Systemic and tumor level iron regulation in men with colorectal cancer: a case control study

BACKGROUND: Increased cellular iron exposure is associated with colorectal cancer (CRC) risk. Hepcidin, a liver peptide hormone, acts as the primary regulator of systemic iron status by blocking iron release from enterocytes into plasma. Concentrations are decreased during low iron status and increased during inflammation. The role of hepcidin and the factors influencing its regulation in CRC remains largely unknown. This study explored systemic and tumor level iron regulation in men with CRC. METHODS: The participants were 20 CRC cases and 20 healthy control subjects. Colonic tissue (adenocarcinoma [cases] healthy mucosa [controls]) was subjected to quantitative PCR (hepcidin, iron transporters and IL-6) and Perls’ iron staining. Serum was analyzed using ELISA for hepcidin, iron status (sTfR) and inflammatory markers (CRP, IL-6, TNF-α). Anthropometrics, dietary iron intake and medical history were obtained. RESULTS: Cases and controls were similar in demographics, medication use and dietary iron intake. Systemically, cases compared to controls had lower iron status (sTfR: 21.6 vs 11.8 nmol/L, p < 0.05) and higher marker of inflammation (CRP: 8.3 vs 3.4 μg/mL, p < 0.05). Serum hepcidin was mildly decreased in cases compared to controls; however, it was within the normal range for both groups. Within colonic tissue, 30% of cases (6/20) presented iron accumulation compared to 5% of controls (1/20) (χ(2) = 5.0; p < 0.05) and higher marker of inflammation (IL-6: 9.4-fold higher compared to controls, p < 0.05). Presence of adenocarcinoma iron accumulation was associated with higher serum hepcidin (iron accumulation group 80.8 vs iron absence group 22.0 ng/mL, p < 0.05). CONCLUSIONS: While CRC subjects had serum hepcidin concentrations in the normal range, it was higher given their degree of iron restriction. Inappropriately elevated serum hepcidin may reduce duodenal iron absorption and further increase colonic adenocarcinoma iron exposure. Future clinical studies need to assess the appropriateness of dietary iron intake or iron supplementation in patients with CRC

Iron and Chronic Inflammation in Obese and Lean Men with Colon Cancer: The Link with Hepcidin

Obesity and excessive iron are independently associated with increased risk for colorectal cancer (CRC). Serum hepcidin, the primary regulator of iron metabolism, is elevated during obesity and results in reduced iron absorption, higher iron in the fecal stream and the implications for CRC risk remains unknown. The main objective of this study was to explore the link with obesity and iron in men with CRC. Incident CRC cases (n=20) and healthy controls (n=20) were recruited to obtain colonic mucosa (tumors for cases; healthy mucosa for controls), serum, dietary intake and medical history. Iron accumulation was assessed by Perl’s Prussian Blue staining. messenger ribonucleic acid (mRNA) expression of hepcidin, divalent metal transporter-1 (DMT-1), ferroportin (FPN) and interleukin-6 (IL-6) were measured in colonic mucosa using rt-PCR. Serum parameters were analyzed by enzyme-linked immunosorbent assay (ELISA) for serum transferrin receptor (sTfR), hepcidin, c-reactive protein (CRP), tumor necrosis-alpha (TNF-α). Obesity was measured with waist circumference (WC) and defined as WC> 102 cm (Obese) or WC<102 cm (Lean). To control for the influence of iron status in the analysis, cases (n=16) and controls (n=15) were matched on hemoglobin and waist circumference. Cases had higher iron accumulation (30%) compared to controls (5%). Cases had lower colonic mRNA expression of hepcidin (2.9 fold; p=0.01) and higher IL-6 (9.40 fold; p=0.001) compared to controls. No significant difference with DMT-1 or FPN was observed between groups. Cases had lower iron status (higher sTfR; p=0.004) and higher circulating markers of inflammation (CRP, p=0.01) compared to controls. Although cases had lower serum hepcidin (p=0.02) compared to controls, levels were within the normal range for adult men. No associations were found by obesity and serum hepcidin in cases or controls. Findings remained similar after matching on hemoglobin and waist circumference. Colonic hepcidin does not contribute to tumor iron retention. The inappropriately normal serum hepcidin in cases is likely due to tumor driven inflammation rather than iron status which suggests 1) decreased duodenal iron absorption resulting in higher iron in fecal stream and colonic exposure 2) increased tumor iron retention. Overall, these findings may have clinical implications for oral iron supplementation during CRC

Clinical Presentation of Acute Gastroenteritis in Children With Functional Abdominal Pain Disorders

Visceral hypersensitivity and abnormal coping are common in children with functional abdominal pain disorders (FAPDs). Thus, it would be expected that children with visceral hypersensitivity would report more pain if their gut is acutely inflamed. The aim of the study was to compare clinical symptoms and somatization of children with and without FAPDs at time of an episode of acute gastroenteritis. Seventy children with acute gastroenteritis and their parents completed the Rome III Diagnostic Questionnaire for Pediatric Functional GI Disorders and the Children's Somatization Inventory. Twenty-one percent of children were diagnosed with an FAPD. Children with FAPDs showed significantly more nongastrointestinal somatic symptoms than children without FAPDs. There were no significant differences in abdominal pain, nausea, vomiting, or school absenteeism between both groups at time of consultation

A comprehensive review of randomized placebo-controlled pharmacological clinical trials in children with functional abdominal pain disorders

OBJECTIVES: Abdominal pain-predominant functional gastrointestinal disorders (AP-FGIDs) are the most common cause of consultation to pediatric gastroenterology; however, no medications have been approved to treat this group of disorders in children. The Food and Drug Administration have published recommendations for clinical trials on AP-FGIDs in adults but not in children. The lack of methodological guidelines and accepted primary endpoints for clinical trials in children hampers the progress of the field, making the approval of new medications difficult. A necessary first step to determine the feasibility of clinical trials in children and provide recommendations on the best design for future trials is to review the methods, ability to recruit, attrition rate, and results of previous clinical trials. We designed a comprehensive review of pharmacological clinical trials in AP-FGIDs in children focused on study design. METHODS: Study eligibility was randomized controlled trials (RCTs) evaluating the efficacy of pharmacological interventions compared with that of placebo in children and adolescents with AP-FGIDs. RESULTS: There is no evidence to support the use of most commonly used drugs in children. Only 7 pharmacological RCTs on AP-FGIDs in children were found. Most studies were single center based and had a small sample size. The methods and outcomes were heterogeneous. Primary endpoints varied widely among studies. Many of the RCTs did not show a consistently significant benefit of the drug over placebo in some or all of the outcomes. We found a considerable risk of bias in most studies. None of the studies have considered minimal clinically important differences in their selection of primary endpoints. CONCLUSIONS: Few randomized clinical trials have been conducted. Most studies have methodological limitations and small sample size. There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures

Construct validity of the pediatric Rome III criteria

Functional gastrointestinal disorders (FGIDs) are common. The diagnosis of FGIDs is based on the Rome criteria, a symptom-based diagnostic classification established by expert consensus. There is little evidence of validity for the pediatric Rome III criteria. The construct validity of the criteria, an overarching term that incorporates other forms of validity, has never been assessed. We assessed the construct validity of the Rome III criteria. Children from 2 schools in Colombia completed the Questionnaire on Pediatric Gastrointestinal Symptoms at baseline and weekly questionnaires of somatic symptoms and disability for 8 weeks (presence and intensity of gastrointestinal symptoms, nongastrointestinal symptoms, impact on daily activities). A total of 255 children completed at least 6 weekly surveys (2041 surveys). At baseline, 27.8% children were diagnosed as having an FGID. Prevalence of nausea (Δ 7.8%, 95% confidence interval [CI] 4.46-11.14), constipation (Δ 4.39%, 95% CI 1.79-6.99), diarrhea (Δ 6.69%, 95% CI 3.25-10.13), headache (Δ 7.4%, 95% CI 3.51-11.09), chest pain (Δ 9.04%, 95% CI 5.20-12.88), and limb pain (Δ 4.07%, 95% CI 1.76-6.37) and intensity of nausea (Δ 0.23, 95% CI 0.127-0.333), diarrhea (Δ 0.30, 95% CI 0.211-0.389), abdominal pain (Δ 0.18, 95% CI 0.069-0.291), headache (Δ 0.17, 95% CI 0.091-0.249), and limb pain (Δ 0.30, 95% CI 0.084-0.516) were higher in children with FGIDs (P < 0.001). Children with FGIDs had greater interference with daily activities (P < 0.001). Children with a Rome III diagnosis had significantly more gastrointestinal and nongastrointestinal complaints, and greater intensity of symptoms and disability than children without an FGID diagnosis. The study suggests that the Rome III pediatric criteria have adequate construct validit

Systemic and tumor level iron regulation in men with colorectal cancer: a case control study.

BackgroundIncreased cellular iron exposure is associated with colorectal cancer (CRC) risk. Hepcidin, a liver peptide hormone, acts as the primary regulator of systemic iron status by blocking iron release from enterocytes into plasma. Concentrations are decreased during low iron status and increased during inflammation. The role of hepcidin and the factors influencing its regulation in CRC remains largely unknown. This study explored systemic and tumor level iron regulation in men with CRC.MethodsThe participants were 20 CRC cases and 20 healthy control subjects. Colonic tissue (adenocarcinoma [cases] healthy mucosa [controls]) was subjected to quantitative PCR (hepcidin, iron transporters and IL-6) and Perls' iron staining. Serum was analyzed using ELISA for hepcidin, iron status (sTfR) and inflammatory markers (CRP, IL-6, TNF-α). Anthropometrics, dietary iron intake and medical history were obtained.ResultsCases and controls were similar in demographics, medication use and dietary iron intake. Systemically, cases compared to controls had lower iron status (sTfR: 21.6 vs 11.8&nbsp;nmol/L, p &lt; 0.05) and higher marker of inflammation (CRP: 8.3 vs 3.4&nbsp;μg/mL, p &lt; 0.05). Serum hepcidin was mildly decreased in cases compared to controls; however, it was within the normal range for both groups. Within colonic tissue, 30% of cases (6/20) presented iron accumulation compared to 5% of controls (1/20) (χ(2) = 5.0; p &lt; 0.05) and higher marker of inflammation (IL-6: 9.4-fold higher compared to controls, p &lt; 0.05). Presence of adenocarcinoma iron accumulation was associated with higher serum hepcidin (iron accumulation group 80.8 vs iron absence group 22.0&nbsp;ng/mL, p &lt; 0.05).ConclusionsWhile CRC subjects had serum hepcidin concentrations in the normal range, it was higher given their degree of iron restriction. Inappropriately elevated serum hepcidin may reduce duodenal iron absorption and further increase colonic adenocarcinoma iron exposure. Future clinical studies need to assess the appropriateness of dietary iron intake or iron supplementation in patients with CRC