Etiology of Vitamin B12 Deficiency.

With this background, we can consider the various causes of vitamin B12 deficiency (see Table 13-5 ). Inadequate diet is obvious but must be present for many years to deplete reserves.

The absorption of vitamin B12 can be impaired by disruption of any one of the steps outlined earlier. With achlorhydria and loss of pepsin secretion (which occurs in some elderly

individuals), vitamin B12 is not readily released from proteins in food. With gastrectomy and pernicious anemia, intrinsic factor is not available for transport to the ileum. With loss of

exocrine pancreatic function, vitamin B12 cannot be released from R-binder-vitamin B12 complexes. Ileal resection or diffuse ileal disease can remove or damage the site of intrinsic factorvitamin

B12 complex absorption. Tapeworm infestation, by competing for the nutrient, can induce a deficiency state. Under some circumstances, for example, pregnancy, hyperthyroidism,

disseminated cancer, and chronic infections,

Figure 13-20Schematic illustration of vitamin B12 absorption.

Figure 13-21Relationship of N5 -methyl FH4 , methionine synthase, and thymidylate synthetase. In cobalamin deficiency, folate is sequestered as N5 -methyl FH4 . This ultimately

deprives thymidylate synthetase of its folate coenzyme (N5,10 -methylene FH4 ), thereby impairing DNA synthesis.

Figure 13-22Role of folate derivatives in the transfer of one-carbon fragments for synthesis of biologic macromolecules. FH4 , tetrahydrofolic acid; FH2 , dihydrofolic acid; FIGlu,

formiminoglutamate; dTMP, deoxythymidylate monophosphate. *Synthesis of methionine also requires vitamin B12 .

TABLE 13-6-- Iron Distribution in Healthy Young Adults (mg)

Pool Men Women

Total 3450 2450

Functional

••Hemoglobin 2100 1750

••Myoglobin 300 250

••Enzymes 50 50

Storage

••Ferritin, hemosiderin 1000 400

Free iron is highly toxic, and the pool of storage iron is tightly bound to either ferritin or hemosiderin.[40] Ferritin is a protein-iron complex found in all tissues but particularly in liver,

spleen, bone marrow, and skeletal muscles. In the liver, most ferritin is stored within the parenchymal cells; in other tissues, such as spleen and bone marrow, it is mainly in the

mononuclear phagocytic cells. Hepatocytic iron is derived from plasma transferrin, whereas storage iron in the mononuclear phagocytic cells (Kupffer cells) is derived from the breakdown

of red cells ( Fig. 13-23 ). Intracellular ferritin is located in both the cytosol and lysosomes, in which partially degraded protein shells of ferritin aggregate into hemosiderin granules. With

a hematoxylin and eosin stain, hemosiderin appears in cells as golden yellow granules. The iron in hemosiderin is chemically reactive and turns blue-black when exposed to potassium

ferrocyanide, which is the basis for the Prussian blue stain. With normal iron stores, only trace amounts of hemosiderin are found in the body, principally in mononuclear phagocytic cells

in the bone marrow, spleen, and liver. In iron-overloaded cells, most iron is stored in hemosiderin.

Very small amounts of ferritin normally circulate in the plasma. Since plasma ferritin is derived largely from the storage pool of body iron, its levels correlate well with body iron stores. In

iron deficiency, serum ferritin is always below 12 μg/L, whereas in iron overload, high values approaching 5000 μg/L can be seen. Of physiologic importance, the storage iron pool can be

readily mobilized if iron requirements increase, as may occur after loss of blood.

Iron is transported in plasma by an iron-binding glycoprotein called transferrin (see Fig. 13-23 ), which is synthesized in the liver. In normal individuals, transferrin is about 33% saturated

with iron, yielding serum iron levels that average 120 μg/dL in men and 100 μg/dL in women. Thus, the total

Figure 13-23The internal iron cycle. Plasma iron bound to transferrin is transported to the marrow, where it is transferred to developing red cells and incorporated into hemoglobin.

Mature red blood cells are released into the circulation and, after 120 days, are ingested by macrophages in the reticuloendothelial system (RES). Here iron is extracted from hemoglobin

and returned to the plasma, completing the cycle. (From Wyngaarden JB, et al [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p. 841.)

Figure 13-24Diagrammatic representation of iron absorption. Mucosal uptake of heme and nonheme iron is depicted. When the storage sites of the body are replete with iron and

erythropoietic activity is normal, most of the absorbed iron is lost into the gut by shedding of the epithelial cells. Conversely, when body iron needs increase or when erythropoiesis is

stimulated, a greater fraction of the absorbed iron is transferred into plasma transferrin, with a concomitant decrease in iron loss through mucosal ferritin.

Figure 13-25Hypochromic microcytic anemia of iron deficiency (peripheral blood smear). Note the small red cells containing a narrow rim of peripheral hemoglobin. Scattered fully

hemoglobinized cells, present due to recent blood transfusion, stand in contrast. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical

School, Dallas, TX.)

TABLE 13-7-- Major Causes of Aplastic Anemia

Acquired

Idiopathic

••Primary stem cell defect

••Immune mediated

Chemical agents

••Dose related

••••Alkylating agents

••••Antimetabolites

••••Benzene

••••Chloramphenicol

••••Inorganic arsenicals

••Idiosyncratic

••••Chloramphenicol

••••Phenylbutazone

••••Organic arsenicals

••••Methylphenylethylhydantoin

••••Streptomycin

••••Chlorpromazine

••••Insecticides (e.g., DDT, parathion)

Physical agents (e.g., whole-body irradiation)

Viral infections

••Hepatitis (unknown virus)

••Cytomegalovirus infections

••Epstein-Barr virus infections

••Herpes varicella-zoster

Miscellaneous

••Infrequently, many other drugs and chemicals

Inherited

Fanconi anemia

required for DNA repair[45] ( Chapter 7 ). Marrow hypofunction in Fanconi anemia becomes evident early in life and is accompanied by multiple congenital anomalies, such as hypoplasia

of the kidney and spleen and hypoplastic anomalies of bone, often involving the thumbs or radii.

Despite all these possible causes, no provocative factor can be identified in fully 65% of the cases, which are lumped into the idiopathic category.

Pathogenesis.

The pathogenesis of aplastic anemia is not fully understood. Indeed, it is unlikely that a single mechanism underlies all cases. Two major etiologies have been invoked: an immunologically

mediated suppression and an intrinsic abnormality of stem cells ( Fig. 13-26 ).

Recent studies suggest that aplastic anemia results most commonly from suppression of stem cell function by activated T cells.[46] It is postulated that stem cells are first antigenically

altered by exposure to drugs, infectious agents, or other unidentified environmental insults. This evokes a cellular immune response, during which activated T cells produce cytokines such

as interferon-g and TNF that prevent normal stem cell growth and development. This scenario is supported by several observations. Immunosuppressive therapy with antithymocyte

globulin combined with drugs such as cyclosporine produces responses in 60% to 70% of patients, and successful bone marrow transplantation requires "conditioning" with high doses of

myelotoxic drugs or radiation. In both instances, it is hypothesized these therapies work by suppressing or killing autoreactive T-cell clones. The target antigens for T-cell attack are not

well defined. In some instances GPI-linked proteins may be the targets of sensitized T cells,

Figure 13-26Pathophysiology of aplastic anemia. Damaged stem cells can produce progeny expressing neo-antigens that evoke an autoimmune reaction, or give rise to a clonal population

with reduced proliferative capacity. Either pathway could lead to marrow aplasia.

Figure 13-27Aplastic anemia (bone marrow biopsy). Markedly hypocellular marrow contains mainly fat cells. A, Low power. B, High power. (Courtesy of Dr. Steven Kroft, Department

of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)

TABLE 13-8-- Pathophysiologic Classification of Polycythemia

Relative Reduced plasma volume (hemoconcentration)

Absolute

Primary Polycythemia vera, rare erythropoietin receptor mutations (low erythropoietin)

Secondary High erythropoietin

Appropriate: lung disease, high-altitude living, cyanotic heart disease

Inappropriate: erythropoietin-secreting tumors (e.g., renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)

More specialized tests are available to measure the levels of specific clotting factors, fibrinogen, fibrin split products, the presence of circulating anticoagulants, and platelet function. With

this overview, we can turn to the various categories of bleeding disorders.

Date: 2016-04-22; view: 650