Hematology (Week 2--Howard) Flashcards
Normal lab values
Total bilirubin: 0..1 - 1.0 mg/dL
Direct (conjugated) bilirubin: 0 - 0.3 mg/dL
Ammonia: 15 - 45
AST: 8 - 20 U/L
ALT: 8 - 20 U/L
PT (prothrombin time): 11 - 15 sec
Platelet count: 150,000 - 400,000 /mm3
Composition of hemoglobin
4 molecules of globin (2 alpha; 2 beta)
4 molecules of heme (each has protoporphyrin IX and Fe2+)
From RBC to bilirubin
RBC engulfed by macrophage –> heme broken down to biliverdin –> biliverdin broken down to bilirubin –> bilirubin (insoluble) binds albumin in plasma and becomes soluble –> complex travels through blood to liver –> liver conjugates bilirubin with glucuronic acid to solubilize bilirubin –> (conjugated bilirubin goes from liver to gallbladder) –> conjugated bilirubin secreted in bile into intestine –> in intestine, glucuronic acid removed and bilirubin converted to urobilinogen –> most urobilinogen remains in intestine, is oxidized by intestinal bacteria to brown stercobilin; some urobilinogen reabsorbed and enters portal blood and some of that urobilinogen transported from blood to kidney where is converted to yellow urobilin and excreted
When does jaundice occur?
Jaundice occurs when serum bilirubin exceeds 3mg/dL
Causes of increased unconjugated bilirubin
Hemolysis
Liver disease
Causes of increased conjugated bilirubin
Liver disease resulting in hepatocyte swelling and/or canaliculi damage
Extrahepatic obstruction of biliary duct (gallstones)
Total, direct, indirect bilirubin
Direct: conjugated bilirubin
Indirect: unconjugated bilirubin
Indirect = total - direct
Common causes of jaundice in neonates
Physiological jaundice: develops 2nd or 3rd day of life; because liver cannot yet conjugate bilirubin (get high unconjugated bilirubin)
Blood type (ABO or Rh) incompatibility: causes RBC hemolysis and (high unconjugated bilirubin); mother Rh negative has Rh antibodies that attack/lyse baby’s Rh positive RBCs
Less common: Glucose-6-PO4-dehydrogenase deficiency (hereditary hemolytic disorder); Gilbert’s diesase (hereditary reduction of bilirubin conjugation)
Kernicterus
Brain damage in newborn due to deposition of unconjugated (insoluble) bilirubin in brain (associates w/membrane lipids and interferes with membrane function)
When >20mg/dL unconjugated bilirubin in blood
Prevented by phototherapy (blue lame in birthing room), which causes bilirubin to be photoisomerized to water-soluble products excreted in bile or urine
Synthesis of heme
Succinyl CoA + glycine converted to ALA by ALA synthase –> ALA converted to porphobilinogen by ALA dehydratase –> 4 porphobilinogens combine to form protoporphyrinogen IX –> –> heme
What happens if VERY first step in the liver (ALA synthesis) is defective?
Lethal!
Where is heme biosynthesized?
Most cells (heme is present in cytochromes and other substances)
Regulation of heme biosynthesis best understood in liver
Primary porphyria
Genetic defect in heme synthesis pathway that causes buildup of heme precursors
Acute porphyria (neuroviscreal or hepatic porphyria): defect in early step; abdominal pain, constipation, vomiting, paralysis, neuropsychiatric disorders; accumulation of toxic ALA and porphobilinogen and deficiency of heme in neurons
Cutaneous porphyria (erythropoietic porphyria): defect in late step; sun light-induced skin lesions, urine and teeth turn red because of accumulated porphyrins (uroporphyrin), anemia; due to photodynamic action on porphyrins converting them to toxic molecules
Combination of acute and cutaneous porphyria: both neurological and skin symptoms
Autosomal dominant, so enzyme activity 50% reduced
Secondary (acquired) porphyria
Chemical, toxic substances (lead) that inhibits heme synthesis or induces ALA synthetase
Why is it bad to have too much iron (Fe2+)?
Toxic free radical (hydroxyl) is created if too uch Fe2+ around
Where is most of the iron in the body found?
RBCs (“functional” compartment)
How much of daily iron need (20-25mg) is recycled?
90% of daily iron need recycled from macrophages that engulfed senescent RBCs
How do we get rid of iron?
No specific way to get rid of iron!
Bleeding, menstruation, sloughed mucosal cells
Transferrin
Binds 2 molecules of Fe3+ in plasma
Protects against free radical generation by free Fe
Transferrin-Fe complex endocytosed into cells by binding transferrin receptors TfR1 or TfR2
Absorption of dietary Fe by duodenum
1) Fe3+ converted to Fe2+ by ferrireductase on membrane
2) Fe2+ in lumen through DMT1 into duodenal enterocyte; Heme through HCP1 into duodenal enterocyte
3) Fe2+ back to Fe3+ and binds apoferritin to form FERRITIN (huge protein that binds 4500 atoms of Fe3+)
4) Fe2+ transported into plasma by membrane protein ferroportin
5) Once in plasma, Fe2+ converted to Fe3+ again by ferroxidase
6) Fe3+ in plasma must bind transferrin
What do plasma levels of ferritin tell us?
Plasma level of ferritin tell us cell level of ferratin (a SMALL amount of ferritin leaks into plasma), and cell level of ferratin tells us person’s Fe level
(Except in inflammatory disorder, liver disease, cancer–then ferritin level can be normal/high but person has really low level of Fe)
What happens to apoferritin synthesis when plasma Fe (ie intracellular levels of Fe) is low?
Apoferritin synthesis inhibited
What happens to Fe3+ in erythroblasts (RBC precursors in stem cells) and other cells?
Fe3+ bound within ferratin
Fe3+ reduced to Fe2+ by ferrochelatase and put into heme
Distribution of Fe in the body
Storage compartment: bone marrow, liver cells, reticulo-endothelial macrophages
Transport compartment: serum transferrin
Functional compartment: hemoglobin, myoglobin, cytochromes, non-heme iron proteins
Causes of anemia (low RBCs or low hemoglobin) due to abnormal Fe metabolism
1) Fe deficiency
2) Defective Fe storage
3) Defective Fe utilization in erythroblasts
Anemia due to Fe deficiency (most common anemia in US)
1) Increased physiological demand (growing adolescent)
2) Inadequate intake (diet or absorption)
3) Chronic blood loss
Why are females more susceptible to iron deficiency anemia?
Females lose 1mg/day like men but additional 0.5-1mg/day because of menstruation
Pregnant women require more (2mg/day) for fetal needs, placenta, and expanded maternal blood volume
Anemia due to defective Fe storage
1) Defect secondary to chronic disease (TB; this is second most common anemia in the US)
2) Due to entrapment of Fe in macrophages (results in low plasma Fe, high intracellular/plasma ferritin)
How is hepcidin involved in anemia due to defective Fe storage
Hepcidin is liver peptide that binds/internalizes ferroportin in macrophages and duodenal enterocytes so now Fe has no way out of the cell
Hepcidin induced by cytokines (so in chronic disease, get low Fe levels in blood but high plasma/intracellular ferritin levels)
Note: giving iron doesn’t help the problem
How is iron transported from mother to fetus?
Ferroportin brings Fe from mother to fetus across placenta
Fetal hepcidin is present to ensure not too much Fe transported to fetus
Anemia due to defective Fe utilization in erythroblasts (in bone marrow)
Called sideroblastic anemia b/c Fe accumulation (as ferritin) in erythroblasts then called sideroblasts (excess ferritin can precipitate to form hemosiderin)
Can be hereditary (X linked) defect in heme synthesis or acquired defect (lead poisoning leading to inhibition of heme synthesis enzymes)
Note: heme made in erythroblasts of bone marrow (and in liver), and here heme not made correctly
Adult-onset hereditary hemochromatosis
Too much iron in body (absorbed from GI tract)
Decreased hepcidin activity (because of defect in HFE) causes increased Fe absorption from duodenum across ferroportin –> high plasma Fe levels and Fe accumulation in tissues
Clinical effects: bronze skin, liver/heart/pancreas damage, manifests in adults
HFE (HLA-linked Fe-loading gene): stimulates hepcidin synthesis
Common in Northern Europeans but incomplete penetrance (also depends on diet, etc)
Juvenile onset hereditary hemochromatosis
Too much iron in body (absorbed from GI tract)
Due to mutation in hepcidin or another gene involved in Fe metabolism
Manifest early in life and are highly penetrant
Hemostasis
A process that minimizes hemorrhage when a blood vessel wall is damaged and that minimizes formation of untimely clots (thrombi) in undamaged vessels
Primary hemostasis
1) Vasoconstriction of damaged vessels (only impt in uterus)
2) Formation of temporary seal by platelets
Secondary hemostasis
Formation of a blood clot/fibrin clot (coagulation)