Liver Functions and Anatomy

Liver Functions

• The liver filters blood and acts as a blood reservoir
• It metabolizes macronutrients and performs endocrine functions
• Bile formation for cholesterol elimination occurs in the liver
• Vitamins and minerals are stored within the liver
• Coagulation factors are produced by the liver
• It is vital for bilirubin and xenobiotic metabolism

Liver Anatomy

• The hepatic triad consists of the hepatic artery, portal vein, and bile duct
• Hepatic zones are structured so zone 1 receives the most nutrients and oxygen from the portal blood
• Zone 3 is nearest the central vein and is oxygen and nutrient-depleted; liver functions differ by zone
• Liver sinusoids have a leaky endothelium and contain Kupffer cells which are resident macrophages
• Space of Disse is the extracellular space between endothelial cells and polarized hepatocytes and drains into lymphatics
• Bile canaliculi are responsible for bile formation, where fluid flow is opposite

Hepatic Blood Flow

• Approximately 1L/min of portal blood and 300 ml/min of arterial blood flows through the liver
• The liver receives 1.3L/min of blood which is 27% of cardiac output
• Portal pressure measures around 9 mmHg, decreasing to near 0 in the hepatic vein
• The liver functions as a blood reservoir due to its low pressure and pliable structure
• About 450 ml of blood can be stored in the liver sinusoids, representing 10% of total blood volume
• Elevated pressure in the right atrium causes the liver to increase its blood volume to 1.0-1.5L
• Lymphatic flow involves a leaky endothelium and a large amount of fluid in the space of Disse
• Roughly 50% of total lymphatic flow is derived from the liver
• Ascites, where elevated liver pressure (3-10mmHg) causes fluid (plasma) to leak, resulting in abdominal edema-distension

Liver regeneration

• The liver can regenerate after partial hepatectomy, approximately 70%
• Mediated by hepatic growth factor
• Liver weight/body weight ratio is relatively consistent
• Living liver donors recover with full regeneration in 2-3 months

Filtration and Surveillance

• Portal circulation carries colonic bacteria through the liver
• Blood cultures from the portal vein can grow colonic bacilli
• Kupffer cells reside in sinusoids, irregularly shaped, and entrap and kill bacteria

Carbohydrate Metabolism

• Insulin stimulates glucose uptake and storage
• Glucokinase is activated, trapping glucose as G6P
• Enzymes for glycogen synthesis (glycogen synthase) are activated
• Liver phosphorylase and glucose phosphatase are inactivated
• Gluconeogenesis is decreased
• The liver releases glucose between meals
• Hepatic glucose production does not require glucagon in the fasted state due to insulin lack and is termed "glucose buffer"

Lipid Metabolism

• Fatty acid synthesis accounts for approximately 70%
• The liver is a key source of phospholipids
• Lipoproteins package and deliver lipids to peripheral cells
• When glucose is in excess of glycogen storage capacity (5-6%), lipogenesis occurs
• Activation of Acetyl-CoA Carboxylase occurs
• Conversion of Acetyl-CoA to Malonyl-CoA occurs
• Triacylglycerols are synthesized and packaged into VLDL for secretion into the blood
• Lipoprotein lipase releases fatty acids in peripheral tissues for storage
• Enzymes are Transcriptionally Regulated by SREBPs
• Serves as the primary site for clearance of remnant lipoproteins
• LDL Receptors are effectors of statins
• Ketogenesis occurs during prolonged fasting

Protein Metabolism

• Amino acids are deaminated requiring gluconeogenesis and lipogenesis
• Deamination results in the formation of ammonia
• Urea is formed for ammonia removal
• Sources include deamination and gut microbiota
• The kidney filters urea
• Plasma proteins are formed accounting for 90% of plasma proteins
• Consequences of liver failure or malnutrition relate to protein production
• Interconversions of amino acids, and synthesis of other compounds from amino acids is possible
• Non-essential amino acids can be synthesized

Liver Storage

• The liver stores Vitamin A in the form of retinoid for 10 months and is present in hepatic stellate cells
• Its active role regulates liver function and pathogenesis
• The liver stores Vitamin D for 3-4 months, and Vitamin B12 for 1 year
• Iron is stored as Ferritin bound to Apoferritin

Hepatic Coagulation Factors

• Fibrinogen, Prothrombin, and Factor VII are synthesized by the liver
• Formation of vitamin K and prothrombin times increase in patients with liver disease

Endocrine function

• Somatomedins are insulin-like growth factors and include IGF-1, which is secreted by the liver in response to Growth Hormone
• IGF-1 insufficiency in Pygmies
• The GH-dependent metabolic effects are largely mediated by insulin-like growth factors (IGFs)
• Transport hormones in blood
• Alterations in binding globulins influence the effective levels of steroid hormones

Bilirubin Metabolism and Elimination

• Hemoglobin degradation results in the end product Bilirubin
• Liver disease can be diagnosed using levels of Bilirubin
• Circulating Bilirubin can be conjugated and metabolized, whether filtering through the kidneys, or secretion in bile
• Excess Bilirubin causes Jaundice
• Jaundice results from conditions like red cell hemolysis, and bile duct obstruction

Drug metabolism

• In phase I, biotransformation is mediated by CYP450 enzymes
• Genetic variants of CYP2D6 and CYP2C19 impact metabolism
• Drug reactions include oxidation, hydrolysis or reduction
• In phase II, conjugation results in acetylation, glucuronidation, sulfation
• Functionalizing with reactive groups, generally inactivates and increasing solubility
• ABC and SLC transporters are used in phase III
• Elimination occurs through the basolateral or apical membrane