HEPATORENAL SYNDROME – LIVER PERSPECTIVE

1. HEPATORENAL SYNDROME – LIVER PERSPECTIVE By Dr. S. Shivakumar M.D., Addl. Professor of Medicine, Govt.Stanley Medical College, Chennai – 600 001.

2. 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

3. 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.

4. 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

5. 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.

6. 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)]

7. 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)

8. 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

9. 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

10. ASCITES AND HRS

11. 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

12. (Contd..) 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 2001 34 ; 6 :1242-1251)

13. 2 HIT HYPOTHESIS SPONTANEOUS BACTERIAL PERITONITIS G.I. BLEED  EABV NEPHROTOXIC DRUGS OVER DIURESIS CHOLESTASIS LARGE VOLUME PARACENTESIS First Hit Second Hit

14. 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

15. 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

16. (Contd..) CHOLESTASIS • Other mechanisms • Endotoxemia • Nephrotoxic effect of  Bile acids • Disturbance of Renal Prostaglandins & Thromboxane Synthesis. • Hepatitis (Alcoholic, Toxic, Viral) + Sinusoidal PHT  HRS common

17. 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.

18. 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.

19. 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

20. Acute Renal Failure Fe Na < 1% > 1% CVP ATN < 5mmHg > 10mm Pre renal Azotemia HRS

21. 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