Severe transient neonatal hyperinsulinism: First Peruvian case series

Abstract

Congenital hyperinsulinism is characterized by dysregulated insulin secretion and is the most common and severe cause of persistent hypoglycemia in pediatrics. Brain damage rates can be as high as 50% due to inadequate treatment. Transient congenital hyperinsulinism is more frequent than permanent congenital hyperinsulinism. Acquired hyperinsulinism due to perinatal stress is often transient, too. Diazoxide is the first-line therapy. However, in Peru, reports about pediatric patients with hyperinsulinism treated with diazoxide are scarce. Our article describes the first Peruvian case series of severe transient neonatal hyperinsulinism treated with diazoxide, with good response and manageable adverse effects. Diazoxide should be included in the Single National Pharmaceutical Request Form for Essential Medicines of Peru to expedite the use of a medication as essential as this one.

Introduction

Defining who is a patient with hyperinsulinism is challenging due to the heterogeneous nature of the subtypes and classifications of the disease. ¹ Neonatal hyperinsulinism can be acquired or genetic (congenital). ¹ Congenital hyperinsulinism is characterized by deregulated insulin secretion and is the most common and severe cause of persistent hypoglycemia in pediatrics.^2–5 Brain damage rates can reach 50% due to delays in diagnosis and inadequate treatment.^5,6 Medical management seeks to maintain euglycemia and reduce insulin secretion, with diazoxide being the first-line therapy.^3,4,6–8 Congenital hyperinsulinism can be transient or permanent, with the transient form being the most frequent. ¹ Acquired hyperinsulinism due to perinatal stress (i.e. birth asphyxia, intrauterine growth restriction, maternal factors such as hypertension/preeclampsia) is often transient, too. ¹

In Peruvian patients, two publications describe three patients with hypoglycemia due to hyperinsulinism treated with diazoxide.^9,10 However, two of these patients had a disease onset after 1 year of age. ¹⁰

Our article aims to describe the first Peruvian case series of severe transient neonatal hyperinsulinism treated with diazoxide between 2021 and 2024 and review the literature. We also hope to raise awareness about the need to include diazoxide in Peru’s List of Essential Medicines.

Case 1

A male newborn of 36 weeks gestational age (GA) presented with recurrent hypoglycemia from birth and required intravenous (IV) dextrose with a glucose infusion rate (GIR) of 10 mg/kg/min to remain euglycemic. At 15 days of life, adrenal insufficiency was evident (ACTH 64.73 pg/mL (9.1–51.3) and cortisol 0.87 μg/dL (4.46–22.7)), and oral hydrocortisone was started at 10.5 mg/m²/day; and 2 days later a critical sample was taken (glucose 30 mg/dL (70–100), pH 7.358 (7.350–7.450), HCO₃ 22.2 mmol/L (21.0–28.0), cortisol 1.71 μg/dL (4.46–22.7), and insulin 1.87 μU/mL (⩽1.25)). At 45 days of life, remission of adrenal insufficiency was evident (ACTH 64.73 pg/mL (9.1–51.3) and cortisol 14.62 μg/dL (4.46–22.7)) and hydrocortisone was discontinued. The next day, diazoxide was obtained, and treatment was started at 4 mg/kg/day, after which the use of dextrose decreased progressively. Twelve days later, the dose of diazoxide was increased to 7.5 mg/kg/day, and due to edema, hydrochlorothiazide was started at 1 mg/kg/day. The next day, the edema subsided, and dextrose was discontinued. At 60 days of age, he was discharged, and at the age of 6 months, diazoxide and hydrochlorothiazide were discontinued (Figure 1).

Figure 1.

Case 1: glucose levels and glucose infusion rate during hospitalization.

Case 2

A 38-week GA male newborn with persistent hypoglycemia, despite receiving IV dextrose at 10.5 mg/kg/min, was hospitalized at 44 days of age, referred from another facility, with results of a critical sample taken at 19 days of life (glucose 38 mg/dL (70–100), pH 7.398 (7.350–7.450), HCO₃ 22.4 mmol/L (21.0–28.0), ACTH 84.8 pg/mL (9.1–51.3), cortisol 8.1 μg/dL (4.46–22.7), GH 20.4 μg/L (>10), insulin 1.3 μU/mL (⩽1.25), and C-peptide 0.6 ng/mL (⩽0.5)).

On the first day, diazoxide was started at 7.4 mg/kg/day, hydrochlorothiazide at 1.1 mg/kg/day, and IV dextrose at 10.4 mg/kg/min, after which dextrose was progressively decreased. Five days later, the diazoxide dose was increased to 11.1 mg/kg/day. On the ninth day, the dose of hydrochlorothiazide was increased to 1.6 mg/kg/day due to eyelid edema. Three days later, adrenal insufficiency was confirmed (ACTH 25 pg/mL (9.1–51.3) and cortisol 1.7 μg/dL (4.46–22.7)), and oral hydrocortisone was started at 11.3 mg/m²/day.

On day 16, hydrochlorothiazide was increased to 2.5 mg/kg/day due to generalized edema. Four days later, no edema was present, and dextrose was discontinued. On day 25, diazoxide and hydrochlorothiazide were discontinued, and 2 days later, he was discharged receiving oral hydrocortisone, but after the first outpatient follow-up, he never returned (Figure 2).

Figure 2.

Case 2: glucose levels and glucose infusion rate during hospitalization.

Case 3

A 38-week-old male neonate with recurrent hypoglycemia since birth was admitted to the hospital at 10 days of life after being referred from another facility where a critical sample had been obtained at 5 days of life (glucose 37 mg/dL (70–100), pH 7.279 (7.350–7.450), HCO₃ 22.4 mmol/L (21–28), ACTH 20.9 pg/mL (9.1–51.3), cortisol 11.1 μg/dL (4.46–22.7), GH 14.7 μg/L (>10), insulin 8.7 μU/mL (⩽1.25), and C-peptide 3.2 ng/mL (⩽0.5)).

The patient required IV dextrose at 19 mg/kg/min on admission. Two days later, diazoxide was started at 4.5 mg/kg/day and hydrochlorothiazide at 1.5 mg/kg/day. Subsequently, parenteral nutrition was started, and the diazoxide dose was increased. Then, GIR was decreased. At 20 days of life, the diazoxide dose was increased to 8.7 mg/kg/day, and 2 days later, due to hyperglycemia, the dose was reduced to 5 mg/kg/day, and parenteral nutrition was discontinued. At 39 days of life, diazoxide and hydrochlorothiazide were discontinued. Five days later, dextrose was discontinued (Figure 3).

Figure 3.

Case 3: glucose levels and glucose infusion rate during hospitalization.

Case 4

A 38-week-old male neonate had recurrent hypoglycemia from birth, so he received IV dextrose at a GIR of up to 24 mg/kg/min on the fifth day of life but without a satisfactory response.

At 6 days of life, a critical sample was obtained (glucose 38.4 mg/dL (70–100), pH 7.297 (7.350–7.450), HCO₃ 18.7 mmol/L (21–28), cortisol 6.66 μg/dL (4.46–22.7), insulin 1.4 μU/mL (⩽1.25), C-peptide 3.7 ng/mL (⩽0.5), and GH 4.32 μg/L (>10)), and 3 days later diazoxide was started at 6 mg/kg/day and hydrochlorothiazide at 1 mg/kg/day, after which GIR was progressively decreased. At 19 days of life, diazoxide and hydrochlorothiazide were increased to 11.4 and 1.4 mg/kg/day, respectively.

At 25 days of life, dextrose was discontinued, and the following day, the dose of diazoxide was decreased. Three days later, it was increased again due to hypoglycemia. At 36 days of life, the dose of diazoxide was increased to 10.8 mg/kg/day, and there was better glycemic control. Forty days later, the patient was discharged, and at 4 months of life, diazoxide and hydrochlorothiazide were discontinued. He is currently being followed for the GH deficiency found in the critical sample (Figure 4).

Figure 4.

Case 4: glucose levels and glucose infusion rate during hospitalization.

In all cases, diazoxide was progressively stopped after self-weaning with weight gain, and glucose levels were monitored with capillary glucose measurements performed at home by the parents before diazoxide was completely stopped. Due to economic limitations, it was difficult for parents to hospitalize their children again for a fasting study to completely stop diazoxide. Thus, outpatient close follow-up was performed based on the capillary glucose measurements obtained at home every day for at least 2 weeks after stopping diazoxide.

Table 1 shows details about perinatal risk factors, patient characteristics at the moment of critical blood sampling, biochemistry and complete blood count before and after starting diazoxide. Unfortunately, we do not have neuropediatric evaluations on follow-up since all patients live in distant regions of Peru and have difficulties attending medical consultations.

Table 1.

Characteristics of each patient at birth, before and after starting diazoxide.

Characteristics	Reference values	Case 1	Case 2	Case 3	Case 4
Perinatal risk factors
Gestational age		35	38	38	38
Birth weight (g)		2295	2240	1910	2460
Birth length (cm)		43	45.2	39	47
AGA/SGA/LGA		AGA	SGA	SGA	AGA
Maternal disease a		None	CMV	CMV	None
APGAR		9/9	8/9	3/8	8/9
Perinatal asphyxia		No	No	No	No
Rh isoimmunization		No	No	No	No
Patient characteristics at the moment of critical blood sampling
Mechanical ventilation		Yes	No	Yes	No
Neonatal sepsis		Yes	Yes	No	Yes
Acidosis		No	No	No	Yes
Urine ketones		N/A	No	N/A	No
Biochemistry before starting diazoxide
ALT (U/L)	<71	15.55	12.8	30.0	26.8
Albumin (g/dL)	3.5–5.0	2.4	N/A	2.8	3.44
Creatinine (mg/dL)	0.10–0.93	0.27	0.25	0.41	0.59
Biochemistry a week after diazoxide was started
ALT (U/L)	<71	20	20.39	45.8	62.33
Albumin (g/dL)	3.5–5.0	N/A	2.99	2.8	3.2
Complete blood count before starting diazoxide
Leucocytes	3564–10,214	7599	8255	5851	11,287
Neutrophils	1700–7600	1291.8	1502	3750	3680
Hb (g/dL)	11.6–14.2	11.1	14.33	13.6	18.55
Platelets	152,400–347,900	256,700	561,000	70,000	49,700
Complete blood count a week after diazoxide was started
Leucocytes	3564–10,214	11,200	8177	6379	9287
Neutrophils	1700–7600	1579	1055	3598	3250
Hb (g/dL)	11.6–14.2	12.1	10	11.3	15.74
Platelets	152,400–347,900	397,000	252,100	54,000	312,000

AGA: appropriate for gestational age; ALT: alanine aminotransferase; CMV: cytomegalovirus infection; Hb: hemoglobin; LGA: large for gestational age; N/A: not available; SGA: small for gestational age.

^aIncludes: preeclampsia, eclampsia, diabetes, obesity, and infections.

Discussion

Knowing the proper management of hyperinsulinism is important to avoid developmental delay, cerebral palsy, epilepsy, and permanent brain damage secondary to recurrent hypoglycemia.^1,4,7,11

The first line of treatment is diazoxide.^3,4,6–8 Although diazoxide saves lives and is on the World Health Organization’s Model List of Essential Medicines 2023, ¹² it is not on the Single National Pharmaceutical Request Form for Essential Medicines of Peru (PNUME). ¹³ Therefore, raising awareness about the need to add it is essential.

In Peruvian patients, there are only two reports of children with hypoglycemia due to hyperinsulinism who were treated with diazoxide.^9,10 One of them included one patient with CH who received diazoxide intermittently. ⁹ The other one described two patients with hyperinsulinism-hyperammonemia syndrome who were diagnosed after 1 year of age. ¹⁰ In our series, all patients had severe transient neonatal hyperinsulinism and used diazoxide without interruptions. Thus, our publication is the first case series to describe the treatment of severe transient neonatal hyperinsulinism with diazoxide in Peru.

Normally, plasma insulin concentrations should be suppressed at a time of hypoglycemia. ¹⁴ Thus, any detectable insulin level during hypoglycemia can suggest hyperinsulinism. ¹⁴ However, according to the current International Guidelines for the Diagnosis and Management of Hyperinsulinism, a detectable insulin or C-peptide level with glucose <50 mg/dL (critical sample) is not sufficient to suspect hyperinsulinism. ³ Insulin should be >1.25 µU/mL and C-peptide >0.5 ng/mL³ since, in people without hyperinsulinism, a critical sample may contain a low level of insulin that is detectable with current methods. ² Our series met the current criteria for insulin and C-peptide.

Some clinicians have stated that hyperinsulinism depends on the relative glucose level. For example, some authors have suggested that a plasma insulin level >13 µU/mL with a glucose concentration <40 mg/dL might suggest the diagnosis of hyperinsulinism. ¹⁵ In other words, for a lower glucose threshold than the currently recommended threshold for obtaining a critical sample by current guidelines, a higher threshold for plasma insulin levels might help to diagnose a patient with hyperinsulinism.

Our cases were transient, which is more frequent than permanent ones, ¹ and required a GIR of 10–24 mg/kg/min before the start of diazoxide. Requiring a GIR >8–10 mg/kg/min is characteristic of hyperinsulinism.^3,6,7,11

Not all cases respond to diazoxide. Those that do respond usually do not have alterations in K-ATP channels (42% of cases). ¹⁶ This group includes those with hyperinsulinism secondary to perinatal stress, so they can use diazoxide if necessary.^5,17 In our series, all our cases responded satisfactorily to diazoxide.

The dose of diazoxide ranges from 5 to 15 (even 20) mg/kg/day orally divided into two to three doses.^3,4,6,7,11 None of our cases required more than 11.5 mg/kg/day. The most frequent side effects are edema and hypertrichosis, and the severe ones include heart failure and pulmonary hypertension.^3,4,6,7,11 It is suggested that diazoxide be started with chlorothiazide at 10 mg/kg/day or hydrochlorothiazide at 1–2 mg/kg/day to avoid fluid retention.^3,4,18 The first two patients in our series had edema. However, they responded well to the use of hydrochlorothiazide.

As diazoxide is excreted by the kidneys, the half-life may be prolonged with renal impairment and a reduced dose may be necessary. ⁶ Our patients did not have renal impairment before starting diazoxide.

Rare adverse events include neutropenia (15.6%) and thrombocytopenia (4.7%). ³ However, the clinical significance of neutropenia in those cases is unknown, and the level of neutropenia that deserves discontinuation of diazoxide is also unknown. ³ Two of our patients had neutropenia before and after diazoxide use; the others always had a normal neutrophil count. Regarding platelet count, two of our patients had thrombocytopenia before diazoxide use. However, after diazoxide use, only one of those patients remained with thrombocytopenia (with a lower platelet count than before) but without signs suggesting spontaneous bleeding, and the rest of the patients still had a normal platelet count.

Diazoxide metabolism involves hepatic oxidation. ¹⁹ Moreover, diazoxide is extensively bound (>90%) to plasma proteins, primarily albumin. ¹⁹ Measuring albumin or assessing liver function is not considered standard of care before starting diazoxide. ¹⁹ However, some authors suggest that hypoalbuminemia may increase the “free diazoxide” concentration, resulting in increased potential toxicity. ¹⁹ Thus, diazoxide should be used with caution in patients with hypoalbuminemia or impaired liver function. ¹⁹ Two of our patients had edema responsive to diuretic management, and significant adverse effects did not occur despite hypoalbuminemia.

Drugs without quality evidence to support them (e.g. nifedipine, sirolimus, etc.) should only be used for experimental purposes. ³ Glucocorticoids used in the past are ineffective, and their risks outweigh any benefits. ³

Genetic studies are recommended in patients who do not respond to diazoxide, require high doses for a prolonged period, or continue to require the drug after 3–6 months. ³ Our cases did not meet these criteria. However, it is important to highlight that for low-resource settings such as Peru, the Open Hyperinsulinism Genes Project is a charity-funded testing service that can be useful for patients with little or no response to treatment, and permanent cases.

The first two cases started taking diazoxide between 44 and 46 days of life because the process of purchasing diazoxide in Peru takes a considerable amount of time, so the entry of this drug into the PNUME would speed up the process.

In Case 1, we considered that ACTH response (64.73 pg/mL (9.1–51.3)) was lower than expected with very low cortisol (0.87 μg/dL (4.46–22.7)). Thus, we suspected central adrenal insufficiency was the most probable explanation.

Although hypoglycemia normally stimulates cortisol secretion, neonates with hyperinsulinemic hypoglycemia might not generate an adequate cortisol counter-regulatory response.^20–22 We hypothesized central adrenal insufficiency in Case 1 might be secondary to hyperinsulinemic hypoglycemia. Replacement doses of cortisol are sometimes recommended if inadequate cortisol response secondary to hyperinsulinism is suspected. ²² Because of this, in Case 1 we administered hydrocortisone treatment until the resolution of adrenal insufficiency 30 days later.

We hypothesized central adrenal insufficiency in Case 2 might be also secondary to hyperinsulinemic hypoglycemia. Unfortunately, after the first outpatient follow-up, the patient never returned, and we could not confirm if central adrenal insufficiency was transient, as in Case 1.

In Case 4, due to GH deficiency, we obtained a hormone profile, which did not show other types of hypopituitarism (TSH 2.45 (0.01–3.48), free T₄ 2.36 ng/mL (1.16–2.50), prolactin 101.8 ng/mL (30–495), LH 12.2 IU/L (0.72–13.53), FSH 1.56 IU/L (1.22–5.19), testosterone 283 ng/dL (75–400), ACTH 20.1 pg/mL (5.0–63.0)).

Some important laboratory tests are unavailable in all Peruvian public health facilities (blood ketones, urine ketones, c-peptide, and free fatty acids). Many times, families must pay for the tests in private laboratories. However, not all families can afford to perform all the tests in private laboratories. Moreover, glucagon is not available in Peru. All these were limitations to conducting additional studies on the patients of this case series.

Additionally, as far as we know, synacthen test (ACTH stimulation test) is unavailable in Peru. Because of this, we had to rely on a new measurement of ACTH and cortisol to conclude a remission of adrenal insufficiency and stop hydrocortisone in Case 1. Moreover, it is important to mention that we do not suggest cortisol replacement with hydrocortisone in absolutely all newborns with random low cortisol levels when synacthen test is unavailable. In our case series, the possibility of administering hydrocortisone was considered only when inadequate cortisol levels were found in a critical sample (when blood glucose was <50 mg/dL).

However, despite limitations, there was a high index of suspicion for neonatal hyperinsulinism in our patients, and treatment with diazoxide was successful. Moreover, there were no adrenal crises after hydrocortisone was stopped or medical illnesses after discharge in Case 1.

In Peru, for every child who requires diazoxide, the hospital where the child is being treated must go through a cumbersome process to import the drug. If the parents of a child wish to import the drug privately, the costs are incredibly high for most Peruvians. All of this often makes it difficult to manage patients with congenital hyperinsulinism properly.

Conclusion

In conclusion, diazoxide is often effective in cases of neonatal hyperinsulinism and produces manageable adverse effects. Therefore, it should be possible to use it quickly to reduce the risk of neurological sequelae in any Peruvian child with neonatal hyperinsulinism, either transient or permanent. However, neonatal hyperinsulinism remains a serious problem in Peru due to the lack of diazoxide availability in almost all the hospitals in our country. Diazoxide must be included in the PNUME to speed up the purchase of this essential drug in Peru.