Definition and Overview
Diabetic autonomic neuropathy (DAN) is one of the common chronic complications of diabetes. It occurs when chronic hyperglycemia and the resulting metabolic abnormalities gradually damage autonomic nerve fibers. The autonomic nervous system regulates involuntary body functions such as cardiovascular, digestive, urinary, sweating, and pupil reactions, so when damaged, various symptoms appear throughout the body.
Diabetic autonomic neuropathy occurs in approximately 20-40% of diabetic patients, and the longer the duration of diabetes, the higher the incidence. In the case of type 1 diabetes patients, approximately 50% of patients with type 1 diabetes show autonomic dysfunction over 25 years or more. The poorer the blood sugar control, the greater the risk, and a 1% increase in glycated hemoglobin (HbA1c) significantly increases the risk of autonomic neuropathy.
Classification
Diabetic autonomic neuropathy is classified as follows depending on the organ system involved.
Cardiac autonomic neuropathy (CAN) is the most clinically significant form. Heart rate control disorders, exercise intolerance, and orthostatic hypotension occur, and the risk of asymptomatic myocardial infarction and sudden death increases. Gastrointestinal autonomic neuropathies include gastroparesis, esophageal motility disorder, diabetic diarrhea, constipation, and fecal incontinence. Genitourinary autonomic neuropathies include bladder dysfunction (neurogenic bladder), male erectile dysfunction, female sexual dysfunction, and retrograde ejaculation. Sudomotor dysfunction includes distal anhidrosis and compensated proximal hyperhidrosis. Pupil abnormalities include reduced pupil dilation in dark places and impaired dark adaptation.
Mechanism of occurrence
Chronic hyperglycemia damages autonomic nerve fibers through several pathways.
Activation of the polyol pathway results in sorbitol and fructose accumulation, causing osmotic stress in nerve cells. Accumulation of advanced glycation end products (AGEs) directly damages nervous tissue and blood vessels. Increased oxidative stress leads to mitochondrial dysfunction and neuronal cell death. A decrease in neurotrophic factor (nerve growth factor, NGF) reduces the maintenance and regeneration ability of autonomic nerve fibers. Damage to the endoneurial vasculature reduces the blood supply to the nerve, resulting in ischemic damage.
Because small-diameter unmyelinated autonomic nerve fibers (C fibers) are damaged before myelinated large-diameter fibers, there is an initially asymptomatic stage in which abnormalities are detected only through heart rate variability tests.
cardiac autonomic neuropathy
Cardiac autonomic neuropathy is the most clinically important among diabetic autonomic neuropathies. According to studies, the 5-year mortality rate in diabetic patients with cardiac autonomic neuropathy is approximately 3.5 times higher than in patients without cardiac autonomic neuropathy.
Initially, resting tachycardia (heart rate >100 beats/min) appears. This is because parasympathetic nerve damage occurs before sympathetic nerve damage, which reduces the parasympathetic nerve's inhibitory effect on heart rate. In heart rate variability tests, the heart rate change (R-R interval variability) according to the breathing cycle decreases.
As the disease progresses, the sympathetic nerves are also damaged, slowing down the normal increase in heart rate and blood pressure during exercise. Painless myocardial infarction may occur, and may be first discovered as an electrocardiogram abnormality or heart function abnormality without chest pain.
Orthostatic hypotension (a decrease in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg when standing) occurs due to impaired sympathetic vasoconstrictor response. Orthostatic hypotension is reported in approximately 6-32% of diabetic patients.
Other autonomic involvement
Gastrointestinal autonomic neuropathy
Gastroparesis occurs in approximately 5-12% of diabetic patients. Gastric emptying is delayed, causing feelings of fullness, nausea, vomiting, and abdominal distension after a meal. It becomes a factor that makes blood sugar control more difficult. Diagnosis is made using gastric scintigraphy.
Constipation (occurring in approximately 60% of diabetic patients) and nocturnal diarrhea (occurring in approximately 20% of diabetic patients) are common diabetic bowel dysfunction.
Urinary autonomic neuropathy
Neurogenic bladder abnormalities in bladder function are reported in approximately 43-87% of diabetic patients. Decreased bladder sensation causes excessive fullness, and decreased detrusor muscle contraction causes repeated residual urine and urinary tract infections.
abnormal sweating
It is characterized by anhidrosis of the distal part (mainly the feet and legs) and compensatory hyperhidrosis of the proximal part (mainly the trunk). Gustatory sweating, which is excessive sweating of the face and neck after a meal, can also occur in diabetic autonomic neuropathy.
diagnosis
The American Diabetes Association (ADA) guidelines recommend the following five tests using heart rate variability as standard evaluation methods.
Deep breathing HRV: Measures the maximum-minimum heart rate difference during deep breathing 6 times per minute. Valsalva manual test: Measures heart rate changes during forced expiration. Stand-to-stand test (30:15 ratio): Measures the heart rate ratio between the 30th and 15th moments after standing up. Changes in blood pressure when standing: Check for orthostatic hypotension. Blood pressure changes during grip strength: Evaluating blood pressure response to static exercise.
If abnormalities are confirmed in three or more of these, clinically confirmed cardiac autonomic neuropathy is diagnosed.
treatment
Blood sugar control is the most important treatment for prevention and progression. In type 1 diabetes, intensive blood sugar control has been confirmed in a randomized controlled trial to reduce the incidence of cardiac autonomic neuropathy by approximately 53%.
For orthostatic hypotension, non-pharmacological methods (compression stockings, sufficient fluid intake, increased salt intake, head elevation) are first applied, and if necessary, fludrocortisone or midodrine is used. For gastroparesis, gastric motility stimulants such as metoclopramide and domperidone are used. PDE-5 inhibitors are effective for erectile dysfunction.