ChemPath 23: Enzymes and Cardiac Markers

Question 1

Where are most enzymes found?

Answer 1

Intracellularly

Question 2

What are the two types of intracellular enzymes?

Answer 2

Cytosolic

Subcellular (w/in organelles)

Question 3

Describe the order of release of intracellular enzymes when cells are damaged

Answer 3

Cytosolic are released first, followed by subcellular

Question 4

In which tissues is ALP present in high concentrations?

Answer 4

Liver

Bones

Intestines

Placenta

Question 5

What is an increase in bone ALP caused by?

Answer 5

Increased osteoblast activity

Question 6

What technique is used to separate isoenzymes?

Answer 6

Electrophoresis

Question 7

List some physiological causes of high ALP.

Answer 7

Pregnancy – 3rd trimester (from placenta)

Childhood – growth spurt

Question 8

List some causes of very high ALP (> 5 x upper limit of normal).

Answer 8

Bone – Paget’s disease, osteomalacia

Liver – cholestasis, cirrhosis

Question 9

List some causes of moderately raised ALP (< 5 x upper limit of normal).

Answer 9

Bone – tumours, fractures, osteomyelitis

Liver – infiltrative disease, hepatitis

Question 10

Describe the ALP levels in osteoporosis.

Answer 10

It is NORMAL unless there is a fracture

Question 11

Which markers are used in acute pancreatitis?

Answer 11

Amylase

Lipase

Question 12

Where else is amylase found? - hence what other condition is it raised in ?

Answer 12

Salivary glands

NOTE: will be raised in parotitis

Question 13

What are the three forms of creatine kinase?

Answer 13

CK-MM = skeletal muscle

CK-BB = brain

CK-MB = cardiac muscle

Question 14

Describe the manifestations of statin-related myopathy.

Answer 14

Can range from myalgia to rhabdomyolysis

Question 15

List some risk factors for statin-related myopathy

Answer 15

Polypharmacy (particularly fibrates and ciclosporin and other drugs metabolised by CYP3A4)

High dose

Genetic predisposition

Previous history of myopathy

Vitamin D deficiency

Question 16

List some other causes of high CK

Answer 16

Muscle damage

Myopathy (e.g. Duchenne muscular dystrophy)

MI

Severe exercise

Physiological (Afro-Caribbeans)

Question 17

What are two other uses of enzymes in clinical medicine?

Answer 17

Markers of therapeutic response and drug toxicity (e.g. TPMT activity should be measured before starting thiopurines (e.g. azathioprine))

Reagents to measure other substances (e.g. glucose oxidase is used to measure plasma glucose)

Question 18

List three cardiac enzymes that used to be used as markers of cardiac damage

Answer 18

Myoglobin
CK-MB
Troponins

AST, LDH - used in the past but now obsolete

Question 19

Where are myoglobins found within cells?

Answer 19

Cytosol

Question 20

Where is CK-MB found within cells?

Answer 20

Within the mitochondria and nucleus

Question 21

Where are troponins found within cells?

Answer 21

Within the contractile apparatus

NOTE: there is also a free cytosolic pool of troponins

Question 22

Describe how troponin levels change with time following an MI

Answer 22

Rise at 4-6 hours post-MI

Peaks at 12-24 hours

Remains elevated for 3-10 days

So, troponins should be measured at 6 hours and 12 hours after the onset of chest pain in a suspected MI

Question 23

Outline the diagnostic criteria for MI

Answer 23

Typical rise and gradual fall in troponin or more rapid rise and fall in CK-MB with at least one of the following:

• Ischaemic symptoms
• Pathological Q waves
• ECG changes suggestive of ischaemia
• Coronary artery intervention
• Pathological findings of acute MI

Question 24

How are biomarkers used when deciding whether to thrombolyse?

Answer 24

None of the current biomarkers rise quickly enough to aid decisions regarding thrombolysis (so it is based on clinical findings and ECG)

Question 25

What are the main biomarkers used in cardiac failure?

Answer 25

ANP – from the atria BNP – from the ventricles BNP is used to assess ventricular function and can be used to exclude heart failure (high negative predictive value)

Question 26

Define 1 international unit of enzyme activity

Answer 26

Quantity of enzyme required to catalyse a reaction of 1 µmol of substrate per minute NOTE: activity is affected by assay conditions such as pH and temperature (so reference ranges may differ between laboratories)

Question 27

Comparison of Myoglobin, CK-MB and Troponins as cardiac biomarkers When does it peak?

Answer 27

Myoglobin: - Lowest peak (around 8-10 hrs after) - Shortest 1/2life so good for detecting reinfarcts (multiple MIs in short period) - Not really used in practice Myoglobin: - Lower peak (around 24 hrs after) - Next shortest 1/2life so good for detecting reinfarcts (multiple MIs in short period) - Not really used in practice Troponins: - Peak 24-48 hrs - Most sensitive and speciifc test - Ideally measure at 6 hrs and 12 hrs post MI for best sensitivity and specificity

Question 28

An 80 year old man was taken to A&E by his carers after they found him on the floor. He said he couldn’t get up after falling, and was on the floor for 18 hours. On examination, he had dry mucous membranes, low skin turgor and dark ‘tea-stained urine’. Microscopy of the urine did not identify red blood cells. Urine dip = Blood +ve What substance causes the urine to be ‘tea-stained’ in colour? Which enzyme would be raised in their blood results + how high?

Answer 28

Tea-stained urine = MYOGLOBIN due to rhabdomyolysis of muscle cells being broken down Blood results usually has raissed CK-MM - often 5x upper limit

Question 29

What marker is raised in the following conditions? ``` Heart failure Statin-related myopathy Muscular dystrophy (Duchenne, Becker) Myositis (dermato, poly) Rhabdomyolysis ```

Answer 29

Heart failure - Raised BNP Statin-related myopathy - Raised CK-MM Muscular dystrophy (Duchenne, Becker) - Raised CK-MM Myositis (dermato, poly) - Raised CK-MM Rhabdomyolysis - Raised CK-MM

Question 30

Which liver enzyme can be measure in blood and specifically suggests obstructive jaundice if levels are raised?

Answer 30

Alkaline Phophatase (ALP)

Question 31

What do the following LFT results mean: ALP + GGT high ALP > GGT GGT > ALP

Answer 31

ALP + GGT high - Billiary obstruction (gallstones, pancreatic cancer?) ALP > GGT - Bone problem (osteomalacia, pagets) - Pregnancy GGT > ALP - Recent alcohol intake

Question 32

An 82 year old man has a 3 month history of progressive deafness (sensorineural) Weber’s test – lateralisation of vibration to the left ear Rinne’s test – AC > BC in both ears Blood results are: Normal Ca, Phosphate, PTH and Raised ALP What is the most likely underlying diagnosis? - Osteomalacia - Primary hyperparathyroidism - Paget’s disease - Tertiary hyperparathyroidism - Osteoporosis

Answer 32

Pagets disease - Normal Ca, phosphate, PTH and High ALP The rinnes and webers test reveals sensorineural hearing deafness - A feature seen in Pagets

Question 33

60 year old man with a BMI of 28 was referred with abdominal pain. His LFTs are: Raised BR, ALP, AST, ALT, GGT and CK ALP is raised more than other markers What is the most likely diagnosis? - Acute pancreatitis - Alcoholic cirrhosis - Viral hepatitis - Haemolytic jaundice - Obstructive jaundice due to gallstones

Answer 33

Although everything is raised, ALP is most raised suggestive of an obstructive cause BMI is high (RF) and has referred abdo pain All these findings point towards obstructive jaundice due to gallstones

Question 34

60 year old man with a BMI of 28 was referred with abdominal pain. His LFTs are: Raised BR, ALP, AST, ALT, GGT and CK AST is raised more than other markers What is the most likely diagnosis? - Acute pancreatitis - Alcoholic cirrhosis - Viral hepatitis - Haemolytic jaundice - Obstructive jaundice due to gallstones

Answer 34

Although everything is raised, AST is most raised suggestive of alcoholic cause (alcoholic hep) Can see AST:ALT ratio 2:1 or

Question 35

What do the following LFT results mean: AST + ALT are high AST > ALT ALT > AST

Answer 35

``` AST and ALT are high: Hepatocyte damage (e.g. hepatitis) ``` ``` AST > ALT: Alcoholic hepatitis (S for Smirnoff) - 2:1 ratio or greater often ``` ``` ALT > AST: Viral hepatitis (L for ViraL) ```

Question 36

What are the following tumour markers used for? ``` CA 125 CA 19-9 PSA CEA AFP ```

Answer 36

CA 125 - Ovarian cancer CA 19-9 - Pancreatic cancer, cholangiocarcinoma PSA - Prostate cancer CEA - Colorectal cancer AFP - HCC, Testicular cancer (teratoma)

Question 37

A man presents with a swollen, inflamed metatarsal joint. A needle aspirate is performed with microscopy identifying needle shaped crystals with negative birefringence. Which enzyme manufactures the material that makes up the crystal? mx of this condition?

Answer 37

Negativ birefringence = Gout - the enzyme responsible is Xanthine Oxidase This is why the treatment of gout can involve the use of Xanthine Oxidase inhibitors such as Allopurinal

Question 38

What conditions are the following nuclear medicine imaging tests used for? Gallium-68-Dotate

Answer 38

Gallium-68-Dotate | - Primary NETs (Neuroendocrine tumours) eg insulinoma, gastrinoma

Question 39

What conditions are the following nuclear medicine imaging tests used for? FDG-PET

Answer 39

FDG-PET | - Abdominal mets

Question 40

What conditions are the following nuclear medicine imaging tests used for? Tech99-sestamibi

Answer 40

Tech99-sestamibi | - Parathyroid disease

Question 41

What conditions are the following nuclear medicine imaging tests used for? MIBG

Answer 41

MIBG | - Phaeochromocytomas

Question 42

What conditions are the following nuclear medicine imaging tests used for? Tec99-pertechnetate

Answer 42

Tec99-pertechnetate | - Thyroid disease (eg Graves)

Question 43

What conditions are the following nuclear medicine imaging tests used for? Tec99-bisphosphonate

Answer 43

Tec99-bisphosphonate | - Bone mets + Pagets