Liver failure

Question 1

Where are proteins made in the body

Answer 1

All circulating proteins except ‘Ỵ-globulins (made by lymphocytes) are synthesized in the liver.

Question 2

Describe the role of the liver in controlling protein metabolism and synthesis

Answer 2

Albumin which maintains intravascular oncotic pressure and transports water-insoluble substances such as bilirubin and some drugs in the plasma.
Transport and carrier proteins such as transferrin
All factors involved in coagulation and components of the complement system.
The liver eliminates nitrogenous waste by degradation of amino acids, conversion to urea and renal excretion.

Question 3

Describe the role of the liver in maintaining blood glucose levels

Answer 3

The liver does this by releasing glucose into the blood stream in the fasted state
either by breakdown of stored glycogen
or by synthesizing glucose from amino acids (from muscle) or glycerol (from adipose tissue).

Question 4

Describe the role of the liver in the metabolism and excretion of bilirubin and bile salts

Answer 4

Bile acids are formed from cholesterol and excreted into bile and pass into the duodenum via the common bile duct (CBD), where they solubilize lipid for digestion and absorption.
Bilirubin is formed from the breakdown of mature red cells and eventually excreted in urine and faeces.

Question 5

Describe the impact of liver disease

Answer 5

Liver disease is common worldwide. Alcohol and non-alcoholic fatty liver disease are the commonest causes in the developed world, chronic viral hepatitis B or C in the developing world. Alcohol excess results in fatty change, alcoholic hepatitis, alcoholic cirrhosis.

Question 6

Describe the link between alcohol and liver disease

Answer 6

Although alcohol acts as a hepatotoxin, the exact mechanism leading to hepatitis and cirrhosis is unknown. Only 10 -20% of people who drink excessively develop cirrhosis; genetic predisposition and immunological mechanisms have been suggested.

Question 7

Describe what is meant by liver failure

Answer 7

§ Defined as – the rate of hepatocyte death > regeneration rate, various aetiologies and a combination of necrotic and/or apoptotic cell death.

Question 8

What is the clinical result of liver failure

Answer 8

Apoptosis (e.g. Acetaminophen=Paracetamol):

Necrosis (Ischaemia):

Clinical result = catastrophic illness…can rapidly lead to coma/death due to multi-organ failure

Question 9

Describe the role of drugs in liver failure

Answer 9

Drugs – Paracetamol overdose, Methyldopa, nitrofurantoin, isoniazid, ketoconazole, methotrexate, amiodarone

Question 10

List some diseases which can predispose to liver failure

Answer 10

Autoimmune Hepatitis
Primary biliary cholangitis - an inhertied abnormality of the immunoregulation leads to a T-lymphocyte mediated attack on bile duct epithelial cells.
Primary sclerosing cholangitis - a chronic cholestatic liver disease characterised by a progressive obliterating fibrosis of intra and extrahepatic ducts, leading to cirrhosis.
Hereditary haemochromatosis- an autosomal recessive disorder which affects 1 in 400 in the population of which 10% are gene carriers. There is excessive iron depostion in various organs eventually leading to fibrosis and functional organ failure
Wilson’s Disease - a rare, recessively inherited disease resulting in decreased secretion of copper into the biliary system.
Budd-Chiari syndrome – thrombosis of the hepatic veins causes occlusion resulting in congestion within the liver which leads to hypoxic damage and necrosis of hepatocytes.
Liver tumours.

Question 11

Describe the early stage symptoms of liver disease

Answer 11

Early stage symptoms tend to be generalised:
Lethargy
Anorexia
Malaise
Pruritus – itchy skin
Right upper quadrant pain

Question 12

Describe the late stage symptoms of liver disease

Answer 12

Peripheral swelling
Abdominal bloating
Bruising
Vomiting of blood 
Confusion and somnolence

Question 13

Why does liver disease have a diversity of signs

Answer 13

The importance of the liver in homeostasis is reflected in the diversity of signs which accompany liver disease.

Question 14

What is the most common sign in liver disease

Answer 14

Jaundice is a common sign in liver disease. Raised bilirubin levels are clinically detectable when the concentration exceeds 40 µmol/l.

Question 15

Describe the signs of liver disease associated with its reduced capacity to metabolise oestrogens

Answer 15

spider naevi – telangiectases consist of a central arteriole with radiating small vessels, found in the distribution of the superior vena cava.
loss of body hair

gynaecomastia - enlargement of the male breast with firm tissue extending concentrically beyond the nipple.
testicular atrophy
palmar erythema - ‘liver palms’ - reddening of palms at the thenar and hypothenar eminences – a non-specific change of hyperdynamic circulation

Question 16

Describe Xanthelasma

Answer 16

Xanthelasma - sharply demarcated yellowish deposit of cholesterol underneath the skin, usually on or around the eyelids

Question 17

Describe caput medusa

Answer 17

Caput medusa indicates severe portal hypertension.
It describes the appearance of distended and engorged paraumbilical veins, which are seen radiating from the umbilicus across the abdomen to join the systemic veins.
Caput medusa is latin for “head of Medusa”, from the apparent similarity to Medusa’s head, which had venomous snakes in place of hair.

Question 18

List some signs of chronic liver dysfunction

Answer 18

clubbed nails, xanthelasma, pruritus (itchy skin causes scratch marks) , ascites, dilated abdominal veins, hepatomegaly, caput medusa, oedema and weight loss, loss of musculature
also bruising

Question 19

What is Dupuytren’s contracture

Answer 19

May be a sign of alcoholic liver disease

Question 20

Describe some other signs of chronic liver dysfunction

Answer 20

Hepatic encephalopathy – disorientation, drowsy, coma, due to accumulation of toxins, primarily derived from the gut, is thought to inducecerebral oedema and changes in the level of consciousness and eventually coma

Fetor Hepaticus – distinctive musty sweet breath odour in severe liver disease.

Hepatic flap – coarse hand tremor

Question 21

What is the clinical result of acute liver failure

Answer 21

Apoptosis (e.g. Acetaminophen=Paracetamol):

Necrosis (Ischaemia):

Clinical result = catastrophic illness…can rapidly lead to coma/death due to multi-organ failure

Question 22

Give some definitions for acute liver failure

Answer 22

Fulminant hepatic failure = rapid development (< 8wks) of severe acute liver injury with impaired synthetic function (INR/PT, albumin) + encephalopathy in person with previously normal liver or well-compensated liver disease

“Sub-fulminant” = < 6 months

Question 23

Describe apoptotic and necrotic acute liver failure

Answer 23

Apoptotic – e.g. paracetamol – NO inflammation.
§ Cytokines active Caspase cascade after oxidative mitochondrial damage.
o Necrotic – e.g. ischaemia – INFLAMMATION.
§ If mitochondria badly damaged so no ATP left

Question 24

List the main causes of chronic liver failure

Answer 24

Viral hepatitis (B, C)
Alcohol Excess
Fatty Liver
Autoimmune Disease
Genetic: Wilson’s, Haemachromatosis
Drug induced e.g. methotrexate

Question 25

Describe acute liver failure in the UK

Answer 25

Relatively uncommon (< 500 deaths/yr)

< 15% of liver transplants/yr (< 100 transplants/yr)

As in USA, over past 30y, Paracetamol (Acetaminophen, ACM) is commonest cause

Question 26

Describe the toxins linked to acute liver failure

Answer 26

Paracetamol
Amanita phalloides
Bacillus cereus

Question 27

What are the other causes of acute liver failure

Answer 27

Diseases of pregnancy
AFLOP, HELLP, hepatic infarction, HEV, Budd-Chiari
Idiosyncratic drug reactions
Single Agent: Isoniazid, NSAID’s, valproate
Drug combinations: Amoxicillin/clavulanic acid, trimethoprim/sulphamethoxazole, rifampicin/isoniazid
Vascular Diseases
Ischaemic hepatitis, post-OLT hepatic artery thrombosis, post-arrest, VOD (veno-occlusive disease)
Metabolic causes
Wilson’s disease, Reye’s syndrome

Question 28

Describe paracetamol poisoning in the UK

Answer 28

Up to 70% of ALF cases
UK has highest rates of paracetamol use for DSH in World
Of all cases of paracetamol self-poisoning
< 10% develop severe liver damage
< 2% develop ALF
worst Px if concurrent alcohol use

Question 29

Describe acute liver failure in the far-east

Answer 29

ALF accounts for 15% of liver transplants/yr in UK,
BUT 70% of transplants in Far East

Differences in aetiology
Usually drug-induced in West

Viral hepatitis in developing world & 
	Far East (endemic) 

Exacerbations of chronic hep B (Hong Kong), Hepatitis E (India)

Question 30

Describe the outcomes of acute liver failure due to hepatocyte failure

Answer 30

§ Diminished protein synthesis: 
o Lower albumin à ascites and oedema. 
o Lower clotting factors à bruising and bleeding. 
o Lower complement à infection, sepsis. 
§ Defective metabolism: 
o Carbohydrate à hypoglycaemia. 
o Protein catabolism à low urea. 
o Ammonia clearance à encephalopathy and coma.

Question 31

What are the symptoms of acute liver failure

Answer 31

§ Initially non-specific – malaise, nausea and lethargy.
§ Jaundice and then encephalopathy (possibly via accumulation of neurotoxic substances in brain affecting astrocyte function).

Question 32

List the causes of death in patients with acute liver failure

Answer 32

Bacterial and fungal infections
Circulatory instability
Cerebral Oedema
Renal failure
Respiratory failure
Acid-base and electrolyte disturbance
Coagulopathy

Question 33

Describe cirrhosis

Answer 33

Cirrhosis is the final common pathway for liver disease. It is characterised by necrosis of liver cells, followed by progressive fibrosis and nodule formation which leads to the impairment of liver cell function and gross distortion of the liver architecture leading to portal hypertension and deterioration of liver function.

Question 34

Describe the aetiology of cirrhosis

Answer 34

Alcohol is the most common cause of cirrhosis in the Western world, but hepatitis B and C are the most common causes world-wide.

Cirrhosis develops in response to chronic liver injury from any cause which is often apparent from the history combined with laboratory investigations. A liver biopsy is performed to confirm the severity and type of liver disease.

Question 35

Describe the pathology of cirrhosis

Answer 35

Histologically, two types of cirrhosis are described. Micronodular cirrhosis: uniform, small nodules up to 3 mm in diameter. This type is often caused by ongoing alcohol damage or biliary tract disease.
Macronodular cirrhosis: nodules of variable size. This type is often seen following chronic viral hepatitis.
There is also a mixed picture, with both small and large nodules.

Question 36

Describe the features of a cirrhotic liver

Answer 36

Scar tissue- tried to regenerate hepatocytes damaged by alcohol
bumpy nodules- inflammation
fatty cysts
artery at bottom of liver- fatty- stopping blood flow from the heart

Question 37

Describe the classifications of acute liver failure

Answer 37

Hyperacute liver failure is when encephalopathy occurs within seven days of the onset of jaundice.
Acute liver failure is when encephalopathy occurs after 8-28 days of jaundice.
Subacute liver failure is when encephalopathy occurs 5-12 weeks after the onset of jaundice.

Question 38

Essentially, what happens in acute liver failure

Answer 38

Acute hepatic failure occurs when there is a massive loss of hepatocytes. It is defined as severe hepatic dysfunction occuring within 6 months of the onset of symptoms of liver disease, with a clinical manifestation of hepatic encephalopathy or coagulopathy.

Question 39

Describe the primary features of acute liver failure

Answer 39

The patient is jaundiced.
Other primary features of hepatic failure can be divided into:
Central Nervous System complications
Coagulopathy
Renal failure
Sepsis
Cardiovascular complications
Metabolic complication

Question 40

Describe sepsis

Answer 40

In liver failure will have bacterial infection occurs 90% of cases and fungal infection in 32% of cases.
Infection most commonly presents within 3 days of hospital admission. Often the normal clinical features of fever and leucocytosis (high white cell count) are absent.
Trials have shown that prophylactic intravenous antibiotic therapy is effective in reducing sepsis in acute hepatic failure

Question 41

Describe the cardiovascular features of acute liver failure

Answer 41

A common complication of acute hepatic failure is a reduction in peripheral resistance which requires a reflex increase in cardiac output to maintain blood pressure. Cardiac failure and hypotension may result if there is pre-existing heart disease

Question 42

Describe the metabolic features of acute liver failure

Answer 42

Hypoglycaemia and Hypoxia are common.

Question 43

Describe the effects of ALF on the CNS

Answer 43

Hepatic encephalopathy is the inevitable consequence of acute hepatic failure.
Accumulation of toxins, primarily derived from the gut, is thought to induce cerebral oedema and changes in the level of consciousness and eventually coma.

Question 44

Describe the renal effects of ALF

Answer 44

Hepatorenal syndrome refers to the occurrence of unexplained renal failure in patients with liver disease or those undergoing surgery for biliary tract obstruction. The kidneys are morphologically normal and, when transplanted into patients with chronic renal failure, function normally.
Renal failure is thought to be due to reduced renal blood flow - more marked in the cortex than the medulla - due to cortical vasoconstriction. The basis for the reduced perfusion is uncertain but may result from the accumulation of a vasoactive substance, thought to be endotoxin, which is usually cleared in the liver.
It is often irreversible and rapidly fatal - patients who develop hepatorenal syndrome have a 95% chance of dying from it, and a mean survival of under 2 weeks. Resolution only occurs if there is dramatic improvement of liver function e.g. via liver transplantation.

Question 45

Describe the effects of ALF on coagulopathy

Answer 45

synthesis of coagulation factors I, II, V, VII, IX, X. Vitamin K dependent factors - II, VII, IX and X - and Factor V are affected first in disease. Factor VII is the earliest of all to decline because of its short half-life (6 hours). Fibrinogen (factor I) synthesis is affected only in severe disease.
inhibition of fibrinolysis / coagulation - the liver is responsible for synthesising plasma anticoagulant proteins, e.g. protein C, protein S and antithrombin III.
clearance of activated coagulation factors - fibrin and tissue plasminogen activator (tPA) are removed from the circulation by the liver’s reticuloendothelial system
absorption of vitamin K - malabsorption occurs in disease
Impairment of any of these mechanisms predisposes to bleeding

Question 46

What can be suggestive of a coagulation defect

Answer 46

bleeding at any site
oozing at venepuncture sites - from excessive fibrinolysis
bruising (see photograph

Question 47

Describe chronic liver failure

Answer 47

Chronic hepatic failure occurs where there is a deterioration in liver function superimposed on chronic liver disease. The acute deterioration may be based on a number of pathological processes, including the underlying disease process itself or a different process which undermines the functional reserve of the liver such as infection, haemorrhage or electrolyte imbalance.
The actual deterioration in the patient’s state may occur very rapidly - the patient may progress through confusion and stupor into coma in a matter of hours.
This sort of hepatic failure is also called decompensation, referring to the fact that previous problems with liver function had been well compensated

Question 48

Describe liver transplants

Answer 48

Emergency liver transplant is the only therapeutic intervention of proven benefit

Timing/selection of pts is crucial
 Unnecessary transplant
 carries < 10% 1-year mortality
 commits pt to lifelong immunosuppression- can't have a transplant if you are septic
 is expensive 
 wastes a precious graft

Question 49

Summarise liver transplants

Answer 49

5% of all transplants in the UK

5 year survival rate with OLT ranges between 60-80%

No recurrence of disease BUT patient will require life-long immunosuppression

Question 50

Describe the clinical differences of the different classifications of ALF and describe what is meant by sub-fulminant

Answer 50

Sub-fulminant = less rapid (<6 months).
o Clinical differences:
§ Cerebral oedema common in fulminant.
§ Renal failure and portal hypertension common in sub-fulminant.