Zinc: an essential ally in cystic fibrosis

The essential role of zinc was demonstrated in the 1930s in animals, but it was not until 1961 that it was considered indispensable for human health by the discovery of a zinc deficiency in humans 1. Since then, interest in this nutrient has increased markedly 1. But what about the importance of zinc in cystic fibrosis?

Risk of zinc deficiency in people with cystic fibrosis

People with cystic fibrosis are at risk for zinc deficiency 2. Despite zinc intakes well above the recommendations 3, the prevalence of insufficient zinc nutritional status can reach 40% in children with fibrocystic fibrosis 4. Similarly, low plasma zinc concentrations have been reported in approximately 30% of infants with cystic fibrosis at the time of neonatal screening5. Note that there is currently no data on the nutritional status of zinc in adults with cystic fibrosis.

It is well known that the pancreatic insufficiency, which affects 85% of people with cystic fibrosis, causes maldigestion and malabsorption of lipids and fat-soluble vitamins (A, D, E and K) as well as significant steatorrhoea (loss of fat in the stool) 6. However, pancreatic insufficiency also leads to the malabsorption of minerals, including zinc 7.

Zinc is absorbed in the small intestine, mainly in the jejunum8. The maintenance of normal zinc nutritional status is based on the efficient intestinal absorption of dietary zinc combined with the reabsorption of zinc from digestive secretions 1. However, it has been suggested that children with cystic fibrosis have a reduction in the absorption of dietary zinc and a decrease in the reabsorption of zinc from digestive secretions 5. These alterations appear to be secondary to maldigestion, malabsorption, and steatorrhoea 5. However, these alterations seem to be only partially corrected by the supplementation of pancreatic enzymes, which is normally prescribed to fibrocystic patients with pancreatic insufficiency, which suggests the involvement of other factors independent of pancreatic involvement 4.

Clinical manifestations of deficiency have also been reported in fibrocystic children 9-10. Zinc deficiency can cause certain clinical symptoms including immune system disruption, susceptibility to infections, reduced taste and smell, growth retardation, diarrhea, and appetite loss 11-12. However, previous clinical manifestations lack specificity, and cystic fibrosis patients often present with similar symptoms that may be independent of zinc status 11. Thus, zinc deficiency cannot be diagnosed by the presence of these clinical signs alone. The measurement of plasma zinc therefore becomes an important diagnostic parameter.

Characteristics and functions of zinc

Zinc is a trace element, meaning it is a nutrient that is needed in small quantities to meet the body's needs. It is the second most abundant mineral in the body after iron 11, and the body of an adult contains about two grams 13. Zinc is essentially localized in cells 9. Over 85% is stored in bones and muscles while only 0.1% is stored in the bloodstream 8. Serum or plasma zinc is not the ideal marker for assessing zinc-11 nutritional status, as zinc may be decreased in the presence of infection, steroid use, trauma, as well as after eating a meal14-15. However, this method is currently the most used to determine the risk of zinc deficiency in the population 11.

Zinc is considered a type 2 nutrient, which means it is required for general and unspecific metabolic functions 14. In fact, it is involved in numerous enzymatic reactions, in protein synthesis and in the growth process 1. This last function also explains why this trace element has been particularly studied in children with cystic fibrosis, who are known to have suboptimal growth. Zinc is actively involved in maintaining immune function, fighting inflammation, and maintaining the defense system against oxidative stress 15. However, individuals suffering from cystic fibrosis present with repetitive infections, chronic inflammation and high oxidative stress.

Where is zinc found?

Zinc is found in many foods such as meats, some seafood, legumes, nuts, whole grain cereals, some fortified breakfast cereals, and dairy products 8-16. Oysters are the best source of zinc that can be found naturally in food 16. Zinc from animal sources is better absorbed in the body than plant-based zinc 1. This is because plants contain phytates, substances that chelate zinc in the small intestine and decrease its absorption 1.

Since zinc is an essential nutrient, it is not surprising to find that several vitamin and mineral supplements contain it in varying concentrations. With regard to cystic fibrosis, zinc is part of the formulation of so-called “specialized” multivitamins and minerals, which mainly provide fat-soluble vitamins (A, D, E, K) affected by malabsorption and whose daily dosage is usually two tablets per day. For example, an AquaDeks® tablet and a SourceCF® tablet contain 5 mg 17 and 15 mg 18 of zinc, respectively. The zinc content of multivitamin and mineral formulas intended for the general population and sometimes used in cystic fibrosis, such as Centrum forte®, is not negligible, as each tablet provides 7.5 mg of zinc 19.

Dietary zinc requirements for adults

As the exact prevalence of zinc deficiency is not known to date, the Cystic Fibrosis Foundation has not issued a specific recommendation regarding daily zinc intakes for people with cystic fibrosis 20. Although in the general population aged 18 and over, the recommended dietary intakes for zinc are 11 mg for men and 8 mg for women 8, the daily requirement for zinc in the presence of cystic fibrosis may be higher 20 because 1) its absorption is reduced and 2) its use by the body may be increased in response to certain complications associated with cystic fibrosis.

Currently, there is no consensus regarding the need for regular dosing or supplementation with zinc for cystic fibrosis patients 4. Zinc supplements are recommended only for those with persistent steatorrhea and insufficient weight gain despite taking pancreatic enzyme supplements 4. To shed light on the need to dose and supplement zinc, the team from the clinic for adult cystic fibro-cystic patients at the Centre Hospitalier Universitaire de Montréal (CHUM) has started the annual dosage of plasma zinc in all its patients since 2009. It turned out that several of them had insufficient zinc levels (results to be published later by the authors). The supplementation protocol was established as follows: in the presence of a plasma level below the reference level (9.2 µmol per liter), a 50 mg zinc gluconate tablet is prescribed daily for a period of three months. This is usually enough to normalize the serum level, which is checked by a blood test done at the end of this period; otherwise, the supplement is prescribed a second time for an additional three months.

Role of zinc in various complications associated with cystic fibrosis

• Zinc and vitamin A

Zinc influences multiple aspects of vitamin A nutritional status (absorption, metabolism, transport, and use) 21, which is generally compromised in patients with cystic fibrosis due to malabsorption. Zinc is required for the hepatic synthesis of retinol binding protein (RBP) 1. RBP is a protein synthesized by the liver that ensures the transport of vitamin A from the liver to target tissues 22. Zinc is required for the release of vitamin A and RBP from the liver into the bloodstream 1.

Zinc deficiency can reduce the synthesis of RBP in the liver, which leads to a decrease in plasma RBP concentration 21. Furthermore, zinc deficiency is commonly associated with low plasma vitamin A concentrations, even in the presence of normal liver vitamin A stores 23. As people with cystic fibrosis are at risk of vitamin A deficient nutritional status, it becomes difficult to discriminate whether vitamin A deficiency derives from malabsorption or is secondary to an underlying zinc deficiency. The measurement of plasma zinc can therefore prove to be an important discrimination tool.

• Zinc and lung function

The importance of zinc in the respiratory system has been particularly emphasized 15. Zinc is an integral part of the structure and function of numerous enzymes involved in lung function 7. It has been observed, in a cohort of children with cystic fibrosis, that a low serum zinc concentration was associated with a decreased forced vital capacity 11.

At the same time, lung function is frequently reduced in people with cystic fibrosis in the presence of inflammation 11. In addition, an inflammatory condition is known to reduce the plasma concentration of zinc 11. Since one of the functions of zinc is to maintain the immune system, a decrease in plasma zinc levels in individuals with reduced lung function could worsen infections and inflammation, resulting in a vicious circle 11.

Studies have shown that taking zinc supplements reduces lung infections in different populations 26-27. Nonetheless, the effectiveness of zinc supplementation has been poorly studied in people with cystic fibrosis 7. In sum, the relationship between plasma zinc and lung function deserves further investigation in cystic fibrosis11.

• Zinc and bone metabolism

The increase in life expectancy in people with cystic fibrosis has contributed to the emergence of multiple complications including osteopenia and osteoporosis 26. According to a recent meta-analysis, the prevalence of osteoporosis and osteopenia is estimated at approximately 23.5% and 38% respectively in adults with cystic fibrosis 26.

It has been suggested that zinc is an important mineral in bone metabolism 27. This nutrient stimulates bone formation and bone mineralization while inhibiting bone degradation 28. Zinc deficiency has been identified as a risk factor for osteoporosis 12. So far, there has been no study looking at the nutritional status of zinc in people with cystic fibrosis in connection with bone complications. However, dietary consumption of zinc may have a beneficial effect in the prevention of osteoporosis by increasing bone mass 28.

• Zinc and diabetes

Diabetes is a secondary complication of cystic fibrosis that appears especially in the early 20s 29. The prevalence of diabetes associated with cystic fibrosis increases with age and can reach more than 40% after the age of 30. Likewise, glucose intolerance is a condition frequently identified in cystic fibrosis 30.

On the one hand, zinc is involved in the metabolism of carbohydrates 31 and in the synthesis and action of insulin 31-32, this hormone secreted by the pancreas in order to regulate blood sugar levels. The literature reports that low plasma zinc concentrations are associated with increased diabetes prevalence in the general population 33. Zinc deficiency has been reported to be correlated with increased blood glucose 32.

On the other hand, oxidative stress contributes to the development and progression of diabetes and its complications 31. Zinc is involved in the structure of several antioxidant enzymes that help in the fight against free radicals 31, these unstable molecules capable of causing oxidative damage. Thus, a zinc deficiency would contribute to the increase in oxidative stress 31. Although there are no studies on diabetes and zinc in the cystic fibrocystic population, this mineral could prevent the development of diabetes by reducing blood glucose concentration, by acting on the secretion and/or action of insulin and by reducing oxidative stress 32.

• Zinc and liver damage

Around a third of patients with cystic fibrosis suffer from liver disease 34. The liver contains 1.8% zinc35 and zinc plays a central role in the regulation of zinc-12 nutritional status. Conversely, zinc is necessary for the liver to function properly 12. Consequently, liver diseases affect the body's zinc levels while zinc deficiency could contribute to the development of liver disorders 12.

Studies have shown that individuals with chronic liver disease or cirrhosis have decreased serum and liver zinc compared to healthy subjects 12. By the same token, some studies have reported that the reduction in plasma zinc has been inversely correlated with the degree of liver damage 12, that is, the greater the severity of liver damage, the lower the plasma zinc concentration. Although no similar research has been carried out in cystic fibrosis, this trace element could have a protective action against the evolution of liver damage 12.

Conclusion

In general, our knowledge of the importance of zinc in the regulation of several systems has increased considerably in recent years. Zinc is certainly a nutrient that should not be overlooked and that is essential in maintaining good health.

With regard to cystic fibrosis, although the nutritional status of zinc has been the subject of several studies in infants and children with fibrocystic fibrosis, no data on the zinc nutritional status of adults with cystic fibrosis and on its association with certain clinical parameters of interest are available in the literature. It is not impossible that zinc nutritional status may also be compromised in adults.

In addition, studies carried out in non-fibrocystic populations demonstrate that zinc plays a beneficial role in certain pathologies, such as diabetes, osteoporosis and liver damage, which are more prevalent in fibrocystic adults. Thus, research is essential in order to elucidate the role of zinc in people with cystic fibrosis of all ages in connection with certain complications associated with cystic fibrosis.

In the absence of specific guidelines or recommendations regarding recommended intakes, supplementation and zinc doses required to achieve a desirable serum level in people with cystic fibrosis, comprehensive nutritional management remains essential in order to improve the health status of people with cystic fibrosis.

Véronic Damphousse Dt.P. Master's candidate
Department of Nutrition University of Montreal

Marjolaine Mailhot M.Sc., D.T.P. Dietitian
Clinic for adults with cystic fibrosis Hospital Center
University of Montreal (CHUM)

Geneviève Mailhot Ph.D., Dt.P. Dietitian
Research center Hospital center
Université Sainte-Justine Department of Nutrition University of Montreal

Montreal (Quebec) Canada

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