A 30-year-old woman was diagnosed with systemic lupus erythematosus (SLE) in 2010 based on alopecia, facial rash, skin, biopsy-confirmed lupus nephritis, positive antinuclear antibodies and anti–double stranded DNA antibodies, and low complement levels. Over the past decade, her maximum exposure to prednisone was 40 mg/day with a minimum maintenance dose of 15 mg/day. She had been treated with multiple immunosuppressants including hydroxychloroquine, cyclophosphamide, mycophenolate mofetil, leflunomide, methotrexate, and azathioprine, due to persistent disease activity. Between 2020 and 2024, she was hospitalised multiple times for high fever, alopecia, facial rash, oral ulcers, vasculitis-like rash on the hands and scalp (online supplementary Fig 1a), and foamy urine (biopsy-confirmed lupus nephritis [class V and IV]) [online supplementary Fig 1b]. During each episode, macrophage activation syndrome (MAS) was identified using the HLH-2004 criteria based on elevated inflammatory indicators [C-reactive protein, interleukin 6 (IL-6), ferritin, C-X-C motif chemokine ligand 10 (CXCL10), chemokine (C-C motif) ligand 5 (CCL5), and interleukin-2 receptor], interferon genes (IFI44, MX1, and IRF1), and immune cell fluctuations (CD64 on neutrophils, CD4⁺ T cells, and CD8⁺ T cells). Dexamethasone and etoposide were administered during acute phases, and sequentially adjusted to cyclosporin A, mycophenolate mofetil, tacrolimus, tofacitinib, baricitinib, ruxolitinib, and telitacicept due to recurrent alopecia, rash, and joint pain. Despite these interventions, MAS relapsed, and prednisone could not be reduced below 30 mg/day.

In September 2023, 1 month after the last MAS episode, the patient again presented with MAS symptoms, including high fever (39°C), alopecia, vasculitis-like scalp rash, and oral ulcers (online supplementary Fig 1a). Laboratory tests revealed leukopenia (white blood cell count=1.25×10⁹/L), thrombocytopenia (platelet count=54×10⁹/L), anaemia (haemoglobin level=108 g/L), elevated C-reactive protein level (73.88 mg/L), erythrocyte sedimentation rate (78 mm/h), lactate dehydrogenase level (592 U/L), ferritin level (4508 ng/mL), splenomegaly, and no schistocytes. Extensive infectious workups, including blood cultures, next-generation sequencing, galactomannan, beta-D-glucan, T-SPOT, echocardiography, bone marrow biopsy, and high-resolution computed tomography, were negative, confirming a diagnosis of SLE-MAS. Given the recurrent nature of her condition, whole-exome sequencing was performed, identifying variants in GATA2 and MEFV of unclear significance (online supplementary Fig 2).

Multidimensional immune endotyping to evaluate disease conditions revealed: (1) abundant autoantibodies (online supplementary Fig 1c), high double-stranded DNA levels (>100 IU/mL detected by the Farr method) and low C3/C4 levels, indicating active SLE; (2) marked hyperinflammation with elevated levels of IL-6 (86.86 pg/mL), interferon gamma (IFN-γ) [42.18 pg/mL], C-reactive protein (99.99 mg/L), serum ferritin (6769 ng/mL), interleukin-2 receptor (1602 U/mL), CXCL10 (233.12 pg/mL) and CCL5 (27996.33 pg/mL); (3) upregulated interferon-stimulated genes (IFI44 176.59, MX1 328.63, and IRF1 84.32); and (4) immune dysregulation with increased neutrophil CD64 index, elevated CD8⁺ T cells, and decreased CD4⁺ T cells (Fig 1). Initial high-dose dexamethasone (10 mg every 12 hours) and cyclosporin A failed to control MAS with recurrence of fever and symptoms after 3 days. Given prior etoposide treatment and the risk of pancytopenia and infection, the treatment regimen was adjusted to include increased dexamethasone, tacrolimus, and intravenous immunoglobulin. Persistent inflammation led to the initiation of emapalumab (50 mg) on day 16 of hospital stay. Within 24 hours, fever subsided, and levels of C-reactive protein, IL-6, IFN-γ, CD64 on neutrophils, and interferon gene expression improved. Emapalumab was administered biweekly for four doses, significantly reducing steroid dependence and shortening the duration of hospitalisation. Three weeks later, the patient was discharged on oral prednisolone (60 mg/day) and tacrolimus (1 mg twice daily). One month later, tacrolimus was switched to baricitinib due to severe hair loss. At 9-month follow-up, inflammation and organ function normalised, enabling tapering of prednisone to 7.5 mg/day with baricitinib (Fig 2). The immune endotype changes, particularly CD8⁺ T-cell proliferation, were identified as a risk factor for MAS in this patient.

Emapalumab has been successfully administered in children with primary haemophagocytic lymphohistiocytosis and relapsed/refractory haemophagocytic lymphohistiocytosis.1 In our case, we jointly assessed the inflammatory state, interferon gene expression, and immune cell fluctuations to quickly identify this patient with SLE-MAS.

Patients with SLE and MAS have a high mortality rate,2 partly due to the difficulty in reaching an early MAS diagnosis since clinical features overlap with those of other conditions. Identifying immune endotypes may help detect MAS early. Interferon gamma plays a key role in SLE by activating neutrophils, CD8⁺ and CD4⁺ T cells, and macrophages, with its dysregulation contributing to MAS pathogenesis.3 In our patient, MAS presented as severe inflammation unresponsive to steroids or immunosuppressants but was effectively controlled by emapalumab. We observed elevated IFN-stimulated genes (IFI44, MX1, and IRF1) that normalised following emapalumab treatment.

Before treatment, the patient exhibited increased CXCL10 and CCL5 levels. Inflammatory markers were elevated, with cell analysis showing increased CD64⁺ neutrophils and CD8+ T cells, alongside reduced CD4⁺ T cells. In MAS, the percentage of CD8⁺ T cells outnumbers that of CD4⁺ T cells. Following emapalumab treatment, these abnormalities resolved, suggesting that excessive type II IFN signalling and CD8⁺ T cell overactivation drive SLE-MAS, potentially defining it as a distinct SLE subtype rather than a mere complication.

This case provides initial clinical evidence for the efficacy of emapalumab in refractory SLE-MAS although these findings are limited by the single-case nature and require validation in larger cohorts. The case highlights the importance of precise immune profiling in SLE-MAS and supports the use of emapalumab as a potential therapeutic strategy for refractory cases.

Concept or design: L Gu.
Acquisition of data: R Guo.
Analysis or interpretation of data: R Guo, S Ye.
Drafting of the manuscript: R Guo, L Gu.
Critical revision of the manuscript for important intellectual content: S Ye, L Gu.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study was supported by Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China (Grant Nos.: 2019NYLYCP0202 and RJTJ24-MS-020). The funder had no role in study design, data collection, analysis, interpretation, or manuscript preparation.

The study was approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China (Ref No.: 2016-083). The patient was treated in accordance with the Declaration of Helsinki. Informed patient consent was obtained for publication of this case report, including the accompanying clinical images.

The supplementary material was provided by the authors and some information may not have been peer reviewed. Accepted supplementary material will be published as submitted by the authors, without any editing or formatting. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by the Hong Kong Academy of Medicine and the Hong Kong Medical Association. The Hong Kong Academy of Medicine and the Hong Kong Medical Association disclaim all liability and responsibility arising from any reliance placed on the content.

1. Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med 2020;382:1811-22. Crossref

2. Borgia RE, Gerstein M, Levy DM, Silverman ED, Hiraki LT. Features, treatment, and outcomes of macrophage activation syndrome in childhood-onset systemic lupus erythematosus. Arthritis Rheumatol 2018;70:616-24. Crossref

3. Pollard KM, Cauvi DM, Toomey CB, Morris KV, Kono DH. Interferon-γ and systemic autoimmunity. Discov Med 2013;16:123-31.

In November 2023, a 47-year-old male was admitted to our hospital for surgical management of an aneurysm in the proximal segment of the descending thoracic aorta (Fig 1). The patient reported no prior relevant medical interventions. Thoracic endovascular aortic repair (TEVAR) was planned. A left common carotid-to-left subclavian bypass, followed by covered stent-graft placement in the descending aorta, was scheduled to extend the proximal landing zone and prevent stent collapse into the aneurysm.

A covered stent graft (28 mm diameter, 150 mm long) [TAG; Gore Medical, Flagstaff [AZ], US] was deployed. Nonetheless, post-deployment angiography revealed that the stent had migrated proximally, unintentionally covering the left common carotid artery. To resolve this complication, a chimney stent was planned for the left common carotid artery. A bare metal stent (10 mm diameter, 40 mm long) [Wallstent; Boston Scientific, Marlborough [MA], US] was deployed but subsequently dislodged and migrated into the ascending aorta due to preoperative underestimation of the vessel diameter and anterior jumping of the stent during deployment (Fig 2a).

Initial attempts to retrieve the stent with a snare catheter and drag it to the femoral artery were unsuccessful (Fig 2b). Subsequently, a single-curved catheter and hydrophilic guidewire were used to selectively cannulate the migrated stent. A balloon catheter was then advanced into the stent and inflated to secure firm attachment, allowing successful traction of the stent into the right iliac artery (Fig 2c).

To restore cerebral perfusion, a second balloon-expandable stent (10 mm × 40 mm) [Express; Boston Scientific, Marlborough [MA], US] was deployed in the left common carotid artery to complete the chimney stent placement. To prevent contralateral flow obstruction and acute ischaemia in the left lower limb due to the right iliac stent, an identical stent was placed via the left femoral artery, creating a kissing stent configuration in the iliac arteries (Fig 2d). Final angiography confirmed the absence of any endoleak and demonstrated patent blood flow in the aortic arch branch vessels and both iliac arteries (Fig 2e).

The patient improved and was discharged 1 week postoperatively. Follow-up computed tomography angiography of the thoracoabdominal aorta at 6 days and 6 months postoperatively revealed proper positioning of the stents, with unobstructed blood flow within the stented vessels (Fig 3).

Thoracic aortic aneurysm (TAA) is a severe vascular disease characterised by abnormal dilation of the thoracic segment of the aorta. Between 1999 and 2020, 47 136 adults in the United States died from TAA.1 The age-adjusted mortality rate significantly decreased from 16.2 per million in 1999 to 8.2 per million in 2013 (annual percentage change: -5.00, 95% confidence interval [95% CI]= -5.54 to -4.54; P<0.001),1 highlighting the impact of targeted interventions.

Conventional management of TAA focuses on controlling blood pressure and heart rate, with elective surgery for eligible patients. Thoracic endovascular aortic repair has emerged as an effective, minimally invasive treatment. A previous study demonstrated that TEVAR significantly reduced 30-day all-cause mortality (odds ratio=0.44, 95% CI=0.33-0.59) and paraplegia (odds ratio=0.42, 95% CI=0.28-0.63) compared with open repair.2 The procedure also lowers the risk of cardiac complications, transfusion need, reoperation for bleeding, renal insufficiency, and pneumonia, with a shorter hospital stay. Nonetheless, no significant differences between the two approaches have been reported for rates of stroke, myocardial infarction, aortic reintervention, or 1-year mortality.

Another study found higher early postoperative mortality with open repair but improved long-term survival.3 Despite these advantages, TEVAR showed a higher overall mean survival rate, making it a strong contender as a first-line treatment for descending TAA. For patients with multiple co-morbidities or poor overall health, traditional open surgery carries excessive risks, further cementing TEVAR as the preferred option for this group.

When TAA is located near the supra-aortic branches, standalone TEVAR may be suboptimal. In such cases, supra-aortic branch reconstruction or bypass is necessary to extend the proximal landing zone, reducing the risk of endoleak and stent collapse into the aneurysm, and preventing catastrophic outcomes. Hybrid procedures, which combine open surgery with endovascular techniques, have emerged as a promising option for high-risk patients. Nonetheless, even hybrid repair for thoracoabdominal aortic pathology carries significant morbidity and mortality for patients deemed unfit for conventional surgery.4 As a result, lifelong regular follow-up is crucial for assessing the long-term performance of the graft.

Thoracic endovascular aortic repair and its graft-related complications—such as endoleak, stent fracture, and migration—can lead to aneurysm expansion, rupture, and the need for reintervention. A retrospective analysis of 123 patients treated with TEVAR for TAA, aortic dissection, penetrating aortic ulcer, intramural haematoma, or traumatic rupture revealed a stent stability rate of 99.1% at 1 year, 94.0% at 3 years, and 86.1% at 5 years.5 Thoracic aortic aneurysm and aortic elongation were identified as key risk factors for stent migration.

Thoracic stent-graft migration is a common complication of TEVAR. Intraoperative dislodgement of branch stents into the ascending aorta is a rare but life-threatening event. In this case, the left common carotid artery stent dislodged into the ascending aorta during the procedure. The conventional response is to convert to open surgery to retrieve the stent, but this increases surgical time and complexity and may be challenging in emergencies. Delayed revascularisation can lead to cerebral infarction or neurological impairment.

Accurate preoperative assessment of vessel diameter, appropriate oversizing, and meticulous intraoperative technique can effectively reduce the risk of stent dislodgement. In this case, a balloon catheter was used to pull the dislodged stent into the right iliac artery, followed by prompt revascularisation of the left common carotid artery, thereby minimising neurological risk. A stent was placed in the left iliac artery to prevent contralateral limb ischaemia. Intraoperative digital subtraction angiography and postoperative computed tomography angiography confirmed proper stent positioning and patency of the graft vessels.

This case demonstrates that the use of a balloon catheter to retrieve dislodged branch stents to a distal location facilitates effective endovascular management. With meticulous intraoperative monitoring, minimally invasive techniques can address complex complications, avoiding the risks associated with open surgery. This approach provides a novel endovascular strategy for managing branch stent dislodgement.

Concept or design: C Zeng, Q Min.
Acquisition of data: R Ye, Y Li.
Analysis or interpretation of data: C Zeng, Q Min, Z Le.
Drafting of the manuscript: X Duan, Q Duan.
Critical revision of the manuscript for important intellectual content: F Liu.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki and provided written informed consent for all treatments and procedures, as well as for publication of this case report and the accompanying clinical images.

1. Goyal A, Saeed H, Shamim U, et al. Trends and disparities in age, sex, ethnoracial background, and urbanization status in adult mortality due to thoracic aortic aneurysm: a retrospective nationwide study in the United States. Int J Surg 2024;110:7647-55. Crossref

2. Cheng D, Martin J, Shennib H, et al. Endovascular aortic repair versus open surgical repair for descending thoracic aortic disease: a systematic review and meta-analysis of comparative studies. J Am Coll Cardiol 2010;55:986-1001. Crossref

3. Chiu P, Goldstone AB, Schaffer JM, et al. Endovascular versus open repair of intact descending thoracic aortic aneurysms. J Am Coll Cardiol 2019;73:643-51. Crossref

4. Moulakakis KG, Mylonas SN, Avgerinos ED, Kakisis JD, Brunkwall J, Liapis CD. Hybrid open endovascular technique for aortic thoracoabdominal pathologies. Circulation 2011;124:2670-80. Crossref

5. Geisbüsch P, Skrypnik D, Ante M, et al. Endograft migration after thoracic endovascular aortic repair. J Vasc Surg 2019;69:1387-94. Crossref

A 58-year-old female presented to our hospital with 1-year history of recurrent mucous stools. She had no significant medical or family history of cancer. Laboratory tests for intestinal pathogens, rheumatological markers, and tumour markers were all within normal limits. Abdominal imaging did not reveal any abnormalities. Colonoscopy showed a laterally spreading tumour measuring approximately 25 mm × 40 mm located about 5 cm from the anal verge. The tumour exhibited granular, nodular, and lobulated features with abundant mucus adhering to the surface (Fig 1a). Despite repeated washing, mucus remained attached to the tumour surface. Subsequently, we performed indigo carmine staining, which revealed well-delineated tumour margins (Fig 1b). Endoscopic ultrasound showed the lesion originated from the mucosal layer. A local biopsy revealed a tubulovillous adenoma with high-grade dysplasia. The patient was deemed suitable for endoscopic submucosal dissection (Fig 1c to e).

Whole tumour pathology was highly unusual, which showed a combination of tubulovillous adenoma with high-grade dysplasia and a neuroendocrine neoplasm (NEN) component. Interestingly, the neuroendocrine tumour had a maximum diameter of approximately 0.3 cm, representing around 3% of the lesion. Immunohistochemistry staining revealed positive expression of CK, Syn, CD56, CgA, Ki-67 (<1%) and CD34 (Fig 2). This pathological manifestation did not align with the current classification of NENs.

About 1.5 years postoperatively, colonoscopy showed a scar at the site of the previous rectal procedure (Fig 1f). Enhanced chest and abdominal computed tomography scans showed slight thickening of the rectal mucosa without evidence of regional or distant lymph node enlargement.

Neuroendocrine neoplasms are a rare type of tumour and encompass three major subtypes: neuroendocrine tumours, neuroendocrine carcinomas and mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN). Among these, MiNENs are a special type with high invasiveness. Our case resembled a MiNEN but exhibited some distinct differences.

In this case, the pathology was special. It did not align with the current World Health Organization classification of NENs.1 These neoplasms, known as MiNENs, are characterised by a combination of neuroendocrine and non-neuroendocrine components, both of which comprise at least 30% of the neoplasm.1 Although our case shared similarities with MiNENs in terms of mixed histology, it differed significantly in the proportion of components, with the neuroendocrine tumour component constituting less than 30%. Evidently, this case did not meet the current definition of MiNENs. In fact, the definition of MiNENs remains controversial.

These mixed tumours (neuroendocrine–non-neuroendocrine neoplasms) were first described in 1924.2 In 2000, a classification system for endocrine tumours was implemented and defined mixed exocrine–endocrine carcinomas as tumours in which each component constitutes at least 30% of the neoplasm.2 In 2010, the World Health Organization classified mixed neuroendocrine and exocrine tumours as mixed adenoneuroendocrine carcinomas.2 Subsequently, in 2017, mixed adenoneuroendocrine carcinomas were reclassified as MiNENs. The term “exocrine” was replaced with “non-neuroendocrine” to encompass a broader range of possible histological variants, including glandular, squamous, mucinous, and sarcomatoid phenotypes.3 As for the threshold of at least 30% for each component, it is highly unusual for a component with a lower representation to affect the biological behaviour of a cancer.2 Nonetheless, the threshold was arbitrarily set without clinical or scientific evidence.4 Given the emergence of our case, we believe that this threshold requires further optimisation.

Regarding the pathology in our patient, we proposed the following explanations. First, there are two widely accepted hypotheses for the origin of MiNENs.5 6 7 8 The first posits that both tumour components originate from a single precursor cell but proliferate and differentiate along distinct pathways. The second hypothesis also suggests a common cellular origin. Nonetheless, it proposes that during tumour progression, a subset of the non-neuroendocrine component accumulates sufficient genetic mutations to transform into neuroendocrine cells. These theories suggest that the composition of MiNENs is dynamic, with potentially varying proportions of components at different stages of tumour development. Second, with growing health awareness and the widespread adoption of endoscopic screening, early-stage tumours are more readily identified. These early-stage neoplasms are typically smaller in size and exhibit a lower degree of malignancy. These factors collectively contribute to the evolving landscape of MiNENs diagnosis and classification, necessitating ongoing refinement of diagnostic criteria and classification systems.

In terms of endoscopic manifestation, there was something worth considering. In this case, the surface of the tumour was repeatedly washed, but mucus adhesion persisted, more similar to the manifestation of mucinous adenocarcinoma or serrated adenocarcinoma.9 Notably, the absence of classic carcinoid syndrome symptoms and negative tumour markers further set this case apart. Although villous tubular adenomas can secrete mucus, the tumour in this case exhibited unusually copious and rapid mucus production. We suspected the neuroendocrine tumour may possess paracrine functions that further stimulated secretion from the adenoma. Nonetheless, there have been no experiments supporting this viewpoint. Experimental validation in the future is needed to elucidate the potential interplay between these neoplastic entities and their secretory mechanisms.

In terms of treatment, although a definitive classification of this tumour type has not been established, the existing treatment principles for NENs remain applicable. For this patient, the neuroendocrine tumour lesion was less than 10 mm in size, with a Ki-67 index of less than 3%, classifying it as a G1 stage tumour, and there was no evidence of metastasis to other organs or tissues. We performed endoscopic submucosal dissection to remove the tumour. Nonetheless, it was important to consider the depth of resection. Resection above the muscularis mucosae may result in incomplete tumour removal, while excision below this layer risks vascular injury. We recommended resection close to the muscularis mucosa to minimise bleeding and to prevent tumour seeding into blood vessels. Another critical consideration was the extent of resection. It was imperative to ensure negative tumour margins to guarantee complete excision of the neoplasm.

Our case indicates that the current classification system for NENs remains inadequate. Specifically, there is no clear classification for tumours that contain a minor component of neuroendocrine cells, highlighting an urgent need for further refinement of MiNENs.

Concept or design: W Zhou, X Ke.
Acquisition of data: W Zhou, X Ke.
Analysis or interpretation of data: W Zhou, X Ke.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: L Liu.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided informed consent for all procedures agreement for publication of this article.

1. Washington MK, Goldberg RM, Chang GJ, et al. Diagnosis of digestive system tumours. Int J Cancer 2021;148:1040-50. Crossref

2. Díaz-López S, Jiménez-Castro J, Robles-Barraza CE, Ayala-de Miguel C, Chaves-Conde M. Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract. World J Gastrointest Oncol 2024;16:1166-79. Crossref

3. Kanthan R, Tharmaradinam S, Asif T, Ahmed S, Kanthan SC. Mixed epithelial endocrine neoplasms of the colon and rectum—an evolution over time: a systematic review. World J Gastroenterol 2020;26:5181-206. Crossref

4. Toor D, Loree JM, Gao ZH, Wang G, Zhou C. Mixed neuroendocrine–non-neuroendocrine neoplasms of the digestive system: a mini-review. World J Gastroenterol 2022;28:2076-87. Crossref

5. Frizziero M, Chakrabarty B, Nagy B, et al. Mixed neuroendocrine non-neuroendocrine neoplasms: a systematic review of a controversial and underestimated diagnosis. J Clin Med 2020;9:273. Crossref

6. Bazerbachi F, Kermanshahi TR, Monteiro C. Early precursor of mixed endocrine-exocrine tumors of the gastrointestinal tract: histologic and molecular correlations. Ochsner J 2015;15:97-101.

7. Scardoni M, Vittoria E, Volante M, et al. Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract: targeted next-generation sequencing suggests a monoclonal origin of the two components. Neuroendocrinology 2014;100:310-6. Crossref

8. Yuan W, Liu Z, Lei W, et al. Mutation landscape and intra-tumor heterogeneity of two MANECs of the esophagus revealed by multi-region sequencing. Oncotarget 2017;8:69610-21. Crossref

9. Lee CT, Huang YC, Hung LY, et al. Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival. Oncotarget 2017;8:35165-75. Crossref

A 6-year-old Chinese boy with short bowel syndrome (SBS) presented to the emergency department with excessive drowsiness. He was born full term with an unremarkable perinatal history and had good past health. At 3 years of age, he underwent extensive small bowel resection and a right hemicolectomy due to intestinal malrotation with midgut volvulus, resulting in a residual length of 66 cm of proximal small bowel and distal colon, with loss of the ileocaecal valve.

Initially dependent on total parenteral nutrition, he achieved enteral autonomy 3 years later, consuming an oral diet supplemented with vitamins, iron, and a hydrolysed formula of 1 kcal/mL, contributing approximately 20% of total energy intake. A timeline summarising key clinical events, including enteral and parenteral nutrition milestones, is presented in the Figure.

He was reviewed monthly by a multidisciplinary team with regular assessments of his nutritional status, growth parameters, and biochemical profile. He demonstrated good growth, maintaining weight and height at the 50th percentile, with regular bowel movements with daily oral loperamide. His biochemical profile, including blood counts, liver function, electrolytes, blood gas, and trace elements, remained stable throughout the follow-up period.

On this admission, the patient was drowsy and lethargic but not confused. Blood tests indicated high anion gap metabolic acidosis, with a pH of 7.31, bicarbonate 10.8 mmol/L, pCO₂ 2.9 kPa, and L-lactate 1.6 mmol/L (reference range, 1.0-2.4 mmol/L). Complete blood counts, liver enzymes, ammonia, electrolytes, glucose levels, and computed tomography of the brain were normal. D-lactic acidosis (D-LA) was confirmed by an elevated serum D-lactate concentration of 1.7 mmol/L (normal range, <0.5 mmol/L). Further enquiry revealed that one week prior, his family had switched to an alternative commercially available enteral formula containing probiotics (Lactobacillus paracasei and Bifidobacterium longum) as the original formula was temporarily out of stock (Table). The rest of his oral diet remained unchanged. Total carbohydrate (CHO) intake accounted for 40% to 50% of his total enteral intake, with the formula contributing 20%.

His condition improved rapidly with bowel rest and oral sodium bicarbonate. He was treated with a course of oral metronidazole. The probiotic-containing formula was stopped, and he was instructed to resume the original probiotic-free hydrolysed formula along with CHO-restricted meals. His carers were re-educated on CHO counting and avoidance of simple sugars. He remained clinically stable the following months, during which he maintained good dietary compliance.

Short bowel syndrome refers to a condition of intestinal malabsorption resulting from loss or surgical resection of the small intestine and is the leading cause of intestinal failure. It encompasses a heterogeneous group of patients with various aetiologies and bowel anatomies. Effective management requires a multidisciplinary approach to promote enteral autonomy, support growth, and prevent complications such as catheter-related bloodstream infections and intestinal failure–associated liver disease.

D-lactic acidosis, first described in SBS by Oh et al in 1979,1 has gained increasing recognition as a rare but serious metabolic complication. It results from intestinal malabsorption and overgrowth of colonic microbiota (eg, Lactobacillus spp, Bifidobacterium spp), leading to excessive fermentation of unabsorbed CHO. The process is exacerbated by factors such as high CHO intake, elevated gut pH, impaired gut motility, antimicrobials, probiotics, and intestinal infections. The overproduction of D-lactic acid leads to a neurological syndrome and high anion gap metabolic acidosis. Clinical manifestations include acidotic breathing, altered mental state, ataxia, slurred speech, nystagmus, gait disturbance, behavioural change, and fatigue. A high index of clinical suspicion and measurement of D-lactic acid are essential for diagnosis, as serum lactate concentration (reflecting L-lactate) is often normal.2 3

The mainstays of acute management of D-LA include correction of metabolic acidosis with bicarbonate and rehydration, restriction of enteral CHO intake, administration of poorly absorbed oral antibiotics, and avoidance of antimotility agents or lactate-containing solutions. Additional treatment may include thiamine and riboflavin supplementation, insulin, and short-chain fatty acids. Metabolic acidosis and neurological symptoms often improve rapidly with early and appropriate intervention. To prevent recurrence, CHO restriction and avoidance of D-lactate–containing foods (eg, pickles and yoghurt) are essential. In selected cases, suppression of abnormal gut flora with antimicrobials or surgery to increase bowel absorptive area may be considered.3 4

Probiotics have gained popularity as health-promoting agents in medicines and dietary supplements, including in the management of SBS to prevent and treat small intestinal bacterial overgrowth. Certain species, such as Lactobacillus casei, produce only L-lactate. Among commercially available probiotics, Lactobacillus and Bifidobacterium are the most commonly used genera.2 5 The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has summarised the latest evidence on probiotic use across various paediatric gastrointestinal disorders.6 Strain-specific benefits have been demonstrated in conditions such as acute gastroenteritis, antibiotic-associated diarrhoea, infantile colic, functional abdominal disorders, and in the prevention of necrotising enterocolitis and nosocomial diarrhoea.6

Animal studies and clinical case reports suggest that probiotics may confer potential benefits in patients with SBS through mechanisms such as enhancement of gut barrier function, suppression of pathogens, and modulation of immune responses.7 Nevertheless, clinical studies evaluating their efficacy remain limited, and there is insufficient evidence to support the routine use in SBS. Conversely, case reports have raised safety concerns, such as the development of D-LA and sepsis in children with SBS following probiotic administration.7 In our case, the addition of probiotics via the new milk formula suggests a possible role of probiotics in the development of D-LA. This highlights the need for cautious and selective use of non–D-lactate–producing probiotic strains in patients at high risk of D-LA.

This report illustrates a case of D-LA in a paediatric patient with SBS, precipitated by the intake of a probiotic-containing enteral formula. Early recognition of D-LA, based on characteristic clinical features and confirmed by D-lactate measurement, with prompt treatment to normalise acidosis and suppress D-lactate production, is essential. Cautious dietary management, including caregiver awareness of formula contents and dietary CHO restriction, is equally important. Despite the increasing medical use of probiotics, there is a lack of clinical trials to support their routine use or provide clear guidance for their use in paediatric SBS. Careful consideration is warranted, with awareness of potential strain-specific benefits and risks, particularly in patients with altered intestinal microbiota and malabsorption.

Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: BPY Leung.
Critical revision for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

The authors would like to acknowledge the multidisciplinary teams involved in the co-management of this case. Special thanks to the dietitians, Paediatric Surgery team, and Paediatric Gastroenterology team at Prince of Wales Hospital, as well as the Paediatric team at Princess Margaret Hospital, for their invaluable contributions to the care and management of the patient.

Findings from this case were presented as a poster at the 23rd Congress of the Parenteral and Enteral Nutrition Society of Asia (PENSA 2023), 19-22 October 2023, Taipei, Taiwan.

This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki and provided written informed consent for all treatments, procedures and the publication of this case report.

1. Oh MS, Phelps KR, Traube M, Barbosa-Saldivar JL, Boxhill C, Carroll HJ. D-lactic acidosis in a man with the short-bowel syndrome. N Engl J Med 1979;301:249-52. Crossref

2. Muto M, Kaji T, Onishi S, Yano K, Yamada W, Ieiri S. An overview of the current management of short-bowel syndrome in pediatric patients. Surg Today 2022;52:12-21. Crossref

3. Bianchetti DG, Amelio GS, Lava SA, et al. D-lactic acidosis in humans: systematic literature review. Pediatr Nephrol 2018;33:673-81. Crossref

4. Kowlgi NG, Chhabra L. D-lactic acidosis: an underrecognized complication of short bowel syndrome. Gastroenterol Res Pract 2015;2015:476215. Crossref

5. Höllwarth ME, Solari V. Nutritional and pharmacological strategy in children with short bowel syndrome. Pediatr Surg Int 2021;37:1-15. Crossref

6. Szajewska H, Berni Canani R, Domellöf M, et al. Probiotics for the management of pediatric gastrointestinal disorders: position paper of the ESPGHAN Special Interest Group on Gut Microbiota and Modifications. J Pediatr Gastroenterol Nutr 2023;76:232-47. Crossref

7. Reddy VS, Patole SK, Rao S. Role of probiotics in short bowel syndrome in infants and children—a systematic review. Nutrients 2013;5:679-99. Crossref

A 56-year-old man was presented to the emergency department of our institution in June 2023 and has had been followed up in our medical clinic for 1 year prior to his current hospital admission. He had been diagnosed with frequent symptomatic premature ventricular complexes with an ectopic burden of 8.2% on extended ambulatory rhythm monitoring. There were also multiple recorded episodes of non-sustained ventricular tachycardia. Beta-blocker was initiated and uptitrated according to clinical symptoms. His family history was remarkable for the sudden cardiac death of his father at the age of 64 years. Subsequent transthoracic echocardiogram of the patient revealed a global hypokinetic left ventricle with a biplane-measured left ventricular ejection fraction (LVEF) of 45%. There was mild left atrial enlargement with a two-dimensional area of 25.7 cm² but no other structural abnormalities. Computed tomography coronary angiogram showed mild to moderate coronary artery disease in three vessels and guideline-directed medical treatment was initiated. Cardiac magnetic resonance imaging (CMR) was scheduled to assess cardiac structures and function, as well as tissue characterisation for features of non-ischaemic cardiomyopathy. He had been scheduled to undergo catheter ablation for frequent symptomatic premature ventricular complexes.

The patient presented to our emergency department with out-of-hospital cardiac arrest. He had been found collapsed adjacent to a swimming pool and a bystander had initiated cardiopulmonary resuscitation. Spontaneous circulation was restored shortly after a single defibrillation delivered by an automated external defibrillator and he was transferred to our hospital immediately. On arrival at the emergency department, he was hemodynamically stable with a Glasgow Coma Scale score of 15. High-sensitive troponin I level was elevated at 44.9 ng/L. Electrocardiogram showed sinus rhythm of 71 beats/min with occasional premature ventricular complexes. There was no ST-segment elevation or significant conduction abnormalities. Bedside echocardiogram showed a similar biplane-measured LVEF of 43% with global hypokinesia. Urgent coronary angiogram showed non-occlusive moderate to severe coronary artery disease in three vessels. Given his current presentation, together with angiographic progression in coronary artery disease, complete revascularisation was performed uneventfully. He was then transferred to our cardiac care unit postoperatively for close monitoring. Inpatient CMR revealed a non-dilated left ventricle with mildly reduced LVEF of 43% with global hypokinesia. There was multifocal patchy mid-wall and subepicardial late gadolinium enhancement (LGE) at the mid-ventricular anterior, anteroseptal and anterolateral walls, as well as basal to mid-ventricular inferior and inferolateral walls (Fig 1). There was no evidence of myocardial infarct. Parametric mapping showed a mild increase in myocardial T1 with values up to 1067 ms to 1080 ms (native T1 values in healthy subjects obtained in our Aera 1.5T magnetic resonance imaging scanner [Siemens, Munich, Germany] is 996±26 ms for males), suggestive of mild diffuse interstitial fibrosis (Fig 2). Prior to hospital discharge, a transvenous implantable cardioverter defibrillator (ICD) was implanted for secondary prevention. Subsequent genetic testing identified a heterozygous pathogenic truncating variant NM_001458.5(FLNC):c.3279del p.(Gly1094Alafs^*4) in the filamin-C gene. The final clinical diagnosis was sudden cardiac arrest secondary to filamin-C variant–associated cardiomyopathy in a patient with non-dilated left ventricular cardiomyopathy (NDLVC) and mid-range ejection fraction.

The filamin-C gene encodes the filamin-C protein that plays essential roles in the sarcomere stability in cardiac muscles. Filamin-C variants have been increasingly recognised as an important cause of cardiomyopathy. It has been identified in approximately 3% to 4% of patients with dilated cardiomyopathy and commonly presents in early-to-mid adulthood with high arrhythmic risks.1

According to the 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure,2 primary prevention ICD is indicated in patients with symptomatic heart failure with an LVEF of lower than 35% despite optimal medical treatment and a reasonable quality of life. Such recommendation is supported by numerous landmark trials including MADIT (Multicenter Automatic Defibrillator Implantation Trial),3 DEFINITE (DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation),4 and SCD-HeFT (the Sudden Cardiac Death in Heart Failure Trial).5 In addition, several additional clinical risk factors should also be considered in sudden cardiac death risk assessment, especially in patients with non-ischaemic cardiomyopathy.2 These risk factors include significant LGE on CMR, younger age, and specific genotypes. Nonetheless these recommendations are ambiguous, and the guideline has not defined, for example, the burden of LGE and variant mechanisms in several high-risk genes that would warrant ICD implantation. Moreover, there are limited recommendations for primary prevention ICD in patients with heart failure with mid-range or preserved ejection fraction.

In the updated 2023 ESC Guidelines for the management of cardiomyopathies,6 a new entity of NDLVC is introduced. An algorithm for consideration of primary prevention ICD similar to that for patients with dilated cardiomyopathy is recommended in this patient population. Patient genotype and imaging features on CMR have been proposed in the early sudden cardiac death risk assessment for patients with NDLVC. A previous study has demonstrated a higher rate of malignant arrhythmic events in patients who are genotype-positive, compared with their genotype-negative counterparts.7 Such association has been observed irrespective of LVEF. Variants in certain genes including lamin A/C, phospholamban, filamin-C, RNA-binding motif protein 20, desmoplakin and plakophilin-2 are associated with a high risk of malignant ventricular arrhythmias and sudden cardiac death. Apart from genotype information, the presence and distribution of LGE on CMR, such as a ring-like pattern of LGE, has also been shown to be a strong risk marker for ventricular arrhythmias.8 Hence, based on the current ESC Guidelines,6 primary prevention ICD should be considered in patients with NDLVC and high-risk genotype and in the presence of additional risk factors such as syncope and LGE on CMR, irrespective of LVEF.

Our case highlights the need to incorporate a patient’s genotype and imaging features on CMR into the personalised risk assessment for sudden cardiac death in patients with NDLVC. This will facilitate a more comprehensive and informative discussion about the indication for primary prevention ICD and improve the clinical outcome for patients with cardiomyopathy.

Concept or design: KWC Lun, DPH Lee.
Acquisition of data: All authors.
Analysis or interpretation of data: KWC Lun, DPH Lee.
Drafting of the manuscript: KWC Lun, DPH Lee.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided consent for all treatments and procedures, and consent for publication of the case report.

1. Agarwal R, Paulo JA, Toepfer CN, et al. Filamin C cardiomyopathy variants cause protein and lysosome accumulation. Circ Res 2021;129:751-66. Crossref

2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726. Crossref

3. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83. Crossref

4. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151-8. Crossref

5. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37. Crossref

6. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023;44:3503-626. Crossref

7. Escobar-Lopez L, Ochoa JP, Mirelis JG, et al. Association of genetic variants with outcomes in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol 2021;78:1682-99. Crossref

8. Meier C, Eisenblätter M, Gielen S. Myocardial late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (CMR)—an important risk marker for cardiac disease. J Cardiovasc Dev Dis 2024;11:40. Crossref