Cholestatic liver disease

Question 1

What are the first changes seen on liver function tests in cholestasis?

Answer 1

The first changes are usually ALP and gammaGT.

Conjugated hyperbilirubinaemia is ususally a later change.

Question 2

How can ischaemia cause sclerosing cholangitis?

Answer 2

It is a process whereby, hypotension leads to ischaemia, which leads to stricture formation.

Question 3

Are there any particular deficiencies that are associated with drug induced liver injury?

Answer 3

Yes there are!

Glutathione s-transferase (GST) deficiency is associated with antibiotic and NSAID therapy
NAT allele deficiency is associated with sulfonamide and isoniazid toxicity
MDR1 and MDR3 transporter mutations are associated with some

There are also HLA types that are associated with particular injuries.

Question 4

What is the M rule of PBC?

Answer 4

Middle age women
AMA
subtype M2
IgM

Question 5

What are the usual presenting symptoms of PBC?

Answer 5

Fatigue seems to be the most common finding. However, pruritis and jaundice are also common

Question 6

What are some serious sequelae of PBC?

Answer 6

Fat soluble vitamin deficiency - particularly vitamin D (leading to osteoporosis)
high lipids
pruritis
cirrhosis

Question 7

Treatment of PBC?

Answer 7

Urso has good evidence and apparently even delays progression to transplant

Question 8

What is the MELD score for transplant listing in PBC? Any other issues that might gain a transplant?

Answer 8

Patients require a score of 16 before being listed

Itch is another reason for listing for transplant

Question 9

Where does primary sclerosing cholangitis occur in the liver? (?periportal or centrilobular?)

Answer 9

PSC is typically a periportal (biliary) disease that can have disease in the intra and extra-hepatic bile ducts

Question 10

How is PSC diagnosed? What does it look like on imaging?

Answer 10

the MRCP shows multifocal strictures and segmental dilatation.

There is an association with an atypical p-ANCA

also, in contrast to PBC, this condition is slightly more associated with males

Question 11

How do we treat PSC these days? Does the treatment of other IBD symptoms change the PSC course?

Answer 11

No. Even though there is an association between the two conditions, treatment of one doesn’t impact the other.

Question 12

Is PSC associated with any risk of malignancy?

Would you do any specific investigations?

Answer 12

Yes, there is a 10 - 15% lifetime risk of cholangiocarcinoma. If found late (or even semi-late), this condition is very hard to treat.

I don’t think there are specific recommendations about this, but Dr Skoein does yearly MRCP and CA19.9

Interestingly, if PSC is associated with IBD, there is an even greater risk of CRC (compared with IBD alone). 1-2 yearly colonoscopies are recommended.

Question 13

Is there a differential for a condition similar to PSC or cholangiocarcinoma, predominantly affects males?

Answer 13

IgG4-associated cholangitis is a recently described condition that is responsive to steroids.

It is characterised by infiltration of IgG4-positive plasma cells in bile ducts and liver. It is also associated with auto-immune PANCREATITIS (not AIH). There is no association with IBD.

Diagnosis is not straight forward, but involves (usually) an ERCP based biopsy or imaging

Question 14

When does intra-hepatic cholestasis of pregnancy occur? What is it? How do we treat?

Answer 14

This is one of the important pregnancy related liver conditions. This one is associated with pruritis and elevated LFTs, usually ALT. It is diagnosed by “unexplained itch and elevated bile salts”

Urso can help the pruritis and elevated LFTs, but overall it is treated by delivery. Unfortunately it is more likely to recur with the next pregnancy.

It usually occurs in 3rd trimester, but can occur in 2nd.

Question 15

What are the characteristics of autoimmune hepatitis?

Answer 15

This is chronic inflammation of the liver. The aetiology is unknown, but it is characterised by:

• “interface hepatitis” with a prominent plasma cell infiltrate (this is an important little phrase for AIH)
• hypergammaglobulinaemia
• circulating autoantibodies

It is a condition of mostly females, and liver biopsy is quite important for diagnosis. The diagnosis is still tricky, and usually is based on a scoring system (calculated before and after treatment)

The main circulating autoantibodies, although not specific for the disease, are antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) in type 1 disease and, in type 2 autoimmune hepatitis, anti-liver-kidney microsome-1 antibodies (ALKM-1) and anti-liver cytosol antibody-1 (ALC-1).

Question 16

What is the natural history of AIH?

Answer 16

It’s not great. First of all, the bloods are sort of predictive. Overall they usually have an ALT/AST > 10x ULN with bridging necrosis and this has a 6 month mortality of 40% (if untreated).

The 10 year survival of untreated is about 27%

If untreated:

• Bridging necrosis means 5 yr cirrhosis of >80%
• interface hepatitis means 17% cirrhosis at 5 years
• mild LFT abnormality is 50% cirrhosis at 5 year

Question 17

How does one treat AIH?

Answer 17

Steroids are the mainstay of treatment.

Steroid sparing agents such as azathioprine or 6-MP are also used. These have an 80% success rate.

If there is no active inflammation, it’s probably not useful to treat the disease.
HOWEVER - even if there is cirrhosis, any active disease should be treated.

Question 18

How do we measure 6-MP when treating patients? What are our goals with this medication?

Answer 18

We aim to keep the active metabolites in a certain range.

With IBD, the target ranges are slightly different than AIH.

In AIH, we aim to get the 6-TG level above 220 and avoid letting the 6MMP level getting above 3000. And usually precede treatment by checking the TMPT level.

Question 19

What conditions cause periportal inflammation?

Answer 19

Drugs (some, not all. Some cause widespread necrosis like paracetamol, and some cause centrilobular),
viral conditions,
autoimmune conditions, such as PSC and AIH