• Two main segments 

• Eight segments 

  • Divided by hepatic veins

• Segments have independent circulation and innervation resection of one does not affect the others

Blood Supply

• Two main vessels

  • Hepatic artery

    • A branch of the coeliac axis

    • supplies 25% of the hepatic blood flow

    • the hepatic artery autoregulates flow ensuring a constant total blood flow

  • Portal vein

    • Drains most of the gastrointestinal tract and the spleen. 

      • It supplies 75% of hepatic blood flow.

  • The normal portal pressure is 5–8 mmHg; flow increases after meals.

Blood distribution

• Pathway from vessels to inferior vena cava

  • Blood flows from vessels into sinusoids in segments

• Runs out through the veins, all returns back to vena cava

• Supply of the caudate lobe

  • Caudate lobe receives independent blood supply

• Circulation of lymph

Hepatic Units

• Acinus 

  • The acinus is the functional hepatic unit. 

  • This consists of parenchyma supplied by the smallest portal tracts containing portal vein radicles, hepatic arterioles and bile ductules. 

  • The hepatocytes near this triad (zone 1) are well supplied with oxygenated blood and are more resistant to damage than the cells nearer the terminal hepatic (central) veins (zone 3).

  • See fig 7.2

• Sinusoids

  • The sinusoids lack a basement membrane and are loosely surrounded by specialist fenestrated endothelial cells and Kupffer cells (phagocytic cells). 

  • Sinusoids are separated by plates of liver cells (hepatocytes). 

  • The subendothelial space between the sinusoids and hepatocytes is the space of Disse, which contains a matrix of basement membrane constituents and stellate cells

• Stellate cells

  • Stellate cells store retinoids in their resting state and contain the intermediate filament, desmin. 

  • When activated (to myofibroblasts) they are contractile and probably regulate sinusoidal blood flow. 

  • Endothelin and nitric oxide play a major role in modulating stellate cell contractility. 

  • Activated stellate cells produce signal proteins for synthesis or inhibition of degradation of extracellular matrix components, including collagen, as well as cytokines and chemotactic signal

Billiary System

- Bile cannuli -> bile ductules -> l/r hepatic duct -> porta hepatis -> common portal duct -> common bile duct w/ cystic duct -> ampulla of vater w/ sphincter of Oddi

• The liver is the principal site of synthesis of all circulating proteins apart from γ-globulins 
  • Albumin
• Controls plasma levels by controlling gluconeogensis and transamination
• Transport of carrier proteins
• Synthesises coagulation factors
• Storage of vitamins and minerals
• Degradation of amino acids produces ammonia -> urea

• Glucose homeostasis and the maintenance of the blood sugar is a major function of the liver. 
• In the immediate fasting state, blood glucose is maintained either by glucose release from breaking down glycogen (glycogenolysis) or by synthesizing new glucose (gluconeogenesis). 
• In prolonged starvation, ketone bodies and fatty acids are used as alternative sources of fuel as the body tissues adapt to a lower glucose requirement

• It synthesizes very-low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs)
• HDLs are the substrate for lecithin-cholesterol acyltransferase (LCAT), which catalyzes the conversion of free cholesterol to cholesteryl ester
• MDLs remove triglycerides 
• Cholesterol may be of dietary origin but most is synthesized from acetyl-CoA mainly in the liver, intestine, adrenal cortex and skin.

• Bile secretion & metabolism
  • Bile formation requires uptake of bile acids and other organic and inorganic ions across the basolateral (sinusoidal) membranes by multiple transport proteins; NTCP and sodium independent OATP2,
  • Two processes are involved in bile secretion across the canalicular membrane of the hepatocyte – bile salt-dependent and bile salt independent processes – each contributing about 230 mL/ day. 
    • Bile salt-dependent process: 
      • the bile acid receptor, farnesoid X, blocks bile acid formation from cholesterol and also regulates the transport proteins (NTCP, OATP2) that increase bile acid uptake by the liver Na+ and water follow the passage of bile salts by diffusion across the tight junction between hepatocytes. 
    • In the bile salt-independent process, water flow is due to other osmotically active solutes such as glutathione and bicarbonate.
  • The bile acids are excreted into bile and then pass via the common bile duct into the duodenum
• Bilirubin metabolism
  • Bilirubin is produced from breakdown of mature red cells by Kupffer cells in the liver and reticuloendothelial system; 15% of bilirubin is formed from catabolism of other haem-containing proteins
    • Normally, 250–300 mg daily. 
  • unconjugated bilirubin is water-insoluble, due to internal hydrogen bonding, and is transported to the liver attached to albumin. 
  • Bilirubin dissociates from albumin and is taken up by hepatic cell membranes and transported to the endoplasmic reticulum by cytoplasmic proteins, where it is conjugated with glucuronic acid and excreted into bile. 
    • conjugated bilirubin is water-soluble and is actively secreted into biliary canaliculi and excreted into the intestine within bile 
  • not absorbed from the small intestine because of its large molecular size
  • In the terminal ileum, bacterial enzymes hydrolyse the molecule, releasing free bilirubin which is then reduced to urobilinogen, some of which is excreted in the stools as stercobilinogen. 
    • The remainder is absorbed by the terminal ileum, passes to the liver via the enterohepatic circulation, and is re-excreted into bile. Then excreted kidneys
      • = When hepatic excretion of conjugated bilirubin is impaired, a small amount is strongly bound to serum albumin and is not excreted by the kidneys; it accounts for the persistent hyperbilirubinemia

• The liver catabolizes hormones such as insulin, glucagon, oestrogens, growth hormone, glucocorticoids and parathyroid hormone. 
• It is also the prime target organ for many hormones (e.g. insulin). 
• It is the major site for the metabolism of drugs and alcohol. 
• Fat-soluble drugs are converted to water-soluble substances that facilitate their excretion in the bile or urine. 
• Cholecalciferol is converted to 25-hydroxycholecalciferol.

• The hepatic reticuloendothelial system contains many immunologically active cells. 
• The liver acts as a ‘sieve’ for bacterial and other antigens carried to it by the portal vein from the gastrointestinal tract. 
  • These antigens are phagocytosed and degraded by the Kupffer cells, which have specific membrane receptors for ligands and are activated by several factors, such as infection. 
  • They are part of the innate immune system and secrete interleukins, tumour necrosis factor (TNF), collagenase and lysosomal hydrolases
    • The cytokines stimulate sinusoidal, stellate, and natural killer cells to release pro-inflammatory cytokines
• Antigens are degraded without the production of antibody, as there is very little lymphoid tissue and thus, they are prevented from reaching antibody-producing sites and thereby prevent generalized adverse immunological reactions
• Cytokines also stimulate hepatic apoptosis.

• Liver function test
  • Serum albumin
    • This is a marker of synthetic function and is useful to gauge the severity of chronic liver disease: a falling serum albumin is a bad prognostic sign.
    •  In acute liver disease initial albumin levels may be normal.
  • Prothrombin time
    • This is also a marker of synthetic function. 
      • Because of its short half-life, it is a sensitive indicator of both acute and chronic liver disease. 
    • Vitamin K deficiency should be excluded as the cause of a prolonged PT by giving an intravenous bolus (10 mg) of vitamin K. 
    • Vitamin K deficiency commonly occurs in biliary obstruction, as the low intestinal concentration of bile salts results in poor absorption of vitamin K.
    • PT times differ greatly between labs depending on assay

• Liver biochemistry
  • Bilirubin
    • serum levels indicate metabolism and bile excretion functions
  • aminotransferase - reflect hepatic damage
    • serum aspartate (AST) and alanine aminotransferases (ALT) - reflecting hepatocellular damage
      • These enzymes (often referred to as transaminases) are contained in hepatocytes and leak into the blood with liver cell damage. 
      • Two enzymes are measured:
        • Aspartate aminotransferase (AST) is primarily a mitochondrial enzyme (80%; 20% in cytoplasm) and is also present in heart, muscle, kidney and brain. 
          • High levels are seen in hepatic necrosis, myocardial infarction, muscle injury and congestive cardiac failure.
        • Alanine aminotransferase (ALT) is a cytosol enzyme, more specific to the liver so that a rise only occurs with liver disease.
  • Alkaline phosphatase - reflect hepatic obstruction
    • This is present in hepatic canalicular and sinusoidal membranes, but also in bone, intestine and placenta.
    • In clinical practice, if the γ-GT is also abnormal the ALP is presumed to come from the liver
    • Serum ALP is raised in both intrahepatic and extrahepatic cholestatic disease of any cause, due to increased synthesis.
    • In cholestatic jaundice, levels may be four to six times the normal limit. 
    • Raised levels also occur with hepatic infiltrations (e.g. metastases), and in cirrhosis, frequently in the absence of jaundice. 
    • The highest serum levels due to liver disease (>1000 IU/L) are seen with hepatic metastases and primary biliary cirrhosis.
  • gamma glutamyl transpeptidase
    • This is a microsomal enzyme present in liver, but also in many tissues. 
    • Its activity can be induced by drugs such as phenytoin and by alcohol. 
    • If the ALP is normal, a raised serum γ-GT can be a useful guide to alcohol intake.
    • However, mild elevations of γ-GT are common, even with a small alcohol consumption and is also raised with fatty liver disease. 
      • It does not necessarily indicate liver disease if the other liver biochemical tests are normal
    • In cholestasis the γ-GT rises in parallel with the ALP as it has a similar pathway of excretion. 
  • total protein and globulin function.
    • This measurement is of little value. 
    • Serum albumin is discussed above. 
    • The proteins in the globulin fraction, raised in liver disease, can be separated by electrophoresis and is usually due to increased circulating immunoglobulins; it is polyclonal (see below).

• Viral markers
  • Viruses are a major cause of liver disease. 
    
    
• Additional: haematological, biochemical, immunological, genetic

• Dipstick tests are available for bilirubin and urobilinogen.
• Bilirubinuria is due to the presence of conjugated (soluble) bilirubin, is found in patients with jaundice due to hepatobiliary disease, but is absent if unconjugated bilirubin is the major cause of jaundice.

• Ultrasound
  • Can show liver and related structure
  • Show presence of stones (white w/ black shadow)
• Endoscopic ultrasound
• CT
• MRI
• Magnetic resonance cholangiopancreatography (MRCP) 
• Plain x-rays of the abdomen 
• Radionuclide imaging - scintiscanning
• Endoscopy
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Percutaneous transhepatic cholangiography (PTC) 
• Angiography

• Histological examination of the liver is valuable in the differential diagnosis of diffuse or localized parenchymal disease.
• Liver biopsy can be performed on a day-case basis

• Acute liver disease
  • This may be asymptomatic and anicteric. 
  • Symptomatic disease, which is often viral, produces generalized symptoms of malaise, anorexia and fever. 
  • Jaundice may appear as the illness progresses.
• Chronic liver disease
  • Patients may be asymptomatic or complain of nonspecific symptoms, particularly fatigue. 
  • Specific symptoms include:
    • Right hypochondrial pain due to liver distension
    • Abdominal distension due to ascites
    • Ankle swelling due to fluid retention
    • Jaundice
    • Haematemesis and melaena from gastrointestinal haemorrhage
    • Pruritus due to cholestasis – this is often an early symptom of primary biliary cirrhosis
    • Breast swelling (gynaecomastia), loss of libido and amenorrhoea due to endocrine dysfunction
    • Confusion and drowsiness due to neuropsychiatric complications (portosystemic encephalopathy).

• Acute liver disease
  • There may be few signs apart from jaundice and an enlarged liver. 
  • Jaundice is a yellow coloration of the skin and mucous membranes and is best seen in the conjunctivae and sclerae.
  • In the cholestatic phase of the illness, pale stools and dark urine are present. 
  • Spider naevi and palmar erythema usually indicate chronic disease but they can occur in severe acute disease
• Chronic liver disease - see figure 7.9
  • The skin
  • The abdomen
  • The endocrine system

• Can be caused by infection, drugs, alcohol, or poison

• Can be caused by infection, autoimmune

• Liver biochemistry
• Haematological tests
• Viral biomarkers: HAV antibodies
• Other tests

• Active immunisation
  • Vaccine leading to body's immune system being activated
• Passive immunisation
  • Given active antibodies, not produced in own body

• Vertical transmission
  • i.e. Mother to child
• Horizontal transmission
  • to other adult individuals

• Clinical features
  • 
    
• Investigations
  • 
    
• Course
  • 
    
• Treatment
  • 
    
• Prevention & prophylaxis

• Types
  • Immune tolerant chronic HBV infection
  • Inactive carrier with chronic HBV infection
  •  Active chronic infection
• Clinical features and investigations of active chronic hepatitis B infection
  • Investigations
  • Histological changes
• Treatment 
  • Classifications: 
    • Moderate to severe active necroinflammation
      • Presence of cirrhosis
    • Immunotolerant patients
  • Antiviral agents
  • Oral therapy
• Prognosis

• Causes

• Incidence: 3-6% of US pop, 1-2% of these NASH
• Estimated prevalence of 25%

• Obesity
• Diabetes
• Hispanic

• Spectrum from simple fatty change to inflammation to cirrhosis

• Fatty liver on ultrasound
• Exclusion of other cause

• Dietary changes
• exercise
• extreme cases might need transplant
• can progress into cirrhosis

• Alcohol
• Viral infections
• NASH
• Autoimmune disorders
• Cholestatic disorders
• Metabolic diseases

• Injury -> cirrhosis can take 5-50 years, affected by risk factors
• Injury -> fibrosis (resolvable!)
  • Inflammatory damage
  • Matrix deposition
  • Parenchymal necrosis
  • Angiogenesis
• Fibrosis -> Cirrhosis (can regress)
  • Disrupted architecture
  • Loss of function
  • Aberrant hepatocyte regeneration

• Destruction of extracellular matrix
  • formation of micro and macro nodules
• Micronodular
• Macronodular
  • aggregated cells, clumps
• Redistribution of blood supply in liver

• Severity
• Type 
• Imaging
• Biopsy

• Transplant
• Reversing damage by removing underlying cause

• 5 year survival rate of 50%
• Depends on influencing factors
  • Genetic
  • Environment

• Indications
  • Mainly: cirrhosis or conditions which result in this
• Contraindication
  • sepsis
  • rate of recurrence of carcinoma is high
• Preparation
• Rejection
• Prognosis
  • 90% 1 year, 70-85% 5 year survival
  • Carcinoma's can recur

• Prehepatic
  • blockage of portal vein before liver
• Intrahepatic
  • distortion of liver itself (pre or post sinusoidal)
• Post-hepatic
  • blockage of passage out of the liver

• Stellate cells:
  • hyperactivated, leading to constant inflammation
  • destroys hepatocytes, extracellular matrix
  • increased sodium retention, increased BP in portal vessels

• Dependent on type
  • pre: thrombosis
  • intra: schistosomiasis
  • post: budd-chiari syndrome

• Resuscitation
• Urgent endoscopy
• Variceal banding or injection sclerotherapy

• Additional management of acute episode
• Management of an acute rebleed
• Prevention of recurrent variceal bleeding
• Long term measures
• Surgical procedures
• Prophylactic measures

• Sodium and water retention
• Portal hypertension
• Low serum albumin

• Swelling

• Drain - multiple litres
• Give fluids

• Cause
  • Heavy use of alcohol
• Types
  • Fatty liver
  • alcoholic hepatitis - acute inflamation, necrosis
  • alcoholic cirrhosis - destruction of normal tissue, leave scar tissue
• Clinical features
  • Abdominal pain
  • weight loss
  • appetite loss
  • weakness
  • intestinal bleeding
  • liver cancer

• Clinical features
• Investigations
• Treatment

• Fatty change
• Alcoholic hepatitis
• Alcoholic cirrhosis
  
  

• Fatty change
• Alcoholic hepatitis
• Alcoholic cirrhosis

• Fatty change
• Alcoholic hepatitis
• Alcoholic cirrhosis

• Fatty change
• Alcoholic hepatitis
• Alcoholic cirrhosis

• Clinical features
• Investigations
• Management
• Prognosis

• Investigations 
• Treatment
• Complications

• Clinical features
  • variable
  • weight loss
  • malaise
  • upper abdominal pain
  • hepatomegaly w/ or w/o jaundice
• Diagnosis
  • serum 
• Treatment
  • depends on site
  • removal/resection

• Hepatocellular carcinoma
  • most common 
  • 90% are positive with Hep B
  • 80% develop cirrhosis
  • Occurrence in multiple nodules
  • can metastasise
  • treated w HBV vax - prevention
• Cholangiocarcinoma
  • arise from bile ducts
  • not related to cirrhosis
  • cholangitis more frequent
  • rarely able to resect
  • mortality within 6 months

• mostly haemangiomas
• hepatic adenomas

• Genetics
• Toxins
• Drugs
• Idiopathic

• Hepatic damage
• Individual drugs

• Co-infection
  • occurs simultaneously with HBV
  • no distinguishable acute phase
• Super infection
  • HBV infection causing flareup in HDV

• Alcohol abuse

• Fatty change
• Alcoholic hepatitis
• Alcoholic cirrhosis

• Fatty liver
• Alcoholic hepatitis
• Alcoholic cirrhosis
• Abdominal pain
• weight loss
• appetite loss
• weakness
• intestinal bleeding
• liver cancer

• independent of cause, need to look at function of liver

• General management
• Fatty liver
• Alcoholic hepatitis
• Alcoholic cirrhosis