Hypoglycaemia E16.2

In 1916, a correlation between increased guanidine levels and hypoglycemia was demonstrated in animal experiments (Eckart 2011).

Shortly after the start of insulin treatment in 1922, hypoglycemia was reported for the first time in Toronto as a side effect of insulin therapy (Plate 2008).

The term "Whipple Triad" was defined by surgeon Allen O. Whipple in 1938 (Karavias 2004).

Hirata was the first to describe autoimmune hypoglycemia in 1970, which was later named after him (Reisch 2004).

The term HAAS (hypoglycemia-associated autonomic insufficiency), a complication of hypoglycemia, was coined by Cryer in 1992 (Dagogo- Jack 2015).

The classification of hypoglycaemias into different stages was made by Cryer in 1993 and modified by Tattershall in the same year (Plate 2008).

There is no generally valid definition for hypoglycaemia (Böhm 2001), even a laboratory-chemical threshold value is difficult to establish. Hypoglycemia is oriented towards non-diabetics (Herold 2020).

The Endocrine Society defines clinical hypoglycemia as a plasma glucose concentration that causes symptoms including impairment of cerebral function.

The surest evidence of hypoglycemia is the Whipple triad:

• Low plasma glucose (normal value about 70 mg / dl [about 3.9 mmol / l]; this should be measured with a precise method - not with the glucose monitor [Kasper 2015]).
• Occurrence of symptoms consistent with hypoglycemia
• after administration of plasma glucose decrease of symptoms (Weihrauch 2020)

Hypoglycemia is differentiated between

• asymptomatic and
• symptomatic course (Herold 2020).

The symptomatic course is internationally divided into 2 forms and is not oriented to specific blood glucose values (Haak 2018).

• 1. mild hypoglycemia:

The patient himself can treat the hypoglycemia by taking carbohydrates (Haak 2018).

• 2. severe hypoglycemia:

The patient is dependent on outside help from relatives, medical staff, etc. He himself is no longer able to treat the hypoglycemia (Haak 2018).

Further subdivisions are:

• 3. very severe hypoglycemia:

Here the patient is also dependent on outside help. He shows as symptoms seizures and / or unconsciousness (Plate 2008).

• 4. probable (possible) hypoglycaemia:

The affected person can correctly treat the occurring hypoglycemic symptoms, but a BG measurement did not occur (Plate 2008).

• 5. relative hypoglycemia:

In poorly controlled diabetics, hypoglycemic symptoms may occur, but the BG is ≥ 70 mg / dl (Plate 2008).

Hypoglycemia most often occurs due to medication for the treatment of diabetes mellitus or contact with alcohol or other drugs. The second most common cause in hospitalized patients is renal failure, liver failure, heart failure, sepsis and inanition (emaciation). (Kasper 2015)

Hypoglycemia rarely occurs in people without diabetes mellitus (Bansal 2020).

Autoimmune hypoglycemia, also known as "Hirata- disease," is rare and occurs preferentially in Japanese and Koreans, but has also been observed in Caucasians (Bansal 2020).

Type 1 diabetics experience an average of two symptomatic hypoglycemias per week and at least one severe one per year (Kasper 2015).

In type 2 di abetics, severe hypoglycemias occur at approximately 0.7 - 12 per 100 person-years. They are particularly common in

• older patients
• long duration of diabetes
• Patients with a history of hypoglycemia (Silbert 2018).

Hypoglycemia represents the most common serious adverse effect of diabetes therapy (Silbert 2018).

There are many causes of hypoglycemia. Therefore, one differentiates between:

• 1. fasting hypoglycaemia, which may occur in e.g.::
  • severe liver disease (leading to decreased gluconeogenesis and glucose release).
  • uremia (due to a lack of substrates for gluconeogenesis [Herold 2020])
  • at the beginning of renal replacement therapy (due to higher insulin sensitivity)
  • severe heart failure (pathogenesis unknown)
  • sepsis (Bansal 2020)
  • glycogenoses
  • neonatal hypoglycemia in diabetic mothers
  • Nesidioblastosis (islet cell hyperplasia due to mutation of the sulfonylurea receptor)
  • Insulinoma (a neuroendocrine tumor originating from the alpha cells of the islets of Langerhans that autonomously produces insulin (Lehnert 2010).
  • extrapancreatic tumors such as hepatocellular carcinoma
  • Failure of contrainsulin hormones due to e.g.:
    • insufficiency of the adrenal cortex (NNR)
    • insufficiency of the anterior pituitary lobe (HVL)
  • renal hypoglycemia such as in:
    • renal diabetes mellitus
  • paraneoplastic secretion of insulin-like peptides such as IGF II (very rare) (Herold 2020)
  • glycogen storage disease type 0, I, III, IV
  • Fanconi-Bickel syndrome (Kasper 2015).
• 2. postprandial (reactive) hypoglycemia (Herold 2020):
  • Diabetes mellitus in the early stages
  • Dumping late syndrome after gastric resection or bariatric surgery (Salehi 2018)
  • diabetic gastroparesis due to autonomic neuropathy
  • increased vegetative sensitivity to adrenergic counterregulation (so-called reactive postprandial or adrenergic postprandial symptom)
  • hereditary defects such as:
    • leucine hypersensitivity
    • Fructose intolerance
• 3. exogenous hypoglycemia (Herold 2020):
  • Overdose of sulfonylureas, glinides (Kasper 2015) and / or insulin (most frequent cause)
  • Alcohol excess with food abstinence
  • Interference of drugs with antidiabetic drugs such as:
    • ACE inhibitors
    • Beta blockers
    • non-steroidal anti-inflammatory drugs
    • Sulfonamides
  • Hypoglycaemia factitia (accidental, criminal, psychotic, suicidal) artificially due to:
    • taking sulfonylureas
    • Insulin injections
• 4. endogenously caused(Bansal 2020):
  • Autoimmune hypoglycemia: Also known as Hirata disease, in which antibodies form against native insulin and/or proinsulin or against the insulin receptor. The syndrome is often associated with other autoimmune diseases (Bansal 2020).
  • Insulinoma (see above "fasting hypoglycemia")
• 5. hormonally caused (Kasper 2015):
  • Deficiency of growth hormones (can lead to hypoglycemia in young children)
  • Cortisone deficiency (leads to impaired gluconeogenesis and low precursors of gluconeogenesis)

diabetes mellitus

• Causes of hypoglycemia in diabetic patients:
  • Overdose of sulfonylureas, glinides (Kasper 2015) and / or insulin (by far the most common cause) due to:
    • omission of food intake
    • intercurrent diseases
    • after readjustment with sulfonylureas, the metabolic situation may improve after approx. 3 weeks and a dose reduction may be necessary
    • too aggressive therapy of DM (HbA1c should not be below 6.5 % in type 2 DM with intensified interconventional insulin therapy [ICT] )
    • the perception of hypoglycaemia weakens with each hypoglycaemia (this is why CGMS [continuous glucose monitoring] with or without CSII [continuous subcutaneous insulin infusion] are now frequently used in type 1 diabetics )
  • heavy physical exertion
  • Interference with blood glucose-lowering medication
  • previous hypoglycaemia (the subsequent reaction to hypoglycaemia weakens with each additional hypoglycaemia)
  • absolute overdose with suicidal, criminal or accidental intent
  • Alcohol ingestion (alcohol inhibits gluconeogenesis but not glycogenolysis [Kasper 2015]).

In diabetics, the following additional factors may also lead to increased hypoglycemia (Kasper 2015):

• Unawareness of hypoglycemia
• history of severe hypoglycaemia
• previous sporting activity
• previous sleep

Glucose is an obligatory metabolic fuel for the brain under physiological conditions. The brain can store glucose for only a few minutes, but cannot stockpile it or synthesize it. It cannot, like other tissues in the body, use an alternative fuel through, for example, precursors of gluconeogenesis produced by the breakdown of triglycerides (Kasper 2015).

If arterial plasma glucose concentration falls below the physiological range of 70 - 110 mg / dl (3.9 - 6.1 mmol / l, redundant counter-regulatory mechanisms kick in and prevent or rapidly compensate for hypoglycemia.

For example, in the fasting state, plasma levels are maintained by hepatic glycogenolysis and by hepatic and renal gluconeogenesis. Normally, the plasma level can be maintained at the normal value for about 8 h. This time value is shortened, however, during fasting. However, this time value is shortened during physical exertion and when glucogen stores have already been depleted by illness or prolonged starvation (Kasper 2015).

Above a certain threshold value, the typical symptoms of hypoglycaemia become apparent (see "Clinical symptoms"). However, this threshold is dynamic. It changes, for example, in:

• poorly controlled diabetes mellitus (in this case it shifts towards higher threshold values)
• after frequent hypoglycaemia (shifts to lower glucose levels than normal)
• aggressively treated diabetes mellitus (shifts to lower glucose levels than normal)
• Insulinoma (shifts to lower glucose levels than normal)

Hypoglycemia causes a sympathoadrenal discharge in which norepinephrine and probably epinephrine cause symptoms such as tremors, palpitations, anxiety, and the acetylcholine causes cholinergic symptoms such as hunger, sweating, paresthesias (Kasper 2015).

Hypoglycemia is differentiated between autonomic and central nervous symptoms. However, the presence of these symptoms is not synonymous with a diagnosis of hypoglycemia (Brabant 1998).

• 1. autonomic symptoms:

Autonomic symptoms are usually noticed first by the patient. However, in recurrent hypoglycemia, autonomic signs may be absent due to HAAS (see "Complications" below).

(Balletshofer 2009)

• parasympatheticotonic reactions:
  • ravenous hunger
  • Weakness
  • Nausea
  • Vomiting (Herold 2020)
• sympathicotonic reactions:
  • Tremor
  • Diaphoresis (secretion of sweat)
  • Agitation
  • Tachycardia
  • Hypertension
  • Increase in respiratory rate
  • Mydriasis (Herold 2020)
• 2. central nervous or neuroglycopenic symptoms:
  • Headache
  • endogenous psychosyndrome with:
    • Irritability
    • Discomfort
    • Confusion
    • Lack of concentration
  • focal signs such as:
    • Aphasia
    • Double vision
    • Hemiplegia
    • Convulsions
  • Coordination disorders
  • primitive automatisms such as:
    • Smacking
    • Grimacing
    • Grasping
  • hypoglycemic shock(hypoglycemic coma)
  • Central respiratory and circulatory disturbances (Herold 2020).

Symptoms that may indicate hypoglycemia:

• Confusion
• Behavioral changes
• Disturbance of consciousness
• Seizure (Kasper 2015).

The symptoms of hypoglycemia do not correlate with the BG- value (Balletshofer 2009).

The most common signs of hypoglycemia are:

• Diaphoresis (secretion of sweat).
• Paleness (Kasper 2015)

In every emergency and every unclear neurological or psychiatric disorder, the BG values should always be checked first, which are usually < 50 mg / dl in the case of hypoglycaemia. In the case of poorly controlled diabetics, however, these values may be much higher. In this case, no neuroglycopenic symptoms are found, but cardiovascular complications may occur due to adrenergic counterregulation (Herold 2020).

In addition to history and laboratory diagnostics (see d.), attention should be paid during and after hypoglycemia to the Whipple triad (Kasper 2015), defined as:

• low plasma glucose (normal value about 70 mg / dl [about 3.9 mmol / l]; this should be measured with a precise method - not with continuous glucose measurement = CGM [Kasper 2015]).
• Occurrence of symptoms consistent with hypoglycemia
• After administration of plasma glucose, resolution of symptoms occurs (Weihrauch 2020)

Neonatal Hypoglycemia:

In neonates with recurrent hypoglycemia who show no improvement after dextrose infusion, hereditary conditions such as Kabuki syndrome should be ruled out (Piro 2020).

Non-diabetics:

In non-diabetics, the cause must be clarified. This can consist of:

• 72 h starvation test (see below)
• oral glucose tolerance test (see below "Laboratory")

• Blood glucose:

Before glucose administration, if possible, a blood sample should be taken to confirm the diagnosis. A low glucose level and resolution of symptoms after glucose administration confirm hypoglycemia (Kasper 2015).

To determine the cause of hypoglycemia, the following should be determined (Kasper 2015):

• HbA1c
• C-peptide
• Plasma insulin
• Proinsulin
• Beta hydroxybutyrate level
• Cortisol (Kasper 2015)
• ACTH
• ACTH stimulation test if necessary (Bansal 2020)
• Growth hormones
• Non-beta cell tumor (e.g. Zollinger- Ellison- tumor [Wegmann 1964])

72 h starvation test:

The starvation test is used to detect hypoglycemia caused by inadequately high (pro-) insulin release, such as can occur in endogenous hyperinsulinism or insulinoma (Krebs 2018).

Here, serum insulin, blood glucose, insulin / glucose quotient and C- peptide are determined.

Results:

- Insulin and C- peptide show a parallel increase in endogenous secretion.

- C-peptide is decreased with exogenous insulin supply(hypoglycaemia factitia).

- Insulin and C-peptide are elevated when sulfonylureas are taken (e.g. with suicidal intent).

- Detection of proinsulin or glibenclamide in the normal range when taking sulfonylureas, elevated in insulinoma (Herold 2020)

Oral glucose tolerance test (oGTT):

This is performed before the 72 h starvation test. This can be used to objectify late hypoglycaemia occurring more than 5 h after food intake (Herold 2020).

Glucagon stimulation test (GST):

The GST is a complementary test that can determine the etiology of hypoglycemia. The test should be performed under steady state conditions.

After overnight fasting, the patient receives an i. v. injection of 1 mg glucagon over 2 min. Plasma glucose and insulin levels are measured at baseline and at well-defined time intervals.

Results:

• Normal:

The maximum insulin response occurs rapidly and does not exceed 100 uU / ml (4,033 ng / l). Serum glucose peaks at 140 + 24 mg / dl after approximately 20 - 30 min.

• Insulin-mediated cause:

Plasma glucose level rises to values of > 25 mg / dl (1.4 mmol / l) after glucagon.

• Insulinoma:

Approximately 15 - 30 min after injection, insulin levels rise to > 160 uU / ml (6,452.8 ng / l). However, some patients (8% in one study) with insulinoma do not secrete insulin.

• Anorexia / liver disease:

In this case, due to depleted hepatic glycogen stores, no hyperglycemic response to glucagon is possible. The insulin response may be slightly increased, but not to the extent seen in patients with insulinoma.

• Medications:

Medications such as diazoxide, diphenylhydantoin, and hydrochlorothiazide may cause false results on GST.

• Non-islet cell tumors:

Patients with non-islet cell tumors, such as hemangiopericytoma or meningeal sarcoma, sometimes show similar responses to patients with insulinoma.

• Indications:

Patients with liver cirrhosis and portocaval anastomosis may have peak insulin levels and therefore cannot be distinguished from patients with insulinoma.

Peak insulin levels may also occur in obese patients, patients with acromegaly, or those treated with aminophylline or sulfonylureas.

• Adverse effects:

The test may cause (severe) hypoglycaemia after 90 - 180 min and after vomiting. For this reason, a physician should be present throughout the test (Bansal 2020).

Test for autoimmune hypoglycemia:

Autoimmune hypoglycemia can be suspected when hypoglycemia is associated with high insulin levels of > 100 uU / ml (4,033 ng / l) and completely suppressed C- peptide levels. Antibodies against insulin or proinsulin are found in this case.

Another form of the disease is antibodies against insulin receptors. In these patients, slightly elevated insulin levels and suppressed C-peptide levels are found.

This test can also be performed outside of hypoglycemia. (Bansal 2020)

• Coma diabeticum
• Epilepsy
• Apoplexy (Herold 2020)

HAAS: Recurrent hypoglycemia can lead to hypoglycemia-associated autonomic failure (HAAS). This mainly affects type 1 diabetics. However, HAAS can also occur in type 2 diabetics (Kasper 2015) and in non-diabetics (Dagogo- Jack 2015).

Mild hypoglycaemia leads to a shift in the glycaemic threshold for counter-regulation during hypoglycaemia, so that counter-regulatory hormones are only released at lower blood glucose levels, leading to a successive deterioration in hypoglycaemia perception. Thus, a vicious circle develops (Plate 2008).

The therapy of HAAS consists of the patient strictly avoiding iatrogenic hypoglycemia for 2 - 3 weeks, since the reduced adrenaline release in the event of hypoglycemia then improves significantly (Plate 2008).

Dementia: Dementia is presumed to occur more frequently in recurrent hypoglycaemia (Herold 2020).

1. causal therapy: if it is possible, the triggering cause should be eliminated (Herold 2020).

2. symptomatic therapy:

• 2. a Mild hypoglycaemia: The patient should take glucose (= dextrose) orally with an initial dose of 20 - 40 mg orally. Sucrose (= cane or beet sugar) or oligosaccharide drinks (= fruit juices, cola) can also be administered (Kasper 2015) such as:
  • Dextrose: 4 platelets of 5 g each or 4 teaspoons of 5 g each.
  • Lump sugar: 6 lumps
  • Cola: 200 ml
  • Apple juice: 200 ml (Danne 2016).

However, if the patient is being treated with an alpha-glucosidase inhibitor such as acarbose, oligosaccharide drinks are unsuitable (Herold 2020 / Kasper 2015).

If the patient is not capable of oral intake due to concomitant diseases, parenteral treatment with glucose infusion is recommended (Kasper 2015).

• 2. b Severe hypoglycemia: In severe hypoglycemia, 40 ml of 40% glucose should be rapidly injected i. v., followed by an infusion of 5% glucose until a BG of about 200 mg / dl can be achieved. If i.v. administration is not possible, e.g. because the patient is receiving initial care from a layperson or is reacting aggressively due to hypoglycaemia, 1 mg glucagon can be injected i.m. or s.c. (Herold 2020). As soon as the patient is able to eat food, this should be done, as glucose can only increase the plasma glucose concentration in the short term (Kasper 2015).

Glycogen deficiency: In patients with glycogen deficiency, such as is the case in alcohol-induced hypoglycemia, glucagon does not work because in this case there is a depletion of glycogen reserves and glucagon works by stimulating glycogenolysis.

Patients should therefore receive glucose i.v. or take glucose orally after awakening under regular BG control or eat a carbohydrate-rich diet (Herold 2020 / Kasper 2015).

Type 1 DM: In mild hypoglycemia, administration of 15-20 g of carbohydrate orally, preferably in the form of glucose every 15 min, is recommended; in severe hypoglycemia without loss of consciousness, 30 g of glucose orally every 15 min.

If loss of consciousness occurs, 50 ml of 40% glucose should be administered i. v. in bolus. If i. v. access is not possible, 1.0 mg glucagon can be given i. m. or s. c. (Haak 2018).

Type 2 DM: Glucagon stimulates, among other things, insulin secretion and should therefore not be used in type 2 DM.

If sulfonylurea-induced hypoglycemia is involved, glucagon can be given together with the somatostatin analogue octreotide, which causes suppression of insulin secretion (Kasper 2015).

Alternatively, glucose can be used: orally 15 - 20 g of glucose every 15 min or, in patients no longer capable of oral intake, 25 g of dextrose 50% as a bolus, followed by an infusion of 10 - 20% dextrose until the hypoglycemia has resolved (Haak 2018).

Autoimmune hypoglycemia: Treatment can be with cortisone or immunosuppressants, but is usually problematic (Kasper 2015).

Reactive hypoglycaemia in vegetative lability: Patients should be encouraged to eat a low-carbohydrate, high-fat and high-protein diet spread over several small meals. Medication may include parasympatholytics or low-dose, non-cardio-selective beta-blockers (Herold 2020).

Insulinoma: Therapy see Insulinoma

Dumping syndrome: The patient should initially be instructed to eat several small, low-carbohydrate, high-protein, high-fat foods. Postprandial horizontal positioning for 40-60 minutes is recommended.

Medication may include spasmolytics, and cholestyramine, calcium carbonate, or loperamide for diarrhea. In the further course, there is often a spontaneous improvement of the symptoms. Surgical intervention should only be performed if the symptoms persist and are resistant to therapy (Brunkhorst 2021).

Hypoglycemia can lead to coma, seizures, and death if left untreated (Haak 2018).

It is estimated that approximately 6 - 10 % of type 1 diabetics die as a result of hypoglycemia (Kasper 2015). Of type 1 and 2 diabetics treated with insulin, approximately 2 - 4 % die from hypoglycemia (Balletshofer 2009).

In diabetics with HAAS, the risk of severe hypoglycemia increases 25-fold (Plate 2008).

Autoimmune hypoglycemia is sometimes self-limiting (Kasper 2015).

The diabetes patient must be informed in detail about the symptoms of hypoglycaemia and its prevention in training groups (Kasper 2015).

Type 1 diabetics should always carry an emergency glucagon kit. Relatives or caregivers should be taught both the symptoms of hypoglycemia and how to use the glucagon syringe in education groups (Haak 2018).

In patients with autoimmune hypoglycemia, nighttime glucose infusion or administration of uncooked cornstarch before bedtime is sometimes required to prevent hypoglycemia (Kasper 2015).

Hypoglycemia indicated by sulfonylurea can last for hours and even days. This should be considered in therapeutic measures (Kasper 2015).

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