Clinical Chemistry

Third class Abdullah A. H. Al-Rubaye

Lecture No. 4 Assist. Lecturer

Trace elements
A trace element is a dietary mineral that is needed in very
minute quantities for the proper growth, development, and
physiology of the human body.

The roles of trace elements in human body are:

1- Trace elements are essential for enzymatic reactions where they attract and
facilitate conversion of substrate molecules to specific end products.
2- They donate or accept electrons in redox reactions that are of primary
importance in the generation and utilization of metabolic energy.
3- They have structural roles and responsible for the stability of important
biological molecules.
4- Trace elements have important actions throughout biological processes, for
example, ıron (Fe) which can bind, transport, and release oxygen in the body.
In fact, although the trace elements are essential components of biological
activities, the excessive levels of these elements can be toxic for the body health
and may lead to many fatal diseases, such as cancers.

Iron
Iron is classified as a trace element in the human body. Iron ions readily form
complexes with certain ligands and are able to participate in redox chemistry
between the ferrous (Fe(II)) and ferric (Fe(III)) states, allowing iron to fill many
biochemical roles as a carrier of other biochemically active substances (e.g.,
oxygen).
Free iron ions in the body also participate in destructive chemistry, primarily
in catalyzing the formation of toxic free radicals. Hence, very little free iron is
normally found in the body. Total iron in the human body is 3 -5 g from which

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

approximately 2 to 2.5 g of iron in hemoglobin, mostly in RBCs and red cell

precursors.
A moderate amount of iron (130 mg) in myoglobin (the oxygen-carrying
protein of muscle). A small (8 mg), but extremely important, pool is in tissue
where iron is bound to several enzymes that require iron for full activity. These
enzymes include peroxidases, cytochromes, and many of the Krebs cycle enzymes.
Iron is also stored as ferritin and hemosiderin, primarily in the bone marrow,
spleen, and liver. This critical pool of iron may be the first to become diminished
in iron deficiency states. Only 3 to 5 mg of iron is found in plasma, almost all of it
associated with transferrin and albumin.

Absorption, Transport, and Excretion of Iron

Absorption of iron occurs predominantly in the duodenum and upper jejunum
the primary means of regulating the amount of iron within the body. Typically,
only about 10% of the 1 g/day of dietary iron is absorbed. To be absorbed by
intestinal cells, iron must be in the Fe(II) (ferrous) oxidation state and bound to
protein. Because Fe(III) is the predominant form of iron in foods, it must first be
reduced to Fe(II) by agents such as vitamin C to absorbed by intestinal cells.
In the intestinal mucosal cell, Fe(II) is bound by apoferritin, then oxidized by
ceruloplasmin to Fe(III) bound to ferritin. From there, iron is absorbed into the
blood by apotransferrin, which becomes transferrin as it binds two Fe(III) ions.
In plasma, transferrin carries and releases iron to the bone marrow, where it is
incorporated into hemoglobin of RBCs. After about 4 months in circulation, red
cells are degraded by the macrophages in the spleen, which return iron to the
circulation, where it is bound and carried by transferrin for reuse. Ferroportin
controls the release of iron from cells.

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

The recently discovered peptide hormone hepcidin largely controls iron

metabolism by its ability to modulate the release of iron from cells by inhibiting
ferroportin.
Iron is lost primarily by desquamation and red cell loss to urine and feces.
With each menstrual cycle, women lose approximately 20 to 40 mg of iron.

Iron deficiency
Reduction in iron stores usually precedes both a reduction in circulating iron
and anemia, as demonstrated by a decreased red blood cell count, mean
corpuscular hemoglobin concentration, microcytic and hypochromic RBCs.

Iron toxicity
Iron overload states are collectively referred to as hemochromatosis, whether
or not tissue damage is present.
Primary iron overload is most frequently associated with hereditary
hemochromatosis (HH). HH is a single-gene homozygous recessive disorder
leading to abnormally high iron absorption, culminating in iron overload.

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

Secondary iron overload may result from excessive dietary, medicinal, or

transfusional iron intake or be due to metabolic dysfunction.
HH causes tissue accumulation of iron, affects liver function, and often leads
to hyperpigmentation of the skin. Some conditions associated with severe
hemochromatosis include diabetes mellitus, arthritis, cardiac arrhythmia or failure,
cirrhosis, hypothyroidism, impotence, and liver cancer.
Iron may play a role as a prooxidant, by contributing to lipid peroxidation,
atherosclerosis, deoxyribonucleic acid (DNA) damage, carcinogenesis, and
neurodegenerative diseases, Fe(III), released from binding proteins, can enhance
production of free radicals to cause oxidative damage.
Condition Serum iron transferrin Ferritin TIBS
Normal range 50–160 µg/dl 200–400 mg/dl 20–250 µg/L 250–350 µg/dl
Iron deficiency Decreased Increased Decreased Increased
Iron overdose Increased Decreased Increased Decreased
Hematochromatosis Increased Slightly decreased Increased Slightly decreased
Malnutrition Decreased Decreased Decreased Decreased
Malignancy Decreased Decreased Increased Decreased
Chronic infection Decreased Decreased Increased Decreased
Viral hepatitis Increased Increased Increased Increased
Acute liver disease Increased Variable/increase Increased Variable/increase
Chronic anemia Decreased Normal/decreased Normal/decreased Decreased
Sideroblastic Increased Normal/decreased Increased Normal/decreased

Table showing laboratory markers of iron status in several disease states

Copper
The copper content in the normal human adult is 50–120 mg. Copper is
distributed through the body with the highest concentrations found in liver, brain,

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

heart, and kidneys. Hepatic copper accounts for about 10% of the total copper in
the body. Copper is also found in cornea, spleen, intestine, and lung.
Copper is a component of several metalloenzymes, including ceruloplasmin,
cytochrome C oxidase, superoxide dismutase, tyrosinase, metallothionein,
dopamine, hydroxylase, lysyl oxidase, clotting factor V.
Ceruloplasmin is the best known yet the least understood copper protein. It is
a globulin, and each 132,000-molecular-weight molecule contains six atoms of
copper.

Absorption, Transport, and Excretion of copper

An average day’s diet may contain 10 mg or more of copper. The amount of
copper absorbed from the intestine is 50%–80% of ingested copper. About half of
dietary copper is excreted in feces.
Copper absorption is impaired in severe diffuse diseases of small bowel, lymph
sarcoma, and scleroderma.
Copper losses in the urine and sweat are approximately 3% of dietary intake.
Menstrual losses of copper are minor.

Copper deficiency
Copper deficiency is observed in premature infants. Copper deficiency is
related to malnutrition, malabsorption, chronic diarrhea, and prolonged feeding
with low-copper, total-milk diets.
Subclinical copper depletion contributes to an increased risk of coronary heart
disease. An extreme form of copper deficiency is seen in Menkes disease. This
invariably fatal, progressive brain disease is characterized by peculiar hair, called
kinky or steely, and retardation of growth.
Clinical forms include progressive mental deterioration, coarse feces,
disturbance of muscle tone, seizures, and episodes of severe hypothermia.

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

Symptoms of Menkes disease usually appear at the age of 3 months and death
usually occurs in 5-year-olds.
Signs of copper deficiency include
(1) Neutropenia and hypochromic anemia in the early stages
(2) Osteoporosis and various bone and joint abnormalities that reflect deficient
copper-dependent cross-linking of bone collagen and connective tissue.
(3) Decreased pigmentation of then skin and general pallor.
(4) Possible neurologic abnormalities ( apnea, psychomotor retardation) in the late
stages.

Copper toxicity
Wilson’s disease is a genetically determined copper accumulation disease that
usually presents between the ages of 6 and 40 years. Its manifestations include
neurologic disorders, liver dysfunction, and Kayser-Fleischer rings (green-brown
discoloration) in the cornea caused by copper deposition.
Early diagnosis of Wilson’s disease is important because complications can
be effectively prevented and in some cases the disease can be halted with use of
zinc acetate or chelation therapy.

Zinc
Zinc is second only to iron in importance as an essential trace element. The
main biochemical role of zinc is its influence on the activity of more than 300
enzymes (from the classes of oxireductases, transferases, hydrolases, lyases,
isomerases, and ligases).
Zinc can be essential for the structure, regulation, and catalytic action of an
enzyme. Zinc occurs in enzymes that realize the synthesis and metabolism of DNA
and RNA. Zinc influences the synthesis and metabolism of proteins, participates in
glycolysis and cholesterol metabolism, maintains membrane structures, effects
functions of insulin, and affects growth factor.

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

Chronic oral zinc supplementation interferes with copper absorption and may
cause copper deficiency. This ability to interfere with copper absorption is also the
basis for using zinc to treat Wilson’s disease. Copper status should be monitored in
patients on long-term zinc therapy.

Absorption, Transport, and Excretion of Zinc

Zinc absorption mainly occurs in the small intestine and especially in the
jejunum.
In blood, the absorbed zinc is distributed between RBCs (80%), plasma
(17%), and white blood cells (3%).
In normal dietary circumstances, about 90% of zinc is excreted in feces.

The factors increasing zinc absorption include:

(1) The presence of animal proteins and amino acids in a meal
(2) Intake of calcium
(3) Intake of unsaturated fatty acids.

The factors decreasing zinc absorption include:

(1) Intake of iron
(2) Taking zinc on empty stomach
(3) The presence of copper at high levels
(4) Age

Zinc deficiency
Zinc deficiency causes growth retardation, slows skeletal maturation, causes
testicular atrophy, and reduces taste perception. Old age, pregnancy, lactation, and
alcoholism are also associated with poor zinc nutrition.
Infants with acrodermatatis enteropathica (zinc malabsorption) usually first
develop characteristic facial and diaper rash. Untreated, symptoms progress and

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

include growth retardation, diarrhea, impaired T-cell immunity, insufficient wound

healing, infections, delayed testicular development in adolescence, and early death.
Zn deficiency in adolescents is manifested by slow growth or weight loss,
altered taste, delayed puberty, dwarfism, impaired dark adaptation, alopecia,
emotional instability, and tremors. In severe cases, lymphopenia may occur; death
follows an overwhelming infection.

Zinc toxicity
Zinc is relatively nontoxic. Nevertheless, high doses (1 g) or repetitive doses
of 100 mg/day for several months may lead to disorders, especially gastrointestinal
tract symptoms, decrease in heme synthesis due to an induced copper deficiency,
and hyperglycemia.
Exposure to ZnO fumes and dust may cause “zinc fume fever.” The
symptoms include chemically induced pneumonia, severe pulmonary
inflammation, fever, hyperpnea, coughing, pains in legs and chest, and vomiting.

Manganese
Manganese is biochemically essential as a constituent of metalloenzymes and
as an enzyme activator. Manganese containing enzymes include arginase, pyruvate
carboxylase, and manganese superoxide dismutase in mitochondria.
Manganese-activated enzymes include hydrolases, kinases, decarboxylases,
and transferases. Many of these activations are nonspecific, so other metal ions
(magnesium, iron, or copper) can replace manganese as an activator.

Absorption, Transport, and Excretion of manganese

Dietary manganese is poorly absorbed (2%–15%), mainly from the small
intestine. Dietary factors that affect manganese absorption include iron, calcium,
phosphates, and fibers.

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 Clinical Chemistry
Third class Abdullah A. H. Al-Rubaye
Lecture No. 4 Assist. Lecturer

Manganese deficiency
Blood clotting defects, hypocholesterolemia, dermatitis, and elevated serum
calcium, phosphorus, and alkaline phosphatase activity have occurred in some
subjects who underwent experimental manganese depletion. Low levels of
manganese are associated with epilepsy.
Manganese deficiency was suggested as an underlying factor in hip
abnormalities, joint disease, and congenital malformation. Manganese deficiency
can cause heart and bone problems and, in children, stunted growth.

Manganese toxicity
Manganese toxicity causes nausea, vomiting, headache, disorientation,
memory loss, anxiety, and compulsive laughing or crying. In chronic form,
manganese toxicity resembles Parkinson’s disease with akinesia, rigidity, tremors,
and masklike faces.
A clinical condition named locura manganica (manganese madness) has been
described in Chilean manganese miners who have experienced acute manganese
aerosol intoxication.