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CLINICAL PATHOLOGY > Laboratory Investigation of Liver and GI tract Disease > Flashcards

Laboratory Investigation of Liver and GI tract Disease Flashcards

1
Q

What are the major functions of the liver?

A
  • Carbohydrate, fat and protein metabolism
  • Synthesis of plasma proteins (e.g albumin)
  • Hormone metabolism
  • Metabolism and excretion of drugs + foreign compounds
  • Storage - glycogen, Vitamin A and B12, plus iron and copper
  • Metabolism + Excretion of bilirubin
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2
Q

List some of the common diseases affecting the liver

A
  • Hepatitis → Damage to hepatocytes
  • Cirrhosis → Increased fibrosis, liver shrinkage, decreased hepatocellular function, obstruction of bile flow
  • Tumours → Frequently secondary (colon, stomach, bronchus)
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3
Q

What is the general biochemical assesment of liver function?

A

Liver Function Test (LFT)

Standard profile includes:

  • Bilirubin
  • Albumin
  • Alanine aminotransferase (ALT) or Aspartate aminotransferase
  • Alkaline phosphatase
  • Gamma glutamyltransferase
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4
Q

What is the general prinicple of liver function tests?

A
  • A type of blood test
  • Is not diagnostic but is used as an aid for
    • Screening for presence of liver disease
    • Assesing prognosis
    • Measuring efficacy of treatments for liver disease
    • Differential diagnosis → Predominantly hepatic/cholestatic
    • Monitoring disease progression
    • Assesing severity → especially in patients with cirrhosis
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5
Q

Describe the metabolism of bilirubin

A
  • Bilirubin is a yellow-orange pigment derived from haem
  • RBCs are broken down in the spleen
  • Bilirubin is unconjugated (and not soluble) its transported via albumin in the circulation
  • Bilirubin will be transported to the liver where it is conjugated into a more soluble form via UDP-glucuronyl transferase
  • Bilirubin → bilirubin diglucuronide
  • Bilirubin will be excreted in the gut where it is broken down into urobilinogen
  • Urobilinogen will be converted to stercobilin (brown in faeces) via gut flora
  • Some urobilinogen will escape into extrahepatic circulation where it is excreted in urine
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6
Q

What is Jaundice?

A

Jaundice is the yellow discoloration of tissue due to bilirubin deposition (hyperbilirubinaemia)

Clinical jaundice may not be evident until the serum/plasma bilirubin concentration is 2x the upper reference of normal, >50 micromol/L

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7
Q

What are causes of Jaundice?

A
  • Haemolysis (increased bilirubin production)
    • Acquired autoimmune haemolytic jaundice, drug induced + spherocytosis
  • Hepatocellular damage (impaired bilirubin metabolism)
    • Toxins or infections
  • Cholestasis (decreased bilirubin excretion)
    • Cirrhosis, tumour or gallstones
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8
Q

Describe Neonatal Jaundice

A
  • Occurs due to immaturity of the bilirubin conjugation enzymes
  • Normally common and transient will resolve in the first 10 days
  • Pathological if there are high levels of unconjugated bilirubin → toxic to newborn
    • Due to HYDROPHOBICITY cross blood-brain barrier and cause kernicterus (brain damage due to toxic bilirubin affecting neurons)
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9
Q

When does neonatal jaundice become urgent?

A

Pale stools in babies with biliary atresia → urgent surgical treatment is essential !!!

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10
Q

How can you treat neonatal jaundice?

A

Phototherapy with UV light = converts bilirubin to water soluble non-toxic form

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11
Q

Describe Gilberts Syndrome

A
  • Results in prehepatic jaundice, Benign liver disorder
  • Caused by a genetic defect UDP-glucuronyl transferase
  • Frequency à 10% of the population
  • Characterised by mild, fluctuating increases in unconjugated bilirubin
    • Caused by decreased ability of the liver to conjugate bilirubin
  • Males more frequently affected then females
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12
Q

What does a standard liver function test include?

A
  • Total bilirubin
  • Alanine aminotransferase (ALT)
  • Alkaline phosphatase (ALP)
  • Albumin
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13
Q

Describe the lab investigations of bilirubin in plasma/blood

A

Measured in serum/plasma sample as:

  • Total bilirubin = unconjugated and conjugated bilirubin
  • Direct = conjugated bilirubin (delta bilirubin)
  • Indirect = unconjugated bilirubin (calculated)

Delta bilirubin is formed by the irreversible covalent addition of bilirubin to albumin that occurs in the presence of prolonged conjugated hyperbilirubinaemia

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14
Q

Describe lab investigations of bilirubin in urine

A
  • Bilirubin in measured in urine using a dipstick
  • Presence of bilirubin in urine indicates presence of conjugated hyperbilirubinaemia
  • Excess conjugated bilirubin will darken urine (e.g hepatitis or impaired flow of bile in patients with biliary obstruction)
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15
Q

What is the signifiance of urobilinogen in urine?

A
  • If urobilinogen is present in the urine it demonstrates that bilirubin is reaching the gut
  • Excess urobilinogen may indicate liver disease such as viral hepatitis and cirrhosis or haemolytic conditions associated with increased red cell destruction
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16
Q

What are liver transaminases? And what are they used to detect?

A
  • Most commonly markers of hepatocyte injury
  • Include ALT (alanine transaminase) + AST (aspartate transaminase)
  • Transaminases catalyse the transfer of an amino group
  • e.g ALT catalyses the transfer of an amino group from alanine to alpha-ketoglutarate
  • ALT is used to identify liver damage from hepatocyte inflammation or necrosis
    • ALT → Predominantly locallised to the liver
    • AST → has a wide tissue distribution located in the heart, skeletal muscle, kidney, brain, erythrocytes, lung + liver
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17
Q

What do elevated levels of transaminases mean?

A
  • Values >20x the upper limit of normal (ULN) may occur with severe liver damage.
    • Acute viral hepatitis, hepatic necrosis induced by drugs or toxins, ischaemic hepatitis induced by circulatory shock
  • Small increases (<5x ULN) may occur in cholestasis due to secondary damage to hepatocytes
    • Fatty liver, chronic viral hepatitis, prolonged cholestatic liver disease, cirrhosis (in compensated cirrhosis values may be normal)
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18
Q

Describe alkaline phosphatase (ALP)

A
  • Enzyme removes phosphate groups from proteins and NAs at an alkaline pH (9-10.5)
  • Enzyme isoforms mainly produced in the liver and bone but also placental intestinal forms
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19
Q

How is alkaline phosphatase used in liver diagnosis?

A
  • ALP levels will increase when there is bile duct obstruction (due to ALP synthesis)
  • Obstruction may be due to
    • extrahepatic (stones, tumour or stricture)
    • intrahepatic (infiltration or space occupying lesion)
      • ALP values >3 x ULN found in intra- & extrahepatic cholestasis
      • ALP values <3 x ULN found in hepatocellular disease
20
Q

When can alkaline phosphatase also increase but isnt liver related?

A

Increases when there is a increase in osteoblastic activity as ALP is also released by bones

For example in

  • Healing fractures
  • Vitamin D deficiency
  • Paget’s Disease
21
Q

How can ALP isoenzymes be seperated?

A
  • The source of an elevated ALP can be determined by gel electrophoresis
  • It is possible to separate ALP isoenzymes into liver, bone and intestinal fractions
  • The placental isoenzyme of ALP can be identified as it is heat stable at 65 degrees for 10 minutes unlike the other isoenzymes
22
Q

Describe gamma glutamyl transferase (GGT)

A

GGT is a membrane bound enzyme which transfers the gamma glutamyl group from peptides such as glutathione to other peptides and L-amino acids

  • Wide tissue distribution, but liver isoenzyme activity predominates in serum
  • Used in combination with ALP (increase in value confirms ALP of hepatic origin)
23
Q

What are the increases in gamma glutamyl transferase due to?

A
  • Increased levels may be due to enzyme induction by alcohol or drugs e.g. anticonvulsants.
  • Increased levels occur in cholestasis and hepatocellular disease
  • Can be increased in non-hepatic disorders, e.g. pancreatitis, myocardial infarction and diabetes mellitus
24
Q

Describe how albumin is to assess liver function

A
  • Concentration widely regarded as an indec of hepatic synthetic function
  • Can be normal in early acute hepatitis due to its long half-life (21-days)
  • Acute or chronic destructive liver diseases of moderate severity show decreased severe albumin
    • Decreases also consistent with
      • Haemodilution (e.g. in pregnant women)
      • Impaired synthesis (e.g. malnutrition)
      • Increased loss (e.g. nephrotic syndrome)
      • Inflammatory leak

But values may be well compensated in liver disease

25
Q

Describe NAFLD

A

NAFLD more prevalent than alcoholic liver disease

  • Prevalence
    • 20% in general population
    • Up to 70% in type 2 diabetes
  • Stages
    • Hepatic steatosis (fat >5% liver volume)
    • Greater risk of progressing to fibrosis, cirrhosis, HCC
  • Major risk factors
    • Obesity
    • Diabetes/ insulin resistance
  • Hypertension
26
Q

Provide a brief overview of the GI tract

A
  • Continuous tube running from mouth to anus
  • Partitioned into many sections with distinct structure, anatomy and function
  • Associated organs include liver, gall bladder and pancreas
  • GI tract is encased in layers of voluntary and involuntary muscle (contraction in waves)
  • Has a large arterial system linking different sections to the circualtion (30% of C.O.)
27
Q

What are gastric ulcers?

A
  • Caused due to a break in the protective stomach mucosal lining
    • Signs + Symptoms
      • Pain in abdomen
      • Waking up with pain in abdomen
      • Bloating, retching and feeling sick
      • Feeling full after a normal sized meal
28
Q

What are the common causes of gastric ulcers?

A
  • H.Pylori (80% of cases)
    • Helix shaped gram negative bacteria survives in gastric acid by secreting urease
  • Use of aspirin and NSAIDs (20% of cases)
    • Non-steroidal anti-inflammatory drugs
29
Q

How is H.Pylori detected?

A
  • Urea breath test
    • Patient drinks a solution containing urea labelled with a uncommon isotope (non-radioactive carbon-13)
    • The detection of isotope labelled CO2 in exhaled breath detected that urea was split by urease secreting H.Pylori
30
Q

What is vitamin B12 and why is it required?

A
  • Water soluble vitamin whcih plays a role in the formation of RBCs acting as a co-factor for DNA and cell metabolism
  • Involved in the conversion of homocysteine to methionine
  • Also known as cobalamin
  • Not produced by the body but taken up via the diet through meat and dairy products
31
Q

How does vitamin B12 get absorbed?

A
  • Vitamin B12 will bind to intrinsic factor in the stomach
  • IF is secreted by parietal cells
  • The B12-IF complex will enter the intestine where it binds to receptors on the mucosal cells of the ileum and is absorbed into the blood stream
32
Q

Describe vitamin B12 deficiency

A

Takes a long time for vitamin B12 deficiency to present itself as the liver contains a large store of vitamin B12

  • Macrocytic anaemia (increased MCV, decreased Hb)
  • Weakness + tiredness
  • Pale skin
  • Glossitis – inflammation of the tongue
  • Nerve problems such as numbing or tingling (severe deficiency)
33
Q

What is pernicious anaemia?

A

Pernicious anaemia is a autoimmune attack on the gastric mucosa causing severe vitamin B12 deficiency

  • Leads to atrophy of stomach wall and IF secretion is absent or severely depleted
34
Q

How can you test for Vitamin B12 deficiency?

A
  • Serum vitamin B12 level: <150 pmol/L indicates probably B12 deficiency
  • Methylmalonic acid → Elevated
  • Homocysteine → Elevated in B12 deficiency as it isnt converted to methionine
    • (less specific than MMA as also elevated in thyroid def + hypothyroidism)
  • Holotranscobalamin (active B12)
35
Q

How can we detect pernicious anaemia?

A

Look for antibodies for Intrinsic factor and anti-parietal cell antibodies are positive in pernicious anaemia

36
Q

What is coeliac disease?

A
  • Autoimmune disorder affecting the small intestine
  • Results from immunological hypersensitivity to ingested gliadin (gluten protein) found in wheat
  • Upon exposure to gluten in small intestine = inflammatory reaction → shortening of villi lining + villous atrophy
37
Q

What are tests of coeliac disease?

A
  • Tissue transglutaminase antibodies (TTG)
    • TTG is an enzyme that deaminates glutamine residues to glutamic acid on the gliadin fragment
    • The enzyme can be a target autoantigen in the immune response, leading to destruction of intestinal epithelial cells and production of anti-TTG antibodies
      • Anti-TTG antibodies belong to the IgA subclass, a proportion of people in the UK (1 in 700 are deficient) in IgA à would produce a false negative (IgA deficient patients with coeliac disease)
      • Alternative test à IgG deaminated gliadin peptide (DGP) antibodies
38
Q

What are other tests of coelaic disease?

A
  • Endomysial antibodies (EMA) – these become elevated as part of ongoing damage of the intestine
  • A duodenal biopsy is the gold standard diagnosis of coeliac disease
  • Gluten challenge = patients already on a gluten-free diet cannot be diagnosed as serology and histology test will be normal until gluten is ingested
39
Q

What is inflammatory bowel disease?

A

Inflammatory bowel disease encompasses 2 distinct autoimmune conditions of the GI tract → ulcerative colitis and Crohn’s disease

40
Q

What is the difference between ulcerative colitis and crohn’s disease?

A

Ulcerative Colitis → Diffuse inflammation affecting mucosa of colon only

Crohn’s Disease → Patchy ulceration affecting any part of the GI tract and may extent through the full thickness of the bowel

Complications include fistulae, abscess formation + stricturing

41
Q

What is the definitive test for IBD?

A

Colonoscopy

42
Q

What is the clinical presentation of irritable bowel disease?

A

Ulcerative colitis and Crohn’s disease have common signs and symptoms

  • Abdominal pain
  • Prolonged diarrhoea with bowel urgency
  • Blood and mucus in stools
  • Fatigue
  • Weight loss and malnutrition

Crohn’s disease may also present with:

  • Perianal lesions
  • Bowel obstruction i.e. abdominal bloating, distension, vomiting/ constipation
43
Q

What do we use to distinguish between IBD and IBS?

A

FACEAL CALPROTECTIN

  • Calprotectin is contained in 60% of the cytoplasmic neutrophil content
  • Any disturbamce in mucosal architecture due to the inflammatory process = neutrophils and calprotectin
  • Calprotectin will be excreted in the stool
  • Stable in stool, exctracted and measured using flurorescence immunoassay
  • Differentiates between IBS and IBD in younger age groups
44
Q

Describe colorectal cancer

A
  • Arises from adenomatous polyps (benign non cancerous growths of colon and rectum)
  • Is asymptomatic until late stages of the disease (poor-prognosis)
  • Early detection greatly improves prognosis and the condition is now routinely screening for individuals > 60 years
  • Tests must detect the small amounts of blood in faeces that may be present in asymptomatic individuals with bowel lesions

*

45
Q

What two methods are used for screening of colorectal cancer?

A
  • Guaic faecal blood (FOB) method = used widely in screening
  • Faecal immunochemical test
46
Q

Describe the faecal immunochemical test

A
  • ‘Dipstick’ test for blood in stool
  • Higher sensitivity than guaic FOB method
  • Testing in symptomatic patients meeting the following 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
  • OC-Sensor FIT kit (made by MAST) -immunoassay test which can be used with an automatic analyser.

CLINICAL PATHOLOGY (52 decks)

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