Cirrhosis and Paracetamol Overdose Flashcards
What is the dual blood supply of the liver?
Hepatic artery - oxygenated blood
Hepatic portal vein - deoxy blood arriving from gut
Why is the liver less susceptible to ischaemic injury?
Due to dual blood supply
Role of the liver in carbohydrate metabolism?
- Storage of glycogen
- Conversion of galactose and fructose to glucose
- Gluconeogenesis
Role of the liver in fat metabolism?
- Oxidation of fatty acids to supply energy
- Synthesis of cholesterol
- Triglyceride synthesis from proteins and carbohydrates
- Lipoprotein synthesis
Role of the liver in protein metabolism and synthesis?
- Synthesis and metabolism of amino acids
- Formation of urea
- Albumin
- C-reactive protein
- Complement C1-C9
How is the liver involved in bilirubin metabolism?
In the liver, bilirubin is conjugated with glucuronic acid, making it soluble in water –> forms conjugated bilirubin.
Most of this then goes into the bile and out into the small intestine.
What vitamins is the liver involved in storing?
A, D, E, K and B12
What vitamins are fat soluble? What does this mean?
A, D, E, K
Bile secreted during digestion is essential for absorbing them so that the body can use them
How is the liver involved in clotting?
The liver is responsible for producing most of these coagulation factors
What veins does the liver comprise?
Portal vein structures (brings blood into liver) and central veins (takes blood away)
What is a liver sinusoid?
A type of capillary known as a sinusoidal capillary that serves as a location for mixing of the oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal vein.
Sinusoids receive blood from terminal branches of the hepatic artery and portal vein and deliver it into central veins. Sinusoids are lined with endothelial cells and flanked by plates of hepatocytes.
What are the 2 main mechanisms of liver injury?
Acute and chronic
What is acute liver injury due to?
Sudden overwhelming insult (drugs, viruses) that causes a significant proportion of hepatocytes to die at once.
What are the possible outcomes after acute liver injury?
Either liver regenerates and recovers, or liver cannot regenerate and needs transplant
What is chronic liver injury due to?
Many causes – drugs, infections and viruses (e.g. Hep C), autoimmune disease, alcohol, obesity
Persistent ongoing damage and injury –> inflammatory response
What does chronic liver injury result in?
Repeated damage and repair through inflammation, regeneration of residual hepatocytes and repair through scar tissue (fibrosis)
Ultimately if the inflammation persists will develop cirrhosis over time
What is ALT? How is it used as a liver test?
ALT is an enzyme found in the liver that helps convert proteins into energy for the liver cells.
When the liver is damaged, ALT is released into the bloodstream and levels increase.
What are the 2 types of drug induced liver injury (DILI)?
- Intrinsic
2. Idiosyncratic
Idiosyncratic vs intrinsic liver injury?
Intrinsic - Intrinsic DILI refers to liver toxicity induced by a drug in a predictable and dose-related manner
Idiosyncratic - A rare adverse drug reaction which occurs less frequently, is associated with a less consistent dose-toxicity relationship and a more varied presentation.
What are the 3 methods of metabolisation of paracetamol by the liver?
- Sulfation (major pathway)
- Glucuronidation (major pathway)
- P450 enzyme (minor pathway)
What does sulphate conjugation and glucuronide conjugation of paracetamol lead to?
Renal excretion
What is the result when paracetamol is metabolised via P450 pathway?
CYP2E1 and CYP1A2 enzymes convert paracetamol to NAPQI (toxic metabolite)
What does NAPQI then bind to in therapeutic doses?
Irreversibly binds to glutathione which can then be renally excreted
This occurs during therapeutic doses with plenty of glutathione available
SAFE
In toxic doses, what happens to NAPQI?
Glutathione becomes depleted quickly, causing NAPQI (toxic metabolite) to build up in liver
Results in hepatic necrosis due to toxicity of NAPQI to hepatocytes
What are the 3 zones of the liver?
Based upon oxygen supply:
Zone 1: encircles the portal tracts where the oxygenated blood from hepatic arteries enters.
Zone 3: is located around central veins, where oxygenation is poor.
Zone 2: is located in between.
What do hepatocytes in zone 3 express high levels of?
Express high levels of cytochrome P450 (drug metabolising enzymes)
How many cells have to be lost to develop acute liver failure?
> 50%
How does acute liver failure (liver cell necrosis) affect release of enzymes?
How is this detected?
Increased release of enzymes:
- AST
- ALT
Detected by lab tests
How does liver cell necrosis affect bilirubin?
What does this result in?
Failure of bilirubin metabolism leading to increased levels of bilirubin (mostly conjugated hyperbilirubinaemia)
Results in jaundice
What is hepatic encephalopathy?
Hepatic encephalopathy is a decline in brain function that occurs as a result of severe liver disease (can cause coma)
How can liver cell necrosis lead to hepatic encephalopathy?
Failure of liver to detoxify nitrogenous compounds –> causes circulation of excitatory amino acids
Toxins build up
How can liver cell necrosis lead to bleeding?
Failure to synthesis clotting factors
How can liver cell necrosis lead to renal failure?
Shock causes low glomerular filtration
How is paracetamol overdose managed?
Early treatment is vital
- Activated charcoal ingestion
- N-Acetyl Cysteine (given via IV or orally)
How does N-Acetyl Cysteine treat paracetamol overdose?
Acetylcysteine converted to L-cysteine which results in the production of glutathione
This glutathione binds the high levels of NAPQI –> reducing liver cell damage
Paracetamol overdose is an example of cell death (necrosis) due to a toxin.
What is the mechanism of this at enzyme level?
Build up of toxic metabolite NAPQI in zone 3 hepatocytes due to lack of Glutathione
Leads to cell injury then death.
Can cause organ failure if severe.
What is the only treatment of severe liver failure?
Transplant
How does hepatitis C affect the liver?
Apoptosis is central for the control and elimination of viral infections.
Hepatitis C causes damage to the liver mainly in the form of inflammation, which then leads to fibrosis. Hepatitis C results in the death of liver cells.
How can the degree of fibrosis in the liver be assessed?
Liver biopsy
What inflammatory cells would be seen in a liver biopsy in cases of severe inflammation?
Lymphocytes, eosinophils, plasma cells, macrophages, granulomas
What is ‘confluent necrosis’?
Refers to substantial areas of liver-cell death.
What is the most common causes of confluent necrosis?
Hepatitis (either viral or drug related), in which case the necrosis is accompanied by an inflammatory reaction
What would the presence of mainly lymphocytes during a liver biopsy indicate?
Maybe viral
What would the presence of mainly plasma cells during a liver biopsy indicate?
Maybe autoimmune hepatitis
What would the presence of mainly granulomas during a liver biopsy indicate?
Underlying biliary pathology
What do liver biopsies look for?
- Presence of inflammation
- Types of inflammatory cells
- Locations of inflammation
- Evidence of necrosis
- Presence of fibrosis/scarring
What would the presence of acidophil bodies in the liver indicate?
Represents a dying hepatocyte often surrounded by normal parenchyma
What is chronic liver disease?
Any disease that causes persistent and ongoing inflammation in the liver.
Results in increasing amounts of fibrosis.
Inflammation & necrosis –> regeneration –> fibrosis
What is cirrhosis?
End stage of chronic liver disease.
Significant fibrosis with nodularity of the parenchyma.
What are a few causes of chronic liver disease?
Infection (e.g Hepatitis B, C) Autoimmune hepatitis Alcohol Obesity Biliary diseases Genetic diseases (e.g. A1AT, Haemochromatosis) Drug induced liver injury
What is the regeneration ability of the liver?
- Can regenerate very quickly when needed (e.g. partial hepatectomy)
- Regeneration of labile and stable cells
- Liver cells usually live 6 months
What is the repair ability of the liver? What can this result in?
- Original tissue replaced by scar tissue
- Original structure and function is lost
Due to ongoing repair and regeneration due to inflammation
With time increasing damage leads to more scarring and less regenerative potential.
Cirrhosis histology?
Regenerative nodules of hepatocytes surrounded by sheets of fibrous tissue
What are the 4 main consequences of cirrhosis?
- Portal hypertension
- Oedema
- Risk of infection
- Carcinogenesis
How can cirrhosis lead to portal hypertension?
Stiff and scarred liver slows blood flow, putting stress on the portal vein.
Liver cells still present, but portal vein blood bypasses the sinusoids so the liver cells cannot perform their functions.
How can portal hypertension lead to oesophageal varices? What is the danger of this?
High blood pressure in the portal vein pushes blood into surrounding blood vessels, including in the oesophagus. These blood vessels have thin walls and are close to the surface. The extra blood causes them to expand and swell.
Danger of catastrophic bleeding.
What are oesophageal varices?
Distended vessels at the bottom of the oesophagus
How can cirrhosis lead to oedema?
- Cirrhosis slows the normal flow of blood through the liver, thus increasing pressure in the portal vein.
- Due to synthetic failure –> low albumin levels
How can low albumin levels lead to oedema?
Albumin and other proteins in the blood act like sponges to keep fluid in your blood vessels.
Low albumin levels can lead to leaky vessels.
How can increased pressure in portal vein lead to oedema and ascites?
The increased pressure in the portal vein can cause fluid to accumulate in the legs (oedema) and in the abdomen (ascites)
How can cirrhosis lead to risk of infection?
Cirrhosis causes immunosuppression (due to diminished ability to synthesise proteins)
Also increased risk of sepsis
How can cirrhosis lead to carcinogenesis?
Late effect of chronic inflammatory replication
Increased risk of hepatocellular carcinoma
What is carcinogenesis?
The initiation of cancer formation.
What is cirrhosis a balance of?
Ongoing injury and attempted repair
What are intrinsic hepatotoxins?
Drugs that can cause liver injury in overdose situations in most normal recipients but are also capable of inducing similar liver damage at lower doses in individuals with genetic or acquired abnormalities in drug metabolism.
