This Month in Gastroenterology

Abstract

Aspirin in the Prophylaxis of Colorectal CancerPast studies have established that aspirin is able to reduce the risk of recurrent adenoma recurrence in patients with a history of colorectal neoplasia. It is still uncertain whether aspirin is also able to decrease the primary risk of colorectal neoplasia. Two large studies, the Physicians’ Health Study and the Women’s Health Study, found no protective effect of intake of a low dose of aspirin for the incidence of colorectal cancer. It has been suggested that the dose of aspirin in these trials was low, and that higher doses of aspirin may have a protective effect in colorectal neoplasia.In this issue of Gastroenterology, Chan et al report on an analysis of the relationship between the risk of colorectal cancer and aspirin use among men enrolled in a large prospective cohort study, the Health Professionals Follow-up Study (HPFS). The HPFS has followed a cohort of 51,529 US male health care professionals since 1986, aged 40–75 at inclusion. Participants have filled out biennial follow-up questionnaires with a response rate of >90%.For the current analysis, men with a previous history of cancer were excluded. From the beginning, the HPFS registered regular use of aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAIDs). From 1992 onward, details on aspirin dosage were also registered. In those reporting colorectal cancer, medical records and pathology results were obtained, and the occurrence of deaths was ascertained from the National Death Index and next of kin.From the HPFS database, 47,363 men were eligible for the current analysis. Men who reported using aspirin ≥2 per week were considered regular users; those who reported fewer intakes were defined as nonregular users. To account for variations over time, a cumulative average aspirin intake, as derived from all available questionnaires until each 2-year follow-up questionnaire was calculated. Incidence rates and relative risks for colorectal cancer were determined.Among the 47,363 eligible men, 975 cases of colorectal cancer occurred over 761,757 person-years period. Similar to previous studies, endoscopy, regular use of multivitamins, and high dietary intake of folate and calcium were associated with a reduced risk of colorectal cancer, and family history of colorectal cancer, early smoking history, alcohol intake, and high intake of red meat were associated with an increased risk of colorectal cancer.Participants who reported regular aspirin use experienced a significantly lower relative risk (RR) of colorectal cancer (multivariate RR, 0.79; 95% confidence interval [CI], 0.69–0.90), even after controlling for other colorectal cancer risk factors (Figure 1). The effect was similar for cancers in the distal or proximal colon or the rectum, and the risk was reduced for both early (stages 1 and 2) and advanced (stages 3 and 4) cancers. Compared with participants without regular use, aspirin use for ≤5 years did not confer a significant risk reduction. In contrast, aspirin use >5 years was associated with a progressive reduction in risk with longer duration (P = .008). The latter was especially the case for cancer stages 2–4.The benefit associated with aspirin use was substantially greater with increasing dose: men reporting 6–14 standard aspirin tablets (325 mg) per week experienced a multivariate RR of 0.72 (95% CI, 0.56–0.92), and those consuming >14 tablets per week experienced a multivariate RR of 0.30 (95% CI, 0.11–0.81; P = .004). The beneficial effect of aspirin persisted for <4 years after discontinuing use. Reduced risk of colorectal cancer was also observed for >5 years of regular use of nonaspirin NSAIDs (multivariate RR, 0.72; 95% CI, 0.55–0.94; P = .008), but not for acetaminophen (multivariate RR, 0.89; 95% CI, 0.65–1.22; P = .32).These data confirm that intake of aspirin is associated with a reduced risk of colorectal cancer, but requires the use of higher doses than those recommended to prevent cardiovascular disease, over a long period. Because the doses needed are associated with increased risk of adverse events such as gastrointestinal bleeding, the study does not support general use for cancer prevention at the population level. Further research is required to characterize those for whom the potential benefits outweigh the hazards of high-dose aspirin in the prevention of colorectal cancer.See page 21.Fatty Liver Disease and Health Care UtilizationWith increasing prevalences of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD), is now the most common cause of chronic liver disease in the Western world. Although NAFLD is most frequently a benign condition, progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma may occur. With rising incidence and increasing numbers of patients with complications, the health care impact of NAFLD is expected to increase in the near future. However, the current health care system cost associated with fatty liver disease (FLD) has not been established.In this issue of Gastroenterology, Baumeister et al report the results of a survey of health care utilization in subjects from the general population with or without FLD. In the Study of Health in Pomerania, a sample of women and men aged 20–79 years in a northeastern region of Germany is followed prospectively. From a sample of 6267 eligible subjects drawn from the population registry, 68.8% responded to a baseline survey, and 76.6% of these responded to a follow-up survey after 5 years.Of the 4310 participants at baseline, 4224 without pre-existing liver disease constituted the analysis sample. Ultrasonography of the liver revealed a hyperechogenic pattern in 1264 subjects (29.9%), and 667 subjects (15.8%) had elevated serum alanine aminotransferase (ALT). FLD was defined as the presence of a hyperechogenic pattern of the liver and elevated serum ALT levels. These groups of subjects had a higher body mass index, a higher waist circumference, and were more commonly male, were older, had fewer years of schooling, and were less physically active. They reported higher alcohol intake, and less current but more former smoking compared with subjects without liver disorders.The combinations of normal or abnormal ALT and hyperechogenic or normal liver pattern allowed identifying 4 subgroups. Modeling of overall health care costs at baseline showed higher costs in all FLD subgroups. Significant increases were seen in those with both a hyperechogenic liver and increased serum ALT levels (31.6%, 95% CI, 2.4–59.3), and in those with elevated ALT and a normal ultrasound 22.3%, 95% CI, 2.7–48.4). Outpatient visits were higher in those with a hyperechogenic liver and normal serum ALT levels.Modeling of overall health care costs after 5 years showed higher numbers in all FLD subgroups, with statistically significant increases in subjects with both a hyperechogenic liver and increased serum ALT levels (37.2%; 95% CI, 11.0–69.9). Outpatient costs were higher in those with hyperechogenic liver and normal serum ALT levels. Diabetes and angina pectoris were related to outpatient and inpatient utilization and costs controlling for FLD. Modeling suggested that type 2 diabetes and angina pectoris acted as mediators of the association between FLD and health care utilization and costs.This study shows that liver hyperechogenity and elevated serum ALT levels are predictors of substantial future excess overall medical costs and utilization, even after controlling for socioeconomic, behavioral, and comorbid variables. The data also suggest that liver hyperechogenicity, besides elevated ALT, is a predictive marker of future health care expenditures. (Figure 2)Figure 2Modeling of increase in overall health care costs (±95% confidence interval) at 5 years’ follow-up according to the presence of a hyperechogenic pattern on ultrasound (US) or elevated ALT levels (ALT) at baseline.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 85.Localized Interluekin-5 Induces Esophageal Wall Thickening and Remodeling in Eosinophilic EsophagitisEosinophilic esophagitis is increasingly more recognized clinically, and is manifested by infiltration of eosinophils with subsequent esophageal thickening that can lead to reflux-like symptoms, dysmotility, dysphagia, and stricture formation. The mechanism driving increased esophageal thickening in eosinophilic esophagitis, remodeling from the normal esophageal layers to layers with fibrosis, is not known.In the study by Mishra et al, biopsy specimens from pediatric patients with eosinophilic esophagitis and experimental mouse models of eosinophilic esophagitis were examined for wall thickness and structural remodeling compared with controls. Human eosinophilic esophagitis specimens had >3-fold increase in the basal layer thickness than controls, with a 3-to 4-fold increase in profibrogenic transforming growth factor-β and MUC5AC expression, and similar to findings obtained from an allergen-induced murine model of eosinophilic esophagitis. Collagen accumulation was evident in the lamina propria and in the stromal papillae, and specifically in the mouse model, in the muscularis mucosa. Interleukin (IL)-5–deficient mice failed to show any increase in collagen after allergen challenge, whereas IL-5 transgenic and specific lymphocyte-derived IL-5 transgenic mice that overexpress IL-5 within lymphocytes demonstrated a 2.5-fold thickened basal layer, and collagen accumulation in the lamina propria and muscularis mucosa (Figure 3). IL-5 transgenic mice deficient in eotaxin-1 (which have markedly decreased numbers of eosinophils) as well as the eosinophil-deficient Δdbl-GATA mice had reduced basal layers and lamina propria thickness compared to controls, indicating the important role of eosinophils and IL-5 (Figure 3). The specific lymphocyte IL-5 transgenic mice had the highest levels of localized eosinophils in the esophagus, as well as the highest localized levels of IL-5 (20-fold over IL-5 transgenics and wild-type mice). Human eosinophilic esophagitis biopsy specimens had a 7-fold increase in IL-5 compared with normals.Figure 3IL-5 transgene-induced esophageal tissue remodeling. Histopathologic analysis was performed on the esophageal tissue sections of wild-type and an IL-5–transgenic mouse after Masson’s trichrome staining, as shown in (A–C). A representative photomicrograph of wild-type esophagus highlighting its basal layer thickness and lamina propria collagen level (A, original magnification, ×100). A representative photomicrograph of CD2–IL-5 transgenic mice demonstrates thickened basal layer and collagen accumulation in the lamina propria and muscularis mucosa (B, original magnification, ×100). Accumulated collagen in the lamina propria and elongated papillae is shown (C, original magnification, ×400). Morphometric analysis of basal layer thickness is shown in (D) and lamina propria collagen thickness is shown in (E). The data is expressed as mean ± SD, n = 12 mice. EP, epithelium; LP, lamina propria; LU, lumen; MS, muscularis mucosa.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The study indicates that IL-5–mediated eosinophilia is a major mechanism driving esophageal remodeling and fibrosis seen in eosinophilic esophagitis.See page 204.A Mechanism for Hepatic Iron Overload Associated With HCV InfectionPatients with chronic hepatitis C virus (HCV) infection often demonstrate the commonly seen feature of increased iron on liver biopsies, but the mechanism for this observation is not known.In the study by Nishina et al, transgenic mice containing the full-length HCV polyprotein region under the murine albumin promoter were examined for iron homeostasis. These mice do not show any liver inflammation, allowing an independent investigation separate from the presence of chronic inflammatory cells. Transgenic mice showed increased hepatic iron content (predominantly in hepatocytes and associated with increased expression of ferritin), increased serum iron, and transferrin saturation, but decreased splenic iron content, at 8 and 14 months of age compared with nontransgenic mice. Hepcidin levels, a peptide hormone secreted by the liver that affects intestinal iron absorption and macrophage iron release, is significantly lower in transgenic mice (Figure 4), with concomitant increase in ferroportin expression in the duodenum and spleen, as well as a smaller extent in the liver. The depressed hepcidin levels in the transgenic mice can be up-regulated in response to inflammation (lipopolysaccharide stimulation), suggesting some form of negative regulatory control over hepcidin expression. Indeed, hepcidin promotor activity was depressed in luciferase assays, presumably by reduced activity at a critical C/EBP-α binding site, and although C/EBP-α protein levels were similar in transgenic and nontransgenic mice, transgenic mice showed reduced DNA binding activity of C/EBP-α. The nuclear protein CHOP, which inhibits C/EBP-α DNA binding activity, was significantly increased in transgenic mice, paralleled an observed increase in reactive oxygen species production (in the absence of inflammation) in the liver of the transgenic mice, and can induce CHOP expression.Figure 4Hepatic Hepatic levels of hepcidin mRNA and prohepcidin. Expression levels of hepcidin mRNA (A) and prohepcidin (B) were measured by real-time RT-PCR and ELISA, respectively. The relative quantities of hepcidin mRNA in the liver were normalized to β-actin mRNA. The relative protein levels of prohepcidin were normalized by protein concentrations and expressed as ng/mg protein. *P < .05 (8 months) and **P < .01 (14 months) versus the same-age nontransgenic mice (TgM). The numbers in parentheses represent the number of animals examined in each group.View Large Image Figure ViewerDownload Hi-res image Download (PPT)This study indicates that HCV-induced reactive oxygen species increases CHOP expression that prohibits C/EBP-α from binding to the hepcidin promoter, reducing its expression. This in turn leads to increased duodenal iron transport and macrophage release of iron that accumulates in the liver.See page 226. Aspirin in the Prophylaxis of Colorectal CancerPast studies have established that aspirin is able to reduce the risk of recurrent adenoma recurrence in patients with a history of colorectal neoplasia. It is still uncertain whether aspirin is also able to decrease the primary risk of colorectal neoplasia. Two large studies, the Physicians’ Health Study and the Women’s Health Study, found no protective effect of intake of a low dose of aspirin for the incidence of colorectal cancer. It has been suggested that the dose of aspirin in these trials was low, and that higher doses of aspirin may have a protective effect in colorectal neoplasia.In this issue of Gastroenterology, Chan et al report on an analysis of the relationship between the risk of colorectal cancer and aspirin use among men enrolled in a large prospective cohort study, the Health Professionals Follow-up Study (HPFS). The HPFS has followed a cohort of 51,529 US male health care professionals since 1986, aged 40–75 at inclusion. Participants have filled out biennial follow-up questionnaires with a response rate of >90%.For the current analysis, men with a previous history of cancer were excluded. From the beginning, the HPFS registered regular use of aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAIDs). From 1992 onward, details on aspirin dosage were also registered. In those reporting colorectal cancer, medical records and pathology results were obtained, and the occurrence of deaths was ascertained from the National Death Index and next of kin.From the HPFS database, 47,363 men were eligible for the current analysis. Men who reported using aspirin ≥2 per week were considered regular users; those who reported fewer intakes were defined as nonregular users. To account for variations over time, a cumulative average aspirin intake, as derived from all available questionnaires until each 2-year follow-up questionnaire was calculated. Incidence rates and relative risks for colorectal cancer were determined.Among the 47,363 eligible men, 975 cases of colorectal cancer occurred over 761,757 person-years period. Similar to previous studies, endoscopy, regular use of multivitamins, and high dietary intake of folate and calcium were associated with a reduced risk of colorectal cancer, and family history of colorectal cancer, early smoking history, alcohol intake, and high intake of red meat were associated with an increased risk of colorectal cancer.Participants who reported regular aspirin use experienced a significantly lower relative risk (RR) of colorectal cancer (multivariate RR, 0.79; 95% confidence interval [CI], 0.69–0.90), even after controlling for other colorectal cancer risk factors (Figure 1). The effect was similar for cancers in the distal or proximal colon or the rectum, and the risk was reduced for both early (stages 1 and 2) and advanced (stages 3 and 4) cancers. Compared with participants without regular use, aspirin use for ≤5 years did not confer a significant risk reduction. In contrast, aspirin use >5 years was associated with a progressive reduction in risk with longer duration (P = .008). The latter was especially the case for cancer stages 2–4.The benefit associated with aspirin use was substantially greater with increasing dose: men reporting 6–14 standard aspirin tablets (325 mg) per week experienced a multivariate RR of 0.72 (95% CI, 0.56–0.92), and those consuming >14 tablets per week experienced a multivariate RR of 0.30 (95% CI, 0.11–0.81; P = .004). The beneficial effect of aspirin persisted for <4 years after discontinuing use. Reduced risk of colorectal cancer was also observed for >5 years of regular use of nonaspirin NSAIDs (multivariate RR, 0.72; 95% CI, 0.55–0.94; P = .008), but not for acetaminophen (multivariate RR, 0.89; 95% CI, 0.65–1.22; P = .32).These data confirm that intake of aspirin is associated with a reduced risk of colorectal cancer, but requires the use of higher doses than those recommended to prevent cardiovascular disease, over a long period. Because the doses needed are associated with increased risk of adverse events such as gastrointestinal bleeding, the study does not support general use for cancer prevention at the population level. Further research is required to characterize those for whom the potential benefits outweigh the hazards of high-dose aspirin in the prevention of colorectal cancer.See page 21. Past studies have established that aspirin is able to reduce the risk of recurrent adenoma recurrence in patients with a history of colorectal neoplasia. It is still uncertain whether aspirin is also able to decrease the primary risk of colorectal neoplasia. Two large studies, the Physicians’ Health Study and the Women’s Health Study, found no protective effect of intake of a low dose of aspirin for the incidence of colorectal cancer. It has been suggested that the dose of aspirin in these trials was low, and that higher doses of aspirin may have a protective effect in colorectal neoplasia. In this issue of Gastroenterology, Chan et al report on an analysis of the relationship between the risk of colorectal cancer and aspirin use among men enrolled in a large prospective cohort study, the Health Professionals Follow-up Study (HPFS). The HPFS has followed a cohort of 51,529 US male health care professionals since 1986, aged 40–75 at inclusion. Participants have filled out biennial follow-up questionnaires with a response rate of >90%. For the current analysis, men with a previous history of cancer were excluded. From the beginning, the HPFS registered regular use of aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAIDs). From 1992 onward, details on aspirin dosage were also registered. In those reporting colorectal cancer, medical records and pathology results were obtained, and the occurrence of deaths was ascertained from the National Death Index and next of kin. From the HPFS database, 47,363 men were eligible for the current analysis. Men who reported using aspirin ≥2 per week were considered regular users; those who reported fewer intakes were defined as nonregular users. To account for variations over time, a cumulative average aspirin intake, as derived from all available questionnaires until each 2-year follow-up questionnaire was calculated. Incidence rates and relative risks for colorectal cancer were determined. Among the 47,363 eligible men, 975 cases of colorectal cancer occurred over 761,757 person-years period. Similar to previous studies, endoscopy, regular use of multivitamins, and high dietary intake of folate and calcium were associated with a reduced risk of colorectal cancer, and family history of colorectal cancer, early smoking history, alcohol intake, and high intake of red meat were associated with an increased risk of colorectal cancer. Participants who reported regular aspirin use experienced a significantly lower relative risk (RR) of colorectal cancer (multivariate RR, 0.79; 95% confidence interval [CI], 0.69–0.90), even after controlling for other colorectal cancer risk factors (Figure 1). The effect was similar for cancers in the distal or proximal colon or the rectum, and the risk was reduced for both early (stages 1 and 2) and advanced (stages 3 and 4) cancers. Compared with participants without regular use, aspirin use for ≤5 years did not confer a significant risk reduction. In contrast, aspirin use >5 years was associated with a progressive reduction in risk with longer duration (P = .008). The latter was especially the case for cancer stages 2–4. The benefit associated with aspirin use was substantially greater with increasing dose: men reporting 6–14 standard aspirin tablets (325 mg) per week experienced a multivariate RR of 0.72 (95% CI, 0.56–0.92), and those consuming >14 tablets per week experienced a multivariate RR of 0.30 (95% CI, 0.11–0.81; P = .004). The beneficial effect of aspirin persisted for <4 years after discontinuing use. Reduced risk of colorectal cancer was also observed for >5 years of regular use of nonaspirin NSAIDs (multivariate RR, 0.72; 95% CI, 0.55–0.94; P = .008), but not for acetaminophen (multivariate RR, 0.89; 95% CI, 0.65–1.22; P = .32). These data confirm that intake of aspirin is associated with a reduced risk of colorectal cancer, but requires the use of higher doses than those recommended to prevent cardiovascular disease, over a long period. Because the doses needed are associated with increased risk of adverse events such as gastrointestinal bleeding, the study does not support general use for cancer prevention at the population level. Further research is required to characterize those for whom the potential benefits outweigh the hazards of high-dose aspirin in the prevention of colorectal cancer. See page 21. Fatty Liver Disease and Health Care UtilizationWith increasing prevalences of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD), is now the most common cause of chronic liver disease in the Western world. Although NAFLD is most frequently a benign condition, progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma may occur. With rising incidence and increasing numbers of patients with complications, the health care impact of NAFLD is expected to increase in the near future. However, the current health care system cost associated with fatty liver disease (FLD) has not been established.In this issue of Gastroenterology, Baumeister et al report the results of a survey of health care utilization in subjects from the general population with or without FLD. In the Study of Health in Pomerania, a sample of women and men aged 20–79 years in a northeastern region of Germany is followed prospectively. From a sample of 6267 eligible subjects drawn from the population registry, 68.8% responded to a baseline survey, and 76.6% of these responded to a follow-up survey after 5 years.Of the 4310 participants at baseline, 4224 without pre-existing liver disease constituted the analysis sample. Ultrasonography of the liver revealed a hyperechogenic pattern in 1264 subjects (29.9%), and 667 subjects (15.8%) had elevated serum alanine aminotransferase (ALT). FLD was defined as the presence of a hyperechogenic pattern of the liver and elevated serum ALT levels. These groups of subjects had a higher body mass index, a higher waist circumference, and were more commonly male, were older, had fewer years of schooling, and were less physically active. They reported higher alcohol intake, and less current but more former smoking compared with subjects without liver disorders.The combinations of normal or abnormal ALT and hyperechogenic or normal liver pattern allowed identifying 4 subgroups. Modeling of overall health care costs at baseline showed higher costs in all FLD subgroups. Significant increases were seen in those with both a hyperechogenic liver and increased serum ALT levels (31.6%, 95% CI, 2.4–59.3), and in those with elevated ALT and a normal ultrasound 22.3%, 95% CI, 2.7–48.4). Outpatient visits were higher in those with a hyperechogenic liver and normal serum ALT levels.Modeling of overall health care costs after 5 years showed higher numbers in all FLD subgroups, with statistically significant increases in subjects with both a hyperechogenic liver and increased serum ALT levels (37.2%; 95% CI, 11.0–69.9). Outpatient costs were higher in those with hyperechogenic liver and normal serum ALT levels. Diabetes and angina pectoris were related to outpatient and inpatient utilization and costs controlling for FLD. Modeling suggested that type 2 diabetes and angina pectoris acted as mediators of the association between FLD and health care utilization and costs.This study shows that liver hyperechogenity and elevated serum ALT levels are predictors of substantial future excess overall medical costs and utilization, even after controlling for socioeconomic, behavioral, and comorbid variables. The data also suggest that liver hyperechogenicity, besides elevated ALT, is a predictive marker of future health care expenditures. (Figure 2)See page 85. With increasing prevalences of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD), is now the most common cause of chronic liver disease in the Western world. Although NAFLD is most frequently a benign condition, progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma may occur. With rising incidence and increasing numbers of patients with complications, the health care impact of NAFLD is expected to increase in the near future. However, the current health care system cost associated with fatty liver disease (FLD) has not been established. In this issue of Gastroenterology, Baumeister et al report the results of a survey of health care utilization in subjects from the general population with or without FLD. In the Study of Health in Pomerania, a sample of women and men aged 20–79 years in a northeastern region of Germany is followed prospectively. From a sample of 6267 eligible subjects drawn from the population registry, 68.8% responded to a baseline survey, and 76.6% of these responded to a follow-up survey after 5 years. Of the 4310 participants at baseline, 4224 without pre-existing liver disease constituted the analysis sample. Ultrasonography of the liver revealed a hyperechogenic pattern in 1264 subjects (29.9%), and 667 subjects (15.8%) had elevated serum alanine aminotransferase (ALT). FLD was defined as the presence of a hyperechogenic pattern of the liver and elevated serum ALT levels. These groups of subjects had a higher body mass index, a higher waist circumference, and were more commonly male, were older, had fewer years of schooling, and were less physically active. They reported higher alcohol intake, and less current but more former smoking compared with subjects without liver disorders. The combinations of normal or abnormal ALT and hyperechogenic or normal liver pattern allowed identifying 4 subgroups. Modeling of overall health care costs at baseline showed higher costs in all FLD subgroups. Significant increases were seen in those with both a hyperechogenic liver and increased serum ALT levels (31.6%, 95% CI, 2.4–59.3), and in those with elevated ALT and a normal ultrasound 22.3%, 95% CI, 2.7–48.4). Outpatient visits were higher in those with a hyperechogenic liver and normal serum ALT levels. Modeling of overall health care costs after 5 years showed higher numbers in all FLD subgroups, with statistically significant increases in subjects with both a hyperechogenic liver and increased serum ALT levels (37.2%; 95% CI, 11.0–69.9). Outpatient costs were higher in those with hyperechogenic liver and normal serum ALT levels. Diabetes and angina pectoris were related to outpatient and inpatient utilization and costs controlling for FLD. Modeling suggested that type 2 diabetes and angina pectoris acted as mediators of the association between FLD and health care utilization and costs. This study shows that liver hyperechogenity and elevated serum ALT levels are predictors of substantial future excess overall medical costs and utilization, even after controlling for socioeconomic, behavioral, and comorbid variables. The data also suggest that liver hyperechogenicity, besides elevated ALT, is a predictive marker of future health care expenditures. (Figure 2) See page 85. Localized Interluekin-5 Induces Esophageal Wall Thickening and Remodeling in Eosinophilic EsophagitisEosinophilic esophagitis is increasingly more recognized clinically, and is manifested by infiltration of eosinophils with subsequent esophageal thickening that can lead to reflux-like symptoms, dysmotility, dysphagia, and stricture formation. The mechanism driving increased esophageal thickening in eosinophilic esophagitis, remodeling from the normal esophageal layers to layers with fibrosis, is not known.In the study by Mishra et al, biopsy specimens from pediatric patients with eosinophilic esophagitis and experimental mouse models of eosinophilic esophagitis were examined for wall thickness and structural remodeling compared with controls. Human eosinophilic esophagitis specimens had >3-fold increase in the basal layer thickness than controls, with a 3-to 4-fold increase in profibrogenic transforming growth factor-β and MUC5AC expression, and similar to findings obtained from an allergen-induced murine model of eosinophilic esophagitis. Collagen accumulation was evident in the lamina propria and in the stromal papillae, and specifically in the mouse model, in the muscularis mucosa. Interleukin (IL)-5–deficient mice failed to show any increase in collagen after allergen challenge, whereas IL-5 transgenic and specific lymphocyte-derived IL-5 transgenic mice that overexpress IL-5 within lymphocytes demonstrated a 2.5-fold thickened basal layer, and collagen accumulation in the lamina propria and muscularis mucosa (Figure 3). IL-5 transgenic mice deficient in eotaxin-1 (which have markedly decreased numbers of eosinophils) as well as the eosinophil-deficient Δdbl-GATA mice had reduced basal layers and lamina propria thickness compared to controls, indicating the important role of eosinophils and IL-5 (Figure 3). The specific lymphocyte IL-5 transgenic mice had the highest levels of localized eosinophils in the esophagus, as well as the highest localized levels of IL-5 (20-fold over IL-5 transgenics and wild-type mice). Human eosinophilic esophagitis biopsy specimens had a 7-fold increase in IL-5 compared with normals.The study indicates that IL-5–mediated eosinophilia is a major mechanism driving esophageal remodeling and fibrosis seen in eosinophilic esophagitis.See page 204. Eosinophilic esophagitis is increasingly more recognized clinically, and is manifested by infiltration of eosinophils with subsequent esophageal thickening that can lead to reflux-like symptoms, dysmotility, dysphagia, and stricture formation. The mechanism driving increased esophageal thickening in eosinophilic esophagitis, remodeling from the normal esophageal layers to layers with fibrosis, is not known. In the study by Mishra et al, biopsy specimens from pediatric patients with eosinophilic esophagitis and experimental mouse models of eosinophilic esophagitis were examined for wall thickness and structural remodeling compared with controls. Human eosinophilic esophagitis specimens had >3-fold increase in the basal layer thickness than controls, with a 3-to 4-fold increase in profibrogenic transforming growth factor-β and MUC5AC expression, and similar to findings obtained from an allergen-induced murine model of eosinophilic esophagitis. Collagen accumulation was evident in the lamina propria and in the stromal papillae, and specifically in the mouse model, in the muscularis mucosa. Interleukin (IL)-5–deficient mice failed to show any increase in collagen after allergen challenge, whereas IL-5 transgenic and specific lymphocyte-derived IL-5 transgenic mice that overexpress IL-5 within lymphocytes demonstrated a 2.5-fold thickened basal layer, and collagen accumulation in the lamina propria and muscularis mucosa (Figure 3). IL-5 transgenic mice deficient in eotaxin-1 (which have markedly decreased numbers of eosinophils) as well as the eosinophil-deficient Δdbl-GATA mice had reduced basal layers and lamina propria thickness compared to controls, indicating the important role of eosinophils and IL-5 (Figure 3). The specific lymphocyte IL-5 transgenic mice had the highest levels of localized eosinophils in the esophagus, as well as the highest localized levels of IL-5 (20-fold over IL-5 transgenics and wild-type mice). Human eosinophilic esophagitis biopsy specimens had a 7-fold increase in IL-5 compared with normals. The study indicates that IL-5–mediated eosinophilia is a major mechanism driving esophageal remodeling and fibrosis seen in eosinophilic esophagitis. See page 204. A Mechanism for Hepatic Iron Overload Associated With HCV InfectionPatients with chronic hepatitis C virus (HCV) infection often demonstrate the commonly seen feature of increased iron on liver biopsies, but the mechanism for this observation is not known.In the study by Nishina et al, transgenic mice containing the full-length HCV polyprotein region under the murine albumin promoter were examined for iron homeostasis. These mice do not show any liver inflammation, allowing an independent investigation separate from the presence of chronic inflammatory cells. Transgenic mice showed increased hepatic iron content (predominantly in hepatocytes and associated with increased expression of ferritin), increased serum iron, and transferrin saturation, but decreased splenic iron content, at 8 and 14 months of age compared with nontransgenic mice. Hepcidin levels, a peptide hormone secreted by the liver that affects intestinal iron absorption and macrophage iron release, is significantly lower in transgenic mice (Figure 4), with concomitant increase in ferroportin expression in the duodenum and spleen, as well as a smaller extent in the liver. The depressed hepcidin levels in the transgenic mice can be up-regulated in response to inflammation (lipopolysaccharide stimulation), suggesting some form of negative regulatory control over hepcidin expression. Indeed, hepcidin promotor activity was depressed in luciferase assays, presumably by reduced activity at a critical C/EBP-α binding site, and although C/EBP-α protein levels were similar in transgenic and nontransgenic mice, transgenic mice showed reduced DNA binding activity of C/EBP-α. The nuclear protein CHOP, which inhibits C/EBP-α DNA binding activity, was significantly increased in transgenic mice, paralleled an observed increase in reactive oxygen species production (in the absence of inflammation) in the liver of the transgenic mice, and can induce CHOP expression.This study indicates that HCV-induced reactive oxygen species increases CHOP expression that prohibits C/EBP-α from binding to the hepcidin promoter, reducing its expression. This in turn leads to increased duodenal iron transport and macrophage release of iron that accumulates in the liver.See page 226. Patients with chronic hepatitis C virus (HCV) infection often demonstrate the commonly seen feature of increased iron on liver biopsies, but the mechanism for this observation is not known. In the study by Nishina et al, transgenic mice containing the full-length HCV polyprotein region under the murine albumin promoter were examined for iron homeostasis. These mice do not show any liver inflammation, allowing an independent investigation separate from the presence of chronic inflammatory cells. Transgenic mice showed increased hepatic iron content (predominantly in hepatocytes and associated with increased expression of ferritin), increased serum iron, and transferrin saturation, but decreased splenic iron content, at 8 and 14 months of age compared with nontransgenic mice. Hepcidin levels, a peptide hormone secreted by the liver that affects intestinal iron absorption and macrophage iron release, is significantly lower in transgenic mice (Figure 4), with concomitant increase in ferroportin expression in the duodenum and spleen, as well as a smaller extent in the liver. The depressed hepcidin levels in the transgenic mice can be up-regulated in response to inflammation (lipopolysaccharide stimulation), suggesting some form of negative regulatory control over hepcidin expression. Indeed, hepcidin promotor activity was depressed in luciferase assays, presumably by reduced activity at a critical C/EBP-α binding site, and although C/EBP-α protein levels were similar in transgenic and nontransgenic mice, transgenic mice showed reduced DNA binding activity of C/EBP-α. The nuclear protein CHOP, which inhibits C/EBP-α DNA binding activity, was significantly increased in transgenic mice, paralleled an observed increase in reactive oxygen species production (in the absence of inflammation) in the liver of the transgenic mice, and can induce CHOP expression. This study indicates that HCV-induced reactive oxygen species increases CHOP expression that prohibits C/EBP-α from binding to the hepcidin promoter, reducing its expression. This in turn leads to increased duodenal iron transport and macrophage release of iron that accumulates in the liver. See page 226. Aspirin Dose and Duration of Use and Risk of Colorectal Cancer in MenGastroenterologyVol. 134Issue 1PreviewBackground & Aims: Long-term data on the risk of colorectal cancer according to dose, duration, and consistency of aspirin therapy are limited. Methods: We conducted a prospective study of 47,363 male health professionals who were ages 40–75 years at enrollment in 1986. Biennially, we collected data on aspirin use, other risk factors, and diagnoses of colorectal cancer. We confirmed all reports of colorectal cancer through 2004 by review of medical records. Results: During 18 years of follow-up, we documented 975 cases of colorectal cancer over 761,757 person-years. Full-Text PDF Impact of Fatty Liver Disease on Health Care Utilization and Costs in a General Population: A 5-Year ObservationGastroenterologyVol. 134Issue 1PreviewBackground & Aims: Fatty liver disease is a common condition in the Western world. Fatty liver may progress to steatohepatitis and cirrhosis. It is not yet known whether fatty liver disease results in higher health care utilization and costs. Methods: We used data from the Study of Health in Pomerania (SHIP), Germany, to assess the relation of fatty liver disease to self-reported health care utilization and costs at baseline and 5 years. The SHIP is a general population cohort study of 4310 adults aged 20 to 79 years at baseline in Pomerania. Full-Text PDF Esophageal Remodeling Develops as a Consequence of Tissue Specific IL-5-Induced EosinophiliaGastroenterologyVol. 134Issue 1PreviewBackground & Aims: Eosinophilic esophagitis (EE) is an increasingly recognized disease that mimics gastroesophageal reflux disease. Recently, EE has been associated with esophageal remodeling, but the mechanisms involved are poorly understood. We hypothesized that the development of EE in patients and in an experimental murine model would be associated with eosinophil-mediated tissue remodeling. Methods: Histopathologic analysis of basal layer thickness and collagen accumulation was performed on the biopsy specimens of normal individuals, EE patients, and mouse esophageal tissue sections following experimental induction of EE in wild-type, eosinophil lineage-deficient, interleukin (IL)-5-deficient, and IL-5 transgenic mice, with the latter 2 mice groups having decreased and increased esophageal eosinophilia, respectively. Full-Text PDF Hepatitis C Virus–Induced Reactive Oxygen Species Raise Hepatic Iron Level in Mice by Reducing Hepcidin TranscriptionGastroenterologyVol. 134Issue 1PreviewBackground & Aims: Despite abundant clinical evidence, the mechanisms by which hepatic iron overload develops in patients with hepatitis C virus (HCV)-associated chronic liver disease remain unknown. The aim of this study was to investigate how hepatic iron overload develops in the presence of HCV proteins. Methods: Male transgenic mice expressing the HCV polyprotein and nontransgenic control mice (C57BL/6) were assessed for iron concentrations in the liver, spleen, and serum and iron regulatory molecules in vivo and ex vivo. Full-Text PDF