Liver Physiology

Describe the blood supply to the liver and its regulation

The basic functional unit of the liver is the lobule which is composed of a roughly hexagonal arrangement of plates of hepatocytes that radiate around a central vein. The central vein empties into the hepatic vein which then empties into the IVC. At the vertices between adjacent lobules are portal triads which consist of branches of the portal vein, bile duct and hepatic artery. Blood from the portal vein and hepatic artery flow and mix in the sinusoids that radiate from the portal triad and drain into the central vein. Sinusoids also contain endothelial cells and Kupffer cells and the endothelium is fenestrated.

Source – Circulation Research 103(9):929-39 · November 2008

Blood flow to the liver is derived from both the hepatic artery and portal vein. Total blood flow to the liver is 1.5L/minute which is almost 25% of cardiac output, of which about 30% is supplied by the hepatic artery and 70% is supplied by the portal vein.

The hepatic artery is a branch of the coeliac trunk. It is a high pressure, high resistance system, that has a muscular coat and contributes 40-50% of the liver’s oxygen supply. It has a baseline oxygen saturation of 98%. The portal vein is valveless and drains blood from the intestines, spleen, stomach, pancreas and gallbladder. It is a low pressure, low resistance system and contributes about 50-60% of the liver’s basal oxygen supply. It has a baseline oxygen saturation of 85% during fasting but this decreases with increased gastrointestinal activity. The mean pressure in the portal vein is 10mmHg whereas the mean pressure in the hepatic artery is 90-100mmHg.

Given the liver’s high resting flow rate, an increase in oxygen demand results in an increased oxygen extraction. Control of liver’s blood flow is via control of hepatic arterial inflow, portal venous inflow and the inter-relationship between these two circuits.

Hepatic arterial flow:

• Autoregulation: decreased hepatic artery pressure down to about a systolic pressure of 80 mmHg results in decreased arterial resistance and thereby increased flow. Conversely increased arterial pressure causes myogenic constriction and thereby increased resistance. Autoregulation is best when the liver is metabolically active, especially in the post-prandial state.
• Flow is proportional to change in pressure divided by resistance. The degree of resistance or the degree of vasoconstriction or dilatation of the hepatic artery is the main mechanism by which hepatic arterial flow is controlled. Factors that affect the resistance of the hepatic artery include:
  • Hormonal factors: angiotensin 2 and vasopressin results in vasoconstriction of the hepatic artery. Alpha agonists cause vasoconstriction whereas beta agonists cause vasodilatation. Low doses of adrenaline cause vasodilatation whilst high doses cause vasoconstriction.
  • Neural control: the hepatic artery has alpha-1 adrenergic vasoconstriction receptors as well as B2 adrenergic, dopaminergic and cholinergic vasodilator receptors

Portal venous flow:

• There is no autoregulation in the portal system: portal flow is proportional to portal pressure and pressure depends primarily on blood flow to the mesenteric and splanchnic arterioles and on the intrahepatic resistance.
• Therefore, factors that increase blood flow through the splanchnic vessels such as digestion and metabolic factors such as glucagon, will increase portal venous flow
• Neural control: the portal vein has alpha-1 adrenergic receptors, activation of which causes venoconstriction 
• Hormonal factors: angiotensin 2 and catecholamines cause vasoconstriction of the portal vein
• Metabolic factors: hypercapnoea and acidosis increases portal venous flow
• A decrease in portal blood flow leads to a passive decrease in intrahepatic pressure and a passive ejection of blood from the hepatic reservoir into the central venous system which increases venous return and thus may increase blood flow in the splanchnic vasculature.

Inter-relationship

• There is inter-relationship between the portal venous and hepatic arterial flow: decreased portal flow causes a decrease in hepatic arterial resistance and therefore increased arterial flow. This is the hepatic arterial buffer response and thought to be secondary to adenosine. The accumulated adenosine also results in the activation of the hepatorenal reflex which reduces renal sodium and water excretion. The hepatic arterial buffer response is capable of buffering between 25-60% of decreased portal flow and helps to minimise the influence of portal venous flow changes on hepatic clearance and to maintain adequate oxygen supply.
• Alterations in hepatic arterial flow do not induce compensatory changes in portal venous flow.

Outline the effect of liver blood flow on drug clearance

Hepatic clearance of a drug is a product of the hepatic extraction ratio and the hepatic blood flow. The hepatic extraction ratio is the fraction of the drug in the blood entering the liver which is irreversibly removed during one pass through the liver. It is determined by the concentration difference of the drug entering and leaving the liver divided by the concentration entering the liver. For drugs with an extraction ratio towards one, most of the drug is eliminated during a single pass through the liver. For those with an extraction ratio closer to 0, most escapes elimination after a single pass. The hepatic extraction ratio is dependent on the extent of protein binding of the drug, as hepatocytes only have access to the unbound fraction, and on the intrinsic clearance of the drug. The effect of liver blood flow on drug metabolism depends on the extraction ratio for that drug.

• For drugs with a low extraction ratio such as diazepam, warfarin and pheyntoin
  • Changes in blood flow have minimal effect on their clearance
• For drugs with a high extraction ratio such as metoprolol, Propofol and morphine
  • Changes in blood flow produce corresponding changes in clearance

Outline the functions of the liver

1. Storage
   1. Approximately 100g of glycogen
   1. Stores fat soluble vitamins:
      1. Vitamin A: the majority of the body’s stores are within stellate cells in the liver as retinyl ester which can then be converted to its active form retinol
      1. Vitamin D: 25 hydroxycholecalciferol is the main storage form of vitamin D
      1. Vitamin E: the liver stores a small amount of vitamin E, while about 90% of vitamin E is stored in adipose tissue
      1. Vitamin K: stores of vitamin K in the body are lower compared to other fat soluble vitamins
   1. Folate: the liver stores limited amounts of folate but deficiency can occur within weeks if intake is inadequate
   1. Vitamin B12: the liver contains about 60% of the body’s vitamin B12 stores which on average is adequate to last approximately 3 years
   1. Stores iron: as ferritin or haemosiderin
   1. Stores copper
   1. Stores excess triglycerides
   1. Reservoir for blood: approximately 500ml
2. Synthetic
   1. Synthesis of the majority of plasma proteins with the exceptions of immunoglobulins and von willebrand factor. Proteins synthesised by the liver include albumin, alpha and beta globulins, and fibrinogen.
   1. Synthesis of bile acids which are then concentrated in the gallbladder: 
   1. Synthesis of 25 hydroxycholecalciferol from cholecalciferol in skin, to be converted to calcitriol in kidney
   1. Synthesis of glucose, lipids and aminoacids
   1. Synthesis of angiotensinogen
   1. Synthesis of erythropoietin in the foetus
3. Metabolic
   1. Carbohydrate metabolism
      1. Glycostat function – maintains a strict BGL range
      1. In times of high glucose availability carries out glycolysis, glycogenesis and fatty acid synthesis. The synthesis of glycogen starts with glucose conversion to glucose-6-phosphate by glucokinase, which is then converted to glucose-1-phosphate and then uridine diphosphate glucose. UDP-glucose is added to the glycogen chain which finally makes glycogen through the action of glycogen synthase.
      1. During times of starvation, stored glycogen can be converted to glucose and gluconeogenesis can also occur. Glycogenolysis occurs via the action of glycogen phosphorylase.
      1. Gluconeogenesis converts lactate into glucose via the Cori cycle, glycerol into glucose via phosphorylation, glycerol and amino acids into glucose by initial conversion to oxaloacetate, other TCA cycle intermediates or pyruvate
   1. Lipid metabolism
      1. Synthesis of fat from proteins and carbohydrates which are then transported in lipoproteins to adipose tissue for storage
      1. Synthesis of cholesterol, phospholipids and most lipoproteins
      1. Oxidation of fatty acids to supply energy: fat split into glycerol and fatty acids which are then split by beta oxidation to form Acetyl-CoA. This can enter citric cycle and be oxidised to provide energy
   1. Protein metabolism
      1. Degradation of amino acids by transamination, deamination and decarboxylation to form glucose or Acetyl CoA
         1. Rate of protein turnover in liver is 10 days vs 180 days in muscle
      1. Oxidative deamination of amino acids where the amino radical removed from the amino acid thus converting it into an alpha ketoacid and ammonia
      1. Urea cycle converts ammonia to urea for urinary excretion
   1. Metabolism of steroid hormones
   1. Conversion of T4 to T3
   1. Acid base balance
      1. Metabolism of organic acid anions such as ketones and lactate as well as metabolism of ammonia
      1. Production of albumin which is a weak acid
4. Immunological
   1. Reticuloendothelial system of the liver filters bacteria from portal blood
   1. Kupffer cells perform scavenger and phagocytic functions, produce prostaglandins that are cyto-protective and secrete other immune-regulatory mediators
   1. Ammonia is detoxified to urea
5. Excretory
   1. Conjugation and excretion of bilirubin: haemoglobin is broken down by haem oxygenase and NADPH-cytochrome p450 to biliverdin which is converted to bilirubin by a reductase enzyme. The bilirubin is bound to albumin and taken to the liver where it is conjugated with glucoronides making it water soluble. It is then secreted into bile and converted to urobilinogen in the gastrointestinal system where the majority is excreted in the faeces some undergoes enterohepatic circulation, and a very small amount is excreted in the urine
   1. Inactivation of toxins and drugs via phase I (oxidation and hydrolysis) and phase II (conjugation) reactions

Describe the physiology of bile and its metabolism

Bile is an aqueous secretion that originates from hepatocytes and is modified distally by absorptive and secretory transport systems in the bile duct epithelium. Approximately 400ml – 1L of bile is produced a day by the liver. It is 97% water in which are dissolved bile acids, bilirubin, cholesterol, lecithin, organic ions, electrolytes, enzymes, proteins and toxins.

The two principal liver bile acids are cholic acid and chenodeoxycholic acid which are formed from cholesterol.

The bile acids combine with glycine and taurine to form conjugated bile acids, the salts of which are secreted into bile. Bile is initially secreted by hepatocytes and contains large quantities of bile acids, cholesterol and other organic molecules. As it flows through bile ducts a watery sodium bicarbonate solution is added. It eventually enters the cystic duct and the gallbladder where it is concentrated and stored or the duodenum where it aids in lipid digestion. About 95% of bile salts are then reabsorbed in the small intestine and undergo enterohepatic circulation while the remainder are excreted in faeces.

The roles of bile are:

• Fat digestion and absorption: it emulsifies large fat molecules into many small particles which aids in absorption of digested fat end products through the mucosal membranes of the intestine. This is the main role of bile salts.
• Excretion of waste products including bilirubin and cholesterol as well as lipid soluble drugs and heavy metals
• Involved in the activation and regulation of the gut’s innate immune system

The regulation of bile formation and secretion involves:

• Bile salts
  • The primary determinant of bile formation is the hepatic excretory rate of bile salts which is controlled by the rate of return of these salts to the liver by the enterohepatic circulation.
• Neural factors
  • Parasympathetic stimulation by vagus nerve stimulates bile production by the liver
• Hormonal factors
  • Cholecystokinin stimulates gallbladder contraction
  • Secretin stimulates secretion of the sodium bicarbonate rich fluid which is added to bile in the ducts
  • Glucagon increases bile secretion
• Duodenal contents
  • Fatty acids and amino acids in chyme entering the duodenum stimulate cholecystokinin which stimulates gallbladder contraction
  • Acidic chyme in duodenum stimulates secretin

Outline the consequences of liver disease

1. Storage
   1. Anaemia secondary to iron, folate and b12 deficiency
   1. Decreased concentrations of fat soluble vitamins
   1. Decreased glycogen stores
2. Synthetic
   1. Decreased synthesis of coagulation factors à shorter half life so affected even in acute liver disease à bleeding. This may be exacerbated by increased fibrinolytic activity due to decreased clearance of plasminogen activators by the liver and decreased production of inhibitors of fibrinolysis such as alpha 2 antiplasmin and plasminogen activator inhibitor 1.
   1. Decreased synthesis of coagulation inhibitors such as antithrombin 3, protein C and S may conversely predispose the patient to thrombosis
   1. Albumin (longer half life) à decreased oncotic pressure à oedema
   1. Decreased activation of vitamin D à hepatic osteodystrophy
3. Metabolic
   1. Carbohydrate:
      1. Glycostat function of liver affected: decreased gluconeogenesis and glycogenolysis which can lead to hypoglycaemia, can also have hyperglycemia especially post-prandial due to increased insulin resistance
   1. Protein metabolism:
      1. Increased protein catabolism and plasma amino acid levels, muscle wasting
      1. Liver is the only organ in which complete urea cycle expressed, converting ammonia to urea à hepatic encephalopathy due to build- up of ammonia
   1. Fats:
      1. Increased plasma free fatty acids due to increased peripheral lipolysis and decreased lipogenesis
      1. Fatty liver and increased serum LDL concentration
   1. Metabolism of steroid hormones
      1. Oestrogen: impaired metabolism à higher levels à palmar erythema, gynaecomastia, hypogonadism
      1. Difficulty metabolising aldosterone à secondary hyperaldosteronism
   1. Acid base
      1. Secondary hyperaldosteronism and decreased albumin can result in a metabolic alkalosis
      1. Decreased metabolism and clearance of lactate: can result in metabolic acidosis
4. Immunological
   1. Cirrhosis associated immune dysfunction
5. Excretory
   1. Clearance of drugs à decreased clearance of certain drugs may result in increased toxicity
   1. Conjugation and excretion of bilirubin à jaundice, pruritis, fat malabsorption
6. Other
   1. Increased portal venous pressure secondary to cirrhosis à portal hypertension à formation of varices, ascites, splenomegaly. The splenomegaly can also result in thrombocytopenia.
   1. Hyperdynamic circulation due to arterial vasodilation (many vasodilators are inactivated in liver), altered sympathetic tone, production of nitric oxide/vasodilators à vasodilatation causes decreased circulatory volume à triggers baroreceptors à renin-angiotensin-aldosterone system + aldosterone sympathetic nervous system + vasopressin à sodium and water retention
   1. Hepatorenal syndrome due to increased activation of RAAS system leading to increased renal vasoconstriction and decreased gfr
   1. Hepatopulmonary syndrome