Functions of the Liver and Liver Function Tests

FUNCTIONS OF THE LIVER

1. Carbohydrate Metabolism

• Glycogen storage - stores large amounts of glycogen, acting as a "glucose buffer," removing excess glucose after meals and releasing it when blood glucose falls
• Conversion of galactose and fructose to glucose
• Gluconeogenesis - when blood glucose is low, converts amino acids and glycerol into new glucose
• Formation of chemical compounds from intermediate carbohydrate metabolites

2. Fat (Lipid) Metabolism

• Beta-oxidation of fatty acids to produce energy (acetyl-CoA), generating ketone bodies (acetoacetic acid) for peripheral tissues
• Synthesis of cholesterol - ~80% is converted to bile salts; remainder transported in lipoproteins
• Synthesis of phospholipids and most lipoproteins (VLDL, HDL, etc.)
• Synthesis of fat from carbohydrates and proteins - stored fat is then transported to adipose tissue
• Cholesterol homeostasis - synthesizes and converts excess cholesterol to bile acids

3. Protein Metabolism

• Deamination of amino acids - required before amino acids can be used for energy or converted to carbohydrates/fats
• Urea synthesis (urea cycle / Krebs-Henseleit cycle) - detoxifies ammonia (from deamination and gut bacteria); without this, plasma ammonia rises rapidly causing hepatic coma and death
• Synthesis of plasma proteins - the liver synthesizes ~90% of all plasma proteins, including:
  • Albumin (most abundant - transport, oncotic pressure)
  • Clotting factors (fibrinogen, prothrombin, factors V, VII, IX, X - vitamin K dependent)
  • Anticoagulants (antithrombin)
  • Acute-phase proteins (CRP, fibronectin, alpha-1 antitrypsin, haptoglobin)
  • Carrier/binding proteins (transferrin, ceruloplasmin, steroid-binding proteins)
  • Can produce up to 15-50 g of plasma proteins/day
• Transamination / synthesis of non-essential amino acids - keto acids are converted to amino acids via transamination

4. Bile Formation and Secretion

• Bile is formed continuously and contains bile salts, bilirubin, cholesterol, phospholipids, water, and electrolytes
• Bile salts (derived from cholesterol) are essential for digestion and absorption of dietary fats and fat-soluble vitamins (A, D, E, K)
• Bilirubin (breakdown product of heme) is conjugated in the liver and excreted into bile

5. Detoxification and Biotransformation

• Phase I reactions (oxidation, hydroxylation, reduction) - mediated by cytochrome P450 (CYP) enzymes, converting xenobiotics and toxins to less lipophilic metabolites
• Phase II reactions (conjugation/esterification with glucuronic acid, sulfate, glycine) - renders metabolites water-soluble for biliary/renal excretion
• Detoxifies drugs (sulfonamides, penicillin, ampicillin, erythromycin, alcohol)
• Metabolizes steroid hormones (estrogen, cortisol, aldosterone, thyroxine) - liver disease leads to hormonal excess
• Kupffer cells (hepatic macrophages lining sinusoids) phagocytose bacteria, endotoxins, and particulate matter from the gut

6. Storage Functions

7. Hemostasis

• Synthesizes pro-coagulant factors: fibrinogen, prothrombin, factors V, VII, IX, X (vitamin K dependent for II, VII, IX, X)
• Synthesizes anticoagulants: antithrombin, protein C, protein S
• Synthesizes fibrinolytic proteins
• Chronic liver disease disrupts the hemostatic balance - can tip toward bleeding or thrombosis

8. Immunological Function

• Kupffer cells form part of the mononuclear phagocyte (reticuloendothelial) system
• Remove gut-derived bacteria and foreign antigens from portal blood
• In cirrhosis/fulminant liver failure, T cell function is impaired

9. Other Important Functions

• Angiotensin synthesis (angiotensinogen production)
• Temperature regulation - significant heat production
• pH balance - helps correct lactic acidosis
• Calcium excretion - a major route for calcium excretion via bile into feces
• Hematopoiesis - in the fetus, the liver is the primary hematopoietic organ

LIVER FUNCTION TESTS (LFTs)

1. Chemical metabolic system - hepatocyte function (aminotransferases)
2. Reticuloendothelial system - Kupffer cells metabolizing hemoglobin (bilirubin metabolism)
3. Biliary secretion system - bilirubin secretion into bile (ALP, GGT)

Key LFT Markers

A. Aminotransferases (Transaminases) - Markers of Hepatocyte Injury

• In acute hepatitis, AST and ALT rise markedly (often >10x upper limit of normal)
• In fulminant hepatic failure, AST/ALT can exceed 10,000 IU/L, with a characteristic disproportionate AST > ALT rise
• In cirrhosis, transaminases are paradoxically normal or only mildly elevated (most liver tissue is replaced by fibrosis)
• AST:ALT ratio > 2:1 suggests alcoholic liver disease

B. Alkaline Phosphatase (ALP) - Marker of Cholestasis

• Derived from biliary epithelium, bone, intestine, placenta
• Raised in: biliary obstruction (cholestasis), hepatic metastases (most sensitive marker), primary biliary cirrhosis, bone disease (Paget's disease, osteoblastic metastases)
• Physiologic elevation: childhood growth, pregnancy
• Decreased in: hypophosphatasia, Wilson's disease, malnutrition

In cholestatic jaundice: ALP >3x upper limit of normal; transaminases <3x ULN In hepatocellular jaundice: transaminases >3x ULN; ALP <3x ULN

C. Gamma-Glutamyl Transferase (GGT) - Marker of Biliary Tract and Alcohol

• Located on biliary epithelial cells of small interlobular bile ducts and hepatocytes of the limiting plate
• Highly sensitive indicator of hepatobiliary injury (principally biliary tract)
• Elevated in: biliary obstruction, alcoholic liver disease (elevated in ~70% of chronic alcoholics, correlates with alcohol consumption, levels 2-3x ULN in heavy drinkers)
• Elevated by drugs: warfarin, barbiturates, phenytoin, valproate, methotrexate
• Used to confirm ALP elevation is hepatic (if GGT is normal with raised ALP, suspect bone origin)

D. Bilirubin - Marker of Bilirubin Metabolism

• Conjugated hyperbilirubinemia is present when >30% of serum bilirubin is conjugated
• In biliary obstruction: predominantly conjugated bilirubin rises with ALP and GGT; other tests normal

E. Albumin - Marker of Hepatic Synthetic Function

• Synthesized exclusively by the liver (100% of circulating albumin)
• Decreases only when >80% of liver tissue is destroyed (cirrhosis, fulminant hepatic failure)
• Low albumin causes: generalized edema, ascites
• Normal albumin in acute hepatitis (insufficient tissue destruction)
• Half-life ~20 days - reflects chronic rather than acute liver function

F. Total Protein

• Liver synthesizes >90% of plasma proteins
• Decreased in cirrhosis and fulminant hepatic failure
• Note: immunoglobulins (gamma globulins) may be elevated in cirrhosis (defective T cell function with excess ineffective immunoglobulin production) - can create a normal "total protein" despite low albumin

G. Prothrombin Time (PT) / INR - Marker of Synthetic Function + Vitamin K Status

• Clotting factors II, VII, IX, X are vitamin K-dependent and synthesized in the liver
• PT/INR prolonged in: liver failure, vitamin K deficiency, warfarin therapy
• Sensitive early indicator of synthetic function (factor VII has a short half-life of ~4-6 hours)
• Severe coagulopathy with elevated APTT and PT seen in cirrhosis and fulminant failure

H. Ammonia (NH3)

• The liver is the only site for ammonia detoxification via the urea cycle
• Elevated when >80% of liver tissue is destroyed
• Causes hepatic encephalopathy at toxic levels
• Pre-analytical care required: specimens must be chilled on ice during transport, tested immediately (ammonia rises ~20% in the first hour); avoid hemolysis; patient should not smoke before the test

Patterns of LFT Abnormalities

• Guyton and Hall Textbook of Medical Physiology
• Ganong's Review of Medical Physiology, 26th Ed.
• Henry's Clinical Diagnosis and Management by Laboratory Methods
• Quick Compendium of Clinical Pathology, 5th Ed.
• Bailey and Love's Short Practice of Surgery, 28th Ed.