Gastroenterology
Volume 137, Issue 5, Supplement , Pages S18-S28, November 2009

Chromium in Parenteral Nutrition: Too Little or Too Much?

  • Adib Moukarzel

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Adib Moukarzel, MD, Hotel Dieu De France Hospital, PO Box 16-6830, Achrafieh, Beirut, Lebanon. fax: (961) 615321

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Hotel Dieu De France Hospital, Saint Joseph University, Beirut, Lebanon; and SUNY Health Science Center Brooklyn, Brooklyn, New York

Received 1 June 2009; accepted 7 August 2009.

Article Outline

Although guidelines for routine parenteral supplements of chromium (Cr) were published, there remain major concerns about the infusion of excess Cr. In addition, little information is available on appropriate dosage for intravenous usage. Cr functions as a regulator of insulin action. In humans, the 3 reported cases of Cr deficiency developed peripheral neuropathy, weight loss, and hyperglycemia. Supplementation of Cr to the parenteral nutrition (PN) solution corrected these abnormalities. For parenteral Cr, concerns arise from the high levels found in sera (up to 40-fold higher) and tissues (10- to 100-fold higher) and their effects on kidneys: In 15 children receiving long-term PN, the glomerular filtration rate was lower than that of non-PN controls and was inversely correlated with Cr indices. Furthermore, in a randomized blinded prospective protocol involving 75 newborns, the group receiving the recommended dose of Cr showed higher levels of creatinine that were positively correlated with Cr intake. Of note, Cr contaminants in PN solutions can increase the amount delivered by 10%–100%. A possible method for estimating adequate Cr to be provided IV is to calculate the amount physiologically absorbed in healthy people. This amount is 10 to 100 times less than the daily recommended parenteral Cr in adults. The accumulated scientific data presented here point to a serious need to lower the recommended amount of parenteral Cr.

Abbreviations used in this paper: Cr, chromium, GFR, glomerular filtration rate, LMWcR, low-molecular-weight chromium-binding substance, PN, parenteral nutrition

 

In long-term unsupplemented patients, chromium (Cr) deficiency has been reported.1, 2 Although guidelines for routine parenteral supplements of Cr have been published,3 there remain major concerns about the infusion of excess Cr.4 In addition, little information is available on appropriate dosage for intravenous use.

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Function 

Cr is a transition element and exists in several valency states. The most oxidated state is hexavalent Cr, which is fairly unstable and potentially toxic in the body. It is the form of Cr associated with industrial exposure and toxicity.

Trivalent Cr is stable and the biologically active form. Trivalent Cr is found in foods and dietary supplements, and it also occurs in organic complexes with nicotinic acid. More than 50 years ago, Schwartz and Mertz extracted from pork kidney a compound they termed “glucose tolerance factor” that corrected hyperglycemia in Cr-depleted rats.5 Glucose tolerance factor is composed of one Cr molecule in the trivalent state, 2 niacin molecules, and 3 amino acids: glycine, cysteine, and glutamic acid. Trivalent Cr is believed to be an essential trace element. However, the evidence for Cr being essential is not definitive.6, 7 Arguments suggesting an essential role for Cr include the following.

1.Serum Cr level is high in newborns and declines in adults.8 In addition, there are significant age-related decreases in the Cr concentrations in hair, sweat, and urine.9, 10 If Cr were simply a contaminant, the amount of contamination in the body would increase with the duration of exposure.

2.Cr deficiency has been reported in adult women with massive bowel resection receiving parenteral nutrition (PN).1, 2, 11 All had glucose intolerance that was reversed by daily Cr supplementation in the PN solution.

3.Rats fed a low-Cr diet develop abnormal glucose tolerance.12

4.Cr absorption is inversely proportional to intake in humans.13 The fact that regulation of Cr absorption exists implies essentiality.

5.Hyperglycemia results in increased urinary Cr excretion.14, 15

6.Cr occurs as a component of metalloenzymes and functions as a coenzyme in various metabolic reactions.16 In addition, the molecule named chromodulin17 and the low-molecular-weight Cr-binding substance (LMWCr) explain at a molecular level the effect of Cr.18, 19

Absorption and Metabolism 

Ingested Cr is absorbed in the small bowel. Based on metabolic balance studies or on urinary excretion from physiologic intakes, estimates for Cr absorption range from 0.4% to 2.5%.13, 20, 21, 22, 23, 24

Cr is transported primarily in the blood bound to transferrin and albumin. It competes with iron for one of the binding sites on transferrin.25 Several studies have investigated possible interactions between iron and Cr. The excessive iron in hemochromatosis may interfere with Cr binding, thereby contributing to the diabetes associated with this condition.26, 27

Total body Cr concentration is the main homeostatic control of Cr gut absorption.13, 23, 24, 28, 29, 30 Dietary bioavailability of Cr is very low, and almost all of the ingested Cr is not absorbed and is excreted in the feces.24, 28 Most absorbed Cr is excreted rapidly in the urine.29

Metabolic Function 

Cr functions as a regulator of insulin action.30, 31, 32 In the presence of optimal levels of Cr, less insulin is required because Cr enhances the activity of insulin.33

Cr is important in promoting insulin action in peripheral tissues.34 In vitro Cr enhances insulin stimulation of glucose oxidation and lipogenesis in adipose tissue.35 In muscle, it increases insulin-induced glycogenesis. Insulin-stimulated amino acid transport is also positively influenced by Cr.34

Vincent has proposed a model for the enhancing effects of Cr on insulin activity17 (see Figure 1). The activation of the insulin receptor stimulates the movement of Cr into the cell. The intracellular Cr binds to a peptide to become the LMWCr. In proportion to its Cr content, the LMWCr activates the insulin receptor and enhances its activity. When the blood glucose level becomes normal and the insulin level decreases, the LMWCr is released from the cell and this terminates its effects.17, 18, 19 Furthermore, Cr may enhance insulin action by increasing the insulin-stimulated translocation of glucose transporters to the cell membrane.36 In addition, other mechanisms for the effect of Cr on insulin have been speculated.37, 38

  • View full-size image.
  • Figure 1. 

    A proposed model for the effect of Cr on insulin action. (1) The inactive form of the insulin receptor is converted to the active form by binding insulin. (2) Insulin receptor activation stimulates the movement of Cr into the cell. (3) Cr binds to a peptide known as Apo-LMWCr. (4) LMWCr binds to the insulin receptor and enhances its activity. (5) The ability of the LMWCr to activate the insulin receptor is dependent on its Cr content. Adapted from Vincent.19

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Deficiency and Toxicity 

Deficiency 

Cr deficiency in animals causes a syndrome of glucose intolerance similar to clinical diabetes. The abnormalities are corrected by giving Cr.

In humans, the first reported case of Cr deficiency was in a woman receiving PN without Cr supplementation for longer than 3 years.1 She developed peripheral neuropathy, weight loss, hyperglycemia, elevated plasma free fatty acid levels, a low respiratory quotient indicating impaired glucose utilization, and increased insulin requirements. Addition of 250 μg of Cr to the daily PN solution for 2 weeks corrected all these abnormalities. The other reported patients receiving PN responded similarly to Cr supplementation.2, 11 While the neuropathy and glucose intolerance may occur despite increased serum Cr levels, they still respond to Cr supplementation.39 Additionally, impaired glucose tolerance in malnourished infants may respond to an oral dose of Cr chloride.40

Because Cr appears to enhance the action of insulin and Cr deficiency has resulted in impaired glucose tolerance, Cr insufficiency has been hypothesized to be a contributing factor to the development of type 2 diabetes.41, 42, 43 However, Cr supplementation trials have not shown consistent benefit.17, 44, 45

Toxicity 

Ingested Cr 

The toxicity of Cr differs widely depending on the Cr valency. Selected Cr compounds (Cr VI, V, and VI), particularly hexavalent ones, are carcinogens, corrosives, and delayed contact sensitizers and have the kidney as their primary target organ. Exposure to Cr VI in dust is associated with an increased incidence of lung cancer and is known to cause dermatitis.

In contrast, there is little evidence that Cr III or trivalent Cr is toxic to humans. Because no adverse effects have been convincingly associated with excess intake of trivalent Cr from food or supplements, the Food and Nutrition Board of the Institute of Medicine did not set an upper level of safe intake for Cr; however, because information is limited, the Food and Nutrition Board acknowledged a potential for adverse effects of high intakes of supplemental trivalent Cr and advised caution.41

Ingested trivalent Cr has a low level of toxicity due partially to its very poor absorption.46 However, parenteral trivalent Cr may have a higher potential toxicity.

Most of the concerns regarding the long-term safety of ingested trivalent Cr arise from studies in cell culture, suggesting trivalent Cr, particularly in the form of Cr picolinate, increases DNA damage.47, 48, 49 Presently, there is no evidence that trivalent Cr increases DNA damage in living organisms,41 and a study in 10 women taking 400 μg/day of Cr as Cr picolinate found no evidence of increased oxidative damage to DNA as measured by antibodies to an oxidized DNA base.50 Several studies have demonstrated the safety of daily doses of up to 1000 μg of Cr for several months.51 In addition, Cr toxicity (at the usual dose) has not been observed in any of the human studies conducted in the past 30 years. However, there have been a few reports of serious adverse reactions to Cr picolinate. Of note, these are isolated cases involving a single subject in each case. Chronic renal failure was reported 5 months after a 6-week course of 600 μg/day of Cr in the form of Cr picolinate,52 and impaired liver function and renal failure were reported after the use of 1200–2400 μg/day of Cr in the form of Cr picolinate over a period of 4 months.53 Additionally, a 24-year-old healthy man developed reversible acute renal tubular necrosis after taking Cr picolinate supplements for 2 weeks.54

For those persons who wish to supplement their diet with Cr, the maximum upper level recommended is 10 mg/day. There appears to be no need to avoid the Cr picolinate form.

Parenteral Cr 

For parenteral Cr, concerns arise from the high levels found in sera and tissues and their effects on kidneys.55, 56, 57, 58 Leung evaluated serum Cr in patients on PN.55 Cr was found in high concentrations in up to 94% of the patients on short-term total PN. Approximately 50% had serum levels >10-fold of normal (upper reference value of 3.8 nmol/L), 18% were >20-fold, and 2% were >40-fold. The major Cr contaminant was detected in the amino acid component and was in the trivalent ionic form.

In another study evaluating somatopsychic responses and their relationship to Cr, every patient who received PN had an increased serum Cr level; some increases were up to 50-fold greater than the normal reference level for serum Cr.56 The investigators concluded that supplementation of Cr in PN solutions appears to be unnecessary for short-term PN because this metal is a known contaminant of these solutions. Efforts are required to find PN components with low or no Cr contamination.

In 1992, we studied children receiving less than the recommended daily parenteral intake of Cr. We found their serum Cr concentrations were 20 times higher than those in non-PN controls.4 This finding has been replicated in other subsequent studies.

In the United States, Mouser et al studied Cr concentrations in serum, urine, and PN solutions in pediatric patients receiving long-term PN.59 The mean baseline serum Cr concentration was 4.9 ± 1.9 μg/L (normal value, <0.3 μg/L); the urine Cr concentration ranged from 3.4 to 32.2 μg/L. The mean ± SD prescribed Cr dosage was 0.18 ± 0.05 μg·kg−1·day−1, and the dosage delivered in PN solutions was 0.41 ± 0.23 μg·kg−1·day−1. The investigators concluded that serum and urine Cr concentrations were abnormally high in infants and children receiving PN solutions supplemented with prescribed normal doses of this trace element, indicating significant Cr contamination of the PN components.

In France, Bougle et al found in 1993 that serum Cr values (18.2 ± 1.8 μg/L) were higher than control values (0.7–0.9 μg/L) in children receiving PN.60

Howard et al measured Cr levels in autopsy tissues (heart, skeletal muscle, liver, and kidney) of 8 patients with short-bowel syndrome who received home PN with the Food and Drug Administration–recommended trace element formulation for an average duration of 14 years.61 These tissue levels were compared with age-matched controls who died without chronic gastrointestinal disorders. Cr levels were 10- to 100-fold higher than normal concentrations in all tissues studied.

An early study pointing to Cr toxicity in children on PN was published in 1992.4 In 15 children receiving PN for a median duration of 9.5 years, the investigators assessed Cr intake, serum Cr concentrations, and renal function. The children's glomerular filtration rate (GFR) was lower than that of non-PN controls (70 vs 110 mL/min per 1.73 m2). The prescribed Cr intake averaged 0.15 μg/kg daily, but the serum Cr concentration was 20 (4 to 42) times higher than that of the controls (2.1 vs 0.10 μg/L; P < .0001). GFR was inversely correlated with the serum Cr concentration (P < .02), daily Cr intake (P < .01), cumulative parenteral Cr intake (P < .01), and PN duration (P < .05). The investigators discontinued Cr supplementation of PN solutions and reassessed the children 1 year later. The calculated Cr intake was 0.05 μg/kg daily (recommended Cr intake is 0.20 μg/kg).62 The serum Cr concentration was lower at this time than during Cr supplementation (mean, 0.50 μg/L; P < .001) and was less than 0.90 μg/L in all patients. Nevertheless, the mean concentration was still significantly higher than that of the controls (P < .01). The GFR did not change significantly (65 mL/min per 1.73 m2). No patient had signs of glucose intolerance or Cr deficiency. Although the patients were receiving less than the recommended Cr intake, their high serum concentrations suggested excessive intake. This study suggested excessive parenteral Cr might contribute to ongoing renal damage over time.

In another study from our group, we hypothesized that premature and newborn infants who have a low GFR at birth, compared with older children, would be at even greater risk for Cr toxicity.63 In a randomized, blinded, prospective protocol, we studied Cr intake and renal function in 75 premature and full-term newborns receiving PN for more than 2 weeks. They were randomly assigned to receive either no additional Cr (control group, n = 37) or the recommended dosage of 0.2 μg·kg−1·day−1 (Cr group, n = 38) in the PN solution. The 2 groups were not statistically different in regard to sex, birth weight, length, indications for PN, antibiotic or diuretic use, or daily weight gain. Surprisingly, there was a significant difference between the 2 groups in terms of caloric and carbohydrate intake during the first 2 weeks of PN. The control group tolerated more carbohydrate and had a higher calorie intake than the Cr group (P < .02). The Cr group showed higher levels of creatinine than the control group as early as the second week of PN, and this difference became significant at the fifth week (P < .03). There was a positive correlation between the creatinine level at the fifth week of PN and the Cr intake (P < .02). The Cr group required more days on PN than the control group (P < .04), and this difference became more evident for patients with birth weights higher than 750 g (P < .01). We concluded that newborns receiving the “recommended” amount of parenteral Cr exhibited not only higher serum creatinine values than infants receiving placebo but also tolerated fewer carbohydrates in the PN and required more days of PN. The clinical significance of our findings in terms of renal function is unknown at the present time, particularly the issue of reversibility. The better tolerance of carbohydrate shown by the control group makes us wonder about the real role of Cr in glucose metabolism in this population. Clearly, further studies are needed for the determination of the optimal dose of parenteral Cr. Of note, this is one of the prospective randomized studies that makes the data and conclusion of this report stronger in pediatrics than in adults.

Patients on long-term PN may receive ample Cr from that present as contaminants of PN fluids without supplementation. Cr content of PN solutions has been extensively studied. The amount of contamination varies widely and is different from one manufacturer to the next and different between lots from the same manufacturer.

In the study of Moukarzel et al, contaminating Cr concentrations were 1.0–1.8 μg/L in PN solutions and 0.9 μg/L in fat emulsions.4 All components of PN tested by Pluhator-Murton et al were contaminated with trace elements not intended to be present, and even the multi-trace element component contained trace elements either greater than or less than what the label claimed.64 In adults, the parenteral amounts of perfused Cr range from 2.4 to 8.1 μg/day for a high-glucose formula and 2.6 to 10.5 μg for a high-lipid formula.65 Mouser et al found the dosage delivered in PN solutions was 0.41 ± 0.23 μg·kg−1·day−1.59 It appears Cr contamination may be sufficient to result in the administration of amounts exceeding current recommendations.66

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Reliable Assessment 

Reliable methods to assess Cr status in humans are limited.

Plasma or Serum Cr Levels 

Plasma or serum Cr levels may not be good indices of Cr status, because blood Cr does not readily equilibrate with tissue Cr stores.67 Plasma Cr levels may be reduced in deficiency but are also reduced by acute illness.68

Cr is present in biological tissues and fluids in minute amounts, so sampling and measuring require meticulous collection. Additionally, making low analytical and reagent blanks is extremely difficult. This is why reported plasma Cr concentrations have declined from >3000 nmol/L in the 1950s to current levels of 2–3 nmol/L. Because plasma Cr is close to the detection limits for graphite furnace atomic absorption, this methodology is unlikely to be a viable clinical assessment technique.41

Furthermore, in patients receiving PN, plasma or serum levels may reflect the amount infused and not the tissue status. In addition, it is not known how long parenteral Cr supplements must be withheld to make the plasma or serum values interpretable.

Cr in Whole Blood or Red Blood Cells 

Cr concentration in red blood cells reflects exposure to hexavalent Cr only. Trivalent Cr cannot penetrate the red blood cell membrane69; thus, red blood cell concentration should not be used to assess trivalent Cr.

Urinary Cr Excretion 

There is some evidence that excess Cr is excreted in the urine and absorption efficiency of Cr in the gut increases with decreasing intake.13 Therefore, it was speculated that a Cr-deficient person might retain a larger fraction of an oral Cr load and excrete correspondingly less. However, urinary excretion of Cr reflects recent dietary Cr intake in a dose-dependent manner69, 70, 71, 72; thus, high urinary level may be a good indicator of exposure to excessive amounts but is not a useful predictor of Cr tissue status.14

Methods Using Glucose Load 

An approach to assessing Cr status might be the standardization of the urinary Cr response following an insulinogenic challenge, such as an oral load of glucose or of glucose plus fructose (for maximal stimulation) with urine collection before and during the 2-hour test.73 We know that young, supposedly Cr-adequate persons increase their Cr excretion following an oral load with simple carbohydrates and that the magnitude of that response is related to the insulinogenic property of the sugar.74 It is reasonable to expect that an individual who does not have adequate stores of biologically active Cr to interact with insulin and its receptors might excrete less of the element than a person with normal stores.

Blood Glucose and Insulin Concentration in Response to a Glucose Load 

There is only one human experiment in which glucose and insulin concentrations in response to a glucose load were monitored at baseline and during a period in which adults were fed low-Cr diets of 5 μg/1000 kcal.75 The glucose challenge test after subjects consumed low-Cr diets for 9 weeks showed a significant increase from baseline in sums of glucose and in glucose level at 90 minutes after the glucose load. Supplementation with 200 μg of Cr as CrCl3 for 5 weeks tended (P < .10) to reduce sums of glucose and insulin concentrations in these subjects. Although this study suggests a role for Cr in regulating blood glucose concentrations, further studies are needed.

Retrospective Evidence of Cr Deficiency 

At present, it appears that the only method for diagnosing Cr deficiency is demonstrating insulin resistance or an abnormal glucose clearance that improves after Cr supplementation76 and reappears after the supplement is withdrawn.73

Level of Cr in Human Tissues 

Reported concentrations of Cr in human tissues may be erroneous due to sampling and analytic problems. Contamination can occur through the needles, blenders, and knives.77 Furthermore, usual methods give Cr concentration of all the Cr valency states and not just trivalent Cr. However, the chemical form is critical; Cr is believed to be biologically active only in an organic form as part of the insulin receptor.16 No relationship has yet been shown between the Cr glucose tolerance factor and the tissue Cr content measured spectroscopically.

Nonetheless, some reliable data are available on normal concentrations of Cr in the livers and spleens of accident victims and infants with sudden infant death syndrome. The average liver Cr concentration in children was 8 (range, 5–15) μg/kg dry wt and spleen Cr concentration was 15 (range, 7–29) μg/kg dry wt.78 Cr can accumulate in kidneys and the heart. Elevated levels have been reported in these organs in Cr platers.77

Cr in Hair and Toenail 

Cr content in hair declines in situations likely to be associated with deficiency.9 However, Cr in hair can reflect metabolically incorporated Cr derived from contamination. A study on shampoos showed a great variability in the levels of Cr in samples from a hair pool.79 Toenail Cr content reflects Cr in several valency states, not necessarily trivalent Cr status.

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Recommendations for Cr Dosage in PN 

Guidelines for parenteral Cr requirements in adults4 and in pediatric patients72 are shown in Table 1. These guidelines should be considered approximations. Individual patient variation should be expected. Cr should be omitted in cases of renal dysfunction. The long-term use of multiple trace element products at recommended doses has been associated with excessive serum concentrations of Cr.4 In addition, many of the components of the PN formulation have been shown to be contaminated with Cr.64 Therefore, patients receiving long-term PN therapy are at risk for Cr toxicity and serum monitoring is necessary. The amount of Cr recommended has not been modified by recent expert opinion despite the high levels and potential toxicity described.80, 81, 82, 83, 84

Table 1. Cr Daily Requirements for PN
Preterm <3 kg (μg·kg−1·day−1)Term neonates 3–10 kg (μg·kg−1·day−1)Children 10–40 kg (μg·kg−1·day−1)Adolescents >40 kg (μg/day)Adults (μg/day)
Cr recommendationsa0.05–0.20.20.14–0.25–1510–15

NOTE. Assumes normal age-related organ function and normal losses.

aThe contamination level in various components of the PN formulation can significantly contribute to total intake. Serum concentrations should be monitored with long-term use.

In 1992, Moukarzel et al showed that the recommendations for Cr in children receiving long-term PN are excessive and inappropriate and recommended a daily dose of 0.05 μg/kg.4 More recently, Howard et al suggested decreasing the daily amount of Cr to 5–10 μg in adults.61

A possible method for estimating adequate Cr to be provided intravenously is to calculate the amount physiologically absorbed in healthy people. Traditionally, it was estimated that oral absorption of Cr varied between 10% and 20%. However, based on metabolic balance studies and on urinary excretion from physiologic intakes, newer estimates of Cr absorption range from 0.4% to 2.5%.41

Recently, the Food and Nutrition Board published the dietary recommended intake for Cr.41 Adequate intake for dietary Cr was set based on estimated mean intakes (Table 2). Adequate intake is the recommended average daily intake based on observed or experimentally determined intake by a group of apparently healthy people. This approach is used when a recommended dietary intake cannot be determined.

Table 2. Adequate Intake of Cra
Life stageAgeMale (μg/day)Female (μg/day)
Infants0–6mo
0.2

0.029 μg·kg−1·day−1

Infants7–12mo
5.5

0.611 μg·kg−1·day−1

Children1–3y11
Children4–8y15
Children9–13y2521
Adolescents14–18y3524
Adults19–50y3525
Adults51–70y3020
AdultsOlder than 70 y3020
Pregnancy14–18y—29
PregnancyOlder than 19 y—30
Breast-feeding14–18y—44
Breast-feedingOlder than 19 y—45

aBased on estimated mean oral intakes.

The Cr adequate intake is 35 μg/day and 25 μg/day for young men and women, respectively (Table 2). If the coefficient of absorption of oral Cr is 0.4%–2.5%, then absorbed Cr is 0.14–0.87 μg/day for men and 0.1–0.55 μg/day for women. This amount is 10 to 100 times less than the daily recommended parenteral Cr in adults.3 Table 3 shows the total Cr absorption calculated from adequate intake and an estimated absorption of oral Cr of 2%.

Table 3. Total Cr Absorptiona
Life stageAgeMale (μg/day)Female (μg/day)
Infants0–6mo
0.004

0.0006 μg·kg−1·day−1

Infants7–12mo
0.011

0.012 μg·kg−1·day−1

Children1–3y0.13
Children4–8y2
Children9–13y0.50.42
Adolescents14–18y0.70.48
Adults19–50y0.70.5
Adults51–70y0.60.4
AdultsOlder than 70 y0.60.4
Pregnancy14–18y—0.58
PregnancyOlder than 19 y—0.6
Breast-feeding14–18y—0.88
Breast-feedingOlder than 19 y—0.9

aCalculated from adequate intake and estimated absorption of oral Cr of 2%. The absorption of oral Cr is estimated to be 0.4%–2.5%. The real amount absorbed is probably less.

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Modifications for Special Populations 

Adults Ages 51 Years and Older 

Research is imperative on Cr needs for this age group because of the paucity of data. Several factors suggest that the elderly might be more vulnerable to Cr depletion than younger adults. These factors include the severely negative Cr balance produced by a high-fiber diet, the possible impacts of medications on Cr metabolism, the decrease with age of Cr concentrations in hair and sweat,9 and the increased prevalence of impaired glucose tolerance with aging.

Pregnancy 

There are several reports of Cr depletion in pregnancy and especially with multiple pregnancies. Tissue analyses indicate that Cr level is higher in tissues at birth and declines rapidly with age. This suggests the need for deposition of Cr in the fetus from the mother. The low concentration of Cr in human milk also indicates that the infant may use stored Cr during the early months of life.

Lactation 

Lactating women need increased amounts of Cr to replace the Cr secreted in human milk. Women do not appear to reduce urinary Cr excretion during lactation to compensate for these increased needs.

Metabolic Stress 

Cr levels are decreased in acute illness (burns, trauma patients). Acute infection appears to reduce the availability of circulating Cr, which may contribute to the altered glucose metabolism characteristic of acute infections even in the presence of elevated insulin levels and other hormonal changes.68

Renal Disease 

Individuals with preexisting renal disease may be at increased risk for Cr toxicity, and therefore Cr supplementation should be reduced or discontinued.41

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Summary Recommendations and Research Priorities 

Major challenges in Cr research remain, such as the following:

•Development of practical methods for diagnosing Cr deficiency

•Development and validation of a useful clinical indicator to identify persons with a marginal Cr status; this would substantially improve the scientific basis not only for Cr supplementation of individuals but also for public health needs

•Cr metabolism and requirements during special situations such as pregnancy, lactation, and advancing age

•Cr absorption in situations in which the subject is receiving PN but tolerates some oral food.

Until Cr status can be easily assessed, the recommendations will be imprecise and adjusting adequate Cr intake for each individual will be challenging. The accumulated scientific data presented here point to a serious need for a consensus conference on parenteral Cr, leading to a probable decrease in the amount parenterally recommended.

Finally, the concentrations of contaminating Cr in PN solutions seem to be high enough to prevent Cr deficiency. These contaminants can increase the amount delivered by 10%–100%. However, changes in purification methods for PN solutions could lead to insufficient concentrations of Cr. Cr contamination of PN solutions should be monitored as well as Cr intake and losses. Serum Cr concentrations and glycosylated hemoglobin should be measured regularly in patients receiving long-term PN.

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Question and Answer Session 

DR SHULMAN: That was a nice talk. One of the points you made at the end is one that worries me quite a bit, and that is that the range of contamination may be quite broad in the PN solution components; that is true for all the trace minerals we are discussing. By implication, if we are depending on contamination to supply adequate amounts of trace minerals, it becomes quite problematic in terms of really knowing what the patient is in fact getting. It raises the question of whether we need to monitor trace minerals in all patients and at what point do we start to do that, because that is a huge undertaking.

DR MOUKARZEL: This is a difficult question. I don't think that a few days of Cr supplementation will decrease the GFR, and therefore the Cr level may not need to be monitored. When we studied patients after 7–10 years of PN, we showed a decrease in GFR. For short-term PN, I think we should follow the current recommendation. If we give Cr for a short time, probably nothing will happen except in newborns. If the long-term patient develops glucose intolerance, Cr deficiency should be considered regardless of Cr level.

DR SHENKIN: First, I congratulate you on a superb talk. I have a comment and a question. I made a comment yesterday about manganese, and I think you have highlighted again the importance of Cr contamination both in terms of the solutions themselves and in terms of the assessment of plasma concentrations. You made the point about stainless-steel needles, and I'm struck by the range of so-called normal plasma concentrations in various reference laboratories. For the benefit of the audience, the upper range of a plasma concentration of Cr should not be more than 0.5 μg/L. If your reference laboratory is quoting anything more than that, then there is a problem in establishing the reference range or there is a problem in the methodology. So firstly, I want to see if you agree with 0.5 μg/L as the upper limit of normal. The second point relates to this issue about gut absorption of Cr. I think you have made again a very important point that absorption of Cr is very low and is lower than that of all of the other essential elements. The body is actively trying to keep Cr out by only letting in as much as 2.5%, which again seems to imply that Cr may be less important than we seem to think. I would like to explore further how necessary is it to add extra Cr because the body is trying so hard to keep it out.

DR MOUKARZEL: I agree with you that over time, the literature shows that the normal Cr level in serum and blood is decreasing progressively. It is decreasing because of mastering the meticulous collection and the sampling, mastering the purification method, and less contamination. Plasma Cr is close to the detection limits for graphite furnace atomic absorption. It is important to note that newborns have high amounts of Cr in their blood and tissues, and this decreases with age. Adults have lower Cr values than newborns. This would not happen if Cr were a contaminant.

DR SHULMAN: I think the question really is, if the requirement for Cr is so low, how likely is it that the contaminants in the solutions will meet these requirements? All the cases of so-called Cr deficiency were many, many years ago, and I wonder if this would still be the case now.

DR MOUKARZEL: There are, to my knowledge, 4 or 5 case reports mainly of women receiving PN for many years who have developed glucose intolerance and the physician thought it could be Cr deficiency. They received Cr, and their glucose intolerance decreased and their peripheral neuropathy went away. Is it certain that these patients really had Cr deficiency? I'm not sure.

DR HOWARD: I think this issue has to be brought out a little more. One of the questions that we are really facing is that we are seeing these high levels of Cr and yet there have been some cases of well-documented Cr deficiency. You have described at high levels of Cr what seems to be Cr toxicity. Could Cr toxicity induce a clinical picture that looks like Cr deficiency? We have examples of this in the micronutrient area, and the one that comes to mind is pyridoxine; with very large amounts of pyridoxine, a peripheral neuropathy can be induced. In other words, there can be doses that appear to block the appropriate receptors and actually block the proper function of the nutrients. We are left with a difficult situation that we do not understand, but at this point it seems we should not be giving the levels we currently are giving. I will be very interested in Dr Jeejeebhoy's comments because he had a central role in describing Cr deficiency. His patient developed symptoms of glucose intolerance and weight loss and these symptoms responded to Cr supplementation, so we have a hard conundrum.

DR MOUKARZEL: There are 2 points I would like to make. First of all, these cases are few and far between, but they keep cropping up. As a matter of fact, there is a recent report of a patient in the intensive care unit who had very high levels of glucose and large doses of insulin were required for management until the patient received Cr. The real problem with Cr is that it decreases with age, and some older people slowly get more and more glucose intolerant. There is a study suggesting that giving glucose tolerance factor, in the form of yeast, is associated with an improvement in glucose tolerance in elderly people. I think the pediatric population should not receive Cr. The focus should be on older people, especially those who are glucose intolerant or frankly diabetic. We should remember glucose intolerance increases Cr losses. A constant drive of hypertonic dextrose is going to deplete Cr reserves.

In terms of the plasma Cr levels, we do not know how much of the Cr is hexavalent or trivalent. Because we live with mounting industrial waste, we are living in an environment where hexavalent Cr is plentiful. So when we measure total Cr, I don't think we know what we are measuring. Remember hexavalent Cr is potentially poisonous. I do think the wise recommendation is that patients on PN, whether supplementing with Cr or not, should be monitored; if they develop unexplained glucose intolerance, then I believe consideration should be given to Cr supplementation.

DR SHIKE: I think, given the uncertainty and the potential for damage, we should use a very simple functional test for Cr deficiency, and that is the glucose level or glucose tolerance test. As a practical approach, those patients who tolerate glucose well should not get Cr. Those who have unexplained high levels of glucose can get a trial of Cr. In the absence of good knowledge of PN requirements, we estimate the amounts we give based on the intake in the general population and fractional absorption, which for Cr is about 2%. We need to remember that parenteral feeding is via the systemic rather than the portal circulation. Thus, the kidney sees a higher amount, which could increase the risk of nephrotoxicity.

DR DELEGGE: Because we think high Cr levels cause renal toxicity and we know Dr Howard's autopsy studies showed high levels of tissue Cr, could Cr be causing the slowly worsening renal function seen in many of our long-term patients or even in short-term neonatal patients?

DR BUCHMAN: A study that we published in 2001 in a rat model on PN looked at the trace mineral content of the major organs. In the kidney, there was significant Cr deposition. We also found renal tubular damage; however, we were not able to separate the tubules from the glomerulae to determine whether the Cr specifically deposited in the tubules. In view of your data on the decreasing GFR that is associated with not only the Cr level but the cumulative Cr dose, do you think the nephropathy that has been described in patients on long-term PN could be related at least in part to Cr excess and do you think such deposition is reversible?

DR MOUKARZEL: I think PN renal impairment could be partially related to Cr toxicity. The most relevant study is our prospective randomized study in newborns, in which we fed PN solutions with either very low or standard Cr. The creatinine level after 5 weeks of PN was higher in the infants receiving Cr. This strongly suggests that Cr has some toxic effect on the kidney. In children receiving PN on a long-term basis, we also showed the GFR was decreased in infants receiving standard Cr. The GFR did not improve 1 year after Cr PN was discontinued, so this toxicity might be irreversible.

DR BUCHMAN: Would you recommend that we discontinue Cr supplementation from all PN and simply follow glucose concentrations over time or glucose tolerance tests?

DR MOUKARZEL: I think currently the Cr contaminant in PN is high, so this is a problem. In 1992, we stopped Cr supplementation in patients on PN and, so far as I know, we have not seen any patients with Cr-related glucose intolerance. Obviously there is a need for a new recommendation. We should probably stop adding Cr to PN, assuming that there is enough Cr contamination in the PN components. We must be careful to monitor these patients for glucose intolerance and/or neuropathy.

DR BUCHMAN: Dr Seidner, you have been a proponent of adding Cr to PN solutions. Did you want to make a comment or have a question?

DR SEIDNER: I want to make a comment, and then I have a question. I have cared for a number of anecdotal cases in which individuals were hyperglycemic and insulin resistant and responded to Cr supplementation; such individuals often had severe diarrhea. Some of these patients had graft-versus-host disease and had low serum levels of Cr. With supplementation, the patients improved and their insulin requirements were diminished, so I concur with your recommendation to individualize therapy.

I don't know if I can agree with taking Cr out of everyone's PN. How are we going to measure whether the solutions we are giving are contaminated? I think we are going to have to decide on a dose and just monitor the patient's level.

DR JEEJEEBHOY: I think what Dr Seidner has pointed out is important; that is, there are a lot of physicians who have had patients who developed glucose intolerance who responded to Cr. These single case experiences are not published, but a lot of people have had this experience, so it is not so rare. It would be interesting to poll physicians managing PN and ask them how many patients they have had with unexplained glucose intolerance. There are also patients on home PN who have been constantly on insulin for reasons that are unknown. I think these people ought to be looked at too.

Finally, we must recognize that patients who have never been on PN but have short bowels develop significant renal disease because of hyperoxaluria and dehydration. Thus, short-bowel patients with renal disease cannot be ascribed to Cr alone.

DR VANEK (Youngstown, OH): Your Cr recommendations were different between short-term and long-term PN. You said that Cr would not be harmful if you gave it for 1 day, 2 days, or 3 days, yet at 7–10 years there is renal failure or renal compromise that you attribute to Cr. That is a broad range of times. Where is your cutoff between short-term PN and long-term PN?

DR MOUKARZEL: That is a difficult question. In the study we conducted in children and adults, it was after an average of 9 years of PN that we saw the decrease in GFR. In our study in newborns and infants, who are more susceptible to toxicity, 5 weeks were enough to show a difference in the creatinine level between the Cr supplemented group and the nonsupplemented group. Therefore, long-term means a few weeks to many years depending on age. The question is whether we need to give them Cr in short-term PN. I think it is unnecessary.

DR WESLEY (Children's Memorial Hospital, Chicago, IL): This is a well-presented and excellent research workshop, and I thank you for the obvious work and homework that went into this event. I am reminded by Dr Vanek's comment that most of the heavy metals are accumulated in the fetus during the third trimester. We know quite a lot about iron and zinc, but we know very little about other heavy metals. I would agree with a lot of the comments that have been made with respect to the timing of the administration of Cr. It might be appropriate in profound prematurity to boost the stores for a few days and then stop.

I am putting on my commercial and industry hat for a moment. There are a number of commercial supplements that include Cr, and a number of institutions will give a multiple trace element solution like MTE-5, just as a matter of course. We might aim toward a consensus conference in the near future and invite our industrial colleagues to take part so we can translate new recommendations for Cr and other elements that we have discussed in this conference and shorten the time from the consensus process to the actual provision of commercially available mixtures.

DR LIPMAN (Washington, DC): I have 2 questions, one for the panel and the second for Dr Shenkin. First, is there a nephropathy associated with long-term PN? As a gastroenterologist, I focus on the liver disease, but I do not recall ever hearing about long-term nephropathy. My second question is, biochemically or in the laboratory, can we differentiate trivalent versus hexavalent Cr in the parenteral solution, blood, or tissues so we know what we're dealing with?

DR BUCHMAN: I'll answer the first part of the question. Nephropathy associated with PN was identified in children by Dr Moukarzel in 1993 and in adults by myself and the rest of our group in 1994. We found that in children, there was a correlation between a reduced creatinine clearance, the amount of amino acids received, and the Cr doses. A large part of the decline could not be identified. Subsequent to that, a group in Lyon, France, found several years ago in adults that despite normal blood creatinine level, these patients, as Dr Jeejeebhoy pointed out, develop chronic dehydration; that seemed to explain a large part of the decrease in GFR, although still we do not have a complete understanding. Oxalates may also contribute even in the absence of nephrolithiasis.

DR SHENKIN: Certainly there are methods for distinguishing between trivalent and hexavalent Cr. It is very difficult to do and certainly difficult to do in routine laboratory testing. I think it is a nuclear magnetic resonance technology that is being used, and the important point is that hexavalent Cr is highly reactive and almost instantly becomes part of biological systems. It is also reduced very rapidly to trivalent Cr. Although hexavalent Cr may well be part of the solution, as soon as it is infused into the body, studies have indicated it is largely converted to trivalent Cr. Part of the toxicity of hexavalent Cr is its extremely high reactivity and high oxidative potential. Having said that, we do not know, as Dr Jeejeebhoy has pointed out, how much of this conversion takes place, where it takes place, what damage it does while it is taking place, and in particular what the form of Cr is in the tissues. We could try to find out the answers to your question, but I don't think it would necessarily help us to decide on whether to give extra Cr to patients who are receiving these contaminants.

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 Conflicts of interest The author discloses no conflicts.

 Funding Supported in part by Saint Joseph University Research Foundation, Beirut, Lebanon.

PII: S0016-5085(09)01507-8

doi:10.1053/j.gastro.2009.08.048

Gastroenterology
Volume 137, Issue 5, Supplement , Pages S18-S28, November 2009

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