Medical Liver Diseases Flashcards
What are the 4 main medical liver diseases?
- jaundice
- acute and chronic hepatitis
- viral
- alcohol, obesity
- drugs
- inherited - haemochromatosis, Wilson’s, alpha-t antitrypsin deficiency
- autoimmune
- cirrhosis
- hepatic failure
When is jaundice visible?
Where is it first visible and how is it classified?
it is visible when bilirubin > 40 umol/l
it is the commonest sign of liver disease
it is first visible in the sclera (white of eye) and is classified according to where the abnormality is in the metabolism of bilirubin
What are the 3 ways of classifying jaundice?
What conditions is each type seen in?
pre-hepatic - too much bilirubin produced:
- haemolytic anaemia
hepatic - too few functioning liver cells:
- acute diffuse liver cell injury
- end stage chronic liver disease
- inborn errors
post-hepatic - bile duct obstruction:
- stone, stricture, tumour in the bile duct or pancreas
What is the first stage in bilirubin metabolism?
- bilirubin-forming molecules (i.e. haem) are taken up by reticuloendothelial cells
- inside these cells, haem oxygenase enzymes break down haem, removing iron and carbon monoxide
- this produces biliverdin
- biliverdin is converted to bilirubin within the reticuloendothelial cell by the enzyme biliverdin reductase
What happens after bilirubin is released from reticuloendothelial cells?
What happens when it enters a hepatocyte?
- bilirubin travels in the blood bound to albumin
- this ensures no bilirubin is excreted in the urine
- at very high concentrations, bilirubin can slowly diffuse into peripheral tissues, where it is toxic
- bilirubin is removed from the circulation in the sinusoids by hepatocytes
- this is a passive process that occurs down a concentration gradient
- when bilirubin enters a hepatocyte, it becomes bound to glucuronyl transferase, which conjugates it ready for excretion
- bilirubin is joined with glucuronic acid in the conjugation process
- small amounts evade this process and become unconjugated bilirubin
What is the purpose of conjugating bilirubin?
the process of conjugation makes the bilirubin water soluble and easier to excrete
in situations where the liver cannot excrete conjugated bilirubin, the kidneys can once plasma concentration exceeds 600umol/L
the kidneys cannot conjugate bilirubin, only excrete it after this process has occurred
What happens to bilirubin that is deconjugated by bacteria in the gut?
bilirubin that is deconjugated by bacteria in the gut is reabsorbed in the colon
this process is more likely when there are bile acids present due to bile salt malabsorption
as a compensatory mechanism in these patients, the body excretes higher concentrations of bile salts and this increases the risk of gallstones
What happens to bilirubin present in the colon?
it is turned into stercobilogens and urobilogens
urobilogens are colourless and stercobilogens give faeces its colour
some urobilogens are absorbed and enter the circulation, where they are removed by the liver and kidneys
Why is bile green?
bilirubin will oxidise back to biliverdin after excretion
What type of bilirubin is present in pre-hepatic, hepatic and post-hepatic jaundice?
What symptoms may the patient notice?
pre-hepatic - too much bilirubin produced:
- unconjugated - bound to albumin, insoluble, not excreted
- patient notices yellow eyes / skin only
hepatic - too few functioning liver cells:
- mainly conjugated - soluble
- patient notices yellow eyes and dark urine
post-hepatic - bile duct obstruction:
- conjugated - soluble, excreted but cannot get into gut
- patient notices yellow eyes, pale stool and dark urine
What liver enzymes are tested for in liver function tests?
What conditions are they high in?
leak from hepatocytes - ALT & AST:
- mild increase for a long time shows chronic liver disease
- very high levels in severe acute liver disease
leak from bile ducts - alkaline phosphatase:
- therefore high in obstructive jaundice and chronic biliary disease
What do the ratios of different enzymes in liver function tests show?
- there may be damage to cells in the liver so that enzymes leak from cells
- there may be enzymes leaking from bile ducts
- relative increase of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) against alkaline phosphatase indicates whether injury is mainly to heptocytes, bile duct cells or both
What other molecules are tested for in liver function tests?
bilirubin:
- usually conjugated with dark urine
albumin:
- low in chronic liver disease
- long half life
clotting factors:
- low in acute liver disease and liver failure
- short half life
What does raised conjugated bilirubin in an LFT indicate?
raised conjugated bilirubin without extrahepatic duct obstruction indicates disease of hepatocytes or intrahepatic bile ducts
What do low levels of clotting factors and albumin in LFTs indicate?
these are proteins manufactured by hepatocytes, so when levels fall this indicates insufficient liver synthetic function
clotting factors are measured by prothrombin time or INR
factors have a short half-life so PT is prolonged just a few days after severe liver injury
poor clotting is seen in patients with obstructive jaundice who cannot absorb fat-soluble vitamins but this is corrected by vitamin K
What is involved in the investigation of jaundice?
- ultrasound scan to check for dilated ducts in obstruction
- only if there are no dilated ducts then a liver biopsy is performed to find out the cause of jaundice
- most (non-obstructive) cases are due to acute hepatitis
What are the histopathological features present in a liver with obstructive jaundice?
What is the first sign?
first sign:
- bile in the liver parenchyma
- jaundice in the skin, patient is yellow
increasing with time:
- portal tract expansion
- oedema
- ductular reaction - proliferation of ductules around the edge of portal tracts
- bile salts and copper can’t get out
- they accumulate in hepatocytes
- bile salts in the skin mean that the patient is itchy
Why is a biopsy performed on the liver to investigate the cause of jaundice?
What would happen if an obstruction causing jaundice was not resolved?
- a patient with jaundice is first investigated with USS to check for bile duct dilatation
- if ducts are not dilated, then liver biopsy may be performed to investigate cause of jaundice
- there are characteristic changes in liver histology that indicate why there is jaundice
- these can distinguish between obstruction to ducts (not always seen on USS) and various patterns of liver cell injury
What features of the liver are shown here?
What is seen on a liver biopsy when someone has obstructive jaundice?
bile pigment is visible in the bile plugs which represent the bile that has been excreted by hepatocytes into intracellular canaliculi
because of low bile flow, it accumulates in the canaliculi where it can be seen
there is also swelling and irregularity of hepatocytes and increased activity of macrophages (Kupffer cells) phagocytosing dead hepatocytes
What portal tract changes are seen on a biopsy in obstructive jaundice?
as time goes on, portal tracts get larger , initially due to swelling (oedema, tissue looks pale)
then ductular reaction (increased number of small bile ducts around the periphery of the tracts) and some associated inflammatory cells including neutrophils
over time, oedema reduces and fibrosis increases
these features combined have a characteristic appearance - “biliary gestalt”
What are the different types of hepatitis?
- viral
- alcohol, obesity
- drugs
- inherited
- haemochromatosis
- Wilson’s
- alpha-t antitrypsin deficiency
- autoimmune
What is hepatitis?
inflammation of the liver (any liver disease that is not neoplastic)
it is used by clinicians for illness with abnormal liver biochemical tests
unless the liver disease is severe, symptoms are mild or non-existent
What is the difference between acute and chronic hepatitis?
acute and chronic refers to the time frame
acute hepatitis:
- has a recent onset and will resolve back to normal as long as the cause does not persist
chronic hepatitis:
- has been present for over 6 months
- results in ongoing liver cell injury and progressive structural liver damage of scarring and remodelling
What is meant by the clinical spectrum of hepatitis?
What determines the severity of the presentation?
the clinical presentation of hepatitis is a consequence of the amount of hepatocytes that are injured/killed and how well the remaining ones can regenerate
at the rare/severe end of the spectrum, hepatocytes die faster than they can be replaced, resulting in rapidly progressing organ failure and possible death
When is liver transplantation needed in hepatitis?
liver transplantation is necessary to save the life of a patient with severe acute liver failure
there is a rapid progression from coagulopathy, encephalopathy (confusion, coma)
What are the clinical effects of acute hepatits due to?
due to liver cell injury, independent of its cause
What are the causes of acute hepatitis?
it is caused by things that damage hepatocytes in the short term
inflammatory injury:
- viral (hepatitis A, B, E), drugs (drug induced liver injury DILI), autoimmune, unknown (‘seronegative’)
- all have a similar pathology spectrum
- if the cause cannot be identified on histology, it is seronegative hepatitis
toxic / metabolic injury:
- e.g. alcohol, drugs (paracetamol)
What is seen in a biopsy of someone with mild acute hepatitis?
the injury and death of individual hepatocytes results in a disordered appearance of the liver cell plates, known as “lobular disarray”
apoptotic hepatocytes produce “spotty necrosis”
hepatocytes vary in size
What is shown here?
severe acute hepatitis with confluent necrosis
whole confluent areas of hepatocytes have died in some or all of the liver
if this affects a high proportion of the liver, the patient will have severe liver failure with risk of death
What is shown here?
How severe is it?
acute hepatitis with bridging necrosis
it is intermediate severity, where there is confluent necrosis of adjacent hepatocytes in a “bridge” between a portal tract and hepatic vein
What features are present in a patient transplanted for acute liver failure?
all of the degrees of liver injury:
- mild hepatitis with lobular disarray
- severe acute hepatitis with confluent necrosis
- acute hepatitis with bridging necrosis
may be seen in different areas of the liver
What is chronic hepatitis defined as?
a persistence of abnormal liver tests for more than 6 months
this is because the cause of the liver injury is not transient
it is chronic liver disease that is caused by something that doesn’t go away
In chronic hepatitis, what is continuing liver damage combined with?
continuing liver damage is combined with the body’s attempts at regeneration of hepatocytes and repair - the wound healing response of angiogenesis and fibrosis
What are the 5 categories of causes of chronic hepatitis?
immunological injury:
- virus, autoimmune, drugs
toxic/metabolic injury:
- fatty liver disease
- alcohol, non-alcoholic fatty liver disease (NAFLD), drugs
- this is the most common group of causes
genetic inborn errors:
- iron, copper, alpha1antitrypsin
biliary disease:
- autoimmune, duct obstruction, drugs
vascular disease:
- clotting disorders, drugs
liver biopsy can usually identify which of these five groups is the cause of chronic liver injury
What are the non-specific features of injury in chronic liver disease?
- injury to liver cells
- inflammation
- formation of scar tissue
- regeneration of hepatocytes
specific pathological features depend on the cause of injury
How is chronic liver disease diagnosed and staged?
liver biopsy is used in diagnosis to determine the cause of the damage and to look for specific features
it is also used to assess the stage of disease by looking at the extent of scarring
the stage is on a continuous spectrum from normal to cirrhosis
How does staging work as a measurement of the progression of chronic liver disease?
during any chronic liver disease, scarring gradually increases and starts to link vascular structures (bridging)
this eventually transforms the liver tissue into separate nodules
the end stage of this is cirrhosis
What is meant by remodelling in chronic liver disease?
How quickly does it progress?
remodelling results in bands of fibrosis that bridge between portal tracts and hepatic veins
this progression happens in all causes of chronic liver disease, although the rate of progression is very variable
(few months to several decades)
What happens once remodelling becomes complete?
How does this affect the cirrhotic liver?
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 is inefficient in its metabolic function, even though it is normal size or larger
what type of viruses are the main cause of viral hepatitis?
hepatotrophic viruses specifically infect the hepatocytes causing liver disease
- A, B and C
- D (delta) is only seen in people with B
- E is waterborne and contracted through zoonosis from pigs
other viruses cause hepatitis as part of systemic disease
EBV, CMV, HSV - usually immunocompromised host
Complete the table for the different hepatotrophic viruses
What is the difference between grade and stage in the pathology of chronic hepatitis?
What method is used to work this out?
liver biopsy is used to find out the severity of chronic viral hepatitis
grade of disease:
- estimation of how much inflammatory injury is currently going on (active injury)
- this can fluctuate over time
stage of disease:
- estimation of the amount of scarring, remodelling and nodular regeneration of the liver
- how far has the disease progressed along a spectrum from normal to cirrhosis?
What are the following Ishak stages of fibrosis?
What is the characteristic range of liver pathology caused by alcohol?
What patients have a similar pathology of liver disease?
alcohol causes a spectrum of:
- fatty change
- alcoholic steatohepatitis
- cirrhosis
this depends on the dose and susceptibility
many patients with metabolic syndrome (obesity, type 2 diabetes, etc.) have a similar pathology of liver disease called ‘non-alcoholic fatty liver disease (NAFLD)’
What other factor, alongside alcohol, leads to large increases in deaths from liver disease?
the combination of risk factors of alcohol and obesity is synnergistic
these lifestyle factors account for a big increase in deaths from liver disease
What are the features of steatohepatitis visible on biopsy?
- fatty change (steatosis)
- ballooned heptocytes with Mallory Bodies
- inflammatory cells
some patients with alcoholic liver injury may just show fatty change
this is a reversible stage of liver injury that may or may not progress to steatohepatitis
What is the arrangement of collagen like in steatohepatitis?
What stain is used to visualise it and how does it change as disease progresses?
Van Gieson stain is used to stain collagen red
the collagen surrounds the hepatocytes like chicken wire
this gradually increases, as well as portal tract fibrosis
the cirrhosis from alcoholic liver disease is characteristically very fibrotic with small nodules of hepatocytes
What is the pathological spectrum of NAFLD like?
What is it associated with and how is it treated?
- it has the same pathological spectrum as alcoholic liver disease
- steatosis, steatohepatitis, cirrhosis, HCC
- associated with metabolic syndrome
- obesity, type 2 diabetes, hyperlipidaemia, also some drugs
- treatment addresses the causes of metabolic syndrome
What actually causes steatosis in NAFLD?
insulin resistance results from excessive 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 it stored in the liver, this leads to “fatty liver” or steatosis
What does steatosis progress to if intervention is not made in NAFLD?
long term, as a result of continuing excess calories, 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 results in cirrhosis eventually
What is the main risk associated with cirrhosis?
Why is it “cryptogenic”?
the cirrhosis is eventually “cryptogenic” because the microscopic features of fatty liver disease eventually disappear as the liver is completely remodelled
there is a risk of hepatocellular carcinoma developing, as in any cause of cirrhosis
What is shown here?
cirrhotic liver with hepatocellular carcinoma
What is meant by drug induced liver injury (DILI)?
it is iatrogenic - induced inadvertently
- by a doctor
- or by medical treatment
- or diagnostic procedures
drugs can cause any pattern of liver injury
What are the 2 different ways of classifying DILI?
intrinsic:
- anyone taking this drug is likely to get liver damage
- e.g. paracetamol
idiosyncratic:
- depends on individual susceptibility (metabolic + immunological)
- reactions can be severe
How is clinio-pathological diagnosis of DILI made?
raised liver enzymes:
- the ratio of ALT : alk phos is used to classify the type of acute liver injury into:
- hepatocellular
- cholestatic
- mixed
biopsy:
- used to exclude other causes of liver injury
- alcohol, NAFLD
- acute presentation of underlying chronic liver disease
- autoimmune
- biliary
- vascular
What drugs can cause liver injury?
How does it improve?
- any drug can cause liver injury
- the same drug can cause different injury in different patients
- the time of onset is variable
- it improves on stopping the drug, so usually causes acute but not chronic liver disease, but not always
What is the commonest cause of acute liver failure in the UK?
paracetamol toxicity
How can paracetamol toxicity damage to the liver be recognised on biopsy?
paracetamol toxicity results in necrosis of a high proportion of hepatocytes in a predictable, zonal distribution, without any 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 causes haemochromatosis?
it is a relatively common abnormality of the HFE gene, the C282Y is the usual severe genotype
this leads to an inborn error of iron metabolism and “bronzed diabetes”
What organs are affected in haemochromatosis and why?
there is a failure of iron absorption regulation and excess iron is stored in various organs
- liver - cirrhosis
- pancreas - diabetes
- skin - pigmented
- joints - arthritis
- heart - cardiomyopathy
patients have high serum levels of transferrin, and high transferrin saturation
What happens when there are large amounts of iron in hepatocytes in haemochromatosis?
large amounts of iron in hepatocytes causes liver injury and eventually cirrhosis, with high risk of hepatocellular carcinoma
What stain is used on liver biopsies to recognise haemochromatosis?
What is the treatment?
liver biopsies are stained with Perl’s stain for iron
large amounts of iron prompt genetic investigations for haemochromatosis
it is treated with frequent venesection to deplete the excess iron and prevent the progression of liver disease
family members are screened using blood tests
What is Wilson disease?
it is a much rarer genetic disease of copper metabolism
it results in too little caeruloplasmin - the copper transport protein in the blood
this leads to patients having low serum copper, high urinary copper and high levels of copper in the liver tissue
Where does copper accumulate in Wilson disease?
copper accumulates in:
- liver - cirrhosis
- eyes - Kayser-Fleischer rings
- this is a ring around the iris that can be seen by slit lamp investigation
- brain - ataxia
What stain is used on a liver biopsy to identify Wilson disease?
How is it treated?
Rhodanine stain is used which turns copper brown
treatment is given to chelate copper and enhance its extraction
some patients present with acute liver failure and haemolysis
this is life-threatening and an indication for super-urgent liver transplantation
What is alpha 1 antitrypsin?
What happens in alpha 1 antitrypsin deficiency?
it is a protein made in the liver excreted into the blood where it functions to neutralise proteolytic enzymes, particularly from active polymorphs
the inborn error of metabolism results in abnormal structure of A1AT, which folds wrongly and can’t be excreted from hepatocytes
(the most common type is PiZZ)
What stain is used to identify alpha 1 antitrypsin deficiency?
How can this damage liver cells?
the accumulated A1AT forms globules of glycoprotein that stain positive with PAS diastase stain
accumulated A1AT damages liver cells and may lead to fibrosis and cirrhosis
What is the consequence of low levels of A1AT in the serum?
there is a failure to inactivate neutrophil enzymes
this makes the patient susceptible to emphysema of the lung, especially if the patient also smokes
What is used in the diagnosis of autoimmune hepatitis?
auto-antibodies:
- anti-nuclear, smooth muscle, etc.
- raised IgG, ALT, other autoimmune diseases
liver biopsy:
- plasma cells, interface hepatitis
What are autoimmune liver diseases?
autoimmune liver diseases are chronic liver diseases due to 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 disease)
Is autoimmune hepatitis more common in men or women?
How is it diagnosed and treated?
more common in women, and can present as acute or chronic hepatitis
diagnosis is based in autoantibodies, raised IgG and raised ALT
liver biopsy is important for diagnosis and shows prominent interface hepatitis with lots of plasma cells
treatment is immunosuppression with the aim of preventing progression of fibrosis to cirrhosis
What do chronic biliary diseases result in?
How are they treated?
both chronic biliary diseases result in gradual destruction of the intrahepatic bile ducts
leading to chronic cholestasis, itching, fatigue and eventually cirrhosis
they can be treated with urso-deoxycholic acid
this is a bile salt analogue which delays disease progression
How is primary biliary cholangitis diagnosed?
What does it look like?
diagnosis:
- anti-mitochondrial antibodies and raised alkaline phosphatase / IgM
bile duct injury:
- there are bile duct granulomas at early stage, then ductopenia and cirrhosis
- granulomatous inflammation leads to destruction of bile ducts
What disease is primary sclerosing cholangitis (PSC) associated with?
it is commoner in men and most patients (90%) also have ulcerative colitis
5% of patients with UC will develop PSC
How is primary sclerosing cholangitis (PSC) diagnosed?
What would a liver biopsy look like?
many patients have pANCA antibodies, but diagnosis is by imaging
a characteristic “pruned tree” appearance is seen on cholangiogram
liver biopsy shows chronic cholestatic changes (periductal onion skin fibrosis)
and then ductopenia (disappearing bile ducts - no longer a duct in every portal tract) and cirrhosis
What is the main risks associated with cirrhosis?
hepatocellular carcinoma
these tumours are often inoperable and only treatable via liver transplant
What is the definition of cirrhosis?
How does this affect pressure inside the liver?
a diffuse hepatic process characterised by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules
liver cells are still present, but portal vein blood bypasses the sinusoids so liver cells cannot perform their functions
pressure inside the liver increases - portal hypertension
How long does it take for cirrhosis to develop?
cirrhosis is the end point of chronic liver disease
it develops over months - decades
the rate of progression is very variable
What are the causes of cirrhosis?
cirrhosis occurs when the cause does not go away
- 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 happens to the liver in cirrhosis?
How does this look microscopically?
the liver is converted into a mass of regenerating nodules wrapped by fibrous scar tissue
microscopically there are regenerative nodules of hepatocytes surrounded by sheets of fibrous tissue
How does fibrosis progress in chronic liver disease?
fibrosis encircles nodules of regenerating hepatocytes
Does a patient have symptoms prior to cirrhosis?
Why do complications occur in cirrhosis?
cirrhosis is the end stage of chronic liver disease
the patient may not have been aware of any symptoms, and may be diagnosed with liver disease for the first time from complications of cirrhosis
complications of cirrhosis are a result of the pathological processes in the liver
What structural changes bring about complications of cirrhosis?
- fibrosis leads to increased liver stiffness and portal hypertension
- there is increased blood flow and a stiff liver, meaning pressure rises in the portal vein
- bleeding oesophageal varices cause massive haemorrhage
How does liver cell failure bring about complications of cirrhosis?
inefficient liver cell function due to shunting of blood (bypasses sinusoids) and fewer hepatocytes results in liver cell failure
- synthetic - oedema, bruising, muscle wasting
- detoxifying - drugs, hormones, encephalopathy
- ascites - low albumin, portal hypertension, hormone fluid retention (aldosterone)
- problems with excretion of bile (jaundice) and bile salts (itching)
Why are patients with cirrhosis more vulnerable to infection?
due to failure of reticuloendothelial cells
the liver is an important site of immune response
What are the 2 different types of hepatic failure?
What are the signs and symptoms?
acute hepatic failure:
- rare
- severe rapid liver injury
chronic hepatic failure:
- end stage chronic liver disease
signs & symptoms:
- ascites
- muscle wasting
- bruising
- gynaecomastia
- spider naevi
- caput medusae - variceal umbilical vein collaterals
When deciding whether to perform a liver biopsy, what factors are considered?
the benefits of a definite diagnosis (rather than presumed from non-invasive investigations) is balanced against risk of haemorrhage and puncture of other organs
liver biopsy is performed under ultrasound guidance and the risk of medical liver biopsy is very low
What is the purpose of performing a liver biopsy?
it can provide information on:
- stage of disease
- cause of disease
- current activity
- response to treatment (if previous biopsies)
