Cirrhosis Pharmacotherapy Summary

Based on the AFP guideline on cirrhosis (2019), AASLD guidelines on portal hypertensive bleeding (2016) and ascites/SBP/HRS (2021), More clinical pearls at pyrls.com
and AASLD/EASL guideline on hepatic encephalopathy (2014)

Overview of Cirrhosis
What is cirrhosis? Cirrhosis
• End-stage of chronic liver disease
• Characterized by advanced fibrosis/scarring Scarring/fibrosis leads to
• Complications include portal hypertension, varices, ascites, increased hepatic resistance
HE, HRS, SBP, liver cancer, and liver failure
• Common causes: alcohol-associated liver disease, chronic Bacterial
viral hepatitis infection, nonalcoholic fatty liver disease Redirection of blood flow Portal Hypertension
translocation
• Diagnosed by liver biopsy (gold standard but invasive) or to collateral veins
clinical findings (imaging, labs, medical history, presentations)

Classification of cirrhosis Spontaneous

Varices Splanchnic Hepatic dysfunction leads to Bacterial
• Child-Turcotte-Pugh (CTP) or Child-Pugh (CP) score vasodilation increase in systemic ammonia Peritonitis
assesses stage and severity of cirrhosis
⚬ Considers total bilirubin, albumin, INR, and degree of
ascites and encephalopathy Activation of endogenous
⚬ Classifies into A (compensated), B (early decompensated), vasoconstrictive systems Hepatic
or C (severely decompensated) (e.g., RAAS) Encephalopathy
• Model for End-Stage Liver Disease (MELD)score assesses
prognosis (3-month mortality) for patients with cirrhosis
Renal vasoconstriction
⚬ 12 or higher predicts increased risk of complications
and sodium retention
Goals of therapy
• Prevent complications of cirrhosis Ascites HE Hepatic encephalopathy
Hepatorenal
• Prevent hepatic decompensation HRS Hepatorenal syndrome
Syndrome
• Reduce mortality SBP Spontaneous bacterial peritonitis

Portal Hypertension (PH) & Varices Spontaneous Bacterial Peritonitis (SBP)

• Scarring of liver impedes blood flow through portal vein, increasing the blood pressure • Often no clear source of infection; mainly Gram-negative bacteria (E. coli, K. pneumoniae)
⚬ Varices = distension in collateral vessels from redirected blood; at risk of variceal hemorrhage but some Gram-positive organisms can be common (S. aureus, E. faecalis, E., faecium)
• PH defined as hepatic venous pressure gradient (HVPG) > 5 mmHg • Diagnosis: polymorphonuclear (PMN) leukocyte > 250/mm3 in the ascitic fluid
⚬ HVPG = difference in pressure between portal vein and hepatic veins • Treatment: antibiotic therapy + IV albumin
⚬ HVPG ≥ 10 mmHg = clinically significant portal hypertension (CSPH) ⚬ Empiric 3rd-gen cephalosporin (e.g., ceftriaxone, cefotaxime) generally recommended
• Primary prophylaxis of variceal hemorrhage ⚬ Broad spectrum agents (e.g., piperacillin/tazobactam) recommended for healthcare-
⚬ A beta-blocker (propranolol 20-40 mg twice daily, nadolol 20-40 mg once daily, or associated or nosocomial infection, those with recent exposure to broad-spectrum
carvedilol 6.25 mg twice daily) continued indefinitely, OR abx, or those admitted with sepsis/septic shock
⚬ Endoscopic variceal ligation (EVL) every 2-8 weeks until variceal eradication ⚬ Add vancomycin if prior MRSA infection or positive MRSA swab
⚬ Add daptomycin for vancomycin-resistant enterococcus
• Treatment of acute variceal hemorrhage ⚬ Meropenem +/- glycopeptide if current or recent exposure to piperacillin/tazobactam
⚬ IV ceftriaxone (1 g/day x max 7 days) + EVL + a vasoactive drug (see below)
⚬ Repeat diagnostic paracentesis 48 hours from initiation; PMN decrease of < 25% from baseline
- Octreotide: 50 mcg bolus → continuous infusion at 50 mcg/hr for 2-5 days, or
may require broadening of antibiotic therapy or investigation of secondary peritonitis
- Vasopressin: continuous infusion at 0.2-0.4 units/min (max 0.8 units/min) for 24 hours
+ concurrent IV nitroglycerin to maintain SBP of 90 mmHg, or • Secondary prevention
- Terlipressin: 2 mg IV every 4 hours during the first 48 hours to control bleeding, ⚬ Long-term prophylaxis with ciprofloxacin 500 mg/day
then 1 mg every 4 hours to prevent rebleeding (total duration 2-5 days) • Primary prevention
• Secondary prophylaxis of variceal hemorrhage ⚬ IV ceftriaxone for patients with variceal hemorrhage (see PH & Varices section)
⚬ A non-selective beta-blocker (propranolol 20-40 mg twice daily or nadolol 20-40 mg ⚬ Generally only needed if high risk of infection present
once daily) continued indefinitely, AND ⚬ Ciprofloxacin for patients with low ascitic fluid protein (< 1.5 g/dL) + and renal dysfunction or liver failure
⚬ EVL every 1-4 weeks until variceal eradication

Hepatorenal Syndrome (HRS)

Ascites • Renal complication due to hemodynamic changes and systemic inflammation
• Accumulation of excess fluid in the abdomen; often the first decompensating event associated with cirrhosis
• Dietary sodium restriction (to 2 g/day) recommended for net fluid loss • Diagnosis of HRS-AKI (acute kidney injury from HRS)
⚬ Cirrhosis with ascites
• Diuretic therapy (aldosterone antagonist + loop diuretic) ⚬ Diagnosis of AKI (↑ SCr by ≥ 0.3 mg/dL in 48 hr OR ≥ 50% ↑ in SCr in the past 7 days)
⚬ Preferred: spironolactone + furosemide ⚬ No response after 2 consecutive days of diuretic withdrawal & plasma volume expansion
⚬ Initially spironolactone 100 mg + furosemide 40 mg per day with albumin infusion
⚬ Titrate to maximum of spironolactone 400 mg + furosemide 160 mg per day ⚬ No current/recent use of nephrotoxic drugs, structural kidney injury, or shock
⚬ At least 72-hour interval needed between dose titrations
⚬ Taper down to the lowest effective dose after fluid is adequately mobilized • Treatment of HRS-AKI
⚬ Vasoconstrictor (terlipressin preferred; norepinephrine also recommended) + albumin
• Monitor daily body weight to assess efficacy of diuretics ⚬ Decrease in SCr to < 1.5 mg/dL or return to baseline within 0.3 mg/dL over
⚬ Up to 0.5 kg/day weight loss is generally appropriate (up to 1 kg/day for those with edema) maximum of 14 days indicates successful response

Hepatic Encephalopathy (HE)

• Believed to be due to ammonia accumulation caused by hepatic dysfunction • Treatment recommended for fully symptomatic overt HE
• Symptoms: impaired memory and motor function, asterixis (“flapping tremor”), ⚬ Lactulose (nonabsorbable disaccharide): preferred treatment
personality changes, coma - 30-45 mL every 1-2 hours until at least 2 soft stools/day are produced
- Thereafter, titrated to maintain 2-3 soft stools/day
• Categorized with West Haven criteria (WHC grades 1 to 4) ⚬ Rifaximin (add-on to lactulose) to prevent HE recurrence after second episode
• Diagnosed by excluding other causes of cognitive dysfunction - 550 mg twice daily
• Short-term protein restriction may be necessary for nitrogen modulation

Reference:
[1] American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and
the American Association for the Study of Liver Diseases. J Hepatol. 2014 Sep;61(3):642-59. doi: 10.1016/j.jhep.2014.05.042. Epub 2014 Jul 8. Erratum in: J Hepatol. 2015 Oct;63(4):1055.
[2] Biggins SW, Angeli P, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 Practice guidance by the American Association for the Study of Liver Diseases. Hepatology.
2021 Aug;74(2):1014-1048. doi: 10.1002/hep.31884.
[3] Garcia-Tsao G, Abraldes JG, et al. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017
Jan;65(1):310-335. doi: 10.1002/hep.28906. Epub 2016 Dec 1. Erratum in: Hepatology. 2017 Jul;66(1):304.
[4] Smith A, Baumgartner K, et al. Cirrhosis: Diagnosis and management. Am Fam Physician. 2019;100(12):759-770.

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