al.¹ is nowhere due to an obsession by the dogma of irreversibility of liver cirrhosis.¹⁹

We agree that cirrhosis can regress to variable extent, but correspondingly maintain that true cirrhosis remains irreversible to variable extent. Convincing proof of complete regression of established cirrhosis has not yet been produced.

Reply
 

We thank Drs. Desmet and Roskams for their comments on this optimistic subject, and we recognize their important publications in this field. This subject was also well discussed recently by Bonis et al.¹ commenting on a nice description of improvement of cirrhosis (disappearance?) in secondary biliary cirrhosis.² We agree that there is no single perfect term to define the improvement of cirrhosis. As a matter of fact we were very prudent and never emphatically stated that treatment can result in a “complete cirrhosis regression.” The proposal of Desmet and Roskams remains ambiguous: “cirrhosis can regress to variable extent, ... but true cirrhosis remains irreversible to variable extent.”

The pathologist of the study, Zach Goodman, applied the METAVIR criteria. From this methodology and as we discussed in the article we used a simple histological end point with its limitations as discussed. It has its limits like another scoring system but was validated for interobserver variation. Of course skilled pathologists as Dr Desmet or Dr Goodman are used to presuming or suspecting cirrhosis in a fragmented small biopsy with many septa.

Because of the limitations of intercostal liver biopsy, sampling error and discordance between pathologists, the recent development of biochemical markers may also be useful for the observation of cirrhosis improvement.³ Among one multicenter study of patients treated 48 weeks with PEG-Interferon and Ribavirin versus Interferon and Ribavirin⁴ we measured the FibroTest and ActiTest in 352 patients, before treatment at baseline and 24 weeks after the end of the treatment.⁵ Among these patients 32 had cirrhosis at baseline. For 15 patients stage remains F4 and the Fibrotest did not significantly changed (0.67 ± 0.05 vs. 0.64 ± 0.05). For 17 patients there was at least one fibrosis stage improvement. These patients had a very significant Fibrotest improvement (Wilcoxon signed-rank test Z value = 3.58; P < 0.0001) from 0.68 to 0.44 for 3 stages improvement, 0.60 to 0.47 for 2 stages improvement and from 0.61 to 0.56 for one stage improvement.

One clinical proof of cirrhosis improvement, unexpected years ago, is the reversal (disappearance) of cirrhosis and its clinical complications by medical treatment. In hepatitis B nucleoside treatment are associated both with cirrhosis improvement⁶ and with disappearance of encephalopathy, jaundice, and ascites.⁷ As such, whilst there are discrepancies and disagreements over nomenclature and terminology as pointed out by Dr. Desmet and colleagues, we believe that our findings are important, real and require further confirmation in subsequent treatment studies in hepatitis C infection and other liver diseases.

Copyright © 2003 by American Gastroenterological Association

Copyright © 2003 by American Gastroenterological Association

V.J. Desmet^a
T. Roskams^a
aUniversity of Leuven, Leuven, Belgium
 

Many patients with cirrhosis or scarring of the liver develop abnormalities in their cardiovascular system as a result of their liver disease. All diseases that result in cirrhosis can lead to these cardiovascular changes but they occur more frequently in patients with more advanced disease.

It is believed that substances circulating in the blood that are normally cleared by a healthy liver can cause a generalized dilatation of the blood vessels throughout the body (except in the kidney where they are intensely constricted) .

The generalized vasodilatation then results in a low blood pressure. Most patients with this form of low blood pressure are asymptomatic because of its very gradual onset and because of a compensatory increased blood flow from the heart.

There is no specific treatment for the development of low blood pressure in patients with cirrhosis other than general, supportive care. The blood pressure will normalize after removal of the diseased liver and transplantation of a healthy liver.

Advances in Endoscopy and Endoscopic Sedation

Sedation

Introduction

The achievement of safe and effective sedation for many endoscopic procedures remains a top priority for clinical gastroenterologists in the United States and around the world. In recognition of the importance of this issue, this year's Digestive Disease Week (DDW) meeting featured many oral and poster presentations, as well as several clinical symposia dedicated to various sedation techniques for gastrointestinal procedures. In addition, this year for the first time, the American Society for Gastrointestinal Endoscopy (ASGE) hosted a well-attended Special Session on Tuesday, May 20, during which Drs. Christopher J. Gostout and Douglas K. Rex discussed sedation regimens and their effects on the operational flow and so-called "efficiency" of endoscopy units.^[1,2]

Many patients receive sedation in order to ensure their safety, comfort, and cooperation during endoscopic procedures. Sedation for endoscopy is not required by most endoscopists to ensure technically adequate procedures. However, at this year's meeting, as in other years, sedation has been shown repeatedly to contribute to superior patient satisfaction, comfort, and willingness to undergo repeat procedure.^[3]

Sedation Regimens

The 2 primary types of sedation for gastrointestinal procedures are intravenous (IV) procedural sedation and general anesthesia. The latter involves the depression of a patient's respiratory drive and requires the presence and expertise of an anesthesiologist. By contrast, IV sedation, also commonly known as "conscious sedation," maintains a patient's ability to breathe spontaneously and protect his own airway. IV sedation can be administered by the endoscopist, who both administers the sedation and performs the procedure, while a qualified nurse monitors the patient's state of consciousness and vital signs.

IV sedation encompasses a continuum of sedation levels ranging from "light" to "deep" sedation. Light sedation implies that the patient retains the ability to respond to vocal commands. Deep sedation implies a medically controlled state of depressed consciousness from which the patient is not easily aroused. The optimal level of sedation differs according to the procedure being performed. Deep sedation or even general anesthesia may be preferred for therapeutic procedures to ensure that a patient remains immobile.

To date, pharmacologic regimens that ensure safe, effective, and efficient sedation for all patients have been idealized, but not necessarily identified. As most gastroenterologists would likely agree, the ideal procedural sedation regimen for endoscopy acts predictably and rapidly on every patient. It also induces a level and duration of sedation that is both safe and appropriate to the procedure being performed. After the procedure, ideal sedation wears off quickly and does not increase recovery time. In all of these ways, ideal sedation regimens facilitate the operational flow and efficiency of an endoscopy unit.

Preferably, ideal sedation does not contribute to the costs of an endoscopy unit. However, as Abraham and colleagues^[3] discussed in an ASGE poster presentation on cost-effectiveness and sedation, the costs of sedation may represent a small sum to pay for achieving patient satisfaction and even willingness to undergo further endoscopic studies. In Canadian dollars, they estimated the additional cost of using sedation for endoscopy to be $103.92 per procedure. Much of this cost was incurred from increased recovery time associated with sedation (29 minutes of recovery time for sedated procedures vs 15 minutes for nonsedated procedures).

Most current standard IV sedation regimens rely on benzodiazepines (eg, diazepam or midazolam) and narcotics (eg, meperidine or fentanyl). Benzodiazepines effect sedation, anxiolysis, and amnesia. Narcotics offer the benefit of analgesia. Most standard IV sedation regimens typically employ the general principle of intermittently bolusing alternate doses of each of these 2, to achieve a desired level of sedation. Currently, there is no one standard sedation regimen and even within individual institutions, the choice of sedation cocktail may depend upon endoscopist preference and the procedure being performed.

Two studies presented at this year's meeting discussed sedation regimens that combine benzodiazepines and narcotic analgesia for gastrointestinal procedures. Mamula and colleagues^[4] presented retrospective data from The Children's Hospital of Philadelphia on the safety and efficacy of fentanyl and midazolam for upper and lower endoscopy in children. Although the investigators did conclude that conscious sedation with this regimen is efficacious and safe, they also reported seeing some side effects in approximately 20% of patients during the 2-month study timeframe, including bradycardia (0.9%), agitation (1.7%), skin reaction (3.4%), vomiting (6.4%), and mild (2.6%) and moderate (11.2%) hypoxemia.

In an adult population, Oringer and colleagues^[5] prospectively randomized patients to receive either fentanyl/midazolam or meperidine/midazolam sedation regimens during outpatient upper and lower procedures. Both patients and physicians were blinded to which arm of the study a patient was assigned. During the course of the study, 55 patients received meperidine and 56 received fentanyl. Although there was no difference in drug-related side effects, use of fentanyl was associated with more procedural pain for patients. Use of fentanyl was also significantly associated with more rapid completion of routine gastrointestinal procedures and with more rapid recovery times. Patients who received fentanyl recovered from procedures by a mean of 77 minutes, whereas patients who received meperidine required a mean of 93 minutes of recovery time.

As the newest trend, propofol continues to gain acceptance among endoscopists as an effective pharmacologic agent for achieving "ideal" sedation. According to Dr. Rex, "Thousands of patients have now undergone procedures with propofol sedation." Nevertheless, the key questions -- who should administer propofol for endoscopic procedures, and how to best monitor patients during sedation to ensure their safety -- remain greatly controversial.

Propofol

Propofol is a short-acting anesthetic that boasts both a rapid onset of action and a short recovery time.^[6] It can produce unconsciousness within 30 seconds, and can be used to induce and maintain a spectrum of sedation levels, ranging from moderate to deep anesthesia. Propofol sedation can be achieved by administering bolus doses as well as by continuous infusion. As an added advantage, no matter how long the sedation period, recovery from propofol will occur within 10-20 minutes once it is discontinued.

The disadvantage of propofol is its relatively narrow therapeutic range. Titrating propofol to achieve conscious sedation without inadvertently inducing general anesthesia requires clinical expertise. Given its high potential to induce respiratory depression and cardiovascular instability, propofol has been routinely administered by anesthesiologists.

Nonanesthesiologist-administered propofol. Of course, it is widely recognized that employing anesthesiologists to administer sedation for routine gastrointestinal procedures is costly, and may pose a dilemma when billing for procedures and sedation separately. As such, anesthesiologist-assisted sedation may not be a realistic option for most endoscopy units. Instead, endoscopists, nurse-anesthetists, nurses, and even patients themselves may be considered appropriate candidates for administering different sedation agents, including propofol.

Several studies during this year's meeting proceedings reported on the feasibility and safety of nurse-administered as well as patient-administered sedation regimens that included propofol.^[7-11]According to Lee and colleagues,^[10] 78% of 500 patients who administered a sedative regimen of propofol and alfentanil to themselves during colonoscopy via a patient-controlled syringe-pump reported that they would be willing to use patient-controlled sedation again for future colonoscopies.

Kulling and Inauen^[11] from Solothurn, Switzerland, presented a prospective assessment of patient safety during nonanesthesiologist-administered sedation for 300 consecutive outpatient colonoscopic and endoscopic procedures. All adults enrolled were screened to ensure that they were otherwise healthy. Patients were then given a standard initial dose of propofol (0.5 mg/kg for patients < 70 years of age and 0.25 mg/kg for patients >/= 70 years), with subsequent 10-mg boluses of propofol administered by the endoscopy nurse to titrate the level of sedation. Colonoscopy patients also received 25 mg meperidine and 20 mg butylscopolamine; endoscopy patients only received the propofol.

In this Swiss study, all patients enrolled were also given nasal cannula oxygen and their vital signs were monitored with pulse oximetry, blood pressure, and sidestream capnography. Of the 300 patients participating in the study, no episodes of frank apnea occurred per real-time graphic assessment of respiratory activity using sidestream capnography. Eleven patients (3.7%) experienced oxygen desaturation to < 90%; 3 patients had increased oxygen requirements; and 22 patients (7.3%) became hypotensive with mean blood pressures < 50 mm Hg.

Kulling and Inauen indicated that the results of this study suggest that nonanesthesiologist-administered sedation with propofol is safe. A review of most investigative presentations at DDW 2003 supports this notion, by suggesting no significant differences in complication rates of hypoxemia and hypotension when comparing propofol and standard sedation regimens.^[7,8,12]

Anesthesiologist-administered propofol. However, a few studies did report relatively high rates of hypoxia and hypotension. For example, Quadri and colleagues[13] reported on the use of propofol administered by an anesthesiologist in a private-practice setting and found a 30% rate of oxygen desaturation to < 90% and a 20% rate of blood pressure readings < 90/60 mm Hg. They also found that sedation with anesthesiologist-administered propofol greatly reduced total time for sedation and recovery of patients undergoing both upper endoscopies and colonoscopies.

Advances in Patient Monitoring

Recent technological advances in electronic vital-sign monitoring may help to ensure the safety of patients undergoing procedures with sedation. In particular, capnography as a real-time graphic measure of ventilatory waveforms has emerged as a monitoring modality that may complement current standard monitoring with continuous pulse oximetry and visual assessment of the patient. During recent DDW meetings, it has been suggested that microstream capnography, which measures end-tidal _PCO₂ while supplying supplemental oxygen with a dual-purpose nasal cannula, may provide an "early-warning system" for impending respiratory compromise and resultant hypoxemia.^[14,15] Many of the sedation studies presented during this year's meeting included monitoring with microstream capnography.

As a new advance this year, Heuss and colleagues^[16] presented a pilot study of a transcutaneous digital monitoring system for simultaneously measuring pulse oximetry and carbon dioxide tension via a built-in digital mixed signal microcontroller that is affixed to a sensor placed on a patient's earlobe. They presented a comparison of the new V-Sign single-ear sensor system vs analogue pulse oximetry applied to the left index fingers of 9 patients undergoing endoscopy. In promising results, they found that the new system detected changes in oxygen saturation a mean of 26 seconds earlier than standard pulse oximetry. They also reported significantly less motion artifact associated with the new single-ear sensor system as compared with traditional analogue pulse oximetry applied to the finger. Such technological advances in monitoring may ultimately improve the ability of gastroenterologists to ensure the safety of their patients during endoscopic procedures, no matter which sedation regimen is employed.

Advances in Endoscopy

The Wireless Capsule Endoscope

No sedation is required for one of the most noteworthy recent advances in endoscopy -- the capsule endoscope, a vitamin pill-sized device that is simply swallowed. The wireless capsule endoscope, < 1.0 cm in length, contains light-emitting diodes, a miniature television camera, a transmitter, and batteries. The patient wears sensors on the abdomen connected to a receiver, and recorded images are subsequently downloaded to a computer for review.

The development of the wireless capsule endoscope was first presented at an ASGE Plenary Session held during DDW 2000 by Dr. Paul Swain, of the Royal London Hospital, United Kingdom.^[17] The capsule method is increasingly recognized as a major improvement for painless imaging of the entire small intestine. At this year's meeting, there were 85 oral and poster presentations regarding the use of the wireless capsule endoscope.

The major indication for capsule endoscopy continues to be the evaluation of the small intestine as the possible source of obscure gastrointestinal bleeding. During this year's ASGE Plenary Session, Enns and colleagues^[18] presented a multicenter international study on capsule endoscopy. Of 272 reviewed studies, 231 were for obscure bleeding or anemia. The diagnostic yield of finding significant lesions to account for the bleeding was approximately 50%.

Gastrointestinal bleeding and anemia are common in patients chronically taking nonsteroidal anti-inflammatory drugs (NSAIDs). Graham and colleagues,^[19] reported on a controlled study using the capsule endoscope to evaluate the small intestine in patients taking NSAIDs. This study examined 20 arthritic patients taking chronic NSAIDs and 20 similar patients who took acetaminophen alone or nothing for their discomfort. Erosions of the small intestine were detected in 58% of the NSAID users and in 17% of non-NSAID users. This finding is compatible with the approximately 15% incidence of abnormalities found in normal individuals by capsule endoscopy.^[20] Severe abnormalities occurred in 33% of NSAID users vs 0% in controls (Figure 1).

Figure 1. Endoscopic photo taken with the capsule endoscope showing an ulcer in the mid-jejunum of a patient with obscure gastrointestinal bleeding. There is blood clot adherent to the ulcer, indicating recent hemorrhage.
This photo was provided with the courtesy of Moshe Rubin, MD, Columbia-Presbyterian Medical Center.

In other reports, the wireless capsule endoscope seemed initially useful in the evaluation of patients with Crohn's disease, and proved more accurate than standard tests, such as contrast radiology, for small bowel Crohn's disease.^[21] There is some small risk, however, that the capsules can become trapped behind unsuspected strictures and require surgical removal, as documented by Enns and colleagues^[16] and Fireman and colleagues.^[22] Nonetheless, the capsule endoscope has proved useful and safe in evaluating obscure small intestinal disease, even in children older than 10 years.^[23]

Continued technical progress was evident, as highlighted in a presentation by Lewkowicz and colleagues,^[24] who described a new capsule device designed to evaluate intestinal narrowing and strictures. If the capsule is retained in the intestine for more than 4 days, it disintegrates into fragments that can pass through small orifices. In another innovation already tested in humans, as reported by Fritscher-Ravens and colleagues,^[25] the capsules could actually be moved painlessly forward and backward in the small intestine using electrical stimulation.

The Wireless pH Monitoring System

Another noteworthy wireless technology that has achieved practical utility is the attachable capsule for esophageal pH monitoring to detect and quantitate gastroesophageal acid reflux. The Bravo system was introduced about 1 year ago, and consists of a capsule-sized sensor with radio transmitter and batteries that is endoscopically attached to the esophageal mucosa using suction and a small pin. The patients wear a small pager-sized receiver, and recorded results are later downloaded into a computer for analysis. Unlike standard pH monitoring systems, there is no uncomfortable and embarrassing nasal catheter, and the pH is recorded for 48 hours rather than the standard 24 hours. The capsule falls off of the mucosa in 1-2 weeks, and is passed out through the gastrointestinal tract.

Lin and colleagues^[26] reported on a series of 245 consecutive studies using the wireless pH monitoring system during this year's meeting proceedings. The method proved very safe, with 2 patients requiring endoscopic removal of the capsules after 2 weeks and premature capsule detachment in 7 patients (3%). Placement of the capsules was carried out with endoscopic guidance in 112 patients and under manometry control in the remaining patients. Endoscopic sedation did not affect the results in the first 24-hours, and the 48-hour results detected more abnormalities than were evident by results obtained in the first 24 hours.

Endoscopic Mucosal Resection

Endoscopic mucosal resection (EMR) has emerged as a major advance in the management of early neoplastic lesions throughout the gastrointestinal tract. This method uses the injection of fluid into the submucosa of the gut wall, allowing the mucosa to be resected over a wide area, while protecting the outer muscle layers. Kinney and colleagues^[27] reported clinical outcomes from a multicenter study using EMR for various superficial lesions of the esophagus, stomach, and colon in 33 patients. They found EMR to be safe and well tolerated, and suggested that EMR was appropriate for early gastrointestinal cancer in patients who were unsuitable for surgery.

Pech and colleagues^[28] made a much stronger recommendation based on the long-term results of a multicenter German experience treating high-grade dysplasia in Barrett's esophagus and early esophageal adenocarcinoma primarily with EMR. They treated 69 patients with EMR, 32 with photodynamic therapy (PDT), and 10 with both EMR and PDT. The patients treated with local therapy were followed for an average of 50 months (range, 37-73 months). The survival rate of 79% was the same as that for a standard German-matched population. Based on their data, this group emphatically recommended that local endoscopic therapy should be the treatment of choice for high-grade dysplasia and mucosal adenocarcinoma in Barrett's esophagus, and should be used preferentially in this setting instead of radical esophagectomy.

Photodynamic Therapy

PDT is a 2-part procedure: Part 1 involves giving a photosensitizing drug that is absorbed into neoplastic tissue; Part 2 directs light, usually from a laser with a specific wavelength, into the target tissue. The activated drug undergoes a photochemical reaction that destroys and ablates the abnormal area. One of the most interesting uses for PDT in gastroenterology is the treatment of high-grade dysplasia and early adenocarcinoma in Barrett's esophagus (Figure 2). Again, the goal of therapy is to avoid the need for radical esophagectomy.

Figure 2. Photodynamic therapy being carried out in a patient with Barrett's esophagus and high-grade dysplasia. The red laser light is being delivered through a centering balloon to an area of Barrett's esophagus. The top of the balloon and the top of the Barrett's segment is evident in the endoscopic photo. The patient received porfimer sodium, a light-sensitizing drug, 48 hours before this laser treatment, which will activate the drug and ablate the mucosa in the treated area.

Overholt and colleagues^[29] reported the results of a large international, multicenter, randomized trial of PDT plus omeprazole (given for acid suppression) vs omeprazole alone for the treatment of high-grade dysplasia in Barrett's esophagus. For PDT, they used the drug porfimer sodium and red laser light (wavelength 630 nm) delivered through a cylindrical diffusing fiber inside of a centering balloon with endoscopic control. At the end of a 24-month minimum follow-up period, high-grade dysplasia was eliminated in 76.8% of the PDT group and in 38.6% of the omeprazole-only group (P < .001). Among the PDT patients, 13% developed cancer vs 28% of those taking omeprazole only (P = .006). The major complication of PDT was esophageal stricture, which occurred in 37% of patients and which was successfully treated with endoscopic dilation in 98%. The study authors concluded that PDT was effective in eliminating high-grade dysplasia and reducing the incidence of cancer in patients with high-grade dysplasia in Barrett's esophagus.

Advances in Pediatric Endoscopy

Multiple sessions during DDW 2003 were again dedicated to the growing understanding of the spectrum of gastrointestinal diseases found in childhood. In a population-based outcomes study using the Kids' Inpatient Database, Guthery and colleagues^[30] found that gastrointestinal disorders in children are a significant source of hospital resource consumption, accounting for $2.6 billion in hospital charges annually in the United States. In line with this, many presentations addressed diagnostic and therapeutic endoscopic techniques that have become invaluable tools in the practice of pediatric gastroenterology, both in the United States and worldwide.

Push enteroscopy. Two studies conducted by the same group in Baltimore, Maryland, addressed the safety and effectiveness of push enteroscopy in children.^[31,32] Push enteroscopy is an endoscopic technique by which an enteroscope is advanced beyond the duodenum. Darbari and Kalloo^[31] presented the diagnostic yield results of a series of 26 children (mean age, 12 years) who underwent push enteroscopy at their institution between the years 2000 and 2002. The most common indications for the procedure were proximal small bowel disease on CT scan or MRI. The push enteroscopy was grossly and histologically normal in 11% of patients who underwent the procedure. Crohn's disease was diagnosed by biopsy in 53% of patients. The same diagnoses would have been attained by standard upper endoscopy in 30% of patients who underwent push enteroscopy. Medical management was changed in over 75% of patients as a result of findings on enteroscopy. No patients had complications from the procedure.

Darbari and colleagues^[32] also reported on 18 children out of 26 total, enrolled in a study that used push enteroscopy to confirm the radiologic suspicion of Crohn's disease based on a screening gadolinium enhanced-MRI. In this secondary data analysis, they found that 14 of 15 patients with jejunoileitis diagnosed by radiologic criteria were confirmed on results of biopsies obtained during push enteroscopy. Three patients with isolated colonic Crohn's disease identified on radiologic studies had normal enteroscopy and small bowel biopsies. According to these investigators, these findings indicate a 93% sensitivity and 100% specificity for diagnostic push enteroscopy in Crohn's disease.

Advances in lower gastrointestinal procedures. In terms of advances in lower gastrointestinal procedural techniques, Pashankar and Bishop[33] presented a new bowel preparation regimen for children that used polyethylene glycol (PEG)-3350.* As many pediatric gastroenterologists are aware, PEG-3350 is far more palatable and effective than most presently available laxatives. To date, there have been no formal studies on its use as a bowel preparation agent for procedures.

In an open-label prospective study of 28 children (14 boys and 14 girls), these investigators prescribed PEG-3350 at a dose of 1.5g/kd/day for 4 days prior to colonoscopy. They gave parents instructions to mix the PEG-3350 in any beverage of the child's choice. There were no dietary restrictions, except for clear fluids on day 4. Patients and their parents were asked to keep a diary during the 4 days of bowel preparation, and were asked specifically about stool frequency, consistency, compliance, ease of preparation, and adverse effects. Serum electrolytes, blood urea nitrogen, creatinine, and serum osmolality were measured in all patients on the day of colonoscopy and were found to be within normal limits. One patient vomited during the preparation, 3 complained of abdominal pain, and 3 complained of nausea. Twenty-two of 28 patients reported the bowel preparation to be "easy," and another 5 stated that it was "okay." Only 1 patient found the preparation to be "unpleasant" and none reported it to be difficult.

Over the 4 days of bowel preparation, stool frequency increased steadily from a baseline mean of 2.6 stools per day to 5.6 on day 4. No patients were reported as being poorly "prepped" by endoscopists, with the great majority receiving a "good" or "excellent" rating for the quality of preparation. As these investigators indicated, PEG-3350 is an attractive option for bowel preparation in children. Not only is it well tolerated, but it also appears to provide an effective clean-out for colonoscopy.

* The United States Food and Drug Administration has not approved this medication for this use.

43% or more remain with undetectable virus 6 months after the cessation of 48 weeks of treatment. In those who achieve a sustained virologic response (SVR), the degree of fibrosis is less as judged on post-treatment liver biopsy; cirrhosis may even regress.

In those individuals with cirrhosis who achieve a sustained virologic response, the risk of developing hepatocellular carcinoma is significantly reduced and it is likely that their chance of developing liver failure is less.

Patients who do not achieve sustained virologic response can still show histologic improvement as demonstrated on liver biopsy post therapy as compared to baseline.

Dr. Heathcote concludes, “Patients with compensated cirrhosis can benefit from therapy while those who are decompensated are prone to more safety issues. Thus, individuals with any evidence of hepatic decompensation should generally not be given interferon-based antiviral therapy, but treatment should be encouraged for those whose status is Child Class A.”

10/31/03

Reference
EJ Heathcote and others. Treatment considerations in patients with hepatitis C and cirrhosis. Journal of  Clinical Gastroenterology 37(5): 395-398. November-December 2003.

www.hivandhepatitis.com 

SourceURL:http://www.gastrohep.com/news/news.asp?id=2352

Cirrhotic patients with spontaneous bacterial peritonitis

Patients with spontaneous bacterial peritonitis frequently develop a
rapidly progressive impairment in systemic hemodynamics, find researchers
in the November issue of Hepatology.

Spontaneous bacterial peritonitis is frequently associated with renal failure.
8 patients developed renal failure during treatment.
Hepatology

In this study, researchers from Spain assessed whether systemic and hepatic
hemodynamics were also altered by this condition.

The team evaluated 23 patients with spontaneous bacterial peritonitis, both
at diagnosis and after infection resolution. They assessed tumor necrosis
factor alpha (TNF-alpha) in plasma and ascitic fluid, plasma renin activity
(PRA) and norepinephrine (NE), as well as systemic and hepatic hemodynamics.

The team found that 8 of the patients developed renal failure during
treatment. At diagnosis, these patients had higher levels of TNF-alpha,
blood urea nitrogen (BUN), PRA and NE, peripheral vascular resistance, and
hepatic venous pressure gradient (HVPG) and lower cardiac output.

The team determined that changes in PRA and NE correlated inversely with
changes in arterial pressure and directly with changes in BUN, Child-Pugh
score, and HVPG.

There were 5 patients in the renal failure group who developed
encephalopathy. Overall, 6 patients in this group died.

Dr Luis Ruiz-del-Arbol's team concluded, "Patients with spontaneous
bacterial peritonitis frequently develop a rapidly progressive impairment
in systemic hemodynamics".

This leads to, "Severe renal and hepatic failure, aggravation of portal
hypertension, encephalopathy, and death".

"This occurs despite rapid resolution of infection and is associated with
an extremely poor prognosis".

Hepatology 2003; 38: 1210-18
28 October 2003

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