T3: Cirrhosis and Paracetamol Poisoning

Question 1

What are the functions of the liver?

Answer 1

Carbohydrate metabolism

1. Storage of large amounts of glycogen
2. Conversion of galactose and fructose to glucose
3. Gluconeogenesis
4. Formation of many chemical compounds from intermediate products of carbohydrate metabolism

Fat metabolism

1. Oxidation of fatty acids to supply energy for other body functions
2. Synthesis of large quantities of cholesterol, phospholipids and most lipoproteins
3. Synthesis of fat from proteins and carbohydrates

Protein metabolism

1. Deamination of amino acids
2. Formation of urea for removal of ammonia from the body fluids
3. Formation of plasma proteins
4. Interconversions of the various amino acids and synthesis of compounds from amino acids

Bilirubin metabolism
Storage of vitamins – A, D, B12, Iron (Ferritin)
Coagulation factors – production of fibrinogen, prothrombin, factor 7, 9 and 10
Detoxification and metabolism of compounds such as drugs and alcohol. Also activation of prodrugs.

Question 2

Give examples of causes of acute and chronic liver injury.

Answer 2

• Acute - due to a sudden overwhelming insult and a significant proportion of the hepatocytes die at once. There are a number of causes such as drugs e.g. paracetamol, viruses such as hepatitis A and E and acute onset of immune hepatitis. Depending on the severity of the insult, the liver cells may regenerate. If there is insufficient amount of cells to regenerate, the patient may require a liver transplant.

Chronic injury - Persistent ongoing damage and injury and repair and regeneration . This leads to a Inflammatory response. Heal through fibrosis and regeneration. Causes include drugs, infections, autoimmune disease and infections. If the insult persistent, the patient will develop cirrhosis, an end stage form of liver disease.

Question 3

What are idiosyncratic hepatotoxins?

Answer 3

Most drug reactions are rare and unpredictable i.e. some people may develop a reaction and others may not.

Question 4

What are intrinsic hepatotoxins?

Answer 4

Drugs like Paracetamol in high doses cause liver injury in everyone.

Question 5

How can paracetamol become toxic?

Answer 5

The liver metabolism, metabolises paracetamol in 3 pathways - 2 major pathways and 1 minor pathway. The minor pathway results in liver injury. Via the P450 pathway, the paracetamol is converted into a toxic metabolite - NAPQI. This binds to glutathione available that is excreted in the liver in therapeutic doses. In unsafe doses, the glutathione is depleted and so there is no excretion. This is approximately more than 4g at a time. NAPQI in the liver results in hepatic necrosis.

Question 6

What are the features of acute liver failure?

Answer 6

Acute liver failure features:

• With increasing necrosis, they release enzymes such as AST and ALT which can be detected.
• Failure of bilirubin metabolism means that we get a build up of bilirubin metabolites - mostly conjugated hyperbilirubinemia leading to jaundice.
• There is a failure to detoxify nitrogenous compounds. This leads to circulation of excretory amino acids leading to hepatic encephalopathy (causes patients to go drowsy and can lead to a coma).
• There is failure to synthesis proteins and as such complement factors II, VII and X become depleted leading to bleeding tendency.
• Shock causes low glomerular filtration leading to renal failure (hepatorenal failure).

Question 7

How is paracetamol poisoning managed?

Answer 7

Treatment is through the ingestion of N-acetyl Cysteine. This is converted to L-cysteine which is converted to glutathione (binds to the NAQPI, reversing the damage). They are also given activated charcoal. Early treatment is crucial.

Question 8

Where is the liver do the cells die?

Answer 8

Zone 3 - around where the central vein is. These tend to be the ones lost - In other zones they are close to the the portal triad and so blood supply is great and so the hepatocytes immediately surrounding tend to be preserved. This can result in the mottled appearance under the microscope. Surrounding this is the confluent necrosis. Once there is 50% cell loss, there is acute liver failure. Zone 3 hepatocytes contain drug metabolizing enzymes and the hepatocytes die by necorosis.

Question 9

How can we see inflammation in a liver biopsy?

Answer 9

• The presence and severity of inflammation is assessed. To asses this you look for the presence of inflammatory cells - lymphocytes (may indicate a viral infection), eosinophils, plasma cells (indicates autoimmune) and granulomas (may indicate there is underlying biliary pathology).
• You then need to see the location of the inflammation portal, peri-portal connective tissue, in the parenchymal or in multiple locations.
• Then look for evidence of necrosis: acidophil bodies (single dying hepatocytes) or confluent necrosis (may indicate active disease)
• Presence of fibrosis and scarring if so how much and where.

Question 10

What is chronic liver disease and cirrhosis?

Answer 10

Any disease that causes persistent and ongoing/repetitive inflammation of the liver.
With the insult, we get inflammation and necrosis. This is healed by regeneration, and if continued eventually necrosis. Cirrhosis is the end stage of liver diseased - it is significant fibrosis with nodularity of the parenchyma. Eventually there is insufficient regeneration and liver failure results. The only cure for end stage liver failure, if eligible, is transplant.

Question 11

What is the regenerative capacity of the liver?

Answer 11

Following inflammation, the liver can regenerate both labile and stable cells. The liver cells usually liver 6 moths. It can regenerate very quickly when needed to e.g. in partial hepatectomy, transplants of partial livers.

Question 12

What are the consequences of cirrhosis?

Answer 12

Consequences of cirrhosis:
1. Portal hypertension - This results from a stiff scarred liver. There is increased blood flow from the portal vein as blood bypasses the hepatocytes and so they cannot perform there function. Pressure increases. This leads to the development of oesophageal varices - distend vessels at the bottom of the oesophagus - (can causes catastrophic bleeding).
2. Oedema - This is a result of synthetic failure and decompensation. The liver can lo longer perform its function. This leads to low albumin and low hormone levels. This can lead to the development of ascites and peripheral oedema (direct effect of low albumin and leaky vessels).
3. Risk of infection - Due to alteration in the immune system leading to an increased risk of sepsis.
Carcinogenesis - late effect of chronic inflammation and cell replication. There is an increased risk of hepatocellular carcinoma. As a result anyone with liver cirrhosis undergoes regular screening ultrasounds and blood tests to identify this at an early stage to identify this as early as possible.

Question 13

What are the causes of chronic liver disease?

Answer 13

Causes (not an exhaustive list):

• Infection (e.g. Hepatitis B, C)
• Autoimmune hepatitis
• Alcohol
• Obesity
• Biliary diseases
• Genetic diseases (e.g. A1AT, Haemochromatosis)
• Drug induced liver injury