Severe refeeding syndrome after human chorionic gonadotropin diet: a potentially lethal complication

Background

Refeeding syndrome is the potentially lethal manifestation of electrolyte and metabolic imbalances in malnourished patients, which can occur after a return to enteral or parenteral nutrition following a prolonged fasting period.1 It was first described historically in connection with prisoners of war during the World War II.2 Nowadays, those typically at risk are patients with anorexia nervosa, oncology patients undergoing chemotherapy, elderly patients, certain postoperative patients and patients with chronic alcoholism.3

Ever since its first description by Simeons in The Lancet in 1954, the human chorionic gonadotropin (hCG) diet has been a popular method to lose weight in a supposedly fast and effective way. In his study, Simeons presented hCG as a new supplement which purportedly mobilised fat during a state of malnourishment. Calorie intake was restricted to 500 kcal/day and participants received 125 IU of hCG daily. This led to a mean reduction of body weight of 250–600 g/day. The weight loss was subsequently attributed to the hCG supplementation.4

A simple internet search reveals a number of websites which propagate the hCG diet as a safe regime with no side effects, emphasising the natural properties of this pregnancy-related hormone and praising a multitude of hCG formulations—oral, nasal or subcutaneous—as essential for achieving the desired weight loss. Neither the lack of evidence of a real effect, nor official warnings, for example, by the FDA, seem to deter people from following this diet.5

We present the case of a man in his mid-20s who developed severe refeeding syndrome following a 3-week course of the hCG diet, which illustrates the potential danger and harm posed by this regime.

Case presentation

The patient presented to the emergency department with a progressive generalised muscle weakness. A day prior to presentation, he had noted an extension deficit of his left big toe. Overnight the muscle weakness worsened, so that he was unable to sit up from a recumbent position. The following day, he experienced extensive weakness to his legs and arms, to the point that he was unable to move on his own. Further history revealed nausea and two instances of emesis following the onset of the muscle weakness. The patient initially denied fever, night sweats or unintended weight loss. Except for loose stools three times a day for several weeks, the review of systems was unremarkable. The patient denied the consumption of tobacco, alcohol, illicit drugs or anabolic substances. He used esomeprazole as required for gastrointestinal reflux. His medical history comprised an upper and lower endoscopy with detection of Helicobacter pylori, which was subsequently eradicated, and an uncomplicated diverticulitis. His last journey abroad was to South America, 2 months prior to presentation.

On examination, we saw a borderline obese patient with a body weight of 88 kg (body mass index (BMI): 29.4 kg/m²), a pulse of 68 bpm, blood pressure of 136/62 mm Hg, a respiratory rate of 14 breaths/min and a tympanic temperature of 37.1°C. The neurological examination revealed an alert, attentive and oriented patient with unremarkable cranial nerve status. His muscle bulk was normal. Muscle tone, however, was flaccid, especially in the extremities, and muscle strength was significantly reduced in his entire body, presenting as paralysis. Intrinsic reflexes were symmetric, 1+ at the biceps, triceps, knees and ankles. There was no sensory loss. Due to the paralysis, ataxia could not be tested for. Cardiopulmonary and abdominal examinations were unremarkable. Furthermore, there was no evidence of hypervolaemia.

Investigations

Blood tests revealed a neutrophilia of 18.3×10⁹/L with normal C reactive protein. Liver function tests were slightly elevated with an aspartate transaminase of 92 U/L (10–50 U/L) and an alanine transaminase of 227 U/L (10–50 U/L). There was a notable increase in muscle enzymes with a creatine kinase (CK) of 896 U/L (<195 U/L) and a myoglobin of 354 ng/mL (28–72 ng/mL). The main findings were a severe hypokalaemia of 1.4 mmol/L (3.5–4.5 mmol/L) and severe hypophosphataemia of 0.22 mmol/L (0.8–1.5 mmol/L). Furthermore, a mild hypomagnesaemia of 0.52 mmol/L (0.66–1.07 mmol/L) was observed. The initial venous blood gas analysis revealed a lactate of 4.2 mmol/L (normal: <2.1 mmol/L). For further values, see table 1.

As expected in severe hypokalaemia, the ECG showed a sinus rhythm with ST segment depression in leads V3–V6 and marked U waves (figure 1).

Differential diagnosis

In summary, this patient presented with muscle paralysis caused by severe hypokalaemia and hypophosphataemia. Furthermore, there was evidence for mild rhabdomyolysis. The increase in muscle enzymes, however, did not seem to be in proportion with the presented symptoms. Thus, a primary muscle pathology like myositis seemed unlikely and did not fit with the electrolyte disorders. Damage to muscles with subsequent destruction is associated with hyperkalaemia, rather than hypokalaemia. The aetiology of the electrolyte imbalance was unclear at this point. The differential diagnosis for a combination of hypokalaemia, hypophosphataemia and hypomagnesaemia includes enteral loss by emesis or diarrhoea. Our patient had reported some diarrhoea, which persisted over the last weeks. However, he described this as mild.

Additional differentials include drug-induced electrolyte loss. Hypokalaemia is a well-known side effect of loop diuretics and laxatives, which can also deplete phosphate and magnesium. Certain anti-infectives, for example, aminoglycosides and amphotericin B, can cause a decrease in serum magnesium and potassium levels.6 Some intravenous iron formulations are known to cause hypophosphataemia.7 As stated above, the history did not reveal intake of any other drugs. Nutritional causes, that is, restricted food intake, appeared to be unlikely as well, as the patient was in a good nutritional state and had initially not reported any weight loss or diet regimes.

Another differential diagnosis is refeeding syndrome, which is characterised by severe electrolyte imbalance, especially depleted potassium and phosphate stores. After we reviewed the patient’s history, he admitted to having followed the hCG diet for the past 3 weeks. For this, he had been restricting his daily calorie intake to 500 kcal/day with an especially low intake of carbohydrates, and he had been administering a daily subcutaneous dose of 1000 IU of hCG. In addition, he had been performing 1–1.5 hours of endurance sports daily. During this period, he lost about 6 kg (mean of 286 g/day). Two days prior to the onset of symptoms, he had ended the diet by eating large amounts of pizza and pasta. With this information, the diagnosis of severe refeeding syndrome could be established, following the ASPEN consensus definition of 2020.8

Treatment

The patient was admitted to the intensive care unit and started on intravenous potassium and phosphate substitution. Additionally, we gave thiamine in high doses, because of the carbohydrate intake before admission.

Outcome

After replacing 494 mmol of potassium, 75 mmol of phosphate and 36 mmol of magnesium within 35 hours, electrolytes normalised. Consequently, the paralysis subsided. During hospitalisation, the patient reported muscle pain, which was growing increasingly worse. This corresponded with an increase in muscle enzymes to a maximum of 1593 ng/mL for myoglobin and 15350 U/L for CK, substantiating the diagnosis of rhabdomyolysis. Values and clinical symptoms improved under volume replacement. Additionally, transition to normal diet took place under the close supervision of a nutritionist.