Cirrhosis laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2]

Overview

A range of laboratory values need to be obtained in the evaluation of cirrhosis, both to determine the severity of the disease, and to determine the causative factor. Liver function tests, complete blood count, basic metabolic panel and coagulation factors are standard in the evaluation of cirrhosis. More specific testing for markers and serum enzymes can be done when certain genetic causes and etiologies are suspected.

Laboratory Findings

• Laboratory abnormalities may be the first indication of cirrhosis.

• Common abnormalities include:
  • Increased serum bilirubin levels
  • Abnormal aminotransferase levels
  • Elevated alkaline phosphatase 
  • Elevated gamma-glutamyl transpeptidase 
  • Prolonged prothrombin time 
  • Elevated international normalized ratio (INR) 
  • Hyponatremia 
  • Thrombocytopenia

Liver function tests:

•  Aminotransferases :
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually moderately elevated
  • AST is more often elevated than ALT
  • LFTs may be normal in cirrhosis patients
• Alkaline phosphatase:
  • Alkaline phosphatase is usually elevated
  • High levels may be seen in patients with underlying cholestatic liver disease such as:
    • Primary sclerosing cholangitis
    • Primary biliary cirrhosis
• Gamma-glutamyl transpeptidase:
  • Non specific
  • Correlates with ALP levels
  • Higher in CLD due to alcohol use:
  • Mechanism of raised GGT in Alcoholic liver disease:
    • Alcohol causes GGT release from hepatocytes
    • Alcohol induces microsomal GGT in liver
  • Bilirubin:
    • Bilirubin levels may be normal or raised
  • Albumin:
    • Albumin levels reflect synthetic function of the liver
    • Serum albumin levels helps grade the severity of cirrhosis
    • Hypoalbuminemia is non specific for liver disease and may be seen in:
      • Heart failure
      • Nephrotic syndrome
      • Protein-losing enteropathy
      • Malnutrition.

• Prothrombin time:
  • Prothrombin time reflects the degree of hepatic synthetic function.
  • Worsening coagulopathy correlates with the severity of hepatic dysfunction.
• Serum chemistries :

Hyponatremia is common in patients with cirrhosis and ascites and is related to an inability to excrete free water. Due to ADH elevation Reflects poor prognosis Progressive rise in serum creatinine: hepatorenal syndrome Hematologic abnormalities:  

Thrombocytopenia: most common Mechanism of thrombocytopenia: caused by portal hypertension with congestive splenomegaly: sequesters circulating platelets decreased thrombopoietin levels Leukopenia/neutropenia: due to hypersplenism with splenic margination. Anemia Mechanism of anemia: Acute and chronic gastrointestinal blood loss  Folate deficiency Direct toxicity due to alcohol  Hypersplenism  Bone marrow suppression ( hepatitis-associated aplastic anemia)  Anemia of chronic disease (inflammation) Hemolysis Other abnormalities — Globulins tend to be increased Disseminated intravascular coagulation  Fibrinolysis Vitamin K deficiency Dysfibrinogenemia Insulin resistance: nonalcoholic fatty liver disease Diabetes:  seen in patients with hemochromatosis

The following findings are typical in cirrhosis:

• Aminotransferases - AST and ALT are moderately elevated, with AST > ALT, however, normal aminotransferases do not preclude cirrhosis.
  • Alcoholic liver disease - AST and ALT are both elevated but less than 300 IU/L with a AST:ALT ratio > 2.0
• Alkaline phosphatase - It is elevated but usually less than two to three times the upper limit. Patients with primary biliary cirrhosis and primary sclerosing cholangitis may have higher levels.
• GGT -- correlates with AP levels. It is typically much higher in chronic liver disease from alcohol.
• Bilirubin - may elevate as cirrhosis progresses.
• Albumin - levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver.
• Prothrombin time - increases since the liver synthesizes clotting factors.
• Globulins - increase due to shunting of bacterial antigens away from the liver to lymphoid tissue which induces immunoglobulin production.
• Serum sodium- hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone.
• Thrombocytopenia - due to both congestive splenomegaly as well as decreased thrombopoietin from the liver, however this rarely results in a platelet count < 50,000/mL.
• Leukopenia and neutropenia - due to splenomegaly with splenic margination.
• Anemia - multifactorial in origin.
  • Acute and chronic GI bleeding
  • Folate deficiency
  • Direct toxicity of alcohol
  • Hypersplenism
  • Bone marrow suppression
  • Anemia of chronic disease
  • Hemolysis
• Coagulation defects - the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.
• Ascitic fluid analysis - Most experts recommend a diagnostic paracentesis be performed if the ascites is new or if the patient with ascites is being admitted to the hospital. The fluid is then reviewed for its gross appearance, protein level, albumin, and cell counts (red and white). Additional tests will be performed if indicated such as Gram stain and cytology.
  • The Serum-ascites albumin gradient (SAAG) is probably a better discriminant than older measures (transudate versus exudate) for the causes of ascites. A high gradient (> 1.1 g/dL) indicates the ascites is due to portal hypertension. A low gradient (< 1.1 g/dL) indicates ascites of non-portal hypertensive etiology. Ascites is broadly classified as two types based on the Serum-ascites albumin gradient (SAAG):
    • Transudate - SAAG > 1.1 g/dL (indicates the ascites is due to portal hypertension).
    • Exudate - SAAG < 1.1 g/dL (indicates the ascites is due to non-portal hypertension etiology).

There is now a validated and patented combination of 6 of these markers as non-invasive biomarkers of fibrosis (and so of cirrhosis) : FibroTest.

Other laboratory studies performed in newly diagnosed cirrhosis may include:

• Serology for hepatitis viruses.
• Autoantibodies
  • ANA - present in autoimmune hepatitis
  • Anti-smooth muscle antibody - present in autoimmune hepatitis
  • Anti-mitochondrial antibody - present in primary biliary cirrhosis
  • Anti-LKM
• Total iron, TIBC, transferrin saturation, and ferritin - elevated totat iron, reduced TIBC, elevated transferrin saturation, and elevated ferritin in hemochromatosis.
• Serum ceruloplasmin- low in Wilson's disease
• Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in distinguishing various causes.
  • Chronic hepatitis B - Chronic hepatitis B can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG and HBV DNA are determined to assess whether or not patients will need antiviral therapy.
• Serum protein electrophoresis - alpha-1 band absent in alpha-1 antitrypsin deficiency.
• Cholesterol and glucose
• Alpha 1-antitrypsin - reduced in alpha-1 antitrypsin deficiency.

Combinations of tests

Clinical prediction rules exist to help diagnosis cirrhosis according to a systematic review by the Rational Clinical Examination project.

• Pohl's Index is if the AST/ALT ratio ≥1 and platelet count ≤ 150,000/mm³ then cirrhosis is very likely.
• The Bonacini score is based on the ALT/AST ratio, platelet count, and INR.
  • A score of > 7 or 8 makes cirrhosis more likely.
  • A score of < 3 makes cirrhosis less likely.

Another method is the Lok index. Online calculators are available (link 1 and link 2).

In diagnosis of cirrhosis (Ishak scores, 5-6) in patients with hepatitis C, the aspartate aminotransferase to platelet ratio index (APRI) ratio > 1 suggests cirrhosis with accuracy of:

• Sensitivity = 79%
• Specificity = 78%

A more recent meta-analysis has focused on the diagnosis of cirrhosis among patients with hepatitis C. Using the Lok index:

• < 0.2 has hegative likelihood ratio of 0.21
• > 0.6 has positive likelihood ratio of 4.4