Disorders of the Blood

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GENERAL PRINCIPLES¹

Definition

Anemia can be divided into three major categories: decreased number of red blood cells, low hemoglobin, and diminished volume of red blood cells. Iron-deficiency anemia (IDA) causes low hemoglobin, classically two standard deviations below normal. The current hemoglobin cutoffs vary by gender and race and decrease slightly with age. Current accepted cutoffs are as follows:

• Age 6 months to 2 years: 10.5 g per dL

• Age 2 years to 12 years: 11.5 g per dL

• Adult female: 12 g per dL (Caucasian); 11.5 g per dL (African American)

• Pregnant: 11 g per dL

• Adult male: 14 g per dL (Caucasian); 12.9 g per dL (African American)

Epidemiology²

Iron deficiency is the most common cause of anemia worldwide. It can also coincide with other causes of anemia. In developed countries, people at highest risk are pregnant women, dieting adolescent females, and recent immigrants. Children who tested iron deficient during infancy were later found to have lower cognitive test scores on recognition and memory.³

Pathophysiology

Iron is one of the main building blocks of hemoglobin. Deficiency, therefore, results in defective synthesis of hemoglobin leading to smaller red cells (microcytosis) with less hemoglobin within the cells (hypochromia).

Etiology

Etiologies for IDA include increased iron loss, inadequate iron intake, decreased iron absorption, and increased iron demand. Normal daily iron loss is 1 mg per day. Additionally, iron loss can also occur from blood loss due to menstruation (20 mg per month), frequent blood donations, and ongoing gastrointestinal (GI) bleeding. Causes of GI blood loss include use of nonsteroidal anti-inflammatory drugs, peptic ulcer disease, angiodysplasia, diverticulosis, malignancy, and, rarely, parasites such as hookworms. Inadequate iron intake can occur in individuals with eating disorders or severe malnutrition (only about 10% of dietary iron is absorbed). Malabsorption is seen with acute illness, inflammatory bowel disease, lead poisoning (which displaces iron), or surgical bowel resection. Iron demand increases in pregnancy (requiring an additional 9 mg of iron per day), lactation, and during rapid growth in infancy.

DIAGNOSIS

Clinical Presentation⁴

With an insidious onset and gradual progression of symptoms, the body can compensate and tolerate low hemoglobin levels (less than 7 g per dL). In elderly individuals, some of these signs and symptoms may be subtle or dismissed as age related. Symptoms may include weakness, leg cramping or restlessness, malaise, fatigue, dyspnea on exertion, palpitations, dizziness, chest pain, headaches, pago-phagia (ice eating), and pica. Cardiovascular signs include tachycardia, systolic murmur, and even high-output cardiac failure. Epithelial changes include pallor of the conjunctiva, lips, and palmar skin creases. Dry skin and nail changes, such as pale, brittle, or spoon-shaped nails (koilonychia), are also found. Angular stomatitis, glossitis, and, rarely, dysphagia from pharyngeal and esophageal webs may also be present.

Laboratory

Lab results vary depending on the stage of iron deficiency. Initial results may show a normocytic normochromic picture, but the ferritin, iron, or red blood cell distribution width is decreased. Once the iron stores are exhausted, the classic hypochromic microcytic picture develops with a low mean corpuscular volume. A peripheral smear may show anisocytosis, poikilocytosis, and target cells.

• A low serum ferritin level, especially below 12 μg per L (normal: 18 to 300 μg per L), indicates iron deficiency. Ferritin is also an acute phase reactant, so elevation may be a sign of inflammation and malignancy.

• Iron-binding capacity (IBC) is increased, usually to more than 375 μg per dL (normal: up to 300 μg per dL).

• Serum iron is decreased, often to less than 60 μg per dL (normal: 100 μg per dL).

• Transferrin saturation is decreased to less than 16%.

• Reticulocyte count, which is indicative of red blood cell replacement and bone marrow function, is often decreased when iron stores are exhausted.

• Other tests, such as erythropoietin level and bone marrow biopsy, can be performed but are rarely necessary.

Differential Diagnosis

Thalassemia, anemia of chronic disease, B₁₂ or folate deficiency, and sideroblastic anemia.

TREATMENT

The first step in treatment is determining the underlying cause. If iron loss is determined to be the cause, iron replacement therapy can be initiated and an evaluation to rule out a GI bleed should be considered. Reticulocyte count should rise within a week and a 2-g per dL hemoglobin increase should be seen within 3 weeks. To replenish the stores, replacement should continue for 6 months. Treatment failures are due to noncompliance, malabsorption, inadequate dosing, ongoing blood loss, or incorrect diagnosis.

Iron Replacement

Oral

This is the preferred method of replacing the iron stores. Ferrous sulfate, which is inexpensive and commonly used, is better tolerated when taken with meals. GI side effects are dose related and include nausea and constipation. Ferrous sulfate 325 mg (65 mg of elemental iron) is taken one to three times daily. Target dose is 150 to 200 mg of elemental iron per day. Medications such as histamine-2 blockers and methyldopa, as well as calcium-rich foods, bran, soy, coffee, and tea all reduce iron absorption. Meat, fish, and vitamin C enhance absorption. Iron needs stomach acid in order to be absorbed, but some research suggests that proton pump inhibitors have not been shown to decrease iron absorption.⁵ Ferrous fumarate 324 mg (106 mg of elemental iron) or ferrous gluconate 324 mg (38 mg of elemental iron) may be better tolerated than ferrous sulfate.

For children, iron supplements in the form of drops, elixir, and syrup are available. The regimen for management of iron deficiency in children is 3 to 6 mg per kg daily of elemental iron. Liquid preparations given by dropper or straw can help prevent staining of teeth.

Parenteral¹

In critically ill and hemodialysis patients, iron is occasionally administered parenterally. If used, a test dose of 25 mg should be given to test for allergic reaction. Iron gluconate (125 mg of 12.5 mg per mL) or iron sucrose (100 mg of 20 mg per mL) is preferred and can be given intravenously daily, if needed, over 5 to 10 minutes. Arthralgias, myalgias, or phlebitis may occur as a delayed reaction, and severe reactions have been noted in patients with collagen vascular disease.

Prevention⁶

Infants over the age of 4 to 6 months require iron supplementation through oral drops or fortified formula. This recommendation is derived from the weight-based iron needs of infants. Their requirements eventually exceed the amount of iron that can be obtained in a practical volume of breast milk. Cow’s milk is not only a poor source of iron, but also inhibits its absorption. Current recommendations are to screen all infants for IDA at the age of 1. During pregnancy, women are screened twice for iron deficiency and all are encouraged to take an iron-containing prenatal vitamin.

REFERENCES

1. Causey MW, Miller S, Foster A, et al. Validation of noninvasive hemoglobin measurements using the Masimo Radical-7 SpHb Station. Am J Surg 2011;201:592.

2. Price EA, Mehra R, Holmes TH, et al. Anemia in older persons: etiology and evaluation. Blood Cells Mol Dis 2011;46:159.

3. Congdon EL, Westerlund A, Algarin CR, et al. Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. J Pediatr 2012;160(6):1027.

4. Allen RP, Auerbach S, Bahrain H, et al. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013;88:261.

5. Annibale B, Capurso G, Chistolini A, et al. Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. Am J Med 2001;111:439.

6. Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics 2010;126(5):1040–1050.

18.2

Megaloblastic Anemia

Sarah M. Balloga

GENERAL OVERVIEW

Macrocytosis is the general term for anemia, with a mean corpuscular volume (MCV) greater than 100 fL. Macrocytosis can be further delineated as megaloblastic and nonmegaloblastic anemia. Common nonmegaloblastic anemia causes include alcoholism, medications, hypothyroidism, liver disease, and myelodysplastic syndromes.

Megaloblastic anemia specifically refers to anemia that is caused by a disruption in RNA and DNA synthesis. This is manifest by the characteristic findings on peripheral smear of macro-ovalocytes and hypersegmented neutrophils. Typically this is caused by vitamin B₁₂ and folate deficiencies.

VITAMIN B₁₂ (COBALAMIN) DEFICIENCY

General Principles

Vitamin B₁₂ plays a vital role in neurologic function, red blood cell production, and DNA synthesis. Humans cannot synthesize B₁₂ and rely solely on dietary sources. Main dietary sources include animal proteins and fortified cereal products. Daily recommended intake is 2.4 mcg per day. Older adults and strict vegetarians often have difficulties obtaining the required B₁₂ from dietary sources.

Digestion begins in the stomach, where gastric acid separates B₁₂ from the food products. B₁₂ is then bound to intrinsic factor that is produced by the gastric parietal cells. Final absorption occurs in the terminal ileum and is stored in the liver. Liver stores can last for up to 5 to 10 years.

Causes of B₁₂ Deficiency

Pernicious anemia is the most common cause of B₁₂ deficiency worldwide. This is an autoimmune atrophic gastritis characterized by the destruction of parietal cells and subsequent reduction in intrinsic factor. Nonimmune-mediated gastritis causes include

• Helicobacter pylori infection and Zollinger–Ellison syndrome

• Dietary deficiencies (elderly, alcoholics, strict vegetarians, breastfed infants of B₁₂-deficient mothers)

• Gastrointestinal malabsorption

• Surgical, that is, ileal resection, gastrectomy, gastric bypass

• Medical, that is, Crohn disease, tapeworm Diphyllobothrium latum

• Prolonged medication use

• Common: histamine H₂ blockers, proton pump inhibitors, and metformin

• Reverse transcriptase inhibitors typically cause macrocytosis and may lead to megaloblastic changes. This known side effect is an effective monitoring tool of patient compliance and no treatment is necessary.

Manifestations of B₁₂ Deficiency

Diagnostically, B₁₂ deficiency can be a challenge as clinical symptoms can lag 5 to 10 years after the onset of dietary deficiencies. Hematologic manifestations include fatigue, weakness, palpitations, tachycardia, and pallor—less commonly, thrombosis. Neurological signs and symptoms include paresthesias, weakness, ataxia, decreased proprioception, and cognitive and behavioral changes.

Other clinical manifestations include dermatological findings (hyperpigmentation, vitiligo), gastrointestinal findings (glossitis, jaundice), and reproductive implications (infertility).

Laboratory Findings

• Anemia (WHO definition: Hgb <13 for men, <12 for women; up to 28% of affected patients may have normal Hgb)

• MVC >100 (up to 17% may have normal MVC)

• Low normal to low B₁₂ levels

• True deficiency is defined as level <200 pg per mL, with low normal levels 200 to 400 pg per mL. Variation depends on local laboratory values.

• Elevated homocysteine and methylmalonic acid levels (substrates that are produced in the process of RNA and DNA synthesis). These become elevated when lacking B₁₂ to complete necessary metabolic steps.

• Methylmalonic acid is considered more sensitive and is the recommended confirmatory test of choice when B₁₂ or folate levels are equivocal.

• Pernicious anemia

• Schilling test is no longer available in the United States

• Elevated levels of anti-intrinsic factor antibodies or antiparietal cell antibodies

• Elevated serum gastrin or pepsinogen.

Treatment

• Treat underlying disorder

• Replacement: Oral supplementation and intramuscular injections are equally efficacious.

• Oral: 1 to 2 mg daily

• Intramuscular: 1 mg daily for 1 week, weekly for 8 weeks, then 1 mg monthly for life.

Follow-Up

• Pernicious anemia: Perform at least one endoscopic evaluation at the time of diagnosis to screen for gastric cancer, monitor for other autoimmune disorders.

• Monitor for other causes of anemia, including iron-deficiency anemia, anemia of chronic disease.

• Perform complete blood count (CBC) every 6 to 12 months to ensure resolution of anemia.

FOLIC ACID DEFICIENCY

General Principles

Similar to B₁₂, folate is a necessary cofactor in DNA synthesis. Daily total intake requirement is 400 to 1,000 mcg. Dietary sources include leafy vegetables, beans, fruits, and fortified cereal grains. The body does not have a large reservoir for folate storage and thus can become depleted rapidly. Clinical symptoms typically begin 6 months after onset of deficiency. Deficiency is becoming uncommon in the United States as federal law mandates cereal grains to be supplemented with folate.

Causes

• Inadequate intake (alcoholics, fad diets, institutionalized individuals, elderly)

• Increased requirements (pregnancy, prematurity)

• Malabsorption: inflammatory bowel disease, gastric bypass, tropical sprue, rare enzyme deficiencies

• Drugs (methotrexate, sulfasalazine, triamterene, trimethoprim–sulfamethoxazole, metformin, phenytoin)

Manifestations

Similar to B₁₂ deficiency with the notable exception of neuropsychiatric findings.

Laboratory Findings

• Anemia

• Macrocytosis

• Hypersegmented neutrophils

• Low folate levels (<4 ng per mL)