Malabsorption anemia and iron supplement induced constipation in post-roux-en-y gastric bypass (RYGB) patients

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1 CE ARTICLE Malabsorption anemia and iron supplement induced constipation in post-roux-en-y gastric bypass (RYGB) patients Frances M. Sahebzamani, PhD, ARNP, FAANP (Assistant Professor) 1, Adrienne Berarducci, PhD, ARNP, FAANP (Associate Professor) 1, & Michel M. Murr, MD, FACS (Professor) 2,3 1 College of Nursing, University of South Florida, Tampa, Florida 2 Division of Surgery, College of Medicine, University of South Florida, Tampa, Florida 3 Bariatric Center of Excellence, Tampa General Hospital, Tampa, Florida Keywords Anemia; obesity; nutrition; surgery; malabsorption syndrome; adherence. Correspondence Frances M. Sahebzamani, PhD, ARNP, FAANP, College of Nursing, University of South Florida, Bruce B. Downs Boulevard, MDN, Room 2010, Tampa, FL Tel: (813) ; Fax: (813) ; fsahebza@health.usf.edu. Received: March 2013; accepted: July 2013 doi: / To obtain CE credit for this activity, go to and click on the CE Center. Locate the listing for this article and complete the post-test. Follow the instructions to print your CE certificate. Disclosure All authors have contributed materially to this manuscript and approved the final draft submitted. None of the authors has a conflict of interest with this work. Abstract Purpose: Over 250,000 bariatric surgical procedures for the management of morbid obesity are performed in the United States annually. The Roux-en-Y gastric bypass (RYGB) is an effective bariatric procedure because of its efficacy in achieving significant weight loss, low complication rates, and outcomes in reducing cardiovascular and all cause mortality. Because food bypasses the portion of the small intestine whereby micronutrients are normally absorbed, micronutrient deficiencies following surgery may lead to iron deficiency anemia. Iron deficiency anemia is estimated to occur in 6% 50% of post-rygb patients. Consequently, the procedure requires lifelong behavioral change to ensure therapeutic iron supplementation. Data sources: A nonsystematic literature search for clinical guidelines, review articles, and research was conducted. Conclusions: Clinical recommendations include prophylactic iron supplementation with ferrous sulfate to prevent iron deficiency anemia. Ferrous sulfate is a well-established cause of constipation possibly resulting in low patient tolerability and subsequent low adherence rates. Clinical implications: Strategies for managing the side effects of iron supplementation including constipation may require a unique approach based on the anatomical and functional changes in the post-rygb patient and the requirement for lifelong iron supplementation. Introduction Obesity (defined as a body mass index [BMI] 30 kg/ m 2 ) has been recognized as a global epidemic and lifethreatening, chronic disease affecting an estimated 35% of adults in the United States (Flegal, Carroll, Kit, & Ogden, 2012). Public health campaigns, exercise, diet, and other interventions aimed at sustained weight loss have been largely unsuccessful. As a result, the popularity of bariatric surgical options addressing obesity has increased nearly 20-fold over the past few years. Over 250,000 bariatric surgical procedures for the management of morbid obesity are performed in the United States annually with more than half of these surgeries performed on women (Flegal et al., 2012). The Rouxen-Y gastric bypass (RYGB) is an effective bariatric procedure because of its efficacy in achieving significant weight loss (60% 70% of excess weight), low complication rates, and outcomes in reducing cardiovascular and all cause mortality (Flegal et al., 2012; Mechanick et al., 2009; Vargas-Ruiz, Hernandez-Rivera, & Herrera, 2008). The RYGB facilitates combined restrictive and malabsorptive mechanisms to promote weight loss and improved metabolic outcomes. The surgical procedure results in the construction of a restrictive pouch that is then anastomosed to the distal small intestine, bypassing approximately 95% of the stomach, the entire duodenum, and up to 150 cm of the jejunum. As food is diverted from the duodenum following RYGB, the portion of the small 634 Journal of the American Association of Nurse Practitioners 25 (2013) C 2013 The Author(s) C 2013 American Association of Nurse Practitioners

2 F. M. Sahebzamani et al. Iron-induced constipation in RYGB patients intestine whereby iron, calcium, and other micronutrients are normally absorbed, the procedure is considered a malabsorptive procedure (Mechanick et al., 2009). As a result, micronutrient-related adverse events following surgical treatment for morbid obesity are likely to include abnormal iron metabolism and subsequent anemia. While significant surgical weight loss provides a dramatic opportunity to reverse obesity-related diseases, it also requires lifelong behavioral change to ensure therapeutic micronutrient supplementation, including iron. Iron deficiency anemia is a common sequela of RYGB estimated to occur in 6% 50% of post bypass patients (Avgerinos, Llaguna, Seigerman, Lefkowitz, & Leitman, 2010; Marinella, 2008; Vargas-Ruiz et al., 2008). Iron deficient anemia has been independently linked with increased inflammatory markers associated with atherosclerosis, increased cardiovascular event risk, and adverse cardiovascular outcomes in women (Arant et al., 2004). As iron stores are depleted, the effects of anemia on inflammatory biomarkers associated with cardiovascular risk and atherosclerosis may attenuate the cardiovascular and metabolic benefits derived from the procedure and subsequent weight loss. Contemporary evidence suggests prophylactic iron supplementation with ferrous sulfate to prevent iron deficiency anemia (Avgerinos et al., 2010; Harbottle, 2011; Mechanick et al., 2009, 2013). Ferrous sulfate is a wellestablished iatrogenic cause of constipation and other unpleasant gastrointestinal side effects, often resulting in low patient tolerability and subsequent low adherence rates. Management strategies for iron-induced constipation in the post-rygb patient have not been systematically studied and may require a unique approach based on the anatomical and functional changes in the post- RYGB patient and the requirement for lifelong iron supplementation. The purpose of this article is to review the issues related to iron supplementation in the management of patients following RYGB surgery. Malabsorption anemia Iron deficiency anemia is a serious postoperative complication of gastric bypass surgery, which can manifest in the immediate postoperative phase as a consequence of surgical blood loss. Later onset anemia typically occurs from 8 weeks to 2 years postoperatively and results from the depletion of iron, folate, and vitamin B12 stores. Late onset anemia has been reported in patients up to 7 10 years postoperatively (Avgerinos et al., 2010; Harbottle, 2011; Mechanick et al., 2009). Iron deficiency has been reported in up to 50% of women who have had the RYGB procedure with a greater risk for anemia occurring in menstruating women. Postsurgical iron deficiency has been attributed to a number of factors, in- Table 1 Common symptoms associated with iron deficiency anemia Fatigue Dyspnea Palpitations Tachycardia Chest pain Pica Hair loss Atrophic glossitis Cheilosis Cold intolerance Brittle nails Pagophagia Source: Buchwald et al. (2004), Sarwer, Wadden, and Fabricatore (2005), von Drygalski and Andris (2009). cluding menstrual blood loss, diminished food intake and intolerance of iron-rich foods such as red meat, impaired conversion of ingested ferric iron to absorbable iron from the loss of gastric acid exposure, and the surgical bypass of the duodenum, which is predominately responsible for iron absorption (Avgerinos et al., 2010; Harbottle, 2011; Mechanick et al., 2009). In addition to malabsorption, iron store depletion can occur as a result of presurgical nutritional deficiencies commonly found in obese men and women (Marinella, 2008). Research has shown a high prevalence of preoperative nutritional deficiencies in morbidly obese bariatric surgical candidates. These nutritional deficiencies have largely been attributed to the consumption of high fat, calorically dense diets containing processed foods low in nutritional value with inadequate amounts of proteins, minerals, and vitamins. Schwieger and colleagues (2010) found a high prevalence of preoperative nutritional deficiencies, including low levels of iron (35%); ferritin (24%); folic acid (24%); vitamin B12 (3.6%); and low hemoglobin, hematocrit and mean corpuscular volume (MCV) (19%) in 114 morbidly obese bariatric surgical candidates (Schweiger, Weiss, Berry, & Keidar, 2010). Thirty-six percent of men and 12% of women in this study had preoperative anemia. Similarly, Flancbaum and colleagues (2006) identified preoperative nutritional deficiencies including low iron (44%), ferritin (8.4%), low hemoglobin (men 41%; women 19.1%), and anemia (men 41%, women 19.1%) in a retrospective review of 379 bariatric surgical candidates (Flancbaum, Belsley, Drake, Colarusso, & Tayler, 2006). Preoperative subclinical, or unrecognized, nutritional deficiencies may further complicate the treatment of postoperative malabsorption deficiencies in post-rygb patients. Clinical presentation Symptoms of iron deficiency are usually nonspecific and may be unrecognized until severe. Table 1 lists the common presenting symptoms for iron deficiency. Iron deficiency is best assessed clinically through the measurement of serum ferritin (Buchwald et al., 2004; Sarwer, 635

3 Iron-induced constipation in RYGB patients F. M. Sahebzamani et al. Table 2 Laboratory diagnostics for iron deficiency anemia in the post- RYGB patient Test Hemoglobin Mean corpuscular volume (MCV) Red cell distribution width (RDW) Transferrin saturation Ferritin Iron Total iron binding capacity (TIBC) Folate B12 Source: Buchwald et al. (2004), von Drygalski and Andris (2009). Result Increased Wadden, & Fabricatore, 2005). Characteristic laboratory findings associated with iron deficiency anemia are listed in Table 2. While iron deficient anemia is clinically recognized by characteristic microcytic changes (low MCV values) on the peripheral blood smear, deficiencies in vitamin B12 leading to characteristic macrocytic changes (high MCV values) may mask, or diminish, the magnitude of microcytic changes and delay diagnosis in post- RYGB patients. It is thought that prevention of folate and vitamin B12 deficiencies following RYGB can be accomplished through postoperative supplementation with a standard multivitamin. While standard multivitamins may prevent folate and B12 depletion, Brolin, Gorman, Milgrim, and Kenler (1991) found that multivitamin supplementation did not adequately prevent iron deficiencies and anemia in post-rygb patients (Brolin et al., 1991). In a subsequent randomized, double blind controlled trial of menstruating women who had undergone RYGB, Brolin et al. (1998) found that supplementation twice daily with oral ferrous sulfate effectively prevented iron deficiency in patients adherent to taking the prescribed supplements, although 20% of this sample abandoned iron supplementation because of unpleasant gastrointestinal side effects (Brolin et al., 1998). Current postoperative RYGB recommendations include lifelong prophylactic iron supplementation (Mechanick et al., 2013). Although there is not a general consensus on the optimal iron replacement formulation for post- RYGB patients, recommendations often include ferrous salts (ferrous fumarate and ferrous sulfate) that are more readily absorbed and available without a prescription. Iron supplements specifically developed for post-rygb patients have not been systematically studied and typically contain ferrous fumarate or ferrous sulfate. Sustained released formulations should be avoided as they reduce the amount of iron present for absorption from the inadequate postoperative intestinal surface (Love & Billett, 2008). While some evidence suggests that oral ferrous fumarate preparations are better tolerated by post-rygb patients (Wax, Pinette, Cartin, & Blackstone, 2007), ferrous sulfate is recommended as the first line replacement supplement because of its efficacy, availability without a prescription, and low cost (Buchwald et al., 2004; Marinella, 2008; Mechanick et al., 2013; Wax et al., 2007). Current recommendations for prevention of postoperative iron deficiency includes 325 mg of ferrous sulfate or ferrous fumarate (65 mg of elemental iron per tablet) twice daily, or a daily dosage of mg of elemental iron (three to four tablets per day) with vitamin C 500 mg for the treatment of diagnosed iron deficiency (Mechanick et al., 2013). In menstruating, anemic women, as many as six tablets of ferrous sulfate per day may be required to correct the iron deficiency anemia following RYGB (Love & Billett, 2008). Although not a first-line treatment option, patients with persistent iron deficiency despite oral supplementation, or patients with severe intolerance to oral supplementation may require intravenous iron supplementation to replenish iron stores. While research has shown successful treatment outcomes with intravenous iron replacement, clinical guidelines for post-rygb administration of intravenous iron preparations vary considerably and access to intravenous iron replacement may be limited in the primary care setting because of: (a) delayed recognition of the severity of the deficiency; (b) a lack of consistent diagnostic criteria, indications, and optimal treatment goals; (c) provider concerns related to potential adverse effects of intravenous iron preparations; and (d) access to infusion centers for monitored treatments (Bailie, 2012; Bloomberg, Fleishman, Nalle, Herron, & Kini, 2005; DeFilipp et al., 2013; Malone, Alger-Mayer, Lindstrom, & Bailie, 2013; von Drygalski & Andris, 2009). Adherence to therapeutic iron supplementation Iron supplementation tolerability and adherence has primarily been studied in relation to pregnancy-induced iron deficient anemia. Tolerability and adherence studies related to long-term iron supplementation have been sparse and results conflicting. al-momen et al. (1996) examined the safety and efficacy of intravenous iron sucrose complex (ISC) administered daily compared with 300 mg of oral ferrous sulfate self-administered three times per day for the treatment of iron deficient anemia in pregnant women and reported no major side effects in the ISC groups, whereas 6% of the oral iron group could not tolerate ferrous sulfate. In subjects receiving oral iron 636

4 F. M. Sahebzamani et al. Iron-induced constipation in RYGB patients supplementation, 30% reported significant gastrointestinal symptoms, including constipation and nausea, and 30% had poor compliance with taking the supplements. Nguyen et al. (2008) examined adherence rates and reported adverse effects of two formulations of prenatal multivitamins in pregnant women (N = 167) randomized to receive small-tablet multivitamins containing either low (35 mg) or high (60 mg) elemental iron concentrations. Subjects in both groups reported low adherence rates (50%) but no difference in reported gastrointestinal irritability from high versus low iron concentrations. The investigators cited perception of tablet size (16 mm 9mm 4mmvs.5mmradius,5mm thickness) as the more definitive factor affecting iron supplement adherence rates. Conversely, other studies (Ahn et al., 2006; Meier, Nickerson, Olson, Berg, & Meyer, 2003) found no significant differences in reported side effects, including constipation, or adherence rates with oral iron supplementation compared to placebo. Moreover, in a comprehensive review of the determinants of compliance with iron supplementation in pregnant women, Galloway and McGuire (1994) identified that poor clinician support and patient teaching, as well as the general unavailability of iron supplements to patients, were the most common reasons why women did not take iron supplements as prescribed (Galloway & McGuire, 1994). In this review, gastrointestinal side effects, including constipation and nausea, were not significantly associated with poor iron supplementation adherence. However, pregnancy is a time limited cause of iron deficiency making short-term adherence more likely. For post-rygb patients, the problem is a permanent one. Ferrous sulfate is a well-established iatrogenic cause of symptomatic constipation, nausea, and dyspepsia that may result in low patient adherence rates. Ideally, ferrous sulfate should be taken on an empty stomach, which may further induce unpleasant gastrointestinal side effects including nausea and constipation (Love & Billett, 2008). The effects of ferrous sulfate induced constipation, dyspepsia, and nausea in this unique, high-risk population on symptom intensity, symptom distress, short- and long-term adherence for the post-rygb patient is largely unknown. Constipation and gastrointestinal symptoms Chronic constipation is estimated to affect up to 34% of the general population and results in an estimated 2.5 million clinic visits annually (Camilleri, Thompson, Fleshman, & Pemberton, 1994). Constipation is typically assessed and managed in the clinical setting based on selfreported symptoms and reported stool frequency. While Table 3 Physical and psychological symptoms associated with constipation Physical Symptoms Infrequent stools Hard stools Difficult stool passage Sensation of incomplete evacuation Bloating Intestinal gas Abdominal discomfort or pain General malaise Psychological Symptoms Anxiety Depression Reported increased stressors Diminished quality of life Source: Camilleri, Thompson, Fleshman, and Pemberton (1994), Lembo and Camilleri (2003), Talley (2007). there is no universally accepted definition for constipation, symptoms typically involve more than reduced stool frequency. Symptoms associated with constipation are listed in Table 3. The use of prescription medications is a common cause of constipation. Depending on the medication prescribed, medication-induced constipation can manifest as slow transit, functional constipation, or as a consequence of pharmacologic alterations in bowel motility (Talley, 2007). Because most patients generally report nondisabling symptoms associated with idiopathic constipation, patients may be reluctant to present to the clinical setting with a primary complaint of constipation and elect to self-manage their constipation through a trial and error approach with a wide variety of dietary changes, including increased dietary fiber, over the counter, or herbal preparations (Petticrew, Rodgers, & Booth, 2001). Thus, self-reported symptoms of constipation are likely to be reported within the context of other presenting comorbidities and managed therapeutically through brief instructions by the clinician for self-management strategies (Petticrew et al., 2001). As the majority of postbariatric surgical patients are followed in primary care settings, unrecognized risks and complications of iron-induced constipation may result in the recommendation of inappropriate self-management strategies for this patient population. For example, traditional self-management treatments, including an increase in consumption of a high fiber diet, are not recommended in postbariatric surgical patients and the inappropriate selection of and resultant side effects from over the counter laxatives may limit successful treatment attempts and lead to the abandonment of iron supplementation in this high-risk population (Camilleri et al., 1994; Lembo & Camilleri, 2003; Petticrew et al., 2001). Higher levels of functional abdominal symptoms have been found in morbidly obese and post-rygb patients, 637

5 Iron-induced constipation in RYGB patients F. M. Sahebzamani et al. which may lower symptom tolerability thresholds for supplement-induced constipation, dyspepsia, and nausea and affect supplement adherence rates. Risk factors for the development of constipation include a diet that is high in refined, roughage-free foods, and sedentary lifestyle and deconditioning, both of which are common in pre- and postsurgical RYGB patients. Insulin resistance and chronic hyperglycemic states may promote central neuropathies resulting in gastroenteropathies and altered bowel motility leading to an increased risk for constipation or diarrhea. Several studies have identified an increased prevalence of functional abdominal symptoms, including abdominal pain and irritable bowel symptoms, in morbidly obese individuals (Delgado-Aros, Camilleri, Garcia, Burton, & Busciglio, 2008; Delgado- Aros et al., 2004; Foster, Laws, Gonzalez, & Clements, 2003; Foster, Richards, McDowell, Laws, & Clements, 2003). A loss of the perception of satiation in morbidly obese individuals is thought to contribute to the observed increased prevalence of functional abdominal symptoms. Approximately 30% 50% of morbidly obese individuals will exhibit overeating or binge eating behaviors (Delgado-Aros et al., 2004). Increased intra-abdominal pressure resulting from prolonged overeating and subsequent gastric distention has been identified as a possible cause of a chronic abdominal compartment syndrome leading to increased and intense gastrointestinal symptoms, including abdominal pain, esophageal reflux, nausea, bloating, and constipation. Consequently, obese patients may experience a higher prevalence of presurgical constipation and other gastrointestinal symptoms. In a sample of 1963 community-dwelling respondents, Delgado-Aros et al. (2004) examined the relationship between BMI and gastrointestinal symptoms in 1963 community-dwelling residents of Olmsted County, Minnesota and found increased BMI to be significantly associated with increased symptoms, including upper abdominal pain (p =.03), vomiting (p =.02), bloating (p =.002), and diarrhea (p =.01; Delgado-Aros et al., 2004). Although not statistically significant, symptoms of lower abdominal pain, nausea, and constipation were more prevalent compared with normal weight participants. Similarly, Foster, Richards, et al. (2003) examined frequency and intensity of gastrointestinal symptoms in 43 prospective RYGB patients and found significantly increased symptoms of abdominal pain (p =.002), irritable bowel (p =.02), and reflux (p =.001) in the RYGB patients compared with nonobese controls. Post-RYGB surgical alterations designed to induce malabsorption of nutrients includes changes that do not typically alter the intestinal track to allow resolution, or inducement, of constipation. The colon is not surgically affected by the surgical procedure. The most common problem potentially affecting stool frequency in post-rygb patients is increased malodorous flatulence and dumping syndrome. However, the direct effects of postsurgical intestinal changes on constipation treatment have not been systematically studied. Dumping syndrome is an intentional consequence of gastric bypass surgery and occurs from osmotic overload in the small intestines from consumption of foods high in simple carbohydrates. The osmolar overload rapidly shifts fluid into the small intestines, which can result in a highly symptomatic vagal reaction. Diarrhea usually does not occur with dumping syndrome as there is usually enough distal bowel to prevent the diarrhea associated with this syndrome (Alvarez-Leite, 2004; Elliot, 2003; Fujioka, 2005). Osmotic agents frequently prescribed for the management of constipation may trigger an exaggerated dumping syndrome-like response in post-rygb patients. Because approximately 95% of the stomach, the entire duodenum, and from cm of the jejunum is bypassed, fat and carbohydrate malabsorption can result in increased flatulence, which may negatively impact quality of life. Further, the equilibrium of the intestinal flora and bacteria may be compromised leading to an increase in bacterial overgrowth resulting in malodorous flatulence and abdominal discomfort (Potoczna et al., 2008). The effects of an increase in dietary fiber or bulking agents, as recommended as the first step in the management of constipation symptoms, may result in an intolerable increase in malodorous flatulence. Similarly, the use of unsupervised stimulant laxatives may result in intolerable increases in symptomatic diarrhea. Unlike bulking agents, osmotic laxatives, or stimulant laxatives, all of which may prove problematic for post- RYGB patients, lubiprostone represents a new class of medication for the management of constipation, which may be better tolerated and efficacious for relieving iron supplement induced constipation in this specific patient population. Lubiprostone increases intestinal fluid, which may result in softened stool, thereby increasing fecal transit (Lacy & Levy, 2007, 2008). Thus, the mechanism of action of lubiprostone may be ideally suited for post- RYGB patients by reducing the risk for: (a) a dumping syndrome reaction potentially associated with the use of osmotic laxatives or, (b) an increase in symptomatic diarrhea and abdominal pain potentially associated with stimulant laxatives. Although generally well tolerated in the wide spectrum of patients participating in the clinical trials for lubiprostone, it has not been studied in post-rygb patients. Further research is needed to improve understanding of the prevalence and symptom experience of iron-induced constipation on postoperative iron supplementation and 638

6 F. M. Sahebzamani et al. Iron-induced constipation in RYGB patients malabsorption anemia. Iron supplementation adherence and adverse gastrointestinal symptoms in post-rygb patients represent a unique clinical challenge for the treatment of iron-induced constipation. Morbidly obese patients who undergo RYGB surgery represent a unique patient population seen in the primary care setting for the management of iron supplement induced constipation and other unpleasant gastrointestinal side effects, supplement adherence, and postsurgical malabsorption iron deficiency anemia. Extant evidence suggests that prior to surgery, morbidly obese patients may experience excess functional gastrointestinal disorders, including chronic constipation. Thus, prospective RYGB candidates may be at high risk for constipation prior to the procedure. The RYGB is a restrictive/malabsorptive procedure, which bypasses approximately 95% of the stomach, the entire duodenum, and from cm of the jejunum, which compromises intestinal absorption capacity and predisposes these patients to the development of significant deficiencies in macro- and micronutrients, vitamins, and minerals. As a result, RYGB patients are at an increased lifetime risk for complications associated with malabsorption deficiencies, including macronutrients (fats and carbohydrates), iron, ferritin, folate, and vitamin B12. Further, the effects of traditional self-management and prescribed medications, including the recommendation for increased dietary fiber, osmotic and stimulant laxatives has not been studied in this patient population and may result in intolerable side effects and suboptimal management of constipation. Lifelong iron supplementation is a key strategy for the prevention of iron deficiency anemia, which may be abandoned by patients because of an unbalanced perception of their unpleasant constipation symptoms versus potential benefit from continued iron supplementation. As iron deficiency may be largely asymptomatic until severe, iron-induced constipation may cause significant symptom intensity and distress leading to nonadherence with replacement therapy. Research on iron supplementation has been primarily conducted in pregnant or postpartum women who require significantly shorter courses of therapeutic replacement therapy. In these studies, nonadherence to iron supplementation rates have been found as high as 30% 50% resulting from side effects of iron supplementation. As the numbers of postbariatric surgical patients increases over the coming years, lifelong iron supplementation will be needed to reduce preventable complications. 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