Clinical Manifestations

The fundamental physiologic manifestation of anemia is a reduced oxygen-carrying capacity of the blood resulting in tissue hypoxia. Symptoms of anemia vary, depending on the body’s ability to compensate for reduced oxygen-carrying capacity (Figure 28-2). Anemia that is mild and develops gradually is usually easier to compensate and may cause problems for the individual only during physical exertion. As the reduction in red blood cells (RBCs) continues, symptoms become more pronounced and alterations of specific organs and compensatory effects become more apparent. Compensation generally involves the cardiovascular, respiratory, and hematologic systems. (Hematologic findings associated with various anemias are listed in Table 28-3 and progression and manifestations of anemias are shown in Figure 28-2.)

A reduction in the number of blood cells in the blood causes a reduction in the consistency and volume of blood. Compensation for a reduced blood volume causes interstitial fluid to move into the intravascular space, expanding plasma volume. This movement maintains adequate blood volume, but the viscosity (thickness) of the blood decreases. The diluted blood flows faster and more turbulently than normal blood, causing a hyperdynamic circulatory state. This hyperdynamic state creates cardiovascular changes—increased stroke volume and heart rate. These changes may lead to cardiac dilation and heart valve insufficiency if the underlying anemic condition is not corrected.

Hypoxemia, reduced oxygen levels in the blood, further contributes to cardiovascular dysfunction by causing dilation of arterioles, capillaries, and venules, thus leading to decreased vascular resistance and increased flow. Increased peripheral blood flow and venous return further contribute to an increase in heart rate and stroke volume in a continuing effort to meet normal oxygen demand and prevent cardiopulmonary congestion. These compensatory mechanisms may lead to heart failure.

Tissue hypoxia creates additional demands and compensatory actions on the pulmonary and hematologic systems. The rate and depth of breathing increase in an attempt to increase the availability of oxygen. These demands are accompanied by an increase in the release of oxygen from hemoglobin. (Mechanisms of oxygen transport and release by hemoglobin are described in Chapter 27.) All of these compensatory mechanisms may cause individuals to experience shortness of breath (dyspnea); a rapid, pounding heartbeat (palpitations); dizziness; and fatigue. In mild, chronic conditions, these symptoms might be present only when demand for oxygen is increased (e.g., during physical exertion), but in severe conditions they may be experienced at rest.

Manifestations of anemia may be observed in other parts of the body. The skin, mucous membranes, lips, nail beds, and conjunctivae become pale as a result of reduced hemoglobin concentration. If anemia is caused by RBC destruction (hemolysis), the skin may become yellowish because of accumulation of the products of hemolysis. Tissue hypoxia of the skin results in impaired healing and loss of elasticity, as well as thinning and early graying of the hair. Nervous system manifestations can occur if the anemia is caused by a vitamin B₁₂ deficiency. Myelin degeneration may occur, causing a loss of nerve fibers in the spinal cord and producing paresthesias (numbness), gait disturbances, extreme weakness, spasticity, and reflex abnormalities. Decreased oxygen supply to the gastrointestinal (GI) tract often produces abdominal pain, nausea, vomiting, and anorexia. A low-grade fever of less than 38.5° C (less than about 101° F) occurs in some anemic individuals and may result from the release of leukocyte pyrogens from ischemic tissues.

When the anemia is severe or acute in onset (e.g., hemorrhage), the initial compensatory mechanism is peripheral blood vessel constriction, diverting blood flow to vital organs. Decreased blood flow detected by the kidneys activates the renal renin-angiotensin response, causing salt and water retention in an attempt to increase blood volume. These situations are emergencies and require immediate intervention to correct the underlying problem that caused the acute loss of blood; therefore, long-term compensatory mechanisms do not develop.

Therapeutic interventions for slowly developing anemic conditions require treatment of the underlying disorder and palliation of associated symptoms. Therapies include transfusions, dietary correction, and administration of supplemental vitamins or iron.

Pathophysiology

The principal disorder in PA is an absence of intrinsic factor (IF), a transporter required for absorption of dietary vitamin B₁₂, which is essential for nuclear maturation and DNA synthesis in erythrocytes. IF is secreted by gastric parietal cells and complexes with dietary vitamin B₁₂ in the small intestine. The B₁₂-IF complex binds to cell surface receptors in the ileum and is transported across the intestinal mucosa.

Deficiency in IF secretion may be congenital or, more often, an autoimmune process directed against gastric parietal cells. Congenital IF deficiency is a genetic disorder that demonstrates an autosomal recessive inheritance pattern.⁵ The autoimmune form of the disease also has a genetic component, as do most autoimmune diseases (see Chapter 9). Family clusters have been identified; 20% to 30% of individuals related to persons with PA also have PA. These relatives, particularly first-degree female relatives, also demonstrate a higher frequency of the presence of gastric autoantibodies. PA is also frequently a component of autoimmune polyendocrinopathy, which is a cluster of autoimmune diseases of endocrine organs (e.g., chronic autoimmune thyroiditis [Hashimoto thyroiditis], type 1 diabetes mellitus, Addison disease, primary hypoparathyroidism, Graves disease, and myasthenia gravis) that frequently present as comorbidities. Autoimmune thyroiditis and type 1 diabetes mellitus, in particular, are associated with PA.

Most cases of PA result from an autoimmune gastritis (type A chronic gastritis) in which gastric atrophy results from destruction of parietal and zymogenic cells. Individuals with PA commonly have autoantibodies against the gastric H⁺-K⁺ ATPase, which is the major protein constituent of parietal cell membranes. Early in the disease process the gastric submucosa becomes infiltrated with inflammatory cells, including CD4 lymphocytes, eventually extending into the lamina propria and causing degeneration of the parietal and zymogenic cells. The parietal and zymogenic cells are destroyed and replaced by mucous-containing cells (intestinal metaplasia). Gastric mucosal atrophy, in which gastric parietal cells are destroyed, results in a deficiency of all secretions of the stomach—hydrochloric acid, pepsin, and IF. A direct correlation exists between the severity of the gastric lesion and the degree of malabsorption of vitamin B₁₂.⁶ Additionally, autoantibodies against IF prevent the formation of the B₁₂-IF complex. Thus, PA is secondary to autoimmune destruction of parietal cells, thus diminishing the production of IF, and the presence of autoantibodies that neutralize the capacity of remaining IF to transport vitamin B₁₂.

Initiation of the autoimmune process may be secondary to a past infection with Helicobacter pylori.⁷ Although active infection with H. pylori is rare in individuals with PA, more than half of these individuals possess circulating antibodies against this microorganism, suggesting a history of infection. The current opinion is that in genetically prone individuals, antigens expressed by H. pylori mimic the parietal cell H⁺-K⁺ ATPase, resulting in production of an antibody that binds and damages the parietal cell (see Chapter 9 for a discussion of antigenic mimicry and autoimmune disease).

Environmental conditions also may contribute to chronic gastritis. These include excessive alcohol or hot tea ingestion and smoking. Complete or partial removal of the stomach (gastrectomy) causes IF deficiency. Drugs known as proton pump inhibitors (PPIs) are used to decrease gastric acidity, but also may decrease cobalamin absorption, although it is not thought that they actually cause PA. Although PA is a benign disorder, individuals with type A chronic gastritis also are at risk for developing gastric adenocarcinoma and gastric carcinoid type I. The incidence of carcinoma in these individuals is 2% to 3%.

Clinical manifestations

PA develops slowly (possibly over 20 to 30 years); 60 years of age is the median age at time of diagnosis. Because of the slow onset of symptoms, PA is usually severe by the time treatment is sought. Early symptoms are often ignored because they are nonspecific and vague and include infections, mood swings, and gastrointestinal, cardiac, or kidney ailments. When the hemoglobin level has decreased significantly (7 to 8 g/dl), the individual experiences the classic symptoms of anemia—weakness, fatigue, paresthesias of the feet and fingers, difficulty in walking, loss of appetite, abdominal pains, weight loss, and a sore tongue that is smooth and beefy red secondary to atrophic glossitis. The skin may become “lemon yellow” (sallow) as a result of a combination of pallor and icterus. Hepatomegaly, indicating right-sided heart failure, may be present in the elderly along with splenomegaly, which is nonpalpable.

Neurologic manifestations result from nerve demyelination that may produce neuronal death. The posterior and lateral columns of the spinal cord also may be affected, causing a loss of position and vibration sense, ataxia, and spasticity. These complications pose a serious threat because they are not reversible, even with appropriate treatment. The cerebrum also may be involved with manifestations of affective disorders, most commonly of the depressive types. An increased prevalence of serum vitamin B₁₂ deficiency has been reported among individuals with Alzheimer disease.

Evaluation and Treatment

Diagnosis of PA is based on a variety of tests (see Table 28-3), which include blood tests, bone marrow aspiration, serologic studies, gastric biopsy, and clinical manifestations. A good test for PA was the Schilling test (no longer offered in most laboratories), which indirectly evaluated vitamin B₁₂ absorption by administering radioactive B₁₂ and measuring excretion in the urine. Low urinary excretion was significant for PA.

Serologic studies, however, have replaced the Schilling test for diagnosing PA. Measuring methylmalonic acid and homocysteine levels, which are elevated early in PA, is more sensitive. The presence of circulating antibodies against parietal cells and intrinsic factor is also useful in diagnosis.⁸ Gastric biopsy reveals total achlorhydria (absence of hydrochloric acid), which is diagnostic for PA because it occurs only in the presence of this gastric lesion.

Replacement of vitamin B₁₂ (cobalamin) is the treatment of choice. Initial injections of vitamin B₁₂ are administered weekly until the deficiency is corrected, followed by monthly injections for the remainder of the individual’s life. The effectiveness of cobalamin replacement therapy is determined by a rising reticulocyte count. Within 5 to 6 weeks, blood counts return to normal. PA cannot be cured so maintenance therapy is lifelong. Conventional wisdom and practice assumed that oral preparations were ineffective because there was no IF to facilitate absorption of vitamin B₁₂. However, recent experience has shown that higher doses of orally administered vitamin B₁₂ will be absorbed across the small bowel and is beneficial.

Untreated PA is fatal, usually because of heart failure. Death occurs after a course of remissions and exacerbations lasting from 1 to 3 years. Since 1926, when replacement therapy began, mortality has been reduced significantly. Today, death from PA is rare, and any relapses that occur are usually the result of noncompliance with therapy.

Pathophysiology

Impaired DNA synthesis secondary to a folate deficiency results in megaloblastic cells with clumped nuclear chromatin. Anemia may result from apoptosis of erythroblasts in the late stages of erythropoiesis. In addition to anemia, folate deficiency in pregnant women is associated with neural tube defects of the fetus. Folate is necessary for the reduction of circulating levels of homocysteine, a risk factor for the development of atherosclerosis (see Chapter 32); thus a folate deficiency increases the risk for developing coronary artery disease. A deficiency of folate also is implicated in the development of cancers, specifically colorectal cancers.

Clinical Manifestations

Clinical manifestations are similar to the cachectic, malnourished appearance of individuals with PA. Specific symptoms include severe cheilosis (scales and fissures of the lips and corners of the mouth), stomatitis (inflammation of the mouth), and painful ulcerations of the buccal mucosa and tongue, characteristic of burning mouth syndrome. Burning mouth syndrome may be secondary to a large number of disorders (e.g., extremely dry mouth, infection, autoimmune disease, nutritional deficiencies, and other conditions). The mechanisms underlying folate deficiency as a cause remain unknown. Gastrointestinal symptoms may be present and include dysphagia (difficulty swallowing), flatulence, and watery diarrhea, as well as histologic and roentgenographic changes of the GI tract suggestive of sprue (a chronic malabsorption syndrome). Undiagnosed inflammatory bowel disease (e.g., Crohn disease, ulcerative colitis) may be the underlying cause of folate malabsorption in some individuals, and folate deficiency may suppress proliferation of the intestinal mucosa, leading to exacerbation of gastrointestinal damage. Neurologic manifestations, such as those that occur in PA, are generally not seen in folate deficiency anemia. Any neurologic symptoms are usually caused by a thiamine deficiency, which often accompanies folate deficiency.

Evaluation and Treatment

Evaluation of folate deficiency is based on measurement of serum folate levels and symptoms. Treatment requires daily oral administration of folate preparations until adequate blood levels are obtained and clinical symptoms are reduced or eliminated. One milligram per day is sufficient for most individuals, although persons with alcoholism may require 5 mg. Prophylactic dosages of 0.1 to 0.4 mg/day are sometimes given during pregnancy. Parenteral administration of folic acid (citrovorum factor or leucovorin) generally is not used except in situations in which an individual has been using drugs that inhibit dihydrofolate reductase. After administration of folate, the manifestations of anemia disappear within 1 to 2 weeks.

After the folate deficiency has been corrected, long-term treatment with folate is not necessary if the appropriate dietary adjustments are made to maintain adequate intake. An intake of folate (400 mcg/day) is recommended as a measure to prevent heart disease.

Pathophysiology

IDA can arise from one of two different etiologies or a combination of both—inadequate dietary intake or excessive blood loss. In both instances there is no intrinsic dysfunction in iron metabolism; however, both deplete iron stores and reduce hemoglobin synthesis. A second category is a metabolic or functional iron deficiency in which various metabolic disorders lead to either insufficient iron delivery to bone marrow or impaired iron use within the marrow. Paradoxically, iron stores may be sufficient but delivery is inadequate to maintain heme synthesis, thus producing a functional or relative iron deficiency.

The most common cause of IDA in developed countries is pregnancy and chronic blood loss.¹¹ Blood loss of 2 to 4 ml/day (1 to 2 mg of iron) is sufficient to cause iron deficiency and may result from erosive esophagitis, gastric and duodenal ulcers, colon adenomas, or cancers. H. pylori infections also have been found to cause IDA of unknown origin, although H. pylori impairs iron uptake. In females, menorrhagia (excessive bleeding during menstruation) is a common cause of primary IDA. Other causes of IDA for both genders are (1) use of medications that cause gastrointestinal bleeding (such as aspirin or nonsteroidal anti-inflammatory drugs [NSAIDs]); (2) surgical procedures that decrease stomach acidity, intestinal transit time, and absorption (e.g., gastric bypass); (3) insufficient dietary intake of iron; and (4) eating disorders, such as pica, which is the craving and eating of nonnutritional substances, such as dirt, chalk, and paper.

Iron in the form of hemoglobin is in constant demand by the body. Iron is recyclable; therefore, the body maintains a balance between iron that is contained in hemoglobin and iron that is in storage and available for future hemoglobin synthesis (see Chapter 27). Blood loss disrupts this balance by creating a need for more iron, thus depleting the iron stores more rapidly to replace the iron lost from bleeding.

Iron also contributes to immune function by regulating immune effector mechanisms (i.e., cytokine activities [interferon-gamma (IFN-γ)], nitric oxide formation, and T-cell proliferation). Acquired hypoferremia may be part of the body’s response to infection. Anemia can be part of the nonspecific acute phase response to any type of inflammation of sufficient degree. Many pathogens require iron for survival; thus hypoferremia would hamper their growth. However, the precise benefits or detriments of iron deficiency and immunity are still controversial.

IDA occurs when the demand for iron exceeds the supply and develops slowly through three overlapping stages. In stage I, the body’s iron stores are depleted. Erythropoiesis proceeds normally, with the hemoglobin content of erythrocytes remaining normal. In stage II, iron transportation to bone marrow is diminished, resulting in iron-deficient erythropoiesis. Stage III begins when the small hemoglobin-deficient cells enter the circulation to replace the normal aged erythrocytes that have been removed from the circulation. The manifestations of IDA appear in stage III when there is depletion of iron stores and diminished hemoglobin production.

Clinical Manifestations

Symptoms of IDA begin gradually, and individuals usually do not seek medical attention until hemoglobin levels have decreased to about 7 to 8 g/dl. Early symptoms are nonspecific and include fatigue, weakness, shortness of breath, and pale earlobes, palms, and conjunctivae (Figure 28-4, A).

As the condition progresses and becomes more severe, structural and functional changes occur in epithelial tissue (see Figure 28-4). The fingernails become brittle, thin, coarsely ridged, and “spoon-shaped” or concave (koilonychia) as a result of impaired capillary circulation (Figure 28-4, B). IDA also is associated with unexplained burning mouth syndrome, as was discussed for folate deficiency. Tongue papillae atrophy and cause soreness along with redness and burning (glossitis) (Figure 28-4, C). The degree of pain experienced is directly associated with the amount of iron deficiency, and these changes can be reversed within 1 to 2 weeks of iron replacement therapy. Individuals also experience dryness and soreness in the epithelium at the corners of the mouth, known as angular stomatitis. Difficulty in swallowing is associated with an esophageal “web,” a thin, concentric, smooth extension of normal esophageal tissue consisting of mucosa and submucosa at the juncture between the hypopharynx and esophagus. The duration of iron deficiency required for web formation is uncertain. Dysphagia also is exacerbated by hyposalivation. The pathophysiology associated with these epithelial lesions is not well understood, but the lesions have the potential to become cancerous.

Nonheme iron is a component of many enzymes in the body (e.g., cytochromes, myoglobin, catalases, peroxidases), particularly those involved in the metabolism of amine neurotransmitters, reduction of nucleotides, and biosynthesis of methionine. Abnormalities and deficiencies of iron-dependent enzymes may account for many of the clinical manifestations of IDA. Individuals with IDA also exhibit gastritis, neuromuscular changes, irritability, headache, numbness, tingling, and vasomotor disturbances. Gait disturbances are rare. The pathogenesis of neurologic symptoms is unknown but may be caused by hypoxia in already compromised cerebral vessels. In the elderly, mental confusion, memory loss, and disorientation are often associated with anemia and may be wrongly perceived as “normal” events related to aging.

Evaluation and Treatment

Initial evaluation is based on clinical symptoms and decreased levels of hemoglobin and hematocrit. Additional measurements, however, are needed to determine the cause of the anemia (see Table 28-3). Iron stores may be measured directly by bone marrow biopsy and iron staining or indirectly by laboratory tests for serum ferritin, transferrin saturation, or total iron-binding capacity. Serum ferritin is a widely accepted and available measurement of iron status that has been used for the past 25 years; 1 mcg/L serum ferritin corresponds to 8 to 10 mg or 120 mcg of storage iron/kg body weight. A limitation on interpretation of serum ferritin levels is that values may be elevated independently of iron status during acute or chronic inflammation, malignancy, liver disease, or alcoholism. A sensitive indicator of heme synthesis is the amount of free erythrocyte protoporphyrin (FEP) within erythrocytes. A test that determines the concentration of soluble fragment transferrin receptor differentiates primary IDA from IDA that is associated with chronic disease.

An indicator of iron levels is the level of serum transferrin receptor (sTfR). Transferrin receptors are membrane glycoproteins that bind circulating transferrin for transport into cells. Soluble forms of the receptor are found in serum. The ratio of serum levels of transferrin receptor to ferritin (R/F) estimates body iron stores and differentiates primary IDA from anemia secondary to chronic disease. A major drawback, however, is the lack of proper standardization for the sTfR assay.

The first step in treatment of IDA is to identify and eliminate sources of blood loss.¹² With ongoing bleeding, any replacement therapy is likely to be ineffective. Iron replacement therapy is required and very effective. Initial doses are 150 to 200 mg/day. Hematocrit levels should improve within 1 to 2 months of therapy; however, the serum ferritin level is a more precise measurement of improvement and total body stores of iron. Once the serum ferritin level reaches 50 mcg/L, adequate replacement of iron has occurred. A rapid decrease in fatigue, lethargy, and other associated symptoms is generally seen within the first month of therapy. Replacement therapy usually continues for 6 to 12 months after the bleeding has stopped but may continue for as long as 24 months. Menstruating females may need daily oral iron replacement therapy (325 mg/day) until menopause.

Parenteral iron replacement is used in instances of uncontrolled blood loss, intolerance to oral iron, intestinal malabsorption, or poor adherence to oral therapy. Iron dextran has been the only parenteral agent available in the United States. Intramuscular injection is the recommended method; however, intravenous (IV) administration is generally preferred because of the ability to administer larger doses. A significant concern in the use of IV dextran is the potential for severe anaphylactic reaction. Delayed allergic reactions are also major concerns.

Newer medications that have recently been approved for parenteral therapy in treating IDA are sodium ferric gluconate complex in sucrose (Ferrlecit) and iron sucrose injection (Venofer). Iron dextran is recommended as the first choice in spite of its higher rate of adverse reactions. For individuals who are intolerant of iron dextran, the two newer agents are safe and effective alternatives. Drawbacks to their use include higher cost and the need for multiple infusions.

Pathophysiology

SAs have multiple etiologies but all share the commonality of altered heme synthesis in the erythroid cells in bone marrow. Mitochondrial aminolevulinic acid (ALA) synthase uses glycine to convert succinyl CoA into ALA.¹⁵ ALA undergoes further enzymatic modification in the cytoplasm to the porphyrin structure, becoming coproporphyrinogen III, which reenters the mitochondria. Within the mitochondria the molecule is progressively converted to protophorphyrin IX, which has ferrous iron (Fe²⁺) inserted by the enzyme ferrochelatase. Disruptions to this pathway lead to the accumulation of iron in the mitochondria and the characteristic sideroblasts.

SAs are either acquired or hereditary. Acquired sideroblastic anemia, which is the most common, occurs as a primary disorder with no known cause (idiopathic) or is associated with other myeloproliferative or myeloplastic disorders. Another form is described as reversible SAs; these are secondary to various conditions such as alcoholism, drug reactions, copper deficiency, and hypothermia. Reversible sideroblastic anemia, associated with alcoholism, results from nutritional deficiencies of folate. Alcohol impairs heme synthesis by reducing the activity of specific enzymes along the biosynthetic pathway and also by direct effects of alcohol or acetaldehyde, or both, on the heme biosynthetic steps or mitochondrial metabolism. Some specific drugs also cause reversible SA and include antituberculous agents (isoniazid [INH], pyrazinamide, cycloserine, and chloramphenicol) that interfere with B₁₂ metabolism or directly injure the mitochondria. Copper deficiency also causes reversible SA by interfering with conversion of ferric iron to ferrous iron. This is extremely rare and is associated with gastrectomy and prolonged parenteral nutrition without copper supplements. Hypothermia causes decreased heme synthesis and incorporation into hemoglobin.

Hereditary sideroblastic anemia is rare and occurs almost exclusively in males, suggesting a predominant recessive X-linked transmission. Hereditary SA (X-linked sideroblastic anemia [XLSA]) has been linked to missense mutations in the erythroid-specific ALAS-E gene Xp11.21.¹⁶ More than 25 missense mutations have been identified. ALAS is the first and rate-limiting enzyme in the heme biosynthesis pathway, and mutations lead to reduced synthesis of protoporphyrin IX and the characteristic accumulation of iron in the erythrocyte. An occasional autosomal recessive transmission affecting females occurs with mitochondrial mutations and deficiencies of ferrochelatase. Other genetic, chromosomal, or enzyme dysfunctions also have been associated with hereditary SA. The anemia of hereditary SA is usually present in infancy or childhood, but may remain undetected until midlife. In some instances, other symptoms (e.g., diabetes or cardiac failure resulting from tissue iron overload) may be the first manifestation of SA. Differentiation of SA from idiopathic hemochromatosis needs to be confirmed because both are characterized by tissue iron deposition.

The leading known cause of primary ASA, myelodysplastic syndrome (MDS), is a group of disorders of hematopoietic stem cells, with all three stem cell lines demonstrating dysplastic characteristics.¹⁷ Initially, all ASAs associated with myelodysplastic syndrome were considered to be one and the same and identified as refractory anemia with ringed sideroblasts. This classification proved unsatisfactory because different outcomes were observed in individuals who had the same apparent disease. Further investigations discovered morphologic and chromosomal characteristics that predicted different clinical courses. Two subsets of myelodysplastic ringed sideroblasts were identified based on the cell lines that were affected. In one subset, dysplastic features were limited to the erythroid line and it was classified as pure SA. Individuals with pure SA require transfusions, which may produce iron overload.¹⁸ With adequate chelation therapy, they are able to survive and thrive for many years. A significant outcome of this condition is the rare occurrence of conversion to leukemia.

The second subset of MDS was characterized by abnormalities of multiple cell lineages. In addition to SA, major alterations of neutrophil and platelet were observed. Infections, frequently fatal, are common secondary to neutropenia and neutrophil dysfunction. Bleeding from thrombocytopenia and platelet dysfunction also is prevalent. Of those who survive, 40% develop acute (myeloblastic) leukemia.