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Ditte S. Kornum 1, 2, * , Astrid J. Terkelsen 3 , Davide Bertoli 4 , Mette W. Klinge 1 , Katrine L. Høyer 1, 2 , Huda H. A. Kufaishi 5 , Per Borghammer 6 , Asbjørn M. Drewesen 7 , Christina Brock 4, 7 and Klaus Krogh 1, 2
Received: February 27, 2021 / Revised: March 25, 2021 / Accepted: March 27, 2021 / Published: March 31, 2021
The autonomic nervous system finely controls the function of several target organs, including the gastrointestinal tract. For example, nerve lesions or other neural pathologies can cause autonomic dysfunction (AD). Some common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson’s disease. Widespread dysregulation throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists to directly verify intestinal dysfunction. Therefore, assessment of segmental enteric physiological function is recommended to make the diagnosis and guide treatment. Several well-established assessment methods exist, but drawbacks such as lack of standardization, radiation exposure, poor interpretation of data, or high cost limit their usefulness. Emerging methods including high-resolution colonic manometry, 3D transit, advanced imaging methods, analysis of intestinal biopsies and microbiota may aid in the evaluation of AD-related gastroenteropathy. This review provides an overview of established and emerging methods of assessment of physiological function in the gut and methods of assessment of extragut autonomic neuropathy, with particular reference to clinical performance, strengths, and limitations for each method.
How Does Diabetes Affect The Digestive System?
Autonomic disorders can involve the parasympathetic, sympathetic and enteric nervous systems with widespread, multisystem consequences . Among other organ manifestations, panenteric gastrointestinal (GI) dysmotility is commonly seen . Not only do motility disorders contribute to gastrointestinal symptoms, they can also affect the absorption of drugs used to treat the underlying disease [3, 4].
Methods for assessing GI motility are generally applicable to all etiologies of autonomic dysfunction (AD), despite different underlying pathophysiologies. Validation of the extent of GI involvement is important to guide diagnosis and effective treatment, especially since gastrointestinal symptoms and objective measures correlate poorly [5, 6, 7, 8]. However, commercially available assessment methods have several inherent limitations and better techniques are needed for assessing gastrointestinal dysfunction. Thus, the main focus of this review is to describe established and emerging methods for assessing bowel dysfunction in AD patients.
The autonomic nervous system includes the sympathetic and parasympathetic nervous systems of the central and peripheral nervous systems that stimulate all internal organs . In addition, and less commonly recognized, the enteric nervous system is also part of the autonomic nervous system . Centrally, the autonomic nervous system is controlled by regions in the pontomesencephalic and bulbopontin layers of the forebrain and in the spinal cord. The peripheral autonomic nervous system works through the postganglionic parasympathetic and sympathetic nervous systems, which communicate with the enteric nervous system in a complex and finely coordinated network [10, 11]. Thus, lesions and pathology of central and peripheral nerves can cause AD . Pure AD can manifest acutely or subacutely, as observed in autoimmune autonomic ganglionopathy or treatment-induced neuropathy (DM) of diabetes mellitus. The latter may be due to a very rapid drop in blood glucose in an uncontrolled DM patient . On the other hand, presentation can be slow, as seen in α-synucleinopathies or neuropathies of various etiologies. α-synucleinopathies are neurodegenerative diseases characterized by abnormal accumulation of α-synuclein protein in nerve fibers or glial cells. The main types of α-synucleinopathies are Parkinson’s disease (PD), dementia with Lewy bodies, multisystem atrophy and pure autonomic failure . Large and small fiber sensory and autonomic neuropathies occur in metabolic disorders (DM, hypothyroidism, uremia), cobalamin deficiency, infections, immune-mediated disorders (gammopathies, vasculitis and celiac disease), neurotoxic exposures (alcoholism and pharmacology). and hereditary disorders (hereditary sensory and autonomic neuropathies, Fabry disease and hereditary transthyretin-mediated amyloidosis) . Autonomic dysfunction is also seen in patients with postural orthostatic tachycardia syndrome (POTS), defined by an abnormal increase in heart rate of at least 30 beats/min within 10 minutes of standing up or during the tilt table test. An increase in heart rate occurs in the absence of orthostatic hypotension and symptoms of orthostatic intolerance must be present for at least 6 months . POTS has been associated with small fiber neuropathy, Ehlers-Danlos syndrome and mast cell activation syndrome [16, 17].
Symptoms of autonomic neuropathy are numerous and the condition is multisystemic due to extensive parasympathetic and sympathetic innervation of multiple organs and structures such as the cardiovascular, gastrointestinal, thermoregulatory, respiratory, genitourinary, pupillomotor, and sudomotor systems. Thus, diagnosis, treatment, and follow-up may involve multiple specialties. Parasympathetic dysfunction can cause sicca syndrome with dry eyes and mouth, mild intolerance due to dilated unresponsive pupils, urinary retention, erectile dysfunction, tachycardia at rest, and decreased gastrointestinal motility. Sympathetic dysfunction is characterized by myotic pupils, orthostatic intolerance with vertigo or syncope, exercise intolerance, anhidrosis and heat intolerance . Gastrointestinal dysfunction can cause gastroparesis and enteropathy with constipation, diarrhea and fecal incontinence and can affect the absorption of oral medications, see below.
Small Bowel Obstruction: Causes, Symptoms, Diagnosis & Treatment
It is important to recognize AD because of the increased morbidity and mortality associated with heart rate variability, arrhythmias, increased blood pressure variability and neurogenic orthostatic hypotension [19, 20]. Acute development of AD may be the first symptom of an underlying paraneoplastic disorder. In addition, early recognition is important to ensure early initiation of conservative or pharmacological treatment targeting orthostatic or postprandial hypotension, supine hypertension, erectile dysfunction and gastroenteropathy, as these conditions can negatively impact quality of life if left untreated. treated. Finally, autonomic tests can monitor the course of dysautonomia and response to treatment.
Studies of gastrointestinal function in AD patients mainly included patients with DM or PD. However, panenteric autonomic neuropathy also occurs with less commonly described etiologies, and clinical evaluation and treatment principles will be similar for most etiologies. All segments of the GI tract can be affected, contributing to a highly variable inter-individual clinical picture and inter-individual symptom fluctuations over time, especially seen in patients with DM . Common gastrointestinal symptoms, such as dysphagia, nausea, vomiting, bloating, early satiety, abdominal pain, constipation, diarrhea, weight loss and fecal incontinence may be present, combined or alone, and can significantly affect quality of life [22, 23 , 24]. Among patients with DM, symptoms of gastroparesis occur in up to 18%, diarrhea in up to 20%, and constipation in up to 60%. In addition, faecal incontinence is commonly reported [25, 26]. The prevalence of gastroparesis and constipation symptoms in PD reaches 50%. In addition, 72% have anorectal dysfunction manifested as effort to defecate but incomplete voiding, with symptoms becoming more severe during disease progression [27, 28]. Constipation occurs in 50% of patients with pure autonomic failure and up to 82% of patients with multiple system atrophy . Orthostatic symptoms in POTS are often associated with severe gastrointestinal symptoms, with nausea, abdominal pain and constipation reported in over 70% [29, 30]. Prominent multi-segmental gastrointestinal symptoms are also commonly seen in hypermobile Ehlers-Danlos syndrome and mast cell activation syndrome, which is relevant as a differential diagnosis [16, 17].
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