Complications of Cirrhosis

Alan Bonder, MDAssistant Professor of Medicine

Harvard Medical SchoolBeth Israel Deaconess Medical CenterCOPYRIG

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Disclosures

• NO conflict of interests to disclose

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Objectives

• Recognize and manage complications from cirrhosis

• Diagnostic tests for patients with cirrhosis

• Screening tests for patients with cirrhosis

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Cirrhosis

• The prevalence of cirrhosis, both worldwide and in the US, is unknown1

– Cirrhosis is an outcome of a variety of causes, and the underlying cause is commonly used for surveillance purposes 2

– Compensated cirrhosis often goes undetected for prolonged periods of time1

• Experts estimate that 5.5 million people in the United States have cirrhosis1. Schuppan D, Afdhal NH. Lancet 2008;371(9615):838-851.2. Available at http://pubs.niaaa.nih.gov/publications/surveillance83/Cirr05.htm. Accessed 01/15/12. 3. Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89

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Decrease in local vasodilators withincrease of local vasoconstrictors

Decreased systemic vascular resistance

CIRRHOSISPortal hypertension

Splanchnic arterial vasodilation

Arterial underfilling

Stimulation of systemic vasoconstrictors

Renal vasoconstriction

Increased systemic andlocal vasodilators

Preserved renalperfusionHepatorenal Syndrome

Early Stages of CirrhosisLate Stages of Cirrhosis

RAAS SNS AVP

Cardenas et al, Schiff�s disease of the liver ,2002

Varices

AscitesCOPYRIG

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Complications of Cirrhosis• Primary complications of cirrhosis include

– Ascites– Jaundice– Variceal hemorrhage– Hepatic encephalopathy

• Other complications that can occur include– Hepatocellular carcinoma – Spontaneous bacterial peritonitis– Hepatic hydrothorax– Hepatorenal syndrome – Portopulmonary hypertension– Portal vein thrombosis – Hepatopulmonary syndrome

Lefton HB et al. Med Clin N Am 2009;93:787-799.

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Outcome of complications(survival)

Complication Survival at 1 year Survival at 3 yearsNon bleeding varices w/o ascites 1

97% ND

Ascites � varices 1, 2 80%� 50%

Bleeding varices � ascites 1 43% ND

Hepatic encephalopathy 3 42% 23%

1. Adapted from D’Amico G et al. J Hepatol 2006;44:217-231. 2. Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89.3. Adapted from Bustamante et al. J Hepatol. 1999;30:890-895.

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Assessment of severity/prognosis

• CPT score– Ascites (none = 1, present = 2, tense =3)– Encephalopathy (none = 1, I-II = 2, III-IV = 3)– INR (< 1.7 = 1, 1.71-2.2 = 2, > 2.2 = 3)– Bili (< 2 = 1, 2-3 = 2, > 3 = 3) – Alb (> 3.5 = 1, 2.8-3.5 = 2, < 2.8 = 3)

• MELD score– 0.957 X log (serum creatinine) + 0.378 X log (serum bilirubin) + 1.120 X log

(INR)

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EVALUATION OF CIRRHOSISassessing prognosis

Child�s (Pugh) Turcotte score

• Empirically developed• Modified in 1972• Predicts survival (1 & 2yr)

– A (5-6) 100%, 85%– B (7-9) 80%, 60%– C (10-15) 45%, 35%

• Limitations– Subjective assessment– Not a continuous severity

score

MELD• 231 patients undergoing

TIPS at 4 US centers• Predicts death within 3

months• Adopted for liver allocation

in Feb 27 2002COPYRIG

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Severity of liver cirrhosis• Prognosis is dependent Compensated verses Decompensated

– Dependent on development of ascites, variceal bleeding, jaundice or encephalopathy

• New classification (to improve prognostication)

Stage Description 1 year mortality1 Compensated cirrhosis with no esophageal

varices1%

2 Compensated cirrhosis with esophageal varices

3.4%

3 Cirrhosis with ascites 20%

4 Cirrhosis with gastrointestinal bleeding 57%

5 Cirrhosis with infection and renal failure 67%

D�Amico et al. J Hepatol 2006; 44: 217-231Arvaniti et al. Gastro 2010; 139; 1246-1256

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Ascites

• Most common complications of cirrhosis– 60% of patients with compensated

cirrhosis develop ascites within 10 years

• 50% mortality within 3 years• Liver Transplant should be consideredCOPYRIG

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Prognosis of Patients with Cirrhosis at Onset of Ascites

Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89.

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Tests for patients with new ascites

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Management of AscitesFirst-Line TherapyTense ascites

Paracentesis

Sodium restriction(<2 Gm/24 Hrs)and diuretics*

Non-tense ascites

*Diuretics: Spironolactone 100 mg/day,furosemide 40 mg/day or bumetanide1 mg/day; uptitrate stepwise to spironolactone 400 mg/day, furosemide160 mg/day or bumetanide 4 mg/day astolerated

RefractoryAscites 10 %

Second-Line Therapy• Repeated large volume paracentesis (LVP)�

• TIPS

• Liver Transplantation�Albumin infusion of 6-8 gm/liter of fluid removed is a consideration for repeated LVP; post-paracentesis albumin infusionmay not be necessary for < 5 liters removed

Adapted from Runyon BA. Hepatology. 2009; 49:2087-2107.

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Refractory ascites

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Management of AscitesProbability of survival without transplantation in patients assigned to TIPS

and in those assigned to paracentesis plus albumin.

Hepatology 2004;40;629 NEJM 2000;342:1701-1707

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Norfloxacin prevents SBP & HRS and improves survival

Probability of developing SBP Probability of developing HRS

Fernandez et al. Gastroenterology 2007; 133: 818

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Treatment of SBP• 1.5 gr/kg at diagnosis and 1gr/kg 48 hours later

30

RENAL IMPAIRMENT (%)

20

0CEFOTAXIME CEFOTAXIME

+ALBUMIN

10

HOSPITAL MORTALITY (%)

30

20

0CEFOTAXIME

10

CEFOTAXIME+

ALBUMIN

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International Ascites Club�s Diagnostic Criteria of Hepatorenal Syndrome.

NEW DIAGNOSTIC CRITERIA FOR HEPATORENAL SYNDROME

1. Cirrhosis with Ascites

2. Serum creatinine > 1.5mg/dl (>133umol/l)

3. No improvement in serum creatinine (decrease to < 1.5mg/dl) after at least 2 days with diuretic withdrawl and volume expansion with albumin 1g/Kg of body weight per day to a maximum of 100g/day

4. Absence of shock

5. No current or recent treatment with nephrotoxic drugs

6. Absence of parenchymal kidney disease as indicated by proteinuria > 500mg/d, microhematuria (> 50 rbc/hpf) and/or abnormal ultrasonography

Salerno et al. Gut 2007;56: 1310-1318

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12

Type-2

Type-1

0.0

0.2

0.4

0.6

0.8

1.0

0 8 106

Months42

Pro

babi

lity

p=0.001

Ginès et al, Gastroenterology 1993

Type 1Rapidly progressive reduction of renal function:>100% increase in serum creatinine to > 2.5 mg/dL in lessthan 2 weeks.

Type 2Stable or less progressive reduction of renal function associated with diuretic resistant ascites to a serum creatinine of > 1.5.

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Hepatic encephalopathy• Covert hepatic encephalopathy (CHE) affects

approximately 20% to 60% of patients with liver disease– Has been called subclinical encephalopathy or minimal

encephalopathy (MHE) in the past– International Society for Hepatic Encephalopathy and

Nitrogen Metabolism has recently endorsed using the term covert encephalopathy

• Overt hepatic encephalopathy (OHE) occurs in– 30% to 45% of cirrhotic patients

– 10% to 50% of patients with TIPS . Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. Mullen KD, Prakash RK. Clin Liver Dis 2012;16:91-93, Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9.

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Hospital discharges associated with HE

21% growth

HE = hepatic encephalopathy; ICD = International Classification of Diseases.*Data calculated using ICD-9-CM codes 291.2 (alcoholic dementia, not elsewhere classified), 348.30 (encephalopathy, not otherwise specified), and 572.2 (hepatic coma). †Includes all listed discharge diagnoses.HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://hcupnet.ahrq.gov. Accessed January 2013.

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HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/HCUPnet/.

$5.9 billion

*Includes codes 348.3 and 572.2

Tota

l Cha

rges

1993-2003$0

$200,000,000

$400,000,000

$600,000,000

$800,000,000

$1,000,000,000

$1,200,000,000

1994 1996 1998 2000 2002 2003

$1,300,000,000

Healthcare costs for HE

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Current Therapy Options for HEDrug Name Drug Class Indication

Lactulose Poorly absorbed disaccharide

• Decrease blood ammoniaconcentration

• Prevention and treatment of portal-systemic encephalopathy

RifaximinNon-aminoglycoside semi-synthetic, nonsystemic antibiotic

Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.

Neomycin Aminoglycoside antibiotic

Not to be used, renal and ototoxic risk

Metronidazole Synthetic antiprotozoal and antibacterial agent Not approved for HE

Vancomycin Aminoglycoside antibiotic Not approved for HE

Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM203247.pdf, accessed 02/17/11 andhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf, accessed 02/17/11.

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Rifaximin Trial

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Rifaximin Trial: Time to First Breakthrough HE Episode Primary End

Point

Prop

ortio

n of

Pat

ient

s W

ithou

tB

reak

thro

ugh

HE

(%)

Rifaximin*(77.9%)

Placebo*(54.1%)

*Rifaximin 550 mg or placebo twice daily

Hazard ratio with rifaximin, 0.42 (95% Cl, 0.28–0.64)P<0.001

Days Since RandomizationBass NM et al. N Engl J Med. 2010;362:1071-1081.

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Driving performance with Covert Encephalopathy

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• Varices decompress the hypertensive portal vein

• Threshold pressure of 10-12 mmHg

• Prevalence of EV ranges from 24-81%

• De novo -8% / year -30% @ 6 years

• Progression -25% with small varices

Varices as a consequence of portal hypertension

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0

20

40

60

80

100

RW Absent Moderate SevereCPT score A B C

s m l s m ls m l

% b

leed

NIEC. N. Engl.J. Med. 1988; 319: 983

Predicting risk of variceal hemorrhage

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Varices-surveillance and management

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b-Blockers -9 randomised trials-4 significant reduction in bleeding-5 reduced mortality, 1 significant

Meta-analysis -significant reduction in bleeding (45%)-lower rates of fatal bleeding (50%)-trend ¯ overall mortality (D’Amico et al. Hepatology. 1995; 22: 332)

Therapeutic response should be assessed by HVPG(Conn et al. Hepatology 1991; 13: 902)

Primary prophylaxis - Drug therapy

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Management of Acute Hemorrhage

• Patients with suspected acute variceal hemorrhage require intensive-care unit setting for resuscitation and management

• Acute GI hemorrhage requires:– Intravascular volume support– Blood transfusions – Maintaining hemoglobin of ~8 g/dL

• Institute short-term (7-day) antibiotic prophylaxis• Initiate therapy with somatostatin (or its analogs)• Perform esophagogastroduodenoscopy within 12 hours;

treat with endoscopic band ligation or sclerotherapy

Garcia-Tsao G et al. Hepatology. 2007;46:922-938.

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Mortality from gastroesophageal variceal bleeding

• Meta-analysis of 1475 patients included in 28 trials of primary prophylaxis between 1960-2000

• Bleed related mortality was reduced from 65% to 40% (p=0.024)

McCormick PA et al Gut 2001;49: 607-608

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Antibiotic Prophylaxis During/After Acute Variceal Bleeding

• Prophylatic ofloxacin vs antibiotics only at diagnosis of infection

• ¯ infections (2/59 vs 16/61)

• Less rebleeding within 7 days

• ¯ blood transfusions for rebleeding

• Prophylactic antibiotics recommended in management of acute variceal hemorrhage

Prob

abili

ty o

f Reb

leed

ing

Follow-up (Months)

0.01 2 3 12 18

1.0

0.8

0.6

0.4

0.2

0 24 30

On-demand antibiotics (n=61)

Prophylactic antibiotics (n=59)

Hou M-C et al. Hepatology. 2004;39:746-753.

Patients at riskProphylactic: 59 48 42 38 17 8 2On demand: 51 36 34 30 19 9 2

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Rising Incidence of Hepatocellular Carcinoma

0

1

2

3

4

5

6

7

1976-

1980

1991-

1995

White Men

91-95

Black Men

91-95

Per 100,000

Represents a 41%

increase in

mortality rate and

a 46% increase in

hospitalization

El-Serag et al. N Engl J Med. 1999;340(10):745-750.

1.4

2.42.8

6.1

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Screening for HCC

• Most studies in HCV are retrospective• 360 patients (167 had HCV)• US q 6 months for mean of 56 months• Compare with 2170 patients not

screened• 75% of those screened had unifocal

disease < 3cm as compared to 15% of those not screened

Solmi et al, Am J Gastroenterol 1996; 91: 1189-1194

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HCC Surveillance-AASLD Guidelines

Non-hepatitis B cirrhosis• Hepatitis C• Alcoholic cirrhosis• Genetic hemochromatosis• Primary biliary cirrhosis

Although the following groups have an increased risk of HCC no recommendations for or against surveillance can be made because a lack of data precludes an assessment of whether surveillance would be beneficial.

• Alpha1-antitrypsin deficiency• Non-alcoholic steatohepatitis• Autoimmune hepatitis

Hepatitis B carriers• Asian males 40 years• Asian females 50 years• All cirrhotic hepatitis B carriers• Family history of HCC• Africans over age 20• For non-cirrhotic hepatitis B carriers

not listed above the risk of HCC varies depending on the severity of the underlying liver disease, and current and past hepatic inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC.

Bruix and Sherman Hepatology Nov 2005

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Non-disease-specific minimal listing criteriaAmerican Society for Transplant physicians and AASLD

(Liver Transplant Surg 1997; 3: 628-637)

• Immediate need for transplant• Estimated 1-year survival of < 90%• Child Pugh score > 7• Portal hypertensive bleeding • Single episode of SBP irrespective of CPTCOPYRIG

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Comparison of mortality for wait list patients versus transplanted patients

HR 3.64 2.35 1.21 0.62 0.38 0.22 0.18 0.07 0.04

P-values <0.001 <0.001 0.41 <0.01 <0.001 <0.001 <0.001 <0.001 <0.001

Merion et al. AJT 2005;5:307-313

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Other potential pharmacotherapy• NSBB reduces bacterial translocation• Rifaximin reduces minimal HE• Rifaximin reduces HVPG• Statins reduce HVPG• Statins reduce the risk of HCC in Diabetics• Anticoagulation decreases risk of PVTCOPYRIG

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Summary• Complications of cirrhosis substantially

reduce overall survival• Advice to patients with cirrhosis

– Avoid alcohol– Advise weight reduction for compensated

cirrhosis– Vaccinate non immune patients

• Inform patients of benefits of smoking cessation, avoid cannabis use, drinking coffee

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Summary

• Medical management has some impact on survival

• Liver transplantation prolongs survivalCOPYRIG

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Website for references

• aasld.org (practice guidelines)

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