Sweating is pathological when it occurs disproportionally to the need of temperature compensation. This may be evident by the formation of droplets on the skin; dripping sweat is not useful for cooling.
Primary HH can be induced by thermal triggers, physical activity, and emotional stress [2
]. While both eccrine and apocrine glands respond to emotional stimuli, findings from Bovell et al. [27
] suggest that the eccrine glands are the main source of fluid transport in HH rather than apocrine or apoeccrine glands.
HH is not necessarily an increase in the absolute amount of sweat, but a change in sweat regulation. Increased sweating does not occur permanently, but small triggers lead to disproportionate sweating [2
]. Because patients can barely control sweating, it leads to stress and significant limitations in their private and professional lives, as can be assessed using the Dermatology Life Quality Index [28
In a recent review, Kristensen et al. concluded that HH is still an underestimated and understudied chronic disorder [6
]. The prevalence of HH is estimated at 1.6% in the UK and between 1.0 and 4.8% in the USA [29
]. However, data on prevalence vary depending on data collection methods and factors such as ethnicity and age. Other sources report a prevalence as high as 16.7% in Poland and 12.3% in Canada (Vancouver region) [32
]. Additionally, there is likely a large number of cases that go undiagnosed due to shame or lack of knowledge [34
]. Although the condition is widespread, it is often not part of the training of physicians and caregivers. Accordingly, the level of knowledge about HH is low, even in a clinical context [9
Differences Between Primary and Secondary HH
Hyperhidrosis can be focal or generalized. Focal HH refers to excessive sweating that is limited to specific parts of the body, whereas generalized HH implicates increased sweating over the entire body. Additionally, HH can be primary or secondary [1
In the majority of patients, primary HH is an idiopathic disorder. Primary focal HH is usually a bilateral symmetrical disorder affecting the palms of the hands, soles of the feet, axillae, or forehead, whereas sweating in primary generalized HH usually affects the head and trunk, or even extremities, groin and glute [5
]. In contrast, secondary HH occurs as a result of an underlying disease, such as endocrine disorders, infections, or neurologic diseases [1
]. Accordingly, the pathological mechanisms of secondary HH are largely determined by the underlying condition [3
]. In the generalized form of HH, it can be difficult to differentiate between primary and secondary HH, and further screening may be required. Secondary focal HH involves regional or asymmetric sweating, or may be compensatory; for example, loss of sweating in one area leads to increased sweating in another [5
Sudomotor function refers to perspiration and the release of sweat to the skin surface to cool the body [35
]. Because sweat is regulated by the ANS, sudomotor function can be affected by ANS dysfunction.
Given the innervation pathways of the hypothalamus, primary HH can be understood to be a neuronal regulation disorder of the ANS involving pathologic hyperactivity of the sympathetic system that results in hyperstimulation of otherwise normal sweat glands [2
]. Alternatively, the etiology of primary HH may be an abnormal central control of emotions, with the sweat center in the hypothalamus being controlled by the influence of the cortex without input from thermoregulatory components [5
]. For example, patients with primary palmar HH show an altered perception of warmth sensation and exaggerated sudomotor responses [37
]. The lowered thresholds may be explained either by a regulatory dysfunction in the autonomic centers of the brainstem that are responsible for inhibiting sensory perception and peripheral autonomic activity or, alternatively, by dysfunction at the cortical level, associated with impaired control of emotional sweating.
A variety of tools are available for analyzing sweat excretion. The most important diagnostic tool is the patient history, including the onset of symptoms, sweating patterns, and familial predisposition, as measured, for example, by the Hyperhidrosis Disease Severity Scale [38
]. However, when the cause of excessive sweating is unclear, laboratory tools that more objectively assess the different responses and sudomotor pathways may provide a more sensitive and quantifiable assessment. These tools can range from quantitative sudomotor axon reflex testing to thermoregulatory sweat testing to sympathetic skin responses [35
]. For example, Hirakawa et al. [40
] used a mental arithmetic problem in a study to induce stress and measure emotional sweating. The choice of test depends on the clinical condition and should be preceded by careful evaluation of the medical history and a neurologic examination of other collateral deficits. Therefore, understanding the test methods and autonomic neurology is critical to interpreting the results [35
Abnormal Sweat Secretion
If HH is understood as a regulatory disorder involving the ANS, an explanation for the abnormal sweat secretion in processes and pathways proximally to the sweat gland level is required. For example, a metabolic explanation for the hyperactivity of sympathetic neurons is offered by data showing a higher expression of ACh and alpha-7 neuronal nicotinic receptor subunits in the sympathetic ganglia [3
]. Other structural changes in patients with HH include a larger number of ganglion cells in the ganglia, thicker myelin sheaths of the affected axons, and larger diameter of the thoracic sympathetic chain ganglia [36
Crucially, the increased sweat secretion in patients with HH is not due to abnormalities in the sweat glands per se, but to regulatory processes that affect the sweat production of the glands. There is no dysfunction in the sweat glands of these patients, nor changes in their size, number, or histologic appearance [2
]. However, while Du et al. [44
] found no significant differences in the morphological characteristics or the number of sweat glands between axillary HH patients and healthy subjects, the authors did detect a significantly higher number of secretory granules in patients who exhibited hypersecretion of axillary sweat glands. This could be explained by a higher expression of aquaporin 5 (AQP5), a selective water-selective channel protein that increases water permeability, in epithelial cells of patients [44
Lin et al. [45
] found that activin A receptor type 1 (ACVR1) is upregulated in the sweat glands of patients with primary axillary HH compared to control subjects. Overexpression of ACVR1 boosted the expression of AQP5 and Na–K–Cl cotransporter 1 (NKCC1), and thus may affect sweat secretion by regulating water and ion channels [45
]. In addition, upregulation of the cholinergic receptor nicotinic alpha-1 subunit (CHRNA1) is a typical feature of sweat glands in patients with primary focal HH. CHRNA1 regulates the binding and gating of ACh neurotransmitters. Silencing of CHRNA1 decreased sweat secretion and the number of sweat secretory granules in a mouse model of HH [46
]. It also decreased the expression of serum ACh, AQP5, and calcium voltage-gated channel subunit alpha-1 C (CACNA1C) in the sweat glands. Thus, upregulation of CHRNA1 is a potential biomarker for primary focal HH. Respectively, its downregulation may be a potential treatment target with the aim of inactivating the sympathetic system [46
Several studies suggest that primary HH has a genetic component as demonstrated by the high frequency of positive family histories for individuals with primary axillar or palmoplantar HH [47
]. While familial predisposition is more or less established, there is still uncertainty about the specific genes involved.
Most studies report autosomal dominant or recessive inheritance [47
]. Results from family genetic studies have identified various loci for primary HH, but the results are inconsistent. For example, a study by Higashimoto et al. [49
] indicated a linkage to loci on chromosome 14q11.2-q13, but this association could not be confirmed using a microsatellite method [50
]. Chen et al. [51
] identified candidate genes on chromosome 2q22.1–q31.1, and Schote et al. [52
], using genome-wide whole-exome sequencing, subsequently found four significant loci which overlap with the locus reported by Chen et al. [51
]. In addition, a genetic polymorphism analysis suggested an association between –116A and K-variants on the BCHE gene in patients with HH, although this association was non-significant [53
Various pathogenic mechanisms have been proposed to explain primary HH, such as the pronounced presence of AQP5 in the epithelial cells of the sweat glands in patients with primary HH, as mentioned earlier [44
]. This possible involvement of the AQP5 gene is also supported by evidence in patients with hypohidrosis, i.e., insufficient secretion of sweat, as a symptom of Sjogren’s syndrome, in whom AQP5 expression is reduced [47
]. However, family genetic studies have not identified loci on the AQP5 gene [49
]. Other candidate genes are the PLB1, PPP1CB, NDR2, and ABC11 genes [47
]. In addition, there are several hereditary disorders associated with HH that refer to different chromosomes, such as nail-patella syndrome with a locus on chromosome 9 [47
It should be noted, however, that analysis of genetics data is difficult: studies differ in their methods for the classification of HH, qualitative and quantitative measurements, review of medical records, and the surveys and interviews used [47
]. Moreover, data can also be susceptible to recall bias as data are often collected from interviews [50
Overall, findings in genetics suggest considerable heterogeneity in the disorder, and it is likely that HH is a multifactorial disorder. Data are still limited, and further genetics studies on large patient cohorts are needed.
While numerous therapeutic strategies exist, there remains an unmet medical need and, in addition, lack of knowledge about the disorder may hinder appropriate treatment. Treatment options depend on the localization of HH. Current therapeutic approaches include topical treatments (e.g., aluminum chloride or topical anticholinergics) as first-line treatments for focal HH. When topical treatments are insufficient or not applicable, local intradermal injections of botulinum toxin, iontophoresis, or microwave thermolysis are indicated. Systemic oral medication, such as anticholinergics, may be considered; however, the use of such medications are limited by systemic anticholinergic side effects. In some countries, endoscopic thoracic sympathectomy is used as last option, which, although rare, may be associated with serious side effects [3
]. For focal axillary HH a variety of local surgical procedures have been described, ranging from curettage, laser-assisted ablation to partial and radical excision techniques [54
]. To identify new potential therapeutic targets and improve treatment options, a good understanding of the genetic components, the signaling pathways involved, and possible explanations of abnormal sweat secretion is necessary. This review article does not contain any new studies with human participants or animals performed by any of the authors.