Liver Function

MLTD 2107 Clinical Chemistry II: Liver Function

Overview

  • Course: MLTD 2107 Clinical Chemistry II

  • Institution: Nova Scotia Community College

  • All rights reserved for intellectual property. Unauthorized reproduction or distribution is strictly prohibited.

Anatomy of the Liver

  • Diagram Descriptions: Anatomy Overview

    • Diaphragm

    • Right lobe of liver

    • Gallbladder

    • Falciform ligament

    • Left hepatic vein

    • Left lobe

    • Inferior vena cava

    • Celiac artery

    • Hepatic artery

    • Common bile duct

    • Portal vein (branch)

Blood Flow and Hepatic Structure

  • Liver Cellular Structure

    • Bile duct, bile canal

    • Kupffer cells: specialized macrophages in the liver

    • Hepatic cells: main functional cells of the liver

    • Branches of hepatic portal vein: bring nutrient-rich blood from digestive organs

    • Branch of hepatic artery: brings oxygen-rich blood to the liver

    • Hepatic sinusoids: capillary-like structures facilitating blood flow

    • Central canal: outflow for blood from the liver

Liver Function: Excretion and Secretion

  • Main Excretory Products

    • Urine

    • Bile: produced from components such as bile acids/salts, bile pigments (mainly bilirubin), cholesterol, phospholipids, proteins, water, and electrolytes

    • Production Statistics:

    • Total bile produced: 3 L/day

    • Total bile excreted: 1 L/day

    • Bilirubin: principal pigment derived from the breakdown of red blood cells (RBCs) after approximately 126 days of their lifespan

    • Iron: returned to stores via transferrin

    • Globin: reverts to amino acids to synthesize new proteins

    • Heme: converts to biliverdin, then to bilirubin within 2-3 hours, and is transported to liver bound to albumin.

Bilirubin Metabolism

  • Forms of Bilirubin

    • Unconjugated Bilirubin:

    • Also known as "Indirect" bilirubin

    • Properties: water-insoluble and toxic

    • Transported in hepatocytes by Ligandin to the endoplasmic reticulum (ER)

    • Conjugated Bilirubin:

    • Subjected to conjugation with glucuronic acid through the enzyme uridyldiphosphate glucuronyl transferase (UDPGT)

    • Resulting in bilirubin diglucuronide, which is water-soluble, enabling transport to bile canaliculi, hepatic duct, and ultimately the intestines.

Important Notes on Bilirubin Handling

  • The liver must be functional to process and eliminate 200-300 mg of bilirubin daily.

  • Bilirubin must undergo conjugation for elimination.

  • Most bilirubin is excreted in feces as urobilin, with a small amount appearing in urine as urobilinogen (UBG).

  • A very small concentration remains in plasma, primarily as unconjugated bilirubin.

Liver Functions: Synthesis and Metabolism

  • Carbohydrate Metabolism

    • Ingested carbohydrates are directed to the liver for:

    • Utilizing glucose for energy

    • Circulating glucose to other tissues

    • Storage as glycogen via glycogenesis

    • Mobilization through glycogenolysis

    • Gluconeogenesis from pyruvate, lactate, and amino acids.

  • Lipid Metabolism

    • Synthesized when nutritional status is adequate.

    • Gathers dietary free fatty acids and those synthesized in the liver

    • Catabolized to yield acetyl-CoA, which is then transformed into triglycerides, phospholipids, cholesterol (70% of body’s cholesterol), very-low-density lipoprotein (VLDL), bile acids, and ketones.

    • Metabolizes and removes lipids using lipoproteins.

  • Protein Synthesis

    • The liver synthesizes all proteins except for immunoglobulins and adult hemoglobin.

    • Synthesized proteins include albumin, coagulation factors, transport proteins, and other significant proteins.

    • Degradation leads to the release of ammonia, entering the urea cycle for processing.

    • Note: Total protein measurement involves a Biuret reaction, where copper ions react with peptide bonds.

Liver Function: Detoxification and Drug Metabolism

  • Acts as a “Gatekeeper” regulating substances between the gastrointestinal tract and systemic circulation.

  • Engages in “first pass” metabolism.

  • Detoxification occurs through two mechanisms:

    • Reversible Binding: Inactivates materials on a temporary basis.

    • Chemical Modification: Involves converting harmful substances into less toxic forms, for instance:

    • Ammonia getting converted via urea cycle

    • Drugs transforming into metabolites before excretion. For instance:

      • Alcohol metabolizes to acetaldehyde, then acetic acid.

Liver Function: Storage

  • Important For Storing:

    • Glycogen: Rapidly mobilized energy source.

    • Bilirubin: Intermediate product of heme metabolism.

    • Amino Acids: Essential for protein synthesis.

    • Lipids: Include phospholipids and other essential fats.

    • Vitamins: A, B12, D, E, K essential to body function.

    • Minerals: Iron (within ferritin) and copper are stored in the liver.

Important Biochemical Pathways in the Liver

Catabolic Pathways

  • Transamination: converting amino acids to ketones and acetyl-CoA.

  • Fatty acid oxidation: breaking down fats to produce ketones.

  • Urea cycle: detoxifying ammonia by converting it to urea.

  • Bilirubin metabolism: processing heme from hemoglobin breakdown.

  • Drug metabolism: processing xenobiotic compounds.

Anabolic Pathways

  • Albumin Synthesis: Essential for maintaining oncotic pressure in blood.

  • Clotting Factor Synthesis: Vital for blood coagulation processes.

  • Lipoprotein Synthesis: Includes synthesis of VLDL and other forms.

  • Gluconeogenesis: Synthesizing glucose from non-carbohydrate sources.

  • Bile Acid Synthesis: Producing bile acids for digestion.

Liver Diseases: Jaundice

  • Definition: Yellowing of skin, sclera of eyes, and mucous membranes.

  • Classification of Jaundice:

    • Prehepatic Jaundice:

    • Often related to hemolytic anemia, where increased bilirubin is presented to the liver.

    • Lab findings show increased unconjugated bilirubin in serum which is not found in urine due to its insolubility.

    • Hepatic Jaundice:

    • Arises from liver defects; can increase either unconjugated or conjugated bilirubin depending on the pathology. Liver function tests typically show elevated liver enzymes and possible protein synthesis decreases.

    • Posthepatic Jaundice:

    • Occurs due to obstruction of bile flow; conjugated bilirubin rises in serum and is excreted in urine; results in pale stools.

Detailed Types of Hepatic Jaundice

  • Unconjugated Hyperbilirubinemia:

    • Gilbert’s Syndrome: Benign hereditary condition leading to intermittent elevated unconjugated bilirubin without signs of hemolysis.

    • Crigler-Najjar Syndrome: Rare condition causing severe unconjugated hyperbilirubinemia due to hereditary conjugation defects.

  • Conjugated Hyperbilirubinemia:

    • Dubin-Johnson Syndrome: Defect in excreting conjugated bilirubin, characterized by dark granules in the liver tissue.

    • Rotor Syndrome: Similar to Dubin-Johnson but without granule formation.

Liver Diseases: Cirrhosis

  • Pathophysiology: Liver damage leading to scar tissue formation, obstructed blood flow, and liver dysfunction.

  • Symptoms: Fatigue, jaundice, nausea, weight loss, ascites, and intense itching.

  • Common Causes: Chronic alcohol use, Hepatitis C, chronic Hepatitis B or D, autoimmune hepatitis, and inherited disorders.

Liver Tumors

  • Types:

    • Primary Tumors: Rare forms originating in the liver.

    • Metastatic Tumors: Majority are secondary cancers, with colon, lung, and breast as primary sources.

    • Benign Tumors: Examples include hepatocellular adenoma and hemangiomas.

    • Malignant Tumors: Most notably, hepatocellular carcinoma (HCC) is common, particularly following cirrhosis or chronic viral hepatitis infection.

Drug and Alcohol-Related Liver Disorders

  • Responsible for 1/3 to 1/2 of acute liver failure cases, primarily due to immune-mediated injury to hepatocytes.

  • Ethanol: Most frequently implicated drug in liver toxicity, where 90% of ingested alcohol is processed through specific metabolic pathways in the liver.

  • Three Stages of Liver Injury from Alcohol:

    1. Alcoholic Fatty Liver: Initial stage with mild inflammation.

    2. Alcoholic Hepatitis: Accompanied by more significant symptoms and enzyme elevations.

    3. Alcoholic Cirrhosis: Advanced stage, severely affecting liver function and overall health prognosis.

Hepatitis Overview

  • Definition: Liver inflammation due to various causes including viral (A, B, C, D, E), bacteria, drugs, toxins, and autoimmune processes.

  • Symptoms: Jaundice, fatigue, abdominal discomfort, elevated liver enzymes.

  • Diagnostic Lab Findings: Marked elevations of transaminases (AST, ALT) and bilirubin levels.

Hepatitis A

  • Epidemiology: Highly prevalent worldwide through fecal-oral transmission, mainly from contaminated food and water.

  • Clinical Markers: Presence of IgM anti-HAV indicates active infection; recovery typically occurs within 3 weeks without chronicity.

Hepatitis B

  • Epidemiology: Approximately 2 billion infected globally, with 350-400 million chronic carriers.

  • Transmission: Blood, sexual contact, and perinatal exposure.

  • Clinical Progression: Most cases are asymptomatic; some may develop fulminant infections with high mortality risk.

  • Laboratory Monitoring: Serologic markers indicate current infection, past infection, and immunological responses.

Hepatitis C

  • Transmission: Primarily through transfused blood products; increasing incidence through drug use and sexual contact.

  • Chronic Infection: About 80% develop chronic infections, significantly increasing the risk of cirrhosis and hepatocellular carcinoma over time.

  • Diagnostic Testing: Anti-HCV antibodies and PCR for serum HCV RNA are critical for both diagnosis and monitoring treatment.

Hepatitis D

  • Can only replicate in the presence of Hepatitis B virus (HBV).

  • Common in carriers of HBV; increases risks for severe liver disease.

Hepatitis E

  • Fecal-oral transmission similar to Hepatitis A, often through contaminated water sources, especially in developing nations.

  • More severe in pregnant women with potentially high fatality rates.

Liver Function Tests: Bilirubin Testing

  • Bilirubin Measurement Techniques:

    • Diazo Reaction: Involves serum reactions to determine total (conjugated + unconjugated) bilirubin concentrations.

    • Conjugated bilirubin is water-soluble, reacting with diazotized sulfanilic acid; unconjugated bilirubin requires accelerator for adequate measurement.

  • Reference Intervals for Bilirubin:

    • Normal ranges:

    • Total bilirubin: 3-17 µmol/L

    • Conjugated: 0-3 µmol/L

    • Unconjugated: 3-14 µmol/L

    • Circulating concentrations exceeding 300 µmol/L indicate severe pathology.

Testing Considerations for Bilirubin

  • Collection: Serum should be protected from light exposure to prevent degradation of bilirubin levels.

  • Common Sources of Errors: Hemolysis can lead to false decreases; significant lipemia may cause false increases.

Enzyme Testing for Liver Function

  • Aminotransferases

    • Elevations in AST and ALT are indicative of hepatocellular damage; differentiation between liver and other organ dysfunctions is essential.

  • Phosphatases

    • Alkaline phosphatase (ALP): Elevated levels indicate biliary obstruction; differentiate from other sources via 5’-nucleotidase testing.

    • GGT: Used for determining hepatobiliary disease versus bone disorders.

  • Testing for Hepatic Synthesis: Includes serum protein levels (especially albumin) and prothrombin time (PT) measurements to assess functional integrity of the liver.

Conclusion and References

  • This study guide collates critical insights regarding liver function, its diseases, and concept assessments pertinent to clinical chemistry and diagnostics.

  • Key References:

    • Clinical Chemistry: Principles, Techniques, and Correlations. 8th Edition, Wolters Kluwer 2018

    • Tietz: Fundamentals of Clinical Chemistry, 6th Edition, Elsevier, 2008.