50 Liver Structure and Function0

Liver Structure and Blood Supply

• Liver weighs approximately 1.5kg and possesses a significant functional reserve
• Liver cells are capable of regeneration
• Liver has a dual blood supply with both the hepatic artery and portal vein delivering blood
• Blood flows through sinusoids, which are blood spaces separating plates of hepatocytes
• Sinusoids are lined by fenestrated endothelium and Kupffer cells (macrophages)
• The Space of Disse lies between sinusoids and hepatocytes and contains hepatic stellate cells
• Venous drainage occurs via the hepatic vein to the inferior vena cava (IVC) to the right ventricle (RV)

Liver Function

• Liver synthesizes most plasma proteins, including those involved in clotting
• Liver produces bile for excretion of bilirubin and digestion of fats and fat-soluble vitamins (ADEK)
• Liver detoxifies both endogenous and exogenous compounds
• Liver plays a role in intermediary metabolism, altering and storing substances
• Liver participates in immune functions, acting as a buffer between the gut and the rest of the body
• Liver stores both normal and abnormal substances
• Liver performs hematopoiesis (blood cell production) in the fetus and infant

Liver Injury

• Liver has a reserve and regenerative capacity, allowing for recovery from acute damage in many cases
• Extensive acute damage can lead to acute liver failure
• Chronic liver damage occurs with ongoing insult and is defined as damage lasting over six months
• Chronic damage can lead to fibrosis and progression to cirrhosis
• Co-existing causes of liver damage can exacerbate the condition
• Patterns of cell damage can vary from single-cell death (apoptosis) to massive hepatic necrosis
• Cell injury can be triggered by direct cytotoxic effects, damage to hepatocytes rendering them antigenic (e.g., HBV), or damage to cells perceived as antigenic (e.g., autoimmune hepatitis)

Assessment of Liver Damage

• Inflammation and necrosis are graded based on extent of damage
• Inflammation can occur in the portal/periportal area or in the lobules (parenchyma)
• Piecemeal necrosis describes a specific pattern of interface inflammation
• Necrosis can be present as single-cell death, spotty necrosis, or bridging necrosis
• Predominant inflammatory cell type is influenced by the cause of liver damage
• Fibrosis is staged based on degree and extent
• Fibrosis can occur in portal areas, periportal areas, and as bridging fibrosis (portal tract to portal tract or portal tract to central vein)
• Cirrhosis represents the end-stage of fibrosis
• Complex scoring systems are used to assess liver biopsy specimens, considering both grade and stage

Cirrhosis

• Cirrhosis is characterized by diffuse distortion of liver architecture, with fibrous bands, regenerative nodules, and distorted vascular relationships
• Cirrhosis impairs liver function, contributing to portal hypertension and increasing the risk of hepatocellular carcinoma
• Vascular changes in cirrhosis include obliteration or thrombosis of veins, formation of collateral channels, and capillarization of sinusoids, leading to an increased hepatic venous pressure gradient (HVPG)
• Cirrhosis represents the end-stage of chronic liver disease, diminishing liver reserve

Portal Hypertension

• Increased resistance to portal blood flow in cirrhosis initiates portal hypertension, raising HVPG
• Splanchnic vasodilatation (via nitric oxide, NO) further contributes to portal hypertension
• Splanchnic vasodilatation reduces total peripheral resistance (TPR) and blood pressure
• The body compensates with increased cardiac output, leading to a hyperdynamic circulation in cirrhosis
• Splanchnic vasodilatation triggers compensatory mechanisms, including activation of the renin-angiotensin-aldosterone system, ADH secretion, sodium and water retention, and renal vasoconstriction

Ascites

• Sodium and water retention in the setting of portal hypertension can lead to ascites
• Ascites occurs due to fluid leakage from peritoneal vessels, increased hydrostatic pressure, and decreased oncotic pressure (low albumin)

Portal Hypertension Shunts

• To decompress portal hypertension, collateral channels form both within and outside the liver
• Therapeutic shunts, such as transjugular intrahepatic porto-systemic shunts (TIPS), can be inserted
• Shunting bypasses the liver, further reducing liver function and exacerbating damage

Compensated vs. Decompensated Cirrhosis

• Compensated cirrhosis may not manifest with biochemical or radiological abnormalities or signs of chronic liver disease or portal hypertension
• Even with compensated cirrhosis, further injury (infection, bleeding, hypotension, alcohol, medications, dehydration, trauma, surgery) can trigger decompensation
• Decompensated cirrhosis is characterized by complications including ascites, hepatic encephalopathy, variceal hemorrhage, hepatorenal syndrome (HRS), jaundice, and infections

Liver Structure & Function

• The liver weighs about 1.5kg
• It has a large functional reserve
• The liver contains stable cells and is able to regenerate
• The liver's blood supply is dual: hepatic artery and portal vein
• Blood travels through sinusoids, which are blood spaces separating plates of hepatocytes
• Sinusoids are lined by fenestrated endothelium and macrophages (Kupffer cells)
• Space of Disse sits between sinusoids and hepatocytes and contains hepatic stellate cells
• Venous drainage is via the hepatic vein to the inferior vena cava (IVC) to the right ventricle (RV)
• Main functions include:
  • Synthesis of most plasma proteins
  • Clotting factors
  • Bile formation
  • Bilirubin: excretion
    • Bile Salts -- digestion
    • Fat/fat-soluble vitamins ADEK
  • Detoxification of endogenous/exogenous compounds
  • Intermediary metabolism
  • Immune function as a buffer between the gut and rest of the body
  • Storage - normal/abnormal
  • Haematopoiesis (foetal/infant)

Liver Damage

• The liver has reserve and regenerative capacity
• Possible outcomes of acute liver damage depend on the degree of damage
  • Extensive damage may result in acute liver failure
  • Transient damage may lead to recovery
  • On-going or repeated insult leads to chronic damage
• Chronic liver disease is defined as damage lasting longer than 6 months
  • Fibrosis develops and progresses to cirrhosis
• The causes of liver damage may coexist, be superimposed, or potentiate each other
• Patterns of cell damage and death include different types of cell injury (reversible or irreversible)
• Triggers for injury include:
  • Direct cytopathic/cytotoxic/ischaemic effects
  • Damage to hepatocytes rendered antigenic (e.g. HBV)
  • Damage to cells perceived as antigenic (e.g. autoimmune hepatitis)
• Different degrees of injury include:
  • Single cell death (apoptosis)
  • Small group cell death (spotty necrosis)
  • Large confluent group cell death (bridging necrosis)
  • Massive hepatic necrosis

Assessing Liver Damage

• Inflammation and/or necrosis is assessed by its extent, termed "grade"
• 炎症是否属于门脉周围、门脉或小叶性？有多少门脉周围、门脉或小叶性炎症？界面炎症= “片状坏死”
• Is necrosis present? Single cells, spotty or bridging?
• Predominant inflammatory cell type depends on aetiology, not whether the disease is acute or chronic in duration.
• Fibrosis is assessed by its degree and extent, termed "stage"
  • Portal fibrosis
  • Periportal fibrosis
  • Bridging fibrosis: portal to portal tract or portal to central vein
  • Cirrhosis
• Liver biopsy is used for complex scoring systems to assess grade and stage independently

Cirrhosis

• A diffuse distortion of liver architecture
• Fibrous bands/septa surround regenerative nodules
• Distorted vascular relationships lead to:
  • Decreased liver function
  • Portal hypertension
  • Risk of hepatocellular carcinoma

Portal Hypertension

• Results from increased hepatic resistance to portal blood flow, and a rise in HVPG (hepatic venous pressure gradient)
• Augmented by splanchnic vasodilatation, which increases portal blood flow
  • Splanchnic vasodilatation also lowers total peripheral resistance (TPR) and blood pressure (BP)
• A compensatory increase in cardiac output leads to the hyperdynamic circulation of cirrhosis
• Splanchnic vasodilatation triggers compensatory mechanisms
  • Activation of the renin-angiotensin-aldosterone system
  • Stimulation of antidiuretic hormone (ADH) secretion
  • Sodium and water retention
  • Reflex renal vasoconstriction = reduced perfusion and glomerular filtration rate (GFR), increasing the risk of hepatorenal syndrome (HRS)

Ascites

• Sodium and water retention, related to portal hypertension, preferentially accumulates fluid in the peritoneal cavity.
• Fluid leaks from peritoneal vessels
• Higher mean hydrostatic pressure due to portal hypertension
• Lower oncotic pressure to keep fluid in due to low albumin

Portal Hypertension & Shunts

• Collaterals develop to decompress portal hypertension:
  • Intrahepatic porto-systemic shunts/collaterals
  • Extrahepatic porto-systemic anastomoses dilate
  • Therapeutic insertion of a shunt (TIPS -- transjugular intrahepatic porto-systemic shunt)
• "Shunted" blood bypasses the liver, further reducing liver function and increasing the risk of hepatic encephalopathy
• "Capillarisation" of sinusoids exacerbates this process
• Shunting reduces perfusion of the liver, worsening the damage

Compensated vs. Decompensated Cirrhosis

• Compensated (Silent) Cirrhosis
  • May or may not have biochemical/radiological abnormality
  • May or may not have signs of chronic liver disease/portal hypertension
  • May or may not have varices on OGD (gastroscopy)
  • Potential for instability, with further injury triggering decompensation (infection, bleeding, hypotension, alcohol, medications, dehydration, trauma, surgery)
• Decompensated Cirrhosis
  • Key complications:
    • Ascites (may become refractory to treatment)
    • Hepatic encephalopathy
    • Variceal hemorrhage
    • Hepatorenal syndrome (HRS)
    • Jaundice
    • Infection (esp. spontaneous bacterial peritonitis)
    • Hepatocellular carcinoma
• Decompensation significantly affects prognosis
  • 1-year mortality:
    • Compensated - 1%
    • Compensated with varices - 4%
    • Decompensated, ascites - 20%
    • Decompensated, other features - >50%

Natural History of Chronic Liver Disease

• Decompensation affects prognosis
• Progression from chronic liver disease to compensated cirrhosis to decompensated cirrhosis can lead to death.
  • Median compensated cirrhosis survival is approximately 9 years.
  • Median decompensated cirrhosis survival is approximately 1.6 years.
  • Variceal hemorrhage, ascites, encephalopathy, and jaundice are all common complications.
  • Orthotopic liver transplant (OLT) may be a treatment option.
• Survival times in cirrhosis are significantly impacted by decompensation.
  • The median survival for patients with cirrhosis overall is 9 years.
  • For patients with decompensated cirrhosis, the median survival is 1.6 years.