CFDB - Cystic Fibrosis DataBase

Vitamin - mineral and other supplementation

A, E, K vitamins supplementation

Background

CF patients  with pancreatic insufficiency are at risk of fat-soluble vitamin deficiency, mainly  because of fat malabsorption  and it has been affirmed (Siwamogsatham O, 2014)  that, despite a near doubling of recorded fat-soluble vitamin supplementation over the past 5 years, there was no parallel increase in blood concentrations of these vitamins, probably because of suboptimal dosages, low adherence, or ongoing issues with malabsorption.

Vitamin A is a group of unsaturated nutritional organic compounds that includes retinolretinalretinoic acid, and several provitamin A carotenoids (most notably beta-carotene). 

 Vitamin A  is present in animal food sources and in  a lot of vegetables. Vitamin A deficiency mainly causes eye and skin troubles, is essential for respiratory, urinary and intestinal epithelia and vitamin A intake influences gut microbiota variations (Li L, 2017).  On the contrary, excessive vitamin A serum levels may determine respiratory, skeletal, and liver problems. Serum  concentration < 0.70 μmol/L (or 20 μg/dl) is defined as vitamin A deficiency. CF patients, above all those   with pancreatic insufficiency,  are at risk of fat-soluble vitamin deficiency, because of fat malabsorption, but also because chronic lung inflammation causes increased turnover of nutrient antioxidants, such as vitamin E and vitamin A. It has been hypothesized (Rivas-Crespo MF, 2013), that FEV1 of young CF patients correlates positively with vitamin A serum level, regardless of age, pancreatic function or nutritional condition. It has been affirmed (Siwamogsatham O, 2014) that, despite a near doubling of fat-soluble vitamin supplementation over the past 5 years, there was no parallel increase in blood concentrations of these vitamins, probably because of suboptimal dosages, low adherence, or ongoing issues with malabsorption. On the contrary, a more recent study (Woestenenk JW, 2015) has shown, on a large sample of children and adolescents, that, although CF patients failed to meet the CF-specific intake recommendations, serum retinol deficiency was found in only 17/862 (2%) of the measurements. Nutritional guidelines for CF usually prescribe vitamin A alone or in combination with other vitamins and it has been stressed that vitamin A supplementation should be individualized according to annual serum retinol measurements, because of both hyper- and hypovitaminosis can cause harm to the patient ( Turck D, 2016).

Vitamin E refers to a group of eight fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of natural vitamin E, of which γ-tocopherol can be found in corn oil, soybean oil, and margarine, and α-Tocopherol, the most biologically active form, can be found most abundantly in wheat germ oil, sunflower and other oilseeds.

Vit E deficiency may cause  peripheral neuropathy, eye problems, cognitive impairment and hemolytic anemia. Up to now, it has not been clarify whether to use plasma/serum a-tocopherol levels or serum a-tocopherol/cholesterol ratio as a biomarker for assessment of vitamin E status.

Even if Vitamin E is considered to have a important role in CF patients, above all  because of its antioxidant effect, a recent study (Woestenenk JW, 2015), about  long-term vitamin E intake and its  effects in paediatric CF patients during a 7-year follow-up period, demonstrated  that serum α-tocopherol deficiency was rare and  no evidence   there is that higher serum α-tocopherol levels  have  protective effects on  pulmonary function.

Even when administered at high doses, no adverse events have been demonstrated.

Nutritional therapeutic guidelines usually recommend vitamin E as sole supplement or in combination with other vitamins. Because bile acids are essential for absorption of vitamin E, patients with cholestasis will need to use a water-soluble preparation. ( Turck D, 2016). 

Vitamin K deficiency occurs in CF patients with pancreatic insufficiency, because of fat- malabsorption and, also,  because of long-term use of antibiotics, bowel  resection and probably ( Krzyzanowska P, 2017) liver dysfunction.

Vitamin K is an essential factor for blood coagulation (prothrombin, factors VII, IX, and X)  and bone metabolism (undercarboxylated osteocalcin and matrix Gla-protein). Therefore, vitamin  K deficiency may cause bleeding and reduced bone formation.

Vitamin K is present in green vegetables and is produced in human gut by bacteria. It can be administered orally or by intramuscular or intravenous injections. There are no routinely used biochemical indicators of vitamin K status. It can be evaluated by measuring serum concentrations of vitamin K, PIVKA-II (protein induced by vitamin K absence) and under carboxylated osteocalcin, but these markers are not usually measured in routine clinical practice due to cost. Prothrombin time can be measured but is insensitive, only becoming elevated in severe deficiency. In a study (Rana M, 2014) about  fat-soluble vitamin deficiency in Australian CF children, it was demonstrated that vitamin K deficiency  was present in 29% of patients  with a prevalence of prolonged prothrombin time of 22.62%. Vit K is deficient in all patients with CF-related liver disease (Krzyzanowska P, 2017) and the risk of developing vitamin K coagulopathy is higher in infants that are exclusively breast fed due to low vitamin K levels in breast milk ( Cottam ST, 2015).

Vitamin K toxicity seems not to be a concern, as there are no known adverse effects of supplementation.

Recently guidelines about vitamin K supplementation have been published ( Turck D, 2016).

 

Issues

Vitamin A supplementation efficacy in correcting low serum levels.

Short- and long-term beneficial effects of vitamin A therapy, including improvement of clinical and laboratory parameters possibly linked to oxidative stress condition.

Short- and long-term toxicity of vitamin A therapy.

Vitamin E supplementation efficacy in correcting low serum levels.

Short- and long-term beneficial effects of vitamin E therapy, also considering improvement of clinical and laboratory parameters linked to oxidative stress condition.

Vitamin K optimal dose and route of administration.

Vitamin K supplementation efficacy in correcting coagulopathy and bone mineral metabolism markers.

Short- and long-term beneficial effects of vitamin K therapy, including clinical outcome related to coagulopathy, bone mineral density, and quality of life.

Short- and long-term vitamin K therapy toxicity.

What is known

A Cochrane Review (de Vries JJV, 2018) didn't find any randomized or quasi-randimized controlled trials on retinoid supplementation, so no conclusions on the supplementation of vitamin A in people with CF can be drawn. Until further data are available, country- or region-specific guidelines regarding these practices should be followed.

A Cochrane Review, updated May 2014, did not find relevant randomized or quasi-randomized controlled trials comparing all preparations of oral vitamin A, at any dose and for any duration in children or adults with and without pancreatic insufficiency, compared with no supplementation. So, until further data will be available, it is suggested that guidelines on the use of vitamin A have to be followed.

Another Cochrane Review, updated Aug 2014, has synthesized existing knowledge of the effect of vitamin A together with other antioxidants therapies such as vitamin C, vitamin E, selenium and glutathione in cystic fibrosis lung disease. One quasi-randomized and nine randomized controlled studies were included, with a total of 436 participants. Results demonstrated that the beneficial effect of antioxidants is very difficult to assess in patients with chronic infection without a very large population sample and a long-term study period.

One Cochrane review, updated November 2010, on antioxidant role of vitamin E, together with vitamin A, vitamin C, and selenium, is available. Regarding vitamin E's role as antioxidant agent it has been pointed out only a significant increase in vitamin E levels after eight weeks of combined antioxidant oral supplement, whereas no evidence of clinical outcome improvement was found. No adverse events were observed.

One (Okebukola PO, 2014) updated March 2017, investigated the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders. According to the data from four studies with a total of 141 participants (two of these in children aged six months to 14.5 years) Vitamin E supplementation showed again to increase E levels, but no benefit of this therapy emerged.

One Cochrane Review, updated  August 2017, is available. Two trials for a total of 32 enrolled patients were included and both reported the restoration of normal serum levels of vitamin K and undercarboxylated osteocalcin after one month of daily supplementation with 1 mg of vitamin K. No associated adverse events were found. Until further evidence is available, the authors suggest to follow the current guidelines.

One interventional study has been competed to evaluate the effects on markers of inflammation, antioxidant levels and oxidative stress of a modified formulation of AquADEKs (AquADEKs-2), which contains standard amounts of fat-soluble vitamins (A, D, E, K) plus several antioxidants (different forms of vitamin E, coenzyme Q10, mixed carotenoids, zinc and selenium) (Sagel SD et al, 2018). The formula  was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation (NCT01859390).

 

 

Unresolved questions

VITAMIN A

Up to now, it is impossible to draw any conclusions on the efficacy and toxicity of regular administration of vitamin A.

VITAMIN E                                    

One phase 2 investigational trial is ongoing about the effect on vascular endothelial function at rest and during exercise of an antioxidant cocktail (Vitamin C, Vitamin E and Alpha Lipoic Acid) compared with BH4 (a cofactor for the production of nitric oxide, which is involved in vasodilation and improves systematic blood flow) NCT02690064.

VITAMIN K

Up to now, it is impossible to draw any conclusions on the efficacy and toxicity of regular administration of vitamin K.

Keywords: Malabsorption; Malnutrition; Nutrition Disorders; Vitamin A Deficiency; Vitamin deficiencies; Supplementation; Vitamins;