HEPATORENAL SYNDROME – LIVER PERSPECTIVE Dr. S. Shivakumar M.D., Addl. Professor of Medicine, Govt.Stanley Medical College, Chennai – 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.

PATHOGENESIS Sinusoidal 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: )]

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: )  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 Severity Na retention  RAS  GFR Pre-Ascitic Cirrhosis +–– Moderate& tense Ascites +++– Refractory Ascites Type II HRS Type I HRS +++

TYPE – 1 HRS TYPE 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 – Mechanism SECOND 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 ; 6 : ) (Contd..)

2 HIT HYPOTHESIS SPONTANEOUS BACTERIAL PERITONITIS G.I. BLEED  EABV OVER DIURESIS CHOLESTASIS LARGE VOLUME PARACENTESIS NEPHROTOXIC DRUGS First HitSecond 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   GFR  ATN   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 + Albumin  Prevents 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 Azotemia HRS

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