Block 6: Anemia of Diminished Erythropoiesis
What common medicines should be avoided when treating iron deficient anemia?
Antacids, tetracyclines, pancreatic enzyme supplements, cholestyramine, etc. b/c can reduce Fe absorption
How is anemia of chronic disease (AoCD) different from Fe deficiency?
AoCD - low serum iron despite adequate levels of Fe stores -- it's associated w/ impaired iron utilization and reduced erythroid proliferation (will see decreased TIBC and increased Ferritin - opposite of iron def)
End lecture 1
Awesome sauce
Major causes of megaloblastic anemia (4)?
B12 and B9 deficiency required for thymidine synthesis Drugs that impair absorption of those vitamins Chemo and anti-retrovirals Inherited forms
What must you also check for in folate deficiency?
B12 deficiency
What form of anemia is associated with cerebellar problems and why?
B12 deficiency It is required for FA synthesis in n. sheaths
Explain normal B12 metabolism. Realize that any problems in this pathway could lead to B12 deficiency.
B12 freed from binding protein in stomach by pepsin Free B12 binds to salivary protein hatocorrin B12 released from haptocorron through pancreatic proteases B12 associates w/ IF (from parietal cells) and endocytosed by ilial enterocytes expressing the IP receptor cubulin B12 absorbed and binds to transcobalamin II in plasma
Which Vit is responsible for 1 C transfers?
B9
What apical NZ is responsible for altering nonheme (i.e. dietary) iron into an absorbable form?
DCB -- duodenal cytochrome b
In what age group is pernicious anemia most common?
Elderly
T or F? In pernicious anemia, atrophic glossitis and atrophic gastritis of all parts of the stomach can be helped with B12 treatment.
FALSE Atrophic gastritis of the fundus is NOT helped by B12 treatment
Inherited form of aplastic anemia?
Fanconi's anemia -- due to autoRECESSIVE defect in DNA repair (most cases are idiopathic though)
Transferrin needs iron in Fe2+ or Fe3+ form?
Fe3+ this is a problem b/c we normally have it in 2+ form b/c iron in Fe2+ form is absorbed into body more easily
What parasite can precipitate B12 deficiency?
Fish tapeworm (tapeworm wrestling ring rope)
Which form of megaloblastic anemia has a more acute onset? Why?
Folate deficiency; the liver has extensive stores of B12 Folate is NOT really stored in the body
Describe mechanistically what happens in cobalamin deficiency?
Folate is sequestered as N5 methyl FH4 so the cofactor for thymidylate synthase is not available Methyl groups are shunted around DNA synthesis is slowed
What malignancy are patients with pernicious anemia at risk for?
Gastric cancer -- due to stomach inflammation through autoimmunity NOTE: these pts are also at increased risk of atherosclerosis and thrombosis
What is the source of folic acid?
Green, leafy vegetables -- also fortified in many foods
In pernicious anemia, pt.s will have anti antibodies directed against what?
H+,K+ ATPase (explains achlorydria) IF
Megaloblastic macrocytic anemias result from impaired _______ that leads to ________ and ______. Why does the increase in cell size occur?
Impaired DNA synthesis that leads to large (mega) erythroid precursors and RBCs Increase in cell size occurs b/c nuclear replication lags behind cytoplasmic maturation
Who has decreased intake of folate?
Inadequate diet Alcoholics Elderly and indigent
State which metabolites are reduced or increased in cobalamin deficiency: N5-methyl FH4 N5,10-methylene FH4 Methyl homocysteine
Increase: N5-methyl FH4 Methyl homocysteine Decrease: N5,10-methylene FH4
Clinical presentation of pernicious anemia?
Insidious onset, can be difficult to diagnose Fatigue, pallor, dyspnea, tachycardia Neurologic symptoms Other associations include: Autoimmune disorders: Type 1 DM, autoimmune thyroiditis, autoimmune adrenalitis)
What is the most common cause of anemia in the world?
Iron deficiency
What is the source of B12/cobalamin?
Meats and animal products -- classic Pt with deficiency = strict vegan
Describe some ways to get B12 deficiency
Vegetarians Impaired absorption IF deficiency Gastrectomy & other malabsorption states Intestinal disease
What are some signs and Sx of anemia?
Weakness Pallor Dyspnea Headache (classically a band distribution) Palpitations Tachycardia
If you are hepcidin resistant or have low hepcidin levels, would lab values of ____ be high or low? a) ferritin? b) transferrin saturation %? c) TIBC? d) iron stores in tissue?
a) HIGH b/c body stores of Fe are increasing w/ increasing absorption b) Transferrin saturation % will increase as it binds more and more of the excess Fe c) TIBC decreases b/c less free transferrin is available (more is bound) d) increased iron stores (b/c increase iron absorption)
Describe lab profile of pt w/ anemia of chronic disease. a) serum Fe b) TIBC c) sat % transferrin d) ferritin
a) serum Fe = LOW (intracell iron bound to ferritin does NOT enter useable pool) b&c) TIBC & transferrin = LOW (less transferrin produced) d) ferritin = HIGH (b/c is an acute phase reactant that's elevated in inflammation)
Which form of anemia is most common in sick hospitalized patients?
anemia of chronic disease
Chronic primary hematopoietic failure with pancytopenia
aplastic anemia
Pathoma: where is iron stored?
bone marrow macrophages & liver liver bag, unlocking macrophage cage (removing hepcidin key)
What is the definition of aplastic anemia?
chronic primary hematopoietic failures w/ pancytopenia (anemia, leukopenia, thrombocytopenia)
What parts of the spinal cord are preferentially affected in B12 deficiency?
dorsal and lateral tracts (subacute combined degeneration)
Where is iron absorbed? What 2 apical transporters absorb iron from the lumen?
duodenum (Dwarf's Den; Pathoma) 1. heme transporter (from animal source) 2. DMT1 (from vegetable source)
Serum Fe (falls/rises) when iron stores are depleted.
falls
Describe the appearance of an aplastic marrow.
fatty infiltrate, fibrous, no hematopoietic cells
This molecule is an excellent measure of total Fe stores in the body
ferritin (note: ferritin & TIBC are almost always opposite each other -- think!)
What serum protein is key in differentiating Fe deficiency from anemia of chronic disease?
ferritin -- it is elevated in AoCD b/c of intracellular stores and it is an acute phase reactant
Basolateral transporter of iron in the gut?
ferroportin (iron porter takes iron from gut to blood)
What are the levels of hepcidin in hemachromatosis?
hemachromatosis = iron overload hepcidin is inappropriately LOW (thus, unreg iron absorption --> hemachromatosis)
What molecule is responsible for sequestering Fe in cellular stores in anemia of chronic disease?
hepcidin note: it also inhibits EPO secretion
If demand for erythropoiesis increases, what happens to hepcidin levels?
hepcidin *DECREASES* b/c need more Fe for more RBC production (allows for more Fe absorption)
If inflammation increases, what happens to hepcidin levels? What cytokine is responsible for this change?
hepcidin *INCREASES* via stim from *IL-6* (reduces iron absorption) (inflamm -> iron sequester in gut)
If plasma levels of Fe and iron stores increase, what happens to hepcidin levels?
hepcidin levels *increase* to prevent over-absorption of iron
In what situation is ferritin a poor estimate of Fe stores? Why?
liver disease or acute inflammation -- ferritin is an acute phase reactant **
What is pure red cell aplasia?
marked hypoplasia of marrow erythroid elements in the setting of *normal* granulopoiesis and thrombopoiesis platelets and granulocytes made normally, but RBCs are not
Causes of iron deficient anemia?
one you'll forget --> PPIs (need acidic environment to absorb iron b/c acid keeps Fe in Fe2+ state, which is more easily absorbed)
Early iron deficient anemia presents w/ _____ and ____, increased _____.
poikilocytosis & ovalocytes increased RDW
What is TIBC?
total iron binding capacity is a measure of transferrin molecules in the blood % saturation = % of transferrin molecules that are bound by iron (normal is 33%) -- all from Pathoma
What is the major transporter of B12 in the plasma?
transcobalamin 2
What transports iron in blood plasma?
transferrin (transferrin shoulder bar double bucket)
What is the treatment for anemia of chronic disease?
treatment of the underlying disease
What should be suspected in older patients with iron deficiency anemia?
tumor; particularly colorectal cancer
What is an ancillary treatment for Fe deficiency anemia? What does it do?
vitamin C; aids Fe absorption
What is the treatment for aplastic anemia in younger patients? older?
younger: allogenic bone marrow transplant old or no donor available: bone marrow suppression
Source of intrinsic factor
Parietal cells in the body of the stomach
What is the most common cause of cobalamin (B12) deficiency?
Pernicious anemia no IF = no B12 absorption in ileum
What can result 5 days after starting Rx to correct folate deficiency
Reticulocytosis
What test is used to distinguish pernicious anemia from other causes of B12 deficiency? How does it work?
Schilling test (radio labeled B12 given w/ IF) This is rarely done today
When your body decides you've had enough iron and it's time to stop iron absorption, what happens?
*Hepcidin* downregulates ferroportin so iron can't be transported from gut into blood (hepcidin HCD key)
What does the blood smear look like for megaloblastic anemias?
*Hypersegmented neutrophils* (> 5 lobes) +term-13 HypERchromic macrocytic RBCs & "macro-ovalocytes" (hypersegment pom-poms)
Enzyme responsible for the oxidation of iron so that it can be incorporated into transferrin (Fe2+ --> Fe3+)?
*hephaestin*
Where is iron found in your body? Explain fully.
- 80% of Fe is functional (in Hb, Mb, or cytochromes) - remaining 20% must be bound to something in storage b/c free Fe is toxic -- bound to either hemosiderin or ferritin in storage <1% is being transported in plasma
What are the 3 components of Plummer-Vinson Syndrome?
- Fe deficiency anemia - esophageal webs - dysphagia (also common to see atrophic glossitis) "the Plummer Found it Easy to uncloG the Drain" - Plummer-Vinson - Fe deficient anemia - Esophageal webs - atrophic Gastritis - Dysphagia
What are the 2 suggested pathophysiologies of aplastic anemia?
- immune mediated (T cells suppress stem cell proliferation) - stem cell abnormality (stem cell can't proliferate)
What are 2 conditions in which a pure red cell aplasia may be seen?
- parvovirus B19 infection - thymoma (he liked this)
Significant clinical features of iron deficient anemia?
1. Koilonychia (spoon brittle nails) 2. Pica (craving non-food dirt, paint, etc -- any way for body to get iron) 3. numbness/tingling (restless leg syndrome) 4. Mouth issues (angular stomatitis & glossitis) 5. normal Sx of anemia (pallor, weakness, dizziness, band headache, palpitations, dyspnea)
What are 3 things that alter the concentration of hepcidin?
1. inflammation 2. demand for erythropoiesis 3. plasma levels of Fe and iron stores
Ferritin levels of less than _____ are indicative of an absence of iron stores
15 ug/dL
What cells are affected in pernicious anemia?
All rapidly proliferating cells, not just bone marrow, blood, & stomach (i.e. common to present with glossitis)
What is the pathology of pernicious anemia?
An autoimmune attack on gastric mucosa causes an absence of IF that leads to cobalamin deficiency Can also lead to chronic gastritis and achlorydria
Which two drug classes can impair the absorption of B12/folate?
Contraceptives Anticonvulsants
What does hypochromia and hyperchromia depend on and what lab value represents this?
Hemoglobin content Represented by MCH
How does iron deficient anemia present on blood smear?
HypOchromic & microcyctic
Cytokine responsible for the increased synthesis of hepcidin?
IL-6 (inflamm --> iron sequestering)
Iron storage pools: a) insoluble storage form of iron in tissues? b) soluble storage form of iron in tissues?
INsoluble = hemosiderin soluble = ferritin (tins of iron)
In megaloblastic anemias, would reticulocyte count be high or low and why?
LOW Aren't synthesizing DNA properly to replicate and make new RBCs "ineffective erythropoiesis"
Five causes of increased MCV?
Mageloblastic anemia (B12/folate) Chemo Reticulocytosis Liver disease Spurious: cold agglutinins, hyperglycemia
Which of the following anemias is hypochromic: Macrocytic Microcytic Normocytic
Microcytic
Prognosis of aplastic anemia?
NO BUENO w/o treatment = rapid deterioration and death
What system is involved in B12 deficiency but NOT in folate deficiency?
Nervous system Therefore if you administer folate to improve anemia you can make the neuro problems worse
How does the bone marrow of a patient with megaloblastic anemia look like?
Nuclear-cytoplasmic asynchrony Megaloblasts -- erythroid cells w/ nucleus, lacy chromatin, and abundant basophilic cytoplasm The nucleus is larger and chromatin pattern is more open but less mature
What is the treatment for B12 deficiency?
Oral *cyanocobalamin* (B12) Note: use injection due to lack of intrinsic factor (pernicious) or if neuro Sx are present Retest B12 levels after 4-6 mo to make sure they're in normal ranges
What syndrome is associated with iron deficiency anemia?
Plummer-Vinson Syndrome
States where you need to increase B12 intake?
Pregnancy Hyperthyroid Disseminated cancer Parasite Bacterial overgrowth in blind loops and bowel diverticula
What type of patients have increased requirements of folic acid?
Pregnant women (supplement to decreases incidence of neural tube defect) Infants (they're growing) Hyperactive hematopoiesis due to hemolytic anemia!!**** (alcohol everywhere around the ring, hemolysis cracked RBC grandfather clock)
Stain used to visualize iron?
Prussian blue
Describe a scenario in which dilutional anemia develops.
Pt has acute blood loss (e.g. gunshot or car accident) and receives ONLY fluids to replace volume loss Sure, EPO increases in response, but it takes 5 days for new RBCs to form
What does hypoproliferative and hyperproliferative depend on and what lab value represents this?
RBC production by marrow Represented by Reticulocyte count
What do the signs and sxs. of Hg/Hct depend on in chronic blood loss?
Rate of blood loss and ability of pt's marrow to keep up w/ blood loss
What lab values are elevated in pernicious anemia?
Serum homocysteine Methylmalonic acid (MMA) (build up because B12 is a requirement for metabolism) Other findings include: leukopenia w/ hypersegmented granulocytes!
T or F? B12 deficiency can present as neuro issues without anemia.
TRUE NOTE: folate therapy could correct anemia of B12 deficiency, but not nerve dysfunction
B12 and folate both assist in the synthesis of what nucleotide for DNA?
Thymidine
Which other autoimmune disorders are associated w/ pernicious anemia?
Thyroiditis Adrenalitis
Which drugs are weak dihydrofolate reductsae inhibitors?
Trimethoprim Pentamidine Triamterene Pyrimethamine
