Investigating GI + Liver disease

Question 1

What are the major functions of the liver?

Answer 1

• carbohydrate metabolism
• fat metabolism
• protein metabolism
• hormone metabolism
• drugs + foreign compounds
• storage
• metabolism and excretion of bilirubin

Question 2

What are common disease processes affecting the liver?

Answer 2

• hepatitis - damage to hepatocytes
• cirrhosis - increased fibrosis, liver shrinkage, decreased hepatocellular function, obstruction of bile flow
• tumours - frequently secondary: colon, stomach, bronchus

Question 3

What are the important liver enzymes and where are they present?

Answer 3

• Transaminases:
  
  • ALT: present in hepatocytes and to far less extent, skeletal muscle
  • AST: present in hepatocytes, cardiac/skeletal muscle and erythrocytes - less liver specific
• Alkaline phosphatase: present in biliary system, bone, placenta + intestine
• Gamma Glutamyl transferase: present in hepatocytes (induced by drugs, ETOH etc) and biliary system (cholestasis)

Question 4

What proteins are important in liver function tests?

Answer 4

• albumin - synthesised in liver, half-life 20days
• clotting factors - inc INR only true test of liver ‘function’
• a₁-antitrypsin - for deficiency
• a-fetoprotein - useful marker for hepatocellular carcinoma
• caeruloplasmin - low levels associated w/ Wilson’s
• ferritin - high levels associated w/ iron overload

Question 5

Describe bilirubin conjugation within the enterohepatic circulation

Answer 5

Question 6

What are patterns of LFTs in:

• inflammatory pattern (hepatocellular damage)
• cholestatic pattern

Answer 6

• albumin concentrations tend to be decreased only in chronic liver disease
• an INR measurement provides a sensitive and rapidly responsive index of hepatic synthetic capacity

Question 7

Are deranged LFTs always clinically significant?

Answer 7

• reference ranges from 2.5^th to 97.5^th centiles
• isolated marginally raised values of up to approx 20% greater than upper limit of ref range are more likely to be statistical outliers rather than significant clinical findings
• conversely, results within ref range may be abnormal for that particular patient
• interpretation must be performed within context of patient’s risk factors, symptoms, concomitant conditions, medications and physical findings

Question 8

How do you interpret a raised ALT?

Answer 8

• first - exclude high EtOH intake, diabetes + inc TGs
• if less than 2x upper limit of normal - suggest repeat in 1-3 months
• a persistently raised ALT (ie. 1.5-3x ULN for 6 months or more) requires further investigation
• >3x ULN (repeat not required), instigate further investigation
• up to 40% of slightly elevated values are found to be normal on re-testing (confiremd in SGH audit)

(NB skeletal muscle contains ALT but at lower levels than in liver)

Question 9

What are further FIRST-LINE investigations for persistently elevated ALT?

Answer 9

• AST for AST/ALT ratio
• FBC
  
  • macrocytosis + inc gGT suggests EtOH xs
  • thrombocytopenia (poss hypersplenism - portal HT)
• Autoantibodies
  
  • AMA +ve -> PBC
  • ASM/ANA +ve -> AIH
• Ferritin
  
  • increased, do iron binding studies, poss haemochromatosis, genetic testing maybe
• HepB surface antigen
  
  • +ve -> chronic infection
• Hep C antibody
  
  • +ve -> chronic infection
• Liver USS

Question 10

What does the AST:ALT ratio tell us?

Answer 10

Question 11

If the first line investigations don’t provide a diagnosis, proceed to second-line. What are the second-line further investigations for persistently elevated ALT?

Answer 11

• anti-tissue transglutaminase antibodies
  
  • +ve -> coeliac disease
• a₁-antitrypsin
  
  • if low -> deficiency; phenotyping required for confirmation
• Caeruloplasmin
  
  • low -> suggests Wilson’s, further specialist investigations required for confirmation (hepatic presentation is usually earlier than neurological presentation)

Question 12

What is the importance of non-alcoholic fatty liver disease, in terms of prevalence and what it may progress to?

Answer 12

• more prevalent than alcoholic liver disease
• most common cause of abnormal LFTs
• prevalence - 20% in gen pop, up to 70% in T2DM
• stages:
  
  • hepatic steatosis (fat >5% liver volume)
  • non-alcoholic steatohepatitis (3-5% of population)
    
    • NASH greater risk of progressing to fibrosis, cirrhosis, HCC
• obesity major risk factor

Question 13

What are the risk factors for:

• developing cirrhosis from NAFLD/NASH
• developing HCC from cirrhosis (from NAFLD/NASH)

Answer 13

Question 14

How do the typical features of NAFLD and alcoholic liver disease differ?

Answer 14

Question 15

How do you interpret raised bilirubin?

Answer 15

• isolated increased bilirubin -> measure conjugated bilirubin
• conjugated bilirubin <30% of total (primary elevation of unconjugated bilirubin):
  
  • Gilbert’s (~3-7% of population)
    
    • total bilirubin levels rarely more than 80-100
    • defect in regulatory part of gene coding for bilirubin UDP-glucuronyl transferase
  • Haemolysis
    
    • check blood film + reticulocytes
  • Crigler-Najjar I + II (rare, paediatric pop)
    
    • absence/partial defect of bilirubin UDP-glucuronyl transferase

Question 16

How do you interpret an isolated raised gamma GT?

Answer 16

• gamma GT has limited utility as a primary liver test
• useful to establish cause of an increased ALP
• not a sensitive or specific marker of alcohol misuse - raised in large no. of pts w/ both alcoholic and non-alcoholic fatty liver disease
• induced by various medications and over-the-counter preparations eg. phenytoin, st John’s wort

Question 17

How do you interpret an isolated raised ALP?

Answer 17

• less than 1.5x ULN -> recheck 1-3 months later
• values more than 1.5x ULN -> check for liver/bone origin w/ GGT
  
  • normal GGT ?bone in origin
  • check ref range appt for age + not third trimester
  • ? vit D deficient
• values more than 1.5x ULN + inc GGT
  
  • made twice, six months apart -> further investigation
  • ALP levels higher in black women, age, CCF, hyperthyroid, preg, some meds
  • check ALP isoenzymes
• Values more than 3x ULN (on one occasion) require further investigation

Question 18

What are tests to check for liver fibrosis?

Answer 18

• procollagen III N-terminal peptide (P3NP)
  
  • used in long term methotrexate treatment to monitor for development of liver fibrosis
• european liver fibrosis test (ELF test)
  
  • 3 serum biomarkers:
    
    • hyaluronic acid (HA)
    • procollagen III amino terminal peptide (PIIINP)
    • tissue inhibitor of metalloproteinase 1 (TIMP-1)
  • uses an algorithm to calculate fibrosis score
  • NICE guidelines July 2016:
    
    • consider ELF in ppl who have been diagnosed w NAFLD to test for advanced liver fibrosis
    • advanced liver fibrosis = ELF score >10.51 + NAFLD

Question 19

What liver tests are used to test for alcohol?

Answer 19

• carbohydrate deficient transferrin (CDT)
  
  • EtOH misuse - commonest reason for inc CDT
  • typically level of alcohol intake required to prod a CDT result of 3.0% is 100-150g EtOH/day
    
    • CDT < or = 1.5% : no XS alcohol intake
    • CDT 1.6-1.9% : intake high but not in range of dependence
    • CDT > or = 2% : XS alcohol intake
• Ethanol metabolites - ethyl glucuronide + ethyl sulphate
  
  • positive for up to 3 days after ethanol consumption
  • potential for detection of occult/denied alcoholism

Question 20

What does faecal calprotectin test for?

Answer 20

• stable zinc + calcium binding protein belonging to S100 family that is derived mostly from neutrophils + monocytes
• released into faeces when neutrophils gather at site of any GI inflammation
• useful for differentiating between IBS and IBD in younger age group (pts <40yrs)
• not a useful marker for malignancy

Question 21

What does faecal elastase test for?

Answer 21

• non-invasive assessment of pancreatic exocrine insufficiency
• has been shown to correlate well w/ more invasive tests of exocrine pancreatic funtion such as the Secretin Pancreozymin test
• pancreatic elastase is also gaining an increasing role of assessment of cystic fibrosis patients

Question 22

What does occult blood (FOBT) test for?

Answer 22

• bowel cancer screening programme
• most labs do not offer FOBT despite NICE guidelines which recommends FOBT testing for pts w/ abdo pain and without rectal bleeding to assess for colorectal cancer who also have:
  
  • abdo pain or
  • weight loss or
  • age <60 + have change in bowel habit or
  • iron-def anaemia
• quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care -> new FIT test to replace FOBT

Question 23

What do the following tumour markers look for?

• CA199
• CEA
• AFPT
• CA125

Answer 23

• CA199: in pts in whom pancreatic cancer is strongly suspected CA19-9 may complement other diagnostic procedures, can be raised in cholestasis due to non-malignant conditions
• CEA: colorectal cancer, but may be raise din IBS, CRF, pleural inflammation, high in smokers
• AFPT: hepatocellular carinoma (in conjunction w USS)
• CA125: ovarian cancer marker, but may be raised in any condition which causes peritoneal inflammation (incl urinary retention + ascites)

Question 24

What is hepatic elastography? What’s it used for?

Answer 24

• transient elastography (FibroScan) is used to assess pts w/ chronic liver disease (hepC/B, alcohol abuse, fatty liver)
• concept is that as more fibrosis + scarring occur, the higher the liver stiffness reading will be
• the reading may be used to:
  
  • estimate existing degree of liver damage
  • monitor disease progression/regression w/ serial measurements
  • guide prognosis + further mgmt, inclduing Rx