1. 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

2. CIRROSI
Alterazione dell’architettura del fegato caratterizzata da noduli e formazione di tessuto collagene
CAUSE: Tutte le cause di danno epatico cronico

3. Progressione del danno epatico cronico
Causa
iniziale
Stadio
finale
Complicanze ●
anni
Fibrosi
Distorsione dell’architettura
epatica
Cirrosi

4. Hepatic Artery
Portal
Vein
Sinusoids
Bile Duct
Central Veins

5. Changes of hepatic microcirculation in cirrhosis
Normal
Cirrhosis
Changes of hepatic microcirculation in cirrhosis

6. Activation of HSC

7. LIVER CIRRHOSIS : from activation of HSC to cirrhotic nodules

8. – Necrosi a ponte porto-centrale
Fibrosi virale
Spazio portale
– Necrosi a ponte porto-centrale
2. – Epatite da interfaccia e sviluppo di setti che circondano il parechima
3. – Perdita di connessioni vascolari con il sistema portale

9. Formazione di setti porto-portali La vena centrolobulare è conservata
fibrosi biliare
Spazio portale
Modello BDL
CBP
CB secondaria
CSP
Formazione di setti porto-portali
La vena centrolobulare è conservata

10. – Secondary to venous outflow problems (e.g. chronic heart failure)
Centrolobular
fibrosis
portal tract
– Secondary to venous outflow problems (e.g. chronic heart failure)
2. - Chronic ETOH consumption
3. – Development of central to central septa and “reversed lobulation”

11. CONSEQUENCES OF DEVELOPING PROGRESSIVE HEPATIC FIBROSIS
structural & functional
intrahepatic resistance
 splanchnic blood flow
(cirrhosis)
HCC
systemic
hyperdynamic circulation
portal hypertension
decrease central
volume
portosystemic collaterals
variceal bleeding
HRS
ascites
hepatic encephalopathy
cardiac output
cardiomyopathy
spontaneous
bacterial peritonitis
hepatopulmonary syndrome

12. 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

13. 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
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

14. 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

15. 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

16. PORTAL HYPERTENSION: pathophysiological sequelae
structural & functional
intrahepatic resistance
 splanchnic blood flow
(cirrhosis)
HCC
systemic
hyperdynamic circulation
portal hypertension
decrease central
volume
portosystemic collaterals
variceal bleeding
HRS
ascites
hepatic encephalopathy
cardiac output
cardiomyopathy
spontaneous
bacterial peritonitis
hepatopulmonary syndrome

17. 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

18. Circoli collaterali Ligamento falciforme Gastro-esofagei
Parete addome e retro
peritoneo
Gastro-esofagei
Vene emorroidarie

19. 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

20. Complicanze maggiori della cirrosi

22. Complicanze maggiori della cirrosi

23. Natural History of Chronic Liver Disease Development of cirrhosis
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Orthotopic liver transplant (OLT)
Development of complications:
NATURAL HISTORY OF CHRONIC LIVER DISEASE – SUMMARY
Variceal hemorrhage
Ascites
Encephalopathy
HRS

24. Mortalità per complicanze di cirrosi epatica - 384 Pts
follow-up: 5 anni
Fattovich G et al, Gastroenterology 1997;112:463

25. Child-Turcotte-Pugh (CTP) Score
Points
1 2 3
Encephalopathy None Grade 1-2 Grade 3-4
(precipitant) (chronic)
Ascites None Mild Moderate
Bilirubin (mg/dl) < >3
Albumin (g/dl) > <2.8
PT (seconds prolonged) < >6
or INR < >2.3
CHILD-TURCOTTE-PUGH (CTP) SCORE
The CTP (or Child) score is based on five parameters: encephalopathy, ascites, bilirubin, albumin and prothrombin time. Each parameter is graded from 1 to 3, therefore the minimal score is 5 and the maximal score is 15. Patients can be listed for liver transplantation if they meet minimal listing criteria, that is, a Child-Pugh-Turcotte score of 7.
Child A: 5-6 pts Child B: 7-9 pts Child C: pts
MINIMAL LISTING CRITERIA: CTP SCORE  7 POINTS

26. MELD (Model for End-Stage Liver Disease)
Predicts 3-month mortality among patients with chronic liver disease on the liver waiting list
MELD = (0.957 x LN (creatinine) x LN (bilirubin) x LN (INR) ) x 10
Minimum score = 6 (risk of death on WL 20%)
Maximum score = 40 (risk of death on WL 100%)

27. Diagnostica della cirrosi con ipertensione portale
Clinico-semeiologica
Misurazione invasiva emodinamica portale
Eco-doppler
Endoscopia digestiva

28. Diagnosi clinico-semeiologica
Splenomegalia
Circoli collaterali superficiali
Gavoccioli emorroidari
Spider Naevi
Edema perimalleolare
Ascite
Asterixis

29. Semeiotica dell’ipertensione portale

33. Definition 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

35. Treatment of 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

36. Diagnostic Criteria of Refractory 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

37. PERITONITE BATTERICA SPONTANEA: definizione ed epidemiologia
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)

38. PERITONITE BATTERICA SPONTANEA: forme cliniche
Classic
CNNA (culture negative neutrocytic ascites)
MNB (monomicrobial non-neutrocytic bacterascites)  carcinosi peritoneale, pancreatite, peritonite TBC
Classica
CNNA
MNB
PMN
> 250
< 250
Colturale + -

39. PERITONITE BATTERICA SPONTANEA: terapia e profilassi
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

41. 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

42. 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
Precipitated
Onset

43. 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

44. 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

45. The Pathophysiology of HRS

47. Diagnosi e classificazione endoscopica
Varici esofagee
Varici fondo

48. Diagnosi e classificazione endoscopica
Gastropatia ipertensiva
GAVE

49. Dilation and Rupture of Varices
Varix P
Flow
Recently, we and others have suggested that changes in portal pressure associated with daily activities may contribute to the proggesive dilatation that precedes the rupture of the varices.
This is because meals and alcoholic beverages cause brisk increases in portal pressure and blood flow, due to the postprandial hyperemia. Similarly, portal pressure increases markedly by even mild exercise and by activities increasing the intra-abdominal pressure.
These repeat bumps in portal pressure cause acute incremets of variceal size, contributing to its proggresive dilatation, coming closer to the lighting point for the explosion of the varices.
Risk increases in portal pressure and collateral blood flow caused by:
Meals
Alcohol
Exercise
Increased intra-abdominal pressure

50. Acute variceal bleeding Sclerotherapy + Drugs vs Sclerotherapy alone Mortality

51. PREVENZIONE RISANGUINAMENTO (profilassi secondaria)
BB + nitrati
fallimento
LEV(+ BB)
successo
fallimento
successo
continuare
Malattia epatica
avanzata
Malattia epatica
stabile
Continuare
+ follow up
TIPS
OLT
TIPS (DSSR)
D´Amico, 2004

52. HEPATIC ENCEPHALOPATHY – NOMENCLATURE
Type A
Associated with Acute liver failure
Type B
Associated with porto-systemic Bypass without intrinsic hepatocellular disease
Type C
Associated with Cirrhosis and porto-systemic shunting
Slide 346
HEPATIC ENCEPHALOPATHY – NOMENCLATURE
Hepatic encephalopathy is subdivided into type A associated with acute liver failure, type B associated with portosystemic bypass without intrinsic hepatocellular disease (portosystemic shunts), and type C when associated with cirrhosis and portosystemic shunting.
Ferenci et al., Hepatology 2002; 35:716
Ferenci et al., Hepatology 2002; 35:716

53. 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

54. 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)
Slide 348
TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS
In cirrhosis, hepatic encephalopathy results from a combination of portosystemic shunting and failure to metabolize neurotoxic substances. Astrocytes are the only cells in the brain that can metabolize ammonia and, in hepatic encephalopathy, changes in the astrocytes are seen (Alzheimer’s type II astrocytosis).

55. CHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY
Characteristics of Type A vs. Type C Hepatic Encephalopathy
Type A
Type C
Rapid onset
Frequently fatal
Main cause:
cerebral edema
Gradual onset
Rarely fatal
Main cause:
shunting / toxin
Precipitant
Treatment: usually effective
Slide 347
CHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY
Type A hepatic encephalopathy is of rapid onset, frequently fatal, and related to cerebral edema. Liver transplantation is the most effective treatment. Type C is of gradual onset, rarely fatal, and is caused by porto-systemic shunting. A precipitating cause can often be found and treatment is usually effective.
Treatment: rarely effective short of liver transplant

56. PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
Ammonia
Upregulation of astrocytic peripheral
benzodiazepine receptors (PBR)
Neurosteroid production
Modulation of GABAA receptor
Hepatic encephalopathy
Slide 349
PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
Ammonia, which crosses the blood-brain barrier, results in up-regulation of astrocytic peripheral-type benzodiazepine receptors which are the most potent stimulants of neurosteroid production. Neurosteroids are the major modulators of GABA, which results in cortical depression and hepatic encephalopathy.

57. PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
Hepatic Encephalopathy Pathogenesis
Toxins
NH3 Shunting
Failure to metabolize NH3
GABA-BD
receptors
Slide 350
PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
This slide demonstrates how ammonia bypasses the liver, either through porto-systemic collaterals or through a created shunt (transjugular intrahepatic porto-systemic shunt) and ultimately reaches the brain.
Bacterial action
Protein load

58. Pathogenesis of Hepatic Encephalopathy: role of GABA-BD receptors

59. 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
Slide 351
HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS.
The diagnosis of hepatic encephalopathy is based on history and physical exam findings. Ammonia levels are unreliable, and there is a poor correlation between the stage of encephalopathy and blood level of ammonia. Therefore, measurements of ammonia are not necessary. Psychometric tests such as the number connection test and the EEG are typically used in research studies and not for clinical diagnosis.

60. STAGES OF HEPATIC ENCEPHALOPATHY
Stage Mental state Neurologic signs
1 Mild confusion: limited attention Incoordination, tremor,
span, irritability, inverted sleep impaired handwriting
pattern
2 Drowsiness, personality changes, Asterixis, ataxia, intermittent disorientation dysarthria
3 Somnolent, gross disorientation, Hyperreflexia, muscle
marked confusion, slurred speech rigidity, Babinski sign
4 Coma No response to pain,
decerebrate posture
Slide 352
STAGES OF HEPATIC ENCEPHALOPATHY
These clinical stages of hepatic encephalopathy depend on the mental state and neurological signs.

61. Severity of Hepatic Encephalopathy
Poor Correlation of Ammonia Levels With Presence or Severity of Encephalopathy
400
350
300
250
Venous total ammonia
mmol/L
200
150
POOR CORRELATION OF AMMONIA LEVELS WITH PRESENCE OR SEVERITY OF HEPATIC ENCEPHALOPATHY
This slide demonstrates the poor correlation between the severity of hepatic encephalopathy and venous ammonia levels. Patients with grade 0 encephalopathy (i.e. no encephalopathy) have ammonia levels that overlap with those with overt encephalopathy stages 1-3. It would be reasonable to obtain ammonia levels in patients admitted with coma (stage 4) of unknown etiology.
100 50
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Severity of Hepatic Encephalopathy
Ong et al., Am J Med 2003; 114:188

62. BLOOD AMMONIA LEVELS ONLY LEAD TO CONFUSION
“Blood ammonia levels cause as much confusion in those requesting the measurement as in the patients in whom they are being measured”
Slide 356
BLOOD AMMONIA LEVELS ONLY LEAD TO CONFUSION
Adrian Reuben
Hepatology 2002;35:983

63. 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
Slide 359
MINIMAL HEPATIC ENCEPHALOPATHY
Minimal hepatic encephalopathy (formerly called “sub-clinical” hepatic encephalopathy) occurs in about 30-70% of patients with cirrhosis without overt hepatic encephalopathy. Minimal hepatic encephalopathy is detected by psychometric and neuropsychological testing alone. Minimal HE may improve with lactulose or synbiotics.

64. 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)
Slide 361
TREATMENT OF HEPATIC ENCEPHALOPATHY
Treatment of hepatic encephalopathy involves 1) identifying and treating the precipitating factor, and 2) using lactulose adjusted to produce 2-3 bowel movements per day. Protein restriction is carried out typically when patients have stage 4 hepatic encephalopathy, but may not be necessary. Long-term protein restriction is not required. A vegetable protein diet is better tolerated than an animal protein diet.

65. Actions of Lactulose NH3 Decreased pH NH4+ Lactic acid NH3 Lactulose
Slide 363
ACTIONS OF LACTULOSE
Lactulose acts by several mechanisms. The acidic pH decreases urease-producing bacteria which produce ammonia. The proton H+ produced combines with NH3 to give NH4, which is non-absorbable, and results in ammonia excretion in stool. The cathartic effect of lactulose is also helpful. It is important to note that data supporting the benefit of lactulose in hepatic encephalopathy are lacking.
Urease-producing bacteria
Increase cathartic effect

66. PROTEIN RESTRICTION IS NOT NECESSARY IN HEPATIC ENCEPHALOPATHY4
Hypoproteic diet
Normoproteic diet 3 2
Hepatic encephalopathy stage 1
Slide 364
PROTEIN RESTRICTION IS NOT NECESSARY IN HEPATIC ENCEPHALOPATHY
In a double-blind, placebo-controlled study performed in 30 patients with acute hepatic encephalopathy, patients were randomized to a normoproteic diet (yellow line) or a hypoproteic diet (blue line). Otherwise, treatment of encephalopathy was routine in both groups. As shown in the slide, there were no differences in the course of hepatic encephalopathy between study groups. Therefore, the study concludes that protein restriction is not necessary in the management of hepatic encephalopathy.
Córdoba et al. J Hepatol 2004; 91:38 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Day
Córdoba, J Hepatology 2004; 91:38

67. Treatment Recommendations - Cirrhosis
Compensated
Decompensated
Hepatoma Surveillance
U/S, AFP q 6 months
Varices Surveillance
Monitor Liver Function
PT, Alb, Bili q 3-6 months
Variceal Bleed
SBP
Ascites
HRS
Encephalopathy
(Garcia-Tsao G, 2003)

68. Management of cirrhosis
Maintain nutrition/reduce salt intake
Prevent bone loss
Prevent bleeding
Prevent encephalopathy
High index suspicion for sepsis
Close control diabetes
Management of complications
Early diagnosis and therapy of HCC
(Selected antiviral therapy)
Appropriate referral to transplant centres

69. Natural History of Cirrhosis in 2008: 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

71. HEPATIC ENCEPHALOPATHY – TREATMENT SUMMARY
Increase ammonia fixation in liver:
Ornithine aspartate
Benzoate
Shunt occlusion or reduction
Slide 365
HEPATIC ENCEPHALOPATHY – TREATMENT SUMMARY
Hepatic encephalopathy can be treated with agents aimed at decreasing ammonia production in the gut. This strategy includes lactulose or non-absorbable antibiotics such as neomycin, metronidazole, or rifaximin. Change in dietary protein from an animal source to a vegetable source may also be beneficial. L-ornithine L-aspartate and benzoate may increase ammonia fixation in the liver. In patients who have a large portosystemic shunt in the absence of liver disease, occlusion of the shunt may be carried out.
Decrease ammonia production in gut:
Lactulose
Antibiotics
Adjustment in dietary protein

72. Liver Transplant Indications Contraindications
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
LIVER TRANSPLANT – INDICATIONS AND CONTRAINDICATIONS
Indications for liver transplantation include cirrhosis of the liver of all causes, intrahepatic malignancy (such as hepatocellular carcinoma), acute liver failure, and metabolic disease such as Wilson’s disease and oxalosis. Extrahepatic malignancy, active infection, substance abuse, cholangiocarcinoma, and non-hepatic comorbidity may be contraindications to transplantation.

74. Child score and survival in 424 patients
1.0
CPT - A .8 .6
CPT - B .4
CPT - C .2
Cum Survival
0.0
200
400
600
800
1000
1200
1400
1600
OLT 1-yr survival
OLT 2-yr survival
Days
Heumann et al

75. MELD and Survival on Transplant Waiting List Probability of survival
100
92.3%
90.7%
<15 80 60
66.0%
Probability of survival
(%) 40
33.8%
30+
MELD AND SURVIVAL ON TRANSPLANT WAITING LIST
This slide demonstrates the relationship between MELD score and risk for 3-month mortality while on the transplant waiting list. The higher the MELD score, the higher the mortality. 20 2 4 6 8 10 12
Months from listing

76. 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
ORGAN ALLOCATION FOR LIVER TRANSPLANT
Within each UNOS region, patients with fulminant hepatic failure have the highest priority. In patients with cirrhosis, the MELD score determines the priority. Among patients with the same blood type, the patient with the highest MELD score gets the priority. Waiting times are used only to break ties when patients have identical MELD scores. MELD scores are updated at regular intervals.

77. United Network for Organ Sharing (UNOS) Regions1 6 7 9 2 10 8 11 5
UNOS REGIONS
There are 11 regions within the United States for organ allocation under the United Network of Organ Sharing (UNOS). 3 4

78. Liver Transplantation in the U.S.
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

79. NATURAL HISTORY OF CHRONIC LIVER DISEASE – SUMMARY
Development of cirrhosis
Chronic liver disease
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Median survival
~ 9 years
Median survival
~ 1.6 years
Development of complications:
Slide 410
NATURAL HISTORY OF CHRONIC LIVER DISEASE – SUMMARY
Orthotopic liver transplant (OLT)
Variceal hemorrhage
Ascites
Encephalopathy
Jaundice

80. MANAGEMENT OF COMPENSATED CIRRHOSIS – SUMMARY
Chronic liver disease
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Diagnosis:
Liver biopsy
Clinical/LSS
Screen for varices (EGD):
Orthotopic liver
transplant (OLT)
Large varices  beta-blockers
Small varices  EGD in 1-2 yrs
No varices  EGD in 2-3 yrs
Slide 411
MANAGEMENT OF COMPENSATED CIRRHOSIS – SUMMARY
Screen for HCC:
Ultrasound and AFP q 6 mos
Measures to stop alcohol use
Hep A and B vaccination

81. MANAGEMENT OF ASCITES – SUMMARY
Chronic liver disease
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Ascites
Diagnosis:
Clinical
US or CAT scan
Orthotopic liver
transplant (OLT)
Treatment:
Slide 412
MANAGEMENT OF ASCITES – SUMMARY
Spironolactone-based
No NSAIDs
Early diagnosis of SBP:
Paracentesis q admission
or with symptoms
No aminoglycosides in SBP

82. MANAGEMENT OF VARICEAL BLEEDING – SUMMARY
Chronic liver disease
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Variceal Bleed
Diagnosis / Treatment:
Endoscopy within 12 hrs
Orthotopic liver
transplant (OLT)
Other Treatment:
Slide 413
MANAGEMENT OF VARICEAL BLEEDING – SUMMARY
Prophylactic antibiotics
Prophylaxis of rebleed:
Beta-blockers prior to d/c or
Serial ligation post d/c

83. MANAGEMENT OF HEPATIC ENCEPHALOPATHY - SUMMARY
Management of Encephalopathy
Chronic liver disease
Compensated
cirrhosis
Decompensated
cirrhosis
Death
Encephalopathy
Diagnosis
Clinical
Orthotopic liver
transplant (OLT)
Treatment:
D/C diuretics
D/C sedatives
Dx paracentesis
Slide 414
MANAGEMENT OF HEPATIC ENCEPHALOPATHY - SUMMARY
No long-term protein restriction

85. 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

86. 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

87. Mediatori vasoattivi nella ipertensione portale
VASODILATATORI
Glucagone
Prostaciclina
Adenosina
Fattore Natriuretico Atriale
VIP
Endotossine
TNF NO
VASOCOSTRITTORI
Norepinefrina
Serotonina
Endotelina
Angiotensina II
Vasopressina

88. Treatment of ascites: Grade 1 Ascites
No specific treatment, only reduction of dietary sodium intake

89. Treatment of ascites: Grade 2 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

90. Treatment of ascites: use of Diuretics in Grade 2 Ascites
Spironolactone: alone at first, mg/d once
Adequate response: weight loss = 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

91. Treatment of ascites: Complications of diuretic therapy
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

92. Treatment of ascites: Contraindications of diuretic therapy
Severe hyponatremia (< 120 mmol/l)
Renal impairment (serum creatinine > 150 umol/l)
Active bacterial infection

93. Treatment of ascites: Grade 3 Ascites
Paracentesis, followed by
Sodium restriction
Diuretic therapy
to reduce the risk of recurrence within 4 wks (90% vs 20%)

94. Treatment of ascites: use of Paracentesis in 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 l
Albumin if paracentesis > 5 l (6-8 g/l of ascites removed)

95. Treatment of ascites: Contraindications and complications of paracentesis
Severe coagulopathy or marked thrombocytopenia (< /ml)
Previous surgery or peritoneal adhesions (risk of bowel perforations)
Bleeding (may be fatal)
Leakage of ascitic fluid
Renal impairment

96. Treatment of ascites: Refractory Ascites
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)

97. Treatment of dilutional hyponatremia
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

98. Therapy of Hepatorenal Syndrome: present and future
Liver Transplantation
Vasopressin Analogues
α-Adrenergic Agonists
Molecular Adsorbent Recirculating System

99. 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

100. 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)

101. HE:FATTORI PRECIPITANTI
ABUSO DI FARMACI (diuretici, sedativi, oppiati)
INFEZIONI INTERCORRENTI
ECCESSO DI ALCOL / PROTEINE
EMORRAGIA DIGESTIVA
INTERVENTI CHIRURGICI
COPROSTASI
IPERAZOTEMIA
ALCALOSI IPOKALIEMICA
HCC

102. HE: TERAPIA MEDICA IDENTIFICARE FATTORE PRECIPITANTE
LIMITARE INTROITO PROTEICO
LATTULOSIO (attenzione meteorismo!)
ANTIBIOTICI TOPICI (Paromomicina, Rifaximina)
CLISTERINI MEDICATI sistematicamente!!!