Chemistry Flashcards

Question

Hemoglobinopathies * Ineritance pattern * Caused by inherent mutations of genes coding for __ synthesis * Thalassemias: * Hemoglobin variants:

Answer 1

Hemoglobinopathies * Autosomal recessive * carriers with 1 affected and 1 normal chromosome are usually healthy/slightly anemic * both parents are carriers, children have * 25% chance of being normal * 25% chance of being severely affected by the disease * 50% chance of being mostly normal * Caused by inherent mutations of genes coding for globin synthesis * Thalassemias: mutations disrupt gene expression --\> reduced production of alpha/beta globin chain * Hemoglobin variants: point mutations of gene in coding region (exons) --\> production of defective globin --\> formation of abnormal hemoglobin

Answer 2

ALPHA-THALASSEMIA * Chromosome 16 * 2 genetic loci for the alpha gene --\> 4 alleles for alpha-hemoglobin (α/α, α/α) * 2 alleles inherited from each parent * Alpha-thalassemia occurs when there is a defect/deletion in one or more of the 4 alleles Alpha-thalassemia can be divided into four categories: * Silent Carriers: * 1 defective/deleted gene, 3 functional genes * (-/α,α/α) * no health problems, +/- low MCV/MCH * Alpha-Thalassemia Trait: * 2 deleted/defective genes, 2 functional genes * alpha thal 1 (-/-,α/α) or alpha thal 2 (-/α,-/α) * +/- mild anemia * Alpha-Thalassemia Major (Hemoglobin H Disease): * 3 deleted/defective genes, 1 functional gene * (-/-,-/α) * persistent anemia & significant health problems * Hb H disease + Hb Constant Spring = severity greater than Hb H disease alone * Hydrops Fetalis: * no functional alpha gene * have hemoglobin Bart * life-threatening unless an intrauterine transfusion is initiated

Answer 3

Alpha-Thalassemia Major (Hemoglobin H Disease): * 3 deleted/defective genes, 1 functional gene, (-/-,-/α) * only 1 alpha gene --\> decreased production of alpha-globin * high β-globin-to-α-globin ratio (a 2- to 5-fold increase in β-globin production) * Hb H formation: tetramer containing only 4 β chains * cannot deliver oxygen in peripheral tissues 2/2 very high oxygen affinity * microcytic hypochromic anemia with target cells and Heinz bodies (precipitated HbH) * Chronic hemolytic anemia (variable) * red cells that contain hemoglobin H are sensitive to oxidative stress and more susceptible to hemolysis, especially with oxidants such as sulfonamides * mature erythrocytes contain more precipitated hemoglobin H and are removed from the circulation prematurely * Subsequent increase in erythropoiesis --\> erythroid hyperplasia * bone structure abnormalities with marrow hyperplasia * bone thinning * maxillary hyperplasia * pathologic fractures

Answer 4

BETA-THALASSEMIA * Chromosome 11 * 1 genetic locus for beta gene --\> 2 alleles for beta-hemoglobin * β⁰- a defective gene is incapable of producing any beta-globin * β⁺ - mutated gene can retain some function * β⁰ or β⁺ does not predict the severity of disease * due to deficit/absent production of beta-globin --\> excess production of alpha-globin * \>200 point mutations have been reported * deletion of both genes is rare Beta-thalassemia can be broadly divided into 3 categories: * Beta-Thalassemia Trait: * 1 defective and 1 normal gene, β⁰/β or β⁺/β * mild anemia, not be transfusion-dependent * low MCV/MCH * HbA2 increased * HbF +/- elevated * Beta-Thalassemia Intermedia: * 2 defective genes, β⁺/β⁺or β⁺/β⁰ * some beta-globin production is still observed * +/- significant health problems that require intermittent transfusion * Beta-Thalassemia Major (Cooley’s Anemia): * 2 defective genes, β⁰/β⁰ or β⁺/β⁰ * no synthesis of beta-globin * severe form of disease, requires lifelong transfusions, +/- shortened lifespan * elevated HbA2 and HbF * excess alpha-globin chain precipitates, leading to hemolytic anemia * due to HbF, no symptoms prior to 6 months of age

Answer 5

Sickle Cell Diseases * HbAS * HbS: 35-40% * HbA2: \< 3.5% * normal Hgb; no apparent illness * HbSS * HbS: \>90% * HbA₂: +/-3.5% * HbA: none * Hgb: 6-8 g/dL; severe disease, chronic hemolysis * HbSβ⁰ * HbS: \>80% * HbA2: \>3.5 * HbA: none * Hgb: 7-9 g/dL; severe sickle cell disease * HbSβ⁺ * HbS: \>60% * HbA2: \>3.5% * HbA: 5-30% * Hgb: 9-12 g/dL; variable mild-moderate sickle cell disease * HbS/α-thalassemia * HbS: 35-40% * HbA2: * HbA: 60% * Hgb: microcytosis * HbSC * HbS: 50% * HbC: 50% * Hgb: 10-12 g/dL; moderate sickling disease, +/- chronic hemolytic anemia * HbS/HPFH * HbS: 60% * HbA2: * HbF: 30-40% * HbA: none * Hgb: 11-14 g/dL; mild sickling disease

Answer 6

HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN HPFH is divided into two major groups: * Deletional HPFH * caused by a variable length deletion in the beta-globin gene cluster * leads to decreased (or absent) beta-globin synthesis and a compensatory increase in gamma-globin synthesis * pancellular/homogenous distribution of HbF in red blood cells * Non-deletional HPFH * broad category of related disorders with increased HbF * Heterocellular distribution of HbF in RBCs * also seen in beta-thalassemia and deltabeta-thalassemia * HbA2 is normal * Both homozygous and heterozygous HPFH are asymptomatic with no clinical or significant hematological change * homozygous HPFH, up to 100% HbF * heterozygous, 20-28% HbF * If HPFH is associated with sickle cell, it can reduce the severity of the disease. * HbS/HPFH: high levels of HbF, few (if any) sickle cell disease-related complications * If HPFH is associated with thalassemia, less severe disease complications

Answer 7

HbS * 10% prevalence of S trait in African Americans * Genetics * Chromosome 11 * sub thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG * (β6glu→val) coding of valine instead of glutamate in position 6 of the Hb beta chain * Under deoxy conditions * decreased solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL * forms a gel-like substance containing Hb crystals called tactoids * gel-like form of Hb is in equilibrium with its liquid-soluble form * factors influence equilibrium: oxygen tension, concentration of Hb S, presence of other hemoglobins * shortened RBC survival, average lifespan 17 days (normal 120 days) * Cells that remain sickled despite re-oxygenation—irreversibly sickled cells (ISCs) in PB smears * sickled cells should return to their normal shape upon exposure to atmospheric oxygen * sickled forms on the PB smear are by definition ISCs * ISC percent is more or less constant in an individual and does not appear to predict or reflect episodic crises * seem to be correlated inversely with that patient's red cell survival. * Splenic sequestration crisis presents as worsening of anemia a/w enlarged, tender spleen * often occur during a viral illness * Children (whose spleens have not yet undergone fibrosis) and adults with SC disease or sickle cell-β+-thalassemia are most susceptible * Hyperhemolytic crisis * sudden exacerbation of anemia in association with profound reticulocytosis and hyperbilirubinemi * has been a/w concomitant G6PD deficiency * Infections are a major source of morbidity/mortality, made worse by functional asplenia * S. pneumoniae most common * Others: Salmonella, Haemophilus (HITB), and M pneumoniae * Neurologic complications are frequent * 1 in 3 patients will have angiographic appearance of moyamoya disease (segmental arterial stenoses with ‘puff of smoke’ collaterals) * Acute hepatic cell crisis (right upper quadrant syndrome) * progressive jaundice, elevated LFTs, and a tender, enlarged liver * usually resolves within 2 weeks, but it may progress to liver failure * Pregnancy * increased rate of both maternal and fetal death * increased risk of pregnancy-induced hypertension (preeclampsia) * increased incidence of intrauterine growth retardation, intrauterine fetal demise, and prematurity * 7 classic sickle cell nephropathies: gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, isosthenuria, pyelonephritis, and renal medullary carcinoma (also increased in AS and SC) * Priapism in up to 40% of male * Ocular complications (proliferative retinopathy) * more common in SC and S/β+ than SS * Osteonecrosis

Answer 8

HbA2' (hemoglobin A2 prime) * clinically insignificant δ-chain variant * 1–2% of African Americans * heterozygotes gel electrophoresis, A2' barely detectable * may underestimate A2 --\> underdiagnosis of β-thalassemia trait * HbA2 and HbA2' levels must be added * easily detectable by HPLC, minor peak in S area HbC (β6glu→lys) * AC * 40-50% of hemoglobin in the in C band (HbA2 + HbC) * generally asymptomatic, scattered target cells * CC * 90% HbC, 7% HbF, 3% HbA2, 0% HbA * mild hemolytic anemia, splenomegaly, and numerous target cells * hexagonal/rod-shaped crystals in the red cells, esp after splenectomy HbE (β26glu→lys) * common in Southeast Asia * thalassemic indices, numerous target cells HbD & G * clinically normal * cellulose acetate - runs with HbS * citrate - runs with HbA * D & G distinguished * HbD is a β-chain defect, while HbG is an α chain defect * HbG: two HbA2 bands (1 normal, 1 abnormal) separated by a distance equal to that separating HbA from HbG HbLepore * Common in Mediterranean, esp Italy * Suspect if \< 30% (~15%) HbS on electrophoresis * Actual HbS rarely this low (RBC exchange) * result of fusion between δ and β genes * cellulose acetate - runs with HbS * inefficiently produced, 8 - 15% of total Hb * HbF up to 20% Hb Constant Spring (CS) * thalassemic indices * mutation in α gene stop codon * produces abnormally long transcript, unstable * αcs gene is inefficient --\> thalassemia * heterozygote hemoglobins produced: * α-β (HbA), αcs-β (HbCS), α-δ (HbA2), αcs-δ * adult: cellulose acetate - 4 bands * newborn: also have α-γ (HbF), αcs-γ High oxygen affinity hemoglobins * A group of hemoglobins with left-shifted oxygen dissociation curves * Ex: HbChesapeake and HbDenver * Most cannot be resolved on gel electrophoresis or HPLC * Clue to their Dx is erythrocytosis on the CBC * HbO2 dissociation curve (P50) is diagnostic Unstable hemoglobins * A group of hemoglobins a/w Heinz bodies and bite cells on PB * Oxidative stresses may precipitate hemolytic crisis * Screening: incubating lysed red cells with 17% isopropanol --\> precipitation of unstable Hbs * Ex: Hbs Hasharon, Koln, & Zurich, only Hb Hammersmith a/w severe hemolysis

Answer 9

Methemoglobin (Hi, hemiglobin) * hemoglobin in which iron is in the oxidized ferric (Fe+++) state instead of ferrous (Fe++) * results from oxidation of hemoglobin * incapable of combining with oxygen * Under normal circumstances, small degree of hemoglobin oxidation * Hi up to 1.5% of total Hb * reduced in the erythrocyte by the NADH-dependent methemoglobin reductase system * Cyanosis results when Hi reaches 10% of total Hb or 1.5 g/dL * blood is grossly chocolate brown * co-oximeter is capable of measuring methemoglobin directly * pulse oximetry and arterial blood gas analyzers * estimate O2 sat by emitting a red light (660 nm) absorbed by reduced hemoglobin and an infrared light (940 nm) absorbed by oxyhemoglobin * Hi absorbs equally at both wavelengths, essentially undetectable * increasing levels of methemoglobin result in decreased measured oxygen saturation towards 85%, form of oxygen saturation gap * Hereditary methemoglobinemia can result from either * deficiency in the reductase system * abnormal Hbs (HbM) upon which this enzyme cannot act * Hb M: group of Hbs that prefer the ferric (methemoglobin) state * 2/2 various aa subs * cyanosis appears at 6 mo * M fetal Hb, cyanosis abates at 6 mo * Most M hemoglobins run with A on routine gels * Acquired methemoglobinemia results from exposure to drugs/chemicals that increase formation of Hi * Ex: nitrites, quinones, phenacetin, and sulfonamides * Hi has a very high affinity for cyanide, Tx for cyanide toxicity involves giving nitrites to generate Hi to chelate cyanide * Treatment: methylene blue, reduces Hi to Hb

Answer 10

HbA2' (hemoglobin A2 prime) * clinically insignificant δ-chain variant * 1–2% of African Americans * heterozygotes gel electrophoresis, A2' barely detectable * may underestimate A2 --\> underdiagnosis of β-thalassemia trait * HbA2 and HbA2' levels must be added * easily detectable by HPLC, minor peak in S area

Answer 11

HbC (β6glu→lys) * AC * 40-50% of hemoglobin in the in C band (HbA2 + HbC) * generally asymptomatic, scattered target cells * CC * 90% HbC, 7% HbF, 3% HbA2, 0% HbA * mild hemolytic anemia, splenomegaly, and numerous target cells * hexagonal/rod-shaped crystals in the red cells, esp after splenectomy * Identification * Alkaline gel: Band in C lane; possibilities - C, E, or O. * Acid gel: Band in C lane * HPLC: peak @ 5 min, small peak just before main peak (HbC1d) * Capillary electrophoresis: peak Zone 2

Answer 12

HbE (β26glu→lys) * common in Southeast Asia * thalassemic indices, numerous target cells * Identification * Alkaline gel: Band in C lane; possibilities are C, E, or O * Acid gel: Band in A lane * HPLC: peak at 3.5 minutes * Capillary electrophoresis: peak in Zone 4

Answer 13

HbD & G * clinically normal * cellulose acetate - runs with HbS * citrate - runs with HbA * D & G distinguished * HbD is a β-chain defect, while HbG is an α chain defect * HbG: two HbA2 bands (1 normal, 1 abnormal) separated by a distance equal to that separating HbA from HbG * Identification of D * Alkaline gel: Band in S lane; possibilities are S, D, G, Lepore * Acid gel: Band in A lane * HPLC: peak at 3.9-4.2 minutes; no additional peak * Capillary electrophoresis: peak in Zone 6. * Identification of G * Alkaline gel: Band in S lane; possibilities are S, D, G, Lepore * Acid gel: Band in A lane * HPLC: peak at 3.9-4.2 minutes; small additional peak (G2) * Capillary electrophoresis: peak in Zone 6.

Answer 14

HbLepore * Common in Mediterranean, esp Italy * Suspect if \< 30% (~15%) HbS on electrophoresis * Actual HbS rarely this low (RBC exchange) * result of fusion between δ and β genes * cellulose acetate - runs with HbS * inefficiently produced, 8 - 15% of total Hb * HbF up to 20% * Identification * Alkaline gel: Band (faint) in S lanel; possibilities - S, D, G, Lepore * Acid gel: Band in A lane * HPLC: peak at 3.7 min (A2 peak); quantity is lower than D, G, or E; small increase in % HbF * Capillary electrophoresis: peak in Zone 6

Answer 15

Hb Constant Spring (CS) * thalassemic indices * mutation in α gene stop codon * produces abnormally long transcript, unstable * α^cs gene is inefficient --\> thalassemia * heterozygote hemoglobins produced: * α-β (HbA), α^cs-β (HbCS), α-δ (HbA2), α^cs-δ * adult: cellulose acetate - 4 bands * newborn: also have α-γ (HbF), α^cs-γ

Answer 16

High oxygen affinity hemoglobins * A group of hemoglobins with left-shifted oxygen dissociation curves * Ex: HbChesapeake and HbDenver * Most cannot be resolved on gel electrophoresis or HPLC * Clue to their Dx is erythrocytosis on the CBC * HbO2 dissociation curve (P50) is diagnostic

Answer 17

Unstable hemoglobins * A group of hemoglobins a/w Heinz bodies and bite cells on PB * Oxidative stresses may precipitate hemolytic crisis * Screening: incubating lysed red cells with 17% isopropanol --\> precipitation of unstable Hbs * Ex: Hbs Hasharon, Koln, & Zurich, only Hb Hammersmith a/w severe hemolysis

Answer 18

On Cellulose Acetate gel at pH 8.6 * S, D, G, Lepore

Answer 19

Cellulose Acetate gel at pH 8.6 * C, E, O and A2

Answer 20

Cellulose Acetate gel at pH 8.6 * A, M

Answer 21

Cellulose Acetate at pH 8.6 * H & Bart run at the (+) end of the gel, past A

Answer 22

Citrate Agar at pH 6.2 * A, A2, D, G, E, M

Answer 23

Identification of HbS * Alkaline gel: Band in S lane; possibilities: S, D, G, Lepore * Acid gel: Band in S lane * HPLC: peak at 4.5 minutes * Capillary electrophoresis: peak in Zone 5

Answer 24

Cytochemical stains for typing blasts * Myeloperoxidase (MPO) * stains the primary (azurophilic) granules indicative of granulocytic differentiation * negative in lymphoblasts, erythroblasts, monoblasts, and megakaryoblasts * fine dusty positivity may be seen in monoblasts * degrades quickly in wet specimens, but is stable in smears for up to a month * Sudan black B (SBB) * stains lipid material found in granulocytic and monocytic cells * Chloroacetate esterase (CAE) * found only in the granulocytic series * monocytes and lymphocytes are negative * Nonspecific esterases (NSE) * include alpha naphthyl acetate esterase and alpha naphthyl butyrate esterase * stain cells of the monocytic series and +/- megakaryocytic, lymphocytic, granulocytic, and erythroid series * Monocyte NSE activity is inhibited by sodium fluoride (NaF) * Periodic acid Schiff (PAS) * positive in most lymphoid and some myeloid blasts * In ALL, it shows “block” positivity, often encircling the nucleus in a “rosary bead” fashion * In AML, when positive, it is usually a diffuse, granular hue of positivity * The vacuoles in the blasts of L3 ALL stain positively with the oil red O stain

Answer 25

Substance Abuse and Mental Health Services Administration (SAMHSA) guidelines for federal workplace drug testing Require testing for 5 abused drugs: 1. amphetamines (amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine; MDMA, ecstasy) 2. cocaine (tested as benzoylecgonine) 3. opiates 4. marijuana (tested as marijuana metabolites) 5. phencyclidine (PCP)

Answer 26

In urine, most drugs can be detected for only 2-3 days after abuse, except for PCP (\_\_ days) and marijuana (up to __ days, from chronic abuse).

Answer 27

Abuse of cocaine and ethanol (alcohol) is dangerous because: * ethanol and benzoylecgonine (inactive metabolite of cocaine) = cocaethylene * cocaethylene: active metabolite with a long half-life

Answer 28

Plasma osmolality = 2 x [Na in mmol/L] + [Glucose mg/dL]/18 + [BUN mg/dL]/2.8 Osmolar gap = Observed osmolality - Calculated osmolality * High osmolar gap can be due to: * ethanol, methanol, and ethylene glycol (overdosed patients) * reduced fractional water content of plasma 2/2 hyperlipidemia or paraproteinemia

Answer 29

Diabetes insipidus * Central/cranial: due to lack of secretion of ADH * Nephrogenic: due to the inability of ADH to work at the collecting duct of the kidney SIADH (syndrome of inappropriate ADH secretion) * hyponatremia (plasma sodium \<131 mmol/L) * decreased plasma osmolality (\<275 mOsm/kg) * urine osmolality \>100 mOsm/kg * high urinary sodium (\>20 mmol/L) with no edema

Answer 30

CO₂ + H₂O = H₂CO₃ = H⁺ + HCO₃^- * Carbonic acid: H₂CO₃ * Bicarbonate: HCO₃^-

Answer 31

Normal pH of arterial blood = 7.35-7.45 Normal bicarbonate level = 23-25 mmol/L Normal pCO2 = 35-45 mmHg Normal chloride level = 95-105 mmol/L

Answer 32

* Metabolic acidosis * Decrease: pH, pCO₂, bicarbonate * Respiratory acidosis * Decrease: pH * Increase: pCO2, bicarbonate * Metabolic alkalosis * Inrease: pH, pCO2, bicarbonate * Respiratory alkalosis * Increase: pH * Decrease: pCO2, bicarbonate

Answer 33

Anion gap = sodium - (chloride + bicarbonate) * The normal value is 8-12 mmol/L (mEq/L)

Answer 34

Causes of normal anion gap metabolic acidosis * loss of bicarbonate buffer from the gastrointestinal tract * chronic diarrhea, pancreatic fistula, and sigmoidostomy * renal loss of bicarbonate * renal tubular acidosis and renal failure Causes of increased anion gap metabolic acidosis (MUDPILES) * Methanol * Uremia * Diabetic ketoacidosis * Paraldehyde * Isopropanol * Lactic acidosis * Ethylene glyco * Salicylate

Answer 35

Metabolic alkalosis * loss of hydrogen ion * gain of bicarbonate * alkali for any of the following reasons: * loss of acid from gastrointestinal tract issues (vomiting, diarrhea) * loss of acid from kidneys (glucocorticoid or mineralocorticoid excess, diuretics) * gain of alkali (e.g. “milk-alkali syndrome,” aka Burnett’s syndrome, excess milk intake and alkali leading to hypercalcemia)

Answer 36

Respiratory acidosis * Increased CO₂ due to type II respiratory failure (hypoventilation) * CNS disorders that damage or suppress the respiratory center (e.g. stroke, tumor, drugs, alcohol, neuropathy) * myopathy affecting muscles of ventilation (e.g. GuillainBarré syndrome, myasthenia gravis) * reduced movement of chest wall (e.g. flail chest, severe obesity) * airway obstruction (e.g. severe acute asthma)

Answer 37

Respiratory alkalosis * Decreased CO₂ (hyperventilation) * CNS stimulation due to drugs such as aspirin, ketamine, * hysteria * bronchial asthma (early stage) * Acute respiratory disturbance: * 10 mmHg pCO₂ change --\> 0.08 units change in pH * Chronic respiratory disturbance * 10 mmHg pCO₂ change --\> 0.03 units change in pH

Answer 38

* Synthesis of clotting factors * Factor VIII is not produced in the liver * Significant Urea synthesis from ammonia and carbon dioxide * Low urea level in fulminant hepatic failure * Liver releases glucose by glycogenolysis and gluconeogenesis * Hypoglycemia in fulminant hepatic failure

Answer 39

* Pre-hepatic jaundice (hemolytic anemia) * Total and unconjugated bilirubin is high * Liver enzymes (ALT, AST, ALP, and GGT) are normal * PT and proteins are normal * Hepatocellular jaundice * Total bilirubin is high * Liver enzymes are elevated * ALT and AST may be very high (in thousands) * ALP \< 3x normal * Total protein and albumin may be normal * PT may be prolonged if liver damage is significant * Cholestatic jaundice * Total bilirubin and conjugated bilirubin is high * Liver enzymes are elevated (typically mildly) * ALP \>3x normal * PT may be prolonged due to lack of absorption of fat-soluble vitamin K * Acute liver disease * PT is the best marker * Total protein and albumin are typically normal * Chronic liver disease * Albumin level is decreased * Total protein could be elevated if hypergammaglobulinemia is present * liver enzymes may or may not be elevated * Liver metastasis * Only ALP and GGT may be elevated * Bone disease or metastasis * Only ALP may be elevated * Alcoholic liver disease * Only GGT is elevated

Answer 40

Congenital Hyperbilirubinemias * Gilbert’s syndrome * CriglerNajjar Type I * CriglerNajjar Type II * Dubin-Johnson * Rotor

Answer 41

Congenital Hyperbilirubinemias * **Gilbert’s syndrome** * Autosomal dominant * Reduced levels of UDP-glucuronyl transferase --\> elevated **unconjugated** bilirubin * increases with fasting * **CriglerNajjar Type I** * Autosomal recessive * Total absence of UDP-glucuronyl transferase * Markedly elevated **unconjugated** bilirubin * may be fatal * **CriglerNajjar Type II** * Autosomal dominant * Reduced levels of UDP-glucuronyl transferase * Elevated **unconjugated** bilirubin * can be treated with enzyme inducer such as phenobarbital * **Dubin-Johnson** * Autosomal dominant * Impaired excretion of **conjugated** bilirubin, causing conjugated hyperbilirubinemia * Melanin pigment found within hepatocytes * **Rotor** * Autosomal dominant * Impaired excretion of **conjugated** bilirubin

Answer 42

Autoimmune liver disease * a/w other autoimmune diseases * Extrahepatic: polyarthritis, pleurisy, and glomerulonephritis * ANA, anti-smooth muscle actin, anti-soluble liver antigen, and anti-liver/kidney microsomal antibodies * Polyclonal hypergammaglobulinemia may be present due to increased IgG

Answer 43

Primary biliary cirrhosis * primarily in women * pruritus precedes other features, +/- secondary hyperlipidemia * Anti-mitochondrial antibody * IgM levels high

Answer 44

Wilson’s disease * autosomal recessive * copper is deposited in the liver * young age * Kayser-Fleischer ring is seen as greenish brown pigment at the sclera cornea junction * Low serum ceruloplasmin

Answer 45

Alpha-1 antitrypsin deficiency * liver disease and panacinar emphysema * Serum alpha-1 antitrypsin level is low * Genetic variants are characterized by their electrophoretic mobility: * medium (M), slow (S), and very slow (Z) * Normal people are MM, homozygotes are ZZ, heterozygotes MZ or SZ

Answer 46

* HLA-B27 = Ankylosing spondylitis, Reactive arthritis * HLA-B46 = Graves’ disease (Asian population) * HLA-B47 = 21-Hydroxylase deficiency * HLA-DR2 = Systemic lupus erythematosus * HLA-DR3 = Type 1 diabetes mellitus, SLE * HLA-DR4 = Myasthenia gravis, Rheumatoid arthritis

Answer 47

Hypersensitivity reactions 4 types: * immediate (type I) * antibody-mediated (type II) * immune complex-mediated (type III) * T cell-mediated (type IV)

Answer 48

Hypersensitivity reactions 4 types: * Immediate (type I) hypersensitivity reaction * host is exposed to an antigen, IgE antibodies are produced, which are bound to the surface of mast cells, that trigger mast cell degranulation * Antibody-mediated (type II) hypersensitivity disorder * antibodies directed against antigens, which are components of cells * Immune complex-mediated (type III) hypersensitivity disorder * large amounts of antigenantibody complexes are formed, may deposit in tissues and cause an inflammatory response * kidneys, joints, and skin * T cell-mediated (type IV) reactions * Delayed-type hypersensitivity (DTH) * classic example is the tuberculin reaction * T cell-mediated cytotoxicity * CD8+T cells are responsible for killing antigen-bearing target cells * cytotoxicity is important against viral infections and tumor cells

Answer 49

The complement pathways * Classic pathway * Activated by IgM and subclasses of IgG (IgG1, IgG2, IgG3) * Fc portion of the Ig interacts with C1q to initiate this process * Activated C1 catalyzes the association of C4 and C2 to make C4b2b (the C3 convertase of the classic pathway) * C4b2b is capable of converting C3 to C3b + C3a * C3b associates with C4b2b to make C4b2b3b (the C5 convertase of the classic pathway) * Alternate pathway * Can be activated in the absence of Ig by: * bacterial cell walls, venoms, or endotoxin * complexed IgA * These substances bind to C3b and prevent its degradation * C3b is present at low levels at all times in peripheral blood, minute amounts of C3 are constantly converted to C3a and C3b * Normally C3b is rapidly inactivated by factor I, unless a suitable surface is present to prevent it and promote the association of C3b with factor B to makeC3bBb (the C3 convertase of the alternate pathway) * C3bBb is capable of converting C3 to C3b + C3a * Abundantly available C3b associates with C3bBb to make C3bBb3b (the C5 convertase of the alternate pathway) * The whole point of both the alternate and classical pathways is to produce a C5 convertase (a molecule capable of converting C5 into C5b + C5a) * Once C5b is formed, it quickly complexes (on the surface of adjacent cells such as bacteria, transfused red cells, etc.) with C6, C7, C8 and C9 to form C5b6789 (the membrane attack complex or MAC) * C3a and C5a are formed as by-products * anaphylatoxins capable of increasing vascular permeability and causing vasodilation * C3b alone, like IgG, when fixed to the surfaces of cells, acts as an opsonin * interacts with receptors on phagocytic cells, leading to ingestion of the bound cell