Dual Hepatic Injury from Refeeding Syndrome and Starvation in a Malnourished Woman After Bariatric Surgery: A Case Report

Introduction

Malnutrition is a condition in which deficiencies in nutrients lead to detrimental effects or even clinical outcomes. Malnutrition is prevalent in numerous diseases, particularly among institutionalized elderly individuals and patients with chronic conditions [1]. Chronic malnutrition has severe consequences, including increased mortality [2].

Nutritional intervention for malnourished patients is critical and occasionally challenging for clinicians. Refeeding syndrome (RFS) is a life-threatening metabolic complication that arises from nutritional replenishment in severely malnourished patients [3–6]. RFS is characterized by electrolyte disturbances, fluid balance abnormalities, altered glucose metabolism, and organ dysfunction resulting from rapid refeeding initiation [3,7] (Table 1). Hepatic injury is infrequently reported but can occur in patients with RFS, due to excessive hepatic fat and glucose deposition [8–10]. Concurrently, starvation-induced hepatic injury can also develop in patients with prolonged malnutrition, as indicated by elevated liver enzyme levels [9–11]. Differentiating between these 2 conditions in malnourished patients with hepatic injury is vital, particularly during nutritional support initiation, as their treatments differ significantly. Furthermore, there are limited reports on the coexistence of both conditions in a single patient.

Bariatric surgery is currently recognized as the most effective treatment for morbid obesity [12]. Although most patients experience successful weight loss following surgery, some can develop severe malnutrition due to eating disorders and malabsorption [13–15]. Consequently, clinicians at all obesity centers should know the potential risk of the development of RFS or starvation-induced disorders as postoperative complications.

In this paper, we report, for the first time, a case involving a young woman with severe malnutrition and extremely low body weight following bariatric surgery, who developed RFS after nutritional supplementation and subsequent starvation-induced liver injury during RFS treatment.

Case Report

A 27-year-old female patient underwent sleeve gastrectomy for obesity 1 year before admission. Her original body weight was 105 kg, with a body mass index (BMI) of 37.2 kg/m2. After surgery, her food intake drastically decreased, and she experienced vomiting after consuming high-protein foods. Occasionally, she induced vomiting to alleviate the sensation of obstruction. She received some postoperative follow-up, with medical advice from endocrine doctors, bariatric physicians, nutritionists, and even psychiatrists after surgery. She also took vitamin D, calcium, and a multivitamin regularly. However, her body weight still declined around 60 kg within 8 months and 72 kg within a year after surgery, due to eating disorder.

The patient was admitted to the hospital for severe malnutrition and amenorrhea for 9 months. Her daily caloric intake was approximately 400 kcal/day for several months before hospitalization. Upon admission, her body weight was 33 kg, with a BMI of 12.4 kg/m2. Her hemoglobin level was 118 g/L, plasma albumin was 54.0 g/L, with slightly elevated liver enzyme levels (aspartate transaminase [AST] 135 U/L, alanine transaminase [ALT] 127 U/L, γ-glutamyltransferase 187 U/L), and normal electrolyte levels. Consistent with her severe malnourishment and amenorrhea, she also showed low fasting blood glucose (3.2 mmol/L), low T3, T4 syndrome (FT3 <0.600 pmol/L, FT4 6.35 pmol/L, TSH 1.67 mIU/L), and extremely low levels of LH, FSH, estrogen, and progesterone. Her abdominal ultrasound appeared normal, while cardiac ultrasound revealed mild to moderate pericardial effusion.

Nutritional assessment and supplementation were initiated immediately upon admission, with a total calorie intake of 600 kcal/day (18 kcal/kg/day), including enteral nutrition and dietary intake. Ten days after the initiation of supplementation, her body weight increased from 33 kg to 34 kg, while her liver enzymes unexpectedly increased (AST 1419 U/L, ALT 334 U/L; Figure 1). Concurrently, she exhibited significant hypophosphatemia, with phosphate levels decreasing from 1.04 mmol/L to 0.63 mmol/L. The other electrolytes levels of the patient, including potassium, natrium, calcium, and magnesium, remained normal. The patient experienced considerable fatigue and decreased hemoglobin and albumin levels. She also had some subcutaneous hemorrhage, with bruises around the venous punctures and subcutaneous injection sites due to coagulation disorders (showed by prolonged plasma thrombin time, international normalized ratio, and decreased fibrinogen), correlated with liver dysfunction. Given the unexplained hepatic enzyme elevation and hypophosphatemia following nutritional supplementation initiation, RFS was considered a likely diagnosis in this patient.

We initiated immediate caloric restriction, with limited intravenous glucose and enteral nutrition at a total rate of 300 kcal/d (9 kcal/kg/d). Moreover, even serum vitamin testing was unfeasible, and continuous administration of phosphate, vitamin B, and vitamin D was provided to avoid vitamin especially thiamine deficiency during RFS. As expected, the patient’s liver function significantly improved 2 days after caloric restriction (AST 789 U/L, ALT 376 U/L). However, 6 days following caloric restriction, the patient exhibited exacerbated fatigue, weakness, lower limb edema, abdominal distension, and recurrent rebound of liver enzymes (AST 1216 U/L, ALT 307 U/L; Figure 1). The patient also had a progressive decline in body weight (from 34 kg to 32 kg), albumin (minimum to 29.2g/L), and hemoglobin (minimum to 77 g/L; Figure 2), with persistent hypophosphatemia despite consistent phosphate supplementation. No evidence of overt bleeding (eg, hematemesis, hematochezia, traumatic bleeding) was found in the patient. Occult blood test of the stool was also negative during hospitalization. Abdominal ultrasound revealed moderate ascites within the abdominal and pelvic cavities. Indicators of autoimmune and virus-related hepatitis tested negative, and no fatty liver was detected by either abdomen ultrasound or hepatic elastography.

Based on these clinical features and relevant literature, we hypothesized that the patient might have had starvation-induced injuries, such as liver damage, severe hypoalbuminemia, and anemia. Consequently, nutritional supplementation was reintroduced at 700–800 kcal/d (22–25 kcal/kg/d) from day 21 during hospitalization, accompanied by continuous administration of phosphate, iron, and vitamins. Following nutritional re-supplementation, the patient’s body weight gradually increased, and her fatigue substantially diminished. Liver enzymes decreased dramatically (from AST 1216 U/L and ALT 451 U/L before caloric intake increment to AST 98 U/L and ALT 105 U/L by day 38, when the patient was discharged).

The patient maintained an 800–1000 kcal/d caloric intake after discharge. During the follow-up visit at 1 month after discharge, the patient gained 4 kg of body weight. Her hemoglobin and albumin levels significantly increased (hemoglobin from 77 g/L to 99 g/L and albumin from 28.8 g/L to 36 g/L; Figure 2), while liver enzymes normalized (AST 64 U/L, ALT 45 U/L).

Discussion

RFS is commonly characterized as a pathological state resulting from water-electrolyte imbalances during nutritional restoration in malnourished patients. Prevalent causes of RFS include anorexia nervosa, cancer with chemotherapy, and chronic illness [5,16,17] (Table 1). The incidence of RFS has been reported to be as high as 15% to 30% in published studies [6,18], with mortality in severe cases reaching up to 70% [19]. RFS is typically characterized by electrolyte disturbances, such as hypophosphatemia, hypokalemia, and vitamin deficiencies, particularly thiamine deficiency [3]. Severe electrolyte imbalances and fluid retention can also result in life-threatening conditions, such as arrhythmias, heart failure, confusion, coma, metabolic acidosis, or even sudden death [7,20]. In our case, with sufficient supplementation of both nutrition and electrolytes, the patient mainly underwent persistent hypophosphatemia without disturbances of other electrolytes during the period of RFS, reflecting that the intractable hypophosphatemia is the most remarkable feature of RFS.

Liver injury, although infrequent, can also occur in RFS. It is potentially associated with hepatic steatosis caused by excessive hepatic fat and glucose deposition with fatty liver, identifiable through ultrasonographic imaging in patients with RFS [8,9]. In the present case, the patient exhibited elevated liver enzyme levels and hypophosphatemia shortly after caloric supplementation, strongly suggesting the development of RFS.

Prevention of RFS in undernourished patients during nutritional replenishment is crucial. Primarily, recognizing high-risk patients is necessary. Pathological conditions, such as anorexia nervosa, inflammatory bowel disease, short bowel syndrome, and chronic infectious disease, are considered significant RFS risks, particularly in patients with extremely low body weight (BMI below 16 kg/m2 or unintended weight loss of >15% over the past 3 to 6 months, according to the NICE Guideline, 2006). Bariatric surgery is the most effective method for sustained weight reduction [21,22]. Although micronutrient deficiencies are prevalent following malabsorptive procedures [23], after surgery, some patients can develop severe malnourishment with extreme weight loss, due to insufficient dietary in-take, long-term malabsorption, or anorexia nervosa [13–15]. In our case, the patient’s body weight decreased dramatically from 105 kg to 33 kg 1 year after bariatric surgery, with a BMI of 12.4 kg/m2 upon admission. Although severe malnourishment after bariatric surgery has been rarely reported [24], it is noteworthy that malnutrition and RFS during nutritional treatment might be potential postoperative complications following bariatric surgery [25,26]. The incidence of RFS after bariatric surgery remains unknown, as only a few reports have documented RFS following bariatric surgery [25,27,28]. If patients exhibit excessive weight loss within a short period after surgery, appropriate nutritional, psychological, or further surgical intervention should be encouraged to prevent the development of severe malnutrition [29]. Second, to avert RFS as a consequence of rapid caloric overload, initial feeding in mal-nourished patients should be gradual. A weight gain of 0.5 to 1.5 kg per week during nutritional supplementation is recommended [16]. NICE guideline authors suggested limiting caloric initiation to 5 kcal/kg/day, with a maximum of 10 kcal/kg/day in high-risk patients with a BMI below 14 kg/m2. Third, daily monitoring of caloric intake, body weight, electrolytes, aminotransferases, and patient physical status is crucial, particularly during the first 3 to 10 days of nutritional reintroduction. If blood phosphorus levels fall below normal, RFS is highly suspected, and nutritional support should be reduced accordingly. Concurrently, vitamin and mineral replacement and correction of electrolyte disturbances are essential for RFS prevention.

In addition to RFS, long-term starvation in malnourished patients can result in hepatic cell injury [30]. Numerous investigations have revealed significant elevations in liver enzymes prior to refeeding initiation in patients with anorexia nervosa, with over 50% of these patients exhibiting elevated serum transaminase levels [9,10]. The pathomechanism of starvation-induced liver injury remains elusive, with potential causes including hepatocyte autophagy [31,32], acute hypoperfusion of hepatocytes, ischemic hepatitis [33], and hepatic steatosis [24].

The differentiation of RFS and starvation-induced liver injury in malnourished patients with elevated liver enzymes is critical yet challenging, as the management of these conditions is contradictory. Caloric restriction is required in RFS [34], whereas adequate caloric replenishment is vital in cases of starvation-induced liver injury [30]. Several factors can aid in differentiating RFS and starvation-induced liver injury. First, RFS is often associated with hypophosphatemia, which is considered the most significant diagnostic marker in RFS [35], and hepatic function typically deteriorates more in RFS than in starvation-induced liver injury. Second, body weight can serve as a distinguishing marker for these conditions, particularly following nutritional reintroduction [36]. Third, liver imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging can help to differentiate starvation and refeeding-induced liver injuries, as RFS is frequently correlated with an enlarged fatty liver [34], while liver imaging appears relatively normal during starvation [37].

In the present case, the patient exhibited persistent hypophosphatemia following nutritional reintroduction and increasing body weight, both strongly indicating the occurrence of RFS. After caloric restriction for RFS treatment, the patient experienced transient liver function recovery, followed by ongoing hepatic impairment. Of note, the patient presented only a moderate decline of hemoglobin and albumin due to RFS but a much sharper and intractable decline during caloric restriction due to starvation (Figure 2), suggesting a more severe deterioration of hemoglobin and albumin might help to distinguish starvation-related injury from RFS. Additionally, no enlarged or fatty liver was detected by liver ultrasound or hepatic elastography. These manifestations suggest the possibility of starvation-induced liver injury resulting from overly stringent and rapid caloric intake restriction during RFS treatment. Following caloric intake re-supplementation, the patient’s body weight gradually increased, and liver enzyme levels progressively normalized before discharge.

Conclusions

Few reports documented RFS and starvation-induced injury in a single patient, with some initially displaying starvation-related injury followed by RFS upon reintroduction of nutrition [9]. Our case underscores the potential for RFS as a complication after bariatric surgery and the possibility of starvation-related injury during RFS treatment, when excessive caloric restriction is employed. Postoperative patients, particularly those with extremely low body weight, are at high risk for these complications. The coexistence of these conditions can increase the challenge for clinicians in discerning different phases throughout the disease course. Also, in malnourished patients who develop RFS, a cautious and gradual reduction of feeding is warranted to prevent the onset of starvation-related complications, including liver injury during RFS treatment.