CHAPTER 46 Anemia and Red Blood Cell Disorders

Introduction

Anemia is a common manifestation of systemic illness. The World Health Organization (WHO) estimates that the number of anemic people worldwide approaches two billion. Women and children are more commonly affected: the WHO estimates that nearly 50% of women and children from developing nations and perhaps a quarter of men are anemic.¹ Anemia in immigrants can be a result of both acquired and inherited causes (Table 46.1). Unfortunately, comprehensive studies describing the incidence and etiology of anemia in immigrant populations are lacking. However, the worldwide geographic distribution of several genetically based red blood cell (RBC) disorders (thalassemia, hemoglobin C and E, ovalocytosis, and sickle cell disease), the prevalence of iron deficiency, and the geographic prevalence of other diseases affecting the hematologic system (malaria, helminth infection, HIV, TB) are well known.^2,³ Therefore, understanding the prior prevalence and geographic distribution of anemia in the country of origin is helpful when evaluating a new immigrant with a hematologic problem (Box 46.1).

Table 46.1 Causes of anemia in immigrants

Box 46.1 Case study 1

You are asked to see a 33-year-old Laotian woman 1 day postoperative for a drop in hemoglobin. She had been in the United States for 2 weeks visiting relatives when she developed acute cholecystitis and underwent a laparoscopic cholecystectomy without difficulty. The pathology indicated acute cholecystitis with pigmented gall stones. Her preoperative CBC showed:

WBC 11 900

Hb 10.3 g/dL

RBC 5.10 m/μL (normal 4.0–5.2 m/μL)

MCV 67.6 fl

Plt 240 k

Postoperatively, she feels well but her hemoglobin has decreased to 8.7 g/dL. There is no evidence of abnormal bleeding and her vital signs are normal. She is a para 5005 and has normal monthly menstrual periods. She is not febrile. Her examination is unremarkable. There is no splenomegaly.

Discussion

Often, anemia is multifactorial and, certainly, in the postoperative setting, could reflect blood loss or a dilutional effect from rehydration. However, Southeast Asians have a high prevalence of globin gene mutations. Estimates suggest 15–20% of patients may have hemoglobin E, and 25% of patients may carry an α-thalassemia mutation. Glucose-6-phosphate dehydrogenase deficiency can be seen in 10–15% of patients but more commonly produces symptoms in males due to the X-linked recessive inheritance pattern.

The differential diagnosis of microcytic anemia includes iron deficiency, thalassemia/hemoglobin E, severe anemia of chronic disease, as well as less common etiologies such as lead ingestion.

Her multiparity and ongoing menstruation put her at risk for iron deficiency; this could be compounded by poor nutrition and/or intestinal blood loss from helminth infection. The microcytic anemia with a ‘normal’ RBC number, however, would implicate uniformly small RBCs as is seen in thalassemia/hemoglobin E.

Pigmented gallstones suggest ongoing RBC turnover indicative of thalassemia or G6PD deficiency. Other systemic signs such as persistent fever could suggest other etiologies such as malaria.

Evaluation

The initial evaluation should begin with a reticulocyte count, peripheral smear evaluation, and a stool specimen for occult blood. Thick and thin smears for malaria were obtained due to her recent arrival from an area endemic for malaria. A total bilirubin and LDH are a quick screen for hemolysis but should be compared to other liver function tests (alkaline phosphatase, AST, ALT) because of the recent gallbladder surgery. A diminished haptoglobin level would help confirm an element of RBC destruction. A ferritin and hemoglobin electrophoresis should be ordered to help distinguish different causes of microcytic anemia. A Heinz body slide, in conjunction with classic peripheral smear findings of spherocytes and ‘bite cells’ would help identify G6PD deficiency. A G6PD activity level should not be ordered at this time since it can be misleadingly normal after an acute hemolytic event.

Additional data

Reticulocyte count:	2.5%
Peripheral smear:	Hypochromic microcytes and ‘pencil-shaped cells’
Peripheral smear:	No fragmented or ‘bite cells’
Stool hemoccult:	Negative
Malarial smear:	Negative
Total bilirubin:	2.1 mg/dL (normal <1.5)
Direct bilirubin:	Normal (elevated indirect bilirubin)
LDH:	275U/L
Alkaline phosphatase:	Normal
AST/ALT:	Normal
Haptoglobin:	<5 mg/dL
Ferritin:	30ng/mL (normal 10–150)
Hemoglobin electrophoresis:	Normal amounts of HbA1, and HbA2, no Hb F or HbE
Heinz body prep:	Negative

Discussion

This patient’s anemia is most likely due to a combination of iron deficiency and α-thalassemia: indeed, the peripheral smear suggests iron deficiency. This case is also an example of how laboratory test results, particularly for the reticulocyte count, ferritin, and hemoglobin electrophoresis, need to be put into clinical context to be appropriately interpreted. Isolated iron deficiency is a hypoproliferative anemia typified by a very low reticulocyte count of 1% or less. Depending on the severity of α-thalassemia, the reticulocyte count can be normal to markedly elevated (5% or greater). The reticulocyte count of 2.5% needs to be interpreted in the clinical context: it is a little too high for isolated iron deficiency but suggests an inadequate bone marrow response if the anemia was entirely due to increased RBC destruction (hemolysis). The elevated bilirubin and LDH combined with the absent haptoglobin and pigmented gallstones confirm an element of hemolysis that does not appear to be due to G6PD deficiency (the Heinz body prep is normal). The ferritin is in the ‘normal range’ albeit the low normal range. As an acute-phase reactant, one would expect the ferritin to be elevated (perhaps above 100 ng/mL) in a patient presenting with inflammation from acute cholecystitis. Therefore, the borderline low ferritin in conjunction with the microcytic indices and peripheral smear morphology would implicate an element of iron deficiency. Lastly, the normal hemoglobin electrophoresis rules out significant β-thalassemia and hemoglobin E; it can be normal, however, in α-thalassemia trait. The normal RBC number in the face of significant microcytosis also lends support for a clinical diagnosis of α-thalassemia as does the evidence of increased RBC turnover (elevated LDH/bilirubin, absent haptoglobin, and pigmented gallstones). A more sophisticated DNA test could be used to confirm a diagnosis of α-thalassemia.

Geographic Distribution of Red Blood Cell Disorders

Malaria affects the tropical regions of the world and it is postulated that most genetically-based RBC disorders, such as the thalassemias, hemoglobinopathies, ovalocytosis, and elliptocytosis provide a selective protective advantage against malaria parasite infection. Indeed, malaria has had one of the most profound evolutionary effects on the human genome: genetic RBC disorders have a high prevalence in areas of the world where malaria once was or still is a major health concern.⁴ It is estimated that 4.83% of the world’s population carry globin gene variants, including 1.67% of the population heterozygous for α- or β-thalassemia and 1.92% carry sickle hemoglobin.⁵ Due to population movement and immigration, these disorders are now seen on all continents of the world. Although accurate epidemiologic data are not available for all parts of the world, it is known that both α- and β-thalassemia are more common in Africa, the Mediterranean, India, and Southeast Asia. Sickle cell disease is seen in 1–2% of infants born in tropical Africa. However, if the heterozygous state provides a selective protective advantage against malaria, the prevalence in adults may be much higher.³ Sickle cell disease is also seen to a lesser extent in India and the Middle East. Glucose 6-phosphate dehydrogenase (G6PD) deficiency is seen with varying frequency throughout Africa, Asia, and Central and South America. Hemoglobin C is most prevalent in West Africa whereas hemoglobin E is seen most exclusively in Southeast Asia. The red cell membrane defect, ovalocytosis, is more prominent in Southeast Asia whereas hereditary elliptocytosis is more common in West and North Africa. Table 46.2 provides an estimate of the frequency of RBC disorders in the three groups with the highest known prevalence: Southeast Asians, Africans, and people from Eastern Mediterranean countries.^3,⁶^–⁸ These estimates are a compilation of WHO data and published data from prenatal screening clinics and newborn testing series. It should be emphasized, however, that even within geographic regions, the heterogeneity of ethnic groups leads to a wide variation in the prevalence of these disorders. Indeed, an excellent example in the developed world is from Italy: the prevalence of hemoglobin disorders in Northern Italy is 1–2% but reaches 12% in Sardinia.⁶

Table 46.2 Estimates of prevalence of genetic RBC disorders in various regions of the world ^3,^6,^7,⁸

Common Acquired Causes of Anemia

Iron deficiency anemia

The WHO estimates that 50% of anemia worldwide can be attributed to iron deficiency; it is the most common nutritional deficiency.¹ Iron balance is a reflection of dietary iron intake, adsorption, and iron (blood) loss. Iron is available in the diet as heme iron from animal protein sources and non-heme iron from vegetable sources. Heme iron is readily absorbed in the diet as is iron in breast milk. In contrast, iron from vegetable sources has low bioavailability. Due to menstruation, lactation, and iron loss during pregnancy, women of reproductive age worldwide have the highest incidence of iron deficiency. This population should be considered for supplementation. Gastrointestinal tract blood loss, the major source of iron loss, has a wide differential diagnosis. This includes peptic ulcer disease and colon cancer as in the general population but also includes helminth infection in immigrant populations. Iron deficiency leads to a microcytic anemia occasionally associated with thrombocytosis. The cells have increased central pallor and occasional elongated ‘pencil cells’ and target cells (Fig. 46.1). The red cell distribution width (RDW) is elevated and the reticulocyte count is low. Serum ferritin is characteristically low (<15 ng/mL) in uncomplicated iron deficiency and is the single best test for assessing iron stores. Since ferritin is also increased by inflammation, iron deficiency can be identified with greater sensitivity by using a higher cutoff value of ferritin of <30–100 ng/mL.⁹ A ratio of soluble transferrin receptor to ferritin level may also be helpful in distinguishing iron deficiency from anemia of chronic disease.

Figure 46.1 Iron deficiency. The red blood cells are small and poorly hemoglobinized (increased central pallor). Note occasional ‘cigar-shaped’ or ‘pencil cells’.

Malaria

The RBC protozoal infection, malaria, is endemic to most of the equatorial areas of the world. The prevalence of malaria in immigrants, particularly from Africa, has been reported to be as high as 15%.¹⁰ Anemia is the most common manifestation of malaria infection but leukopenia and thrombocytopenia (often from splenomegaly) may also occur. The pathophysiology of anemia is multifactorial: not only is there parasite-mediated RBC destruction and increased splenic removal, malaria infection also suppresses RBC production by the bone marrow.¹¹ Therefore, the reticulocyte response may not be as vigorous as in a purely hemolytic process. Occasionally, malaria infection is associated with immune-mediated RBC destruction and a positive direct Coombs test due to adsorption of immunoglobulin and complement onto the RBC surface. Severe acute intravascular hemolysis may rarely occur (blackwater fever) leading to hemoglobinemia, hemoglobinuria, and severe hyperbilirubinemia. Recurrent malaria infection can be immunosuppressive and can be complicated by secondary bacterial or viral infection. Fifty percent of patients develop some degree of splenomegaly which contributes to the pancytopenia often seen in chronically infected patients.

HIV

Human immunodeficiency virus infection and AIDs can cause a plethora of hematologic problems. Early on during HIV infection, immune thrombocytopenia is common as is the development of antiphospholipid antibodies. Anemia is the most common manifestation of HIV infection and is multifactorial due to both direct and indirect effects of the virus.¹² Anemia is most often a hypoproliferative, low reticulocyte anemia due to anemia of chronic disease. Often, there is a blunted erythropoietin response. Coombs-positive autoimmune hemolytic anemia also occurs with increased frequency in HIV infection. Antiretroviral therapy often causes macrocytosis.

Anemia of chronic disease

Anemia of chronic disease (ACD), perhaps best termed anemia of acute or chronic inflammation, is a hypoproliferative anemia resulting from inflammatory cytokine effects on RBC production.⁹ The hallmark is cytokine-induced disturbance of iron homeostasis. Iron, present in the bone marrow, is sequestered in reticuloendothelial cells and is not available for RBC and hemoglobin production. Often, ACD is a normochromic-normocytic anemia but it can progress to a microcytic anemia. The reticulocyte count is low, whereas the ferritin is characteristically >100 ng/mL and is often elevated. The erythropoietin response is blunted. Table 46.3 lists common causes of ACD.

Table 46.3 Common causes of anemia of chronic disease

Infections

Viral including HIV

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