1. Treatment of chronic liver disease

2. Treatment Cause ( Etiology) Cause ( Etiology) Complication Complication

3. Etiology Infection Infection Alcohol Alcohol Autoimmune Autoimmune Cholestatic Cholestatic Infiltrative Infiltrative Metabolic Metabolic Vascular Vascular Drugs Drugs

4. Complications Ascites Ascites GI bleed GI bleed SBP SBP Edema Edema Hepatoma Hepatoma Encephalopathy Encephalopathy Hepatorenal syndrome Hepatorenal syndrome

5. Viral hepatitis Hepatitis B Hepatitis B  Nucleoside analogues  Lamivudine  Adefovir  Telbivudine  Entecavir  Tenofovir  Interferon Hepatitis C  Alfa interferon  Pegylated interferon  Ribavirin

6. Autoimmune hepatitis Autoimmune hepatitis  Prednisone  Azathioprine  New drugs Budesonide Budesonide Cyclosporine Cyclosporine Tacrolimus Tacrolimus Rapamycin Rapamycin Mycophenolate mofetil Mycophenolate mofetil NAFLD  Weight loss  Underlying disease  Silymarin/metformin  Bariatric surgery

7. Alcohol Alcohol  Abstinence  Fatty liver  Liver transplant Wilson disease  Penicillamine  Trientine  Zinc acetate  Tetrathiomolybdate Family screening

8. PBC PBC  Ursodeoxycholic acid  Symptomatic Cholestyramine/Rifampicin Cholestyramine/Rifampicin Calcium/vitamin D Calcium/vitamin D  PSC  ERCP  Liver transplant Hemochromatosis  Phlebotomy  Family screening  Alpa1 antitrypsin deficiency  4-phenylbutyric acid  Liver transplant  Genetic counseling

9. Liver insufficiency Variceal hemorrhage Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency Cirrhosis Ascites Encephalopathy Jaundice Portal hypertension Spontaneous bacterial peritonitis Hepatorenal syndrome COMPLICATIONS OF CIRRHOSIS

10. Varices/ Variceal Hemorrhage Varices/ Variceal Hemorrhage Variceal obliteration Variceal obliteration Portal pressure Resistance to portal flow Cirrhosis Resistance to portal flow Splanchnic arteriolar resistance Portal blood inflow Variceal Band Ligation or Sclerotherapy MECHANISM OF ACTION OF ENDOSCOPIC THERAPY IN PORTAL HYPERTENSION

11. Predictors of hemorrhage:  Variceal size  Red signs  Child B/C Predictors of hemorrhage:  Variceal size  Red signs  Child B/C NIEC. N Engl J Med 1988; 319:983 Variceal hemorrhage Varix with red signs PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE

12. Treatment of Varices / Variceal Hemorrhage Recurrent hemorrhage Recurrent hemorrhage Variceal hemorrhage Variceal hemorrhage Varices No hemorrhage Varices No hemorrhage No varices Management depends on the size of varices MANAGEMENT OF PATIENTS WITH VARICES WHO HAVE NEVER BLED

13. Treatment of Varices / Variceal Hemorrhage Recurrent hemorrhage Recurrent hemorrhage Variceal hemorrhage Variceal hemorrhage Medium/ large varices No hemorrhage Medium/ large varices No hemorrhage Small varices No hemorrhage Small varices No hemorrhage No varices 1)  -blockers (propranolol, nadolol) indefinitely 2) Endoscopic Variceal Ligation in patients intolerant to  - blockers 1)  -blockers (propranolol, nadolol) indefinitely 2) Endoscopic Variceal Ligation in patients intolerant to  - blockers MANAGEMENT OF PATIENTS WITH MEDIUM/LARGE VARICES WITHOUT PRIOR HEMORRHAGE

14. Treatment of Varices / Variceal Hemorrhage Control of hemorrhage Recurrent hemorrhage Recurrent hemorrhage Variceal hemorrhage Variceal hemorrhage Medium/ large varices No hemorrhage Medium/ large varices No hemorrhage Small varices No hemorrhage Small varices No hemorrhage No varices CONTROL OF ACUTE VARICEAL HEMORRHAGE

15. Treatment of Acute Variceal Hemorrhage General Management: IV access and fluid resuscitation IV access and fluid resuscitation Do not over transfuse (hemoglobin ~ 8 g/dL) Do not over transfuse (hemoglobin ~ 8 g/dL) Antibiotic prophylaxis Antibiotic prophylaxis Specific therapy: Pharmacological therapy: Terlipressin, Somatostatin and analogues, Vasopressin + Nitroglycerin Pharmacological therapy: Terlipressin, Somatostatin and analogues, Vasopressin + Nitroglycerin Endoscopic therapy: Ligation, Sclerotherapy Endoscopic therapy: Ligation, Sclerotherapy Shunt therapy: TIPS, surgical shunt Shunt therapy: TIPS, surgical shunt General Management: IV access and fluid resuscitation IV access and fluid resuscitation Do not over transfuse (hemoglobin ~ 8 g/dL) Do not over transfuse (hemoglobin ~ 8 g/dL) Antibiotic prophylaxis Antibiotic prophylaxis Specific therapy: Pharmacological therapy: Terlipressin, Somatostatin and analogues, Vasopressin + Nitroglycerin Pharmacological therapy: Terlipressin, Somatostatin and analogues, Vasopressin + Nitroglycerin Endoscopic therapy: Ligation, Sclerotherapy Endoscopic therapy: Ligation, Sclerotherapy Shunt therapy: TIPS, surgical shunt Shunt therapy: TIPS, surgical shunt TREATMENT OF ACUTE VARICEAL HEMORRHAGE

16. Endoscopic Variceal Band Ligation Bleeding controlled in 90% Bleeding controlled in 90% Rebleeding rate 30% Rebleeding rate 30% Compared with Sclerotherapy: Compared with Sclerotherapy: Less rebleeding Less rebleeding Lower mortality Lower mortality Fewer complications Fewer complications Fewer treatment sessions Fewer treatment sessions Bleeding controlled in 90% Bleeding controlled in 90% Rebleeding rate 30% Rebleeding rate 30% Compared with Sclerotherapy: Compared with Sclerotherapy: Less rebleeding Less rebleeding Lower mortality Lower mortality Fewer complications Fewer complications Fewer treatment sessions Fewer treatment sessions ENDOSCOPIC VARICEAL BAND LIGATION

17. Transjugular Intrahepatic Porto systemic Shunt HepaticveinHepaticvein Portal vein SplenicveinSplenicvein Superior mesenteric vein TIPSTIPS THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

18. Gastric Varices Pretreatment cyanoacrylate Post-treatment cyanoacrylate ENDOSCOPIC IMAGES OF GASTRIC VARICES

19. Mild Mild and Severe Portal Hypertensive Gastropathy Severe Mosaic pattern Mosaic pattern + red spots Carpinelli et al. Ital J Gastroenterol Hepatol 1997; 29:533 ENDOSCOPIC IMAGES OF MILD AND SEVERE PORTAL HYPERTENSIVE GASTROPATHY

20. Ascites and Hepatorenal Syndrome ASCITES AND HEPATORENAL SYNDROME

21. Natural History of Ascites HVPG >10 mmHg Extreme Vasodilation HVPG >10 mmHg Extreme Vasodilation HVPG >10 mmHg Severe Vasodilation HVPG >10 mmHg Severe Vasodilation HVPG >10 mmHg Moderate Vasodilation HVPG >10 mmHg Moderate Vasodilation HVPG <10 mmHg Mild Vasodilation HVPG <10 mmHg Mild Vasodilation Hepatorenal Syndrome Hepatorenal Syndrome Refractory Ascites Refractory Ascites Uncomplicat ed Ascites Uncomplicat ed Ascites Portal Hypertension No Ascites Portal Hypertension No Ascites NATURAL HISTORY OF ASCITES

22. Diagnostic Paracentesis IndicationsIndications ContraindicationsContraindications New-onset ascites New-onset ascites Admission to hospital Admission to hospital Symptoms/signs of SBP Symptoms/signs of SBP Renal dysfunction Renal dysfunction Unexplained encephalopathy Unexplained encephalopathy New-onset ascites New-onset ascites Admission to hospital Admission to hospital Symptoms/signs of SBP Symptoms/signs of SBP Renal dysfunction Renal dysfunction Unexplained encephalopathy Unexplained encephalopathy None None DIAGNOSTIC PARACENTESIS

23. Management of Uncomplicated Ascites Definition: Ascites responsive to diuretics in the absence of infection and renal dysfunction Sodium restriction Effective in 10-20% of cases Effective in 10-20% of cases Predictors of response: mild or moderate ascites, Urine Na excretion > 50 mEq/day Predictors of response: mild or moderate ascites, Urine Na excretion > 50 mEq/dayDiuretics Should be spironolactone-based Should be spironolactone-based A progressive schedule (spironolactone  furosemide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide) A progressive schedule (spironolactone  furosemide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide) Sodium restriction Effective in 10-20% of cases Effective in 10-20% of cases Predictors of response: mild or moderate ascites, Urine Na excretion > 50 mEq/day Predictors of response: mild or moderate ascites, Urine Na excretion > 50 mEq/dayDiuretics Should be spironolactone-based Should be spironolactone-based A progressive schedule (spironolactone  furosemide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide) A progressive schedule (spironolactone  furosemide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide) MANAGEMENT OF UNCOMPLICATED ASCITES

24. Sodium Restriction 2 g (or 5.2 g of dietary salt) a day 2 g (or 5.2 g of dietary salt) a day Fluid restriction is not necessary unless there is hyponatremia (<125 mmol/L) Fluid restriction is not necessary unless there is hyponatremia (<125 mmol/L) Goal: negative sodium balance Goal: negative sodium balance Sodium Restriction 2 g (or 5.2 g of dietary salt) a day 2 g (or 5.2 g of dietary salt) a day Fluid restriction is not necessary unless there is hyponatremia (<125 mmol/L) Fluid restriction is not necessary unless there is hyponatremia (<125 mmol/L) Goal: negative sodium balance Goal: negative sodium balance Management of Uncomplicated Ascites MANAGEMENT OF UNCOMPLICATED ASCITES: SODIUM RESTRICTION

25. Diuretic Therapy Dosage Spironolactone 100-400 mg/day Spironolactone 100-400 mg/day Furosemide (40-160 mg/d) for inadequate weight loss or if hyperkalemia develops Furosemide (40-160 mg/d) for inadequate weight loss or if hyperkalemia develops Increase diuretics if weight loss <1 kg in the first week and < 2 kg/week thereafter Increase diuretics if weight loss <1 kg in the first week and < 2 kg/week thereafter Decrease diuretics if weight loss >0.5 kg/day in patients without edema and >1 kg/day in those with edema Decrease diuretics if weight loss >0.5 kg/day in patients without edema and >1 kg/day in those with edema Side effects Side effects Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia Diuretic Therapy Dosage Spironolactone 100-400 mg/day Spironolactone 100-400 mg/day Furosemide (40-160 mg/d) for inadequate weight loss or if hyperkalemia develops Furosemide (40-160 mg/d) for inadequate weight loss or if hyperkalemia develops Increase diuretics if weight loss <1 kg in the first week and < 2 kg/week thereafter Increase diuretics if weight loss <1 kg in the first week and < 2 kg/week thereafter Decrease diuretics if weight loss >0.5 kg/day in patients without edema and >1 kg/day in those with edema Decrease diuretics if weight loss >0.5 kg/day in patients without edema and >1 kg/day in those with edema Side effects Side effects Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia Management of Uncomplicated Ascites MANAGEMENT OF UNCOMPLICATED ASCITES: DIURETIC THERAPY

26. Definition and Types of Refractory Ascites Occurs in ~10% of cirrhotic patients Diuretic-intractable ascites Diuretic-intractable ascites Therapeutic doses of diuretics cannot be achieved because of diuretic-induced complications Diuretic-resistant ascites Diuretic-resistant ascites No response to maximal diuretic therapy (400 mg spironolactone + 160 mg furosemide/day) Diuretic-intractable ascites Diuretic-intractable ascites Therapeutic doses of diuretics cannot be achieved because of diuretic-induced complications Diuretic-resistant ascites Diuretic-resistant ascites No response to maximal diuretic therapy (400 mg spironolactone + 160 mg furosemide/day) 20% 80% DEFINITION AND TYPES OF REFRACTORY ASCITES

27. Spontaneous Bacterial Peritonitis (SBP) Complicates Ascites and Can Lead to Renal Dysfunction SBP HVPG >10 mmHg Extreme Vasodilation HVPG >10 mmHg Extreme Vasodilation HVPG >10 mmHg Severe Vasodilation HVPG >10 mmHg Severe Vasodilation HVPG >10 mmHg Moderate Vasodilation HVPG >10 mmHg Moderate Vasodilation HVPG <10 mmHg Mild Vasodilation HVPG <10 mmHg Mild Vasodilation Hepatorenal Syndrome Hepatorenal Syndrome Refractory Ascites Refractory Ascites Uncomplicated Ascites Uncomplicated Ascites Portal Hypertension No Ascites Portal Hypertension No Ascites SPONTANEOUS BACTERIAL PERITONITIS (SBP) COMPLICATES ASCITES AND CAN LEAD TO RENAL DYSFUNCTION

28. Early Diagnosis of SBP Diagnostic paracentesis: Diagnostic paracentesis: If symptoms / signs of SBP occur If symptoms / signs of SBP occur Unexplained encephalopathy and / or renal dysfunction Unexplained encephalopathy and / or renal dysfunction At any hospital admission At any hospital admission Diagnosis based on ascitic fluid Diagnosis based on ascitic fluid PMN count >250/mm 3 Diagnostic paracentesis: Diagnostic paracentesis: If symptoms / signs of SBP occur If symptoms / signs of SBP occur Unexplained encephalopathy and / or renal dysfunction Unexplained encephalopathy and / or renal dysfunction At any hospital admission At any hospital admission Diagnosis based on ascitic fluid Diagnosis based on ascitic fluid PMN count >250/mm 3 EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)

29. Microorganisms Isolated in Spontaneous Bacterial Peritonitis Microorganism % of Cases Gram-negative bacilli72 Gram-positive cocci29 Microorganism % of Cases Gram-negative bacilli72 Gram-positive cocci29 MICROORGANISMS ISOLATED IN SPONTANEOUS BACTERIAL PERITONITIS (SBP)

30. Treatment of Spontaneous Bacterial Peritonitis Recommended antibiotics for initial empiric therapy Recommended antibiotics for initial empiric therapy i.v. cefotaxime, i.v. cefotaxime, i.v. amoxicillin-clavulanic acid i.v. amoxicillin-clavulanic acid avoid aminoglycosides avoid aminoglycosides Minimum duration: 5 days Minimum duration: 5 days Recommended antibiotics for initial empiric therapy Recommended antibiotics for initial empiric therapy i.v. cefotaxime, i.v. cefotaxime, i.v. amoxicillin-clavulanic acid i.v. amoxicillin-clavulanic acid avoid aminoglycosides avoid aminoglycosides Minimum duration: 5 days Minimum duration: 5 days TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)

31. Indications for Prophylactic Antibiotics to Prevent Spontaneous Bacterial Peritonitis Patients who have recovered from SBP (long-term) Patients who have recovered from SBP (long-term) Norfloxacin 400 mg p.o. daily, indefinitely Norfloxacin 400 mg p.o. daily, indefinitely Weekly Quinolones Weekly Quinolones Patients who have recovered from SBP (long-term) Patients who have recovered from SBP (long-term) Norfloxacin 400 mg p.o. daily, indefinitely Norfloxacin 400 mg p.o. daily, indefinitely Weekly Quinolones Weekly Quinolones INDICATIONS FOR PROPHYLACTIC ANTIBIOTICS TO PREVENT SPONTANEOUS BACTERIAL PERITONITIS (SBP)

32. Characteristics of Hepatorenal Syndrome Renal failure in patients with cirrhosis, advanced liver failure and severe sinusoidal portal hypertension Renal failure in patients with cirrhosis, advanced liver failure and severe sinusoidal portal hypertension Absence of significant histological changes in the kidney (“functional” renal failure) Absence of significant histological changes in the kidney (“functional” renal failure) Marked arteriolar vasodilation in the extra-renal circulation Marked arteriolar vasodilation in the extra-renal circulation Marked renal vasoconstriction leading to reduced glomerular filtration rate Marked renal vasoconstriction leading to reduced glomerular filtration rate Renal failure in patients with cirrhosis, advanced liver failure and severe sinusoidal portal hypertension Renal failure in patients with cirrhosis, advanced liver failure and severe sinusoidal portal hypertension Absence of significant histological changes in the kidney (“functional” renal failure) Absence of significant histological changes in the kidney (“functional” renal failure) Marked arteriolar vasodilation in the extra-renal circulation Marked arteriolar vasodilation in the extra-renal circulation Marked renal vasoconstriction leading to reduced glomerular filtration rate Marked renal vasoconstriction leading to reduced glomerular filtration rate CHARACTERISTICS OF HEPATORENAL SYNDROME (HRS)

33. Two Types of Hepatorenal Syndrome Type 1 Rapidly progressive renal failure (2 weeks) Rapidly progressive renal failure (2 weeks) Doubling of creatinine to >2.5 Doubling of creatinine to >2.5 Type 2 More slowly progressive More slowly progressive Creatinine >1.5 mg/dL or Creatinine Clearance 1.5 mg/dL or Creatinine Clearance < 40 ml/min Associated with refractory ascites Associated with refractory ascites Type 1 Rapidly progressive renal failure (2 weeks) Rapidly progressive renal failure (2 weeks) Doubling of creatinine to >2.5 Doubling of creatinine to >2.5 Type 2 More slowly progressive More slowly progressive Creatinine >1.5 mg/dL or Creatinine Clearance 1.5 mg/dL or Creatinine Clearance < 40 ml/min Associated with refractory ascites Associated with refractory ascites TYPES OF HEPATORENAL SYNDROME (HRS)

34. Management of Hepatorenal Syndrome Proven efficacy  Liver transplantation Under investigation  Vasoconstrictor + albumin  Transjugular intrahepatic portosystemic shunt (TIPS)  Vasoconstrictor + TIPS  Extracorporeal albumin dialysis (ECAD) Ineffective  Renal vasodilators (prostaglandin, dopamine)  Hemodialysis Proven efficacy  Liver transplantation Under investigation  Vasoconstrictor + albumin  Transjugular intrahepatic portosystemic shunt (TIPS)  Vasoconstrictor + TIPS  Extracorporeal albumin dialysis (ECAD) Ineffective  Renal vasodilators (prostaglandin, dopamine)  Hemodialysis MANAGEMENT OF HEPATORENAL SYNDROME

35. Hepatic Encephalopathy

36. Pathophysiology of Hepatic Encephalopathy Ammonia Upregulation of astrocytic peripheral benzodiazepine receptors (PBR) Neurosteroid production Modulation of GABA receptor Hepatic encephalopathy Ammonia Upregulation of astrocytic peripheral benzodiazepine receptors (PBR) Neurosteroid production Modulation of GABA receptor Hepatic encephalopathy PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

37. Hepatic Encephalopathy is a Clinical Diagnosis Clinical findings and history important Clinical findings and history important Ammonia levels are unreliable Ammonia levels are unreliable Ammonia has poor correlation with diagnosis Ammonia has poor correlation with diagnosis Measurement of ammonia not necessary Measurement of ammonia not necessary Number connection test Number connection test Slow dominant rhythm on EEG Slow dominant rhythm on EEG Clinical findings and history important Clinical findings and history important Ammonia levels are unreliable Ammonia levels are unreliable Ammonia has poor correlation with diagnosis Ammonia has poor correlation with diagnosis Measurement of ammonia not necessary Measurement of ammonia not necessary Number connection test Number connection test Slow dominant rhythm on EEG Slow dominant rhythm on EEG HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS

38. STAGES OF HEPATIC ENCEPHALOPATHY Confusion Drowsiness Somnolence Coma 1 1 2 2 3 3 4 4 Stage Stages of Hepatic Encephalopathy

39. Treatment of Hepatic Encephalopathy Identify and treat precipitating factor Identify and treat precipitating factor Infection Infection GI hemorrhage GI hemorrhage Prerenal azotemia Prerenal azotemia Sedatives Sedatives Constipation Constipation Lactulose (adjust to 2-3 bowel movements/day) Lactulose (adjust to 2-3 bowel movements/day) Protein restriction, short-term (if at all) Protein restriction, short-term (if at all) Identify and treat precipitating factor Identify and treat precipitating factor Infection Infection GI hemorrhage GI hemorrhage Prerenal azotemia Prerenal azotemia Sedatives Sedatives Constipation Constipation Lactulose (adjust to 2-3 bowel movements/day) Lactulose (adjust to 2-3 bowel movements/day) Protein restriction, short-term (if at all) Protein restriction, short-term (if at all) TREATMENT OF HEPATIC ENCEPHALOPATHY

40. Liver transplant All patients with end stage liver disease should be assessed for liver transplant when ever is proven to significantly prolong survival and improve quality of life in a coast effective manner over natural history of the liver disease and other medical and non transplant surgical intervention. All patients with end stage liver disease should be assessed for liver transplant when ever is proven to significantly prolong survival and improve quality of life in a coast effective manner over natural history of the liver disease and other medical and non transplant surgical intervention.