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. 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. • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. • 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. 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. 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. • 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. • 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. 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. 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. 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. GOTTA
• malattia metabolica, uomo mezzetà e anziani e
donne post-menopausa
• per iperuricemia, si manifesta con artriti e
nefrolitiasi.
