Iron Deficiency Anemia

What happens to serum iron studies in iron deficiency state?

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  Ferritin is the storage form of iron. When the body iron stores are low, serum ferritin is low.

  
  
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  Low iron stores result in compensatory increase in synthesis of transferrin. (Transferrin is a serum protein that binds and transports iron to various tissues.)

  
  
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  Increase in transferrin means increase in serum iron binding capacity.

  
  
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  As serum iron is low, the iron saturation is low. Iron saturation refers to the number of iron molecules that are bound to transferrin molecule.

Serum iron studies cofirms iron defeciency state. NSIM is to treat the iron deficiency and find the cause.

Rx: Iron replacement therapy (IV or oral) and supportive transfusion as needed. Follow-up response with reticulocyte count and iron studies.

Etiology

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  Main etiology is bleeding.

  
  
  
  
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    Less than 50 years: likely etiology in this age group is menorrhagia in females, and peptic ulcer disease in males.

    
    
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    More than 50 years: consider colon cancer. Check fecal occult blood test and do colonoscopy.

  
  
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  Prematurity: most of the iron stores in the newborns is acquired from mother during third trimester of pregnancy.

  
  
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  In children, there is increased demand for iron, thus decreased intake of iron can easily result in iron deficiency.

  
  
  
  

  ⁴ Cow milk is low in iron.

  In children, if there is no response to iron supplementation, gastrointestinal bleeding due to Meckel’s diverticulum is the potential cause.
  
  
  
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  Chronic mechanical hemolysis (e.g., in mechanical heart valve).

  
  
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  Increased demand after erythropoietin treatment in end-stage renal disease (ESRD) patients.

Anemia of Chronic Disease

Etiology: Any cause of chronic inflammation such as collagen vascular diseases, active malignancy, chronic infection (e.g., chronic osteomyelitis), etc.

Pathphysiology: Increase in inflammatory mediators signal liver to produce hepcidin that blocks the release of iron from its storage form. Increased iron stores mean high serum ferritin

leading to negative feedback for transferrin synthesis (low total iron binding capacity [TIBC]). As iron is not released from its storage form, serum iron and iron saturation is low.

Management: Treat underlying cause.

Supportive Rx: In patients with Hb < 10 g/dL, iron replacement therapy is indicated if ferritin < 100 ng/mL OR iron (transferrin) saturation < 20%. Erythropoietin-stimulating agents are given (e.g., darbepoetin) after ensuring adequate iron stores.

Sideroblastic Anemia

Pathophysiology: Inadequate or abnormal synthesis of protoporphyrin to make heme. This will result in idle iron not being used for hemoglobin synthesis (so serum ferritin, serum iron, and iron saturation is high).

Etiology:

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  Hereditary (congenital)

  
  
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  Alcohol

  
  
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  Vit B₆ (pyridoxine) deficiency: it can be hereditary or acquired (e.g., due to isoniazid use)

  
  
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  Copper or lead poisoning

  
  
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  Clonal sideroblastosis, likely due to underlying myelodysplastic syndrome

  
  

  Diagnostic evaluation: usually history and iron study point toward the diagnosis.

The most specific test is bone marrow biopsy with iron staining (Prussian blue stain) of specimen. In absence of protoporphyrin to complete the hemoglobin synthesis, iron dedicated for heme synthesis becomes trapped in mitochondria of erythrocyte precursors (mitochondria is where heme biosynthesis begins). This shows up like an apparent ring around the nucleus, hence called ringed sideroblasts (white arrows). Sometimes you can see stippled RBCs (basophilic stippling) on peripheral blood smear.

Some types of refractory sideroblastic anemia are associated with myelodysplastic syndrome and development of leukemia. Presence of sideroblasts along with high MCV points toward this development.

Management: Treat underlying cause.

Thalassemia

Definition: Abnormal production of globin protein (of hemoglobin) due to hereditary genetic defect.

Diagnostic evaluation:

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  When to suspect: Microcytic anemia with normal iron panel, and normal red cell distribution width (RDW). Peripheral blood smear shows homogenous hypochromic cells and target,

  
  
  
  

  ⁶ When “target cells” (2) are mentioned in a test question, think of the following conditions: Hemoglobinopathies (hemoglobin C, sickle cell disease, thalassemias, etc.) Liver disease Splenectomy

  or tear drop cells(see ‘1’ on the right image).
  
  
  
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  NSIDx is hemoglobin assay

  
  
  
  

  ⁷ FYI, Hb assaying methods include high-performance liquid chromatography, capillary electrophoresis, and isoelectric fusing. These newer methods are preferred over traditional gel electrophoresis.

  
  
  
  
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  Confirmatory testing includes DNA-based methods (e.g., PCR).

Hemoglobin Assay

To undestand hemoglobin assays, we need to know about different types of hemoglobin.

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  In alpha thalassemias, there is reduced synthesis of all forms of hemoglobin. Four gamma (γ) chains can fuse to form Bart’s hemoblogin, and percentage of Bart’s hemoblogin corresponds with severity of alpha thalassemia. In 3 or 4 genes-deleted severe alpha thalassemias, excess of β chains can fuse to form β-globin tetramer (HbH).

  
  
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  In beta thalassemia, there can be compensatory increase in Hb A₂ or HbF.

Management

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  Severe anemia is treated with regular blood transfusion.

  
  
  
  

  ⁸ This can lead to secondary hemochromatosis (iron overload) later in life. Now serum iron panel will show elevated ferritin and increased iron saturation.

  
  
  
  
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  Splenectomy can decrease the need for transfusion. Spleen is where donor erythrocytes are naturally destroyed.

Prenatal Screening for Thalassemias

Indication: pregnant patients with abnormal screening complete blood count (CBC) (low MCV with normal RDW), or in couples with positive family hx.

Test of choice is hemoglobin assay of both parents.

If hemoglobin assay is negative in at least one parent, the risk of clinically important disease is low. Reassure the parents-to-be. If both are carriers, only then there is a risk of clinically important disease in the baby. Offer counseling and further prenatal diagnostic options.

Other notable causes of macrocytosis:

Vitamin B₁₂ Deficiency

Mechanism of vitamin B₁₂ absorption: Vitamin B₁₂ is released from food in presence of gastric acid. It then binds with intrinsic factor (secreted from gastric parietal cells) in the duodenum, which requires presence of pancreatic enzymes. This vitamin B₁₂–intrinsic factor complex is absorbed by ileum into the circulation.

Etiology of vitamin B12 deficiency:

Additonal manifestation (neurological symptoms): Vitamin B₁₂ deficiency can result in excessive production of methylmalonic acid, which is toxic to myelin sheath leading to demyelination. Patients may develop decreased position and vibratory sense. Glove stocking peripheral neuropathy is common, but note that any nervous system can be involved (autonomic neuropathy, motor paralysis, cranial nerves involvement, dementia, etc.)

Diagnostic Evaluation

Treatment: Oral or intramuscular vitamin B₁₂ supplementation. In patients with significant anemia, neurological symptoms, or pernicious anemia, start intramuscular vitamin B₁₂ injections.

Otherwise, oral vit B12 can be given.

Schilling Test

Even though it is not used for diagnosis nowadays, it is asked on exam, as it requires knowledge of mechanism of vitamin B₁₂ absorption.

How it is performed: Intramuscular vitamin B₁₂ is first given to saturate all the serum vitamin B₁₂ receptors. Next step is oral administration of radiolabeled (RL) vitamin B₁₂. If absorption is intact, the absorbed RL vitamin B₁₂ will be directly excreted with urine (as there are no seats left to bind in receptors).

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  If urinary excretion of RL (radio-labeled) vitamin B₁₂ is high, then the deficiency is related to poor intake.

  
  
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  If urinary excretion of RL vitamin B₁₂ is low, then NSIDx is to add intrinsic factor to oral RL vitamin B₁₂.

  
  
  
  
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    If urinary excretion is high, dx of intrinsic factor deficiency is made.

    
    
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    If urinary excretion is still low, then other dx that can be considered are pancreatitis (test normalizes after pancreatic enzyme supplementation), bacterial overgrowth (normalizes when the test is repated after a trial period of empiric antibiotic therapy), etc.

Folate Deficiency

Treatment: Replace folate (almost always orally, because the MCC of folate deficiency is due to decreased intake or absorption).

Autoimmune Hemolytic Anemia

Hereditary Spherocytosis

Background: It is mostly of autosomal dominant inheritance. It is due to genetic defect of structural proteins that are involved in giving the biconcave shape to RBCs. One of the commonly involved protein is called spectrin.

Pathophysiology: RBCs in this disorder are spherocytic, they cannot squeeze through the splenic sinusoids and are subsequently eaten up by splenic macrophages. These patients have chronically elevated bilirubin (due to chronic hemolysis), which in turn increases the risk of calcium bilirubinate gallbladder stones formation.

When to suspect: Features of extravascular hemolytic anemia with positive family hx, +/- biliary colic. Spherocytes are seen in peripheral blood smear and direct Coomb’s test is negative. Work-up: Best screening test is eosin-5-maleimide binding test (a flow cytometric test). If this is not available, other tests that can be done are osmotic fragility test, acidified glycerol lysis time test, or the cryohemolysis test.

Management: Oral folate replacement and transfusions as required. If moderate to severe anemia, splenectomy can be done (remove the organ where the RBCs are being destroyed).

How to differentiate between autoimmune IgG hemolytic anemia and hereditary spherocytosis?

Glucose-6-Phosphate Dehydrogenase Deficiency

Background: This is an X-linked recessive

hereditary disorder with deficiency of glu-cose-6-phosphate dehydrogenase (G6PD), which is a powerful antioxidant in RBCs. In patients of African American descent, it usually presents in a milder form, whereas patients of Mediterranean descent have more severe form.

Precipitating factors: Acute intravenous hemolysis occurs whenever there is an increased oxi-dative stress:

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  Any infection (MC precipitaing factor).

  
  
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  Drugs: sulfamethoxazole, primaquine, quinine, dapsone, isoniazid,

  
  
  
  

  ¹⁴ Isoniazid + anemia: think of G6PD deficiency (when acute) or sideroblastic anemia (when presentation is insidious)

  
  

  Thrombosis is the MCC of death in paroxysmal nocturnal hemoglobinuria (PNH).

  nitrofurantoin, etc.
  
  
  
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  Fava beans.

Work-up:

Rx: Supportive transfusion during an acute episode, treat underlying problem and avoid oxidant stress.

Paroxysmal Nocturnal Hemoglobinuria

Background: It is due to hereditary genetic defect in red cell membrane protein—phosphatidy-linositol glycan (PIG-A), aka decay-accelerating factor (proteins CD55 and CD59). This leads to easy binding of complement system to the red cell causing intravascular lysis of RBC, especially in acidic environment. This disorder is also associated with increased risk of varying degree of bone marrow failure (causing pancytopenia) and myelodysplastic syndrome.

Clinical pathophysiology: Nocturnal hemolysis can occur due to development of mild acidosis related to sleep-induced hypoventilation. Patients may present with early morning red urine. Hemolysis can also develop after exercise.

Along with acute hemolysis, patients also have increased risk of venous thrombosis, especially in uncommon locations such as hepatic vein or cerebral vein. Arterial thombosis has also been reported.

Work-up: NSIDx is flow cytometry, which will show absent or reduced expression of CD55/CD99. Older methods of detection are acidified hemolysis test (Ham’s test) and sugar water test (sugar is metabolized by RBCs into lactic acid).

Management

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  Supportive: Blood transfusion as needed and iron/folate supplementation.

  
  
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  For ongoing hemolysis, prednisone (steroids) might be helpful.

  
  
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  For patients with significant disease, give eculizumab (monoclonal antibody that inhibits complement activation).

  
  
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  In patients with severe disease, bone marrow transplantation can be done.

Diagnosis

For acute presentation, NSIDx is peripheral blood smear to look for sickled cells. To make the definitive diagnosis, use hemoglobin assay.

Acute presentation of sickle cell disease (acute anemia and acute painful crises)

Acute vaso-occlusive sickling crisis

Acute clumping of sickled RBCs in the arteries and arterioles can cause ischemia/infarction. Depending on location, it can present with the following:

Stepwise management of acute vaso-occlusive sickling crisis

Other Presentations of Sickle Cell Disease

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  Calcium bilirubinate gallstones.

  
  
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  Osteomyelitis—MCC is Staphylococcus aureus (!).

  
  
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  Pulmonary hypertension.

  
  
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  Nephrogenic diabetes insipidus.

Chronic/Preventive management of patients with sickle cell disease

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  Within the first 3 months of age, prophylactic penicillin is initiated and continued until age 5. After this, decision to continue prophylaxis is made on a case-by-case basis.

  
  
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  All patients with underlying chronic hemolysis should be on oral folate therapy.

  
  
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  In symptomatic patients, hydroxyurea is recommended. Hydroxyurea increases production of HbF and decreases production of HbS, thus decreasing risk of sickling crisis.

  
  
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  Functional asplenia: By the time patients reach late childhood, they usually have fibrosed spleen due to recurrent splenic infarction (rightly called autosplenectomy). So, all patients with sickle cell disease should receive prophylaxis indicated in asplenia.