Anemia of Diminished Production

At the beginning of the lecture someone asked the Dr. a question about the online lecture: Q: At the same levels of hemoglobin people don’t have the same symptoms A: The reason is that the athlete needs all his hemoglobin to perform at his full capacity and they can't afford to lose any of their muscles mass or hemoglobin, on the other hand normal people don’t need a lot of hemoglobin just to breathe and see things. The message here is to look at the bigger picture and look at the patient instead of the numbers. Brief recap on the previous lecture: 1. The definition of anemia: which is the decrease in the RBC mass whether it shows symptoms or not. 2. It's difficult to measure the RBC mass so instead we use hemoglobin hematocrit 3. We have 2 systems of Classifications of anemia: one depends on the cause and the other depends on the MCV(low-microcytic, high -macrocytic, normal-normocytic anemia). 1. Microcytic anemia is common in Jordan and it is caused by 4 major “diseases” 2 are common and 2 are not: iron deficiency, thalassemia, lead poisoning and sideroblastic anemia. 2. Macrocytic anemia on the other hand is caused by B12 or folate deficiency and thyroid or liver diseases. 3. Normocytic anemia we have decreased bone marrow production or increased consumption(I think what the Dr. meant here is increased blood loss) and we differentiate between them by the reticulocyte count. Now on to the lecture: Anemia of diminished production Which includes: • Iron deficiency anemia: the most common • Anemia of chronic disease: also, very common • Megaloblastic anemia: which is caused by vit B12 or folate deficiency Others: • anemia in liver disease • anemia in renal disease • aplastic anemia • myelophthisic anemia 2|Page (1) Iron deficiency anemia Most of the iron in our body is found in hemoglobin(two thirds of our iron). And 25% in other places. We have two major factors to transfer iron: 1. transferrin which is extracellular, so it's found in the blood. (and is normally one third occupied) 2. Ferritin which is intracellular (technically the major place to find ferritin is inside the cells however there's a small amount found in the serum and it's a very sensitive marker for iron deficiency in fact if we measured the ferritin level in the serum it could be low even before iron levels become low, so in very early stages of anemia serum ferratin levels will decrease faster than iron levels). * the control of iron content in the body is at the level of absorption, which explains why we don’t have any mechanism for excreting iron. What comes in stays in except for the 1-2 mg per day and that's why when someone gets excessive amounts of iron(not from food) it accumulates in their body; an example is patients who take regular blood transfusions due to thalassemia or sickle cell anemia. Every RBC has a specific amount of hemoglobin and it will accumulate in these patients' liver and heart in fact the major cause of death in thalassemia patients is cardiomyopathy as a result of iron overload. Iron absorption The Dr. said the most important thing about this picture is Hepcidin: which will monitor how much iron we have in our body ; if we have enough iron hepcidin levels will be elevated then goes to the intestinal mucosa(since iron is absorbed in the duodenum) and inhibits iron absorption. On the other hand, if we have iron deficiency hepcidin levels will fall causing higher iron absorption. 3|Page With that being said, iron deficiency is still the most common cause of anemia and it could also cause other symptoms in other systems, but basically what brings the patient to attention is low hemoglobin and anemia. Iron deficiency can result from (1) Dietary : inadequate intake (2) impaired absorption (3) increased requirement (4) chronic blood loss (which is the most common cause) Which clinical scenario is more serious? A 19-year-old lady, with sever menorrhagia presenting with shortness of breath on exertion, fatigue, pallor and a hemoglobin of 7.6g/dl, low MCV. meaning she has microcytic anemia A 79-year-old asymptomatic gentleman who, on routine checkup, was found to have a hemoglobin of 11g/dl and low MCV. In men the normal hemoglobin is 13 so it's slightly decreased For the first patient while she's more acute and more symptomatic we know the cause(menstruation) we'll just have to give her iron supplements. While in the elderly man he doesn’t have physiological chronic blood loss, so something is missing, his anemia doesn’t need treatment since it's not that severe and it’s asymptomatic BUT it's very important to know the underlying cause. In men with anemia at any age it's very important to rule out malignancy, specifically lower GI malignancy. In conclusion the elderly man scenario is more serious * So, we have to think of anemia as fever; when a child comes in with a fever, we don’t just give him paracetamol we have to find out the infection causing it first and treat it with the proper antibiotics. We have to treat the cause not the symptom, so anemia is a symptom due to a cause. Pathogenesis of iron deficiency (1) Negative iron balance due to any reason. (2) Compensation by storage iron. (3) Progressive deficiency until complete depletion and end of storage iron. (4) Anemia develops accompanied by low ferritin and low transferrin saturation. Iron is stored in hemoglobin and it's also stored in the reticular endothelial system= macrophages found in the bone marrow. Erythroid cells are produced in the bone 4|Page marrow it undergoes a series of maturation and at one point it will need to incorporate iron to produce hemoglobin, the erythroid cell will take this iron from macrophages (the macrophages got this iron form phagocytosing old RBCs. -not mentioned by the Dr. just for understanding the concept-)after the wipeout of all the bone marrow's storage of iron the hemoglobin production decreases leading to symptoms of anemia. The morphology of iron deficiency is not specific, the cells will have severe variation in size something called anisocytosis. Which is measured by RDW(red cell distribution weight) which will be high because of the variability in the sizes of RBCs. Another common finding -though nonspecific- is pencil cells blunt ended pencil shaped cells.(arrow) This is normal bone marrow the blue color is a stain called Prussian Blue stain which detects iron which is very abundant in the bone marrow. In this picture we can't see any blue staining indicating iron deficiency anemia. These sample are obtained by bone marrow aspiration which is a very aggressive procedure and usually it's not performed in iron deficiency, because there are other lab tests that are more accurate and specific so there is no need to subject our patient to such painful procedure clinical presentation mostly asymptomatic, however if we have symptoms, they are nonspecific such as: 1. 2. 3. 4. Shortness of breath Skin pallor Easily tired If severe enough it can cause angina and heart disease 5|Page As mentioned before iron deficiency anemia could present with other symptoms than its hemoglobin effects such as: 1. Inflammation of the tongue(glossitis) 2. Pica which is eating something that isn’t edible such as soil 3. Skewing of the fingernails 4. Esophageal webs causing dysphagia Lab findings • • • • • • • • • Low hemoglobin and hematocrit: simply because it's anemia. Low MCV: because it's microcytic anemia. Low MCH: because it's hypochromic anemia. Low iron levels Low ferritin: which usually decreases before the decrease in serum iron as mentioned before. High TIBC(total iron binding capacity): it basically reflects the number of empty "chairs" on the transferrin molecule so when there's no iron we have high numbers of empty "chairs" leading to increased TIBC. High RDW Low hepcidin: because there's no iron. Low transferrin saturation: because there's no iron to bind to transferrin. Treatment Treat by iron supplementation and treating the underlying cause. (2) Anemia of chronic disease We now know that iron deficiency anemia is the most common type of anemia, but anemia of chronic diseases is the most common type in hospitalized patients; typically, the elderly with multiple comorbidities like diabetes, hypertension and kidney disease etc. These chronic diseases can be anything such as chronic microbial infection, autoimmune inflammation, idiopathic and malignancy. How does the anemia of chronic disease happen? 6|Page IL-6 is high in patients with chronic inflammation despite the cause of that inflammation. IL-6 increases the levels of hepcidin production in the nuclei of the liver. So, in chronic disease anemia hepcidin level is high(because of IL-6) in contrary to iron deficiency anemia in which hepcidin level are low. As we mentioned before Hepcidin stops absorption of iron from the duodenum, and it also prevents the erythroid cell from obtaining iron from macrophages in the bone marrow. The Dr. compared iron deficiency anemia to not having money while anemia of chronic disease is when you have money, but you can't use it. Theories of why hepcidin increases: is to deprive the microbes from iron so we can decrease their function though not provenThese were mentioned in the slide as other roles of elevated hepcidin levels in this case:inhibit erythropoietin and subsequently decreases EP proliferation, possible immunologic role for hepcidin. Clinical presentation • Mild anemia; mostly normocytic but sometimes it can be mildly microcytic meaning MCV is either normal or slightly low. • Signs and symptoms of underlying disease. Lab findings • Low HB and Hct • Can be hypochromic microcytic or normochromic normocytic. • High ferritin and low TIBC (exactly opposite to iron deficiency anemia). Ferritin is high because it's an acute phase reactant meaning its levels increase when we have an acute inflammation.TIBC is low because we have enough iron in the body, we just can't use it. (3) megaloblastic anemia It causes macrocytic anemia meaning that we have a high MCV. Caused by Vitamin B12 or folate deficiency. 7|Page B12 and folate have something to do with DNA synthesis so deficiency in them will cause defects in DNA. B12 absorption happens at many levels and combines an detaches with different proteins. In order for B12 to be absorbed at the terminal ilium it must be bound to intrinsic factor which is found in the stomach and secreted by parietal cells. B12 stores in our body are enough for 4-10 years. Causes of B12 deficiency B12 deficiency could be caused by decreased dietary intake but it's rare since we can find B12 in many foods, you have to be strictly vegetarian for at least 5 years to become deficient. Inflammation in the terminal ilium(crohn's disease, TB or resection of the terminal ilium) Any disruption to the pathway of absorption could lead to deficiency. Pernicious anemia meaning the patient doesn’t have parietal cells anymore It’s an autoimmune attack on gastric mucosa. three types of antibodies 1-parietal canalicular antibodies 2-blocking antibodies. 3-intrinsic factor–B12 complex antibodies. *Increase the risk of gastric malignancy (low grade lymphoma=MALToma and adenocarcinoma) in patient with pernicious anemia. Symptoms of B12 deficiency Nonspecific anemia symptoms: pallor of skin, shortness of breath etc. Megaloblastic anemia also affects other type of cells such as platelets and WBC, so we see other symptoms not related to anemia such as leukopenia and thrombocytopenia = pancytopenia. In B12 deficiency only(not in folate), we have neurological symptoms: 8|Page • Numbness, Unsteady gate, Loss of position sense Folate deficiency Could be caused by decreased dietary intake since our stores of folate aren’t as much as B12. But is mostly happens in pregnant women due to requirement of pregnancy. Some medication such as anticonvulsants and chemotherapy may cause B12 and folate deficiency by interfering with the pathway of their synthesis and then resulting in megaloblastic anemia Nonspecific symptoms of anemia, weakness, fatigue…etc. GI symptoms due to the effect on GI epithelial lining cells. NO neurological symptoms Lab findings: Diagnose by serum and RBC folate levels, MCV levels are high. (4) Anemia in liver disease Chronic liver disease such as alcoholic hepatitis and Hepatitis C. Multiple etiologies: *Iron deficiency is the most common. *Hypersplenism: increase in the function of the spleen (caused by a liver disease) with or without an increase in its size it can cause anemia. *Therapy related hemolytic anemia and suppression of EPO receptor (medications with side effects). *Alcoholic-cirrhosis-induced folate deficiency: since alcohol interferes with folate metabolism and absorption. Morphology: Spur cells (blunt projections on blood cells) around RBCs 9|Page (5) Anemia of renal disease Related to decrease EPO(erythropoietin) production by the damaged kidney. High levels of inflammatory cytokines Hemolysis Chronic bleeding Folate deficiency in patients on dialysis. Morphology: echinocytes (sharp projections) (6) Aplastic anemia Aplasia means lack of formation so all blood cells in bone marrow are deficient; myeloid, erythroid and lymphoid. So, it’s similar to folate and B12 deficiency anemia in that it presents with pancytopenia. Aplastic anemia refers to a syndrome of chronic primary hematopoietic failure and attendant pancytopenia (anemia, neutropenia, and thrombocytopenia). Causes of aplastic anemia: for the most part it's idiopathic certain mechanism such as viral infection, toxins, radiation, chemicals etc. some inherited diseases such as Fanconi anemia and telomerase defects. The mechanism of aplastic anemia All bone marrow cells come from stem cells which have 2 functions; to mature into different cells and to proliferate to replace itself. It's suggested that aplastic anemia is an autoimmune disease resulting from T lymphocytes attacking stem cells causing these cells to lack the ability to proliferate and differentiate and since the stem cells are affected all the subsequent cells won't be produced causing aplastic anemia. 10 | P a g e Typically, the spaces between the bone trabeculae consists of hematopoietic cells and fat cells and the percentage between hematopoietic cells and fat varies depending on the age so, people our age will have 70% hematopoietic cells(cellularity), in the elderly it could be 30% cellularity. Here the cellularity is almost zero the cells are wiped out because of aplastic anemia Clinical features • Any age with no gender predilection • Respond well to immunosuppressive therapy, BM transplantation is the treatment of choice with 5-year survival of more than 75%. • No splenomegaly: splenomegaly happens as compensatory mechanism when the bone marrow has failed to produce blood cells the spleen steps up, but in aplastic anemia the problem is in the stem cells that are found in the bone marrow and the spleen. • Bone marrow exam is a must for diagnosis because of the similarity of the symptoms with leukemia. Lab findings • Normocytic and occasionally macrocytic anemia. • No increased reticulocyte count (they're low). • Stigmata of pancytopenia: causes recurrent infection (leukocytopenia) as well as pallor and shortness of breath (anemia) also bleeding(thrombocytopenia) also these patients have similar symptoms as leukemia. (7) Myelophthisic anemia Result from something replacing and infiltrating the bone marrow Extensive infiltration of the marrow by tumors or other lesions. • Metastatic cancer (lung, breast, prostate), tuberculosis and fibrosis, lipid storage disorders, osteosclerosis Leukoerythroblastic reaction on peripheral blood: the problem here isn’t in the hematopoietic cells production it's in then being displaced out of the bone marrow.(mentioned next page) 11 | P a g e 1- tear drop RBC :found in any condition that replaces blood cells (left arrow) 2- immature erythroid precursor cell(middle arrow) 3- immture myeloid cell: normally we should never see these cells in the peripheral blood they have no function to do, but they're here since something is pushing them out (right arrow) All this is called Leukoerythroblastic reaction we see it in myelofibrosis and myelophthisic anemia Clinically: Patients present with anemia and thrombocytopenia. While WBC are usually less affected. Treatment is directed at the underlying etiology. _ Questions: -All the following can be found in iron deficiency anemia, except: Low ferritin Low serum iron Low TIBC Low transferrin saturation Low MCV -Anemia of chronic disease is caused by elevated levels of: A. Hepcidin B. Iron C. Ferritin D. B12 E. Neutrophils - All the following are true regarding megaloblastic anemia, except: A. defective DNA synthesis, resulting in nuclear immaturity B. macrocytic anemia C. can be seen in the setting of pernicious anemia D. most common cause is nutritional deficiency of B12 E. can be associated with neurological symptoms in the case of B12 deficiency. - The most common cause of anemia in patients with liver disease is: A. Iron deficiency B. Hypersplenism C. Therapy related hemolytic anemia D. Therapy related suppression of EPO receptor E. Alcoholic-cirrhosis-induced folate deficiency - One of the following can cause myelophthisic anemia: A. Tuberculosis B. B12 deficiency C. Folate deficiency D. Iron deficiency E. Anemia of chronic disease A. B. C. D. E. 12 | P a g e