The human body is capable of a wide variety of positions, as exemplified by this energetic yoga position, "astavakrasana".
Human positions refer to the different physical configurations that the human body can take.
There are several synonyms that refer to human positioning, often used interchangeably, but having specific nuances of meaning.
Position is a general term for a configuration of the human body.
Posture means an intentionally or habitually assumed position.
Pose implies an artistic, aesthetic, athletic, or spiritual intention of the position.
Attitude refers to postures assumed for purpose of imitation, intentional or not, as well as in some standard collocations in reference to some distinguished types of posture: "Freud never assumed a fencer's attitude, yet almost all took him for a swordsman."
Bearing refers to the manner of the posture, as well as of gestures and other aspects of the conduct taking place.
Basic positions
While not moving, a human is usually in one of the following basic positions:
All-fours
This is the static form of crawling which is instinctive form of locomotion for very young children. It was a commonly used childbirth position in both Western and non-Western cultures, in which context it is known as the Gaskin Maneuver. This position is sometimes viewed as sexually explicit due to its association with sexual initiation or availability.
Inner two vertical kneeling. Outer two squatting/kneeling.
Kneeling is a basic human position where one or both knees touch the
ground. It is used as a resting position, during childbirth and as an
expression of reverence and submission. While kneeling, the angle
between the legs can vary from zero to widely splayed out, flexibility
permitting. It is common to kneel with one leg and squat with the other leg.
While kneeling, the thighs and upper body can be at various angles in particular:
Vertical kneel: where both the thighs and upper body are vertical – also known as "standing on one's knees"
Sitting kneel: where the thighs are near horizontal and the buttocks sit back on the heels with the upper body vertical - for example as in Seiza, Virasana, and Vajrasana (yoga)
Taking a knee: where the upper body is vertical, one knee is
touching the ground while the foot of the other leg is placed on the
ground in front of the body
Paul Cézanne portrait of a man in a sitting position
Sitting requires the buttocks resting on a more or less horizontal structure, such as a chair
or the ground. Special ways of sitting are with the legs horizontal,
and in an inclined seat. While on a chair the shins are usually
vertical, on the ground the shins may be crossed in the lotus position or be placed horizontally under the thigh in a seiza.
Squatting is a posture where the weight of the body is on the feet (as with standing) but the knees and hips are bent. In contrast, sitting, involves taking the weight of the body, at least in part, on the buttocks against the ground or a horizontal object such as a chair seat.
The angle between the legs when squatting can vary from zero to widely
splayed out, flexibility permitting. Squatting may be either:
full – known as full squat, deep squat, grok squat, Asian squat, third world squat, (sitting) on one's haunches, (sitting) on one's hunkers, or hunkering (down)
partial – known as partial, standing, half, semi, parallel, shallow, intermediate, incomplete, or monkey squat
Crouching is usually considered to be synonymous with full squatting. It is common to squat with one leg and kneel with the other leg.
One or both heels may be up when squatting. Young children often
instinctively squat. Among Chinese, Southeast Asian, and Eastern
European adults, squatting often takes the place of sitting or standing.
Although quiet standing appears to be static, modern instrumentation shows it to be a process of rocking from the ankle in the sagittal plane. The sway of quiet standing is often likened to the motion of an inverted pendulum.
There are many mechanisms in the body that are suggested to control
this movement, e.g. a spring action in muscles, higher control from the
nervous system or core muscles.
Although the posture is not dangerous in itself, there are
pathologies associated with prolonged intervals of unrelieved standing.
One short-term condition is orthostatic hypotension, and long-term conditions are sore feet, stiff legs, and low back pain.
Some variations of standing are:
Standing with arms akimbo, that is with hands on hips, elbows pointing outward
Standing contrapposto, with most of the weight on one foot so that its shoulders and arms twist off-axis from the hips and legs in the axial plane
Standing at attention,
upright with an assertive and correct posture: "chin up, chest out,
shoulders back, stomach in", arms at the side, heels together, toes
apart
Certain asanas
postures were originally intended primarily to restore and maintain a
practitioner's well-being, to improve the body's flexibility and
vitality, and to promote the ability to remain in seated meditation for
extended periods.
The human body can be suspended in various stable positions, where the support is above the center of gravity. The positioning may be voluntary or involuntary.
In addition to the lithotomy position still commonly used by many obstetricians, childbirth positions that are successfully used by midwives and traditional birth-attendants the world over include squatting, standing, kneeling, and on all fours, often in a sequence.
Dance position is a position of a dancer or a mutual position of a dance couple assumed during a dance. Describing and mastering proper dance positions is an important part of dance technique.
Eating positions vary in different regions of the world, as culture
strongly influences the way people eat their meals. For example, in most
of the Middle Eastern countries, eating while sitting on the floor is
most common, and it is believed to be healthier than eating while
sitting at a table.
Eating in a reclining position was favored by the Ancient Greeks at a celebration they called a symposium, and this custom was adopted by the Ancient Romans. Ancient Hebrews also adopted this posture for traditional celebrations of a Passover Seder, to symbolize freedom. The biblical prophetAmos associates "those who recline at banquets" with the false sense of security among the Israelites whom he is warning to repent.
The heat escape lessening position (HELP) is a way to position
oneself to reduce heat loss in cold water. It is taught as part of the
curriculum in Australia, North America, and Ireland for lifeguard and
boating safety training. It essentially involves positioning one's knees
together and hugging them close to the chest using one's arms.
The recovery position or coma position refers to one of a series of variations on a lateral recumbent or three-quarters prone position of the body, into which an unconscious but breathing casualty can be placed as part of first aid treatment.
A "straddle" or "astride" position is usually adopted when riding a horse, donkey, or other beast of burden, with or without the aid of a saddle. The position is also used for sitting on analogous vehicles, such as bicycles, motorcycles, or unicycles, and
on furniture, such as certain types of seating, and bidets. The posture is also used on some types of specialized workbenches (such as a shaving horse). By definition, an essential feature is having one leg on each side of whatever is being straddled. The related sidesaddle position allows riding without straddling, but is somewhat less secure against accidental dismounting or falling.
The straddle posture is often intermediate between standing and
sitting positions, allowing body weight to be supported securely, while
also affording a high degree of upper body mobility and dynamic balance during vigorous or extended motions.
Sex positions are positions which people may adopt during or for the
purpose of sexual intercourse or other sexual activities. Sexual acts
are generally described by the positions the participants adopt in order
to perform those acts.
Stress positions place the human body in such a way that a great
amount of weight is placed on just one or two muscles and joints.
Forcing prisoners to adopt such positions is a method of ill-treatment used for extracting information or as a punishment, possibly amounting to torture. Such positions also are sometimes used as a punishment for children.
Submissive positions
Submissive
positions are often ceremonial and dictated by culture. They may be
performed as a mutual sign of respect between equals or as a sign of
submission to a higher-ranking individual or to a ceremonial object.
Bowing
is the lowering of the head and torso towards the person or object of
reverence, often briefly. The extent of a bow ranges from a simple head
nod to a 90–degree bending at the waist. Though less common in Western
cultures, it remains an important sign of respect in many Eastern
cultures, and is also used in the ceremonies of various religions.
In bowing and scraping, the right hand is placed across the abdomen while the right leg is drawn or "scraped" back during a bow.
In Western cultures, it is often considered proper for women to perform a curtsey by bending the knees instead of a bow.
Genuflection (or genuflexion) is bending at least one knee to the ground, was from early times a gesture of deep respect for a superior.
Humans using a running gait. The runner in the back and on the far right are in the suspended phase, in which neither foot touches the ground.
A gait is a manner of limb movements made during locomotion. Human gaits are the various ways in which humans can move, either naturally or as a result of specialized training. Human gait is defined as bipedalforward propulsion of the center of gravity of the human body, in which there are sinuous
movements of different segments of the body with little energy spent.
Various gaits are characterized by differences in limb movement
patterns, overall velocity, forces, kinetic and potential energy cycles,
and changes in contact with the ground.
Classification
Human
gaits are classified in various ways. Each gait can be generally
categorized as either natural (one that humans use instinctively) or
trained (a non-instinctive gait learned via training). Examples of the
latter include hand walking and specialized gaits used in martial arts. Gaits can also be categorized according to whether the person remains in continuous contact with the ground.
Foot strike
One variable in gait is foot strike – which part of the foot connects with the ground first.
forefoot strike – toe-heel: ball of foot lands first
mid-foot strike – heel and ball land simultaneously
heel strike – heel-toe: heel of foot lands, then plantar flexes to ball
Sprinting typically features a forefoot strike, but the heel does not usually contact the ground.
Some researchers classify foot strike by the initial center of
pressure; this is mostly applicable to shod running (running while
wearing shoes). In this classification:
a forefoot strike has the initial center of pressure in the front one-third of shoe length;
a mid-foot strike is in the middle third;
a rear-foot strike (heel strike) is in the rear third.
Foot strike varies between types of strides. It changes significantly
and notably between walking and running, and between wearing shoes
(shod) and not wearing shoes (barefoot).
Typically, barefoot walking features heel or mid-foot strikes, while barefoot running
features mid-foot or forefoot strikes. Barefoot running rarely features
heel strikes because the impact can be painful, the human heel pad not
absorbing much of the force of impact. By contrast, 75% of runners wearing modern running shoes use heel strikes;
running shoes are characterized by a padded sole, stiff soles and arch
support, and slope down from a more-padded heel to a less-padded
forefoot.
The cause of this change in gait in shoe running is unknown, but Lieberman noted that there is correlation between the foot-landing style and exposure to shoes.
In some individuals the gait pattern is largely unchanged (the leg and
foot positions are identical in barefoot and shoes), but the wedge shape
of the padding moves the point of impact back from the forefoot to the
mid-foot.[5]
In other cases it is believed that the padding of the heel softens the
impact. This results in runners modifying their gait to move the point
of contact further back in the foot.
A 2012 study involving Harvard University runners found that
those who "habitually rear-foot strike had approximately twice the rate
of repetitive stress injuries than individuals who habitually forefoot
strike."
This was the first study to investigate the link between foot strike
and injury rates. However, earlier studies have shown that smaller
collision forces were generated when running forefoot strike compared to
rear-foot strike. This may protect the ankle joints and lower limbs
from some of the impact-related injuries experienced by rear-foot
strikers.
In a 2017 article called "Foot Strike Pattern in Children During
Shod-Unshod Running", over 700 children aged 6 to 16 were observed using
multiple video recording devices in order to study their foot strike
patterns and neutral support. Rear foot strike was most common, in both
shod and unshod running, and in both boys and girls. There was a
significant reduction in rear foot strike from shod to unshod: boys shod
- 83.95% RFS, boys unshod - 62.65% RFS; girls shod - 87.85% RFS, girls
unshod - 62.70% RFS.
As-of 2021 there was a very low level of evidence to suggest a
relationship between foot strike pattern and runner injury. Studies used
retrospective designs, low sample size and potentially inaccurate
self-reporting.
Control of gait by the nervous system
The central nervous system
regulates gait in a highly ordered fashion through a combination of
voluntary and automatic processes. The basic locomotor pattern is an
automatic process that results from rhythmic reciprocal bursts of flexor
and extensor activity. This rhythmic firing is the result of Central Pattern Generators (CPGs),
which operate regardless of whether a motion is voluntary or not. CPGs
do not require sensory input to be sustained. However, studies have
identified that gait patterns in deafferented or immobilized animals are
more simplistic than in neurologically intact animals. (Deafferentation
and immobilization are experimental preparations of animals to study
neural control. Deafferentation involves transecting the dorsal
roots of the spinal cord that innervate the animal's limbs, which
impedes transmission of sensory information while keeping motor
innervation of muscles intact. In contrast, immobilization involves injecting an acetylcholineinhibitor, which impedes the transmission of motor signals while sensory input is unaffected.)
The complexity of gait arises from the need to adapt to expected
and unexpected changes in the environment (e.g., changes in walking
surface or obstacles). Visual, vestibular, proprioceptive, and tactile
sensory information provides important feedback related to gait and
permits the adjustment of a person's posture or foot placement depending
on situational requirements. When approaching an obstacle, visual
information about the size and location of the object is used to adapt
the stepping pattern. These adjustments involve change in the trajectory
of leg movement and the associated postural adjustments required to
maintain their balance. Vestibular information provides information
about position and movement of the head as the person moves through
their environment. Proprioceptors in the joints and muscles provide
information about joint position and changes in muscle length. Skin
receptors, referred to as exteroceptors, provide additional tactile
information about stimuli that a limb encounters.
Gait in humans is difficult to study due to ethical
concerns. Therefore, the majority of what is known about gait
regulation in humans is ascertained from studies involving other animals
or is demonstrated in humans using functional magnetic resonance imaging during the mental imagery of gait. These studies have provided the field with several important discoveries.
Locomotor centers
There are three specific centers within the brain that regulate gait:
Mesencephalic Locomotor Region
(MLR)- Within the midbrain, the MLR receives input from the premotor
cortex, the limbic system, cerebellum, hypothalamus, and other parts of
the brainstem. These neurons connect to other neurons within the
mesencephalic reticular formation which then descend to the via the
ventrolateral funiculus to the spinal locomotor networks. Studies where
the MLR of decerebrate
cats have been stimulated either electrically or chemically have shown
that increased intensity of stimulation has led to increased speed of
stepping. Deep brain stimulation of the MLR in individuals with
Parkinson's has also led to improvements in gait and posture.
Sub thalamic Locomotor Region (SLR)- The SLR is part of
hypothalamus. It activates the spinal locomotor networks both directly
and indirectly via the MLR.
Cerebellar
Locomotor Region (CLR)- Similar to the SLR, the CLR activates the
reticulo-spinal locomotor pathway via direct and indirect projections.
These centers are coordinated with the posture control systems within
the cerebral hemispheres and the cerebellum. With each behavioral
movement, the sensory systems responsible for posture control respond.
These signals act on the cerebral cortex, the cerebellum, and the
brainstem. Many of these pathways are currently under investigation, but
some aspects of this control are fairly well understood.
Regulation by the cerebral cortex
Sensory
input from multiple areas of the cerebral cortex, such as the visual
cortex, vestibular cortex, and the primary sensory cortex, is required
for skilled locomotor tasks. This information is integrated and
transmitted to the supplementary motor area (SMA) and premotor area
of the cerebral cortex where motor programs are created for intentional
limb movement and anticipatory postural adjustments. For example, the
motor cortex uses visual information to increase the precision of
stepping movements. When approaching an obstacle, an individual will
make adjustments to their stepping pattern based on visual input
regarding the size and location of the obstacle. The primary motor cortex is responsible for the voluntary control for the contralateral leg while the SMA is linked to postural control.
Regulation by the cerebellum
The cerebellum plays a major role in motor coordination, regulating voluntary and involuntary processes. Regulation of gait by the cerebellum is referred to as “error/correction,”
because the cerebellum responds to abnormalities in posture in order to
coordinate proper movement. The cerebellum is thought to receive
sensory information (e.g. visual, vestibular) about actual stepping
patterns as they occur and compare them to the intended stepping
pattern. When there is a discrepancy between these two signals, the
cerebellum determines the appropriate correction and relays this
information to the brainstem and motor cortex. Cerebellar output to the
brainstem is thought to be specifically related to postural muscle tone
while output to the motor cortex is related to cognitive and motor
programming processes.
The cerebellum sends signals to the cerebral cortex and the brain stem
in response to sensory signals received from the spinal cord. Efferent
signals from these regions go to the spinal cord where motor neurons
are activated to regulate gait. This information is used to regulate
balance during stepping and integrates information about limb movement
in space, as well as head position and movement.
Regulation by the spinal cord
Spinal reflexes not only generate the rhythm of locomotion through CPGs but also ensure postural stability during gait. There are multiple pathways within the spinal cord which play a role in regulating gait, including the role of reciprocal inhibition and stretch reflexes
to produce alternating stepping patterns. A stretch reflex occurs when
a muscle is stretched and then contracts protectively while opposing
muscle groups relax. An example of this during gait occurs when the
weight-bearing leg nears the end of the stance phase. At this point the
hip extends and the hip flexors are elongated. Muscle spindles
within the hip flexors detect this stretch and trigger muscle
contraction of the hip flexors required for the initiation of the swing
phase of gait. However, Golgi tendon organs
in the extensor muscles also send signals related to the amount of
weight being supported through the stance leg to ensure that limb
flexion does not occur until the leg is adequately unweighted and the
majority of weight has been transferred to the opposite leg. Information from the spinal cord is transmitted for higher-order processing to supraspinal structures via spinothalamic, spinoreticular, and spinocerebellar tracts.
Natural gaits
The so-called natural gaits, in increasing order of speed, are the walk, jog, skip, run, and sprint.While other intermediate-speed gaits may occur naturally to some
people, these five basic gaits occur naturally across almost all
cultures. All natural gaits are designed to propel a person forward but can also be adapted for lateral movement.
As natural gaits all have the same purpose; they are mostly
distinguished by when the leg muscles are used during the gait cycle.
Walk
Walking involves having at least one foot in contact with the ground at all times. There is also a period of time within the gait cycle where both feet are simultaneously in contact with the ground.
When a foot is lifted off the ground, that limb is in the "swing phase"
of gait. When a foot is in contact with the ground, that limb is in the
"stance phase" of gait. A mature walking pattern is characterized by
the gait cycle being approximately 60% stance phase, 40% swing phase. Initiation of gait is a voluntary process that involves a preparatory postural adjustment where the center of mass
is moved forward and laterally prior to unweighting one leg. The center
of mass is only within a person's base of support when both feet are in
contact with the ground (known as double limb stance). When only one
foot is in contact with the ground (single limb stance), the center of
mass is in front of that foot and moving towards the leg that is in the
swing phase.
Skip
Skipping is a gait children display when they are about four to five years old. While a jog is similar to a horse's trot, the skip is closer to the bipedal equivalent of a horse's canter.
In order to investigate the gait strategies likely to be favored at low
gravity, a study by Ackermann and Van Den Bogert ran a series of
predictive, computational simulations of gait using a physiological
model of the musculoskeletal system, without assuming any particular
type of gait. They used a computationally efficient optimization
strategy, allowing for multiple simulations. Their results reveal
skipping as more efficient and less fatiguing than walking or running
and suggest the existence of a walk-skip rather than a walk-run
transition at low gravity.
Gait patterns in children
Time and distance parameters of gait patterns are dependent on a child's age.
Different age leads to different step speed and timing. Arm swinging
slows when the speed of walking is increased. The height of a child
plays a significant role in stride distance and speed. The taller the
child is the longer the stride will be and the further the step will be.
Gait patterns are velocity
and age dependent. For example, as age increases so does velocity.
Meanwhile, as age increases, the cadence (rate at which someone walks
that is measured in steps per minute) of the gait pattern decreases.
Physical attributes such as height, weight, and even head circumference
can also play a role in gait patterns in children. Environmental and
emotional status also play a role in with speed, velocity, and gait
patterns that a child uses. Besides, children of different genders will
have different rates of gait development. Significant developmental
changes in gait parameters such as stride time, swing time, and cadence
occur in a child's gait two months after the onset of independent
walking, possibly due to an increase in postural control at this point
of development.
By the age of three, most children have mastered the basic
principles of walking, consistent with that of adults. Age is not the
only deciding factor in gait development. Gender differences have been
seen in young children as early as three years old. Girls tend to have a
more stable gait than boys between the ages of 3–6 years old. Another
difference includes the plantar contact area. Girls showed a smaller
contact area in plantar loading patterns than boys in children with
healthy feet.
Sex differences
There are sex differences in human gait patterns: females tend to walk with smaller step width and more pelvic movement. Gait analysis generally takes biological sex into consideration. Sex differences in human gait can be explored using a demonstration created by the BioMotion Laboratory at York University in Toronto.
Efficiency and evolutionary implications
Even though plantigrade locomotion usually distributes more weight toward the end of the limb than digitigrade locomotion,
which increases energy expenditure in most systems, studies have shown
that humans are economical walkers, but not economical runners, which is
said to be consistent with evolutionary specialization for both
economical walking and endurance running.
For the same distance, walking with a natural heel-first gait
burns roughly 70% less energy than running. Differences of this
magnitude are unusual in mammals. Kathyrn Knight of the Journal of Experimental Biology
summarizes the findings of one study: "Landing heel first also allows
us to transfer more energy from one step to the next to improve our
efficiency, while placing the foot flat on the ground reduces the forces
around the ankle (generated by the ground pushing against us), which
our muscles have to counteract." According to David Carrier of the University of Utah,
who helped perform the study, "Given the great distances
hunter-gatherers travel, it is not surprising that humans are economical
walkers."
Key determinants of gait
A normal gait pattern depends on a range of biomechanical features, controlled by the nervous system for increased energy conservation and balance.
These biomechanical features of normal gait have been defined as key
determinants of gait. It is therefore necessary for the refined
neurological control and integration of these gait features for accuracy
and precision with less energy expenditure. As a result, any
abnormality of the neuro-musculo-skeletal system may lead to abnormality
in gait and increased energy expenditure.
The six kinematics or determinants of gait, described below, were introduced by Saunders et al. in 1953, and have been widely embraced with various refinements.
Recent studies have suggested that the first three determinants might
contribute less to reducing the vertical displacement of the center of mass (COM).
These determinants of gait are known to ensure economical locomotion, by the reduction in vertical center of mass
(COM) excursion leading to reduction in metabolic energy. It is
therefore suggested that the precise control of these determinants of
gait
leads to increased energy conservation. These kinematic features of
gait are integrated or coordinated in order to ensure a circular arc
trajectory of the COM, as theory proposed as the 'compass gait (straight
knee)'. The theory underlying the determinants run contrary to that of
the 'inverted pendulum' theory with a static stance leg acting as a
pendulum that prescribes an arc.
The six determinants of gaits and their effects on COM displacement
and energy conservation are described below in chronological order:
Pelvic rotation: This kinematic feature of gait operates under the theory of compass gait model. In this model, the pelvis
rotates side to side during normal gait. In effect, it aids in the
progression of the contralateral side through reduced hip flexion and
extension. Its effect on the reduction of metabolic energy and the
increased energy conservation is through the reduction of vertical COM
displacement. This notion of reduction of metabolic cost may be disputed
by a study done by Gard and Childress (1997),
who stated that there may be minimal effect of pelvic rotation on
vertical COM displacement. Furthermore, other studies have found pelvic
rotation to have little effect on the smoothing of COM trajectory. Pelvic rotation has been shown to account for about 12% reduction in the total COM vertical displacement.
Pelvic tilt/Obliquity: Normal gait results in tilting of the swing
phase side, in relation to the control by the stance side hip abductors.
As a consequence, there is the neutralization of raising of COM during
the transition from hip flexion to extension. Its effect on the
reduction of metabolic
energy and the increased energy conservation is via the reduction of
vertical COM trajectory or peak form compass gait model. Pelvic
obliquity's effects on reduction of vertical displacement of COM has
been examined and been shown to only reduce vertical displacement of COM
by at most, only 2–4 mm.
Knee flexion at stance phase: The knee usually supports the body
weight in flexed position during walking. The knee is usually fully
extended at heel strike and then begins to flex (average magnitude of 15
degrees) when foot is completely flat on the ground. The effects of the
stance-phase knee flexion is to lower the apex of vertical trajectory
of the COM via shortening of the leg resulting in some energy
conservation.
But recent studies testing this third determinant of gait have reported
varied results. It was found out that stance-phase knee flexion did not
contribute to the reduction in vertical trajectory of COM.
Furthermore, Gard and Childress (1997) indicated that maximum COM is
reached at mid-stance when knee is slightly flexed, depicting minor
reduction of the maximum height of the COM by a few millimeters.
Foot and ankle motions: Saunders et al. showed relationship between angular displacement and motions of foot, ankle and knee.
This results in two intersecting arcs of rotation at the foot during
stance phase at heel contact and heel rise. At heel contact the COM
reaches its lowest point of downward displacement when the foot is
dorsiflexed, and the knee joint fully extended in order for the
extremity to be at its maximum length. The ankle rockers at heel strike
and mid-stance leads to decrease COM displacement through the
shortening of the leg. Studies by Kerrigan et al. (2001) and Gard &
Childress (1997) have showed the major role played by heel rise in
reducing the COM vertical displacement.
Knee motion: The motion of the knee is related to those of the ankle
and foot motions and results in the reduction of COM vertical
displacement. Therefore, an immobile knee or ankle could lead to
increases in COM displacement and energy cost.
Lateral pelvic displacement: In this key gait feature, the
displacement of the COM is realized by the lateral shift of the pelvis
or by relative adduction
of the hip. Correction of disproportionate lateral displacement of the
pelvis is mediated by the effect of tibiofemoral angle, and relative
adduction of the hip, which results in reduction in vertical COM
displacement.
It is clear that these kinematic features play a critical role in
ensuring efficiency in normal gait. But there may be the need for
further extensive testing or validation of each of the key determinants
of gait.
Abnormal gaits
Abnormal gait is a result of one or more of these tracts being disturbed. This can happen developmentally or as the result of neurodegeneration. The most prominent example of gait irregularities due to developmental problems comes from studies of children on the autism spectrum. They have decreased muscle coordination, thus resulting in abnormalities in gait. Some of this is associated with decreased muscle tone, also known as hypotonia, which is also common in ASD. The most prominent example of abnormal gait as a result of neurodegeneration is Parkinson's.
Although these are the best understood examples of abnormal gait,
there are other phenomena that are described in the medical field.
Antalgic gait: limping caused by pain that appears or worsens when bearing weight on one limb, due to injury, disease, or other painful conditions
Trendelenburg gait: occurs in unstable hip due to congenital dislocation of hip, gluteus medius muscle weakness
Abnormal gait can also be a result of a stroke. However, by using
treadmill therapy to activate the cerebellum, abnormalities in gait can
be improved.
Literary references
The author of the DeuterocanonicalBook of Sirach observes that "a man's attire, and excessive laughter, and gait, shew what he is". Bibilical writer J. J. Collins suggests that this verse quotes a traditional maxim.
Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.
Copper is an essential trace element that is vital to the health of all living things (plants, animals and microorganisms). In humans, copper is essential to the proper functioning of organs and metabolic processes. The human body has complex homeostatic
mechanisms which attempt to ensure a constant supply of available
copper, while eliminating excess copper whenever this occurs. However,
like all essential elements and nutrients, too much or too little
nutritional ingestion of copper can result in a corresponding condition
of copper excess or deficiency in the body, each of which has its own
unique set of adverse health effects.
Daily dietary standards for copper have been set by various
health agencies around the world. Standards adopted by some nations
recommend different copper intake levels for adults, pregnant women,
infants, and children, corresponding to the varying need for copper
during different stages of life.
Copper proteins
have diverse roles in biological electron transport and oxygen
transportation, processes that exploit the easy interconversion of Cu(I)
and Cu(II). Copper is essential in the aerobic respiration of all eukaryotes. In mitochondria, it is found in cytochrome c oxidase, which is the last protein in oxidative phosphorylation. Cytochrome c oxidase is the protein that binds the O2 between a copper and an iron; the protein transfers 4 electrons to the O2 molecule to reduce it to two molecules of water. Copper is also found in many superoxide dismutases, proteins that catalyze the decomposition of superoxides by converting it (by disproportionation) to oxygen or hydrogen peroxide:
Cu+-SOD + O2− + 2H+ → Cu2+-SOD + H2O2 (oxidation of copper; reduction of superoxide)
Cu2+-SOD + O2− → Cu+-SOD + O2 (reduction of copper; oxidation of superoxide)
The protein hemocyanin is the oxygen carrier in most mollusks and some arthropods such as the horseshoe crab (Limulus polyphemus). Because hemocyanin is blue, these organisms have blue blood rather than the red blood of iron-based hemoglobin. Structurally related to hemocyanin are the laccases and tyrosinases. Instead of reversibly binding oxygen, these proteins hydroxylate substrates, illustrated by their role in the formation of lacquers. The biological role for copper commenced with the appearance of oxygen in Earth's atmosphere.
Several copper proteins, such as the "blue copper proteins", do not
interact directly with substrates; hence they are not enzymes. These
proteins relay electrons by the process called electron transfer.
Photosynthesis functions by an elaborate electron transport chain within the thylakoid membrane. A central link in this chain is plastocyanin, a blue copper protein.
Chemical compounds which were developed for treatment of Wilson's disease have been investigated for use in cancer therapy.
Optimal copper levels
Copper deficiency and toxicity can be either of genetic or non-genetic origin. The study of copper's genetic diseases,
which are the focus of intense international research activity, has
shed insight into how human bodies use copper, and why it is important
as an essential micronutrient.
The studies have also resulted in successful treatments for genetic
copper excess conditions, empowering patients whose lives were once
jeopardized.
Researchers specializing in the fields of microbiology, toxicology, nutrition, and health risk assessments
are working together to define the precise copper levels that are
required for essentiality, while avoiding deficient or excess copper
intakes. Results from these studies are expected to be used to fine-tune
governmental dietary recommendation programs which are designed to help
protect public health.
Essentiality
Copper is an essential trace element (i.e., micronutrient) that is required for plant, animal, and human health.
It is also required for the normal functioning of aerobic (oxygen-requiring) microorganisms.
Copper's essentiality was first discovered in 1928, when it was
demonstrated that rats fed a copper-deficient milk diet were unable to
produce sufficient red blood cells. The anemia was corrected by the addition of copper-containing ash from vegetable or animal sources.
Fetuses, infants, and children
Human milk is relatively low in copper, and the neonate's liver stores fall rapidly after birth, supplying copper to the fast-growing body during the breast feeding period. These supplies are necessary to carry out such metabolic functions as cellular respiration, melanin pigment and connective tissue synthesis, iron metabolism, free radical defense, gene expression, and the normal functioning of the heart and immune systems in infants.
Since copper availability in the body is hindered by an excess of iron and zinc
intake, pregnant women prescribed iron supplements to treat anemia or
zinc supplements to treat colds should consult physicians to be sure
that the prenatal supplements they may be taking also have
nutritionally-significant amounts of copper.
When newborn babies are breastfed, the babies' livers and the
mothers' breast milk provide sufficient quantities of copper for the
first 4–6 months of life. When babies are weaned, a balanced diet should
provide adequate sources of copper.
Cow's milk and some older infant formulas are depleted in copper. Most formulas are now fortified with copper to prevent depletion.
Most well-nourished children have adequate intakes of copper. Health-compromised children, including those who are premature, malnourished, have low birth weights, develop infections, and who experience rapid catch-up growth
spurts, are at elevated risk for copper deficiencies. Fortunately,
diagnosis of copper deficiency in children is clear and reliable once
the condition is suspected. Supplements under a physician's supervision
usually facilitate a full recovery.
Homeostasis
Copper is absorbed, transported, distributed, stored, and excreted in the body according to complex homeostatic processes which ensure a constant and sufficient supply of the micronutrient while simultaneously avoiding excess levels.
If an insufficient amount of copper is ingested for a short period of
time, copper stores in the liver will be depleted. Should this depletion
continue, a copper health deficiency condition may develop. If too much
copper is ingested, an excess condition can result. Both of these
conditions, deficiency and excess, can lead to tissue injury and
disease. However, due to homeostatic regulation, the human body is
capable of balancing a wide range of copper intakes for the needs of
healthy individuals.
Many aspects of copper homeostasis are known at the molecular level. Copper's essentiality is due to its ability to act as an electron donor or acceptor as its oxidation state fluxes between Cu1+(cuprous) and Cu2+ (cupric). As a component of about a dozen cuproenzymes, copper is involved in key redox
(i.e., oxidation-reduction) reactions in essential metabolic processes
such as mitochondrial respiration, synthesis of melanin, and
cross-linking of collagen.
Copper is an integral part of the antioxidant enzyme copper-zinc
superoxide dismutase, and has a role in iron homeostasis as a cofactor
in ceruloplasmin. A list of some key copper-containing enzymes and their functions is summarized below:
Enzyme catalyzing melanin and other pigment production
The transport and metabolism of copper in living organisms is
currently the subject of much active research. Copper transport at the
cellular level involves the movement of extracellular copper across the cell membrane and into the cell by specialized transporters. In the bloodstream, copper is carried throughout the body by albumin, ceruloplasmin,
and other proteins. The majority of blood copper (or serum copper) is
bound to ceruloplasmin. The proportion of ceruloplasmin-bound copper can
range from 70 to 95% and differs between individuals, depending, for
example, on hormonal cycle, season, and copper status. Intracellular
copper is routed to sites of synthesis of copper-requiring enzymes and
to organelles by specialized proteins called metallochaperones. Another set of these transporters carries copper into subcellular compartments.
Certain mechanisms exist to release copper from the cell. Specialized
transporters return excess unstored copper to the liver for additional
storage and/or biliary excretion.
These mechanisms ensure that free unbound toxic ionic copper is
unlikely to exist in the majority of the population (i.e., those without
genetic copper metabolism defects).
Absorption
In
mammals copper is absorbed in the stomach and small intestine, although
there appear to be differences among species with respect to the site
of maximal absorption. Copper is absorbed from the stomach and duodenum in rats and from the lower small intestine in hamsters.
The site of maximal copper absorption is not known for humans, but is
assumed to be the stomach and upper intestine because of the rapid
appearance of 64Cu in the plasma after oral administration.
Absorption of copper ranges from 15 to 97%, depending on copper content, form of the copper, and composition of the diet.
Various factors influence copper absorption. For example, copper absorption is enhanced by ingestion of animal protein, citrate, and phosphate. Copper salts, including copper gluconate, copper acetate, or copper sulfate, are more easily absorbed than copper oxides.Elevated levels of dietary zinc, as well as cadmium, high intakes of phytate and simple sugars (fructose, sucrose) inhibit dietary absorption of copper. Furthermore, low levels of dietary copper appear to inhibit iron absorption.
Some forms of copper are not soluble in stomach acids and cannot
be absorbed from the stomach or small intestine. Also, some foods may
contain indigestible fiber that binds with copper. High intakes of zinc
can significantly decrease copper absorption. Extreme intakes of Vitamin C
or iron can also affect copper absorption, reminding us of the fact
that micronutrients need to be consumed as a balanced mixture. This is
one reason why extreme intakes of any one single micronutrient are not
advised.
Individuals with chronic digestive problems may be unable to absorb
sufficient amounts of copper, even though the foods they eat are
copper-rich.
Several copper transporters have been identified that can move copper across cell membranes.Other intestinal copper transporters may exist. Intestinal copper
uptake may be catalyzed by Ctr1. Ctr1 is expressed in all cell types so
far investigated, including enterocytes, and it catalyzes the transport
of Cu+1 across the cell membrane.
Excess copper (as well as other heavy metal ions like zinc or
cadmium) may be bound by metallothionein and sequestered within
intracellular vesicles of enterocytes (i.e., predominant cells in the small intestinal mucosa).
Distribution
Copper released from intestinal cells moves to the serosal (i.e., thin membrane lining) capillaries where it binds to albumin, glutathione, and amino acids in the portal blood. There is also evidence for a small protein, transcuprein, with a specific role in plasma copper transport
Several or all of these copper-binding molecules may participate in
serum copper transport. Copper from portal circulation is primarily
taken up by the liver. Once in the liver, copper is either incorporated
into copper-requiring proteins, which are subsequently secreted into the
blood. Most of the copper (70 – 95%) excreted by the liver is
incorporated into ceruloplasmin, the main copper carrier in blood.
Copper is transported to extra-hepatic tissues by ceruloplasmin, albumin and amino acids, or excreted into the bile. By regulating copper release, the liver exerts homeostatic control over extra-hepatic copper.
Excretion
Bile is the major pathway for the excretion of copper and is vitally important in the control of liver copper levels.
Most fecal copper results from biliary excretion; the remainder is
derived from unabsorbed copper and copper from desquamated mucosal
cells.
Postulated Spectrum of Copper Metabolism
Dose range
Approximate daily intakes
Health outcomes
Death
Gross dysfunction and disturbance of metabolism of other nutrients; hepatic
"detoxification" and homeostasis overwhelmed
Toxic
>5.0 mg/kg body weight
Gastrointestinal metallothionein induced (possible differing effects of acute and chronic
(exposure)
100 μg/kg body weight
Plateau of absorption maintained; homeostatic mechanisms regulate absorption of copper
Adequate
34 μg/kg body weight
Hepatic uptake, sequestration and excretion effect homeostasis;
glutathione-dependent uptake of copper; binding to metallothionein; and
lysosomal excretion of copper
11 μg/kg body weight
Biliary excretion and gastrointestinal uptake normal
9 μg/kg body weight
Hepatic deposit(s) reduced; conservation of endogenous copper; gastrointestinal
absorption increased
Deficient
8.5 μg/kg body weight
Negative copper balance
5.2 μg/kg body weight
Functional defects, such as lysyl oxidase and superoxide dismutase activities reduced; impaired substrate metabolism
2 μg/kg body weight
Peripheral pools disrupted; gross dysfunction and disturbance of metabolism of other
nutrients; death
Dietary recommendations
Various
national and international organizations concerned with nutrition and
health have standards for copper intake at levels judged to be adequate
for maintaining good health. These standards are periodically changed
and updated as new scientific data become available. The standards
sometimes differ among countries and organizations.
Adults
The World Health Organization recommends a minimal acceptable intake of approximately 1.3 mg/day.
These values are considered to be adequate and safe for most of the
general population. In North America, the U.S. Institute of Medicine
(IOM) set the Recommended Dietary Allowance (RDA) for copper for healthy
adult men and women at 0.9 mg/day. As for safety, the IOM also sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of copper the UL is set at 10 mg/day. The European Food Safety Authority reviewed the same safety question and set its UL at 5 mg/day.
Adolescents, children, and infants
Full-term
and premature infants are more sensitive to copper deficiency than
adults. Since the fetus accumulates copper during the last 3 months of
pregnancy, infants that are born prematurely have not had sufficient
time to store adequate reserves of copper in their livers and therefore
require more copper at birth than full-term infants.
For full-term infants, the North American recommended safe and
adequate intake is approximately 0.2 mg/day. For premature babies, it is
considerably higher: 1 mg/day. The World Health Organization has
recommended similar minimum adequate intakes and advises that premature
infants be given formula supplemented with extra copper to prevent the
development of copper deficiency.
Pregnant and lactating women
In North America, the IOM has set the RDA for pregnancy at 1.0 mg/day and for lactation at 1.3 mg/day.
The European Food Safety Authority (EFSA) refers to the collective set
of information as Dietary Reference Values, with Population Reference
Intake (PRI) instead of RDA. PRI for pregnancy is 1.6 mg/day, for
lactation 1.6 mg/day – higher than the U.S. RDAs.
Food sources
Foods rich in copper
Foods contribute virtually all of the copper consumed by humans.
In both developed and developing countries, adults, young children, and adolescents who consume diets of grain, millet, tuber,
or rice along with legumes (beans) or small amounts of fish or meat,
some fruits and vegetables, and some vegetable oil are likely to obtain
adequate copper if their total food consumption is adequate in calories.
In developed countries where consumption of red meat is high, copper
intake may also be adequate.
As a natural element in the Earth's crust, copper exists in most
of the world's surface water and groundwater, although the actual
concentration of copper in natural waters varies geographically.
Drinking water can comprise 20–25% of dietary copper.
In many regions of the world, copper tubing that conveys drinking water can be a source of dietary copper.
Copper tube can leach a small amount of copper, particularly in its
first year or two of service. Afterwards, a protective surface usually
forms on the inside of copper tubes that slows leaching.
In France and some other countries, copper bowls are traditionally used for whipping egg white,
as the copper helps stabilise bonds in the white as it is beaten and
whipped. Small amounts of copper may leach from the bowl during the
process and enter the egg white.
Supplementation
Copper
supplements can prevent copper deficiency. Copper supplements are not
prescription medicines, and are available at vitamin and herb stores and
grocery stores and online retailers. Different forms of copper
supplementation have different absorption rates. For example, the
absorption of copper from cupric oxide supplements is lower than that from copper gluconate, copper sulfate, or carbonate.
Supplementation is generally not recommended for healthy adults
who consume a well-balanced diet which includes a wide range of foods.
However, supplementation under the care of a physician may be necessary
for premature infants or those with low birth weights, infants fed
unfortified formula or cow's milk during the first year of life, and
malnourished young children. Physicians may consider copper
supplementation for 1) illnesses that reduce digestion (e.g., children
with frequent diarrhea or infections; alcoholics), 2) insufficient food consumption (e.g., the elderly, the infirm, those with eating disorders
or on diets), 3) patients taking medications that block the body's use
of copper, 4) anemia patients who are treated with iron supplements, 5)
anyone taking zinc supplements, and 6) those with osteoporosis.
Many popular vitamin supplements include copper as small
inorganic molecules such as cupric oxide. These supplements can result
in excess free copper in the brain as the copper can cross the
blood-brain barrier directly. Normally, organic copper in food is first
processed by the liver which keeps free copper levels under control.
Copper deficiency and excess health conditions (non-genetic)
If insufficient quantities of copper are ingested, copper reserves in
the liver will become depleted and a copper deficiency leading to
disease or tissue injury (and in extreme cases, death). Toxicity from
copper deficiency can be treated with a balanced diet or supplementation
under the supervision of a doctor. On the contrary, like all
substances, excess copper intake at levels far above World Health
Organization limits can become toxic.
Acute copper toxicity is generally associated with accidental
ingestion. These symptoms abate when the high copper food source is no
longer ingested.
In 1996, the International Program on Chemical Safety, a World
Health Organization-associated agency, stated "there is greater risk of
health effects from deficiency of copper intake than from excess copper
intake". This conclusion was confirmed in recent multi-route exposure
surveys.
The health conditions of non-genetic copper deficiency and copper excess are described below.
Copper deficiency
There
are conflicting reports on the extent of deficiency in the U.S. One
review indicates approximately 25% of adolescents, adults, and people
over 65, do not meet the Recommended Dietary Allowance for copper.
Another source states less common: a federal survey of food consumption
determined that for women and men over the age of 19, average
consumption from foods and beverages was 1.11 and 1.54 mg/day,
respectively. For women, 10% consumed less than the Estimated Average
Requirement, for men fewer than 3%.
Acquired copper deficiency has recently been implicated in adult-onset progressive myeloneuropathy and in the development of severe blood disorders including myelodysplastic syndrome.Fortunately, copper deficiency can be confirmed by very low serum metal and ceruloplasmin concentrations in the blood.
Other conditions linked to copper deficiency include osteoporosis, osteoarthritis, rheumatoid arthritis,
cardiovascular disease, colon cancer, and chronic conditions involving
bone, connective tissue, heart and blood vessels. nervous system and
immune system. Copper deficiency alters the role of other cellular constituents involved in antioxidant activities, such as iron, selenium, and glutathione, and therefore plays an important role in diseases in which oxidant stress
is elevated. A marginal, i.e., 'mild' copper deficiency, believed to be
more widespread than previously thought, can impair human health in
subtle ways.
Populations susceptible to copper deficiency include those with genetic defects for Menkes disease,
low-birth-weight infants, infants fed cow's milk instead of breast milk
or fortified formula, pregnant and lactating mothers, patients
receiving total parenteral nutrition, individuals with "malabsorption syndrome" (impaired dietary absorption), diabetics,
individuals with chronic diseases that result in low food intake, such
as alcoholics, and persons with eating disorders. The elderly and athletes may also be at higher risk for copper deficiency due to special needs that increase the daily requirements.
Vegetarians may have decreased copper intake due to the consumption of
plant foods in which copper bioavailability is low. On the other hand,
Bo Lönnerdal commented that Gibson's study showed that vegetarian diets
provided larger quantities of copper.
Fetuses and infants of severely copper deficient women have increased
risk of low birth weights, muscle weaknesses, and neurological problems.
Copper deficiencies in these populations may result in anemia, bone
abnormalities, impaired growth, weight gain, frequent infections (colds,
flu, pneumonia), poor motor coordination, and low energy.
Copper excess is a subject of much current research. Distinctions
have emerged from studies that copper excess factors are different in
normal populations versus those with increased susceptibility to adverse
effects and those with rare genetic diseases.
This has led to statements from health organizations that could be
confusing to the uninformed. For example, according to a U.S. Institute
of Medicine report,
the intake levels of copper for a significant percentage of the
population are lower than recommended levels. On the other hand, the
U.S. National Research Council
concluded in its report Copper in Drinking Water that there is concern
for copper toxicity in susceptible populations and recommended that
additional research be conducted to identify and characterize
copper-sensitive populations.
Excess copper intake causes stomach upset, nausea, and diarrhea and can lead to tissue injury and disease.
While the cause and progression of Alzheimer's disease are not well understood, research indicates that, among several other key observations, iron, aluminum, and copper
accumulate in the brains of Alzheimer's patients. However, it is not
yet known whether this accumulation is a cause or a consequence of the
disease.
Research has been ongoing over the past two decades to determine
whether copper is a causative or a preventive agent of Alzheimer's
disease.
For example, as a possible causative agent or an expression of a metal
homeostasis disturbance, studies indicate that copper may play a role in
increasing the growth of protein clumps in Alzheimer's disease brains, possibly by damaging a molecule that removes the toxic buildup of amyloid beta (Aβ) in the brain. There is an association between a diet rich in copper and iron together with saturated fat and Alzheimer's disease.
On the other hand, studies also demonstrate potential beneficial roles
of copper in treating rather than causing Alzheimer's disease. For example, copper has been shown to 1) promote the non-amyloidogenic processing of amyloid beta precursor protein (APP), thereby lowering amyloid beta (Aβ) production in cell culture systems 2) increase lifetime and decrease soluble amyloid production in APP transgenic mice, and 3) lower Aβ levels in cerebral spinal fluid in Alzheimer's disease patients.
Furthermore, long-term copper treatment (oral intake of 8 mg
copper (Cu-(II)-orotate-dihydrate)) was excluded as a risk factor for
Alzheimer's disease in a noted clinical trial on humans
and a potentially beneficial role of copper in Alzheimer's disease has
been demonstrated on cerebral spinal fluid levels of Aβ42, a toxic
peptide and biomarker of the disease.
More research is needed to understand metal homeostasis disturbances in
Alzheimer's disease patients and how to address these disturbances
therapeutically. Since this experiment used Cu-(II)-orotate-dihydrate,
it does not relate to the effects of cupric oxide in supplements.
Copper toxicity from excess exposures
In
humans, the liver is the primary organ of copper-induced toxicity.
Other target organs include bone and the central nervous and immune
systems.
Excess copper intake also induces toxicity indirectly by interacting
with other nutrients. For example, excess copper intake produces anemia
by interfering with iron transport and/or metabolism.
The identification of genetic disorders of copper metabolism leading to severe copper toxicity (i.e., Wilson disease)
has spurred research into the molecular genetics and biology of copper
homeostasis (for further information, refer to the following section on
copper genetic diseases). Much attention has focused on the potential
consequences of copper toxicity in normal and potentially susceptible
populations. Potentially susceptible subpopulations include hemodialysis
patients and individuals with chronic liver disease. Recently, concern
was expressed about the potential sensitivity to liver disease of
individuals who are heterozygote
carriers of Wilson disease genetic defects (i.e., those having one
normal and one mutated Wilson copper ATPase gene) but who do not have
the disease (which requires defects in both relevant genes). However, to date, no data are available that either support or refute this hypothesis.
Acute exposures
In
case reports of humans intentionally or accidentally ingesting high
concentrations of copper salts (doses usually not known but reported to
be 20–70 grams of copper), a progression of symptoms was observed
including abdominal pain, headache, nausea, dizziness, vomiting and
diarrhea, tachycardia, respiratory difficulty, hemolytic anemia, hematuria, massive gastrointestinal bleeding, liver and kidney failure, and death.
Episodes of acute gastrointestinal upset following single or
repeated ingestion of drinking water containing elevated levels of
copper (generally above 3–6 mg/L) are characterized by nausea, vomiting,
and stomach irritation. These symptoms resolve when copper in the
drinking water source is reduced.
Three experimental studies were conducted that demonstrate a
threshold for acute gastrointestinal upset of approximately 4–5 mg/L in
healthy adults, although it is not clear from these findings whether
symptoms are due to acutely irritant effects of copper and/or to
metallic, bitter, salty taste.
In an experimental study with healthy adults, the average taste
threshold for copper sulfate and chloride in tap water, deionized water,
or mineral water was 2.5–3.5 mg/L. This is just below the experimental threshold for acute gastrointestinal upset.
Chronic exposures
The
long-term toxicity of copper has not been well studied in humans, but
it is infrequent in normal populations that do not have a hereditary
defect in copper homeostasis.
There is little evidence to indicate that chronic human exposure to copper results in systemic effects other than liver injury.
Chronic copper poisoning leading to liver failure was reported in a
young adult male with no known genetic susceptibility who consumed
30–60 mg/d of copper as a mineral supplement for 3 years.
Individuals residing in U.S. households supplied with tap water
containing >3 mg/L of copper exhibited no adverse health effects.
No effects of copper supplementation on serum liver enzymes,
biomarkers of oxidative stress, and other biochemical endpoints have
been observed in healthy young human volunteers given daily doses of 6
to 10 mg/d of copper for up to 12 weeks.
Infants aged 3–12 months who consumed water containing 2 mg Cu/L for 9
months did not differ from a concurrent control group in
gastrointestinal tract (GIT) symptoms, growth rate, morbidity, serum
liver enzyme and bilirubin levels, and other biochemical endpoints.)
Serum ceruloplasmin was transiently elevated in the exposed infant
group at 9 months and similar to controls at 12 months, suggesting
homeostatic adaptation and/or maturation of the homeostatic response.
Dermal exposure has not been associated with systemic toxicity
but anecdotal reports of allergic responses may be a sensitization to
nickel and cross-reaction with copper or a skin irritation from copper.
Workers exposed to high air levels of copper (resulting in an estimated
intake of 200 mg Cu/d) developed signs suggesting copper toxicity
(e.g., elevated serum copper levels, hepatomegaly). However, other
co-occurring exposures to pesticidal agents or in mining and smelting
may contribute to these effects.
Effects of copper inhalation are being thoroughly investigated by an
industry-sponsored program on workplace air and worker safety. This
multi-year research effort is expected to be finalized in 2011.
Measurements of elevated copper status
Although
a number of indicators are useful in diagnosing copper deficiency,
there are no reliable biomarkers of copper excess resulting from dietary
intake. The most reliable indicator of excess copper status is liver
copper concentration. However, measurement of this endpoint in humans is
intrusive and not generally conducted except in cases of suspected
copper poisoning. Increased serum copper or ceruolplasmin levels are not
reliably associated with copper toxicity as elevations in
concentrations can be induced by inflammation, infection, disease,
malignancies, pregnancy, and other biological stressors. Levels of
copper-containing enzymes, such as cytochrome c oxidase, superoxide
dismutase, and diaminase oxidase, vary not only in response to copper
state but also in response to a variety of other physiological and
biochemical factors and therefore are inconsistent markers of excess
copper status.
A new candidate biomarker for copper excess as well as deficiency
has emerged in recent years. This potential marker is a chaperone
protein, which delivers copper to the antioxidant protein SOD1 (copper,
zinc superoxide dismutase). It is called "copper chaperone for SOD1"
(CCS), and excellent animal data supports its use as a marker in
accessible cells (e.g., erythrocytes) for copper deficiency as well as excess. CCS is currently being tested as a biomarker in humans.
Hereditary copper metabolic diseases
Several rare genetic diseases (Wilson disease, Menkes disease, idiopathic copper toxicosis, Indian childhood cirrhosis) are associated with the improper use of copper in the body. All of these diseases involve mutations of genes containing the genetic codes
for the production of specific proteins involved in the absorption and
distribution of copper. When these proteins are dysfunctional, copper
either builds up in the liver or the body fails to absorb copper.
These diseases are inherited and cannot be acquired. Adjusting
copper levels in the diet or drinking water will not cure these
conditions (although therapies are available to manage symptoms of
genetic copper excess disease).
The study of genetic copper metabolism diseases and their
associated proteins are enabling scientists to understand how human
bodies use copper and why it is important as an essential micronutrient.
The diseases arise from defects in two similar copper pumps, the Menkes and the Wilson Cu-ATPases.
The Menkes ATPase is expressed in tissues like skin-building
fibroblasts, kidneys, placenta, brain, gut and vascular system, while
the Wilson ATPase is expressed mainly in the liver, but also in mammary
glands and possibly in other specialized tissues. This knowledge is leading scientists towards possible cures for genetic copper diseases.
Menkes disease
Menkes
disease, a genetic condition of copper deficiency, was first described
by John Menkes in 1962. It is a rare X-linked disorder that affects
approximately 1/200,000 live births, primarily boys.
Livers of Menkes disease patients cannot absorb essential copper needed
for patients to survive. Death usually occurs in early childhood: most
affected individuals die before the age of 10 years, although several
patients have survived into their teens and early 20s.
The protein produced by the Menkes gene is responsible for transporting copper across the gastrointestinal tract (GIT) mucosa and the blood–brain barrier.
Mutational defects in the gene encoding the copper ATPase cause copper
to remain trapped in the lining of the small intestine. Hence, copper
cannot be pumped out of the intestinal cells and into the blood for
transport to the liver and consequently to rest of the body. The disease therefore resembles a severe nutritional copper deficiency despite adequate ingestion of copper.
Symptoms of the disease include coarse, brittle, depigmented hair
and other neonatal problems, including the inability to control body
temperature, intellectual disability, skeletal defects, and abnormal
connective tissue growth.
Menkes patients exhibit severe neurological abnormalities,
apparently due to the lack of several copper-dependent enzymes required
for brain development, including reduced cytochrome c oxidase activity. The brittle, kinky hypopigmented hair of steely appearance is due to a deficiency in an unidentified cuproenzyme. Reduced lysyl oxidase activity results in defective collagen and elastin polymerization and corresponding connective-tissue abnormalities including aortic aneurisms, loose skin, and fragile bones.
With early diagnosis and treatment consisting of daily injections of copper histidineintraperitoneally and intrathecally
to the central nervous system, some of the severe neurological problems
may be avoided and survival prolonged. However, Menkes disease patients
retain abnormal bone and connective-tissue disorders and show mild to
severe intellectual disability. Even with early diagnosis and treatment, Menkes disease is usually fatal.
Ongoing research into Menkes disease is leading to a greater understanding of copper homeostasis, the biochemical mechanisms involved in the disease, and possible ways to treat it.
Investigations into the transport of copper across the blood/brain
barrier, which are based on studies of genetically altered mice, are
designed to help researchers understand the root cause of copper
deficiency in Menkes disease. The genetic makeup of transgenic mice is
altered in ways that help researchers garner new perspectives about
copper deficiency. The research to date has been valuable: genes can be
turned off gradually to explore varying degrees of deficiency.
Researchers have also demonstrated in test tubes that damaged DNA
in the cells of a Menkes patient can be repaired. In time, the
procedures needed to repair damaged genes in the human body may be
found.
Wilson's disease
Wilson's disease is a rare autosomal (chromosome 13) recessive genetic disorder of copper transport that causes an excess of copper to build up in the liver. This results in liver toxicity, among other symptoms. The disease is now treatable.
Wilson's disease is produced by mutational defects of a protein that transports copper from the liver to the bile for excretion.
The disease involves poor incorporation of copper into ceruloplasmin
and impaired biliary copper excretion and is usually induced by
mutations impairing the function of the Wilson copper ATPase. These
genetic mutations produce copper toxicosis due to excess copper
accumulation, predominantly in the liver and brain and, to a lesser
extent, in kidneys, eyes, and other organs.
The disease, which affects about 1/30,000 infants of both genders,
may become clinically evident at any time from infancy through early
adulthood. The age of onset of Wilson's disease ranges from 3 to 50
years of age. Initial symptoms include hepatic, neurologic, or psychiatric disorders and, rarely, kidney, skeletal, or endocrine symptomatology. The disease progresses with deepening jaundice and the development of encephalopathy, severe clotting abnormalities, occasionally associated with intravascular coagulation, and advanced chronic kidney disease. A peculiar type of tremor in the upper extremities, slowness of movement, and changes in temperament become apparent. Kayser-Fleischer rings,
a rusty brown discoloration at the outer rims of the iris due to copper
deposition noted in 90% of patients, become evident as copper begins to
accumulate and affect the nervous system.
Almost always, death occurs if the disease is untreated.
Fortunately, identification of the mutations in the Wilson ATPase gene
underlying most cases of Wilson's disease has made DNA testing for
diagnosis possible.
If diagnosed and treated early enough, patients with Wilson's disease may live long and productive lives. Wilson's disease is managed by copper chelation therapy with D-penicillamine
(which picks up and binds copper and enables patients to excrete excess
copper accumulated in the liver), therapy with zinc sulfate or zinc
acetate, and restrictive dietary metal intake, such as the elimination
of chocolate, oysters, and mushrooms.
Zinc therapy is now the treatment of choice. Zinc produces a mucosal
block by inducing metallothionein, which binds copper in mucosal cells
until they slough off and are eliminated in the feces. and it competes with copper for absorption in the intestine by DMT1 (Divalent Metal transporter 1). More recently, experimental treatments with tetrathiomolybdate
showed promising results. Tetrathiomolybdate appears to be an excellent
form of initial treatment in patients who have neurologic symptoms. In
contrast to penicillamine therapy, initial treatment with
tetrathiomolybdate rarely allows further, often irreversible, neurologic
deterioration.
Over 100 different genetic defects leading to Wilson's disease have been described and are available on the Internet at. Some of the mutations have geographic clustering.
Many Wilson's patients carry different mutations on each chromosome 13 (i.e., they are
compound heterozygotes). Even in individuals who are homozygous for a mutation, onset and severity of the disease may vary. Individuals homozygous
for severe mutations (e.g., those truncating the protein) have earlier
disease onset. Disease severity may also be a function of environmental
factors, including the amount of copper in the diet or variability in
the function of other proteins that influence copper homeostasis.
It has been suggested that heterozygote carriers of the Wilson's
disease gene mutation may be potentially more susceptible to elevated
copper intake than the general population. A heterozygotic frequency of 1/90 people has been estimated in the overall population. However, there is no evidence to support this speculation.
Further, a review of the data on single-allelic autosomal recessive
diseases in humans does not suggest that heterozygote carriers are
likely to be adversely affected by their altered genetic status.
Other copper-related hereditary syndromes
Other diseases in which abnormalities in copper metabolism appear to be involved include Indian childhood cirrhosis
(ICC), endemic Tyrolean copper toxicosis (ETIC), and idiopathic copper
toxicosis (ICT), also known as non-Indian childhood cirrhosis. ICT is a
genetic disease recognized in the early twentieth century primarily in
the Tyrolean region of Austria and in the Pune region of India.
ICC, ICT, and ETIC are infancy syndromes that are similar in their apparent etiology and presentation. Both appear to have a genetic component and a contribution from elevated copper intake.
In cases of ICC, the elevated copper intake is due to heating
and/or storing milk in copper or brass vessels. ICT cases, on the other
hand, are due to elevated copper concentrations in water supplies.Although exposures to elevated concentrations of copper are commonly
found in both diseases, some cases appear to develop in children who are
exclusively breastfed or who receive only low levels of copper in water
supplies.
The currently prevailing hypothesis is that ICT is due to a genetic
lesion resulting in impaired copper metabolism combined with high copper
intake. This hypothesis was supported by the frequency of occurrence of
parental consanguinity
in most of these cases, which is absent in areas with elevated copper
in drinking water and in which these syndromes do not occur.
ICT appears to be vanishing as a result of greater genetic
diversity within the affected populations in conjunction with
educational programs to ensure that tinned cooking utensils are used
instead of copper pots and pans being directly exposed to cooked foods.
The preponderance of cases of early childhood cirrhosis identified in
Germany over a period of 10 years were not associated with either
external sources of copper or with elevated hepatic metal concentrations. Only occasional spontaneous cases of ICT arise today.
Cancer
The role of copper in angiogenesis associated with different types of cancers has been investigated.
A copper chelator, tetrathiomolybdate, which depletes copper stores in
the body, is under investigation as an anti-angiogenic agent in pilot and clinical trials. The drug may inhibit tumor angiogenesis in hepatocellular carcinoma, pleural mesothelioma, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, and kidney cancer.
The copper complex of a synthetic salicylaldehyde pyrazole hydrazone
(SPH) derivative induced human umbilical endothelial cell (HUVEC)
apoptosis and showed anti-angiogenesis effect in vitro.
The trace element copper had been found promoting tumor growth. Several evidence from animal models indicates that tumors concentrate
high levels of copper. Meanwhile, extra copper has been found in some
human cancers.
Recently, therapeutic strategies targeting copper in the tumor have
been proposed. Upon administration with a specific copper chelator,
copper complexes would be formed at a relatively high level in tumors.
Copper complexes are often toxic to cells, therefore tumor cells were
killed, while normal cells in the whole body remained alive for the
lower level of copper. Researchers have also recently found that cuproptosis,
a copper-induced mechanism of mitochondrial-related cell death, has
been implicated as a breakthrough in the treatment of cancer and has
become a new treatment strategy.
Some copper chelators get more effective or novel bioactivity
after forming copper-chelator complexes. It was found that Cu2+ was
critically needed for PDTC induced apoptosis in HL-60 cells.
The copper complex of salicylaldehyde benzoylhydrazone (SBH)
derivatives showed increased efficacy of growth inhibition in several
cancer cell lines, when compared with the metal-free SBHs.
SBHs can react with many kinds of transition metal cations and thereby forming a number of complexes.
Copper-SBH complexes were more cytotoxic than complexes of other
transitional metals (Cu > Ni > Zn = Mn > Fe = Cr > Co) in MOLT-4 cells,
an established human T-cell leukemia cell line. SBHs, especially their
copper complexes appeared to be potent inhibitors of DNA synthesis and
cell growth in several human cancer cell lines, and rodent cancer cell
lines.
Salicylaldehyde pyrazole hydrazone (SPH) derivatives were found to inhibit the growth of A549 lung carcinoma cells. SPH has identical ligands for Cu2+ as SBH. The Cu-SPH complex was found to induce apoptosis in A549, H322 and H1299 lung cancer cells.
In
addition to being an essential nutrient for humans, copper is vital for
the health of animals and plants and plays an important role in
agriculture.
Plant health
Copper
concentrations in soil are not uniform around the world. In many areas,
soils have insufficient levels of copper. Soils that are naturally
deficient in copper often require copper supplements before agricultural
crops, such as cereals, can be grown.
Copper deficiencies in soil can lead to crop failure. Copper
deficiency is a major issue in global food production, resulting in
losses in yield and reduced quality of output. Nitrogen fertilizers can
worsen copper deficiency in agricultural soils.
The world's two most important food crops, rice and wheat, are
highly susceptible to copper deficiency. So are several other important
foods, including citrus, oats, spinach and carrots. On the other hand, some foods including coconuts, soybeans and asparagus, are not particularly sensitive to copper-deficient soils.
The most effective strategy to counter copper deficiency is to
supplement the soil with copper, usually in the form of copper sulfate. Sewage sludge is also used in some areas to replenish agricultural land with organics and trace metals, including copper.
Animal health
In livestock, cattle and sheep commonly show indications when they are copper deficient. Swayback,
a sheep disease associated with copper deficiency, imposes enormous
costs on farmers worldwide, particularly in Europe, North America, and
many tropical countries. For pigs, copper has been shown to be a growth
promoter.
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