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SEM 4: Clinical Biochemistry > Lab Investigation of Liver and GI Tract Disease > Flashcards

Lab Investigation of Liver and GI Tract Disease Flashcards

1
Q

Largest organ in the body

A

The liver

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2
Q

Structure of the liver

A
  • Comprised of the right large lobe and the left smaller lobe
  • Has a dial blood supply: the portal vein supplies nutrients, the hepatic artery supplies oxygen and the hepatic vein is the drainage.
  • Substances for excretion from the liver are secreted from hepatocyes into canaliculi.
  • The bile canaliculi merge and form bile ductules, which merge to become a bile duct and eventually the common hepatic duct
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3
Q

Functions of the liver

A
  • Carbohydrate metabolism
  • Fat metabolism
  • Protein metabolism
  • Synthesis of plasma proteins
  • Hormone metabolism such as peptide and steroid hormones
  • Metabolism and excretion of drugs and foreign compounds
  • Storage of glycogen vitamin A and vitamin B12, as iron and copper
  • Metabolism and excretion of bilirubin
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4
Q

Liver disease: Hepatitis

A
  • Inflammation of the liver

- Damage to hepatocytes

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5
Q

Liver disease: Cholestasis

A
  • Scarring of the liver
  • Blockage
  • Intra or extra hepatic which can lead to backflow and distrupt the liver function
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6
Q

Liver disease: Cirrhosis

A
  • Increased fibrosis
  • Liver shrinkage
  • Decreased hepatocellular function
  • Obstruction of bile flow
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7
Q

Liver disease: Tumours

A
  • Primary cancer
  • Frequently secondary: colon stomach, bronchus
  • Liver metastasis secondary to lung colon
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8
Q

Purpose of a liver function tests

A

Look for pattern of results, a single result doesn’t provide a diagnosis alone

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9
Q

What are LFT used for?

A
  • Screening for the presence of liver disease
  • Assessing prognosis
  • Measuring the efficacy of treatments for liver disease
  • Differential diagnosis, predominantly hepatic or cholestatic
  • Monitoring disease progression
  • Assessing severity
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10
Q

What do liver function tests include?

A
  • Bilirubin - only one which actually detects liver function, the other detects liver damage
  • Albumin
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Alkaline phosphatase
  • Gamma glutamyltransferase
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11
Q

What is the standard LFT?

A
  • Bilirubin
  • Alanine
  • ALT
  • Alkaline phosphatase (ALP)
  • Albumin
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12
Q

Hepatocellular damage (inflammatory pattern)

A

There is normal or slightly raised bilirubin, very high ALT, normal or slightly raised ALP and normal albumin.

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13
Q

Cholestatic pattern

A

There is high or very high bilirubin, normal or slightly raised ALT, very high ALP and normal albumin.

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14
Q

How to look for the difference between Inflammatory pattern and Cholestatic pattern?

A

To detect the difference measure ALP and ALT.

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15
Q

What decreases in chronic liver disease?

A

Albumin concentrations only tend to decrease in chronic liver disease

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16
Q

Bilirubin

A
  • Yellow/orange pigment derived from haem
  • Occurs in two forms, either conjugated (with albumin) or unconjugated
  • Conjugated: binds tightly but reversibly to albumin it’s so hydrophobic
  • Conjugation occurs in the liver and excreted in bile
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17
Q

Bilirubin metabolism

A
  1. Red blood cells are broken down in the spleen, into globin and haem
  2. Haem is converted into bilirubin and iron is taken to be recycled.
  3. Bilirubin is then gets carried to the liver bound to albumin.
  4. Albumin bound bilirubin is stripped off albumin and gets absorbed into hepatocytes.
  5. It is then broken down by UDP glucuronyl transferase
  6. It then goes to the small intestine where it is broken down to colourless substances: urobilinogen and sterocobilinogen.
  7. Both of these can get oxidised to yellow urinary urobilin and brown faecal stereocobilin.
  8. Urobilinogen can also enter the hepatic portal vein and get excreted by the kidney.
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18
Q

Jaundice

A

The yellow discolouration of tissue due to bilirubin deposition.

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19
Q

Clinical Jaundice

A
  • May not be evident

- Until serum/plasma bilirubin concentration is 2x upper reference so more than 50umol/L.

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20
Q

How does high plasma/serum bilirubin occur?

A

Due to imbalance between excretion and production.

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21
Q

How do you get unconjugated and conjugated bilirubin?

A

Unconjugated bilirubin elevation: due to production increase production of bilirubin that is beyond liver conjugated capacity

Conjugated bilirubin elevation: due to obstruction of bilirubin flow

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22
Q

Jaundice: Pre-hepatic

A
  • Haemoglobin to bilirubin
    Caused by:
  • Excessive RBC breakdown
  • Haemolysis occurs - too much production of bilirubin
  • Crigler-Najjar, Gilbert’s - genetic disorder of UDP
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23
Q

Jaundice: Cholestatic (Intrahepatic)

A 
Dysfunction of hepatic cells 
Caused by: 
- Viral hepatitis 
- Drugs 
- Alcoholic hepatitis 
- Cirrhosis 
- Pregnancy 
- Infiltration
- Congenital disorder
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24
Q

Jaundice: Extra-hepatic

A 
Obstruction of biliary drainage: an increase in conjugated bilirubin but no ability to excrete it. 
Caused by: 
- Common duct stone 
- Carcinoma 
- Biliary stricture 
- Sclerosing cholangitis 
- Pancreatitis
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25
Q

Neonatal Jaundice

A
  • Common and transient normally resolved in the first 10 days
  • Normally due to the immaturity of bilirubin conjugation enzymes
  • There are high levels of unconjugated bilirubin which is toxic to the newborn because they can cross the BBB and damage the brain leading to Kernicterus leading to sleepiness, drowsiness, and seizures
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26
Q

How is neonatal jaundice treated?

A
  • With phototherapy with UV light which helps convert the bilirubin to water-soluble form which is less toxic.
  • Conjugated bilirubin levels are increased due to physiological reasons
  • Babies may have pale stools with biliary atresia, urgent surgical treatment is essential
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27
Q

Gilbert’s syndrome

A
  • Mutation in the gene coding for the UDP glucronyl transferase enzyme
  • Benign liver disorder in 10% of the population
  • Characterized by mild, fluctuating increases in unconjugated bilirubin
  • Caused by decrease in the ability of the liver to conjugate bilirubin
  • Affects more males than females
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28
Q

Liver transaminases

A

ALT and AST

  • Commonly measured markers of hepatocyte injury
  • Due to them leaking out during cell damage
  • Catalyse the transfer of amino
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29
Q

ALT

A
  • Localised in the liver
  • Cytosolic
  • Used to identify liver damage arising from hepatocyte inflammation or necrosis
  • Values are increased in almost every liver disease
  • High values: severe liver damage
  • Small values in cholestasis due to secondary damage to hepatocytes
  • Moderate: fatty liver, chronic viral hepatitis, prolonged cholestatic liver disease, and cirrhosis
  • Highest elevation: in acute viral hepatitis, hepatic necrosis induced by drugs or toxins, ischaemic hepatitis induced
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30
Q

AST

A
  • Wide tissue distribution, so found in the heart, skeletal muscle, kidney, brain, erythrocytes, lung and liver
  • Cytosolic but also found in the mitochondria
  • Values are increased in almost every liver disease
  • High values: severe liver damage
  • Small values in cholestasis due to secondary damage to hepatocytes
  • Moderate: fatty liver, chronic viral hepatitis, prolonged cholestatic liver disease, and cirrhosis
  • Highest elevation: in acute viral hepatitis, hepatic necrosis induced by drugs or toxins, ischaemic hepatitis induced
31
Q

Why can there be false values of AST and ALT in cirrhosis?

A

May show a decrease due to more tissue being present to damage

32
Q

Alkaline phosphatase (ALP)

A
  • Enzyme isoforms produced in the liver and bone but also placental and intestinal forms
  • Increased in bile duct obstructions such as in cholestasis; obstructions could be extrahepatic stones, and intrahepatic.
  • ALP higher than 3x the ULN in intra and extrahepatic cholestasis
  • ALP lower than 3x the ULN in hepatocellular disease
  • High in osteoblastic activity, such as healing fractures, vitamin D deficiency and Paget’s disease
  • Produced by a number of tissues - the source is determined by gel electrophoresis
  • The placental isozyme is different and identified as it is stable at 65 degrees for 10 mins
33
Q

Gamma-glutamyl Transferase (GGT)

A
  • Membrane-bound enzyme that transfers the gamma-glutamyl group from peptides such as glutathione to other peptides and to L amino acids
  • Wide range of tissue distribution, but liver isoenzyme activity predominates in the serum
  • Used in combination with ALP, high values confirm ALP of hepatic origin
  • High levels due to enzyme induction by alcohol or drugs such as anticonvulsants
  • High levels can occur during cholestasis and hepatocellular disease
  • Can be high in non-hepatic disorders such as pancreatitis, myocardial infarction, and diabetes mellitus
34
Q

High ALP and High GGT

A

Hepatic cause such as cholestasis

35
Q

High ALP and Normal GGT

A

Bone source of ALP

36
Q

Normal ALP and High GGT

A

Excess alcohol intake

37
Q

Albumin

A
  • Major circulating plasma protein
  • Synthesised in the liver alone
  • Low concentration is associated with hepatic synthetic function
  • Has a long half-life of 21 days
  • It can appear normal in acute hepatitis
  • Acute or chronic destructive liver diseases of moderate severity show decreased serum albumin.
  • Decreased in albumin also consistent with:
    • > Haemodilution: drop-in albumin in pregnant women as more volume
    • > Impaired synthesis e.g. malnutrition
    • > Increased loss e.g. nephrotic syndrome
    • > Inflammatory leak
  • The values may be normal in well-compensated liver disease
38
Q

What is albumin a marker for?

A

It is a crude marker of synthetic function - helps with plasma necrotic pressure.

39
Q

Which is more prevalent: non-alcoholic fatty liver disease (NAFLD) or alcoholic liver disease?

A

NAFLD is more prevalent than alcoholic liver disease

40
Q

Prevalence of NAFLD

A
  • 20% in the general population

- Up to 70% in type 2 diabetes

41
Q

Stages of NAFLD

A

Hepatic steatosis (fat >5% liver volume)
Greater risk of progressing to fibrosis, cirrhosis, HCC
In NAFLD, there is increased ALT

42
Q

Major risk factors of NAFLD

A
  • Obesity
  • Diabetes/insulin resistance
  • Hypertension
43
Q

How to distinguish between NAFLD and alcoholic liver disease?

A

Measure both AST and GGT

  • GGT is increased or normal in NAFLD but considerably increased in alcoholic liver disease
  • AST is normal in NAFLD and increased in alcoholic liver disease
44
Q

The NAFLD fatty liver fibrosis algorithm

A
  • For patients with NAFLD or liver diseases of unknown aetiology, the next step is to determine the chances of liver fibrosis.
  • FIB4 score (<1.3) or NAFLD fibrosis score (<1.455) signify a lot of risk of advanced fibrosis.
  • Higher cut off points should be used for older patients
  • Second-line tests include serum markers such as ELF and imaging modalities such as ARFI.
  • For children, the text should be consulted for modification of recommendation
45
Q

Overview of the GI tract

A
  1. Oesophagus (ingestion: release enzymes)
  2. Stomach (digestion: lower pH and release enzymes)
  3. Duodenum (digestion: small intestine; increase pH and add pancreatic enzymes and bile)
  4. Jejunum (absorption: small intestine; see below)
  5. Ileum (absorption: small intestine; see below)
  6. Colon (absorption: large intestine; stabilise pH, signal to handle incoming nutrients, modify hunger)
46
Q

What is the GI tract?

A

It is a very long tube broken down into different organs with different functions and micro-environments. Effective digestion and absorption require continuous modification of gut contents.

47
Q

How do contents move along the GI tract?

A

Via peristalsis and takes about 30% of the cardiac output

48
Q

Gastric ulcers

A
  • Caused by a break in the protective stomach mucosal lining
49
Q

Signs and symptoms of gastric ulcers

A
  • Pain in the abdomen that may come and go, and they may be eased with antacid
  • Waking up with a feeling of pain in the abdomen
  • Bloating, retching and feeling sick
  • Feeling particularly full after a normal size meal
50
Q

Common causes of gastric ulcers

A
  • Helicobacter pylori (80%)

- Use of aspirin and NSAIDs (20%)

51
Q

Helicobacter pylori

A

A helix-shaped gram-negative bacteria which survives gastric acid by secreting urease.

52
Q

H. pylori action

A
  1. First H. pylori secrete urease which neutralises the gastric acid.
  2. This allows more bacteria to come and proliferation occurs.
  3. The acid then attacks the epithelial cells which degrade them leading to peptic ulcers.
53
Q

Detection of H. pylori

A
  1. Detection of H. pylori can be done by the urea breath test which is a non-invasive procedure.
  2. The patient drinks a solution containing urea labeled with an known isotope.
  3. The detection of isotope-labeled carbon dioxide in exhaled breath indicates that urea was split by the H. pylori secreting urease in the stomach.
54
Q

Vitamin B12

A

A water-soluble vitamin that has an essential role in the nervous system and the formation of red blood cells as a co-factor for DNA synthesis. It cannot be produced in the body and so is obtained from diet.

55
Q

Vitamin B12 absorption

A
  1. When vitamin B12 enters the body, it becomes bound to intrinsic factors secreted by parietal cells of the stomach.
  2. The B12-IF complex enters the intestine where it binds to receptors on the mucosal cells of the ileum and is absorbed into the blood stream.
  3. The liver contains large stores of vitamin B12, therefore it can take a long time for vitamin B12 deficiency to present itself.
56
Q

Pernicious anaemia

A

An autoimmune attack on the gastric mucosa which causes severe vitamin B12 deficiency. This leads to the atrophy of the stomach wall and the IF secretion is absent or depleted.

57
Q

Signs and symptoms of pernicious anaemia

A
  • Macrocytic anaemia so increased MCV and decreased Hb
  • Weakness and tiredness
  • Pale skin
  • Glossitis = inflammation of the tongue
  • Nerve problems such as numbness or tingling due to myelin sheath abnormalities.
58
Q

Testing for Vit. B12 deficiency

A
  • Low serum vitamin B12 levels (<150) indicate a vitamin B12 deficiency
  • Methylmalonic acid (MMA) is elevated in vit. B12 deficiency but can also be elevated in renal disease
  • Homocysteine is also elevated in vit. B12 deficiency due to not being converted to methionine.
  • However, although it is a readily available test, it is less specific than MMA because it is also elevated in folate deficiency and hypothyroidism
  • Measurement of B12 bound transcobalamin may be the first detectable marker for B12 deficiency
  • Intrinsic factors and anti-parietal cell antibodies are positive in pernicious anaemia
59
Q

Coeliac disease

A

An autoimmune disorder affecting the small intestine. The disease results from immunological hypersensitivity to ingested gluten protein (gliadin)
- Upon exposure to gluten in the small intestine, there is an inflammatory reaction leading to the shortening of the villi lining and villous atrophy.

60
Q

Signs, symptoms and who does coeliac affect?

A
  • Affects up to 1% of the population can present at any age
  • Classic symptoms of coeliac disease include anaemia, weight loss, GI problems such as diarrhoea, abdominal distension and malabsorption.
  • Severe coeliac disease can lead to anaemia and osteoporosis
61
Q

Testing for coeliac diease

A
  • Test for levels of IgA: low levels of IgA result in IgA deficient patients with coeliac disease as a proportion of the healthy population are deficient in IgA, therefore this test will produce low levels (false negative)
  • An alternative test can use in these patients which is IgG deamidated gliadin peptide antibodies (DGP)
  • Other tests are:
    • > Endomysial antibodies (EMA) which become elevated as part of ongoing damage to the intestine
    • > A duodenal biopsy is the gold standard of coeliac disease
    • > Gluten challenge: patients already on gluten-free diets cannot be diagnosed as serology and histology tests will be normal until gluten is ingested
62
Q

Tissue transglutaminase antibodies

A
  • TTG is an enzyme that deaminates glutamine residues to glutamic acid on the gliadin fragment
  • TTG can act as an autoantigen in the immune response leading to destruction of intestinal epithelial cells and the production of anti-TTG antibodies
  • Anti-TTG antibodies is a subclass of IgA, in coeliac disease: high levels are expected.
63
Q

Inflammatory bowel disease (IBD)

A

Two distinct autoimmune conditions of the GI tract, which are ulcerative colitis and Crohn’s disease
Clinical presentations of IBD is the same in both types

64
Q

What is the test for IBD?

A

Colonoscopy

65
Q

Ulcerative Colitis

A

Diffuse inflammation affecting the mucosa of the colon only

66
Q

Crohn’s disease

A

Patchy ulceration affecting any part of the GI tract and may extend through the full thickness of the bowel.
Complications include fistulae, abscess formation, and structuring

67
Q

Clinical presentation of IBD

A
  • Abdominal pain
  • Prolonged diarrhoea with bowel urgency
  • Blood and/or mucus in stools
  • Fatigue
  • Weight loss and malnutrition
  • Crohn’s disease may also be present with: Perianal lesions, Bowel obstruction such as abdominal bloating, distension, vomiting or constipation
68
Q

Irritable Bowel Syndrome

A
  • Not a disease but a functional disorder presenting with vague GI symptoms - whereas IBD is inflammation of the intestinal system
  • Only distributed in the area of intestines; whereas GI has extraintestinal manifestations
  • Not treated with anti-inflammatory medications
  • Surgical interventions are not necessary
  • Important to look at the biomarkers to determine whether it is IBS or IBD so that money is not wasted on unnecessary procedures such as colonoscopy.
69
Q

Calprotectin

A
  • Cytosolic protein content in neutrophils
  • Excreted in stools
  • Any disturbance in the mucosal architecture due to the inflammatory process results in the leakage of neutrophils and calprotectin
70
Q

Faecal calprotectin

A
  • Zinc and calcium-binding protein released by neutrophils in inflammation
  • Stable in stools and extracted and measured using a fluorescence enzymes immunoassay
  • Useful for differentiating IBS and IBD in younger age groups
71
Q

Colorectal Cancer

A
  • Third most common malignancy in the western world
  • Arises predominantly from adenomatous polyps
  • Often asymptomatic until late-stage disease (poor prognosis)
  • Early detection greatly improves prognosis, and the condition is now routinely screened for in individuals > 60y.
  • Tests must detect small amounts of blood in faeces that may be present in asymptomatic individuals with bowel lesions
  • Guaiac faecal occult blood (FOB) method widely used in screening, however, there are a lot of interferences with this method
72
Q

Faecal Immunochemical Test (FIT)

A
  • Dipstick test for blood in the stool
  • Higher sensitivity than Guaic FOB method
  • It is a guide referral for suspected colorectal cancer patients who do not meet the criteria for a suspected cancer pathway patient
  • Patients must meet the criteria:
    • > Over 50y with unexplained abdominal pain or weight loss
    • > 50 to 60y with changes in bowel habit or iron-deficiency anaemia
    • > 60y or over with anaemia without iron deficiency
73
Q

Measurement of FIT

A
  • Quantitative measurement of Hb in faeces

- OC sensor kit which is an immunoassay test

SEM 4: Clinical Biochemistry (7 decks)

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