What is anemia and what three parameters are used to test for it?
Anemia is insufficient red cell mass to adequately deliver oxygen to peripheral tissues. Anemia is diagnosed on the basis of Hemoglobin concentration (HGB), Hematocrit level (HCT), and RBC count (cells x 10^12/L)
What does the reference range mean?
Only means the normal range of values, and 3% of individuals are below that range and 3% are above. Abnormal values alone do not diagnose any disorders.
What broad factors influence hemoglobin and hematocrit levels in individuals?
Age and geography. Children from 3months to 10years have lower levels that newborns and adults. HGB and HCT levels are also different in Denver than at sea level.
Is HCT measured directly in the CBC?
No, it is calculated later.
What are some morphological signs of iron deficiency?
Enlargened central area of pallor, hypochromia, microcytosis, tear drop cells, eliptocyte cells
Facts about reticulocytes.
Reticulocytes contain stainable fragments of mRNA, and are thus detectable in the blood. Normally only spend 1 day in blood before they mature, but in anemia they may appear early in their cycle and spend 3-4 days maturing. Normally make up ~1% of blood (1/120), may be 3-5 times more. Marrow can only increase production 6-8 times, max.
What is the first question in classifying the cause of anemia, and what paths does it lead to?
Is anemia associated with other hematological abnormalities? That is, are the WBC and Platelet counts low? If yes, suspect bone marrow issues. If no, investigate if there is an appropriate reticulocyte response?
If there are no other hematological abnormalities associated with anemia, and there is an appropriate reticulocyte response, what is the next step in diagnosis and what paths does it lead to?
Determine if there is evidence of hemolysis (Increased bilirubin, increased lactic dehydrogenase, decreased haptoglobin). If yes, evaluate for cause of hemolysis. If no, evaluate for hemorrhagic causes of anemia.
If there are no other hematological abnormalities associated with anemia, and there is NOT an appropriate reticulocyte response, what is the next step in diagnosis and what paths does it lead to?
Determine the red blood cell indices (MCV). MCV 100 - evaluate for macrocytic anemia.
What determines how much impact anemia has on a patient?
RBC is only one component of the mass transport of O2. The lungs and cardiovascular system may also help compensate for RBC shortcomings. The degree of stress on the body depends on the extent of the anemia, the ability of the other systems to compensate, and the speed at which the anemia develops.
What are the clinical signs and symptoms of anemia?
Symptoms: shortness of breath, fatigue, rapid heart rate, dizziness, claudication, angina, pallor. Signs: tachycardia, tachypnea, dyspnea, pallor
Five basic facts about Fe (iron)
1) Fe exists in two valence states with different activity (2+, 3+) 2) Fe forms insoluble hydroxides in aqueous solutions unless bound (protein, heme, etc) 3) Fe more soluble at low pH 4) Fe balance is controlled by absorption, there is no active excretion mechanism 5) Fe losses each day are small, loss from exfoliation of the skin, mucosal membranes, in urine or with menstruation.
Where four locations is iron typically found in the body?
Hemoglobin (65%) & Myoglobin (6%) actively use iron. Iron is stored in large quantities in Ferritin (13%) and Hemosiderin (12%). Transferrin is important as a transporter, but only has a small amount at any one time (0.1%).
How and where is iron absorbed?
Iron is absorbed in the duodenum. Fe3+ (ferric) is converted to Fe2+ (ferrous) and then imported into cells where some is bound to Ferritin and some is excreted through ferroportin on the basolateral aspect and reconverted to Fe3+ (ferric).
Two classes of factors that influence iron absorption and examples of each.
Intraluminal and Extraluminal factors. Intraluminal factors include Gastric factors (low pH, gastroferrin), proteins/AA, Vitamin C, Phytates, oxalates, amount of iron ingested. Extraluminal factors include Erythropoietic activity.
Describe the iron cycle.
Iron is absorbed from food in the duodenum and enters the plasma bound to transferrin (can hold 2 moles of Fe3+). Fe is taken to bone marrow, moves into hemoglobin in circulating erythrocytes, erythrocytes are eventually degraded by reticuloendothelial macrophages and Fe returns to transferrin in the plasma or storage on Ferritin.
How do plasma ferritin levels indicate cellular ferritin levels?
Plasma ferritin is proportional to cellular ferritin so testing of plasma levels is good indicator of cellular levels.
How is plasma iron taken up into a cell?
Iron in the plasma, bound to transferrin, attaches to transferrin receptors on the surface of erythropietic cells and the complex is pinocytosed. The pH of the vesicle drops and the iron is released and absorbed into the cytoplasm through a di-metal transporter. Thus, iron goes directly to red cell precursors.
What is hepcidin and what role does it play in the iron cycle?
Hepcidin is a 25 AA protein produced in the liver (hep) which has anti-bacterial properties (cidin). Its synthesis is increased by inflammation/infection and by iron overload. It is a negative regulator of many steps of the iron cycle, including iron absorption by intestinal epithelia, transport across the placenta, and iron release from macrophages. During infection, its inhibition of ferroportin (flips it over) causes increased iron retention in macrophages contributing to anemia, and has implications in iron resistant, iron deficiency anemia.
What are the important points in the development of iron deficiency, and what are the three stages leading to iron deficiency anemia?
Early deficiency (iron depletion) is characterized by increased transferrin, decreased ferritin. Iron deficient erythropoiesis continues these trends and also displays decreased serum iron and decreased transferrin saturation. Iron deficiency anemia further continues all of these trends and manifests with microcytic cells.
What are the characteristics of iron deficiency?
Decrease in hemoglobin production, decrease in cell proliferation. Neuromuscular defects: defective muscle performance, neuropsych dysfunction. Epithlial: nails and tongue changes (ridges, koilonychia, papillary atrophy). Upper and lower GI issues. Immune dysfunction affects innate (phagocytes) and adaptive (lymphocytes).
What are three broad causes of iron deficiency anemia?
Decreased iron intake, increased iron loss, increased need for iron.
How is anemia diagnosed?
DECREASED O2 carrying capacity (HGB & HCT), cell production (reticulocyte count & index), cell size (microcytosis, MCV), hemoglobin concentration (MCHC). INCREASED range in cell sizes (Increased RDW).
Differential diagnoses for iron deficiency anemia
Anemia of chronic inflammation/infection. Anemia of chronic disease. Thalassemia. Sideroblastic anemias.
How is iron deficiency anemia treated?
Oral iron at 150-200 mg per day for adults, or 4-6 mg/kg/day in 3 doses. SC or IV iron is also available. Normal response: Serum iron will go up within 24 hours, reticulocyte count in 5-7 days, HGB in 30 days, ferritin recovers much later b/c it is the storage pool, and the last to recover is the MCV/FEP/RDW parameters because the deficient cells still last for 90 days.
What causes iron overload?
High iron in diet, high rates of absorption (abnormal HFE gene), repeated transfusions. HFE codes for a protein in duodenal crypt cells and reticuloendothelial cells which acts as a cofactor for iron absorption.
What are the consequences of iron overload?
Increased serum iron (sat >50%), Increased Ferritin, increased liver iron. Organ damage may result: Cardiac (arrhythmia, failure), liver (dysfunction, failure), endocrine dysfunction (pancreatic endocrine: diabetes)
What is the treatment for iron overload?
Hemochromotosis -> therapeutic phlebotomy Hemosiderosis -> iron chelators