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TI2 > Lab investigation of endocrine disorders > Flashcards

Lab investigation of endocrine disorders Flashcards

1
Q

What are the main functions of the liver?

A
  • Carb metabolism (glycogenesis, glycogenolysis, gluconeogenesis)
  • Fat metabolism (cholesterol synth and bile acid production)
  • Protein metabolism (transamination)
  • Synthesis of plasma proteins (albumin etc)
  • Hormone metabolism (IGF-1, angiotensinogen)
  • Metabolism and excretion of drugs and foreign compounds
  • Storage (glycogen, vit A, B12, plus iron and copper)
  • Metabolism and excretion of bilirubin
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2
Q

What is the blood supply for the liver?

A
  • 2/3 comes from the portal vein (from gut, rich in nutrients)
  • 1/3 from the hepatic artery (rich in oxygen)
  • Blood leaves through the hepatic veins
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3
Q

What is the structure of the liver?

A
  • Each lobe has multiple liver lobules -
    hexagonal plates of hepatocytes radiating from a central vein, carrying blood from the liver
  • Each lobule further divided into acini
  • Each acini is supplied by the portal triad (hepatic artery proper, hepatic portal vein and the bile duct)
  • Substances for excretion are secreted from hepatocytes into canaliculi
  • Bile canalicli merge to form bile ductules, which merge to become the bile duct, and eventually the common hepatic duct
  • Excess bile is stored in gall bladder or secreted into duodenum via sphincter of oddi
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4
Q

What is the process of bilirubin metabolism?

A
  • in spleen, reticuloendothelial cells break Hb into haem and globin. Haem is further broken down into iron and bilirubin
  • bilirubin is insoluble, so binds to albumin (unconjugated bilirubin = 95%)
  • makes its way to the liver and taken up by hepatocytes
  • Bilirubin taken off and converted by UDP-glucuronyl transferase
  • Excess soluble bilirubin is secreed into duodenum, then converted to urobilinogen
  • This can either be taken up by gut through portal vein to liver, or excreted after production of sterobilin
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5
Q

What lab investigations can we do for bilirubin?

A
  • An increase in total bilirubin = hyperbilirubinaemia
  • Total bilirubin = un/conjugated bilirubin (and delta)
  • Direct = conjugated bilirubin (and delta)
  • Indirect = unconjugated bilirubin (calculate rather than measure)
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6
Q

What is delta bilirubin?

A
  • iireversible binding of bilirubin to albumin and so cannot be excreted
  • occurs in the presence of prolonged conjugated hyperbilirubinaemia
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7
Q

How do we measure direct bilirubin in blood?

A
  • Diazo method
  • Conjugated bilirubin (and delta) react directly with a diaznoium ion in an acidic membrane
  • The colour intensity of the red azobilirubin dye is directly proportional to direct bilirubin conc when measured at 546nm
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8
Q

How do we measure total bilirubin in blood?

A
  • Diazo method
  • Same as the direct bilirubin method, but an accelerating agent (alcohol/caffiene/sodium benzoate) is used in a strongly acidic medium, causing dissociation of uncojugated bilirubin from albumin
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9
Q

How can we measure bilirubin in urne?

A
  • Simple dipstick method
  • As unconjugated bilirubin is protein bound - not normally found in urine. Thus the presence of bilirubin in the urine will turn the urine a brown colour
  • Seen in cases of hepatitis or impaired flow of bile in patients with biliary obstruction
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10
Q

How do we measure urobilinogen in urine?

A
  • If there is urobilinogen in the urine, it demonstrates that bilirubin is reaching the gut - detected by dipstick
  • Excess urobilinogen in urine may indicate liver disease such as viral hepatitis and cirrhosis or hameolytic conditions associated with increased RBC destruction
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11
Q

How can you tell if bilirubin is in faeces?

A
  • Stools appear pale in colour as there is no stercobilin
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12
Q

What is jaundice?

A

Yellow discolouration of tissue due to bilirubin deposition

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13
Q

What causes jaundice?

A
  • Haemolysis - increased bilirubin production - Acquired autoimmune haemolytic jaundice, drug induced and spherocytosis
  • Hepatocellular damage (impaired bilirubin metabolism) - toxins or infections
  • Cholestasis (decreased bilirubin excretion) - cirrhosis, tumours or gallstones
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14
Q

What are LFTs?

A
  • Insensitive indicators of hepatic function, but can be highly sensitive indicators of liver damage
  • Rarely provide diagnosis on their own
  • Usually includes Total bilirubin, ALT, ALP, Gamma GT and albumin
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15
Q

What is ALT?

A
  • Alanine aminotransferase
  • IC cytoplasmic enzyme that catalyses the transfer of an amino group from alanine to 2-oxyglutarate
  • Most specific marker for liver injury (with GGT)
  • ALT is also expressed by kidneys, and cardiac and skeletal muscle - so better to look at all LFTs together
  • Used to identify liver damage arising from hepatocyte inflammation of necrosis
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16
Q

What is AST?

A
  • Aspartate aminotransferase
  • An IC cytoplasmic and mitochondrial enzyme catalysing the transfer of an amino group from aspartate to 2-oxyglutarate
  • Less liver specific than ALT, little use in measuring both enzymes
  • Only indication of measuring both ALT and AST is to determine the AST:ALT (<0.8 suggests non-alcoholic fatty liver disease, >1.5 it is more likely to be alcoholic liver disease)
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17
Q

What is GGT?

A
  • Gamma glutamyl transferase
  • Membrane bound enzyme that transfers gamma glutamyl group from peptides like glutathione to other peptides and to L-amino acids
  • Relatively specific marker for liver injury as it is found on the canalicular membrane of hepatocytes
  • Increases in GGT are looked at in conjunction with the ALP result
18
Q

What is ALP?

A
  • Alkaline phosphatase
  • membrane bound glycoprotein enzyme that removes phosphate molecules from proteins and nucleic acids; maximum activity of pH 9-10.5
  • Found in a number of tissues, greatest concentrations in bone, liver, intestine and placenta
  • Of major value in the diagnosis of cholestatic disease along with GGT - cholestasis stimulates enhanced synthesis of liver ALP (enzyme induction)
  • Elevated in children and correlates well with rate of bone growth, also increased in pregnant women due to placenta
19
Q

How do we interpret different ALP and GGT results?

A
  • Increased both - suggestive of hepatic cause (usually due to cholestasis)
  • Increased ALP and normal GGT - suggestive of bone source of ALP
  • Normal ALP and increased GGT - suggestive of excess alcohol intake
20
Q

How can we determine the source of elevated ALP?

A
  • Electrophoresis
  • Can separate ALP isoenymes into liver, bone and intestinal fractions based on their charge
  • Unlike others, placental isoenzyme of ALP can be indentified as it is heat stable at 36C for 10 mins
21
Q

What is albumin?

A
  • Essential plasma protein - maintains plasma oncotic pressure (to stop leakage from vessels) and binds several hormones, drugs, anions and FAs
  • Crude indicator of the synthetic capacity of the liver due to its long half-life and because its levels can be creased by the acute phase response
22
Q

How can we measure ALT?

A

Measure its catalytic activity rather than its mass

  • L-Alanine + 2-oxyglutarate –> ALT –> pyruvate + L-glutamate
  • Pyruvate + NADH + H+ –> Lactate dehydrogenase –> L-lactate + NAD+
  • The rate of NADH oxidation is directly proportional to the catalytic ALT activity. NADH oxidation is determined by measuring its decrease in absorbance at 340nm
23
Q

How do we measure AST?

A
  • Assayed the same way as ALT, with alanine being replaced with aspartate and oxaloacetate being produced rather than pyruvate
24
Q

How do we measure GGT?

A

GGT to catalyse the transfer of a gamma- glutamyl group from the donor L-γ-glutamyl-3-carboxy-4-nitroaniline to a glycine acceptor. This reaction yields 5-amino-2-nitrobenzonate, which absorbs at 415 nm (Theodorsen reaction). The rate of formation of 5-amino-2-nitrobenzonate is directly proportional to the activity of GGT in the sample

25
Q

How do we measure ALP?

A

The cleavage of p-nitrophenyl phosphate by ALP yield phosphate and p-nitrophenol. The p-nitrophenol released absorbs at 450 nm, which is directly proportional to the catalytic activity of ALP.

26
Q

How do we measure albumin?

A

Dye binding assay: at a pH of 5.2-6.8 Bromcresol purple (BCP) binds with albumin, causing a change in absorbance that is measured at 600 nm.

27
Q

What is the anatomy of the GIT?

A
  • 7-10m continuous tube that runs from the mouth to the anus
  • Encased in layers of voluntary and involuntary muscle
  • Effective digestion and absorption requires a continuous modification of gut contents
  • hormone signalling allows different parts of the GIT to switch on and switch off - Enteric endocrine system
28
Q

What causes gastric ulcers?

A
  • Caused by a break in the protective mucosal lining of the stomach, allowing acid to damage the underlying epithelium
  • 80% caused by H.pylori infection
  • 20% caused by use of NSAIDs
29
Q

What are signs of gastric ulcers?

A
  • Pain in the abdomen - may come and go
  • Waking up with pain in abdomen
  • Bloating, retching and feeling sick
  • Feeling particularly full after normal sized meal
30
Q

How does H.pylori cause ulcers?

A
  • Flagellum allows it to burrow through the mucus to the epithelial cells using corkscrew motility
  • It then secretes urease, which causes the neutralisation of the gastric acid around it - allowing it to survive and proliferate
  • They can then damage the mucosal layer and cause epithelial damage
31
Q

How can we detect H.pylori infection?

A
  • Urea (hydrogen) breath test - rapid and non-invasive procedure
  • Pt swallows urea labelled with an uncommon isotope (radioactive C14 or non-radioactive C13)
  • The detection of the isotype-labelled CO2 in exhaled breath indicates that the urea was split, indicating that urease is present, and so H.pylori is present
32
Q

How do we absorb Vit B12?

A
  • Cannot be produced by our body, so we have to get it in diet
  • B12 is water soluble vitamin that has an essential role in the NS and the formation of RBCs - co-factor for DNA synthesis
  • B12 enters the stomach and binds to IF (released by parietal cells of stomach)
  • 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
33
Q

What are the signs of B12 deficiency?

A
  • Liver can store 3-5 yrs worth of B12, so takes a long time to present
  • Macrocytic anaemia (increased MCV, decreased Hb)
  • Weakness and tiredness
  • pale skin
  • Glossitis
  • Nerve problems (numbness/tingling)
34
Q

What is pernicious anaemia?

A
  • Severe B12 deficiency is usually caused by pernicious anaemia, an autoimmune attack on the gastric mucosa
  • Leads to atrophy of the stomach wall and the secretion of IF is absent or almost absent
  • Other patients produce Abs to IF, blocking the IF-B12 complex from being absorbed in the ileum
  • If anti-IF Ab is present, pernicious anaemia is very likely, but its absence doesnt rule it out
35
Q

What is coeliac disease?

A
  • Autoimmune disorder, primarily affecting the small intestine
  • Results from immunological hypersensitivity to ingested gliadin (gluten protein) found in wheat, barley and rye
  • 1/100 people in the UK
  • Classic symptoms of coeliac disease include GI problems such as diarrhoea, abdominal distention, malabsorption and loss of appetite
  • Upon exposure to gluten in the small intestine, there is an inflammatory reaction leading to the shortening of the villi lining (villus atrophy)
36
Q

How do we test for coeliac disease?

A

A duodenal biopsy is gold standard diagnosis

- look for endomysial antibodies and TTG antibodies

37
Q

What are tissue transglutamate antibodies?

A
  • TTG is an enzyme that deaminates glutamine residues to glutamic acid on the gliadin fragment
  • The enzyme is a target autoantigen in the immune response seen in coeliac
  • IgA antibodies to TTG are found in 96% of coeliac patients
  • Also test for IgG antibodies to TTg as 1/250 people are deficient in IgA
38
Q

How do we measure TTG IgA?

A
  • Have antigen coated well
  • Add specific Ab to be measured
  • Add enzyme-conjugated secondary Ab
  • Add substrate and measure the colour given off
39
Q

What are endomysial Abs?

A
  • The endomysial is the supporting structure that surrounds the middle third of oesophagus - endomysial antibodies are indicative of coeliac
  • The test isnt as sensitive as TTG antibody test
40
Q

How do we look for endomysial antibodies?

A
  • Diluted serum/plasma samples are incubated on monkey oesophagus tissue
  • Slide is washed and fluorescein-labelled antibodies against IgA and IgG is added
  • Excess Ab is removed and slide read under microscope
41
Q

What is calprotectin?

A
  • Small calcium-binding protein that contributes to ~60% of the cytosolic protein content in neutrophils
  • In the presence of active intestinal inflammation (like in IBD) neutrophils migrate to the intestinal mucosa from circulation
  • Any disturbance in mucosa architecture due to inflammation results in leakage of neutrophils, and hence calprotectin is excreted in faeces
42
Q

How do we measure faecal calprotectin?

A
  • Use fluorescence sandwich immunoassay
  • Homogenise 100mg of faecal material
  • Use capture Ab, add faeces, if calprotectin present then it will stick, use detector Ab to stick to calprotectin with fluorescent label

TI2 (20 decks)

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