HEPATORENAL SYNDROME

– LIVER PERSPECTIVE

Dr. S. Shivakumar M.D.,

Addl. Professor of Medicine,

Govt.Stanley Medical College,

Chennai – 600 001.

By

HRS-TYPES

Type I – HRS Rapidly progressive Renal Failure with a

doubling of S.Cr. > 2.5mg/dl or Ccr < 20ml/min in < 2 weeks.

Type II HRS Slowly progressive S.Cr to > 1.5mg/dl (or ) Ccr < 40ml/min in the absence of other potential

causes of Renal Failure. Liver Criteria

Chronic or Acute liver disease with Liver failure & PHT

DEFINITION OF HRS

HRS Type II Status of Ascites (Refractory) to be clarified

HRS Type I Not clear whether type I & II HRS are two distinct

entities or two different stages.

Role of precipitating factors not defined.

Does not explain what determines whether a

patient will gradually evolve into Type II HRS

with progressive worsening GFR or acutely

develop Renal Failure with its grave prognosis.

PATHOGENESISSinusoidal PHT + Severe Hepatic decompensation

Splanchnic Arterial Vasdilatation ++

Central Arterial Hypovolemia

Sympathetic Activation / Renin / Angiotensin / Aldosterone / ADH

Renal vasoconstriction

Intra Renal - Vasoconstrictors / Vasodilators

Renal Vasoconstriction

HRS

SINUSOIDAL PHT & SEVERE HEPATIC DECOMPENSATION

A. POST SINUSOIDAL PHT HRS has been successful treated by TIPS

Occlusion of TIPS by angioplasty balloon Acute reduction of Renal Blood Flow (RBF)

Release of balloon with elimination of PHT RBF returned to baseline

Presinusoidal PHT - Not associated with HRS.

Hepato-Renal Reflex – Sympathetic / Adenosine.

Sectioning the Renal Sympathetic supply abolished Renal effect improves Renal function in HRS.

SINUSOIDAL PHT &

SEVERE HEPATIC DECOMPENSATION

B. ACUTE HEPATITIS – Alcoholic Hepatitis

TNF - Imp. mediator of Circulatory disturbance

Vascular permeability & Vasodilation

NO HRS

Acute TNF therapy (Infiximab) Improves

Systemic haemodynamic derangement

[Mokeyer et al (Gut 2003; 52:1182-1187)]

SINUSOIDAL PHT &

SEVERE HEPATIC DECOMPENSATION

C. ACUTE LIVER FAILURE Induced by hepatotoxin – Galactosamine

Acute Liver failure Endothelin HRS. Improved by bosentan

( R.Anand et al GUT 2002;50: 111-117)

Acute Liver failure Intrahepatic portosystemic Vasodialtion HRS

(P Javle et al GUT 1998 ; 272 – 279)

SINUSOIDAL PHT &

SEVERE HEPATIC DECOMPENSATION

liver borne diuretic factor (LBDF)

synthesis

Bilirubin

Predisposes to HRS.

Renal vasoconstrictors

Not metabolized in liver.

Blockade of Natriuretic peptide receptors

RBF & GFR

HRS-TYPE 2- PATHOGENESIS

Extreme Over activity of endogenous vasoconstrictor

system overcomes the Intra Renal Vasodilatory

mechanism.

Na retention is intense Refractory Ascites

Survival

50% - 5 months

20% -1yr

ASCITES AND HRS

SeverityNa

retention RAS GFR

Pre-Ascitic

Cirrhosis+ – –

Moderate& tense

Ascites++ + –

Refractory

Ascites+++ ++ +

Type II HRS +++ +++ ++

Type I HRS +++ +++ +++

TYPE – 1 HRSTYPE 1 HRS (S.Cr. > 2.5mg/dl in < 2 Weeks)

Although it can arise spontaneously, it is frequently associated with a precipitating factor.

Reversible with Vasoconstrictor & Does not recur

FIRST & SECOND HIT HYPOTHESIS OF HRS

(2-Hit hypothesis)

FIRST HIT

Splanchnic & Systemic vasodilation

( EABV) Liver dysfunction Sinusoidal pH

HRS – MechanismSECOND HIT Spontaneous Bacterial Peritonitis

Factors Exaggerating EABV Overdiuresis

Large volume paracentesis

G.I.Bleed

Cholestatic jaundice

Nephrotoxic drugs

Idiopathic-24%

( Florence Wong &Laurence Blendis –

Hepatology 2001 34 ; 6 :1242-1251)

(Contd..)

2 HIT HYPOTHESIS

SPONTANEOUS BACTERIALPERITONITIS

G.I. BLEED

EABV OVER DIURESIS

CHOLESTASISLARGE VOLUME PARACENTESIS

NEPHROTOXICDRUGS

First Hit Second Hit

SPONTANEOUS BACTERIAL PERITONITIS (SBP)

30% of patients with SBP HRS despite adequate treatment

Sepsis (SIRS) Production of cytokines Endotoxins Production of N.O. Arterial Vasodilatation

Important Predictors Creatinine before infection.

Bilirubin > 4mg/dl (cholestasis)

Intestinal decontamination with Antibiotics & Volume expansion with IV Albumin Improves Splanchnic Haemodynamics

CHOLESTASIS (S.BILIRUBIN >4MG/DL)

Cholestasis (In the absence of PHT) Vasodilatation &

impaired Vascular responsiveness to Circulating

Vasoconstrictors.

Cholestasis + PHT Complements Circulatory changes

Type 1 HRS

Cholestasis + Cirrhosis Predisposes to HRS

Cholestasis + other 2nd Hit Risk factors Predisposes to

HRS

CHOLESTASIS

Other mechanisms

Endotoxemia

Nephrotoxic effect of Bile acids

Disturbance of Renal Prostaglandins &

Thromboxane Synthesis.

Hepatitis (Alcoholic, Toxic, Viral) + Sinusoidal

PHT HRS common

(Contd..)

GASTROINTESTINAL BLEED  Acute Blood loss

GFRATN GFR Type 1 HRS

Decompensated Cirrhosis with Variceal Bleed Develop Systemic inflammatory Response syndrome (SIRS) Cytokine NO exacerbates hyperdynamic response

Predictor of HRS Renal function before GI bleed

SIRS - Fever / Tachycardia / Tachypnoea / Leucocytosis

Treatment- antibiotics protect circulating Blood volume.

Prophylactic Oral Antibiotics reduces SBP.

DIURETICS

 Higher incidence of renal impairment in

hospitalised patients with tense ascites treated

with Diuretics compared to Paracentesis.

Plasma renin activity - Esp.when there is no

peripheral edema.

Diuretics + AlbuminPrevents HRS

Diuretics have other effects on kidney apart

from Intravascular volume.

LARGE VOL. PARACENTESIS(LVP)

Large volume paracentesis GFR

Exaggeration of Arterial vasodilatation

Stimulation of vasconstrictors system

Only 32% - had activation of vasoconstrictor

system.

Depends on Hemodynamic stability before

paracentesis ( PRA)

Treat with 6-8g IV Albumin with LVP

Acute Renal Failure

Fe Na

< 1% > 1%

CVP

< 5mmHg

ATN

> 10mm

Pre renal

AzotemiaHRS

CONCLUSIONS

Definition of HRS - Evolve definite Liver criteria

Type 2 HRS - Refractory Ascites usually associated

Type 1 HRS - ‘TWO HIT’ Hypothesis -

precipitating factors

Arterial Vasodilatation (Splanchnic & Systemic) -

important mechanism for HRS

Other Mechanisms Hepato renal Reflex,TNF,

Endothelin, Bilirubiin, Liver borne Diuretic factor