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Pathology - Sideroblastic Anemia (Lead Poisoning)
Sideroblastic anemia is owing to lead poisoning, most likely from pica (an abnormal need for non-nutritive items) for ingesting lead paint chips from an old inner city structure. Lead is absorbed through the GI tract from ingestion (or in the lungs from inhalation) and accumulates in the bones and teeth of youngsters (as detected on physical examination). Radiographs will show lead lines in the epiphyses of long bones. GI and neurologic (including encephalopathy) symptoms can emerge. Lead impacts enzyme function, including aminolevulinic acid (δ-ALA) dehydrase, causing increased δ-ALA and ferrochelatase, blocking the incorporation of iron into the heme molecule, resulting in increased protoporphyrin. Inhibition of ribonuclease results in persistence of ribosome in the RBC and generates coarse basophilic stippling. Sideroblastic anemia can potentially be the result of an X-linked mutation in the δ-ALA synthase gene, or vitamin B6 deficiency (a cofactor for δ-ALA synthase). Increased iron buildup in the mitochondria due to faulty heme production results in ringed sideroblasts.
Sideroblastic anemia is owing to lead poisoning, most likely from pica (an abnormal need for non-nutritive items) for ingesting lead paint chips from an old inner city structure. Lead is absorbed through the GI tract from ingestion (or in the lungs from inhalation) and accumulates in the bones and teeth of youngsters (as detected on physical examination). Radiographs will show lead lines in the epiphyses of long bones. GI and neurologic (including encephalopathy) symptoms can emerge. Lead impacts enzyme function, including aminolevulinic acid (δ-ALA) dehydrase, causing increased δ-ALA and ferrochelatase, blocking the incorporation of iron into the heme molecule, resulting in increased protoporphyrin. Inhibition of ribonuclease results in persistence of ribosome in the RBC and generates coarse basophilic stippling. Sideroblastic anemia can potentially be the result of an X-linked mutation in the δ-ALA synthase gene, or vitamin B6 deficiency (a cofactor for δ-ALA synthase). Increased iron buildup in the mitochondria due to faulty heme production results in ringed sideroblasts.
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Pathology -Pernicious Anemia (Vitamin B12 Deficiency)
Pernicious anemia is the most prevalent form of vitamin B12 (cobalamin) deficient anemia. The fundamental problem is decreased secretion of intrinsic factor (IF) from the stomach mucosa due to autoimmune atrophic gastritis, where autoantibodies result in the death of IF and hydrochloric acid-secreting parietal cells. After cleavage of R-factor, IF binds to vitamin B12 to facilitate absorption of the vitamin in the terminal ileum. Vitamin B12 deficiency is slow to develop as the liver can store several years supply of cobalamin; however, other causes can include decreased gastric acid secretion (prevents pancreatic enzyme cleavage of Rfactor), other absorptive disorder (Celiac’s disease, Crohn’s disease, bacterial overgrowth), and a pure vegan (not vegetarian) diet. In dietary deficiency, administration of radiolabeled cobalamin will result in increased urinary excretion of the radiolabeled vitamin, as it is absorbed normally. In pernicious anemia, increased urine excretion will only be noticed after the administration of exogenous IF (a positive Schilling test). As in this case, it is more likely in people with a personal history (Hashimoto’s thyroiditis) or a familial history (RA) of autoimmune illnesses. Vitamin B12 deficiency can be distinguished from folate-deficiency anemia by the presence of neurologic symptoms, including peripheral neuropathy with sensorimotor changes, decreased vibratory sense and proprioception (indicated here with balance changes and a positive Romberg’s sign), hyperspasticity, and mild cognitive impairment.
Pernicious anemia is the most prevalent form of vitamin B12 (cobalamin) deficient anemia. The fundamental problem is decreased secretion of intrinsic factor (IF) from the stomach mucosa due to autoimmune atrophic gastritis, where autoantibodies result in the death of IF and hydrochloric acid-secreting parietal cells. After cleavage of R-factor, IF binds to vitamin B12 to facilitate absorption of the vitamin in the terminal ileum. Vitamin B12 deficiency is slow to develop as the liver can store several years supply of cobalamin; however, other causes can include decreased gastric acid secretion (prevents pancreatic enzyme cleavage of Rfactor), other absorptive disorder (Celiac’s disease, Crohn’s disease, bacterial overgrowth), and a pure vegan (not vegetarian) diet. In dietary deficiency, administration of radiolabeled cobalamin will result in increased urinary excretion of the radiolabeled vitamin, as it is absorbed normally. In pernicious anemia, increased urine excretion will only be noticed after the administration of exogenous IF (a positive Schilling test). As in this case, it is more likely in people with a personal history (Hashimoto’s thyroiditis) or a familial history (RA) of autoimmune illnesses. Vitamin B12 deficiency can be distinguished from folate-deficiency anemia by the presence of neurologic symptoms, including peripheral neuropathy with sensorimotor changes, decreased vibratory sense and proprioception (indicated here with balance changes and a positive Romberg’s sign), hyperspasticity, and mild cognitive impairment.
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Pathology - Folate-Deficiency Anemia
Folate-deficiency anemia is the most usually caused by a decreased dietary intake of folate, but can also come from malabsorptive disorders, increased folate usage, and some medicines (5-fluorouracil, methotrexate, trimethoprim-sulfa, phenytoin). Both folate and B12 are involved in the production of deoxythymidine monophosphate. Without production of the nucleic acid thymine, DNA synthesis is impaired, resulting in persistent cell proliferation without division, producing macrocytosis. Thus, RBCs are larger than normal (high MCV) and neutrophils have an increased number of nuclear lobes (hypersegmented neutrophils). Populations at risk for folate-deficiency anemia include those with diets lacking in green vegetables and animal protein, including indigent, elderly (tea and toast diet), and alcoholic patients in particular.
Alcohol also hinders the release of folate from the liver, further contributing to the shortfall. Symptoms include those of anemia including fatigue, weakness, headaches, and irritability as well as aphthous ulcers, poor growth, and a swollen tongue. This patient likely has not eaten adequately since the death of his wife. Folate stores normally only last 2 to 3 months. Other indications of self-neglect include absence of appropriate medical care for hypertension and indicators of dehydration (dry mucous membranes and delayed capillary refill).
Folate-deficiency anemia is the most usually caused by a decreased dietary intake of folate, but can also come from malabsorptive disorders, increased folate usage, and some medicines (5-fluorouracil, methotrexate, trimethoprim-sulfa, phenytoin). Both folate and B12 are involved in the production of deoxythymidine monophosphate. Without production of the nucleic acid thymine, DNA synthesis is impaired, resulting in persistent cell proliferation without division, producing macrocytosis. Thus, RBCs are larger than normal (high MCV) and neutrophils have an increased number of nuclear lobes (hypersegmented neutrophils). Populations at risk for folate-deficiency anemia include those with diets lacking in green vegetables and animal protein, including indigent, elderly (tea and toast diet), and alcoholic patients in particular.
Alcohol also hinders the release of folate from the liver, further contributing to the shortfall. Symptoms include those of anemia including fatigue, weakness, headaches, and irritability as well as aphthous ulcers, poor growth, and a swollen tongue. This patient likely has not eaten adequately since the death of his wife. Folate stores normally only last 2 to 3 months. Other indications of self-neglect include absence of appropriate medical care for hypertension and indicators of dehydration (dry mucous membranes and delayed capillary refill).
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Pathology - Anemia of Chronic Disease
Anemia of chronic disease (ACD) is the most common anemia in hospitalized patients. The patho-genesis can involve decreased EPO production in patients with renal illness; however, more typically, as in this example, chronic inflammatory mediators (e.g., tumor necrosis factor-α, interleukin-1) result in increased synthesis and secretion of hepcidin from the liver. Hepcidin limits the release of iron from macrophages, such that it is sequestered from erythrocyte progenitor cells. As there is no actual deficiency of iron levels in the body, ferritin is still high, and the TIBC is low. However, since iron is being held inside macrophages, serum iron and the transferrin percent saturation is low. Erythrocytes may be either normocytic or microcytic. Inflammatory mediators can also influence EPO, further worsening the anemia. Chronic infections (e.g., TB) can also cause ACD. This patient’s anemia arises from many years of RA and is not related to pneumonia, which she is more susceptible to from her RA medications. The disparity between serum iron and serum ferritin is diagnostic. Although not mentioned in this case, patients with RA are also frequently treated with methotrexate, which inhibits tetrahydrofolate and can lead to folate-deficiency anemia.
Anemia of chronic disease (ACD) is the most common anemia in hospitalized patients. The patho-genesis can involve decreased EPO production in patients with renal illness; however, more typically, as in this example, chronic inflammatory mediators (e.g., tumor necrosis factor-α, interleukin-1) result in increased synthesis and secretion of hepcidin from the liver. Hepcidin limits the release of iron from macrophages, such that it is sequestered from erythrocyte progenitor cells. As there is no actual deficiency of iron levels in the body, ferritin is still high, and the TIBC is low. However, since iron is being held inside macrophages, serum iron and the transferrin percent saturation is low. Erythrocytes may be either normocytic or microcytic. Inflammatory mediators can also influence EPO, further worsening the anemia. Chronic infections (e.g., TB) can also cause ACD. This patient’s anemia arises from many years of RA and is not related to pneumonia, which she is more susceptible to from her RA medications. The disparity between serum iron and serum ferritin is diagnostic. Although not mentioned in this case, patients with RA are also frequently treated with methotrexate, which inhibits tetrahydrofolate and can lead to folate-deficiency anemia.
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Pathology - Aplastic Anemia
Aplastic anemia may occur after carbamazepine medication and subsequently developed invasive aspergillosis. Aplastic anemia originates from defective or inadequate multipotent myeloid stem cells (acquired or hereditary), or antigen receptor change causing T-cell activated stem cell suppression (caused by medications, infection, or other factors). The result is decreased erythrocytes, leukocytes, and platelets, known as pancytopenia.
Bone marrow is hypocellular with fatty infiltration. Aplastic anemia is more typically idiopathic, and myelotoxic medicines (alkylating agents, antimetabolites) most commonly employed for cancer therapy generate doserelated suppression. However, certain drugs might result in aplastic anemia in an unanticipated form, including carbamazepine (first-line treatment of TN), chloram-phenicol, streptomycin, hydralazine, and indomethacin to mention a few. Medication side effects might be overwhelming, but it is most important to concentrate on the most prevalent and the most serious. Aplastic anemia can result in significant infection (by opportunistic organisms as in this case) from neutropenia and bleeding from thrombocytopenia. Other causes include certain viruses (parvovirus B19, EBV, HIV) and Fanconi’s anemia.
Aplastic anemia may occur after carbamazepine medication and subsequently developed invasive aspergillosis. Aplastic anemia originates from defective or inadequate multipotent myeloid stem cells (acquired or hereditary), or antigen receptor change causing T-cell activated stem cell suppression (caused by medications, infection, or other factors). The result is decreased erythrocytes, leukocytes, and platelets, known as pancytopenia.
Bone marrow is hypocellular with fatty infiltration. Aplastic anemia is more typically idiopathic, and myelotoxic medicines (alkylating agents, antimetabolites) most commonly employed for cancer therapy generate doserelated suppression. However, certain drugs might result in aplastic anemia in an unanticipated form, including carbamazepine (first-line treatment of TN), chloram-phenicol, streptomycin, hydralazine, and indomethacin to mention a few. Medication side effects might be overwhelming, but it is most important to concentrate on the most prevalent and the most serious. Aplastic anemia can result in significant infection (by opportunistic organisms as in this case) from neutropenia and bleeding from thrombocytopenia. Other causes include certain viruses (parvovirus B19, EBV, HIV) and Fanconi’s anemia.
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Pathology - Sickle-Cell Anemia
Sickle-cell anemia is an autosomal recessive disorder most commonly encountered in African Americans. Sickle hemoglobin (HbS) is the result of a missense mutation of valine for glutamic acid at the sixth position of the β-globulin chain. Patients homozygous for the sickle-cell gene (HbSS) do not produce any normal HbA and develop anemia starting around 6 to 9 months of life, resulting from decreased HbF and increased production of HbS. Deoxy-genated hemoglobin molecules cluster and polymerize into needle-like fibers, causing the erythrocytes to assume a sickle shape. Recurrent sickling produces membrane damage and intravascular hemolysis. In addition, aberrant cell shape results in microvascular occlusion, which can trigger pain crises, such as in bones, the lungs, or penis (priapism). Dactylitis (painful swelling of the hands and feet) in infants due to bone infarcts is a common initial presenting symptom; however, the most frequent presentation is painless hematuria.
Autosplenectomy (associated with Howell-Jolly bodies present on peripheral smear) often occurs by 2 years of age, which increases risk for infection by encapsulated organisms (e.g., pneumococcus, Neisseria, Salmonella). Family history is frequently notable, like with this child’s uncle who presumably died of sickle-cell problems. The heterozygous condition (HbS, sickle-cell trait) does not result in anemia and conveys resistance to Plasmodium falciparum malaria.
Sickle-cell anemia is an autosomal recessive disorder most commonly encountered in African Americans. Sickle hemoglobin (HbS) is the result of a missense mutation of valine for glutamic acid at the sixth position of the β-globulin chain. Patients homozygous for the sickle-cell gene (HbSS) do not produce any normal HbA and develop anemia starting around 6 to 9 months of life, resulting from decreased HbF and increased production of HbS. Deoxy-genated hemoglobin molecules cluster and polymerize into needle-like fibers, causing the erythrocytes to assume a sickle shape. Recurrent sickling produces membrane damage and intravascular hemolysis. In addition, aberrant cell shape results in microvascular occlusion, which can trigger pain crises, such as in bones, the lungs, or penis (priapism). Dactylitis (painful swelling of the hands and feet) in infants due to bone infarcts is a common initial presenting symptom; however, the most frequent presentation is painless hematuria.
Autosplenectomy (associated with Howell-Jolly bodies present on peripheral smear) often occurs by 2 years of age, which increases risk for infection by encapsulated organisms (e.g., pneumococcus, Neisseria, Salmonella). Family history is frequently notable, like with this child’s uncle who presumably died of sickle-cell problems. The heterozygous condition (HbS, sickle-cell trait) does not result in anemia and conveys resistance to Plasmodium falciparum malaria.
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Pathology - α-thalassemia trait
α-thalassemia trait (minor), a disease of α-chain synthesis more typically reported in African American and southeastern Asian cultures. In this variation, two α-chain deletions exist. In African Americans, the losses are on separate chromosomes (α/- α/-), but the losses are on the same chromosome (-/- α/α) in Asians. The lack of two chains results in a global drop in all normal adult hemoglobin synthesis (HbA, HbA 2 , HbF); consequently, the electrophoresis is normal (relative quantities are the same as all hemoglobin types require the α-chain and are equally affected). With normal ferritin, the diagnosis is made by microcytic anemia and an elevated erythrocyte count, which is peculiar to thalassemias in anemias. Teardrop erythrocytes are a result of membrane damage due to removal of excess globin. Other α-thalassemias result from deletion of one, three, and four α-chains. One deletion produces an asymptomatic carrier without anemia. Three deletions generate hemoglobin H (HbH) illness, which produces a severe hemolytic anemia with HbH (four β-chains) identifiable by electrophoresis. Four deletions resulted in hemoglobin Bart (four γ-chains) illness, which creates hydrops fetalis in utero and is incompatible with life.
α-thalassemia trait (minor), a disease of α-chain synthesis more typically reported in African American and southeastern Asian cultures. In this variation, two α-chain deletions exist. In African Americans, the losses are on separate chromosomes (α/- α/-), but the losses are on the same chromosome (-/- α/α) in Asians. The lack of two chains results in a global drop in all normal adult hemoglobin synthesis (HbA, HbA 2 , HbF); consequently, the electrophoresis is normal (relative quantities are the same as all hemoglobin types require the α-chain and are equally affected). With normal ferritin, the diagnosis is made by microcytic anemia and an elevated erythrocyte count, which is peculiar to thalassemias in anemias. Teardrop erythrocytes are a result of membrane damage due to removal of excess globin. Other α-thalassemias result from deletion of one, three, and four α-chains. One deletion produces an asymptomatic carrier without anemia. Three deletions generate hemoglobin H (HbH) illness, which produces a severe hemolytic anemia with HbH (four β-chains) identifiable by electrophoresis. Four deletions resulted in hemoglobin Bart (four γ-chains) illness, which creates hydrops fetalis in utero and is incompatible with life.
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Pathology - Iron Deficiency Anemia
Iron-deficiency anemia is most likely linked to GI hemorrhage. Iron-deficiency anemia is the most common anemia, typically due to loss of iron from chronic bleeding; however, decreased intake, increased utilization (pregnant women, infants), malabsorptive disorders (celiac’s disease), and some hemoglobinopathies (paroxysmal nocturnal hemoglobinuria) can also be causative. As iron reserves drop, so does serum ferritin (which is the protein bound physiologically accessible form of iron). The TIBC of transferrin increases to maximize use of available iron; nevertheless, the fraction of saturated binding sites decreases due to shortage of available iron. In summary, test data demonstrate decreased serum iron, ferritin, and hemoglobin saturation with increased TIBC. Any unexplained iron-deficiency anemia in an older patient (postmenopausal woman) with a positive FOBT should trigger a colonoscopy to rule-out colon cancer. TSH is tested to rule-out hypothyroidism and liver function tests to screen for harmful side effects of simvastatin as causes of the patient’s presenting problems.
Iron-deficiency anemia is most likely linked to GI hemorrhage. Iron-deficiency anemia is the most common anemia, typically due to loss of iron from chronic bleeding; however, decreased intake, increased utilization (pregnant women, infants), malabsorptive disorders (celiac’s disease), and some hemoglobinopathies (paroxysmal nocturnal hemoglobinuria) can also be causative. As iron reserves drop, so does serum ferritin (which is the protein bound physiologically accessible form of iron). The TIBC of transferrin increases to maximize use of available iron; nevertheless, the fraction of saturated binding sites decreases due to shortage of available iron. In summary, test data demonstrate decreased serum iron, ferritin, and hemoglobin saturation with increased TIBC. Any unexplained iron-deficiency anemia in an older patient (postmenopausal woman) with a positive FOBT should trigger a colonoscopy to rule-out colon cancer. TSH is tested to rule-out hypothyroidism and liver function tests to screen for harmful side effects of simvastatin as causes of the patient’s presenting problems.
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Pathology - β-thalassemia major
β-thalassemia major is established by the lack of HbA 1 (composed of α-2 and β-2) on electrophoresis.
In contrast to heterozygous β-thalassemia minor, the patient is homozygous for deletion of the β-hemoglobin gene.
Therefore, absence of β-chain synthesis enhances production of HbA 2 (α-2, δ-2) and HbF (α-2, γ-2). The anemia is a result of inefficient erythropoiesis; nevertheless, breakdown products of excess α-chains also results in intramedullary destruction of RBC precursors and peripheral hemolysis. The overall loss in hemoglobin results in a microcytic, hypochromic anemia. Resulting tissue hypoxia drives EPO production, which causes marrow growth and bone deformity, as evidenced by the hypertrophied mandible of this infant. Increased iron absorption from marrow expansion coupled with transfusion-dependent survival often results in heart failure owing to hemochromatosis.
Patients with β-thalassemia minor are largely asymptomatic unless rarely during pregnancy.
β-thalassemia major is established by the lack of HbA 1 (composed of α-2 and β-2) on electrophoresis.
In contrast to heterozygous β-thalassemia minor, the patient is homozygous for deletion of the β-hemoglobin gene.
Therefore, absence of β-chain synthesis enhances production of HbA 2 (α-2, δ-2) and HbF (α-2, γ-2). The anemia is a result of inefficient erythropoiesis; nevertheless, breakdown products of excess α-chains also results in intramedullary destruction of RBC precursors and peripheral hemolysis. The overall loss in hemoglobin results in a microcytic, hypochromic anemia. Resulting tissue hypoxia drives EPO production, which causes marrow growth and bone deformity, as evidenced by the hypertrophied mandible of this infant. Increased iron absorption from marrow expansion coupled with transfusion-dependent survival often results in heart failure owing to hemochromatosis.
Patients with β-thalassemia minor are largely asymptomatic unless rarely during pregnancy.
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Pathology - Tetanus
A highly infected wound may requires tetanus treatment. A highly contaminated wound with no history of tetanus vaccine requires tetanus and diphtheria (Td) toxoid as well as tetanus immune globulin (TIG).
Previously immunized patients do not require TIG and only require the Td toxoid if it has been greater than 5 years since their last immunization. Clean, mild wounds require Td toxoid only for unvaccinated patients (or patients with incomplete vaccination series) or those who have greater than 10 years since their last vaccine. TIG is not typically given for clean, small wounds.
A highly infected wound may requires tetanus treatment. A highly contaminated wound with no history of tetanus vaccine requires tetanus and diphtheria (Td) toxoid as well as tetanus immune globulin (TIG).
Previously immunized patients do not require TIG and only require the Td toxoid if it has been greater than 5 years since their last immunization. Clean, mild wounds require Td toxoid only for unvaccinated patients (or patients with incomplete vaccination series) or those who have greater than 10 years since their last vaccine. TIG is not typically given for clean, small wounds.
