What are the functions of the liver and how is liver function assessed and managed?

Liver Functions and Assessment

Primary Functions of the Liver

The liver serves four major physiological functions: metabolism and synthesis, excretion, storage, and detoxification of potential toxins. 1

• The liver acts as the body's largest discrete organ and functions as the "central laboratory" of the organism, performing both catabolic and anabolic metabolic processes 2
• It maintains physiological homeostasis through digestive, endocrine, and immune-regulatory roles, including metabolism, detoxification, and immune response 3
• The liver is positioned strategically between the portal and general circulation, allowing it to take up nutrients from the gastrointestinal tract, store them, and provide nutrients to other organs 4
• It serves as the largest reticulo-endothelial cell network in the body, playing a critical role in host defense against invading microorganisms 5
• The liver clears potentially damaging substances including bacterial products, drugs delivered by portal blood, and microorganisms that reach the circulation 4

Initial Laboratory Assessment of Liver Function

The initial assessment of hepatic function requires a comprehensive panel including serum bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), prothrombin time expressed as international normalized ratio (INR), albumin, and platelet count. 6, 7

Hepatocellular Injury Markers

• ALT is the most specific marker for liver injury due to low concentrations in other tissues, with normal values of 29-33 IU/L in men and 19-25 IU/L in women 7, 8
• AST is less specific than ALT as it is also present in heart, skeletal muscle, kidneys, brain, and red blood cells 8
• Aminotransferase elevation severity is classified as: mild (<5× upper reference limit), moderate (5-10× upper reference limit), or severe (>10× upper reference limit) 7, 8
• An AST/ALT ratio >2 suggests alcoholic liver disease, while a ratio <1 suggests non-alcoholic fatty liver disease (NAFLD) 7, 8

Cholestatic Markers

• Elevated ALP levels indicate cholestatic liver disease and require GGT confirmation for hepatic origin 7, 8
• GGT elevation confirms the hepatic source of elevated ALP, distinguishing it from bone or other non-hepatic sources 8

Synthetic Function Markers

• Decreased albumin levels reflect the liver's synthetic capacity and suggest chronic liver disease 6, 7
• Prolonged prothrombin time/INR measures clotting factors synthesized by the liver and indicates impaired synthetic function 6, 7
• These synthetic markers represent true liver function rather than just injury or cholestasis 8

Additional Essential Tests

• Platelet count serves as a surrogate marker for portal hypertension, with thrombocytopenia suggesting advanced liver disease 6, 7
• Complete blood count, blood urea nitrogen, and creatinine assess kidney function; creatinine is an established prognostic marker in patients with liver disease 6

Diagnostic Approach Based on Pattern of Abnormalities

Hepatocellular Pattern (Predominant Aminotransferase Elevation)

When ALT/AST elevation predominates over ALP, exclude common hepatic diseases with a hepatitis panel including HBsAg, hepatitis B surface antibody, hepatitis B core antibody (HBcAb), HBcAb IgM (in acute viral hepatitis), and HCV antibodies. 6, 7

• Confirm viral load in patients positive for HBsAg, HBcAb IgG (isolated HBcAb IgG may indicate chronic HBV infection), and HCV antibodies 6
• Patients with positive viral load should be evaluated by a hepatologist for antiviral therapy 6
• For persistent or significant elevations, perform additional serologic testing for autoimmune markers, iron studies, α1-antitrypsin, ceruloplasmin, and imaging studies (ultrasound, CT, or MRI) 7

Cholestatic Pattern (Predominant ALP Elevation)

• Abdominal ultrasound is essential to distinguish extrahepatic (biliary obstruction) from intrahepatic cholestasis 8
• Conjugated (direct) hyperbilirubinemia predominates in obstructive jaundice, resulting from impaired biliary excretion 9

Scoring Systems for Hepatic Functional Reserve

Child-Pugh Classification

The Child-Pugh score incorporates laboratory measurements (serum albumin, bilirubin, prothrombin time) and clinical assessments (encephalopathy, ascites) to classify patients as having compensated (class A) or decompensated (classes B and C) cirrhosis. 6, 7

• Advantages include ease of performance at the bedside and inclusion of clinical parameters 6
• This classification has been traditionally used for assessment of hepatic functional reserve in patients with cirrhosis 6

MELD Score

The Model for End-Stage Liver Disease (MELD) is a numerical scale ranging from 6 (less ill) to 40 (gravely ill) derived using serum bilirubin, creatinine, and INR. 6, 7

• Originally devised to assess mortality for patients undergoing transjugular intrahepatic portosystemic shunts 6
• Adopted by the United Network for Organ Sharing (UNOS) to stratify patients on the liver transplantation waiting list according to their risk of death within 3 months 6
• Advantages include objective scoring based on widely available laboratory tests and inclusion of renal function measurement 6
• Clinical assessments of ascites and encephalopathy are not included 6
• It remains unclear whether MELD is superior to Child-Pugh as a predictor of survival in patients with liver cirrhosis 6

Albumin-Bilirubin (ALBI) Grade

The ALBI grade considers serum albumin and bilirubin levels and is especially helpful in predicting survival outcomes in patients with stable decompensated cirrhosis. 6, 7

Advanced Assessment of Hepatic Functional Reserve

Portal Hypertension Evaluation

Assess for clinically significant portal hypertension through evidence of esophagogastric varices, splenomegaly, splenorenal shunts, recanalization of the umbilical vein, and thrombocytopenia. 6

• Evidence of portal hypertension may be evident on CT/MRI 6
• Esophageal varices can be evaluated using esophagogastroduodenoscopy or contrast-enhanced cross-sectional imaging 6
• Clinically relevant portal hypertension (CRPH) is defined as hepatic venous pressure gradient (HVPG) >10 mmHg 6
• Portal hypertension should be balanced with the extent of hepatectomy and liver function indicators when determining eligibility for resection 6

Non-Invasive Fibrosis Assessment

Simple fibrosis scores (FIB-4, NAFLD Fibrosis Score) are useful for initial risk stratification, with FIB-4 <1.3 or NAFLD Fibrosis Score ≤-1.455 indicating low risk of advanced fibrosis. 7, 8

• For patients >65 years, use higher cut-offs: FIB-4 <2.0 8
• Elastography techniques (transient elastography/FibroScan®, MR elastography) can quantify the degree of cirrhosis-related fibrosis 6, 7
• Liver stiffness measurement (LSM) above 12-14 kPa predicts significant risk of post-hepatectomy liver failure 6
• Non-focal liver biopsy and transjugular liver biopsy with pressure measurements may be performed for further assessment of hepatic functional reserve before hepatic resection in patients with cirrhosis 6

Indocyanine Green (ICG) Kinetics

ICG retention rate at 15 minutes (ICG R15) can be measured at bedside with non-invasive pulse dye densitometry devices, with various cut-offs guiding decision-making for liver resective procedures. 6

• Limit resection and segmentectomy to patients with ICG R15 below 20-25% and 30-35%, respectively 6
• ICG R15 provides dynamic liver function determination for liver resection planning 6

Critical Pitfalls to Avoid

Normal LFTs Do Not Exclude Liver Disease

Liver disease can develop silently with no signs or symptoms, and patients can progress through significant fibrosis to cirrhosis with persistently normal liver function tests. 7, 8

• 2.5% of healthy individuals will have abnormal elevation of a given liver chemistry test 7
• Standard LFTs are only 38% sensitive and 83% specific for detecting hepatic fibrosis, making them inadequate screening tools when used in isolation 7
• Advanced liver fibrosis may present with normal LFTs 7
• When cirrhosis is suspected based on risk factors (chronic alcohol use, viral hepatitis), perform fibrosis assessment even if LFTs are normal using non-invasive fibrosis scores like FIB-4 or NAFLD Fibrosis Score 7

Pattern Recognition Over Absolute Values

• Hepatocellular vs. cholestatic patterns guide differential diagnosis more than absolute values 8
• The degree of LFT elevation does not correlate with fibrosis stage 7
• Only 3.9% of patients with abnormal ALT/AST are diagnosed with significant liver disease within 5 years 8

Albumin Interpretation

• Multiple non-hepatic conditions cause hypoalbuminemia; do not over-interpret albumin as liver-specific 8

Spectrum Effect

• Consider the spectrum effect when applying non-invasive tests to populations with risk factors for liver disease 7
• Temporary events such as renal failure or spontaneous bacterial peritonitis may affect the assessment of liver function 7

Monitoring Strategy for At-Risk Patients

For patients with known risk factors but normal LFTs, perform elastography to detect occult fibrosis, screen for portal hypertension with platelet count and imaging, and consider upper endoscopy to assess for varices. 7

• Initiate hepatocellular carcinoma surveillance if cirrhosis is confirmed, regardless of LFT values 7