This Month in Gastroenterology
Article Outline
- Consequences of Severe Diarrhea in Childhood
- H2 Blockers as an Alternative to Proton Pump Inhibitors in Patients on Clopidogrel
- A Modified and Safer NSAID for Colorectal Cancer Chemoprevention
- A Role for FGF Receptors-1 and -2 in Mediating Detoxification During Liver Regeneration
- Copyright
Consequences of Severe Diarrhea in Childhood
Acute diarrhea and its complications remain a major cause of morbidity and mortality in children in developing countries. Most episodes of acute diarrhea are short lived, but a subset with acute onset and a duration of >14 days is referred to as persistent diarrhea. Especially persistent diarrhea is associated with a disproportionately high morbidity and mortality, and may lead to undernutrition, impaired development, and increased morbidity and mortality from other childhood diseases. The impact of “prolonged episodes of acute diarrhea,” with a duration of 7–13 days, is less well known, and was identified as a priority for further research by and international Working Group on Prolonged Diarrhea.
In this issue of Gastroenterology, Moore et al have reported the results of an analysis of diarrheal episodes from a 10-year prospective birth cohort study in Brazil's developing northeast region. Between August 1989 and March 2000, all pregnant women in a 5-block area in a shantytown, Gonçalves Dias, located in Fortaleza were identified and invited to participate. From participants, detailed demographic and socioeconomic parameters were registered and nurses visited the home of each newborn child 3 times per week during the first 45 months of the study, to record diarrheal illnesses. Thereafter, visits occurred twice per week. Diarrhea was defined as ≥3 looser than normal stools during the preceding 24 hours. Acute diarrhea was defined as an episode of diarrhea lasting <7 days, whereas prolonged episodes of acute diarrhea and persistent diarrhea were defined as episodes lasting 7–13 days and ≥14 days, respectively. Children with diarrhea were visited daily by study nurses until 48 hours after the resolution of the diarrhea. At each visit, height and weight were measured and information was obtained on stool consistency and character, accompanying symptoms, and nutritional status. Specimen cups for stool sample collection were distributed to the homes of children with acute diarrhea and every 3 months from control children without diarrhea. Referral to a pediatrician was indicated with severe or bloody diarrhea or in case of a worrisome clinical condition.
A total of 414 children (47% males) were enrolled during the study period, with a mean follow-up of 1125 days resulting in 1276 child-years. Overall 2.55 episodes of diarrhea occurred per child-year with a mean duration of 4.2 days per episode. Of 3257 episodes, 84% were acute diarrhea, 12% were prolonged episodes of acute diarrhea, and 5% were persistent diarrheal illnesses (Figure 1A). All diarrhea episodes peaked at 6–12 months. Maternal education and early weaning were significant risk factors for prolonged episodes of acute diarrhea, whereas birth weight, family income, crowding, and lack of a toilet in the home were not significant risk factors. Cryptosporidium and Shigella species were isolated more frequently from prolonged episodes of acute diarrhea than from control specimens (P < .05) whereas Ascaris ova were found more frequently in controls than in prolonged episodes of acute diarrhea specimens (P < .01) and Giardia was more common in persistent diarrhea specimens (P < .05).
Figure 1.
(A) Proportions of total diarrhea morbidity accounted for by acute (<7 days), prolonged (7–13 days), and persistent (≥14 days) episodes and by days of illness. (B) Proportional hazard curves of time to first persistent diarrhea (≥14 days) episode in children with or without a prolonged episode of diarrhea (7–13 days) in the first year of life.
Children with prolonged episodes of acute diarrhea before the age of 1 year were significantly more likely to develop persistent diarrhea later in childhood compared with those without episodes of acute diarrhea (P < .005; Figure 2B). Three months after all types of diarrhea episodes, significant decreases were observed in weight for age and height for age. However, with children progressing from acute diarrhea to prolonged episodes of acute diarrhea, worse scores occurred in weight for age and height for age.
This cohort study in children is the first to assess prolonged episodes of acute diarrhea as a separate class of diarrhea. It shows that prolonged episodes of acute diarrhea account for significant morbidity, that they are associated with early weaning, low maternal schooling, and undernutrition, and may predispose to future episodes of persistent diarrhea. Shigella and Cryptosporidium species are important causes of prolonged episodes of acute diarrhea in this cohort. The data suggest that targeting prolonged episodes of acute diarrhea could have a substantial impact on the burden and complications of diarrhea in children.
See page 1156.
H2 Blockers as an Alternative to Proton Pump Inhibitors in Patients on Clopidogrel
Clopidogrel, together with aspirin, is increasingly prescribed after percutaneous coronary artery intervention for coronary artery disease. Recently, a number of observational studies reported an increased risk of recurrent myocardial infarction and death in patients receiving concomitant clopidogrel and proton pump inhibitor (PPI) therapy. Based on these reports, and on emerging evidence that some PPIs may attenuate the antiplatelet effect of clopidogrel, possibly through inhibition of cytochrome CYP2C19, the Food and Drug Administration in the United States has issued an alert about potential interactions between PPIs and clopidogrel. On the other hand, coprescription of PPIs and clopidogrel is extremely common because (1) there is major comorbidity between coronary artery disease and gastroesophageal reflux disease, and (2) there is an increased risk of gastrointestinal bleeding with combined clopidogrel and aspirin, for which prophylactic PPI has been recommended. To date, there is no established alternative strategy in patients receiving clopidogrel who require acid suppressive therapy. H2 blockers (H2RAs) could be an alternative, but they may also inhibit CYP2C19. In addition, it has been suggested that suppression of intragastric acidity by itself may affect the absorption of clopidogrel and diminish it's clinical efficacy, and this would also be the case for other types of acid suppressive drugs.
In this issue of Gastroenterology, Wu et al report the results of a population-based, retrospective cohort study to evaluate the risk of serious adverse outcomes in patients receiving clopidogrel for acute coronary syndromes (myocardial infarction or unstable angina) who used concomitant H2RAs or PPIs. The authors assessed the files of patients who were hospitalized between July 2002 and June 2005 with an acute coronary syndrome from Taiwan's National Health Insurance Research Database. Prescription records were used to ascertain use of clopidogrel, H2Ras, and PPIs, and to identify exposure to CYP2C19 inhibitors and inducers during the follow-up period. Relevant gastrointestinal, cardiovascular, and other comorbidities were identified from the files. The primary outcome was the composite end point of rehospitalization for acute coronary syndromes or mortality within 3 months of rehospitalization.
A total of 6552 patients with acute coronary syndromes were included in the study. They were subdivided into cohorts of clopidogrel alone, PPI alone, H2RA alone, clopidogrel with PPI, and clopidogrel with H2RA. The 1-year cumulative incidence rates of rehospitalizations for acute coronary syndromes or all-cause mortality were significantly higher in the clopidogrel plus H2RA (26.8%; 95% confidence interval [CI], 21.5%–33.0%) and clopidogrel plus PPI cohort (33.2%; 95% CI, 27.8%–39.4%) than the clopidogrel alone cohort (11.6%; 95% CI, 10.8%–12.5%; P < .0001; Figure 2). No significant differences were found between the clopidogrel alone, PPI alone, and H2RA alone cohorts. In addition, revascularization procedures or coronary artery bypass graft surgery were significantly higher in the clopidogrel plus H2RA cohort (8.9%; 95% CI, 5.9%–13.4%) and the clopidogrel plus PPI cohort (11.4%; 95% CI, 8.0%–16.1%) compared with the clopidogrel alone cohort (4.0%; 95% CI, 3.5–4.5; P < .0001). The H2RAs and PPIs alone cohorts did not differ from clopidogrel alone. All-cause mortality within 3 months of rehospitalization were significantly higher in the clopidogrel plus H2RA cohort (7.1%; 95% CI, 4.3%–11.6%) and the clopidogrel plus PPI cohort (11.4%; 95% CI, 8.0%–16.11%) compared with the clopidogrel alone cohort (1.7%; 95% CI, 1.4%–2.1%; P < .0001), and again the H2RAs and PPIs alone cohorts did not differ from clopidogrel alone.
Figure 2.
Cumulative incidences of all-cause mortality or rehospitalization for acute coronary syndromes for the clopidogrel plus H2RA cohort, the clopidogrel plus PPI cohort, the clopidogrel alone cohort, the H2RA alone cohort, the and PPI alone cohort.
This is the probably the first study to investigate whether H2RA would be an alternative to PPI in patients receiving clopidogrel who are at risk for atherothrombotic diseases. The findings confirm the increased risk of concomitant use of clopidogrel and PPIs, but also show that H2RAs are not an appropriate alternative to PPIS in patients receiving clopidogrel, because concomitant use of H2RAs was also associated with increased risk of rehospitalization for acute coronary syndromes or mortality.
See page 1165.
A Modified and Safer NSAID for Colorectal Cancer Chemoprevention
Nonsteroidal anti-inflammatory drugs (NSAIDs) have a chemopreventive effect on the development of colorectal neoplasia, but toxicities have precluded a general recommendation for mass usage solely for this purpose. The development of safer NSAIDs that are as effective but much less toxic might allow wider utilization for the purpose of chemoprevention.
In the study by Mackenzie et al, a modification of the carboxyl moiety of the NSAID sulindac to form phospho-sulindac was done with its properties studied, including its anti-tumor effects and toxicity. Phospho-sulindac was >14.2-fold more potent than sulindac for inhibiting colon cancer cell growth through reducing dose-dependent cell proliferation and induced concentration-dependent apoptosis, features not observed in normal colon epithelial cells. Phospho-sulindac induced oxidative stress to trigger apoptosis, and reduced the level of polyamines (particularly spermidine and spermine) by inducing SAT1 enzyme activity 4.4-fold (compared with sulindac at 2.5-fold), all of which could be blocked with N-acetylcysteine or siRNA to SAT1. Phospho-sulindac suppressed nuclear factor-κB activation, but increased cyclo-oxygenase (COX) activity (and subsequent prostaglandin E2 production) unlike sulindac that inhibits COX activity. Like the synergism between sulindac and difluoromethylornithine (DFMO) for reducing cancer growth, phospho-sulindac synergized even greater with DFMO than sulindac, reducing cell growth, inhibiting cell-cycle phase transitions, and increasing apoptosis through more marked reduction in polyamines. Phospho-sulindac was more effective in inhibiting tumor growth in vivo over sulindac, and combining phospho-sulindac with DFMO reduced tumor burden in Apcmin mice by 90.2% over controls. Phospho-sulindac showed no genotoxicity, and showed no evidence for gastrointestinal toxicity as compared with significant toxicity and mortality with sulindac (Figure 3).
Figure 3.
Phospho-sulindac (P-S) is a safe and effective antitumor agent against colon cancer in vivo. (A) Acute gastrointestinal toxicity of sulindac and P-S. Rats were treated with P-S, sulindac, indomethacin or vehicle and at day 5, the number and sizes of small intestinal ulcerations were counted and scored. (B) Survival curve for mice treated daily for 3 weeks with equimolar doses of P-S or sulindac. (C) Effect of P-S and sulindac on colon cancer xenografts in nude mice. Left panel: Tumor volume growth over time for each treatment. Center panel: Photographs of mouse xenografts. Right panel: Mass of dissected xenographs. All values are means + SEM. *P < .05 versus vehicle-treated mice; #P < .05 versus sulindac-treated mice.
This study indicates that phospho-sulindac is more potent but safer than sulindac for colon cancer chemoprevention, and synergizes with DFMO making it more effective. Although analgesic properties were not addressed and do not have direct role for chemoprevention, modifying its carboxyl moiety and its inability to block COX suggests that any analgesia would be via a non-COX mechanism. Phospho-sulindac should be explored in humans for its chemopreventive potential.
See page 1320.
A Role for FGF Receptors-1 and -2 in Mediating Detoxification During Liver Regeneration
Liver regeneration is critical after hepatic injury to regain function. Fibroblast growth factor receptor (FGFR)-4 has been shown to protect the liver from chronic liver injury and fibrosis, but the roles of other FGFRs, specifically FGFR-1 and -2, in liver injury or regeneration are not known.
In the study by Böhm et al, FGFR-1 and -2 liver-specific knockout mice were generated, and their livers were injured with carbon tetrachloride and partial hepatectomy to study the effects of the two receptors. Before CCl4 treatment, knockout mice were phenotypically similar to controls, with no histologic or biochemical abnormalities. With CCl4 treatment, the acute hepatic injury showed lower numbers of inflammatory cells and cytokines than control, but there was no difference in chronic injury including the extent of fibrosis. With partial hepatectomy after ketamine or buprenorphine anesthesia, >40% of knockout mice died within 48 hours, and the level of mortality was rectified by switching to the less hepatotoxic isoflurane anesthesia (94% survival), with improvement of hepatic necrosis. This suggested that the functional activity of the in situ liver after partial hepatectomy is rate limiting for survival. Indeed, transcription factors Dbp and Tef are significantly elevated by 24 hours after partial hepatectomy in control mice, but not in knockout mice, similar to the Dbp and Tef targets Cyp2c38 and Cyp2a5 that are both P450 enzymes that help to metabolize the anesthetics. Because primary cultured hepatocytes demonstrated loss of FGF7-induced signaling from the FGFR-1 and -2 liver-specific knockout mice and levels of FGF-1, FGF-2, and FGF-7 increased after partial hepatectomy, replacement of FGF-7 by intraperitoneal injection did restored FGF-7–induced downstream signaling and up-regulated Dbp and Tef and their targets Cyp2c38 and Cyp2a5 in control mice but not knockout mice (Figure 4).
Figure 4.
FGF-7 activates a cytoprotective response in the liver. FGFR1/2 knockout (ko) mice and control (ctrl) littermates were injected intraperitoneally with saline or 5 μg FGF7. Mice were humanely killed 10 or 30 minutes after injection, and RNAs from the liver were analyzed by qRT-PCR for expression of Dbp and Tef (top panels) or Cyp2a5 and Cyp2c38 (bottom panels).
The study indicates that FGFs control the expression of Dbp and Tef and their P450 targets through the FGFR-1 and -2 receptors, and loss of these receptors causes impaired detoxification and thus increased liver injury during hepatic regeneration. Therapeutic application of FGFs could be considered to prevent hepatic necrosis after operative resection.
See page 1385.
PII: S0016-5085(10)01225-4
doi:10.1053/j.gastro.2010.08.007
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
