CHI is the main cause of persistent hypoglycaemia in infancy and childhood. Early detection and appropriate management is crucial for avoiding neurologic complications. In patients requiring surgery distinguishing focal from diffuse disease can fundamentally change the surgical management to focal curative pancreatectomy and near-total palliative pancreatectomy, respectively. Furthermore, preoperative localisation of focal disease is vital for identifying the focal lesion during curative surgery. Three modalities have been introduced for these purposes: PVS, ASVS and 18F-DOPA PET. To establish the diagnostic value of each modality a systematic review and meta-analysis was conducted.
Over 1,400 original publications were identified through a systematic review of the literature. Of these articles, only 13 articles reported original data on the diagnostic and localisation accuracy of PVS, ASVS, and/or 18F-DOPA PET in patients requiring surgery for CHI.
Aside from the sensitivity, 18F-DOPA PET was superior in every parameter of diagnostic accuracy, including the parameters that are considered most informative in evaluating diagnostic accuracy (i.e. positive LR, negative LR, DOR, AUC, and the Q* statistic; Table ). Furthermore, 18F-DOPA PET was found to be superior in localising focal CHI (pooled localisation accuracy, 0.82) when compared to PVS (pooled localisation accuracy, 0.76) and ASVS (pooled localisation accuracy, 0.64).
With an estimated specificity of 1.00 a positive PET scan rules in every patient with focal CHI. The possibility of false-positive results due to F-DOPA accumulation in the gall bladder and alimentary tract were not observed [37
]. The astounding specificity of 18
F-DOPA PET scanning is further supported by reports detecting focal CHI in ectopic pancreatic tissue [38
However, with an estimated sensitivity of 0.75 (range 0.67–1.00), a negative 18
F-DOPA PET scan cannot rule out focal CHI in patients requiring surgery. False-negative results can occur due to several reasons, including the inability of small and thin lesions to accumulate sufficient F-DOPA to be visualized. The smallest lesion detected by 18
F-DOPA PET reported in the literature has measured 5
4 mm in diameter [35
]. Moreover, focal lesions may be missed near the left kidney, gall bladder, and duodenum due to elimination of F-DOPA through the kidneys, liver, biliary tract, gall bladder, and duodenum, especially when focal lesions are small in size. Localisation accuracy of 18
F-DOPA PET suffered from similar problems.
Besides being diagnostically more accurate, 18F-DOPA PET has some important additional advantages over both PVS and ASVS. Most notably, PET scanning is non-invasive, simple, and remains free of reported complication in the medical literature.
It must be said, however, that 18
F-DOPA PET is not free of risks. It exposes patients to a small but significant fraction of ionizing radiation, albeit far less than the alternative angiographic methods. The effective dose of 1 minute of abdominal fluoroscopy in paediatrics is estimated to be 1 mSv per minute [40
]. Since ASVS and PVS procedures can last up to several hours the accumulative exposure to ionizing radiation is substantial. Radiation dosimetry from combined PET/CT, using 80 mAs and 140 kVp for the CT-scan, is approximately 3 to 5 mSv. The estimated risk of eventual death from radiation-induced malignancy in paediatrics by an effective dose of 10 mSv was one in 1,000 [41
]. Intelligent dose reduction based on the principles of as low as reasonably achievable is essential for the safest possible care of children [43
Developments in the field of nuclear medicine, especially hybrid PET/MRI scanning, could further reduce the radiation burden associated with 18
F-DOPA PET scanning and should—in the near future—be strived for as the ultimate modality to diagnose and localize CHI [44
Our systematic review and meta-analysis has several limitations. The meta-analysis reported here combined results from studies with both low and high probability of bias. Furthermore, sample sizes varied greatly among included studies, where the smallest sample included only four patients [29
]. Nevertheless, even when incorporating studies with small sample sizes, combining the results of multiple studies increases the diagnostic accuracy of outcome estimates to the levels that are largely unachievable by stand-alone studies [45
]. Furthermore, combining results from multiple studies can detect homogeneity among their results making estimated diagnostic accuracy generalizable to other clinics.
Although the majority of included studies reported a clinically applicable domain, the overall methodological quality of papers was generally poor. The most consistent flaw in study methodology was insufficient blinding of the assessor of the reference standard to the outcome of the index test and vice versa. Only three studies reported sufficient blinding protocols [16
]. Furthermore, a considerable amount of studies had missing data, either resulting from non-standardized selection of the domain or from a failure to perform the reference standard on all included patients. Studies with small sample sizes and high probability of bias tended to overestimate the diagnostic accuracy and could have attributed to the observed heterogeneity among study results.
Risk of publication bias assessment was considered inappropriate and not meaningful. Application among meta-analysis with small number of studies (n
10) yields low statistical power [46
]. Furthermore, large in-between study heterogeneity could lead to false-positive claims of publication bias [47
]. Both were applicable to our meta-analysis. Therefore, publication bias assessment was not performed
Despite these limitations, homogeneous study results were observed for most parameters relating to the diagnostic accuracy of ASVS, PVS, and 18F-DOPA PET. Therefore, we feel confident that the estimated parameters of diagnostic accuracy approach the levels achieved in a clinical setting. Nonetheless, the low number of studies included, the low number of study subjects, and the poor overall methodological quality of the included studies limit the power of this meta-analysis in providing strong conclusions and recommendations. A well-designed cross-sectional trial investigating a large population of children with CHI should be performed to make stronger conclusions and recommendations about the diagnostic superiority of 18F-DOPA PET as claimed by the results of this systematic review and meta-analysis.