Britain’s National Institute for Health and Care Excellence (NICE) has developed a screening, assessment and management guidelines to prevent RFS or mortality if it occurs.5 Short Nutritional Assessment Questionnaire (SNAQ) has also been validated for screening and diagnosing malnutrition.6 However, both NICE and SNAQ have low sensitivity and specificity scores on retrospective validation analyses.4 The important thing is for clinicians to have a high index of suspicion, especially for persons who may be at risk of developing RFS such as persons with poorly managed mental health disorders, substance use disorders, malabsorption, malignancies, starvation in protests, military recruits, athletes, child abuse and critically ill patients.7
Despite the recognition of starvation and RFS for many years, the metabolism of starvation and the changes that occur during refeeding is not completely understood.8 Glucose is the main source of energy production and the excess is stored as glycogen in the liver or muscles. When glycogen store capacity is exceeded, glucose is converted to fat and stored as fatty acids in adipose tissue. This results in reduction of blood glucose levels and a consequent reduction in insulin production from the pancreatic islet cells.9
With starvation, the body begins to break down stored glycogen and is depleted in about 72 hours without food. Gluconeogenesis begins from non-carbohydrate sources for obligate glucose users like brain and erythrocytes. This is accompanied by fatty acids metabolism to form ketone bodies for production of energy. The net result of starvation is the depletion of fats, proteins, potassium, phosphate and magnesium.10 This depletion affects major organs like lung, heart, liver, intestines and kidneys with complications such as hypotension, bradycardia and hypothermia.11
The primary goal in caring for nutritionally depleted patients is the preservation of functional protein8. With the resumption of feeding, particularly glucose, there is an increased production of insulin. Insulin intrinsically enhances protein formation and prevents degradation of protein.12 It pushes potassium and phosphate intracellularly for phosphorylation during the breakdown of glucose in glycolysis, Kreb’s cycle and the electron transfer system. Hypophosphatemia is generally accepted as the hallmark of RFS even though it is not the only cause of hypophosphatemia. Other causes of hypophosphatemia include chronic alcoholism, insulin administration, vitamin D deficiency, hyperparathyroidism and Fanconi syndrome.13
Hypophosphatemia decreases Adenosine triphosphate (ATP, the energy currency), cyclic adenosine monophosphate (cAMP, 2nd messenger for many biological processes) and 2,3-Diphosphoglycerate (2,3-DPG, in the erythrocyte), due to decreased glycolysis.14 The 2,3-DPG fall increases haemoglobin oxygen affinity, so low phosphorus level induces tissue hypoxia. ATP levels may also decrease in myocardial and skeletal muscles and can result in dysfunction and death of various cell types and therefore the appearance of cardiovascular and neuromuscular symptoms.15
In addition to hypophosphataemia, RFS is characterised by hypomagnesaemia, hypokalaemia, thiamine and other vitamins (B6 and B12) deficiencies, trace metal deficiencies (e.g. selenium and zinc), glucose and lipid imbalance, and a spurious hyponatremia with fluid balance abnormalities. Hypomagnesaemia is associated with refractory hypokalaemia and hypocalcaemia which can lead to clinical signs and symptoms and could mask RFS symptoms.16 Thiamine is required for metabolism of pyruvic and lactic acids, and links glycolysis to the Kreb’s cycle. Deficiency of thiamine causes fatal acidosis.4 Insulin is antinatriuretic and fluid retention occurs as a sequelae causing death by pulmonary oedema.17 These abnormalities to a greater extent explains the clinical features of RFS manifested by our patient. Table 2 depicts general clinical presentation.3
Table 2
| Neurological | Cardiovascular | Others |
Hypophosphatemia | Weakness, paraesthesias, lethargy, confusion, coma, sudden death | arrhythmias, cardiac failure, left ventricular dysfunction, | Dyspnoea, haemolysis, increased susceptibility to infection, tissue hypoxia, rhabdomyolysis |
Hypomagnesaemia | Hyporeflexia, fasciculations, psychosis, delirium, vertigo, apathy, depression, irritability | arrhythmias, ECG changes | Hypocalcaemia (tetany, ataxia, muscle weakness, tremor) |
Hypokalaemia | | Arrhythmias, ECG changes | Constipation, fatigue, paralytic ileus, rhabdomyolysis |
Sodium retention | | Fluid overload, congestive heart failure, tachycardia, peripheral oedema | Acute lung oedema, decreased haematocrit, decreased serum albumin levels |
Thiamine deficiency | Dry beriberi, Wernicke’s encephalopathy (nystagmus, ataxia, ophthalmoplegia, confusion), Korsakoff syndrome (anterograde and retrograde amnesia, confabulations) | Wet beriberi | |
The incidence of RFS is not exactly known due to the lack of consensus of its definition and decreased awareness so being under-diagnosed. A study of inpatients of an internal medicine department revealed an incidence of 8% in the study population.18 Screening patients who may be at risk of RFS and adopting the management guidelines can prevent the condition. Early diagnosis of the syndrome when it occurs with timely correction of the deficient ions and vitamins can reduce the risk of mortality.
The principle for managing RFS as agreed by the ASPEN consensus in 2019 is to “start low and go slow”.4 The complex metabolic changes occur largely due to the fast re-introduction of calories. One can begin with 25% of the required calorie per day and graduated over the subsequent 3–5 days.4 The ions implicated need to be monitored daily and replaced when low except for hyponatremia whose correction can cause pontine myelinosis.19 With the poor integrity of the GI tract, parenteral replacement of the ions and the vitamins may be ideal while correcting the energy deficiency.