Liver Anatomy, Function, and Biochemistry

Anatomy of Liver

• Large organ, typically weighing between 1.2 to 1.5 kg in adults, but this can vary based on factors such as body size and health status.

• Located beneath and closely attached to the diaphragm, primarily in the upper right quadrant of the abdominal cavity, allowing it to be protected by the rib cage.

• Divided unequally into two main lobes: the larger right lobe and the smaller left lobe, separated by the falciform ligament which attaches the liver to the anterior abdominal wall.

• Extremely vascular organ, receiving a dual blood supply from:

  • Hepatic artery: Supplies oxygenated blood, accounting for about 25% of the liver's blood supply.

  • Portal vein: Carries nutrient-rich blood from the digestive organs to the liver, making up approximately 75% of its blood supply; this blood contains substances absorbed from the intestines.

• Approximately 1500 mL of blood passes through the liver per minute, ensuring continuous filtration, metabolism, and detoxification processes.

Functions of Liver

• Performs over 500 chemical functions and produces over 160 different proteins crucial for various physiological processes.

• Stores and releases sugar as glycogen, maintaining blood glucose levels and providing a readily available energy source.

• Metabolizes, detoxifies, and synthesizes various substances, including drugs, hormones, and waste products, ensuring their safe removal or utilization by the body.

• Primary site for drug metabolism:

  • Enzymes convert prodrugs to active metabolites or active drugs to inactive forms, modulating their pharmacological effects.

  • Primary mechanism is via cytochrome P-450 enzymes, a family of enzymes responsible for the metabolism of a wide array of drugs and toxins; genetic variations in these enzymes can significantly affect drug metabolism rates between individuals.

Excretory Function - Bilirubin

• Excretion of endogenous and exogenous substances into bile or urine, with bilirubin being a key example.

• Measurement of bilirubin in blood or urine assesses hepatic anion transport, providing valuable insights into liver function and potential dysfunction.

Normal Bilirubin Metabolism

• Approximately 80% of bilirubin is formed daily from haemoglobin released from old RBCs, while the remaining 20% is derived from enzymes and other products, highlighting the importance of efficient RBC turnover.

• Degradation of RBCs occurs in the reticuloendothelial system (spleen, liver, bone marrow); the globin portion of Hb is returned to the amino acid pool.

• The heme portion is converted to bilirubin, which is bound by albumin and transported to the liver, ensuring safe transport through the bloodstream.

• This form of bilirubin is referred to as unconjugated or indirect bilirubin, which is crucial in diagnosing different types of jaundice.

• Unconjugated bilirubin is insoluble in water and cannot be removed from the body until conjugated by the liver, emphasizing the liver's central role in bilirubin excretion.

• In the liver cell, unconjugated bilirubin flows to the sinusoidal spaces, is released from albumin, and is picked up by a carrier protein called ligandin. Ligandin enhances the solubility of unconjugated bilirubin within hepatocytes.

• Ligandin transports unconjugated bilirubin to the endoplasmic reticulum where it is conjugated in the presence of the enzyme uridine diphosphate glucuronosyltransferase (UDPGT). This conjugation makes bilirubin water-soluble.

• Conjugated bilirubin is water-soluble and can be secreted from the hepatocyte into bile canaliculi. These canaliculi form a network that transports bile through the liver.

• Once in the hepatic duct, it combines with secretions from the gall bladder and is expelled through the common bile duct to the intestines, aiding in the digestion and absorption of fats.

• In the gut, bacteria convert bilirubin to urobilinogen, which is colourless. This conversion is part of the normal breakdown process.

• Approximately 80% of urobilinogen is oxidised to urobilin and stercobilin and excreted in the faeces, giving stool its characteristic brown color.

• Approximately 20% may be reabsorbed by the gut and re-excreted by either the liver or the kidney, contributing to the enterohepatic circulation of bilirubin.

Bilirubin Metabolism and Jaundice

• Total Bilirubin reference range: <17 \mu mol/L

• Jaundice: Total bilirubin \geq 35 \mu mol/L - Clinically apparent with yellow discolouration of sclera and skin; visible jaundice typically indicates significant underlying pathology.

  • Divided into three categories: pre-hepatic, hepatic, and post-hepatic, each reflecting different stages or causes of bilirubin dysregulation.

• Icterus: Clinical laboratory term for serum or plasma sample with yellow discolouration due to elevated bilirubin; differs from jaundice as it specifically refers to lab samples.

Pre-hepatic Jaundice

• Not due to liver dysfunction but due to problems in the blood (excessive breakdown), such as hemolytic anemia or internal hemorrhage.

• The liver cannot cope with the demand of breakdown- the unconjugated bilirubin overwhelms the liver's processing capacity.

• Increase in bilirubin production is greater than excreting capacity, leading to elevated levels of unconjugated bilirubin in the blood.

• Example: haemorrhage or hemolytic anemia where RBCs are destroyed at an accelerated rate.

Hepatic Jaundice

• Normal load of bilirubin that cannot be conjugated and/or excreted by damaged liver cells, indicating primary hepatocellular dysfunction.

• The first indication of liver problem, often manifesting as abnormal liver function tests before jaundice is clinically evident.

• May be due to hepatitis (viral or drug-induced), cirrhosis, infiltration, tumours, or drugs.

• Hepatitis may be viral or drug-induced; test for viral hepatitis to determine the specific type, as viral hepatitis can cause significant liver inflammation and damage.

• Metastasis usually goes to the liver due to its extensive blood supply and central role in filtering blood from other parts of the body.

• Low plasma albumin indicates the liver is not working well, leading to less conjugated bilirubin and impaired synthetic function of the liver.

• Increase in conjugated bilirubin because it is not excreted well, causing it to accumulate in the bloodstream.

• Alkaline phosphatase levels are 2-3x higher, suggesting cholestasis or bile duct obstruction within the liver.

Post-hepatic Jaundice

• Biliary flow is obstructed, resulting in less bile; conjugated bilirubin cannot be excreted into the intestines and is regurgitated into systemic circulation, often due to mechanical obstruction of the bile ducts.

• Examples: gallstones, biliary structures, pancreatic tumours, cholangitis (swelling of bile duct system from infection).

• Pale stools because no urobilinogen is excreted, resulting in a lack of normal pigmentation in the stool.

• Alkaline phosphatase levels are 10x higher, indicating significant obstruction of the biliary system.

Vacutainer Colours for Biochemistry Tests

• Yellow/red vacutainer for biochemistry tests requiring serum samples.

• Purple vacutainer for HBA1c and screening of thalassemia, as it contains EDTA which preserves blood cells.

• Grey vacutainer for normal glucose levels, containing fluoride and oxalate to inhibit glycolysis.

Hyperbilirubinaemia

• Defined as elevated serum or plasma bilirubin levels above the reference range of the laboratory, due to disorders of bilirubin metabolism. This can result from increased production, impaired uptake, conjugation, or excretion of bilirubin.

• Classified based on the form of bilirubin present in serum:

  • Unconjugated (indirect) hyperbilirubinaemia, indicating issues prior to liver conjugation.

  • Conjugated (direct) hyperbilirubinaemia, reflecting problems in bilirubin excretion after liver conjugation.

Basic Liver Responses to Injury

• Fatty change (fatty liver): accumulation of triglycerides in hepatocytes due to various metabolic or toxic insults.

  • Seen in diabetes mellitus (DM), alcoholism, Reye's syndrome (in children, associated with a virus like Epstein-Barr), pregnancy, obesity. These conditions impair lipid metabolism within the liver.

• Cholestasis: Obstruction of bile flow, leading to accumulation of bile acids and bilirubin in the liver.

  • Intra-acinar: viral hepatitis, drug, alcohol, pregnancy causing obstruction within the liver.

  • Extra-acinar: primary biliary cirrhosis, tumours, polycystic liver disease, sclerosing cholangitis, conditions outside the liver affecting bile ducts.

• Storage of abnormal material such as iron (hemochromatosis) or copper (Wilson's disease).

• Liver cell necrosis: Death of hepatocytes due to various causes, like ischemia, toxins, or infections; can be focal or widespread.

• Fibrosis: Scarring between lobules, disrupts overall architecture, potentially leading to cirrhosis and liver failure.

  • Can be found with a biopsy and staged to assess the severity of liver damage.

Biochemical Testing for Liver Disease

• Liver function tests (LFTs) - misnomer, not a true test of function; better termed as liver tests or liver chemistries.

• Elevated serum aminotransferase levels and alkaline phosphatase levels are markers of liver injury, not indices of the degree of liver function. These enzymes are released from damaged liver cells.

• Measures of hepatic synthetic function: albumin, bilirubin, prothrombin time, ALT, and AST. These tests reflect the liver's ability to synthesize proteins and clear waste products.

• If total bilirubin is elevated, test for indirect bilirubin to differentiate between conjugated and unconjugated hyperbilirubinemia.

• GPT = ALT (Alanine Aminotransferase), GOT = AST (Aspartate Aminotransferase).

• Liver function tests are best referred to as liver tests or chemistries to avoid confusion about their actual capabilities.

• Abnormal LFTs are the first indication of underlying liver disease, but normal results do not preclude significant liver disease. Some conditions may not cause significant enzyme elevations initially.

• Incidence of clinically significant unsuspected liver disease is approximately 1%, making routine screening valuable in at-risk populations.

• Sequential testing may allow assessment of the effectiveness of therapy and monitor disease progression or response to treatment.

• Symptoms: yellowing, fever, vomiting, abdominal pain, fatigue, and dark urine. These symptoms can indicate liver dysfunction.

• INR: Test that helps assess the proper function of clotting factors. It is prolonged when the liver's synthetic function is impaired.

Liver Disease Causes

• Liver-cell damage: increase in GOT,GPT

  1. Cholestasis: retained conjugated bilirubin direct and increase ALP (epithelial cell lining)

  2. Reduced mass of functioning cells: increase in prothrombin time (INR), decrease in albumin levels

  3. Look at bilirubin levels (total and conjugated/direct): increase levels in conjugated bilirubin levels = impaired hepatic excretory function, usually accompanied by an increase in ALP

• Biochemical testing: enzymatic results can co-exist between these conditions, but one usually predominates; plus, run other non-enzymatic liver tests.

• Auto-antibody screen: test for autoimmune diseases, such as autoimmune hepatitis or primary biliary cholangitis.

• Viral tests: exclude viral hepatitis, including hepatitis A, B, C, D, and E, which can cause acute or chronic liver damage.

Bilirubin Testing

1. Helpful in differentiating between the causes of jaundice

   • Serum bilirubin:

     • Spectrophotometer - absorbance 455nm -> routine = measure total bilirubin

     • Indirect bilirubin = unconjugated bilirubin

     • Direct bilirubin = conjugated bilirubin

     • Routinely measured = total bilirubin

     • Occasionally = direct -> indirect derived by subtracting direct from total. These measurements are crucial for diagnosing various liver conditions.

     • Interferences: lipaemia, haemolysis, increased exposure to light, refrigeration if not measured immediately - affect turbidity of sample and spectrophotometer readings. Proper sample handling is essential for accurate results.

   • Urine urobilinogen - commercial strips, which can indicate liver dysfunction or hemolytic anemia.

   • Faecal urobilinogen - visual inspection, semi-quantitative method, providing insights into bilirubin metabolism and excretion.

2. Assess cellular damage

   • Damage to the liver cell membrane affecting plasma enzyme activities:

   • But care should be taken as enzymes present in other tissues may be elevated due to damage in these tissues - use differential diagnosis, as AST and ALT are not exclusive to the liver.

Impaired Levels of Transaminases

• Alanine transaminases - ALT/GPT

• Aspartate transaminases - AST/GOT

• Non-hepatic causes of elevated AST/ALT should be considered if no other liver problem can be found: muscle injury, heart conditions, or thyroid disorders can elevate these enzymes.

Transaminases: AST and ALT

• ALT and AST are the most widely ordered liver chemistries that reflect injury to the liver; elevations indicate hepatocyte damage.

• Their levels increase in the serum with the death of hepatocytes (either by necrosis or apoptosis).

• Levels help to differentiate between the type of cell damage:

  • ALT/GPT - localised in the liver - predominantly localised to the cytosol, making it a more specific marker for liver damage.

  • AST/GOT- more widely distributed in liver mainly as well as cardiac, skeletal, kidney and brain tissue - more localised in the mitochondria, thus less specific to the liver.

  • Inflammation/infection - hepatocellular = cytoplasmic membrane damage- high inc in ALT, inc in AST

  • Infiltrative disorders = damage to mitochondrial and cytoplasmic membrane - high inc. in AST and inc in ALT - ex. Liver cell necrosis, where both mitochondrial and cytoplasmic enzymes are released.

• The degree of elevation of AST and ALT is useful in distinguishing acute and chronic liver diseases; very high levels often suggest acute damage, while moderate elevations may indicate chronic conditions.

• AST to ALT ratio can be very useful; when greater than 2.0, this typically suggests alcoholic liver disease since alcohol is a mitochondrial toxin, damaging mitochondrial AST.

• AST is removed from serum twice as quickly as ALT, affecting the interpretation of their relative levels over time.

Gamma-glutamyltransferase - GGT

• Associated with alcohol consumption and various liver conditions.

• Derived from ER of cells of the hepatobiliary track; it is induced by alcohol and certain drugs.

• Intake of alcohol or drugs make reticulum proliferate - increased synthesis of GGT: Increase in GGT = not necessarily hepatocellular damage - very sensitive measurement, but lacks specificity.

• Has limited use as primary liver test - consider ultrasound - look for fatty liver or non-alcoholic fatty liver, to evaluate liver structure and detect abnormalities.

Assess Synthetic Function

3. Only if impairment is severe = abnormal levels of the following

   • Albumin: major protein formed by the liver

     1. A decrease in albumin is not a very specific indicator of impaired synthetic capacity, as it can be affected by malnutrition, nephrotic syndrome, and other conditions.

     • Exclusively synthesised by the liver and has a circulating half-life of approximately 3 weeks

     • A reduction in albumin (normal > to 3.5 gm/dl) usually indicates liver disease of more than 3 weeks duration, reflecting chronic liver impairment.

   • Prothrombin time: used to assess blood clotting; clotting factors are made by the liver

     2. Low liver cell mass ( functioning) = less cells , thus less synthetic ability

     • Blood tests : increase in PT and decrease in albumin

     • Cholestasis = leads to prolonged PT since fat-soluble vitamin K cannot be absorbed to make prothrombin, as bile is necessary for proper fat absorption.

     • Increased synthesis of ALP which is regurgitated into plasma : blood tests show increase conjugated bilirubin- direct , increase in ALP, increase in prothrombin , pale stools; these findings suggest cholestatic liver disease.

Hepatocellular failure

• Severe damage to hepatocytes (e.g., severe hepatitis, advanced cirrhosis, overdose of liver toxins, such as paracetamol in children).

• Symptoms: weight loss, nausea, vomiting, jaundice, fatigue, weakness, asc

I cannot generate a table directly here. However, I can provide the information that would typically be in such a table, detailing liver diseases and how they affect various biochemical markers:

Pre-hepatic Jaundice

• Cause: Hemolytic anemia, internal hemorrhage (excessive RBC breakdown)

• Bilirubin Levels: Increased unconjugated bilirubin

• Other Markers: Normal ALT/AST, normal ALP

Hepatic Jaundice

• Cause: Hepatitis (viral, drug-induced), cirrhosis, liver tumours

• Bilirubin Levels: Increased conjugated and unconjugated bilirubin

• Other Markers: Elevated ALT/AST (variable, can be very high in acute hepatitis), ALP may be slightly elevated

• Additional Notes: Low plasma albumin (in chronic conditions), prolonged prothrombin time (INR)

Post-hepatic Jaundice

• Cause: Gallstones, biliary strictures, pancreatic tumours (obstruction of bile ducts)

• Bilirubin Levels: Increased conjugated bilirubin

• Other Markers: Elevated ALP (often 10x higher than normal), moderately elevated ALT/AST

• Additional Notes: Pale stools (lack of urobilinogen)

Fatty Liver Disease

• Cause: Diabetes, alcoholism, obesity

• Bilirubin Levels: Usually normal

• Other Markers: Mildly elevated ALT/AST, GGT may be elevated

• Additional Notes: Ultrasound can detect fatty changes in the liver

Alcoholic Liver Disease

• Cause: Chronic alcohol consumption

• Bilirubin Levels: May be normal or elevated

• Other Markers: Elevated AST/ALT (AST:ALT ratio > 2:1), elevated GGT

Liver Cell Necrosis

• Cause: Ischemia, toxins, infections

• Bilirubin Levels: May be normal or elevated

• Other Markers: Very high ALT/AST

Cholestasis (Intrahepatic)

• Cause: Viral hepatitis, drugs, alcohol, pregnancy

• Bilirubin Levels: Elevated conjugated bilirubin

• Other Markers: Elevated ALP, moderately elevated ALT/AST

Cholestasis (Extrahepatic)

• Cause: Primary biliary cirrhosis, tumours, polycystic liver disease

• Bilirubin Levels: Elevated conjugated bilirubin

• Other Markers: Elevated ALP, moderately elevated ALT/AST

General Markers and What They Indicate

• ALT/AST: Indicate hepatocyte damage. ALT is more specific to the liver.

• ALP: Indicates cholestasis or bile duct obstruction.

• GGT: Sensitive to alcohol consumption and biliary disease but lacks specificity.

• Albumin: Indicates synthetic function of the liver; low levels suggest chronic liver disease.

• Prothrombin Time (INR): Indicates synthetic function of the liver related to clotting factors; prolonged time suggests liver damage.

• Bilirubin (Total, Direct/Conjugated, Indirect/Unconjugated): Indicates bilirubin metabolism and excretion issues. Elevated levels cause jaundice.

To accurately diagnose a patient, it's important to consider the overall clinical picture, including symptoms, medical history, and a