Cirrhosis of the Liver

Ramón Bataller, M.D.
Pere Ginès, M.D.
Institut de Malalties Digestives i Metabòliques, Hospital Clinic, Barcelona, Spain

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

A diffuse disorganization of normal hepatic structure by extensive fibrosis associated with regenerative nodules
High morbidity and mortality
Advanced disease is usually irreversible
Insidious onset of symptoms
Generalized weakness, anorexia, malaise, weight loss
Loss of skeletal muscle mass
Symptoms may be absent or minor in "compensated" cirrhosis
Symptoms of hepatocellular dysfunction and portal hypertension
- Progressive jaundice, skin hyperpigmentation, pruritus, xanthelasmas
- Bleeding from gastroesophageal varices
- Ascites
- Neuropsychiatric symptoms
- Coagulopathy, mucosal bleeding in advanced disease
- Malnutrition
- Fat-soluble vitamin deficiency
- Nervous system, heart, and pancreatic symptoms in alcohol-related liver disease
Complications
- Ascites
- Gastrointestinal bleeding
- Hepatorenal syndrome
- Spontaneous bacterial peritonitis
- Hepatopulmonary syndrome
- Hepatic encephalopathy
- Hepatocellular carcinoma

Differential Diagnosis

Hepatic encephalopathy
- Intracranial lesions
- Central nervous system infections
- Other metabolic causes of encephalopathy
- Toxic encephalopathy from alcohol drugs
- Postseizure encephalopathy
- Psychiatric disorders

Best Tests
Physical Examination

Liver is enlarged in initial phases, decreased in advanced disease
Splenomegaly
Ascites and/or peripheral edema
Altered mental status, decreased consciousness, asterixis in patients with hepatic encephalopathy
Muscle wasting, palmar erythema, vascular spiders, gynecomastia, axillary hair loss, testicular atrophy, fetor hepaticus
Dupuytren contractures, parotid gland enlargement, peripheral neuropathy in alcoholic patients

Laboratory Tests

Serum aspartate aminotransferase (AST): frequently elevated, but levels > 300 U/L uncommon

Serum alanine aminotransferase (ALT): may be relatively low (AST/ALT > 2)

Prothrombin time: frequently prolonged

Serum albumin levels: decreased

Total serum globulin concentration: increased in advanced cirrhosis

Alkaline phosphatase: moderately increased; markedly increased in patients with biliary disease

Blood count

Leukopenia and thrombocytopenia may be present
Normocytic anemia; may be microcytic, hypochromic, macrocytic, or hemolytic

Serum cholesterol and triglyceride levels: may be increased in biliary obstruction; low in advanced cirrhosis

Blood glucose: glucose intolerance and diabetes mellitus may be present

Respiratory alkalosis may be present

Serum magnesium and phosphate levels: hypomagnesemia and hypophosphatemia

Creatinine and urea blood levels: elevated in renal failure in patients with ascites

Viral serologies to identify causative agent

α-Fetoprotein serum levels: at diagnosis and every 6 mo to detect early hepatocellular carcinoma (HCC)

Imaging

Real-time ultrasound

Demonstrates morphologic characteristics of cirrhosis
- Irregular/nodular liver edges
- Altered liver structure
- Signs of portal hypertension, such as portocollateral veins

Detects hepatic steatosis, ascites, splenomegaly, and portal vein thrombosis
Rules out extrahepatic causes of jaundice
Detects early HCC

Color flow Doppler ultrasound

Shows portal hemodynamics
Detects hepatic tumors and tumor vascularization

Dynamic studies using CT and MRI: useful in assessing cirrhosis and diagnosing hepatic tumors; expensive

Endoscopy: to assess presence and size of esophageal varices

Liver Biopsy

Unequivocally establishes diagnosis

Helps determine cause and extent of liver damage

Percutaneous biopsy for most patients; transjugular biopsy for those with severe coagulopathy (INR > 1.5 and/or platelet count < 50,000/mm³)

Use with caution in patients with ascites or severe obesity

Subject to sampling error, especially in macronodular cirrhosis

Histologic findings

Extensive fibrosis and regenerative nodules
Periportal lymphocyte infiltration indicates HCV-induced cirrhosis
Mallory bodies, polymorphonuclear leukocyte (PMN) infiltration, and steatosis indicate alcohol-induced cirrhosis and/or nonalcoholic steatohepatitis (NASH)
Biliary involvement indicates primary biliary cirrhosis (PBS)
Massive iron deposition indicates hemochromatosis

Best Therapy

Adequate caloric and protein intake

Mild exercise, including walking and swimming

Surgery and general anesthesia carry increased risks

Zinc sulfate (50–200 mg/day) for zinc deficiency

Topical testosterone for male patients with hypogonadism

Calcium and vitamin D for patients at high risk for osteoporosis

Aminobisphosphonates for decreased bone mineralization

Vaccination against hepatitis A, hepatitis B, pneumococci, and influenza

Avoid hepatotoxic medications

Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and nephrotoxic antibiotics (e.g., aminoglycosides) in patients with ascites

Pegylated interferon plus ribavirin

Consider for patients with compensated cirrhosis due to hepatitis C virus (HCV) infection
For patients with decompensated cirrhosis awaiting orthotopic liver transplantation (OLT), initiate several months before OLT to prevent graft reinfection
Response lower than in noncirrhotic patients
May worsen existing anemia and/or thrombocytopenia
Pegylated interferon
- Dose:
  - Alpha 2a, 180 µg/wk S.C.
  - Alpha 2b: 1.5 µg/kg/wk S.C.
- Ribavirin
  - Dose: 800–1,200 mg/day p.o.
- Orthotopic liver transplantation
  - 1-year survival rate, 85%; 5-year survival rate, > 70%
  - Indications
    - Hepatocellular liver disease
      - Serum bilirubin > 3 mg/dl
      - Serum albumin < 2.5 g/dl
      - Prothrombin time >5 sec above control
    - Cholestatic liver disease
      - Serum bilirubin > 5 mg/dl
      - Intractable pruritus
      - Progressive bone disease
      - Recurrent bacterial cholangitis
    - Both hepatocellular and cholestatic liver disease
      - Recurrent or severe hepatic encephalopathy
      - Refractory ascites
      - Spontaneous bacterial peritonitis
      - Recurrent portal hypertensive bleeding
      - Progressive malnutrition
      - Hepatorenal syndrome
    - Hepatocellular carcinoma (< 3 nodules; no nodule > 5 cm; no portal invasion)
  - Contraindications
    - Severe cardiovascular or pulmonary disease
    - Active drug or alcohol abuse
    - Malignancy outside the liver
    - Sepsis
    - Psychosocial problems jeopardizing posttransplant care

Pruritus

Cholestyramine, 4 g/day

Ursodeoxycholic acid, 10 mg/kg/day

Naltrexone, 50 mg/day

Rifampicin, 10 mg/kg/day

Ondansetron, 8 mg q. 12 hr

HBV-Related Cirrhosis

Lamivudine: may improve or stabilize liver disease in some patients; resistance can develop with prolonged treatment

Dose: 100 mg/day

Adefovir: active against wild-type and lamivudine-resistant HBV

Dose: 10 mg/day

Entecavir: active against wild-type and lamivudine-resistant HBV

Dose: 0.5–1.0 mg/day

Alcohol-Induced Cirrhosis

Abstinence from alcohol

Nutritional support

Colchicine may be helpful

Superimposed Alcoholic Hepatitis

Glucocorticoid: alternative therapy; improves short-term survival

Methylprednisolone, 40 mg/day for 4 wk, then tapered for 1–2 wk

Pentoxifylline: alternative therapy; increases short-term survival

Dose: 400 mg q. 8 hr
Cost/mo: $20

Primary Biliary Cirrhosis

Ursodeoxycholic acid: relieves pruritus and improves biochemical blood test results, may decrease need for liver transplantation

Dose: 13–15 mg/kg/day

Cirrhosis Due to Autoimmune Hepatitis

Use immunosuppressant therapy with caution because it may favor infections

Cirrhosis Due to Genetic Metabolic Diseases

Hemochromatosis

Phlebotomy

Wilson Disease

Copper chelators (e.g., D-penicillamine, trientine)
Zinc

Best References

Blei AT: Lancet 365:1383, 2005

Bosch J, et al: Semin Hematol 41:8, 2004

Cardenas A, et al: J Hepatol 42(suppl):S124, 2005

Gines P, et al: N Engl J Med 350:1646, 2004

Wright TL: Hepatology 36:S185, 2002

October 2005