Medical Liver Disease Flashcards
How is unconjugated bilirubin produced? Where?
Bilirubin is produced by RBC breakdown in the spleen (unconjugated)
Where and how is bilirubin conjugated? What is the purpose of this?
Bilirubin is conjugated in the liver with glucuronic acid to make it soluble and excreted (this is also how drugs are metabolised)
Once that bilirubin reaches the gut, what happens to it?
- Bacteria unconjugate the majority of it so it cannot be absorbed
- BUT some bilirubin is re-absorbed from the gut (along with some bile acids)
What is eneterohepatic circulation?
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver.
What is the commonest sign of liver disease?
Jaundice
At what levels of bilirubin does jaundice become visible?
>40umol/l
Where is jaundice first visible?
First visible in sclera (white of eye)
How is jaundice classified?
Classified according to where the abnormality is in the metabolism of bilirubin;
- Pre-hepatic
- Hepatic
- Post-hepatic
What occurs during pre-hepatic jaundice? What is the most common cause of this?
In pre-hepatic jaundice, there is excess production of bilirubin that overtakes the ability of liver to conjugate the bilirubin and excrete into the gut. –> haemolytic anaemia is most common cause (RBCs broken down excessively)
What is Gilbert’s syndrome? What type of jaundice does it cause?
Gilbert’s syndrome is a mild liver disorder in which the liver does not properly process bilirubin (harmless). Occasionally a slight yellowish color of the skin or whites of the eyes may occur. Other possible symptoms include feeling tired, weakness, and abdominal pain.
Pre-hepatic jaundice (too much bilirubin for liver to deal with)
What occurs during hepatic jaundice?
There is dysfunction of the hepatic cells; liver loses the ability to conjugate bilirubin (often too few functioning cells).
This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture’.
What are the 3 major causes of a loss of functioning liver cells causing hepatic jaundice?
- Acute diffuse liver cell injury
- End stage chronic liver disease
- Inborn errors of metabolism
What causes post-hepatic jaundice?
Bile duct obstruction by a stone, stricture, tumour, narrowing (e.g. bile duct, pancreas).
Describe the bilirubin in pre-hepatic jaundice. What are the symptoms?
- This bilirubin is unconjugated (has not reached liver yet) so is insoluble and instead is bound to albumin
- It cannot be excreted by kidneys/liver so causes yellow eyes/skin only
Describe the bilirubin in hepatic jaundice. What are the symptoms?
- Bilirubin is mainly conjugated so is water soluble
- Symptoms; yellow eyes/skin and dark urine
Describe the bilirubin in post-hepatic jaundice. What are the symptoms?
- Bilirubin is conjugated so is soluble and can be excreted
- BUT bilirubin cannot get out of the bile duct into the gut
- Symptoms; yellow eyes/skin, dark urine and pale stools (as bilirubin that would normally give colour to stools is no longer there)
In which type of jaundice would you see dark urine?
Hepatic AND post-hepatic
In which type of jaundice would you see pale stools?
In post-hepatic jaundice
In which type of jaundice would you see yellow eyes/skin only?
Pre-hepatic jaundice
What are the 4 main components of liver function tests (LFTs)?
- Bilirubin (conjugated and unconjugated)
- Liver enzymes (this is a ‘damage’ test rather than a ‘function’ test)
- Albumin
- Clotting factors
What can the bilirubin result from the LFT indicate?
Gives idea if pre-hepatic, hepatic or post-hepatic cause depending on if bilirubin is conjugated or unconjugated
What does a rise in liver enzymes indicate?
Liver damage/disease –> released by dead/dying liver cells
What are the 2 main types of liver enzymes tested for in LFTs?
- Those that leak from hepatocytes; ALT, AST aminotransferases
- Those that leak from bile ducts; Alk phos
Which liver enzymes leak from hepatocytes?
ALT, AST aminotransferases
Which liver enzymes leak from bile ducts?
Alk phos
What can the relative increase of Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) vs Alkaline phosphatase indicate?
Indicates whether injury is mainly to hepatocytes, bile duct cells or both
What would a mild increase in ALT/AST aminotransferases indicate?
Chronic liver disease
What would very high levels of ALT/AST aminotransferases indicate?
Severe acute liver disease
What would raised Alk phos levels indicate?
Obstructive jaundice and chronic biliary disease
Describe albumin levels in chronic liver disease
Low
What are clotting factors and albumin synthesised by? How does liver function affect their levels?
Clotting factors and albumin are proteins manufactured by hepatocytes - levels fall when insufficient liver synthetic function
What can cause low albumin levels?
- Chronic liver insufficiency
- Insufficient intake due to poor diet or malabsorption
- Increased urinary excretion due to leaky glomeruli = nephrotic syndrome
Describe half life of albumin?
Long
How are levels of clotting factors affected by liver disease? Why?
- Short half life –> low levels in acute liver disease and liver failure
- The factors have a short half life so PT is prolonged after just a few days of severe liver injury
Why is poor clotting also seen in patients with obstructive jaundice?
Malabsorption of vitamin K results in hypoprothrombinaemia and a fall in the concentration of the other vitamin K-dependent pro- and anticoagulation factors.
I.e. lack of bile –> vitamin K not absorbed –> lack of clotting factors
After the initial LFTs, what 2 other investigations can be done?
- Ultrasound scan to check for dilated ducts in obstruction
- Only if no dilated ducts do a liver biopsy to find out the cause of jaundice
What are most non-obstructive jaundice cases caused by?
Acute hepatitis
What is the first histopathological feature in a liver with obstructive jaundice?
Bile in the liver parenchyma (liver looks green)
Which other histological features become apparant over time in obstructive jaundice?
- Portal tract expansion
- Oedema
- Ductular reaction – proliferation of ductules around the edge of portal tracts
- Bile salts and copper can’t get out
- Accumulate in hepatocytes
- Bile salts in skin = itch
What characterises a ductular reaction?
Characterised by the proliferation of reactive bile ducts induced by liver injuries (pathologically recognised as bile duct hyperplasia).
What causes an ‘itch’ in obstructive jaundice?
Bile salts accumulating in skin
What is hepatitis?
Inflammation of the liver causing raised liver enzymes (of any cause)
What defines acute vs chronic hepatitis?
- Acute hepatitis –> Acute liver injury caused by something that goes away
- Chronic hepatitis –> Chronic liver disease caused by something that doesn’t go away and features result from balance of damage and attempts at repair
Clinical presentation of acute hepatitis?
Wide clinical sepctrum; asymptomatic, malaise, jaundice, coagulopathy, encephalopathy, death
What does that lasting effect of acute hepatitis depend on?
Depends on how many hepatocytes are damaged at once, and how good the liver is at regenerating – can lose up to 40/50% of liver cells in healthy adult liver and it can regenerate back to it’s normal mass within weeks
What are the 4 major causes of acute hepatitis?
- Viral hepatitis
- Drug induced hepatitis
- Autoimmune hepatitis
- Unknown cause (seronegative)
What is an acidophil body?
An acidophilic (eosinophilic / pink-staining on H&E) globule of cells that represents a dying hepatocyte often surrounded by normal parenchyma.
What are the 5 major categories of causes of chronic hepatitis?
- Immunological injury - virus, autoimmune, drugs
- Toxic/metabolic injury - fatty liver disease (alcoholic or non-alcoholic), drugs
- Genetic inborn errors - iron, copper, alpha 1 antitrypsin
- Biliary disease - autoimmune, duct obstruction, drugs
- Vascular disease - clotting disorders, drugs
Clinically ‘chronic hepatitis’ is a persistence of abnormal liver tests for how long?
More than 6 months
What is the most common category of causes of chronic hepatitis?
Toxic/metabolic injurys - fatty liver disease, drugs
Which test is often used to identify which of these 5 categories is the cause of chronic hepatitis?
Liver biopsy
Describe the progression of fibrosis in chronic liver disease
- Remodelling results in bands of fibrosis that bridge between portal tracts and hepatic veins (portal –> bridging fibrosis)
- Gradually remodelling becomes complete, and hepatocytes form nodules surrounded by fibrous tissue
- Portal blood entering the liver can flow through vessels in the fibrous tissue, and not percolate through sinusoids
- The cirrhotic liver therefore is inefficient in its metabolic function, even though it is or normal size or larger
Despite the cirrhotic liver being normal or even of a larger size, why is it ineffective in its metabolic function?
Portal blood entering the liver can flow through vessels in the fibrous tissue, and not percolate through sinusoids.
Which forms of hepatitis are bloodborne?
B and C
What are the hepatotrophic viruses?
- A, B, C, E
- D = only in people with Hep B
Which other viruses can cause hepatitis as part of systemic disease?
EBV, CMV, HSV (usually immunocompromised host)
How is hepatitis E transmitted?
- Is a waterborne virus
- Spread through contact with the faeces or vomit of an infected person
- Also linked to undercooked pork and pork products (zoonosis)
For Hep A,
- transmission?
- does it cause acute jaundice?
- can it progress to chronic hepatitis?
- treatment?
- prophylaxis?
- faeco-oral, food/water
- jaundice common
- does NOT progress to chronic hepatitis
- none (mild)
- vaccine, Ig
For Hep B,
- transmission?
- does it cause acute jaundice?
- can it progress to chronic hepatitis?
- treatment?
- prophylaxis?
- parenteral, maternal, IVDA
- jaundice common
- 10% progress to chronic
- treatment required
- vaccine
For Hep C,
- transmission?
- does it cause acute jaundice?
- can it progress to chronic hepatitis?
- treatment?
- prophylaxis?
- parenteral, contaminated blood, IVDA
- jaundice uncommon
- >70% progress to chronic
- treatment required
- no vaccine
Does hep A cause chronic hepatitis?
No
Liver biopsy is used to find out the severity of chronic viral hepatitis. What are the two components of this?
- Grade of disease
- Stage of disease
What does the grade of the disease from a liver biopsy tell you?
An estimation of how much inflammatory injury is currently going on (can change over time)
What does the stage of the disease from a liver biopsy tell you?
A-n estimation of the scarring, remodelling and nodular regeneration of the liver (fibrosis) – how far has the disease progressed along a spectrum from normal to cirrhosis?
How can alcohol affect the liver?
- Fatty change (steatosis)
- Alcoholic steatohepatitis
- Cirrhosis
Depends on dose and susceptibility
Significant driver of mortality from liver disease
What diseases can cause non-alcoholic fatty liver disease (NAFLD)?
Many patients with metabolic syndrome (obesity, type 2 diabetes, etc)
What is steatohepatitis?
Steatohepatitis is a type of fatty liver disease, characterised by inflammation of the liver with concurrent fat accumulation in liver.
What 4 features would a liver biopsy show in steatohepatitis?
- Fatty change (steatosis)
- Ballooned hepatocyte with Mallory Body
- Inflammatory cells
- Collagen surrounding liver cells
What are Mallory bodies?
Cytoplasmic hyaline inclusions of hepatocytes (indicate alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), cholestatic liver diseases, primary biliary cirrhosis (PBC) etc)
What is the pathological spectrum of non-alcoholic fatty liver disease?
- Same pathological spectrum as alcoholic liver disease
- Steatosis –> steatohepatitis –> cirrhosis –> HCC
What condition is NAFLD associated with?
Metabolic syndrome” – obesity, type 2 diabetes, hyperlipidaemia, also some drugs
What is now recognised to be the commonest cause of liver disease?
NAFLD
Treatment of NAFLD?
Address the causes of metabolic syndrome
Define steatosis
Fatty change; abnormal retention of fat (lipids) within a cell or organ.
Steatosis vs steatohepatitis?
Steatosis (fatty liver) is an accumulation of fat in the liver. When this progresses to become associated with inflammation, it is known as steatohepatitis.
How is drug-induced liver injury (DILI) typically caused?
Iatrogenic;
- by a doctor
- or by medical treatment
- or diagnostic procedures
Intrinsic DILI vs idiosyncratic DILI?
Intrinsic DILI –> liver toxicity induced by a drug in a predictable and dose-related manner e.g. paracetamol
Idiosyncratic DILI –> occurs less frequently, is associated with a less consistent dose-toxicity relationship and a more varied presentation (often metabolic or immunological)
Same drug can cause different injury in different patients!
What is the commonest symptoms of DILI?
Jaundice
Does DILIu sually cause acute or chronic liver disease?
Acute - improves on stopping drug
Which aspects of DILI should you be sure to ask about in a patient’s history?
Good history of all drugs including over the counter and “herbal” remedies
What is the commonest cause of acute liver failure in the UK?
Paracetamol toxicity
How is paracetamol metabolised?
- Metabolised by liver
- 95% of metabolites are benign
- 5% of metabolites are toxic
- Metabolites conjugated with glutathione by the liver
- Then excreted
How does paracetamol overdose affect the liver?
- Overdose –> run out of glutathione
- Cannot conjugate NAPQI (toxic metabolite of paracetamol) so it builds up –> toxic effect on liver
Treatment for paracetamol overdose?
N-acetylcysteine (if given <8 hours of overdose)
Clinical presentation of liver failure due to paracetamol overdose?
- 0-24h –> Mild symptoms
- Nausea, vomiting , sweating
- Jaundice maybe
- 24-72h –> Increasing liver cell death
- 3-5 days –> Massive necrosis, liver failure and death
- Can cause encephalopathy
- Can cause coagulopathy
Which hepatocytes are affected first in paracetamol overdose? Why?
- Zone 3 hepatocytes due to high levels of P450 enzymes here (so this is where toxic NAPQI builds up)
- Also these hepatocytes are furthest from blood supply
What is haemochromatosis?
An inborn error of metabolism involving a a failure of iron absorption regulation causing excess iron to be stored in various organs – including liver, pancreas, skin, joints, heart.
If iron builds up (as in haemochromatosis), how does this affect;
- liver
- pancreas
- skin
- joints
- heart
- cirrhosis
- diabetes
- pigmented skin
- arthritis
- cardiomyopathy
Which gene is often implicated in haemochromatosis?
HFE gene
Treatment of haemochromatosis?
Venesection - to deplete iron stores to normal
What is transferrin?
Transferrin is a blood-plasma glycoprotein which transports iron through the blood .
Transferrin levels in haemochromatosis?
- Patients have high serum levels of transferrin
- High transferrin saturation (with iron)
What is Wilson’s disease?
An inborn error of copper metabolism causing copper to accumulate in the body
How does Wilson’s disease affect the;
a) liver
b) eyes
c) brain
a) cirrhosis
b) kayser fleischer rings
c) ataxia etc
What are Kayser-Fleischer rings?
Dark rings that appear to encircle the iris due to excess copper
Investigations for Wilson’s disease?
Patients have low serum copper, high urinary copper (24 hour urine collection) and high levels of copper in the liver tissue.
Treatment for Wilson’s disease?
Chelate copper and enhance its excretion (eg penicillamine)
What are the 3 most common inherited liver diseases?
- Haemochromatosis
- Wilson’s disease
- Alpha 1 antitrypsin deficiency
What is alpha 1 antitrypsin?
A protein made in the liver excreted into blood where it functions to neutralise proteolytic enzymes, particularly from active polymorphs
What occurs in alpha 1 antitrypsin deficiency?
- Abnormal structure of A1A1 - folds wrongly and can’t be excreted from hepatocytes
- Accumulates in liver cells and injures them – cirrhosis
- Its insufficiency in the blood can then lead to failure to inactivate neutrophil enzymes –> can cause emphysema
How can A1AT deficiency lead to emphysema?
Insufficient A1AT in blood –> failure to inactivate neutrophil enzymes –> emphysema (especially in smokers)
Is autoimmune liver disease more common in males or females?
Females
What occurs in autoimmune hepatitis?
Disturbance of the immune system with recognition of ‘self antigens’ leading to chronic inflammation and destruction of hepatocytes (autoimmune hepatitis) or bile ducts (chronic biliary diseases).
Which autoantibodies can cause autoimmune liver disease?
Anti-nuclear, smooth muscle etc
Investigations for autoimmune liver disease?
- Auto-antibodies (anti-nuclear, smooth muscle, etc.)
- Raised IgG
- Raised ALT
- Other autoimmune diseases
Liver biopsy results in autoimmune liver disease?
Liver biopsy is important for diagnosis, and characteristically shows prominent interface hepatitis with lots of plasma cells.
What is interface hepatitis?
Necrosis of the limiting plates, by inflammatory cells. It may be identified as actual necrosis of cells or by irregularity of the limiting plates which is caused IOS’s hepatocytes and replacement with inflammatory cells and/or fibrosis.
Treatment of autoimmune liver disease?
Immune suppression
Which 2 autoimmune diseases affect the bile ducts?
- Primary biliary cholangitis (PBC)
- Primary sclerosing cholangitis
Who is PBC most commonly seen in?
Middle aged women
Which autoantibodies are present in PBC?
Anti-mitochondrial antibodies
Diagnosis of PBC?
- Anti-mitochondrial antibodies
- Elevated alkaline phosphatase
What occurs during PBC?
- Anti-mitochondrial antibodies
- Granulomatous inflammation leads to destruction of bile ducts (ductopenia) and cirrhosis
Who is PSC more common in?
Men
What disease is PSC associated with?
Associated with ulcerative colitis (90%) BUT only 5% patients with ulcerative colitis will develop PSC
Which autoantibodies are present in PSC?
pANCA antibodies (anti-neutrophil)
Liver enzyme levels in PSC?
Raised alk phos
Imaging result in PSC?
- ‘Pruned tree’ on biliary imaging
- Periductal “onion skin” fibrosis
- Chronic cholestatic changes and ductopenia and cirrhosis
Define cirrhosis
Diffuse hepatic process characterised by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules.
Why does the function of hepatocytes decrease in cirrhosis?
- Liver cells still present, but portal vein blood bypasses the sinusoids so the hepatocytes cannot perform their function
- And often fewer liver cells (240 billion à 172 billion)
How does cirrhosis affect pressure inside the liver? What does this cause?
Pressure inside the liver increases causing portal hypertension.
Causes of cirrhosis?
Cirrhosis is the end stage of all chronic liver disease.
- Alcohol
- Non-alcoholic steatohepatitis (metabolic syndrome)
- Chronic viral hepatitis – B, C
- Autoimmune liver disease – autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis
- Metabolic – iron, copper, alpha 1 antitrypsin
Microscopic features of cirrhosis?
- Regenerative nodules of hepatocytes
- Surrounded by sheets of fibrous tissue
Structural changes in the liver (fibrosis) leads to portal hypertension. What are the effects of this?
- Increased blood flow (speed and pressure), stiff liver
- Pressure rises in portal vein
- Oesophageal varices / haemorrhoids/ caput medusa
- Bleeding oesophageal varices can cause massive haemorrhage
What are the danges of oesophageal varices?
Bleeding oesophageal varices can cause massive haemorrhage.
Why can portal hypertension lead to oesophageal varices?
High blood pressure in the portal vein (portal hypertension) pushes blood into surrounding blood vessels, including vessels in the esophagus.
What are caput medusae?
A network of painless, swollen veins around your bellybutton caused by portal hyertension
Why can cirrhosis cause oedema?
Synthetic function of liver fails –> reduced albumin –> oedema
Why can cirrhosis cause bruising?
Liver failure –> lack of clotting factors
Why can cirrhosis cause muscle wasting?
Endocrine changes
Why can cirrhosis cause encephalopathy?
Loss of detoxifying ability of liver –> toxic metabolites build up in blood
Why can cirrhosis cause ascites?
- Low albumin
- portal hypertension
- hormone fluid retention (aldosterone)
Why can cirrhosis cause jaundice?
Bilirubin build up
Why can cirrhosis cause itching?
Build up of bile salts
Why can cirrhosis cause vulnerability to infection?
Loss of reticulo-endothelial cells
What is acute hepatic failure?
Rare - severe rapid liver injury
Symptoms of chronic hepatic failure (end stage liver disease)?
- Ascites
- Muscle wasting
- Bruising
- Gynaecomastia
- Spider naevi
- Varices, Caput medusae = variceal umbilical vein collaterals
What structural changes occur in chronic liver failure?
Fibrosis;
- Portal hypertension
- Increased blood flow, stiff liver
- Pressure rises in portal vein
- Oesophageal varices
- Caput medusae
How does chronic liver disease affect liver cells?
Liver cell failure –> fewer hepatocytes +/- blood bypasses sinusoids
- Synthetic - oedema, bruising, muscle wasting
- Detoxifying –hormones – gynaecomastia
- Encephalopathy – ‘liver flap’
- Ascites
- Excretion (especially chronic biliary disease)
- Bile - jaundice
- Bile salts – itching
Why does jaundice lead to dark urine?
- Only jaundice involving conjugated bilirubin leads to dark urine (i.e. not pre-hepatic jaundice)
- Conjugated bilirubin is water soluble and is excreted in the urine, giving it a dark colour (bilirubinuria).
Which antibody is raised in autoimmune hepatitis?
IgG
What is characterised by interface hepatitis?
Autoimmune hepatitis
What is the signature autoantibody of primary biliary cholangitis (PBC)?
Anti-mitochondrial autoantibodies (AMA)
