Pouliot-Cirrhosis-2024.pptx

Cirrhosis Jonathon Pouliot, MS, PharmD, BCPS Associate Professor Pharmacotherapy I Learning Objectives • Review liver function and associated complications seen in liver failure • Recall definition, pathophysiology, clinical presentation, and laboratory abnormalities commonly encountered in cirrho...

Cirrhosis Jonathon Pouliot, MS, PharmD, BCPS Associate Professor Pharmacotherapy I Learning Objectives • Review liver function and associated complications seen in liver failure • Recall definition, pathophysiology, clinical presentation, and laboratory abnormalities commonly encountered in cirrhosis • Given clinical information, determine a Child-Pugh classification and/or calculate a MELD score to determine cirrhosis disease severity • Given a patient scenario, design a pharmacologic plan for esophageal varices prophylaxis • Design a treatment regimen for hepatic encephalopathy with evaluation of efficacy and patient monitoring Learning Objectives • Construct a full treatment plan for a patient suffering from ascites with consideration for sodium intake/restriction, diuretic therapy, albumin use, and non-pharmacologic interventions. • Design a treatment plan for spontaneous bacterial peritonitis (SBP) including acute care, monitoring, and evaluation for prophylaxis (primary and secondary). • Understand coagulopathy in cirrhosis and principles of acute treatment for bleeding complications in cirrhotic patients • If given a patient case, evaluate a patient presenting with cirrhosis and prioritize complications and treatment strategies based on severity Review of Liver Function • Filtration/Toxin Clearance • • • • Bilirubin Ammonia Hormones Other toxins • Metabolism • Drugs via CYP and other enzymatic processes • Digestion • Bile salts and biliary flow • Protein Production/Synthesis • Clotting factors • Blood proteins (albumin, etc) • Storage • Fatty acids • Glucose • Fat-soluble vitamins (ADEK) Cirrhosis • “Irreversible fibrosis of the liver… end stage of chronic damage to the liver.” • 8th leading cause of death in US • 45% mortality • Causes: • Hepatitis • B and C mostly • Alcohol abuse • NAFLD • Gallstones/biliary obstructions • Medications • Other New Engl J Med. Non-Alcoholic Fatty Liver Disease (NAFLD) • ’Catch-all’ term for liver disease NOT associated with significant alcohol intake or other cause Wang et al. Ann Intern Med. NAFLD NAFL NASH • Most common (~80% of cases) • Isolated hepatic steatosis • Steatosis only seen without progression of liver disease • Similar on imaging, need biopsy to determine NAFL vs. NASH • Less common • Steatosis present • Progressive disease due to inflammation, hepatocyte damage, and possible fibrosis • Can progress to cirrhosis and hepatocellular carcinoma Wang et al. Ann Intern Med. 2018;169(9):ITC65-80 NAFLD Diagnosis • Often asymptomatic and an incidental finding • Patient evaluation • Past medical history  dyslipidemia, metabolic syndrome, cardiovascular disease, diabetes, obesity, etc • Alcohol use • Other social history • Objective findings • Elevated liver function labs • Steatosis on imaging • Differential diagnosis Wang et al. Ann Intern Med. 2018;169(9):ITC65-80 NAFLD Risk Stratification Wang et al. Ann Intern Med. 2018;169(9):ITC65-80 NAFLD Treatment • 3 Goals: • Preventing disease progression • Promoting regression • Managing comorbidities • Lifestyle modifications are mainstays of therapy • Medications • Vitamin E may provide benefit • Certain diabetes medications (metformin, pioglitazone) • Obeticholic acid (Ocaliva)  REGENERATE study completed and showed benefit but no FDA approval • Cenicriviroc  AURORA phase 3 trial ongoing Wang et al. Ann Intern Med. 2018;169(9):ITC65-80 Cirrhosis Progression Garcia-Tsao et al. Hepatology. Pathophysiology • Repetitive injury to hepatocytes  hepatocyte inflammation and fat deposits  Repeated injury overcomes reparative processes • Hepatocyte death nodule formation  collagen deposition and further fibrosis • Functional decline occurs after significant progression of cirrhosis • Two clinical stages: • Compensated and decompensated • Based on presence or absence of complications Garcia-Tsao et al. Hepatology. Pathophysiology Clinical Presentation • Asymptomatic until advanced disease • Hepatomegaly and splenomegaly • Jaundice/scleral icterus Clinical Presentation • Asterixis ( https://www.youtube.com/watch?v=sEnp2ss8VoA) • Pruritis, erythema, spider angiomas Clinical Presentation • Caput medusae Lab Findings • Hepatic Damage • AST • ALT • Alkaline Phosphatase • Filtration/Toxin Clearance Issues • Bilirubin • Ammonia • Synthetic Dysfunction • PT/INR • PTT • Albumin • Other Labs • CBC • Bone marrow suppression due to alcohol toxicity • Platelets • splenomegaly resulting from portal hypertension Diagnostics • Ultrasound • CT Scan • MRI • Angiography • ERCP • Endoscopic Retrograde Cholangiopancreatography • Biopsy Severity of Disease – ChildPugh • Originally used to grade risk of mortality for patients undergoing surgery for esophageal variceal bleeding • Now used for general prognosis cirrhotic patients • Combination of clinical evaluation (encephalopathy and ascites) and lab values (bilirubin, albumin, and PTT) • Components focused on liver function decline and progression of disease Severity of Disease – ChildPugh Child-Pugh Example • Patient with moderate confusion, ascites that responds to diuretic therapy, and the following labs: • Bilirubin – 4.6mg/dL • Albumin – 2.2 mg/dL • PT/INR – 2.4 • Child-Pugh Score: Severity of Disease - MELD • Model for End Stage Liver Disease (MELD) • Predicts 3 month mortality for end stage liver disease patients • YOU DO NOT NEED TO CALCULATE THIS FOR THE EXAM!! Severity of Disease - MELD Cirrhosis Complications • Portal Hypertension • Varices and variceal bleeding • Hepatic Encephalopathy • Ascites • Spontaneous Bacterial Peritonitis • Coagulopathy • Hepatorenal Syndrome • Other complications • Hypoglycemia, drug metabolism considerations, etc Portal Hypertension • Hepatic venous pressure gradient (HVPG) • Gradient between portal and central venous system • Portal HTN if HVPG > 5mmHg • Major complications • Varices • Ascites • Splenomegaly Garcia-Tsao et al. Hepatology. 2017;65(1):31035 Portal Hypertension Garcia-Tsao et al. Hepatology. Portal Hypertension Complications • Gastric and esophageal varices (GEV) are main complication of PH • Varices occur when HVPG approaches 10mmHg and risk of rupture/bleeding increases as HVPG increases • Endoscopy at cirrhosis diagnosis is important Garcia-Tsao et al. Hepatology. Varices • Diagnosed via endoscopy • Classified by size • Small – 5mm or less • Med/Large > 5mm • Also look for red wale signs • Red spots that indicate higher risk of rupture/bleeding • Concern is for rupture/bleeding and treatment aimed at prevention of bleeding Garcia-Tsao et al. Hepatology. PH/Varices Treatment Garcia-Tsao et al. Hepatology. PH/Varices Treatment • Guidelines recommend primary prophylaxis for patients with PH and varices when patient is at high risk of bleeding, defined as: • Medium to large varices are present • Small varices with positive red wale signs • Decompensated cirrhosis with small varices • Treatment of choice is non-selective beta-blockers • Goal for treatment is prevention of variceal bleeding • HVPG reduced below 12mmHg or >20% decrease from baseline Garcia-Tsao et al. Hepatology. PH/Varices Treatment Treatment Dose Goal Follow-up propranolol 20-40mg BID to start Titrate every 2-3 days up to 160mg/day (ascites) or 320mg/day (no ascites) Resting HR 55-60 BPM SBP>90mmHg Vitals at follow-up visits No endoscopy followup nadolol 20-40mg daily to start Titrate every 2-3 days up to 80mg/day (ascites) or 160mg/day (no ascites) Resting HR 55-60 BPM SBP>90mmHg Vitals at follow-up visits No endoscopy followup carvedilol 6.25mg once daily initially then increase to BID after 3 days Max dose 12.5mg/day (unless other indication) SBP>90mmHg No endoscopy followup Endoscopic variceal ligation Done every 2-8 weeks until eradication of varices Varices eradicated Endoscopy 3-6 months after finish then 612months later Garcia-Tsao et al. Hepatology. Endoscopic Variceal Ligation Garcia-Tsao et al. Hepatology. Variceal Bleeding • Varices can weaken and eventually rupture and bleed • If the only cirrhosis complication, mortality 20%. If other complications, mortality up to 80% • High risk event in cirrhosis patients (underlying coagulopathy) • HVPG > 20mmHg high risk of re-bleeding and death • Risk factors for bleeding: • Alcohol use, diet, underlying GERD, increased pressure (coughing, straining, exercise) Garcia-Tsao et al. Hepatology. Variceal Bleeding • Presentation should be considered a medical emergency • Classic GI bleed signs/symptoms +/- hemodynamic instability • Initial treatment: • ABCs (airway, breathing, circulation) • Volume resuscitation • PRBCs • Initiate when hemoglobin <7g/dL to maintain 7-9g/dL • Restrictive vs liberal transfusion strategy? • Goals: • Control bleeding • Prevent early recurrence (5 days) • Prevent 6 week mortality Garcia-Tsao et al. Hepatology. Variceal Bleeding • Correcting coagulopathy? • Antibiotic prophylaxis • Associated with decreased infection, re-bleeding and death • Ceftriaxone 1g Q24h for up to 7 days • Octreotide • Somatostatin analog, increases vascular tone in mesenteric circuit so decreases blood flow to the GI tract • Dose  50mcg bolus then 50mcg/hr continuous infusion for 2-5 days • Endoscopy • Within 12hrs and should be diagnostic and therapeutic if source is found Garcia-Tsao et al. Hepatology. Variceal Bleeding • Trans-jugular Intrahepatic Portosystemic Shunt (TIPS) • Overcomes pressure by shunting blood flow around liver • Should be done in 72hrs if patient is at high risk of failure/re-bleeding • Otherwise should be used as a ’rescue’ • Indication to stop octreotide after TIPS performed Garcia-Tsao et al. Hepatology. Variceal Bleeding Summary • Medical emergency! • Life saving measures first • Volume replacement to maintain hemodynamics • PRBC restrictively • Antibiotic prophylaxis • Endoscopy +/- intervention • Octreotide • TIPS if high risk • Secondary prophylaxis with beta-blockers (after octreotide stopped) • PPI? Garcia-Tsao et al. Hepatology. Recurrent Bleeding Hepatic Encephalopathy • Loosely defined as altered mental status or cognitive function changes in the setting of cirrhosis • Complex pathophysiology • Nitrogenous gut neurotoxin build up due to liver dysfunction • Alteration of gut flora • Blood flow shunted away from liver so clearance of toxins decreased • Some components of HE are unknown • Significant burden on healthcare, more than other Vilstrup et al. Hepatology. complications Hepatic Encephalopathy Vilstrup et al. Hepatology. Hepatic Encephalopathy • Diagnosis  rule out other potential causes for confusion • Serum ammonia concentrations • Asterixis presence • Classified by: • • • • Underlying disease Severity Time course Presence of precipitating factors • Infection, GI Bleed, diuretic overdose, electrolyte disorder, constipation Vilstrup et al. Hepatology. Hepatic Encephalopathy Treatment • Active treatment at first • Options: • Lactulose occurrence • Rifaximin • Primary prophylaxis not • Zinc replacement recommended for all • Branched-chain amino acids patients (BCAAs) • Secondary prophylaxis • Neomycin recommended • Metronidazole • Recurrent, intractable HE is an indication for liver transplant Vilstrup et al. Hepatology. Hepatic Encephalopathy Treatment • Lactulose • Acidifies the gut trapping NH3 by converting it to NH4+ and then stimulating removal • FIRST LINE for HE • Inexpensive • Dosing: • 25mL every 1-2hours titrated to 2-3 soft/loose stools per day • Usually dosed at 30-45mL Q4-6hrs for maintenance Vilstrup et al. Hepatology. Hepatic Encephalopathy Treatment • Rifaximin • Antimicrobial that decreases ammonia producing bacteria in the gut • Studied as an adjunctive agent (not monotherapy) • When added to lactulose therapy, shown to decrease recurrence of HE and HE-related hospitalizations • Dosing  550mg PO BID • Other options: • BCAAs have shown benefit as an alternative or addition to current therapy • Neomycin and metronidazole are listed as low grade Vilstrup et al. Hepatology. 2014;60(2):715-35 alternatives in the guidelines Ascites • Fluid retention in the peritoneal space • Combination of portal hypertension and decreased plasma protein (osmotic gradient) • Poor prognostic factor when present in cirrhosis patient • 1st decompensation-defining finding • Differentiating from other causes important Biggins et al. Hepatology. Ascites Biggins et al. Hepatology. Diagnostic Paracentesis • Recommended for new-onset ascites • Lab evaluation: • Ascitic fluid cell count and differential • Ascitic fluid total protein • Serum-ascites albumin gradient (SAAG) • Culture if infection suspected • SAAG Evaluation • SAAG = Serum albumin – Ascites albumin Biggins et al. Hepatology. Ascites Classifications Biggins et al. Hepatology. Ascites Treatment • Stop alcohol consumption (if alcohol-related) • Avoid exacerbating medications/diet • Sodium restriction (<2 grams/day) • Fluid restriction only if Serum Na < 125mmol/L • Diuretics • Therapeutic paracentesis • Albumin or baclofen for severe muscle cramps/spasms Biggins et al. Hepatology. Ascites Treatment • Sodium restriction • <2000mg per day • Takes a few weeks for effect • May be effective for mild ascites but often diuretics needed for moderate-refractory • Guidelines recommend urine sodium monitoring to assess compliance • Fluid restriction • Only if sodium < 125mEq/L • Restriction <1000mL/day Biggins et al. Hepatology. Ascites Treatment - Diuretics • Guideline recommendation  spironolactone 100mg + furosemide 40mg daily to start • • • • Monotherapy generally not recommended Titrate every 3-5 days maintaining the ratio 100:40 Once ascites is controlled, titrate down to lowest effective dose Adjust plan based on serum K+, serum Na+, SCr and body weight • Alternatives: • Amiloride 10-40mg/day if gynecomastia with spironolactone (eplerenone not studied in liver disease) • Triamterene, metolazone, HCTZ have been used but HCTZ could exacerbate hyponatremia Biggins et al. Hepatology. Ascites Treatment • Medications to avoid or without evidence for use • NSAIDs • ACE inhibitors/ARBs • Vasopressin receptor antagonists (vaptans) • Use with caution and only short-term for hyponatremia • Midodrine CAN be used in hypotensive ascitic patients • Non-selective beta blockers are NOT contraindicated in refractory ascites but use with caution if patient is hypotensive, hyponatremic or kidney injury Biggins et al. Hepatology. Ascites Treatment Paracentesis • Usually reserved for refractory ascites • Symptom relief but not disease-modifying • Albumin • Stabilizes circulatory function after fluid removal • Guidelines recommend use for paracentesis with >5L removed • 6-8grams per liter removed recommended • Improves survival • Refractory patients may require chronic albumin Biggins et al. Hepatology. Ascites Treatment • If refractory ascites develops, treatment options include: Serial paracenteses Scheduled albumin administration TIPS procedure Liver transplantation (this process should be expedited) • Peritoneovenous shunt if not a TIPS or transplant candidate • • • • Biggins et al. Hepatology. Spontaneous Bacterial Peritonitis • Infection of fluid in the peritoneal space not associated with a known intraabdominal infection • Most common type of infection in cirrhosis patients (36%) • 12% of patients with cirrhosis presenting with ascites • 50% community-acquired, 25% healthcare associated, and 25% nosocomial • Diagnosis: • Paracentesis prior to antibiotic exposure • Ascitic fluid polymorphonuclear leukocyte (PMN) > 250 cells/mm3 • Clinical presentation  fever, abdominal tenderness, redness, etc Biggins et al. Hepatology. SBP Treatment • Most common SBP isolates: • Escherichia coli, Klebsiella pneumoniae, Staph aureus, Enterococcus sp. • Increased incidence of multi-drug resistant organisms (MRDOs), up to 35% • Treat SBP if signs/symptoms present and PMN count >250/mm3 • IV antibiotics empirically • If NO MDROs suspected  3rd generation cephalosporin (cefoxatime or ceftriaxone) • If MDROs suspected  piperacillin/tazobactam or meropenem • For nosocomial infections, treat based on antibiogram • Tailor antibiotics based on paracentesis culture results • Albumin 1.5g/kg then 1g/kg on day 3 • Especially helpful in kidney injury and jaundice • Repeat paracentesis in 48hrs if lack of improvement Biggins et al. Hepatology. SBP Prophylaxis • Primary prophylaxis • GI bleeding  ceftriaxone 1gram/day for 7 days • Cirrhosis + ascites with <1.5g/dL ascitic fluid + impaired renal function or Child-Pugh >9 and Bili > 3 • Secondary prophylaxis • If one occurrence of SBP, patient should receive long-term prophylaxis • Options: • Oral ciprofloxacin is preferred • Oral Bactrim DS is also used Biggins et al. Hepatology. Coagulation and Bleeding • Complicated pathophysiology • Thrombocytopenia/neutropenia secondary to splenomegaly • Direct bone marrow suppression from alcohol • Nutritional deficiencies (intake and absorption) • Leads to fewer and less functional blood cells and therefore increased risk of infection and bleeding Coagulation and Bleeding • Protein synthesis deficiency as cirrhosis progresses • Clotting factor production decreased AND vit. K absorption decreased • Leads to increased risk of bleeding • INR will be elevated but not a ‘therapeutic’ measure Clinical Controversy • What happens when a cirrhosis patient with an elevated INR comes in with acute major bleeding? • No data for reversal options • 4 factor PCC, activated Factor VII, FFP, etc • INR does not correlate to magnitude of anticoagulation • Guidelines recommend AGAINST FFP and no recommendation for platelets • So what would you do? What happens in practice? Garcia-Tsao et al. Hepatology. Other Issues • Hypoglycemia • Lack of hepatocytes in advanced liver disease • Eventual depletion of storage and release of glucose in the liver • Hyponatremia • Ascites leads to dysregulation in free water elimination • Often hypervolemic hypotonic hyponatremia • Negative prognostic factor John et al. World J Gastroenterol. 2015;21(11): Drug Dosing Considerations • Pathophysiology of disease affects all aspects of ADME • Absorption decreased due to gastric blood flow • Distribution affected by fluid overload and decreased blood proteins • Metabolism affected by hepatocyte dysfunction • Elimination affected by biliary flow changes and renal blood flow • Hepatic drug metabolism affected • Phase I (CYP450) affected • Phase II (conjugation processes) relatively unaffected Pharmacologic Considerations • Sedating medications • Benzodiazepines, opiates, etc • Medications with significant liver metabolism • NSAIDs, ACEi/ARB, and other nephrotoxic medications • Hepatotoxic medications • Important to have a good drug info reference and when in doubt, look it up! Hepatorenal Syndrome • Development of renal failure in advanced cirrhosis not otherwise explained • Occurs in 10% of cirrhosis patients and associated with extremely poor prognosis • Two Types • Type I  rapidly progressing renal failure defined as SCr>2.5mg/dL or 50% reduction in CrCl to <20mL/min in <2 weeks • Type II  Moderate and steady renal Wadei decline et with al. Clin J Am Soc 2006;1:1066-79 Biggins etSCr>1.5mg/dL al. Hepatology. Nephrol. HRS Pathophysiology • Almost always presents when patient has some degree of ascites • Peripheral and splanchnic vasodilation • RAAS activation and renal vasoconstriction • Cardiac dysfunction and compensation mechanisms worsening renal injury ggins et al. Hepatology. 2021;74(2):1014-1048 Wadei et al. Clin J Am Soc Nephrol. 2006;1:1066-79 HRS Treatment • Type 1 requires hospitalization • Central access usually necessary for monitoring and drug administration • Stop diuretics  ascites managed with paracentesis • Albumin for volume expansion  20-40grams per day in divided doses • Vasopressin and other cardiovascular support • Potential for dopamine? • TIPS • Renal replacement therapies • Liver transplant ggins et al. Hepatology. 2021;74(2):1014-1048 Wadei et al. Clin J Am Soc Nephrol. 2006;1:1066-79 End Stage Liver Disease • Important to remember that complications are happening concurrently • Dynamic disease state requiring thorough knowledge of pathophysiology of complications • Liver transplantation is the only curative intervention • Hepatocellular carcinoma may develop in advanced cirrhosis patients Liver Transplantation • Patients should be evaluated for liver transplantation • Cause of cirrhosis matters and if substances involved, abstinence must be established • Child-Pugh and MELD score are part of patients rank on transplant list • Comprehensive evaluation process that involves multidisciplinary efforts Questions