Suspected congenital hyperinsulinism in a Shiba Inu dog

Abstract A 3‐month‐old male intact Shiba Inu dog was evaluated for a seizure disorder initially deemed idiopathic in origin. Seizure frequency remained unchanged despite therapeutic serum phenobarbital concentration and use of levetiracetam. The dog was documented to be markedly hypoglycemic during a seizure episode on reevaluation at 6 months of age. Serum insulin concentrations during hypoglycemia were 41 U/μL (reference range, 10‐29 U/μL). The dog was transitioned to 4 times per day feeding, diazoxide was started at 3.5 mg/kg PO q8h, and antiepileptic drugs were discontinued. No clinically relevant abnormalities were identified on bicavitary arterial and venous phase contrast computed tomographic imaging. The dog remained seizure‐free and clinically normal at 3 years of age while receiving 5.5 mg/kg diazoxide PO q12h and twice daily feeding. Seizures later occurred approximately twice per year and after exertion, with or without vomiting of a diazoxide dose. Blood glucose curves and interstitial glucose monitoring were used to titrate diazoxide dose and dosing interval. Congenital hyperinsulinism is well recognized in people but has not been reported in veterinary medicine.

Borderline hypoglycemia was thought to represent juvenile fasting hypoglycemia. The dog was anesthetized and high-field magnetic resonance imaging of the head performed (1.5T Intera, Philips Medical Systems, Eindhoven, the Netherlands). Sagittal and transverse plane T2-weighted turbo-spin echo (T2W TSE), fluid attenuated inversion recovery (FLAIR), transverse plane T2* gradient echo, and sagittal and transverse T1-weighted (T1W TSE) images were acquired before and after IV injection of gadolinium contrast (0.1 mM/kg gadobutrol; Bayer plc, Strawberry Hill, UK). Imaging identified a focal, well-demar-   3 Considering signalment and history, the index of suspicion usually is high enough for a neoplastic process that surgical exploration, intraoperative imaging and partial pancreatectomy are warranted, with histopathology used as a confirmatory test. Computed tomography has been reported to have a sensitivity of 71% for identifying pancreatic insulinomas 4 and dual phase contrast CT now is recommended 5 for increased sensitivity. Repeated dual phase contrast CT identified no such abnormalities in this dog, and thus hyperinsulinism was presumed to result from a diffuse pancreatopathy. Furthermore, the previously reported age range of dogs with insulinoma is 4 to 14 years 6,7 and in 50% of cases the disease is already metastatic at the time of presentation. 8 Although survival times of 2 to 4 years have been reported after combined surgical and medical management of insulinoma,, 8 medical treatment alone is associated with significantly shorter median survival times when compared to surgical and follow-up medical treatment, with the longest reported survival of a patient receiving medical management only being 549 days. 6,9 A diagnosis of insulinoma was excluded based on absence of nodular pancreatic lesions on 2 CT examinations, signalment and long-term stability without relapse.
In people, hyperinsulinism in infancy can be transient or persistent. Transient causes of hyperinsulinism include being the infant of a diabetic mother, perinatal stress or asphyxia, erythroblastosis fetalis, sepsis, and umbilical artery catheter placement. Hyperinsulinism in these situations tends to resolve within days to weeks. 10  Congenital hyperinsulinism is the most common cause of persistent hyperinsulinemic hypoglycemia in infants 12 and can occur in both focal and diffuse forms. The focal form lends itself to partial pancreatectomy, but the focal nature is challenging to confirm, requiring genotyping, fluorine-18 L-3,4-dihydroxyphenylalanine positron emission tomography, 13 intraoperative ultrasonography, 14 intraoperative frozen section histopathology, 15 or some combination of these for confirmation. The diffuse form may require subtotal pancreatectomy as part of management, but it is infrequently curative. 15,16 Diazoxide responsiveness is an important feature used in people to allow characterization of CHI. Among diazoxide-responsive CHI patients, a genetic mutation is only identified in 27% to 47% of patients. Among those with mutations identified, the most common are KATP channel mutations, GLUD1 mutations (causing glutamate dehydrogenase dysfunction and hyperinsulinism with hyperammonemia) and GCK (glucokinase) mutations, with the remainder being rare mutations in genes such as HNF4A, HADH, UCP2, and HNF1A. 11,17 Patients without identifiable mutations may experience spontaneous resolution over time, but the timescale of resolution is unpredictable. 18 This same study suggested that lack of an identifiable genetic mutation and a response to diazoxide are associated with disease remission.
Despite a positive response to diazoxide treatment, insufficient evidence was available to confirm an etiology in our case. Two cases termed nesidioblastosis have been reported in the veterinary literature (a 6-year-old cat and a 6-year-old dog). 19,20 In these cases, adultonset hypoglycemia resolved with partial pancreatectomy in a dog, and pancreatic histopathology disclosed diffusely increased islet area in the pancreas without evidence of malignancy and multifocal micronodular hyperplasia of endocrine and exocrine tissue in a cat. Both cases were managed successfully by partial pancreatectomy.
Infectious diseases, such as bartonellosis and babesiosis, have been reported as causes of hyperinsulinemic hypoglycemia in dogs.
The dog of our report was not tested for these diseases because of systemic stability and a low index of clinical suspicion. 21 35,36 Consideration also could be given to the use of somatostatin analogues (eg, octreotide) in the dog of this report, should management of clinical signs prove problematic in the future, or during any further supply difficulties. 37 3 | SUMMARY Although a relatively novel and extremely rare disease, CHI (of multiple etiologies) is a differential diagnosis for persistently hypoglycemic juvenile dogs, and even may be considered in normoglycemic patients with a history of seizures as evidenced by our dog and the dog of previous case report. 19 Medical management with diazoxide has proven successful thus far, but surgical management and even spontaneous disease remission both remain possibilities. The affected dog appears to have a good midrange to long-term prognosis.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

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Authors declare no off-label use of antimicrobials.

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Authors declare human ethics approval was not needed for this study.