’Review article

Refeeding syndrome in the gastroenterology

practice: how concerned should we be?
Gonçalo Nunesa, Mariana Britoa, Carla Adriana Santosa and Jorge Fonsecaa,b

Clinical nutrition is emerging as a major area in gastroenterology practice. Most gastrointestinal disorders interfere with digestive
physiology and compromise nutritional status. Refeeding syndrome (RS) may increase morbidity and mortality in
gastroenterology patients. Literature search using the keywords “Refeeding Syndrome”, “Hypophosphatemia”,
“Hypomagnesemia” and “Hypokalemia”. Data regarding definition, pathophysiology, clinical manifestations, risk factors,
management and prevention of RS were collected. Most evidence comes from case reports, narrative reviews and scarse
observational trials. RS results from the potentially fatal shifts in fluid and electrolytes that may occur in malnourished patients
receiving nutritional therapy. No standard definition is established and epidemiologic data is lacking. RS is characterized by
hypophosphatemia, hypomagnesemia, hypokalemia, vitamin deficiency and abnormal glucose metabolism. Oral, enteral and
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parenteral nutrition may precipitate RS. Awareness and risk stratification using NICE criteria is essential to prevent and manage
malnourished patients. Nutritional support should be started using low energy replacement and thiamine supplementation.
Correction of electrolytes and fluid imbalances must be started before feeding. Malnourished patients with inflammatory bowel
disease, liver cirrhosis, chronic intestinal failure and patients referred for endoscopic gastrostomy due to prolonged dysphagia
present high risk of RS, in the gastroenterology practice. RS should be considered before starting nutritional support. Preventive
measures are crucial, including fluid and electrolyte replacement therapy, vitamin supplementation and use of hypocaloric
regimens. Gastroenterology patients must be viewed as high risk patients but the impact of RS in the outcome is not clearly
defined in current literature. Eur J Gastroenterol Hepatol 30:1270–1276
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Introduction (TPN) being reported [7]. Nowadays, RS is an important

condition emerging in the modern clinical nutrition literature. It
Clinical nutrition and especially artificial nutrition is a
is defined as the potentially fatal shifts in fluid and electrolytes
major area of gastroenterology clinical practice [1].
that may occur in malnourished patients after nutritional
Several gastrointestinal disorders reduce digestion and
support institution [8–10]. In the past 20 years, more and more
absorption mechanisms, induce systemic inflammation and
cases have been reported addressing the problem of RS in
consequently influence normal metabolic pathways, which different clinical scenarios [11–14]. Liver cirrhosis, inflamma-
may affect energy and protein intake. Thus, basic training tory bowel disease (IBD), acute and chronic pancreatitis,
and knowledge of nutritional issues are essential to malabsorption syndromes, gastrointestinal cancer and short
approach the most prevalent digestive diseases that may bowel syndrome are important digestive diseases that may
compromise a healthy nutritional status [2–5]. induce long periods of fasting or significant reduced ingestion,
The first report of refeeding syndrome (RS) was performed cause malnutrition and therefore potentially increase the risk of
in the late 40’s after World War II, when starved American RS [2–5]. Most gastroenterological patients eligible for artificial
prisoners in Japan were released. Those patients were markedly nutritional support may be at risk of RS.
malnourished and deprived of an adequate nutritional intake The present report aims for the following:
for several weeks. When oral feeding was resumed, they
developed unexplained symptoms including severe diarrhea, (1) Review RF and its clinical importance in a gastro-
heart failure, convulsions and coma, leading to death without a enterology perspective.
clear identified cause [6]. After these early reports, few data (2) Highlight the risk factors to develop RS and strategies
were published until 1981 when RS was revisited, with two to early detection, treatment and prevention.
more fatal cases associated with total parenteral nutrition (3) Discuss how concerned gastroenterologists should be
with RS in their daily clinical practice.
European Journal of Gastroenterology & Hepatology 2018, 30:1270–1276
Keywords: gastroenterology, malnutrition, refeeding syndrome Materials and methods
a
Gastroenterology Department, GENE – Artificial Feeding Team, Hospital Garcia
de Orta, Almada and bCiiEM, Centro de Investigação Interdisciplinar Egas Moniz, A systematic literature search was performed using PubMed,
Monte da Caparica, Portugal Embase and Google. We combined the keywords ‘Refeeding
Correspondence to Gonçalo Nunes, MD, Gastroenterology Department, Hospital Syndrome’, ‘Hypophosphatemia’, ‘Hypomagnesemia’ and
Garcia de Orta, Avenue Torrado da Silva, 2805-267 Almada, Portugal ‘Hypokalemia’. All articles published in English or in other
Tel: + 351 965 492 185; fax: + 351 212 957 004; e-mail: [email protected] languages with English abstracts were initially eligible.
Received 13 February 2018 Accepted 27 April 2018 Review articles and clinical guidelines from the past 10 years

0954-691X Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001202 1270

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RS in the gastroenterology practice Nunes et al. www.eurojgh.com 1271

were emphasised. Articles without English abstracts were hypophosphatemia has been reported to be as frequent as
excluded. 25%, taking place 72 h after starting nutritional support.
Fifty-one publications were considered, including the Mean phosphorus concentration of 1.9 mmol/l mostly
following: manifested by neuromuscular symptoms was described by
some authors. Incidence appears to be superior in patients
(1) Twenty-five review articles or clinical guidelines. with hematopoietic tumours, with moderate to severe mal-
(2) Thirteen case reports. nutrition and aged 60 years old or older [23,24].
(3) Eleven observational trials. In a well-designed prospective cohort study of a het-
(4) Two systematic reviews. erogeneous group of intensive care unit patients, 34% of
the patients experienced hypophosphatemia soon after
No randomized controlled trials were found. The feeding was started [25]. Moreover, 6% of the patients
authors also included three additional observational stu- presented severe hypophosphatemia with a serum phos-
dies of their previous published experience in the field of phorus level below 0.32 mmol/l. Starvation for a period as
nutrition applied to the gastroenterology practice that short as 48 h and poor nutritional status predisposed
could concern RS. Data regarding definition, pathophy- patients to this syndrome [25].
siology, diagnosis and clinical manifestations, risk factors, The effect of RS in patient outcome and mortality is not
management and prevention of RS were collected to be clearly established, and clinical studies are scarce. A recent
included in this review. trial with 337 critically ill patients found a 36.8% pre-
valence of refeeding hypophosphatemia; these patients
Results presented low mortality if a low caloric intake was pro-
vided [26]. Some other trials showed high mortality rates
Refeeding syndrome concept and more prolonged admissions in intensive care units in
RS is a life-threatening condition and can be defined as the patients with RS [27].
potentially fatal shifts in fluids and electrolytes, resulting Studies in gastroenterology patients are currently not
from hormonal and metabolic changes that may occur in available, and most evidence comes from case reports
malnourished patients receiving nutritional therapy. signaling less favorable outcome. A study in patients with
However, no strict international agreed definitions or well- gastrointestinal fistula described 15% incidence of RS and
defined and validated diagnostic criteria were reported higher patient morbidity [5]. Nevertheless, the effect of RS
[6–8,15–18]. Despite clinical trials on this subject are dif- in mortality of gastroenterology patients was not well
ficult to perform, recent guidelines were published and characterized [2–4].
reviewed the best available evidence for managing this Actually, epidemiologic data regarding RS appear to be
condition, namely those from the National Institute for misleading, as in addition to the imprecise definition, epi-
Health and Clinical Excellence (NICE) in England and demiologic data can vary according to the patient sub-
Wales [19]. Nevertheless, because clinicians are often not group, type of nutrition, route of feeding and clinician
aware of the problem, RS still occurs, and as it often goes awareness. Incidence rates may be as wide as 0% and 80%
undetected, it may be much more frequent than diag- in the first 72 h of refeeding according to different studies,
nosed [20]. and clinical consequences are poorly predictable [28].
RS was commonly associated with TPN and usually
remembered in this context because all nutrients and Pathophysiology
energetic subtracts directly reach systemic circulation [16, The pathophysiology of RS is not clearly established;
17]. Nevertheless, it may occur with the application of however, the sudden reactivation of anabolism caused by
either oral, enteral or parenteral route. The main clinical insulin secretion appears to be the most important
features of RS include fluid-balance abnormalities, mechanism [29,30].
abnormal glucose metabolism, hypophosphatemia, hypo- In the postprandial period of healthy patients, glucose is
magnesemia, hypokalemia and vitamin deficiency, espe- uptaken and stored as glycogen in liver cells, a pathway
cially thiamine. These features may lead to heart failure, mediated by insulin. Insulin also inhibits the breakdown of
cardiac dysrhythmias, neuromuscular symptoms, hemato- fat stores (lipolysis). With starvation, glucose levels begin
logic dysfunction and death [6–8]. to fall within 24–72 h, inhibiting insulin secretion. At this
point, normal glycemia is maintained through gluconeo-
Epidemiology
genesis of lactate, glycerol and protein subtracts to pre-
The incidence of RS is unknown, largely because of unclear serve organs that depend on glucose metabolism such as
definitions and diversity of its clinical features. There is no brain, renal medulla and red blood cells. In simple star-
unequivocal consensus on how many of the typical vation (not associated with inflammation), fat becomes the
abnormalities are required to diagnose RS [21,22]. Using a main energy source for glucose independent tissues
proxy marker to show patients at risk of RS, namely those through ketone bodies synthesis and β-oxidation of fatty
with severe hypophosphatemia, one study demonstrated a acids. Metabolic rate tends to decrease, and body home-
rate of 0.43% in hospital patients, with malnutrition being ostasis can be maintained at strict limits, with a relative
one of the strongest risk factors [15]. In parenterally fed deficit in all macronutrients, micronutrients and electro-
patients, the incidence of hypophosphatemia ranges from lytes [29].
30% when phosphorus was provided in the feed to 100% The reintroduction of feeding in a malnourished patient
when parenteral nutrition without phosphorus was admi- after a period of starvation results in a switch from catabolic
nistered [15]. Moreover, in patients with cancer, severe to anabolic processes caused by a sudden rise in serum

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1272 European Journal of Gastroenterology & Hepatology November 2018 • Volume 30 • Number 11

Fig. 1. Schematic representation of pathogenic mechanisms involved in refeeding syndrome.

insulin concentration. Insulin also stimulates the movement phosphorus concentration may induce multisystem dys-
of extracellular phosphate, magnesium and potassium to function in different metabolic pathways. The most com-
the intracellular stores decreasing its blood concentration mon manifestations are cardiac (heart failure and
and water content that follows the osmotic gradient. dysrhythmias), skeletal (rhabdomyolysis), neurological
Moreover, reactivation of carbohydrate-dependent meta- and hematological with dysfunction in the three blood cell
bolic pathways increases the demand for vitamins that work lines [29,36]. Dyspnea, tiredness, palpitations, myalgia,
as enzymatic cofactors leading to vitamin deficiency. The muscle weakness, paresthesia, seizures, delirium and
serum electrolyte and vitamin deficiency occur in varying bleeding are possible complaints reported by the patients.
degrees and have a nonconsistent clinical consequence with Respiratory failure and difficult weaning from ventilator as
different effects in different patients. This may justify the well as coma and sudden death are extreme clinical sce-
wide spectrum of biochemical abnormalities seen in RS and narios associated with severe hypophosphatemia [29].
its poor unpredictable clinical manifestations [29,30].
Pathophysiology of RS is represented in Fig. 1. Hypomagnesemia
Magnesium is an abundant intracellular cation and plays
Clinical manifestations
an important role in bone metabolism, central nervous and
The clinical manifestations of RS are variable and asso- cardiovascular systems. It is a cofactor of most enzyme
ciated with fluid and electrolyte abnormalities that usually complexes and also contributes to maintain the electro-
affect membrane potential in different cell types. chemical gradient of cellular membranes. Mild hypo-
Symptoms may be subtle and reflect the type and severity magnesemia is not clinically significant in most cases.
of biochemical alterations [8–10,29–35]. Severe hypomagnesemia is defined as serum magnesium
less than 1.0 mEqs/l and may induce mainly cardiac and
Hypophosphatemia neuromuscular dysfunction with similar clinical manifes-
tations to those of hypophosphatemia. Gastrointestinal
Phosphorus is predominantly intracellular and essential for
symptoms such as abdominal pain, change in bowel
all cellular processes and the integrity of cell membranes.
habits, vomiting and anorexia may also be reported.
Many enzymes and second messengers are activated by
Hypomagnesemia is also a cause of refractory hypokale-
phosphate or c-AMP binding. Phosphorus is required for
mia [29,37].
energy production in the form of ATP. Phosphate also
regulates the oxygen affinity for haemoglobin and plays an
Hypokalemia
important role in the renal acid–base buffer system [36].
Hypophosphatemia is the most typical hallmark of RS. Potassium is the main cation of the intracellular fluid, and
Although not pathognomonic, it is highly suggestive, its functions include maintenance of water osmotic and
especially when it develops in malnourished patients under acid–base balance and the regulation of neuromuscular
artificial nutrition (parenteral or enteral route) [22]. activity. Potassium also stimulates cell growth, and
Hypophosphatemia is generally considered severe when its concentration in muscle is associated with muscle
serum inorganic phosphate concentration is less than mass and glycogen storage. As in hypophosphatemia and
1.5 mg/dl. Although hypophosphatemia may result in hypomagnesemia, the clinical manifestations are uncom-
several and variable clinical manifestations, many patients mon unless the deficit is moderate to severe (< 3 mEqs/l).
remain asymptomatic [33]. Nevertheless, low serum Patients usually present overlapping symptoms with

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RS in the gastroenterology practice Nunes et al. www.eurojgh.com 1273

hypophosphatemia and hypomagnesemia. Hypokalemia Table 1. National Institute for Health and Clinical Excellence criteria that
may be associated with cardiac dysrhythmia, being a confers patients a high risk of developing refeeding syndrome
dangerous alteration in RS and a potential cause of death NICE criteria – high risk of refeeding syndrome
in these patients. Hypokalemia is also a common cause of One or more of the following
metabolic alkalosis [29,33]. BMI <16 kg/m2
Unintentional weight loss of > 15% in the previous 3–6 months
Little or no nutritional intake for > 10 days
Vitamin deficiency
Low levels of potassium, phosphorus or magnesium before refeeding
Although malnutrition can induce different type of vitamin OR
Two or more of the following
deficits, thiamine (vitamin B1) deficiency is of most BMI <18.5 kg/m 2

importance in RS. It is an essential coenzyme in carbohy- Unintentional weight loss of > 10% in the previous 3–6 months
drate metabolism, and its deficiency may result in Little or no nutritional intake for > 5 days
History of alcohol abuse or drugs including insulin, chemotherapy, antacids or
Wernicke–Korsakoff syndrome manifested by ophthal- diuretics
moparesis, ataxia, encephalopathy, amnesia and con-
fabulation [29,38]. Deficiencies in pyridoxine (vitamin B6),
cyanocobalamin (vitamin B12) and folate are common in BMI below 14 kg/m2 or fasting for 2 or more weeks have
malnourished patients and may be exacerbated by RS as extremely high risk [19,49–51].
well as deficiency in trace elements like selenium, zinc and Patients with high risk or extremely high risk of RS
iron, but these are less established features [33]. should have thiamine prescribed before nutritional support
and maintained during the first 10 days of feeding. Enteral
Sodium and water balance route should be used if possible and multivitamins added
When feeding is restarted, water follows electrolyte shift to to cover other types of vitamin and trace element defi-
maintain electrochemical gradient. This shift induces ciencies not commonly assessed with standard laboratorial
intravascular depletion and decreases renal excretion of protocols. Intravenous route is advisable to patients under
sodium and water. Other mechanisms of sodium and TPN. There is no consensus on what is the exact dose of
water retention are also activated including vasopressin thiamine to be supplied. The oral dose varies according to
secretion and activation of the renin-angiotensin- authors from 100 mg daily to 100 mg three times a day.
aldosterone system. Those compensatory mechanisms Intravenous administration using doses of 50–250 mg at
may lead to congestive heart failure and pulmonary edema least 30 min before the diet was advisable. Higher doses
manifested by fatigue, dyspnea and peripheral edema. must be used in alcoholic patients as they tend to have
Furthermore, hyperglycemia developed after refeeding increased deficit from baseline [33,50]. However, no strict
may contribute to hyponatremia and worsen neuromus- recommendations can be performed given the lack of
cular symptoms [29,39,40]. strong evidence in current literature.
Serum electrolytes, especially sodium, potassium, mag-
Risk factors, prevention and management nesium and phosphorus, should be measured before
starting nutritional support [28,51–53]. TPN should not
The risk of RS appears to increase with the duration of
be started in patients with severe fluid and electrolyte
fasting and severity of malnutrition. Specific subgroups
imbalance. According to several authors, complete nor-
have been considered at increased risk such as patients
malization before feeding is not necessary, but correction
with anorexia nervosa and those with chronic alcoholism.
Patients with diabetes mellitus, patients under radiation should be started from the beginning and maintained
and/or chemotherapy or patients submitted to bariatric alongside feeding. Nevertheless, although normal electro-
surgery are also at risk. Some authors tried to standardize lyte intervals for serum concentration of these ions are
the individual risk factors and published the NICE criteria defined, no cut-offs working as a target or pre-requisite to
that predispose patients to high risk of RS when present start or stop feeding are clearly established, and this may
(Table 1) [20,41–45]. be mostly depended on patient clinical status, symptoms
RS may only be detected considering the possibility of and evaluation of serum levels.
its existence. It is important to be aware of this condition The best method for electrolyte repositioning has not
and anticipate problems to help minimise its occurrence. yet been determined [28,53]. Hypophosphatemia, hypo-
Prevention is the key to successful management [46–50]. magnesemia and hypokalemia are often treated with
Four steps must be considered: intravenous supplementation, but this is not without risks.
Oral administration may be considered in patients with
(1) To assess patient risk before refeeding. oral route, but potassium and magnesium salt formula-
(2) To prescribe thiamine. tions are often not tolerated causing dyspepsia, bloating
(3) To monitor electrolytes closely. and changes in bowel habits [53–55]. Table 2 summarizes
(4) To feed and hydrate gradually [51]. the way of electrolyte correction currently used by our
artificial feeding team being adapted from evidence of
All patients undergoing intensive nutritional support current literature, although this information is scattered
either by oral nutritional supplements, enteral or par- and varies according to different authors and protocol of
enteral nutrition should have the risk of RS assessed. each center. If serum electrolyte falls during refeeding,
Patients who had little or nothing by mouth for more than correction should be optimized. Feeding may be reduced
5 days are considered to have moderate risk. Patients who but should not be completely discontinued as it can con-
fulfilled NICE criteria are at high risk of RS and those with tribute to increased deficits. Daily monitoring is advisable

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1274 European Journal of Gastroenterology & Hepatology November 2018 • Volume 30 • Number 11

until the patient is stable with the nutritional protocol These recommendations alert to the need for well-
prescribed, which usually occurs in the first 10 days [53]. A formulated and standardized guidelines, which are still
summary of RS prevention and management is represented poor available. Although dedicated dietitians may play a
in Fig. 2. central role in prevention and management of RS, invol-
Finally, feeding and hydration should be performed vement of an hospital multidisciplinary nutritional team
gradually and adapted according to patients’ risk of RS composed by gastroenterologists (or other medical doc-
[52]. In patients with moderate risk, nutrition should be tors), dietitians, pharmacists and nurses may help in the
started with 50% of energy needs in the first 48 h. implementation of this four-step approach. It is a physician
According to recent guidelines, patients at high risk (NICE competence the definition of the clinical indication for
criteria) should have nutrition started at a maximum of nutritional support and the prescription of an artificial
10 kcal/kg/day, which may be increased slowly over nutrition regimen that must consider the risk of RS. It is
4–7 days, targeting 100% of energy needs after 1 week as also a medical task the monitoring of fluid and electrolyte
laboratorial monitoring allows. In patients with extremely status, the reposition therapy if disturbances are evident
high risk, more caution is necessary with nutritional sup- and the adaptation of energy supply according to clinical
port started at a maximum of 5 kcal/kg/day and, as sug- and laboratorial evaluation. When TPN is needed, phar-
gested by some authors, under continuous cardiac macists are essential to select and prepare the bags, indi-
monitoring during the first days given the high risk of vidually adapted to the patients’ characteristics. Nurses are
hypokalemia and cardiac dysrhythmia [19,51]. Fluid bal- strikingly important as they take care of patients, give
ance, blood pressure, heart rate and glycemia should be them the prescribed diets and being the staff that con-
monitored regularly and fluids containing glucose avoided, tinuously monitor patients, have to be aware of RS and its
as they contribute to serum insulin concentration rise and clinical manifestations and potential complications.
worsen intravascular electrolyte depletion [51]. Moreover, nutrition teams can guide and educate other
health professionals in the prevention and management of
RS. However, more research is needed to provide detailed
Table 2. Simplified serum electrolyte correction in patients under artificial information about this condition, especially with respect to
nutrition preventive protocols and therapeutic measures [19,33].
Electrolyte correction in patients under artificial nutrition
Implications to the gastroenterology clinical practice
Oral administration may be considered if mild deficits and enteral route available
Hypokalemia Potassium chloride Protein-energy malnutrition is a high prevalent condition
Central vein: 80 mEq/l infused until 40 mEq/h
Peripheral vein: 60 mEq/l infused until 20 mEq/h
in gastroenterology wards. NICE criteria identify patients
Hypomagnesemia Magnesium sulfate at high risk of RS and should be applied to every patient
1–2 g in 6–12 h intervals prior starting nutritional support therapy.
Dilution in 100 ml saline solution infused in 30 min
Hypophosphatemia Monopotassium phosphate
Several patients with IBD and especially Crohn’s disease
10 mmol in 6 h intervals (until 40–50 mmol/day) often present in gastroenterology wards with disease flares
Dilution in 100 ml saline solution infused in 30 min that compromise food intake and contribute to deterioration
of nutritional status. It is not uncommon that those patients
Although oral administration may be considered if deficits are mild and enteral
route is available, most patients underwent intravenous infusion to achieve a quick present established malnutrition owing to their high
correction and due to possible gastrointestinal adverse events of oral formulations inflammatory burden and negative energetic balance. This

Fig. 2. Algorithm for prevention and management of refeeding syndrome according to patient risk stratification. A hospital multidisciplinary nutritional support
team is essential and should play a central role in managing patients under artificial nutritional support to detect and prevent complications like RS. NICE,
National Institute for Health and Clinical Excellence.

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RS in the gastroenterology practice Nunes et al. www.eurojgh.com 1275

nutritional deficiency may be caused by reduced ingestion fluid imbalances should be started before feeding and
owing to anorexia, vomiting and patient adherence to monitored alongside.
restrictive diets by fear of exacerbation of underlying dis- Many patients with IBD, chronic liver disease, and intestinal
orders or need to perform endoscopic or surgical proce- failure and those referred for endoscopic gastrostomy owing
dures. All these factors place patients with IBD at high risk to prolonged dysphagia present established malnutrition and
of RS, especially if artificial nutritional support has to be are at risk of RS according to NICE criteria. Thus, gastro-
performed to optimize nutritional status by either enteral or enterologists should be concerned about RS when prescribing
parenteral route [5,14]. artificial nutrition and be proficient in its prevention, early
Patients with chronic liver disease who are managed by detection, diagnosis and management. However, potential
gastroenterologists in everyday practice also show high effect in the outcome of gastroenterology patients is not clearly
prevalence of malnutrition [56]. Malnutrition in these established as most evidence comes from case reports, few
patients has a well-established negative effect, in the out- observational retrospective trials and expert opinions. Well-
come increasing complications and mortality. RS should designed randomized controlled trials are needed to improve
be prevented in this population and even more if alco- the level of scientific evidence and make robust recommenda-
holism, a common etiology of CLD, is present [56]. tions in this area.
Another group of patients that could be at high risk of
developing RS are those who are referred for percutaneous
Acknowledgements
endoscopic gastrostomy to perform long-term enteral
nutrition owing to chronic disease that cause prolonged Conflicts of interest
dysphagia [4,57,58]. Patients with neurologic disorders There are no conflicts of interest.
and head and neck cancer are included in this group.
Ingestion less than 50% of daily needs is observed in most
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