What is the diagnostic algorithm for liver disease?

Diagnostic Algorithm for Liver Disease

Begin with a comprehensive liver chemistry panel including AST, ALT, alkaline phosphatase (ALP), bilirubin, albumin, INR, and platelet count to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, which then directs subsequent diagnostic steps. 1, 2

Step 1: Initial Laboratory Assessment

Obtain the following baseline tests 2, 3:

• Aminotransferases (AST, ALT): Elevations indicate hepatocyte injury, with ALT being more liver-specific 2
• Alkaline phosphatase and GGT: Elevated in cholestatic disease 2, 3
• Bilirubin (total and direct): Indicates hepatobiliary dysfunction 2
• Albumin: Reflects synthetic function; decreased levels suggest chronic disease 2
• INR/Prothrombin time: Measures clotting factor synthesis 2
• Platelet count: Thrombocytopenia suggests advanced disease or portal hypertension 2
• Complete blood count and comprehensive metabolic panel 3

Classify Severity of Aminotransferase Elevation 2:

• Mild: <5× upper reference limit
• Moderate: 5-10× upper reference limit
• Severe: >10× upper reference limit

Step 2: Pattern Recognition

Hepatocellular Pattern (Predominant AST/ALT Elevation) 1, 3

When AST and ALT are elevated disproportionately to ALP, perform the following serologic tests 2, 3:

• Viral hepatitis panel: HBsAg, anti-HBs, anti-HBc, anti-HCV 2, 3
• Autoimmune markers: ANA, anti-smooth muscle antibody, anti-LKM 3
• Iron studies: Ferritin, transferrin saturation (for hemochromatosis) 3
• Ceruloplasmin: For Wilson's disease in patients <40 years 3
• Alpha-1-antitrypsin level and phenotype 3

AST:ALT ratio >2 suggests alcoholic liver disease, while ratio <1 is more consistent with non-alcoholic fatty liver disease (NAFLD) 1, 2

Cholestatic Pattern (Predominant ALP Elevation) 1, 3

When ALP is elevated ≥3× upper limit of normal with minimal transaminase elevation, proceed as follows 4:

• Confirm hepatic origin: Check GGT to verify ALP is from liver rather than bone 4
• Obtain abdominal ultrasound: Distinguish extrahepatic (biliary obstruction) from intrahepatic cholestasis 4, 3
• If biliary dilation present: Proceed to ERCP or MRCP 5
• If no biliary dilation: Consider primary biliary cholangitis (anti-mitochondrial antibody), primary sclerosing cholangitis, drug-induced cholestasis 3, 4

Step 3: Imaging Studies

Abdominal ultrasound is the initial imaging modality of choice for all patients with abnormal liver tests 1, 3:

• Assesses for hepatic steatosis, cirrhotic morphology, focal lesions, biliary dilation, and splenomegaly 1, 3
• Identifies features of cirrhosis: surface nodularity, caudate lobe hypertrophy, portal hypertension 1

CT or MRI may be obtained if ultrasound is inadequate or focal lesions require further characterization 1

Step 4: Risk Stratification for Fibrosis

For NAFLD or Unexplained Liver Disease 1

Use non-invasive fibrosis scores as first-line assessment 1:

Calculate FIB-4 score (age, AST, ALT, platelets) 1:

• <1.3 (or <2.0 if age >65): Low risk of advanced fibrosis
• 1.3-2.67: Intermediate risk—proceed to second-line testing
• >2.67: High risk of advanced fibrosis

Calculate NAFLD Fibrosis Score (NFS) (age, BMI, diabetes, AST, ALT, platelets, albumin) 1:

• <-1.455 (or <-0.12 if age >65): Low risk
• -1.455 to 0.676: Intermediate risk
• >0.676: High risk

Second-Line Fibrosis Assessment for Intermediate Risk 1

Transient elastography (FibroScan) 1:

• <7.8 kPa: Low probability of advanced fibrosis
• >16 kPa: High probability of cirrhosis—refer to hepatology 1

Alternative elastography methods: ARFI, 2D shear wave elastography, or MR elastography 1

Enhanced Liver Fibrosis (ELF) panel may be used if elastography unavailable 1

Step 5: Indications for Liver Biopsy

Consider liver biopsy in the following situations 1:

• High-risk patients with diabetes and/or metabolic syndrome where NASH with advanced fibrosis is suspected 1
• Findings suggesting cirrhosis: Thrombocytopenia, AST>ALT, hypoalbuminemia 1
• When coexisting liver diseases cannot be excluded (e.g., autoimmune hepatitis, drug-induced injury, Wilson's disease) 1
• Discordant or indeterminate non-invasive test results 1
• Before initiating high-risk therapies where histologic confirmation would alter management 1

Important caveat: Up to 20% of patients with alcohol use have a secondary or coexisting etiology requiring biopsy for definitive diagnosis 1. Additionally, liver biopsy has limitations including sampling error, observer variability, and procedural risks 1.

Step 6: Referral Criteria

Urgent referral to hepatology 3:

• ALT >8× ULN or >5× baseline
• ALT >3× ULN with total bilirubin >2× ULN (Hy's Law—suggests drug-induced liver injury with risk of acute liver failure)
• Evidence of acute liver failure (encephalopathy, coagulopathy)

Routine referral to hepatology 1, 3:

• Persistent elevation >2× ULN after 3 months
• FibroScan >16 kPa or imaging suggesting advanced fibrosis/cirrhosis 1
• Abnormal liver tests with negative extended workup and no clear etiology 1

Step 7: Management of Confirmed Cirrhosis

Once cirrhosis is established, initiate surveillance protocols 1:

• HCC screening: Ultrasound every 6 months 1
• Variceal screening: Upper endoscopy to assess for esophageal varices 1
• Cardiovascular risk assessment: Given increased cardiovascular risk in NAFLD 1
• Transplant evaluation: When appropriate based on MELD score and clinical decompensation 1, 2

Common Pitfalls to Avoid

Normal liver enzymes do not exclude significant liver disease: Up to 50% of NAFLD patients and patients with advanced fibrosis may have normal transaminases 1, 6. A normal ALT does not exclude NASH 1.

Do not rely on single laboratory values: Approximately 2.5% of healthy individuals will have abnormal values by statistical definition 2, 3. Repeat testing and clinical correlation are essential 7.

AST:ALT ratio reversal in advanced disease: While AST:ALT <1 typically suggests NAFLD, this ratio may reverse (>1) in later stages, so elevated AST:ALT does not exclude NAFLD 1.

Screening is not currently recommended even in high-risk populations (diabetes, metabolic syndrome), though obtaining ALT/AST in these patients may be reasonable given high disease burden 1.