Pruritis is a common symptom of many systemic and cutaneous localized diseases and diabetes mellitus is a common syndrome with multiple long term complications, including diabetic painful neuropathy. The involvement of small fibre neurons, in diabetic neuropathy, is recognized as the main pathophysiology. While the C fibres that mediate the sensation of pain and pruritus may belong to different neuronal circuits, there is evidence of cross talk between them. We therefore posit that pruritus may be a symptom of diabetic neuropathy. It should be viewed as an equivalent of microvascular disease, with its accompanying clinical significance and therapeutic implications
Keywords: Cardiovascular equivalent, Diabetes mellitus, Diabetes neuropathy, Pain, Itch pruritus, Pruritus.
Pruritus is an unpleasant sensory perception which causes an intense desire to scratch, and impact quality of life. Pruritus is defined as "the sensation that is relieved on scratching the skin". Chronic pruritus is a continuous itching lasting longer than six weeks. Pain, on the other hand is a subjective unpleasant sensory, emotional and cognitive experience that is associated with actual or perceived tissue damage. Chronic pain is defined as pain lasting more than 3 to 6 months. In the tropical setting, itch may be associated with infectious dermatoses such as Candida and scabies. These conditions are not discussed in this opinion piece. Activation of pain-related sensory fibres inhibits the scratching response in rodents, suggesting that there may be existence of crosstalk between the pain and itch signalling pathways.1,2
Itch of a duration of over 2 weeks is a common symptom, being reported by 8.4% of the general population.3 Various systemic clinical conditions may be associated with pruritus, and endocrine conditions can be one of them (Table-1). The British Association of Dermatologists (BAD)2018 guidelines, on generalized pruritus in adults without dermatosis, classify such patients as having underlying systemic disease (secondary pruritus) or generalized pruritus of unknown origin (GPUO).4 Their list of causes of generalized pruritus without rash mentions 15 etiologies, with endocrine disease being mentioned at 8th position. The authors state that the common occurrence of diabetes and obesity, as well as pruritus, make it difficult to confirm an epidemiological link between them. They discourage routine endocrine investigations for the work up of nonspecific generalized pruritus, unless there are "supporting clinical features suggesting diabetes".4 Fasting glucose and glycated haemoglobin are listed as optional screening tests, and are not included in the list of recommended investigations.
BAD describes neuropathic pruritus as being "caused by pathology located at any point along the afferent pathway of the nervous system".5 This pathway includes the small fibres that may be affected in diabetic neuropathy. BAD clearly states that neuropathic pruritus should be referred to the appropriate specialist for care, and does not encourage intervention by the dermatologist. Psychogenic pruritus or functional itch disorder is identified as a distinct clinical condition, with its own diagnostic criteria (Image-1). One of the three compulsory criteria states that somatic causes, including cutaneous and systemic, should be ruled out. Of the seven optional criteria, at least four overlap the symptomatology of diabetic painful neuropathy: worsening at night; predominance during rest or inaction; improvement with psychotropic drugs; and improvement with psychological therapy.
The International Forum for the Study of Itch (IFSI) classifies itch as having six etiologic factors, including dermatologic, systemic, neurologic, psychogenic/ psychosomatic, mixed and others.7 Though some researchers describe diabetic itch as a systemic pruritis,8,9 others feel that presence of dermatologic and neurologic components support its inclusion in the mixed etiology.8,9 While some causes of itch in diabetes are easily discernible, such as candidal infection, others are not clearly obvious. The occurrence of generalized itch in diabetes is variable, ranging from 2.72 to 27.5% A detailed review of epidemiological studies dealing with itch in diabetes suggests that while data is scarce, there is a significant burden of itch in persons with diabetes.8
Studies have shown that the prevalence of truncal pruritus of unknown origin (TPUO) in diabetic subjects is significantly higher than that in age-matched nondiabetic subjects (11.3 vs. 2.9%). TPUO is found to be associated with symptoms and signs of Diabetic Peripheral Neuropathy (DPN), including autonomic neuropathy changes, therefore it might be a newly recognized symptom of Diabetic neuropathy.9
Both skin xerosis and neuropathy are implicated in the development of itch in persons with diabetes. Sensory as well as autonomic dysfunction contribute to the itch noted with neuropathy. Numbness of soles and palms, absent tendon reflexes, and abnormal results of head up tilt test are shown to be associated with itch.9 Persons with higher postprandial glucose have a greater chance of experiencing generalized itch. The relationship between hyperglycaemia and skin infections is also well-documented, though is beyond the scope of the current discussion.
Comparing Pruritus and Pain
Itch and pain have more similarities than differences. Both are unpleasant, but both inform the body about potential harm. Both are attention seeking devices which aim to prevent further damage. Both use C fibres for transmission, through the subset of pruritus associated C fibres is unique and different and itching sensation is thought to be transmitted by small unmyelinated sensory c-fibres.10 In some persons with atopic dermatitis and nostalgia parasthetica, however, a painful stimulus can be perceived as an itch.
Pain originates in various nociceptors, from where the stimulus travels, through polymodal small C fibres, as well as alpha-delta fibres. Pruritus or itch, is a response to stimulation of dermal polymodal free nerve ending. Such stimulation activates a unique C fibre pathway, which is insensitive to mechanical stress. Neurotransmitters including histamine, prostaglandins and proteases are released, and these create a sensation of itch.11
The proinflammatory mediators involved in itch and pain are similar, but their release is regulated by different cells. While the predominant cells that contributes to pruritus are the lymphocytes, pain is regulated by macrophages and dendritic cells. The same ion channels are used by both for downstream propagation of both itch and pain.
Different theories are proposed for pain and itch inter connection one Intensity theory suggests that neurons would discriminate between the two depending upon the intensity of stimulation. The same cell could be weakly or strongly activated, producing the sensation of itch or pain, respectively. Another theory suggests that both sensations requires separate populations of neurons for whom detection of itch or pain is mutually exclusive (Image-2).
The same parts of the brain, i.e., the amygdala, hippocampus and hypothalamus, are activated by itch and pain. Similar psycholological components are involved in interpreting both sensations. Both of them are complex multidimensional sensations which straddle the entire spectrum of the biopsychosocial model of health and disease.
Chronic itch and chronic pain impact the brain's neural plasticity in a negative manner, preventing it from adapting to stimuli in an appropriate manner. Many treatment modalities, both non-pharmacological and pharmacological are common to these conditions, and underscore their similarity. All these aspects reinforce our belief that pain and pruritus should be viewed as equivalents.
Diabetic Painful Neuropathy
Diabetic painful neuropathy (DPN) is a microvascular complication of diabetes which is associated with an increased risk of other micro-vascular, as well as macrovascular dysfunction, including chronic kidney disease. Usually, DPN occurs in persons with long standing and/or poorly controlled diabetes. At times, neuropathic symptoms herald the onset of diabetes. It is possible that pruritus can be a presenting symptom of diabetes, or of lack of control in a previously well- controlled individual with diabetes Truncal itch and scalp itch especially, are associated with diabetes. It is also possible that pruritus is associated with an impact on cardiovascular health and outcomes that is similar to that of neuropathy or nephropathy. It must be mentioned here that uraemic pruritus is itself a major cause of itch.
Timely glycaemic control helps reduce the risk of peripheral neuropathy and other vascular complications. It becomes imperative, therefore, to manage diabetes as early as possible. This means that pruritus, as a symptom, should not be ignored in persons with or without diabetes. Glucovigilance should be practiced in persons presenting with pruritus, and the clinical approach followed should be similar to that practiced for patients with neuropathy.
We therefore propose that pruritus should be viewed as a microvascular equivalent in persons with diabetes, with all attendant impact on health. Early detection and management of itch, as well as good glycaemic control, will help mitigate the burden of disease in the short term, and improve vascular and overall outcomes in the long term.
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