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
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