10. Approach to cirrhosis*****

Resident Editor: Kenneth Pettersen, MD

Faculty Editor: Jennifer C. Lai, MD, MBA

BOTTOM LINE

✔ Refer to hepatologist early to ensure adequate workup, treatment and potential transplant center referrals. 

✔ INR is poorly correlated with bleeding risk, but is a good measure of synthetic function

✔ People with cirrhosis require regular screening for varices and progression to HCC

✔ Adequate nutritional intake including high-protein diet prevents muscle wasting and improves mortality

Background

  • Cirrhosis is the 8th leading cause of death in the US, accounting for ~30,000 deaths/year
  • Most common causes are viral > alcohol > fatty liver
  • Complications include encephalopathy, bleeding, ascites, edema, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), hepatocellular carcinoma (HCC), malnutrition, and physical frailty

Signs and Symptoms

  • Ask about fatigue, confusion, sleep disturbance, easy bruising, lower extremity edema, fever, weight change, diarrhea, pruritus, increasing abdominal girth, pain
  • Look for ascites, spider angiomata, palmar erythema, gynecomastia/testicular atrophy, hepato-splenomegaly, caput medusa, jaundice, asterixis, hyperactive reflexes

Evaluation

  • Diagnostics: 
    • Serologies for HBV (HBV surface antigen) and HCV (HCV antibody)
    • Assess risk factors for NAFLD including BMI, A1C, and lipids
    • Evaluate for total alcohol consumption
    • Autoimmune disease markers including ANA, anti-smooth muscle antibody, and quantitative IgG
    • In cases of diagnostic uncertainty, consider iron studies, alpha-1-antitrypsin, anti-mitochondrial antibodies, and ceruloplasm
  • CBC to evaluate cytopenias (particularly thrombocytopenia), macrocytosis
  • Liver panel: total bilirubin, alkaline phosphatase, and transaminases (may be normal in cirrhosis once liver has "burned out")
  • INR/albumin to assess hepatic synthetic function
  • Basic metabolic panel to evaluate renal function and presence of hyponatremia
  • Assess severity and mortality risk by calculating MELD-Na score: total bilirubin, creatinine, INR, and serum sodium
  • Abdominal ultrasound findings that suggest cirrhosis include: nodular and/or shrunken liver, left hepatic lobe hypertrophy, splenomegaly, main portal vein diameter > 12 mm, and/or presence of ascites
  • Referral to a hepatologist can help with diagnosis of underlying chronic liver disease or confirmation of the presence of cirrhosis through elastography (non-invasive fibrosis assessment), such as Fibroscan, or a liver biopsy if needed

Management

  • Acetaminophen OK, maximum total dose 2 grams per day
  • Statin use for primary or secondary cardiovascular prophylaxis is not contraindicated in cirrhosis and may be beneficial, particularly for patients with NAFLD
  • Vaccinate for hepatitis A and hepatitis B if not immune, pneumovax
  • Highlights of disease-specific therapy (see specific sections for further details):
    • NAFLD: weight loss (5-10%) with diet and exercise
    • Anti-viral therapy for chronic HBV (entecavir or tenofovir) and HCV (oral direct-acting antivirals) prevents decompensation
    • Alcohol cessation
      • Among alcoholics with Child-Pugh C cirrhosis, those who stop drinking have 65% survival at 3 years compared to 0% among those who continue drinking
      • Pharmacotherapeutic options for the treatment of alcohol use disorder in cirrhosis includes baclofen (30-270 mg daily) or gabapentin (900 – 1800 mg daily). Exercise caution with naltrexone (liver toxicity) and benzodiazepines (hepatic clearance)
  • Optimize nutrition, including high (not low) protein diet – aim for 1.2-1.5 grams of protein per kg body weight per day

Ascites and Volume Overload

  • Tap new ascites to confirm origin [serum-ascites albumin gradient (SAAG) >1.1 g/dL suggests portal hypertensive origin)] and rule out spontaneous bacterial peritonitis
  • ~50% 1-year survival once ascites develops; at risk for SBP, hyponatremia, and hepatorenal syndrome
  • For symptomatic ascites, try stepwise approach:
    • Salt restrict to < 2000 mg NaCl per day
    • Start spironolactone 50-100 mg PO daily and furosemide 20-40 mg PO daily (ensure 5:2 ratio)
    • Increase spironolactone and furosemide in similar ratios (start 5:2)
      • maximum: 400 mg of spironolactone, 160 mg of furosemide daily
    • Aim for 0.5-1 kg/day of fluid removal, monitor electrolytes and renal function
    • If serum Na < 130, then fluid restrict patient to 1-1.5 liters per day
  • Refractory (diuretic-resistant) ascites may require repeated large-volume paracentesis (LVP) of > 5 liters or TIPS
    • After LVP, administer 6-8 grams of albumin IV per liter of ascites removed to reduce risk of post-paracentesis circulatory dysfunction (PCD)
    • Consider TIPS if requiring >1-2 LVP per month
  • SBP prophylaxis with TMP-SMX DS daily or ciprofloxacin 500 mg PO daily
    • ~70% recurrence within 1 year without ppx
    • Indications:
      • (1) low protein ascites (<1.5 g/dL) AND impaired renal or liver function, i.e. Cr ≥ 1.2, BUN ≥ 25, Na ≤ 130, bilirubin ≥ 3, Child Pugh Score ≥ 9, 
      • (2) ongoing GI bleed, OR 
      • (3) prior history of SBP

Hepatic Encephalopathy

  • Assess for potential precipitants (infection, meds, bleeding, dehydration)
  • No benefit to restricting protein intake
  • Start lactulose 15-30 mL PO BID and titrate to at least 3 bowel movements daily
  • Consider adding rifaximin 550mg PO BID for refractory encephalopathy or intolerance of lactulose 
  • Probiotics may help to manage hepatic encephalopathy and improve quality of life

Varices

  • Screen all patients with new diagnosis of cirrhosis with upper endoscopy (EGD), incidence ~50% in all cirrhotic patients
  • Repeat screening every 3 years if compensated, and annually if decompensated 
  • Generally, patients with large varices, high-risk small varices, or Child-Turcotte-Pugh class C with varices should be on primary prophylaxis with either non-selective beta-blockade (NSBB) OR serial endoscopic variceal ligation (EVL)
    • Start with propranolol 20 mg PO BID , nadolol 20-40 mg daily, or carvedilol 6.25 mg PO BID; titrate to goal HR 55-60 or decrease resting pulse by 25% (dose decrease or discontinue if SBP < 90 mmHg
    • If cannot tolerate beta-blockade due to side effects (~15%), then should undergo serial banding every 1-2 weeks until varices obliterated
  • Secondary prophylaxis with EVL plus NSBB if there is a history of variceal bleed 
  • Patients with recurrent variceal hemorrhage should be considered for transjugular intrahepatic portosystemic shunt (TIPS)

HCC

  • Screen with ultrasound (+/- AFP) every 6 months
  • Screen all patients with cirrhosis, regardless of etiology 
    • Patients with HBV and HCV cirrhosis have a 5% annual risk of developing HCC
  • If lesion is characteristic for HCC on quad-phase CT/MRI, refer to hepatology
    • Do not refer for a biopsy without consultation with a hepatologist
  • Treatment options include local regional therapy [e.g., transarterial chemoembolization (TACE), radiofrequency ablation (RFA)], resection, transplantation, or systemic therapy (e.g., sorafenib, nivolumab)

Malnutrition/Physical Frailty

  • Up to 90% of patients with cirrhosis are under-nourished and up to one-quarter are physically frail
  • Malnutrition/frailty are associated with increased hospitalizations and mortality in this population
  • Encourage intake of high quality protein: 1.2-1.5 grams / kg body weight per day.  
    • Protein should NOT be restricted in the setting of hepatic encephalopathy.
  • Exercise should consist of both aerobic and resistance exercises
    • Recent studies have demonstrated reduction in portal hypertension with weight loss and supervised physical activity program
  • Consider referral to a dietitian and/or physical therapist 

When to refer

  • Refer to hepatologist at time of diagnosis to assist with etiology, staging, and management
  • MELD-Na score (calculated from bilirubin, creatinine, INR and Na) helps predict 90-day mortality and is used to prioritize transplant allocation. 
  • Refer patients to a transplant center when MELD >15 and/or they have evidence of portal hypertensive complications.
  • Contraindications to transplant are transplant center specific. Most centers require that patients have adequate psychosocial support, documented alcohol sobriety for 6 months (although an increasing number of transplant centers offer transplant with <6 months), and be absent of severe medical comorbidities that would excessively increase perioperative risk or otherwise limit post-transplant survival.   Acute alcoholic hepatitis, HIV infection, chronic methadone or buprenoprhine use, marijuana use, are no longer absolute contraindications to liver transplantation – a limited number of centers offer liver transplantation to patients with any of these characteristics.

References

Addolorato G, Antonio M, Barrio P, Gual A. “Treatment of alcohol use disorders in patients with alcoholic liver disease.” Journal of Hepatology 2016; 65: 618–630.

Berzigotti, A et al. “Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study.” Hepatology 2017;65:1293-1305.

Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Alexandria (VA): American Association for the Study of Liver Diseases 2011; 53: 1020-2.  

Chalasani, Naga et al.  “The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases.” Hepatology 2018; 67: 328-357.

Dalal, Rohan et al. “Probiotics for people with hepatic encephalopathy.” Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD008716.

Fattovich G et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology, 1997. 112: 463-472.

Gines, Pere et al.  “Management of Cirrhosis and Ascites,” The New England Journal of Medicine 2004; 350: 1646-54.

Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. “Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, diagnosis, and Management: 2016 Practice Guidelines by the American Association for the Study of Liver Diseases.” Hepatology 2017; 65: 310-335.

Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46(3):922-38.

Ge P, Runyon B. “Treatment of Patients with Cirrhosis.” New England Journal of Medicine, 2016; 375:767-777.

Martin P, DiMartini A, Feng S, Brown R, Fallon M. “Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the AASLD and the American Society of Transplantation.” The American Association for the Study of Liver Diseases (2013).

Sakuma K et al. (1982) Prognosis of hepatitis B virus surface antigen carriers in relation to routine liver function tests: a prospective study. Gastroenterology 83: 114-117

Starr, Paul and Raines, Daniel.  “Cirrhosis: Diagnosis, Management and Prevention.” American Family Physician.  2011; 84 (12) 1353-1359.

Runyon BA, AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2013 Apr;57(4):1651-3.

Wong, Florence.  “Management of ascites in cirrhosis.” Journal of Gastroenterology and Hepatology. 27(2012) 11-20.