Cirrhosis Update Robert S. Brown, Jr., MD, MPH Vice Chair, Transitions of Care Interim Chief, Division of Gastroenterology & Hepatology Weill Cornell Medical College
CIRRHOSIS Definition Irreversible fibrous scarring within the liver which has lead to the development of regenerative nodules Estimated 3-4 million people in the U.S. have CLD and cirrhosis! CLD 15-20 million
Portal Hypertension
Resistance x Flow = Portal Hypertension Increased Resistance (Architectural changes secondary to fibrous tissue formation; active vasoconstriction due to decrease in formation of endogenous NO) Increased Blood Flow (Splanchnic arteriolar vasodilation ) Increased Portal Pressure Adapted from Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Portal Hypertension Consequences of portal hypertension produce symptoms: Gastroesophageal varices Ascites Enlarged spleen Hepatic encephalopathy" From: http://www.merck.com/mmhe/sec10/ch135/ch135d.html. Accessed 02/15/11.
Gastroesophageal Varices
Gastroesophageal Varices Gastroesophageal varices present in ~50% of patients with cirrhosis Presence correlates with severity of liver disease 40% of Child A patients have varices 85% of Child C patients have varices Cirrhotic patients without varices develop them at a rate of 8% per year Patients with small varices develop large varices at a rate of 8% per year Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Gastroesophageal Variceal Hemorrhage Occurs at a yearly rate of 5% to 15% Most important predictor of hemorrhage is size of varices Other predictors of hemorrhage are: Decompensated cirrhosis (Child B/C) Endoscopic presence of red wale marks Associated with a mortality of 20% at 6 weeks Bleeding ceases spontaneously in 40% of patients Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Cirrhosis Screening and Surveillance Management Esophagogastroduodenoscopy No varices Small varices (<5 mm), Child B/C, red wales Medium or large varices Repeat endoscopy in 3 years (well compensated); in 1 year if decompensated No beta-blocker prophylaxis Beta-blocker prophylaxis Child Class A, no red wales: Beta blockers Child class B/C, red wales: Beta blockers, or endoscopic band ligation" Adapted from Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Management of Acute Hemorrhage Patients with suspected acute variceal hemorrhage require intensive-care unit setting for resuscitation and management Acute GI hemorrhage requires: Intravascular volume support Blood transfusions Maintaining hemoglobin of ~8 g/dl Institute short-term (7-day) antibiotic prophylaxis Initiate therapy with somatostatin (or its analogs) Perform esophagogastroduodenoscopy within 12 hours; treat with endoscopic band ligation or sclerotherapy Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Management of Acute Hemorrhage (cont) TIPS (transjugular intrahepatic portosystemic shunt) indicated if hemorrhage uncontrolled or recurrent bleeding despite pharmacologic and endoscopic therapy Balloon tamponade should be temporary measure used prior to more definitive therapy Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Bacterial Infection and Variceal Bleeding Variceal bleeding associated with increased risk of bacterial infection SBP (spontaneous bacterial peritonitis), urinary tract infection, pneumonia or bacteremia Develops in 20% of patients within 48 hours and in 35% to 66% of patients within 2 weeks Compared to patients without infection, presence of infection is associated with Failure to control bleeding (65% vs 15%) Early rebleeding Mortality (40% vs 3%) Vivas S et al., Dig Dis Sci. 2001;46:2752-2757.
Antibiotic Prophylaxis During/After Acute Variceal Bleeding Prophylatic ofloxacin vs antibiotics only at diagnosis of infection infections (2/59 vs 16/61) Less rebleeding within 7 days blood transfusions for rebleeding Prophylactic antibiotics recommended in management of acute variceal hemorrhage Probability of Rebleeding 1.0 0.8 0.6 0.4 0.2 Patients at risk Prophylactic antibiotics (n=59) On-demand antibiotics (n=61) 0.0 0 1 2 3 12 18 24 30 Follow-up (Months) Prophylactic: 59 48 42 38 17 8 2 On demand: 51 36 34 30 19 9 2 Hou M-C et al. Hepatology. 2004;39:746-753.
Ascites
Ascites Most common complication of cirrhosis Only occurs when portal hypertension has developed ~60% of patients with compensated cirrhosis develop ascites within 10 years 50% mortality rate within 3 years Patients should generally be considered for liver transplantation referral Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89. European Association for the Study of the Liver. J Hepatol. 2010;53:397-417.
Prognosis of Patients with Cirrhosis at Onset of Ascites Probability of Survival 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 Years Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89.
AASLD Practice Guidelines: Ascitic Fluid Analysis Routine Optional Unusual Unhelpful Cell count and differential Culture in blood culture bottles Acid-fast bacteria smear and culture Albumin Glucose Cytology Lactate Total protein Lactose dehydrogenase Trigylceride ph Cholesterol Amylase Bilirubin Fibronectin Gram s stain Glycosaminoglycans Runyon BA. Hepatology. 2009; 49:2087-2107.
Management of Ascites First-Line Therapy Tense ascites Paracentesis Sodium restriction (<2 Gm/24 Hrs) and diuretics* Non-tense ascites Refractory Ascites 10 % Second-Line Therapy Repeated large volume paracentesis (LVP) TIPS Liver Transplantation *Diuretics: Spironolactone 100 mg/day, furosemide 40 mg/day or bumetanide 1 mg/day; uptitrate stepwise to spironolactone 400 mg/day, furosemide 160 mg/day or bumetanide 4 mg/day as tolerated Albumin infusion of 12 gm/liter of fluid removed is a consideration for repeated LVP; post-paracentesis albumin infusion may not be necessary for < 5 liters removed Adapted from Runyon BA. Hepatology. 2009; 49:2087-2107.
Spontaneous Bacterial Peritonitis (SBP)
Spontaneous Bacterial Peritonitis: Diagnosis Diagnosis of SBP: Positive ascitic fluid bacterial culture Elevated ascitic fluid absolute PMN count (ie, 250 cells/mm 3 [0.25 x 10 9 /L]) No evident intra-abdominal source of infection Runyon BA. Hepatology. 2009; 49:2087-2107.
Prevention of SBP Prophylaxis Risk factors for development of SBP Ascitic fluid protein concentration <1.0 g/dl Variceal hemorrhage Prior episode of SBP Prophylactic antibiotics Drug Therapy Norfloxacin Ceftriaxone Double-strength sulfamethoxazole/trimethoprim Ciprofloxacin Dose /Duration 400 mg/day orally 1g/day IV for 7 days 5-7 doses/week 750 mg as single oral dose/week Intermittent dosing of prophylactic antibiotics may select resistant flora; daily dosing preferred Runyon BA. Hepatology. 2009; 49:2087-2107.
Renal Dysfunction
Renal Injury in Cirrhosis Hospitalized patients with cirrhosis Pre-renal 68% Chronic renal failure 1% Intra-renal (ATN, GMN) 32% ARF / AKI 19% Post-renal (obstructive) <1% Volume-responsive 66% Infection Hypovolemia Vasodilators Other Not volume-responsive HRS type 1 25% ARF: Acute renal failure Garcia-Tsao G et al. Hepatology. 2008;48:2064-2077. ATN: Acute tubular necrosis HRS: Hepatorenal syndrome HRS type 2 9% GMN: Glomerulonephritis AKI: Acute kidney injury
Survival is Decreased with Renal Dysfunction Survival in Cirrhosis Based on Level" of Renal Dysfunction" Survival Among Patients With Cirrhosis and Hepatorenal Syndrome 1.0 1.0 Survival 0.8 P<0.001 0.6 Creatinine <1.2 mg/dl 0.8 0.6 0.4 0.2 Creatinine 1.2-1.5mg/dL 0.4 0.2 Refractory ascites Creatinine >1.5mg/dL Type 1 hepatorenal syndrome 0.0 0.0 0 1 2 3 4 5 0 1 2 3 4 5 6 Years Months Survival Blackwell: Science, Oxford, UK. Gines et al. N Engl J Med. 2004;350:1646-1654.
Prevention of Acute Renal Injury in Cirrhotics Prevent/treat volume depletion or vasodilatation Careful use of diuretics Avoidance of diarrhea with use of lactulose Use of albumin after large-volume paracentesis Avoid use of aminoglycosides and NSAIDs Aggressively treat hypovolemia/hypotension occurrence Garcia-Tsao G et al. Hepatology. 2008;48:2064-2077.
Hepatorenal Syndrome
Hepatorenal Syndrome: Risk Factors Development of bacterial infections, particularly SBP, is the most important risk factor Hepatorenal syndrome develops in ~30% of patients with spontaneous bacterial peritonitis Treatment with albumin infusion/antibiotics reduces the risk of developing hepatorenal syndrome and improves survival European Association for the Study of the Liver. J Hepatol. 2010;53:397-417.
Hepatorenal Syndrome: Prognosis The prognosis of hepatorenal syndrome is poor Average median survival ~ 3 months High MELD score and type 1 hepatorenal syndrome are associated with very poor prognosis Median survival of patients with untreated type 1 hepatorenal syndrome is ~ 1 month European Association for the Study of the Liver. J Hepatol. 2010;53:397-417.
Hepatic Encephalopathy (HE)
Treatment Goals for OHE Provision for supportive care Identification and removal of precipitating factors Infection, GI bleed, dehydration Reduction of nitrogenous load from gut Correction of electrolyte abnormalities Long-term therapy assessment Control of potential precipitating factors Higher likelihood of recurrent encephalopathy Assessment of need for liver transplantation Adapted from Blei AT et al. Am J Gastroenterol. 2001;96(7):1968-1976.
Current Therapy Options for HE Drug Name Drug Class Indication Lactulose Rifaximin Neomycin Metronidazole Vancomycin Poorly absorbed disaccharide Non-aminoglycoside semi-synthetic, nonsystemic antibiotic Aminoglycoside antibiotic Synthetic antiprotozoal and antibacterial agent Aminoglycoside antibiotic Decrease blood ammonia concentration Prevention and treatment of portal-systemic encephalopathy Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients 18 years of age. Not to be used, renal and ototoxic risk Not approved for HE Not approved for HE Adapted from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/gastrointestinaldrugs AdvisoryCommittee/UCM203247.pdf, accessed 02/17/11 and http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf, accessed 02/17/11.
Lactulose Currently the mainstay of therapy of HE; ~70% to 80% of patients with acute and chronic HE improve with lactulose treatment Mechanism of action: A non-absorbable dissacharide that is fermented in the colon Metabolism by the bacterial flora in the colon to lactic acid lowers the colonic ph Cathartic effect can increase fecal nitrogen excretion with up to a 4-fold increase in stool volume Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. Ferenci P. Semin Liver Dis. 2007;27(suppl 2):10-17. Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547.
Lactulose (cont) Administered orally, by mouth or through a nasogastric tube or via retention enemas Dose: 45 to 90 g/day, titrated to achieve 2 to 3 soft stools per day with a ph below 6 Principal side effects include abdominal distension, cramping, diarrhea, electrolyte changes, and flatulence Systematic review of clinical studies found insufficient evidence to support or refute the use of lactulose for HE Ferenci P. Semin Liver Dis. 2007;27(suppl 2):10-17. Als-Nielsen et al. BMJ 2004;328:1046-1051. Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547.
Rifaximin Minimally absorbed (<0.4%) oral antibiotic Broad-spectrum in vitro activity against aerobic and anaerobic enteric bacteria No clinical drug interactions reported No dosing adjustment required in patients with liver disease or renal insufficiency Approved for overt recurrent HE risk reduction in patients 18 years of age In registration trials, 91% of patients were given lactulose concomitantly Bass NM. Semin Liver Dis. 2007;27(suppl 2):18-25. Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.
Rifaximin Trial: Randomization and Follow-Up Rifaximin 550 mg BID: n=140 Placebo: n=159 Discontinued: n=52 (37%) Breakthrough HE: n=28 Adverse event: n=8 Death: n=6 Patient request: n=6 Exclusion criteria: n=1 Other: n=3 Randomization 1:1 N=299 (Randomized Controlled Trial) Discontinued: n=93 (58%) Breakthrough HE: n=69 Patient request: n=9 Adverse event: n=7 Death: n=3 Exclusion criteria: n=3 Other: n=2 Completed Study: n=88 Completed Study: n=66 Bass NM et al. N Engl J Med. 2010;362:1071-1081.
Rifaximin Trial: Lactulose Use at Baseline and During Study Rifaximin (n=140) Placebo (n=159) Lactulose use at baseline no (%)* 128 (91.4%) 145 (91.2%) Lactulose use during study no (%)* 128 (91.4%) 145 (91.2%) *During the study, 3 patients discontinued therapy with lactulose and 3 patients started therapy with lactulose (1 in the rifaximin group and 2 in the placebo group). Bass NM et al. N Engl J Med. 2010;362:1071-1081.
Rifaximin Trial: Time to First Breakthrough HE Episode Primary End Point Proportion of Patients Without Breakthrough HE (%) *Rifaximin 550 mg or placebo twice daily Hazard ratio with rifaximin, 0.42 (95% Cl, 0.28 0.64) P<0.001 Rifaximin* (77.9%) Placebo* (54.1%) Days Since Randomization Bass NM et al. N Engl J Med. 2010;362:1071-1081.
Rifaximin Trial: Time to First HE- Related Hospitalization Key Secondary End Point Proportion of Patients Without HE-Related Hospitalization (%) *Rifaximin 550 mg or placebo twice daily Hazard ratio with rifaximin, 0.42 (95% Cl, 0.28 0.64) P<0.001 Rifaximin* (86.4%) Placebo* (77.4%) Days Since Randomization Bass NM et al. N Engl J Med. 2010;362:1071-1081.
Rifaximin Trial: Rifaximin Improves Health-Related Quality of Life" CLD,Questionnaire Domain Scores: Differences in least square means of time-weighted average values and 95% CI intervals, rifaximin (n=101) vs. placebo (n=118) groups Domain P-value Fatigue 0.0087 Abdominal symptoms 0.0090 Systemic symptoms 0.0160 Activity 0.0022 Emotional function 0.0065 Worry 0.0436 Overall 0.0093-1 -0.5 0 0.5 1 1.5 Favors Placebo Favors Rifaximin LSMean difference and 95% Cl Sanyal A et al. Aliment Pharmacol Ther 2011;34:853-861.
Rifaximin Trial: Side Effects Similar to Placebo Incidence of adverse events did not differ significantly between 2 study groups (P>0.05 for all comparisons) Adverse Events Reported in 10% of Patients in Either Study Group Event Any event, n (%) Nausea Diarrhea Fatigue Peripheral edema Ascites Dizziness Headache Bass NM et al. N Engl J Med. 2010;362:1071-1081. Rifaximin (n=140) 112 (80.0) 20 (14.3) 15 (10.7) 17 (12.1) 21 (15.0) 16 (11.4) 18 (12.9) 14 (10.0) Placebo (n=159) 127 (79.9) 21 (13.2) 21 (13.2) 18 (11.3) 13 (8.2) 15 (9.4) 13 (8.2) 17 (10.7)
Hepatocellular Carcinoma (HCC)
HCC Incidence Tripled Over the Last Three Decades Incidence Rate 9 8 7 6 5 4 3 2 1 0 SEER 9 data Joinpoint model 1975 1980 1985 1990 1995 2000 2005 Men Overall Women Altekruse SF, JClin Oncol. 2009 Mar 20;27(9):1485-9."
AASLD Practice Guidelines on Screening & Surveillance for HCC AASLD recommends surveillance using AFP + US every 6-12 months for at-risk patient groups: Hepatitis B carriers Asian males >40 years Asian females >50 years All cirrhotic hepatitis B carriers Family history of HCC Africans >20 years Non-cirrhotic hepatitis B carriers with high HBV DNA levels or more severe current/past levels of inflammatory activity Cirrhosis due to hepatitis C, alcohol, or other causes Bruix & Sherman. AASLD Practice Guideline: Management of Hepatocellular Carcinoma, Hepatology 2005; 42(5):1208.
Imaging Studies AASLD Criteria - HCC Nodules > 1 cm (previously 2 cm) with both early arterial enhancement and rapid venous/ late phase wash out on dynamic contrast CT/ MRI Any other findings require biopsy or interval growth for HCC diagnosis AASLD Guidelines Updated July 2010. Hepatology 2011;53:1020-2. Hepatolgoy 2010;000:1-35.
Liver Biopsies of HCC are rarely Needed! Risks Pain Bleeding Needle Tract Seeding Mis-diagnosis
Health Maintenance of the Cirrhotic Patient Vaccinations Bone disease screening, surveillance and management HCC Screening and Surveillance Varices Screening and Surveillance Nutritional Support Vitamin assessment for Vit A and D deficiency Mineral assesment: Zinc and Mg++ Review Medication List
Question 1 Patients with cirrhosis A. Have an annual risk of developing HCC of 1-5% B. Are at highest risk of dying from complications of portal hypertension C. Should not use statins for hyperlipidemia D. A and B E. All of the Above
Question 2 A 45 year old man with cirrhosis from HCV should receive all of the following except A. Endoscopy and nadolol if varices are present B. Vaccination for Hepatitis A and B if not immune C. Antibiotic prophylaxis for dental procedures D. Hepatic imaging and AFP every 6 months E. Counseling on blood borne precautions
Question 3 The following does not occur as a complication of portal hypertension A. Varices B. Hydrothorax C. Encephalopathy D. Renal Failure E. Jaundice
Question 4 The preferred first line treatment for variceal bleeding includes A. Beta blockers B. Octreotide drip C. Endoscopic sclerotherapy D. TIPS
Enter question text... Most common complication of cirrhosis is? A. Overt hepatic encephalopathy B. Esophageal varices C. Ascites D. Hepatorenal syndrome