Liver and Gallbladder Anatomy & Functions

Review of Liver and Gallbladder Anatomy and Functions

• The liver metabolizes carbohydrates, lipids, proteins, hormones, and vitamins.
• The liver detoxifies and excretes waste products and toxins.
• It forms triglycerides and cholesterol and excretes bilirubin and bile acids.
• The liver produces most clotting factors and synthesizes proteins.
• It converts ammonia to urea and maintains glucose homeostasis via glycogen storage.
• The liver receives oxygenated blood from the hepatic artery and partially oxygenated blood from the intestinal tract and spleen via the portal vein.
• Blood returns to the circulation via the hepatic vein.
• The portal triad consists of the hepatic artery, portal vein, and bile duct.
• Hepatocytes are organized into zones 1-3, with Zone 3 being most susceptible to necrosis under hypoxic conditions.
• Hepatocytes secrete bile, which drains into interlobular ducts, then hepatic ducts, and to the gallbladder for storage (except in horses).
• The cystic duct from the gallbladder and hepatic ducts from the liver form the common bile duct, terminating at the major duodenal papilla.

Hepatocellular Injury

• Hepatocellular injury involves sublethal injury or necrosis of liver cells.

Diagnostic Enzymes (Leakage Enzymes)

• Leakage enzymes are serum enzymes used to detect hepatocellular injury.
• They are found in the cellular cytoplasm and/or organelles.
• They are released into the blood when cell membrane disruption occurs, increasing serum activity within hours of the injury.

Alanine Aminotransferase (ALT)

• ALT has the highest concentration in hepatocytes in dogs and cats.
• It is the primary test for hepatocyte injury in these species.
• It is not as useful in horses and ruminants.
• ALT can also increase with severe muscle damage.
• It increases within 1-2 days of acute injury and decreases over several weeks as the injury resolves.
• The magnitude of increase does not indicate cause or severity.
• Causes of elevation include hypoxia, metabolic alterations (lipid accumulation), bacterial toxins, inflammation, neoplasia, toxins/drugs (corticosteroids, phenobarbital), and trauma.

Aspartate Aminotransferase (AST)

• AST is found in hepatocytes and skeletal/cardiac myocytes, making it less liver-specific than ALT.
• It's preferred over ALT for detecting hepatocyte injury in horses and ruminants.
• It has a shorter half-life than ALT.
• Causes of increase are similar to ALT, and AST can also increase due to hemolysis.

Sorbitol Dehydrogenase (SDH)

• SDH is found in high concentrations in the hepatocyte cytoplasm in all species.
• It is a liver-specific enzyme and preferred over AST for detecting hepatocyte injury in horses and ruminants.
• Low in vitro stability limits routine use.

Lactate Dehydrogenase (LDH)

• LDH is not liver-specific and is found in many cell types.
• It increases with hemolysis, muscle damage, and hepatocellular injury.

Glutamate Dehydrogenase (GDH)

• GDH is a cytoplasmic enzyme that increases with hepatocellular necrosis.
• It is considered liver-specific in birds but has low sensitivity.

Cholestasis

• Cholestasis refers to obstructed bile flow.

Diagnostic Enzymes (Inducible Enzymes)

• Inducible enzymes are serum enzymes used to detect cholestasis.
• They are present on cell membranes or organelle membranes and require a stimulus to induce their production.
• Increased serum activities are detected slowly, over several days.
• Hepatocyte injury (swelling, inflammation, necrosis) can alter bile flow, increasing the activity of leakage and inducible enzymes.

Alkaline Phosphatase (ALP)

• ALP is an inducible enzyme on cell membranes, found in the liver, bone, kidney, intestine, pancreas, and placenta.
• Dogs also have a corticosteroid-induced ALP (C-ALP) produced by hepatocytes.
• L-ALP half-life is longer in dogs (~3 days) than in cats (~6 hours), so marked elevations are less common but clinically significant in cats.
• Utility for detecting cholestasis in horses and ruminants is inferior to GGT.
• Elevated L-ALP causes include intrahepatic or posthepatic cholestasis (toxins, drugs, degenerative diseases, necrosis/swelling impairing bile flow, metabolic diseases, neoplasia, inflammatory diseases).
• Elevated B-ALP occurs in young, growing animals, bone lysis/remodeling, feline hyperthyroidism, canine hyperparathyroidism, osteosarcoma, fracture repair, and rickets.
• Elevated C-ALP (dogs only) is seen with endogenous or exogenous corticosteroids.

γ-Glutamyltransferase (GGT)

• GGT is an inducible enzyme found on cell membranes of hepatocytes, biliary epithelial cells, renal tubular epithelial cells, and mammary epithelial cells.
• Increased activity is seen during cholestasis
• It is a more sensitive indicator of cholestasis than ALP in horses, ruminants, and avian species.
• It can also be increased in severe hepatic necrosis in horses and ruminants.
• Necrosis of biliary epithelium can increase GGT.
• High GGT activity is also present in the colostrum of some species.

Comparing Leakage and Cholestatic Enzymes

• ALT is most useful for hepatocyte injury in dogs and cats, while AST and especially SDH are preferred in horses and ruminants.
• GGT is a more sensitive indicator of cholestasis than ALP in horses and ruminants.
• Marked ALP elevations are less common but more significant in cats.
• Dogs have C-ALP, which can be induced by corticosteroids.
• Hepatocellular injury results in elevated leakage enzymes (ALT, AST, SDH).
• Cholestasis results in elevated inducible enzymes (ALP, GGT) and may be accompanied by elevated leakage enzymes due to secondary hepatocyte injury.
• Altered bile flow can lead to concurrent increases in cholestatic enzymes in some cases of hepatocellular injury.
• Diseases of hepatic necrosis often show elevated ALT, AST, and/or SDH with normal ALP, GGT, and bilirubin.
• In feline hepatic lipidosis, ALP is often more elevated than GGT, which can help differentiate it from cholangiohepatitis.

Bilirubin Production and Metabolism

• Bilirubin is a pigment produced in macrophages by the degradation of heme from red blood cells (RBCs).
• Heme is converted to biliverdin, then to unconjugated bilirubin.
• Unconjugated bilirubin circulates bound to albumin and is taken up by the hepatocyte membrane.
• Hepatocytes convert unconjugated bilirubin to conjugated bilirubin, which is water-soluble.
• Conjugated bilirubin is secreted into bile canaliculi, then to the intestine, where bacteria convert it to urobilinogen, which is eliminated in feces.
• Conjugated bilirubin can also be passed through the urine (bilirubinuria), which can precede hyperbilirubinemia.
• Bilirubin measurement reflects the liver's ability to take up, conjugate, and excrete bilirubin.
• It serves as a marker of liver disease (with or without cholestasis) and can provide supportive evidence for hemolytic anemia.

Hyperbilirubinemia

• Hyperbilirubinemia is an increased serum concentration of bilirubin, leading to icterus (jaundice) when >3.0 mg/dL.
• This is visible as yellow discoloration of sclera, skin, and gingiva.
• Automated analyzers may measure total bilirubin only or both unconjugated (indirect) and conjugated (direct) bilirubin.
• Elevated total bilirubin requires determining the source.
• Unconjugated bilirubin reflects pre-hepatic hyperbilirubinemia, while conjugated bilirubin suggests intra-hepatic or post-hepatic cholestasis.

Categories of Hyperbilirubinemia

• Pre-hepatic hyperbilirubinemia relates to increased bilirubin production due to hemolysis or severe internal hemorrhage; this primarily increases unconjugated bilirubin.
• Hepatic hyperbilirubinemia is due to decreased hepatic bilirubin uptake and/or decreased conjugation, reflecting the loss of hepatic function from various liver diseases, anorexia in horses, or sepsis; this primarily increases unconjugated bilirubin.
• Post-hepatic hyperbilirubinemia is cholestasis, which is decreased secretion of bilirubin into bile or physical obstruction of bile flow; this primarily increases conjugated bilirubin.

Bile Acids and Ammonia Metabolism

• Bile acids are synthesized in the liver from cholesterol, conjugated, and secreted into bile to aid in fat digestion in the intestine.
• They are reabsorbed from the GIT into the portal blood, taken up by hepatocytes, and recycled (enterohepatic circulation).
• Serum bile acid testing is a good indicator of hepatobiliary function but not specific for the underlying disease.
• Increased bile acids correlate to liver enzyme elevations but normal bilirubin when liver disease is suspected but not proven.
• It is not recommended if the animal is icteric.
• It is used to monitor liver function in known hepatic disease.
• Typically, fasting and postprandial samples are taken in dogs and cats, with the higher value being interpreted (>25 µmol/L suggestive of hepatobiliary disease).
• A single sample is usually taken in horses, ruminants, and llamas.
• Marked increases in horses (40-100 µmol/L) can indicate hepatic necrosis, lipidosis, neoplasia, or cirrhosis.
• Increased bile acid concentrations can be due to portosystemic shunts, liver failure, cholestasis, or premature gallbladder contraction.
• Decreased concentrations are not typically observed in liver failure due to efficient recirculation but can occur with small intestinal disease.
• Ammonia is produced by GI tract microflora from amino acid and urea metabolism.
• It is transported to the liver via the portal vein, where ~85% is converted to urea by hepatic urea cycle enzymes, and ~15% enters systemic circulation.
• Baseline ammonia testing prefers plasma over serum, requires samples be kept on ice and analyzed ASAP.