Abnormal Clinical

Chemistry & TDM in Cancer

Dr. Kinjalka Ghosh

Assistant Professor,
Department of Biochemistry,
Tata Memorial Hospital, Parel, Mumbai.
 Altered Clinical Chemistry

1. Tumour Related
– Crabtree Effect
– Warburg Effect
2. Humoral Factors (Inflammation/Immune)
3. Iatrogenic
 Altered Clinical Chemistry
1. Hypoglycemia
2. Hypercalcemia
3. Hypocalcemia
4. Hypophosphatemia
5. TLS
6. SIADH
7. Cushing Syndrome
8. Abnormal Liver Function
 Hypoglycemia
• Rare but severe complication
– First described in 1930 by Doege in a case of
mediastinal fibrosarcoma
• In most cases, hypoglycemia is due to a
paraneoplastic secretion of ‘big’ insulin-like
growth factor-II (IGF-II)
• Severe metabolic emergency
 Hypoglycemia
Clinical Laboratory findings Associated
presentation cancers
•Sweating For non–islet cell tumor Mesothelioma
•Anxiety hypoglycemia: Sarcomas of
•Tremors low glucose, the Lung & GI
•Palpitations low insulin (often <1.44-3.60 µIU/mL), HCC
•Hunger low C-peptide (often <0.3 ng/mL),
•Weakness elevated IGF-2:IGF-1 ratio (often >10:1) Hodgkins (Ab)
•Seizures
•Confusion For insulinomas:
•Coma low glucose, elevated insulin,
elevated C-peptide,
normal IGF-2:IGF-1 ratio
 Hypophosphatemia
• Tumor-induced osteomalacia
– Specific tumors and over expression of FGF23 .
• FGF23 inhibits renal tubular phosphate reabsorption and
renal conversion of 25-hydroxyvitamin D to
1,25dihydroxyvitamin D, leading to the biochemical and
skeletal abnormalities.
• Patients with tumor-induced osteomalacia are characterized
biochemically by hypophosphatemia, hyperphosphaturia,
inappropriately low or normal 1,25dihydroxyvitamin D
concentration, and increased alkaline phosphatase
concentration.
 Hypophosphatemia
• The diagnosis of tumor-induced osteomalacia can be
challenging. Localization of the tumor can be difficult, as it
typically grows slowly.
• Besides routine laboratory tests ,serum FGF23 should be
ordered when tumor-induced osteomalacia is suspected.
• Tumorinduced osteomalacia can be differentiated from
certain heritable hypophosphatemias (X-linked
hypophosphatemia and autosomal dominant
hypophosphatemia) by genetic testing.
 Hypophosphatemia (rare)
Clinical Laboratory findings Associated cancers
presentation

•Muscle Weakness Hypophosphatemia Hemangiopericytoma.

•Bone Pain Neurofibromatosis,
•Pathological Phosphate: Low Bone neoplasms,
fractures ALP: Elevated Pseudotumors
PTH: Elevated
Vitamin D: Low
Urine phosphate:
Elevated FGF23
 Hypercalcemia
• 10% of all patients with advanced cancer
• Poor prognosis
• Mechanism of Hypercalcemia:
– Humoral hypercalcemia of malignancy (80%)-
PTHrP
– Skeletal Metastasis- (Osteolysis)
– Tumor Secretion of Vit-D
– Tumor Secretion ectopic PTH
 Hypercalcemia
Clinical presentation Laboratory findings Associated
cancers

•Altered mental status Hypercalcemia: Breast

•Weakness Mild:10.5-11.9mg/dL Multiple
•Ataxia Mod:12-13.9 mg/dL Myeloma
•Lethargy Severe: >14 mg/dL RCC
•Hypertonia, SCC (Lung)
•Renal failure, Low/N: PTH (<20 pg/mL) Lymphoma
•Nausea/vomiting, Ovarian
•Hypertension, Elevated PTHrP Endometrial
•Bradycardia
 HypoCalcemia
1. Pseudohypocalcaemia
2. Calcium chelators
3. Hypocalcaemia in the critically ill
4. Acute pancreatitis
5. Acute hyperphosphataemia
6. PTH deficiency
7. Magnesium depletion
8. Ectopic calcitonin secretion by the tumour
9. Oncological drugs
10. Vitamin D deficiency
11. Malabsorption
12. Osteoblastic metastases
Diagnostic approach to the cancer
patient with hypocalcaemia
 Cancers Associated
• Prostate
• MTC
• Thyroid Cancer
• Breast
 Tumor Lysis Syndrome
• When cancerous tumors break down very
quickly, intracellular substances need to be
cleared by the kidneys.
• If they can’t keep up, patient develops tumor
lysis syndrome (TLS).
 Tumor Lysis Syndrome
Clinical Laboratory findings Associated cancers
presentation
Lethargy Raised: Lowered: Lymphoma
Edema
K>6 Ca<7 Leukemia
Fluid overload
P>4.5 Blastoma Liver &
Congestive heart failure
Cardiac dysrhythmias UA> 8
Urea
Brain
Syncope
Sudden death LDH
Cairo-Bishop criteria. Blood
Radiation/Drugs
anorexia, tests must show at least a
vomiting, 25% increase in the levels of
Methotrexate
cramps, certain substances.
seizures,
spasms, Howard criteria. Laboratory
altered mental status results must show two or
tetany more unusual measurements
within a 24-hour period.
 SIADH • Bartter-Schwartz criteria
1. Hyponatremia with
corresponding hypo-
osmolality
2. Continued renal excretion
of sodium
3. Urine less than maximally
dilute
4. Absence of clinical
evidence of volume
depletion
5. Absence of other causes
of hyponatremia
6. Correction of
hyponatremia by fluid
restriction

>100
 SIADH
Clinical presentation Laboratory findings Associated
cancers
•Ataxia Hyponatremia: 1. SCLC
•Headache Mild:130-134 mmol/L 2. Mesothelioma
•Nausea Mod:125-129 mmol/L 3. Prostrate
•Fatigue Severe: <125 mmol/L. 4. Endometrial
•Cramps 5. Lymphoma
•Anorexia Increased urine 6. Breast
•Confusion osmolality 7. Adrenal
•Lethargy (>100 mOsm/kg in the
•Seizures context of euvolemic
•Respiratory hyponatremia)
depression
•Coma
Cushing Syndrome
 Cushing Syndrome
Clinical Laboratory findings Associated cancers
presentation
1. Muscle Hypokalemia (usually Small cell lung cancer,
weakness, <3.0 mmol/L), Bronchial carcinoid
2. Peripheral Elevated baseline (~50%-60% of cases)

edema, serum cortisol (>29.0 Thymoma

3. Hypertension, µg/dL), MTC
Weight gain, Normal to elevated GI
4. Centripetal fat midnight serum ACTH Pancreatic
distribution (>100 ng/L) not Adrenal
suppressed with Ovarian
dexamethasone
Failure to respond to high-dose dexamethasone
suppression distinguishes ectopic (ie,
paraneoplastic) Cushing syndrome from a
pituitary source
 Liver function Test
• Metabolic Organ
• Metastasis
• Tumor Related
• Pattern Recognition
• LFT & Chemotherapy
• Limitations
 Liver Function Tests
1. Synthetic function
– Albumin
– PT/INR
2. Cellular injury
– AST
– ALT
3. Cholestasis, or duct injury
– ALP
– GGT
– D. Billirubin
 Measures of liver synthetic function
• Albumin
– Most abundant plasma protein
– Produced exclusively by the liver at a rate of 10–
15 g a day.
– Transports small molecules and drugs
– Maintains plasma oncotic pressure
– Hypoalbuminaemia: more common in chronic
liver disease than in acute toxicity.
– Adverse prognostic feature in many solid tumours.
 Measures of liver synthetic function
• Prothrombin time
– is a measure of the extrinsic pathway of the coagulation
cascade.
• The international normalised ratio
– is the ratio of a patient’s prothrombin time to a normal (control)
sample raised to a power, based on an international sensitivity
index that corrects for variations between laboratories and
reagents.
• The test is elevated most commonly when oral
anticoagulants (ie, warfarin) are being given, or in vitamin K
deficiency.
• Increased prothrombin time because of liver dysfunction is
a marker of severe synthetic abnormalities, which can be
used to predict survival and outcomes in various disorders
 Altered LFT
• Potential causes other than cancer or the
chemotherapy agent should be considered
• Work-up of a patient who presenting with
abnormal LFT:
– Cholestatic
– Hepatitic
Common non-malignant causes of
abnormal LFT
1. Synthetic Function
Common non-malignant causes of
abnormal LFT
2. Cellular Injury
 Common non-malignant causes of
abnormal LFT
3. Cholestasis/ Duct Injury

S
 Effect of cancer on liver function
• Tumours in or around the liver and biliary tree
can affect liver function:
– Directly reducing the volume of functional
healthy liver
– Intrahepatic and extrahepatic biliary obstruction.
 Effect of cancer on liver function
• Portal-vein thrombosis:
– hypercoagulable state/ direct portal-vein infiltration
might occur, compromising vascular supply to healthy
liver parenchyma and thus drug metabolism.
• A rare paraneoplastic disorder (called Stauffer’s
syndrome) :
– RCC and is characterised by abnormal cholestatic
biochemical tests, prolonged international normalised
ratio, and hepatosplenomegaly without evidence of
direct liver involvement by the tumour or of intrinsic
liver disease.
 Effect of cancer on liver function
• Humoral and immunological factors
• Histological evidence of liver damage:
– colony-stimulating factors, IL-1 & IL-6.
• Indirectly affect drug metabolism in the liver.
• Cancers generate a host of inflammatory responses
– cytokines such as interleukin 6 and tumour necrosis factor α,
– which manifests clinically by raised serum acute-phase reactants such
as C-reactive protein, cachexia, and fever.
• This inflammatory response is associated with decreased
CYP3A4 activity in the liver, as measured in patients with
cancer by use of an erythromycin breath test.
 Effect of cancer on liver function
• In vitro evidence from transgenic mice suggests that
reduced CYP3A4 activity occurs through transcriptional
repression of the liver cytochrome P450 gene.
• The association between inflammation and CYP3A4
activity has implications for the treatment of
inflammation in patients with cancer and its potential
effect on chemotherapy drug metabolism.
• Inflammatory response might affect the regulation and
expression of drug transporters and thus drug
clearance.
 Paraneoplastic Syndromes
• The frequency of paraneoplastic syndrome is
only about 10-20 percent of all malignancies.
• Neurological paraneoplastic syndromes make
up about 1 percent of those with cancer.
• Treatment of neurological paraneoplastic
syndromes involves treating the cancer and, in
some cases, suppressing the immune
response that's causing signs and symptoms.
 TDM in Cancer
• Necessity
– Toxicity
– Narrow Therapeutic Index
• Adverse Effects
• Incomplete Treatment
• Customization
 Methotrexate (MTX)
• ALL in children
• Choriocarcinoma
• Ca-breast
• Ca-tongue
• Ca-pharynx
• Ca-testes
• Maint. of remission in leukemia
• Severe, debilitating psoriasis.
• High-dose methotrexate administration followed by
leucovorin rescue is effective in treatment of
– Ca-lung and Osteogenic sarcoma
 Why??
• Nonspecific cytotoxin,
• Severe, unwanted cytotoxic effects such as
– myelosuppression,
– gastrointestinal mucositis,
– hepatic cirrhosis
 Methotrexate (MTX)
• breast cancer • Common Side effects
– nausea
• leukemia – feeling tired
– fever
• lung cancer – leukopoenia
• lymphoma – oral ulcers
• Other side effects
• osteosarcoma may include
– liver disease
– lung disease
– lymphoma
– severe skin rashes
Methotrexate
 MTX
Folic Acid Folic acid is a natural
substrate for
dihydrofolate reductase,
in the synthesis of
nucleotides essential for
DNA synthesis.
Due to it’s structural
similarity to folic acid,
Methotrexate
methotrexate binds to
and inhibits
dihydrofolate reductase.
Leucovorin is a
formulation of reduced
folate used to counter-
act the effects of
Leucovorin methotrexate.
 MTX
• Homogenous enzyme Immunoassay
– G6PD
• Linearity up to 2 umol/L
• Toxic conc.
– 24h- 5umol/L
– 48h- 0.5umol/L
– 72h- 0.05 umol/L
 Foods that contain Folic Acid

• Dark green leafy vegetables (spinach)

• Broccoli.
• Kidney, lima, black and lentil beans.
• Peas.
• Beer (Brewers yeast)
• Whole grains.
• Wheat germ.
• Oranges / orange juice.
 TDM
• Cyclosporin
• Vancomycin
• Amikacin
Thank You!