Chromium Deficiency

Etiology

Current literature debates the classification of chromium as an essential trace element. This debate is partly because chromium is ubiquitous in typical human diets and is often a by-product of food processing, particularly secondary to contact with stainless steel components of machinery used in food processing or cooking in stainless steel cookware. The average American diet provides unintentional consumption of approximately 30 μg of chromium per day. This value is within the adequate intake range set by the Food and Nutrition Board of the National Academy of Sciences Institute of Medicine.[5] In addition, there are no documented deficiencies in healthy humans.[6]

However, clinical data suggest that older adults and individuals with acute metabolic disruptions due to severe trauma or infection (or both) are at risk for chromium deficiency. Acute infection has also been associated with decreased circulating chromium levels, which is believed to account for the hyperglycemia often observed in this setting. Furthermore, patients with impaired absorption, especially those with short bowel syndrome who are subsequently on parenteral nutrition lacking added chromium, are also at risk for this disease.[3]

Although urinary loss accounts for most chromium loss in patients with functional kidneys, prolonged continuous renal replacement therapy has not been associated with abnormal chromium levels.[3]

Epidemiology

Chromium deficiency has not been identified in healthy individuals following an oral diet. Less than 10 cases of chromium deficiency were reported several decades ago, and in these cases, individuals who developed glucose intolerance and insulin resistance while on total parenteral nutrition appeared to benefit from chromium supplementation. The healthcare providers administered 5 to 16 μg of intravenous chromium daily, considerably higher compared to the typical serum values of chromium in healthy individuals. This administration suggests that chromium supplementation may have a pharmacological role in treating glucose intolerance or insulin resistance. However, it may not have any role as an essential trace element in individuals consuming a typical balanced diet.[5] Importantly, the blood and urine concentrations of chromium were above normal in these cases where chromium concentrations were reported, even before the supplementation was initiated.[6]

Most scientific panels and experts currently maintain that there is no evidence of chromium deficiency in humans who consume a typical oral diet. A compounding factor for this lack of clinical cases is that the methods available for evaluating chromium levels are unreliable.[6]

Pathophysiology

Chromium Absorption

Only 0.4% to 2.5% of dietary chromium is absorbed from the small intestine.[3] This absorption occurs through passive diffusion and depends on the total body chromium concentration.[6] In serum, chromium binds to transferrin and albumin. At the tissue level, it is believed to undergo endocytosis.[2]

Chromium is primarily excreted in the urine, with normal levels ranging between 3 and 50 µg/d. Factors that increase urinary chromium loss include metabolic stress and glucose intolerance.[6] Biliary excretion through the small intestine can also occur, but most of the chromium in feces is from unabsorbed dietary chromium.[3][6]

Organic chromium compounds are better absorbed compared to inorganic forms. Factors that improve chromium absorption include simultaneous ascorbic acid supplementation, zinc deficiency, and iron deficiency.[6]

Postulated Physiological Function of Chromium

Older studies suggest that chromium enhances the effect of insulin on peripheral tissues by increasing the number of insulin receptors, insulin's internalization, and expression of glucose transporters, specifically GLUT1 and GLUT4.[3] However, recent analyses have shown numerous defects in the clinical research conducted to deduce these functions.[6]

The exact biological function of chromium is still unknown. The theoretical chromium-binding molecule or chromodulin involved in chromium-driven glucose metabolism has not been identified.[6]

In a published statement by the European Food Safety Authority (EFSA) titled "Scientific Opinion on Dietary Reference Values for Chromium," the panel concluded that the physicochemical properties of trivalent chromium do not support a catalytic role. However, the panel acknowledged that trivalent chromium may act as a cofactor, enhancing the interaction between insulin and its peripheral receptors by inducing a conformational change. Despite this potential role as a cofactor, the panel questioned the existence of the previously postulated chromium-binding molecule or chromodulin.[EFSA Journal 2014;12(10):3845] Finally, the EFSA panel concluded that the essentiality of chromium could not be supported and that setting reference values for recommended daily chromium intake is unwarranted.

History and Physical

The paucity of chromium deficiency cases and the unclear physiological function of chromium make it challenging to outline a clear clinical picture. Currently, no guidelines definitively outline the signs and symptoms associated with chromium deficiency.[2]

In healthy individuals, there is no evidence of any signs or symptoms that can be attributed to chromium deficiency.[EFSA Journal 2014;12(10):3845] The few reported cases of chromium deficiency consist of individuals receiving long-term total parenteral nutrition without added chromium supplementation. Some cases involved individuals with short gut syndrome. The only apparent clinical manifestation of chromium deficiency in these individuals was glucose intolerance with increasing insulin requirements to maintain euglycemia. Weight loss, peripheral neuropathy, and elevated plasma-free fatty acid concentrations were also noted in some individuals. These case reports noted a reversal of glucose intolerance in these patients when chromium was added to the total parenteral nutrition formulation.[3]

In current clinical practice, chromium deficiency is suspected in critically ill individuals who have unexplained glucose intolerance or escalating insulin requirements. Patients suspected of this disease should undergo a comprehensive clinical evaluation, including a detailed history, to determine the timing of metabolic derangements and to identify potential risk factors. Prior or current diagnoses of malnutrition, including anorexia nervosa and alcoholism, should be carefully noted. Procedural and trauma history should also be obtained. Severe trauma, extensive burns, and short bowel syndrome can all lead to decreased chromium absorption and increased demand for chromium due to the alterations in catabolic and anabolic processes. Patients who have had an extended hospital stay with prolonged dependence on total parenteral nutrition should also be assessed for any signs of this disease.[7]

Evaluation

Chromium deficiency can be directly assessed by measuring plasma concentrations of chromium. Current measures of serum chromium levels suggest a typical range between 1 and 5 µg/L. However, clinical studies have shown that serum chromium levels are poor markers for true chromium deficiency as they do not correlate with chromium stores found in the liver, spleen, bone, and soft tissues. There is also evidence that serum chromium levels may be reduced in acute illness even though total body stores of chromium are adequate.[3]

Urinary chromium levels have also been used in the past. Many original case reports identifying chromium deficiency used urinary chromium levels to assess these patients. However, urinary chromium levels are poor indicators of actual true chromium status. Similar to serum chromium sources, urinary sources only reflect recent dietary chromium intake and do not correlate with chromium tissue stores in the body.[3]

Another method of detecting chromium deficiency is measuring glucose tolerance after chromium administration. Although this method is an indirect measure of chromium deficiency, it is the most clinically useful and reliable method of detecting this disease.[3]

Given the limitations of laboratory testing, routine use of chromium levels or glucose tolerance testing for monitoring is not recommended. Even with critically ill patients on total parenteral nutrition, routine monitoring of chromium levels is not recommended. When chromium deficiency is suspected, glucose tolerance testing before and after chromium administration is the preferred testing method for this disease.[3]

Treatment / Management

Recommended Adequate Intake and Replacement Doses

According to the Food and Nutrition Board of the National Academy of Sciences Institute of Medicine, chromium's adequate intake value is 35 μg/d for men and 25 μg/d for women. The recommendation is based on the observation that more than 98% of the individuals meeting the adequate intake value of chromium have no evidence of chromium deficiency.[5]

Chromium supplementation is also recommended in enteral and parenteral nutrition. According to current guidelines, enteral nutrition should provide at least 35 µg/d of chromium. For parenteral nutrition, the recommended chromium intake ranges from 10 µg to a maximum of 15 µg per day. The guiding authorities acknowledge the controversy surrounding chromium supplementation, noting that these doses have been used safely and effectively for many years. In the absence of studies with lower doses of chromium in enteral and parental nutrition, continued supplementation at these levels is recommended.[3] 

When chromium deficiency is suspected based on insulin resistance, the recommended chromium supplementation dosage through parenteral nutrition solutions is 200 to 250 µg/d for 2 weeks. Insulin resistance should be reassessed after this 2-week trial. Alternatively, intravenous chromium supplementation may be provided in dosages between 3 to 20 µg/h through a 10-hour infusion for a maximum of 4 days. This recommendation is limited to critically ill individuals with insulin resistance. Generalization to patients with diabetes, obesity, and nondiabetic individuals is not recommended.[3] Single-element chromium additives for intravenous infusions are not readily available in most countries. Therefore, in most cases, multi-element solutions added to parenteral nutrition solutions are used.

Efficacy of Chromium Replacement

Importantly, all of the supplemented chromium in total parenteral nutrition solutions is introduced into the bloodstream. In healthy individuals on oral diets, only about 0.5% of chromium is absorbed into the bloodstream. With an average dietary intake of 30 μg/d, approximately 0.15 μg of chromium enters the bloodstream daily. In the original case studies identifying chromium deficiency, the total parenteral nutrition solutions provided more chromium compared to the average chromium-sufficient diet (where chromium concentrations were reported) even before treatment with additional chromium. Treating chromium deficiency in these patients involved providing chromium doses that were 100- to 1000-fold higher compared to what is typically obtained from a typical diet. This observation raises doubts about whether chromium deficiency alone was responsible for their symptoms and questions the essentiality of chromium for normal physiological functions. At best, these cases provide evidence for the pharmacological effects of high-level chromium supplementation in patients with altered glucose and carbohydrate metabolism.[5]

A counter-argument for this pharmacological effect of chromium supplementation in individuals with glucose intolerance is that approximately an equal number of patients did not respond to chromium supplementation compared to those who did.[5] A clinical trial assessing the effect of chromium supplementation on glucose tolerance in 5 acute-care patients who were started on total parenteral nutrition upon hospital admission reported a possible benefit in 2 patients and minimal or no benefit in 3 patients.[EFSA Journal 2014;12(10):3845]

Some authors suggest that this lack of efficacy may be due to ineffective dosing.[8] Animal studies have shown that insulin sensitivity increases in a dose-dependent manner with the addition of chromium to the diet in rats fed a severely low chromium diet (less than 20 µg/kg for 6 months). In these clinical trials, the daily doses utilized to achieve the beneficial effects of chromium supplementation in rodents ranged from 80 to 1000 μg/kg.[2](B3)

An added effect of chromium supplementation in critically ill patients with insulin resistance is decreased inflammatory markers. A recent meta-analysis assessing the anti-inflammatory effects of chromium supplementation found a significant overall reduction in high-sensitivity C-reactive protein and tumor necrosis factor-α levels with chromium supplementation. Notably, the clinical trials included in this meta-analysis were not restricted to critically ill patients. The analysis concluded that chromium administration decreases high-sensitivity C-reactive protein levels in individuals with type 2 diabetes, obesity, and women with polycystic ovarian syndrome. The most significant effect on high-sensitivity C-reactive protein levels was achieved when the chromium supplementation dose was less than 400 μg/d, and the duration was less than or equal to 12 weeks. The meta-analysis did not report any significant effect of chromium supplementation on interleukin-6 levels.[9] An essential limitation of this analysis is that it contained trials with a heterogeneous population and different metabolic processes. Generalization of these data without further clinical trials is not recommended.(A1)

Chromium Supplementation for the Management of Other Health Conditions

Chromium supplementation beyond adequate intake levels in patients without any evidence of chromium deficiency is not recommended. Chromium supplementation for managing hyperglycemia and dyslipidemia in patients without any evidence of chromium deficiency is not recommended. An exception can be made for critically ill individuals with severe insulin resistance and hyperglycemia. Importantly, this recommendation does not apply to all patients with diabetes. A therapeutic trial of high-dose chromium supplementation in critically ill individuals with insulin resistance should be limited to 4 days.[3]

Clinical data do not support the use of oral chromium supplementation to reduce the risk of diabetes and glucose intolerance in healthy or at-risk individuals. The American Diabetes Association states that there is insufficient data to support the use of chromium for glycemic control or to decrease the risk of diabetes in healthy individuals. The United States Food and Drug Administration states that the relationship between chromium supplementation and insulin resistance or type 2 diabetes is highly uncertain.[5] According to the United States National Institutes of Health (NIH) Chromium Factsheet, the clinical significance of slight improvement in glycemic control in patients with diabetes who were given chromium supplementation as adjuvant therapy is unclear.[NIH Chromium Factsheet]

Similarly, chromium supplementation does not appear to have any beneficial effect on body weight or serum lipids.[NIH Chromium Factsheet] The marketed benefit of chromium supplementation in reducing weight and increasing lean body mass is highly questionable. A 2013 Cochrane Review stated that the effect of chromium supplementation on lean body mass is of debatable clinical relevance. The conclusion of the study indicated that there was no reliable evidence to support the use of chromium supplementation in overweight or obese individuals.[10](A1)

The effect of chromium on other cardiovascular risk factors, such as hypertension, has also been studied. A 2021 meta-analysis comprising 11 randomized controlled trials noted a significant decrease in systolic and diastolic blood pressures in patients supplemented with chromium.[11] Further large-scale and well-designed studies are warranted to confirm these findings.(A1)

Differential Diagnosis

The differential diagnosis for chromium deficiency predominantly includes diseases predisposing patients to insulin resistance and glucose intolerance. Diagnoses to consider in individuals with symptoms consistent with chromium deficiency include:

• Obesity
• Metabolic syndrome
• Type 2 diabetes
• Lipodystrophy
• Glucocorticoid use
• Pregnancy
• Type A and type B insulin resistance [12]

New-onset diabetes is undoubtedly prominent on the list of possible diagnoses as it is a common cause of insulin resistance. Pancreatic issues, such as pancreatic obstruction or inherent dysfunction, may cause similar presentations. The most common causes of insulin resistance and poor glucose tolerance are obesity and metabolic syndrome, which must be ruled out before considering true chromium deficiency as the cause of these symptoms.

Prognosis

In the absence of relevant data, the prognosis for patients with chromium deficiency is considered highly favorable. Morbidity and mortality attributable to chromium deficiency have not been observed clinically nor described in the literature.[5]

Complications

Complications Associated with Chromium Deficiency

Healthy individuals do not directly exhibit any specific symptoms that can be attributed to low chromium intake.[13] Complications of chromium deficiency may be related to the downstream imbalances associated with hyperglycemia.

Chromium deficiency has also been linked to high-inflammatory status (high-sensitivity C-reactive protein levels) and a potential increase in cardiovascular complications.[3] However, no conclusive evidence has been reported directly linking these complications to chromium deficiency.

Clinical studies have shown an association between chromium deficiency and metabolic syndrome.[14] Most of these studies were small and had a heterogenic profile of individuals. Despite the measured correlation, a causative relationship has not been established. After reviewing currently available clinical data, the United States NIH declares that chromium supplementation does not benefit patients with metabolic syndrome.[NIH Chromium Factsheet]

Chromium deficiency has also been associated with neurocognitive disease. As insulin resistance is associated with pathological changes observed in Alzheimer disease, treatment of glucose intolerance in patients with mild cognitive impairment was postulated to reduce the risk of dementia. A 2010 placebo-controlled, double-blind trial evaluating the effect of chromium supplementation in older adults with mild cognitive impairment reported that chromium supplementation led to reduced semantic interference in learning, recognition of memory tasks, and recall. The conclusion of the study indicated that chromium supplementation enhances cognitive inhibitory control and cerebral function.[15] A 2018 Cochrane Review assessing the effect of vitamin and mineral supplementation in individuals with mild cognitive impairment stated that the quality of the data supporting chromium supplementation in these individuals was too low to draw any conclusions.[16]

Complications Associated with Trivalent Chromium Supplementation

Complications from trivalent chromium supplementation are rare. This rarity is likely because the energy required to oxidize trivalent chromium to the toxic forms is too high for biological systems.[EFSA Journal 2014;12(10):3845] Nevertheless, isolated cases of renal and hepatic failure with high-dose oral chromium supplementation, ranging from 600 to 2400 µg/d, have been reported.[3] Oral supplementation is less likely to cause toxicities as the element is poorly absorbed. Without many reported adverse effects, an upper limit of tolerable intake has not been established for trivalent chromium supplementation.[5] 

In adults, there are no reported cases of chromium toxicity with long-term total parenteral nutrition using recommended doses of chromium supplementation. The nephrotoxic effects of chromium may be more pronounced in pediatric populations, where an inverse correlation between serum chromium levels and renal function has been described. Current guidelines recommend foregoing chromium supplementation in parenteral nutrition given to children or significantly reducing the dose to mitigate this complication.[3]

Embryotoxicity from trivalent chromium supplementation has not been reported in humans. However, a recent study using in vitro fertilization to generate mouse embryos revealed direct embryotoxicity of trivalent chromium. These effects were most pronounced during the preimplantation period.[17]