Alpha-fetoprotein (AFP)
- 70,000 D M.W. glycoprotein, synthesized by both fetal liver and yolk sac
cells.
- In Cancerology, AFP is useful for the diagnosis and permits post therapeutic
follow-up of hepatocellular carcinomas (particularly those following liver
cirrhosis), teratocarcinomas (particularly from ovaries and testis), and liver
metastases from different cancers (especially digestive ones).
- In hepatology, AFP is a marker of intensive liver regeneration (viral hepatitis).
- In obstetrics, AFP measurement can be used to diagnose fetal neural tube
defects in maternal serum and amniotic fluid samples withdrawn between 14-22
weeks of pregnancy. Moreover, an increased AFP level can indicate fetal distress
or multiple pregnancy and a decreased level can implicate toxemia, slow fetal
growth or a placental tumor.
- AFP measurement can also be used during pregnancy, particularly when screening
pregnancies for Down’s syndrome. In this case, the AFP assay must always be
associated with other clinical and biological data such as free beta-HCG level,
maternal age and gestational age. Importantly, only statistical information
about the possible risk can be established.
Reference Range:
- <10 ng/mL in adult serum as a tumor marker.
In obstetrics, an accurate interpretation of AFP levels needs to take into
account real gestational age.
Carcinoembryonic antigen (CEA)
- 180,000 D M.W. glycoprotein, mainly secreted and excreted by digestive tract
glandular cancers (of the colon, rectum, pancreas, stomach) and their metastases.
- Currently, the CEA assay’s clinical interest is mainly demonstrated in the
field of colorectal cancers. In the breast and lung-cancer fields, CEA level
is related to metastatic dissemination, and its variations are considered
useful indicators when monitoring patient response to therapy. Besides, the
association of CEA with calcitonin is helpful in diagnosing thyroid medullary
cancer and in following up any release.
Reference Range:
Ferritin
- Ferritin is the major iron storage protein (450,000 D) for the body. It
is known that one molecule of ferritin is capable of binding 4000-5000 atoms
of iron. Therefore, serum ferritin level becomes a common diagnostic tool
in the evaluation of iron status.
- Serum ferritin levels vary with age and sex. There is a sharp rise in serum
ferritin levels in the first month of life, coinciding with the depression
of bone marrow erythropoiesis. Within two or three months, erythropoiesis
becomes reactivated and there is a drop in the concentration of serum ferritin.
By six months, the concentration is reduced to fairly low levels where they
remain throughout childhood. There is no sex difference until the onset of
puberty, at which time ferritin levels rise, particularly in males. There
is a significant positive correlation between age and serum ferritin levels
in females, but not in males.
- It has been reported that patients with iron deficiency anemia (IDA) have
serum ferritin levels approximately one tenth of normal subjects, while patients
with iron overload (hemochromatosis, hemosiderosis) have serum ferritin levels
much higher than normal.
- In both adults and children, chronic inflammation results in a disproportionate
increase in ferritin levels in relation to iron reserves. Elevated ferritin
levels also are observed in acute and chronic liver disease, chronic renal
failure and in some types of neoplastic diseases.
- Reference Range:
- 27-300 ng/mL in males; 10-130 ng/mL in females;
< 8 ng/mL in patients with IDA.
Carbohydrate antigen 19-9 (CA 19-9)
- a mucin-type glycoprotein synthesized by normal human pancreas cells and
by the bile ducts, and also by the gastric, colic, endometric and salivary
epithelia.
- CA 19-9 level is temporarily raised in cases of benign inflammatory diseases
of bilio-digestive origin.
- In neoplastic pathology, CA 19-9 level is useful not only for digestive
tract tumors (pancreatic, gastric and colo-rectal adenocarcinomas) but also
for bile duct cancers, ovarian mucinous cystadencarcinomas and uterine adenocarcinomas.
- The assay of CA 19-9 should under no circumstances be considered to be a
cancer screening test. A low CA 19-9 level does not exclude the possible presence
of a malignant tumor, just as a high level is not systematically indicative
of one’s existence.
- Reference Range:
CA-125
- CA-125 is found in a high percentage of non-mucinous ovarian tumors of epithelial
origin and can be detected in serum. CA-125 does not occur on the surface
epithelium of normal ovaries. Exceptions are inclusion cysts, metaplasia and
papillary neoplasia.
- CA-125 has been found in the amnion and in the coelomic epithelium; both
of these tissues are of fetal origin. In tissues of adult origin, the presence
of CA-125 has been demonstrated in the epithelium of the oviduct, in the endometrium
and in the endocervix.
- Clearly elevated values are sometimes found in various benign gynecological
tumors. Slight elevations of CA-125 are also found in early pregnancy, various
autoimmune diseases, hepatitis, chronic pancreatitis and liver cirrhosis.
- Nowadays, CA-125 is the most important tumor marker for monitoring the therapy
and progress of patients with serous ovarian carcinoma. Among the malignant
tumors, CA-125 elevations are also found in breast cancer and bronchial carcinoma.
- Reference Range:
Prostate specific antigen
(PSA)
- PSA, a 34,000 D M.W. glycoprotein, is the most important marker for the
detection, staging and monitoring of men with prostate cancer. PSA is produced
by the prostate epithelial cells and plays a role in the liquefaction of seminal
fluid.
- Two forms of PSA exist simultaneously in serum: the major portion of circulating
PSA is bound to endogenous protease inhibitors (such as α1 anti-chymotrypsin
andα2 macroglobulin), whereas a smaller portion remains free or uncomplexed.
- Reference Range:< 3 ng/mL in healthy male serum.
It has been found that there is a gradual increase in PSA levels with age.
However, this increase is not linear and the above reference range may need
to be modified to take this into account.
- For men with a level of total PSA between 4-10 ng/mL, the free PSA/total
PSA ratio is found to be higher in cases of benign prostatic hyperplasia (BPH)
than in those of prostate cancer.
Thyroid-stimulating hormone (TSH)
- TSH released from the anterior pituitary is the principal regulator of thyroid
function. Its secretion is in response to thyrotropin-releasing hormone (TRH)
from the hypothalamus.
- Human TSH affects a large number of metabolic processes in the thyroid gland
by binding its cellular membrane receptor and activating adenylate cyclase,
which in turn facilitates the production of cyclic AMP to elicit a cascade
of metabolic effects intracellularly. This stimulation results in increased
synthesis and release of the thyroxine (T4) and triiodothyronine (T3), and
maintenance of the physical and functional integrity of the thyroid gland.
- The major clinical use for TSH measurement is for the assessment of thyroid
status. In patients with intact hypothalamic-pituitary function, TSH is measured
to:
- exclude hypothyroidism (↑TSH) or hyperthyroidism (↓TSH);
- monitor T4 replacement treatment in primary hypothyroidism or antithyroid
treatment in hyperthyroidism;
- follow T4 suppression of the trophic influence of TSH in “cold nodules”
and non-toxic goiter;
- assess the response to TRH stimulation testing.
- Reference Range:
Thyroxine (T4)
- The hypothalamic-pituitary-thyroid axis controls the synthesis, release
and action of T4 and T3.
- Most of the T4 (99.97%) and T3 (99.7%) are bound to carrier proteins (thyroxine-binding
globulin and prealbumin) once released in to the circulation. Importantly,
it is those unbound or free hormones that correlate with the functional thyroid
state in most individuals.
- T4 and T3 regulate normal growth and development by maintaining body temperature
and stimulating calorigenesis. Additionally, T4 and T3 affect all aspects
of carbohydrate metabolism as well as certain areas of lipid and vitamin metabolism.
Fetal and neonatal development also require thyroid hormones.
- Elevated levels of T4 occur in Graves’ disease, subacute thyroiditis, toxic
nodule, or secondary hyperthyroidism. Decreased levels occur in primary hypothyroid
diseases such as Hashimoto’s thyroiditis and neonatal hypothyroidism or secondary
hypothyroidism due to defects at the hypothalamic-pituitary level.
- Reference Range:
Triiodothyronine (T3)
- In euthyroid individuals, only 20% of the total concentration of T3 in the
systemic circulation comes from direct secretion from the thyroid gland. The
ramaining 80% of total T3 is derived from enzymatic monodeiodination of T4
to T3 by the deiodinases in the peripheral tissues.
- In developing hypothyroidism, an increased conversion of T4 to T3 can be
found in a compensatory fashion to the developing hypothyroxinemia in an attempt
to maintain normal concentrations of the biologically active T3.
- During long periods of stimulation of the thyroid gland by thyroid-stimulating
immunoglobulins (Grave’s disease), the thyroid gland will secrete large quantities
of T3, which significantly increase the T3/T4 ratio when compared to the euthyroid
state.
- Elevated levels of T3 occur in Graves’ disease, and most other classical
causes of hyperthyroidism. Decreased levels occur in primary hypothyroid diseases
such as Hashimoto’s thyroiditis and neonatal hypothyroidism or secondary hypothyroidism
due to defects at the hypothalamic-pituitary level.
- Reference Range:
Free thyroxine (free T4)
- Most of the T4 (99.97%) are bound to carrier proteins (thyroxine-binding
globulin and prealbumin) once released in to the circulation. Importantly,
it is those unbound or free hormone that correlates with the functional thyroid
state in most individuals.
- In the absence of binding abnormalities, measurement of total T4 can provide
a reliable reflection of clinical thyroid status. However, changes in binding
proteins can occur which affect the level of total T4 but leave the level
of free T4 unchanged.
- Measurement of free T4 levels along with other thyroid tests and clinical
findings can establish borderline hyperthyroid and hypothyroid diagnoses.
- Reference Range:
Prolactin
- Human prolactin is secreted by the anterior lobe of the pituitary gland
and its secretion is controlled by the hypothalamus primarily through the
release of dopamine (prolactin inhibiting factor) and serotonin (prolactin
releasing factor).
- The primary physiological function of prolactin is to stimulate and maintain
lactation in women. Elevated prolactin levels may be detected during the eighth
week of pregnancy with levels continuing to rise throughout gestation. In
the absence of breast feeding, prolactin levels return to normal within three
weeks after birth. Prolactin levels are usually elevated post-partum and in
newborns.
- Abnormally high levels of prolactin are often associated with female infertility,
impotence and infertility in men, primary hypothyroidism (since TRH can also
stimulate the secretion of prolactin), pituitary tumors (prolactinomas), and
renal failure. Hyper-prolactinemia has also been associated with the inhibition
of ovarian steroidgenesis, follicle maturation, and secretion of LH and FSH.
- Various drugs are found to affect prolactin levels.
Administration of L-dopa and bromocriptine suppresses prolactin secretion.
Administration of psychotropic drugs, anti-hypertensive drugs, estrogen and
TRH tend to increase prolactin secretion.
- Reference Range:
- 0-20 ng/mL in both normal male and female
Luteinizing hormone (LH)
- Human LH is secreted by the gonadotropic cells of the anterior lobe of the
pituitary gland in response to gonadotropin releasing hormone (GnRH) from
the medial basal hypothalamus. In the female, LH stimulates the final maturation
of the follicle, follicular rupture, and ovulation.
- In a normal menstrual cycle, negative feedback by estradiol suppresses LH
secretion in the follicular phase. As the follicle develops (in response to
FSH), estradiol production increases which triggers an increase in GnRH and
an increased sensitivity of the pituitary to GnRH. A GnRH surge results in
the preovulatory (mid-cycle) surge of LH and ovulation. Following this surge,
LH is suppressed during the luteal phase due to negative feedback from progesterone
and estradiol.
- In the menopausal female, LH levels are elevated in response to decreased
production of ovarian estrogens and progesterones, which eliminates the negative
feedback mechanism on the pituitary gland. As a result, ovulation and menstrual
cycles decrease and eventually cease.
- In the male, LH is often referred to as interstitial cell-stimulating hormone
and influences the production of testosterone by the Leydig cells of the testes.
- Concentrations of LH and FSH in serum are commonly determined in investigations
of menstrual cycle, fertility, and pubertal developmental abnormalities, such
as premature ovarian failure, menopause, ovulatory disorders and pituitary
failure.
- The ratio of LH/FSH has been used to assist in the diagnosis polycystic
ovary disease. Low concentrations of LH and FSH may indicate pituitary failure
while elevated levels of LH and FSH along with decreased levels of gonadal
steroids may indicate gonadal failure (menopause, ovariectomy, premature ovarian
syndrome, Turners syndrome). Low concentrations of gonadotropin are usually
observed in females taking oral steroid-based contraceptives. In the male,
elevated LH and FSH with low levels of gonadal steroids may indicate testicular
failure or anorchia. In Klinefelter’s syndrome LH may be elevated due to Sertoli
cell failure.
- Reference Range:
- 2.12-10.89 mIU/mL in follicular phase;
19.18-103.03 mIU/mL in midcycle;
- 1.20-12.86 mIU/mL in luteal phase;
- 10.87-58.64 mIU/mL post-menopause
Follicle stimulating hormone (FSH)
- Human LH is secreted by the gonadotropic cells of the anterior lobe of the
pituitary gland in response to gonadotropin releasing hormone (GnRH) from
the medial basal hypothalamus. In the female, FSH stimulates follicular growth
and, in conjunction with LH, stimulates estrogen secretion and ovulation.
- In the menopausal female, FSH levels are elevated in response to decreased
production of ovarian estrogens and progesterones, which eliminates the negative
feedback mechanism on the pituitary gland. As a result, ovulation and menstrual
cycles decrease and eventually cease.
- In the male, FSH stimulates spermatogenesis through receptors on the Sertoli
cells which are present in the seminiferous tubules of the testes.
- Concentrations of LH and FSH in serum are commonly determined in investigations
of menstrual cycle, fertility, and pubertal developmental abnormalities, such
as premature ovarian failure, menopause, ovulatory disorders and pituitary
failure.
- The ratio of LH/FSH has been used to assist in the diagnosis polycystic
ovary disease. Low concentrations of LH and FSH may indicate pituitary failure
while elevated levels of LH and FSH along with decreased levels of gonadal
steroids may indicate gonadal failure (menopause, ovariectomy, premature ovarian
syndrome, Turners syndrome). Low concentrations of gonadotropin are usually
observed in females taking oral steroid-based contraceptives. In the male,
elevated LH and FSH with low levels of gonadal steroids may indicate testicular
failure or anorchia. In Klinefelter’s syndrome LH may be elevated due to Sertoli
cell failure.
- Reference Range:
- 3.85-8.78 mIU/mL in follicular phase;
- 4.54-22.51 mIU/mL in midcycle;
- 1.79-5.12 mIU/mL in luteal phase;
- 16.74-113.59 mIU/mL post-menopause;
- 0.00-3.00 mIU/mL pre-puberty.
Total β-human chorionic gonadotropin (Total
β-hCG)
- HCG is a glycoprotein hormone produced by the placenta. Shortly after implantation
of a fertilized ovum into the uterine wall, the trophoblast begins to produce
hCG. The hormone maintains steroid secretions of the corpus luteum until the
placenta can do so; therefore, hCG is an excellent marker for pregnancy.
- Healthy, non-pregnant individuals have low (<5 mIU/mL) to undetectable
hCG in serum.
- During a normal pregnancy, serum hCG is approximately 50 mIU/mL in the week
after conception, and doubles every 1.5-3 days for the first six weeks. Levels
continue to rise until the end of the first trimester, then gradually fall
to a lower level for the remainder of the pregnancy. Usually low or rapidly
declining levels may indicate an abnormal condition such as an ectopic pregnancy
or impending spontaneous abortion. After delivery, hCG returns to <5 mIU/mL
and is usually undetectable several days postpartum.
- In non-pregnant status, hCG is useful for the diagnosis and monitoring of
trophoblastic tumors either of ovarian origin (moles, chorionic carcinoma,
chorioepithelioma) or of testicular origin (seminomatous germ cell tumors
or non-seminomatous tumors having a trophoblastic cell component).
Testosterone
- In men, testosterone is synthesized almost exclusively by the Leydig cells
of the testes. Its secretion is regulated by luteinizing hormone (LH), and
is subject to negative feedback via the pituitary and hypothalamus. Testosterone
promotes the development of the secondary sex characteristics in men and serves
to maintain the function of the prostate and seminal vesicles.
- In women, small quantities of testosterone with no specific effects are
formed in the ovaries. Increased production of testosterone in women can cause
virilization (depending on the increase).
- Testosterone is determined in men when reduced testosterone production is
suspected, e.g. in hypogonadism, estrogen therapy, chromosome aberrations
(as in the Klinefelter’s syndrome) and liver cirrhosis.
- The determination of testosterone in women is helpful in the diagnosis of
androgenic syndrome (AGS), polycystic ovaries (Stein-Leventhal syndrome) and
when an ovarian tumor, adrenal tumor, adrenal hyperplasia or ovarian insufficiency
is suspected.
- Reference Range:
Cortisol
- Cortisol is the major glucocorticoid secreted by the adrenal cortex and
plays a role in anti-inflammation, blood pressure maintenance, and synthesis
of carbohydrate from protein.
- In the normal individual, cortisol is involved in a negative feedback loop
with ACTH (adrenocorticotropic hormone) through the hypothalamus-pituitary-adrenal
cortex axis (HPA axis). Malfunction of any organ in the HPA axis will result
in alteration of cortisol levels. Physical and psychological stress, diurnal
variation and low blood sugars will also affect the rate of cortisol secretion.
- The evaluation of adrenal gland function by measurement of plasma or serum
cortisol levels aids in the diagnosis of normal and abnormal states. Combinations
of morning and evening measurements and stimulation and suppression tests
can offer strong evidence for diagnosis of specific adrenal-related diseases.
For example, excess cortisol levels are found in Cushing’s syndrome (adrenal
cortical hyperfunction) while decreased levels are found in Addison’s disease
(chronic adrenal insufficiency).
- Reference Range:
- 7-25 μg/dL in the morning (8:00 AM),
- 2-9 μg/dL in the evening (4:00 PM).
Vitamin B12 (Cobalamins)
- Vitamin B12 is a coenzyme that is involved in two very important metabolic
functions vital to normal cell growth and DNA synthesis: (1) the synthesis
of methionine, and (2) the conversion of methylmalonyl CoA to succinyl CoA.
- Vitamin B12 deficiency may be due to several reasons:
- In pernicious anemia, defects in the secretion of intrinsic factor can
result in inadequate vitamin B12 absorption from food.
- Since the amount of vitamin B12 absorbed is directly proportional to
the length of functional intestine, gastrectomy, malabsorption due to
surgical resections, and a variety of bacterial or inflammatory diseases
affecting the small intestine may also lead to vitamin B12 deficiency.
- Insufficient dietary intake is rare and vitamin B12 deficiency can occur
only after years of abstinence from all animal products.
- Deficiency of vitamin B12 can lead to megaloblastic anemia and ultimately
to severe neurological problems. Because vitamin B12 and folic acid are linked
by the reaction pathway for methionine synthesis, a deficiency in either will
disrupt this metabolic pathway and lead to the same medical problems.
- Elevated levels of vitamin B12 have been associated with pregnancy, the
use of oral contraceptives and multivitamins, and in myeloproliferative diseases
such as chronic granulocytic leukemia and myelomonocytic leukemia. An elevated
vitamin B12 level in itself has not been known to cause clinical problems.
- Reference Range:
Folate (Folic acid)
- Folate is a coenzyme for the transfer of single carbon units, and is vital
to normal cell growth and DNA synthesis.
- Deficiency of folate can lead to megaloblastic anemia and ultimately to
severe neurological problems. Because vitamin B12 and folic acid are linked
by the reaction pathway for methionine synthesis, a deficiency in either will
disrupt this metabolic pathway and lead to the same medical problems.
- Folate deficiency can be caused by insufficient dietary intake, malabsorption,
or excessive folate utilization ( such as during pregnancy, alcoholism, hepatitis,
or other liver-damaging diseases).
Reference Range:
Insulin
- Insulin is a hormone secreted by the beta cells of the pancreas. It regulates
the uptake and utilization of glucose, and is also involved in the regulation
of protein synthesis and triglyceride storage. An increase in the amount of
glucose in circulation stimulates insulin secretion. In turn, insulin stimulates
the uptake of glucose into the tissues and inhibits the breakdown of glycogen
in the liver. As the glucose level comes back to baseline, so does insulin.
- The measurement of insulin is used in the following investigations:
- Diagnosis of diabetes:
Insulin levels under basal conditions or after glucose administration
are useful for assessing the ability of the pancreas to secrete insulin.
Insulin levels are normally low in patients with insulin-dependent diabetes
mellitus (IDDM; an autoimmune disease at which the insulin secreting beta
cells in the pancreas are destroyed). On the contrast, insulin levels
are normal or elevated in patients with non-insulin dependent diabetes
mellitus (NIDDM; a disorder at which the beta cells can still secret insulin
but the body has developed resistance to the hormone).
- Early detection of diabetes:
The insulin response to the administration of glucose may be blunted well
before the onset of clinical manifestations.
- Follow-up and stabilization of insulin-treated diabetics:
Insulin assays can be useful at the onset of insulin therapy to evaluate
the duration of action of various insulin preparations.
- Predicting complications of NIDDM:
The persistent elevation of insulin is a risk factor for the development
of coronary disease.
- Diagnosis of insulinoma:
Pancreatic beta-cell tumors may produce a state of hyperinsulinism leading
to hypoglycemia.
- Reference Range:
- 6-22 μU/mL for insulin;
0.3-2.5 ng/mL for C-peptide.
Free βsubunit of human chorionic gonadotropin
(free β-hCG)
- Free β-HCG measurement is usually applied during pregnancy, particularly
when screening pregnancies for Down's syndrome. In this case, the Free β-HCG
assay must always be associated with other clinical and biological data such
as AFP level, maternal age and gestational age. Importantly, only statistical
information about the possible risk can be established.
Parathyroid hormone (PTH)
- PTH is synthesized in the parathyroid glands as a 115 amino acid precursor.
After further proteolytic breakdown, biologically active PTH in the circulation
becomes one of the most important regulators of calcium homeostasis.
- Only intact PTH (containing the 1-84 amino acid sequence) and PTH fragments
containing the 1-34 amino acid sequence are found to contain biological activity.
- PTH and its fragments are cleared from the circulation by both the kidneys
and liver. The clearance of C-terminal fragments is slower than the clearance
of the intact PTH and is more dependent upon renal mechanisms. Therefore,
in patients with severe or end-stage renal failure, C-terminal fragments accumulate
to very high levels.
- Reference Range:
- 13-54 pg/mL for intact PTH;
- 0.4-1.4 ng/ml for PTH C-terminal;
- 40-100 pmol/L for PTH-mm.
Acetylcholine receptor
antibody (AchR Ab)
- Autoantibodies to the acetylcholine receptor are responsible for failure
of the neuromuscular junction in myasthenia gravis and measurement of the
AchR Ab can be of considerable value in disease diagnosis.
- Reference Range:
- 0-0.2 n moles/L in healthy normal donors.
0-1500 n moles/L are expected for myasthenic patients.
- For patients with autoimmune diseases other than
myasthenia gravis,
- 0-0.5 n moles/L of AchR Ab may be found in the
serum.