Describe the important functional links of liver
Important functional links: portal vein + biliary tree that connects liver to duodenum.
Liver’s function is intimately associated with the bowel.
What is the functional unit of the liver? What is the portal tract? What direction does blood and bile flow?
Functional unit is the acinus
Bottom left: portal triad (aka portal tract) – proper hepatic artery, common bile duct and hepatic portal vein. (NB: the portal triad also contains lymphatic vessels and branch of the vagus nerve).
Top right: terminal hepatic venule
Zone 1 is near the portal tract.
Zone 3 is near the terminal venule.
The hepatic portal vein (~85%) distributes its blood into the hepatic sinusoids. The blood passes through sinusoids and drain into the hepatic venule.
The hepatic artery also supplies blood to the liver (~15%), which passes along the same route.
In the opposite direction, the hepatocytes synthesise bile, which travel in cannaliculi (cannot be seen by light microscopy as very small) to the portal tract. Bile collects in the bile duct and passes into the biliary tree.
What are the cells of the liver?
- Hepatocytes (~60%): “Liver” function
- Endothelial cells (sinusoidal – leaky – so hepatocytes are bathed in plasma): sinusoidal circulation
- Kupffer cells (macrophages, native of the liver): “filter” portal blood e.g. microbes from the GI tract
- Stellate cells: control and produce extracellular matrix (normally very little but increases in liver disease => scarring)
- Biliary epithelium (bile is toxic so epithelium is very resilient and tight): line bile ducts
- NK cells: immune reaction (the liver can function as a primary or a secondary immune organ)
Describe Liver Vasculature. What can portal hypertension lead to?
Portal vein supplies 85% of blood
Liver “handles” nutrients and toxins in portal venous blood
Low pressure circulation
Disruption of vasculature e.g. by fibrosis causes portal hypertension
Portal hypertension leads to ascites (accumulation of fluid in the peritoneal cavity) and porto-systemic shunting (flow back-ups => dilated veins)
- Oesophageal varices
- Capute medusa
- Superior haemorrihoidal veins
- Dilated veins are thin walls: increased pressures can lead to leakage => catastrophic haemorrhage
Are all hepatocytes equal?
Zone 1: mostly synthesis/export of proteins (environment has more oxygen and nutrients)
Zone 3: metabolism of other stuff especially toxins, complicated compounds and drugs (environment has less oxygen and nutrients)
We believe the distribution of nutrients and oxygen determines the function of the hepatocytes.
What does the liver do?
“Handles” portal venous blood
Metabolism of nutrients
- Glucose homeostasis
- Lipid metabolism
- Protein (metabolism and) synthesis
- (many functions not specific functions of the liver – but liver is by far the most important site)
Bilirubin metabolism and bile production
Metabolism of drugs and toxins (most important site, but not the only site)
Describe how the liver is a glucose buffer
When glucose levels are high the liver synthesises glycogen
During fasting the liver releases glucose
75% from glycogen
25% from gluconeogenesis
If liver function is poor, blood glucose levels rise to 2-3x higher than normal after a meal
Describe how the liver is involved in protein metabolism and protein synthesis
- Deamination of amino acids (specific to liver)
- Urea production => removal of NH4
- Urea production is specific to the liver.
- Amines from gut flora are absorbed from gut, taken up by liver, converted to urea within the cells, urea is water-soluble and transported to blood and excreted by kidneys
- Major site of plasma protein synthesis
- 90% of plasma proteins
- Up to 50g per day
- Proteins include albumin (most important in terms of volume – albumin maintains osmotic pressure + important transporter), lipoproteins (facilitate metabolism of fat), coagulation factors and acute phase proteins (important in acute inflammation)
Describe the role of albumin in the body
Oncotic pressure in plasma
Transport of bilirubin
Transport of drugs
Low albumin e.g. in liver disease => oedema and ascites
So someone with liver disease may have ascites due to either/both hypoalbuminaemia and raised portal pressure.
Describe how the liver is involved in haemostasis and how liver disease can lead to coagulopathy
- Important site for synthesis of coagulation factors
- Vitamin K dependent (II, VII, IX, X)
- Other clotting components (prothrombin, fibrinogen)
Patients with advanced liver disease may have abnormal clotting so it is important to check this before doing a liver biopsy, which causes bleeding from the liver.
Describe how the liver is involved in lipid metabolism
Oxidation of fatty acids => energy
Synthesis of phospholipid (important for cell membranes)
Fat synthesis => esterified to triglyceride => LPL => adipose tissue
What are bile salts? What do they do?
Dissolve in water and form micelles (hydrophobic centre and hydrophilic exterior)
Solubilise fat (make it water-soluble)
- Increase access of lipases
- Facilitate absorption of fat
Reabsorbed via enterohepatic circulation after secretion by liver => bile duct => into gut.
Transported to liver via portal vein (so can be recycled)
- 2-4g pool of bile salts recirculates 6-10x per day
- 0.6g daily bile salt loss
Describe the metabolism of bilirubin
Damaged/aged red cells are converted into Heme => Biliverdin => Bilirubin.
Bilirubin (not water soluble) is transported via albumin to be absorbed in the liver. It is decoupled from albumin and taken up by hepatocytes.
Usually metabolised by conjugation with Glucuronide, Sulphate and others
Conjugated Bilirubin is excreted in bile and in the gut, is converted to urobilinogen (water-soluble) by gut bacteria and urobilinogen is reabsorbed, transported to liver via portal vein (very effective enterohepatic circulation)
What happens to the reabsorbed urobilinogen?
Of that reabsorbed urobilinogen
- 95% Urobilinogen re-excreted in bile
- 5% Urobilinogen excreted by kidneys – urobilinogen is water-soluble so some escape into the blood
- - Some Urobilinogen converted by gut bacteria into urobilin and stercobilin (dark coloured stools)
Describe the possible causes of jaundice including the consequences of obstructive jaundice
Jaundice: “elevated bilirubin in the blood, usually becomes clinically apparent when the bilirubin is twice the upper limit of normal”
Haemolytic jaundice (too much haemoglobin saturates body’s capacity to deal with it => non-water soluble). The bilirubin is unconjugated
Hepatic jaundice (probably most common cause of jaundice): many causes of hepatocyte injury can cause jaundice by reducing bilirubin conjugation => unconjugated hyperbilirubinaemia
Obstructive jaundice: due to obstruction in bile flow (clinically different)
- Bilirubin cannot get into gut!
- Conjugated bilirubin escapes into blood
- Conjugated bilirubin excreted by kidneys (dark urine)
- No urobilinogen reabsorbed
- No bilirubin, urobilinogen excreted
- No stercobilin (pale stools) => steatorrhoea
- Commonest cause is gallstones (often obstruction is intermittent), 2nd most common cause is pancreatic cancer (carcinoma of the head in particular => blocking bile duct)
Describe how the liver is involved in drug metabolism
Xenobiotics are metabolised in the liver
Phase 1 (oxidation, reduction, hydrolysis e.g. Cytochrom P450)
Phase 2 (conjugation) e.g. glutathione
Pharmacological action of drugs depends on rate of metabolism to inactive compounds
Enzyme induction can lead to important drug interactions e.g. antiepileptics – especially if drugs are given for a long time.
Compare alcohol metabolism to paracetamol metabolism in the liver
- Alcohol dehydrogenase (certain populations don’t have this enzyme especially Far Eastern populations => low tolerance)
- CYP 450 enzymes (inducible and can interact with other drugs)
- Chronic alcoholics will inevitably have a selection of induced enzymes, that will make them sensitive to other drugs.
- Most is conjugated to glutathione or sulphate and excreted by the kidneys
- A small proportion is metabolised via CYP forming a toxic metabolite (NAPQI)
- Paracetamol poisoning is due to the toxic metabolite, not paracetamol itself
- NAPQI causes liver necrosis
The CYP450 enzymes that metabolise alcohol overlap with the CYP450 enzymes that metabolise paracetamol so alcoholics suffer paracetamol overdose at a much lower dose compared to a normal healthy adult.
What happens when the liver goes wrong?
What happens when the liver goes wrong?
- Faulty glucose homeostasis (late sign)
- Increased amines in blood
- Reduced plasma proteins (oedema and coagulopathy)
- Portal hypertension
- The liver has a large reserve capacity and liver failure is pretty advanced before clinical signs become apparent (indicative of ~85% loss – advance disease)
Liver disease is the fifth ‘big killer’ in England & Wales, after heart, cancer, stroke and respiratory disease. Liver disease is the only major cause of death still increasing year-on-year.
How may be the surgical sieve be applied to the classification of liver disease
Toxic injury to the liver
- Drug induced
- Industrial and environmental toxin
Infectious agents and parasites
- Hepatitis virus
- Primary biliary cirrhosis
- Primary malignant tumours
- Metastatic malignant tumours
- Benign hepatic tumours
- Alpha-1-antitrypsin deficiency
- Wilson’s disease
What are the different types of clinical presentation of liver disease?
Acute Liver Disease / “failure”
- Acute loss of liver parenchyma (commonest reason is alcohol, immunological, viral)
Acute on chronic liver disease
- Acute liver cell damage in abnormal liver (progressive disease)
End stage liver disease
- Systemic consequences of altered liver architecture (cirrhosis)
Describe Chronic Liver Damage including cirrhosis
Constant or repetitive damage provokes deposition of extracellular matrix, which leads to disturbances in hepatic metabolism, blood flow, bile flow and parenchymal remodelling. The end stage of this process is liver cirrhosis.
Cirrhosis: nodules of regenerating hepatocytes surrounded by bands of fibrous scar issue – liver can’t regenerate because of all the scarring.
What are the possible causes of cirrhosis?
- Alcoholic liver disease
- Non-alcoholic fatty liver disease (associated with conditions such as diabetes mellitus, obesity and hypercholesterolaemia).
Viral such as chronic hepatitis C (more common worldwide than alcoholic disease, risk of hepatocellular carcinoma)
Describe the pathophysiology in alcoholic liver disease
Alcohol (ethanol) is the most frequently abused drug throughout the world.
UK: symptoms of alcohol addiction 7% male, 2% female
Urban areas: alcoholic liver cirrhosis is the 4th most frequent cause of death within 25-64 year olds (increasingly frequent in young adults)
Can lead to steatosis (fatty liver) and alcoholic hepatitis (uncommon but hospital admission has 50% mortality)
Alcohol => Steatosis => Hepatocyte Injury / Inflammation => Stellate Cell Activation
Normally stellate cells are quiescent and reside in the space of Disse between sinusoid and hepatocyte. Activated stellate cells cause “myofibroblast” proliferation, contraction, chemotaxis and fibrogenesis. Activated Kupffer cells release cytokines that promote proliferation, contraction, chemotaxis and this all leads to hepatocyte dysfunction and death.
Apart from cirrhosis, what else can alcoholic liver disease cause? Describ the systemic effects of cirrhosis
Alcohol can also cause perivenular fibrosis (fibrosis around the terminal hepatic venule – where alcohol is metabolised) to begin with before progressing to alcoholic liver fibrosis => cirrhosis.
Systemic effects of cirrhosis include hepatic encephalopathy, malnutrition, spider naevi on skin, oesophageal varices, portal vein hypertension, splenomegaly, periumblical caput medusa, haemorrhoids, ascites
Cirrhosis is also the commonest risk factor for hepatocellular carcinoma.
Mallory hyaline can been in alcoholic hepatitis under light microscopy
Describe Hepatitis C
Hepatitis C virus (HCV) is an RNA virus
HCV infects over 170 million people worldwide
Parenteral route of infection seems to be most prevalent, with high rates of infection seen in intravenous drug abusers, haemophiliacs and recipients of unscreened blood transfusions.
HCV infection occurs in approximately 0.3-0.7% of the UK population (inferred from the level of infection seen in UK blood donors)
It is incurable
Hepatitis C rarely presents acutely (fulminant hepatitis) so it is normally a long-term, progressive disease (10-30 years)
Describe Primary Biliary Cirrhosis
Primary Biliary Cirrohosis (PBC)
Chronic destructive cholangitis
Autoimmune but immunosuppressive therapy is ineffective (unpredictable, progressive)
Incidence is 5/100,000, >90% female over 40 years of age
Anti-mitochondrial antibodies are positive in 95% of cases
Median survival after diagnosis is 12 years without treatment (reflects progression to cirrhosis and complications)
The bile duct is attacked by lymphocyte and macrophage infiltrate => ‘vanishing bile duct’ syndrome eventually
Describe Primary Sclerosing Cholangitis (autoimmune)
Cholangitis characterised by periductal fibrosis
Incidence is 1-5/100,000, 75% male, 89% have ulcerative colitis (strong link with IBD)
pANCA are positive in 80% of cases – immunosuppressive therapy not effective
Median survival after diagnosis is 10-20 years without treatment
8% develop cholangiocarcinoma
“Onion skin” – concentric scarring
Describe Hereditary Haemochromotosis
Most common autosomal recessive genetic disorder
>90% of patients are homocygote for C282Y mutation in HFE
Prevalence of homocygosity is approx. 1:220-300 (0.45%) in white northern Europpean populations, prevalence heterocygosity is 11%.
Only 20% become symptomatic: 80% male, 50-70 years
Fully developed cases develop liver cirrhosis (100%0, diabetes (75%), skin hyperpigmentation (75-80%)
Diagnosis: transferrin saturation > 50%, genetic testing
Patients treated before cirrhosis have a normal life expectancy (otherwise <10 years)