Refeeding and metabolic syndromes: two sides of the same coin

Refeeding syndrome describes the metabolic and clinical changes attributed to aggressive rehabilitation of malnourished subjects. The metabolic changes of refeeding are related to hypophosphatemia, hypokalemia, hypomagnesemia, sodium retention and hyperglycemia, and these are believed to be mainly the result of increased insulin secretion following high carbohydrate intake. In the past few decades, increased consumption of processed food (refined cereals, oils, sugar and sweeteners, and so on) lowered the intake of several macrominerals (mainly phosphorus, potassium and magnesium). This seems to have compromised the postprandial status of these macrominerals, in a manner that mimics low grade refeeding syndrome status. At the pathophysiological level, this condition favored the development of the different components of the metabolic syndrome. Thus, it is reasonable to postulate that metabolic syndrome is the result of long term exposure to a mild refeeding syndrome.Refeeding syndrome represents a group of metabolic and clinical changes that occur in severely malnourished patients undergoing aggressive nutritional support.¹ Metabolic changes include: hypophosphatemia, hypokalemia, hypomagnesemia, sodium retention and hyperglycemia.² Although clinical changes cover most organ systems, including cardiovascular, gastrointestinal, musculoskeletal, respiratory, neurological and hematological abnormalities, these changes are the outcome of the metabolic changes in a scale that is synergistically related to the degree of the metabolic changes, in which under severe conditions multiple organ failure may occur leading to death.¹ On the other hand, metabolic syndrome is a name for a group of risk factors that occur together, increasing the risk for coronary artery disease, stroke and type 2 diabetes. These factors are: central obesity, high triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure and raised blood glucose.³ Classification according to the US National Cholesterol Education Program Adult Treatment Panel III requires the presence of at least three of the above factors.³The pathophysiology of refeeding syndrome is related to the fact that under conditions of starvation, the body shifts from carbohydrate to fat and protein utilization (state of catabolism) to produce glucose and energy.² Therefore malnutrition, which usually exists in different disease states including cancer, Marasmus/Kwashiorkor, neurological problems, respiratory diseases, gastrointestinal and liver diseases, and so on,^{2, 4} is the major risk factor for refeeding syndrome.^{2, 4} Upon refeeding, especially with carbohydrate, the body shifts back instantaneously to carbohydrate metabolism (state of anabolism).² Concomitantly, insulin secretion is increased leading to an increase in the cellular uptake of glucose and macrominerals (in particular phosphorus, potassium and magnesium) mainly occurring in the liver and muscles, and thus resulting in hypophosphatemia, hypomagnesaemia and hypokalemia.² Simultaneously, insulin resistance prevails as indicated by the coexistence of hyperglycemiam and hyperinsulinemia,^{1, 2, 4} which reduces sodium clearance leading to sodium retention and thus resulting in fluid retention and expansion of the extracellular fluid volume.^{1, 2} Thus, the clinical manifestations of these macromineral abnormalities have serious deleterious effects, some of which are hypotension, bradycardia, weakness, heart failure and arrhythmias.⁴ In brief, refeeding syndrome is the consequence of the ingestion of a high carbodydrate–low macrominerals diet following prolonged fasting.In normal subjects and under normal conditions, energy metabolism is known to fluctuate diurnally, as meal ingestion causes a shift to carbohydrate metabolism and an increase in both energy expenditure and carbohydrate oxidation.⁵ Meal ingestion ensues an increase in cellular uptake and utilization of glucose and macrominerals (predominantly phosphorus, potassium and magnesium), as a result of increased insulin secretion and demand for metabolic processes (for example, phosphorylation and so on). Therefore, plasma status of these macrominerals depends on insulin secretion (that is highly dependent on carbohydrate intake) and their meal content of marominerals. Ingestion of pure glucose is known to be associated with a reduction in plasma concentration of these macrominerals and their inclusion in a meal was reported to improve their status.⁶ Thus, it is reasonable to postulate that under normal conditions the postprandial metabolic changes following the ingestion of high carbohydrate–low macrominerals diet resemble those of the refeeding syndrome but to a lower extent. Hence, what remains to be elucidated is whether the dietary changes that have occurred in the past few decades favored the consumption of high carbohydrate–low macrominerals diets and thus have exacerbated these metabolic changes.Evidence from epidemiological studies reveal that the increased prevalence of the ‘Western diet'' is implicated in the increased prevalence of obesity, diabetes and hypertension, observed in Africa, Asia, South America, Australia/New Zealand and Oceania.^{7, 8, 9, 10} Western diet is characterized by the consumption of refined (cereals) carbohydrates, sugars, sweeteners (especially high fructose corn syrup), oils and fats.^{7, 8} The implication of the Western diet has further been proposed to promote the incidence of insulin resistance¹¹ and metabolic syndrome.¹² Furthermore, the increased intake of fructose-based sweeteners has been also reported to be associated with the development of metabolic syndrome and obesity.¹³ This association was proposed to be related to its capacity to “sequester phosphate”,¹⁴ stimulate triglyceride synthesis^{13, 15, 16} and promote insulin resistance.^{13, 17}During the past few decades, the major changes in dietary habits, as have been discussed earlier in this paper, are mainly related to a dramatic increase in the intake of: (1) macromineral (P, K and Mg)-free commodities, such as oils, sugar and sweeteners, which contains negligible amounts of the above macrominerals) and (2) refined cereals commodities, where refinement is known to reduce the content of these macrominerals by about 70%. Cereals are known to contribute to more than 50% of the total energy intake in most countries;¹⁸ therefore, the shift from whole grain cereals (whole wheat, brown rice) to refined cereals would be expected to result in substantial reduction in the intake of these macrominerals. A further reduction would be expected from the increased consumption of macrominerals-free commodities. In developed and transitional countries, the consumption of these (above) commodities is known to be inversely related to socioeconomic status, mainly because of their high energy density (kcal g⁻¹ food) and low energy cost (US$ per 1000 kcal). This has also been proposed to be an important factor behind the high prevalence of obesity and metabolic syndrome among urban people of low socioeconomic status.¹⁹It is well known that in the past few decades, urbanization has increased in most countries. The changes in the consumption of the different food groups based on the change in gross national product per capita of the country and change in urbanization was studied by Popkin and Gordon–Larsen⁹ and Drewnowski and Popkin.²⁰ Increased urbanization worldwide was found to be associated with increased consumption of vegetable fats and sugars. At the same time, a direct relationship was reported to be present between urbanization and gross national product per capita and the increase in the consumption of fats and sweeteners. High gross national product per capita was associated with higher consumption of vegetable, animal fats and sugars with a sharp decrease in the consumption of complex carbohydrates.²⁰ Rapid urbanization worldwide has a major influence on accelerating the nutrition transition. It was also reported that an increased production and consumption of sweeteners derived from starch has been observed in the last several decades.²¹ For example, in the year 2000, the caloric consumption of sweeteners increased by one-third more than in the year 1962. Similarly, in the United States, the daily caloric intake was reported to increase, mainly from energy-dense and nutritiously poor food choices,^{8, 22, 23, 24, 25, 26, 27} such as fast food, salty snacks^{8, 22, 23, 24} and added caloric sweeteners.^{8, 21, 28} In addition to fast food choices lacking essential nutrients,^{8, 29, 30} fruit and vegetable consumption was observed to be far lower than the recommended levels.^{8, 21, 22}It can therefore be deduced that the high intake of refined carbohydrates, fats and sweeteners accompanied with the low intake of fruits and vegetables, leads to a diet that is deficient or suboptimal in vitamins and minerals (including potassium, phosphorus and magnesium). Thus, the increased prevalence of metabolic syndrome among people consuming high quantities of commodities containing low levels of these macrominerals may implicate these macrominerals in the development of metabolic syndrome, as is the case in its implication in refeeding syndrome. Thus, decreased intake of these macrominerals would be expected to undermine their postprandial concentration, and it is yet to be determined whether such undermining would have any health implications. Such a question can be clarified by looking at the relationship between these macrominerals and the different components of the metabolic syndrome.