Rarer Causes of Cirrhosis Flashcards
1
Q
What is primary biliary cirrhosis?
(also known as primary biliary cholangitis)
A
- 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
2
Q
What 3 factors build up in the blood in primary biliary cirrhosis?
A
- 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
3
Q
What is the result of increased bile acids in the blood?
A
pruritis
4
Q
What is the result of raised bilirubin in the blood?
A
jaundice
5
Q
What is the result of raised cholesterol in the blood?
A
- 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
6
Q
What is the consequence of a lack of bile acids in the gut?
A
- 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
7
Q
What is the typical presentation of primary biliary cirrhosis?
A
- pruritis
- xanthelasma / xanthomas
- steatorrhoea / pale stools
- fatigue
- GI disturbance / abdominal pain
- jaundice
- signs of cirrhosis / liver failure (e.g. ascites, spider naevi, splenomegaly)
8
Q
What are the associations of primary biliary cirrhosis?
A
- middle-aged women
- rheumatoid conditions
- other autoimmune diseases (e.g. thyroid / coeliac)
rheumatoid conditions = RA, Sjogren’s syndrome, systemic sclerosis)
9
Q
How is primary biliary cirrhosis diagnosed?
A
- LFTs
- autoantibodies
- ESR / IgM are both raised
- liver biopsy (used for diagnosis and staging of disease)
10
Q
What do LFTs show in primary biliary cirrhosis?
A
- 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
11
Q
What autoantibodies are present in primary biliary cirrhosis?
A
- 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
12
Q
What is involved in the treatment of primary biliary cirrhosis?
A
- ursodeoxycholic acid
- colestyramine
- liver transplant (in end-stage liver disease)
- immunosuppression with steroids considered in some patients
- fat-soluble vitamin supplementation
13
Q
What is ursodeoxycholic acid used for?
A
it reduces intestinal absorption of cholesterol
14
Q
What is colestyramine used for?
A
- it binds to bile acids to prevent their absorption in the gut
- this reduces pruritis associated with raised bile acids
15
Q
What is the disease progression like in primary biliary cirrhosis?
A
- disease course / symptoms are highly variable
- some individuals can live decades without symptoms
- advanced cirrhosis and portal hypertension are the most significant end results
16
Q
What are the other issues / complications associated with primary biliary cirrhosis?
A
- 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
17
Q
What imaging is required before a diagnosis of PBC can be made and why?
A
- RUQ USS or MRCP
- needed to exclude extrahepatic biliary obstruction prior to diagnosis
18
Q
What is haemochromatosis?
A
an iron storage disorder in which there is excessive total body iron and iron deposition in tissues
19
Q
What are the majority of cases of haemochromatosis caused by?
A
- 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
20
Q
When does haemochromatosis typically present?
A
- 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)
21
Q
What are the symptoms of haemochromatosis?
A
- bronze / slate-grey discolouration of the skin
- joint pain
- problems with memory / mood
- erectile dysfunction / amenorrhoea
- chronic tiredness
- hair loss
22
Q
How is haemochromatosis diagnosed?
A
- 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
23
Q
Why can haemochromatosis not be diagnosed through ferritin level alone?
A
- 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)
24
Q
How did haemochromatosis used to be diagnosed?
A
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
25
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
26
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
## Footnote
endocrine / sexual problems are due to iron deposits in the pituitary gland and gonads
27
Why does arthritis occur in haemochromatosis?
* **calcium deposits** in the joints leads to **chondrocalcinosis / pseudogout**
* this causes arthritis
28
What is involved in the management of haemochromatosis?
* **venesection**
* **monitoring serum ferritin**
* avoid alcohol
* genetic counselling
* monitoring / treating complications
## Footnote
venesection = a **weekly protocol of removing blood** to decrease total iron
* this should keep transferrin saturation < 50% and ferritin < 50 ug/L
29
What complications of haemochromatosis are irreversible / reversible?
30
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**
## Footnote
sclerosis = stiffening / hardening of the bile ducts
cholangitis = inflammation of the bile ducts
31
What causes primary sclerosing cholangitis?
* the **cause is unknown**
* it is thought to be due to a variety of genetic, autoimmune and environmental factors
32
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
## Footnote
there are also a less common associations with Crohn's and HIV
33
What are the risk factors for primary sclerosing cholangitis?
* male gender
* aged between 30 - 40
* ulcerative colitis
* family history
34
How does primary sclerosing cholangitis typically present?
* jaundice
* pruritis
* **chronic RUQ pain**
* fatigue
* hepatomegaly
35
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
36
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**
37
What autoantibodies are associated with PSC?
* antineutrophil cytoplasmic antibody (p-ANCA) in 94%
* antinuclear antibodies (ANA) in 77%
* anticardiolipin antibodies (aCL) in 66%
38
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**
## Footnote
this is the gold-standard
39
What are the associations / complications of PSC?
* fat soluble vitamin deficiency
* **acute bacterial cholangitis**
* colorectal cancer
* **cholangiocarcinoma** (10-20%)
* cirrhosis / liver failure
* biliary strictures
40
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
41
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**
42
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
43
What is Wilson's disease?
the excessive **accumulation of copper** in the body and its deposition in the tissues
44
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**
## Footnote
ATP7B is also referred to as the "Wilson disease protein"
45
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
46
How do patients typically present in Wilson's disease?
* most patients will present with 1 or more of:
1. hepatic problems (40%)
2. neurological problems (50%)
3. psychiatric problems (10%)
47
Why do hepatic problems occur in Wilson's disease?
* copper deposition in the liver leads to **chronic hepatitis**
* this eventually leads to **cirrhosis**
48
Why do psychiatric / neurological problems occur in Wilson's disease?
due to copper deposition in the central nervous system
49
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**
50
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)
51
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
52
What sign is present in the eyes in Wilson's disease?
* **Kayser-Fleischer rings** in the cornea
* they are brown circles surrounding the iris
## Footnote
due to deposition of copper in **Descemet's corneal membrane**
53
How are Kayser-Fleischer rings identified?
* they are usually visible to the naked eye
* proper assessment is made using a **slit lamp examination**
54
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**
55
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
## Footnote
caeruloplasmin is the protein that carries copper in the blood
56
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)
57
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
58
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
59
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
60
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**
61
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
62
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
63
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
64
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
65
What is seen on liver biopsy in A1AT deficiency?
* **periodic acid-Schiff-positive staining globules** in hepatocytes
* this stain highlights the mutant A1AT proteins
## Footnote
also known as PAS staining
66
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
