Multimodal imaging of a left anterior descending artery fistula with a dissecting interventricular septal aneurysm: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Multimodal imaging of a left anterior descending artery fistula with a dissecting interventricular septal aneurysm: a case report
Danling Xie, MD; Guoliang Yang, PhD; Chun Li, MD; Hui Li, MS; Xianglin Hao, PhD; Yun Zhang, MD; Mingxun Xie, MD; Yali Xu, PhD
Department of Ultrasound, The Second Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing, China
 
Corresponding author: Dr Yali Xu (xuyali1976@163.com)
 
 Full paper in PDF
 
Case presentation
A 37-year-old male attended for evaluation of an interventricular septal (IVS) mass incidentally discovered during a routine physical examination. On admission he was hypertensive at 153/85 mm Hg) with heart rate 93 bpm. Electrocardiogram findings revealed occasional premature ventricular contractions with horizontal ST-segment depression and T-wave inversion, suggestive of myocardial ischaemia. Laboratory results were normal. Transthoracic echocardiography (TTE) identified a well-defined, ovoid mass within the inferior segment of the IVS, appearing as a complex solid-cystic mass lesion. The mass measured approximately 35 × 31 × 40 mm3 (anteroposterior × transverse × longitudinal) [Fig 1a]. The left ventricular apical cavity was compressed by the mass. Colour Doppler imaging showed blood flow within the lesion, with diastole filling and systole outflow (Fig 1b). Notably, the cystic cavity exhibited minimal changes during the cardiac cycle. Continuous-wave Doppler at the lesion (Fig 1c) revealed bidirectional blood flow across systole and diastole. Tracking revealed a 4.3-mm dilated coronary artery branch at the heart’s apex as the flow’s source, with no proximal stenosis or dilation in the coronary arteries. Contrast TTE (cTTE) detected a small (1-2 mm) left anterior descending (LAD) artery fistula within the IVS, with delayed cystic enhancement relative to the left ventricle but simultaneous with the IVS myocardium post-contrast, and no infiltration of the solid component (Fig 1d-e, SV1). These findings indicated the presence of a coronary artery fistula originating from the LAD artery that drains into an IVS forming a dissecting aneurysm.
 
Coronary computed tomography angiography showed no proximal left coronary artery dilation but mild distal dilation. The aneurysm showed significant enhancement and slight calcification, with no enhancement observed in the surrounding myocardium (Fig 1f). Cardiac magnetic resonance confirmed the findings, showing the mass with slightly high T1-weighted and predominantly high T2-weighted signal intensities, encircled by a low-signal intensity ring, with no significant myocardial enhancement post-contrast (Fig 1).
 

Figure 1. Preoperative imaging examination. (a) Transthoracic echocardiography (TTE) shows a cystic-solid echo area in the interventricular septum (IVS) at the apical four-chamber view (asterisk). (b) Colour Doppler demonstrates blood flow entering the cystic cavity (asterisk) through the fistula (yellow arrow). (c) Spectral Doppler shows bidirectional, high-velocity blood flow at the fistula site during systole and diastole. (d) Contrast TTE shows that the cystic cavity enhances later than the left ventricle, with no infiltration of the solid component. (e) Coronary computed tomography angiography confirms distal left anterior descending dilation into the IVS. (f) Cardiac magnetic resonance suggests a high signal in the cyst cavity, with surrounding myocardium showing low-signal intensity (blue arrow)
 
The patient underwent surgical correction of the coronary artery fistula and reduction of the dissecting aneurysm of the interventricular septum (DAIS). Intraoperatively, the LAD was observed penetrating the myocardium, forming a sac-like cavity due to the convergence of the coronary fistula into the myocardial layer of the IVS. Histopathology from a myocardial biopsy showed fibrosis (Fig 2a-d). At 3-month postoperative follow-up, TTE showed a reduced IVS cystic cavity (Fig 2e), and cTTE confirmed fistula closure with no contrast entering the cavity (Fig 2f).
 

Figure 2. Surgical and postoperative assessment. (a) Intraoperative image shows resection of the solid component within the dissected aneurysm (green arrow). (b, c) Histology reveals myocardial degeneration (yellow arrows, 40×) and interstitial fibrosis (20×, dashed line box). (d) Masson’s trichrome staining confirms interstitial fibrosis (20×, dashed line box). (e) Postoperative transthoracic echocardiography (TTE) demonstrates almost no visible interventricular septal cystic cavity, with no discernible colour Doppler flow signal (asterisk). (f) Contrast TTE confirms the absence of contrast in the fibrotic myocardium (white arrow)
 
Discussion
Cardiac space-occupying lesions include tumours and non-neoplastic conditions, occurring anywhere in the heart.1 Dissecting aneurysm of the interventricular septum often results from a ruptured Valsalva aneurysm, myocardial infarction, or trauma.2 Aneurysms within the IVS caused by congenital coronary artery fistulas are rare, with only a few reported cases.3 4 5 These cases often present with marked dilation of the involved coronary artery trunk and dynamic fluctuations in the cystic cavity dimensions throughout the cardiac cycle. The cavity typically expands during diastole and contracts during systole.
 
In this case, the absence of dilation in the main trunk of the coronary artery could be attributed to the fistula’s origin from a small branch of the LAD artery, with a narrow internal diameter and minimal shunting volume. As the patient was young, the coronary arteries exhibited greater elasticity, leading to a reduced propensity for dilation in the main trunk.
 
In this case, the cystic cavity in the IVS showed minimal size change throughout the cardiac cycle due to a blind-ending coronary artery fistula that prevented left ventricular communication. Chronic shunting from the coronary artery fistula led to the gradual enlargement of a dissecting aneurysm within the interventricular septum, compressing adjacent myocardium and branches of the coronary arteries. This compression resulted in localised myocardial ischaemia and subsequent myocardial fibrosis, as demonstrated by both the patient’s electrocardiogram and pathological findings. The fibrosis and high-velocity flow at the fistula site contributed to myocardial thickening and reduced elasticity, impairing the cavity’s expansion and contraction, and resulting in minimal size variation.
 
Transthoracic echocardiography is often the initial imaging choice for coronary artery fistulas into the IVS, providing critical haemodynamic and anatomical data, but its limitations may result in misdiagnosis. Coronary computed tomography angiography and cardiac magnetic resonance provide detailed assessments of coronary anatomy and myocardial fibrosis, complementing TTE. Coronary computed tomography angiography provides diagnostic clarity with the caveat of radiation exposure, especially for repeated scans. Cardiac magnetic resonance, while valuable for its soft tissue characterisation, presents cost considerations for patients. Contrast TTE, valued for its safety, cost-effectiveness, and timeliness, excels in visualising myocardial perfusion and detecting congenital cardiac defects, enhancing diagnostic precision when TTE results are indeterminate. In our case, cTTE, with its high sensitivity to blood flow signals, rapidly delineated the shunt and accurately mapped the fistula. The contrast agent, perfusing the myocardium via the coronary arteries, resulted in delayed opacification of the interventricular septum compared with the left ventricle, thereby disclosing DAIS. This comprehensive diagnostic profiling was pivotal for tailored treatment strategies and prognostic enhancement. This marks the first instance, to our knowledge, where cTTE has been utilised to diagnose DAIS.
 
Author contributions
Concept or design: D Xie, G Yang, C Li.
Acquisition of data: D Xie, C Li, H Li, X Hao, Y Zhang.
Analysis or interpretation of data: D Xie, H Li, X Hao, Y Zhang, M Xie, Y Xu.
Drafting of the manuscript: D Xie, G Yang, Y Xu.
Critical revision of the manuscript for important intellectual content: D Xie, G Yang, C Li, Y Xu.
 
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.
 
Conflicts of interest
The authors declared no conflicts of interest.
 
Acknowledgement
The authors thank Prof Yunhua Gao who provided guidance and assistance in the diagnosis.
 
Funding/support
This study was supported by the Individualized Training Program for Key Supported Talents, part of the Excellent Talents Database at the Army Medical University (Grant No.: 2019R038).
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. The patient provided written consent for publication of this case report.
 
References
1. Maleszewski JJ, Anavekar NS, Moynihan TJ, Klarich KW. Pathology, imaging, and treatment of cardiac tumours. Nat Rev Cardiol 2017;14:536-49. Crossref
2. Zhang JP, Meng H, Wang H. Dissecting aneurysm of the interatrial and interventricular septum with concomitant ventricular septal defect-multimodality cardiac imaging and surgical repair. Echocardiography 2016;33:932-5. Crossref
3. Zhi Ku L, Xia J, Lv H, Song LC, Ma XJ. Giant interventricular septal dissecting aneurysm resulting from congenital coronary fistula. Circ Cardiovasc Imaging 2022;15:e013861. Crossref
4. Wu Q, Jin Y, Zhou L, Liu Y, Wu D. A dissecting aneurysm of interventricular septum resulting from congenital coronary artery fistula. J Clin Ultrasound 2019;47:55-8. Crossref
5. Tekinhatun M, Cihan F, Demir M. Interventricular septal dissecting aneurysm resulting from congenital coronary fistula: a case report. Echocardiography 2023;40:1140-3. Crossref

Frontal lobe epilepsy and hibernoma: a case report

Hong Kong Med J 2025 Apr;31(2):159–61 | Epub 3 Apr 2025
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Frontal lobe epilepsy and hibernoma: a case report
Rongjun Zhang, M Med#; Zhigang Gong, PhD#; Wenbing Jiang, M Med
Department of Neurosurgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, China
# Equal contribution
 
Corresponding author: Dr Rongjun Zhang (zhangrongjun2000@163.com)
 
 Full paper in PDF
 
 
Case presentation
A 69-year-old female presented to the clinic with a 2-year history of intermittent headaches. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) examination (Fig 1a and b) revealed a space-occupying lesion in the right frontal lobe, suggestive of a meningioma. Preoperatively, the patient experienced a single episode of epilepsy lasting for 2 minutes, relieved by antiepileptic medication.
 

Figure 1. (a, b) Preoperative magnetic resonance imaging (MRI) scan in the transverse position. The space-occupying lesion appears slightly hypointense on T1-weighted imaging, with significant and uniform enhancement on the contrast-enhanced scan. It seems to have a broad base connected to the dura mater. The adjacent brain parenchyma shows mild compression and displacement. (c, d) Postoperative MRI scan: transverse T1-weighted and contrast-enhanced images at 3 years postoperatively. The T1-weighted scan shows mixed, slightly hypointense signals in the surgical area. The contrast-enhanced scan reveals patchy enhancements around the surgical site, likely indicating gliosis. (e, f) Specimen images show the tumour is greyish-yellow in colour with a complete capsule. Numerous tiny blood vessels are distributed across the surface of the capsule. When cut open, lipid droplet-like fluid flows out, and scattered tiny vascular sections are visible within the sectioned tissue
 
Cranial surgery was performed based on the preoperative CT localisation. The tumour was completely separated and excised, measuring 4 × 3 × 2 cm3, greyish-yellow in colour, and encapsulated (Fig 1e). The encapsulated surface was rich in blood vessels. Upon opening, the tumour was yellow, and lipid droplet-like fluid was observed on the surface (Fig 1f).
 
Postoperative pathology indicated a hibernoma. Haematoxylin and eosin staining revealed a complete thin capsule attached to the outside of the tumour that was lobulated. A network of capillaries could be seen inside. Under the microscope, polygonal/round cells with eosinophilic granular cytoplasm were seen. The cell nuclei were round and centrally located. In addition, many small vacuolated brown adipocytes and unilocular adipocytes were seen, with a considerable amount of blood vessels, spindle cells, and collagen fibres infiltrating around the tumour cells (Fig 2).
 

Figure 2. (a) Microscopy following haematoxylin and eosin staining (100 μm) reveals polygonal/round cells with eosinophilic granular cytoplasm, and round nuclei centrally located in the cells under the microscope. Additionally, numerous small vacuolated brown adipocytes and unilocular adipocytes can be seen, along with a considerable amount of blood vessels, spindle cells, and collagen fibres infiltrating around the tumour cells. (b) Immunohistochemistry (50 μm) shows scattered positivity for Ki-67. (c) Immunohistochemistry (50 μm) shows CD34 positivity in the vessels
 
Immunohistochemistry showed CD34 to be positive in the vessels, and Ki-67 scattered positive with a proportion of <1%. Immunohistochemistry results were as follows: CK (-), S-100 (-), MDM2 (-), CDK4 (-), P53 (-), CD34 (vascular +), CD117 (-), and Ki -67 (+, <1%) [Fig 2].
 
Postoperative re-examination confirmed complete removal of the tumour, and the patient had no further epileptic seizures. Three years later, cranial MRI follow-up revealed no tumour recurrence (Fig 1c and d).
 
Discussion
Hibernomas are rare benign tumours composed of brown adipose tissue.1 They are asymptomatic and slow-growing. Compared with lipomas originating from white adipose tissue, hibernomas are exceedingly rare, with <200 cases reported in the literature.2 These tumours most commonly occur in the proximal axial skeleton, where fetal brown adipose tissue exists and continues into adulthood. They are most frequently found in the interscapular region, upper mediastinum, axilla, retroperitoneum, and neck. According to literature reports, hibernomas are extremely rare in the cranial cavity. In 1972, Vagn-Hansen et al3 reported a case of intracranial hibernoma. Due to medical constraints at the time, detailed case descriptions of CT and MRI images were not available. Therefore, the diagnosis of this patient has significant clinical significance and academic value. The rarity of intracranial hibernomas in clinical diagnosis can easily be overlooked or misdiagnosed as other more common intracranial tumours such as meningiomas. Clinicians and pathologists need to remain highly vigilant for this rare tumour to ensure timely and accurate diagnosis and treatment.
 
Imaging characteristics of hibernomas
In radiology, differentiation between hibernomas and meningiomas is challenging. Hibernomas typically present as low- to medium-intensity on T1-weighted MRI and high intensity on T2-weighted MRI. Due to their origin from adipose tissue, hibernomas may show signal suppression in the fat-suppressed sequence of MRI. Due to the rich vascular supply inside the tumour, MRI post-contrast enhancement is evident. Also, due to the high fat content of hibernomas, they may appear as low density or iso-density lesions on CT scans.
 
Meningiomas typically present as iso- to high-intensity on both T1- and T2-weighted MRI and show significant uniform enhancement following contrast administration. Meningiomas often accompany the dural tail sign, an important distinguishing feature in imaging. Furthermore, the density of meningiomas on CT scans is quite uniform, with significant enhancement following contrast administration. Therefore, while there is overlap in imaging between hibernomas and meningiomas, detailed radiological analysis, especially the combination of fat-suppressed sequences and tumour enhancement characteristics, can help distinguish the two and increase diagnostic accuracy.
 
Pathological characteristics of hibernomas
Pathological diagnosis is the gold standard for confirming hibernomas. Histological features include small multilocular brown adipocytes that have a rich granular cytoplasm and central or eccentric round or oval nuclei. Unlike the single large lipid droplet in white adipocytes, brown adipocytes contain multiple small lipid droplets and abundant mitochondria, giving the cytoplasm a granular appearance. In addition, hibernomas usually have a rich vascular network. Immunohistochemical staining showing vascular CD34 positivity can further confirm the diagnosis. Hibernoma cells have varying degrees of S-100 protein and CD34 expression according to the literature.4 5 Combining these pathological features can effectively distinguish hibernomas from other intracranial tumours such as meningiomas.
 
Conclusion
The diagnostic process of this case of intracranial hibernoma emphasises the importance of clinicians and pathologists when facing uncommon intracranial tumours. Detailed imaging analysis and pathological examination facilitate accurate differential diagnosis, providing the best treatment plan for patients. More case reports and research are needed to further enrich the understanding and treatment strategies of intracranial hibernomas.
 
Author contributions
All authors contributed to the concept or design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. 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.
 
Conflicts of interest
The authors declared no conflicts of interest.
 
Acknowledgement
The authors thank Dr Yanqing Li and Dr Qinyi Wang from the Department of Pathology at Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine for their expertise and assistance in the diagnosis and analysis of the patient’s condition.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The study was approved by the Ethics Committee of Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, China (Ref No.: 2024-005). The patient was treated in accordance with the Declaration of Helsinki. The patient provided written consent for publication of this case report.
 
References
1. Klevos G, Jose J, Pretell-Mazzini J, Conway S. Hibernoma. Am J Orthop (Belle Mead NJ) 2015;44:284-7.
2. Furlong MA, Fanburg-Smith JC, Miettinen M. The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases. Am J Surg Pathol 2001;25:809-14. Crossref
3. Vagn-Hansen PL, Osgård O. Intracranial hibernoma. Report of a case. Acta Pathol Microbiol Scand A 1972;80:145-9. Crossref
4. Vassos N, Lell M, Hohenberger W, Croner RS, Agaimy A. Deep-seated huge hibernoma of soft tissue: a rare differential diagnosis of atypical lipomatous tumor/well differentiated liposarcoma. Int J Clin Exp Pathol 2013;6:2178-84.
5. Suster S, Fisher C. Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors. Am J Surg Pathol 1997;21:195-200. Crossref

Rethink personalised sudden cardiac death risk assessment in non-dilated left ventricular cardiomyopathy: a case report

Hong Kong Med J 2025;31:Epub 14 Apr 2025
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Rethink personalised sudden cardiac death risk assessment in non-dilated left ventricular cardiomyopathy: a case report
Kevin WC Lun, MB, BS, MRCP1 #; Jonan CY Lee, MB, ChB, FRCR2; Eric CY Wong, MB, BS, FHKCP1; Michael KY Lee, MB, BS, FHKCP1; Derek PH Lee, MB, ChB, FHKCP1 #
1 Division of Cardiology, Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR, China
2 Department of Diagnostic and Interventional Radiology, Queen Elizabeth Hospital, Hong Kong SAR, China
# Equal contribution
 
Corresponding author: Dr Kevin WC Lun (lkw708@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
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.
 

Figure 1. Multifocal patchy mid-wall and subepicardial late gadolinium enhancement at mid-ventricular anterior, anteroseptal and anterolateral walls, as well as basal to mid-ventricular inferior and inferolateral walls (arrows). (a-c) Short axis views of the left ventricle. (d) Apical four-chamber view of the left ventricle. (e, f) Apical two-chamber view of the left ventricle
 

Figure 2. T1 mapping of the left ventricle. Parametric mapping shows mildly increased myocardial T1 values up to 1067 ms to 1080 ms, suggestive of mild diffuse interstitial fibrosis
 
Discussion
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 ≤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.
 
Author contributions
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
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.
 
References
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

Pneumothorax associated with a displaced thoracoamniotic Somatex shunt in an infant with congenital pulmonary airway malformation: a case report

Hong Kong Med J 2025 Feb;31(1):68–71 | Epub 10 Feb 2025
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Pneumothorax associated with a displaced thoracoamniotic Somatex shunt in an infant with congenital pulmonary airway malformation: a case report
Viola YT Chan, FHKAM (Obstetrics and Gynaecology)1; WT Tse, FHKAM (Obstetrics and Gynaecology)2; MC Chan, FHKAM (Paediatrics)3; Kenneth KY Wong, PhD, FHKAM (Surgery)4; WC Leung, FHKAM (Obstetrics and Gynaecology)1; TY Leung, FHKAM (Obstetrics and Gynaecology)2
1 Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong SAR, China
2 Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Hong Kong SAR, China
3 Department of Paediatrics, Kwong Wah Hospital, Hong Kong SAR, China
4 Division of Paediatric Surgery, Department of Surgery, Queen Mary Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Viola YT Chan (cyt141@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
A 32-year-old nulliparous pregnant woman at 21 weeks of gestation was referred to Kwong Wah Hospital in March 2021 for fetal right cystic lung mass (2.16×1.99×2.50 cm3). Repeat examination at 22 weeks of gestation revealed a right multicystic lung mass (3.46×2.46×2.37 cm3) with a dominant 2-cm cyst, suggestive of macrocystic congenital pulmonary airway malformation (CPAM). There was mild mediastinal shift but no hydrops. The CPAM volume ratio, calculated as (length×height×width×0.52)/head circumference, was 0.51. Amniocentesis with chromosomal microarray analysis showed no copy number variants. At 26 weeks of gestation, the lesion had enlarged to 5.73×4.28×4.26 cm3 (CVR=2.16), with mediastinal shift and mild ascites but no polyhydramnios. At 27 weeks of gestation, the lesion was dominated by a single cyst that measured 6.15×4.25×4.1 cm3 (CPAM volume ratio=2.09), with moderate polyhydramnios, ascites and skin oedema suggestive of fetal hydrops. Intramuscular betamethasone was administered for fetal lung maturation in view of the high risk of preterm delivery. Fetal thoracoamniotic shunting was offered to relieve the mass effect and fetal hydrops. The next day, a Somatex shunt (SOMATEX Medical Technologies, Berlin, Germany) was inserted into the CPAM under ultrasound guidance and 800 mL amniotic fluid was drained via the shunt cannula. Examination 9 days later showed CPAM with reduced size (2.3×1.7×1.5 cm3; CVR=0.12), shunt in situ, and no hydrops (Table).
 

Table. Antenatal course of the congenital pulmonary airway malformation of the baby
 
At 29 weeks of gestation, the patient went into preterm prelabour with rupture of membrane that sealed off spontaneously. Serial ultrasound examinations showed satisfactory fetal growth, collapsed CPAM with shunt in situ, normal liquor volume and no hydrops (Table). Labour was induced at 38 weeks of gestation for oligohydramnios. A 2.75-kg female baby was delivered by vacuum extraction for maternal exhaustion, with paediatrician standby. The Apgar scores of the baby were 8 at 1 minute and 10 at 5 minutes and the arterial cord blood pH was 7.31, with base excess of -7.1 mmol/L. The shunt was specifically searched for immediately after delivery but the skin was intact (Fig a). The baby was given continuous positive airway pressure because of respiratory distress and was transferred to the neonatal intensive care unit. Urgent chest X-ray revealed the shunt in the right chest with right pneumothorax (Fig b). A chest drain was inserted and the baby was intubated. Computed tomography of the thorax of the baby on day 1 of life showed an irregular 4.2×3.5×2.5 cm3 cystic lesion in the right lung with the distal end of the shunt migrated between the chest wall and the scapular, abutting the right subscapularis muscle. Thoracoscopy on day 6 of life confirmed that one end of the shunt was within the CPAM in the right middle lobe, while the other end was at the subscapular space. The shunt was removed intact and near-total right middle lobe excision was performed thoracoscopically. The baby was successfully weaned off oxygen 3 weeks postoperatively and discharged 5 weeks later.
 

Figure. (a) Intact skin overlying the right chest wall of the newborn immediately after birth. (b) Chest X-ray showing the internally displaced Somatex shunt in the right middle lobe (arrow), with pneumothorax
 
Discussion
Congenital pulmonary airway malformations are uncommon lung lesions characterised by an overgrowth of terminal respiratory bronchioles that are often immature and non-functioning. A CPAM is considered macrocystic if at least one cyst is >5 mm and microcystic if the lesion appears echogenic on ultrasound examination. Although a microcystic CPAM may regress spontaneously after 26 to 28 weeks of gestation, most macrocystic CPAMs do not.1 Fetuses with large cystic lesions are also at risk of pulmonary hypoplasia and development of fetal hydrops due to compression of lung tissue and venous return. The survival of a hydropic fetus with congenital lung lesion has been reported to be 38%, compared with 87% for a fetus without hydrops.1 Studies have demonstrated a favourable outcome following thoracoamniotic shunting for macrocystic CPAM, with reduction in lesion volume, resolution of hydrops and improved survival.2 3 A systematic review showed an improved survival from 3% to 62% in hydropic fetuses treated with shunting.4 In a single-centre case series, survival was significantly associated with gestational age at birth, hydrops resolution and higher percent reduction in the size of the lung lesion following shunting.3
 
Although thoracoamniotic shunting improves fetal outcome, complications such as shunt occlusion, displacement, dislodgement, bleeding and chest wall deformation have been reported.3 5 6 7 Following successful drainage of the lesion, its surrounding normal lung parenchyma expands and grows. This may result in inward migration of the shunt. In a retrospective review,5 thoracoamniotic shunts inserted for primary pleural effusions and macrocystic CPAMs were antenatally displaced in 8.5% of fetuses, of which two-thirds migrated into the thorax. Re-shunting may be required if the displaced shunt fails to drain and fluid re-accumulates.5 Retained intrathoracic shunts may be managed conservatively as they are well tolerated without untoward postnatal sequalae.5 8 Nonetheless surgical removal may be necessary if the baby develops complications such as respiratory distress or tension pneumothorax.7 9
 
The Somatex shunt is commonly used to treat fetuses with obstructive urinary tract disorders. Recently, thoracoamniotic shunting with a Somatex shunt has been reported effective in relieving fetal pleural effusions with good survival rate although shunt dislodgement and entrapment has been reported in four of eight cases.10 Thoracoscopic removal of a displaced Somatex shunt has been reported necessary in a newborn with respiratory distress and progressive pleural effusion.7 In comparison with other commonly used shunts, such as Harrison and Rocket, Somatex insertion has multiple advantages including a finer introducer (1.2 mm) but a bigger shunt lumen (2.4 mm). It is also made of metal facilitating its easy identification antenatally on ultrasound or postnatally with X-rays or computed tomography.
 
A thoracoamniotic shunt should be clamped immediately following delivery to prevent air from entering the thorax and causing pneumothorax.2 In the current case, we did not expect air to enter the pleural cavity because the shunt was buried inside the skin of the baby. Our hypothesis is that air may have entered from the lung tissue into the pleural space via the displaced shunt. This is similar to the reported case of tension pneumothorax due to an internally displaced thoracoamniotic shunt communicating between the CPAM and the pleural cavity and diagnosed following neonatal resuscitation for apnoea.9 Both cases illustrate that pneumothorax is a possible and potentially life-threatening complication of an internally displaced shunt. It should be anticipated at birth and preparations made for emergency needle thoracocentesis. Obstetricians should be aware of the possible complications of thoracoamniotic shunts, and paediatricians should be alerted so that the newborn can receive prompt assessment and treatment.
 
Author contributions
Concept or design: VYT Chan, WC Leung, TY Leung.
Acquisition of data: VYT Chan, WT Tse, MC Chan, KKY Wong.
Analysis or interpretation of data: VYT Chan.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: KKY Wong, WC Leung, TY Leung.
 
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.
 
Conflicts of interest
As an editor of the journal, KKY Wong was not involved in the peer review process. Other authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient and her baby were treated in accordance with the Declaration of Helsinki. Parental consent was obtained for the patient’s baby, and informed consent was obtained from the patient for all treatments and procedures, and publication of the case report.
 
References
1. Walker L, Cohen K, Rankin J, Crabbe D. Outcome of prenatally diagnosed congenital lung anomalies in the North of England: a review of 228 cases to aid in prenatal counselling. Prenat Diagn 2017;37:1001-7. Crossref
2. Schrey S, Kelly EN, Langer JC, et al. Fetal thoracoamniotic shunting for large macrocystic congenital cystic adenomatoid malformations of the lung. Ultrasound Obstet Gynecol 2012;39:515-20. Crossref
3. Peranteau WH, Adzick NS, Boelig MM, et al. Thoracoamniotic shunts for the management of fetal lung lesions and pleural effusions: a single-institution review and predictors of survival in 75 cases. J Pediatr Surg 2015;50:301-5. Crossref
4. Knox EM, Kilby MD, Martin WL, Khan KS. In-utero pulmonary drainage in the management of primary hydrothorax and congenital cystic lung lesion: a systematic review. Ultrasound Obstet Gynecol 2006;28:726-34. Crossref
5. Abbasi N, Windrim R, Keunen J, et al. Perinatal outcome in fetuses with dislodged thoraco-amniotic shunts. Fetal Diagn Ther 2021;48:430-9. Crossref
6. Makishi A, Kiyoshi K, Funakoshi T. EP21.22: Fetal chest wall deformity after thoracoamniotic shunting using a double-basket catheter for chylothorax: a case report. Ultrasound Obstet Gynecol 2016;48:362-3. Crossref
7. Sham GT, Chung PH, Chan IM, Leung WC, Wong KK. Thoracoscopic removal of a displaced thoracoamniotic shunt in a newborn with antenatal pleural effusion—a case report. Transl Pediatr 2020;9:702-6. Crossref
8. Tan AP, Tan B, Wright A, Kong JY. Management dilemma in thoracoamniotic shunt migrations. BMJ Case Rep 2023;16:e255760. Crossref
9. Law BH, Bratu I, Jain V, Landry MA. Refractory tension pneumothorax as a result of an internally displaced thoracoamniotic shunt in an infant with a congenital pulmonary airway malformation. BMJ Case Rep 2016:2016:bcr2016216324. Crossref
10. Chung MY, Leung WC, Tse WT, et al. The use of Somatex shunt for fetal pleural effusion: a cohort of 8 procedures. Fetal Diagn Ther 2021;48:440-7. Crossref

First experience using a wireless oesophageal pH monitoring system in children in Hong Kong: three case reports

Hong Kong Med J 2025 Feb;31(1):65–7 | Epub 11 Feb 2025
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
First experience using a wireless oesophageal pH monitoring system in children in Hong Kong: three case reports
Adrian CH Fung, MB, BS, FRCSEd (Paed); Kenneth KY Wong, PhD, FRCSEd (Paed)
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China
 
Corresponding author: Prof Kenneth KY Wong (kkywong@hku.hk)
 
 Full paper in PDF
 
 
Twenty-four–hour pH monitoring is indicated for evaluation of gastroesophageal reflux symptoms in children, as well as part of a preoperative work-up for those who require long-term nasogastric tube feeding or a gastrostomy. Its use is nonetheless restricted by the need to keep a nasal catheter in place for at least 24 hours. This can cause great discomfort and may be poorly tolerated by children, especially those with behavioural issues. Wireless pH monitoring can improve patient satisfaction and the overall sensitivity of diagnosing gastroesophageal reflux (Fig 1). Despite its rising popularity among adults, its use has been limited in children. This report documents the first experience in Hong Kong of a wireless oesophageal pH monitoring system in children with gastrointestinal symptoms and feeding problems.
 

Figure 1. Wireless pH monitoring capsule system
 
Case presentations
Case 1
A 9-year-old girl with good previous health and normal development presented to a surgical clinic in March 2023 with recurrent epigastric pain and heartburn. She was prescribed a proton pump inhibitor without symptom improvement. As her parents were keen to determine the cause of her symptoms, upper endoscopy and a pH study were offered. With consideration of patient comfort and the sensitivity of the test, wireless oesophageal pH monitoring was arranged. Endoscopy under general anaesthetic revealed mild antral gastritis but was otherwise unremarkable. An antral biopsy confirmed mild gastritis without Helicobacter pylori. The oesophagogastric junction (OGJ) was measured as 34 cm from the incisor, and a wireless pH monitoring capsule (Bravo; Medtronic Inc, Minneapolis [MN], United States) was inserted at 30 cm under direct endoscopic visualisation (Fig 2a). Post-insertion endoscopy confirmed secure placement at a satisfactory position (Fig 2b). An X-ray after the procedure further confirmed the good position of the capsule (Fig 2c). pH monitoring lasted 96 hours, with a DeMeester score of 6.8. The girl initially complained of mild chest discomfort and a globus sensation during swallowing on the first 2 days post procedure but this resolved spontaneously after 4 days. The capsule passed spontaneously within 3 weeks of the procedure. The diagnosis of gastritis was made after excluding gastroesophageal reflux by pH monitoring; the patient was prescribed a short course of a proton pump inhibitor that resolved the symptoms.
 

Figure 2. Case 1. (a) Deployment of wireless oesophageal pH monitoring capsule under endoscopic view (arrow showing a piece of mucosa in the suction chamber). (b) Endoscopic view following successful deployment of wireless oesophageal pH monitoring capsule. (c) Chest X-ray showing the position of the wireless oesophageal pH monitoring capsule (circle)
 
Case 2
A 6-year-old girl with known glucose phosphate isomerase deficiency, cerebral ataxia and mild intellectual impairment presented to the same surgical clinic in January 2023. She had feeding problems with failure to thrive and needed supplemental milk feeding via a nasogastric tube. Given her medical background and neurodevelopment, she could not tolerate nasogastric tube insertion during her regular revision and required frequent sedation during the procedure. Owing to the anticipated requirement for long-term tube feeding, her parents were advised of the need for gastrostomy tube insertion and a preoperative pH study. As both the patient and parents could not accept a conventional 24-hour pH study, a wireless oesophageal pH monitoring system was inserted under monitored anaesthetic care. The upper endoscopy was unremarkable with no sign of oesophagitis or gastritis. Bravo was inserted at 25 cm from the incisor (ie, 5 cm from the OGJ). Monitoring continued for 96 hours, with a DeMeester score of 0.7. The capsule passed without any complications within 3 weeks of the procedure. The patient was well and there were no adverse events during the study period. In view of the negative pH study, an anti-reflux procedure was deemed unnecessary and subsequently only a laparoscopic gastrostomy was performed.
 
Case 3
A 16-year-old boy with recurrent postprandial heartburn and vomiting presented to the same surgical clinic in March 2024. Medical treatment with proton pump inhibitors elicited no improvement and he was referred for work-up for an anti-reflux procedure. At the time of referral, as capsule pH monitoring was not available locally, a catheter-based 24-hour pH-impedance probe was attempted. Nonetheless the patient could not tolerate the procedure with repeated vomiting and failure of catheter insertion. Given the parents’ wish to have a definitive diagnosis prior to initiating an anti-reflux procedure, pH study was rearranged with the wireless oesophageal pH monitoring system under monitored anaesthesia care. The procedure was well tolerated and the patient was able to complete a 96-hour pH study. The overall DeMeester score was 16.1. During the study period, Day 2 was the patient’s worst day, with acid exposure time at 5.9% and DeMeester score at 22.1. There was significant improvement following resumption of a proton pump inhibitor on Day 3 with acid exposure time at 1% and DeMeester score at 3.5. With the diagnosis of significant gastroesophageal reflux disease confirmed, the parents agreed to proceed with laparoscopic fundoplication.
 
Discussion
According to the joint updated guidelines of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition in 2018,1 24-hour pH monitoring is indicated in children with persistent symptoms of gastroesophageal reflux disease despite proton pump inhibitor treatment. The aim is to correlate persistent troublesome symptoms with acid gastroesophageal reflux events, clarifying the role of acid reflux and determining the efficacy of acid suppression therapy.1 Twenty-four–hour pH monitoring is also recommended as pre-gastrostomy work-up in children to guide patient selection for a concomitant anti-reflux procedure.2 Nonetheless conventional transnasal catheter pH monitoring, although still widely used, is frequently criticised for causing great patient discomfort, limiting the patient’s mobility during the test and, more importantly, being neither tolerable nor inducing compliance by children with neurodevelopmental and behavioural issues,3 as illustrated by Case 2. Not only is the quality of life of patients jeopardised, the unpleasant experience may also restrict reflux-provoking activities, limiting the accuracy and sensitivity of the test and yielding false lower values, as illustrated by Case 3.
 
To overcome these difficulties, the wireless oesophageal pH monitoring system uses a capsule attached to the mucosal wall of the oesophagus for pH monitoring (Fig 1). It consists of a 6.0×6.3×26.0 mm3 capsule-based device, equipped with an internal battery and a pH electrode. The device is attached to the distal wall of the oesophagus, approximately 4 to 6 cm from the OGJ, under direct endoscopic visualisation.3 4 It transmits pH data to a mobile phone–sized recorder via radio telemetry, thus obviating the need for a transnasal pH probe. The capsule enables data to be recorded for at least 48 hours and up to 96 hours, with minimal patient discomfort. The capsule detaches from the oesophageal mucosa and is expelled in stools, with spontaneous sloughing of the oesophageal mucosa and uneventful healing, usually over 3 to 7 days. Its clinical use in children has been established in the United Kingdom and the United States, demonstrating a high success rate, with better tolerance than standard transnasal pH monitoring in children with behavioural issues and an improvement in the detection rate of gastroesophageal reflux disease by 16% through extended recording time.3 4 As illustrated by Case 3, not only is the procedure tolerated, the successful extension of study for a duration of 96 hours may result in a higher diagnostic yield and provision of more information, eg, effect of pump on and off (whether patient was on proton pump inhibitor).5 Currently, the wireless pH monitoring system is intended to be used in adults and children from 4 years of age but is contraindicated in those with bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers or implantable cardiac defibrillators. In situations where the wireless pH capsule needs to be removed, for instance in patients with severe discomfort or failure of spontaneous passage, cold snare and hot snare (when cold snare is not sufficient) can be applied to safely remove the capsule with only thin superficial oesophageal mucosal tissue.6
 
To the best of our knowledge, our centre is the first to introduce and report the use of the wireless oesophageal pH monitoring system in children in Hong Kong. The procedure was smooth, with no equipment or technical failure, and all patients could be discharged on the same day of the procedure. Since Case 1 was the first patient at our centre to receive the device, a chest X-ray was taken to double confirm its position. Nonetheless a post-procedure chest X-ray is not routine for the paediatric population since the device position can be confirmed with endoscopy, as in the adult population. All patients tolerated the pH study well except for the complaint of a self-limiting globus sensation in one patient (Case 1). All parents reported no difficulty in utilising the mobile pH recording system. All capsules were expelled from the patients within 3 weeks of the procedure without any complication.
 
Wireless oesophageal pH monitoring cannot easily diagnose some conditions such as functional belching and rumination syndrome due to the lack of impedance monitoring. Nonetheless these cases highlight that it is well tolerated and feasible in evaluating gastroesophageal reflux symptoms in children and provides a sensible alternative to standard transnasal pH monitoring. In addition, it may result in a higher diagnostic yield and more comprehensive clinical information. As clinicians, we are obliged to keep track of technological advancements and strive to provide holistic and optimal care for children, improve patient satisfaction and shorten their hospital stay.
 
Author contributions
Both authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Both 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.
 
Conflicts of interest
As an editor of the journal, KKY Wong was not involved in the peer review process. The other author has disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patients were treated in accordance with the Declaration of Helsinki. Verbal consent was obtained from the patients for the publication of the case reports.
 
References
1. Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:516-54. Crossref
2. Fung AC, Ooi YN, Hui HM, Mok MK, Chung PH, Wong KK. Prophylactic anti-reflux procedure for children undergoing laparoscopic gastrostomy: rethinking of the routine practice. World J Surg 2024;48:739-45. Crossref
3. Rodriguez L, Morley-Fletcher A, Winter H, Timothy B. Evaluation of gastroesophageal reflux disease in children on the autism spectrum: a study evaluating the tolerance and utility of the BRAVO wireless pH monitoring. J Pediatr Gastroenterol Nutr 2022;75:450-4. Crossref
4. Rao NM, Campbell DI, Rao P. Two years’ experience of using the Bravo wireless oesophageal pH monitoring system at a single UK tertiary centre. Acta Paediatr 2017;106:312-5. Crossref
5. Zeki SS, Miah I, Visaggi P, et al. Extended wireless pH monitoring significantly increases gastroesophageal reflux disease diagnoses in patients with a normal pH impedance study. J Neurogastroenterol Motil 2023;29:335-42. Crossref
6. de Hoyos A, Esparza EA, Loredo ML. Cold and hot snare endoscopic techniques for removal of the Bravo pH monitoring capsule. Digestion 2009;79:14-6. Crossref

Collapsing glomerulopathy as a rare cause of rapidly progressive renal failure in adolescence: two case reports

Hong Kong Med J 2024 Dec;30(6):502–5 | Epub 23 Dec 2024
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Collapsing glomerulopathy as a rare cause of rapidly progressive renal failure in adolescence: two case reports
Yeşim Özdemir Atikel, MD1; Betül Öğüt, MD2; İpek Işık Gönül, MD2; Necla Buyan, MD1; Sevcan A Bakkaloğlu, MD1
1 Department of Pediatric Nephrology, Gazi University Faculty of Medicine, Gazi University, Ankara, Turkey
2 Department of Pathology, Gazi University Faculty of Medicine, Gazi University, Ankara, Turkey
 
Corresponding author: Prof Yeşim Özdemir Atikel (yesozdemir@gmail.com)
 
 Full paper in PDF
 
 
Case presentations
Case 1
A 17-year-old male was referred to our institution in January 2016 due to elevated serum creatinine level of 1.85 mg/dL and nephrotic proteinuria level of 6839 mg/day. He had a history of epilepsy and had used various antiepileptic drugs (phenobarbital, valproic acid, and carbamazepine) from the ages 3 to 14 years. Physical examination revealed lower extremity oedema and a blood pressure of 140/90 mm Hg. Laboratory tests on admission showed a blood urea nitrogen level of 24 mg/dL, serum creatinine level of 1.68 mg/dL and a serum albumin level of 2.7 g/dL. Urine microscopy revealed three red blood cells per high-power field. A 24-hour urine collection revealed massive proteinuria level of 10.957 mg/day (296 mg/m2/h). Serum complement levels were normal and autoimmune tests (antinuclear antibodies, anti–double-stranded DNA antibodies, anti–glomerular basal membrane antibodies, and anti-neutrophil cytoplasmic antibodies) were negative. Viral serology, including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, Epstein–Barr virus, cytomegalovirus, and parvovirus, was also negative. Abdominal ultrasound revealed increased echogenicity in the renal parenchyma.
 
Treatment with enalapril at a dose of 0.4 mg/kg/day was started. Kidney biopsy was performed on the seventh day after admission and showed compatibility with collapsing glomerulopathy (CG) [Fig 1]. Methylprednisolone boluses of 1 g were administered for 5 consecutive days, followed by oral prednisone at a dose of 60 mg/m2/day. By the 15th day, serum creatinine levels were at 2.1 mg/dL, serum albumin level at 1.9 g/dL, and 24-hour urine protein level at 17.8 g/day. Mycophenolate mofetil was added to the treatment regimen. On the 40th day, serum creatinine level had increased to 4.2 mg/dL with proteinuria of 13.3 g/day, leading to the initiation of rituximab and tapering of prednisolone. By the 60th day, mycophenolate mofetil was discontinued due to leukopenia; however, the patient had completed the 4 doses of weekly 375 mg/m2/dose rituximab treatment. Additionally, he received albumin infusions, diuretics, and antihypertensives. Since the clinical features and laboratory parameters did not improve, the patient underwent plasma exchange. After two sessions, haemodialysis was required due to worsening symptoms, uncontrolled hypervolaemia, and renal failure. No additional immunosuppressive was given at that time and the patient continued to receive haemodialysis. Genetic testing for mutations of the NPHS1 and NPHS2 genes were negative.
 

Figure 1. Case 1. Renal biopsy findings showing (a) a haematoxylin and eosin stain of a glomerulus with segmental podocyte hyperplasia (arrows) causing segmental collapse on the underlying capillary lumen (×200) and (b) periodic acid–Schiff stain revealing a segmental collapse (arrow) in the glomerular capillary walls with podocyte hyperplasia (×200)
 
Case 2
Another 17-year-old male was admitted to our institution in February 2016 for syncope. He had a history of headaches with intermittent vomiting for the previous 2 months and had been treated with metamizole, domperidone, zolmitriptan, and diclofenac. His mother had a history of minimal change disease aged 6 years. The patient’s blood pressure was measured as 200/120 mm Hg, and hypertensive retinopathy was observed during the ophthalmological examination. Initial serum creatinine level was 4.7 mg/dL and serum albumin level was 3.4 g/dL. Ferritin and parathyroid hormone levels were 274 ng/mL and 220 pg/mL, respectively. Microscopic urinalysis showed eight red blood cells per high-power field. He had nephrotic proteinuria of 3820 mg/day (91.5 mg/m2/h). Viral serology and autoimmune tests (antinuclear antibodies, anti–double-stranded DNA antibodies, anti–glomerular basal membrane antibodies, and anti-neutrophil cytoplasmic antibodies) were negative and complement levels were normal. Abdominal ultrasound revealed increased renal echogenicity. Cranial magnetic resonance imaging showed signs of posterior reversible encephalopathy syndrome. Hypertension was controlled using intravenous and oral antihypertensives (esmolol, captopril, amlodipine, doxazosin, and minoxidil). On the fourth day, the serum creatinine level increased to 5.9 mg/dL and the albumin level decreased to 2.4 g/dL. Kidney biopsy showed severe CG (Fig 2). Because the findings were chronic, no steroids or other immunosuppressive treatment were administered. Genetic testing for mutations of the NPHS1 and NPHS2 genes was negative. By the fifth month, the patient’s serum creatinine level had reached 6.9 mg/dL. After 1 year of peritoneal dialysis, he received a renal transplant.
 

Figure 2. Case 2. Renal biopsy findings showing (a) global glomerular collapse with pronounced podocyte hyperplasia (white arrows) filling the Bowman’s space in the form of pseudo-crescent formation (black arrows) [haematoxylin and eosin stain, ×400] and (b) the same glomerulus with periodic acid–Schiff stain (×400)
 
Discussion
Collapsing glomerulopathy is a histopathological pattern of podocytopathies.1 It was previously classified as a variant of focal segmental glomerulosclerosis (FSGS), known as collapsing FSGS.2 3 4 However, it is more severe at the initial stage and progresses more rapidly to end-stage kidney disease compared with non-collapsing FSGS, even when treatment is given.2 3 4 5 It typically presents with nephrotic proteinuria and elevated serum creatinine level, and is rare among children.3 5
 
Both patients had high serum creatinine level, nephrotic proteinuria, and hypertension. To establish the exact diagnosis and determine the prognosis, a kidney biopsy was performed as the gold standard for diagnosis. Histopathological findings of CG include glomerular capillary collapse in at least one glomerulus; hyperplasia and hypertrophy of visceral epithelial cells leading to pseudo-crescent formation; presence of periodic acid–Schiff-positive hyaline droplets in visceral epithelial cell cytoplasm; and severe tubulointerstitial inflammation in the early stages. Glomerulosclerosis and interstitial fibrosis are observed in the late stages, and immunofluorescence assay is typically negative.1 2 3 4 6 Kidney biopsies in both cases showed advanced CG with global glomerulosclerosis and interstitial fibrosis (Figs 1 and 2).
 
Collapsing glomerulopathy can be either idiopathic (primary), genetic (familial), or reactive (secondary).1 The idiopathic form is characterised by the loss of maturity markers and the re-expression of immaturity markers leading to the proliferation of immature podocytes.1 Secondary causes of CG include infections (human immunodeficiency virus, parvovirus B19, cytomegalovirus, hepatitis C virus, severe acute respiratory syndrome coronavirus 2), drugs (including valproic acid and anabolic steroids), autoimmune diseases (such as systemic lupus erythematosus), and malignancies.1 2 3 4 7 Genetic CG is associated with mitochondrial dysfunction that causes podocyte proliferation.1 Case 1 had a history of long-term use of antiepileptic drugs (phenobarbital, valproic acid, and carbamazepine). However, we found no other aetiological factors in either patient. Therefore, we concluded that while the aetiology in Case 1 could be idiopathic or valproic acid–related, it was idiopathic in Case 2.
 
There is no specific treatment for CG2; as such, the mainstay of therapy is for the disorders resulting from nephrotic syndrome (such as hypertension and oedema), treatment of the underlying conditions (such as infections and autoimmune diseases), and immunosuppressive therapy.8 Possible factors for progression to end-stage kidney disease in CG include a serum creatinine level >2 mg/dL at the time of biopsy, proteinuria >8 g/day and lack of remission, collapsing lesions in >20% of glomeruli, and the severe tubular changes and interstitial fibrosis.3 9 10 In Case 1, the rationale for aggressive immunosuppressive treatment was based on an initial serum creatinine level of 1.6 mg/dL, intense polymorphonuclear leukocytes and eosinophil infiltration, and 2 out of 24 glomeruli showing glomerulosclerosis. Case 2 did not receive immunosuppressive treatment due to the chronicity of the disease and advanced global glomerulosclerosis (67%). The Table summarises the clinical findings in both patients.
 

Table. Initial findings and clinical course of both patients
 
Conclusion
It is important to recognise that CG is a separate clinicopathological entity from FSGS. Due to the poor response to immunosuppressive drugs and the potential for renal transplantation, we recommend avoiding aggressive immunosuppressive therapy for patients with poor prognostic factors at the time of diagnosis. This approach helps minimise the side-effects of cumulative immunosuppression.
 
Author contributions
Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: Y Özdemir Atikel, SA Bakkaloğlu.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Declaration
The two cases have been presented during oral presentations at the IPNA Teaching Course of the 5th Southeastern Europe Pediatric Nephrology Working Group Meeting inSkopje, Macedonia, 10-11 June 2016.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
Both patients were treated in accordance with the Declaration of Helsinki. Written informed consent for publication was obtained from both patients and their parents.
 
References
1. Barisoni L, Schnaper HW, Kopp JB. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol 2007;2:529-42. Crossref
2. Albaqumi M, Soos TJ, Barisoni L, Nelson PJ. Collapsing glomerulopathy. J Am Soc Nephrol 2006;17:2854-63. Crossref
3. Mubarak M. Collapsing focal segmental glomerulosclerosis: current concepts. World J Nephrol 2012;1:35-42. Crossref
4. Ferreira AC, Carvalho D, Carvalho F, Galvão MJ, Nolasco F. Collapsing glomerulopathy in Portugal: a review of the histological and clinical findings in HIV and non-HIV patients. Nephrol Dial Transplant 2011;26:2209-15. Crossref
5. Gulati A, Sharma A, Hari P, Dinda AK, Bagga A. Idiopathic collapsing glomerulopathy in children. Clin Exp Nephrol 2008;12:348-53. Crossref
6. Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: collapsing glomerulopathy. Am J Kidney Dis 2015;66:e3-4. Crossref
7. Nasr SH, Kopp JB. COVID-19–associated collapsing glomerulopathy: an emerging entity. Kidney Int Rep 2020;5:759-61. Crossref
8. Cutrim ÉM, Neves PD, Campos MA, et al. Collapsing glomerulopathy: a review by the Collapsing Brazilian Consortium. Front Med (Lausanne) 2022;9:846173. Crossref
9. Laurinavicius A, Hurwitz S, Rennke HG. Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study. Kidney Int 1999;56:2203-13. Crossref
10. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int 1996;50:1734-46. Crossref

Use of burosumab in two young children with X-linked hypophosphataemic rickets in Hong Kong: two case reports

Hong Kong Med J 2024 Dec;30(6):506–8 | Epub 26 Nov 2024
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Use of burosumab in two young children with X-linked hypophosphataemic rickets in Hong Kong: two case reports
Joanna YL Tung, MB, BS, FHKAM (Paediatrics)1; Sammy Wong, MB, ChB, FHKAM (Paediatrics)2; Queenie WS See, MB, BS, FHKAM (Paediatrics)3; Joyce Chan, MB, ChB, FHKAM (Radiology)4; Evelyn Kuong, MB, BS, FHKAM (Orthopaedics)5
1 Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong SAR, China
2 Department of Paediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China
3 Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
4 Department of Radiology, Hong Kong Children’s Hospital, Hong Kong SAR, China
5 Department of Orthopaedics and Traumatology, Hong Kong Children’s Hospital and Duchess of Kent Children’s Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Joanna YL Tung (tyl404@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentations
Two Chinese girls (22 months and 26 months of age [Case 1 and Case 2, respectively]) presented in August 2021 and November 2021 with progressive bowing of the lower limbs since infancy. Neither had any significant family history. Physical examination revealed rachitic deformity, waddling gait, and short stature. Further investigations showed hypophosphataemia, isolated hyperphosphaturia and a high serum alkaline phosphatase (ALP) level with normal serum calcium, 25(OH) vitamin D, and parathyroid hormone levels. Characteristic clinical and radiographical findings suggestive of hypophosphataemic rickets were also evident (Fig). Molecular testing confirmed a diagnosis of X-linked hypophosphataemia (XLH) with heterozygous pathogenic PHEX (phosphate-regulating endopeptidase homologue on the X chromosome) variants detected in both patients [Case 1: c.2104C>T, p.(Arg702); Case 2: (c.1699c>T) (Arg567)]. Neither set of parents was affected. Both girls were commenced on conventional treatment with phosphate solution and alfacalcidol for around 3 months with only fair improvement. They were then started on burosumab at a starting dose of 0.8 mg/kg every 2 weeks, titrated up to 2 mg/kg (20 mg) 4 months later based on fasting serum phosphate level. Despite maximum doses of burosumab, serum phosphate level remained slightly below the normal range for both patients. Nevertheless there was ongoing clinical improvement in ALP level, the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, growth velocity, and healing of rickets in both patients. After burosumab treatment for 24 months, both patients had significant clinical, biochemical, and radiological improvement (Table and Fig). They were followed up by the multidisciplinary team at the Hong Kong Children’s Hospital. No treatment-related adverse reactions or disease-related complications (including skull deformities, dental abscess, and hearing problem) were observed.
 

Figure. Clinical and radiological improvements of the two patients after burosumab treatment for 30 months. (a-d) Case 1. (e-h) Case 2. Before treatment ([c] and [g]), both patients had widening of growth plate with lucencies in the metaphyseal margins, with bowing seen in both the diaphyseal and metaphyseal bone. After treatment ([d] and [h]), there was a significant reduction in metaphyseal lucencies with improvement in bone density. Reduction in the width of the growth plates was observed. Extent of bowing of long bones also showed improvement after treatment.
 

Table. Serial biochemical changes of the two patients after burosumab treatment for 30 months
 
Discussion
X-linked hypophosphataemia is the most common cause of genetic rickets, with a prevalence of 1:20 000 to 1:60 000.1 2 It is caused by mutations in the PHEX gene and results in an increased level of the fibroblast growth factor 23 (FGF-23) hormone. This leads to impaired renal reabsorption of phosphate, low serum 1,25-dihydroxyvitamin D concentration, and reduced intestinal phosphate absorption, and ultimately, chronic hypophosphataemia. Patients typically present in early childhood with signs and symptoms of rickets and osteomalacia, progressive bowing deformities of the lower limbs, bone pain and stunted growth, as in our patients.
 
X-linked hypophosphataemia is conventionally treated with oral phosphate and active vitamin D analogues but this does not address the underlying pathogenesis and may only partially correct the biochemical derangement and skeletal deformities. Patients often require repeated orthopaedic procedures, eg, hemiepiphysiodesis or even multiple corrective osteotomies to maintain the mechanical axis of the lower limbs. Surgical correction is fraught with technical difficulties due to osteomalacia and there are high rates of recurrence. Moreover, conventional treatment is associated with long-term side-effects such as hyperparathyroidism and nephrocalcinosis.
 
Burosumab, a monoclonal antibody to FGF-23 for XLH treatment, was approved by the United States Food and Drug Administration3 and the European Medicines Agency4 in 2018. Subsequently, a phase III trial to evaluate 61 children with XLH aged 1 to 12 years for 64 weeks5 and another trial evaluating children with XLH aged 5 to 12 years for 160 weeks6 further supported its safety and effectiveness in terms of improved total Rickets Severity Score and fasting serum phosphate level. These outcomes were also measured in our patients and similar improvements observed. With the approval of burosumab, there has been a paradigm shift in the treatment of XLH in Western countries. Nevertheless conventional treatment continues to be the norm in most parts of our region—partly attributed to the high cost of burosumab, and partly due to the lack of published regional experience with burosumab in the clinical setting.
 
In our patients, the dose of burosumab was titrated up slowly to the maximum dose based on age-specific fasting phosphate level, as per various clinical practice recommendations.7 8 With the maximum dose, fasting serum phosphate level improved but failed to reach that of the age-specific normal range. Other secondary causes including vitamin D deficiency and hyperparathyroidism were excluded. Nevertheless improvement in other clinical parameters including serum ALP level, the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, growth velocity, and clinical and radiological evidence of rickets healing were observed. We have maintained our two patients on the same dose with ongoing clinical improvements observed. This is consistent with the recently published opinion based on early experience in seven European countries, recommending that a serum phosphate concentration below the age- and sex-specific range may be acceptable and the same maintenance dose continued as improvements in other clinical parameters are maintained.9 This is based largely on expert opinion with no data on the proportion of patients who do not achieve a normalised phosphate level and no comparison of clinical outcomes.
 
X-linked hypophosphataemia is a rare, genetic multisystem disease. In addition to the skeletal manifestations, around two-thirds of affected individuals have associated dental and periodontal issues, such as spontaneous periapical abscesses, related to poor dentin mineralisation.10 Some patients also have other complications including craniosynostosis and impaired hearing. Consequently, most guidelines recommend a multidisciplinary approach for this group of patients.7 8 Despite treatment with burosumab, some complications cannot be mitigated. Dental abscess, a well-known complication in patients with XLH, has not been consistently shown to be ameliorated by burosumab treatment. In the phase 3 burosumab trial,5 dental abscess was observed at a higher rate in the treatment group than the control arm. This implies that the pathophysiology of dental abscess is not mediated only by the FGF-23 pathway. This highlights the importance of a multidisciplinary approach to the management of XLH, as recommended by recent international clinical practice guidelines7 and regional consensus statements.8 At the Hong Kong Children’s Hospital, this group of patients is seen in the multidisciplinary bone clinic with input from a paediatric endocrinologist, orthopaedic surgeon, geneticist, dental surgeon, radiologist, and case manager (nurse practitioner). This orchestrated, coordinated multidisciplinary care is particularly important to maximise the effect and overall clinical outcome of burosumab treatment that remains remarkably expensive.
 
To the best of our knowledge, this is the first report of real-world experience of XLH treated with burosumab outside clinical trials in Asia. The target of a normal phosphate level may not be achievable in practice, and treatment response should also be guided by other clinical parameters. Further research into factors that affect the biochemical outcome and the clinical response of groups with different biochemical outcome is needed. A multidisciplinary approach should be adopted in the care of children with XLH.
 
Author contributions
Concept or design: JYL Tung.
Acquisition of data: JYL Tung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: JYL Tung.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Declaration
Preliminary results for these two cases were presented as a poster at the 12th Asia Pacific Paediatric Endocrine Society Biennial Scientific Meeting 2022 (South Korea, 5-8 October 2022).
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patients were treated in accordance with the Declaration of Helsinki. Consent for all treatments, procedures, and consent for publication was obtained from parents of the patients.
 
References
1. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 2009;160:491-7. Crossref
2. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 2016;174:125-36. Crossref
3. United States Food and Drug Administration. FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia. 2018 Apr 17. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-inherited-form-rickets-x-linked-hypophosphatemia. Accessed 28 Oct 2024.
4. European Medicines Agency. EU/3/14/1351—orphan designation for treatment of X-linked hypophosphataemia. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-14-1351. Accessed 28 Oct 2024.
5. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019;393:2416-27. Crossref
6. Linglart A, Imel EA, Whyte MP, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with X-linked hypophosphatemia. J Clin Endocrinol Metab 2022;107:813-24. Crossref
7. Sandy JL, Simm PJ, Biggin A, et al. Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab. J Paediatr Child Health 2022;58:762-8. Crossref
8. Munns CF, Yoo HW, Jalaludin MY, et al. Asia-Pacific consensus recommendations on X-linked hypophosphatemia: diagnosis, multidisciplinary management, and transition from pediatric to adult care. JBMR Plus 2023;7:e10744. Crossref
9. Mughal MZ, Baroncelli GI, de Lucas-Collantes C, et al. Burosumab for X-linked hypophosphatemia in children and adolescents: opinion based on early experience in seven European countries. Front Endocrinol (Lausanne)2023;13:1034580. Crossref
10. Baroncelli GI, Mora S. X-linked hypophosphatemic rickets: multisystemic disorder in children requiring multidisciplinary management. Front Endocrinol (Lausanne) 2021;12:688309. Crossref

Alectinib-induced haemolytic anaemia in anaplastic lymphoma kinase–positive non–small-cell lung cancer: a case report

Hong Kong Med J 2024 Oct;30(5):414–6 | Epub 14 Oct 2024
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Alectinib-induced haemolytic anaemia in anaplastic lymphoma kinase–positive non–small-cell lung cancer: a case report
Toby CH Leung , MB, ChB; Tommy CY So, MB, BS, FHKAM (Radiology)
Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Toby CH Leung (lch423@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
A 70-year-old Chinese woman was diagnosed with stage IV anaplastic lymphoma kinase (ALK)–positive non–small-cell lung carcinoma with intrapulmonary, pleural and lymph node metastasis in December 2022. Her private oncologist first prescribed lorlatinib in mid-December 2022. The drug had been well tolerated by the patient and there was no evidence of myelotoxicity.
 
The patient attended a public hospital for further care in February 2023. Lorlatinib was switched to alectinib on 17 March 2023. Her baseline haemoglobin level was 11.1 g/dL on 16 March 2023 prior to commencement of alectinib. Subsequent follow-ups on 13 April and 3 May revealed that her haemoglobin level had fallen to 10 g/dL and 8.7 g/dL, respectively (Fig 1a). Mean cell volume was 65.4 fL. She had no clinical signs or symptoms suggestive of acute blood loss.
 

Figure 1. (a) Temporal relationship between haemoglobin level and the use of different anaplastic lymphoma kinase inhibitors. (b) Trend of different biochemical markers related to haemolytic anaemia
 
Peripheral blood smear showed marked red cell sphero-acanthocytosis (Fig 2). The previously normal bilirubin level rose to 43 μmol/L and lactate dehydrogenase (LDH) level to 317 IU/L. Haptoglobin level was very low (<0.06 g/L) [Fig 1b]. Direct Coombs test (DAT) was negative. Alectinib had been withheld since 3 May 2023 in view of the potential differential diagnosis of drug-induced haemolytic anaemia. After suspending alectinib, the haemoglobin level remained static for 1 week (8.7 g/dL on 10 May 2023). It then increased slowly over the following week (9.1 g/dL on 15 May 2023) [Fig 1a]. Lactate dehydrogenase level also decreased to 278 IU/L, with total bilirubin level decreased to 24 μmol/L and direct bilirubin level normalised (Fig 1b).
 

Figure 2. Peripheral blood smear showing sphero-acanthocytosis of red cells (yellow arrows) [Wright-Giemsa stains, ×1000]
 
Since the anaemia of the patient had improved, another ALK inhibitor, brigatinib, was prescribed on 18 May 2023, at 90 mg daily. Her haemoglobin level increased to 9.7 g/dL after 2 weeks. Total bilirubin level was normalised on 1 June 2023 (Fig 1a). Brigatinib was then stepped up to 180 mg daily (full dose) as it was well tolerated.
 
The patient demonstrated a favourable response to ALK inhibitors as evidenced by a continuously decreasing cancer embryonic antigen level. A contrast computed tomography scan of the thorax, abdomen and pelvis on 30 May 2023 showed partial response after 5 months of lorlatinib and alectinib. The primary lung tumour at the right lower lobe showed a partial response, decreasing from 6.2 cm to 1.5 cm in size. There was no evidence of bone metastasis.
 
Discussion
Anaemia caused by alectinib is uncommon although clinical trials have reported clinically significant anaemia (grade ≥3) in around 7% of cases.1 Nonetheless there are limited reports of alectinib-induced haemolytic anaemia.2 Misawa et al3 described a case of grade 4 anaemia due to drug-induced haemolytic anaemia in 2023. No such case has been reported in Hong Kong to date.
 
The index patient demonstrated alectinib-induced haemolytic anaemia with morphological change to erythrocytes and negative DAT result. The blood smear of sphero-acanthocytosis combined with altered bilirubin, LDH and haptoglobin was strongly suggestive of haemolytic anaemia. The improvement in haemoglobin, bilirubin and LDH levels following suspension of alectinib suggested that the haemolytic anaemia was drug induced.
 
Drug-induced haemolytic anaemia is usually due to drug-induced immune haemolytic anaemia.4 Nonetheless in this case, an autoimmune cause was excluded due to the patient’s negative DAT result even though 5% to 10% of DAT-negative cases may have an immune component.2 Differential diagnoses of DAT-negative haemolytic anaemia include membranopathies (eg, hereditary spherocytosis), thrombotic microangiopathies (eg, thrombotic thrombocytopenic purpura), enzymopathies (eg, glucose-6-phosphate dehydrogenase), infection (eg, malaria or Clostridium), and haemoglobinopathies (eg, sickle cell disease).5 Our patient had no signs of infection or history of haematological disease. The temporal relationship between administration of alectinib and the occurrence of haemolytic anaemia favoured a diagnosis of drug-induced haemolysis. The laboratory findings were also consistent with other case reports.6
 
The precise mechanism is uncertain. It has been postulated that alectinib induces erythrocyte membrane changes.3 The presence of spherocytes in the peripheral blood film may arise from these membrane changes (Fig 2). Additional investigation is warranted to further understand the underlying mechanism.
 
Our patient developed haemolytic anaemia within 2 months of commencing alectinib. Misawa et al3 reported that grade 4 haemolytic anaemia could occur after 3 years. Regular monitoring of haemoglobin should be undertaken in patients prescribed alectinib. Haemolytic anaemia workup, including peripheral blood smear, bilirubin, haptoglobin and LDH levels, should be considered if indicated.
 
This case demonstrated no cross reactivity among other ALK-positive first-line targeted therapies (lorlatinib and brigatinib). Our patient first commenced lorlatinib following a private consultation and later switched to alectinib with funding support. The patient continues her treatment with brigatinib. There was no documented drop in haemoglobin level after lorlatinib, and following discontinuation of alectinib and initiation of brigatinib, her haemoglobin level showed an improving trend. Limited case reports of alectinib-induced haemolytic anaemia have been managed by discontinuation of therapy or rechallenge with alectinib at a reduced dosage.2 3 6 To the best of our knowledge, cross reactivity among first-line ALK tyrosine inhibitors (lorlatinib, alectinib and brigatinib) has not been reported. Our case demonstrates that it is safe to switch treatment to an alternative ALK inhibitor when alectinib-induced haemolytic anaemia occurs. The drug-induced haemolytic anaemia is specific to alectinib.
 
Conclusion
This case highlights the importance of interval haemoglobin monitoring. A persistent drop in haemoglobin level following initiation of alectinib warrants prompt investigations for possible differential diagnosis of alectinib-induced haemolytic anaemia. This case also suggests that it is safe to switch to an alternative ALK inhibitor in the presence of alectinib-induced haemolytic anaemia.
 
Author contributions
Both authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Both 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.
 
Conflicts of interest
Both authors have disclosed no conflicts of interest.
 
Acknowledgement
The authors thank Dr Kenneth Mung from the Department of Pathology of Pamela Youde Nethersole Eastern Hospital for providing microscopic photos of the blood smear of the patient.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. The patient provided consent for all treatments and procures, and consent for publication of this case report.
 
References
1. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non–small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:1056-64. Crossref
2. Okumoto J, Sakamoto S, Masuda T, et al. Alectinib-induced immune hemolytic anemia in a patient with lung adenocarcinoma. Intern Med 2021;60:611-5. Crossref
3. Misawa, K, Nakamichi S, Iida H, et al. Alectinib-induced severe hemolytic anemia in a patient with ALK-positive non–small cell lung cancer: a case report. Onco Targets Ther 2023;16:65-9. Crossref
4. Garbe E, Andersohn F, Bronder E, et al. Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study. Br J Haematol 2011;154:644-53. Crossref
5. Palmer D, Seviar D. How to approach haemolysis: haemolytic anaemia for the general physician. Clin Med (Lond) 2022;22:210-3. Crossref
6. Gullapalli V, Xu W, Lewis CR, Anazodo A, Gerber GK. A multi-centre case series of alectinib-related erythrocyte membrane changes and associated haemolysis. J Hematop 2021;14:131-6. Crossref

Sodium nitrite–induced methaemoglobinaemia: a case report

Hong Kong Med J 2024 Oct;30(5):412–3 | Epub 9 Oct 2024
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Sodium nitrite–induced methaemoglobinaemia: a case report
CY Yeung, FHKCEM, FHKAM (Emergency Medicine)1; HG Lam, MB, BS1; FL Lee, FHKCEM, FHKAM (Emergency Medicine)1; Francis KC Chu, FHKCEM, FHKAM (Emergency Medicine)1; CK Chan, FHKAM (Emergency Medicine), FHKCEM (Clinical Toxicology)2
1 Accident and Emergency Department, Queen Elizabeth Hospital, Hong Kong SAR, China
2 Hong Kong Poison Control Centre, Hospital Authority, Hong Kong SAR, China
 
Corresponding author: Dr Francis KC Chu (ckcf01@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
A 27-year-old man with a history of previous suicide attempts, depression and borderline personality disorder intentionally ingested 10 g of sodium nitrite (NaNO2) in a suicide attempt. The patient reported learning about this method of suicide through the internet and was aware of fatal cases that had occurred overseas. He checked the lethal dosage of NaNO2 and purchased the NaNO2 salt online. He dissolved 10 g of NaNO2 in beer and consumed the mixture. He vomited immediately and then instructed his girlfriend to call an ambulance. He denied co-ingestion of any other substances. After consulting the Hong Kong Poison Information Centre, the ambulance crew administered 50 g of activated charcoal to the patient on the way to the emergency department.
 
The patient arrived at the emergency department 30 minutes following the ingestion. Upon arrival, the patient complained of dizziness and dyspnoea. He denied any chest pain, syncope or loss of consciousness. Physical examination revealed mild respiratory distress and both peripheral and central cyanosis. He was fully alert with a Glasgow Coma Scale score of 15/15. There was no fever. Tachycardia with heart rate 124 beats per minute was noted and blood pressure was 104/58 mm Hg. His respiratory rate was 26 breaths per minute and oxygen saturation 79% on oxygen was administered via a non-rebreathing mask. The methaemoglobin (met-Hb) level measured by a pulse CO-oximeter was 21.7%. A point-of-care venous blood gas showed pH 7.37, partial pressure of carbon dioxide of 6.24 kPa, partial pressure of oxygen of 1.9 kPa, and a base excess of 1 mmol/L. Electrocardiogram showed normal sinus rhythm with no ischaemic changes. Chest X-ray showed no consolidation and abdominal X-ray revealed no radiopaque foreign body.
 
In view of the potential lethal ingestion, the patient was intubated for airway protection and gastric lavage was performed using a total of 6-L normal saline until the effluent became clear. The methaemoglobinaemia was treated with 100-mg methylene blue given intravenously (2 mg/kg body weight). The initial blood met-Hb level and lactate level were 69.9% and 4.2 mmol/L, respectively. The patient was admitted to the intensive care unit where an additional dose of 100-mg methylene blue was administered. The met-Hb level decreased from 69.9% to 49.4%, 2.3%, and 0.2% after 2 hours, 6 hours, and 14 hours, respectively. Lactate level also decreased from 4.2 to 2.1 mmol/L. After a night in the intensive care unit, the patient was extubated and transferred to the emergency medicine ward. The patient was later assessed by a psychiatrist and was discharged home after 2 days.
 
Discussion
Sodium nitrite is a white-to-yellow, odourless, water-soluble compound that is used as a pharmaceutical precursor, in food processing, and as a therapeutic agent for the treatment of cyanide poisoning. Worldwide, there is a growing trend of NaNO2 being used for suicidal intentions.1 2 It is a highly toxic substance that is rapidly absorbed after ingestion. The reported lethal dose of ingested NaNO2 ranges from 0.7 g to 6 g.2
 
Sodium nitrite oxidises ferrous iron to ferric iron in the haemoglobin, leading to methaemoglobinaemia. Methaemoglobin reduces the oxygen-carrying capacity of haemoglobin and causes a left shift in the oxyhaemoglobin dissociation curve with consequent tissue hypoxia.
 
Clinical features of methaemoglobinaemia depend on the level of met-Hb, ranging from asymptomatic to headache, dizziness, anxiety, tachypnoea and, in more severe cases, coma, seizures, lactic acidosis, and death. The clinical features corresponding to the associated met-Hb level are shown in the Table.3
 

Table. Clinical features at different methaemoglobin levels3
 
The management of NaNO2 poisoning includes supportive treatment and administration of an antidote for methaemoglobinaemia. The source of oxidative stress should be identified and further exposure should be avoided. Although the efficacy is unproven, activated charcoal may be considered for gastrointestinal decontamination if the patient presents early (within 2 hours) at the hospital with no contraindications.4 Supplementary oxygen is administered to patients who experience hypoxia and cyanosis.
 
Methylene blue is an effective antidote for methaemoglobinaemia. It acts as an oxidising agent and is converted to leukomethylene blue by NADPH methaemoglobin reductase, which can increase the metabolism of met-Hb through the nicotinamide adenine dinucleotide phosphate pathway. It is indicated in patients with symptomatic methaemoglobinaemia who exhibit signs of tissue hypoxia or have a met-Hb level >20%. For patients with underlying anaemia and cardiovascular, pulmonary or central nervous system compromise, methylene blue can be considered at a lower met-Hb level. Glucose-6-phosphate dehydrogenase deficiency is a relative contraindication for methylene blue due to the potential risk of methylene blue—induced haemolysis. Nonetheless a single dose use is generally acceptable in severe cases.
 
There is a rising trend of suicidal attempt using NaNO2 in western countries resulting in severe methaemoglobinaemia and, in some cases, death.1 2 In Hong Kong, two young ladies committed suicide and NaNO2 was found at the scene; both were certified dead before reaching the hospital.5 With the ease of purchasing items online and the widespread promotion of suicide methods on the internet, more cases can be expected in the near future. Imposing regulations on the consumer sale of highly concentrated NaNO2, which is lethal when ingested, is important in poison control. In 2024, the United States banned the sale of consumer products with a concentration of NaNO2 >10%.6
 
Conclusion
Intentional ingestion of NaNO2is an emerging and life-threatening cause of methaemoglobinaemia. Early recognition, gastrointestinal decontamination, and treatment with methylene blue along with supportive measures can be life-saving. This case report serves as a reminder for healthcare providers to be vigilant in their assessment of patients who present with unexplained respiratory distress, cyanosis, and desaturation despite oxygen supplementation. It is important to consider methaemoglobinaemia as a possible cause.
 
Author contributions
All authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. 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 had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the tenets of the Declaration of Helsinki. Patient consent has been obtained for all treatments and procedures, and verbal consent for publication was obtained from the patient.
 
References
1. Stephenson L, Wills S, van den Heuvel C, Humphries M, Byard RW. Increasing use of sodium nitrite in suicides—an emerging trend. Forensic Sci Med Pathol 2022;18:311-8. Crossref
2. McCann SD, Tweet MS, Wahl MS. Rising incidence and high mortality in intentional sodium nitrite exposures reported to US poison centers. Clin Toxicol (Phila) 2021;59:1264-9. Crossref
3. Hong Kong College of Emergency Medicine Clinical Toxicology Course Book. Hong Kong College of Emergency Medicine; 2023: 222.
4. Nelson LS, Howland MA, Lewin NA, editors. Goldfrank’s Toxicological Emergencies. 11th ed. McGraw-Hill Companies; 2019.
5. Two 22-year-old women in suicide pact at Ching Ping House in Sheung Shui consumed alcohol, drugs and sodium nitrite moments before their death. Dimsum Daily Hong Kong 2023 Jan 5: Local. Available from: https://www.dimsumdaily.hk/two-22-year-old-women-in-suicide-pact-at-ching-ping-house-in-sheung-shui-consumed-alcohol-drugs-and-sodium-nitrite-moments-before-their-death/. Accessed 5 Jan 2023.
6. Darby M. U.S. House passes legislation banning the sale of a poison. Utah Rep. Celeste Maloy was co-sponsor. Desert News 2024 May 17. Available from: https://www.deseret.com/utah/2024/05/17/house-passes-legislation-banning-sale-of-poison-linked-to-suicide/. Accessed 2 Oct 2024.

Aggressive renal angiomyolipoma with renal vein and inferior vena cava thrombus: a case report

Hong Kong Med J 2024 Oct;30(5):409–11 | Epub 22 Aug 2024
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Aggressive renal angiomyolipoma with renal vein and inferior vena cava thrombus: a case report
Phoebe HW Lo, MB, BS1; HM Kwok, MB, BS, FRCR1; FH Ng, MB, ChB, FRCR1; HY Lo, MB, BS, FHKAM (Pathology)2; Johnny KF Ma, MB, BS, FRCR1
1 Department of Radiology, Princess Margaret Hospital, Hong Kong SAR, China
2 Department of Pathology, Princess Margaret Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Phoebe HW Lo (lph218@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
A 58-year-old Chinese woman with good past health presented with a 2-day history of right lower abdominal pain. Routine biochemical blood tests revealed a white blood cell count of 9.1 × 109/L and normal renal function (creatinine level: 49 μmol/L). An urgent contrast-enhanced computed tomography scan revealed acute diverticulitis in the caecum. Incidentally, a solitary well-defined homogenous fat-density mass with unenhanced density of -63 Hounsfield units was evident at the right renal sinus, with extension into the right renal vein and inferior vena cava (IVC) [Fig 1]. Findings were suggestive of an aggressive renal angiomyolipoma (AML) with right renal vein and IVC thrombus. The patient was referred to an urologist. Subsequent robotic-assisted laparoscopic radical nephrectomy and IVC thrombectomy were performed uneventfully.
 

Figure 1. (a) Axial and (b) sagittal contrast-enhanced computed tomography images of the patient show a homogeneous fat-density mass of -63 Hounsfield units at the right renal sinus with extension into the right renal vein and inferior vena cava (arrow in [b])
 
The surgical specimen provided by the pathologist demonstrated the right renal vein depicted as a purple red strip and fatty tumour (Fig 2a). Microscopic examination revealed all features of a typical AML including mature adipocytes, myoid spindle cells, and thick-walled blood vessels (Fig 2b). It was also positive on Melan A (Fig 2c) and HMB-45 stains (Fig 2d).
 

Figure 2. (a) The surgical specimen of the patient on glass slide (haematoxylin and eosin [H&E] staining, not under microscope) includes the renal vein (RV) and fatty tumour (Tumour). (b) The high-powered H&E stained slide (×100) shows the tumour containing all features of angiomyolipoma including mature adipocytes (A), myoid spindle cells, and thick-walled blood vessels (B). Immunohistochemical staining shows tumour cells positive for Melan A (c) and HMB-45 (d) [both ×100]
 
Discussion
Angiomyolipoma is a common benign renal mesenchymal neoplasm composed in variable proportions of adipose tissue, smooth muscle cells, and abnormal vessels. It is most commonly sporadic (80%) or associated with genetic syndromes such as tuberous sclerosis.1 A renal mass with visualisation of macroscopic fat density on computed tomography is virtually diagnostic of AML. Therefore, visualisation of fat density in the intravascular compartment is indicative of tumour invasion.
 
Cases of aggressive AML with renal vein and IVC thrombus have been reported. A literature review2 of 26 cases of invasive renal AML reported that a large size and right-sided location of the tumour may be contributing factors in AML with intravascular invasion. This may be related to the shorter and straighter course of the right renal vein. Two variants of renal AML, namely, classic and epithelioid, have been described. The epithelioid variant has been reported to exhibit aggressive behaviour with IVC thrombus.3 In this case, the patient had a classic subtype of renal AML with mature adipocytes (Fig 2b) and no epithelioid cells.
 
The optimal treatment is robotic nephrectomy and IVC thrombectomy irrespective of tumour size, since IVC thrombus can be life threatening with higher risks of vessel occlusion and tumour embolus. A multi-institutional study in 2016 retrospectively reviewed 32 cases of robotic radical nephrectomy and IVC thrombectomy and demonstrated a favourable outcome with adequate robotic experience including less blood loss, earlier patient discharge, and fewer complications compared with open nephrectomy.4 Inferior vena cava thrombectomy follows similar surgical principles to that for renal cell carcinoma with IVC thrombus. Proper visualisation and mobilisation of the kidney, renal vein and IVC allow selective vascular clamping, namely, the infrarenal and suprarenal IVC as well as the renal vein. The IVC is then exposed and the tumour is dissected away from the IVC. The cavotomy is then closed and nephrectomy is performed.
 
We describe a classic subtype of renal AML extending into the renal vein and IVC, managed by robotic-assisted laparoscopic nephrectomy and IVC thrombectomy. Computed tomography and other imaging modalities are essential to diagnose AML and for proper surgical planning. With proper visualisation of the kidney, renal vein and IVC, a safe and successful outcome of robotic nephrectomy and IVC thrombectomy is achieved.
 
Author contributions
Concept or design: PHW Lo, HM Kwok, FH Ng, JKF Ma.
Acquisition of data: PHW Lo, HM Kwok, FH Ng, HY Lo.
Analysis or interpretation of data: PHW Lo, HM Kwok, HY Lo.
Drafting of the manuscript: All authors.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
This study was approved by the Kowloon West Cluster Research Ethics Committee of Hospital Authority, Hong Kong [Ref No.: KW/EX-23-010(180-06)]. The patient has given a consent statement for publication of this case report.
 
References
1. Martignoni G, Amin M.B. Pathology and genetics of tumours of the urinary system and male genital organs. In: Ebie JN, Sauter G, Epstein JI, editors. World Health Organization Classification of Tumours. Lyon, France: IARC; 2004: 65-7.
2. Islam AH, Ehara T, Kato H, Hayama M, Kashiwabara T, Nishizawa O. Angiomyolipoma of kidney involving the inferior vena cava. Int J Urol 2004;11:897-902. Crossref
3. Fox C, Salami SS, Moreira DM, et al. Aggressive renal angiomyolipoma of the lipomatous variant with inferior vena cava thrombus: a case report and review of the literature. Urol Case Rep 2013;2:9-11. Crossref
4. Abaza R, Shabsigh A, Castle E, et al. Multi-institutional experience with robotic nephrectomy with inferior vena cava tumor thrombectomy. J Urol 2016;195:865-71. Crossref

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