Enzymes and cardiac markers Flashcards
What is an enzyme?
a substance (usually a protein) that increases the rate of a chemical reaction without itself being changed in the overall process.
What is clinical enzymology?
Is the application of the science
of enzymes to the diagnosis and
treatment of disease
Why should we measure enzymes?
Identify diseases of abnormalities in enzyme concentration or function e.g. inherited metabolic diseases
To detect tissue injury
Since most enzymes are intracellular, how do we measure them?
Small amounts of the intracellular enzymes are routinely detected in plasma as a result of normal cell turnover
Levels of the intracellular enzymes increase following tissue injury
Why do enzyme levels increase?
Leaky membranes (cytosolic enzymes)
Cell necrosis (cytosolic and sub cellular enzymes)
Which enzymes come first in cell injury?
Cytosolic first, then sub-cellular
What are the ‘other’ causes of increased enzymes?
Increased synthesis
Decreased clearance
How are enzymes distributed across tissues?
Few are highly cell specific
Most others more widely distributed
Which tissues make ALP?
Liver
Bone
Placenta
Intestine
How can enzymes be markers of disease?
in serum to detect injury to a tissue that makes the enzymes (increased levels)
in the tissue to identify abnormalities in or absence of the enzymes, which may cause disease (usually decreased levels)
How can iso enzymes help?
Some enzymes may exist in different forms – iso-enzymes
Individual iso-enzymes are characteristic to particular tissues
Measuring an additional enzyme that is released only by one of the tissues in question
What is ALP for?
Present in high concentration in liver, bone, intestine and placenta
Pathological increases most frequently due to liver or bone diseases
Increased in bone diseases associated with increased osteoblastic activity
A 39 year old woman with BMI of 43, presented with elevated alkaline phosphatase and RUQ pain. Your laboratory does not offer iso-enzyme testing. What other enzyme can you measure?
GGT
How can you differentiate the cause of a raised ALP?
Liver and bone ALP can be
differentiated by
GGT measurement
Electrophoretic separation
Bone specific ALP immunoassay now
available
What are the physiological causes of a raised ALP?
Pregnancy (placental ALP) – 3rd trimester
Childhood- especially during growth spurt
What are the pathological causes of a raised ALP?
> 5x Upper limit of normal
Bone ( Pagets, Osteomalacia)
Liver ( cholestasis, cirrhosis)
< 5 x Upper Limit Normal
Bone ( tumours, fractures, osteomyelitis)
Liver (infitrative disease,hepatitis)
ALP not increased in osteoporosis unless complicated by fractures
What is amylase?
Secreted by exocrine pancreas
High serum amylase activity in acute pancreatitis
Usually > 10 times upper limit of normal
Remember salivary isoenzyme exists
Small increases may be seen in other acute abdomen states
What is creatine kinase?
Most widely used marker of muscle damage
Three forms - dimers containing the M (muscle) and B (brain) subunits
CK-MM- skeletal muscles
CK-MB (1 & 2) – cardiac muscles
CK- BB – brain – activity minimal even in severe brain damage
CK-MM accounts for almost entire normal plasma activity
What is statin related myopathy?
Spectrum - myalgia to rhabdomyolysis
Risk Factors
Polypharmacy ( fibrates – gemfibrosil, cyclosporin, other drugs metabolised by the CYP 3A4 system)
High dose
Genetic predisposition
Previous history of myopathy with another statin
What are non MI causes of raised CK?
Muscle damage due to any cause
Myopthy e.g. Duchenne muscular dystrophy (>10xULN)
Myocardial Infarction (>10xULN)
Severe exercise (5xULN)
Physiological – Afro-Caribbean (<5xULN)
What are the ‘other’ uses of enzymes?
Markers of therapeutic response / drug toxicity e.g. Measurement of thiopurine methyltransferase (TPMT) activity is encouraged prior to commencing the treatment of patients with thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine
As reagents for measurement of other substances e.g. Glucose oxidase enzyme used to measure glucose in plasma
What are the consequences of ACS?
Plaque rupture
Intracoronary thrombus
Reduced blood flow
Myocardial ischaemia
Myocardial necrosis
How do cardiac enzymes change in MI?
CK raises first then AST then LDH
How do modern cardiac enzymes change in MI?
Myoglobin then Cardiac troponin and CK-MB then a smaller peak of cardiac troponin
How does the current marker of choice for MI change over time?
The current marker of choice for myocardial injury (not an enzyme!)
Rise 4-6 hours post MI
Peak at 12 -24 hours post MI
Remain elevated for 3 -10 days
When should you measure troponin?
6 and 12 hours after pain onset
What is the diagnostic criteria for acute MI?
Either one of the following
(1) Typical rise and gradual fall (troponin) or more rapid
rise and fall (CK-MB) with at least one of the following:
(a) ischemic symptoms
(b) pathologic Q waves on the ECG
(c) ECG changes indicative of ischemia
(d) coronary artery intervention
(2) Pathologic findings of an acute MI
What are the biomarkers in HF?
Natriuretic peptides
Atrial natriuretic peptide – secreted by the atria
Brain natriuretic peptide – secreted by the ventricles
BNP can be measured to assess ventricular function
BNP can be used to exclude heart failure in the clinical setting
How is enzyme activity measured?
One International Unit (U) of enzyme activity is defined as the quantity of enzyme that catalyses the reaction of one μmol of substrate per minute
Activity of an enzyme is dependent on assay conditions such as temperature, pH
What is Km (Michaelis-Menten constant)?
The Michaelis-Menten constant or Km = [substrate] at which the reaction velocity is 50% of the maximum.
What does Km show?
high Km indicates weak affinity
low Km indicates strong affinity
What are enzymes a marker of?
Organ specific injury- released in response to cellular injury
How do you find which organ an enzymes comes from?
The clinical context
The enzyme may be predominantly released by one tissue after injury (e.g., serum ALT is mostly from the liver)
Where is ALP from?
Intrahepatic or extrahepatic bile ducts
Bone
Placenta
Intestine
When is ALP elevated in bones?
Fracture, Paget’s disease, Osteomalacia, Rickets, cancer (primary or metastasis), 1o hyperparathyroidism with bone involvement, renal osteodystrophy
Childhood
When is ALP elevated in placenta?
Pregnancy (last trimester)
Germ-cell tumours
When is ALP elevated in intestines?
ALP not routinely used for the investigation of bowel disorders
Where is ALT?
Liver
Kidney
Pancreatitis
MI
How is ALT measured for Liver, kidney, pancreas and heart?
Hepatitis (viral, alcohol), non-alcoholic fatty liver disease, liver ischaemia, paracetaomol overdose,
*not used for diagnosis of renal impairment better biomarkers available (creatinine, eGFR, albuminuria)
*Not used for pancreatitis, amylase is better
*Not used for MI, high-sensitivity troponin I or T is better
Which organs are GGT present?
Hepatobiliary
Enzyme induction
Pancreas
Kidney
How is GGT used in hepatobiliary disease?
Hepatitis, alcoholic liver disease, cholestatic liver disease
Hepatobiliary disease (γ-GT not useful for distinguishing between hepatic and biliary disease, the ALT:ALP ratio is more useful)
How is GGT used in Enzyme induction?
Alcoholics (with or without liver disease), rifampicin, phenytoin, phenobarbitone
Enzyme induction* (increased intracellular γ-GT levels so more is released during normal cell turnouer)
How is GGT used in pancreas?
Pancreatitis (but γ-GT not used for diagnosing pancreatitis, serum amylase is better)
How is GGT used in kidney?
Not used in kidney disease because there are much better biomarkers (creatinine, eGFR, albuminuria)
How is GGT used in kidney?
Not used in kidney disease because there are much better biomarkers (creatinine, eGFR, albuminuria)
Which organs have LDH?
White blood cells
Red blood cells
Placenta
Skeletal muscle
Liver injury
Cardiac
Which diseases have raised LDH in these organs:
White blood cells
Red blood cells
Placenta
Skeletal muscle
Liver injury
Cardiac
Lymphoma
Haemolysis
Germ-cell testicular cancer (seminoma)
Myositis
Hepatic disease but better biomarkers available
Better biomarkers available
Where is serum amylase?
Pancreas
Salivary gland
Macro amylase
In which diseases is serum amylase elevated?
Pancreas- Acute pancreatitis, perforated duodenal ulcer, bowel obstruction (causes secondary injury to pancreas)
Salivary gland- Stones, infection (e.g., mumps)
Macro amylase- amylase bound to immunoglobulin, often benign but causes confusion. If you suspect this, request amylase electrophoresis for amylase isoenzymes (Benign)
Where is creatine kinase from?
Skeletal muscle
Cardiac muscle
When is CK elevated?
Rhabdomyolysis, Myositis, polymyositis, dermatomyositis, severe exercise,
myopathy (Deuchene muscular dystrophy, statins)
*slightly higher levels in individuals of Afro-Carribean descent
Cardiac injury but not used for this purpose (high-sensitivity troponin is better and used instead).
What is Troponin 1?
Located within cardiac and skeletal myocytes where it participates in muscle contraction
What are the causes of raised tropnonin?
Primary cardiac injury: ACS, myocarditis, cardiomyopathy, aortic dissection
Secondary cardiac injury: PE, Systemic infection
How do you make a diagnosis with troponin?
History + exam + ECG + Troponin = diagnosis
Factors affecting troponin result: Age, gender, acute or chronic kidney disease, Time of test..
How do enzymes change in MI?
IF ALT > 1000 what might it be?
Paracetamol overdose
Viral Hepatitis
Ischaemic cardiomyopathy
What is the clinical application of troponin?
- When did the chest pain begin?
- Take troponin I on admission
- Take 2nd troponin 3 hours later
50% increase or decrease suggestive of cardiac myocyte injury
If someone has a STEMI what is the long term management?
Urgent cardiology review
Coronary revascularisation
If someone has an NSTEMI (cardiac chest pain, ECG (not necessary) and serial troponins >50% change between results or > ref range), what is the long term management?
Urgent cardiology review
If someone has unstable angina what is the long term management?
Urgent cardiology review
What is the management of usntable angina?
Senior review and discharge
What is the management of chest pain of uknown cause?
Senior review -> non cardiac chest pain
How do you differentiate NSTEMI and unstable angina?
NSTEMI:
Serial troponins
>ref range and/or
>50% change between results
Unstable Angina:
Serial troponins
<50% change between results
How do you differentiate between stable angina and chest pain of unknown cause?
Stable angina: Exertional chest pain
Chest pain ?cause: Chest pain
Both have: normal 12 lead ECG, serial tropnins
Why are there gender specific cut offs for tropnin?
Men and women have different sized hearts
Will tropnin be high <1 hr?
No- you need to measure something else as well
It begins to rise at 2-4 hours
