Diseases of the hepatobiliary system Flashcards
What is the commonest sign of liver disease?
Jaudice
When is jaundice visible?
When bilirubin >40umol/l
What is pre-hepatic jaundice?
Too much bilirubin produced
- Haemolytic anaemia
What is hepatic jaundice?
Too few functioning liver cells
- Acute diffuse liver cell injury
- End stage chronic liver disease
- Inborn errors
What is post hepatic jaudice?
Bile duct obstruction
- stone, stricture, tumour – bile duct, pancreas
What kind of bile is in excess in pre-hepatic jaundice?
Unconjugated – bound to albumin, insoluble, not excreted
- patient notices yellow eyes/skin only
What kind of bile is in excess in hepatic jaundice?
Mainly conjugated,
Soluble
- patient notices yellow eyes and dark urine
What kind of bile is in excess in post-hepatic jaundice?
conjugated - soluble, excreted, but can’t get into gut
- patient notices yellow eyes, pale stool and dark urine
Which liver enzymes leak from hepatocytes?
ALT and AST
What does a mild increase of ALT/AST over a long time indicate?
Chronic liver disease
What do very high levels of ALT/AST indicate?
Severe acute liver disease.
What does Alk Phos leak from?
Bile duct
What does a high alk phos reading indicate?
Obstructive jaundice and chronic biliary disease.
What does raised conjugated bilirubin without extrahepatic duct obstruction indicate?
Disease of hepatocytes or intraheptic bile ducts.
Why might albumin be low?
Has long half life so levels may be low in chronic liver insufficiency.
How are clotting factors measured?
PT and INR
What is INR?
International normalised ratio - ratio of pt’s clotting time to normal control.
Why might PT/INR be prolonged?
Severe liver injury
Obstructive jaundice - can’t absorb fat soluble vitamins
What is the first histopathological sign of obstructive jaundice?
Bile in the liver parenchyma
- jaundice in the skin, patient is yellow
What are the other histopathological signs of obstructive jaundice?
Portal tract expansion
Oedema
Ductular reaction – proliferation of ductules around the edge
Bile salts and
- copper cant get out
- Accumulate in hepatocytes
(bile salts in skin – patient is itchy)
What is the first investigation in someone with jaundice?
USS to check for bile duct dilation.
If ducts not dilated biopsy performed.
What are most non-obstructive cases of jaundice due to?
Acute hepatitis
What is the clinical definition of hepatitis?
Liver enzymes raised, any cause
What is the histopathological defenition of hepatitis?
Inflammation seen on biopsy.
What does the clinical presentation of hepatitis depend on?
The amount of hepatocytes that are injured/killed and how well the remaining ones can regenerate.
What are the commonest causes of acute hepatitis in the UK?
Alcohol
Paracetamol toxicity
What are the other causes of acute hepatitis?
Viral
- A, B & E
Drug induced
Autoimmune
Seronegative (i.e. idiopathic)
What are the histopathological features of mild acute hepatitis?
Lobular disarray
Inflammatory cells
Hepatocytes vary in cells
Spotty necrosis
What are the histopathological features of severe acute hepatitis?
Confluent panacinar necrosis
What is bridging necrosis and where is it seen?
Confluent necrosis of adjacent hepatocytes in a ‘bridge’ between a portal tract and hepatic vein.
Seen in acute hepatitis of intermediate severity
What are the causes of chronic hepatitis?
Immunological injury - virus
- autoimmune
- drugs
Toxic/metabolic injury
- fatty liver disease
- alcohol, non-alcoholic fatty liver disease (NAFLD)
- drugs
Genetic inborn errors
- iron
- copper
- alpha1antitrypsin
Biliary disease
- autoimmune
- duct obstruction
- drugs,
Vascular disease
- clotting disorders
- drugs
What is the pathology of chronic liver disease?
Injury to liver cells, inflammation, formation of scar tissue and regeneration of hepatocytes
- Non-specific features of injury
Specific pathological features depend on the cause of injury
How are biopsies used in liver diease?
To determine the cause of the damage
- specific features, if present
To assess the stage of disease
- how much scarring,
- spectrum from normal to cirrhosis
What are the stages of liver disease?
A normal
B portal fibrosis
C bridging fibrosis
D cirrhosis
What are the features of stage D?
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.
What are the characteristics of the Hep A virus?
Type - Picorna RNA
Route - Faeco-oral
Acute jaundice - common
Chronic hepatitis? - never
Chronic infection worldwide - none
Treatment - none
Prophylaxis - Vaccine Ig
What are the characteristics of the Hep B virus?
Type - Hepadna DNA
Route - parenteral
Acute jaundice - common
Chronic hepatitis? - 10% adults
Chronic infection worldwide - 350m
Treatment - IFN, lamivundine + new ones
Prophylaxis - Vaccine Ig
What are the characteristics of the Hep C virus?
Type - Flavivirus RNA
Route - parenteral
Acute jaundice - uncommon
Chronic hepatitis? - >70%
Chronic infection worldwide - 170m
Treatment - IFN, ribovarin + new ones
Prophylaxis - none
In which infection only would you see hepatitis d?
Only in people with Hep E
What is the epidemiology of Hep E?
Waterborne, increasingly recognised in UK in last few years, zoonosis, pigs
Which viruses also cause hepatitis as part of systemic disease?
EBV
CMV
HSV
What kind of hepatitis is caused by alcohol?
Alcoholic steatohepatitis
What are the histopathological changes seen in alcoholic steahepatitis?
Fatty change
Ballooned hepatocytes with Mallory Bodies
Inflammatory cells
Fibrosis in portal tracts
What is non-alcohol fatty liver disease (NAFLD)?
Same pathological spectrum as alcoholic liver disease
- Steatosis
- steatohepatitis
- cirrhosis
- HCC
What is NAFLD associated with?
Metabolic syndrome
- obesity
- type 2 diabetes
- hyperlipidaemia
- also some drugs
Commonest cause of liver disease.
What is the pathogenesis of NAFLD?
Insulin resistance results from excess of calorie intake over the body’s demands.
Fat is stored in the body in various compartments including the liver - this depends on genetic factors.
If stored in the liver, this is seen as fatty liver or steatosis.
Long term, as a result of continuing excess calories, plus other factors, some people with steatosis develop steatohepatitis.
This is liver cell injury, inflammation and fibrosis due to liver cell stress, when the liver cell mitochondria start to be injured by the oxidative stress of too much energy transfer.
This evolves slowly and is reversible in the early stages – but if continuous for years results in cirrhosis.
The cirrhosis is eventually ‘cryptogenic’ because the microscopic features of fatty liver disease eventually disappear as the liver is completely re-modelled.
What is the classification of drug-induced liver injury?
Intrinsic
- predictable
- anyone taking this drug is likely to get liver damage
- e.g. paracetamol overdose
Idiosyncratic
- rare and unpredictable
- metabolic
- immunological
- e.g. amoxicillin
What ratio is used to determine to classify acute liver injury into hepatic, cholecystatic or mixed?
Ratio of ALT:Alk phos
(x upper limit of normal)
> 5 hepatocellular (hepatitic)
What are the simplified standardised criteria for DILI?
- Onset of abnormal LFTs after intake of drug
- ‘suggestive’ 5-90 days
- ‘compatible’ 90 days - Improvement (50% reduction) in LFTs after stopping drug
- ‘Very suggestive’
What are the hitopathological features of intrinsic hepatotoxicity seen in paracetamol overdose?
Uniform zonal necrosis
No inflammation
Hepatocytes around the portal tracts are spared and able to regenerate the liver back to normal if the toxicity is not too severe and the patient survives
What is the toxic metabolite of paracetamol?
N-acetyl-p-benzoquinone-imine (NAPQI)
What is given to reverse paracetamol overdose?
N-acetyl cystein - restores Glutathione
What is the definition of cirrhosis?
Defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules.
Liver cells still present, but portal vein blood bypasses the sinusoids so the liver cells cannot perform their functions.
Pressure inside the liver increases, portal hypertension
What are the causes of cirrhosis?
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
What does cirrhosis convert to liver into?
A mass of regenerating nodules wrapped by fibrous scar tissue.
What are the complications of cirrhosis?
Structural changes, fibrosis
- Portal hypertension – see below
- Increased blood flow, stiff liver
- Pressure rises in portal vein
- Oesophageal varices
Liver cell failure
- fewer hepatocytes +/- blood bypasses sinusoids
- Synthetic - oedema, bruising, muscle wasting
- Detoxifying – drugs, hormones, encephalopathy,
- Ascites – low albumin, portal hypertension, hormone fluid retention (aldosterone)
Excretion
- Bile - jaundice
- Bile salts – itching
Reticulo-endothelial cells
- Vulnerable to infection
What is alpha 1 antitrypsin?
Alpha 1 antitrypsin
- protein made in the liver excreted into blood
- functions to neutralise proteolytic enzymes, particularly from active polymorphs.
What is alpha 1 antitrypsin deficiency?
This inborn error of metabolism results in abnormal structure of A1AT
- folds wrongly and can’t be excreted from hepatocytes.
- there are many types, the commonest is PiZZ
The accumulated A1AT forms globules of glycoprotein
- stain positive with PAS diastase stain.
This damages liver cells
- may lead to fibrosis and cirrhosis
- very variable, sometimes in childhood, sometimes in adulthood.
What other disease does alpha 1 antitrypsin deficiency play a part in?
The low levels of A1AT in the serum make the patient susceptible to emphysema of the lung, especially if the patient also smokes.
What is haemochromatosis?
- Relatively common abnormality of the HFE gene, the C282Y is the usual severe genotype.
- Leads to a failure of iron absorption regulation, and excess iron is stored in various organs – including liver, pancreas, skin, joints, heart.
- Patients have high serum levels of transferrin, and high transferrin saturation.
- Large amounts of iron in hepatocytes cause liver injury and eventually cirrhosis and high risk of hepatocellular carcinoma.
What stain is used in liver biopsies to detect haemochromatosis?
Perl’s stain
What is the treatment for haemochromatosis?
Frequent venesection
What is Wilson disease?
Too little caeruloplasmin – the copper transport protein in the blood. Copper accumulates in
- liver: cirrhosis
- eyes: Kayser-Fleischer rings
- brain: ataxia, etc
Patients have low serum copper, high urinary copper (24 hour urine collection) and high levels of copper in the liver tissue.
Some patients present with acute liver failure and haemolysis. This is life threatening and an indication for super-urgent liver transplantation.
What stain is used in biopsy to test for copper?
Rhodanine stain
What is the treatment for Wilson disease?
Chelation
What are the systemic effects of liver failure?
Ascites
Muscle wasting
Bruising
Gynaecomastia
Spider naevi
- small clusters of dilated capillary vessels in the skin due to hormone imbalance
Caput medusa
- dilated veins radiating around the umbilicus in patients with severe portal hypertension, due to recanalisation of the embryonic vitelline vein to the umbilicus.
What is portal hypertension?
Increased pressure of blood in the portal veins (
What are the main causes of hypertension?
Pre-sinusoidal
Sinusoidal
Post-sinusoidal
What are the complications of portal hypertension?
Splenomegaly
- low platelets
Oesophageal varices
- haemorrhage
Piles
- perianal
- varices
- most aren’t due to portal hypertension
Part of cause of ascites
What is pre-sinusoidal portal hypertension?
Due to disease of the portal vein or its intrahepatic branches. The liver cell function is well preserved and the patient has problems from oesophageal varices and splenomegaly but not ascites. Pre-hepatic causes can be treated by a shunt procedure to decompress the portal vein into the hepatic vein.
What is sinusoidal portal hypertension?
Due to disease within the liver parenchyma. This is the commonest cause, a result of any of the causes of cirrhosis. Because there is also liver cell insufficiency, the patients also have ascites, (low albumin, disturbed metabolism of aldosterone, fluid regulating hormone) – and so risk developing liver failure if they have a shunt procedure.
What is post-sinusoidal portal hypertension?
The blood can’t flow out of the liver due to obstruction at a level between the intrahepatic branches of the hepatic veins (usually drug induced injury) and the right atrium (e.g. constrictive pericarditis). Budd Chiari syndrome (rare) is thrombosis of the hepatic vein, and is nearly always associated with an pro-coagulant clotting disorder. This causes ascites and an enlarged liver (hepatomegaly). It can usually be successfully treated by stenting the veins and anticoagulation.
What is a major risk factor for hepatocellular carcinoma (HCC)?
Cirrhosis
70% malignant tumours in cirrhotic patients
What percentage of HCC is found in non-cirrhotic patients?
2%
What is the epidemiology of HCC?
Male»female
Increasing incidence in West – obesity, alcohol.
Geographical variation ++ depending on prevalence of viral hepatitis
What are the clinical features of HCC?
- worsening liver function
- weight loss
What surveillance is performed in patients with cirrhosis?
6 monthly ultrasound scan
What protein might be used to detect HCC?
Alpha feto-protein in serum.
- raised in 75% but only 50% non-cirrhotic patients
What is the macroscopic appearance of HCC?
Expansile soft nodules, often green (bile)
What is the distribution of HCC?
Involvement of
- Portal vein 60%
- Hepatic vein 20%
- Bile duct 5%
What is the histopathological appearance of HCC?
Cancer cells look a bit like hepatocytes,
May produce bile = diagnostic
Confirm with immunohistochemistry
What is the prognosis of HCC?
Very poor (
What are the treatment options for HCC?
Surgery - if non-cirrhotic or small, peripheral
Transplant
- 1 tumour
What are the TNM stages for HCC?
pT1
- Solitary tumour without vascular invasion
pT2
- Solitary tumour with vascular invasion or multiple tumours , none more than 5cm in greatest dimension
pT3a
- Multiple tumours, any more than 5cm
pT3b
- Single or multiple tumours of any size involving a major branch of the portal vein or hepatic vein.
pT4
- Tumour(s) with direct invasion of adjacent organs other than the gall bladder or with perforation of visceral peritoneum
What are the early stages of HCC?
pT1 and pT2
Which cancer metastasises to the liver and forms a few large nodules?
Large bowel
Which five cancers form multinodular/infitrative metastases?
Lung
Pancreas
Breast
Stomach
Melanoma
What is ‘the other primary liver cancer’?
Cholangiocarcinoma
- adenocacinoma arising in the bile ducts
What are the two types of cholangiocarcinoma?
Intrahepatic
- From small intrahepatic ducts
- Peripheral, mass forming, presents late
- Risk factor – none or cirrhosis
Perihilar - From large ducts, - Causes obstructive jaundice early - Risk factor: bile duct disease primary sclerosing cholangitis Liver flukes
How much bile is excreted bile the liver per day?
0.5-1 litre per day
Where is bile concentrated?
The gall bladder
What is bile composed of?
bile salts
phospholipids
cholesterol
bilirubin
calcium salts
mucin from peribiliary glands
What are gallstones?
When constituents precipitate.
10-20% adults in UK.
What are the risk factors for gallstones?
Cholesterol stones
- yellow, opalescent
Pigment stones
- small black – in haemolytic anaemia
Mixed stones (most common)
10% contain calcium - visible on plain Xray
What are the complications of gallstones?
Inflammation of the gallbladder (cholecystitis)
Mucocele
Predisposition to carcinoma of the gallbladder
Obstruction of the biliary system resulting in biliary colic and jaundice
Infection of static bile, causing cholangitis and liver abscesses
Gallstone ileus due to intestinal obstruction by a gallstone that has entered the gut through a fistulous connection with the gallbladder
Pancreatitis.
What are the indications for a cholecystectomy?
Pain
Gallstones
Pancreatitis
Gall bladder polyp (rarely)
What are the features of acute cholecystitis?
Duct blocked by stone.
Initially sterile, later infected.
Large, swollen, congested, ulcerated.
Complications – empyema, rupture
What are the features of chronic cholecystitis?
Usually gall stones
Small, fibrotic, stones,
Fibrosis, Rokitansky Aschoff sinuses
What percentage of gall bladder cancers are discovered during routine cholecystectomies?
50%
