on 30-Mar-2021 (Tue)

Iron deficiency, as defined by one of the tests listed below (see 'Diagnosis' below), affects a large proportion of the world's population, especially women of childbearing age, children, and individuals living in low- and middle-income countries.

In all of the studies that evaluate the scope of the problem, iron deficiency is more prevalent than iron deficiency anemia (low hemoglobin or hematocrit caused by iron deficiency), and females are affected more than males.

For females, iron deficiency anemia was present in nearly 20,000 per 100,000 population (approximately one in five). For both decades and for virtually every population (males, females, different regions of the world), iron deficiency accounted for the largest proportion of cases of anemia. These findings are illustrated in the figure (figure 1).

Iron deficiency anemia in older adults is also greater than that seen in the general population. In a series of 190 adults in the community >65 years of age with anemia, 12 percent were due to iron deficiency [6].

Carrier status for a hereditary hemochromatosis variant in the HFE gene (C282Y or H63D) did not correlate with the prevalence of iron deficiency in any racial or age group in HEIRS participants.

Various blood donor series from a number of North American and European countries have estimated the rate of subclinical iron deficiency in the range of 5 to 15 percent [9,10]. This has led some experts to consider screening for iron deficiency and/or recommending iron supplementation for blood donors, as discussed separately.

The major causes of iron deficiency are decreased dietary intake, reduced absorption, and blood loss.

Overt bleeding is obvious and not difficult for the clinician to recognize, often by history alone:

● Traumatic hemorrhage

● Hematemesis or melena

● Hemoptysis

● Heavy menstrual bleeding

● Pregnancy and delivery

● Hematuria

Other causes of blood loss that may be overlooked include:

● Frequent blood donation

● Excessive diagnostic blood testing

● Underestimation of the degree of heavy menstrual bleeding

● Pregnancy and lactation, with a greater likelihood as the number of pregnancies increases

● Occult bleeding, typically gastrointestinal (eg, gastritis, malignancy, angiodysplasia) but may also include hemolysis with urinary losses

● Exercise-induced blood loss, often due to occult gastrointestinal bleeding (see "Exercise-related gastrointestinal disorders", section on 'Gastrointestinal bleeding')

● Gastrointestinal parasites (eg, hookworm, whipworm), especially in developing countries

Typical iron loss during pregnancy has been estimated at approximately 1000 mg for pregnancy, delivery, and nursing. Menstrual blood losses account for approximately 1 mg of iron loss per day.

Typical iron loss during hemodialysis may be as much as 2 g per year, which is highly likely to produce iron deficiency without supplementation.

In a 2012 series of 621 patients with definite or probable iron deficiency anemia, cancer and high-risk adenomas were identified in 51 of 310 (16 percent) of the individuals who underwent endoscopy [17].

Iron is absorbed in the upper gastrointestinal tract; the duodenum is the site of maximal absorption [20].

The most clinically important are disorders that affect the mucosal cells responsible for iron absorption, such as celiac disease, atrophic gastritis, Helicobacter pylori infection, and bariatric surgery. Inherited disorders that interfere with iron absorption are very rare.

Dietary heme iron (iron from meat rather than plant sources) is better absorbed than non-heme iron. A review of published studies that evaluated vegetarians and non-vegetarians found that those who consumed a vegetarian diet were more likely to be iron deficient [21]. However, non-heme iron is available from a wide array of vegetables and supplemented grains and cereals, as summarized in the table (table 1).

A number of foods may impair iron absorption such as tannates, phosphates, phytates (mineral-binding compounds found in whole grains and seeds), and foods high in calcium (table 2).

It would be very difficult to develop iron deficiency solely due to these dietary factors, but they may contribute to iron deficiency in the setting of blood loss, or, less commonly, extremely low intake [16].

Celiac disease (also called gluten-sensitive enteropathy or nontropical sprue) is a disorder of small bowel inflammation triggered by exposure to gluten in susceptible individuals. It predominantly affects White populations of northern European ancestry, with a prevalence of approximately 1 in 70 to 1 in 300 (0.3 to 1 percent) in these populations.

Celiac disease can contribute to anemia by several mechanisms, including iron deficiency, reduced absorption of supplemental iron, and malabsorption of other nutrients required for red blood cell (RBC) production including vitamin B12, folic acid, and copper [22]. There may also be a component of anemia of chronic disease/anemia of inflammation (ACD/AI) as well as blood loss, although the contribution (if any) of gastrointestinal blood loss from celiac disease to iron deficiency is unclear [22].

Gastritis related to an autoimmune mechanism (eg, anti-parietal cell antibodies) or H. pylori has also been implicated in causing iron deficiency [25,26].

In another series of 71 patients with iron deficiency anemia who did not have an obvious source of blood loss and underwent upper and lower endoscopy, diagnoses related to reduced absorption included atrophic gastritis in 19 (27 percent) and H. pylori in 13 (18 percent), as well as celiac disease in four (6 percent) [14].

Bariatric surgery — Iron needs to be conjugated to vitamin C, amino acids, or sugars in the presence of gastric acid to protect it from the alkaline secretions in the proximal jejunum, which will otherwise convert the iron to ferric hydroxide (rust), which is unabsorbable. Bariatric surgery includes a number of procedures that promote weight loss by limiting gastric reservoir capacity and/or shortening the length of functional small intestine, which causes malabsorption. Procedures that bypass the duodenum such as roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (BPD-DS) have the greatest risk of causing iron deficiency because they reduce the site of maximal absorption and in some cases reduce gastric acid availability.

Medications — An acidic gastric environment facilitates absorption of iron, especially non-heme iron. However, reduced gastric acidity by itself is unlikely to cause clinically significant iron deficiency in an individual with an adequate dietary iron intake and a normally functioning gastrointestinal tract.

However, these studies indicate association rather than causation; individuals taking a PPI are more likely to have gastrointestinal conditions that lead to bleeding or reduced iron absorption, such as those listed above.

If an individual with iron deficiency is taking a PPI, antacid, or histamine receptor blocker, we do not attribute iron deficiency to the medication without performing an evaluation for bleeding or reduced iron absorption as indicated for the individual. Further, we take the opportunity to re-evaluate whether the PPI is actually indicated, and we review the symptoms that led to PPI use and make sure they are properly evaluated.

These individuals may lose an average of 2 g of iron per year, mainly from repeated blood testing and blood losses within the hemodialysis circuit [32]. Thus, iron deficiency will develop in almost all patients undergoing dialysis who are treated with EPO, as well as some individuals with chronic renal failure not receiving dialysis, unless supplemental iron is administered.

Urinary – Chronic or intermittent intravascular hemolysis with hemosiderin accumulation in urinary epithelial cells may lead to iron loss through urinary shedding of these cells. Examples include individuals with intensive athletic training, prosthetic heart valve-associated hemolysis, or paroxysmal nocturnal hemoglobinuria (PNH).

Pulmonary – Pulmonary hemosiderosis, such as in individuals with diffuse alveolar hemorrhage or idiopathic pulmonary hemosiderosis may lead to iron loss through iron-laden alveolar or bronchial epithelial cells. These conditions also may cause a component of functional iron deficiency, in which iron is trapped in pulmonary macrophages.

IRIDA due to TMPRSS6 mutation – Iron refractory iron deficiency anemia (IRIDA) is a rare inherited disorder in which absorption of oral iron is markedly impaired. IRIDA is caused by loss-of-function mutations of the TMPRSS6/matriptase 2 gene, which encodes a serine protease that cleaves membrane-bound hemojuvelin [33-42]. Membrane-bound hemojuvelin promotes hepcidin synthesis and impairs iron absorption in the gut; cleavage of membrane-bound hemojuvelin reduces hepcidin synthesis, increasing iron absorption. Loss of TMPRSS6 function thus causes iron deficiency due to inappropriately high hepcidin levels, with markedly reduced iron absorption and increased sequestration of iron in macrophages [39,43-48].

SLC11A2 mutation – Iron deficiency anemia has also been described in individuals with mutations in the SLC11A2 gene, which encodes the divalent metal transporter DMT1 [49-53].

High-intensity athletics — Iron deficiency may be seen in some athletes due to gastrointestinal bleeding or reduced iron intake [54,55]. Other causes of anemia may also contribute.

Normal body iron content — The normal body iron content in an adult is approximately 3 to 4 grams. The majority of iron is present in circulating red blood cells (RBCs), with additional iron in myoglobin and certain enzymes, as well as iron in storage and transport forms (figure 3)

Typical amounts of iron in these sites is as follows ( table 3):

● RBCs – Approximately 2 g, corresponding to approximately 2000 mL (25 to 30 mL/kg) of RBCs

● Iron-containing proteins (eg, myoglobin, cytochromes, catalase) – Approximately 400 mg

● Plasma iron bound to transferrin – 3 to 7 mg

● Storage iron in the form of ferritin or hemosiderin – Approximately 0.8 to 1 g (men); approximately 0.4 to 0.5 g (women)

Storage iron in adult men has been estimated as being approximately 10 mg/kg, and is found mostly in the monocyte-macrophage system in the liver, spleen, and bone marrow. Adult women have less storage iron, depending upon the extent of menses, pregnancies, deliveries, lactation, and iron intake. In one study, 93 percent of women in the United States 20 to 45 years of age had iron stores of 5.5 ± 3.4 mg/kg, while the other 7 percent had an iron deficit of 3.9 ± 3.2 mg/kg [56].

Iron deficiency occurs in several stages, as illustrated by progressive changes in laboratory findings (table 4) [11,15]. These stages are defined by the extent of depletion, first of iron stores and then of iron available for hemoglobin synthesis. Eventually, if negative iron balance continues, production of iron-deficient RBCs and anemia occurs.

In the first stage, iron stores can be totally depleted without causing anemia. Once these stores are depleted, there is still enough iron present in the body within the "labile" iron pool from the daily turnover of red cells for normal hemoglobin synthesis, but the individual becomes vulnerable to development of anemia should there be further iron losses. Some individuals with extremely low levels of serum ferritin, but without anemia, may have symptoms of fatigue or show decreased exercise tolerance at this stage.

Further loss of iron results in anemia, which is initially normocytic with a normal absolute reticulocyte count (table 4). This stage of iron deficiency is common in the United States. As noted above, it has been estimated that the proportion of menstruating women in the United States who have minimal or absent iron reserves is at least 20 percent and may be as high as 65 percent [58,59]. Common laboratory findings at this stage include:

● Low levels of ferritin and serum iron (Fe).

● Increased levels of transferrin (Tf; total iron binding capacity [TIBC]). If only transferrin concentrations are available, they can be converted to the TIBC (in mcg/dL) by multiplying the transferrin concentration (in mg/dL) by 1.389.

● Low percent saturation of transferrin (ie, Fe/TIBC or Fe/Tf, stated as a percent).

● Increased unsaturated iron binding capacity (UIBC = TIBC - Fe).

More profound deficiency results in the classical findings of anemia with RBCs that are hypochromic (low mean corpuscular hemoglobin [MCH]) and microcytic (low mean corpuscular volume [MCV]). Reticulocyte production cannot be increased in the setting of iron deficiency, and the reticulocyte count becomes inappropriately low (despite being in the "normal" range in many cases). It is worth noting, however, that other concomitant causes of anemia such as vitamin B12 deficiency may cause macrocytosis and obscure the microcytosis caused by iron deficiency.

Erythropoiesis-stimulating agents – Another mechanism of functional iron deficiency is treatment with erythropoiesis-stimulating agents (erythropoietin and darbepoetin) in individuals with renal insufficiency or cancer and chemotherapy-induced anemia. In these cases, iron stores may be available but their release into the circulation may not be rapid enough to support the increased erythropoietic rate; thus, these individuals have insufficient iron stores to respond to the ESA; this is also referred to as iron restricted erythropoiesis.

Symptoms of anemia — The usual presenting symptoms in adults with iron deficiency are primarily due to anemia. The same symptoms may also be present in those with severely reduced iron stores and extremely low serum ferritin who are not anemic. Typical symptoms include [16]:

● Fatigue

● Pica (Pagophagia)

● Restless legs syndrome

● Headache

● Exercise intolerance

● Exertional dyspnea

● Weakness

The classic presentation pattern in a patient without comorbidities is a multigravid woman who presents with tiredness and fatigue and a complete blood count (CBC) that shows anemia with low MCV (eg, hemoglobin 8 g/dL, MCV 75 fL) and a peripheral blood smear that shows microcytic, hypochromic RBCs (picture 1). Iron studies are likely to show low iron in the range of 10 mcg/dL, low ferritin (below 30 ng/mL), and increased transferrin (around 400 mcg/dL) or high TIBC, with a low calculated transferrin saturation (TSAT; below 20 percent). Such a patient is likely to have a brisk response to iron therapy. It is also important to consider the possibility of gastrointestinal blood loss, even in a menstruating woman.

Pica and ice craving — Pica refers to a desire for or compulsion to eat substances not fit as food; the term is derived from the Latin word for magpie (Pica pica), a bird that gathers non-food objects [62]. These substances may include earth substances such as clay or dirt (geophagia); paper products including wallpaper or toilet paper; starches including corn starch, laundry starch, fabric softener sheets, or raw rice or pasta (amylophagia); or ice (pagophagia).

Overall, pica may be seen in many clinical settings and is not considered specific for iron deficiency. However, pagophagia (pica for ice) is considered quite specific for iron deficiency [63,65,66]. It may be present in patients who are not anemic and responds rapidly to treatment with iron (disappears during iron infusions), often before any increase is noted in the hemoglobin concentration. In one study of 55 unselected patients with iron deficiency anemia secondary to gastrointestinal blood loss, pica was present in 32 (58 percent), which manifested as pagophagia in 28 (51 percent of the total; 88 percent of those with pica) [65].

Beeturia — Beeturia is a phenomenon in which the urine turns red following ingestion of beets. Beeturia is increased in individuals with iron deficiency but the finding is not specific for iron deficiency. It has been noted in approximately 10 to 14 percent of healthy individuals following ingestion of beets and in as much as 49 to 80 percent of individuals with iron deficiency [67-69].

Beeturia is caused by increased intestinal absorption and subsequent excretion of the reddish pigment betalaine (betanin) present in beets. Betalaine, a redox indicator, is decolorized by ferric ions, which presumably explains the predisposition to beeturia when adequate amounts of iron are not available for decolorization of this pigment.

Restless legs syndrome — Restless legs syndrome (RLS), also called Willis-Ekbom disease, is a disorder in which there is an unpleasant or uncomfortable urge to move the legs during periods of inactivity. The discomfort is relieved by movement, often instantaneously. A number of changes in the central nervous system have been correlated with RLS. Of these, reduced iron in the central nervous system has been a consistent finding, regardless of total body iron stores.

RLS is common in the general population, in some series affecting 5 to 15 percent of adults, especially in White populations. Iron deficiency may be one of the more common causes of RLS, and RLS may be one of the more common clinical manifestations of iron deficiency. As an example, in a series of 251 patients with iron deficiency anemia referred to a community-based hematology practice, the prevalence of clinically significant RLS was 24 percent, approximately nine times higher than that seen in the control population [70].

While overall findings linking RLS to iron deficiency are not conclusive, they warrant the measurement of hemoglobin and iron parameters in individuals who present with this symptom, and administration of iron when stores are low.

Findings on examination — The physical examination in individuals with iron deficiency (with or without anemia) may be normal or it may reveal one or more of the following findings [16,73]:

● Pallor

● Dry or rough skin

● Atrophic glossitis with loss of tongue papillae, which may be accompanied by tongue pain or dry mouth (picture 2 and picture 3) [74]

● Cheilosis (also called angular cheilitis) (picture 4 and picture 5)

● Koilonychia (spoon nails) (picture 6 and picture 7)

● Esophageal web, which may be accompanied by dysphagia (eg, Plummer-Vinson or Patterson-Kelly syndrome; rare)

● Alopecia (rare) in especially severe cases [75]

● Chlorosis (pale, faintly green complexion; extremely rare)

The more severe of these findings, including chlorosis and Plummer-Vinson syndrome, which were more common during the early 1900s, have virtually disappeared [76,77]. Patients with more severe anemia may have tachycardia, a cardiac murmur, or (rarely) hemodynamic instability [16].

For individuals with gastrointestinal blood loss, the stool may show overt or occult blood. However, absence of blood in the stool does not eliminate the possibilities of gastrointestinal bleeding or iron deficiency (or the need to evaluate for a source of gastrointestinal bleeding when appropriate), because bleeding may be intermittent.

INTRINSIC VALUE

Tughlaq's Token coin

Proton pump inhibitors (PPIs) effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane.

Proton pump inhibitor (PPI) therapy is indicated in the following clinical situations:

● Peptic ulcer disease – PPIs are first-line antisecretory therapy in the treatment of peptic ulcer disease. (See "Peptic ulcer disease: Treatment and secondary prevention", section on 'Initial antisecretory therapy'.)

● Gastroesophageal reflux disease – PPIs are indicated in patients with gastroesophageal reflux disease, including for the treatment of erosive esophagitis and as maintenance therapy in patients with severe erosive esophagitis or Barrett’s esophagus. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Severe or frequent symptoms or erosive esophagitis'.)

● Zollinger-Ellison syndrome – PPIs, often in high doses, are required to control gastric acid hypersecretion in patients with gastrin-secreting tumors. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)", section on 'Proton pump inhibitors'.)

● NSAID-associated ulcers – PPIs are indicated in the primary prevention of gastroduodenal ulcers associated with NSAID use. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

● Eradication of Helicobacter pylori – PPIs are a component of several first-line and salvage therapy regimens for H. pylori infection. (See "Treatment regimens for Helicobacter pylori in adults".)

PPIs are benzimidazole prodrugs which accumulate specifically and selectively in the secretory canaliculus of the parietal cell [1]. Within that space, they undergo an acid catalyzed conversion to a reactive species, the thiophilic sulfonamides, which are permanent cations. The rate of conversion varies among the compounds and is inversely proportional to the pKa of the benzimidazole (rabeprazole >omeprazole, esomeprazole, and lansoprazole >pantoprazole) (table 1) [2].

Proton pump inhibitors (PPIs) inhibit H-K-ATPase, the final step of gastric acid secretion by parietal cells.

PPIs are similar in structure and mechanism of action, but PPIs differ in their pKa, bioavailability, peak plasma levels, and route of excretion (table 1). The magnitude of these differences are small and their clinical relevance has not been established.

PPIs are most effective when the parietal cell is stimulated to secrete acid postprandially, a relationship that has important clinical implications for timing of administration. Because the amount of H-K-ATPase present in the parietal cell is greatest after a prolonged fast, PPIs should be administered before the first meal of the day. In most individuals, once-daily dosing is sufficient to produce the desired level of acid inhibition, and a second dose, which is occasionally necessary, should be administered before the evening meal [1]

Once-daily PPI dosing for five days inhibits maximal gastric acid output by approximately 66 percent. Since PPIs inhibit only activated enzyme present in the canalicular membrane, the reduction of gastric acid secretion after an initial dose will probably be suboptimal. As inactive enzyme is recruited into the secretory canaliculus, acid secretion will resume, albeit at a reduced level. After the second dose is given on the next day, more H-K-ATPase will have been recruited and subsequently inhibited, and after the third dose, additional recruitment and further acid inhibition will probably occur. Thus, the occasional use of a PPI taken on an "as needed" basis does not reliably provide adequate acid inhibition and does not produce a consistent or satisfactory clinical response (in contrast to the H2 antagonists, which have a more rapid onset of action) [1].

Restoration of acid secretion after discontinuing PPIs depends upon enzyme turnover and the biological reversibility of the disulfide bond. Maximal acid secretory capacity may not be restored for 24 to 48 hours [1].

Plasma levels of PPI correlate with their metabolism, and differences may contribute to varying dose requirements and clinical efficacy. As an example, one study examined the effect of variable metabolism of omeprazole when using this agent to treat H. pylori in 62 Japanese patients [3]. While eradication was achieved in all individuals homozygous for a CYP2C19 mutation (ie, slow metabolizers), successful treatment was achieved in only 60 and 29 percent of heterozygotes and wild type homozygotes, respectively.

HIV protease inhibitors - PPIs may decrease the absorption of certain HIV protease inhibitors. PPIs are contraindicated in patients being treated with rilpivirine. Atazanavir should not be used in patients who require a PPI dose equivalent to >20 mg omeprazole daily.

Methotrexate - Coadministration of PPIs with high dose methotrexate appears to be correlated with delayed methotrexate elimination and potentially may lead to methotrexate toxicity if not monitored appropriately.

Clopidogrel - Some data suggest decreased activation of clopidogrel when used in conjunction with omeprazole due to shared hepatic cytochrome P450-mediated metabolism. In 2009, the United States Food and Drug Administration concluded that patients taking clopidogrel should consult with their clinician if they are taking or considering taking a PPI, including over-the-counter PPI preparations [13,14]. However, the relevance of these data remains highly controversial. The interaction of clopidogrel and PPIs are discussed in detail separately.

Magnesium – We obtain serum magnesium levels prior to starting a PPI in patients who are expected to be on long-term (≥1 year) treatment or in patients who take PPIs in conjunction with other medications associated with hypomagnesemia (eg, diuretics). In addition, we obtain magnesium levels periodically in such patients while they are taking a PPI. The frequency of testing is based on the clinical history and the presence of symptoms of hypomagnesemia. As an example, in patients with a history of arrhythmias or QT interval prolongation, we monitor magnesium levels every six months. The management of hypomagnesemia is discussed in detail separately.

Vitamin B12 – We also obtain vitamin B12 levels yearly in patients on long-term PPIs [15]. However, routinely monitoring vitamin B12 levels is controversial.

There are insufficient evidence to support routine bone density monitoring or calcium supplementation due to proton pump inhibitor use alone [16].