REFEEDING SYNDROME - CAUSES, TREATMENT AND RISKS

Refeeding syndrome is an often-silent consequence of increasing nutritional intake in deficient individuals. It is an important, under-represented issue that deserves more public attention^[1]; particularly in those that are keen to correct nutritional deficits through supplementation. At best, refeeding syndrome defeats the point of nourishment, and at worst, the outcome can be fatal.

While the following article discusses refeeding syndrome and highlights important aspects of enhancing nutrition, it is not a substitute for expert help. The skills of a trained healthcare professional are necessary to devise a protocol able to treat severe nutritional deficiencies.

What is Refeeding Syndrome?

Refeeding syndrome refers to a condition of malnourishment that arises as a result of reintroducing nutrients after a period of severe deprivation.

During starvation, the body switches metabolic modes and starts to efficiently make use of stored nutrients. Instead of using glucose to maintain cellular metabolism, fats and proteins are used, which reduces both energy requirements and production. This typically induces weight loss and muscle wasting. After a prolonged time, there are not enough reserves to sustain optimal energy production and the metabolism slows down to a very low (emergency) energy state.

Upon reintroduction of food, metabolic activity is forced to increase in order to assimilate and process nutrients. Insulin and glucose levels rise dramatically in response to sudden feeding and basic nutrients are used up in order to facilitate a metabolic shift back towards glucose metabolism. This can cause additional symptoms of malnutrition, known as refeeding syndrome, until the metabolism has normalized and nutritional status is regained.

If the person does not have enough basic cellular reserves to sustain an increase in metabolic activity, the outcome can easily be fatal. Hospitalization is often required for severe cases.

History and Current Prevalence

Widespread famine is a recurrent theme in human history that has affected all continents and populations across the globe. Droughts, wars, and crop decimation due to disease, pests or natural disasters have caused food shortages and mass starvation. When the food supply was normalized, many individuals continued to have deficiencies as a result of refeeding syndrome and some even suffered lethal complications. Refeeding syndrome was first characterized after World War II in prisoners of war who were severely starved before their release^[2]. 

While the current incidence of refeeding syndrome is not well recorded, associated conditions such as alcoholism, illness and nutritional deficiencies are becoming more prevalent; potentially increasing the risk. Starvation still plagues much of the world today as well, particularly in developing countries.

Common Refeeding Syndrome Symptoms

Symptoms of refeeding syndrome can vary widely depending on what nutrient is missing, the degree of deficiency and what form is used for replenishment. Often a severe deficiency of one or more essential nutrients disrupts the utilization of other nutrients. This tends to cause high or low levels of other nutrients and cellular substances, which then give rise to the symptoms of deficiency. Treating the deficiency may not correct other cellular imbalances, especially if the nutritional deprivation was extreme and/or prolonged.

In general, refeeding kick starts the metabolism. The irony of refeeding is such that it requires resources to make use of the missing nutrients and correct overall metabolism. Deficits in magnesium, potassium and phosphorus are common in refeeding syndrome, alongside thiamine (vitamin B1). Compromised health of the cardiovascular system, kidneys, and digestive organs may also contribute to an increased risk of electrolyte disturbance, reduced metabolic status and refeeding syndrome.

Deficiencies in these critical nutrients may result in one or more of the following symptom subsets:

1. Hypophosphatemia: Phosphorus depletion is common in refeeding syndrome and is regarded by some as the main biochemical feature.^[3] The majority of diets have more than enough phosphate to service energy requirements and as such, phosphorus malnutrition is rare. Mild cases are often asymptomatic or with mild weakness. Severe cases may give rise to seizures, altered cognition, numbness, severe weakness, muscle pain and potential heart failure. Hypophosphatemia is associated with frail bones, osteoporosis, ATP and energy deficits, diabetic ketoacidosis, aluminum and magnesium antacids, diuretics, sepsis and alcoholism. Starvation, above-average phosphate excretion, chronic glucocorticoid excess, severe malabsorption, and metabolic shifts that increase cellular phosphate uptake can all cause hypophosphatemia.^[4]
2. Hypomagnesemia: Symptoms include fatigue, stiffness, tremors and twitches, apathy, delirium, coma, irregular heartbeat, and reduced oxygenation. Magnesium deficiency may cause hypocalcemia and hypokalemia^[5]. Hypomagnesemia is associated with diabetes^[6], hypertension, coronary heart disease, thyroid diseases, hypercalcemia, alcoholism, chemo-drugs, long-term diuretic use and osteoporosis.^[7]
3. Hypokalemia: Potassium links insulin release, metabolism, nutrient uptake and the renin-angiotensin-aldosterone system which maintains blood and water pressure in the body^[8]. Symptoms include muscle weakness and wasting, cramps, digestive symptoms, and in severe cases, paralysis, respiratory failure and death. Hypokalemia is associated with hypomagnesemia, hypertension, diabetes, cardiovascular issues, kidney damage, cardiac arrhythmias, hypothermia, alkalosis, beta-adrenergic inhibitors, diuretics, periodic paralysis and diseases of the blood.^[9]
4. Thiamine Deficiency: Vitamin B1 (Thiamine) is vital for energy metabolism and may become depleted in refeeding syndrome, pregnant and lactating women, those that have had gastric by-pass surgery and after long-term diuretic use. It is also associated with alcoholism, malnourishment, a diet high in processed grains and chronic disease. Symptoms of severe deficiency comprise the well-described disease states: wet beriberi and cardiovascular edema; dry beriberi and demyelination; or Wernicke-Korsakoff syndrome.^[10]

As magnesium, potassium and phosphate serve to regulate other minerals, such as sodium and calcium, a few of the following additional symptoms may be experienced:

• Severe fatigue
• Insulin resistance
• Hypertension
• Agitation or excessive restlessness
• Increased overall sensitivity

Both refeeding syndrome and malnourishment increase the risk of mortality, comorbidity, and complications pertaining to disease and treatment.

How is Refeeding Syndrome Diagnosed?

Refeeding syndrome is diagnosed in the context of chronic malnourishment and replenishment. A clinical examination will give clues to a skilled healthcare practitioner as to whether the patient is at a high risk of refeeding syndrome or not.

Signs the practitioner will look for include rapid weight loss (especially in muscle and fat mass), digestive symptoms, edema, ascites, and reduced functional capacity. If nutrient deficiency, starvation or wasting is suspected, blood tests are commonly employed to check nutritional status.

There is no formally agreed upon standard for diagnosing refeeding syndrome. The American Society for Parenteral and Enteral Nutrition (ASPEN) has proposed guidelines for practitioners assessing refeeding syndrome severity. These involve testing blood electrolyte and thiamine levels:

• Mild refeeding syndrome is indicated by a 10-20% reduction in one or more of serum phosphorus, potassium or magnesium.^[11]
• Moderate refeeding syndrome is indicated by a 20-30% reduction in one or more of serum phosphorus, potassium or magnesium.
• Severe refeeding syndrome is indicated by a >30% decrease in one or more of serum phosphorus, potassium or magnesium within 5 days of reintroducing food. Severe thiamine deficiency and/or organ dysfunction within 5 days of refeeding are other indicators of severe refeeding syndrome.

Additional markers of nutritional deficiency that may be tested for include serum albumin, prealbumin, transferrin, retinol-binding protein, and C - reactive protein, cholesterol and nitrogen status. Each of these is known to be reduced in infection, malnourishment and various disease states^[12].

Differential Diagnosis

There are very few conditions that could be mistaken for refeeding syndrome and vice versa. They include:

• Fluid overload, which depletes all electrolytes
• Long QT syndrome and other independently-associated heart arrhythmias

Who is at an Increased Risk of Refeeding Syndrome?

Any condition that serves to impair metabolism, digestive function and nutrient absorption can lead to malnourishment.

In recent years, chronic inflammation has been proven to contribute negatively towards undernutrition by promoting muscle wastage and inhibiting cellular protein production^[13]. In line with this, chronic inflammation and a form of undernutrition can be seen in many disease states, particularly those that are advanced.

Some of the diseases associated with the highest risk of refeeding syndrome include:

• Diabetes
• Cancer^[14]
• Liver cirrhosis and fatty liver diseases
• Kidney disease
• Metabolic syndrome
• Beriberi
• Anorexia nervosa
• Depression
• Chronic fatigue and fibromyalgia
• Some autoimmune conditions such as multiple sclerosis

Alcoholics and those with drug abuse disorders are also at a high risk of refeeding syndrome.

Cardiovascular diseases^[15] and hypertension may increase the risk of refeeding syndrome as it is often associated with electrolyte disturbances.

Nutrient levels may also be reduced in the case of the following:

• Aging
• Food deprivation
• During severe injury or post-surgical recovery
• Ingesting clay
• Severe dehydration
• Excess toxin exposure and poisoning
• Chronic stress
• Cyclic infections
• Excessive radiation
• Some pharmaceutical drugs that interfere with nutrient assimilation or electrolyte levels, such as Theophylline

7 Tips for Avoiding Refeeding Syndrome When Enhancing Nutritional Status

The following tips may help those interested in nutritional supplementation.

1. Get Expert Help

This cannot be stressed enough, particularly in very severe cases of malnourishment. A physician will perform an assessment of the patient’s energy requirements and be able to ascertain how to best approach refeeding. Extreme scenarios may require hospitalization, while mild to moderate cases may require additional supplementation and very specific nutritional guidance.

The physician is also important for assessing the patient throughout the refeeding process and ensuring that all body functions normalize. In critically ill patients, this process may take a few months or longer.

2. Take It Slow and Be Careful

Whether recovering from an illness or simply wanting to improve nutritional intake, it’s always best to take it slow with supplements. From a state of extreme deficiency, every incremental increase in a nutrient instigates an increase in metabolic activity. If one does not have the energy to sustain increased metabolism, refeeding syndrome ensues.

From this perspective, starting off slow is by far a better approach. Nutritional variety and consistency are of more value to the body than quantity, particularly if the risk of refeeding syndrome is high.

Working with a nutritionist, functional medicine practitioner or similarly skilled physician can ensure that the supplement protocol is properly calculated. Often dietary and lifestyle changes need to accompany refeeding and are incorporated into a program that works with the metabolism of the patient.

3. Cut Out Any Known Causes of Malnutrition

Alcoholism, drug abuse disorders, severe depression and anorexia nervosa are common causes of chronic malnourishment. These conditions tend to make safe refeeding more of a challenge due to a high relapse rate in the behavior that causes the malnourishment. Psychotherapy and/or behavioral therapy may be of benefit, as well as a diet plan that serves to establish a healthy eating pattern. Cultivating motivation and a positive mindset is very important for success, both of which often require social support.

Starvation, long-term fasting (more than 3 days) and attempting extreme health fad diets are other causes that ought to be avoided. It is highly unadvisable to follow a heavily restricted diet plan without the guidance of a skilled healthcare professional, even if other people have seemingly benefitted. Diet is an individualized affair and what may work for one person, may be a disaster for the next.

Suddenly stopping a prescription medication may lead to adverse effects that can increase the risk of refeeding. If a medication is suspected of facilitating malnourishment, talk to your healthcare provider about it before attempting to do something on your own.

4. Focus on Thiamine and Electrolyte Replacement

Even in healthy individuals that want a seemingly harmless nutrient boost, subclinical deficiencies may be present that can facilitate mild to moderate refeeding syndromes when attempting a new supplement. It can be a good idea to get thiamine and electrolyte levels assessed by a healthcare professional, and to regulate bodily stores of these nutrients first. As all B vitamins tend to have a synergistic action in the cell^[16], low thiamine status may increase the risk of other B vitamin deficiencies.

It should be noted that refeeding is not limited to depleting these nutrients alone. Other essential minerals and vitamins may also be required to facilitate an increase in nutritional intake. This is another reason why opting for the help of a specialist is advisable, particularly if the risk of refeeding syndrome is increased due to a medical condition.

5. Optimize Digestion with a Clean Diet Plan

It would be a mistake to increase nutritional intake and not to bother with following a healthy diet plan. Diet is a key component of enhancing digestive function and promoting the most optimal absorption of nutrients possible.

A balanced diet is generally high in nutritious foods and low in processed foods. A variety of fiber-rich foods are required for sustaining a healthy microbiome^[17], which in turn optimizes nutritional uptake and energy metabolism^[18]. A diet high in fruits, vegetables, nuts, seeds, wholegrains and legumes is ideal. Depending on any particular digestive complaints and/or the type of malnutrition of the person, protein-rich foods, such as grains, meat, eggs and dairy products, may or may not be appropriate.

If one is unsure of how to adopt a balanced diet, consulting a nutritionist is highly advisable.

Many cases of refeeding syndrome are precipitated by digestive impairments and an inability to absorb dietary nutrients^[19]. This is particularly true of starvation, alcoholism, aging and states of disease. In these cases, components of a healthy diet should be introduced slowly, with an emphasis on maximal absorption upfront. A healthcare physician is essential for guiding individuals in this position with an appropriate meal plan.

Lastly, since refeeding increases metabolism, it’s important to maintain constant blood sugar levels throughout the day and prevent potential blood sugar spikes. Eating properly prepared meals and having healthy snacks on hand can go a long way towards preventing blood sugar spikes. Special precautions need to be strictly adhered to for severely starved individuals.

6. Make Sure To Get Adequate Sleep

Often underestimated, and almost as important as diet in this equation, would be sleep. Sleep is a master regulator of many vital processes in the body, including hormone release, nutrient uptake and energy metabolism^{[20] [21]}. Every cell in the body has a clock that is governed by circadian cues, including those comprising the microbes and organs that drive the process of digestion.

When we regulate our sleep cycle, we make sure to fall asleep at the appropriate time in a dark setting and wake up at an appropriate time in order to receive the light. This ensures that metabolism “takes place on time”.

Moreover, states of low energy and nutritional depletion^[22] can cause sleep difficulty, as well as a reduced capacity for cellular regeneration^[23]. This is particularly true of the nervous system and the immune system^[24]. Deep sleep is the only time that the glymphatics system is able to collect and dispose of toxins from the deeper compartments of the brain.^{[25] [26]}

Thus if sleep is compromised in a person that requires refeeding, it may substantially increase the risk of refeeding syndrome by promoting increased inflammation and/or limiting nutrient uptake.

7. Do Not Attempt Exercise Until Metabolically Stable

Metabolism is heavily affected by physical activity levels. In the context of nutritional deprivation, physical activity is likely to become exhausting very quickly^[27]. Prolonged overexertion can increase the risk of refeeding syndrome in those that are deficient as it promotes further depletion of nutrients and energy.

In spite of this risk, exercise is also an important part of reestablishing a healthy metabolism^[28]. Caution needs to be taken to prevent overexertion when engaging in physical activity; especially after a period of starvation, injury or critical illness. Rest and relaxation should be emphasized over physical activity. Exercise should not be implemented until after adequate refeeding has taken place, and in the absence of refeeding syndrome.

Conclusion

Refeeding syndrome can be a serious adverse complication of hasty refeeding in severely deficient people. Chronic states of disease, alcoholism and starvation substantially increase the risk of refeeding syndrome. The help of a healthcare practitioner is important for assessing nutrient levels and for minimizing the risk when attempting to refeed for a nutritional deficiency. Consuming a healthy diet, resting enough, sleeping deeply and remaining adequately hydrated may help to lower the risk.

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