What is Non-Diabetic Hypoglycemia?
Hypoglycemia is a condition that occurs when the sugar level in your blood is lower than it should be; specifically, less than 55mg/dl (or less than 3mmol/L). This can be measured if possible when you notice symptoms. Hypoglycemia can happen at different times for different people – it could occur while fasting, after a meal, or related to exercise. Doctors will look for signs of hypoglycemia if you meet three key criteria: medical evidence of low blood sugar, signs that match up with hypoglycemia, and if these signs go away once your blood sugar is corrected. It’s best if this testing is done when the symptoms naturally appear, and if it’s practical to confirm with a low blood sugar test.
While hypoglycemia is commonly seen in people with diabetes, it’s not common in those who don’t have diabetes. In non-diabetic individuals, hypoglycemia can happen due to a number of different reasons. Therefore, it’s crucial that doctors take an in-depth look at your medical history and conduct a thorough examination. The right tests should be done to find out the cause of the hypoglycemia. How it’s treated depends on what’s causing it.
Let’s also touch on hypoglycemia in children. This condition usually happens because of an inborn error in their metabolism (a natural body process) and often affects multiple systems in the body.
What Causes Non-Diabetic Hypoglycemia?
There are many things that can cause hypoglycemia (low blood sugar) in people that don’t have diabetes. This condition of low blood sugar can mainly be classified into two groups:
1. Caused by too much insulin (hyperinsulinism)
2. Not related to insulin
In the first group, when hypoglycemia is caused by too much insulin in a non-diabetic adult, it’s usually due to conditions like Insulinoma (a tumor that makes insulin) and islet cell hyperplasia (a condition where the cells in the pancreas that make insulin grow more than normal). Hypoglycemia can also be caused by taking too much insulin from an outside source or certain medicines that stimulate the body to produce more insulin such as sulphonylureas and glinides.
In the second group where hypoglycemia is not related to insulin, causes can include alcohol, failure of internal organs like the liver or kidneys, serious illness, various kinds of diseases, severe infections, brain malaria, anorexia nervosa (eating disorder), glycogen storage disease (a disorder affecting the way the body processes certain sugars), surgerical weight loss procedures, certain types of tumors, autoimmune conditions where the body attacks its own insulin or insulin receptors, and certain medications. Hypoglycemia caused by medications is quite common. There are many medications that can cause hypoglycemia, including some types of antibiotics, anti-malarial drugs, glucagon, lithium, blood pressure drugs, and non-selective B-blockers.
In children, hypoglycemia is mainly caused by inborn errors of metabolism (IEM). These include glycogen storage disease, defects in breaking down fatty acids, defects in creating ketones (a type of fuel the body can use), and disorders of gluconeogenesis (the process of making glucose). There are also rare genetic disorders like galactosemia and hereditary fructose intolerance, where the body can’t break down certain sugars like galactose and fructose. Other genetic mutations can cause congenital hyperinsulinism (hyperinsulinism present from birth), with certain genes like KCNJ11 and ABCC8 being involved in 40% to 50% of all cases.
Risk Factors and Frequency for Non-Diabetic Hypoglycemia
Non-diabetic hypoglycemia, or low blood sugar, is less common than the same condition in patients with diabetes. A study of around 38,898 hospitalized patients found that only 36 out of 10,000 patients admitted with non-critical illness experienced this condition. People aged 65 and above were found to be 50% more likely to have an episode of hypoglycemia.
The occurrence rate of Insulinoma, a condition that can lead to hypoglycemia, is relatively small—about 0.4 per 100,000 people per year. This condition affects more women (59%) and typically becomes significant around the age of 47 years. Hypoglycemia is also a known side effect of weight-loss surgeries, especially Roux-en-Y gastric bypass surgery. A study found that the risk of hospital admission due to hypoglycemia increased 2 to 7 times for patients who underwent this surgery, but the overall risk was quite low (approximately 0.2% of cases). For comparison, the risk in the general population was even lower (0.04%).
In another study, less than 1% of patients who had the Roux-en-Y gastric bypass needed hospitalization due to hypoglycemia and less than 10% of patients may develop significant hypoglycemia. In a smaller study with 40 patients, 75% were found to have mild hypoglycemia without symptoms.
- Non-diabetic hypoglycemia is less common than hypoglycemia in diabetic patients.
- In a study of 38,898 patients, only 36 out of 10,000 patients admitted with non-critical illness experienced hypoglycemia.
- People aged 65 and above are 50% more likely to have an episode of hypoglycemia.
- The incidence of Insulinoma is about 0.4 per 100,000 people per year, affecting more women (59%)
- Weight-loss surgeries, like the Roux-en-Y gastric bypass, can increase the risk of hypoglycemia by 2 to 7 times, although the overall risk remains low (approx. 0.2% of cases).
- Less than 1% of patients who had the Roux-en-Y gastric bypass needed hospitalization due to hypoglycemia and less than 10% may develop significant hypoglycemia.
- In a study with 40 patients, 75% were found to have mild hypoglycemia without symptoms.
Signs and Symptoms of Non-Diabetic Hypoglycemia
Hypoglycemia, or low blood sugar, can bring about a variety of symptoms. If it gets severe, it can lead to two types of symptoms: autonomic (includes feeling shaky, sweaty, heart palpitations, anxiety, hunger, and tingling) and neuroglycopenic (includes sleepiness, dizziness, weakness, seizures, and confusion). Diagnosis of hypoglycemia is based on three key aspects known as Whipple’s triad:
- Symptoms and signs that match hypoglycemia
- Laboratory tests showing low blood sugar
- Improvement of symptoms once the blood sugar level is restored to normal
Patients might have a history of autonomic and neuroglycopenic symptoms. Detailed information about the onset, types, and timing of symptoms could be helpful. Hypoglycemia is classified into two types: reactive hypoglycemia, which happens after meals, and fasting hypoglycemia. Some people might experience weight gain, usually seen in Insulinoma, while cancer often causes weight loss. Knowing about any existing diseases, medicines used, and family history would also matter. Past surgeries like gastric bypass are worth knowing about. Some people might show signs related to other health conditions like Addison’s disease (commonly presents as increased skin pigmentation), other autoimmune diseases, and history of gastric bypass.
In infants and children, hypoglycemia can often be traced back to a metabolic disorder and may be accompanied by symptoms like enlarged liver, seizures, weight loss, vomiting, cataract, and short height. Signs of hypoglycemia can be vague, but can include sweating, paleness, rapid heartbeat, increased blood pressure, confusion, and cognitive impairment. These symptoms can usually be reversed when blood sugar levels get back to normal. However, overlooked and prolonged hypoglycemia can result in neurological damage, sometimes permanent, though this is rare. A physical examination might also reveal some important clues such as indicators of autoimmune disease, abnormal liver size and signs of earlier surgeries.
Testing for Non-Diabetic Hypoglycemia
When someone shows signs of Whipple’s triad, which includes symptoms like confusion, weakness, and vision problems due to low blood sugar (hypoglycemia), doctors will need to determine why this is happening. They will order several lab tests. These might involve checking kidney function (urea & electrolytes test), assessing how well the liver is working (liver function tests), measuring the level of glucose in the blood after fasting, and looking at levels of insulin, C-peptide, and proinsulin when the blood sugar is low. They may also test for certain medications (sulfonylurea and meglitinide screen), measure a type of blood acid (beta-hydroxybutyrate), and examine hormone levels (cortisol and IGF-1 and IGF-2 levels). In some cases, they might also check for antibodies that target insulin or insulin receptors.
There are two main types of hypoglycemia: reactive and fasting.
Reactive hypoglycemia usually happens after meals. It can be caused by having too many insulin-producing cells in the pancreas (islet cell hyperplasia), an overactive immune response against insulin (autoimmune syndrome due to anti-insulin antibodies), an issue with how the liver regulates glucose (glycogen storage disease), or changes in digestion and insulin production after surgery on the stomach (gastric surgery). If your doctor suspects you have reactive hypoglycemia, you might get a mixed meal test, which assesses how your body reacts to food.
Fasting hypoglycemia tends to occur when you haven’t eaten. This can be a result of conditions like insulinoma (a tumor that produces insulin), various cancers, alcohol use, or certain medications. If your doctor thinks you might have an insulinoma, they’ll likely ask you to do a 72-hour fast. This is the best way to confirm this condition. During this test, doctors will see if your insulin and C-peptide levels are high while your blood sugar is low and you haven’t recently used certain medications. They’ll also test to see whether your levels of beta-hydroxybutyrate (a substance created when the body uses fat for energy) stay below a certain limit, as this could suggest insulinoma.
If you have signs of an insulinoma, you might also get imaging tests like a CT scan, MRI, or abdominal ultrasound, which can allow doctors to see the tumor. If these don’t reveal the tumor, other tests might be conducted, like endoscopic ultrasonography (an ultrasound performed through a tube inserted into the body) or a selective arterial calcium stimulation test (a procedure where doctors measure insulin levels after injecting calcium into specific arteries). People diagnosed with insulinomas are also usually tested for other disorders that can occur together with these tumors, such as overactive parathyroid glands (hyperparathyroidism) or pituitary diseases.
In rare cases, hypoglycemia results from genetic disorders that affect how the body metabolizes food (inborn errors of metabolism or IEM). This could be due to a variety of diseases, such as glycogen storage disease (where blood sugar can get low if you don’t eat, often associated with an enlarged liver), glucokinase activating mutation (where blood sugar drops after meals), an inherited condition defined by exercise-induced low blood sugar (Monocarboxylate 1 mutation), fatty acid oxidation defect (a disorder that impairs the body’s ability to use fat for energy) or gluconeogenesis disorder (a disease that prevents the body from producing its own glucose). Outcomes of these conditions vary greatly but often involve unique dietary and medicinal treatments.
Treatment Options for Non-Diabetic Hypoglycemia
Hypoglycemia, also known as low blood sugar, in non-diabetic patients can generally be managed with simple lifestyle changes. Eating smaller meals more regularly, and having one to two snacks between meals can help control blood sugar levels. It’s also recommended to avoid foods high in sugar, as well as alcohol and caffeine. If a medicine is causing hypoglycemia, it may need to be stopped.
In specific cases like reactive hypoglycemia that occurs after gastric bypass surgery, adjusting the diet to include low-glycemic index foods and taking specific medication, like acarbose, can help manage the condition.
In case these methods are not effective and the patient is experiencing severe symptoms, certain medical procedures are recommended. For example, restoration of gastric constriction (which slows down the emptying of the stomach) might be considered, and in more severe cases, part of the pancreas might be removed.
It’s important to mention that if someone has insulinomas, which are tumors in the pancreas that produce an excess of insulin, the primary treatment is often surgical removal of the tumor. However, for patients who are at high risk during surgery, various medications, such as diazoxide, somatostatin analogs (octreotide, lanreotide), verapamil, phenytoin, and everolimus are commonly used. Alternatively, fine needle chemical ablation with alcohol, which is a minimally invasive procedure, has been used effectively to treat hypoglycemia, according to a study.
In infants and children born with metabolic disorders, different measures may be taken. For example, children with galactosemia are put on a milk-free diet, and those with hereditary fructose intolerance should eliminate fructose from their diet. Others like those with glycogen storage disease require a high protein diet with frequent low carbohydrate meals. Hormone replacement can be used to treat cortisol and growth hormone deficiency. In the case of Nesidioblastosis, a condition that causes hypoglycemia, medication and potentially surgical removal of part of the pancreas might be needed.
What else can Non-Diabetic Hypoglycemia be?
Doctors may diagnose low blood sugar (hypoglycemia) in two ways. These methods are based on whether the patient has low blood sugar without any symptoms or normal blood sugar levels but experiences symptoms typically associated with hypoglycemia.
If a person seems to have low blood sugar levels but doesn’t show any symptoms related to hypoglycemia, it could be due to some specific conditions. For example, if a blood sample is taken without a certain chemical (like fluoride) that stops blood cells from using up the sugar in the tube before testing, it could cause a falsely low result. This situation may also occur in people with certain diseases like leukemia or severe hemolytic disease, where blood cells rapidly use up the glucose.
On the other hand, a person may have normal blood sugar levels but still experience symptoms often associated with low blood sugar. These symptoms include shaking, rapid heart rate, sweating, anxiety, and feeling excessively hungry. Various conditions can cause these symptoms, such as:
- Eating after a long time (Postprandial syndrome)
- Heart-related conditions (like irregular heartbeats or valvular disease)
- Overactive thyroid (Hyperthyroidism)
- A type of tumor called pheochromocytoma
- Effects of certain medications
- Mental health conditions
What to expect with Non-Diabetic Hypoglycemia
The outlook for low blood sugar (hypoglycemia) in people who don’t have diabetes can differ based on what’s causing the drop in blood sugar.
If hypoglycemia is a result of an Inborn Error of Metabolism (IEM), which is a rare genetic disorder that affects metabolism, it will require lifelong treatment and regular check-ups.
Hypoglycemia due to hormone deficiencies often responds well to treatment that replenishes these hormones. If a medication is causing the hypoglycemia, discontinuing that drug is needed.
The chances of good outcomes for a type of pancreatic tumor called an insulinoma depend on its stage. Most patients with non-cancerous (‘benign’) insulinomas see favorable results with surgery. The outlook varies, however, for those with cancerous (‘malignant’) insulinomas.
For people with hypoglycemia connected to non-insulin-producing tumors, the outlook depends on whether surgery can completely remove the tumor. Full surgical removal of the tumor can likely cure this type of hypoglycemia in many cases, whilst partial surgery may help alleviate symptoms. Despite this, a comeback of low blood sugar is possible and may require medical treatments like steroids.
Finally, the prognosis of low blood sugar due to weight-loss (bariatric) surgery varies and could require reversing the weight-loss operation.
Possible Complications When Diagnosed with Non-Diabetic Hypoglycemia
If hypoglycemia is not treated, it can lead to serious health issues like:
- Feeling anxious
- Having seizures
- Confusion or difficulty thinking
- Collapsing or falling into a coma
- Heart rhythm problems and heart arrest
- Failure of multiple organs in the body
- Unintended weight loss or gain
- Potentially, death
