OVERVIEW

What is the function of the pancreas?

The pancreas is the second largest gland in the human body after the liver. Located in the upper abdomen near the spine, it is an elongated organ surrounded by the liver, stomach, greater omentum, spine, abdominal blood vessels, spleen, duodenum, and transverse colon, making its position highly concealed.
Although small in size, the pancreas has significant functions. It is a vital organ responsible for both digestive and endocrine functions:

• The digestive function is primarily achieved through pancreatic juice secreted by pancreatic acinar cells, which contains enzymes such as trypsin, amylase, and lipase.

• The endocrine function is mainly carried out by various cells within the pancreatic islets, each secreting different hormones.

What are pancreatic islets?

Scattered throughout the pancreas are small clusters of cells called pancreatic islets. If the pancreas is likened to a vast ocean, the islets are like isolated islands.
The islets contain various cell types: alpha (α) cells, beta (β) cells, delta (δ) cells, and PP cells.

• Among these, β cells constitute the largest proportion and primarily secrete insulin, which is crucial for regulating blood sugar levels in the body. If β cells are significantly damaged or cease functioning due to certain reasons, insufficient insulin production can lead to elevated blood sugar levels, eventually resulting in diabetes if exceeding specific thresholds. Conversely, if β cells proliferate excessively and secrete too much insulin, it can cause hypoglycemia.

• Additionally, α cells secrete glucagon, δ cells produce gastrin and somatostatin, and PP cells secrete pancreatic polypeptide—each with distinct roles.

What is islet cell hyperplasia?

The medical term "islet cell hyperplasia" originated in the first half of the 20th century and remains controversial. Currently, it refers to the abnormal proliferation of β cells under microscopic examination, accompanied by excessive insulin secretion, leading to reduced blood sugar levels, related symptoms, and potential organ dysfunction or structural damage.

What are the types of islet cell hyperplasia?

Islet cell hyperplasia is categorized into two conditions:

• One is persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also known as congenital hyperinsulinism, noninsulinoma pancreatogenous hypoglycemia syndrome (NPHS), familial hyperinsulinemic hypoglycemia, primary islet cell hypertrophy, or primary islet cell hyperplasia. It is the most common cause of persistent hypoglycemia in newborns and infants. Below, it will be uniformly referred to as "PHHI." Click here to learn more about PHHI.

• The other occurs after gastrointestinal surgery, particularly gastric bypass surgery, leading to islet cell hyperplasia. Below, it will be temporarily referred to as "secondary islet cell hyperplasia."

The following sections will describe these two conditions separately.

Is islet cell hyperplasia common? Who is at risk?

No. In fact, this disease is extremely rare. Very few patients receive a definitive diagnosis, and most cases are discovered and confirmed incidentally.
Literature reviews indicate that PHHI is more common in young children. Its incidence in individuals of Northern European descent is approximately 1 in 30,000 live births. In populations with high consanguinity rates or founder effects (e.g., Saudi Arabia: 1 in 2,675; Central Finland: 1 in 3,200), the incidence increases. Data for China are currently lacking.
In recent years, with the rise of bariatric surgery, cases of secondary islet cell hyperplasia following gastric bypass surgery have increased, leading to more clinical reports. However, due to the small overall sample size, no clear patterns have been identified.
There is insufficient evidence to suggest a gender preference for this disease.

SYMPTOMS

What are the manifestations of islet cell hyperplasia?

• Hypoglycemia:
  Islet cell hyperplasia leads to inappropriate autonomous insulin secretion, and elevated insulin levels can cause hypoglycemia.
  This condition is the most common cause of persistent hypoglycemia in newborns and infants, which may present as life-threatening hypoglycemia on the first day after birth or as mild symptomatic hypoglycemia during childhood or adolescence (which may be difficult to recognize).
  Most patients with islet cell hyperplasia experience postprandial hypoglycemia (ranging from immediately after meals to up to 5 hours later), while fasting hypoglycemia is rare. The main symptoms of hypoglycemia include intense hunger, palpitations, trembling hands, cold sweats, irritability, and behavioral abnormalities.
  Hypoglycemic episodes may recur repeatedly, gradually becoming more frequent, prolonged, and severe. In severe cases, hypoglycemic coma may occur.

• Whipple's Triad:
  Whipple's Triad refers to: ① Hypoglycemic symptoms occurring after fasting or exercise; ② Blood glucose levels below 2.8 mmol/L (50 mg/dl) during an episode; ③ Immediate relief of hypoglycemic symptoms after glucose administration.

• Macrosomia:
  Among PHHI (persistent hyperinsulinemic hypoglycemia of infancy) infants, one-third exhibit macrosomia. Most PHHI infants show hypoglycemic symptoms within the first few hours to days after birth, such as feeding difficulties, lethargy, tremors, and hypotonia.

• Other manifestations:
  May be accompanied by gradual weight gain, as well as declines in memory and cognitive function.

What adverse effects can islet cell hyperplasia cause?

Persistent hypoglycemia in newborns and infants may present as life-threatening hypoglycemia on the first day after birth, leading to severe neurological damage, or as mild symptomatic hypoglycemia during childhood or adolescence (which may be difficult to recognize).
Recurrent or prolonged hypoglycemic episodes may result in neurological sequelae, including psychomotor retardation, cognitive deficits (short-term memory, visuomotor integration, and arithmetic ability), and epilepsy.
Severe hypoglycemia can lead to hypoglycemic coma, which increases the risk of accidental injuries such as falls.

CAUSES

What causes islet cell hyperplasia?

The exact cause of this disease is currently unknown.

• 50% of PHHI patients have a genetic basis, which can be caused by defects in at least 9 genes (including ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4α, HNF1α, UCP2, etc.). Genetic defects disrupt the normal regulatory relationship between glucose concentration and insulin secretion in children, leading to insulin secretion even when blood sugar is low, resulting in hypoglycemia. Some PHHI patients have no obvious family history of inheritance.

• Secondary islet cell hyperplasia may be related to factors such as reduced gastric volume after surgery and altered food diversion pathways.

Is islet cell hyperplasia contagious?

No. This disease is not contagious.

Is islet cell hyperplasia hereditary?

PHHI may be hereditary, but this has not been fully clarified.
As mentioned earlier, certain genetic mutations may increase susceptibility to islet cell hyperplasia. Therefore, in theory, family members carrying the same gene mutation have a higher probability of developing the same disease compared to normal individuals.
In children, most PHHI cases with a clear molecular basis are inherited in an autosomal recessive manner.

DIAGNOSIS

Is the diagnosis of islet cell hyperplasia difficult?

Yes, it is very difficult.
For infants and young children, macrosomia accounts for one-third of PHHI cases in newborns. Therefore, when encountering macrosomia clinically, screening for PHHI should be considered.
For adults, on one hand, such cases are extremely rare, and most doctors have insufficient knowledge and low vigilance for this condition. On the other hand, the disease is highly insidious and difficult to identify accurately in its early stages. As a result, when clinicians encounter such cases, they often only arrive at a definitive diagnosis after ruling out common diseases through exclusion methods, typically when conventional theories fail to explain the symptoms.
Moreover, in many cases, due to the inability to obtain pancreatic surgical specimens and the lack of pathological evidence, the condition can only be highly suspected but not definitively diagnosed.

Which diseases can islet cell hyperplasia be confused with?

Due to its clinical manifestations of blood glucose dysregulation, this condition is often misdiagnosed as insulinoma, pancreatic neuroendocrine tumors, type 2 diabetes, dumping syndrome, etc., requiring doctors to rule them out one by one.

• Insulinoma and other pancreatic neuroendocrine tumors: These also exhibit excessive insulin secretion, leading to hypoglycemia symptoms and Whipple’s triad. Imaging studies such as contrast-enhanced CT or MRI can sometimes locate tumor lesions in the pancreas, aiding diagnosis. However, in some cases, clear lesions may not be detectable on imaging, requiring surgical intervention for accurate localization. Only after lesion removal and pathological confirmation can insulinoma or other pancreatic neuroendocrine tumors be definitively diagnosed.

• Type 2 diabetes: Patients with type 2 diabetes often require oral insulin secretagogues or insulin injections for treatment. Overdosing these medications can cause hypoglycemia. In such cases, diagnosing islet cell hyperplasia is particularly challenging and requires ruling out excessive stimulation of endogenous insulin production or the presence of insulin antibodies before considering islet cell hyperplasia.

• Dumping syndrome: This can occur after gastrointestinal anastomosis, especially following the intake of large amounts of simple carbohydrates. It is characterized by postprandial sweating, weakness, dizziness, and palpitations due to reduced blood volume (rather than hypoglycemia).

How is islet cell hyperplasia diagnosed?

To establish a diagnosis of islet cell hyperplasia, the following criteria must be met:

• Specific medical history: Episodic hypoglycemia in young children or gastric bypass surgery in adults.

• Presence of hypoglycemia symptoms: Recurrent episodes, possibly including Whipple’s triad.

• Evidence of pancreatic hyperinsulinemia;

And

• Exclusion of other conditions: Imaging studies, endoscopy, or intraoperative exploration must rule out rare conditions such as islet cell tumors or ectopic pancreas.

• Pathological confirmation: Findings may include pancreatic cell cluster hyperplasia, increased and variably sized islets, pancreatic duct hyperplasia, or newly emerging islets.

Multiple diagnostic approaches are recommended, including non-invasive imaging, invasive endoscopic ultrasound, biopsy, and genetic testing, to confirm the diagnosis and identify specific genetic defects.

What tests should patients with islet cell hyperplasia undergo for evaluation?

• Biochemical tests: During hypoglycemic episodes, elevated plasma insulin, C-peptide, and proinsulin levels, along with reduced β-hydroxybutyrate levels, may be observed.

• Imaging studies: Abdominal ultrasound, contrast-enhanced CT, MRI, endoscopic ultrasound, and nuclear scans can help locate pancreatic lesions.

• Endoscopy: Evaluates for ectopic pancreas. Combined with endoscopic ultrasound, it aids in lesion localization, while fine-needle aspiration biopsy can obtain tissue samples.

• Intraoperative exploration and ultrasound: For patients with inconclusive preoperative evaluations, intraoperative techniques can help locate lesions that conventional methods may miss.

• Insulin measurement: Assesses peripheral blood insulin levels. Intraoperatively, insulin levels can be measured in venous blood drained from the pancreatic head, body, and tail. Localized insulin elevation suggests insulinoma or focal hyperplasia, while uniform elevation indicates diffuse islet cell hyperplasia.

• Insulin release test: Typically performed alongside an oral glucose tolerance test. Blood glucose elevation stimulates β-cell insulin release, and plasma insulin levels are measured at fasting and at 0.5, 1, 2, and 3 hours post-glucose intake to evaluate β-cell function.

• Pathological examination: May reveal pancreatic cell cluster hyperplasia, increased and variably sized islets, interstitial lymphocytic or plasma cell infiltration, or duct hyperplasia. Polymorphic β-cells with large, indistinct nucleoli are considered markers of excessive insulin production. These changes can be diffuse or segmental.

• Genetic testing: Identifying PHHI genetic subtypes guides treatment. For example, patients with ABCC8 or KCNJ11 mutations are less likely to respond to diazoxide, whereas those with GLUD1, HNF4A, or HADH mutations may benefit. Paternal uniparental disomy (UPD) causes focal lesions (not diffuse), making surgery more suitable (UPD involves paternal DNA insertion into the maternal allele in patients with specific ABCC8/KCNJ11 mutations).

TREATMENT

Which department should patients with islet cell hyperplasia see?

Patients should first visit an endocrinologist. Other specialists who encounter similar symptoms, including gynecologists, pediatricians, and surgeons, should consult an endocrinologist for evaluation.
For pediatric cases that have been confirmed or are highly suspected, genetic counseling and genetic testing are recommended to identify specific mutations and guide treatment.
For suspected or newly diagnosed islet cell hyperplasia cases where surgery is being considered, a joint consultation with a surgeon and endocrinologist is advised to provide further treatment recommendations.

How should islet cell hyperplasia be treated?

Treatment decisions for islet cell hyperplasia require caution, and a multidisciplinary approach involving endocrinologists, pediatricians, and surgeons is strongly recommended to develop a treatment and follow-up plan.
The general treatment principles include controlling hypoglycemia and reducing insulin secretion.
For pediatric patients:

• During acute hypoglycemic episodes, intravenous glucose and/or enteral nutrition should be administered to maintain blood glucose levels within a safe range (above 3.5 mmol/L).

• The long-term treatment goal is to reduce insulin secretion and maintain normal blood glucose levels through medication or surgery to protect neurological function. Although drug therapy often fails, it should be attempted before considering surgery.

What are the commonly used medications for islet cell hyperplasia?

• Diazoxide: This is the first-line treatment, but its effectiveness depends on the molecular defect type. Infants with certain ABCC8 or KCNJ11 mutations, or mutations in glucokinase or monocarboxylate transporter 1 genes, are unlikely to respond to diazoxide. If no clear effect is observed within 48 hours of treatment, alternative therapies should be considered.

• Somatostatin analogs: If diazoxide fails, somatostatin analogs (e.g., octreotide) can be tried. Octreotide is often combined with diazoxide to control blood glucose.

• mTOR inhibitors: For example, sirolimus. However, this treatment requires more clinical experience and theoretical support.

When is surgery required for islet cell hyperplasia?

Patients with paternal uniparental disomy of ABCC8 or KCNJ11 often have focal lesions, making them better candidates for surgery.
For infants older than a few weeks with confirmed hyperinsulinemia and hypoglycemia unresponsive to medication, surgical exploration is necessary. While open surgery is an option, laparoscopic exploration is preferred due to its lower invasiveness. Laparoscopy allows full visualization of the pancreas, intraoperative ultrasound, and biopsy to confirm or rule out the diagnosis.
Although surgery is widely accepted for partial pancreatic resection to alleviate hyperinsulinemia, the extent of resection remains debated:

• Focal lesion resection: If a focal lesion is detected, it should be identified and removed.

• Partial pancreatectomy: Diffuse lesions may require subtotal pancreatectomy (removing 95%–99% of the pancreas, though this remains controversial).

For both children and adults with infrequent or mild hypoglycemia, uncertain diagnosis, or no clear lesion and reluctance for surgery, close follow-up is recommended.

Are there other treatments for islet cell hyperplasia?

Patients with PHHI (persistent hyperinsulinemic hypoglycemia of infancy) typically have persistent hypoglycemia unresponsive to feeding and often require intravenous glucose. However, adults with mild secondary islet cell hyperplasia may start with dietary adjustments, such as reducing free carbohydrate intake and distributing carbohydrate intake evenly throughout the day to minimize postprandial glucose fluctuations.
Some patients who undergo partial pancreatectomy may develop diabetes later and require glucose-lowering therapy. Exocrine pancreatic insufficiency may also occur, necessitating oral digestive enzyme supplements.

DIET & LIFESTYLE

What should patients with islet cell hyperplasia pay attention to?

Suspected and confirmed patients with islet cell hyperplasia can live normally like healthy individuals, with no impact on daily life. However, some preparations are needed to prevent hypoglycemic episodes, such as:

• Avoid excessive physical exertion, labor, or exercise that may trigger hypoglycemia;

• Keep easily absorbable sugary foods, such as fruit candies, readily available;

• Maintain regular eating habits with appropriate portion sizes and avoid prolonged fasting.

Are there any dietary precautions for patients with islet cell hyperplasia?

There are no specific food restrictions. However, as mentioned earlier, those who have undergone gastric bypass surgery should reduce the intake of free carbohydrates (e.g., sugar and sugary processed foods) and evenly distribute carbohydrate consumption (including staple foods like rice and noodles) throughout the day.

Do patients with islet cell hyperplasia need regular follow-ups?

Yes, regular follow-ups are necessary.
For PHHI children successfully treated with medication, blood glucose should be monitored at home, especially during illnesses or after fasting for more than 14–16 hours. Maintain stable blood sugar levels to avoid hypoglycemic episodes. After 4–6 years of treatment, patients should be reassessed to determine whether continued treatment is needed.
On the other hand, regular imaging and tumor marker tests should be completed to evaluate for pancreatic neoplasms. If detected, a comprehensive examination should be conducted as early as possible to decide whether surgical intervention is required.

What other precautions should patients with islet cell hyperplasia take?

Be aware of secondary injuries caused by hypoglycemic episodes, such as falls, accidents, or workplace injuries.

PREVENTION

Can Islet Cell Hyperplasia Be Prevented? How to Prevent It?

Currently, there are no known prevention methods.
However, for patients who have been diagnosed or are highly suspected, active treatment should be pursued to reduce personal harm, functional impairment, and socioeconomic losses caused by the disease. The most reasonable approach is to undergo regular follow-up examinations at a specialized clinic.

Special Notes on Islet Cell Hyperplasia

Due to the intrinsic connections among islet cell tumors, pancreatic neuroendocrine tumors, insulinomas, glucagonomas, somatostatinomas, and VIPomas, it is highly impractical to separately explain these diseases in a completely clear and thorough manner. There is inevitable overlap between these conditions, and readers should connect them horizontally for better understanding.
Related topics include: pancreatic neuroendocrine tumors, insulinomas, etc.