Liver dysfunction in AHF syndromes: clinical and prognostic

implications

J. ParissisHeart Failure Clinic

Attikon University Hospital,Athens, Greece

Disclosures:

Research grants from Abbott USA and Orion Pharma Finland as

ALARM investigator, and Novartis international.

• Ten liver function tests were evaluated in a study of 135 cases of chronic protracted congestive heart failure of which 54 came to autopsy.

• Seventy-four per cent of the patients had at least one abnormal determination although only 30 per cent of the tests performed were out of the normal range.

• There is definite impairment of liver function in congestive heart failure. The exact basis for this change remains unknown.

Circulation. 1950;2:286-297

The Splanchnic Vasculature: Capacitance Function and Cardiac Pre-load

Verbrugge et al. J Am Coll Cardiol 2013;62:485–95

Hepatorenal Reflex

Verbrugge et al. JACC 2013

Pathophysiology in HFCan ischemic hepatitis be attributed only to hypotension?

Samski et al. JACC 2013

Transaminases in Ischemic Hepatitis

Sharp rise and fallALT/LDH<1.5

Cardio Hepatic Interactions•FORWARD HF/CARDIOGENIC SHOCK HYPOXIC HEPATITIS

• BACKWARD HF/CHRONIC CONGESTIONCIRRHOTIC LIVER

• LIVER CIRRHOSIS CIRRHOTIC CARDIOMYOPATHY

Distribution of abnormal liver enzymes in HF

Auer J. Eur Heart J 2013;34:711–714

CHF: prevalence & clinical significance of liver dysfunction

Association with• NYHA• JV distention, edema• EF• RVSP• TR

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18.3

50

45

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0Bilirubin γGT ALP ALT/AST Αlbumin

Poelzl (2014)

CHARM (2009)

Allen et al. Eur J HF 2009Poelzl et al. Eur J Clin Invest 2012

GGT, T-Bil, GGT, T-Bil, and ALPALP are related to disease severity

p <0.0001 p <0.0001p <0.0001

Poelzl G, et al. EJCI, 2012, 42:153

AST, AST, and ALTALT are not related to disease severity

p=0.168 p=0.495

Poelzl G, et al. EJCI, 2012, 42:153

CHF: prevalence & clinical significance of liver dysfunction

Allen et al. Eur J HF 2009

Prevalence and Prognostic Significance of Elevated g-Glutamyltransferase in Chronic HF

Poelzl et al. Circ Heart Fail. 2009;2:294-302

Prevalence of elevated GGT was 42.9% in men (GGT >65 U/L) and 50.2% in women(GGT> 38 U/L) with CHF.

Synergistic effect of hepatic and renal dysfunction on outcomes in CHF patients

Poelzl et al. Eur J Inter Med 2013;24:177–182

MELD score=11.2x(ln INR)+0.378x(ln bil)+0.957x(ln creat)+0.643

MELD-XI score=5.11x(ln bil)+11.76x(ln creat)+9.44

Cardiohepatic syndrome in CHF: general concepts

TheThe cardio-hepatic syndrome cardio-hepatic syndrome in chronic in chronic heart failure is :heart failure is :

- frequentfrequent

- characterized by a predominantly predominantly cholestatic cholestatic enzyme pattern

-- associated with disease severity associated with disease severity

- related to prognosisrelated to prognosis

AHF: prevalence & clinical significance of LFTs

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0Bilirubin γGT ALP ALT/AST Αlbumin

SURVIVE

ESCAPE

EVEREST

Abnormal LFTs:

Nikolaou et al. Eur Heart J 2013Ambrosy et al. Eur J Heart Fail 2012Scholfild et al. J Cardiac Fail 2014

Prevalence of elevated ALT and aspartate AST at admission by ejection fraction and clinical profile at presentation

European Heart Journal: Acute Cardiovascular Care 2013 2: 99

Additive values of abnormal transaminases and abnormal alkaline phosphatase on a short- andlong-term outcome

Nikolaou M, Parissis J, …, Mebazaa A. EHJ 2013;34:742-749

Assessment of Acute Heart Failure Syndromes: the role of hepatic dysfunction

Modified from Nohria et al. Am J Cardiol 2005;96[suppl]:32G–40G

High Transaminases plus ALP

High Transaminases

High ALP Normal

GGT levels in ADHF: prognostic value and relationship with renal function

Serum creatinine

Parissis et al. Int J Cardiol 2014

eGFReGFR and GGTGGT are related to CVPCVP

p = 0.007 p = 0.001

Poelzl G, courtesy

eGFR GGT

Standardized regression

coefficient beta

P-value Standardized regression

coefficient beta

P-value

Male gender 0.207 0.011 0.182 0.023

Age 65a -0.096 0.224 -0.022 0.776

Ischemic aetiology -0.160 0.054 0.192 0.020

Diabetes -0.049 0.550 0.210 0.117

Hypertension -0.211 0.008 -0.87 0.261

Alcohol consumption -0.041 0.601 -0.087 0.266

LV-EF 35% -0.164 0.047 0.006 0.945

NYHA III/IV -0.065 0.459 0.118 0.178

CVP -0.225 0.008 0.337 <0.001

CI 0.060 0.470 0.017 0.835

Determinants of worsening renal and hepatic function (n = 205)

Poelzl G, courtesy

Levosimendan, compared to dobutamine, reduces enzymatic markers associated with liver congestion: A SURVIVE subanalysis

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80 75 11180 75 111Baseline, μ, IU/L

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80 75 111Baseline, μ, IU/L

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80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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80 75 111Baseline, μ, IU/L

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80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

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*P-value from repeated measures ANCOVA model for treatment effect, model also included effects for time (all were p<0.05) and treatment -by-time interaction (all were p=NS). †Point estimates from ANCOVA model with baseline as covariate. Error ba rs are standard errors.

80 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

80 75 11180 75 111Baseline, μ, IU/L

0.008 0.002 <0.001P-value*

Nikolaou M, Parissis J, …, Mebazaa A. EHJ 2013

Impact of Liver Injury on Drug Metabolism

CRSCHS

HRS

Take Home Messages• Abnormal liver biochemistry is highly prevalent in chronic and

acute heart failure.• Elevated hepatic enzymes may have important prognostic

implications in chronic and acutely decompensated chronic heart failure (ADHF).

• Increased central venous pressure may be related with cholestasis in ADHF, while reduced cardiac output may additionally affect hepatic function by causing liver injury and transaminase release.

• Hepatic dysfunction is closely related with renal dysfunction in ADHF. These conditions may have synergistic prognostic implications.

• Drugs that protect liver function may improve outcomes in ADHF patients.

• More prospective trials targeting to liver function protection are needed in ADHF patients.