Treatment of chronic liver disease

Treatment Cause ( Etiology) Cause ( Etiology) Complication Complication

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ascites and Hepatorenal Syndrome ASCITES AND HEPATORENAL SYNDROME

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

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

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

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

Diuretic Therapy Dosage Spironolactone mg/day Spironolactone mg/day Furosemide ( mg/d) for inadequate weight loss or if hyperkalemia develops Furosemide ( 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 mg/day Spironolactone mg/day Furosemide ( mg/d) for inadequate weight loss or if hyperkalemia develops Furosemide ( 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

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 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 mg furosemide/day) 20% 80% DEFINITION AND TYPES OF REFRACTORY ASCITES

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

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)

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)

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)

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)

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)

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)

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

Hepatic Encephalopathy

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

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

STAGES OF HEPATIC ENCEPHALOPATHY Confusion Drowsiness Somnolence Coma Stage Stages of Hepatic Encephalopathy

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

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.