Clinical Biochemistry

Clinical Biochemistry
Aaser Abdelazim
Professor of Medical Biochemistry and Molecular Biology
FAIMER fellow 2021 (Medical Education)
Clinical Chemistry Consultant
aaserabdelazim@yahoo.com
Aaser Abdelazim ----Clinical Biochemistry 1
8/15/23

Tumors and tumor
markers
1. To define tumor
2. To list the local and systemic effect of tumors.
3. To describe cancer Cachexia.
4. To explain the ectopic hormone production.
5. To explain the consequences of tumor treatment.
6. To classify different types of tumor markers.
7. To describe the clinical use for common tumor markers.
8. To state the future of tumor markers.
9. To interpret clinical cases for tumors and tumor markers.
1
8/15/23

TUMOR
It is uncontrolled growth of the cells in a particular tissue. It may be a malignant
(cancer) or benign cell tumor.
Malignant tumor (cancer) cells
Diminished control of growth.
Invasion of local tissues.
Spread (metastasis).
Benign tumor cells
Diminished control of growth.
No Invasion of local tissues.
No Spread (No metastasis).
CAUSES OF TUMORS
Radiation
Chemicals
Oncogenes
[UV, X-rays and gamma rays]
[benzene, asbestos, aflatoxins, smoking]
[these genes promote development of tumors] – Proto-
oncogenes promote normal development (growth and
differentiation )
8/15/23

BIOCHEMICAL EFFECT OF TUMOR GROWTH
1) Obstruction of blood vessels, lymph, or ducts.
2) Damage to nerve.
3) Effusions.
4) Bleeding.
5) Infection.
6) Necrosis of surrounding tissues and eventual
death of patients. Aaser Abdelazim ----Clinical Biochemistry
q Tumor cells may secret toxins locally or
in the circulation.
q Both endocrine and non-endocrine tumor
cells can secrete hormones.
q All these substances may be used as a
tumor markers.
4
8/15/23

Aaser Abdelazim ----Clinical Biochemistry
LOCAL EFFECT OF TUMORS
Local spread of tumor can induce a wide range of abnormalities which commonly request a
biochemical tests
(1) Carcinoma of head of pancreas: induce an obstruction of bile duct which induce:
qElevation of ALP: it the 1st sign of patients that there is some thing wrong!.
qJaundice (later on).
(2) Liver is a common site also for metastasis: which induce an elevation in GGT, ALP and after great
destruction of cells AST, ALT also were elevated.
(3) Metastatic spread of tumors may induce complete system failure: e.g. adrenal cortex destructed
by metastatic tumors induce impaired Aldosterone and cortisol secretion which may be fatal.
(4) Leukemia and lymphoma: induce
qHigh serum uric acid (due to cell turnover).
qHigh LDH:
qLactic acidosis: insufficient blood supply enforce tumor cells to perform anaerobic glycolysis.
(5) Renal failure may be induced by tumors due to: obstruction of UT, hyperclacemia, Bence-Jones
proteinuria, hyperuricemia and nephrotoxicity of nephrotoxic drugs.
5
8/15/23

CANCER CACHEXIA
qThis term describes the characteristic wasting observed in cancer patients.
qThe features includes: anorexia, lethargy, weight loss, muscle weakness, anemia
and pyrexia.
Factors lead to development of cachexia：
Factor Comment
(1) Inadequate food intake Induce weight loss
(2) Impaired digestion and absorption Food loss
(3) Competition between the host and tumors cells for
the nutrients
Large tumor cells have a high metabolic rate
which deprive other host cells from nutrients
so the cancer patients characterized by low
blood cholesterol.
(4) Increase energy requirement of the cancer patients The host cell respond to tumors like its
response to injuries and this consume a lot
of energy.
qCancer cachexia may cause: infection, dysphagia, persistent vomiting and diarrhea.
qTumor cells secretes or induce the release of some hormones or hormonal agents that
induce cachexia like tumor necrosis factor secreted from activated macrophages.
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8/15/23

ECTOPIC HORMONE PRODUCTION
It is a common feature of some tumors to secret hormones even though they are of non
endocrine origin. This called ectopic hormone production.
(a) The condition resolves after
surgical removal or irradiation: good
evidence but it may be due to tumor
secretion of the releasing factor e.g.
secretion of GH may be due to
secretion of GHR
(b) Hormone level in the arterial supply
of the tumor is less than its level in
venous drainage: good evidence
especially if combined with (a).
(c) Extraction of the hormone from
the tumor: good evidence but may be
due to absorption of the hormone by the
tumor.
Evidence for
ectopic hormone
production
7
(d) Determination of hormone mRNA
and its detection in secretory granules
in tumors: definitive evidence.
Tumors secret hormones:
qSmall cell carcinoma
qTumors secreting ACTH induce cushing ‘s syndrome
qTumors secreting PTH: induce hypercalcemia.
8/15/23

Consequence of tumor treatment
Consequence Comment
(1) Gonadal failure Due to radiotherapy and chemotherapy.
(2) Hypomagnesaemia and hypokalemia Due to the use of cytotoxic drugs.
(3) Folate deficiency In cisplatin patients treated with methotrexate.
(4) Hyperuricemia In patients treated with cytotoxic drugs
inducing massive cell death particularly in
lymphomas and some leukemias and it is
known as (tumor lysis syndrome).
qMeasurement of hormone receptors is very important
in the treatment of some tumors like (breast cancer).
qEstrogen receptors very important for the
Progesterone synthesis as presence of both receptors
indicates the integrity of Estrogen receptors.
qWhen patient treated by anti-estrogen (Tamoxifen)
both receptors presence indicate no effect of drug.
Clinical note:
8
8/15/23

TUMOR MARKERS
qThe tumor marker (Biological markers) is a substance which can be related to the presence
or progress of the tumor.
qThese substances can be synthesized and released by the tumor cells.
qHigh amount of these markers in patients plasma indicate the presence of the tumor.
qThese markers can be found in circulation, body fluids, or associated with cells.
qTumor markers can be one of several substances which normally secreted in the body like
oHORMONES: like HCG secreted by choriocarcinomas.
oENZYMES: like acid phosphatase secreted by prostate cancer.
oTUMOR ANTIGENS: like PSA in prostate cancer or CEA carcinoembryonic antigen
in colorectal cancers.
oPROTEINS: like alpha-fetoprotein in Hepatocellular carcinoma.
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8/15/23

THE COMMON TUMOR MARKERS
Breast cancer
CA125, CEA, HER2
Stomach cancer
CEA
Colon cancer
CEA
Pancreatic cancer
CEA, CA19-9
Ovarian cancer
CEA, CA125
Lung cancer
CA125, CEA
Liver cancer
AFP
Prostate cancer
PSA
Testicular cancer
AFP, HCG
8/15/23

THE USE OF TUMOR MARKERS
Monitoring treatment
1) A decline in the tumor marker level
indicates the success of the
treatment.
2) The rate of this decline should
match the predicated level of tumor
marker half life.
3) A fewer than the predicated
indicate incomplete elimination of
the tumor.
Assessing follow-up
1) It is very important to the patients
to continue follow-up the marker
level even when it reaches its
stabilized level.
2) An increase in the level again may
indicates the tumor recurrence.
Diagnosis
1) It is rare to use the markers for
diagnosis.
2) While presence of radiological
reports or histopathological
examinations with markers help in
confirmation.
Prognosis
1) The tumor marker should be
correlate with the tumor mass.
2) High mass increase the marker
level.
Screening
1) It can be used for detecting the
asymptomatic population.
2) The tumor markers should not be
used in the routine clinical practice.
3) But this appeared to be theoretical
in most cases.
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8/15/23

Suspected malignancy
/confirmed malignancy
Measure the tumor
marker baseline
Intervention
Surgery
Radio-
therapy
Chemo-
therapy
Falling tumor marker
Monitor tumor markers at
increasing time intervals
Rising tumor marker
Frequent tumor marker
measurement
THE USE OF TUMOR
MARKERS
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8/15/23

PROPERTIES Of A TUMOR MARKER
Sensitive
ü It should be positive in all patient
with particular cancer.
Specific
ü It should be negative in all normal
population.
ü Only detected or elevated in
cancer patients.
Reliability
ü Its level reflects the stage of the
disease.
ü Not be low when the tumor
progressed or high when tumor is
stable.
Stability
ü Stable when the disease is stable.
ü Not fluctuated during the stable
stages of the tumor.
N.B. In fact there is no ideal marker which fulfills all these
properties. As will a marker achieves more properties as it will
be better.
8/15/23

MARKERS WITH ESTABLISHED CLINICAL VALUE
qMarkers play a major role in the management of germ cell tumors and
choriocarcinoma.
qBut some tumors are resistant to chemotherapy. This makes their use not
mandatory.
Clinical situations where tumors markers have been found to be useful
Marker Tumor Screening Diagnosis Prognosis Monitoring Follow-up
AFP Germ cell √ √ √ √
AFP Hepatoma √ √ √ √
HCG Germ cell √ √ √ √
HCG Choriocarcin
oma
√ √ √ √ √
CA 125 Ovarian √ √ √
Acid phosphatase Prostate √ √ √
Prostate specific antigen
(PSA)
Prostate √ √ √
CEA Colorectal √ √
Calcitonin
Medullary
carcinoma
of thyroid
√ √ √ √
Hormones Endocrine √ √ √
Paraprotein Myeloma √ √ √
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8/15/23

Marker Tumor Specimen Clinical use
AFP Testicular
Serum, plasma, amniotic
fluid
Management of cancer
AFP -L3%
Hepatocellula
r
Serum Risk assessment
B2-microglobulin (B2M) Blood cells Serum, urine, CSF Monitoring progression, recurrence
CA (Carcinoma Antigen) 15-3 Breast serum/plasma Monitoring and response to therapy
CA 19-9 Pancreas Serum/plasma Monitoring
CA 27-29 Breast Serum Monitoring and response to therapy
CA 125 Ovarian Serum/plasma Monitoring and response to therapy
CEA (Carcinoembryonic antigen) Colon Serum/plasma Monitoring and response to therapy
C-kit GIT Tissue Detection of tumor
EGFR Colon Tissue Therapy selection
ER Breast Tissue Prognosis; Response to therapy
HER2/neu Breast serum./tissue Monitoring progression, therapy selection
HCG Testicular Serum Staging of cancer
HE4 Ovarian Serum Monitoring progression, recurrence
Fecal occult blood (hemoglobin) Colorectal Feces Detection of tumor
Free PSA Prostate Serum Screening
Total PSA Prostate Serum Diagnosis and monitoring
Thymoglobulin (Tg) Thyroid Serum/plasma Monitoring
THE CLINICAL USE OF TUMOR MARKERS
•HER- Human epidermal growth factor receptor
•HE- Human epididymis protein
•EGFR-epidermal growth factor receptor
8/15/23

A PRACTICAL APPLICATIONS OF
TUMOR MARKERS
A CASE OF TESTICULAR TERATOMA
qAbout 75-95% of cases with testicular teratoma have abnormalities in one of AFP and HCG and used in
the confirmation of the diagnosis.
qHigh levels of AFP>10,000 kU/L indicate very bad prognosis for such case.
qThe level of AFP fell in response to chemotherapy and declined to the lower levels.
qContinued monitoring for such marker will be the warning sound for tumor recurrence.
16
8/15/23

THE FUTURE FOR TUMOR MARKERS
1. Monoclonal antibodies were constructed against the tumor cell and membrane.
2. This led to the development in the era of markers discovering.
3. Many markers related to this subject see the light and others still not.
4. The way now is to seek for the ((perfect)) marker which could be used in the population of
[screening-diagnosis-prognosis-monitoring- treatment-follow-up of tumor recurrence].
5. The new technique ((proteomics)) introduce a valuable tool for discovering of such perfect
markers nowadays.
Malignancies
Therapy, Diagnosis and Prognosis
Genetic
instability
Impact of
progression
Impact of
prognosis
impact of
genesis
PROTEOMICS/ONCOPROTEOMICS
Proteomics/malignancies studies
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8/15/23

Clinical case study (1) tumors and tumors markers
A 72 years old man, had complained of pains in his lower chest
and abdomen for two months. His GP detected dullness at both
lung bases and referred him to chest physician. On 23th of June he
admitted to the hospital. Examinations revealed an enlarged liver.
He had been heavy drinker. Biochemistry results were:
1)What is your differential diagnosis on the light of the livers
functions?
2)How might AFP be helpful in this case?
Dat
e
Bilirubin
(µmol/l)
ALP
(U/L)
AST
(U/L)
ALT
(U/L)
LDH
(U/L)
GGT
(U/L)
23/6 24 1540 83 98 --- 719
1/7 25 2170 80 107 430 1020
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8/15/23

Clinical case answer
1)What is your differential diagnosis on the light of the livers
functions?
•High levels of ALP and GGT with moderate elevation of AST and ALT
indicates liver cholestasis.
•The cholestasis may be due to
1.Hepatocelluar carcinoma (HCC) as alcohol-induced liver cirrhosis
is the common predisposing factor for HCC in western societies.
2.Or due to liver cirrhosis.
2)How might AFP be helpful in this case?
AFP considered the marker of choice in this case as it is specific
marker for HCC diagnosis.
19
8/15/23

Clinical case study (2) tumors and tumors markers
56 years old woman admitted to hospital with anxiety and depression. The patient
was evaluated for fatigue, constipation and high serum cancer antigen (CA19-9)
levels 1400 u/mL 12 years after initial elevation (8000 u/mL). After diagnosis of
hypothyroidism she was treated while her CA 19-9 still high with no discernible cause
by repeated CT scan for her chest and abdomen . All body scan revealed no
abnormalities., normal immunological tests (AMA, ANA, ASMA), serum protein
electrophoresis and fecal occult blood test. Her lab values are the following :-
!"#$% &'$(")$%*"#+,$#% -"."*")/"%*')0"%
!12% 34% 5678769%µ:;<=
>!7 56? 5648@64 )0;A,
!B$',%/CB,"#$"*B,% 3D5 @558355%<0;A,%
=E=%/CB,"#$"*B,% @9@ F%@D5%<0;A,%
G(,(*+H()I $B$',% @6@ 5638@6D%<0;A,%
G(,(*+H()I ()A(*"/$% 56? 5648@6D%
J1! @D :K$B 75%:;=
J=! @@ :K$B 75%:;=
J=&% LM 9D8@7@%:;=%
NJ%@M8M @755 F%75%:;<=
8/15/23

Questions
1.What are the patients most striking clinical and lab findings?
2.How do you explain these findings?
3.What is the cause of these findings ?
4.What is the patients most likely diagnosis?
5.What is the clinical significance of this diagnosis
1. High serum TSH, low FT4, high TC and LDL, normal LFTs and negative antibodies
associated with autoimmune diseases.
2. The persistent elevation of CA 19-9 with normal imaging evidences may indicates
[begin condition, presence of tumors not detected by imaging studies performed-an
interfering e.g. presence human anti-mouse anti bodies in patient serum causing false
results- an incidental finding with no apparent cause].
3. Cancer antigen [CA 19-9] is associated with malignancies if its level increased over
1000 u/ml. its specificity and sensitivity is high in pancreatic cancer. While it can be
increased in gasteric, colon, biliary and hepatocellular malignancies. It is uncommon
that CA19-9 to increase in non-malignant disorders while records showed that it can be
increased in thyroditis, hepatic, renal and pulmonary disorders. At this case the
patient is completely normal and all investigations exclude all causes of CA19-9
elevation.
4. Most likely diagnosis (unexplained increase in serum CA19-9 in relatively healthy
individual)
5. The high persistent level of CA19-9 limits the clinical use of this marker as a tool
for screening and follow-up of pancreatic cancer. In general its use for screening.
8/15/23

Quizzes on
tum
ors and
tum
or m
arkers
Quizzes on tumors and tumor markers
1. On of them not a character of benign tumor?
a)Uncontrolled growth
b)Localized inside particular tissue
c)Invade the affected tissue
d)Capsulated
2. The local effect of cancer of head of pancreas is:
a)Bleeding
b)Obstruction of caniculi
c)Endocrine hormonal production
d)Toxin production
3. The most reliable cause of cancer cachexia is:
a)High invasion of tumors
b)Metastasis of malignant tumors
c)Completion with host cells
d) production of mediators inhibits appetite
4. Complete organ failure is a form of local effect of tumor is seen in:
a)Pancreatic cancers
b)Adrenal tumors
c)Lung cancers
d)Colon cancer
8/15/23

Quizzes on
tum
ors and
tum
or m
arkers
Quizzes on tumors and tumor markers
5. Extraction of a hormone from the tumor tissue indicates:
a)Tumor recurrence
b)Tumor recovery
c)Ectopic hormone production
d) tumor severity
6. Tumor necrosis factor is a factor which can induces cancer:
a)Cachexia
b)Metastasis
c)Invasion
d)Growth
7. Liver is a common organ for cancer:
a)Mediators
b)Toxins
c)Excretions
d)Metastasis
8. On of them a biochemical picture for leukemia and lymphoma:
a)High serum ALP
b)High levels of AFP
c)Hypolipidemia
d)Hyperuricemia
8/15/23

TOXICOLOGY
1. To define toxicology.
2. To list investigations in poisoned patient.
3. To explain how to confirm poisoning.
4. To measure level of poison levels
5. To recall common causes of poisoning.
6. To List biochemical tests for poisons.
7. To List common sources of metal poisoning.
8. To describe the sequelae and action limits for toxic metals
9. To interpret clinical cases related to poisoning
2
8/15/23

WHAT DO TOXICOLOGY MEANS?
Science which involves the investigations of poisoned patient.
COMMON BIOCHEMICAL DETERMINATIONS IN CASES OF SUSPECTED POISONING
Serum urea, electrolytes and LFTs
Blood glucose
Blood gases
8/15/23

BIOCHEMICAL TESTS IN DRUGS AND POISONS
Drug /poison Biochemical test
Carbon monoxide (CO) Blood carboxyhemoglobin
Digoxin Blood digoxin and serum potassium (K)
Cocaine Serum CK and urine myoglobin
Ethylene glycol Blood gases and serum calcium
Insulin Blood glucose
Iron Serum iron
Methanol Blood gases
Organophosphorus compounds Serum cholinesterase
Dapsone, oxidizing agents Blood methemoglobin
Paracetamol Blood paracetamol and LFTs
Salicylates Blood Salicylates and blood gases
Theophylline Theophylline and serum potassium
8/15/23

Few symptoms
specific for a
poison
Poison screen
Poison level
üSome poisons have a specific signs or symptoms
üMany poisons are just diagnosed from clinical
symptoms and did not need further lab
measurements.
üDrug/ poison screen on urine specimen.
üIt is only useful to confirm poison taken.
üMay give no indications about poison severity.
üBlood level is a useful tool to know the severity of
toxicity.
üAlthough it may be not needed for treatment
protocol of patient.
CONFIRM POISONING
8/15/23

MEASURING OF POISON LEVELS
Why measure
DRUGS level?
üTo assess the prognosis
üHalf life of drug may determine the time of
recovering
üDifferential diagnosis of coma.
üConfirmation of brain death.
üMonitoring of drug abuse.
üInvestigation of suspected non-accidental
poisoning.
8/15/23

COMMON CAUSES OF POISONING
Poison Poisoning conditions Investigations
SALICYLATES ü There is a difficulty to detect the
toxicity early which leads to severe
metabolic acidosis from which the
patient may not recover.
ü Cases with salicylate poisoning are
treated with sodium carbonate to
eliminate acidosis.
Simple qualitative test
for salicylate.
Normal levels (30-
300mg/L) or (2.17-7.2
mmol/l)
PARACETAMOL ü Induces severe hepatic and renal
damage.
ü Specific therapy with [N-
acetylcycteine IV] should be started
with in 12 hrs of admission before the
clinical, hematological and
biochemical changes developed.
ü Alcohol abuse patients are more likely
to be affected by this poisoning.
ü Time of ingestion to plasma
concentration is very important.
LFTs – RFTs and
paracetamol level
8/15/23

0 2 4 6 8 10 12 14 16 18 20 22
1.5
1.0
0.5
0.0
Plasma paracetamol mmol/l
Treatment not
required
Too
early
for
prognosis
Time after ingestion (hours)
Treatment
required
Treatment
unlikely
to
be
helpful
PROGNOSIS CHART FOR PARACETAMOL POISONING
8/15/23

COMMON CAUSES OF POISONING
THEOPHYLLINE ü Develop arrhythmias with
hypokalaemia after 24-48 hrs.
ü the matter may be danger lead to
deaths.
Simple qualitative test
for theophylline.
METHANOL and
ETHYLENE GLYCOL
ü Methanol is metabolized to formic
acid while ethylene glycol is
metabolized to oxalic acid.
ü The toxicity form these two
compounds is uncommon.
ü They induce sever metabolic acidosis
with a development of severe
hypocalcaemia in case of ethylene
glycol.
ü The main route of treatment is giving
ethanol with keeping the plasma level
at 20 mmol/l.
No need for
measurement of
methanol and ethylene
glycol if the poisoning
is confirmed.
8/15/23

CHRONIC POISONING
1+1 = ?
1+1 = ?
1+1 = ?
üGradual raising in drug concentration for a period of time
üIt is usually happen with drugs of un corrected doses.
ü In chronic poisoning, the drug/toxin plasma level is of a great assistant in
assessing patient case and correcting of drug doses.
üAnother form of chronic toxicity is due to additive effect of two drugs [like
alcohol and benzodiazepines] they are usually not toxic if they taken alone while
with when they be taken together with over dose with induce numerous deaths.
8/15/23

CASE STUDY (1)
A 38yrs man presented to hospital afternoon, claiming to have taken
100 aspirin tablets early in the day. He was hyperventilating and
complaining of ringing in his ears. He felt anxious. But his pupils
were of normal size and no other abnormalities were observed. He was
given gasteric lavage and blood was taken for salicylate, urea,
blood gases and electrolytes. The results were as follow:
Na+ K+ CL- HCO3 Urea Creatinine
(µmol/l)
H+
(nmol/l)
PCO2
(Kpa)
PO2
(Kpa)
mmol/l
140 3.7 102 20 8.1 110 35 3.7 13.3
Salicylate 4.6 mmol/l
a) Comment of the following results?
b) What are the other information would be useful in determining a
line of treatment?
8/15/23

Answer of CASE STUDY (1)
An over dose of Aspirin (salicylate poisoning)
1) The man has a high anion gap with about 18 mmol/l[look anion gap]
2) While salicylate poisoning is usually associated with metabolic
acidosis here the man develop a respiratory alkalosis which is
dominant at this stage of poisoning.
3) The cause of respiratory alkalosis is the direct effect of
salicylate on respiratory centers to compensate the acidosis.
4) Other information about the possibility of paracetamol poisoning
also as many analgesics contains aspirin and paracetamol
Na+ K+ CL- HCO3 Urea Creatinine
(µmol/l)
H+
(nmol/l)
PCO2
(Kpa)
PO2
(Kpa)
mmol/l
135-
145
3.5-5 95-106 22-28 2.5-7.1 60-110 40 5.1-5.6 10.5-13.5
kPa (kilopascal)
Reference ranges
8/15/23

Anion gap
1) Anion gap = [Na+K]-[Cl-HCO3] normal is 20 mEq/l
2) With out K --à anion gap =[Na]-[Cl-HCO3] normal is 8-16 mEq/l
3) Anion gap may be high in: [lactic acidosis, ketoacidosis, DKA,
alcohol abuse, toxins like methanol, ethylene glycol, aspirin,
cyanide, iron, urea and renal failure].
4) Anion gap is low in: hypoalbuminemia, multiple myeloma.
5) Anion gap may normal in: gastrointestinal loss of HCO3 as in
diarrhea, renal loss of HCO3, renal dysfunction, hypoaldosterone.
6) In critical ill patients with hypoalbuminemia: anion gap should be
corrected- albumin corrected anion gap= [calculated anion gap]+
2.5[normal albumin (4.4 g/dl)]- [observed albumin]
7) Delta ratio [AG]-12/24-[HCO3] thid reflects either an increase in
AG or decrease in HCO3 ratio scale is [<0.4 NAGMA, 0.4-0.8 mixed
NAGMA + HAGMA, 0.8-2 pure HAGMA, >2 mixed HAGMA+ metabolic
acidosis]
HAGMA(high anion gap metabolic acidosis) NAGMA (normal anion gap metabolic acidosis).
8/15/23

METAL POISONING
The oldest form of poisoning be known to man.
It was with unknown mechanism but now
mechanism of toxicity is well-known and many
treatments are available.
Elemental metals are usually less toxic than
their organic or non-organic salts
Toxicity of metals depends on the rate of their
absorption and amount of ingestion not on the
time or duration of ingestion.
INTRODUCTION
8/15/23

METALS ASSOCIATED WITH POISONING
Conditions for metal poisoning:
OCCASIONAL SUICIDE
MURDER ATTEMPTS
ENVIRONMENTAL CONTAMINATIONS
DRUG ADMINISTRATION
MURDER ATTEMPTS
Clinical effect of metal poisoning:
RENAL TUBULAR
DAMAGE
GASTROINTESTINAL
EROSIONS
NEUROLOGICAL
DAMAGE
8/15/23

DIAGNOSIS of metal poisoning:
Plasma level of metal.
Urinary excretion of
metal.
Biochemical parameters
related to metal toxicity.
Common sources of metal poisoning:
Arsenic
Aluminum
Cadmium
Mercury
Lead
8/15/23

ARSENIC
ü It usually occurs as ions AS+3 and AS+5
ü Arsenic usually found in insecticides.
ü Acute poisoning – [violent
gastrointestinal pain and vomiting -
shock].
ü Chronic poisoning – [persistent
diarrhoea, polyneuropathy and
dermatitis].
o Hair analysis [>0.5
µg/g] in hair
indicates exposure.
o Urine analysis is very
important to confirm
the occupational
exposure.
ALUMINIUM
ü Sources:-[antacids (500 mg/tablet)
and water (50-1000µg/L) ].
ü Acute poisoning: extremely rare.
ü Poisoning in renal dysfunction
patients is the most important [bone
disease (Aluminum osteodystrophy),
cerebral dysfunction (dialysis
dementia)]
o Plasma Aluminium
levels [look the table]
o Bone content from a
biopsy [>100µg/g]
indicates Al
accumulation.
8/15/23

CADMIUM
ü Chronic poisoning occurred to industrial
workers exposed to cadmium fumes – and
smoker people as they have twice blood level
of Cd than that non smokers.
ü Chronic poisoning induces [nephropathy
(increase of stone formation), bone disease
and hepatopathy]
o Plasma and urine
levels of cadmium.
o B2- microglobin in
urine as a
confirmatory test.
o Renal functions.
LEAD
ü Sources of poisoning includes [industrial
exposure, lead leaches from water pipes,
contamination by lead containing-lead,
contaminating dirts eaten by children (pica),
environmental pollution by petrol].
ü Organic lead poisoning leads to neurological
disorders.
ü Inorganic lead poisoning leads to [anemia,
constipation, abdominal colic and peripheral
and motor neuron deficiencies]. Many cases
develop encephalopathy and coma.
ü Clinical appearance:- blue line on the gums.
o High levels of
protoporphyrin
levels in
erythrocytes. [lead
inhibits a number
of enzymes
responsible for
haem synthesis
(porphoblinogensy
nthase and
ferrocheletase)].
o Lead level in whole
blood and urine.
8/15/23

MERCURY
ü Poisoning with mercury can be acute or
chronic.
ü Sources:- mercury vapor, inorganic (mercuric
chloride) and organic (methylmercury) salts of
mercury.
ü Mercurous salts generally are less toxic than
mercuric salts.
ü Mercury Poisoning leads to respiratory distress
and metallic taste in mouth. Symptoms
includes [nausea, vomiting, muscular tremors,
CNS disorders and renal damage].
o Blood and urine
mercury levels.
o Hair and nail
contents.
8/15/23

Metal Action
limits/indicatio
n of toxicity
Clinical sequelae
Arsenic >0.5 µg/g hair Diarrhoea, polyneuropathy,
gastrointestinal pain, vomiting,
shock, renal failure.
Aluminium >3µmol/l in
plasma – chronic
>10µmol/l- acute
Encephalopathy and osteodystrophy.
Cadmium >90 nmol/l in
blood or > 90
nmol/24h in
urine
Renal damage, hepatocellular damage
and bone disases.
Lead >2µmol/l in
blood or >0.72
µmol/l in urine.
Acute:- colic seizures and coma
Chronic:- enemia and encephalopathy.
Mercury >120 nmol/mmol
of creatinine in
urine
Nausea, vomiting, nephropathy,
neurological dysfunctions.
Bismuth >5 nmol/l in
blood
Acute:- renal failure
Chronic:- encephalopathy
References and action range for poisoning metals
8/15/23

CASE STUDY (2)
A 12yrs old Asian girl presents with nausea and vomiting and non-
localizing neurological signs. She has been using brightly coloured
facial cosmetics obtained abroad.
a) What is the most likely diagnosis?
b) What the biochemical investigations would be appropriate?
a) Suspected lead toxicity
B) Many imported cosmetics agents contain lead. Children may ingest
these agents accidently and develop lead poisoning. Therefore
erythrocyte protoporphyrin level and whole blood level of lead
should be measured.
8/15/23

Therapeutic drug
monitoring (TDM)
1. To define therapeutic drug monitoring (TDM).
2. To list samples for TDM.
3. To interpret drug levels.
4. To explain indications of TDM.
5. To list Drugs for which TDM is appropriate.
6. To describe the therapeutic range of the drug.
7. To describe the drug inteaction
8. To interpret clinical case for TDM.
3
8/15/23

qBranch of clinical chemistry specializes in
measurement of concentration of narrow
therapeutic window medication.
qTherapeutic drug monitoring (TDM) is :
measurement of drug concentration in
plasma, or saliva as a mean for calculation of
drug dosage adequacy.
qDrug effect is assessed by observing
patients clinical state.
qThe curve will give information about:
1) Half life of the drug.
2)Volume of drug distribution which estimate
the correct dose once or several times
doses.
THERAPEUTIC DRUG MONITORING
(TDM):
Figure (1): concentration of drug in plasma
45
8/15/23

Sampling for TDM
Before taking the samples for TDM important things should be taken in mind like:
1)Ask the patient about the compliance.
2)Check for drug interaction.
3)Note the doses and time of last dose.
4)Take the sample at appropriate time (the best time to take the sample is just before the dose this
known as trough (low) concentration.
INTERPERTATION OF DRUG LEVELS
qHigher or lower levels than the expected depend on the
compliance and changes occurring with other drug or in
kidneys and liver.
qCumulative reports are very useful for the comparison
between levels.
qEach drug has a population reference range with minimal
toxicity and maximal therapeutic effect and the therapeutic
dose for a patient may be toxic to the other. 46
8/15/23

Why we should perform TDM?
üIf the drug is toxic at low doses
(drug toxicity)- drugs with
narrow therapeutic window.
üThe drug can interact with other
drugs (drug interaction)
üIf drug should be taken with care
and accurate intervals and
dosage (drug compliance)
üIf drug can not be optimized by
clinical observation alone.
üFor therapy cessation
monitoring.
TDM
47
8/15/23

TDM is unnecessary when
üClinical outcomes is unrelated to
the dose or to plasma
concentration.
üDose need not to be
individualized
üThe pharmacological effect of
the drug can be quantified.
üWhen concentration-effect
relationship remains
unestablished.
üDrugs with wide therapeutic
range such as Beta blockers and
calcium channel blockers.
8/15/23

Drugs for which TDM is appropriate
Drug group Members
1. CARDIO-ACTIVE DRUGS Aminodarone
Digoxin
Desopyramide
Lignocaine
Procainamide
Propranolol and quinidine
2. ANTIBIOTICS Gentamycin , amikacin , and tobramycin
3. ANTIDEPRESSANTS Lithium , tricyclic antidepressants
4. ANTIEPILEPTIC DRUGS Phenytoin, phenobarbitone, benzodiazepines,
carbamazepine, valproic acid and ethosuximide
5. BRONCHODILATORS Theophylline
6. CANCER CHEMOTHERAPY Methotrexate
7. IMMUNOSUPPRESSIVES Cyclosporines
8/15/23

Drugs for which TDM is appropriate
Although many drugs are prescribed in the specialists units only small groups of them need to be measured and need
TDM most of them have a low therapeutic index means that toxic dose not far from therapeutic dose (table 1 show
them)
Drug
Reason for TDM
Notes
Toxicity Interactions Compliance
Phenytoin √ √ √ Has saturable kinetics
Digoxin
√ √ √
Should be measured in
patients with borderline renal
function
Theophylline
√ √ √ Has low therapeutic index
(common toxicity)
Methotrexate
√ If it slowly excreted patients
need folate
Cyclosporin
√
Nephrotoxic
(need to measure Creatinine
)
Carbamazapine √ √ √ Anticonvulsant drug
Primidone √
Metabolized to
phenobarbitone and both
should be measured
Phenobarbitone √ Epilepsy treatment
Gentamycin and Both peak and trough
50
8/15/23

Sub-therapeutic levels Toxic levels
1. Non compliance
2. Dose too low
3. Malabsorption
4. Rapid metabolism
1. Overdose
2. Dose too high
3. Dose too frequent
4. Impaired renal function
5. Reduced hepatic metabolism
Plasma
concentration
of the drug
Risk of toxicity
Therapeutic level therapeutic response
Sub-therapeutic effect
Sub-therapeutic or toxic levels
Therapeutic range
51
8/15/23

DRUG INTERACTIONS
qInterference of one drug with the metabolism and excretion of the other; on the other
hand addition of one drug will alter the plasma concentration of the another.
qIn these circumstances it is useful to lower the dose or discontinue the drug for a time.
EXAMPLE:
Patients with chronic asthma controlled on THEOPHYLLINE usually develop a sever chest infection, the
patients in this case were prescribed ERYTHROMYCIN which will interfere with theophylline inducing
tachycardia and dizziness. So we enforced to stop theophylline for two days and once the infection was
clear; the original dose of theophylline will restart.
Absorption Distribution
Metabolism Excretion
Affected
drug
Interacting drug (s)
Increase
decrease
Interacting drug (s)
Increase plasma level of affected
drug
decrease plasma level of affected
drug
52
8/15/23

TDM Case study
It appears to have a digoxin toxicity. Although the level of digoxin was not so high
(usually the detected level not a reliable to induce digoxin toxicity). So what happen?!
The matter is that there were other factors intensifying or lead for appearance of
such toxicity like her [H+] and K levels. Also she appeared to have a problem with
kidneys appeared from high creatinine level which in case lead to decrease the
excretion of digoxin.
53
8/15/23

Clinical chemistry in
pregnancy
1. To explain biochemical changes occurring during pregnancy
2. To list pathological changes during pregnancy.
3. To explain diabetic pregnancy.
4
8/15/23

Maternal physiology
Maternal physiology is dramatically changed during the third trimester of pregnancy
8/15/23

Maternal physiology changes
Condition Changes Causes
WEIGHT GAIN There was a weight gain [12.4±4
kg]
qConception products(fetus placenta and
amniotic fluid).
qMaternal fat store (25% of weight gain).
qMaternal water retention(5 liters increase).
RESPIRATORY
FUNCTIONS
qMild hyperventilation
qThere is a fall in PCO2
qLow HCO3 due to renal
excretion .
qAn increase in O2 consumption
(20%)
qCentrally mediated action of progesterone in
the early pregnancy.
RENAL FUNCTION qIncrease the renal blood flow
qHigh GFR
qCrCL = 150 ml/min (30th
week).
qLow urea and creatinine
qReduction in renal threshold
of glucose (glucosuria) in (70%
of pregnant).
qHigh excretion of uric acid and
amino acid in urine.
qIncrease plasma volume and COP
qTubular reabsorption impairments.
CARBOHYDRATES
METABOLISM
qLow fasting blood glucose Due to high utilization rate.
8/15/23

Maternal physiology changes
Condition Changes Causes
PROTEIN METABOLISM qLow serum albumin
qHigh levels of:
-ALP (placental origin)
-Transferrin
-Hormone-binding
glycoproteins(T3 binding
globulins).
-Fibrinogen
qECF expansion
qSynthesis of placenta
HORMONAL CHANGES qHigh levels of estrogen and
progesterone , HCG, PL
qDue to placental production
8/15/23

Pregnancy associated pathology
Thyrotoxicosis
Morbidity during pregnancy
Diabetes mellitus
Hypertension
Renal disease
Pregnancy associated
conditions
8/15/23

Diabetic pregnancy
Diabetic before pregnancy
Diabetic during pregnancy
Maternal hyperglycemia Hyperinsulinisim üLarge bloated fetus
üHypoglyemic
Baby of diabetic mother
Large and bloated
Hypoglycemic (fatal)
Probability to respiratory
distress syndrome
8/15/23

Hypertension in pregnancy
Pregnancy- induced hypertension
Placental insufficiency
Fetal intrauterine growth retardation
Eclampsia
Investigations
üBlood pressure
üSerum urates
ü24-h protein excretion in urine
üCreatinine clearance
8/15/23

Paediatric Clinical
chemistry
5
1. To describe the respiratory functions at birth
2. To describe the infancy renal functions.
3. To explain the changes in electrolytes and fluids during infancy.
4. To explain the changes in liver functions during infancy
5. To describe energy metabolism in infants.
6. To explain gastrointestinal functions in infants.
7. To explain changes in calcium levels during infancy.
8/15/23

Pediatric Clinical chemistry
Intrauterine life Baby life (independent existence)
Biochemical changes
Mature functions not
attained for weeks, or
months
(1) RESPIRATORY FUNCTIONS
üFetal Hb has more affinity to O2 than baby Hb.
üOxygen dissociation curve moved to left.
üAt low PO2 fetal Hb can delivers more O2 to tissues this
explains the ability of neonates to survive levels of
hypoxia which would not be possible in adults.
ü fetus has more Hb than baby. Which induce efficient
oxygenation during fetal life.
üAlthough the fetus has a high PCO2, during labor normal
lungs inflate and there is an increase in PO2 and decline in
PCO2
8/15/23

Respiratory distress syndrome
Lack of surfactant
Failure of alveolar expansion and subsequent alveolar collapse ‒
ventilation abnormalities.
Øhypoventilation will lead to respiratory acidosis.
ØHypoxaemia will lead to metabolic acidosis.
ØMore immature baby greater risk for RDS .
Normal
Endogenous surfactant
supply, normal
expansion of alveoli.
Respiratory distress
syndrome
No surfactant, no
expansion
Surfactant therapy
Exogenous supply of
surfactant
8/15/23

(2) RENAL FUNCTIONS
üAll glomeruli are formed by 36 weeks gestation.
üGFR is reduced at birth due to decreased renal blood flow.
üSerum creatinine rises in first few weeks after birth and
then falls with in 4 weeks, remains low for 5 years. Then
gradually increased to adult level.
üImmature proximal tubular function lead to reduced
glucose and HCO3 reabsorption(low serum HCO3).
üGlycosuria and aminoaciduria are normal in neonates.
üA baby's ability to concentrate urine is poor (urine
osmolality 600 mmol/kg).
üLimited excretion of water and electrolytes (strict care
should be taken during intravenous invasion of babies).
8/15/23

(3) FLUID AND ELECTROLYTE BALANCE
Newborn
Water 75%
Adult
Water 60%
1st week
ECF contracts
1 year old
Total body water
(60%) and ECF
(25%)
a) Infants are very sensitive for water loss –
Ø due to immature renal tubular function at this time.
Ø Losses at this age due to frequent diarrhoea.
b) Dehydrated child depleted more water than
Sodium due to –
Ø Immature renal tubular functions.
Ø Larger body surface in related to body weight.
c) The response of dehydration treatment in
children should be monitored by assessing
fluid balance and urine output and body weight.
8/15/23

(4) LIVER FUNCTION
(A) INABILITY TO CONJUGATE ALL BILIRUBIN
Jaundice (1st week)
Full-term babies
RAPID RESERVATIONS
Premature babies
SEVERE JAUNDICE
AND RESERVATION
TAKES LONG TIME
a) Jaundice in 1st 24 hours usually is pathological due to RBCs destruction (ABO incompatibility or
rhesus incompatibility).
b) High unconjugated bilirubin increased and binds more albumin until its saturation it well go to
brain and conjugate proteins in brain (kernicterus) neurotoxic and may lead child death.
c) Jaundice which lasts for more than 10 days after birth should be investigated. It may be due to
–galactosemia – cystic fibrosis- G6PD deficiency- hypothyroidism.
d) High conjugated bilirubin is a different condition it may be due to [neonatal hepatitis] from
mother or [biliary atresia] where biliary drainage is disordered and need surgical interference.
8/15/23

(5) ENERGY METABOLISM
Before birth
üChief source of energy is mother glucose via
placenta.
üExcess glucose stored as glycogen in liver.
üFree fatty acids can cross placenta and stored as
fat in depot fat
Adult
At birth
üGluconeogenesis and glycogenolysis are
proceeding to maintain blood glucose.
üLipolysis is operated for fatty acids production.(FAs
are the main source until feeding)
Neonatal hypoglycemia (<2mmol/l)
Light-for-dates babies or premature babies (depleted glycogen store)
Babies of diabetic mother (high insulin secretion) hyperinsulinaemia
Nesidioblastosis (hyperinsulinemia even without a diabetic mother) unknown
cause
Inborn errors of metabolism (glycogen storage disease)
8/15/23

(6) GASTROINTESTINAL FUNCTIONS
At birth
üDisacchridases (maltase, lactase, sucrase) are
present.
ü1st 7 days the lactose can be absorbed unchanged
and can be appeared in normal child.
ü Proteases like (rennin and pepsin) also are
present. but some proteins are absorbed as it is?!
Adult
üTransient and asymptomatic hypocalcaemia
can be occur in preterm infants.
(7) CALCIUM
Neonatal hypocalcaemia
Preterm infants
Infants with respiratory distress syndrome
Infants of diabetic mother
Asphyxiated infants
8/15/23

CASE STUDY (1)[pediatric clinical chemistry]
A baby of diabetic mother weighted 1.64 kg when born at gestational
age (32 weeks). The baby was well at birth but her condition
deteriorated with hours and she had respiratory problems.
a) What biochemical determinations should be requested on this baby?
b) Why is it important to consider each request carefully?
a) Biochemical tests mainly will be performed for monitoring RDS,
neonatal hypoglycemia and neonatal hypocalcaemia so the requested
test are [blood gases, blood glucose, and serum calcium].
B) According to this infant condition it looks like a preterm infant
and these infants have a very low blood volume which may reaches
(100 ml) only in related to her weight. Many investigations well
be requested for her so strict careful should be taken to collect
a small amount of blood as high amount of blood may be lead to
anemia and dangerous consequences.
8/15/23

Screening the
newborn for disease
6
1. To define screening programme for newborn diseases.
2. To describe the need for screening programmes.
3. To explain the diseases for which a screening tests is mandatory.
4. To describe the screening programme for congenital hypothyrodism.
5. To describe the screening programme for phenylketonuria.
6. To explain common biochemical tests for inborn errors of metabolism.
7. To list common inborn errors of metabolism.
8/15/23

NEONATAL SCREENING PROGRAMMES
Capillary sampling technique for
neonates
Posterior medial third of foot
(plantar aspect)
Filter paper card (Guthrie card) for
collection of babies blood spots
üMany countries establish many programmes for screening neonates for
disease.
üCapillary blood sample are collected on Guthrie card and can be send for
lab even through mail.
8/15/23

WHY WE ESTABLISH A NEONATAL SCREENING PROGRAMME?!
Does the disease have a relatively high incidence?
Can the disease be detected within days of birth?
Can the disease be identified by a biochemical marker
which can be easily measured?
Will the disease be missed clinically and would this
cause irreversible damage to the baby?
Is the disease treatable and will the results of screening
test be available before any irreversible damage to the
baby has occurred?
Cost-
effectiveness
questions
üThere are a major screening programmes for Hypothyroidism and Phenylketonuria
(PKU) in many countries.
üBut in other countries due to population mix leading to setting up a specific screening
programmes (e.g Adrenal hyperplasia in Yupik Eskimo)
üOn the other hand there is no screening programme for PKU in Finland (very low
incidence).
8/15/23

CONGENITAL HYPOTHYROIDISM
q There is no clinical signs of abnormal baby with hypothyroidism
at birth.
q undetected or untreated congenital hypothyroidism induce
mental retardation and cretinism.
q The base for the screening test is [high blood TSH].
q Confirmatory sample (serum) should be taken for serum TSH
when screening test is positive.
q Thyroxine treatment starts as soon as possible after diagnosis.
(10 µg/kg) increased gradually to (100-200 µg/kg) at age of
12yrs old. [absence of clinical signs of both hypothyroidism and
hyperthyroidism and normal T4 and TSH] is a good evidence of
treatment programme.
q Just positive screening test is obtained, mother's thyroid
functions should be assessed [maternal auto antibodies] can
cross placenta and block fetal thyroid. At this condition child
thyroid will be returned normal after birth.
q TSH screening test not used for secondary hypothyroidism due
to pituitary disorders
Features of cretinism
8/15/23

Why TSH is better used for diagnosis CH more than T4
1. TSH is more sensitive and specific for CH.
2. the rate of false positive results is higher using primary T4 strategy.
The best time for blood collection for CH
The ideal time to obtain the blood spot is 3-5 days after birth to minimize the false positive
high TSH values due to the physiological neonatal TSH surge that elevates TSH levels
and causes dynamic T4 and total triiodothyronine (T3) changes in the first 1 or 2 days
after birth.
Comment on results for CH program
In some laboratories, the threshold cut-off is adjusted based on the age of the infant
when the blood spot is obtained. The cutoff for reporting an elevated TSH is a level
above 20 to 25 mU/mL in most screening programs. Whichever method is used, babies
whose initial TSH is >50 mU/mL are most likely to have permanent CH, whereas a TSH
level between 20 and 49 mU/mL is frequently a false positive or represents transient
hypothyroidism. Transient CH is particularly common in premature infants in borderline
iodine-deficient areas.
8/15/23

PHENYLKETONURIA (PKU)
q PKU arises from impaired function or loss of
phenylalanine hydroxylase which converts
Phenylalanine to tyrosine.
q Clinical features include [poor feeding,
irritability, eczema, mental retardation, and
reduced melanin formation].
q The base for screening test is [high
phenylalanine in blood spot].
q The goal of treatment is to reduce blood
phenylalanine.
q Data tells about the capability to reduce
mental retardation through dietary control by
keeping Phenylalanine low up to 10 years old.
But current views is the lifelong therapy is
necessary.
8/15/23

CASE STUDY (1)[screening programmes for newborn diseases]
The blood spot analysis on 6-days old baby girl indicated a high TSH
(28 mU/l). A second blood sample was quickly obtained for repeat TSH
concentration. The lab reported a TSH level (6mU/l).
a) What further investigations should be carried out?
There are no other investigations needed. But parents should assured
that their daughter have not congenital hypothyroidism.
Over 99% of normal 6-days old babies have a TSH level < 10 mU/l.
While the majority of babies with congenital hypothyrodism have a
blood TSH level > 100 mU/l.
So babies with TSH level of (15-40 Um/l) are equivocal and second
sample should be tested.
If the second sample result is normal, usually there is no further
investigations will be done.
8/15/23

INBORN ERRORS OF METABOLISM
üClassical genetic disease resulted from single gene
mutations which resulted in reduced protein or
defective protein.
üInborn errors of metabolism: defined as a block in
metabolic pathways due to a defect in a
particular enzyme.
ü usually in inborn error the defective protein is an
enzyme.
üBut there are some exceptions like
§ Familial hypercholesterolemia
§ Cystinuria
§ Hartnups disease
A
B
C
D
STOP
X
Y
X
(A) INTRODUCTION
8/15/23

(B) POSSIBLE CONSEQUENCES OF DEFECT IN THE INBORN ERRORS
(a) Absence of the end product D
X
(b) Accumulation of the intermediates
B
C
(c) Diversion through minor side-pathways X
Y
C
(d) Absence of negative feedback
8/15/23

(C) MECHANISM OF INBORN ERRORS DISEASE
Accumulation of a substance
Reduced product
Diversion of intermediates
Failure of negative feedback mechanisms
Failure of transport mechanism
Inborn errors of metabolism can be clinically manifested through:
8/15/23

(D) CLINICAL DIAGNOSIS OF INBORN ERRORS OF METABOLISM
Clinical presentations is usually non-specific [poor feeding, lethargy, vomiting]
Specialist tests used to diagnose inborn errors of metabolism are extensive and wide.
Defects of clinical diagnosis
Useful clues increase suspicion of inborn errors of metabolism
If parents are cousins [Consanguious mating]
History of unexplained premature death in an older sibling
Onset of symptoms following change in feeding regime.
Dysmorphic features
Unusual smell
Inborn errors of metabolism Smell
Maple syrup urine disease Maple syrup
PKU Musty
Isovaleric acidaemia Sweaty feet/ cheese
Trimethylaminuria Fish
Hypermethioninaemia Cabbage
8/15/23

(E) LABORATORY DIAGNOSIS OF INBORN ERRORS OF METABOLISM
INVESTIGATIONS FOR INBORN ERRORS OF METABOLISM
I. Some investigations are specific while others are not. E.g presence of cataract in clinical
examinations need a request examination test for Galactosemia which is the
measurement of galactose-1-phosphate uridyltransferase in RBCs.
II. Lab investigations are very useful for direction to other investigations and when there
is an absence of clues.
III. These investigations includes:
Test Indications
Plasma urea üWhen there is neurological distress/intoxication
üUrea cycle disorders.
Organic acids (urine )/amino
acids in plasma and urine
For a large groups of inborn errors of metabolism
Plasma lactate Acidosis, hypoglycemia, neurological distress
galactose-1-phosphate
uridyltransferase
It is specific for Galactosaemia
8/15/23

Classification of Inborn errors of metabolism on the basis of clinical and laboratory
features.
Presentation Most likely diagnosis
Intoxication –ketoacidosis [Blood H not
so high]
Maple syrup urine disease [amino acid disorders]
Intoxication – ketoacidosis Organic acid disorders
Energy deficiency – lactate acidosis Congenital lactic acidosis
Intoxication- high ammonia-no
ketoacidosis
Urea cycle disorders
Energy deficiency –no metabolic
disturbances
Proxisomal diosrders – non-ketotic hyperglycemia
Storage disorders - no metabolic
disturbances
Lysosomal storage disease
Hypoglycemia – hepatomegaly –
abnormal LFTs
Glycogen storage disease
8/15/23

Biochemical investigations that help to direct further investigations
Test Comment
Urinalysis
Reducing substances Reducing substances other than glucose may indicate galactose and
directing to galactosemia
Ketones Strong positive [hypoglycemia], low (hypoketosis) fatty acid oxidation
disorders.
PH PH<5.5 points to an organic acid disorders
Blood
Anion gap [(Na + K)-(Cl +
HCO3)]
High anion gap Metabolic acidosis [>20 mmmol/l] indicates organic acids
disorders
Hypoglycemia Relatively non-specific as it occurs in many neonates and compatible
with [organic acids disorders-amino acids disorders- glycogen storage
diseases- galactosemia- fatty acids oxidation defects].
Hyponatremia It found with ambiguous genitalia suspect (congenital adrenal
hyperplasia)
Respiratory Alkalosis It found with neurological distress suspect (urea cycle disorders)
Abnormal LFTs Relatively non-specific it found with [galacotsemia- glycogen storge
disease- tyrosinemia-alpha-1- antitrypsin deficiency]
Hyperammoniemia High plasma ammonia strongly suspect urea cycle disorders
8/15/23

Selected inborn errors of metabolism (1)
Inborn error Pathway affected Main features
Acute intermittent prophyria Disorder of haem synthesis - Abdominal pain and neurological
disorders –high urinary prophblinogen
Adrenoleucodystrophy Accumulation of long chain fatty
acids
Adrenal insufficiency and
neurodegenerative disorders
Agammaglobulinemia Absence of immunoglobulins
production especially IgA
Recurrent respiratory infection
Alpha-1-antitrypsin
deficiency
Protease and alpha-1-
antitrypsin
Liver diseases and pulmonary
emphysema
Biotinidase defeciency Failure of biotin recycling Organic aciduria- developmental
delay- alopecia –seizures-hypotonia
and hearing loss
Congenital adrenal
hyperplasia
Steroid hromones biosynthesis
(21-hydroxylase) synthesis of
cortisol and aldosterone
Hyponataermia
Cystic fibrosis Cystic fibrosis transmembarane
conductase regulator (CFTR)
defection
Bicarbonate and chlorides exchanges
disorders
Cystinuria Increase the excretion of
cystine, lysine, arginine, and
ornithine
Renal calculi
8/15/23

Selected inborn errors of metabolism (2)
Inborn error Pathway affected Main features
Cystinosis Defect in membrane transport
of cystine
Cystine crystals deposit in kidneys,
liver, spleen, bone marrow and cornea.
Familial
hypercholesterolemia
Reduced the number of
functional LDL receptors
High total cholesterol, LDL and
triglycerides with low HDL.
Galactosemia Deficiency of galactose-1-
phospahte uridyl transferase
Failure to thrive- vomiting- vomiting –
diarrhoea-infant may die early or
develop metal retardation, liver
disease, cataract and renal tubular
damage.
Glucose-6-phosphate
dehydrogenase deficiency
HMP-shunt Neonatal jaundice- hemolytic crises
induced by drugs.
Glycogen storage disease
type (I) von Gierk's disease
Deficiency of glucose-6-
phosphatase
High store of glycogen in liver – induce
hepatomegaly, hypoglycemia, followed
by hyperlipidemia and lactic acidosis
Haemochromatosis High absorption and deposition
rates of iron in tissues
High serum iron- chronic fatigue-skin
pigmentation and hypogonadism
Homocystinuria Defeciency of cystathionine
synthase
Accumulation of sulfur- containing
amino acids –eye problems, mental
retraction and osteoporosis.
Lesch-Nyhan syndrome HGPRTase deficiency Delayed motor development
8/15/23

Clinical chemistry in
the eldery
7
1. To describe the biochemical changes in geriatric patients.
2. To explain thyroid problems in elderly patients.
3. To explain the prevalence of diabetes in related to age.
4. To explain changes in bone, gonadal and pituitary functions in elderly patients
8/15/23

BIOCHEMICAL CHANGES IN ELDERY
q Many organs show gradual decline in function even there is no a disease.
q Usually this decline is with no clinical consequence due to the considerable function
reserve of the organ.
q The problem which face the clinical biochemist here is how to differentiate between
biochemical consequences of ageing and factors related to the disease.
q Interpretation of biochemical results in eldery need an establishment of an age-related
reference ranges.
q The most common metabolic diseases in eldery are
A. Thyroid diseases
B. Diabetes mellitus
C. Renal diseases
D. Pituitary disease
E. Impaired gonadal functions
F. Bone disease
Biochemical assessment in geriatric patient
Test Associated conditions
Potassium Hypokalemia
Urea, creatinine Renal disease
Ca, P, ALP Bone disease
TP, Albumin Nutritional state
Glucose Diabetes mellitus
Thyroid function
tests
Hypothyroidism
Hematological
tests and occult
fecal blood
Blood and bleeding
disorders
8/15/23

Several considerations during interpretations of test results in elderly people
!"#$%&'()*%"#+,"(+-#*'(.('*)*%"#+",+/)0+('$1/*$ %#+'/&'(/2+
!"#&%*%"#+ -#*'(.('*)*%"#+
3104/%#%4)/+&%$"(&'($+ 5,*'#+1#&%)6#"$'&+74"88"#+%#+'/&'(/2+
9"/2.:)(8)42+ ;)#2+8'&%4)*%"#$+4)#+),,'4* /)0+('$1/*$+'<6<+
4"(*%4"$*'("%&$=+/%*:%18=+>59?+<
?/4":"/$+)/$"+),,'4*+8)#2+/)0+&)*)<+
;)/#1*(%*%"#+ !"88"#+%#+'/&'(/2+)#&+),,'4*$+8)#2+&)*)+@.("*'%#$A/%.%&$A
$16)($AB%*)8%#$A8%#'()/$C
D'/)*%B'+%88"0%/%*2++)#&+
"0'$%*2+
E')&%#6+*"+8)(F'&+4:)#6'$+%#+/)0 ('$1/*$+
G"8'"$*)*%4+8'4:)#%$8$+ -*+&%8%#%$:'&+H%*:+.("6('$$+",+)6'+
I%"/"6%4+B)(%)0%/%*2+ J:'+0%"/"6%4)/+B)(%)0%/%*2 %#4(')$'$+H%*:+)6'<+
Reference range Normal Normal for age
Normal healthy range Normal data for adults Abnormal data for elderly
8/15/23

THYROID DISEASE
qAlthough the disease is common in eldery it is
misinterpreted as its signs in eldery like signs of normal
ageing process signs.
qThe interpretation of T3, T4 and TSH in elderly may be
not simple as in young person with the active signs of
the disease.
qGeriatric patients also may take drugs which affect
thyroid functions [table]
Drugs commonly affect thyroid
functions
Drug Effect
Osterogens Increase TBG
Androgens Decrease TBG
Glucocorticoids Decease TBG
Phenytoin,
salicylates
Inhibit TBG binding
L-DOPA and
glucocorticoids
Supress TSH
Lithium Inhibits T4 secretion
Amiodarone,
propanolol
Inhibit T4-T3
conversion
Cholestyramine
,colestipol
Reduce oral T4
absorption
8/15/23

DIABETES MELLITUS
qDiabetes mellitus (NIDDM) is common in old age due to insulin
resistance and obesity.
qBy way glucose tolerance is declined with age even in absence of
diabetes mellitus.
qRenal threshold of glucose is increased [>220mg/dl].
qAll these observations make the diagnosis of diabetes mellitus in
geriatric patient difficult.
RENAL DISEASE
PITUITARY DISEASE
qPitutray gland decreased in size with age. And the incidence of microadenomas and
focal necrosis increases.
qGonadotropin and AVP secretion increases – GH secretion decreased
qRenal functions gradually declined through life.
qThe upper limit for both creatinine and urea will increase
qCreatinine clearance falls even though the amount of creatinine
produced is low due to the low muscle mass in elderly.
qThe ability of kidneys to concentrate and dilute urine is declined
also by age. Age-related Cr clearance
Age specific Prevalence of diabetes mellitus
8/15/23

GONADAL FUNCTION
qBoth ovarian and testicular hormone secretion decline.
qMenopause in women can induce distressing symptoms-or serious bone disease.
qThere are benefits for post-menopause hormone replacement therapy (HRT)
ü To Reduce menopause distressing symptoms.
ü To Maintain bone structure.
ü To Reduce the risk of coronary heart disease.
BONE DISEASE
qBone disease is more common in elderly patients than young.
qOsteoporosis is the most common.
qThe risk of Hip fracture is increasing by age due to reduction in bone mass/volume.
qBone loss accelerates when the oestrogen production is reduced after menopause.
qAlthough we can find a normal biochemical indices for calcium and calcium metabolism in elderly they
can develop a severe primary osteoporosis.
qVitamin D still the main cause of osteomalacia in elderly. Assessment can be done through
measurement of circulating [25-hydroxycholecalciferol].
qSevere osteomalacia characterized by fall in serum calcium and vitamin D, high PTH, ALP.
qPaget's disease: due to high activity osteoclastic cell lead to high bone resorption. There was a severe
bone pain and very high ALP with high urinary excretion of (hydroxyproline).
qMyeloma is also frequently encountered in elderly.
8/15/23

NUTRITION IN ELDERLY PATIENTS
qNutritional deficiencies are common in geriatric patients due to:
ü Neglected old patients.
ü Those who fail to eat balanced diet.
ü Loss of appetite in old patients.
qRecently, nutritional deficiencies can lead to a reduction in immunity and increase
susceptibility to infection in elderly patients.
Common nutritional deficiencies and associated diseases and disorders in elderly
Nutrient Associated disease/disorder
Proteins calories Decrease cell mediated immunity
Antioxidants
[A,C,E vitamins]
T-cells functions, infections, cancers, CHD
Flavno
ids
Cancers and CHD
Minerals [MgàCHD and stroke] [Se-à cancers] , [Zn-à immune functions]
Vitamins B6,
B12, folate
CHD
8/15/23

Nutritional
assessments
8
1. To define malnutrition
2. To explain the consequences of malnutrition.
3. To describe the biochemical tests for assessment of malnutrition.
4. To list the biochemical tests for vitamin deficiency.
5. To explain Preoperative nutritional assessment
6. To outline nutritional support.
8/15/23

8/15/23 Aaser Abdelazim ----Clinical Biochemistry 94
•Decrease
intake
•Loss of
nutrients
Decrease
the
nutrient
store
Specific
metabolic
and
biochemical
effects
Clinical
signs and
symptoms
Consequence of mal nutrition
MALNUTRITION
qMalnutrition is a common problem world wide.
ü Poverty and alcoholism
ü Hospitalized patients.
qProtein-calories malnutrition not only encountered while vitamins and trace elements also
is occurred. Especially after major surgical operations and chronic illness.
qMalnutrition is a wide expression for both food inadequacy and food excess.

ASSESSMENT OF MALNUTRITIONC
HISTORY EXAMNATION BIOCHEMICAL INVESTIGATIONS
qChange in weight
qPoor wound healing
qExposed to heavy infections
qHistory of food and water
intake over past 7 days.
qAsking about appetite
qTypes of food intake
Examine:
qHeight
qWeight
qArm circumference
qSkin-fold thickness
qBody mass index(BMI)
BMI =
Weight (Kg)
(Height)2 meters
qProteins : but affected by
other factors e.g. liver
qBlood glucose: low and
ketosis in starvation
qLipids: fasting plasma TGs
qVitamins:
qMinerals: trace and major
elements . See the Table.
BMI Nutritional state
< 18.5 Underweight
18.5-24.9 Normal weight
25-29.9 Overweight
> 29.9 Obese

BIOCHEMICAL ASSESSMENT OF MALNUTRITION
Test Comments Factors affecting the test
Plasma proteins
Declined in
malnutrition
üLiver diseases
üHydration state
üRenal diseases
üAlbumin may fall in response to acute injuries.
Blood glucose Lowered
It may be falls in starvation and also can be
increased in cases of injuries and stress response.
Lipids Lowered
qTriglycerides may falls
qSome fatty acids are measured if there is a
suspecting for special deficiency.
qFecal fats can be measured to assess the
malabsorption.
Vitamins Lowered
Special assessment for individual deficiencies see
the table.
Major minerals Declined
Their quantities (> 5 gm in the body) like Sodium,
potassium, chloride, phosphorus their levels
reflects the dietary intake.
Trace elements Declined
Their quantities (<5 gm in the body) like
manganese, copper, fluoride. They reflect
deficiencies and usually found bound to protein.
8/15/23

Lab assessment of vitamins deficiency:
Vitamin Deficiency state Lab assessments
WATER SOLUBLE VITAMINS
Ascorbate Scurvy Plasma level
Thiamine (B1) Beri-Beri Plasma level /Transketolase activity
Riboflavin (B2) Rare single deficiency Plasma level /GRD activity
Pyridoxine (B6) Dermatitis/anemia Plasma level/AST activity
Cobalamine (B12) Pernicious anemia Serum B12/full blood count
Folate Megaloblastic anemia Serum/blood folate/ CBC
Niacin Pellagra Urinary niacin metabolites
FAT SOLUBLE VITAMINS
Vitamin A Blindness Serum vitamin A
Vitamin D Osteomalcia /rickets Serum 25-hydroxychalciferol
Vitamin E Anemia/ neuropathy Serum vitamin E
Vitamin K Defective clotting Prothrombin time PT

Preoperative nutritional assessment
qNutritional assessment is necessary before and after surgical operations.
qThe patient should be in good nutrition state before the operation as patient should allow
to build up a reserve before the surgery.
>10% body weight loss
Is weight loss associated with reduced functioning?
e.g muscle weakness
Is patient under septic or metabolic stress?
Treatment
Provide enternal or parenteral nutrition
PROCEED TO SURGERY
NO
YES
YES
NO
8/15/23

Spectrum of nutritional support:
NUTRITIONAL SUPPORT
qNutritional support ranges from simple dietary advice to long term parenteral nutrition (TPN).
qIn between there was a long spectrum. As the there is a more serious clinical condition the support
become intensive and important.
qClinical biochemistry play the major role to determine such serious conditions e.g. (diabetes mellitus,
iron deficiency, hyperlipidemia etc.).
qThe major role of clinical biochemical labs here is to monitor the patients which receive such kind of
nutritional support.
OBESITY
Reduced
calories
CONSTIPATION
High
fiber diet
LACTOSE
INTOLERANCE
Dietary
restriction
COELIAC
DISEASE
Gluten-
free diet
PRENICIOUS
ANEMIA
B12
injection
Severe
anorexia
malignancies
Enternal
nutrition
Major
surgery
and
sepsis
TPN

PATIENTS REQUIREMENTS OF NUTRIENTS
(1) Energy
Harris-Benedict equation
for energy need calculation
Principle Sources Of Energy:
qCARBOHYDRATES: (4 Kcal/g)
qLIPIDS: (9 Kcal/g)
qAMINO ACIDS: (4 Kcal/g)
(2) Nitrogen
qAmino acids provide nitrogen and
also yield energy.
qProteins should be 10-15 % of total
calories requirements
(3) Vitamins And Trace Elements
qThey called micronutrients because
they needed by minute amount.
qRecommended Dietary allowances
(RDAs) postulate these requirements

Average daily requirements of
vitamins
Average daily
requirements of essential
trace elements
Average daily requirements of vitamins and essential trace elements/day

Points Malabsorption Malnutrition
Definition Interruption of normal digestion,
absorption or transport of nutrients
form GIT
Resulted from malabsorption or
inadequate food intake.
Etiology Disorders of GIT mucosa Disorders of GIT
Starvation
Inadequate food intake
Nutrients deficiency
8/15/23

Clinical Biochemistry

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