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BILIRUBIN - keywords
O metalloporphyrins block competitively COOH N N [-] 80 % RBC 20 % shunt heme/ineffective erythropoiesis limit hemolysis block heme oxygenase O ivIg ABO and Rh asap N 4Z-15Z N COOH O2 COOH COOH Fe++ NADPH O2 Fe+++ CO ? O N N N N O heme biliverdin bilirubin IXα polar polar apolar crosses placenta crosses placenta crosses placenta heme oxygenase biliverdin reductase microsomes cytoplasm inducible only mammals and sh fi HO 1: spleen, liver HO 2: brain limit hemolysis block heme oxygenase OFRs biliverdin bilirubin BVR at Bf < 70 nmol/L B is recycled to neutralize large amounts of OFRs BVR main membrane antioxidant ? (like glutathion in cytoplasm) BVR expression in penumbra role in Alzheimer’s the jaundice of the cell PNAS Greenberg 2002 Bf limit hemolysis block heme oxygenase (at pH 7.4 with pK 8.0) H+ H+ 80 % monitor Bf H+ H+ H+ 16 % 2% H+ H+ max solubility 70 nMol/L at pH 7.4 > 70 < 1000 nMol/L oligomers and metastable aggregates: self-aggreagation ongoing from about TSB 85 µMol/L fl unsoluble macroprecipitates if Bf > 1000 nMol/L reversible membrane effects: altered lipid polarity and uidity irreversible membrane effects Bf > 70 nMol/L (4 µg/dL) Bf underestimated at higher [ ] FFAs allosteric interaction at FFA/A molar ratio of 2-3 direct interaction at loose sites >3 Balb TPN, hypoglycaemia, heparin, infection, hypothermia loose binding primary tight binding several sites equimolar would be 8.2 mg per gram (B 10 mg/dL = 171 µmol/ L) competitive displacement by organic anions drug interaction (ceftriaxone 3.0, furosemide 1.07, cefotaxim 1.05, rifampycin) sick preterms (0.5) < sick terms (0.7) < healthy terms (0.9) limit hemolysis block heme oxygenase monitor Bf maintain albumin level avoid displacers monitor FFAs glutathion S transferase (ligandin) Disse space Kuppfer cell hepatocyte transition to normal level in about 10 days = second stage of physiological icterus prevents re ux into blood sinusoid endothelium limit hemolysis block heme oxygenase bile canaliculus carrier mediated, facilitated diffusion passive diffusion at high levels of Bf maturation in brain does not explain regional pattern of kernicterus monitor Bf maintain albumin level avoid displacers monitor FFAs increase uptake enhance glucuronidation glucuroconjugation day 3 diconjugates ~ 21 % of the conjugated fraction COHb %/TCB% adult levels achieved after a few weeks; low levels contribute to early peak in physiological jaundice; normal function at > 50 % levels induction of endoplasmic reticulum mass by phenobarbitone requires 2-5 days (plant derivatives used in Asia); phenobarbitone may alter brain bilirubin oxidation fl screen for G6PDH UDPGT - promotor: Gilbert’s - gene: Crigler-Najjar I/II - G6PDHdef (drugs, teas, mothballs, favism) enterohepatic recirculation Disse space Kuppfer cell hepatocyte follows deconjugation role of meconium evacuation sinusoid endothelium limit hemolysis block heme oxygenase bile canaliculus excretion into bile mono- and diconjugates photo-isomers lumirubin ß and γ isomers saturable, rate limiting, carrier mediated calciumbinding BF x 6 > 250 µmol/L 340 = alert 510 = never monitor Bf maintain albumin level avoid displacers breast feeding monitor FFAs jaundice ≠ breast milk jaundice (ßglucuronidase) increase uptake enhance glucuronidation prevent recirculation Causes/risk factors for increased plasma unconjugated bilirubin Haemolysis Traumatic birth associated with haemorrhage and tissue contusion Neonatal polycythaemia Sepsis Hypoxia Hypoglycaemia Autosomal-inherited disorders Crigler–Najjar types 1 and 2 Gilbert's disease Galactosaemia Fructose intolerance Congenital hypothyroidism Crigler–Najjar type 1 (UDPGT 1 exon) Crigler–Najjar type 2 (UDPGT af nity for bili) Gilbert's disease (UDPGT promotor) Unconjugated hyperbilirubinaemia 200–400 µmol/l, needs phototherapy, phenobarbitone=no effect Unconjugated hyperbilirubinaemia 100–400 µmol/l, needs phototherapy, phenobarbitone effective Unconjugated hyperbilirubinaemia 100–300 µmol/l is common and usually resolves after brief exposure to phototherapy Alagille's Variable—includes paucity of bile ducts, pulmonary artery stenosis, triangular facies (JAG1, notch signalling) Alpha-1 antitrypsin de ciency Growth restriction in utero, severe cholestasis often with pale stools, 2% present with vitamin-K(protease inhibitor chro 14) sensitive coagulopathy Bile acid synthesis disorders hydroxy-steroid dehydrogenase Normal GGT, low serum bile acids, no pruritis oxosteroid reductase Severe jaundice and coagulopathy 25diOHcholanic cleavage Normal GGT, elevated ALP and cholesterol, pruritis Cystic brosis Jaundice, hepatomegaly, meconium ileus, inspissated bile syndrome, pale stools Dubin–Johnson syndrome Conjugated bilirubin (30–400 µmol/l), transaminases normal, centri-lobule pigment granules on liver biopsy PFIC type 1 Byler's disease (MDR1) PFIC type 2 (bile salt export pump) PFIC type 3 (MDR3) Normal GGT, normal cholesterol, variable jaundice, pruritis (diarrhoea±pancreatitis) Normal GGT, no intestinal symptoms, giant cell hepatitis common Elevated GGT, troublesome pruritis Accumulation of very long-chain fatty acids (C27), large fontanelle, high forehead, profound hypotonia fi Zellweger's (bile acid side chain) fi Conjugated hyperbilirubinaemia, but no accumulation of bile acids in the liver and normal liver function tests fi Rotor syndrome H+ toxicity= [Bf] x exposure time H+ limit hemolysis block heme oxygenase monitor Bf maintain albumin level avoid displacers monitor FFAs brain capillary astrocyte decreased glu reuptake inhibited PKC activity endothelium neuron mitochondrion ependyma prevent recirculation limited para- and transcellular diffusion transmembrane passage not restricted contact time: CBFlow (CO2), congestion and duration of jaundice increase uptake enhance glucuronidation prevent capillary injury reduce contacttime open BBB local hemolysis apoptosis necrosis at higher [] regional selectivity (motor and auditory) enhanced by hypoxia neurones 1.5 more sensitive than astroglia limit hemolysis block heme oxygenase monitor Bf maintain albumin level avoid displacers monitor FFAs ursodeoxycholic acid inhibitor of apoptosis proteins increase uptake enhance glucuronidation prevent recirculation acidosis more BH2 aggregation higher CBF injury to BBB effect on alb binding ? prevent capillary injury reduce contacttime prevent apoptosis treat acidosis BBB bidirectional, facilitated diffusion R A TP OA MD MR P MRP P maintain albumin level avoid displacers monitor FFAs increase uptake enhance glucuronidation low CSF protein & similar ratio B/A prevent recirculation MDR steep [] gradient B-CSF - ef ux of lipophilic substances - inhibitors of MDR may contribute to KI: ceftriaxone, verapamil, rifampicin fl monitor Bf MR OATPA MRP OATPA ABC transporter (ATP hydrolysis) unidirectional towards blood fi bili induces MRP1, promotes traf cking from Golgi to plasma membrane MRP OATPA limit hemolysis block heme oxygenase MDR ABC transporter (ATP hydrolysis) unidirectional either to CSF or to blood upregulated by astrocytes at BBB prevent capillary injury reduce contacttime prevent apoptosis treat acidosis enhance extrusion limit hemolysis block heme oxygenase monitor Bf maintain albumin level avoid displacers monitor FFAs 4Z,15Z bilirubin conjugation bilirubin oxidation increase uptake enhance glucuronidation prevent recirculation prevent capillary injury reduce contacttime prevent apoptosis treat acidosis enhance extrusion limit hemolysis block heme oxygenase ≥ 30 Mw/cm2/nm monitor Bf surface area maintain albumin level avoid displacers monitor FFAs around 460 nm increase uptake enhance glucuronidation 4Z,15Z 4Z,15E fi lumi con gurational isomers - immediate - T1/2 > 12 hours - reversible in bile and gut lumirubins - slower generation - intensity-dependent - T1/2 short (few hours) - irreversible prevent recirculation prevent capillary injury reduce contacttime prevent apoptosis treat acidosis enhance extrusion effective photoR/ limit hemolysis block heme oxygenase monitor Bf maintain albumin level avoid displacers monitor FFAs increase uptake enhance glucuronidation prevent recirculation prevent capillary injury reduce contacttime prevent apoptosis treat acidosis enhance extrusion effective photoR/ limit hemolysis block heme oxygenase monitor Bf to prevent kernicterus is much more than just following phototherapy schemes to understand all options, all molecular steps in the bilirubin metabolism have to be understood maintain albumin level avoid displacers monitor FFAs increase uptake enhance glucuronidation prevent recirculation prevent capillary injury reduce contacttime prevent apoptosis treat acidosis enhance extrusion effective photoR/