Gueli Objectives Flashcards
Understand the fundamental composition of plasma.
91% water; 7% blood proteins (fibrinogen, albumin, globulin); 2% nutrients (amino acids, sugars, lipids), hormones (EPO, insulin, etc.), and electrolytes (sodium, potassium, calcium, etc)
Understand the mechanisms whereby RBCs generate ATP.
ATP is generated via anaerobic glycolysis from glucose absorbed from the surrounding plasma. Pentose phosphate shunt is used as well. The absence of mito ensures that absorbed oxygen will be carried to peripheral tissues and not ‘stolen’ by the mito. In addition to Hb, cytosol contains enzymes to prevent and repair ROS damage and enzymes to generate energy. ~5-10% of glucose metabolized is used to generate NADPH to maintain glutathione in the reduced state.
Understand that methemoglobinemia is generated when the ferrous iron (Fe2+) of hemoglobin is oxidized to ferric iron (Fe3+).
Recall that methemoglobin CAN NOT BIND OXYGEN. Oxidation is done by ROS. NADH generated from glycolysis can reduce methemoglobin to normal hemoglobin.
Understand the importance of glucose-6-phosphate dehydrogenase in the regeneration of reduced glutathione in RBCs.
In the absence of this enzyme (X-linked disease), RBC’s will not be able to handle excess oxidative stress and hemolytic anemia will result.
Understand the impact that 2,3 bisphosphoglycerate, temperature, pH and carbon dioxide have on the affinity of hemoglobin for oxygen.
2,3 BPG levels are increased in tissues. It stabilizes the deoxy state of Hemoglobin, thus allowing for the release of oxygen. Increased temperature, H+ increase, PCO2 increase, and 2,3 BPG increase all decrease Hb affinity for oxygen.
Understand the composition of the RBC cytoskeleton.
Just know that a destabilized skeleton destabilizes the lipid membrane, causing the RBC to become a spherocyte. Hereditary spherocytosis is a disorder that most commonly is missing ankyrin, which causes spherocytes. Osmotic fragility test is diagnostic.
Understand the role of hepcidin in the regulation of iron metabolism.
Hepcidin is the keystone regulator of systemic iron homeostasis. It is produced by the liver in response to inflammation and increased iron stores. Binds to ferroportin and triggers its internalization and degradation in lysosomes. Ferroportin transports ferrous across the cell membrane to the plasma. Decreases Fe release from macrophages, enterocytes, and hepatocytes. I.E. it decreases the amount of Fe absorption, Fe not released from enterocyte and gets sloughed off. Hepcidin deficit induces iron overload; an excess of hepcidin is implicated in Anemia of Chronic Disease (AOCD; iron stores increased, but decreased iron utilization).
Understand how to use iron studies and serum ferritin to delineate between anemia of chronic disease and iron deficiency anemia.
Iron deficiency: decreased serum iron, Increased transferrin or TIBC, decreased ferritin, decreased % transferrin saturation (serum iron/ TIBC).
Chronic disease: decreased serum iron, decreased transferrin or TIBC, increased ferritin
In cytosol, most iron stored in ferritin. Most iron storage occurs in hepatocytes (orally ingested), RES macrophages (recycled heme iron), and bone marrow (recycled heme iron).
Understand the genetic basis of HFE C282Y/C282Y hereditary hemochromatosis Type I.
Classical HFE gene mutations resulting in a cysteine-to-tyrosine substitution at amino acid 282 (C282Y) or an aspartate-to-histidine substation at a.a. 63 (H63D). Results in hepcidin deficit, which causes iron overload. Classic triad: DM, Hepatomegaly, Hyperpigmentation
Understand the difference between the absorption of heme iron versus non-heme iron.
Heme iron is absorbed better than non-heme iron/fe3+. Sources of heme iron are hemoglobin and myoglobin in beef, chicken, fish, etc. Sources of non-heme iron are cereal and vegetables.
Understand how numerous proteins involved in iron metabolism are regulated at the level of translation.
Low oxygen pressure and low iron concentration facilitate HIF1/2 transcriptional activity (binds to hypoxia response elements), which impacts expression of numerous iron metabolism genes (e.g. EPO gene)
Understand the manner in which heme is converted to bilirubin and how bilirubin is transported in the body.
Heme is oxidized and cleaved to produce carbon monoxide and biliverdin. Biliverdin is reduced to bilirubin, which is transported to the liver complexed with SERUM ALBUMIN. Bilirubin is then CONJUGATED IN THE LIVER with glucuronic acid and excreted in the bile. Vast majority is defecated, some urinated.
Understand how to differentiate between diseases that cause an elevation in the indirect (unconjugated) bilirubin and those that cause an increase in the direct (conjugated) bilirubin.
Get a bilirubin fraction.
In marked intravascular hemolysis, destruction of RBCs increases the amount of indirect (unconjugated) bilirubin transported to the liver.
If the concentration of unconjugated bilirubin exceeds the capacity of hepatocytes to conjugate it to the more soluble diglucuronide through interaction with hepatic UDP-glucuronate, both the total and unconjugated bilirubin levels in the blood increase
More unconjugated bilirubin is then secreted by the liver into the bile
The increase in unconjugated bilirubin, which is not very water soluble, can precipitate within the gallbladder lumen, leading to the formation of pigemented (calcium bilirubinate) gallstones (eg, SCA)
Think biliary obstruction if levels of direct (conjugated) bilirubin is elevated.
Understand the symptoms and pathophysiology underlying Acute Intermittent Porphyria.
Symptoms are the 5 P’s (Painful abdomen, Port wine – colored urine, Polyneuropathy, Psychological disturbances, Precipitated by drugs). Porphobilinogen deaminase deficiency, leading to build up of porphobilinogen, delta- ALA, uroporphyrin (urine). Treat with glucose and heme, which inhibit ALA synthase.
Understand the role of Vitamin B6 in the synthesis of heme, and how isoniazid is associated with Vitamin B6 deficiency.
Delta-ALA synthase (rate limiting enzyme in heme production), requires vitamin B6 AKA pyridoxal phosphate. Thus a deficiency in vitamin B6 slows heme production and is associated with a microcytic, hypochromic anemia. Isoniazid (Tb medication) depletes B6 stores, so you need to supplement, otherwise you will get peripheral neuropathy, CNS effects, and anemia.
