Cirrhosis and complications Cengiz Pata Gastroenterology Department Yeditepe University
Jan 04, 2016
Cirrhosis and complications
Cengiz Pata
Gastroenterology Department Yeditepe University
Overview
1) Criteria for Referral for Transplantation
2) Varices3) Ascites/TIPS4) S.B.P.5) Encephalopathy6) Hepatorenal Syndrome7) Hepatocellular Carcinoma
Etiology
• Enfections (HBV, HCV, HDV, HGV)• Hereditary disease (Wilson, Hemokromatozis, Alfa-1
antitripsin,tyrosinemia)• Toksic (alchol,drugs(Mtx)• İmmünologic (OİH)• Vasculer (corpulmonare, Budd Chiarry, Portal ven
trombosis)• Bilier Disease (PBS, Cystic
Fibrosis,Sarcoidosis,PSK,PFIK,SBS)• Malnutrision , Bypass surgery• İndian Child Age Disease• NAFLD
Reasons for Liver Transplantation: U.S.
Etiology % Disease from Hepatitis C 40 IDU 65%, BT 5%, others Alcohol 30 alcoholism PBC/PSC 10 congenital Hemochr <5 genetic HBV 5 vertical/horizontal
Biliary atresia 30 congenital Metabolic d/o 20 congenital
Fibrosis Progression: Hepatitis C
Slide courtesy of Bennett, MD.
CirrhosisSevere Fibrosis
Normal Liver Mild fibrosis
CIRRHOTIC LIVERCIRRHOTIC LIVER
CIRRHOTIC LIVERCIRRHOTIC LIVER
How do we know if a patient has cirrhosis/ portal
hypertension ?• Liver biopsy: Stage IV scarring• CT scan: hypertrophied L lobe, nodular
contour, enlarged portal vein, splenomegaly, varices, ascites
• Labs: low platelet count, elevated bilirubin, prolonged INR
• Physical exam: spider angiomata, jaundice, splenomegaly, ascites, leg edema
Timing of referral for consideration of liver
transplant ? 1 point 2 points 3 points
Albumin (g/l) >3.5 2.8-3.5 <2.8
Ascites None Slight Moderate
Bilirubin (mg/dl) <2 2-3 >3
Encephalopathy None Mild-Mod Severe
Prothrombin/INR 1-4 s/1.7
4-6 s/1.7-2.2
>6 s/>2.2
A: 5-6, B: 7-9, C: 10 or more
Modification for Bilirubin in PBC/PSC: 1-4, 4-10, >10
Timing of referral for consideration of liver transplant ?
• Since February 2002, listing for transplantation is on the basis of a MELD score and a CPT score
• MELD (Model for End-Stage Liver Disease): developed at Mayo Clinic as a separate “liver disease severity index”
• MELD: 0.38xloge(bilirubin, mg/dl) + 1.12xloge(INR) + 0.96 xloge(creatinine, mg/dl) + 0.64x etiology
Website: www.unos.org
Implication for Transplant
• Many of complications of cirrhosis were formerly considered reasons to “increase a patient’s status,” specifically:
1) Refractory variceal bleeding 2) Refractory hepatorenal syndrome 3) Refractory hepatic
encephalopathy- were accepted as reasons to make
patients on the list for transplant “2A,” and give them higher priority
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
Figure 1. Treatment Flow Sheet for Patients with Cirrhosis
SBP Ascites Hepatorenal Synd.
(Garcia-Tsao G, 2003)
Vaccination- in HCV,against HAV, HBV
Variability in Natural History of Cirrhosis
• Natural history is clearly variable based on:
- ongoing alcohol consumption, leading to acute exacerbations in portal pressures, particularly increasing risk for variceal hemorrhage
- relation between cirrhosis etiology and HCC (HBV>HCV>?NASH)
Morbidity and Mortality in Compensated Cirrhosis Type C: A Retrospective Follow-up Study of
384 Patients
0
5
10
15
20
25
30
35
HCC Varix Bl >1 compl
Complication
Fattovich G et al, Gastroenterology 1997;112:463
Ascites Enc/J
Mean follow-up:5 years
Morbidity and Mortality in Compensated Cirrhosis Type C: A Retrospective Follow-
up Study of 384 Patients
• 26% of patients decompensated during follow-up (8% HCC, 18% other)
• Odds of decompensation: 12% at 3 years, 18% at 5 years, 29% at 10 years
• Probability of survival after decompensation: 50% at 5 years
• Death: 51 (13%): roughly 1/3 HCC, 1/3 liver failure, 1/3 unrelated to cirrhosis
Fattovich G et al, Gastroenterology 1997;112:463
Effect of Hepatitis B and C Virus Infections on the Natural History of Compensated
Cirrhosis: A Cohort Study of 297 Patients
0
5
10
15
20
25
HCC Ascites Varix Bl Enceph/J >1 Compl
HCV+:136HBV+:161
Fattovich G et al, Am J Gastro 2002;97:2886
Median f/u:6.5 years
Effect of Hepatitis B and C Virus Infections on the Natural History of Compensated
Cirrhosis: A Cohort Study of 297 Patients
• HCV: 53% decompensated (17% HCC, 36% other) HBV: 34% decompensated (14% HCC, 20% other)• Probability of 5-year survival after decompensation:
HBV 28%, HCV 47%• Death or liver transplant: 70 (22% of HBV, 26% of
HCV)
Fattovich G et al, Am J Gastro 2002;97:2886
Gines, Hepatology 1987.
PROBABILITY OF DEVELOPING DECOMPENSATED CIRRHOSIS
257 patients with compensated cirrhosis
time in months
number being followed
Cirrhosis Natural History Studies Summary
• No decompensation: 80% 10-year survival• Decompensation is variable, imperfectly
predicted. Portal HTN vs. synthetic dysfunction
• HCC, ascites: the 2 principal forms of decompensation
• Risk of decompensation: roughly 4-5% per year in a patient with Child’s A cirrhosis
• After decompensation, probability of 5-yr survival without transplant: 35-50%
Time to disease progressionDB treatment and off-treatment
follow-upPercentage with
disease progression
Time to disease progression (months)
Placebo (n=215) ITT populationLamivudine (n=436) p=0.001
Lamivudine
Placebo
P=0.001
21%
9%
Risks of Complications of Cirrhosis
Cirrhosis
VaricealBleeding
HCC
Ascites
Encephalopathy
adapted from Bennett WG et al, Ann Intern Med 1997;127:855
0.4%
1.5%
2.5%
1.1%
percent per year
Death
Liver Transplant
11%
?20+%
?30+%
Median Survival Times in Cirrhosis
• Compensated Cirrhosis 9 yrs• Decompensated Cirrhosis 1.6 yrs
– Jaundice– Encephalopathy– Ascites– Variceal hemorrhage
• SBP 9 mos• HRS type II 6 mos• HRS type I 2 wks
Bleeding VaricesBleeding Varices
Varices-Background
• Management of acute or acutely-bleeding varices is accepted: a) IV octreotide
b) band ligation > sclerotherapy for esophageal varices, TIPS placement (or attempts at glue injection at some sites) for acutely-bleeding gastric varices. 7 days of antibiotics recommended
• Controversies: 1) Primary prophylaxis 2) Secondary prophylaxis
Primary Prophylaxis- Varices
• 15-25% of unselected cirrhotics screened endoscopically will have large or high-risk varices
• Mortality of first variceal hemorrhage remains high, 20-35%
D’Amico G et al, Hepatology 1995;22:332-54
• Fewer studies on prevalence of gastric varices in unselected cirrhotics; 4% ?
Sarin S et al, Hepatology 1992;16:1343-49
Prevention of FIRST Variceal HemorrhageMeta-Analysis (11 trials)
Control Beta-blocker
Absolute Rate
DifferenceBleeding
Rate 25% 15% -10%
(- 16 to –5)Death Rate
27% 23% -4%(- 9 to 0)
Large Varices
30%(n=411
)
14%(n=400)
-16%(- 24 to –8)
SmallVarices
7%(n=100
)
2%(n=91)
-5%(-11 to 2)
D’Amico et al. Sem Liv Dis 1999
Prediction of Large Varices
• Platelet count, Child-Pugh class independent risk factors for the presence of any varices (plts <90K) and large varices (plts <80K) in 300 cirrhotics without prior bleeding being evaluated for OLT
Zaman A et al, Arch Int Med 2001;161:2564-70
Zaman et al, Arch Int Med 2001
Clinical Feature No varices (n=97)
Small varices (n=109)
Large varices (n=94)
Encephalopathy
34%
47% 54%
Platelets (mean)
129,000 107,000 76,000
Splenomegaly (u/s)
62% 61% 73%
Ascites 44% 53% 63%
Platelet count OR 2.3, p=.001Child-Pugh class OR 2.75, p=.007
Multivariate Predictorsof Large Varices:
Primary Prophylaxis
• Beta-blockers reduce the incidence of first variceal hemorrhage compared to placebo
Poynard T et al., NEJM 1991;324:1532-1538
• Band ligation may be more effective than Propranolol in high risk patients
Sarin S et al, NEJM 1999;340:988-93
Primary Prophylaxis of Varices: An algorithm
• It is reasonable to perform endoscopic screening in all cirrhotics (stable, willing to be tx’d); it should likely be performed in all Child’s C cirrhotics
Beta blockade (Propranolol, Nadolol, goal HR 55-60) is the preferred approach; band ligation is an alternative for high risk varices or in patients who can’t tolerate Propranolol
- not as many data in gastric varices nor portal gastropathy, but prophylaxis may be similar
Secondary Prophylaxis of Varices
• Variceal hemorrhage has a 2-year recurrence rate of 80%
• Once acute bleeding has resolved, two large trials have found that beta-blockade and band ligation have similar efficacy in controlling rebleeding
Minyana J et al, Hepatology 1999;30:215A Patch D et al, J Hepatology 2000;32:34
Secondary Prophylaxis of Varices
• Banding sessions are typically repeated at 7-14-day intervals until obliteration, typically 2-4 sessions
• TIPS vs endoscopic tx: rebleeding less with TIPS, but worse encephalopathy, no change in mortality
Papatheodoridis GV, Hepatology 1999;30:612-22
Beta-blockers or banding are first-line
Hepatic encephalopathy
• GIS bleeding• Enfection• higher protein • diuresis• constipation• Elektrolit inbalance• Dehidratation• Sedative• Hepatik injury• Portasistemic shunt
Hepatic encephalopathy
• Liver failure, failure of CNS
• 1 year survive %40
• NH3, Glutamine,katekolamine, serotonine,GABA
Stages of Hepatic encephalopathy
0-1 : psychometric tests slow1 : abnormal sleep, dyscordination2 : lethargy, ataxia, disarthria,behavirol
dysinhibition, asterix, poor tests3 :confusion, delirium, semi stupor, incontinence,
disorientation, amnesia, rigidity, paranoia, abnormal reflex, nistagmus, babinski
4 : coma, no cognition, no behavior, decortica or decerebrate, dilated pupils
Hepatic encephalopathy
Treatment• General support
• Treatment of etiologic factor
• Medical : Lactulose, antibiotic (neomycin,metronidazole)
Flumazenil
• Transplantation
HRS
• impaired renal function• İmpaired arteriel circulation• Renal vazoconstruction• GFR↓• No pathologic lesion• 1 mounths survival %95• %7-15• Type 1:weeks, agrrevation important ( diuretic,
parasenthesis, SBP..)• Type 2 : mounths, better prognose
Hepatorenal Syndrome
• 2 types: Type I: rapid development of renal dysfunction (Cr rising to >2.5mg/dl in 2 weeks): median survival 2 weeks
Type II: slower rise, Cr >1.5mg/dl Management: 1) Ensure Diagnosis 2) Liver Transplantation
HRS• Major CriteriaGFR low (cre1.5mg/dl↑ or Cre clirence 40↓)No shock, nefrotocsic drug, enfection or loss of fluidGood function after stoping diuretic and 1,5 lt saline No paranchymal disease or nefrolithiasis on US500mg/d↓/day proteinuri
• Minor CriteriaUrine volume 500↓Urine Na 10 mEg/L↓Higher urine osmolarite than plasmaSerum Na 130 mEg/L↓50 red cell↓ urine
HRS
• Dopamine
• Mizoprostole
• Vazopressine (Orlipressin,terlipressin)
• TIPS
• MARS
• Transplantation
Uriz J Hepatol 2000;33:43-18
TERLIPRESSIN+ ALBUMIN IN HRS
U Heemann et al. Hepatology 2002; 36: 949-958
EXTRACORPOREAL ALBUMIN DIALYSIS MARS
Natural History of Cirrhosis in 2005: Altered by What
We Do• More aggressive screening, for
varices, HCC will mean problems are identified earlier
• Ablative therapies for HCC• Obliteration of varices/ beta-
blockade• TIPS• Liver Transplantation