Iron Nutrition and Metabolic Surgery: The Next Quality Improvement Challenge

| March 1, 2019 | 0 Comments

by Peter N. Benotti, MD; G. Craig Wood, MS; and Christopher D. Still, DO, FACN, FACP

Drs. Benotti, Wood, and Still are with the Geisinger Obesity Institute, Geisinger Medical Center in Danville, Pennsylvania.

Funding: No funding was provided.

Disclosures: The authors report no conflicts of interest relevant to the content of this article.

Bariatric Times. 2019;16(3):8–11.

Abstract

Iron deficiency is a well-known and common nutritional complication of metabolic surgery. In addition to the known adverse effects of metabolic surgery on iron absorption, recent evidence suggests that the chronic low-grade systemic inflammation which commonly accompanies severe obesity alters iron availability and absorption, rendering patients with severe obesity at increased risk for iron deficiency and explains the high prevalence of iron deficiency among candidates for metabolic surgery.

Awareness of the physiology of the inflammatory response, its effects on iron homeostasis, and its complicating effects on the diagnosis and management iron deficiency should be a priority for those providing nutritional care for metabolic surgery patients.

During the past decade, metabolic surgery has led all surgical specialties in quality improvement with many important advances in surgical safety and perioperative management, which have resulted in sharply reduced levels of morbidity and mortality. These advances have established metabolic surgery as the most effective treatment for severe obesity and its adverse health consequences.1

Metabolic surgical procedures are designed to cause permanent changes in gastrointestinal anatomy and physiology that lead to life-long nutritional consequences, thus mandating close monitoring by skilled providers on a long-term basis. The most well-known and prevalent nutritional concern is the effect of metabolic surgery on iron nutrition. Recent discoveries suggest that obesity, in association with systemic inflammation, is also associated with iron deficiency and that this has an important impact on the postoperative risks of iron deficiency and anemia, conditions that can detract from the health restoring effects of metabolic surgery. The purpose of this review is to summarize the current knowledge related to obesity, metabolic surgery, and iron nutrition and to suggest opportunities for quality improvement.

Iron Homeostasis

Iron is vital to health. Its major role is as a constituent of the hemoglobin molecule, necessary for oxygen transport and as a component of myoglobin providing oxygen storage in muscle. Its ability to shift from the ferric to ferrous state contributes to its important role in electron transport and oxidative phosphorylation for adenosine triphosphate (ATP) production. These important functions explain the fatigue and loss of energy that is characteristic of iron deficiency states.

Dietary iron is available as heme iron, derived from animal myoglobin, hemoglobin, and cytochromes, as well as elemental iron, found primarily in plant-derived or fortified foods. Dietary iron usually is ingested in the ferric form and is kept soluble by gastric acid, which keeps it in the reduced form. Additional dietary acids, such as ascorbic acid, also facilitate reduction and solubility of elemental iron.2 Iron absorption takes place in the duodenum and proximal small intestine, and gastric acid is required to maintain iron solubility for absorption.3 The major reduction in gastric acid and lack of food contact with the duodenum and proximal jejunum explain, in part, the pathogenesis of iron deficiency complicating metabolic surgery.

Iron homeostasis is tightly regulated according to body need because of the limited capability to excrete iron. Absorbed iron is transported in the circulation bound to transferrin for distribution to storage sites or to tissues where it is needed. Iron is stored primarily in the liver and bone marrow in the form of ferritin. When available iron is sufficient, absorbed iron is retained in duodenal enterocytes in the form of ferritin until iron is needed, then exported to transferrin for distribution. When iron availability is limited, release of iron from enterocytes and from storage sites is increased.3–5 

The major hormone regulator of body iron availability is hepcidin, a protein produced in the liver. When body iron is replenished, hepcidin production is stimulated and levels rise, which results in inhibition of release of iron from enterocytes and from storage sites, leading to a fall in transferrin-bound iron and reduced availability of iron for erythropoiesis and other functions. Conversely, when iron supplies are limited or there is a need for erythropoiesis, hepcidin levels fall, which enhances iron release from enterocytes, hepatocytes, and macrophages.6

Alterations in Iron Homeostasis Related to Obesity

An understanding of the pathophysiology of low-grade systemic inflammation and its strong association with increasing adipocyte mass in obesity is important because of the recently discovered links between inflammation and iron homeostasis, as well as the suspected association between systemic inflammation and obesity-related comorbid disease. Expansion of adipocytes in response to dietary energy excess results in immune activation, altered adipocyte function, and secretory activity that results in the release of inflammatory mediators.7 Several investigators have demonstrated that the levels of inflammatory biomarkers, such as C-reactive protein (CRP) and cytokines, are increased in direct relation to body mass index (BMI).8,9 Recent studies of CRP levels in large cohorts of candidates for metabolic surgery have found that a CRP level greater than three was present in 88 percent of the cohort,10 and the mean CRP level among surgical candidates is elevated at 8.9±6.9ng/L,11 a level consistent with clinically significant inflammation.

In the setting of immune activation and inflammation in patients with severe obesity, the synthesis of hepcidin, which is also an acute phase reactant, is stimulated by increased levels of Interleukin 6 (IL-6), resulting in elevated hepcidin levels.12,13 Hepcidin upregulation in inflammation results in iron sequestration in enterocytes, liver, and reticuloendothelial macrophages, thus reducing plasma iron availability.6 The result is the development of a functional iron deficiency where body iron stores can be adequate, but iron absorption and availability for erythropoiesis and other functions are limited by hepcidin-mediated iron sequestration.14 In obesity, like other chronic disease states, functional iron deficiency can be present with ferritin levels up to 100ng/mL. Several recent studies have documented the presence of elevated hepcidin levels and diminished iron absorption in patients with obesity.13,15 

The common association of chronic low-grade systemic inflammation with obesity underlies the observation that obesity is associated with an increased risk of iron deficiency16 and the high prevalence of iron deficiency and anemia reported among candidates for bariatric surgery when assessment of the presence of inflammation was included in the iron nutrition evaluation.10,17 Because the physiology of inflammation does interfere with absorption of oral iron, it is likely that these patients will respond poorly to oral iron supplementation, and clinical trials are needed to see if restoration of iron stores with parenteral iron or enhanced oral supplement dosing might be more effective in restoring iron stores and lessening the risk of postoperative iron deficiency.18,19

Assessment of Iron Nutrition Status

Nutritional assessment for iron is a challenge because systemic inflammation and the acute phase response affect the laboratory tests of iron nutrition. Under normal circumstances, ferritin is released to the circulation in relationship to the amount of stored iron. The ferritin level is thus considered as an accurate measurement of iron stores.2 The lower limit of normal for serum ferritin is 12ng/mL, and varying low levels of ferritin have been used as the threshold for iron deficiency in studies of iron status before and after metabolic surgery. However, because ferritin is an acute phase reactant, it loses its specificity as a determinant of iron status when inflammation is present, and blood levels increase with inflammation.2,4

Until recently, all of the studies of iron status in candidates for metabolic surgery have defined iron deficiency by a threshold low level of ferritin ranging from 9 to 24ng/mL. The prevalence of iron deficiency and anemia among candidates for metabolic surgery found in these studies was 6 to 24 percent and 6 to 22 percent, respectively.20–26 Several recent studies have included an assessment of inflammation to capture patients with functional iron deficiency.10,17 Assessment of the degree of inflammation can be easily carried out by measuring the level of CRP.27 

Proposed criteria for the diagnosis of absolute iron deficiency include a ferritin level below the lower limit of normal, and, when inflammation is present (high sensitivity CRP>3mg/L), a ferritin between the lower limit of normal and 100ng/mL.10 An alternative proposed threshold for iron deficiency in the presence of inflammation (CRP>5ng/mL), is a transferrin saturation less than 20 percent in the presence of a normal ferritin level.17 When inflammation is assessed, the prevalence of iron deficiency among surgical candidates in these studies is much higher. 

A detailed summary of the available laboratory tests for iron status, as well as their efficacy, can be found in an excellent review by Camaschella.4 In addition, the assessment of the level of serum transferrin receptor (sTfR) is another useful test in the assessment of iron status. The transferrin receptor is released to the circulation from cellular membrane-bound transferrin receptor. Iron deficiency is associated with increased transferrin receptor gene expression and serum levels. Espression and levels are reduced by iron repletion.4,28 In the setting of anemia related to functional iron deficiency, sTfR levels are not increased, and use of the calculated ratio of sTfR/Log ferritin level can accurately distinguish between actual iron depletion and functional iron deficiency.29

On the basis of recent study of the association between obesity, systemic inflammation, and iron homeostasis, it appears as though an assessment of iron status in patients with obesity should include an investigation for the presence of inflammation by measuring levels of CRP. Recent evidence suggests that iron-depleted patients with severe obesity and inflammation will have elevated hepcidin levels and impaired iron absorption, rendering them less likely to replete iron nutrition with diet or oral supplementation until inflammation resolves after surgical weight loss. Inflammation-induced alterations in iron homeostasis explain the high prevalence of iron deficiency among candidates for metabolic surgery and likely predispose them to worsening alterations in iron nutrition after surgery. Increasing awareness of the physiological impact of inflammation on iron status supports the addition of iron depletion to the list of obesity-related comorbid conditions.

Many of the studies of iron status in candidates for metabolic surgery also reveal significant deficiencies of other nutrients, which provides additional evidence supporting the need for a full nutritional assessment for all surgical patients.22,24,26 Established evidence-based guidelines support a nutritional screen as the standard of care for all surgical candidates. Despite this, a recent large study suggests that micronutrient assessment and screening is occurring in less than 25 percent of patients.30 

Iron Status after Metabolic Surgery

Iron deficiency and anemia are common after metabolic surgery. In our registry cohort from Geisinger Medical Center (Danville, Pennsylvania) including 2,116 patients who underwent metabolic surgery followed for 5.3±3.3 years, 66 percent developed mild anemia (Hgb<12gm/dL), 35 percent developed moderate anemia (Hgb<10gm/dL), and 12.5 percent developed severe anemia (Hgb<8gm/dL) during the study interval.20 Although parameters of iron status were not reported in this study, increasing degrees of anemia correlated strongly with increases in the degree of microcytosis (p<0.0001). The reported prevalence of iron deficiency reported by others up to five years after surgery is 20 to 50 percent.23,31–36 In these studies, the diagnosis of iron deficiency is based on a low threshold level of ferritin only, which defines absolute iron deficiency. This invites speculation that failure to consider the impact of inflammation on ferritin levels in these studies might result in underestimation of the prevalence of iron deficiency by failing to consider functional iron deficiency. The optimal methods to measure iron status in the presence of inflammation is an important subject for future study.

Although the vast majority of studies of postoperative iron status deal with patients undergoing Roux-en-Y gastric bypass (RYGB), a number of intermediate term studies after sleeve gastrectomy (SG) and biliopancreatic diversion with duodenal switch (BPDS) demonstrate a similar high prevalence of iron deficiency. A prospective study of iron absorption using labeled isotopes demonstrated similar reductions in iron absorption after SG and RYGB with no observed procedure-related differences in anemia or iron deficiency.37 Several additional studies, including our own results, support these findings18,38,39 suggesting that preservation of the duodenum and proximal jejunum does not protect against postoperative iron deficiency.

Following BPDS, nutrient deficiencies are common, but longer-term studies of iron nutrition are limited, with results from small studies with iron deficiency rates of 20 to 60 percent and anemia rates of 20 to 50 percent.40–44

Why is Iron Deficiency Such a Problem after Metabolic Surgery and What Can be Done?

There are multiple factors which contribute to this potentially modifiable nutritional complication which, if untreated, can potentially nullify many of the health benefits of metabolic surgery. Multiple factors render the candidate for metabolic surgery at major risk for clinically significant postoperative iron deficiency:

Severe obesity is a major risk factor for iron deficiency because of the association between obesity and systemic inflammation, which limits both iron availability and oral iron absorption, predisposing to both absolute and functional iron deficiency. This factor together with the high percentage of menstruating young women who undergo metabolic surgery contribute the high frequency of iron deficiency and anemia among candidates for metabolic surgery. Accurate pre-operative nutritional assessment for iron status is essential because patients with pre-operative anemia and/or iron deficiency are at a higher risk for the development of severe anemia after surgery.12,20 Emerging evidence regarding the potential adverse effects of inflammation on iron nutrition13–15 suggest that assessment of the extent of inflammation by measuring the level of CRP should be a part of the assessment of iron status. When inflammation is present (CRP level>3mg/L), a ferritin level between the lower limit of normal and 100ng/mL is likely to be consistent with iron deficiency.10 These individuals will be less likely to absorb oral iron until inflammation subsides with surgical weight loss and, therefore, might be candidates for liberal use of parenteral iron supplementation. Additional studies are needed to address the recognition and management of functional iron deficiency among candidates for metabolic surgery. In addition, data suggesting that skilled nutritional assessment does not occur in a large fraction of patients undergoing metabolic surgery provide a major opportunity for quality improvement.30

Metabolic surgery results in permanent alterations of foregut anatomy and physiology, which include major reduction in gastric reservoir size as well as acid production, as well as bypass of the duodenum and proximal jejunum, the major locations of mucosal transporters for iron. Liberal postoperative use of medication for acid suppression is also a factor. Surgery is also accompanied by major reductions in food intake, which can accompany anorexia, aversion to food, and intolerance to meat, an important source of heme iron.45–47 Several studies have documented that iron intake after metabolic surgery is reduced below the minimal daily requirement.48,49 These factors explain the high probability of negative iron balance during the early postoperative period. Although this has been recognized, and evidenced-based guidelines have been developed mandating nutritional assessment for preoperative patients and iron supplementation at a dose of 45 to 60mg/day after surgery,50 the level of evidence supporting these guidelines is admittedly weak, mandating additional systematic study. The current guidelines are based on a randomized prospective trial conducted by Brolin et al51 in 1998, one of the few high-quality clinical studies of iron nutrition after gastric bypass. In this prospective randomized trial, investigators demonstrated the protective benefits of supplementation on iron status but not on anemia in the early postoperative interval after RYGB.

Multiple other issues contribute to the high prevalence of iron deficiency after metabolic surgery. Major limitations in perioperative nutritional screening,30 failure to consistently provide supplements,52 poor patient adherence to supplementation,53 the association of iron supplementation with troublesome gastrointestinal side effects,54 large gaps in nutritional follow-up,55 and the absence of specialized nutritional care after surgery. Considered together, these issues define a growing challenge for quality improvement. Historically, metabolic surgeons have relied on referring primary care providers to provide the nutritional surveillance and follow-up after surgery. The findings summarized here suggest that surgical providers need to become more familiar with best practice guidelines for nutritional care and that specialized patient-centered nutritional management should emerge as the standard of care. Two recent small studies in a total of 48 patients suggest that the use of oral iron supplements closely supervised by nutrition specialists for patients in the late postoperative period after RYGB can improve iron status and anemia.56,57 

Future Considerations

These findings provide evidence supporting the need for an increased focus on iron nutrition in metabolic surgery programs because this is a potentially modifiable nutritional complication that can detract from the health benefits of surgical weight loss. The chronic fatigue associated with iron deficiency alone or iron deficiency anemia has adverse effects on exercise tolerance and overall feeling of well-being. There is a need for systematic study of pre- and postoperative iron nutrition with close follow-up by nutritional specialists to provide evidence-based guidelines for the management of patients with systemic inflammation and iron nutrition abnormalities, and to establish indications for the use of parenteral iron replacement. The newer parenteral iron formulations have improved safety and are commonly used in postoperative patients with iron deficiency anemia who do not respond to oral supplementation. Potential target groups for inclusion in clinical trials are premenopausal candidates for metabolic surgery and surgical candidates with pre-operative iron deficiency because these patients are at the highest risk for postoperative severe anemia. Using Cox regression, we have identified the following independent risk factors for the development severe anemia after surgery: men and women aged 40 or older, preoperative anemia, pre-operative low ferritin level, and a rapid six-month weight loss trajectory. A post-RYGB severe anemia (hemoglobin<8) risk scoring system using these risk factors and their hazard ratios was developed to better identify patients at risk. The scoring system allows 1 point for pre-RYGB anemia, 1 point for six-month post-RYGB weight loss more than 35 percent, 2 points for women, 2 points for men aged 40 or more, and 2 points for a pre-RYGB low ferritin level. The final score ranged from 0 (lowest risk) to 6 (greatest risk). Higher scores are associated with higher rates of severe anemia.20 

The adverse clinical effects of iron deficiency and severe anemia after metabolic surgery and the fact that it is potentially correctable should be a stimulus for additional research and improved quality of nutritional care.

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