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AP0510 Medical Biochemistry > Liver Function and Testing > Flashcards

Liver Function and Testing Flashcards

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USMLE® Step 1 flashcards
1
Q

Liver

A
  • Weight: ~1.2 – 1.6 kg
  • 4 lobes
  • Blood supply: hepatic artery (25%), portal vein (75%)
  • Majority of blood from GI tract
  • “First pickings” of absorbed nutrients
  • Multifunctional: one of the most important metabolic organs in the mammalian body
  • only human organ that can regenerate itself
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2
Q

Processes that liver is involved in

A
  • Waste management and treatment
  • Recycling
  • Production and storage of many essential molecules
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3
Q

Liver in carbohydrate metabolism

A
  • Major role in maintaining blood glucose levels
  • Synthesis and storage of glucose units as glycogen (animal starch) during periods of carbohydrate availability
  • During fasting glucose levels maintained by glycogenolysis
  • Gluconeogenesis occurs mainly in the liver
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4
Q

Liver in lipid metabolism

A
  • Synthesis of almost all lipoproteins, phospholipids, cholesterol and endogenous triglycerides: malfunction can have severe cardiovascular consequences
  • Breakdown products of cholesterol are excreted in bile
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5
Q

Liver in protein synthesis

A
  • Plasma proteins including special carrier proteins and coagulation factors are synthesised in hepatic cells
  • Immunoglobulins are not synthesised in the liver
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6
Q

Cofactors

A
  • Vitamin D metabolism
  • Vitamins A, D, E, K, B9 (folate) and B12 are stored in the liver along with copper and fats
  • most important site of iron storage
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7
Q

Liver in excretion and detoxification

A
  • Detoxification of xenobiotics (drugs, toxins etc..)
  • Conversion of ammonia to urea
  • Conjugation of various compounds with ‘solubility-enhancing modifications’ such as glucuronation and sulfation to improve excretion: cholesterol, bilirubin, toxins
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8
Q

What happens after senescence of RBCs

A
  • erythrocytes, average life span: 120 days

- released Hb is split into globin (protein) and haem (Fe-containing porphyrin system)

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9
Q

Steps in bilirubin metabolism

A
  • Haem degraded to bilirubin via biliverdin by haem oxygenase and bilverdin reductase
  • Bilirubin complexed with albumin and complex is transported to liver
  • Hepatocytes take up bilirubin-albumin complex
  • Conjugation of bilirubin with glucuronides to increase solubility and subsequent secretion in bile
  • Bacterial breakdown to urobilinogens (excreted in faeces). ~20% urobilinogen reabsorbed and re-excreted in bile and urine
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10
Q

Bacterial breakdown to urobilinogens

A
  • Urobilinogen and stercobilinogen are colourless
  • Bilirubin-derived pigments responsible for colour of urine (urobilin) and faeces (stercobilin)
  • Pale stool can indicate problems with bilirubin metabolism
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11
Q

Bilirubin - protective role

A
  • Yellow pigment responsible for jaundice: potential cause of permanent brain damage or death in newborn babies
  • 1987: publication of a study which demonstrated that bilirubin has antioxidant property in vitro
  • Considerable evidence: minute amount (nanomolar) has important protective function, damage caused by highly reactive free radicals
  • Inverse relationship between serum bilirubin concentration within the reference range and future risk of coronary artery disease (CAD)
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12
Q

What is liver function testing used for?

A
  • Assessing the most likely type of disease and possible underlying causes
  • Determining the severity/stage of the disease
  • Monitoring response to treatment
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13
Q

Tests that can detect abnormalities in liver function

A
  • Indirect measures: Total Bilirubin (and derivatives) levels in blood and urine, Total protein and albumin levels in plasma, Prothrombin time
  • Measurement of enzymatic activity that has ‘leaked’ into the plasma due to hepatocellular damage, Alanine (ALT) and Aspartate (AST) aminotransferases
  • Other enzymatic activities used to indicate abnormalities in liver function, Alkaline phosphatase (ALP), gamma-Glutamyl Transferase (GGT)
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14
Q

Direct bilirubin (measurement in serum)

A
  • primarily conjugated bilirubin
  • all water soluble bilirubin
  • formation of azidopyroles: add diazonium salt directly to sample. Will react with conjugated bilirubin
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15
Q

Indirect bilirubin (measurement in serum)

A
  • unconjugated bilirubin

- calculated as the difference (= Total–Direct)

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16
Q

Total bilirubin (measurement in serum)

A
  • sum of conjugated and unconjugated
  • both forms, unconjugated bilirubin is solubilized by an accelerator (caffeine-sodium benzoate)
  • formation of azidopyroles: add caffeine-sodium benzoate reagent followed by diazonium salt. All bilirubin will react
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17
Q

What happens at the end of reaction (measurement of bilirubin in serum)

A
  • Add ascorbic acid to stop the reaction
  • Add alkaline tartrate to produce the blue-coloured form of the azidopyroles
  • Measure absorbance = 600 nm
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18
Q

Measurement of bilirubin in urine

A
  • Same principle as for serum, but with a different diazonium salt
  • Has to be done on fresh urine
  • Only conjugated bilirubin ends up in the urine (unconjugated bilirubin is water insoluble)
  • Test will detect about 3 mmol/L
  • False positive found in patients on large doses of chlorpromazine
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19
Q

Measurement of urobilinogen in urine

A
  • p-dimethylaminobenzaldehyde and an acid buffer which reacts with urobilinogen
  • Will detect urobilinogen in urine from some normal subjects
  • False positives occur with p-aminosalicylic acid and some sulphonamides
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20
Q

Measurement of protein

A
  • Total protein of biological fluids: (serum, urine, cerebral spinal fluid (CSF))
  • Biuret test: under alkaline conditions cupric ions (Cu2+) react with proteins with at least two peptide bonds
  • Reagent contains Na+/K+-tartrate to form complex with the Cu2+ ions and maintain solubility in alkaline solution, iodide included as antioxidant
  • absorbance of Cu+-protein complex at 540 nm directly proportional to concentration of protein in the sample
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21
Q

Conditions of measurement of total protein

A
  • Either serum or plasma may be used for biuret assay but serum is preferred
  • fasting specimen is desirable (not essential) to decrease risk of lipaemia
  • Haemolysis should be avoided
  • Specimens that have been frozen and thawed should be thoroughly mixed before assay
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22
Q

Properties of albumin

A
  • Globular protein with a molecular mass of 66.3 kDa
  • Normally: most abundant protein in plasma (~½ the protein mass)
  • Levels range: 35-50 g/L
  • Abnormally high levels are a consequence of dehydration
  • Levels typically lower in hospital in-patients
  • Synthesized primarily by the liver
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23
Q

Functions of albumin

A
  • Maintenance of colloidal osmotic pressure (COP) in both vascular and extravascular spaces, with continuous equilibrium between them (primary)
  • Transport of a large number of compounds including free fatty acids, metallic ions, hormones, drugs and bilirubin
24
Q

Measurement of albumin

A
  • Typical: automated dye-binding methods which use bromocresol green (BCG) or purple (BCP) dyes - great affinity for albumin
  • absorbance of albumin-BCG complex is measured at 628 nm, is proportional to albumin concentration in the sample
  • use of serum rather than plasma is recommended: overestimate albumin in the presence of fibrinogen and heparin
  • Erroneous if overall serum protein pattern is abnormal
25
Q

a-Fetoprotein (AFP): Fetal Albumin

A
  • Normally present in foetal serum and to lesser extent maternal serum and urine (clears fast)
  • Abnormal levels can indicate birth defects
  • Detection via antibody test
  • Normally undetectable beyond infancy
  • Elevated levels in males and non-pregnant females can indicate several tumours: Hepatocellular carcinoma, Metastases affecting the liver
26
Q

Measurement of prothrombin time

A
  • Most coag factors are produced in the liver
  • Measured in blood plasma from blood sample with added anticoagulant citrate (binds Ca2+)
  • Coag is started by adding: excess Ca2+ to reverse the effect of the citrate, thromboplastin (factor III, degrades in sample, so needs to be added to start the reactions)
  • Coag time is measured optically
27
Q

Measurement of Alanine Aminotransferase (ALT)

A
  • ALT converts l-alanine to pyruvate. The latter can be detected via follow-up reactions
  • Monitor decrease in absorbance at 340 nm
  • Incubate sample with 2,4-dinitrophenylhydrazine for 20 min, stop reaction by adding a strong base
28
Q

Measurement of Aspartate Aminotransferase (AST)

A
  • AST converts l-aspartate to oxaloacetate. The latter can be detected via follow-up reactions
  • Monitor decrease in absorbance at 340 nm
  • Incubate sample with 2,4-dinitrophenylhydrazine for 20 min, stop reaction by adding a strong base
29
Q

Measurement of Alkaline Phosphatase (ALP)

A
  • ALP activity is determined by measuring rate of conversion of pNPP to pNP in presence of Mg2+ and Zn2+
  • change in absorbance is measured at 410/480 nm (ideally 415 nm), directly proportional to ALP activity – yellow colour
30
Q

Measurement of gamma-Glutamyl Transferase (GGT)

A
  • GGT catalyses transfer of g-glutamyl group from substrate, g-glutamyl-3-carboxy-4-nitroanilide to glycylglycine, yielding yellow-coloured 5-amino-2-nitrobenzoate
  • change in absorbance is measured at 405 nm, directly proportional to GGT activity in the sample
31
Q

Non-laboratory tests

A
  • Ultrasound: good for visualising large bile ducts, fatty liver, large masses; cheap, non-invasive; unable to detect inflammation/cirrhosis (unless advanced)
  • ERCP (Endoscopic retrograde cholangio-pancreatography): can visualise smaller bile ducts, head of pancreas; expensive, invasive
  • Liver Biopsy: can see hepatic pathology, hepatocytes; gold standard; expensive, invasive
32
Q

What is the underlying pathology detected with which test?

A
  • Hepatocellular damage: leakage of particular enzymes into the extracellular fluid (plasma); Alanine (ALT) and Aspartate (AST) aminotransferases
  • General impairment of metabolism: lack of albumin and coagulation factors (prothrombin time), bilirubin levels (not exclusive to liver function)
  • Biliary tract involvement: increased levels of ALP and GGT, bilirubin levels
  • Bilirubin levels generally only affected in the long-term
33
Q

Causes of Biliary Obstruction

A
  • impaired bile secretion: cystic fibrosis, inflammation (sepsis, hepatitis), toxins, drugs (inhibit bile transport), hormones
  • obstruction of bile flow: primary biliary cirrhosis, primary sclerosing cholangitis, gallstones, tumours (Ca head of pancreas, metastatic cancer, etc)
34
Q

Aminotransferases

A
  • AST isn’t specific to hepatocyte damage, can also be raised due to myocardial infarction, ALT is specific to hepatocyte damage
  • Leak out of damaged hepatocytes
  • AST:ALT ratio sometimes useful (if >1 and total levels elevated, cause most likely not liver-related)
  • Non-hepatic causes of elevated AST & ALT: coeliac disease, haemolysis, hyperthyroidism
35
Q

gamma-glutamyltransferase (GGT)

A
  • Most sensitive indicator of hepatobiliary disease but is not specific
  • Produced in hepatocytes and biliary epithelial cells but also pancreas, renal tubules and intestine
  • Many drugs induce GGT synthesis causing elevated plasma levels despite normal liver function e.g. phenytoin, barbiturates, alcohol
  • Also associated with CVD and other clinical conditions e.g. pancreatic disease, MI, COPD, renal failure, DM
  • If other tests of hepatocellular damage are normal, a high level may suggest liver disease
36
Q

Jaundice/Hyperbilirubinaemia

A
  • Cause: abnormal metabolism or retention of bilirubin
  • External characteristic: brownish-yellow pigmentation of skin, sclera and mucous membranes
  • Not exclusively associated with liver disease
  • Not all liver diseases cause hyperbilirubinaemia
37
Q

Unconjugated Hyperbilirubinaemia

A
  • Excess of bilirubin is unconjugated - Jaundice (in adults levels) rarely exceeds 100 mmol/L
  • Not result of liver disease but due to either: haemolysis: increased bilirubin production, gilbert’s syndrome: decreased conjugation activity in liver (harmless in isolation), transient neonatal jaundice: liver enzymes not yet fully active
  • Excess bilirubin exceeds capacity of liver to remove and conjugate the pigment
  • More bilirubin is excreted in bile and urinary urobilinogen is increased
38
Q

Conjugated Hyperbilirubinaemia

A
  • Leakage of bilirubin from liver cells or biliary system into bloodstream - normal excretion route is blocked
  • Water-soluble conjugated bilirubin entering systemic circulation is excreted in urine - deep orange-brown colour
  • Complete biliary obstruction - no bilirubin reaches gut, no urobilin is formed and stools are pale
  • Separate measurement of conjugated and unconjugated bilirubin - assess relative contributions of defective conjugation and other causes
39
Q

Types of jaundice

A
  • Prehepatic: increased bilirubin production, haemolysis
  • Hepatic: defect in bilirubin metabolism (impaired uptake/conjugation/secretion), genetic defects, primary liver disease
  • Posthepatic: defect in bilirubin excretion, bile duct obstruction, pancreatic head Ca
40
Q

Causes of prehepatic jaundice

A
  • Causes of haemolytic jaundice: acute or chronic haemolytic anaemia, neonatal physiological jaundice
  • Underlying causes: inherited RBC disorders, Vit B12 deficiency, Blood type (A, B, AB, 0) and rhesus factor (+/-) incompatibility, drugs
41
Q

Prehepatic jaundice

A
  • Increased destruction of RCs brings larger load to liver than it can handle
  • Additional bilirubin is conjugated and excreted into intestinal tract, increased amount of urobilinogen is formed in colon
  • Some is reabsorbed and returned to liver
  • Liver can’t pick up large amounts of urobilinogen - increased amounts excreted in urine
  • determination of urobilinogen in urine and stool are useful in diagnosis of haemolytic anaemia
42
Q

Conjugation failure (hepatic jaundice)

A
  • Crigler-Najjar disease: deficiency of UDP-glucuronyl transferase (less severe: Gilbert’s syndrome: decreased UDP-glucuronyl transferase activity)
  • Neonatal physiological jaundice (transient)
43
Q

Post-conjugation failure (hepatic jaundice)

A
  • Dubin-Johnson syndrome: mutation in multidrug transporter prevents transport of conjugated bilirubin into the bile
44
Q

Hepatic jaundice

A
  • Viral, toxic hepatitis and cirrhosis involve overall damage, necrosis of liver cells
  • Injured cells lose ability to remove and conjugate bilirubin = increase in unconjugated bilirubin
  • damaged cells provide a path for leakage of bilirubin glucuronides back into the sinusoids = increase in conjugated bilirubin as well
  • Not capable of removing all the urobilinogen from portal blood and more reaches the general circulation
  • Kidney excretes excess urobilinogen and conjugated bilirubin into the urine in appreciable quantities
45
Q

Post-hepatic jaundice

A
  • obstruction of common bile duct by: stones, neoplasms, spasms or strictures
  • Produces a condition known as obstructive jaundice
  • Conjugated bilirubin can’t reach intestine, so no urobilinogen is produced for recirculation to liver or excretion in stool
  • Faeces vary in colour from light brown to chalky white
  • Urine doesn’t contain urobilinogen but does contain appreciable amounts of conjugated bilirubin
  • blood contains increased amounts of unconjugated and conjugated bilirubin, caused by regurgitation and liver cell impairment
46
Q

Obstructive Cholestasis

A
  • Typically accompanied by elevated ALP

- Can cause secondary hepatic damage

47
Q

Liver disease

A
  • Severe consequences of liver diseases due to central role in many vital processes
  • Eg: Hepatic encephalopathy due to ammonia build-up in blood (ammonia detoxification is impaired)
  • liver is a resilient organ: damage needs to be substantial in order for clinical abnormalities to manifest themselves
48
Q

Most common diseases affecting the liver

A
  • Hepatitis with hepatocyte damage
  • Cirrhosis
  • Tumours (often secondary)
49
Q

Toxic hepatitis

A
  • Damage by external toxins: paracetamol (acute overdose), carbon tetrachloride, alcohol
  • Long-term alcohol abuse can also cause cirrhosis
50
Q

Causative agents of viral hepatitis

A
  • Hepatitis A, B, C, D, E and G
  • Epstein-Barr
  • cytomegalovirus
51
Q

Viral hepatitis (I)

A
  • B, C and D: contracted through blood of infected person (unsafe injection or unscreened blood transfusion)
  • B and C also through unprotected sex
  • D only infects persons infected with B
  • A and E typically transmitted via contaminated water or food - closely associated with poor sanitation and poor personal hygiene
  • At present effective vaccines are available for all hepatitis types except C
52
Q

Viral hepatitis (II)

A
  • severe cases of hep B or C hepatic failure may develop
  • some cases of hep B, persistent antigenaemia occurs, may lead to development of chronic liver disease
  • Hep A infection never leads to chronic disease - a full recovery within 2 months with no permanent liver damage
  • 20% of patients with hep C will develop cirrhosis over a period of 20-30 years – liver transplant
  • Chronic hep C infection is also associated with increased risk of developing liver cancer
53
Q

Viral hepatitis diagnosis

A
  • hepatocellular injury is due to host immune reactions against virus infected cells
  • During early acute phase plasma aminotransferases rise, with concentrations >50X the normal reference limit
  • As acute illness subsides aminotransferase activity returns to normal
  • Aminotransferases may be moderately elevated for longer in chronic cases
  • Plasma bilirubin levels rise more slowly, peaking at 10-20X the reference limit
  • ALP and GGT activities are generally only mildly elevated
54
Q

Cirrhosis

A
  • Liver fibrosis - the accumulation of tough, fibrous scar tissue in liver
  • Over time results in cirrhosis of the liver - functional capacity of liver becomes disrupted
  • Further serious complications may include portal hypertension, liver failure and liver cancer
  • Irreversible
55
Q

Causes of cirrhosis

A
  • chronic excessive alcohol intake
  • autoimmune disease
  • persistence of hepatitis B virus
  • metabolic diseases e.g. Wilson’s disease
56
Q

Cirrhosis diagnosis

A
  • detecting and assessing liver fibrosis: trans-abdominal needle biopsy of the liver
  • Painful and hazardous and is time-consuming and subject to inter-observer variability = poor reference standard
57
Q

Indirect markers for fibrosis

A
  • Markers released into the blood due to liver inflammation (ALT and AST)
  • Markers synthesised, regulated or excreted by the liver (clotting factors, cholesterol, bilirubin)
  • Processes that become disturbed by impaired liver function (insulin resistance)

AP0510 Medical Biochemistry (21 decks)

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