Week 6 - E - Chronic liver disease (1) - Non-alcoholic fatty liver disease / steatohepatitis, Autoimmune - P.B.C/A.I.H/P.S.C

Question 1

What duration is needed for a classification of chronic liver disease? What does this progress to if left untreated? What is the pathology of chronic liver disease?

Answer 1

Duration of chronic liver disease is >6 months of disease -> it can present acutely or duration may be subclinical It will progress to cirrhosis if left untreated Pathology of chronic liver disease is due to recurrent inflammation and repair

Question 2

List as many causes of chronic liver disease that you can think of

Answer 2

* Chronic alcohol use * Non-alcoholic fatty liver disease * Chronic hepatitis B (more common if exposure in childhood) or C infection * Autoimmunity - Primary biliary sclerosis, primary sclerosing cholangitis, autoimmune hepatitis * Genetic disorders - haemochromatosis, a1-antitrypsin deficiency, wilson’s disease * Budd-chairi (hepatic vein events) * Drugs eg methotrexate

Question 3

This set of flashcards will discuss the following (alcohol and viral hepatitis have already been flashcarded) * Non-alcoholic fatty liver disease * Autoimmunity - Primary biliary sclerosis, primary sclerosing cholangitis, autoimmune hepatitis * Genetic disorders - haemochromatosis, a1-antitrypsin deficiency, wilson’s disease * Budd-chairi (hepatic vein events) * Drugs eg methotrexate Neficiency, wilson’s disease What does NAFLD stand for? How common is it?

Answer 3

NAFLD - stands for non-alcoholic fatty liver disease It is the commonest disease in the world (affecting approx 30% of the world population)

Question 4

Which people does NAFLD occur in? What is the spectrum of the disease?

Answer 4

NAFLD occurs in people who typically have associated metabolic disorders - obesity, diabetes, hyperlipidaemia, hypertension Spectrum of disease Steatosis - increased fat in hepatocytes -> Steatohepatitis - fat with inflammation -> Progressive fibrosis and finally cirrhosis

Question 5

NAFLD is thought to represent the hepatic manifestation of the metabolic syndrome and hence insulin resistance is thought to be the key mechanism leading to steatosis. How is NAFLD diagnosed? What is the treatment of NAFLD?

Answer 5

NAFLD is diagnosed by ultrasound- typically an incidental finding in an asymptomatic patient of fatty changes on liver ultrasound NAFLD is treated at current by controlling and addressing risk factors * Control diabetes / hyperlipidaemia / hypertension * Weight loss / exercsie * Avoid alcohol consuumption

Question 6

Non-alcoholic steatohepatitis is when there is fat deposition with inflammation of the hepatocytes Used to take a biopsy to diagnose NASH - * What are the aggregates of proteins seen on biopsy in steatohepatitis? - typically seen in alcoholic hepatitis but may be seen in other chronic causes of liver disease such as NASH * What is seen on LFTs in NASH?

Answer 6

Mallory-hyaline bodies are seen - they are highly eosinophilic and therefore stain pink They are damaged intermediate filaments found in the cytoplasm of liver cells (hepatocytes) LFTs in NASH - raised ALT (and AST) Treatment same as NAFLD

Question 7

PRIMARY BILIARY CIRRHOSIS (CHOLANGITIS) Autoimmune liver disease’s - PBC, AIH, PSC Primary biliary cirrhosis aka primary biliary cholangitis What is the pathogenesis of this condition?

Answer 7

Primary biliary cirrhosis is a rare autoimmune condition of unknown aetiology The interlobular bile ducts are damaged by chronic autoimmune granaulomatous inflammation

Question 8

What causes the chronic autoimmune granulomatous inflammation of the interlobular bile ducts in primary biliary cholangitis? What can this inflammation lead to?

Answer 8

The majority of cases are associated with autoimmune antibodies which attack specific antigens on mitochondria that are expressed on the bile duct cells (specifically the pyruvate dehydrogenase complex (PDC-E2) antigen found in mitochondria) This inflammation of the interlobular bile ducts can lead to cholestasis, liver injury, fibrosis, cirrhosis and portal hypertension

Question 9

What is the typical presentation of a patient with primary biliary cirrhosis? What are other presenting features?

Answer 9

The typical presentation is itching in a middle aged women (f:m 9:1) Associated symptoms: * Fatigue * Itch without rash * Xanthelasma and xanthomas - deposit of cholesterol beneath the skin Late on jaundice may also occur

Question 10

What are the complications of primary biliary cirrhosis? (what can occur due to reduced flow of bile)

Answer 10

Due to inflammation of the bile ducts Cholestasis -> inflammation -> fibrosis -> cirrhosis -> portal hypertension and hepatocellular carcinoma Jaundice due to increase in bilirubin Malabsorption of fat soluble vitamins due to cholestasis * Can cause osteomalacia and coagulopathies

Question 11

What is seen on LFTs carried out in primary biliary cirrhosis?

Answer 11

LFTs give a cholestatic picture Raised ALP and GGT (mildly raised AST and ALT) Late disease can cause a * raised bilirubin * decreased albumin * increased prothrombin time

Question 12

What is the diagnostic tests carried out for primary biliary cholangitis? Which antibodies are raised in this condition?

Answer 12

diagnoses - 2of 3 * Positive anti-mitochondiral antibody M2 subtype * Cholestatic LFTs * Liver biopsy - not usually needed anti-mitochondrial antibodies (AMA) M2 subtype are present in 98% of patients and are highly specific Anti smooth muscle antibodies (ASMA) in 30% of patients raised serum IgM

Question 13

Why is there an itch in cholestatic liver disease?

Answer 13

Cholestatic liver disease increases levels of bile salt which accumulate under the skin causing itch

Question 14

What is given for the symptomatic treatment of PBC: Pruritus? Vitamins? What is the actual first and second line medical treatment for the disease?

Answer 14

Pruritus can be managed with colestyramine - bile acid sequestrant - binds bile in the gastrointestinal tract to prevent its reabsorption. Give fat soluble vitamins (vit A, D, E, K) * Urseodoxycholic acid is first line - secondary bile acid - shown to improve liver biochemistry and histological progression * If it fails, obeticholic acid is second line - a semi-synthetic bile acid

Question 15

Most will not develop symptoms in their life time The majority with PBC symptoms do not develop liver failure * Itch can be particularly problematic If first line (ursodeoxycholic acid (UDCA) and second line (obeticholic acid) fail to work, what may have to be considered?

Answer 15

Liver transplant is considered for intractable itch or for end stage liver disease, or for disease that will not respond to treatment

Question 16

Autoimmune hepatitis What is this formerly known as? What is the pathogenesis of autoimmune hepatitis?

Answer 16

Autoimmune hepatitis is formerly known as chronic active hepatitis or lupoid hepatitis It us caused by abnormal T cell function and auto-antibodies against hepatocyte surface antigens Classification is done by the type of antibodies (two main types of classification)

Question 17

What is seen on liver function tests in autoimmune hepatitis? What immunoglobulin is raised in the blood?

Answer 17

LFTs * Raised bilirubun, AST, ALT and ALP * Raised PT also There is also a raised IgG in the blood

Question 18

There is type 1 and type 2 autoimmune hepatitis Which age group does each affect? Which antibodies are positive in both?

Answer 18

Type 1 is by far more common (seen in 80%) * Bimodal peak in age (teens and 45-70) * Anti-smooth muscle antibody positive, Anti-nuclear antibody positive Type 2 * Seen in children and young adults * Exclusively anti-liver/kidney microsomal type (LKM) antibodies

Question 19

Type 2 autoimmune hepatitis is less common, and less treatable We will discuss the typical features of Type 1 What is the typical presentation of a patient with autoimmune hepatitis?

Answer 19

Typical presentation is female (usually in teens or middle aged (45-70)) Present with symptoms similar to viral epatitis * Fever, malaise, anorexia, jaundice, amenorrhoea common, hepatosplenomegaly * Stigmata of chronic liver disease

Question 20

Diagnoses of autoimmmune hepatitis * Serology shows elevated AST and ALT (as well as raised bilirubin and PT) * Raised IgG It is important to rule out other causes of chronic liver disease If levels of GGT and ALP are markedly raised, what should you suspect?

Answer 20

If levels of GGT and ALP are raised, this can make diagnosis challenging * bile duct injury should be suspected and a diagnosis of sclerosing cholangitis or AIH-sclerosing cholangitis overlap syndrome should be considered.

Question 21

Liver biopsy is the confirmation test in autoimmune hepatitis - Essential to establish the diagnosis, evaluate disease severity, and determine the need for treatment What is seen here?

Answer 21

Chronic hepatitis on histology - inflammation with ‘piecemeal necrosis’ and bridging necrosis Piecemeal necrosis aka interface hepatitis generally refers to a necrosis that occurs in fragments

Question 22

What is the treatment of autoimmune hepatitis?

Answer 22

Treated with High dose corticosteroids to induce remission which are tapered down to a maintenance dose Azathioprine is a choice of drug as a steroid sparing agent to maintain remission Liver transplant is there is failure to respond to medical therapy or decompensated cirrhosis

Question 23

Primary sclerosing cholangitis What is the pathogenesis of primary sclerosing cholangitis? What condition is associated with this?

Answer 23

Primary sclerosing cholangitis occurs due to autoimmune chronic inflammatory inflammation and destruction of the large and medium sized intra/extra hepatic bile ducts It is associated with ulcerative colitis

Question 24

What happens due tot he inflammation / destruction of the bile ducts in patients with primary sclerosing cholangitis? What are two important future complications to monitor for in patients with PSC?

Answer 24

Due to the intra and extra hepatic bile duct inflammation, this leads to periductal fibrosis and inflammation characterised by cholestasis and progressive jaundice It is important to monitor for cholangiocarcinoma and colo-rectal carcinoma in this condition as they are at an increase risk (yearly colonoscopy + ultrasound to monitor)

Question 25

How does primary sclerosing cholangitis present?

Answer 25

Disease is more common in males Features cholestasis: jaundice and pruritus right upper quadrant pain fatigue

Question 26

What is seen on LFTs in primary sclerosing cholangitis? Which antibody is raised? Which investigation is usually diagnostic for the condition?

Answer 26

LFTs show a cholestatic pattern * Raised ALP, GGT, bilirubin p-ANCA is often positive (also positive in UC) Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) are the standard diagnostic investigations

Question 27

What is seen on MRCP or ERCP in the diagnosis of PSC? Liver biopsy role is limitied in the diagnosis of this condition, what may be seen?

Answer 27

MRCP (preferred method) or ECRP showing multiple biliary strictures giving a ‘beaded’ appearance Liver biopsy may show a fibrous and obliterative inflammation around the bile ducts often term as onion-skinning fibrosis

Question 28

What is the mainstay treatment for end stage disease of primary sclerosing cholangitis? What is the treatment to maintain bile flow?

Answer 28

Liver transplant is the only proven long term treatment of primary sclerosing cholangitits although usually reserved for end-stage disease Colestyramine can be given for pruritus Ursodeoxycholic acid may be given to maintain bile flow and may improve LFTs but has not shown evidence of survival benefit