1. Iron deficiency

Iron is an essential compound of hemoglobin that is involved in the blood transport of oxygen from the lungs to tissues and organs.

Although the body has reserves in iron, a deficiency in iron supply through diet depletes these reserves resulting in anemia [2].

Anemia is due to the incapacity of the body, and specifically the bone marrow, to produce enough hemoglobin for red blood cells transport of oxygen, resulting in microcytic and hypochromic anemia.

• What Causes Iron Deficiency?

Blood Loss

Rapid blood loss through injury, surgery, or childbirth, significantly depletes iron reserves as new blood, and therefore, new hemoglobin is required to compensate for the blood loss.

Chronic blood loss can also be a result of nosebleeds, hemorrhoids, ulcers, menstruation, intestinal cancers.

It is estimated that iron deficiency anemia affects more than 1.2 billion individuals worldwide [3].

Enteropathies

Any alterations of the function of the intestines such as inflammation (Enteritis), can results in the malabsorption of nutrients, including iron.

• Iron Rich Food

To prevent iron deficiency, there are foods that are rich in iron including dark-green leafy vegetables, nuts and seeds, meat, fish, tofu, eggs, brown rice, and dried fruit. Dietary iron supplements are also commercially available.

2. Zinc deficiency

Zinc is an essential factor for many enzymatic reactions and is involved in the synthesis of nucleic acid synthesis (DNA and RNA).

It is also necessary for the growth and maintenance of healthy hair and skin.

Zinc deficiency results in slower growth and development of infants and children, loss of appetite, hair loss, loss of smell, altered immune response, and delayed wound healing.

• What Causes Zinc Deficiency?

In addition to dietary causes, alcoholism, exercise, and diarrhea have been associated with zinc deficiency.

It can also be caused by a rare hereditary disorder known as acrodermatitis enteropathica that affects the mucosal membrane of the intestine.

• Zinc Rich Food

To prevent zinc deficiency, there are foods that are rich in iron such as oysters, beef, lobster, pork, cereals, crab, chicken, pumpkin seeds, baked beans, dairy products (milk, yogurt, cheese), cashews, chickpeas, and oatmeal. Dietary zinc supplements are also commercially available.

3. Iodine deficiency

Iodine is essential for the synthesis of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), which are necessary for growth, cellular metabolism, and for the regulation of body temperature. 

Iodine deficiency results in reduced production of T3 and T4 resulting in a condition known as hypothyroidism characterized by an enlargement of the thyroid gland and the appearance of goiter.

Hypothyroidism leads to symptoms such as impaired mental function, hoarse voice, tiredness, dry skin, a gain of weight, aches, and intolerance to cold.

• What Causes Iodine Deficiency?

Insufficient Intake of Iodized Salt, veganism (e.g., no dairy products and eggs), pregnancy, living in regions that have low iodine soils can all contribute to iodine deficiency.

• Iodine Rich Food

To prevent iodine deficiency, there are foods that are rich in iodine such as seaweed, bread, cod, oysters, dairy products (milk, yogurt, and cheese), eggs, shrimps, and tuna.

4. Calcium deficiency

Calcium is essential for the contraction of muscles, the formation of bones and teeth, the regulation of cardiac rhythm, coagulation, neurotransmission, and several metabolic and enzymatic reactions.

The most known effect of calcium deficiency is osteoporosis associated with the reduction of bone strength.

• What Causes Calcium Deficiency?

Lactose intolerance individuals can result in decreased consumption of dairy products that are rich in calcium. In post-menopausal women, the decrease in estrogen level reduces the absorption of calcium and increases its mobilization from the bones and its elimination through urine.

• Calcium Rich Food

To prevent calcium deficiency, there are foods that are rich in calcium such as dairy products (milk, yogurt, cottage cheese, mozzarella), Tofu, soymilk, sardines, salmon, soybeans, spinach, turnip greens, kale, and beans 

5. Magnesium deficiency

Magnesium is necessary for the function of the nervous system and muscles and is involved in the production of energy (ATP).

It is also involved in the regulation of blood glucose, blood pressure, and the metabolism of calcium and potassium.

Deficiency in magnesium can lead to tiredness, loss of appetite, nausea, and vomiting.

A severe deficiency manifests with cramps, numbness, seizures, and cardiovascular symptoms. If intreated magnesium deficiency can cause hypocalcemia and chondrocalcinosis.

• What Causes Magnesium Deficiency?

Magnesium deficiency can be due to chronic alcoholism, gastrointestinal diseases (e.g., malabsorption), poorly controlled diabetes, and certain types of medications such as antibiotics, diuretics, chemotherapeutic agents, and proton-pump inhibitors [3].

• Magnesium Rich Food

To prevent magnesium deficiency, there are foods that are rich in magnesium including green leafy vegetables, such as spinach, nuts, seeds (chia and pumpkin seeds), legumes, and whole grains. Dietary magnesium supplements are also commercially available.

6. Selenium deficiency

Selenium is essential for the metabolism of thyroid hormones, DNA synthesis, protection from infection and oxidative damage (antioxidant), and for reproduction.

Selenium deficiency leads to the development of a viral disease in children and young women, known as Keshan disease, that is characterized by cardiomyopathy [4].

A combination between selenium deficiency and iodine deficiency can cause goiter and hypothyroidism.

• What Causes Selenium Deficiency?

Selenium deficiency mostly affects people living in selenium-deficient regions and people who are under kidney dialysis.

• Selenium Rich Food

To prevent selenium deficiency, there are foods that are rich in magnesium include such as Brazil nuts, organ meats, and seafood.

7. Fluoride deficiency

Fluoride is naturally found in the body as calcium fluoride and is required for new bone formation and for preventing teeth decay.

Fluoride deficiency can lead to tooth decay and fracture of bones.

• What Causes Fluoride Deficiency?

Although fluoride is sufficiently available through food products made with fluoridated tap water and fluoridated tap water, adequate intake of fluoride can reduce teeth decay (caries) and bone fractures.

• Fluoride Rich Food

Foods that are rich in fluoride include black tea, raisins, wine, fluoridated water, lamb, and carrots.

Conclusion

Iron, calcium, zinc, iodine, magnesium, selenium, and fluoride are essential for the function of the bones, muscles, heart, and brain. They are also involved in vital metabolic reactions as coenzymes. Any deficiency in one of these minerals can have severe health consequences such as diseases that affect both adults and developing embryos.

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I. How is Pyrophosphate Produced in the joints?

Chondrocytes are specialized cells that control the synthesis of cartilage, from collagen and proteoglycan, and its degradation by enzymes such as collagenase, cathepsins, and proteinases. They also produce inorganic pyrophosphate (PPi) that is used for the formation of calcium pyrophosphate crystals [1].

II. Causes of Chondrocalcinosis

1- Magnesium Deficiency

When there is an excess of calcium pyrophosphate production by the chondrocytes, enzymes including alkaline phosphatase (ALP) and inorganic pyrophosphatases, transform calcium pyrophosphate back into inorganic pyrophosphate.

However, the enzymatic activity of alkaline phosphatase (ALP) requires the presence of magnesium (Mg). Therefore, deficiency in Mg supply results in excessive production and accumulation of calcium pyrophosphate crystals that cannot be transformed into inorganic pyrophosphate (PPi) by alkaline phosphatase (ALP).

2- Post-Injury Arthritis

Although the mechanism is not known, a study that included 3350 arthroscopy samples found an association between chondrocalcinosis and post-traumatic degenerative changes in the meniscus of the knee [2].

3- Hypercalcemia

Hypercalcemia is the presence of calcium at a high level in the blood. It is mainly caused by alterations of the parathyroid function, cancer, vitamin D disorders, and high bone turnover (bone resorption and replacement).

Crystals that are generated in the joint during chondrocalcinosis are made from calcium and inorganic pyrophosphate (PPi) through a process known as nucleation. During hyperglycemia, there is an excess of calcium that increases the formation of calcium pyrophosphate.

4- Acromegaly

Acromegaly is a disorder that is associated with an increased release of growth hormone (GH) by the pituitary gland due to the presence of a tumor.  

Growth hormone (GH) is known to stimulate the activity of the insulin growth factor -1 (IGF-1) that limits the capacity of chondrocytes to produce inorganic pyrophosphate necessary for the formation of calcium pyrophosphate crystals.

Therefore, the increase of growth hormone (GH) by the pituitary gland tumor also increases the stimulation of IGF-1, and thus, should limit the activity of chondrocytes. However, due to the overstimulation of IGF-1, chondrocytes become insensitive and develop resistance to its inhibiting activity leading to excessive production of inorganic pyrophosphate (PPi) and calcium pyrophosphate crystals that accumulate in the joints.

Hypothyroidism

Hypothyroidism is a disorder characterized by a reduced production of the thyroid hormones thyroxine (T4), and triiodothyronine (T3), by the thyroid which is mainly due to iodine deficiency. Iodine is an essential component in the synthesis of T3 and T4. The most common disease associated with hypothyroidism is simple goiter.

Thyroid hormones are known to inhibit the proliferation of mature chondrocytes into hypertrophic chondrocytes that produce mineralized cartilage; however, during hypothyroidism, this inhibition is lifted as these hormones are not sufficiently produced resulting in excessive production of calcium pyrophosphate crystals in the joints.

Gitelman Syndrome

Gitelman Syndrome is a genetic disorder of the kidney characterized by low blood levels of magnesium, potassium, and chloride. The low availability of magnesium (Mg) results in magnesium deficiency leading to excessive production and accumulation of calcium pyrophosphate crystals that cannot be transformed into inorganic pyrophosphate (PPi) by alkaline phosphatase (ALP).

Wilson Disease

Gitelman Syndrome is a genetic disorder characterized by excessive accumulation of copper in the body resulting in neurological and liver anomalies.

Although the mechanism by which copper increases the production of calcium pyrophosphate crystals by chondrocytes is not well known, it was proposed that copper increases the expression of a growth factor known as transforming growth factor-beta 1 (TGFb1) that is involved in stimulating the production of inorganic pyrophosphate (PPi) by chondrocytes.

Another potential mechanism is the association between copper accumulation that excessively stimulates the expression of insulin growth factor -1 (IGF-1) leading to chondrocytes insensitivity to the inhibiting effect of insulin growth factor -1 (IGF-1).

Hemochromatosis

Hemochromatosis is a genetic disorder characterized by excessive intestinal absorption of iron and its accumulation in tissues and organs of the body.

Although the mechanism by which hemochromatosis promotes chondrocalcinosis is not known, it is possible that the accumulation of iron in the joints may promote the function of chondrocytes in producing calcium pyrophosphate crystals through anomalies in iron homeostasis [3].

Pseudogout

Pseudogout or calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by the deposition of calcium pyrophosphate crystals in the joints.

Although the cause is unknown, it is suggested that the cause may be related to the excessive breakdown of ATP (Adenosine triphosphate) into pyrophosphate which is secreted by the cells of the joints.

How is Chondrocalcinosis Diagnosed?

Chondrocalcinosis manifests with stiffness and inflammation of the joints. It is diagnosed through needle collection of synovial liquid to look for the presence of calcium pyrophosphate crystals. Imaging techniques include X-rays, CT (computerized tomography) scan, MRI (Magnetic resonance imaging), and ultrasound.

The diagnosis is also based on the coexistence of stiffness and inflammation of the joints together with diseases and metabolic disorders such as magnesium deficiency, hypothyroidism, acromegaly, Gitelman Syndrome, Wilson disease, and hypercalcemia.

How is Chondrocalcinosis Treated?

The treatment of chronic chondrocalcinosis appears to be irreversible due to the degeneration of the cartilage tissue. However, the treatment of temporary chondrocalcinosis requires treatment of its related causes. Symptoms such as pain and inflammation are treated using nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids.

Conclusion

Chondrocalcinosis appears to affect mainly and equally women and men over the age of 50; however, it can also affect individuals at a younger age, if associated with post-traumatic injury. Magnesium deficiency appears to be the main cause, and therefore, diet supplementation should help from chondrocalcinosis if there is no degeneration of the joint cartilage.

Although the cellular mechanisms of chondrocalcinosis are not well known, they appear to be associated with alterations in the function of chondrocytes and enzymes that ensure the homeostasis between inorganic pyrophosphate (PPi) production and calcium pyrophosphate crystals generation.

Finally, the stiffness and inflammation associated with chondrocalcinosis can be significantly debilitating for the affected individuals resulting in poor quality of life, and therefore, its early detection can considerably reduce its progression to irreversible degeneration of the cartilage.

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