Abstract

Adults with celiac disease may be complicated by iron deficiency anemia, largely because the primary site of intestinal involvement in celiac disease, the duodenum, is also the most important site for intestinal absorption of iron. In some, iron deficiency anemia may be the sole presenting feature of celiac disease even in the absence of diarrhea or weight loss. Even in treated and long-standing celiac disease, persistence of iron deficiency anemia, or even its new appearance, may be important as clinical markers for an additional or superimposed cause including ulcerative or neoplastic disease, including lymphoma. Other rare causes include a hemolytic disorder, sometimes immune-mediated, anemia associated with a chronic inflammatory disease process, or a sideroblastic anemia, reported to also respond to a gluten-free diet.

1. Introduction

Iron deficiency anemia may be caused by chronic blood loss, intravascular hemolysis, with renal iron loss as hemosiderin (eg., paroxysmal nocturnal hemoglobinuria), and impaired iron absorption. More specifically, iron deficiency anemia may complicate diseases, especially involving the proximal small intestine, such as established adult celiac disease or be the only presenting and sole clinical feature in occult celiac disease ¹. Interestingly, this relationship has been reported to be poorly appreciated, even among subspecialty physicians, such as practicing hematologists ². At the same time, gastrointestinal specialists, including surgeons, may focus efforts on detection of colorectal malignancy, particularly in the cecum, causing insidious blood loss.

2. Microcytic Anemia and Iron Deficiency

Worldwide, microcytic anemia is very common being caused not only by iron deficiency, but also from other causes including hemoglobinopathies, such as thalassemia, or anemias associated with an underlying chronic inflammatory disease, or a sideroblastic anemia ³. Iron is a critical component of the heme group in hemoglobin for oxygen transport as well as other proteins, including cytochromes and myoglobin. Some have suggested that this may cause fatigue associated with iron deficiency alone (without anemia), particularly in females ⁴. Due to menstruation, pre-menopausal females may be at increased risk for iron deficiency and pregnancy may further increase their requirements for iron. Iron deficiency may also commonly occur in athletes, possibly related to increases in gastrointestinal blood loss, low grade intravascular hemolysis and urinary iron loss ^{5, 6}. If celiac disease is also present, the degree of iron deficiency may be further exacerbated.

3. Mucosal Iron Uptake and Absorption

Iron enters the duodenal epithelial cell in ferrous form through the apical or brush border membrane transport protein, the divalent metal transporter (DMT1) ⁷. This protein spans the brush border membrane structure and may transport other divalent metals. Ordinarily, this carrier operates in a co-transport mode with uni-valent protons ⁸. Human mutations in the DMT1 protein have been described that have been associated with a microcytic anemia ⁹. Interestingly, DMT-1 appears to be ordinarily located near the most luminal aspect of the villus, but with iron deficiency, evidence for DMT-1 localization may be extended all along the villus surface ¹⁰. Moreover, different DMT-1 transcripts have been identified, depending on the presence of an iron-responsive portion that permits DMT-1 up-regulation during iron starvation in celiac disease ¹¹. DMT-1 transport of iron requires conversion of ferric ion (mainly from food) to a ferrous form through the activity of ferric reductases on the apical or brush border membrane. An acidic surface microvillus membrane microenvironment is also needed. After epithelial cell uptake, a large amount of iron may be stored in the form of ferritin within the epithelial cell, itself. Later, controlled and regulated delivery of iron from the epithelial cell through its basolateral membrane occurs.

Iron exits the duodenal epithelial cell by means of a different carrier protein, ferroportin, or the so-called metal transporter, MTP1, localized within the basolateral membrane. There, iron sequentially binds to an independent glycosylated protein, transferrin, that facilitates iron delivery through the bloodstream to developing red blood cells. Transferrin may transport two ferric ions to distant target tissues. Before binding to transferrin, ferrous ions must be converted back to ferric ions by ferroxidases (eg., hephaestin, ceruloplasmin) ¹². Iron uptake into target cells may be eventually reduced if there is deficiency of these ferroxidase activities. Excessive iron may be transported to the liver for storage and eventual release for transport to developing red blood cells.

4. Control or Regulation of Iron Absorption

Iron storage in the body is generally maintained within a controlled range. With low stores of iron, absorption of iron is increased; with iron overload, absorption of iron is decreased ¹³. This homeostasis of body iron is regulated by hepcidin ¹⁴.

Hepcidin is synthesized by hepatocytes and secreted into the circulation. This protein is found in free form in plasma and undergoes renal filtration. Hepcidin controls iron flow into the plasma through ferroportin. After hepcidin binds to ferroportin, endocytosis occurs with intracellular lysosomal destruction of hepcidin. This impairs iron absorption with release of iron into the circulation prevented from both enterocytes and hepatocytes. Mutations in the ferroportin protein have been reported that inhibit hepcidin binding and result in iron overload ^{15, 16}. Hepcidin may also be regulated by a bone marrow suppressor of hepcidin that responds to increased erythropoietin due to hypoxia or significant bleeding ^{17, 18}. Hypoxia and cellular iron deficiency might also increase ferroportin independent of hepcidin control.

5. Causes of Iron Deficiency in Celiac Disease

This includes reduced duodenal iron absorption, in large part, due to reduced duodenal mucosal absorptive surface area that occurs preferentially in celiac disease. This also reflects the primary intestinal site of enterocyte uptake of iron, particularly of dietary origin. In untreated celiac disease, the duodenal mucosa poorly absorbs iron, even if provided in a form that supplements normal dietary sources.

Several reports have also suggested that occult blood loss may occur in celiac disease from the mucosal disease per se ^{19, 20}. In some, iron deficiency anemia may suggest a second cause including a superimposed ulcerative small intestinal disorder. Benign mucosal ulcers, so-called non-granulomatous ulcerative jejuno-ileitis, or even malignant ulcers, sometimes due to an occult or cryptic lymphoma, could be responsible ^{21, 22}. This may result in occult blood loss, positive fecal occult blood tests, and eventually over time, iron deficiency and anemia. The converse may also be true. Individuals with malignancy (eg., colorectal cancer) and iron deficiency anemia may be subsequently discovered to have celiac disease as an added cause for iron deficiency ²³. Although colonic malignancies are very rare in celiac disease ²⁴, critical vigilance is important to exclude these other added or second causes of iron deficiency anemia, even if celiac disease has been previously defined.

A less common cause of iron loss in celiac disease is related to intravascular hemolysis, often due to an associated autoimmune disorder. In this setting, increased urine losses of iron may occur. This appears to be a rare source of iron loss ^{25, 26} and improvement with a gluten-free diet has been recorded ²⁶. Colorimetric methods may detect hemosiderin in the urine and further hematologic evaluation may be indicated.

Other rare causes of microcytic anemia (not due to iron deficiency) may co-exist with celiac disease. These include anemia associated with a co-existent chronic inflammatory disease along with a rare sideroblastic anemia associated with pyridoxine deficiency ²⁷. In a single case study, the sideroblastic anemia in a celiac completely responded to a gluten-free diet. Another disorder, rarely associated in children with celiac disease with pulmonary hemosiderosis is the Lane-Hamilton syndrome ²⁸. Some have suggested improvement with a gluten-free diet ²⁸, while others in a much larger series of sero-positive patients reported that steroids and immunosuppressants were required ²⁹. Finally, some celiac patients with gastric involvement ³⁰ were apparently complicated by Helicobacter pylori infection thought to be responsible for iron deficiency ³¹.

Early historical studies confirmed that iron absorption was limited in untreated celiac disease (especially, if iron deficient) and this could be improved with a gluten-free diet ³². As noted above, the main source of deficient iron in untreated celiac disease appears to be due to impaired uptake related to markedly reduced iron mucosal absorptive surface in the duodenum. Since this is the primary site of iron absorption, diseases with abnormal proximal small intestinal mucosa, such as untreated celiac disease, will often be associated with iron deficiency anemia.

However, other factors in celiac disease could play a role. For example, some iron regulatory proteins (DMT1, ferroportin, hephaestin, transferrin receptor protein mRNA) have been measured in controls and iron deficient patients using endoscopic biopsies from the duodenum. These were increased in celiac disease while body iron stores were decreased. However, similar results were defined in iron deficiency states in the absence of celiac disease. These results led to the conclusion that the up-regulation in iron absorption capacity in celiac disease may not be related directly to celiac disease per se but simply to the iron deficient state ³³. Further studies are needed.

6. Conclusion

Iron is a key micronutrient that may be depleted in adults with celiac disease. It may be complicate well established disease and clinical features of iron deficiency may lead to extra-intestinal symptoms and signs presenting as previously unrecognized occult celiac disease. In some, diarrhea and weight loss may be absent. Of course, even in well established celiac disease, the appearance of iron deficiency should lead to exclusion of other causes, including a lymphoma. While reduced duodenal mucosal surface absorptive area due to untreated celiac disease may be largely responsible, recent studies have documented alterations in expression of important iron regulatory proteins, but these changes appear to reflect the iron deficient state, rather than celiac disease per se.

Also important, recent clinical experience has documented that iron refractory or iron resistant forms of iron deficiency in celiac disease may completely resolve with a gluten-free diet alone to treat the duodenal mucosal disorder, rather than treatment with oral iron ³⁴. Duodenal mucosal disease is critical in this setting, but in some, altered erythropoiesis due to the underlying chronic intestinal inflammatory process may also be important. Careful follow-up of these celiac patients is required to ensure that both the celiac disease and their iron deficient state resolves.

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