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