Manganese is essential to all known living organisms; it
activates numerous enzyme systems including those involved with glucose
metabolism, energy production and superoxide dismutase; it is a major
constituent of several metalloenzymes, hormones, and proteins of humans.
Manganese is part of the developmental process and the structure of the
fragile ear bones and joint cartilage. Excessive levels of Mn found in
certain community water supplies and in some industrial processes can
produce a Parkinsonian syndrome or a psychiatric disorder (locura manganica)
Deficiency diseases of Mn are very striking ranging from severe birth
defects (Congenital ataxia, deafness, Chondrodystrophy), asthma,
convulsions, retarded growth, skeletal defects, disruption of fat and
carbohydrate metabolism to joint problems in children and adults (TMJ,
Repetitive Motion Syndrome, Carpal Tunnel Syndrome.
Repetitive Stress Injury or Repetitive Motion Syndrome now costs corporate
America $20 billion dollars per year and accounts for 56% of the 331,600
gradual onset work related illnesses. In 1991 orthopedic surgeons performed
100,000 Carpal Tunnel operations (at $4,000 per surgery) with a lost work,
wages and medical cost of over $29,000 per case.
Deficiency Diseases of Manganese
- Congenital ataxia
- Deafness (malformation of otolithes)
- "Slipped Tendon"
- Defects of chondroitin sulfate metabolism (poor cartilage formation)
- Repetitive Motion Syndrome
- Carpal Tunnel Syndrome
- Infertility (failure to ovulate; testicular atrophy)
- Still births or spontaneous abortions (miscarriages)
- Loss of libido in males and females
- Retarded growth rate
- Shortened long bones
At risk for The Repetitive Motion Syndromes are those working in the fields
of computers (journalism, airline reservations, directory assistance, law,
data entry, and graphic design and securities brokerage. Chief among the
blue-collar victims are the auto assembly workers, chicken pluckers, meat
cutters, postal employees, dock workers, etc. Repetitive Motion Syndrome was
observed three centuries ago in monks who were scribes and was described in
1717 by Bernardo Ramazzini, an Italian physician (considered the father of
Repetitive Motion Syndrome victims have reached such numbers that federal
legislation has been passed in the form of OSHA and Americans with
Disabilities Act (ADA) to ensure work place safety. Large numbers of
ergonomically correct keyboards and devices have been developed, we see
literally millions of people at work with Velcro wrist, neck, elbow, finger,
knee, back and hip supports - all for manganese deficiencies!!! The
allopathic medical profession would still prefer to spend your money than to
admit that the human flesh needs Manganese.
Manganese is an essential trace mineral nutrient. Manganese is needed for
normal brain and muscle function, building bones, blood clotting,
cholesterol synthesis, fat synthesis, and DNA and RNA synthesis. Manganese
activates the enzyme responsible for the formation of urea, the waste
product of protein degradation. In carbohydrate metabolism manganese is
required for the synthesis of glucose from non-carbohydrate substances (gluconeogenesis).
Manganese assists the action of superoxide dismutase, which degrades
superoxide, a free radical and a highly damaging form of oxygen. In
addition, manganese is required to synthesize components of
mucopolysaccharides (glycosaminoglycans), components of connective tissue. A
manganese-dependent enzyme of the brain synthesizes the amino acid,
glutamine, as a way of removing ammonia, a toxic product of nitrogen
metabolism. Conditions possibly associated with manganese deficiency include
osteoporosis, rheumatoid arthritis, lupus erythrematosis, allergies,
alcoholism and diabetes.
The body contains low levels of manganese, and only minute amounts are
required each day to maintain this level. The manganese concentration in
tissues is stable primarily due to carefully controlled excretion.
There is no Recommended Dietary Allowance for manganese. Instead the Food
and Nutrition Board has estimated a safe and adequate daily intake as 2.0 to
5.0 mg for adults. Symptoms of manganese deficiency in experimental animals
include pancreatic pathology and diabetes-like symptoms, impaired growth,
reproductive abnormalities, skeletal abnormalities, convulsions and ataxia
(abnormal muscle movements). Certain groups might be deficient in manganese:
women, especially those on weight loss diets; anyone on a calorie-restricted
diet; aged people; and vegetarians.
While manganese is relatively non-toxic, too much manganese can interfere
with the absorption of other minerals like iron. High manganese intake can
cause nerve damage, immune system malfunction, and damage to pancreas, liver
and kidney. Excessive calcium supplements can interfere with manganese and
iron uptake because they all use the same entry mechanism into intestinal
cells. (See also allergy, immediate fat metabolism.)
Freeland-Graves, Jeanne, "Manganese: an Essential Nutrient for Humans,"'
Nutrition Today, (November-December 1988), pp. 13-19
Manganese - Biochemical Function
Manganese is both an activator, and a constituent of several enzymes. Those
activated by manganese are numerous and include hydrolases, kinases,
decarboxylases and transferases, but most of these enzymes can also be
activated by other metals, especially magnesium. This does not apply,
however, to the activation of glycosyltransferases or possibly to that of
xylosyltransferase. Manganese metalloenzymes include arginase, pyruvate
carboxylase, glutamine synthetase, and manganese superoxide dismutase.
A. Enzyme Activity
Like other essential trace elements, Mn can function both as an enzyme
activator and as a constituent of metalloenzymes. Manganese-containing
enzymes include arginase, pyruvate carboxylase, and Mn-superoxide dismutase.
While the number of Mn metalloenzymes is limited, the enzymes that can be
activated by Mn are numerous. They include hydrolases, kinases,
decarboxylases, and transferases (Groppel and Anke, 1971). Whether an
activator or a component of the enzyme proper, Mn is often the priority
cation, but another cation, especially magnesium (Mg), can partially
substitute for Mn with little or no loss in enzymatic activity. Thus,
biotin-dependent enzymes such as pyruvate carboxylase continue to fix CO,
during Mn deficiency because Mg substitutes for Mn in the enzyme.
B. Bone Growth
In most species studied, Mn-deficient bones are considerably shortened and
thickened. Manganese is essential for development of the organic matrix of
the bone, which is composed, largely of mucopolysaccharide. Impairment in
mucopolysaccharide synthesis associated with Mn deficiency has been related
to the activation of glycosyltransferases (Leach, 1971). These enzymes are
important to polysaccharide and glycoprotein synthesis, and Mn is usually
the most effective of the metal ions required.
While it would be tempting to suggest a relationship between manganese and
the pathogenesis of osteoporosis based on various studies, more
investigation and exposition are required in view of the prevalence of the
disease worldwide. Overt human manganese deficiency has rarely been seen in
man, but subliminal deficiency symptoms may go unnoticed for years because
most nutrient deficiencies are not instantaneous, especially when looking at
bone health. Bone mass in adults changes slowly, and we can expect a
substantial lag between diet and its expression in skeletal mass.
Effects on reproduction were among the first signs of Mn deficiency to be
observed. The deficiency can cause an irreversible congenital defect in
young chicks, rats, and guinea pigs characterized by ataxia and loss of
equilibrium. Shils and McCollum (1943) found several stages of Mn deficiency
in female rodents: (1) birth of viable young with ataxia; (2) nonviable
young that die shortly after birth; and (3) disturbance of estrus, with no
reproduction. Impaired or irregular estrus has also been observed in cattle
and swine. Hidiroglou (1975), on the basis of Mn tissue -distribution
studies of the reproductive tract of normal and anestrus ewes, has suggested
that Mn has a role in corpus luteum functioning. In laying hens, Mn
deficiency has resulted in a decreased rate of egg production, poor shell
quality, reduced hatchability, and an embryonic deficiency called
chondrodystrophy. Testicular degeneration has been reported in Mn-deficient
rats, mice, and rabbits (Leach, 1978).
The essentiality of manganese has been demonstrated in numerous species. The
changes of manganese deficiency vary according to the degree and duration of
deficiency at different stages of the life cycle. The main manifestations of
manganese deficiency include a high neonatal death rate, impaired growth,
abnormal skeletal development, congenital ataxia, disturbed or depressed
reproductive function, and defects in lipid and in carbohydrate metabolism.
Many of these gross manifestations of manganese deficiency are now believed
to be due to a defect in the synthesis of mucopolysaccharides. Although
available information on manganese deficiency in man is limited, these
findings suggest that manganese may play a role as one potential factor in
the development of intrauterine malformations. Further research is needed to
support and clarify this suggestion.
D. Lipid Metabolism
A metabolic association between Mn and choline has been known for some time.
Fatty liver in rats induced by Mn deficiency is alleviated by either Mn or
choline. Also, Mn deficiency increases fat deposition and backfat thickness
in pigs. Both Mn and choline are needed for prevention of perosis in
poultry. Manganese is involved in the biosynthesis of choline. Furthermore,
the changes in liver ultrastructure that arise in choline deficiency are
very similar to those in Mn deficiency (Bruni and Hegsted, 1970).
Deficiencies of Mn and choline both appear to affect membrane integrity.
Manganese also has a role in cholesterol biogenesis (Davis et al., 1990).
We may postulate a number of ways in which manganese may play a role in
lipid and lipoprotein metabolism, which may be ultimately related to the
development of atherosclerosis.
Manganese may affect cell membrane fluidity and/or permeability by its
function as a cofactor for enzymes involved in cholesterol and fatty acid
biosynthesis. Changes in cholesterol and fatty acid composition of cell
membranes would in turn alter lipid:lipid and lipid:protein ratios, which
would ultimately affect membrane fluidity/permeability. Furthermore,
manganese, by being a cofactor of MnSOD, protects membranes from free
radical formation and preserves the integrity of its lipid components.
Glycoproteins are integral components of the arterial extracellular matrix
and play an important role in maintaining structural integrity and normal
function of the arterial wall including regulating permeability and
retention of plasma components, controlling vascular cell growth, and
interacting with lipoproteins. Manganese, as a specific activator of
glycosyltransferases, may also affect glycosylation of glycoproteins on cell
membranes including receptors. This would alter receptor composition and
structural properties and affect lipoprotein binding and their ultimate
Manganese may also affect lipoprotein composition and metabolism by its role
in stabilizing lipoprotein structure due to its high affinity in complexing
with the polar heads of lipoprotein phospholipids and amino acid residues.
Furthermore, manganese may modify intramolecular interaction of the
lipoprotein particle with its receptor by bridging the anionic groups of
cell membrane glycosaminoglycans with certain amino acid residues and
phospholipids on the surface of the lipoprotein. Finally, manganese may play
a crucial role in the glycosylation of plasma apolipoproteins in the liver
Golgi apparatus by specifically activating glycosyl transferases.
Glycosylation as a prerequisite for normal lipoprotein secretion has been
speculated." Manganese deficiency may result in abnormal lipoprotein
formation and impairment of lipoprotein secretion from the liver, thus
resulting in fatty liver formation observed in many studies. Structural
alteration of the lipoprotein particle may affect apolipoprotein
conformation and thus its recognition and eventual catabolism by cell
This review clearly points to the need for more research with animal models
to unravel the mechanism(s) of manganese on lipid and lipoprotein metabolism
and with humans to determine the possible role of dietary manganese in the
development of atherosclerosis.
E. Carbohydrate Metabolism
Glucose utilization is impaired by Mn deficiency. Necropsy has revealed
gross abnormalities in the pancreas such as aplasia or marked hypoplasia of
all cellular components, so Mn may in some way be involved in insulin
formation or activity. Rats deficient in Mn had fewer insulin receptors per
cell compared to controls (Baly et al., 1990). Biosynthesis of glycoproteins
may be impaired in Mn-deficient animals. Prothrombin is a glycoprotein whose
synthesis has long been known to be controlled by vitamin K. Manganese is
also required, and a Mn deficiency reduces the vitamin K-induced clotting
response (Doisey, 1974).
The intracellular concentration of manganese can be one regulator of
carbohydrate metabolism, and therefore fluctuations in its concentration may
provide a mechanism of cellular metabolic control. Considerable evidence is
accumulating that manganese has a critical role in the regulation of both
pancreatic exocrine and endocrine function. Manganese deficiency in
experimental animals results in a diabetic-like glucose intolerance. This
may result in part from alterations in processes comprising glucose
homeostasis including pancreatic insulin synthesis, secretion and
degradation, as well as peripheral insulin action on target tissues.
Interestingly, diabetes itself may result in marked changes in manganese
metabolism. The functional significance of these changes is the subject of
debate. An excess of manganese can also affect insulin and carbohydrate
metabolism. These metabolic alterations may contribute to the pathological
consequences of manganese toxicity. While to date there is only a single
case report of a diabetic subject responding in a positive manner to
manganese supplements, the elucidation of manganese's role in signal
transduction pathways and transcription processes will without question
contribute to our understanding of the pathogenesis and potential treatment
of diabetes and other disease states involving alterations in manganese
F. Cell Function and Structure
Abnormalities in cell function and ultrastructure, particularly involving
the mitochondria, occur in Mn deficiency (Hurley and Keen, 1987). Manganese
deficiency caused alterations in cell membrane integrity in the liver,
pancreas, kidney, and heart in aged mice (Bell and Hurley, 1973).
G. Immune Function
Manganese plays a role in immunological function (Hurley and Keen, 1987).
Interaction of Mn with neutrophils and macrophages has been demonstrated,
possibly through interactions with the plasma membrane of cells employed in
the immune response (Rabinovitch and Destefano, 1973).
H. Brain Function - Epilepsy
Manganese deficiency or toxicity can affect brain function (Hurley, 1984).
Manganese-deficient rats, whether they are ataxic or not, are more
susceptible to convulsions (Hurley et al., 1963). Papavasiliou et al. (1979)
reported that humans with convulsive disorders, including epileptics, showed
whole blood Mn concentrations significantly below normal.
That a relationship exists between epilepsy and blood manganese
concentration has been repeatedly shown. While this relationship seems to be
independent of the anticonvulsant therapy used in epilepsy, the seizures
associated with the epilepsy apparently cause an increase in the manganese
concentrations in the liver. However, the evidence that seizure frequency is
responsible for the decreased blood concentrations of epileptics is not as
strong. Increased susceptibility to seizures of animals exposed to manganese
deficiency in utero combined with the lack of increased susceptibility to
seizures when the exposure to manganese deficiency begins postnatally
indicates that congenital effects of manganese deficiency are responsible
for the increased seizure susceptibility. The lower levels of manganese in
the blood and brain of the genetically epilepsy prone rat support a genetic
relationship between abnormal manganese metabolism and epilepsy. Glutamine
synthetase, the most obvious link between seizures and manganese, has been
compared between epileptic and normal animals, but at this writing no
differences have been found.
Other manganese dependent enzymes have been identified in the brain, and
some of these have also been associated with seizures. While it is still
possible that the lower blood manganese concentrations found in epileptics
are an epiphenomenon of seizure activity, the evidence for a genetic
relationship between the occurrence of seizures and abnormal manganese
metabolism is growing. These two hypotheses proposed to explain the
abnormalities in manganese metabolism found in epileptics are not mutually
exclusive, and it is possible that both are true. The validity of the
seizure frequency hypothesis by no means excludes a genetic relationship
between epilepsy and abnormal manganese metabolism. At the same time, the
existence of a genetic relationship between manganese and epilepsy does not
exclude an effect of seizure frequency on blood and tissue manganese
concentrations. Since we are as yet unable to assign cause and effect in
this relationship with any assurance, much work remains to be done to
identify the biochemical basis for the relationship.
I. Wound Healing
Wound healing in manganese-deficient rats was compared with wound healing in
control rats fed a complete diet. An acrylic cylinder wound-healing model
was used. Second generation deficient male and female animals were used for
the wound healing studies. Deficient animals had lower growth rates, lower
bone weights, and typical bone changes. The dry weights of wound healing
tissues were significantly lower in the manganese-deficient animals. The
total glycosaminoglycan levels of the manganese -deficient and control
animals were not different as indicated by uronic acid content. The
chondroitin-4-sulfate level was decreased significantly in the wound healing
tissue of manganese-deficient rats, but the levels of hyaluronic acid and
dermatan sulfate were not significantly different in the deficient and
control groups. The incorporation of 1-14C-glucosamine into
chondroitin-4-sulfate of the wound healing tissue was significantly
decreased in the manganese-deficient animals. From these observations, it
may be concluded that manganese is required for the synthesis of
chondroitin-4 -sulfate and that manganese is required for normal wound
Deficiency and Toxicity
Manganese deficiency has been produced in many species of animals, but not,
so far, in humans. Signs of manganese deficiency include impaired growth,
skeletal abnormalities, disturbed or depressed reproductive function, ataxia
of the newborn, and defects in lipid and carbohydrate metabolism.
Unequivocal evidence of manganese deficiency in humans has not so far been
reported, but a possible case of such deficiency was described by Doisy. A
man fed a semipurified formula diet found to be low in manganese (0.35
mg/day) lost weight and suffered depressed growth of hair and nails,
dermatitis and hypocholesterolemia, but responded to being fed a mixed
hospital diet; supplementation with manganese alone was not tried.
Another possible case of manganese deficiency in humans was reported by
Friedman et al. Men fed a diet containing only 0. 11 mg of manganese/day for
39 days exhibited decreased serum cholesterol and a fleeting dermatitis (miliaria
crystallina). Calcium, phosphorus and alkaline phosphatase activity in blood
increased. However, because short-term manganese supplementation (10 days)
did not reverse these changes, the suggestion that the syndrome was
attributable to manganese deprivation was not substantiated.
Other possible signs of manganese deprivation have been reported. A diabetic
patient who was not responsive to insulin injections responded to oral
manganese with decreased blood glucose concentrations. In addition,
wholeblood manganese concentrations have been reported to be low in patients
with certain types of epilepsy.
Manganese is often considered to be among the least toxic of the trace
elements when administered orally. Thus, reported cases of human toxicity
caused by oral ingestion of large amounts of manganese are few. The most
common form of manganese toxicity is the result of chronic inhalation of
large amounts of airborne manganese in mines, steel mills and some chemical
industries. The major signs of manganese toxicity in animals are depressed
growth, depressed appetite, impaired iron metabolism and altered brain
function. Signs of toxicity in Chilean manganese miners were first
manifested in the form of severe psychiatric abnormalities, including
hyperirritability, violent acts and hallucinations; these changes were
called manganic madness. As the disease progressed, there was a permanent
crippling neurological disorder of the extrapyramidal system with
morphological lesions similar to those of Parkinson disease.
Epidemiology of Deficiency and Toxicity
The natural incidence of effects attributable to abnormal manganese
nutrition is apparently exceedingly low. It has been suggested that the high
incidence of cartilage disorders in children in some geographical areas may
be the result of low intakes of manganese.
POPULATIONS WITH SUBOPTIMAL STATUS
Another type of model to study manganese deficiency is the use of human
populations reported to have suboptimal status of the mineral. This method
may be practical, as gross deficiencies of manganese have not been observed
among free-living humans. A number of disease states have been associated
with poor manganese nutriture. These include (patients with) epilepsy,'
exocrine pancreatic insufficiency, rheumatoid arthritis, hydralazine
syndrome,"' Mseleni joint disease, multiple sclerosis, senile cataracts,
osteoporosis, and those on chronic hemodialysis.
For example, two small studies in humans have been conducted that suggest a
link between manganese and osteoporosis. Strause and Saltman reported that
serum values of manganese in osteoporotic patients were 25% of those of
normal subjects. However, no information was given as to the number of
subjects or methods used, and values reported for serum manganese in the
control subjects (0.04 mg/L or 40 mcg/L) are much higher than those reported
by others (1 mcg/L).
Yet evidence that a relationship exists is seen in a pilot study by the
author. Twenty-three osteoporotic and healthy postmenopausal women matched
for age were tested for the presence or absence of osteoporosis by dual
photon absorptiometry. Bone mineral density and number of nontraumatic
fractures in the osteoporotic and control groups were 0.88 versus 1.29
g/Cm-sq. and 15 versus 0, p > 0.0001, respectively. Plasma levels of
manganese averaged 29% less in the osteoporotic women, compared to the
healthy controls. In addition, the response of the plasma to an oral load of
manganese was significantly greater in the osteoporotic versus the control
group, as indicated by areas under the curve. These data suggest that the
osteoporotic women in this study had an impairment of manganese absorption
Another population that may have poor manganese nutriture is epileptic
patients. Tanaka observed that 1/3 of children in a convulsive disorders
clinic had lower blood manganese than neurologically normal children.
Treatment of one child having a blood manganese level of 0.65 mcg/L with 20
mg Mn per day increased the level to 1.2 mcg/L and paralleled a reduction in
the number of seizures. In 52 humans treated for epilepsy, Papavasiliou et
al. observed a relationship between low whole blood and hair levels of
manganese and high seizure activity. Patients with the lowest levels of
whole blood manganese had the greatest frequency of seizures. In 44
epileptic patients treated for uncontrolled seizures, Carl et al. found that
mean whole blood levels of manganese were lower than that of a normal
population (0.84 versus 1. 19 mcg/L. But the most significant finding was
that the subjects who had epilepsy for unknown reasons had significantly
lower values of whole blood manganese (0.66 versus 0.94 mcg/L) than those
who had a history of trauma, which might have caused the epilepsy.
In children, models of a manganese deficiency might be found in those with
inborn errors of metabolism associated with poor manganese nutriture. These
include phenylketonuria (PKU), maple syrup urine disease, galactosemia, and
methylmalonic acidemia. Also, children with Perthes' disease, a disorder in
which there is abnormal growth with disproportionately small lower arms and
feet, have been found to have lower levels of blood manganese.
As new parameters to assess manganese nutriture are developed, the above
populations might be utilized to test the responsiveness of test parameters
to alterations in manganese status.
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