Cirrosi Epatica Definizione Meccanismi della fibrogenesi epatica Fisiopatologia dellipertensione...
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Transcript of Cirrosi Epatica Definizione Meccanismi della fibrogenesi epatica Fisiopatologia dellipertensione...
Cirrosi Epatica
• Definizione• Meccanismi della fibrogenesi epatica• Fisiopatologia dell’ipertensione portale• Complicanze maggiori della cirrosi• Cenni di terapia delle complicanze• Management della cirrosi
compensata/scompensata
CIRROSI
Alterazione dell’architettura del fegato caratterizzata da noduli e formazione di tessuto collagene
CAUSE: Tutte le cause di danno epatico cronico
●
Causa iniziale
Stadiofinale
Complicanze
anni
Cirrosi-Fibrosi-Distorsione dell’architettura epatica
Progressione del danno epatico cronico
Hepatic ArteryPortal Vein
Sinusoids
Bile Duct
Central Veins
Normal Cirrhosis
Changes of hepatic microcirculation in cirrhosis
Activation of HSC
LIVER CIRRHOSISLIVER CIRRHOSIS : from activation of HSC to : from activation of HSC to cirrhotic nodulescirrhotic nodules
CellsCells of the of the Hepatic Sinusoid Hepatic Sinusoid
Hepatocyte
Sinusoidal endotheliumSinusoidal endothelium
Space of Disse
HepaticHepatic
Stellate Stellate CellCell
Kupffer CellKupffer Cell
Spazio portale
Fibrosi viraleFibrosi virale
1.1. –– Necrosi a ponte porto-centraleNecrosi a ponte porto-centrale
2. –2. – Epatite da interfaccia e sviluppo di setti che Epatite da interfaccia e sviluppo di setti che circondano il parechimacircondano il parechima
3. –3. – Perdita di connessioni vascolari con il sistema portale Perdita di connessioni vascolari con il sistema portale
fibrosi biliarefibrosi biliare
Spazio portale
Formazione di setti porto-portaliFormazione di setti porto-portali
La vena centrolobulare è conservataLa vena centrolobulare è conservata
Modello BDL Modello BDL
CBPCBP
CB CB secondaria secondaria CSPCSP
portal tract
1.1. –– Secondary to venous outflow problems (e.g. chronic Secondary to venous outflow problems (e.g. chronic heart failure) heart failure)
2. - Chronic ETOH consumption2. - Chronic ETOH consumption
3. –3. – Development of central to central septa and Development of central to central septa and “reversed lobulation”“reversed lobulation”
CentrolobularCentrolobular fibrosisfibrosis
CONSEQUENCES OF DEVELOPING PROGRESSIVEHEPATIC FIBROSIS
structural & structural & functionalfunctional
intrahepatic resistanceintrahepatic resistance splanchnic blood flowsplanchnic blood flow
(cirrhosis)(cirrhosis)HCCHCC
portal hypertensionportal hypertension
variceal bleedingvariceal bleeding
hepatic encephalopathyhepatic encephalopathy
hepatopulmonary syndromehepatopulmonary syndrome
portosystemic collateralsportosystemic collaterals
systemic systemic hyperdynamic circulationhyperdynamic circulation
ascitesascites
spontaneousspontaneousbacterial peritonitisbacterial peritonitis
cardiac output cardiomyopathy
decrease central volume
HRS
Ipertensione portale• Condizione fisiopatologica causata dall’aumento della pressione venosa nel distretto portale • Principale conseguenza della cirrosi epatica e principale meccanismo delle sue principali complicanze cliniche
• Riconosce anche cause extraepatiche, in cui le manifestazioni cliniche dominanti dipendono dalla sede di origine della ipertensione portale
• Flusso epatico: 1.5 l/min(80% venoso, portale)
• Pressione portale: 7 mmHg (diretta o wedge)
• Pressione sovra-epatiche/atrio dx: 3-5 mmHg
• Gradiente porto-epatico (HVPG): ≤5
Anatomia e Fisiologia della circolazione portale
Sistema venoso ad alta portata e bassa resistenza che drena il sangue dagli organi addominali per convogliarlo al fegato; da questo, attraverso i sinusoidi e le vene sovrepatiche, raggiunge la vena cava inferiore e la circolazione sistemica
Classificazione e cause
• Cause Pre-epatiche• Trombosi portale• Trombosi splenica
• Cause Intraepatiche• Presinusoidali• Sinusoidali• Postsinusoidali
• Cause post-epatiche• Membrana cavale• Pericardite costrittiva• Insufficienza tricuspidale• Grave scompenso cardiaco destro
Cause di ipertensione portale intraepatica
• Pre-sinusoidali• Schistosomiasi, sarcoidosi, tossici, fibrosi epatica
congenita, malattie mielo proliferative
• Sinusoidali o miste• Cirrosi, epatite alcolica, iperplasia nodulare
rigenerativa
• Post-sinusoidali• Malattia veno-occlusiva• Sindrome di Budd-Chiari
PORTAL HYPERTENSION: pathophysiological sequelae
structural & functionalstructural & functional intrahepatic resistanceintrahepatic resistance splanchnic blood flowsplanchnic blood flow
(cirrhosis)(cirrhosis)HCCHCC
portal hypertensionportal hypertension
variceal bleedingvariceal bleeding
hepatic encephalopathyhepatic encephalopathy
hepatopulmonary syndromehepatopulmonary syndrome
portosystemic collateralsportosystemic collaterals
systemic systemic hyperdynamic circulationhyperdynamic circulation
ascitesascites
spontaneousspontaneousbacterial peritonitisbacterial peritonitis
cardiac output cardiomyopathy
decrease central volume
HRS
Conseguenze dell’ ipertensione portale
• Splenomegalia ed ipersplenismo
• Circoli collaterali ed emorragie digestive
• Shunt porto-sistemici ed encefalopatia porto-sistemica
• Vasodilatazione splancnica ed alterazioni della emodinamica sistemica
Circoli collaterali
Ligamento falciforme
Gastro-esofagei
Vene emorroidarie
Gastro-esofagei
Parete addome e retroperitoneo
Conseguenze degli shunts portosistemici
• Riducono il flusso portale• Aumentano insufficienza epatica• NON riducono significativamente la pressione
portale• Favoriscono la circolazione iperdinamica• Favoriscono iperammoniemia• Endotossinemia• Encefalopatia porto sistemica
Complicanze maggiori della cirrosiComplicanze maggiori della cirrosi
Complicanze maggiori della cirrosiComplicanze maggiori della cirrosi
Compensatedcirrhosis
Compensatedcirrhosis
Decompensatedcirrhosis
Decompensatedcirrhosis
Development of cirrhosis
Development of cirrhosis
DeathDeathChronic
liver disease
Chronic liver
disease
Orthotopic liver
transplant (OLT)
Orthotopic liver
transplant (OLT)
Development of
complications:
Development of
complications: Variceal
hemorrhage Ascites Encephalopathy HRS
Variceal hemorrhage
Ascites Encephalopathy HRS
Natural History of Chronic Liver Disease
Mortalità per complicanze di Mortalità per complicanze di cirrosi epatica - 384 Ptscirrosi epatica - 384 Pts
0
5
10
15
20
25
30
35
HCC Ascit Varix Bl Enceph/J >1 compl
Complicanze
Fattovich G et al, Gastroenterology 1997;112:463
follow-up: 5 anni
Child-Turcotte-Pugh (CTP) Child-Turcotte-Pugh (CTP) ScoreScore
Child-Turcotte-Pugh (CTP) Child-Turcotte-Pugh (CTP) ScoreScore
Child A: 5-6 pts Child B: 7-9 pts Child C: 10-15 ptsChild A: 5-6 pts Child B: 7-9 pts Child C: 10-15 pts
Points1 2 3
Encephalopathy None Grade 1-2 Grade 3-4 (precipitant) (chronic)
Ascites None Mild Moderate
Bilirubin (mg/dl) <2 2-3 >3
Albumin (g/dl) >3.5 2.8-3.5 <2.8
PT (seconds prolonged) <4 4-6 >6or INR <1.7 1.7-2.3 >2.3
Points1 2 3
Encephalopathy None Grade 1-2 Grade 3-4 (precipitant) (chronic)
Ascites None Mild Moderate
Bilirubin (mg/dl) <2 2-3 >3
Albumin (g/dl) >3.5 2.8-3.5 <2.8
PT (seconds prolonged) <4 4-6 >6or INR <1.7 1.7-2.3 >2.3
MINIMAL LISTING CRITERIA: CTP SCORE 7 POINTS MINIMAL LISTING CRITERIA: CTP SCORE 7 POINTS
Predicts 3-month mortality among patients with chronic liver disease on the liver waiting list
MELD = (0.957 x LN (creatinine) + 0.378 x LN (bilirubin) + 1.12 x LN (INR) + 0.643) x 10
Minimum score = 6 (risk of death on WL 20%)
Maximum score = 40 (risk of death on WL 100%)
Predicts 3-month mortality among patients with chronic liver disease on the liver waiting list
MELD = (0.957 x LN (creatinine) + 0.378 x LN (bilirubin) + 1.12 x LN (INR) + 0.643) x 10
Minimum score = 6 (risk of death on WL 20%)
Maximum score = 40 (risk of death on WL 100%)
MELD (MELD (MModel for odel for EEnd-nd-Stage Stage LLiver iver DDisease)isease)MELD (MELD (MModel for odel for EEnd-nd-Stage Stage LLiver iver DDisease)isease)
Diagnostica della cirrosi con ipertensione portale
• Clinico-semeiologica
• Misurazione invasiva emodinamica portale
• Eco-doppler
• Endoscopia digestiva
Diagnosi clinico-semeiologica
• Splenomegalia
• Circoli collaterali superficiali
• Gavoccioli emorroidari
• Spider Naevi
• Edema perimalleolare
• Ascite
• Asterixis
Semeiotica dell’ipertensione portale
Definition of ascitesDefinition of ascites
• Uncomplicated Grade 1 (mild) detectable only by US Grade 2 (moderate) moderate symmetrical
abdominal distension Grade 3 (large) marked abdominal distension
• Refractory Ascites that cannot be mobilized or early recurrence of ascites not prevented by medical therapy
Diuretic-resistant Diuretic-intractable
• Bed rest unproven benefit
• Dietary sodium restriction to 5.2 g/d (90 mmol)
• Diuretics Anti-Mineralocorticoids Spironolactone,
Canrenoate, Canrenone Loop diuretics Furosemide, Torasemide, Ethacrynic
Acid Other potassium-sparing diuretics Amiloride,
Triamterene
Treatment of Ascites
• Treatment duration Intensive diuretic therapy (spironolactone 400 mg/d +
furosemide 160 mg/d) for at least 1 wk Salt-restricted diet (< 90 mmol or 5.2 g of salt/d)
• Lack of response Weight loss < 0.8 kg over 4 days Urinary sodium output < sodium intake
• Early ascites recurrence Grade 2 or 3 ascites within 4 wks of initial mobilization
• Diuretic-induced complications Hepatic Encephalopathy, Renal Impairment, Hyponatremia,
Hypo/Hyperkalemia
Diagnostic Criteria of Refractory Diagnostic Criteria of Refractory AscitesAscites
Infezione del liquido ascitico
PMN > 250/mm3 e colturale + su liquido ascitico
Microbiologia: G-: E. Coli, K. Pneumoniae (60%)G+: Strepto (25%)Anaerobi: rari
Non evidente sorgente di infezione addominale trattabile chirurgicamente
10-25% dei cirrotici ospedalizzati con ascite
Mortalità elevata (17-50%)
Alto rischio di recurrence: 43-70% (6-12 mesi)
PERITONITE BATTERICA SPONTANEA: definizione ed epidemiologia
PERITONITE BATTERICA SPONTANEA: forme cliniche
1. Classic2. CNNA (culture negative neutrocytic ascites)3. MNB (monomicrobial non-neutrocytic
bacterascites) carcinosi peritoneale, pancreatite, peritonite TBC
Classica CNNA MNB
PMN > 250 > 250 < 250
Colturale
+ - +
Cefotaxime: 2g/12 hrs per 5-10 gg
Ciprofloxacina: 400 mg/12 hrs per 5 gg, poi orale
Se non risposta: Stafilo?
+ Albumina: 1.5 g/kg alla diagnosi, 1 g/kg dopo 48 hrs (prevenire HRS!)
Chinolonico long-term (Norfloxacina 400 mg/die) soprattutto se proteine < 1 g/dl nel liquido ascitico
PERITONITE BATTERICA SPONTANEA: terapia e profilassi
Definition of Hepatorenal Syndrome (HRS)
• Type I HRS Rapid and progressive renal failure with a
doubling of serum creatinine to a level greater than 2.5 mg/dl or a halving of the creatinine clearance to less than 20 ml/min in less than 2 wks
• Type II HRS More chronic form with a slowly
progressive increase in serum creatinine level to greater than 1.5 mg/dl or a creatinine clearance of less than 40 ml/min
DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS
Renal failure
Type-2 Type-1
Consequence
Survival
Moderate and steady
Refractory ascites
Months
Severe and progressive
Terminal hepatorenal failure
Days
Spontaneous PrecipitatedOnset
Definition of Hepatorenal Syndrome:Major Criteria
• Chronic or acute liver disease with liver failure and portal hypertension
• Low glomerular filtration rate (serum creatinine > 1.5 mg/dl or creatinine clearance < 40 ml/min)
• Absence of shock, excessive fluid loss, ongoing bacterial infection and recent treatment with nephrotoxic drugs
• No sustained improvement in renal function following expansion with 1.5 l of isotonic saline
• Proteinuria < 0.5 g/dl• No US evidence of renal tract disease
Definition of Hepatorenal Syndrome:Minor Criteria
• Urine volume < 500 ml/d• Urine sodium < 10 mmol/d• Urine osmolality < plasma osmolality• Urine red cell count < 50/high power
field• Serum sodium < 130 mmol/l
The Pathophysiology of HRS
TERLIPRESSIN FOR HEPATORENAL SYNDROME
Effect of albumin
Terlipressin plus albumin
Terlipressin
1210864 14 Days
0.2
0.4
0.6
0.8
p<0.05
2
90%
30%
1.0P
rob
ab
ilit
y
Ortega et al, Hepatology 2002
Varici esofagee
Varici fondo
Diagnosi e classificazione endoscopica
Diagnosi e classificazione endoscopica
Gastropatia ipertensiva GAVE
Dilation and Rupture of Varices
Varix
PFlow
Risk increases in portal pressure and collateral blood flow caused by:• Meals• Alcohol• Exercise• Increased intra-abdominal pressure
Acute variceal bleeding Sclerotherapy + Drugs vs Sclerotherapy alone
Mortality
PREVENZIONE RISANGUINAMENTO (profilassi secondaria)(profilassi secondaria)
BB + nitrati fallimento LEV(+ BB)
successo fallimento successo
Malattia epatica avanzata
Malattia epaticastabile
Continuare+ follow up
continuare
TIPS(DSSR)
TIPSOLT
D´Amico, 2004D´Amico, 2004
Hepatic EncephalopathyNomenclature
Hepatic EncephalopathyNomenclature
Type AAssociated with Acute liver failure
Type BAssociated with porto-systemic Bypass without intrinsic hepatocellular disease
Type CAssociated with Cirrhosis and porto-systemic shunting
Type AAssociated with Acute liver failure
Type BAssociated with porto-systemic Bypass without intrinsic hepatocellular disease
Type CAssociated with Cirrhosis and porto-systemic shunting
Ferenci et al., Hepatology 2002; 35:716Ferenci et al., Hepatology 2002; 35:716
HEPATIC ENCEPHALOPATHY – NOMENCLATURE
Encephalopathy of acute liver failure (Type A)
Encephalopathy of acute liver failure (Type A)
Rapid deterioration in the level of consciousness
Increased intracranial pressure (ICP) Reduced cerebral perfusion pressure Neuropathologically, there is brain edema Pathogenesis is multifactorial with
ammonia playing a major role
Rapid deterioration in the level of consciousness
Increased intracranial pressure (ICP) Reduced cerebral perfusion pressure Neuropathologically, there is brain edema Pathogenesis is multifactorial with
ammonia playing a major role
Type C Hepatic Encephalopathy is the
Encephalopathy of Cirrhosis
Type C Hepatic Encephalopathy is the
Encephalopathy of Cirrhosis Neuropsychiatric complication of cirrhosis
Results from spontaneous or surgical / radiological portal-systemic shunt + chronic liver failure
Failure to metabolize neurotoxic substances
Alterations of astrocyte morphology and function (Alzheimer type II astrocytosis)
Neuropsychiatric complication of cirrhosis
Results from spontaneous or surgical / radiological portal-systemic shunt + chronic liver failure
Failure to metabolize neurotoxic substances
Alterations of astrocyte morphology and function (Alzheimer type II astrocytosis)
TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS
Treatment: rarely effective short of liver transplant
Treatment: rarely effective short of liver transplant
Characteristics of Type A vs. Type C Hepatic Encephalopathy
Characteristics of Type A vs. Type C Hepatic Encephalopathy
Gradual onset
Rarely fatal
Main cause: shunting / toxin
Precipitant
Treatment: usually effective
Gradual onset
Rarely fatal
Main cause: shunting / toxin
Precipitant
Treatment: usually effective
Rapid onset
Frequently fatal
Main cause:cerebral edema
Rapid onset
Frequently fatal
Main cause:cerebral edema
Type AType A Type CType C
CHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY
Pathophysiology of Hepatic Encephalopathy
Ammonia
Upregulation of astrocytic peripheral
benzodiazepine receptors (PBR)
Neurosteroid production
Modulation of GABAA receptor
Hepatic encephalopathy
Ammonia
Upregulation of astrocytic peripheral
benzodiazepine receptors (PBR)
Neurosteroid production
Modulation of GABAA receptor
Hepatic encephalopathy
PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
Hepatic Encephalopathy Pathogenesis
Hepatic Encephalopathy Pathogenesis
Bacterial actionProtein load
Bacterial actionProtein load
Failure to metabolize
NH3
Failure to metabolize
NH3
NH3 Shunting
NH3 Shunting
GABA-BD receptorsGABA-BD receptors
ToxinsToxins
PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
Pathogenesis of Hepatic Encephalopathy: role of GABA-BD receptors
Hepatic Encephalopathy Is A Clinical Diagnosis
Hepatic Encephalopathy Is A Clinical Diagnosis
Clinical findings and history important
Ammonia levels are unreliable
Ammonia has poor correlation with diagnosis
Measurement of ammonia not necessary
Number connection test
Slow dominant rhythm on EEG
Clinical findings and history important
Ammonia levels are unreliable
Ammonia has poor correlation with diagnosis
Measurement of ammonia not necessary
Number connection test
Slow dominant rhythm on EEG
HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS
Stage Mental state Neurologic signsStage Mental state Neurologic signs
1 Mild confusion: limited attention Incoordination, tremor,
span, irritability, inverted sleep impaired handwritingpattern
2 Drowsiness, personality changes, Asterixis, ataxia, intermittent
disorientation dysarthria
3 Somnolent, gross disorientation, Hyperreflexia, musclemarked confusion, slurred speech rigidity, Babinski sign
4 Coma No response to pain, decerebrate posture
1 Mild confusion: limited attention Incoordination, tremor,
span, irritability, inverted sleep impaired handwritingpattern
2 Drowsiness, personality changes, Asterixis, ataxia, intermittent
disorientation dysarthria
3 Somnolent, gross disorientation, Hyperreflexia, musclemarked confusion, slurred speech rigidity, Babinski sign
4 Coma No response to pain, decerebrate posture
Stages of Hepatic EncephalopathyStages of Hepatic Encephalopathy
STAGES OF HEPATIC ENCEPHALOPATHYSTAGES OF HEPATIC ENCEPHALOPATHY
Ong et al., Am J Med 2003; 114:188Ong et al., Am J Med 2003; 114:188
Poor Correlation of Ammonia Levels With Presence or Severity of
Encephalopathy
Venous total
ammoniamol/L
Venous total
ammoniamol/L
00
400400
350350
300300
250250
200200
150150
100100
5050
Grade 0Grade 0 Grade 1Grade 1 Grade 2Grade 2 Grade 3Grade 3 Grade 4Grade 4
Severity of Hepatic EncephalopathySeverity of Hepatic Encephalopathy
“Blood ammonia levels cause as much confusion in those requesting the measurement as in the patients in whom they are being measured”
“Blood ammonia levels cause as much confusion in those requesting the measurement as in the patients in whom they are being measured”
Adrian ReubenHepatology 2002;35:983
Adrian ReubenHepatology 2002;35:983
BLOOD AMMONIA LEVELS ONLY LEAD TO CONFUSION
Minimal Hepatic Encephalopathy
Occurs in 30-70% of cirrhotic patients without overt hepatic encephalopathy
Detected by psychometric and neuro-psychological testing
May improve with lactulose or synbiotics (probiotics and fermentable fiber)
Predicts overt encephalopathy
Occurs in 30-70% of cirrhotic patients without overt hepatic encephalopathy
Detected by psychometric and neuro-psychological testing
May improve with lactulose or synbiotics (probiotics and fermentable fiber)
Predicts overt encephalopathy
MINIMAL HEPATIC ENCEPHALOPATHY
Treatment of Hepatic Encephalopathy
Treatment of Hepatic Encephalopathy
Identify and treat precipitating factor Infection GI hemorrhage Prerenal azotemia Sedatives Constipation
Lactulose (adjust to 2-3 bowel movements/day)
Protein restriction, short-term (if at all)
Identify and treat precipitating factor Infection GI hemorrhage Prerenal azotemia Sedatives Constipation
Lactulose (adjust to 2-3 bowel movements/day)
Protein restriction, short-term (if at all)
TREATMENT OF HEPATIC ENCEPHALOPATHY
Actions of LactuloseActions of Lactulose
LactuloseLactulose
Lactic acidLactic acid
Decreased pHDecreased pHNH3NH3
Urease-producing bacteria
Urease-producing bacteria
Increase cathartic effectIncrease cathartic effect
NH3NH3
NH4+NH4+
ACTIONS OF LACTULOSE
Córdoba, J Hepatology 2004; 91:38Córdoba, J Hepatology 2004; 91:38
DayDay00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414
Hepatic encephalopath
y stage
Hepatic encephalopath
y stage
00
11
22
33
44
Hypoproteic dietHypoproteic dietNormoproteic diet Normoproteic diet
Protein Restriction Is Not Necessary in Hepatic Encephalopathy
Protein Restriction Is Not Necessary in Hepatic Encephalopathy
PROTEIN RESTRICTION IS NOT NECESSARY IN HEPATIC ENCEPHALOPATHY
Variceal Bleed
Monitor Liver FunctionPT, Alb, Bili q 3-6 months
Hepatoma SurveillanceU/S, AFP q 6 months
Varices Surveillance
Compensated Decompensated
Encephalopathy
Treatment Recommendations - Cirrhosis
SBP Ascites HRS
(Garcia-Tsao G, 2003)
Maintain nutrition/reduce salt intakeMaintain nutrition/reduce salt intake
Prevent bone lossPrevent bone loss
Prevent bleedingPrevent bleeding
Prevent encephalopathyPrevent encephalopathy
High index suspicion for sepsisHigh index suspicion for sepsis
Close control diabetesClose control diabetes
Management of complicationsManagement of complications
Early diagnosis and therapy of HCCEarly diagnosis and therapy of HCC
(Selected antiviral therapy)(Selected antiviral therapy)
Appropriate referral to transplant centresAppropriate referral to transplant centres
Management of cirrhosisManagement of cirrhosis
Natural History of Cirrhosis in Natural History of Cirrhosis in 2008: Altered by What We Do2008: Altered by What We Do
More aggressive screening HCC identified earlier Ablative therapies for HCC (down-
staging) Obliteration of varices/beta-
blockade TIPSS Liver Transplantation
Hepatic EncephalopathyTreatment: Summary
Hepatic EncephalopathyTreatment: Summary
Decrease ammonia production in gut: Lactulose Antibiotics Adjustment in
dietary protein
Decrease ammonia production in gut: Lactulose Antibiotics Adjustment in
dietary protein
Increase ammonia fixation in liver: Ornithine aspartate Benzoate
Increase ammonia fixation in liver: Ornithine aspartate Benzoate
Shunt occlusion or reduction
Shunt occlusion or reduction
HEPATIC ENCEPHALOPATHY – TREATMENT SUMMARY
Liver TransplantLiver Transplant
Decompensated cirrhosis - all causes
(hepatitis C most common indication)
Intrahepatic malignancy
Acute liver failure
Metabolic disease
Decompensated cirrhosis - all causes
(hepatitis C most common indication)
Intrahepatic malignancy
Acute liver failure
Metabolic disease
Extrahepatic malignancy
Active infection
Active substance abuse
Advanced cardiopulmon-ary disease
Extensive portal venous thrombosis
Extrahepatic malignancy
Active infection
Active substance abuse
Advanced cardiopulmon-ary disease
Extensive portal venous thrombosis
IndicationsIndications ContraindicationsContraindications
Child score and survival in 424 patients
Child score and survival in 424 patients
Days
16001400120010008006004002000
Cum
Sur
viva
l1.0
.8
.6
.4
.2
0.0
CPT - A
CPT - B
CPT - C
OLT 1-yr survivalOLT 1-yr survival
OLT 2-yr survivalOLT 2-yr survival
Heumann et alHeumann et al
100100
6060
00
8080
4040
2020
00 22 44 66 88 1010
Months from listingMonths from listing
Probability of
survival(%)
Probability of
survival(%)
1212
<15<15
15 - 2015 - 20
20 - 2920 - 29
30+30+
92.3%92.3%
90.7%90.7%
66.0%66.0%
33.8%33.8%
MELD and Survival on Transplant Waiting List
Organ Allocation for Liver Transplant
Organ Allocation for Liver Transplant
Fulminant hepatic failure has highest priority
MELD score determines priority in cirrhosis
Amongst patients with same blood type, highest MELD score determines priority
Waiting time used only to break ties with identical MELD scores
MELD scores are updated at regular intervals
Fulminant hepatic failure has highest priority
MELD score determines priority in cirrhosis
Amongst patients with same blood type, highest MELD score determines priority
Waiting time used only to break ties with identical MELD scores
MELD scores are updated at regular intervals
United Network for Organ Sharing (UNOS) Regions
United Network for Organ Sharing (UNOS) Regions
2299
11
1111
33
1010
77
88
44
55
66
Current 1- and 3-year survival rates are 90% and 80%, respectively
During 2005, ~6,000 liver transplantations were performed
During 2005, ~17,000 patients were on the waiting list and ~2,000 died on it or were removed from it because they became too sick for transplant
Main problem is the shortage of donors Expansion of donor pool: marginal livers,
split-livers, live donors
Current 1- and 3-year survival rates are 90% and 80%, respectively
During 2005, ~6,000 liver transplantations were performed
During 2005, ~17,000 patients were on the waiting list and ~2,000 died on it or were removed from it because they became too sick for transplant
Main problem is the shortage of donors Expansion of donor pool: marginal livers,
split-livers, live donors
Liver Transplantation in the U.S.Liver Transplantation in the U.S.
Compensatedcirrhosis
Compensatedcirrhosis
Decompensatedcirrhosis
Decompensatedcirrhosis
Development of cirrhosis
Development of cirrhosis
Orthotopic liver
transplant (OLT)
Orthotopic liver
transplant (OLT)
DeathDeath
Median survival~ 9 years
Median survival~ 9 years
Median survival
~ 1.6 years
Median survival
~ 1.6 years
Chronic liver
disease
Chronic liver
disease
Development of
complications:
Development of
complications:
Variceal hemorrhage
Ascites Encephalopathy Jaundice
Variceal hemorrhage
Ascites Encephalopathy Jaundice
Natural History of Chronic Liver Disease
NATURAL HISTORY OF CHRONIC LIVER DISEASE – SUMMARY
Liver biopsy Clinical/LSS Liver biopsy Clinical/LSS
Large varices beta-blockers Small varices EGD in 1-2 yrs No varices EGD in 2-3 yrs
Large varices beta-blockers Small varices EGD in 1-2 yrs No varices EGD in 2-3 yrs
Ultrasound and AFP q 6 mos Ultrasound and AFP q 6 mos
Measures to stop alcohol use Hep A and B vaccination Measures to stop alcohol use Hep A and B vaccination
Compensatedcirrhosis
Compensatedcirrhosis
Decompensatedcirrhosis
Decompensatedcirrhosis
Orthotopic liver
transplant (OLT)
Orthotopic liver
transplant (OLT)
DeathDeathChronic
liver disease
Chronic liver
diseaseDiagnosis:Diagnosis:
Screen for varices (EGD):Screen for varices (EGD):
Screen for HCC:Screen for HCC:
Management of Compensated Cirrhosis
MANAGEMENT OF COMPENSATED CIRRHOSIS – SUMMARY
Compensatedcirrhosis
Compensatedcirrhosis
Decompensatedcirrhosis
Decompensatedcirrhosis
Orthotopic liver
transplant (OLT)
Orthotopic liver
transplant (OLT)
DeathDeathChronic
liver disease
Chronic liver
disease
Diagnosis:Diagnosis:
Treatment:Treatment:
Early diagnosis of SBP:Early diagnosis of SBP:
Clinical US or CAT scan
Clinical US or CAT scan
Spironolactone-based No NSAIDs
Spironolactone-based No NSAIDs
Paracentesis q admission or with symptoms No aminoglycosides in
SBP
Paracentesis q admission or with symptoms No aminoglycosides in
SBP
AscitesAscites
Management of AscitesManagement of Ascites
MANAGEMENT OF ASCITES – SUMMARY
Compensatedcirrhosis
Compensatedcirrhosis
Decompensatedcirrhosis
Decompensatedcirrhosis
Orthotopic liver
transplant (OLT)
Orthotopic liver
transplant (OLT)
DeathDeathChronic
liver disease
Chronic liver
disease
Diagnosis / Treatment:Diagnosis / Treatment:
Other Treatment:Other Treatment:
Prophylaxis of rebleed:Prophylaxis of rebleed:
Variceal BleedVariceal Bleed
Endoscopy within 12 hrs
Endoscopy within 12 hrs
Prophylactic antibiotics Prophylactic antibiotics
Beta-blockers prior to d/c or
Serial ligation post d/c
Beta-blockers prior to d/c or
Serial ligation post d/c
Management of Variceal Bleeding
MANAGEMENT OF VARICEAL BLEEDING – SUMMARY
Compensatedcirrhosis
Compensatedcirrhosis
Decompensatedcirrhosis
Decompensatedcirrhosis
Orthotopic liver
transplant (OLT)
Orthotopic liver
transplant (OLT)
DeathDeathChronic
liver disease
Chronic liver
disease
DiagnosisDiagnosis
Treatment:Treatment:
EncephalopathyEncephalopathy
Clinical Clinical
D/C diuretics D/C sedatives Dx paracentesis
D/C diuretics D/C sedatives Dx paracentesis
No long-term protein restriction
No long-term protein restriction
Management of Encephalopathy
MANAGEMENT OF HEPATIC ENCEPHALOPATHY - SUMMARY
Cenni di terapia dell’ipertensione portale
• Farmaci antifibrotici: una promessa ancora non mantenuta
• L’unica terapia in grado di modificare la progressione è, al momento, il trattamento del fattore etiologico di base (es no Et-OH)
• Il target della terapia è quello di ridurre, farmacologicamente o “chirurgicamente” il gradiente venoso porto-epatico
• L’end-point clinico è la prevenzione primaria o secondaria del sanguinamento da varici
Terapia dell’ipertensione portale
• Vasocostrittori arteriolari splancnici
• Beta bloccanti non selettivi
• Vasopressina ed analoghi
• Somatostatina ed analoghi
• Terapia Endoscopica
• Scleroterapia
• Legatura
• Terapia Chirurgica
• H shunt (mesocavale)
• Splenorenale distale
• TIPS
Mediatori vasoattivi nella ipertensione portale
VASODILATATORI
• Glucagone
• Prostaciclina
• Adenosina
• Fattore Natriuretico Atriale
• VIP
• Endotossine
• TNF• NO
VASOCOSTRITTORI
• Norepinefrina
• Serotonina
• Endotelina
• Angiotensina II
• Vasopressina
• No specific treatment, only reduction of dietary sodium intake
Treatment of ascites: Grade 1 Ascites
• Bed rest unproven benefit
• Dietary sodium restriction to 5.2 g/d (90 mmol)
• Diuretics Anti-Mineralocorticoids Spironolactone, Canrenoate,
Canrenone
Loop diuretics Furosemide, Torasemide, Ethacrynic Acid
Other potassium-sparing diuretics Amiloride, Triamterene
Treatment of ascites: Grade 2 Ascites
• Spironolactone: alone at first, 100-200 mg/d once• Adequate response: weight loss = - 0.5 kg/d (1 kg/d if
peripheral edema)• If not adequate response: stepwise increase • If failure to spironolactone 200 mg/d after 2-3 wks: + Furosemide (20-40 mg/d) • If failure: maximal doses of spironolactone 400 mg/d +
furosemide 160 mg/d• Canrenoate, Amiloride (5-30 mg/d), or Torasemide
may be used alternatively
Treatment of ascites: use of Diuretics in Grade 2 Ascites
• Electrolyte imbalance (hyponatremia, hypo/hyperkalemia, metabolic acidosis, metabolic hypochloremic alkalosis)
if hyperkalemia > 6 mmol/l: stop spironolactone
if hypokalemia < 3.5 mmol/l: stop furosemide
• Renal impairment• Hepatic Encephalopathy• Gynecomastia• Testis hypotrophia• Muscle cramps (also related to effective hypovolemia):
may benefit from albumin, Zn sulfate
Treatment of ascites: Complications of diuretic therapy
• Severe hyponatremia (< 120 mmol/l)
• Renal impairment (serum creatinine > 150 umol/l)
• Active bacterial infection
Treatment of ascites: Contraindications of diuretic therapy
• Paracentesis, followed by
• Sodium restriction
• Diuretic therapy
to reduce the risk of recurrence within 4 wks (90% vs 20%)
Treatment of ascites: Grade 3 Ascites
• Effective and safe in single session
• All ascitic fluid may be removed, even though in large amount
• Plasma volume expansion once paracentesis has been completed
Plasma substitute if paracentesis < 5 lAlbumin if paracentesis > 5 l (6-8 g/l of ascites
removed)
Treatment of ascites: use of Paracentesis in Grade 3 Ascites
• Severe coagulopathy or marked thrombocytopenia (< 50.000/ml)
• Previous surgery or peritoneal adhesions (risk of bowel perforations)
• Bleeding (may be fatal)• Leakage of ascitic fluid• Renal impairment
Treatment of ascites: Contraindications and complications of
paracentesis
• Repeated total paracentesis, followed by
• Sodium restriction
• Diuretic therapy (if tolerated; stop when urine sodium output < 30 mmol/d)
• TIPS (if paracentesis are not tolerated any more)
Treatment of ascites: Refractory Ascites
• No published controlled trials• Water restriction is ineffective• Plasma volume expansion with colloids
may have some benefit• Vasopressin-2 receptor antagonists seem
to be promising
Treatment of dilutional hyponatremia
Therapy of Hepatorenal Syndrome:present and future
• Liver Transplantation
• Vasopressin Analogues
• α-Adrenergic Agonists
• Molecular Adsorbent Recirculating System
Therapy of Hepatorenal Syndrome:Vasopressin Analogues (Ornipressin, Terlipressin)
• Rationale: increase of splanchnic and systemic vascular resistance, resulting in a redistribution of the circulating blood volume, via suppression of the RAA and sympathetic activities
• Useful in combination with albumin and low-dose dopamin
Therapy of Hepatorenal Syndrome:α-Adrenergic Agonists (midodrine)
• Rationale: improvement of systemic vasoconstriction and urinary sodium excretion
• Effective in combination with plasma volume expansion and octreotide (an inhibitor of the release of endogenous vasodilators)
HE:FATTORI PRECIPITANTI
• ABUSO DI FARMACI (diuretici, sedativi, oppiati)• INFEZIONI INTERCORRENTI• ECCESSO DI ALCOL / PROTEINE• EMORRAGIA DIGESTIVA• INTERVENTI CHIRURGICI• COPROSTASI• IPERAZOTEMIA• ALCALOSI IPOKALIEMICA• HCC
HE: TERAPIA MEDICA
• IDENTIFICARE FATTORE PRECIPITANTE• LIMITARE INTROITO PROTEICO• LATTULOSIO (attenzione meteorismo!)• ANTIBIOTICI TOPICI (Paromomicina,
Rifaximina)• CLISTERINI MEDICATI sistematicamente!!!