Rarer Causes of Cirrhosis Flashcards
What is primary biliary cirrhosis?
(also known as primary biliary cholangitis)
- the immune system attacks the small bile ducts in the liver
- there is obstruction to the outflow of bile, resulting in cholestasis
- the back-pressure of bile obstruction eventually leads to fibrosis, cirrhosis + liver failure
What 3 factors build up in the blood in primary biliary cirrhosis?
- bile acids
- cholesterol
- bilirubin
- they are usually secreted through the bile ducts into the intestines
- they build up in the blood when there is an obstruction to their outflow
What is the result of increased bile acids in the blood?
pruritis
What is the result of raised bilirubin in the blood?
jaundice
What is the result of raised cholesterol in the blood?
- xanthelasma - cholesterol deposits in the skin
- xanthomas - larger deposits of cholesterol in the skin / tendons
- cholesterol deposits in blood vessels, increasing the risk of cardiovascular disease
What is the consequence of a lack of bile acids in the gut?
- bile acids aid the gut in digesting fats
- a lack of bile acids results in malabsorption of fats
- steatorrhoea occurs as a result
- steatorrhoea = greasy, fatty stools
the stools are also pale in colour due to a lack of bilirubin, which usually gives them a dark colour
What is the typical presentation of primary biliary cirrhosis?
- pruritis
- xanthelasma / xanthomas
- steatorrhoea / pale stools
- fatigue
- GI disturbance / abdominal pain
- jaundice
- signs of cirrhosis / liver failure (e.g. ascites, spider naevi, splenomegaly)
What are the associations of primary biliary cirrhosis?
- middle-aged women
- rheumatoid conditions
- other autoimmune diseases (e.g. thyroid / coeliac)
rheumatoid conditions = RA, Sjogren’s syndrome, systemic sclerosis)
How is primary biliary cirrhosis diagnosed?
- LFTs
- autoantibodies
- ESR / IgM are both raised
- liver biopsy (used for diagnosis and staging of disease)
What do LFTs show in primary biliary cirrhosis?
- ALP is the first liver enzyme to be raised
- other liver enzymes + bilirubin are raised in later disease
ALP is the first enzyme to be raised in most obstructive pathology
What autoantibodies are present in primary biliary cirrhosis?
- anti-mitochondrial antibodies are most specific to PBC and form part of the diagnostic criteria
- anti-nuclear antibodies are present in 35%
AMA M2 subtype are highly specific to PBC
What is involved in the treatment of primary biliary cirrhosis?
- ursodeoxycholic acid
- colestyramine
- liver transplant (in end-stage liver disease)
- immunosuppression with steroids considered in some patients
- fat-soluble vitamin supplementation
What is ursodeoxycholic acid used for?
it reduces intestinal absorption of cholesterol
What is colestyramine used for?
- it binds to bile acids to prevent their absorption in the gut
- this reduces pruritis associated with raised bile acids
What is the disease progression like in primary biliary cirrhosis?
- disease course / symptoms are highly variable
- some individuals can live decades without symptoms
- advanced cirrhosis and portal hypertension are the most significant end results
What are the other issues / complications associated with primary biliary cirrhosis?
- distal renal tubular acidosis
- hypothyroidism
- osteoporosis
- hepatocellular carcinoma
- hyperpigmentation over pressure points
- finger clubbing
RTA = kidneys fail to remove acids from the blood into the urine, resulting in acidosis
What imaging is required before a diagnosis of PBC can be made and why?
- RUQ USS or MRCP
- needed to exclude extrahepatic biliary obstruction prior to diagnosis
What is haemochromatosis?
an iron storage disorder in which there is excessive total body iron and iron deposition in tissues
What are the majority of cases of haemochromatosis caused by?
- a mutation in the human haemochromatosis protein gene (HFE)
- this gene is important in regulating iron metabolism
- this is located on chromosome 6
- the mutation is autosomal recessive
there are other genes that can less commonly cause haemochromatosis
When does haemochromatosis typically present?
- usually presents around the age of 40
- this is because it takes time for the iron to build up and become symptomatic
- it presents later in females (usually post-menopause)
- menstruation regularly eliminates iron from the body via the bleeding
it usually starts with non-specific symptoms such as lethargy / arthralgia (particularly of the hands)
What are the symptoms of haemochromatosis?
- bronze / slate-grey discolouration of the skin
- joint pain
- problems with memory / mood
- erectile dysfunction / amenorrhoea
- chronic tiredness
- hair loss
How is haemochromatosis diagnosed?
- blood tests for ferritin and transferrin saturation are performed
- if BOTH ferritin + transferrin saturation are raised, genetic testing is performed to confirm the diagnosis
- transferrin saturation >55% in men or >50% in women
- ferritin > 500 ug/l
Why can haemochromatosis not be diagnosed through ferritin level alone?
- ferritin is an acute phase reactant
- it is raised in inflammation
- transferrin saturation distinguishes between high ferritin due to iron overload (high) or due to inflammation (low / normal)
How did haemochromatosis used to be diagnosed?
liver biopsy with Perl’s stain
- this establishes the iron concentration in the parenchymal cells
it used to be the gold-standard prior to the use of genetic testing
What other investigations may aid in the diagnosis of haemochromatosis?
CT abdomen:
- shows non-specific increase in attenuation of the liver
MRI:
- gives a more detailed picture of liver deposits of iron
- can show iron deposits in the heart
What are the potential complications of haemochromatosis?
- type 1 diabetes
- cirrhosis / HCC
- cardiomyopathy
- hypothyroidism
- arthritis (particularly of the hands)
- endocrine / sexual problems such as hypogonadism, impotence, infertility & amenorrhoea
endocrine / sexual problems are due to iron deposits in the pituitary gland and gonads
Why does arthritis occur in haemochromatosis?
- calcium deposits in the joints leads to chondrocalcinosis / pseudogout
- this causes arthritis
What is involved in the management of haemochromatosis?
- venesection
- monitoring serum ferritin
- avoid alcohol
- genetic counselling
- monitoring / treating complications
venesection = a weekly protocol of removing blood to decrease total iron
- this should keep transferrin saturation < 50% and ferritin < 50 ug/L
What complications of haemochromatosis are irreversible / reversible?
What is primary sclerosing cholangitis?
- a condition in which the intrahepatic or extrahepatic ducts become strictured and fibrotic
- this obstructs the flow of bile out of the liver and into the intestines (cholestasis)
- chronic bile obstruction eventually results in hepatitis, fibrosis + cirrhosis
sclerosis = stiffening / hardening of the bile ducts
cholangitis = inflammation of the bile ducts
What causes primary sclerosing cholangitis?
- the cause is unknown
- it is thought to be due to a variety of genetic, autoimmune and environmental factors
What condition is primary sclerosing cholangitis associated with?
ulcerative colitis
- around 80% cases are established alongside UC
- only 4% of patients with UC have PSC
there are also a less common associations with Crohn’s and HIV
What are the risk factors for primary sclerosing cholangitis?
- male gender
- aged between 30 - 40
- ulcerative colitis
- family history
How does primary sclerosing cholangitis typically present?
- jaundice
- pruritis
- chronic RUQ pain
- fatigue
- hepatomegaly
What will LFTs show in primary sclerosing cholangitis?
- they show a “cholestatic picture”
- ALP is raised the most
- initially, only ALP is raised
- there may be a rise in bilirubin and the transaminases as the disease progresses to hepatitis
Why are autoantibodies measured in primary sclerosing cholangitis?
- there are no autoantibodies that are highly sensitive or specific to PSC
- they are NOT useful in diagnosis
- they can indicate whether there is an autoimmune component to the disease that may respond to immunosuppression
What autoantibodies are associated with PSC?
- antineutrophil cytoplasmic antibody (p-ANCA) in 94%
- antinuclear antibodies (ANA) in 77%
- anticardiolipin antibodies (aCL) in 66%
How is primary sclerosing cholangitis diagnosed?
magnetic resonance cholangiopancreatography (MRCP)
- this involves an MRI scan of the liver, bile ducts and pancreas
- it may show bile duct lesions / strictures
this is the gold-standard
What are the associations / complications of PSC?
- fat soluble vitamin deficiency
- acute bacterial cholangitis
- colorectal cancer
- cholangiocarcinoma (10-20%)
- cirrhosis / liver failure
- biliary strictures
What is involved in the management of PSC?
- ERCP to dilate / stent strictures
- colestyramine to prevent pruritis caused by raised bile acids
- monitoring for complications
- the only curative option is liver transplant
What is involved in an ERCP procedure?
endoscopic retrograde cholangio-pancreatography
- an endoscope is inserted to a point in the duodenum where the bile ducts empty into the GI tract
- it passes through the sphincter of Oddi and into the ampulla of Vater
- from the ampulla of Vater, the bile ducts can be entered
- XRs / injecting contrast are used to identify any strictures
How can ERCP be used in the management of PSC?
- any identfied biliary strictures can be stented during the same procedure
- this allows for improved flow through the ducts and symptomatic relief
What is Wilson’s disease?
the excessive accumulation of copper in the body and its deposition in the tissues
What causes Wilson’s disease?
- it is an autosomal recessive inherited disorder
- caused by a mutation in the ATP7B copper-binding protein
- this is located on chromosome 13
ATP7B is also referred to as the “Wilson disease protein”
When does the onset of symptoms typically begin in Wilson’s disease?
- usually between 10 to 25 years
- children tend to present with liver disease
- young adults tend to present with neurological disease
How do patients typically present in Wilson’s disease?
- most patients will present with 1 or more of:
- hepatic problems (40%)
- neurological problems (50%)
- psychiatric problems (10%)
Why do hepatic problems occur in Wilson’s disease?
- copper deposition in the liver leads to chronic hepatitis
- this eventually leads to cirrhosis
Why do psychiatric / neurological problems occur in Wilson’s disease?
due to copper deposition in the central nervous system
What are the typical neurological symptoms associated with Wilson’s disease?
- they can be subtle (e.g. concentration / coordination difficulties)
- dysarthria (speech difficulty)
- dystonia (abnormal muscle tone)
- parkinsonism
Why does Parkinsonism occur in Wilson’s disease?
How can this be identified?
- due to deposition of copper in the basal ganglia
- characterised by a triad of rigidity, bradykinesia & tremor
- these symptoms are symmetrical (opposed to asymmetrical in Parkinson’s disease)
What are the psychiatric symptoms associated with Parkinson’s disease?
- can range from mild depression to full psychosis
- Wilson’s disease is often missed and treatment is delayed
What sign is present in the eyes in Wilson’s disease?
- Kayser-Fleischer rings in the cornea
- they are brown circles surrounding the iris
due to deposition of copper in Descemet’s corneal membrane
How are Kayser-Fleischer rings identified?
- they are usually visible to the naked eye
- proper assessment is made using a slit lamp examination
What are the other features associated with Wilson’s disease?
- haemolytic anaemia (destruction of RBCs)
- renal tubular damage leading to renal tubular acidosis
- osteopenia (loss of bone mineral density)
- blue nails
What is the initial investigation for Wilson disease?
serum caeruloplasmin
- a LOW serum caeruloplasmin is suggestive of Wilson disease
- this can be falsely normal / elevated in cancer / inflammatory conditions
- it is NOT specific to Wilson disease
caeruloplasmin is the protein that carries copper in the blood
How is serum copper different in Wilson disease?
- there is REDUCED total serum copper
- this is because 95% of plasma copper is carried by ceruloplasmin
- there is also reduced caeruloplasmin
- there is an increase in free serum copper (not bound by caeruloplasmin)
What is the gold-standard test for diagnosing Wilson disease?
- liver biopsy for liver copper content
- genetic analysis of the ATP7B gene can also be performed
Other than biopsy, how else can Wilson disease be diagnosed?
24-hour urinary copper excretion
- this will be elevated
- this involves collecting all the urine for 24 hours so is rarely performed due to inconvenience
What is involved in the treatment of Wilson disease?
treatment is with copper chelation
- penicillamine is the first-line medication
- trientene hydrochloride can also be used
What is alpha-1-antitrypsin deficiency and why does it occur?
- alpha-1-antitrypsin (A1AT) is an enzyme produced in the liver that inhibits neutrophil elastase
- elastase breaks down connective tissues
- in A1AT deficiency, there is an autosomal recessive defect in the gene for A1AT
- this is located on chromosome 14
What organs are affected by A1AT deficiency?
liver:
- cirrhosis and HCC in adults after 50 years
- cholestasis in children
lungs:
- bronchiectasis and emphysema (i.e. COPD) after 30 years
- typical presentation is in young patients who are non-smokers
Why does liver disease occur in A1AT deficiency?
- an abnormal “mutant” version of A1AT is produced
- this mutant protein becomes trapped within the liver
- it builds up to cause liver damage that progresses to cirrhosis and HCC
Why does A1AT deficiency cause disease within the lungs?
- the lack of a normal, functioning A1AT leads to an excess of protease enzymes
- these attack the connective tissue in the lungs
How is A1AT deficiency diagnosed?
- there is low serum A1AT
- genetic testing for the A1AT gene can be performed
- liver biopsy
- high-resolution CT thorax to diagnose bronchiectasis / emphysema
What is seen on liver biopsy in A1AT deficiency?
- periodic acid-Schiff-positive staining globules in hepatocytes
- this stain highlights the mutant A1AT proteins
also known as PAS staining
What is involved in the management of A1AT deficiency?
- stop smoking (this accelerates emphysema)
- manage symptoms (e.g. bronchodilators)
- monitor for complications
- organ transplant for end-stage liver / lung disease
- IV alpha-1-antitrypsin protein concentrates are NOT currently recommended by NICE as there is ongoing debate about the possible benefits
