Week 1 Flashcards
Hemoglobinuria
large numbers of RBCs break down in bloodstream, urine may turn red or brown
Hematuria
presence of intact RBCs in urine which occurs after kidney damage or damage to vessels along urinary tract
Jaundice
bilirubin is not conjugated in the liver to UDP-glucuronate and diffuses into peripheral tissues if the bile ducts are obstructed
Pyruvate Kinase deficiency
most common enzymopathy of glycolysis
• ATP generated via glycolysis is decreased by 50%
• Clinical expression ranges from severe hemolytic anemia in neonates to a fully compensated anemia
• Anemia and/or jaundice are recognized in infancy or early childhood
• Lab: Small dense crenated cells (echinocytes) on smear
• Tx: folic acid supplementation, splenectomy
➢ Congenital Methemoglobinemia
- Patients appear cyanotic (blue) with few clinical problems
- Excess methemoglobin due to def in cytochrome b5 reductase
- Etiology: genetics → inherited hemoglobin M disease
- Single AA substitution in heme-binding pocket → stabilizes ferric state
➢ Acquired Methemoglobinemia
- Etiology: ingestion of oxidants such as nitrites, quinones, aniline, sulfonamides; benzocaine, lidocaine, or dapsone use
- Tx: administration of reducing agents → ascorbic acid or methylene blue
• 2,3-BPG
2,3-BPG stabilizes the deoxy form of Hb which facilitates the release of O2 to tissues (beneficial in high altitude locations)
1,3 BPG – BPG mutase → 2,3-BPG
If defective BPG mutase, Hb will not release O2 to tissues → hypoxia and hemolysis
• Glucose-6-Phosphate Dehydrogenase (G6PD)
First enzyme that catalyzes pentose phosphate pathway
Lifetime of RBC correlates with G6PD activity (due to anucleate nature of RBCs) → decrease G6PD results in increased oxidative damage → hemolysis
When rate of hemolysis substantially exceeds normal rate of RBC production, the number of RBCs drops below normal → hemolytic anemia
G6PD allows for NADPH to be produced which mediates glutathione reaction thus aiding in eliminating ROS
• G6PD Deficiency: most common enzyme deficiency in the world
➢ Symptoms: dark urine, pale skin, weakness, jaundice, hepatomegaly, splenomegaly, tachycardia, fever
➢ X-linked disease with many G6PD variants (~300)
• Variant proteins have reduced stability and lowered activity → reduced RBC lifespan → more likely to lyse under oxidative stress
• Severity of disease depends on mutation
➢ G6PD deficient patients are resistant to malaria
➢ Etiology: genetic, hereditary, primaquine prophylaxis
➢ Labs: peripheral smear shows – Heinz bodies (inclusions of denatured Hgb), bite cells, blister cells
2,3-BPG:
• Stabilizes deoxy form of Hgb → facilitates O2 release to tissues
➢ Shifts O2 saturation curve to the right
• 2,3-BPG is regulated by BPG mutase
• If defective, Hgb will not release O2 to tissues → hypoxia, hemolysis
o Hereditary Spherocytosis
• 75% are autosomal dominant; 25% are autosomal recessive
• Etiology:
Ankyrin deficiency most common
30-45% - Ankyrin and spectrin deficiencies
30% Spectrin alone
20% Band 3 mutations alone
• Pathophysiology
Aberrant interaction between lipid bilayer and skeleton → spherocyte
Spectrin loss caused by defect in a membrane protein that attaches to spectrin rather than primary spectrin defect
• Clinical Features:
Anemia, jaundice, splenomegaly
Onset occurs at any age; severe in neonates
• Labs:
Peripheral smear – spherocytes and reticulocytosis
Elevated indirect bilirubin (non-conjugated bilirubin) → 50-60% cases
Negative direct antiglobulin test (DAT)
High MCHC due to cellular dehydration
Gold Standard: Incubated Osmotic Fragility Test at 37⁰C – measures ability of RBCs to swell in graded series of hypotonic solutions
• Tx: splenectomy (corrects anemia but not RBC defect)
Weigh risk-reward benefit: give pneumococcal, meningococcal, Hib vaccines several weeks before splenectomy; prophylactic Pen VK in children
Folic acid supplementation
Note: people without spleens, any infection is serious
Ferroportin
transports Fe2+ across membrane to plasma → used to make RBCs
Ferritin
stores iron intracellularly; hemosiderin (conglomeration of ferritin molecules) = long-term iron storage
o Hepcidin
- In Hepatocytes iron uptake is similar to that of other cells
- Hepcidin is key regulator of iron homeostasis
- Hepcidin is a 25 AA polypeptide produced in response to inflammation (AOCD, IL6) and results in increased iron stores
- Hepcidin binds to ferroportin and triggers its internalization and degradation in lysosomes and decreases Fe release from macrophages, enterocytes, and hepatocytes
- This results in increased intracellular [Fe] & decreased bioavailability of Fe
- Hepcidin deficiency results in iron overload whereas an excess of hepcidin is implicated in AOCD (anemia of chronic disease)
- Ultimately, hepcidin prevents the release of iron from cells
• Regulation of Hepcidin
o Iron stores, erythropoietic activity, hemoglobin, oxygen content, and inflammation all regulate the expression of hepcidin through the HAMP gene
o Increase in transferrin saturation signals to hepatocytes to increase hepcidin expression via HFE and TfR2 dependent manner
• Hemosiderin
long-term storage of iron (multiple ferritins) → not susceptible to depletion treatments such as phlebotomy and chelation
• AOCD
hypoproliferative anemia secondary to inflammation
• Characterized by increased iron stores, but decreased iron utilization (decreased bioavailability)
• Assoc. with: TB, AIDS, Hodgkin’s, Non-Hodgkin’s Lymphoma, RA, SLE, etc.
• Pathophysiology: increased inflammatory cytokines via monocytes and T cells
o IL-6, IL-1β, IL-1α, TNF-α, and IFN-α ultimately induce hepcidin, inhibit erythropoietin (EPO) production, and suppresses erythropoiesis
o This results in a shorter RBC life span
o Hereditary Hemochromatosis,
• Types 1-3 have autosomal recessive inheritance
o HFE Hemochromatosis
- HFE is a transmembrane protein belonging to MHC class I and is expressed in the liver
- Through its interaction with TfR1 and TfR2 it regulates hepcidin expression
- Most common form of HH
- Etiology: genetic mutation – C282Y mutation in HFE gene on chromosome 6p21.3
- > 90% Caucasian hemochromatosis patients are homozygous; mainly effects males
- Autosomal recessive inheritance
- Due to mutation there is a lack of interaction between HFE and TfR2 causing:
- Decreased hepcidin expression and storage of iron in macrophages
- Increased Fe absorption and serum iron and Tf Sat
- C282Y/C282Y incomplete penetrance results in:
- Elevated serum ferritin in < 50% of female and ~75% of male homozygotes
- Organ damage in less than 30%
- Clinical manifestations: Classic triad – diabetes, hepatomegaly, hyperpigmentation
- Labs:
- Increased: serum iron, serum ferritin, transferrin iron saturation
- Decreased: TIBC, (free?) transferrin
- Management: maintenance phlebotomy
o Acute Intermittent Porphyria
• Etiology: autosomal dominant deficiency of PBG deaminase (chromosome 11q24); ~227 point mutations identified, < 10% of those with mutations have clinical expression
• Pathophysiology: gene mutation resulting in accumulation of PBG and ALA
• Symptoms:
GI (95%): pain, vomiting, constipation, tender abdomen (not rigid)
Hyponatremia in severe attack
Neuropathy (2/3): motor, sensory, psychiatric
CV (70%): increased BP, tachycardia
Photosensitivity NOT present
• Risks: increased risk for hepatocellular carcinoma (HCC)
• Dx: urine is clear initially but darkens with light exposure due to oxidation of porphyrinogens to porphyrins (caused by excess PBG, ALA)
o Vitamin B6
o Vitamin B6 deficiency is often associated with microcytic, hypochromic anemia due to slowed heme production as d-ALA synthase requires pyridoxal phosphate
o Sources of Vitamin B6: beans, legumes, nuts, breads, fish, eggs, cereals
o B6 is important for maintaining healthy brain function, formation of RBC, and breakdown of protein and synthesis of antibodies in support of the immune system
o Patients that are being treated for TB with isoniazid can acquire vitamin B6 deficiency since isoniazid (INH) competitively inhibits reactions that utilize Vitamin B6 for functioning
• Thus Vitamin B6 supplementation should be used when patients undergo isoniazid treatment to prevent peripheral neuropathy and facilitate metabolism of carbs, proteins, and fatty acids
isoniazid
Vitamin B6 supplementation should be used when patients undergo isoniazid treatment to prevent peripheral neuropathy and facilitate metabolism of carbs, proteins, and fatty acids
o Porphyria Cutanea Tarda
- Enzyme deficiency: hepatic uroporphyrinogen decarboxylase (URO-D); > 30 mutations
- Autosomal dominant inheritance in 1/3 of cases that have ~50% URO-D activity
- Precipitating factors to decrease URO-D activity:
- Increased iron stores (may be caused by down-regulation of hepcidin)
- Hepatitis C ( >50% of patients with sporadic form are HCV positive)
- HFE hemochromatosis
- Alcohol; estrogens
- Symptoms: bullous dermatosis (blistering skin lesions), scarring, hypertrichosis (excessive hair growth), hyperpigmentation
- Associated diseases: HFE hemochromatosis, African iron overload
- Dx:
- Elevated urine total porphyrins (uroporphyrin»_space;>coproporphyrin)
- Screen for HFE C282Y homozygosity and other forms of iron overload
- Evaluate for viral hepatitis/other liver diseases
- Treatment:
- Avoid precipitating factors (i.e. alcohol)
- Phlebotomy – 500 ml (1 unit)/week until remission
- Iron chelation if phlebotomy not possible due to comorbid anemia dx
Interferons
• IFNs are cytokines that limit the spread of certain viral infections
• Different subtypes:
➢ Type 1 (IFNα and IFNβ) are produced by cells infected by virus
➢ Type 2 (IFNγ) is released by activated TH1 cells
• mDCs
which now express MHC II, bind CD4 T helper cells (To) through TCRs (T cell receptors); once bound mDC releases IL-12 to act on To causing it to mature and differentiate into:
Th1 – fights bacteria, viruses
Th2 – fights parasites, allergies
Th17 – fungi, extracellular bacteria; directs neutrophil activity
Treg – turns off Th1, Th2, and Th17; lymphocyte homeostasis
• These mature T cells then secrete IL-2 to act upon themselves (autocrine signaling) to produce more of their specific mature Th cell type
• Immature B cells
(express IgM and IgD) enter germinal center of lymph node and undergo clonal expansion and somatic hypermutation = process of mutation affecting the variable regions of immunoglobulin genes (antibodies)
• B cell then binds to antigen bound by FDC which causes a cascade to occur within the B cell resulting in expression of MHC II on the B cell surface
Once B cell binds to antigen, it loses IgD → mature B cell
• Now a mature B cell can bind to a mature T cell (i.e. Th1); this process allows the B cell to undergo isotype/class switching (goes from IgM to IgG)
• The mature B cell can then become either a:
Plasma cell – loses surface Ig, but has high volume secretion of Ig (pumps out antibody); these antibodies contribute to mast cell activation in innate immunity
Memory cell – retain surface Ig specific to antigen it was presented, remains in body and is able to respond to secondary infection to the invading organism
o When the antigen is eliminated, the immune response switches off
o Note, lymphocytes (T/B cells) originate from the thymus and bone marrow, respectively
