Celiac Crisis Complicated by Refeeding Syndrome: A Case Report and Pediatric-Adapted Diagnostic Criteria

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting clinical case, coeliac crisis although well described is relatively rare.

• I think the discussion around antibodies needs to include the ESPGHAN non biopsy criteria, may children don't need a scope. The whole paragraph would need to be re-written.
• The use of steroids in coeliac crisis as opposed to refractory coeliac disease is uncertain and this need to be discussed in more detail
• The proposed criteria for crisis in children are reasonable but would need greater numbers, evidence and consensus to be useful
• The management and assessement of re-feeding syndrome in this situation need much greater clarification

Author Response

This is an interesting clinical case, coeliac crisis although well described is relatively rare.

 

I think the discussion around antibodies needs to include the ESPGHAN non biopsy criteria, may children don't need a scope. The whole paragraph would need to be re-written.

We thank the Reviewer for this important suggestion. We agree that the role of serology-based diagnosis and the ESPGHAN non-biopsy criteria is highly relevant, particularly in pediatric patients and even more so in critically ill children presenting with celiac crisis.

We have therefore substantially revised the paragraph discussing serology and diagnosis, explicitly integrating the ESPGHAN non-biopsy criteria and their clinical implications in this context.

 

The use of steroids in coeliac crisis as opposed to refractory coeliac disease is uncertain and this need to be discussed in more detail.

We appreciate this comment and agree that the role of corticosteroids in celiac crisis deserves careful clarification.

 

The proposed criteria for crisis in children are reasonable but would need greater numbers, evidence and consensus to be useful.

We fully agree with the Reviewer that the proposed pediatric-adapted criteria require validation in larger cohorts and broader expert consensus before they can be considered definitive or universally applicable.

However, given the extreme rarity of celiac crisis in the pediatric population and the current absence of any validated diagnostic framework for children, we believe that proposing structured, evidence-informed criteria may represent a first step toward standardization. Our criteria are not intended as definitive diagnostic standards but rather as a pragmatic clinical tool derived from the adult consensus criteria by Jamma et al.

We have revised the manuscript to clarify that these criteria are hypothesis-generating and intended to stimulate multicenter validation studies and expert discussion, rather than to establish formal consensus recommendations.

 

The management and assessement of re-feeding syndrome in this situation need much greater clarification.

We thank the Reviewer for highlighting this crucial aspect. We modified the discussion.

Reviewer 2 Report

Comments and Suggestions for Authors

In this article, the authors presented a case of a 23-month-old girl who developed Celiac Crisis with severe multisystem involvement. The patient's clinical evolution was complicated by refeeding syndrome, ileo-ileal intussusception, coagulopathy with deep vein thrombosis.
The authors proposed pediatric-adapted diagnostic criteria to facilitate earlier diagnosis and standardize management.
Introductio is well presented, as is the objective of this article.
I recommend that you include in the case presentation, the patient's anthropometric data at the time of admission to your clinic (weight, waist, head circumference, chest circumference, abdominal circumference, arm circumference). Otherwise, the presentation of the case is correct and detailed. The figures are clear.
Please review the article from a technical editing perspective (spacing, numbering, grammar), including table 2 (missing number 4).
The article presents 40 references being up to date.

Author Response

In this article, the authors presented a case of a 23-month-old girl who developed Celiac Crisis with severe multisystem involvement. The patient's clinical evolution was complicated by refeeding syndrome, ileo-ileal intussusception, coagulopathy with deep vein thrombosis.
The authors proposed pediatric-adapted diagnostic criteria to facilitate earlier diagnosis and standardize management.
Introduction is well presented, as is the objective of this article.

I recommend that you include in the case presentation, the patient's anthropometric data at the time of admission to your clinic (weight, waist, head circumference, chest circumference, abdominal circumference, arm circumference). 

We thank the Reviewer for this valuable suggestion. We fully agree that detailed anthropometric data would enhance the clinical characterization of severe malnutrition; unfortunately, the specific measurements requested (head circumference, chest circumference, abdominal circumference, arm circumference) were not available for this patient, except for weight and height now added in the text.

 

Otherwise, the presentation of the case is correct and detailed. The figures are clear.
Please review the article from a technical editing perspective (spacing, numbering, grammar), including table 2 (missing number 4).

The manuscript has been carefully revised.

 

The article presents 40 references being up to date.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors present a highly interesting case of celiac disease in early childhood, namely celiac crisis complicated by refeeding syndrome, highlighting an unusual and severe mode of onset, drawing attention to important adaptations of the diagnostic criteria.

The case is reported in accordance with standard case report guidelines, following a clear chronological structure and providing sufficient clinical, laboratory, and imaging data to support the diagnosis.

The description of complications (refeeding syndrome, intussusception, deep vein thrombosis) is appropriate, though a short comment on their pathophysiological link to severe malnutrition and celiac crisis could strengthen the clinical interpretation.

Furthermore, the discussion section is well documented, offering relevant statistical data on atypical and severe presentations of celiac disease similar to other reported case, as well as associated complications.

I believe that this case report may be considered for publication in its current form.

Author Response

The authors present a highly interesting case of celiac disease in early childhood, namely celiac crisis complicated by refeeding syndrome, highlighting an unusual and severe mode of onset, drawing attention to important adaptations of the diagnostic criteria.

The case is reported in accordance with standard case report guidelines, following a clear chronological structure and providing sufficient clinical, laboratory, and imaging data to support the diagnosis.

 

The description of complications (refeeding syndrome, intussusception, deep vein thrombosis) is appropriate, though a short comment on their pathophysiological link to severe malnutrition and celiac crisis could strengthen the clinical interpretation.

We thank the Reviewer for this valuable suggestion. We agree that briefly outlining the pathophysiological mechanisms linking severe malnutrition and celiac crisis to the observed complications can further enhance the clinical interpretation of the case.

 

 

Furthermore, the discussion section is well documented, offering relevant statistical data on atypical and severe presentations of celiac disease similar to other reported case, as well as associated complications.

I believe that this case report may be considered for publication in its current form.

Reviewer 4 Report

Comments and Suggestions for Authors

overall well organized case study. Diagnostic criteria validity claim based on single case study seems inappropriate. Authors might report their lab reports as a suggested tool to be validated through proper validation design.

1. Title and abstract are informative. Abstract summarizes the report very well. It will be beneficial to report the proposed diagnostic criteria in abstract.
2. Introduction is well structured , with range of references around globe pertaining to same case. It will be beneficial to add some details of refeeding syndrome in the introduction.
3. Better to describe uncommon clinical terms..e.g. Asthenia (line 76). Why GFD was not started at this stage? Mention any particular reason or guideline for that.
4. Though description of case is detailed, it will be beneficial to give diagnostic criteria of celiac crisis. It is better to rephrase para starting from line 90, mentioning more explicitly adapted criteria for CC diagnosis and how it was confirmed.
5. Why GFD was initiated here and not early? Line 94
6. If Journal guidelines allow, it will be better to report lab findings with reference ranges described in para 107 -115 in tabular form. It will give a better perspective and clarity.
7. Conclusion can be rephrased to include final diagnostic criteria in a couple of lines.
8. Diagnostic criteria validity claim based on single case study seems inappropriate. Authors might report their lab reports as a suggested tool to be validated through proper validation design.

Author Response

Overall well organized case study. Diagnostic criteria validity claim based on single case study seems inappropriate. Authors might report their lab reports as a suggested tool to be validated through proper validation design.

We fully agree with the Reviewer that the proposed pediatric-adapted criteria require validation in larger cohorts and broader expert consensus before they can be considered definitive or universally applicable.

However, given the extreme rarity of celiac crisis in the pediatric population and the current absence of any validated diagnostic framework for children, we believe that proposing structured, evidence-informed criteria may represent a first step toward standardization. Our criteria are not intended as definitive diagnostic standards but rather as a pragmatic clinical tool derived from the adult consensus criteria by Jamma et al.

We have now clarified in the manuscript that the reported laboratory findings should be interpreted as preliminary observations, potentially serving as a basis for future validation studies conducted with rigorous methodological design.

 

Title and abstract are informative. Abstract summarizes the report very well. It will be beneficial to report the proposed diagnostic criteria in abstract.

We agree that mentioning the proposed criteria in the Abstract would improve clarity and highlight the novelty of the manuscript. We discussed the criteria in the abstract.

 

Introduction is well structured, with range of references around globe pertaining to same case. It will be beneficial to add some details of refeeding syndrome in the introduction.

We added details of refeeding syndrome in the introduction.

 

Better to describe uncommon clinical terms..e.g. Asthenia (line 76). Why GFD was not started at this stage? Mention any particular reason or guideline for that.

We thank the Reviewer for this observation.

The term ‘severe asthenia’ has been replaced with ‘fatigue’.

Regarding the delayed initiation of a gluten-free diet, the clinical presentation at the initial evaluating center was interpreted in the context of standard diagnostic pathways (stable clinical condition). The presence of low-titer positive celiac serology led clinicians to plan diagnostic confirmation by endoscopy according to existing guidelines (ESPGHAN).

 

Though description of case is detailed, it will be beneficial to give diagnostic criteria of celiac crisis. It is better to rephrase para starting from line 90, mentioning more explicitly adapted criteria for CC diagnosis and how it was confirmed.

We agree with the Reviewer and have rephrased the indicated paragraph. In the revised version, we clearly outline the required components of the diagnosis (acute gastrointestinal deterioration attributable to celiac disease), and we explicitly detail how our patient fulfilled major and minor criteria.

 

Why GFD was initiated here and not early? Line 94

Regarding the delayed initiation of a gluten-free diet, the clinical presentation at the initial evaluating center was interpreted in the context of standard diagnostic pathways. The presence of low-titer positive celiac serology led clinicians to plan diagnostic confirmation by endoscopy according to existing guidelines (ESPGHAN), rather than to recognize an evolving celiac crisis and initiate a gluten-free diet at that stage.

 

If Journal guidelines allow, it will be better to report lab findings with reference ranges described in para 107 -115 in tabular form. It will give a better perspective and clarity.

We thank the Reviewer for this suggestion. We have therefore added a table summarizing key laboratory findings with reference ranges (table 1).

 

Conclusion can be rephrased to include final diagnostic criteria in a couple of lines.

We agree and have rephrased the Conclusions to briefly summarize the proposed pediatric-adapted diagnostic criteria.

 

Diagnostic criteria validity claim based on single case study seems inappropriate. Authors might report their lab reports as a suggested tool to be validated through proper validation design.

We fully agree with the Reviewer that the proposed pediatric-adapted criteria require validation in larger cohorts and broader expert consensus before they can be considered definitive or universally applicable.

However, given the extreme rarity of celiac crisis in the pediatric population and the current absence of any validated diagnostic framework for children, we believe that proposing structured, evidence-informed criteria may represent a first step toward standardization. Our criteria are not intended as definitive diagnostic standards but rather as a pragmatic clinical tool derived from the adult consensus criteria by Jamma et al.

We have revised the manuscript to clarify that these criteria are hypothesis-generating and intended to stimulate multicenter validation studies and expert discussion, rather than to establish formal consensus recommendations.

 

Reviewer 5 Report

Comments and Suggestions for Authors

The authors present an interesting and clinically relevant case of pediatric celiac crisis. The manuscript is clearly written and addresses an important diagnostic and management challenge in pediatric gastroenterology. The following comments are intended to help strengthen the clarity and impact of the manuscript.

In the absence of standardized pediatric diagnostic criteria, how was celiac crisis distinguished from other causes of acute severe malabsorption and metabolic instability in this case?

Were any identifiable triggers, such as infection or recent interventions, present prior to disease onset, and how might they have contributed to the celiac crisis?

How did the development of refeeding syndrome and thrombotic complications alter the clinical management, and what preventive strategies would you recommend?

Given the rarity of celiac crisis in high-income countries, which early clinical or laboratory features should prompt heightened suspicion in young children?

Could you clarify how the adapted diagnostic criteria proposed in this report differ from existing definitions and support earlier diagnosis and improved outcomes?

Given the initial weakly positive celiac serology, what factors supported proceeding toward a diagnosis of celiac crisis prior to histological confirmation?

How did the presence of severe coagulopathy and subsequent thrombotic complications influence the diagnostic workup and timing of endoscopic evaluation?

What clinical and laboratory findings led you to suspect early refeeding syndrome following initiation of a gluten-free diet, and how was this managed?

Author Response

The authors present an interesting and clinically relevant case of pediatric celiac crisis. The manuscript is clearly written and addresses an important diagnostic and management challenge in pediatric gastroenterology. The following comments are intended to help strengthen the clarity and impact of the manuscript.

We sincerely thank the Reviewer for the insightful and clinically oriented comments, which helped us to clarify diagnostic reasoning, clinical decision-making, and the translational relevance of this case. Each point is addressed below.

In the absence of standardized pediatric diagnostic criteria, how was celiac crisis distinguished from other causes of acute severe malabsorption and metabolic instability in this case?

We thank the Reviewer for this important question. In the absence of validated pediatric criteria, the diagnosis of celiac crisis was established through a comprehensive clinical assessment. This integrated rapid clinical deterioration with profuse diarrhea, severe weight loss, dehydration, and metabolic derangements; biochemical evidence of profound malabsorption, including hypoalbuminemia and multiple micronutrient deficiencies; celiac antibodies; and the exclusion of alternative causes of acute enteropathy through microbiological, immunological and imaging investigations.

 

Were any identifiable triggers, such as infection or recent interventions, present prior to disease onset, and how might they have contributed to the celiac crisis?

No identifiable infectious triggers or recent surgical or pharmacological interventions were documented prior to CD onset. Stool cultures, viral antigen assays, and parasitological investigations yielded negative results. Although infections are recognized precipitants of celiac crisis, spontaneous onset in young children has also been described, particularly in the context of delayed diagnosis and severe malnutrition.

 

How did the development of refeeding syndrome and thrombotic complications alter the clinical management, and what preventive strategies would you recommend?

We thank the Reviewer for this important point. The suspicion of early refeeding syndrome, along with the development of thrombotic complications, had a substantial impact on the patient’s clinical management. Consistent with ASPEN consensus recommendations caloric intake was carefully restricted and gradually increased, parenteral nutrition was avoided, and electrolytes and phosphate levels were closely monitored. We have revised the manuscript to clarify suggested management. Early and proactive supplementation with vitamins and micronutrients, particularly thiamine, was implemented, while anticoagulation therapy was maintained due to the documented deep vein thrombosis.

 

Given the rarity of celiac crisis in high-income countries, which early clinical or laboratory features should prompt heightened suspicion in young children?

The diagnosis of celiac crisis is primarily clinical. As proposed in our adapted pediatric criteria and supported by this case and the available literature, early features that should raise suspicion include chronic or progressively worsening diarrhea associated with rapid weight loss or growth faltering, abdominal pain, vomiting, marked fatigue or behavioral changes, hypoalbuminemia, metabolic acidosis, electrolyte imbalances, in the absence of an alternative explanation. We modified the text accordingly.

 

Could you clarify how the adapted diagnostic criteria proposed in this report differ from existing definitions and support earlier diagnosis and improved outcomes?

We thank the Reviewer for the opportunity to clarify the novelty of our proposed criteria. These adapted criteria differ from previous definitions in that they are specifically tailored to pediatric patients, incorporating developmental indicators such as growth curve deceleration (crossing of percentiles) and behavioral changes, and requiring confirmed celiac disease by serology and/or histology.

In addition, we propose a distinction between major and minor criteria, providing explicit parameters for the classification of organ and metabolic dysfunction, to address aspects that were only broadly described in prior reports and integrating features frequently observed in pediatric case series but not included in adult-based criteria.

 

Given the initial weakly positive celiac serology, what factors supported proceeding toward a diagnosis of celiac crisis prior to histological confirmation?

We have revised the manuscript (result and discussion) to better emphasize that:

 

Although the initial serology showed only mildly elevated anti-tTG IgA levels (2× ULN), several clinical elements strongly supported a diagnosis of celiac disease complicated by celiac crisis.

 

The patient presented with a rapidly progressive and severe clinical picture characterized by chronic profuse diarrhea, 30% weight loss, severe iron-deficiency anemia, hypoalbuminemia, electrolyte imbalance, growth deceleration, and metabolic instability requiring hospitalization. This constellation fulfilled our modified pediatric criteria for celiac crisis (acute gastrointestinal deterioration associated with major and multiple minor criteria).

 

EMA was positive at the initial evaluation, increasing the specificity of serological findings. Third, upon clinical deterioration, repeat serology demonstrated markedly elevated titers (IgA anti-tTG 20× ULN; IgG anti-DGP 19× ULN; EMA positive), confirming autoimmune activation consistent with celiac disease.

 

How did the presence of severe coagulopathy and subsequent thrombotic complications influence the diagnostic workup and timing of endoscopic evaluation?

As now better reported in the text (results and discussion), Severe coagulopathy (PT ratio up to 3.31; PTT ratio 1.86) significantly impacted the diagnostic strategy. Due to the high bleeding risk, esophagogastroduodenoscopy with duodenal biopsies was contraindicated, and the scheduled procedure was suspended.

 

The need for plasma transfusion and vitamin K administration further highlighted the patient’s unstable hemostatic status. Shortly after femoral venous access placement, the development of thrombophlebitis and deep vein thrombosis confirmed a profoundly altered coagulative balance in the setting of malnutrition, systemic inflammation, and probable vitamin deficiencies.

 

Given this scenario, proceeding with endoscopy would have exposed the patient to an unacceptable procedural risk. The markedly elevated repeat anti-tTG IgA levels (>10× ULN) with positive EMA fulfilled ESPGHAN criteria for a non-biopsy diagnosis of celiac disease. Therefore, the diagnostic process shifted toward a serology-based confirmation, and initiation of a gluten-free diet was prioritized over histological evaluation.

 

What clinical and laboratory findings led you to suspect early refeeding syndrome following initiation of a gluten-free diet, and how was this managed?

After initiating the gluten-free diet, the patient developed clinical deterioration characterized by marked hyperphagia, persistent abdominal pain, irritability, in the context of severe baseline malnutrition and hypoalbuminemia.

Laboratory findings at referral included severe hypoalbuminemia, micronutrient deficiencies, dyslipidemia, and metabolic imbalance, consistent with a high risk for refeeding syndrome. The combination of significant prior weight loss (−30%), prolonged malnutrition, and the metabolic shift induced by renewed caloric intake raised strong suspicion for incipient refeeding syndrome.

In response, we implemented a structured preventive strategy in accordance with ASPEN recommendations.

We have revised the manuscript to better discuss and clarify the diagnostic reasoning and management strategy (see new paragraph in discussion).

Reviewer 6 Report

Comments and Suggestions for Authors

The paper is very interesting and it gives amy informations, particularly for young doctors, about the management of this rare but important condition. The paper is fit for the publication but I suggest:

At page 3, line 114, it is important to underline that the value of anti tTG antibodies > 200 U/ml (more 10 times than normal value < 20 U/ml) is an indication to rule out an histological diagnosis of Celiac Disease and the patient may start Gluten Free Diet without Upper Endoscopy with duodenal biopsies

This concept may be also explained at page 6, line 192 and at page 7, line 205

Author Response

The paper is fit for the publication but I suggest:

At page 3, line 114, it is important to underline that the value of anti tTG antibodies > 200 U/ml (more 10 times than normal value < 20 U/ml) is an indication to rule out an histological diagnosis of Celiac Disease and the patient may start Gluten Free Diet without Upper Endoscopy with duodenal biopsies

This concept may be also explained at page 6, line 192 and at page 7, line 205.

We fully agree with the Reviewer, we have revised the manuscript to better emphasize that anti-tTG IgA values exceeding 10 times the upper limit of normal (ULN) allow a diagnosis of Celiac Disease without histological confirmation, in agreement with the ESPGHAN guidelines.

Specifically:

• in result: we clarified that anti-tTG IgA levels >10× ULN, with normal value, confirmed by positive EMA, fulfill the criteria for a non-biopsy diagnosis of Celiac Disease according to ESPGHAN guidelines. We explicitly stated that, in this setting, upper endoscopy with duodenal biopsies is not mandatory and a gluten-free diet may be started without histological confirmation.

• in discussion: we expanded the discussion to reiterate the applicability of the ESPGHAN non-biopsy diagnostic approach, particularly in the context of Celiac Crisis, where endoscopy may be contraindicated due to severe clinical instability. We further clarified that, in such high-titer serological cases, the diagnosis remains primarily clinical and serology-based, with histology reserved for stable or atypical presentations.

We believe these modifications strengthen the manuscript by aligning it more clearly with current ESPGHHAN recommendations and by better supporting the diagnostic rationale adopted in our case.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors are to be congratulated on making very appropriate changes based on the initial review. This clarifies many key issues including non-biopsy criteria and the role of steriods.

Futher clarification around the lack of consensus around diagnostic criteria for CC in children incorporating the proposed criteria now reads very well.