Successfully reported this slideshow.
Disordini del metabolismo intermedio
Disordini del metabolismo delle lipoproteine

    • lipoproteine
     • complessi di proteine, lipidi e colesterolo
     •...
ECTION 3             DISORDERS OF INTERMEDIARY METABOLISM

     • lipoproteine divise 5 classi:
50
                       ...
• proteine associate a lipoproteine si chiamano
  apolipoproteine
• necessarie ad assemblamento, struttura e funzione
• ap...
TABLE 350-1 MAJOR LIPOPROTEIN CLASSES                                                                                     ...
Pathway esogeno
1. trigliceridi assunti con la dieta sono idrossilati da lipasi ed emulsionati da bile
2. colesterolo, aci...
2418                                     Exogenous                          Endogenous                        mediated end...
Pathway endogeno


1. fegato produce VLDLs, simili a chilomicroni ma con Apo-B100
2. HDL trasferisce a VLDLs Apo-E ed Apo-...
Trasporto inverso del colesterolo
   • tutte le cellule sintetizzano il colesterolo, solo quelle epatiche (acidi biliari) ...
ex-
ion
 ns-                                        Macrophage
 ells
 rse               Free
                   cholestero...
TABLE 350-3 FREDERICKSON CLASSIFICATION OF HYPERLIPOPROTEINEMIAS                                                          ...
Emocromatosi
• patologia a carattere ereditario in cui è aumentato l’assorbimento di
  ferro intestinale
• il ferro in ecc...
Terminologia
• Emocromatori ereditaria: dovuta alla mutazione di
  un gene (spesso è HFE)
• eccesso di ferro secondario: n...
• quasi sempre associata a mutazione HFE
• prevalenza moto alta, fino 1/10 nei paesi del nord
  europa. Espressività variab...
• HFE lega β2-microgobulina e recettore transferrina
  segnalando a epatociti il valore della ferritina plasmatica
• se la...
End-stage liver disease may be
   Family                       General                                         though resu...
Le porfirie
• disordini mebabolici risultanti da un enzima
  mutato con perdita di funzione nelle tappe della
  sintesi del...
• all’85% la sintesi avviene nel prec. eritroide, al 15% nel
  fegato
• heme libero regola espressione ala-sintasi
• class...
• 5 sono epatiche e di queste solo la PTC ha
  manifest. cutanee, le altre le hanno acute:
 • agente tossico es. farmaco l...
TABLE 352-1       HUMAN PORPHYRIAS: MAJOR CLINICAL AND LABORATORY FEATURES                                                ...
which complex with
                                                                         Small doses (e.g., 12
        ...
Disofrdini metabolismo purinico e pirimidinico

    • iperuricemia:per aumentato catabolismo delle
      purine o per dife...
GOTTA


• malattia metabolica, uomo mezzetà e anziani e
  donne post-menopausa
• per iperuricemia, si manifesta con artrit...
Upcoming SlideShare
Loading in …5
×

Metabolismo Intermedio

1,894 views

Published on

Published in: Education, Technology, Business
  • Be the first to comment

Metabolismo Intermedio

  1. 1. Disordini del metabolismo intermedio
  2. 2. Disordini del metabolismo delle lipoproteine • lipoproteine • complessi di proteine, lipidi e colesterolo • essenziali per il trasporto di clesterolo, trigliceridi, vitamine lipofile • core idrofobico (trigliceridi, esteri colesterolo), circondato da lipidi idrofili, (fosfolipidi, colesterolo) e proteine
  3. 3. ECTION 3 DISORDERS OF INTERMEDIARY METABOLISM • lipoproteine divise 5 classi: 50 0.95 Disorders of VLDL • chilomicroni Lipoprotein Metabolism 1.006 Daniel J. Rader, Helen H. Hobbs IDL Density, g/mL • VLDLs very low density lipotropeins 1.02 Chylomicron remnants oteins are complexes of lipids and proteins that are essential for LDL nsport of cholesterol, triglycerides, and fat-soluble vitamins. • IDLs intermediate-density lipotropeins usly, lipoprotein disorders were the purview of specialized lipidol- 1.06 Chylomicron but the demonstration that lipid-lowering therapy significantly 1.10 HDL s the clinical complications of atherosclerotic cardiovascular • LDLs (ASCVD) has brought low-density lipoproteins these the diagnosis and treatment of 1.20 ers into the domain of the internist. The number of individuals 5 10 20 40 60 80 1000 re candidates for lipid-lowering therapy has continued to in- • HDLs high-density lipoproteins The development of safe, effective, and well-tolerated pharma- Diameter, nm agents has greatly expanded the therapeutic armamentarium FIGURE 350-1 The density and size-distribution of the major le to the physician to treat disorders of lipid metabolism. classes of lipoprotein particles. Lipoproteins are classified by density ore, the appropriate diagnosis and management of lipoprotein and size, which are inversely related. VLDL, very low density lipopro- ers is of critical importance in the practice of medicine. This tein; IDL, intermediate-density lipoprotein; LDL, low-density lipopro- r will review normal lipoprotein physiology, the pathophysiolo- tein; HDL, high-density lipoprotein. rimary (inherited) disorders of lipoprotein metabolism, the dis-
  4. 4. • proteine associate a lipoproteine si chiamano apolipoproteine • necessarie ad assemblamento, struttura e funzione • apolipoproteine attivano enzimi importane per il metabolismo delle lipoproteine e fungono da ligandi per recettori • Apo A-I sintetizzata da fegato e intestino • Apo-B100 sintetizzata da fegato • Apo B-48 sintetizzata da intestino
  5. 5. TABLE 350-1 MAJOR LIPOPROTEIN CLASSES 24 Apolipoproteins Density, Electrophoretic Other Lipoprotein g/mLa Size, nmb Mobilityc Major Other Constituents Chylomicrons 0.930 75–1200 Origin ApoB-48 A-I, A-IV, C-I, C-II, C-III Retinyl esters Chylomicron remnants 0.930–1.006 30–80 Slow pre-β ApoB-48 E, A-I, A-IV, C-I, C-II, C-III Retinyl esters VLDL 0.930–1.006 30–80 Pre-β ApoB-100 E, A-I, A-II, A-V, C-I, C-II, C-III Vitamin E IDL 1.006–1.019 25–35 Slow pre-β ApoB-100 E, C-I, C-II, C-III Vitamin E LDL 1.019–1.063 18–25 β ApoB-100 Vitamin E HDL 1.063–1.210 5–12 α ApoA-I A-II, A-IV, E, C-III LCAT, CETP paroxonase Lp(a) 1.050–1.120 25 Pre-β ApoB-100 Apo(a) Note: All of the lipoprotein classes contain phospholipids, esterified and unesterified size and surface charge of the particle, with β being the position of LDL and α being the cholesterol, and triglycerides to varying degrees. position of HDL. a The density of the particle is determined by ultracentrifugation. Abbreviations: VLDL, very low density lipoprotein; IDL, intermediate-density lipopro- bThe size of the particle is measured using gel electrophoresis. tein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Lp(a), lipoprotein A; cThe electrophoretic mobility of the particle on agarose gel electrophores reflects the LCAT, lecithin-cholesterol acyltransferase; CETP, cholesteryl ester transfer protein. TRANSPORT OF DIETARY LIPIDS (EXOGENOUS PATHWAY) ide). The triglycerides of VLDL are derived predominantly from the es- • la densità dipende dalla quantità di lipidi The exogenous pathway of lipoprotein metabolism permits efficient terification of long-chain fatty acids in the liver. The packaging of transport of dietary lipids (Fig. 350-2). Dietary triglycerides are hydro- hepatic triglycerides with the other major components of the nascent lyzed by lipases within the intestinal lumen and emulsified with bile ac- VLDL particle (apoB-100, cholesteryl esters, phospholipids, and vita- • colesterolo plasmatico più trasportato in HDL ids to form micelles. Dietary cholesterol, fatty acids, and fat-soluble vitamins are absorbed in the proximal small intestine. Cholesterol and min E) requires the action of the enzyme microsomal triglyceride transfer protein (MTP). After secretion into the plasma, VLDL acquires retinol are esterified (by the addition of a fatty acid) in the enterocyte to multiple copies of apoE and apolipoproteins of the C series by transfer • trigliceridi più trasportati in chilomicroni e VLDLs form cholesteryl esters and retinyl esters, respectively. Longer-chain fat- ty acids (>12 carbons) are incorporated into triglycerides and packaged from HDL. As with chylomicrons, the triglycerides of VLDL are hydro- lyzed by LPL, especially in muscle and adipose tissue. After the VLDL with apoB-48, cholesteryl esters, retinyl esters, phospholipids and cho- remnants dissociate from LPL, they are referred to as IDLs, which con- lesterol to form chylomicrons. Nascent chylomicrons are secreted into tain roughly similar amounts of cholesterol and triglyceride. The liver the intestinal lymph and delivered via the thoracic duct directly to the removes approximately 40–60% of IDL by LDL receptor–mediated en-
  6. 6. Pathway esogeno 1. trigliceridi assunti con la dieta sono idrossilati da lipasi ed emulsionati da bile 2. colesterolo, acidi grassi e vitamine lipofile sono assorbiti nel primo tratto intestino tenue 3. colesterolo e retinolo sono esterificati in enterociti per aggiunta di acido grasso 4. chilomicroni (Apo-B48) sono formati e rilasciati in linfatico e successivamente dal dotto toracico passano in circolo 5. le cellule endoteliali dei capillari del t. adiposo, muscoli e cuoe hanno lipoprotein lipasi (LPL) ancorata ai capillari, questo enzima, che ha Apo-CII (trasferito ai chilomicroni da HDL) come cofattore, idrossila trigliceridi e svuotando i chilomicroni 6. Apoliporoteine dei chilomicroni e il loro contenuto di colesterolo e fosfolipidi passa ad HDL, i questo modo si formano i «remanents» dei chilomicroni 7. i «remanents» vengono ricaptati dal fegano che ha recettori per Apo-E 8. nel giro di 12h da pasto, normalmente, non rimangono più né chilomicroni né suoi remanents nel circolo
  7. 7. 2418 Exogenous Endogenous mediated endocytosis. HDL cholesterol can Dietary lipids en up directly by hepatocytes via the scave Bile acids class BI (SR-BI), a cell surface receptor that + LDL selective transfer of lipids to cells. cholesterol HDL particles undergo extensive remo the plasma compartment by a variety of LDLR proteins and lipases. The phospholipid tra Small Liver has the net effect of transferring phosph intestines Peripheral other lipoproteins to HDL. After CETP-m tissues exchange, the triglyceride-enriched HDL much better substrate for HL, which hydro ApoC's ApoE glycerides and phospholipids to generate ApoB particles. A related enzyme called endothe drolyzes HDL phospholipids, generating particles that are catabolized faster. Remod influences the metabolism, function, and centrations of HDL. Chylomicron Chylomicron remnant VLDL IDL DISORDERS OF LIPOPROTEIN METABOL Capillaries Capillaries Frederickson and Levy classified hyperlipo according to the type of lipoprotein partic mulate in the blood (Type I to Type V) (Ta PART 15 LPL LPL classification scheme based on the molec FFA FFA and pathophysiology of the lipoprotein di plements this system and forms the basis fo The identification and characterization of sible for the genetic forms of hyperlipidem Muscle Adipose Muscle Adipose vided important molecular insights into th of structural apolipoproteins, enzymes, an Endocrinology an FIGURE 350-2 The exogenous and endogenous lipoprotein metabolic path- ways. The exogenous pathway transports dietary lipids to the periphery and the liver. lipid metabolism (Table 350-4). The endogenous pathway transports hepatic lipids to the periphery. LPL, lipoprotein lipase; FFA, free fatty acid; VLDL, very low density lipoprotein; IDL, intermediate-density PRIMARY DISORDERS OF ELEVATED APOB-CONT lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor. LIPOPROTEINS A variety of genetic conditions are associa accumulation in plasma of specific classes o
  8. 8. Pathway endogeno 1. fegato produce VLDLs, simili a chilomicroni ma con Apo-B100 2. HDL trasferisce a VLDLs Apo-E ed Apo-C 3. i trigliceridi delle VLDL vengono idrossilati da LPL, in questo modo si formano le IDL 4. le IDL sono per metà rimosse dal fegato tramite legame con Apo-E 5. Lipasi epatica (HL) rimodella IDL in LDL mantenendo solo sal Apo-B100 6. LDL costituisce circa metà del colesterolo plasmatico 7. LDL rimosse per il 70% da fegato attraverso endocitosi per legame con LDL-R
  9. 9. Trasporto inverso del colesterolo • tutte le cellule sintetizzano il colesterolo, solo quelle epatiche (acidi biliari) e intestinali lo possono allontanare dall’organismo • HDL facilita il trasporto inverso del colesterolo • HDL (Apo-AI) prodotto in intestino e fegato ha forma appiattita e contiene colesterolo e fosfolipidi • LCAT è enzima plasmatico associato a HDL che esterifica colesterolo che migra nel core e HDL diventa tondeggiante • il colesterolo delle HDL può arrivare al fegato per via diretta e indiretta • via indiretta: colesterolo viene scambiato con trigliceridi di lipoproteine con Apo- B, alla fine giungerà a fegato perché queste lipoproteine verrano captate da LDL- R. Le HDL con più trigliceridi sono poi rimodellate ha HL. • via diretta: recettori scavenger nelle cellule epatiche captano HDL e fanno passare selettivamente i lipidi nelle cellule
  10. 10. ex- ion ns- Macrophage ells rse Free cholesterol Fig. IDL LDL tine VLDL LDLR ApoA-I CET ApoA-I ires P Liver site LCAT SR-BI the A1 C ETP Small Nascent coi- intestines Mature HDL HDL ter- DL ter- Chylomicrons Peripheral cells ted ster ires ddi- FIGURE 350-3 HDL metabolism and reverse cholesterol transport. This pathway
  11. 11. TABLE 350-3 FREDERICKSON CLASSIFICATION OF HYPERLIPOPROTEINEMIAS 2 Phenotype I IIa IIb III IV V Lipoprotein, elevated Chylomicrons LDL LDL and VLDL Chylomicron and VLDL Chylomicrons VLDL remnants and VLDL Triglycerides ++++ -- ++ ++ to +++ ++ ++++ Cholesterol + to ++ +++ ++ to +++ ++ to +++ -- to + ++ to +++ LDL-cholesterol ↓ ↑ ↑ ↓ ↓ ↓ HDL-cholesterol +++ + ++ ++ ++ +++ Plasma appearance Lactescent Clear Clear Turbid Turbid Lactescent Xanthomas Eruptive Tendon, tuberous None Palmar, tuberoeruptive None Eruptive Pancreatitis +++ 0 0 0 0 +++ Coronary 0 +++ +++ +++ +/– +/– atherosclerosis Peripheral 0 + + ++ +/– +/– atherosclerosis Molecular defects LPL and apoC-II LDL receptor, ApoB-100, PCSK9, Unknown ApoE ApoA-V and ApoA-V and ARH, ABCG5 and ABCG8 Unknown Unknown Genetic nomenclature FCS FH, FDB, ADH, ARH, sitosterolemia FCHL FDBL FHTG FHTG Note: LPL, lipoprotein lipase; apo, apolipoprotein; FCS, familial chylomicronemia syn- familial combined hyperlipidemia; FDBL, familial dysbetalipoproteinemia; FHTG, familial drome; FH, familial hypercholesterolemia; FDB, familial defective apoB; ARH, autosomal hypertriglyceridemia recessive hypercholesterolemia; ADH, autosomal dominant hypercholesterolemia; FCHL, Lipid Disorders Associated with Elevated LDL-C with Normal ing complication of homozygous FH is accelerated atherosclerosis, Triglycerides • FAMILIAL HYPERCHOLESTEROLEMIA (FH) FH is an au- which can result in disability and death in childhood. Atherosclerosis of- tosomal codominant disorder characterized by elevated plasma levels ten develops first in the aortic root, where it can cause aortic valvular or of LDL-C with normal triglycerides, tendon xanthomas, and prema- supravalvular stenosis, and typically extends into the coronary ostia,
  12. 12. Emocromatosi • patologia a carattere ereditario in cui è aumentato l’assorbimento di ferro intestinale • il ferro in eccesso tende ad accumularsi nelle cellule parenchimali dove può provocare danno tissutale • emosiderina è il nome del pigmento che contiene il ferro nelle cellule • emosiderosi indica la presenza di ferro evidenziabile nei tessuti • emocromatori è una condizione di progressivo eccesso di ferro che danneggia l’organo provocando anche fibrosi. • manifestazioni cliniche dell’emocromatosi possono essere la cirrosi, DM, artrite, cardiomiopatia, ipogonadismo ipogonadotrofico, iperpigmentazione, spider angioma, ittero,
  13. 13. Terminologia • Emocromatori ereditaria: dovuta alla mutazione di un gene (spesso è HFE) • eccesso di ferro secondario: nei casi di eritropoiesi aumentata ma inefficace (talassemia, anemia sideroplastica), manifestazioni cliniche simili a emocromatosi. In questi casi è aumentato l’assorbimento di ferro, inoltre i pz. sono trattati con trasfusioni e spesso che supplemento di ferro.
  14. 14. • quasi sempre associata a mutazione HFE • prevalenza moto alta, fino 1/10 nei paesi del nord europa. Espressività variabile influenzata da fattori ambientali. Più comune negli uomini (no mestruazioni)
  15. 15. • HFE lega β2-microgobulina e recettore transferrina segnalando a epatociti il valore della ferritina plasmatica • se la ferritina non si lega al complesso, gli epatociti secernono hepcidin che fa aumentare un carrier per i metalli su microvilli intestinali. Ne segue un aumentato assorbimento di ferro • ne segue un eccesso e un accumulo che sovraccarica i lisosomi, favorisce la perossidazione dei lipidi e la sintesi di collagene determinando tutte le manifestazioni cliniche sopra descritte
  16. 16. End-stage liver disease may be Family General though results are improved if the member Individual population The available evidence indicates th ty in hemochromatosis is reversed Transferrin saturation or TS 45% Reassure, unsaturated iron-binding capacity retest later? PROGNOSIS TS 45% The principal causes of death ar Normal and or portal hypertension, and hep other genotypes Counsel and HFE Genotype consider non-HFE Life expectancy is improved b hemochromatosis and maintenance of these stores C282Y Homozygote C282Y/H63D Heterozygote vival rate with therapy increases f Serum omy, the liver decreases in size, li Serum ferritin, LFTs ferritin 300 mg/L Observe, skin decreases, and cardiac failur Transferrin saturation LFTs normal retest in 1–2 years about 40%, but removal of exces or arthropathy. Hepatic fibrosis m Serum ferritin Serum ferritin 1000 mg/L 300–1000 mg/L, and/or LFTs abnormal irreversible. Hepatocellular carcin LFTs normal who are cirrhotic at presentation No iron overload Investigate and in treated patients is probably re Liver biopsy treat as tocellular carcinoma rarely develo appropriate Confirmed rhotic stage. Indeed, the life exp iron overload the development of cirrhosis is n The importance of family scr Phlebotomy ment cannot be overemphasized by family studies should have p FIGURE 351-3 Algorithm for screening for HFE-associated hemo- moderately to severely increased chromatosis. LFT, liver function test; TS, transferrin saturation. (From priate intervals is also importa EJ Eijkelkamp et al: Can J Gastroenterol 14:121, 2000; with permission.) most manifestations of the disea
  17. 17. Le porfirie • disordini mebabolici risultanti da un enzima mutato con perdita di funzione nelle tappe della sintesi dell’eme • classificate in epatiche o eritropoietiche a seconda del sito di sovraproduzione del precursore eme • la porfiria cutanea tarda (compare intorno ai 30-40anni) è la più comune (l’unica sporadica) è epatica e si manifesta con bolle cutanee dopo esposizione cute a sole
  18. 18. • all’85% la sintesi avviene nel prec. eritroide, al 15% nel fegato • heme libero regola espressione ala-sintasi • classificate in epatiche o eritropoietiche, o in acute o cutanee • le porfirie epatiche acute hanno manifestazioni prevalentemente neurologiche con dolore neuropatico addominale, • quelle eritropoietiche generalmente con manifestazioni cutanee • per determinare difetto si misura il tipo di porfirine nel plasma o urine e si dimostra il difetto genetico
  19. 19. • 5 sono epatiche e di queste solo la PTC ha manifest. cutanee, le altre le hanno acute: • agente tossico es. farmaco le scatena, pero’ anche dieta, malattia, siga, alcool • nelle acute e nella PTC si cerca di allontanare farmaco o dieta che l’ha scatenata • nelle croniche il trapianto osseo • protezione solare.
  20. 20. TABLE 352-1 HUMAN PORPHYRIAS: MAJOR CLINICAL AND LABORATORY FEATURES 24 Principal Enzyme Symptoms Increased Porphyrin Precursors and/or Porphyrins Deficient Activity % Porphyria Enzyme Inheritance NV or CP of Normal Erythrocytes Urine Stool Hepatic Porphyrias 5-ALA dehydratase- ALA-dehy- AR NV ~5 Zn-protoporphyrin ALA, Coproporphyrin III — deficient porphyria dratase (ADP) Acute intermittent HMB- AD NV ~50 — ALA,a PBG, Uropor- — porphyria (AIP) synthase phyrin Porphyria cutanea URO-decar- AD CP ~20 — Uroporphyrin, 7-car- Isocoproporphyrin tarda (PCT) boxylase boxylate porphyrin Hereditary copro- COPRO- AD NV & CP ~50 — ALA, PBG, Copro- Coproporphyrin III porphyria (HCP) oxidase porphyrin III Variegate porphyria PROTO- AD NV & CP ~50 — ALA, PBG, Copro- Coproporphyrin III (VP) oxidase porphyrin III Protoporphyrin Erythropoietic Porphyrias Congenital erythro- URO-syn- AR CP 1–5 Uroporphyrin I Uroporphyrin I Coproporphyrin I poietic porphyria thase Coproporphyrin I Coproporphyrin I (CEP) Erythropoietic proto- ADa CP ~20–30 Protoporphyrin — Protoporphyrin porphyria (EPP) Ferroche- latase aPolymorphism in intron 3 of wild-type allele affects level of enzyme activity and clinical cessive; CP, cutaneous photosensitivity; COPRO, coproporphyrinogen; HMB, hydroxyme- expression. thylbilane; ISOCOPRO, isocoproporphyrin; NV, neurovisceral; PBG, porphobilinogen; Abbreviations: AD, autosomal dominant; ALA, 5’-aminolevulinic acid; AR, autosomal re- PROTO, protoporphyrinogen; URO, uroporphyrinogen. ylase), catalyzes the sequential removal of the four carboxyl groups REGULATION OF HEME BIOSYNTHESIS
  21. 21. which complex with Small doses (e.g., 12 given, because stan increases in photose can diagnose or ex ment of PCT in pati ministration of eryth HEREDITARY COPROP HCP is an autosom the half-normal act acute attacks, as in but much less com tacks and cutaneou less common than deroporphyria, a bi with clinical sympt FIGURE 352-3 Typical cutaneous lesions in a patient with por- Clinical Features phyria cutanea tarda. Chronic, crusted lesions resulting from blister- attacks in AIP. The ing due to photosensitivity are on the dorsum of the hand of a PCT which are virtually patient. (Courtesy of Dr. Karl E. Anderson; with permission.) women. HCP is ge
  22. 22. Disofrdini metabolismo purinico e pirimidinico • iperuricemia:per aumentato catabolismo delle purine o per difetto escrezione, • iperuricemia se > 408 μmol/L • complicazioni sono gotta, nefrolitiasi, nefropatia per risp. infiammatoria • in sindr. metabolica iperinsulinemia correla con difetto escrezione urati
  23. 23. GOTTA • malattia metabolica, uomo mezzetà e anziani e donne post-menopausa • per iperuricemia, si manifesta con artriti e nefrolitiasi.

×