Biochemistry Flashcards
Prothrombin Time (PT) / INR
Measures coagulation along extrinsic as well as common pathway
INR is a corrected lab value of PT - measures responsiveness to warfarin
Causes of increased PT/INR
Deficiency ofextrinsic or common path, intravascular coagulation, anti-phospholipid syndrome (assoc with SLE), vitamin K deficiency, liver disease, warfarin.
APTT (PTT)
Measures coagulation along intrinsic path and common path
Components of intrinsic pathway
12, 11, 9, 8
Disorders causing increased PTT
Intrinsic pathway or common probs, von willebrand disease, anti phosph, vitamin k def, liver disease, hemophilia, warfarin (but PT is better), unfractioned heparin
Activated protein C
Requires protein S cofactor, inhibits intrinsic path
Antithrombin III
Inhibitor of clotting cascade. Inhibits thrombin, and factors 2 + 7 = 9 10 11 12
t-PA (tissue plasminogen activator)
Fibronoylytic agent - ie breakdown of blood clots. Bind fibrin and converts plasminogen to plasmin. Plasmin breaks fibrin down into degradation product, ie D diners.
Primary hémostases
Goal: form a weak platelet plug, preventing extent of hemorrhage. Secondary hémostases further seals plus.
Steps:
Vasoconstriction, platelet adhesion, platelet activation, platelet aggregation.
Endothelin 1 (ET-1)
Mediates vasoconstriction in the first step of primary hemostasis. Extremely potent vasoconstrictor peptide synthesised by injured epithelium.
Von willebrand factor
Synthesized by megakaryocytes, stored in alpha granules of platelets, and in weibel-palade bodies of endothelium.
Mediates adhesion by binding both GPIb and exposed collagen on subendothelium.
Von willebrand disease
Genetic deficiency of vWF, resulting in bleeding diatheses bc decreased ability for platelet adhesion (VwF binds GPib and exposed collagen)
Bernard Soulier syndrome
Deficiency of GPIb. Mutations inhibiting expression, impairing binding of platelets to vWF on endothelial cells. Have thrombocytopenia and enlarged platelets.
Endothelial cell products
Synthesized PGI2/prostacyclin and nitric oxide (NO), potent inhibitors of aggregation.
Products of activated platelets
Secrete TXA2 - potent inducer of activation and aggregation.
Aspirin
Inhibitor of COXI, thus decreases TXA2 synthesis (inhibiting platelet aggregation). Low dose aspirin important because it also blocks formation of PGI2 by endothelial cells which we need, but at low doses, endothelial cells can regenerate fast enough for this not to matter.
Thrombasthenia of Glanzman and Niegli
Genetic deficiency of GPIIB/IIIa - decreased ability to facilitate platelet aggregation, bleeding disorder.
Pancreatitis indicators
(Right) Upper quadrant pain radiating to the back, elevated serum amylase and lipase
So could be an obstruction in ampulla of vater
Biliary colic
Could arise from obstruction of cystic duct - intermittent pain in épigastrium or R upper quadrant, radiates to scapula. Gallblader may become inflamed resulting in cholecystitis.
Obstruction of common bile duct presents with symptoms similar to obstruction of cystic duct
Diverticulitis
Inflammation of one or more diverticula.- could lead to microperforations of affected colon. Sigmoid colon most commonly affected. Left lower quadrant pain, change in bowel habits, nausea, vomiting, constipation, diarrhoea.
Acromegaly
Excess GH in adults - typically caused by pituitary adenoma. Large tongue, deep voice, coarsening faces, frontal bossing, impaired glucose tolerance (insulin resistance)
Increased serum IGF-1
Allopurinol
Inhibits Xanthine Oxidase. Prevents formation of Uris acid in purine metabolism. Not the treatment of choice in acute gout flares - used more for chronic gout treatment. For acute flares use NSADs ie indomethacin.
Classic Galactosemia
AR. Galactose-1-phosphate uridyltransferase deficiency (couples G1P with UTP to form UDP galactose)
Can result in cataracts. Poor feeding, vomiting, diarrhoea followed by hepatomegaly, jaundice, renal problems, neurological symptoms. Accumulation of G1P and galactose
Non-classical galactosemia
Galactokinase deficiency. Galactosemia and galactosuria. G1p is NOT formed. Galacticol accumulates if galactose (lactose) in diet –> cataracts. Rarer than classical and less severe.
Alkaptonuria
AR defect in tyrosine metabolism. Deficiency of homogentisic acid oxidase, increased homogentisic acid levels in blood and urine. Homogentisate in urine is oxidised to alkapton on standing (black brown colour)
Deposition of dark blue/gray pigment throughout body (ochronosis)
MODY
AD form of non-insulin dependent diabetes - age of onset less than 25 yo.
MODY type 2 - diabetes related to mutations in glucokinase. Inability to phosphorylase glucose to G6P during glycolysis. –> resultant higher threshold for glucose-stimulus insulin secretion.
Type VII Glycogen Storage Disease (Tarui disease)
Defect in PFK-1, responsible for phosphorylation of F6P to F16BP. Exercise-induced muscle cramps and weakness, hepatomegaly, ketosis, hyperlipidemia, mildly elevated transaminases.
Cori Cycle
Process of waste removal from muscle to liver. Pyruvate to lactate in the muscle by LDH to regenerate NAD+ to allow glycolysis to proceed. Lactate enters bloodstream to liver. LDH in liver catalyses reverse reaction. Pyruvate ultimately converted back to glucose via gluconeogenesis.
Increased anion gap metabolic acidosis
MUDPILES - methanol, uraemia, diabetic ketoacidosis, propylene glycol, iron or isoniazid, lactic acidosis, ethylene glycol, salicylate toxicity
Salicylate toxicity
Uncoupling agents.- allowing ETC to dissipate
Initial raise in CO2 from ETC stimulates central respiratory centre - increase in respiration –> respiratory alkalosis. Acid metabolites then build up in blood causing metabolic acidosis. Mixed.
Glycogen storage disease type II (pompe disease)
AR.Deficiency in lysosomal acid maltase - presents early infancy with hypotonia, poor feeding, failure to thrive, cardiac insufficiency caused by hypertrophic cardiomyopathy. hepatomegaly may be present but only due to cardiac insufficiency. Macroglossial
Accumulation of glycogen in lysosomes and cytoplasm, resulting in tissue destruction.
SAM
primary methyl donor, helps methylate DNA. After donation, is hydrolysed to homocysteine and adenosine, Regeneration of methionine from homocysteine requires folate and B12.
How is excess nitrogen breakdown from skeletal muscle transported to liver for excretion
NH3 produced in protein catabolism is toxic. NH3 is transferred from glutamate to pyruvate in a transamination reaction, forming alanine and alpha ketoglutarate. Alanine exits muscle, travels in blood to the liver, where it is transaminated in reverse, regenerating pyruvate and glutamate. Pyruvate is used in gluconeogenesis, and glutamate provides one NH3 to form urea.
Homocystinuria
AR. Incl in most newborn screens. Defect in cystathione B synthase, elevated levels of homocysteine. Homocysteine is converted to cystathione via cystathione B synthase or it can regenerate methionine.
Subluxations of lens, arterial disease, binds CT.
COP II and COP I transport
COP II is anterograde - from rough ER to cis-golgi. And from cis golgi to trans golgi. COP I is retrograde
Cri du Chat
Partial deletion of short arm of chromosome 5. (5p). Most cases are de novo mutation. Cry like meowing, microcephaly, facial abnormalities, intellectual disabilities, poor muscle tone, ventricular septal defect.
Orotic Aciduria
Macrocytic anemia, inadequate pyrimidine synthesis. Orotic acid normally converted to UMP by UMP synthase. Megaloblastic anemia refractory to folate and vitamin B12 supplementation.
OTC deficiency
X linked R. Ornithine transcarbamoylase deficiency. Most common urea cycle disorder. Prevents conversion of ornithine and carbamoyl phosphate to citrulline, preventing elmination of ammonia. Excess carbamoyl phosphate converted to orotic acid, leading to elevate levels.
Orotic aciduria also have elevated orotic acid levels, but here we see hyperammonemia (differential)
Alpha amantin
Inhibit RNA Pol II - RNA pol II transcribes mRN.
Kwashiorkor
Insufficient protein intake. Capillary oncotic pressure decreases, tissue edema. Swollen belly due to ascites (fluid in peritoneal cavity), dilated bowel loops, enlarged, fatty liver. Fatty liver due to decreased apolipoprotein synthesis - fats trapped in liver that would normally be exported.
Osteogenesis Imperfecta Type I
AD. Normal quality collagen in insufficient quantities. Multiple bone fractures, scoliosis, joint laxity, blue sclera, hearing loss.
Azidothymidine (AZT)
Antiviral nucleoside. Treatment of HIV in combination with other anti-virals - hinders REPLICATION ability of HIV by lack of 3’ OH incorporation.
Didanosine (DD)
Antiviral nucleoside. No 3’OH - HIV, hinders ability to replication. Reverse transcriptase has 100-300x affinity for dd and AZT than host cell, but there are still side effects. Gamma pol in mitochondria can be affected
Tenofovir
Anti-viral nucleotide. No 3;OH on pentose sugar – termination. Used in HIV
Acyclovir
Anti-viral nucleoside. Deoxygunaosine analogue. Thymidine kinase adds 1P, host kinase adds another. Only affected cells have thymidine kinase and viral DNA pol - chain termination. Treat herpes and varicella zoster,
Cytosine Arabinoside (AraC)
Anti-cancer. AraC triphosphate in cells, bad stereochemistry – termination. Used in leukaemia (acute myeloid lymphoma) - only for blood cancer because rapidly degen in blood
Adenosine arabinoside (AraA)
Anti-cancer. Has 3’OH, but planar configuration. Used for relapsed childhood acute lymphoblastic anemia.
Decitabine
DNA hypomethylating agent. Incorporated in DNA - C5 replaced by N, so can’t methylate. Causes hypomethylation – transcription of tumour suppressor.
Used in myelodysplastic syndrome and AML
5-azacytidine
RNA hypomthylating agent (cytidine analogue)
Similar mech as decitbine?
Leukocyte differential count, in order normal ranges
(Neutrophils Like Making Everything Better)
- Neutrophils 54-62%
- Lymphocytes - 25-33%
- Monocytes - 3-7%
- Eosinophils 1-3%
- Basophils 0.- 0.75%
Neutrophil
(Normal count, 54-62%) - Acut inflammatory response cell, increased in bactrial infectinos. Specific granules leukocytes alkaline pohsphatase, colllagnas, lysozyme, lactoferrin. Lysosomes incl proteinases, acid phosphatase, myeloperoxidase, and B-glucuronidase.
Monocytes
3-7% , differentiate into macrophages in tissues. Monocyte - in the blood.
Eosinophils
Major Basic protein defends parasitic infections. Phagocytose antigen-antibody complexes.
Basophils
Mediate allergic reaction, densely basophilic granules. Contain heparin (anticoagulant) and histamine (vasodilator).
Mast Cell
Allergic reaction in local tissues. Same precursor as basophils but not same cell type.
Fetal erythropoeisis locations
Yolk Sac (3-8), Liver (6 wks to birth), Spleen (10-28 wks), bone marrow (18 wks to adult)
Anticoagulants
Heparin , enhances activity of antithrombin.
Antithrombin targets thrombin and factor Xa.
Protein C cleaves Va and VIIIa
Plasminogen, activated to plasmin via tPA, plasmin then initiates fibrinolysis - cleave fibrin mesh, destruction of coagulation factors.
Forms of microcytic, hypochromic anemia
Iron deficiency (low iron, increased TIBC, decreased ferritin)
Alpha thalassemia (hydrops fetalis if 4 allele deletion (form HbBarts, gamma tetramers))
B thalassemia: minor: increased HbA2
major: homo, target cells and anisopoikilocytosis, increased HbF
Lead poisoning: inhibits ferrocheletase and ALA dehydratase
Sideroblastic anemia: x-linked ALA synthase defect. Genetic, acquired, vitamin B6 def etc.
Folate deficiency
Megaloblastic anemia – impaired DNA synth, maturation of precursor cells
Malnutrition, malabsorption
Findings: increased homocystein, normal methylmalonic acid. No neuro symptoms
Vitamin B12 deficiency
Megaloblastic anemia. INsuff intake, malabsoprtion (crohns, ileal resec), pernicious anemia
Findings: INcreased homocysteine, increasd methylmalonic acid
Neurologic: degeneration bc B12 involved in fatty acid paths and myelin synth.
Orotic Aciduria
Deficiency of UMP synthase (orotic acid to UMP)AR, megaloblastic anemi refractory to folate and B12. No hyperammonemia (veruss ornithine transcarbamylase deficiency, inceased orotic acid with hyperammonemia)
Hereditary Spherocytosis
Extravascular hemolysis - defect in proteins interacting with RBC membrane skeleton and pm (ankyrin, band 3, prot 4.2, spectrin) - premature removal by spleen, small round RBCs decreased surface area. Splenomegaly.
Acute Intermittent Porphyria (AIP)
Porphobilinogen Deaminase def. (PBC to HMB). Porphobilinogen, gam-ALA, and coporphobilinogen(urine) accumulate
Painful abdomen, Port win coloured urine, polyneuropathy, psych disturbance, precipitated by drugs (cyp p-450, induces ALA synthase 1 liver, increases production of ALA etc increased buildup)
Treat with glucose and heme - inhibit ala synthase
Porphyria Cutanea Tarda
Uroporphyrinogen Decarboxylase def. Uroporphyrin accumulates (tea-coloured urine) - blistering cutaneous photosensitivity. Most common porphyria AD
Actinomycin D
Intercalates DNA. Childhood tumours, wilms tumor. Adver effects: myelosuppression.
Etoposide
Inhibits Topoisomese II – increased DNA degradation. Clinical use for solid tumors, leukemias, lymphomas.
Topotecan
inhibits Topoisomerase I. Prevents DNA unwinding an replication. Colon cancer, ovarian and small cell lung cancers.
Hydroxyurea
Inhibits ribonuclotide reductase, decreased Dna Synthsis (S-phase specific), clinical use in melanoma, CML, sickle cell disease (increases HbF).
Menopause findings
Decreased estrogen, so high increased in FSH, increased LH (no surge), Increased GnRH
Hot flashes, Atrophy of vag, osteoporosis, coronary artery disease, sleep disturbances.
