Abstract
Background
Little is known about primary intestinal lymphangiectasia (PIL) in Chinese children. Insufficient awareness can lead to delayed diagnosis and treatment, which may adversely affect the prognosis of affected children. This study aimed to investigate the clinical features and treatment outcomes for PIL in infants and young children in China, providing a basis for clinical diagnosis and treatment.
Methods
This is a single-center retrospective study. The clinical information of children was gathered and a retrospective analysis was conducted on the clinical manifestations, potential complications, nutritional conditions, laboratory findings, imaging tests, endoscopic and pathological assessments, treatment outcomes, and other relevant parameters of infants and young children diagnosed with PIL.
Results
A total of 42 cases of infants and young children with PIL were analyzed, and it was found that PIL was most frequently diagnosed in infants under 1 year of age (95.2%). All of the children presented with diarrhoea. Other manifestations were limb edema in 37 cases (88.1%) and lymphatic effusions in 20 cases (47.6%). Tetany and generalized convulsions were reported in 35.7% of children, with a high prevalence. Concurrent infections were identified in 73.8% of cases, primarily respiratory infections and sepsis. Ten children (23.8%) were malnourished at their initial visit, presenting with stunting, wasting and underweight status. Anemia (54.8%) and electrolyte imbalances (100%) were prevalent, particularly hypomagnesemia (88.1%). Imaging studies revealed intestinal protein loss, predominantly in the jejunum and above. The predominant endoscopic appearance was of scattered white snowflakes or granules in the duodenum. Some patients with normal endoscopic duodenal findings showed typical lymphatic dilatation on histopathology. Treatment involved diet and nutrition adjustment, albumin infusion, electrolyte correction and anti-infective therapy, resulting in improvement in 39 cases and ineffectiveness in 3 cases upon evaluation.
Conclusions
In our cohort of infants and young children, PIL was mainly diagnosed in infants under 1 year of age (95.2%). The main symptoms were diarrhea (100%) and edema (88.1%). There was a notable prevalence of limb convulsions (35.7%), anemia (54.8%) and hypomagnesemia (88.1%). The majority of infants and toddlers (92.9%) diagnosed with PIL showed positive outcomes with dietary and pharmacological intervention.
Keywords: Primary intestinal lymphangiectasia (PIL), pediatric, hypomagnesemia, limb convulsions
Highlight box.
Key findings
• In infant and young children cohorts, primary intestinal lymphangiectasia (PIL) was mainly diagnosed in infants under 1 year of age. In addition to typical symptoms such as diarrhea, edema, and hypoalbuminemia, the incidence of limb convulsions, hypomagnesemia, anemia and concurrent infections was also high.
What is known and what is new?
• PIL typically presents as protein-losing enteropathy with diarrhea and edema. The medium-chain triglycerides diet is effective.
• The incidence of hypomagnesemia in infants and young children diagnosed with PIL was notably elevated, surpassing that of hypocalcemia.
• A significant proportion of infants and young children with PIL exhibited tetany and generalised convulsions (35.7%), with most experiencing multiple episodes of convulsions.
What is the implication, and what should change now?
• Recurrent limb convulsions, alongside low levels of calcium and magnesium, should be recognized as indicative factors warranting consideration for a PIL diagnosis in infants and young children.
Introduction
Primary intestinal lymphangiectasia (PIL) is characterized by protein-losing enteropathy resulting from the dilation and rupture of intestinal lymphatic vessels. The etiology and pathogenesis of PIL remain unclear, possibly linked to congenital dysplasia of the lymphatic system (1). Typically manifesting in early childhood, particularly in children under 3 years of age, the prevalence of PIL is presently undetermined, with most cases being sporadic (2,3).
The major clinical feature of PIL is peripheral edema. Other manifestations include pleural effusion, pericarditis, chylous ascites, abdominal pain, diarrhea, fat-soluble vitamin deficiency, weight loss and stunting (4). Clinical presentation and severity of PIL in children can vary based on the extent and location of affected lymphatic vessels, often presenting with nonspecific symptoms that pose challenges in diagnosis. Diagnosis is made by the constellation of clinical, biochemical, endoscopic, and histological findings (5). The management of PIL depends on lifelong dietary modifications, including a high-protein diet, limited intake of long-chain fats and supplementation with medium-chain triglycerides (MCT) instead, along with vitamin supplementation. Other pharmacologic (e.g., octreotide) may be indicated as well. Rarely, surgical resection may be required in cases of segmental PIL (4,6).
Due to its rarity, there is a limited number of comprehensive studies on PIL, primarily consisting of case reports. Moreover, there is a scarcity of relevant data from China, contributing to a lack of awareness among pediatricians. In this study, we retrospectively analyzed the clinical data of infants and young children who were diagnosed with PIL in Beijing Children’s Hospital in China to understand the clinical characteristics and treatment response of PIL in infants and young children, and to improve the knowledge about PIL in Chinese children. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-187/rc).
Methods
Patients
A retrospective study was conducted at Beijing Children’s Hospital, focusing on infants and young children diagnosed with PIL. Case data and medical images of patients admitted to the gastroenterology unit between January 2016 and December 2023 were retrieved. Information was retrieved from the electronic case data system of the ward and the endoscopy data system of the endoscopy centre. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Clinical Research Ethics Committee of Beijing Children’s Hospital Affiliated to Capital Medical University of the National Children’s Medical Center (No. [2024]-E-093-R), and the requirement for informed consent was waived due to the retrospective nature of this research.
The inclusion criteria for the research subjects involved (7): (I) with typical clinical signs of diarrhea and edema; (II) reduction in the absolute number of peripheral blood lymphocyte count; (III) simultaneous reduction of plasma albumin and immunoglobulin G (IgG) levels; (IV) endoscopy and pathology confirmed the lymphatic vessels of the small intestine are dilated; and (V) evidence of increased intestinal protein loss. A suspected diagnosis was made if the first three criteria were met, and a confirmed diagnosis was made if the last two criteria were met [for cases where endoscopic and pathological findings are inconsistent or atypical, the diagnosis must meet the following criteria simultaneously: (I) radionuclide imaging demonstrates intestinal protein loss or lymphatic malformation; and (II) clinical improvement on MCT therapy]. Additionally, subjects were limited to infants and young children aged 0–3 years.
Exclusion criteria: (I) trauma to the chest and abdomen, fibrosis of the lymphatic drainage tract, constrictive pericarditis, inflammatory bowel disease, systemic lupus erythematosus, tuberculosis, lymphoma, cirrhosis, intestinal obstruction, malignant tumors, diseases of the nervous system, parasitic infections and other secondary small intestinal lymphangiectasia; (II) those with incomplete clinical data.
Clinical data collection
Clinical data collection involved obtaining information such as the patient’s name, gender, age, disease duration, weight, height, maternal and childbirth history, past medical history, family history, clinical symptoms, physical examination findings, laboratory test results, imaging studies, endoscopic and pathological findings, as well as internal medicine and nutritional therapy details.
Nutritional status assessment
As per the 2006 World Health Organization (WHO) growth and development standards for children and adolescents (8). The WHO Anthro software was employed to determine the height-for-age Z-score, weight-for-age Z-score, and weight-for-height Z-score. Stunting was classified as a height-for-age Z-score of less than −2, underweight as a weight-for-age Z-score below −2, and wasting as a weight-for-height Z-score under −2.
Criteria for assessing effectiveness
Evaluation of the clinical efficacy of children post-treatment was conducted following the provision of comprehensive medical and nutritional care. Evaluation standards include: (I) significant improvement—symptoms disappear, with normal levels of albumin and lymphocytes; (II) improvement—noticeable relief in symptoms, though albumin or lymphocyte levels may remain low; (III) ineffectiveness—symptoms persist without improvement in albumin and lymphocyte levels. The efficacy of treatment response was assessed at the time of discharge.
Statistical analysis
SPSS software (version 22.0, IBM Corporation, Armonk, NY, USA) was used for data processing and statistical analysis. Measurement data following a normal distribution were presented as (mean ± standard) and group comparisons were conducted using the t-test. For data not conforming to a normal distribution, the representation was median (interquartile range), and group comparisons were made using the Mann-Whitney U test. Count data was expressed as counts and percentages (%). Intergroup comparisons were performed using the Chi-squared test or Fisher’s exact probability test. A statistically significant difference was denoted by a P value of less than 0.05.
Results
General information and demographic characteristics
During the study period, a total of 67 children were suspected of having PIL based on clinical manifestations, of whom 42 met the inclusion and exclusion criteria after completing a comprehensive assessment and were diagnosed with PIL. Among the 42 confirmed cases of PIL in infants and young children, there were 20 boys and 22 girls aged between 3 months and 2 years and 1 month, with an average age of (11.2±20.5) months. For children with PIL, the duration of symptoms before diagnosis ranged from nine days to 10 months, with an average disease duration of (50.8±37.5) days. There were 31 cases with a disease duration of more than one month and 11 cases with a disease duration of less than one month. The length of hospitalisation ranged from 8 to 70 days, with a mean length of hospitalisation of (23.5±12.3) days. Maternal and childbirth history revealed one premature infant. No family history of PIL was identified.
Clinical manifestations
All children presented with diarrhea as the predominant symptom. The frequency of diarrhea varied from two to over 30 times per day, with an average of (8.9±5.7) times. Based on qualitative documented qualitative assessments in the electronic health records (EHR) documentation (clinician notes), the majority of diarrhoea episodes were described as having watery or mushy stools. Additional symptoms included abdominal distension (26.2%), vomiting (23.8%), and fever (33.3%). This study identified a high prevalence of tetany and general convulsions among children with PIL, accounting for 35.7% of cases, with most children experiencing tetany or general convulsions at least twice. Edema was observed in 88.1% of cases, predominantly in the lower limbs and eyelids. Furthermore, 47.6% (20/42) of children displayed lymphatic effusions, comprising peritoneal, pleural, and pericardial effusions in 14, 4, and 3 cases, respectively (Table 1). Among these children, most cases (19/20, 95.0%) exhibited isolated effusions, and one patient (5.0%) presented with concurrent peritoneal and pleural effusions.
Table 1. Demographic characteristics and clinical symptoms of infants and young children with PIL.
| Clinical features | PIL (n=42) |
|---|---|
| Age | |
| ≤1 year | 40 (95.2) |
| >1 year | 2 (4.8) |
| Gender, male | 20 (47.6) |
| Course of disease | |
| ≥1 month | 31 (73.8) |
| <1 month | 11 (26.2) |
| Frequency of diarrhea | |
| ≥5 per day | 33 (78.6) |
| <5 per day | 9 (21.4) |
| Edema | |
| Localized edema of the eyelids, face, dorsum of the feet, and both lower extremities | 27 (64.3) |
| Generalized edema | 10 (23.8) |
| Tetany and general convulsions | 15 (35.7) |
| Single episode | 5 (11.9) |
| Recurrent episodes (≥2) | 10 (23.8) |
| Abdominal bloating | 11 (26.2) |
| Vomit | 10 (23.8) |
| Fever | 14 (33.3) |
| Lymphatic effusions | 20 (47.6) |
| Peritoneal effusion | 14 (33.3) |
| Pleural effusion | 4 (9.5) |
| Pericardial effusion | 3 (7.1) |
Data are presented as number (%). PIL, primary intestinal lymphangiectasia.
Concurrent infections and malnutrition
In our study on PIL, it was found that 31 out of 42 children had concurrent infections, resulting in a high infection rate of 73.8%. Among these cases, ten children had more than two kinds of mixed infection. The primary infection observed was a respiratory system infection, followed by sepsis. The etiology of sepsis showed 2 cases of Enterobacter cloacae, 1 case of Enterococcus faecium, 1 case of Hemolytic Staphylococcus, 1 case of Staphylococcus hominis, and 1 case of Gram-positive cocci. Additionally, ten children (23.8%) were diagnosed with malnutrition, which included 6 cases of stunting, 1 case of underweight, and 4 cases of wasting. One case presented with both stunting and underweight (Table 2).
Table 2. Nutritional status and concurrent infections in infants and young children with PIL.
| Concurrent infections and nutritional status | PIL (n=42) |
|---|---|
| Malnutrition | |
| Stunting (height for age Z-score <−2 SD) | 6 (14.3) |
| Under-weight (weight for age Z-score <−2 SD) | 1 (2.4) |
| Wasting (weight for height Z-score <−2 SD) | 4 (9.5) |
| Concurrent infections | 31 (73.8) |
| Pneumonia | 21 (50) |
| Bronchitis | 5 (11.9) |
| Sepsis | 6 (14.3) |
| CDAD | 3 (7.1) |
| Oral candidiasis | 2 (4.8) |
| Cytomegalovirus infection | 2 (4.8) |
| Rotavirus | 1 (2.4) |
| Urinary tract infection | 1 (2.4) |
Data are presented as number (%). CDAD, clostridioides difficile-associated diarrhea; PIL, primary intestinal lymphangiectasia; SD, standard deviation.
Laboratory tests
The total serum protein and albumin levels notably declined in 42 children diagnosed with PIL, with concurrent reductions observed in prealbumin and fibrin levels to varying extents. All children exhibited electrolyte imbalances, most notably decreased levels of magnesium and calcium in the blood. Specifically, hypomagnesemia was present in 88.1% of cases, while hypocalcemia was evident in 61.9% of cases. Lymphopenia was evident in 85.7% of cases, while haemoglobin levels dropped in 54.8% of cases. The greatest reduction in immunoglobulins was observed for IgG, with 73.2% of children showing a decrease. This was followed by reductions in IgM and IgA (Table 3).
Table 3. Laboratory indicators for infants and children with PIL.
| Laboratory testing | PIL (n=42) |
|---|---|
| Total protein (<60 g/L) | 42 (42/42, 100%) |
| Albumin (<35 g/L) | 42 (42/42, 100%) |
| Globulin (<20 g/L) | 41 (41/42, 97.6%) |
| Prealbumin (<150 g/L) | 35 (35/42, 83.3%) |
| Fibrinogen (<2 g/L) | 26 (26/41, 63.4%) |
| Triglyceride (>1.7 mmol/L) | 3 (3/42, 7.1%) |
| High density lipoprotein (<1 mmol/L) | 36 (36/42, 85.7%) |
| Potassium (<3.5 mmol/L) | 14 (14/42, 33.3%) |
| Sodium (<135 mmol/L) | 20 (20/42, 47.6%) |
| Phosphorus (<1.25 mmol/L) | 12 (12/42, 28.6%) |
| Magnesium (<0.8 mmol/L) | 37 (37/42, 88.1%) |
| Total calcium (<2.1 mmol/L) | 26 (26/42, 61.9%) |
| Blood glucose (<3.9 mmol/L) | 1 (1/42, 2.4%) |
| Alanine transaminase (>40 U/L) | 14 (14/42, 33.3%) |
| Hemoglobin (<110 g/L) | 23 (23/42, 54.8%) |
| Absolute lymphocyte count (<1.48×109/L) | 36 (36/42, 85.7%) |
| Total leukocyte count (<4×109/L) | 15 (15/42, 35.7%) |
| Erythrocyte sedimentation rate (>20 mm/h) | 1(1/31, 3.2%) |
| IgA (<0.08 g/L) | 20 (20/41, 48.8%) |
| IgG (<1.8 g/L) | 30 (30/41, 73.2%) |
| IgM (<0.2 g/L) | 21 (21/41, 51.2%) |
| IgE (>15 IU/mL) | 9 (9/41, 22.0%) |
Values in parentheses represent the threshold of abnormality (cutoff values), denominators indicate number of patients tested for each parameter. IgA, immunoglobulin A; IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M; PIL, primary intestinal lymphangiectasia.
Radionuclide scintigraphy
Infants and young children with PIL underwent a Technetium-99m Labeled Human Serum Albumin (99mTc-HSA) imaging examination, revealing intestinal protein loss in 39 cases. Of these, 12 cases exhibited protein loss in the jejunum or above, 4 cases in the ileum or above, and 5 cases in the terminal ileum or above. Eighteen cases had unspecified locations of protein loss. Additionally, children received concurrent Technetium-99m Labeled Dextran (99mTc-DX) lymphoscintigraphy, showing possible thoracic duct outlet obstruction in 12 cases and increased abdominal radioactivity in 15 cases. Intestinal tube-like radioactive concentration or local radioactivity elevation in the abdomen was observed in 13 cases, and two cases displayed diffuse abdominal radioactivity augmentation.
Endoscopy and pathology results
Infants and young children with PIL underwent gastroscopy and gastric and duodenal mucosal biopsy pathology. During endoscopy, 29 cases presented scattered white snowflakes and granules in the duodenum. Despite no visualized endoscopic findings in 9 children, typical features of lymphangiectasia were evident in the pathology results. Pathological examination of the duodenal mucosa revealed tortuous and dilated lymphatic vessels in the mucosa and submucosa in 28 cases, along with infiltration of monocytes, lymphocytes, and eosinophils in some instances. Positive immunohistochemical staining for the lymphatic endothelial marker D2-40 was observed in 27 cases. Seven children exhibited the typical endoscopic features of PIL. However, histopathology may have been limited by the depth of sampling and did not reveal the characteristic dilation of lymphatic vessels (Figure 1).
Figure 1.
Images of typical endoscopic and histopathological features of PIL in children. (A) Endoscopy revealed diffuse white granular changes in the mucosa of the descending duodenum (as indicated by the black arrow) (magnification ×2.5). (B) Histopathological examination of the duodenal mucosal tissue (descending portion) showed dilated lymphatic vessels (as indicated by the black arrow) (H&E staining, magnification ×100). (C) Histopathological examination of the duodenal mucosal tissue (descending portion) demonstrated positivity for the lymphatic endothelial marker D2-40 (as indicated by the black arrow) (immunohistochemical staining, magnification ×100). H&E, hematoxylin and eosin; PIL, primary intestinal lymphangiectasia.
Internal medicine and dietary nutritional treatment
Forty-two children were administered albumin infusion for hypoalbuminemia, 37 of whom also received diuretics. Twenty-four cases were treated with immunoglobulin, 11 with plasma transfusion, and 17 with red blood cell transfusion for severe anaemia. All the children presented varying levels of electrolyte imbalance and were treated accordingly. One child underwent abdominal puncture for excessive ascites. Nutritional interventions included formula containing MCT, high-protein, long-chain fatty acid-restricted dietary adjustment therapy, along with fat-soluble vitamins supplementation. In severe cases, 31 children received partial or total parenteral nutrition before transitioning to enteral nutrition containing MCT following improvement in gastrointestinal symptoms. In cases of severe diarrhea, four children were treated with octreotide, with a success rate of 3 out of 4 (Table 4).
Table 4. Treatment of infants and young children with PIL.
| Treatment | PIL (n=42) |
|---|---|
| Medical treatment | |
| Intravenous administration of albumin | 42 (100.0) |
| Diuretics | 37 (88.1) |
| Correcting electrolyte imbalances | 42 (100.0) |
| Intravenous administration of immunoglobulin | 24 (57.1) |
| Octreotide | 4 (9.5) |
| Plasma infusion | 11 (26.2) |
| Red blood cell transfusion | 17 (40.5) |
| Paracentesis or thoracentesis | 1 (2.4) |
| Nutritional therapy | |
| Parenteral nutrition | 31 (73.8) |
| Dietary therapy composed of high protein and medium-chain triglycerides | 42 (100.0) |
| Fat-soluble vitamins | 42 (100.0) |
Data are presented as number (%). PIL, primary intestinal lymphangiectasia.
Evaluation of efficacy after treatment
After receiving medical assistance and dietary therapy, children were assessed for treatment effectiveness at discharge. Forty-two children diagnosed with PIL underwent assessment to measure their clinical conditions, such as resolution of diarrhea and reduction of edema, along with monitoring serum albumin and absolute lymphocyte count levels pre- and post-treatment. The findings indicated significant improvement in 3 cases, improvement in 36 cases, and ineffectiveness in 3 cases. A comparison of serum albumin and absolute lymphocyte counts before and after treatment revealed a significant increase in albumin levels post-treatment, demonstrating statistical significance (P<0.001) (Table 5).
Table 5. Efficacy after treatment of infants and young children with PIL.
| Laboratory metrics | At diagnosis | After therapy | t/Z | P |
|---|---|---|---|---|
| Albumin (g/L) | 20.2±6.4 | 29.6±7.1 | −6.368 | <0.001 |
| Absolute lymphocyte count (×109/L) | 1.34 (0.74, 1.29) | 1.63 (0.85, 2.08) | −1.624 | 0.10 |
| Clinical manifestations | ||||
| Diarrhea | 42 [100] | 4 [9.5] | ||
| Pedal edema | 37 [88.1] | 7 [16.7] | ||
| Therapeutic effect | Improved, 39 [92.9] | Ineffectiveness, 3 [7.1] |
Data were presented as n [%], or mean ± standard, or median (interquartile range). Treatment efficacy was assessed at discharge, with a median length of stay of approximately 3 weeks. PIL, primary intestinal lymphangiectasia.
Discussion
PIL is a rare protein-losing intestinal disorder affecting both children and adults, presenting challenges for prospective research due to its low prevalence. This retrospective study examined the clinical data of 42 infants and young children diagnosed with PIL at Beijing Children’s Hospital over the past 8 years. The findings revealed that the majority of cases (95.2%) were diagnosed in infants under 1 year old. Common clinical signs observed in the children included watery and mushy stools (100%) and edema (88.1%), along with abdominal distension, vomiting, and other symptoms; gastrointestinal bleeding was infrequent. Lymphatic effusions were present in 20 cases (47.6%).
These results are similar to previous studies on the incidence of oedema and lymphatic effusions in patients with PIL. For instance, in a paediatric study, a cohort of 28 children diagnosed with PIL revealed a prevalence of recurrent systemic oedema (64%), foot oedema (93%), chronic diarrhoea (78.6%), and various occurrences of ascites, pleural effusion, and pericardial effusion (9). Another retrospective analysis of 84 cases of PIL reported limb oedema in 78% of patients, ascites in 41% and diarrhoea in 62% (10). A Chinese study showed that the main manifestations of PIL in 50 cases were oedema (86%), ascites (48%), and diarrhoea (76%) (11). However, the incidence of diarrhoea in our cohort was relatively high, potentially reflecting selection bias towards gastrointestinal symptoms, as all enrolled children were infants and toddlers admitted to the gastroenterology ward.
This study assessed the nutritional status of children and found that 23.8% of infants and young children with PIL were malnourished, primarily due to stunting, with a low incidence of being underweight. The data on underweight might be underestimated due to factors like edema. The research showed that all children experienced decreased serum total protein and albumin (100%), with varying degrees of reductions in prealbumin (83.3%), immunoglobulin G (IgG) (73.2%), and fibrin (63.4%). The results revealed a widespread decline in serum protein indicators among infants and young children with PIL. Additionally, this study found that some children had elevated alanine transaminase levels, which may be related to the pathophysiological changes or complications of the disease itself, such as increased hepatic metabolic burden due to massive protein loss, malabsorption of nutrients (such as vitamin deficiency), disrupting the stability of liver cell membranes, and secondary infections. However, further and more in-depth research is needed to confirm the exact factors.
A relatively high proportion of children presented with anemia (54.8%) in this study, with 40.5% of cases requiring red blood cell transfusion due to severe anemia. Anemia in children with PIL has been rarely discussed. One case report in adults with PIL described iron deficiency anemia secondary to gastrointestinal bleeding (12). Another report highlighted a chronic refractory anemia in an adult patient with PIL; nutritional therapy was found to alleviate symptoms of protein-losing enteropathy, but did not resolve anemia (13). Gastrointestinal bleeding in patients with PIL is exceptional and is secondary to small non-specific ulcers on the intestinal mucosa or a possible decrease in the clotting factors (14). Our study concluded that infants and young children with PIL had a high prevalence of severe anemia, almost no gastrointestinal bleeding symptoms, often necessitating red blood cell transfusion despite aggressive nutritional intervention. Some studies have suggested that the high incidence of anemia may be related to chronic occult bleeding caused by malabsorption or vascular malformations (3,15,16). However, further in-depth research is needed to explore the causes and mechanisms. In summary, gastrointestinal bleeding was not typical in patients with PIL, but anemia may still be a common manifestation of PIL in infants and young children.
This study revealed that children had hypomagnesemia (88.1%), hypocalcemia (61.9%), hyponatremia (47.6%), hypokalemia (33.3%), and hypophosphatemia (28.6%). Among these cases, 31% involved hypokalemia and hypomagnesemia, 21.4% involved hypomagnesemia and hypophosphatemia, and 4.8% involved hypokalemia and hypophosphatemia. This study demonstrates that electrolyte disorders were prevalent among all infants and young children with PIL, particularly showing a higher incidence of decreased levels of blood magnesium and blood calcium. There was a higher prevalence of hypomagnesaemia than hypocalcaemia. Various factors contribute to low magnesium levels in children, such as inadequate dietary intake, gastrointestinal malabsorption, excessive renal excretion, drug-related causes, and endocrine influences. In the case of patients with PIL, hypomagnesemia is primarily attributed to losses from diarrhea, impaired absorption, reduced albumin levels, and other related factors (17).
It is worth noting that this study found that children with PIL had a high incidence of tetany and generalized convulsions (35.7%), and that recurrent episodes of convulsions were the main type. Both hypomagnesemia and hypocalcemia can cause neuromuscular hyperexcitability, leading to carpopedal spasm and epileptic seizures. In this study, hypomagnesemia (93.3%) and hypocalcemia (60%) were observed among children with tetany and generalized convulsions (n=15), with incidence rates higher than those of hyponatremia and hypokalemia (both 26.7%). Previous studies have shown that vitamin D deficiency and hypomagnesaemia were significant factors in the manifestation of tetany; hypocalcaemic tetany is an uncommon presentation in PIL (6). Hypomagnesemia can impact the functionality of nerve, muscle, and cardiac conduction systems by inducing changes in the excitatory membrane (18). Hypomagnesemia often presents with nonspecific symptoms. Early manifestations may include fatigue and gastrointestinal disturbances, while severe deficiency can cause neuromuscular excitability (tremors, fasciculations, cramps), seizures, cardiac arrhythmias, and neuropsychiatric changes. Clinical symptoms of hypomagnesemia are often correlated with a rapid decrease in magnesium levels compared to a gradual change (19). Moreover, magnesium ion homeostasis is interconnected with calcium levels, as magnesium deficiency can disrupt cyclic adenosine monophosphate production by magnesium-dependent adenylate cyclase, leading to decreased parathyroid hormone (PTH) release and exacerbating hypocalcemia (20). Therefore, it is critical to test the serum levels of magnesium, calcium, vitamin D, and PTH in children with PIL, especially those with tetany and generalized convulsions.
Infants and young children with PIL may be at higher risk of hypocalcemia and vitamin D deficiency due to chronic diarrhea and malabsorption of fat. A study showed that 25% (7/28) of patients with PIL experienced symptomatic hypocalcemia (tetany) (9). Limb convulsions can serve as an early sign of PIL in children (21,22). Notably, our investigation revealed a notably elevated occurrence of athermal tetany and generalized convulsions (35.7%) among patients with PIL, likely associated with reduced serum calcium and magnesium levels. Consequently, recurrent limb convulsions, hypocalcemia, and hypomagnesemia in infants should be considered as potential diagnostic indicators of PIL. Furthermore, certain conditions like Hennekam syndrome, linked to intestinal lymphangiectasia and seizures, necessitate careful consideration during differential diagnosis (5,6,23). Both hypomagnesemia and hypocalcemia can trigger heightened neuromuscular activity. The simultaneous presence of these two conditions increases the likelihood of seizures. Moreover, decreased magnesium levels can lower the threshold for tetany and generalized convulsions induced by hypocalcemia (24). Therefore, for children with PIL experiencing convulsions due to low magnesium and calcium levels, it is crucial to correct both mineral imbalances. For patients with hypocalcemia, if calcium supplementation is ineffective, blood magnesium levels must be checked. If hypomagnesemia is also present, hypomagnesemia should be corrected first, or both conditions should be corrected simultaneously; otherwise, hypocalcemia will be difficult to improve. In addition, it should be noted that a decrease in albumin can lead to a “false” decrease in total calcium measurements. It is necessary to assess the true level of ionized calcium rather than blindly supplementing calcium. Vitamin D deficiency and hypomagnesemia played a significant role in the tetany manifestation; vitamin D supplementation is frequently advised along with calcium to enhance absorption when hypocalcemia is due to vitamin D deficiency (6).
Patients with PIL are at risk of potential immune dysfunction due to lymphocytopenia and hypogammaglobulinemia; there have been reports of individual cases of opportunistic infections (25). Recurrent, multiple, and severe infections often complicate both diagnostic evaluation and therapeutic management of PIL, especially in children. A concurrent infection rate of 73.8% was observed in children with PIL in this study, primarily involving respiratory system infections, followed by sepsis. Therefore, special attention should be directed towards infection prevention and prompt anti-infective treatment in children with PIL. Studies indicate that low CD4 counts and IgG levels in children with PIL are linked to recurrent and opportunistic infections, increasing morbidity and mortality rates (26). However, no correlation was found in this study between infection rates and reduced IgG levels.
The diagnosis of PIL typically relies on identifying characteristic endoscopic features and conducting histopathology examination of the small intestine. Our research indicated that endoscopic findings may not always align precisely with histological results. Despite no visualized endoscopic findings in 9 children, typical features of lymphangiectasia were evident in the pathology results. Even when endoscopic findings appear normal, underlying histopathological abnormalities may still be present, emphasizing the importance of obtaining tissue samples for confirmation. In addition, in instances of segmental or localized lesions, negative results from gastrointestinal endoscopy may necessitate further investigation through capsule endoscopy and enteroscopy for precise detection and localization. Capsule endoscopy may be useful for diagnosing intestinal lymphangiectasia in children and determining both the extent of the lesions and appropriate follow-up (27). Enteroscopy is preferred when a histopathological biopsy is needed. Additionally, seven children exhibited characteristic endoscopic features of PIL (white villi, lymphangiectasia), but histopathology may be limited by sampling depth, etc., and typical lymphatic vessel dilation was not observed. In these cases, diagnosis was ultimately confirmed by functional studies, scintigraphy demonstrated intestinal protein loss or lymphatic malformation in these cases, while clinical response to MCT-based diet provided additional supportive evidence.
There are currently no standardized recommendations and guidelines for the clinical treatment and management of PIL in children. However, dietary therapy remains the primary approach for treating PIL. This includes restricting long-chain fatty acids, supplementing with MCT, and providing a high-protein nutritional diet for children with PIL. The study primarily focused on infants, who were mainly treated with enteral nutrition preparations containing MCT. These preparations typically had an MCT content ranging from 50% to 60%, with three exceptional cases receiving short-term (<1 month, the short-term duration was intentionally limited to prevent essential fatty acid deficiency), high-MCT formulations (87–97% MCT content). The majority of children showed positive treatment response and tolerance to this approach. In cases where MCT diet therapy is ineffective, this may be related to factors such as severe and widespread involvement or irreversible structural abnormalities of the lymphatic systemin in children with PIL, resulting in limited treatment efficacy. For severe cases or children unable to tolerate dietary therapy, parenteral nutrition can be considered as an alternative treatment. Other potential treatment options include combining drug therapies such as octreotide, corticosteroids, anti-plasmin, heparin, rapamycin, and everolimus with dietary interventions (21). Our research showed that 4 severely ill children were treated with octreotide in conjunction with enteral nutrition, resulting in effectiveness for 3 cases and poor outcomes for 1 case. Octreotide, a somatostatin analogue, is known to reduce splanchnic blood flow, intestinal motility, and triglyceride absorption, making it a potential treatment option for patients unresponsive to dietary therapy. Research shows octreotide may help to maintain serum albumin levels, improve clinical findings, and decrease the requirement of albumin infusions in refractory cases of PIL (28). But it is suggested that octreotide be reserved for patients with localized intestinal lymphatic involvement, as its efficacy may be limited in cases of generalized lymphangiectasia. As per some experts’ recommendations, sirolimus is an effective and safe drug and can be the first drug of choice for patients with extensive lymphangiectasis (29).
In addition to dietary and nutritional therapy, children with PIL often require comprehensive supportive treatment, including albumin infusion, diuretic therapy, correction of electrolyte imbalances, treatment for anemia, intravenous immunoglobulin infusion, and antimicrobial therapy. For patients with significant fluid accumulation, invasive procedures such as needle aspiration and drainage are required. In this study, all patients received albumin supplementation therapy, with 24 of them also receiving intravenous immunoglobulin infusion. It is important to emphasize that the specific dosage and duration of intravenous albumin and immunoglobulin as alternative therapies should be dynamically adjusted based on the patient’s levels and clinical scenarios (5), such as edema severity, fluid accumulation volume. It is worth noting that improvements in biochemical indicators following albumin infusion often have a temporary nature. Studies indicate that albumin infusions may transiently increase serum albumin levels, though this elevation does not necessarily correlate with meaningful clinical improvement (30). Therefore, healthcare providers should be cautious not to mistakenly equate the post-infusion elevation of albumin levels with clinical improvement. In terms of treatment strategy, albumin infusion is primarily indicated for symptomatic management in patients with massive serous pleural effusion or severe edema. During the acute phase of treatment, short-term albumin infusion exerts a transitional therapeutic effect by increasing plasma colloid osmotic pressure (23). However, due to ongoing intestinal protein loss, the effects of this treatment are transient and essentially represent symptomatic relief rather than curative therapy. Therefore, long-term, effective etiological treatment remains the primary therapeutic strategy.
PIL is generally considered a mild disease, with a positive outlook for most affected children. Effective management can greatly enhance clinical outcomes, normalize lab results, and aid in recovery and growth (31). A study by Desai et al. found that 63% of 27 patients with PIL treated with MCT experienced improvement (32), while 63% of 38 children with PIL benefited from dietary intervention (10). Long-term dietary therapy is often crucial for treatment success, particularly in pediatric cases (3). Our study assessing 42 infants and children with PIL revealed positive outcomes in 39 cases, though 3 cases showed no improvement. Most of the treatment was effective and well tolerated; clinical symptoms and laboratory tests were improved to some extent. It is worth noting that most of the children’s symptoms improved, but laboratory indices did not completely return to normal. While treatments are generally well-received and effective, some challenges persist in managing PIL, especially in severe cases that may have a poor prognosis. Further research is needed to develop more effective treatments for these cases to improve symptoms and outcomes.
This study is subject to certain limitations. Firstly, PIL is a rare disease, and this research was confined to a single centre, so there is a limited number of cases. Secondly, the study was retrospective, with clinical data primarily sourced from case reviews. Consequently, some data may be incomplete, and certain key indicators, such as the type of anaemia (microcytic, normocytic or macrocytic) and the underlying mechanisms (iron, vitamin B12 or folate deficiency), ionic calcium, faecal alpha-1-anti-trypsin and vitamin D, may not have been analysed thoroughly due to incomplete testing data. Furthermore, our study has several limitations with regard to electrolyte abnormalities. While electrolyte disturbances in PIL may reflect enteric losses, clinicians should remain vigilant for refeeding syndrome, as this cannot be excluded as a contributor to the observed hypomagnesaemia, hypokalaemia, and hypophosphataemia, particularly in patients with severe malnutrition who received aggressive nutritional support. Lastly, as the study conducted at Beijing Children’s Hospital focused on evaluating the treatment response at discharge, treatment efficacy was assessed during hospitalisation (median duration about 3 weeks). Most children achieved resolution of acute symptoms with initial nutritional therapy, which was a temporary treatment response. All patients required ongoing MCT dietary therapy after discharge. Although we observed promising short-term outcomes, the retrospective nature of the study and the nationwide distribution of patients prevented us from conducting a comprehensive assessment of long-term treatment efficacy. The lack of standardised follow-up data significantly limits our ability to assess sustained treatment efficacy, and our inability to track long-term outcomes and recurrence rates substantially constrains our ability to interpret treatment durability. Therefore, we deeply regret the incompleteness of clinical data and long-term follow-up data, as this is both a limitation of this study and an important direction for future prospective studies.
Conclusions
PIL is an uncommon condition in infants and young children, typically observed in those under the age of one. When presented with symptoms such as diarrhea, edema, recurrent limb convulsions, low calcium, and low magnesium, consideration should be given to a potential diagnosis of PIL. The diagnosis of PIL requires a multimodal approach, with endoscopic visualization of characteristic lymphatic dilation (e.g., white villi, mucosal speckling) providing diagnostic clues, while histopathological confirmation remains the gold standard for definitive diagnosis. While there is a lack of robust evidence guiding specific treatment approaches, dietary and nutritional interventions were generally regarded as safe and beneficial for the management of PIL in most affected infants and young children.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Clinical Research Ethics Committee of Beijing Children’s Hospital Affiliated to Capital Medical University of the National Children’s Medical Center (No. [2024]-E-093-R), and the requirement for informed consent was waived due to the retrospective nature of this research.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-187/rc
Funding: This work was supported by research grants from the National Key R&D Program of China (No. 2022YFC2703603), Beijing Natural Science Foundation (No. J230009), and High-Level Public Health Technical Personnel Project (Academic leader-02-04).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-187/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-187/dss
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