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!!!