> Table of Contents > Cirrhosis of the Liver
Cirrhosis of the Liver
Kathleen M. Donahue, DO
image BASICS
DESCRIPTION
A chronic hepatocellular disease involving inflammation, necrosis, and fibrosis potentially leading to liver failure and/or cancer
EPIDEMIOLOGY
  • Predominant age: 40 to 50 years old
  • Predominant sex: male > female; more women get cirrhosis from alcohol abuse.
  • Ninth leading cause of death among U.S. adults
ETIOLOGY AND PATHOPHYSIOLOGY
  • Chronic hepatitis C (26%)
  • Alcohol abuse (21%)
  • Hepatitis C with alcoholic liver disease (15%)
  • Nonalcoholic steatohepatitis/obesity (˜10%)
  • Hepatitis B plus hepatitis D infection (15%)
  • Other: hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, secondary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, &agr;1-antitrypsin deficiency, granulomatous disease (e.g., sarcoidosis); drug-induced liver disease (e.g., methotrexate, &agr;-methyldopa, amiodarone); venous outflow obstruction (e.g., Budd-Chiari syndrome, veno-occlusive disease); chronic right-sided heart failure; tricuspid regurgitation; and rare genetic, metabolic, and infectious causes
Genetics
Hemochromatosis, Wilson disease, and &agr;1-antitrypsin deficiency in adults are associated with cirrhosis.
RISK FACTORS
Alcohol abuse, intravenous drug abuse, obesity, blood transfusion
GENERAL PREVENTION
  • Mitigate risk factors (e.g., alcohol abuse): >80% of chronic liver disease is preventable.
  • Limit alcohol consumption and advise weight loss in overweight or obese patients.
    • Elevated BMI and alcohol have an additive effect on liver disease (1).
COMMONLY ASSOCIATED CONDITIONS
Diabetes, alcoholism, drug abuse, depression, obesity
image DIAGNOSIS
PHYSICAL EXAM
Physical exam may be normal until end-stage disease.
  • Skin changes: spider angiomas, palmar erythema, jaundice, scleral icterus, ecchymoses, caput medusa, hyperpigmentation
  • Hepatomegaly (small, fibrotic liver in end-stage disease)
  • Splenomegaly (if portal hypertension)
  • Central obesity
  • Abdominal fluid wave, shifting dullness (ascites)
  • Gynecomastia
  • Dupuytren contractures
  • Pretibial, presacral pitting edema and clubbing (especially in hepatopulmonary syndrome)
  • Asterixis, mental status changes
  • Muscle wasting, weakness
  • Fetor hepaticus with severe portal-systemic shunting
DIFFERENTIAL DIAGNOSIS
Steatohepatitis, other causes of portal hypertension (e.g., portal vein thrombosis, lymphoma); metastatic or multifocal cancer in the liver; vascular congestion (e.g., cardiac cirrhosis); acute alcoholic hepatitis
DIAGNOSTIC TEST & INTERPRETATION
Initial Test (lab, imaging)
  • Aspartate aminotransferase/alanine aminotransferase (AST/ALT): mildly elevated, typically AST > ALT; enzymes normalize as cirrhosis progresses.
  • Elevated alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and total/direct bilirubin
  • Anemia from hemolysis, folate deficiency, and/or splenomegaly
  • Decreased platelet count
  • Impaired synthetic liver function
    • Low albumin and cholesterol
    • Prolonged prothrombin (PT), international normalized ratio (INR), partial thromboplastin time (PTT). Vitamin K-dependent clotting factors (II, VII, IX, X)
  • Progressive cirrhosis
    • Elevated ammonia level, BUN, sodium, and potassium
  • &agr;-Fetoprotein level to screen for hepatocellular carcinoma
  • Abdominal ultrasound q6-12mo to screen for hepatocellular carcinoma
  • Doppler ultrasound to assess liver parenchyma and hepatic/portal veins
  • MRI best follow-up test for HCC if &agr;-fetoprotein elevated and/or liver mass found on ultrasound
  • Noninvasive modalities, such as elastography, are being researched as an alternative to liver biopsy (2).
Follow-Up Tests & Special Considerations
Consider the following:
  • Hepatitis serologies (particularly B and C)
  • Serum ethanol and GGT if alcohol abuse suspected
  • Antimitochondrial antibody to screen for primary biliary cirrhosis
  • Anti-smooth muscle and antinuclear antibodies to screen for chronic active (autoimmune) hepatitis
  • Iron saturation (>50%) and ferritin (markedly increased) to screen for hemochromatosis; if abnormal, check hemochromatosis (HFE) genetics/mutation analysis.
  • &agr;1-antitrypsin phenotype screen
  • Ceruloplasmin level to screen for Wilson disease; if low, check copper excretion (serum copper plus 24-hour urine copper).
Diagnostic Procedures/Other
  • Liver biopsy: required for definitive diagnosis, percutaneous if INR <1.5 and no ascites; otherwise, transjugular. Serologic testing gaining use as a surrogate for biopsy.
  • Ultrasound-based elastography: noninvasive alternative to liver biopsy, not widely available; relies on increased “stiffness” of abnormal tissue to evaluate for fibrosis
  • Endoscopy if portal hypertension to rule out esophageal varices/portal hypertensive gastropathy (3)[C]
Test Interpretation
  • Fibrous bands and regenerative nodules are classic biopsy features of cirrhosis.
  • Other histologic findings vary with etiology
    • Alcoholic liver disease: steatosis, polymorphonuclear (PMN) leukocyte infiltrate, ballooning degeneration of hepatocytes, Mallory bodies, giant mitochondria
    • Chronic hepatitis B and C: periportal lymphocytic inflammation
    • Nonalcoholic steatohepatitis (NASH): identical to alcoholic liver disease; steatosis may be absent in advanced disease (“burned-out NASH”).
    • Biliary cirrhosis: PMN infiltrate in wall of bile ducts, inflammation increased in portal spaces, progressive loss of bile ducts in portal spaces.
    • Hemochromatosis: intrahepatic iron stores increased (iron stain or weighted biopsy tissue)
    • &agr;1-antitrypsin deficiency: positive periodic acid-Schiff (PAS) bodies in hepatocytes
image TREATMENT
Outpatient care except for major GI bleeding, altered mental status, sepsis/infection, rapid hepatic decompensation and renal failure.
GENERAL MEASURES
  • Abstain from alcohol, drugs, hepatotoxic medications, and hepatotoxic herbs.
  • Pneumococcal, hepatitis A/B, and influenza vaccines
  • NASH: weight reduction, exercise, optimal control of lipids/glucose
MEDICATION
First Line
Treat the underlying cause first (note prescribing precautions in decompensated cirrhosis).
  • Hepatitis C: Goal of treatment is to eradicate hepatitis C virus (HCV) RNA in serum. Combination therapy of pegylated interferon (PEG-IFN) with ribavirin is the standard of care for most genotypes.
  • Hepatitis B: Goal of treatment is to achieve HBeAg seroconversion. Adefovir 10 mg PO daily, entecavir 0.5 to 1.0 mg PO daily, telbivudine 600 mg PO daily, or lamivudine 100 mg PO daily for minimum of 1 year, or continue for at least 6 months after HBeAg seroconversion; alternatively, PEG-IFN &agr;-2a 180 &mgr;g SC weekly for 48 weeks. Lamivudine is no longer recommended as first-line agent due to high rates of resistance.
  • Alcoholic hepatitis: Treat withdrawal; discriminant function >32 may benefit from prednisolone, 40 mg/day for 28 day with 2 to 4 weeks taper, to reduce mortality. Pentoxifylline for patients unable to tolerate steroids
  • Biliary cirrhosis: ursodeoxycholic acid (ursodiol) 13 to 15 mg/kg PO divided BID-QID with food (4)[A]; bile acid sequestrants (BAS) are first-line therapy for pruritus: cholestyramine 4 to 8 g PO BID; antihistamines; rifampicin 150 to 300 mg PO BID, or opiate antagonists such as naltrexone 50 mg/day can be used for pruritus if ursodiol is ineffective.
  • P.205

  • Wilson disease: initial treatment with penicillamine 1,000 to 1,500 mg/day PO BID-QID or trientine 750 to 1,500 mg/day PO BID-TID on empty stomach. Trientine (Syprine) is better tolerated. After 1 year, zinc acetate 150 mg/day PO BID-TID for maintenance. Zinc for presymptomatic, pregnant, and pediatric populations.
  • Autoimmune (chronic active) hepatitis: prednisone 30 to 60 mg/day initially, maintenance 5 to 20 mg/day with or without azathioprine (Imuran) 0.5 to 1.0 mg/kg; adjust to keep transaminase levels normal. The combination is preferred. Discontinue maintenance after at least 24 months of treatment if AST and ALT are normal.
  • Esophageal varices: propranolol 40 to 160 mg or nadolol 40 mg daily to lower portal pressure by 20 mm Hg, systolic pressure from 90 to 100 mm Hg, and pulse rate by 25% (3)[A].
  • Ascites/edema: low-sodium (<2 g/day) diet and spironolactone 100 to 400 mg/day with or without furosemide 40 to 160 mg/day PO; torsemide may substitute for furosemide.
  • Encephalopathy: lactulose 15 to 45 mL BID, titrate to induce three loose bowel movements daily. Combination therapy with rifaximin (550 mg PO BID) is recommended regimen to prevent recurrent hepatic encephalopathy (5)[B].
  • Pruritus: ursodiol, cholestyramine, or antihistamines (e.g., hydroxyzine)
  • Renal insufficiency: Stop diuretics and nephrotoxic drugs, normalize electrolytes, and hospitalize for plasma expansion or dialysis.
  • Prophylactic antibiotics for invasive procedures, GI bleeding, or history of spontaneous bacterial peritonitis (3)[A]
  • Proton pump inhibitor for esophageal varices requiring banding or portal hypertensive gastropathy (6)[A]
ISSUES FOR REFERRAL
Evaluate for liver transplant at onset of complications (ascites, variceal bleeding, encephalopathy), jaundice, or liver lesion suggestive of hepatocellular carcinoma and/or when evidence of hepatic dysfunction develops (Child-Turcotte-Pugh >7 and Model for End-stage Liver Disease [MELD] >10).
SURGERY/OTHER PROCEDURES
  • Varices: endoscopic ligation, typically 4 to 6 treatments (if acute bleed, use pre-esophagogastroduodenoscopy [EGD] octreotide as vasoconstrictor); transjugular intrahepatic shunt (TIPS) second-line or salvage therapy for acute bleed (3)
  • Ascites: if tense, therapeutic paracentesis every 2 weeks PRN; caution if pedal edema absent
  • Fulminant hepatic failure: liver transplantation
  • Hepatocellular carcinoma: curable if small with radiofrequency ablation or resection and transplant
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Zinc sulfate 220 mg BID may improve dysgeusia and appetite; adjunct for hepatic encephalopathy
  • Milk thistle (silymarin) may lower transaminases and improve symptoms.
  • Danshen and huang qi injections may promote improvement; further studies needed (7)[B].
  • Hepatotoxicity and drug interactions are common with many herbal medications (8).
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Major GI bleeding, altered mental status, sepsis/infection, rapidly progressing hepatic decompensation, renal failure
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Regular physical conditioning may help with fatigue.
Patient Monitoring
  • Once stable, monitor liver enzymes, platelets, and PT q6-12mo.
  • Patients over 55 years with chronic hepatitis B or C, elevated INR, or low platelets are at highest risk for HCC. Serial &agr;-fetoprotein and liver ultrasound screening q6-12mo in patients with cirrhosis (9)[C].
  • Endoscopy at diagnosis and every 3 years (compensated) and every 1 year (decompensated) to screen for varices (3)[C]
DIET
  • Protein (1.0 to 1.5 g/kg body weight), high fiber, daily multivitamin (without iron), and sodium (<2 g/day, essential if ascites/edema)
  • Protein restriction is no longer recommended (10).
  • Coffee consumption has a graded and inverse association with liver cancer (11)[A].
PATIENT EDUCATION
  • Educate about when to seek emergency care (e.g., hematemesis, altered mental status).
  • Maintain sobriety and smoking cessation (no cannabis).
  • Update required immunizations; hepatitis C transmission precautions
PROGNOSIS
  • At diagnosis of cirrhosis, expect 5 to 20 years of asymptomatic disease.
  • After onset of complications, death typically within 5 years without transplant
    • 5% per year develop HCC.
    • 50% of cirrhotics develop ascites over 10 years; 50% 5-year survival once ascites develops
    • Acute variceal bleeding is the most common fatal complication; 30% mortality
    • Median survival after complications (ascites, variceal bleeding, encephalopathy) develop is 1.5 years (7).
    • With transplant, 85% survive 1 year; after transplant, ˜5% annual mortality
  • <25% of eligible patients receive a transplant because of donor organ shortage.
REFERENCES
1. Hart CL, Morrison DS, Batty GD, et al. Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. BMJ. 2010;340:c1240.
2. Tsochatzis EA, Gurusamy KS, Ntaoula S, et al. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol. 2011;54(4): 650-659.
3. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938.
4. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50(1):291-308.
5. Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458-1463.
6. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007;82(3): 286-296.
7. Zhu C, Cao H, Zhou X, et al. Meta-analysis of the clinical value of danshen injection and huangqi injection in liver cirrhosis. Evid Based Complement Alternat Med. 2013;2013:842824.
8. Verma S, Thuluvath PJ. Complementary and alternative medicine in hepatology: review of the evidence of efficacy. Clin Gastroenterol Hepatol. 2007;5(4):408-416.
9. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7(8):448-458.
10. Tsiaousi ET, Hatzitolios AI, Trygonis SK, et al. Malnutrition in end stage liver disease: recommendations and nutritional support. J Gastroenterol Hepatol. 2008;23(4):527-533.
11. Bravi F, Bosetti C, Tavani A, et al. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin Gastroenterol Hepatol. 2013; 11(11):1413-1421.
Additional Reading
&NA;
  • Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Ann Intern Med. 2013;158(11):807-820.
  • Nierhoff J, Chávez Ortiz AA, Herrmann E, et al. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis. Eur Radiol. 2013;23(11):3040-3053.
See Also
&NA;
Algorithm: Cirrhosis
Codes
&NA;
ICD10
  • K74.60 Unspecified cirrhosis of liver
  • K70.30 Alcoholic cirrhosis of liver without ascites
  • K74.69 Other cirrhosis of liver
Clinical Pearls
&NA;
  • 80% of chronic liver disease that leads to cirrhosis is preventable (primarily alcohol abuse).
  • Check abdominal ultrasound every 6 months for early detection of hepatocellular carcinoma.
  • Update necessary immunizations and treat underlying cause (hepatitis C, alcohol abuse, etc.).