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Group C
Wedyan Meshreky
Helen Naguib
Sharon Naguib
Part One

Ms DF recently diagnosed with
leukaemia and is receiving Lasparaginase, amongst other cytotoxic
agents. There have been a number of
reports linking the use of Lasparaginase to diabetes mellitis.
Explain..
Diabetes Mellitus

Serum glucose levels are regulated by
absorption, cellular uptake, gluconeogenesis,
glycogenolysis.
 These processes are regulated by the
pancreas, intestine, liver, kidneys and
muscle.
 Hyperglycaemia can result from disruption of
the hormones involved in glucose regulation
such as insulin or glucagon or from
dysfunction of the organs involved in glucose
homeostasis.
L-asparaginase
Anti-leukaemic agent used in
combination with prednisone and
vincristine for remission induction.
 Malignant cells must acquire asparagine
from surrounding fluid (such as blood)
for protein synthesis whereas normal
cells can synthesise their own
asparagine.

Cont..
Asparaginase is an enzyme derived
from micro-organisms.
 It deaminates asparagine to aspartic
acid & ammonia in the plasma and ECF.
 Therefore its deprives tumour cells of
the AA asparagine for protein synthesis
and so the cells die.

L-asparaginase & Diabetes




Hyperglycaemia is a well recognised side effect of
therapy with L-asparaginase.
Hyperglycaemia & glycosuria without ketonemia
occurs in 1-14% of patients treated with Lasparaginase, but is reversible upon discontinuation
of the drug.
Insulin therapy is frequently required.
Hyperglycaemia can be worsened by the concurrent
administration of high dose glucocorticoids in
combination therapy.
Is the mechanism known?
Inhibition of insulin or insulin receptor
synthesis leading to a combined insulin
deficiency/resistance syndrome is the
presumed mechanism.
 It is unclear as to why L-asparaginase
targets insulin, insulin receptors, thyroid
binding protein and albumin synthesis
but not other proteins such as glucagon.

Other mechanisms?
Another mechanism for the
development of transient or permanent
diabetes mellitus is pancreatitis which
occurs in 1-2% of L-asparaginase
treated patients.
 Incidence of pancreatitis rises when
L-asparaginase is combined with other
cytotoxic agents.

Part two..

L-asparaginase may affect other clinical
chemistry parameters such as
potassium and lipids.
Please explain..
Hypertriglyceridemia
Parson’s et al observed an increase in fasting
TG levels concluding it was due to an
increase in endogenous synthesis of VLDLs
 Apo-B100 is a major protein found in VLDLs
increased levels detected suggesting an
overproduction of VLDLs.

Hypertriglyceridemia…

Mechanism is unclear
 Although the incidence of
hypertriglyceridemia was 67%, this was found
not to be associated with pancreatitis.
Hypercholesterolaemia
Changes in cholesterol levels not found
to be related to treatment with lasparaginase.
 Most likely to be associated with the use
of corticosteroids.

HDL
HDL levels in px’s with ALL found to be
low
 Decrease in HDL levels due to either
- decreased formation, or
- Increased removal from circulationlow
HDL levels indicative of active cell
proliferation

HDL…
During and after treatment with lasparaginase HDL levels increased
 Structural change in HDL particle from a
high to a lower density particle
 L-asparaginase decreases hepatic
protein synthesis
 Changes in lipid metabolism is
reversible

Hyperkalaemia
TLS – release of intracellular contents
leading to: hyperuricaemia,
hyperphosphataemia, hypocalcaemia
and hyperkalaemia.
 Can lead to renal failure.

Hyperkalaemia…

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-
-
Treatment:
Px should receive IV fluids (no K+)
Use of sodium bicarbonate, insulin or
glucose can cause transcellular shift of
K+ into muscle cells  decrease in K+
levels.
Monitor px for signs of hyperkalaemia
Part Three

Describe techniques used in the general
monitoring of proteinuria and
specifically, the measurement of
albumin levels in urine
Dipstick Method

Semi-quantitative
 Inexpensive
 Takes less than 5 minutes to complete
 Most common commercial method
Basic Principle

Uses a pH-dependent dye-buffer
combination.
 Paper spot impregnated with a citrate buffer,
pH3 and a tetrabromphenol-blue indicator
Relies on the ability of amino acid groups in
proteins to bind and alter the colour of the
acid-base indicators.
 Most sensitive to Albumin because it contains
the most amino groups.
RESULTS

YELLOW = NO
PROTEIN
 GREEN =PROTEIN
Interpretation of Results
GRADE
negative
Trace
PROTEIN
(mg/dL)
<10
10-20
1+
30
2+
100
3+
300
4+
1000
False
.
Positive results
Alkaline
urine (pH>7.5)
Dipstick
immersed for too long
Presence
of penicillin, sulfonamides or
tolbutamide
False
Negative results
Dilute
urine
Low
molecular weight proteins
Non Albumin
Proteins
Proteins eg, Bence Jones
The Sulfosalicylic Acid (SSA)
Turbidity Test

Qualitative measure
 Requires a few millilitres of freshly voided,
centrifuged urine.
 An equal amount of 3% SSA is added to the
specimen
 Acidification causes precipitation of protein in the
sample.
 Detects albumin, globulins and Bence-Jones proteins
 In alkaline urine, it is a more accurate measure than
the dipstick.

The turbidity of the suspension is proportional
to the amount of protein precipitated
 Amount of protein is also graded from 1 to 4