See “Refeeding Syndrome in Children in Developing Countries Who Have Celiac Disease” by Agarwal et al on page 522.
Celiac crisis is a life-threatening syndrome observed in patients with untreated celiac disease (CD), particularly children. Common manifestations of celiac crisis include severe diarrhea, hypoproteinemia, and metabolic and electrolyte changes (1). The term “celiac crisis” was introduced in 1953 by Andersen and Di Sant’Agnese who reported on the disease onset in 58 children with CD admitted to the Department of Pediatrics of Columbia University, New York, during the years 1939–1951. In that series of young children (most younger than 2 years), a celiac crisis was found in 24 of 52 patients (46%) who underwent serum protein determination (2). At that time, the overall mortality associated with CD was still high in Western countries (15%), and a celiac crisis was often the precipitating cause of death (3). The celiac crisis has nearly disappeared in Europe and North America (4). The reasons for this change are most likely related to improved infant nutrition, decreased infection rate, and reduced lag time between CD development and diagnosis; however, CD is now increasingly recognized as a primary health problem in many developing countries. Not surprising is that recent series of celiac crisis are mostly reported from countries where a large proportion of the population has a poor living standard, particularly India.
Refeeding syndrome (RFS) is defined as the potentially fatal shifts in fluid and electrolytes that may occur in malnourished patients who are abruptly refed, either enterally or parenterally. These shifts result from hormonal and metabolic changes and may cause serious clinical complications, such as hypotension, cardiac arrhythmias, respiratory failure, neurological manifestations, and death (5). Hypophosphatemia is the biochemical hallmark of RFS. The syndrome is complex and may also feature abnormal sodium and fluid balance; changes in glucose, protein, and fat metabolism; thiamin deficiency; hypokalemia; and hypomagnesemia (6).
Can an RFS worsen the prognosis of celiac crisis in children, particularly in developing countries? This is what Agarwal et al (7) suggest in an article in this issue of JPGN. They describe 5 cases of RFS of 35 children with CD admitted to the Department of Pediatric Gastroenterology in Lucknow, India, during 2010. All 5 children were severely malnourished (body mass index <14 kg/m2) and their clinical features fulfilled the criteria for celiac crisis except that symptoms worsened after introduction of the gluten-free diet. These patients showed anemia, hypophosphatemia, hypokalemia, hypoalbuminemia, hypocalcemia—in other words, the typical features of RFS. Instead of using steroids, which is the standard treatment for the celiac crisis, they were managed as RFS in terms of correction of electrolyte and vitamin deficiencies and gradual feeding leading to successful outcome in all of them (7).
The reasons why the celiac crisis may evolve into an RFS are not entirely clear. Authors suggest a role for excessive early feeding, either given enterally or parenterally, and steroid therapy. Spontaneous food intake is typically reduced in children with active CD. Starting treatment with the gluten-free diet leads to improvement in the child's feeding attitude, but this happens gradually during a period of weeks rather than days. Instead, iatrogenic factors could well play a role, particularly related to excessive use of parenteral nutrition, intravenous glucose infusions, and steroid administration. Both glucose administration and steroids lead to increased insulin secretion. Insulin stimulates glycogen, fat, and protein synthesis. This process requires minerals such as phosphate and magnesium and cofactors such as thiamin. Insulin stimulates the transport of potassium, magnesium, and phosphate into the cells. These processes result in a decrease in the serum levels of phosphate, potassium, and magnesium, all of which are already depleted. The clinical features of the RFS occur as the result of the functional deficits of these electrolytes and the rapid change in the metabolic rate (6).
By showing that CD can be a life-threatening condition requiring intensive hospital care in a significant portion (14%) of patients diagnosed with this condition at a referral Indian center, the study by Agarwal et al adds an important piece to the evaluation puzzle of the CD-related burden of disease in their country. Diarrhea that lasts for >2 weeks is still a common cause of mortality in infants and children in India (8). CD is being more frequently recognized in that country, both in children and in adults, particularly in the “celiac belt,” a part of north India where wheat is a staple food (9). In a recent large, community-based screening study performed in the northern part of India, an overall CD prevalence of 1.04% was found, a figure that is similar to European (10) and North American data. Only 2 of 10,488 screened subjects had already been diagnosed as having CD, however, indicating that just a tiny fraction of overall CD cases had been correctly recognized on clinical grounds (2% vs 17%–20% in Europe). Interestingly, only 2 subjects with diagnosed CD were found to be positive at the serum anti-tTG test, a finding indicating poor adherence to the dietary treatment (11). Heavy underdiagnosis of CD is a major problem not only in India but also in many other parts of the world, for example, north Africa (12) and the Middle East. Recent epidemiological data also suggest that CD is much more common than previously thought in China (13). This situation of underdiagnosis depends on poor awareness of CD epidemiology and clinical spectrum; scarcity of diagnostic facilities; more emphasis on other chronic enteropathies, for example, intestinal tuberculosis and chronic infections; and lack of commercial gluten-free wheat substitutes. Of note, the frequency of CD is likely to increase in the near future in many developing countries, given the diffuse tendency to adopt a Western, “gluten-rich” diet.
Agarwal et al are to be congratulated for showing that prompt diagnosis and treatment of the celiac crisis/RFS combination may save the lives of children. Educational programs are urgently needed in India and in many other countries to increase the awareness of the high prevalence of CD and clinical polymorphism. An improved attitude about CD case finding could significantly reduce the morbidity and mortality associated with this chameleonic disease.
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