Iron Deficiency Anemia Due to Malabsorption

Article written and reviewed by Dr Luca Moretti

Iron deficiency anemia due to malabsorption is a less common but clinically relevant cause of iron deficiency in industrialized countries and many vulnerable populations, characterized by deficiency secondary to insufficient intestinal iron absorption despite adequate dietary intake. The predominant mechanism is reduced intestinal iron absorption, but low intake and chronic losses may coexist and should be assessed in the clinical context.

For an overview of iron physiology and the pathogenesis of iron deficiency anemia, see the main page.

Etiology, Pathogenesis and Pathophysiology

Iron deficiency anemia due to malabsorption develops when dietary iron cannot be adequately absorbed from the gastrointestinal tract, particularly in the duodenum and proximal jejunum, the principal sites of absorption of both heme and nonheme iron. The main causes can be divided into three categories:

• Intestinal mucosal disorders: conditions that directly injure enterocytes or mucosal structure, such as celiac disease, a gluten related enteropathy, Crohn disease when localized to the small intestine, autoimmune enteropathies, tropical sprue and chronic infectious diseases, including giardiasis, HIV and intestinal tuberculosis.
• Surgical resections and intestinal bypasses: duodenectomy, total or subtotal gastrectomy, gastric bypass and bariatric procedures, which can reduce absorptive surface, alter gastric acidity or exclude the duodenum from chyme transit, thereby reducing iron absorption.
• Alterations of the gastric environment: atrophic gastritis, achlorhydria and prolonged proton pump inhibitor use may reduce iron solubilization and absorption in selected patients.

Impaired iron absorption causes progressive depletion of stores, reflected by ferritin, followed by reduced serum iron and development of hypochromic, microcytic anemia. Unlike malnutrition due to low intake, dietary intake may be adequate, but the absorption defect may prevent replenishment of iron stores.

In chronic or severe forms, iron deficiency is frequently accompanied by malabsorption of other micronutrients, including fat soluble vitamins, vitamin B12, folate and calcium, producing clinical manifestations of multiple deficiencies.

Risk factors and prevention

Specific risk factors for anemia due to malabsorption include conditions that alter gastrointestinal physiology and are often already known from the medical history:

• Known diagnosis of celiac disease or Crohn disease involving the small intestine
• History of gastrointestinal surgery, including duodenal or jejunal resection, gastrectomy or bariatric bypass
• Chronic treatment with proton pump inhibitors or antacids at high doses
• Short bowel syndrome and rare disorders of intestinal transport
• Selected intestinal infections that damage the mucosa. Hookworm infection causes iron deficiency mainly through chronic blood loss and should be considered in the differential diagnosis.

Prevention is complex and requires optimal management of the underlying disorder, including control of celiac disease, treatment of inflammatory bowel disease and nutritional assessment in patients undergoing bariatric surgery, together with careful monitoring of iron status and targeted supplementation with iron and other micronutrients in individuals at risk.

Clinical Manifestations

In addition to the typical clinical manifestations of iron deficiency, see general clinical features, the clinical picture of iron deficiency anemia due to malabsorption often includes signs and symptoms of the underlying intestinal disorder and has several distinctive features:

• It is frequently associated with chronic diarrhea, steatorrhea, weight loss and signs of deficiency of other nutrients, including vitamin deficiency, skin abnormalities and neuropathies.
• It may be the first sign of an unrecognized intestinal disorder, especially in adults and older adults, such as late onset celiac disease or previously undiagnosed Crohn disease.
• In patients who have undergone bariatric surgery, iron deficiency may appear months or years after the procedure, often without obvious gastrointestinal symptoms.
• In children, in addition to the symptoms described, growth delay, poor appetite, irritability and multiple nutritional deficiencies are observed.
• In chronic intestinal infestations, general symptoms such as malaise and fatigue may be associated with signs specific to the parasitic disease.

Careful assessment of extrahematologic signs, including vitamin malabsorption, gastrointestinal disturbances and known chronic intestinal disease, helps distinguish this form from other causes of iron deficiency anemia.

Investigations and Diagnosis

Diagnosis of iron deficiency anemia due to malabsorption requires an integrated pathway based on:

• Detailed medical history: assessment of previous surgery, known intestinal disorders, medications, chronic gastrointestinal symptoms and signs of malabsorption.
• Physical examination: assessment for signs of malnutrition such as weight loss and vitamin deficiencies, possible abdominal masses, skin abnormalities, glossitis, cheilitis and koilonychia.
• Laboratory tests: generally microcytic and hypochromic anemia with reduced ferritin, serum iron and transferrin saturation and increased transferrin. Other deficiencies, including vitamin B12, folate, fat soluble vitamins, albumin, calcium and magnesium, often coexist.
• Second line tests targeted according to clinical suspicion:
  • Anti tissue transglutaminase antibodies and duodenal biopsy for suspected celiac disease
  • Fecal calprotectin, colonoscopy and intestinal imaging for suspected inflammatory bowel disease
  • Tests directed at the suspected cause, such as celiac serology, endoscopy, imaging or selected microbiologic investigations
  • Radiologic and endoscopic investigations to assess intestinal transit and morphology
• Response to therapy: failure to respond to oral iron is an indirect sign of malabsorption and may guide the diagnosis in uncertain cases.

The differential diagnosis includes all other causes of iron deficiency anemia, but coexistence of clinical and laboratory signs of malabsorption makes this form readily identifiable in specialist centers.

Treatment and Prognosis

Management of iron deficiency anemia due to malabsorption requires a multidisciplinary and sequential approach:

• Correction of the underlying disorder: adoption of a gluten free diet in celiac disease, treatment of inflammatory bowel disease, treatment of relevant intestinal infections and surgical correction, when possible, of anatomic abnormalities or complications.
• Iron therapy: oral iron may be adequate in mild forms or when residual absorption is sufficient. Intravenous iron is preferred when malabsorption is clinically significant, the oral response is inadequate or more rapid correction is required.
• Supplementation of other micronutrients: vitamin B12, folic acid, fat soluble vitamins, calcium and magnesium often need to be replaced according to documented deficiencies.
• Patient education: particular attention should be paid to dietary adherence, monitoring of hematologic and nutritional parameters and regular follow up at specialist centers.

Prognosis depends on reversibility of malabsorption and the timeliness of diagnosis and treatment. In patients with chronic disorders, long term monitoring and repeated courses of iron supplementation are often required.

Complications

Complications of iron deficiency anemia due to malabsorption may be particularly serious because of both anemia and concomitant deficiency of other essential nutrients:

• Worsening systemic manifestations: the combination of anemia, vitamin deficiencies and hypoproteinemia may worsen physical performance, infection risk and general condition.
• Developmental complications in children: neurocognitive and behavioral abnormalities may be associated with prolonged iron deficiency; neuropathies suggest primarily concomitant vitamin deficiencies.
• Increased risk of osteoporosis and fractures with prolonged vitamin D and calcium deficiency.
• Increased risk of obstetric complications in pregnant women.
• Frequent recurrence of anemia when the underlying disease is not optimally managed.

Multidisciplinary care, management of gastroenterologic complications and nutritional surveillance are essential to prevent permanent harm and improve patients’ quality of life.

Bibliography
1. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832-1843.
2. Lopez A et al. Iron deficiency anaemia. Lancet. 2016;387(10021):907-916.
3. Johnson-Wimbley TD et al. Diagnosis and management of iron deficiency anemia in the 21st century. Ther Adv Gastroenterol. 2011;4(3):177-184.
4. DeLoughery TG, Jackson CS, Ko CW, Rockey DC. AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review. Clin Gastroenterol Hepatol. 2024;22(8):1575–1583.
5. Baumgart DC et al. Crohn's disease. Lancet. 2012;380(9853):1590-1605.
6. Ludvigsson JF et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63(8):1210-1228.
7. Snook J, et al. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut. 2021;70(11):2030–2051.
8. Fletcher A, Forbes A, Svenson N, Thomas DW; A British Society for Haematology Good Practice Paper. Guideline for the laboratory diagnosis of iron deficiency in adults (excluding pregnancy) and children. Br J Haematol. 2022;196(3):523–529.
9. Ko CW, Siddique SM, Patel A, et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020;159(3):1085-1094.
10. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721-1741.