Practical Management of Cirrhotic
Patients with HCC
The hepatologist’s perspective
Natural History of Hepatic Cirrhosis
Cirrhosis
development
Complications
development
Compensated
cirrhosis
Decompensated
cirrhosis
Prognosis
factors
Complications
risk
Survival in
compensated
cirrhosis
Survival after
decompensated
cirrhosis
D’Amico G et al. Journal of Hepatology 2006; 44(1): 217-31
Natural History of Hepatic Cirrhosis
Variceal bleeding
Oesophageal
varices
Spontaneous
bacterial peritonitis
Portal
hypertension
Hepatic
encephalopathy
Ascites
Liver cirrhosis
HCC
Hepatorenal
syndrome
Hypermetabolism
Hepatopulmonary
syndrome
Portopulmonary
hypertension
S.Fagiuoli e Gruppo di lavoro sull’Epatocarcinoma - Gestione della terapia medica dell’epatocarcinoma - Springer 2011
Practical Management of HCC Sorafenib-Treated
Cirrhotic Patients
1. Management of the patient prior to treatment
initiation
2. Management of the hepatopathic patient
during sorafenib treatment
S.Fagiuoli e Gruppo di lavoro sull’Epatocarcinoma - Gestione della terapia medica dell’epatocarcinoma - Springer 2011
Clinical Management of Patients
with Chronic Hepatopathy
1. Management of chronic hepatopathy and treatment
of its causes, in order to prevent or postpone, when
possible, cirrhosis development
2. Management of the patient with compensated liver
cirrhosis; lifestyle, antiviral treatment if indicated,
follow-up and treatment of portal hypertension and its
consequences
3. Management of decompensated cirrhosis (ascites,
SBP and infections, encephalopathy, gastrointestinal
bleeding, hepatorenal syndrome)
S.Fagiuoli e Gruppo di lavoro sull’Epatocarcinoma - Gestione della terapia medica dell’epatocarcinoma - Springer 2011
Management of patients with HCC: the need for a
multidisciplinary approach
Management of HCC requires
consideration of both tumourand liver-related factors
As over 85% of patients with HCC
have liver cirrhosis, treatment
requires input from:
Hepatology
Oncology
 Hepatologist
PATIENT
 Oncologist
Treatment options are diverse
necessitating input from:
 Surgeons (transplantation and
resection)
Surgery
Radiology
 Interventional radiology
S.Fagiuoli e Gruppo di lavoro sull’Epatocarcinoma - Gestione della terapia medica dell’epatocarcinoma - Springer 2011
Summary: HCC – a complex and
challenging disorder
The treatment of HCC must take into account that in
most patients the tumour co-exists with chronic liver
disease
The treatment of HCC requires a multidisciplinary
approach that should include each of the following
disciplines:
 Surgery and transplantation
 Interventional radiology
 Hepatology
 Oncology
Peck-Radosavljevic M, et al. Eur J Gastroenterol Hepatol 2009; epub ahead of print, doi: 10.1097/MEG.0b013e328333df23.
Clinical Management of Patients
with Compensated Liver Cirrhosis
Clinical Management of Patients
with Compensated Liver Cirrhosis
Cirrhosis
Compensated
Basal support
Monitor Liver
Function
Varices
Surveillance
(PT, Alb, Bili q 3-6 months)
Variceal Bleed
SBP
Ascites
Decompensated
Antiviral
treatment
(HBV/HCV)
Hepatorenal
Syndrome
HCC Surveillance
(U/S, AFP q 3-6 months)
Encephalopathy
General Notions – 1
 Healthy lifestyle and adequate diet
 Absolute abstention from toxics (alcohol, drugs, etc..)
 Treatment of potential drugs dependence
 Scheduling and, if necessary, adjustment of antiviral
therapy
 Strict clinical follow-up, both laboratory and
instrumental, according to accurate diagnostic
algorithms
Clinical Management of Patients
with Compensated Liver Cirrhosis
Cirrhosis
Compensated
Basal support
Monitor Liver
Function
Varices
Surveillance
(PT, Alb, Bili q 3-6 months)
Variceal Bleed
SBP
Ascites
Decompensated
Antiviral
treatment
(HBV/HCV)
Hepatorenal
Syndrome
HCC Surveillance
(U/S, AFP q 3-6 months)
Encephalopathy
Portal Hypertension
Superior vena cava
In a cirrhotic patient portal
hypertension is related to:
 Intrahepatic resistances increase
Azygos vein
Esophagus
Esophageal
varices
Volume
increased splein
Inferior vena cava
Suprahepathic vein
 Liver structural alterations
 Loss of vascular bed
Gastric
veins
Portal vein
pressure
increases up to
20-30 mmHg
Splenic vein
Portal pressure increase over 6-10 mmHg (physiological range)
Gradient increase between portal and sovrahepatic pressure
(HVPG) above the normal range (3-5 mmHg)
Linee guida AISF 2006
Gastroesophageal Varices – 1
 Consequences of portal hypertension
 40-90% of cirrhotic patients
– 40% of Child A patients
– 85% of Child C patients
– >85% of HCC patients
 Incidence of varices: 8%
each year
Esophagoscopic
view (at cardia)
Azygos vein
Cirrhotic liver
Diaphragm
 Primary predictive factor
of varices development:
HVPG>10 mmHg
Esophageal branches of left
gastric vein
Short gastric vein
AASLD Practice Guidelines. Hepatology 2007; 46(2): 608-9; Linee guida AISF 2006
Gastroesophageal Varices – 2
 Bleeding at least once in 2040% of cirrhotic patients
 Bleeding incidence: 5-15%
each year
Esophagoscopic
view (at cardia)
Azygos vein
 Primary bleeding predictive
factors: varices size, red color
signs, Child status
Cirrhotic liver
Diaphragm
 Bleeding causes more than
30% of deaths
 30% of cirrhotic patients die
after the first bleeding episode
 2/3 of patients have another
bleeding episode by 1 year
Esophageal branches of left
gastric vein
Short gastric vein
AASLD Practice Guidelines. Hepatology 2007; 46(2): 608-9; Linee guida AISF 2006
Prevention of a First Episode of Bleeding
From Gastroesophageal Varices
Screening EGDS is recommended
at diagnosis of cirrhosis
Absence of varices
Compensated cirrhosis:
EGDS every 3 years
Decompensated cirrhosis: EGDS at the time of
decompensation and then
every year
AASLD Practice Guidelines. Hepatology 2007; 46(2): 608-9; Linee guida AISF 2006
Prevention of a First Episode of Bleeding
From Gastroesophageal Varices
Small varices (<5 mm) that never bleeded
Child A status and absence
of red color signs
Increased risk of haemorrhage
(Child B/C status or varices
with red color signs)
Follow-up (EGDS every year);
nonselective β-blockers
(no long term benefits
demonstrated)
Nonselective β-blockers
AASLD Practice Guidelines. Hepatology 2007; 46(2): 608-9; Linee guida AISF 2006
Prevention of a First Episode of Bleeding
From Gastroesophageal Varices
Medium/large varices that never bleeded
NO haemorrhage risk
Increased risk of haemorrhage
(Child B/C status or varices
with red color signs)
β-blockers
(endoscopic ligation or
intolerance or non compliance)
Nonselective β-blockers
or endoscopic ligation
AASLD Practice Guidelines. Hepatology 2007; 46(2): 608-9; Linee guida AISF 2006
Clinical Management of Patients
with Compensated Liver Cirrhosis
Cirrhosis
Compensated
Basal support
Monitor Liver
Function
Varices
Surveillance
(PT, Alb, Bili q 3-6 months)
Variceal Bleed
SBP
Ascites
Decompensated
Antiviral
treatment
(HBV/HCV)
Hepatorenal
Syndrome
HCC Surveillance
(U/S, AFP q 3-6 months)
Encephalopathy
HBV Cirrhosis and Antiviral Therapy
Specific antiviral therapy recommended in patients
with liver cirrhosis due to replicating B virus infection
HbeAg
HBV DNA (PCR)
ALT
+/-
Detectable
Cirrhosis Compensated:
Treatment strategy
HBV DNA >2,000 IU/ml - Treat, LAM/ADV/ETV/LdT
may be used as initial therapy. LAM and LdT not
preferred due to high rate of drug resistance
HBV DNA <2,000 IU/ml - Consider treatment if ALT
elevated
Decompensated:
Coordinate treatment with transplant center, LAM (or
LdT) + ADV or ETV preferred. Refer for liver transplant
+/-
Undetectable
Cirrhosis
Compensated: Observe.
Decompensated: Refer for liver transplant
Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal; IFN α, interferon alpha; pegIFN-α,
pegylated interferon alpha; LAM, lamivudine; ADV, adefovir; ETV, entecavir; LdT, telbivudine.
Lok AS et al. Hepatology 2007; 45: 507-539; Carosi G, Rizzetto M. Dig Liver Dis 2008, 40: 603-617
HBV Cirrhosis and Antiviral Therapy
Strict laboratoristic follow-up in patients with liver
cirrhosis due to non-replicating B virus infection
HbeAg
HBV DNA (PCR)
ALT
Treatment strategy
+/-
Detectable
Cirrhosis
Compensated:
HBV DNA >2,000 IU/ml-Treat, LAM/ADV/ETV/LdT may
be used as initial therapy. LAM and LdT not preferred
due to high rate of drug resistance
HBV DNA <2,000 IU/ml-Consider treatment if ALT
elevated
Decompensated:
Coordinate treatment with transplant center, LAM (or
LdT) + ADV or ETV preferred. Refer for liver transplant
+/-
Undetectable
Cirrhosis Compensated: Observe.
Decompensated: Refer for liver transplant
Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal; IFN α, interferon alpha; pegIFN-α,
pegylated interferon alpha; LAM, lamivudine; ADV, adefovir; ETV, entecavir; LdT, telbivudine.
Lok AS et al. Hepatology 2007; 45: 507-539; Carosi G, Rizzetto M. Dig Liver Dis 2008, 40: 603-617
HBV Cirrhosis and Antiviral Therapy
In specific conditions, profilaxis is also indicated
in non-replicating hepatitis B virus carriers:
 In case of antitumor chemotherapy or immunosuppressant
treatments (anti-TNF, anti-CD20, anti CD-56, long term steroids
treatment, cyclophosphamide, methotrexate, leflunomide,
cyclosporin, tacrolimus, azatioprin and micophenol acid)
 Moreover, in HBsAg negative, anti HBc-positive patients
with a haematologic disease treated with fludarabin, monoclonal
antibodies, marrow transplant
Lok AS et al. Hepatology 2007; 45: 507-539; Carosi G, Rizzetto M. Dig Liver Dis 2008, 40: 603-617
HCV and Antiviral Therapy
Recommended in patients with compensated liver
cirrhosis due to hepatitis C virus
 Early liver cirrhosis
 Absence of hepatic encephalopathy or ascites
 Adequate hematological profile
 Absence of contraindications and good compliance
Ghany MG et al Hepatology 2009; 49(4): 1335-74
Which of sorafenib related
adverse events are relevant
in cirrhotic patients?
Blood and Lymphatic System Disorders
Thrombocytopenia
Bleeding Risk
Infection Risk (SBP..)
Neutropenia
Lymphopenia
Evaluation of Immunoprophylaxis
in Hepatitis B Virus Carriers
Metabolism and Gastrointestinal Disorders
Hyponatraemia
Renal failure
Dehydration,
Ipoalbuminemia
Diarrhea,
vomiting
Ascites
Drugs Interactions
Potential enhancing of adverse events
Antialdosteronic drugs
Gynaecomastia
Clinical Management of Hepatopathic Patients
During Sorafenib Treatment
1. Continue hepatopathy follow-up
2. Decompensation prevention
3. Decompensation management
Clinical Management of Patients
with Decompensated Liver Cirrhosis
Clinical Management of Patients
with Decompensated Liver Cirrhosis
Cirrhosis
Compensated
Variceal Bleed
SBP
Decompensated
Ascites
Hepatorenal
Syndrome
Encephalopathy
Decompensated Cirrhosis: Triggering Events
 Gastrointestinal bleeding
 Infections (digestive and extradigestive)
 Underlying hepatopathy flare-up
 Drugs and toxics
 Alcohol
 Surgery
 Heart failure
 Dehydration
 Ipertermia
 Trauma
 Burns
 Lack of adherence or inadequate therapy …
AASLD Guidelines 2005; Hepatology 2005; 41(6): 1407-32; AISF Guidelines 2005: Dig Liv Dis 2005
Cirrhosis Decompensation
Variceal bleeding
Oesophageal
varices
Spontaneous
bacterial peritonitis
Portal
hypertension
Ascites
Liver cirrhosis
Hepatorenal
syndrome
Hypermetabolism
Hepatic
encephalopathy
Hepatopulmonary
syndrome
Portopulmonary
hypertension
Algorithm for Acute Bleeding Treatment
Hematemesis and/or melena in cirrhotic patient
Hemodynamic stabilization (1)
Stable
Unstable,
prolonged bleeding
Endoscopy
Sengstaken
Blakemore tube
Not ongoing
bleeding
Ongoing bleeding
Rebleeding
prevention
Sclerotherapy or
varices ligation
Bleeding stops
Stable
Bleeding continues
Unstable
TIPS
Bleeding stops
Bleeding continues
Surgical shunt
(1) Fluids, hemoderivates, plasma expanders, vasoactive agents (terlipressin, somatostatin, octreoide)
Modificato da: Dib N et al. CMAJ 2006; 174(10): 1433-43
Secondary Bleeding Prevention
β-blockers + endoscopic ligation
Recurrent
haemorrhages
TIPS
AASLD Guidelines 2007; Hepatology 2007; 46(2): 608-9; Linee guida AISF 2006
TIPS Indications
1. Varices bleeding refractory to
medical/endoscopic therapy
2. Prevention of rebleeding of
oesophageal, gastric or
ectopics (including intestinal
and anorectal) varices
Esophagus
Shunt
Coronary v.
Liver
Stomach
3. Refractory ascites if intolerant
to “large volume” paracentesis
Spleen
Portal vein
Splenic vein
Kidney
Superior mesenteric
vein
Left renal vein
Inferior mesenteric
vein
Inferior vena cava
Linee guida AISF 2006; AASLD Guidelines 2005: Hepatology 2005; 41(6): 1407-32
Cirrhosis Decompensation
Variceal bleeding
Oesophageal
varices
Spontaneous
bacterial peritonitis
Portal
hypertension
Ascites
Liver cirrhosis
Hepatorenal
syndrome
Hypermetabolism
Hepatic
encephalopathy
Hepatopulmonary
syndrome
Portopulmonary
hypertension
Ascites
Non pharmacological measures:
 Bed rest and sodium restriction
 Fluid restriction in case of iponatriemia (<125 mEq/L)
Pharmacological measure:
 Diuretic antialdosteronic drugs (spironolactone up to 400 mg/die)
 In case of lack of efficacy add loop diuretics (furosemid up to 160
mg/die)
Investigating SBP: broad-spectrum antibiotics if necessary
AISF Guidelines 2005: Dig Liv Dis 2005; Bolondi L et al. Clin Gastroenterol Hepatol 2006;
4(11): 1395-402; Ghassemi S et al. Best Pract Res Clin Gastroenterol 2007; 21(1): 77-93
Refractory Ascites
Large volume evacuative paracentesis
– <5 L followed by plasmatic expansion with synthetic plasma
expanders, not requiring volume expansion with albumin
Larger volumes paracentesis must be followed by volume
expansion preferably with albumin (8 g/L of removed ascites)
TIPS if intolerance to large volume paracentesis
AISF Guidelines 2005: Dig Liv Dis 2005; Bolondi L et al. Clin Gastroenterol Hepatol 2006; 4(11): 1395-402;
Ghassemi S et al. Best Pract Res Clin Gastroenterol 2007; 21(1): 77-93
TIPS Indications
1. Varices bleeding refractory to
medical/endoscopic therapy
2. Prevention of rebleeding of
oesophageal, gastric or
ectopics (including intestinal
and anorectal) varices
Esophagus
Shunt
Coronary v.
Liver
Stomach
3. Refractory ascites if intolerant
to “large volume” paracentesis
Spleen
Portal vein
Splenic vein
Kidney
Superior mesenteric
vein
Left renal vein
Inferior mesenteric
vein
Inferior vena cava
Linee guida AISF 2006; AASLD Guidelines 2005: Hepatology 2005; 41(6): 1407-32
Renal Failure in Cirrhotic Patients
First step: differential diagnosis
Type
UNa (mmol/L)
Uosm/Posm
<15
>1.1
Hemorrage, vomiting, diarrhoea
Adjusted by volume expansion
Variable
>1.1
Weight loss >1 kg/die
Adjusted by diuretic withdrawal and
volume expansion
Hepatorenal s.
<10
>1.1
Spontaneous, triggered by sepsis
Not adjusted by volume expansion
Acute tubular necrosis
>15
<1.1
Severe hypotension, sepsis,
nephrotoxic drugs
Pre-renal
Due to diuretics
Chornic organic
>15
Clinical features
Variable crioglobulinaemia, diabetes,
nephrotic syndrome, amyloidosis,
Berger disease
UNa: sodium urinary concentration; Uosm: urinary osmolarity; Posm: plasmatic osmolarity
AISF Guidelines 2005: Dig Liv Dis 2005
Hepatorenal Syndrome (HRS)
Diagnosis (Ascites Club New Criteria):
 Cirrhosis with ascites
 Creatinin blood levels increase >1.5 mg/dl
 No improvement in creatinin blood levels 2 days after diuretic
treatment withdrawal and volume expansion with albumin
 No recent treatment with nephrotoxic drugs
 No organic renal disease (proteinuria, microematuria and
ultrasound renal abnormalities)
Salerno et al. GUT 2007; 56(9): 1310-1318
Hepatorenal Syndrome (HRS)
HRS I
Rapid decline in renal
function: 2 fold creatinin
blood level increase (>2.5
mg/dl)
or ≥50% CC reduction
(≤ 20 ml/min) in 2 weeks
Previously known
as: “acute”
or “severe”
or “terminal” HRS
Bad prognosis:
in pre-OLT era
median survival 1.7
weeks
Often identifyed
acute triggering
event (e.g.
infection)
HRS II
Mild and slowly
progressive decline
in renal function
Described as
epiphenomenon of
refractory ascites
Better prognosis: in
pre-OLT era
median survival
6-12 months
Triggering event
not identifyed
Angeli P. Journal of Hepatology 2008; 48 (Suppl 1): S93-103
Hepatorenal Syndrome Management
 Identify and adjust triggering causes
 Volemy adjustement (diuretic treatment interruption,
emoderivates, plasma-expanders)
 Vasoconstrictors:
– Albumin and terlipressin
– Midodrin+octreoide+albumin
Angeli P. Journal of Hepatology 2008; 48 (Suppl 1): S93-103
Cirrhosis Decompensation
Variceal bleeding
Oesophageal
varices
Spontaneous
bacterial peritonitis
Portal
hypertension
Ascites
Liver cirrhosis
Hepatorenal
syndrome
Hypermetabolism
Hepatic
encephalopathy
Hepatopulmonary
syndrome
Portopulmonary
hypertension
Hepatic Encephalophaty (HE)
(West-Haven)
Hassanein T, et al. Am J Gastroenterol 2009; 104(6): 1392-400
Hepatic Encephalophaty (HE)
Hepatic Encephalopathy Scoring Algorithm (HESA)
Hassanein T, et al. Am J Gastroenterol 2009; 104(6): 1392-400
Hepatic Encephalopaty Management
Triggering factors
adjustment
 Protein production
and absorption
Medical therapy
 Intestinal hemorrage
 Uncorrect use of diuretics and/or sedative
agents
 Hypokaliaemia and alkalosis
 Excessive protein intake
 Constipation, infections
 TIPS or porta-caval anastomosis
 Hepatopathy worsening
 Nephropathy
 Lactulose
 Lactulose
 Ramified chain AA
 L-ornithin L aspartate
Als-Nielsen B et al. BMJ 2004; 1; 328(7447): 1046; AASLD Guidelines 2005: Hepatology 2005; 41(6): 1407-32
Grade III/IV
Hepatic Encephalopaty Management
 Admission in ICU or hepatic subintensive Therapy
Unit (orotracheal intubation, semi-ortopnoic position,
continuous monitoring..)
 Intracranic pressure monitoring
 Endocranic hypertension therapy
– Mannitol
– Hypertonic saline
– Hyperventilation
– Steroids
– Hypotermia
 Epileptic episodes management
Als-Nielsen B et al. BMJ 2004; 1; 328(7447): 1046; AASLD Guidelines 2005: Hepatology 2005; 41(6):1407-32