IUHS Student-2-Student USMLE Step 1 Recall
Hematology
Macrocytic/Megaloblastic Anemia MCV>100
Megaloblastic Anemias
there are 2 kinds: (1) pernicious anemia, the major form of vitamin B12 deficiency anemia, and (2) folate deficiency anemia...
both have in common the fact that there is
impaired DNA synthesis and distinctive morphologic changes in the blood and bone marrow...the erythroctyes are abnormally large and thought to be related to defective cell maturation and division...
vit B12 and folate are coenzymes in DNA synthesis
and a deficiency in these results in defective nuclear maturation due to deranged or inadequate synthesis of DNA...thus, there appears to be asynchronism between the cytoplasmic maturation and nuclear maturation...
Vit B12, Pernicious Anemia
the main cause is malabsorption...
atrophic gastritis with failure of production of intrinsic factor (IF)...
which can cause fatty degeneration of the myocardium...
macrocytosis anemia...hyperchromic...
in contrast to a normal, mature neutrophil, which has from two to five nuclear lobes, the neutrophil in Pernicious Anemia has at least six lobes and is an illustration of
neutrophilic hypersegmentation
...granulocytic hypersegmentation is significant and among the first hematologic findings in the peripheral blood of patients who have megaloblastic anemia in its developmental stages...neutrophilic segmentation
is generally considered a sensitive indicator of megaloblastic anemia...HLA-DR5 association
...absorption of vitamin B12 requires IF, which is secreted by the parietal cells of the fundic mucosa along with hydrochloric acid...
initially the vitamin is released from its protein-bound form by the action of pepsin in the acidic environment of the stomach...
the liberated vitamin B12 binding proteins called cobalophilins, or R-binders...in the duodenum, R-vitamin B12 complexes are broken down by the action of pancreatic proteases, and the released vitamin B12 then attaches to IF
...in this form, IF-vitamin B12 complex is transported to the ileum, where it adheres to IF-specific receptors on the ileal cells...
vitamin B12 then traverses the plasma membrane to enter the mucosal cell...it is picked up from the cell by a plasma protein, transcobalamin II, which is capable of delivering it to the liver and other cells of the body, particularly the rapidly proliferating pool in the bone marrow and mucosal lining of the gastrointestinal tract...
there is a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and nuclear changes in the mucosal cells similar to those found in the erythroid precursors...parietal cells are in the body and fundus...
three types of antibodies...75% have type I antibodies that block binding of vitamin B12 to IF...type II antibodies prevent binding of IF or IF-vitamin B12 complex to its ileal receptor...type III antibodies present in 85-90% of patients and localize in the microvilli of the canalicular system of the gastric parietal cell, directed against the alpha and beta subunits of the gastric proton pump...
it is suspected that an autoreactive T-cell response initiates gastric mucosal injury, which then triggers the formation of autoantibodies...these antibodies cause further injury to the epithelium, and after the mass of IF-secreting cells falls below a threshold (and the reserves of stored vitamin B12 are depleted), anemia develops...
CNS lesions are found in approximately three quarters of all cases of fulminant pernicious anemias
...the principal alterations involve the spinal cord, where there is myelin degeneration of the dorsal and lateral tracts, sometimes followed by loss of axons...these changes give rise to spastic paraparesis, sensory ataxia, and severe paresthesias in the lower limbs...the schilling test, which measures intestinal absorption of Vit B12 with and without IF, is used to diagnose pernicious anemia...
decreased production of platelets is responsible for thrombocytopenia in Vit B12 deficiency...
insidious on onset, so that by the time the patient seeks medical attention, the anemia is usually marked...
elevated methylmalonate...
methylmalonic aciduria
...Progressive spastic paraparesis, optic nerve atrophy, sensory ataxia, and marked paresthesias of the legs...demyelinization of lateral corticospinal tracts...
diagnostic
features include
(1) moderate to severe megaloblastic anemia;
(2) leukopenia with hypersegmented granulocytes;
(3) mild to moderate thrombocytopenia;
(4) neurologic changes related to involvement of the posterolateral spinal tracts;
(5) achlorhydria even after histamine stimulation;
(6) inability to absorb an oral dose of cobalamin
(assessed by urinary excretion of radiolabeled cyanocobalamin given orally, called the schilling test;(7) low serum levels of vitamin B12;
(8) excretion of methylmalonic acid in the urine; and
(9) a striking reticulocytic response and improvement in hematocrit levels after parenteral administration of vitamin B12...serum antibodies to IF are highly specific for pernicious anemia...their presence attests to the cause of B12 deficiency, rather than the presence or absence of cobalamin deficiency...
the cytologic aberration in the gastric mucosa are associated with an increased risk of gastric cancer...linitis plastica of the stomach, which typically has a signet ring cell pattern of adenocarcinoma diffusely involving the stomach
...with parenteral vit B12, the anemia can be cured and the peripheral neurologic changes reversed, or at least halted in their progression...
macrocytosis anemia...hyperchromic...
low hemoglobin levels, multiple neurologic findings (due to demyelination at first and then axonal degeneration) include numbness and paresthesias, weakness, ataxia, difficulties with mentation, and abnormal deep tendon reflexes and pathological reflexes, high output failure, sallow color are consistent with pernicious anemia...
Anemia of Folate Deficiency
a deficiency of folic acid, more properly pteroylmonglutamic acid, results in a
megaloblastic anemia having the same characteristics as those encountered in vitamin B12 deficiency...however, the
neurologic changes seen in vit B12 deficiency do not occur...macrocytosis anemia...
in contrast to a normal, mature neutrophil, which has from two to five nuclear lobes, the neutrophil in
Folate Deficiency has at least six lobes and is an illustration of neutrophilic hypersegmentation...granulocytic hypersegmentation is significant and among the first hematologic findings in the peripheral blood of patients who have megaloblastic anemia in its developmental stages...neutrophilic segmentation
is generally considered a sensitive indicator of megaloblastic anemia...the prime function of folic acid, specifically
tetrahydrofolate (FH4) derivatives, is to act as an intermediate in the transfer of one-carbon units such as formyl and methyl groups to various compounds...in this process, FH4 acts as an acceptor of one-carbon fragments from compounds such as serine and formiminoglutamic acid, and the FH4 derivatives so generated donate the acquired one-carbon fragments for the synthesis of biologically active molecules...
FH4 then may be viewed as the biologic middleman in this trade...
the most important metabolic processes dependent on such one carbon transfers are (1) the synthesis of purines; (2) the synthesis of methionine from homocystein, a reaction that also requires vitamin B12; and (3) the synthesis of deoxythymidylate monophosphate...
in the first two reactions, FH4 is regenerated from its one-carbon carrier derivatives and is available to accept another one-carbon fragment and re-enter the donor pool...
in the synthesis of thymidylate, a dihydrofolate is produced that has to be reduced by dihydrofolate reductase to FH4 to re-enter the pool...
the reductase step is significant, since this enzyme is susceptible to inhibition by various drugs...
among the biologically active molecules whose synthesis is dependent on folates, thymidylate is perhaps the most important...
deoxythymidylate monophosphate is required for DNA synthesis...it should be apparent from our discussion that
suppressed synthesis of DNA, the common denominator of folic acid and vitamin B12 deficiency, is the immediate cause of megaloblastosis...macrocytosis anemia...
folate is reabsorbed in the jejunum
...decreased intake, increased requirements (such as in pregnancy), and impaired use...
dietary inadequacies are most frequently encountered in chronic alcoholics, the indigent, and the elderly....
folic acid antagonists, such as methotrexate, 6-mercaptopurine, and cyclophosphamide, inhibit dihydrofolate reductase and lead to a deficiency of tetrahydrofolate
...megaloblastic anemia resulting from a deficiency of folic acid is identical to that encountered in vitamin B12 deficiency...
thus, the recognition of folate deficiency requires the demonstration of (1) decreased folate levels in serum or red cells and (2) increased excretion of FIGlu after an administered dose of histidine...
macrocytosis anemia...
low serum levels of folate and
increased serum homocysteine...
increased homocysteine leads to thrombosis, like MI...