characteristics of anemia of chronic and inflammatory diseases may include slow involuntary weight loss and hypoalbuminemia. Weight loss occurs despite efforts to increase caloric intake. Certain chronic infections and inflammatory diseases cause several changes in the blood cell production system. These include a slightly shortened red blood cell life span and an isolation of iron in inflammatory cells (macrophages) that result in a decrease in the amount of iron available to make RBC. In the presence of these effects, a low-to-moderate grade anemia develops.
Conditions associated with the anemia of chronic and inflammatory diseases include the following:
•Advanced age
•AIDS
•Chronic Bacterial Endocarditis
•Chronic Renal Failure
•Congestive Heart Failure
•Crohn's Disease
•Juvenile Rheumatoid Arthritis
•Osteomyelitis
•Rheumatic fever
•Ulcerative Colitis
Macrocytic anemias
The metabolic interrelationship between folate and vitamin B12 may explain why a single deficiency of either leads to the same hematological changes. The most common cause of macrocytic anemia is megaloblastic anemia due to impaired DNA synthesis. Vitamin B12 and folate coenzymes are required for thymidylate and purine synthesis. A deficiency of either or both nutrients retards DNA synthesis that triggers dyspoiesis (abnormal rate of RBC maturation in bone marrow) and pancytopenia (decrease in the production of RBC). While the macrocytic RBC is the hallmark of macrocytic anemia, other rapidly dividing cells are affected. Other physiological changes may include, sore tongue due to glossitis or atrophy of tongue, skin changes, and flattening of intestinal villi (Guyton, 2006).
RNA synthesis is unaffected by a deficiency of folate or vitamin B12 but, there is a build up of cytoplasmic components in a slowly dividing cell making the RBC larger than normal. The primary defect in DNA synthesis caused by folate or vitamin B12 deficiency is a depletion of thymidine triphosphate (dTTP). This leads to retarded mitosis and nuclear maturation. The RBC have shortened life spans and reduced capacity to carry hemoglobin. Iron is stored as serum iron or ferritin rather than in hemoglobin (Guyton, 2006).
The first sign of inadequate folic acid intake is a decrease in serum folate concentration followed by a decrease in erythrocyte folate concentration and a rise in homocysteine levels. When folate supply to the bone marrow becomes rate limiting for erythropoiesis, macrocytic cells are produced. Macrocytic anemia is not evident in the early stages of folate deficiency because of the 120-day lifespan of normal erythrocytes.
When dietary vitamin B12 is deficient, the body cannot convert N5methyl THF to the active form of folate, tetrahydrofolate (THF). Without adequate vitamin B12, folate is trapped in an unusable form (Guyton, 2006). When dietary folate is deficient, the same problems occur because there are inadequate amounts of THF needed for the cascade of reactions required for DNA synthesis (Guyton, 2006). A B12 deficiency will eventually cause a folate deficiency because folate cannot be converted into an active form without vitamin B12 (Bostom, 1996).
One of the earliest clinical signs of both folate and vitamin B12 deficiency is hyper-segmentation of > 5 percent of neutrophils. Hyper-segmentation may also occur in uremia, myeloproliferative disorders, myelofibrosis and as a congenital lesion in 1% of the population. More testing is required to differentiate between megaloblastic and pernicious anemia.
The abnormal RBC cannot conform to the size of small capillaries. Instead, they fracture and hemolyze, thus shortening their lifespan. The macrocytic RBC has a reduced capacity to carry hemoglobin. Dietary iron is absorbed by the body and stored as serum iron or ferritin rather than in hemoglobin. Once the folate and/or vitamin B12 deficiency is treated through dietary supplements, the iron stores from the serum iron and ferritin will shift back to the RBC and the hemoglobin and hematocrit will return to normal levels. Homocysteine levels may or may not return to normal levels with folate supplementation.
Megaloblastic Anemia
Megaloblastic anemia is a folate deficiency commonly seen in middle-aged and older adults. It has been associated with an increased risk for heart disease and end stage renal disease because of the association with elevated homocysteine levels (Morrison, 1996; Pancharuniti, 1994; Robinson, 1996). It may be due to increased needs, a deficient diet, malabsorption of folate and/or a vitamin B12 deficiency. Malabsorption of folic acid may occur in individuals with diseases of the small intestine including ileitis, tropical and nontropical sprue, overgrowth of bacteria, hemolytic anemia, liver disease, malnutrition and following biliopancreatic diversion with and without duodenal switch (BPD/DS) weight loss surgery (Aills, 2008).
Some medications are folate antagonists and interfere with nucleic acid synthesis. The most common folate antagonists are anticonvulsants, antimalarials, alcohol, aminopterin and methotrexate. Megaloblastic anemia occurs after approximately 5 months of folate depletion.
The initial clinical signs and symptoms of megaloblastic anemia are low levels of hemoglobin, hematocrit and red cell folate. However, elevated levels of serum iron, MCV, ferritin and homocysteine are common. Falsely elevated concentrations of red cell folate are seen in patients with raised reticulocyte counts and low levels occur in vitamin B12 deficiency. Plasma folate can be used to assess status however; it is affected by recent folate intake.
Treatment for megaloblastic anemia is based on its etiology. Folate supplementation of 1 mg or more daily can compensate for vitamin B12 deficiency in DNA synthesis reversing macrocytic anemia and thereby masking vitamin B12 deficiency. Undiagnosed vitamin B12 deficiency will result in progressive permanent neurological damage including permanent changes in cognitive abilities. Individuals taking known folic acid antagonists will require prescription strength supplemental folate for as long as these medications are taken. Individuals with malabsorption disorders due to disease or weight loss surgery will require supplemental folic acid for a lifetime.
Pernicious Anemia
Pernicious anemia is due to a vitamin B12 deficiency commonly seen in older adults, vegetarians and individuals who have had malabsorptive weight loss surgery. Early signs and symptoms include pallor, weakness, lightheadedness, smooth, sore tongue, diarrhea alternating with constipation, numbness and tingling of extremities, gait abnormalities, personality changes, irritability, confusion, cognitive changes, depression and numbness of the hands and feet. Permanent nerve lining damage and significant cognitive decline will result from an untreated vitamin B12 deficiency.
Absorption and utilization of vitamin B12 is a multi step process. Dietary vitamin B12 is bound to a protein carrier. An acidic environment is required for the body to cleave the protein carrier from vitamin B12. Once vitamin B12 is released from its protein carrier in the stomach, it must form a complex with intrinsic factor (IF) for absorption in the terminal ileum. IF is synthesized in the stomach in the presence of an acidic environment. Without IF, B12 cannot be absorbed, body stores are depleted and the body produces enlarged immature RBC. It is categorized as a macrocytic normochromic anemia, however about 40 percent of the cases are normocytic (Allen, 1990; Carmel, 1996; Koepke,
