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RENAL DISEASE AND HCV

Renal manifestations of hepatitis C infection.

Daghestani L, Pomeroy C
Department of Veterans Affairs Medical Center, Lexington, Kentucky, USA.

Hepatitis C is an important cause of renal disease, and renal complications may be the presenting manifestation of hepatitis C infection. About half of patients present with evidence of renal insufficiency, and up to one quarter present with nephrotic syndrome. Others present with proteinuria or evidence of diminished renal function.

The pathogenesis of hepatitis C-associated renal disease remains incompletely defined, but most evidence suggests that glomerular injury results from deposition of circulating immune complexes in the subendothelium and mesangium. Membranoproliferative glomerulonephritis, with or without cryoglobulinemia, is the most common renal lesion.

Interferon alpha-2b is currently the treatment of choice. However, success is limited, with many patients failing to respond or suffering relapse upon discontinuation of therapy. Studies of newer treatment modalities, such as longer courses of interferon or the use of ribavirin or immunosuppressive agents, are underway. Hepatitis C-associated renal disease may progress to end-stage renal failure requiring dialysis in about 10% of patients.

Viral hepatitis as a cause of renal disease

Department of Medicine, Tulane University School of Medicine, New Orleans LA 70112, USA Krane NK, Gaglio P

Viral hepatitis has become a recognized cause of both acute and chronicrenal disease. Acute and chronic viral infections may result in formation ofimmune complexes that can become deposited in the glomerular capillarybasement membrane, stimulating both cytokine production and complementactivation and producing a variety of glomerular lesions. Chronic viral infections may also result in production of mixed polyclonal IgG and monoclonal IgM cryoglobulins, which result in systemic vasculitic syndromes that also involve the kidney. Glomerular injury through these mechanisms may< become clinically manifested as either acute glomerulonephritis or the nephrotic syndrome. Because of the worldwide prevalence of hepatitis B and C infections, they are important public health problems that may lead to a variety of important renal diseases. Further understanding of the mechanisms by which these viruses induce injury will allow more effective treatment strategies to reverse the renal diseases induced by hepatotropic viral infection   

 
Irritable Bowel Syndrome: From Epidemiology to Treatment
Nicholas J. Talley, MD, PhD  


Introduction
The management of irritable bowel syndrome (IBS) and other functional gastrointestinal disorders remains a significant challenge to the physician at the front lines of disease management. At this year's meeting of the American College of Gastroenterology, new information on the epidemiology, pathophysiology, and management of IBS and related conditions was presented.

This report discusses some of the more key and interesting data presented during this meeting, and thus provides the relevant context for highlighting their implications on clinical practice.

Epidemiology, Impact, and Practice Variations
Symptom Complexes
One of the difficulties in managing patients with IBS remains the multitude of symptoms that many describe either spontaneously or on systems review. Sometimes this confounds management because such complaints may lead to extensive evaluations, even if the patient clearly has a positive clinical diagnosis of IBS and there are no alarm features present. However, the exact prevalence of the combinations of different functional gastrointestinal symptom complexes remains unclear.

To examine the prevalence of gastrointestinal symptoms, Tutega and colleagues[1] reviewed 1069 employees of an integrated healthcare system in Salt Lake City, Utah, 623 of whom responded to a validated questionnaire. They found a striking overlap between IBS and functional dyspepsia: 70% of individuals with IBS also had functional dyspepsia, whereas 43% of subjects with dyspepsia also had IBS. Moreover, more individuals with such overlap reported consulting a physician than those who had IBS or dyspepsia alone.

In a community survey from Olmsted County, Minnesota, Locke and colleagues[2] evaluated a similar number of subjects drawn from the general population. Six hundred fifty-seven of 935 eligible subjects responded to a validated questionnaire. These study authors found that symptom complex overlap was much more the rule than the exception in this community sample. This applied to IBS with constipation as well as IBS with diarrhea in terms of overlap with upper gastrointestinal tract symptoms. It is important to note that there was no predominant pattern of overlap identified consistent with a common underlying pathophysiology. Hence, artificial subdivision of these functional gastrointestinal complaints may not be particularly helpful in terms of management.

These data arguably challenge the subdivision of the functional gastrointestinal disorders into finer and finer categories, which has been the tendency over the past decade.[3]

Ethnic Differences
An area that has been understudied in IBS is the issue of ethnic differences in disease manifestation and presentation. Wigington and colleagues[4] studied black and white patients with IBS and evaluated the symptomatic presentations. A similar prevalence of IBS was found among both blacks and whites. However, there were some unexplained sociodemographic differences between the groups. For example, blacks with IBS and diarrhea were significantly more likely to have lower incomes compared with white patients, who tended to have higher incomes. Age, sex, and education differences were not observed, however.

Such differences may be explained by confounding. Alternatively, there may be different etiologic explanations for IBS in different races (eg, genetic) yet a common final pathway in terms of symptom expression. However, confirmation of racial differences in IBS in the United States, which to date has been largely ignored, is still required.

Bowel Pattern
One issue that remains controversial in IBS is subdivision into bowel pattern subgroups. In particular, what defines an alternating bowel pattern is unclear from the literature. Indeed, there is no definitive guidance from the Rome committees regarding this issue. Simply defining patients not fitting into an arbitrary diarrhea or constipation subgroup as an alternator may be overly simplistic and even misleading.

In a study by Locke and coworkers,[5] the investigators aimed to determine what individuals meant when they said that they had an alternating bowel pattern, as based on a large community survey. A valid questionnaire was mailed to 4029 randomly selected individuals in Olmsted County, of whom 3022 eligible subjects provided data. Overall, 7.6% of the population had a self-reported alternating bowel pattern, compared with 9.2% who stated that their usual bowel pattern was constipation and 2.5% who said that their usual bowel pattern was diarrhea. It was interesting to note that the feeling of incomplete rectal evacuation and passage of mucus were significant predictors of reporting an alternating bowel pattern in this general population. Of those individuals who reported an alternating bowel pattern, 59% met symptom criteria for constipation based on standard and accepted groupings of individual symptoms, whereas 35% met symptom criteria for diarrhea and 20% met criteria for both (25% met criteria for neither).

These findings suggest that "alternators" may not comprise a distinct subgroup from constipation and diarrhea in this population. Further work is needed to define an appropriate, clinically relevant subclassification of IBS based on colonic symptoms. The latter could be very useful in terms of making management strategies more logical and evidence-based.

Primary-Care vs Gastroenterology Clinics
The approach to management of IBS in practice has been little evaluated. In particular, it is unclear how gastroenterologists and primary-care physicians treat IBS in the United States.

Whitehead and colleagues[6] studied 1665 patients diagnosed with a functional bowel disorder in both gastroenterology and primary-care clinics of a large health maintenance organization; some interesting differences in management were noted. Primary-care physicians more commonly prescribed laxatives than did gastroenterologists. About one quarter of patients in both settings were prescribed antidiarrheal agents and about one quarter were prescribed antispasmodics, but only 1 in 10 were given antidepressants and 1 in 10 prescribed anxiolytics or muscle relaxants. Approximately one third of patients had lifestyle changes suggested to them, or were advised to exercise -- and this approach was similar in both clinical practice settings. Gastroenterologists were more likely to tell their patients about the certainty of diagnosis than were primary-care physicians, although this presumably reflects standard practice in primary care. However, surprisingly, gastroenterologists were less likely to explain the cause of the symptoms than were primary-care physicians (40% vs 54%), which was significant.

Other data suggest that explanation, reassurance, and education are all important in reducing subsequent visits to clinic for patients with IBS.[7] Therefore, such differences in practice patterns may have real clinical relevance. Gastroenterologists and primary-care physicians achieved only modest patient satisfaction levels, which may be improved with the adoption of more appropriate management strategies.

Pathogenesis
Postinfectious IBS
There continues to be major interest in postinfectious IBS. Marshall and colleagues[8] investigated an outbreak of acute gastroenteritis (that was attributed to a viral pathogen) and the subsequent development of IBS. This study documented a large foodborne outbreak of severe acute gastroenteritis at a meeting of the Canadian Society of Gastroenterology Nurses and Associates. The attendees were subsequently surveyed and followed-up. The study authors obtained a 71% response rate; 107 respondents (77%) described an acute enteric illness during the outbreak. Among those subjects who had enteric illness, the incidence rate of IBS at 3 months was 24%, although by 6 months the rate had dropped to 14%, compared with 3% and 11% among controls, respectively.

Hence, although there was an increased incidence of IBS among subjects at 3 months, by 6 months there was no difference in the rates. Vomiting appeared to be indicative of some protection from the development of postinfectious IBS, although this effect remains unexplained. These study results are consistent with other published data that suggest that postinfectious IBS is a distinct subgroup with more diarrhea and less psychiatric illness.[9] It seems likely that infection can precipitate IBS in individuals who are otherwise predisposed. Whether subclinical infection could explain the increased incidence rates in the control patients as well is unclear. Unfortunately, at this time there is no way to prevent the development of IBS in individuals so exposed. A recent trial of high-dose prednisone failed to demonstrate any benefits in postinfectious IBS.[10]

Relationship Between Menstrual Cycle and IBS Symptoms
Some women with IBS report an exacerbation of symptoms across the menstrual cycle. Heitkamper and colleagues[11] studied 195 women with IBS who reported that they often felt bloated and distended. The study authors used a daily diary as well as a standardized questionnaire to assess bloating and other gastrointestinal symptoms in menstruating women during perimenstrual and non-perimenstrual days. Bloating was associated with menses-type symptoms; they also noticed that bloating was worse on days with loose or hard stools. Could these findings reflect abnormal visceral pain perception in different phases of the menstrual cycle?

Wrzos and associates[12] evaluated 11 women, 5 of whom had IBS, and induced distention with a rectal barostat to experimentally cause visceral-type pain. They found that the thresholds for sensation were lower in patients with IBS than in healthy volunteers as would be expected, with no differences in somatic sensation. It was interesting to note that in the healthy volunteers -- but not in the patients with IBS -- there were lower pressure thresholds in the follicular vs luteal phase for each sensation level. The level of anxiety was not associated with the changes observed. Hormonal changes during the menstrual cycle may therefore affect "normal" individuals differently from those with IBS. Most likely, the threshold for pain sensation is set lower in IBS and is not modulated by hormonal changes during menses.

Overall, these data suggest that menstrual cycle hormonal fluctuations in IBS are unlikely to be a major explanation for changes in symptoms. Although chemical castration of women with leuprolide has been proposed as a therapy for IBS, trials with this agent had methodologic limitations and thus, such an approach cannot be recommended.[13]

Serotonin Signaling
There remains major interest in serotonin signaling in IBS. Moses and colleagues,[14] in a follow-up of previous work, evaluated serotonin (5-hydroxytryptamine; 5-HT) content, serotonin release, and serotonin transporter levels in patients with IBS with either constipation or diarrhea, ulcerative colitis, and controls. They found that 5-HT content in colonic biopsies was reduced in patients with IBS as well as in patients with ulcerative colitis. There were actually increased enterochromaffin cells (which store serotonin) in individuals with IBS compared with controls. The presence of the 5-HT transporter was reduced in patients with IBS, but also was reduced in those with ulcerative colitis.

These data suggest that in the setting of IBS, more 5-HT is released, but less can be removed because there is less transporter available. Unfortunately, these findings are not specific to IBS. Moreover, the results no longer seem to explain the differences between patients who present with IBS and constipation and those who present with IBS with diarrhea, contradicting earlier findings from the same group.[15] It is possible, however, that in individuals with constipation there may be greater serotonin receptor desensitization than in those with diarrhea despite the greater availability of 5-HT, which could explain the clinical differences between IBS with constipation and IBS with diarrhea.

Treatment
5-HT4 Receptor Agonist Therapy (Tegaserod)
Tegaserod is approved by the United States Food and Drug Administration for treatment of women with IBS and constipation, and in clinical trials, this agent has been shown to be more efficacious than placebo for this condition as well.[16] Other work has evaluated the role of tegaserod in chronic constipation, which is distinct from IBS in terms of the absence of significant abdominal pain linked to the defecation disturbance.

A large randomized controlled trial evaluating the use of tegaserod in chronic constipation was reported on during this year's meeting.[17] Patients (n = 1264) with significant constipation, defined as less than 3 complete spontaneous bowel movements per week and at least 1 other constipation symptom, were enrolled in this study. They found a significantly greater increase in the number of complete spontaneous bowel movements on active treatment compared with placebo: 36% for 2 mg tegaserod twice daily and 40% for 6 mg tegaserod twice daily, compared with 27% for placebo.

This finding suggests that tegaserod* does provide a therapeutic benefit in functional constipation -- although whether this applies particularly to individuals with slow-transit constipation rather than patients with pelvic-floor dysfunction was not evaluated. Furthermore, this study population was 86% women; therefore, the benefit of the drug in men remains unknown.

Hypnosis
Other novel approaches to management are also undergoing investigation. Palsson and colleagues[18] looked at the value of hypnosis for treating IBS in a pilot study.

Hypnosis was performed by a novel home-treatment course via an audio compact disc recording. The investigators studied 19 patients with IBS and found that 53% responded to treatment by the 3-month follow-up timepoint. The control group comprised 57 patients with IBS from a separate study. Only 26% of these controls responded by 3 months to standard medical care, although the groups may not be directly comparable. Nonresponders to hypnosis tended to be patients with higher anxiety scores. Previously, hypnosis has been shown to be beneficial both in IBS and functional dyspepsia in randomized, controlled (but not blinded) studies.[19] Hypnosis is therefore promising and additional work is needed in this area, particularly if simple strategies can be used to save on therapist time and costs.

Role of Diet
Another intriguing area that is currently undergoing more active exploration, is the potential role of dietary modification in IBS. There has, however, been a lack of population-based studies evaluating nutrient consumption in individuals with and without IBS.

Saito and colleagues[20] presented their findings from a case-control study conducted in Olmsted County comparing dietary consumption of specific nutrients in subjects who had a presumed functional gastrointestinal disorder with controls (ie, those without symptoms). A validated food frequency questionnaire was applied. Patients with functional gastrointestinal symptoms consumed a higher percentage of fat, but there were no other major differences observed between the 2 groups, although there was a modestly lower percentage of carbohydrate, vitamin C, and sugar consumed by individuals with functional gastrointestinal complaints.

Drisko and colleagues[21] performed an open-label study evaluating 20 patients with a history of IBS with diarrhea who failed standard medical treatment. Patients had a food-elimination diet provided for 1 month based on the results of serum IgE and IgG food and mold panels. In addition, probiotics were provided in months 2-5 during controlled food challenges. Of the 19 patients who completed the trial, there was significant improvement in terms of pain, stool frequency, and quality of life after the intervention. However, this was not a controlled trial, and therefore the results require confirmation in randomized clinical trials.

A controlled trial of food-elimination diet demonstrating promising results was reported during Digestive Disease Week 2003.[22] In this study, 150 patients were randomized to either receive a diet excluding all foods to which they had positive IgG antibodies or to a sham exclusion diet. The investigators observed that symptom severity scores were significantly reduced in the active-therapy arm. The role of withdrawal diets in IBS remains to be adequately documented, but this strategy represents a nonpharmacologic approach to management that may be useful.

Concluding Remarks
This year's meeting of the American College of Gastroenterology presented more information on IBS and its diverse manifestations. Within this setting, it is no surprise that this condition continues to present a challenge to the clinician in practice.

Unfortunately, the pathophysiology of IBS remains obscure and therefore more work is needed to understand both postinfectious IBS and the role of serotonin signaling. Advances in management have been slower than anticipated, but efforts remain under way in testing novel therapeutic targets for this very common disease entity.

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

 

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