General Medicine and Oral Medicine Review: Zinc Deficiency - A Forgotten Pandemic

Zinc deficiency (Header Image: Acrodermatitis enteropathica)

Zinc deficiency affects about 2.2 billion people around the world. It is a condition poorly understood and frequemtly neglected in clinical practice. It causes 450,000 deaths/annum in children under the age of 5yrs.

It may be either a qualitative or a quantitative deficiency, occuring in multiple formats in soil/plants/animals.  Serum zinc is not a reliable biomarker for zinc status in humans.

Zinc deficiency is related to poor dietary intake, inadequate absorption, increased loss, or increased use.

Dietary intake

• 25% of the world's population is at risk.
• Increasing the amount of zinc in the soil and thus in crops is an effective preventative measure.

Zinc plays an essential role in numerous biochemical pathways. It affects many organ systems, including:

• the skin
• gastrointestinal tract
• central nervous system
• immune system
• skeletal system
• reproductive systems

A lack of zinc thus has numerous manifestations, the most common of which are an increased rates of diarrhoea, pneumonia, and malaria.

Classification

Zinc deficiency can be classified:

• acute, e.g. in total parenteral nutrition
• chronic, e.g. dietary deficiency or inadequate absorption.
• mild, as typically accompanies dietary deficiency
• severe, as typically accompanies congenital defective absorption.

 

Signs and symptoms

 

Skin, nails and hair

Zinc deficiency may manifest as:

• Acne. Research suggests that people with acne have lower blood and skin levels of zinc. Taking zinc by mouth appears to help treat acne. However, applying zinc to the skin in an ointment does not seem to help treat acne uless used in combination with the antibiotic, erythromycin.

        https://www.nlm.nih.gov/medlineplus/druginfo/natural/982.html

• Eczema

https://www.mayoclinic.org/drugs-supplements/zinc/evidence/hrb-20060638

• xerosis (dry scaling skin)

 

 

• seborrheic dermatitis

 

 

• alopecia and

• Impared wound healing

 

 

Oral Cavity

Zinc deficiency can manifest as:

• non-specific oral ulceration

 

• stomatitits

 

• white tongue coating - (personal note: white coating may be removed by rinsing/brushing with tinned [not bottled] pineapple juice).

 

• angular cheilitis

 

• Geographic Tongue (Erythema Migrans)

Some pattents with Georgraphic Tongue have been found to be deficient in zinc and may benefot from zinc supplements if serum levels are found to be low.

Serum Zinc 9.2-20 μmol/L

Gibson J et al. Geographic tongue: the clinical response to zinc supplementation. J Trace Elem Experim Med 1990; 3:203-8.

 

 

• burning mouth syndrome (Oral Dysthesia)

Peripheral Neuropathy

Zinc has a protective effect against diabetes-induced peripheral nerve damage by stimulating metallothionein synthesis and downregulating oxidative stress. https://www.researchgate.net/publication/260683761_Zinc_Supplemen tation_Alleviates_Diabetic_Peripheral_Neuropathy_by_Inhibiting_Oxidative_Stress_and_Upregulating_Metallothionein_in_Peripheral_Nerves_of_Diabetic_Rats  The stimulation of meallothionein synthesis and down regulation of oxidative stress may also have a role to play in the management of oral dysthesia and burning mouth syndrome. 

Vision, smell and taste

Severe zinc deficiency may disturb the sense of smell and taste. Night blindness  may be a feature of severe zinc deficiency,however most reports of night blindness are associated with deficiency of vitamin A.

Immune system

 

Impaired immune function in people with zinc deficiency can lead to the development of respiratory, gastrointestinal, or other infections, e.g., pneumonia. The levels of inflammatory cytokines (e.g., IL-1β, IL-2, IL-6, and TNF-α) in blood plasma are affected by zinc deficiency. Zinc supplementation produces a dose-dependent response in the level of these cytokines. During inflammation, there is an increased cellular demand for zinc and impaired zinc homeostasis from zinc deficiency is associated with chronic inflammation.

Diarrhoea

Zinc deficiency contributes to an increased incidence and severity of diarrhoea especially in malnourished children.

Hunger

Zinc deficiency may lead to anorexia and anorexia nervosa. The use of zinc in the treatment of anorexia has been advocated since 1979 by Bakan. At least 15 clinical trials have shown that zinc improved weight gain in anorexia. A 1994 trial showed that zinc doubled the rate of body mass increase in the treatment of anorexia nervosa. Deficiency of other nutrients such as tyrosine, tryptophan and thiamine could contribute to this phenomenon of "malnutrition-induced malnutrition".

Cognitive function and hedonic tone

Cognitive functions, such as learning and hedonic tone, are impaired with zinc deficiency. Moderate and more severe zinc deficienies are associated with behavioral abnormalities, such as irritability, lethargy, and depression (e.g., involving anhedonia). Zinc supplementation produces a rapid and dramatic improvement in hedonic tone (i.e., general level of happiness or pleasure) under these circumstances. Zinc supplementation has been reported to improve symptoms of ADHD and depression.

Psychological disorders

Plasma zinc levels have been alleged to be associated with many psychological disorders. An increasing amount of evidence suggests that zinc deficiency could play a role in depression. Zinc may be an effective treatment.

Growth

Zinc deficiency in children can cause delayed growth and has been claimed to be the cause of stunted growth in one third of the world's population.

Pregnancy

Zinc deficiency during pregnancy can negatively affect mother and foetus. Animal studies indicate that maternal zinc deficiency can upset both the sequencing and efficiency of the birth process. An increased incidence of difficult and prolonged labor, hemorrhage, uterine dystocia and placental abruption has been documented in zinc deficient animals. These effects may be mediated by the defective functioning of estrogen via the estrogen receptor, which contains a zinc finger protein. A review of pregnancy outcomes in women with an inherited defect of zinc absorbtion, acrodermatitis enteropathica, reported that out of every seven pregnancies, there was one abortion and two malfunctions, suggesting the human fetus is also susceptible to the teratogenic effects of severe zinc deficiency. However, a review on zinc supplementation trials during pregnancy did not report a significant effect of zinc supplementation on neonatal survival.

Zinc deficiency can interfere with many metabolic processes when it occurs during infancy and childhood, a time of rapid growth and development when nutritional needs are high. Low maternal zinc status has been associated with less attention during the neonatal period and worse motor functioning. In some studies, supplementation has been associated with motor development in verylow birth weight infants and more vigorous and functional activity in infants and toddlers.

Testosterone production

Zinc is required to produce testosterone. Thus, zinc deficiency can lead to reduced circulating testosterone, hypogonadism and delayed puberty.

Prostatic Hypertrophy

The concentration of zinc in the prostate is higher than that in any other soft tissue in the body. Zinc levels in prostate adenocarcinoma are markedly lower than those in the surrounding normal prostate tissues. Several findings that link zinc with the suppression of prostate cancer cell growth and inhibition of prostate tumor cell invasion suggest that high intraprostatic zinc levels may protect against prostate carcinogenesis. However, results of other studies suggest that high intraprostatic zinc concentrations may adversely affect prostate cancer risk. For example, zinc enhances the activity of telomerase, an enzyme thought to be responsible for unlimited proliferation of tumor cells and whose activity is increased in prostate cancer. Zinc has also been found to antagonize the potential inhibitory effect of bisphosphonates on prostate tumor cell invasion.

https://jnci.oxfordjournals.org/content/95/13/1004.full

Causes of Zinc Deficiency

Dietary deficiency

A diet which is high in phytate containing whole grains, high in foods grown in zinc deficient soil, or high in processed foods containing little or no zinc can result in zinc deficiency. Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency.

In the U.S., the Recommended Dietary Allowance (RDA) is 8 mg/day for women and 11 mg/day for men.  Dietary Zinc is sourced from meat, beans, or nuts. The recommended intake per day of zinc is 15 mg for adults and children over the age of four.

Inadequate absorption

Acrodermatitis enteropathica is an inherited deficiency of the zinc carrier protein ZIP4 resulting in inadequate zinc absorption. It presents as growth retardation, severe diarrhea, hair loss, skin rash (most often around the genitalia and mouth) and opportunistic candidiasis and bacterial infections

Numerous small bowel diseases which cause destruction or malfunction of the gut mucosa enterocytes and generalized malabsorption are associated with zinc deficiency.

Increased loss

• Exercising,
• high alcohol intake
• diarrhoea
• Changes in intestinal tract absorbability and permeability due, in part, to viral, protozoal, or bacteria pathogens may also encourage fecal losses of zinc.

Increased utilisation

• Exercising
• Childhood growth
• Pregnancy

 

Chronic disease

The mechanism of zinc deficiency in some diseases has not been well defined; it may be multifactorial.

Wilson's disease, sickle cell disease, chronic kidney disease, chronic liver disease have all been associated with zinc deficiency.mIt can also occur after bariatric surgery, mercury exposure and tartrazine.

Although marginal zinc deficiency is often found in depression, low zinc levels could either be a cause or a consequence of mental disorders and their symptoms.

Mechanism

As biosystems are unable to store zinc, regular intake is necessary.

Zinc functions in the body in three areas:

• catalytic
• structural
• regulatory

Zinc is only common in its +2 oxidative state, where it typically coordinates with tetrahedral geometry. It is important in maintaining basic cellular functions such as DNA replication, RNA transcription, cell division and cell activations. However, having too much or too little zinc can cause these functions to be compromised.

In its catalytic role, zinc is a critical component of the catalytic site of hundreds of metalloenzymes. In its structural role, zinc coordinates with certain protein domains, facilitating protein folding and producing structures such as ‘zinc fingers’. In its regulatory role, zinc is involved in the regulation of nucleoproteins and the activity of various inflammatory cells. For example, zinc regulates the expression of metallothionein, which has multiple functions, such as intracellular zinc compartmentalisation and antioxidant function. Thus zinc deficiency results in disruption of hundreds of metabolic pathways, causing numerous clinical manifestations, including impaired growth and development, and disruption of reproductive and immune function.

Pra1 (pH regulated antigen 1) is a candida albicans protein that scavenges host zinc.

Prevention

Five interventional strategies can be used:

• Adding zinc to soil, (agronomic biofortification), increases crop yields and provides more dietary zinc.
• Adding zinc to food, (fortification).

• Adding zinc rich foods to diet. The foods with the highest concentration of zinc are proteins, especially animal meats, the highest being oysters. Per ounce, beef, pork, and lamb contain more zinc than fish. The dark meat of a chicken has more zinc than the light meat. Other good sources of zinc are nuts, whole grains, legumes, and yeast. Although whole grains and cereals are high in zinc, they also contain chelating phytates which bind zinc and reduce its bioavailability.[3]

• Oral repletion via tablets (e.g. zinc gluconate) or liquid (e.g. zinc acetate). Oral zinc supplementation in healthy infants more than six months old has been shown to reduce the duration of any subsequent diarrheal episodes by about 10 hours.
• Oral repletion via multivitamin/mineral supplements containing zinc gluconate, sulfate, or acetate. It is not clear whether one form is better than another. Zinc is also found in some cold lozenges, nasal sprays, and nasal gels.

Epidemiology

Severe zinc deficiency is rare, and is mainly seen in persons with acrodermatitis enteropathica, a severe defect in zinc absorption due to a congenital deficiency in the zinc carrier protein ZIP4 in the enterocyte. Mild zinc deficiency due to reduced dietary intake is common. Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency. Zinc deficiency is thought to be a leading cause of infant mortality.

Providing micronutrients, including zinc, to humans is one of the four solutions to major global problems identified in the Copenhagen Consensus from an international panel of economists.

History

Significant historical events related to zinc deficiency began in 1869 when zinc was first discovered to be essential to the growth of an organism (Aspergillus Niger). In 1929 Lutz measured zinc in numerous human tissues using the dithizone technique and estimated total body zinc in a 70 kg man to be 2.2 grams. Zinc was found to be essential to the growth of rats in 1933. In 1939 beriberi patients in China were noted to have decreased zinc levels in skin and nails. In 1940 zinc levels in a series of autopsies found it to be present in all tissues examined. In 1942 a study showed most zinc excretion was via the feces. In 1950 a normal serum zinc level was first defined, and found to be 17.3 - 22.1 micromoles/liter. In 1956 cirrhotic patients were found to have low serum zinc levels. In 1963 zinc was determined to be essential to human growth, three enzymes requiring zinc as a cofactor were described, and a report was published of a 21-year-old Iranian man with stunted growth, infantile genitalia, and anemia which were all reversed by zinc supplementation. In 1972 fifteen Iranian rejected army inductees with symptoms of zinc deficiency were reported: all responded to zinc. In 1973 the first case of acrodermatitis enteropathica due to severe zinc deficiency was described. In 1974 the National Academy of Sciences declared zinc to be an essential element for humans and established a recommended daily allowance. In 1978 the Food and Drug Administration required zinc to be in total parenteral nutrition fluids. In the 1990s there was increasing attention on the role of zinc deficiency in childhood morbidity and mortality in developing countries. In 2002 the zinc transporter protein ZIP4 was first identified as the mechanism for absorption of zinc in the gut across the basolateral membrane of the enterocyte. By 2014 over 300 zinc containing enzymes have been identified, as well as over 1000 zinc containing transcription factors.

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