Hiperpotliwość – Patofizjologia i mechanizm

Hiperpotliwość
Patofizjologia i mechanizm

Hiperpotliwość to zaburzenie charakteryzujące się nadmiernym wydzielaniem potu, przekraczającym fizjologiczne potrzeby termoregulacji, dotykające 1-3% populacji. Patofizjologia pierwotnej hiperpotliwości opiera się na nadaktywności układu współczulnego i zwiększonym uwalnianiu acetylocholiny z zakończeń nerwowych, przy upośledzonym mechanizmie ujemnego sprzężenia zwrotnego do podwzgórza. Gruczoły potowe ekrynowe u pacjentów nie wykazują zmian histologicznych, natomiast obserwuje się powiększenie zwojów współczulnych. Genetyka odgrywa istotną rolę, z loci PPH zlokalizowanym na chromosomie 14q11.2-q13 lub 2q31.1, dziedziczenie autosomalne dominujące. W patogenezie bierze udział także oksydacyjne uszkodzenie komórek oraz nadekspresja receptorów, takich jak ACVR1 i CHRNA1. Hiperpotliwość dzieli się na pierwotną (ogniskową, symetryczną, bez przyczyny) oraz wtórną, związaną z chorobami endokrynologicznymi, neurologicznymi, nowotworami, infekcjami lub lekami (np. inhibitory acetylocholinoesterazy, opioidy, SSRI, TLPD, glikokortykosteroidy). Diagnostycznym kryterium pierwotnej hiperpotliwości jest brak pocenia podczas snu oraz utrzymywanie się objawów co najmniej 6 miesięcy.

Patogeneza Hiperpotliwości

Hiperpotliwość (nadmierne pocenie) to zaburzenie charakteryzujące się wydzielaniem potu w ilościach przekraczających fizjologiczne potrzeby związane z termoregulacją organizmu. Nadmierne pocenie dotyka około 1-3% populacji i może mieć istotny wpływ na jakość życia pacjentów, powodując upośledzenie funkcjonowania społecznego i zawodowego oraz prowadząc do stresu emocjonalnego.¹²³

Mechanizm pierwotnej hiperpotliwości

Pierwotna hiperpotliwość związana jest z nadmierną aktywnością układu współczulnego, powodującą zwiększone uwalnianie acetylocholiny z zakończeń nerwowych. W stanie patologicznym, mechanizm ujemnego sprzężenia zwrotnego acetylocholiny jest najprawdopodobniej upośledzony, co może wyjaśniać, jak fizjologiczna odpowiedź może stać się patologiczna. To zaburzenie powoduje, że organizm produkuje więcej potu niż jest to konieczne do ochłodzenia ciała.¹²

Uważa się, że podwzgórzowy ośrodek pocenia, który kontroluje dłonie, stopy i w niektórych przypadkach pachy, różni się od innych ośrodków podwzgórzowych i znajduje się pod wyłączną kontrolą kory mózgowej, bez wpływu elementów termoczułych. Ponieważ emocjonalne pocenie nie występuje podczas snu lub sedacji, jednym z kryteriów pierwotnej hiperpotliwości jest brak pocenia się podczas snu.¹²

W badaniach histologicznych gruczoły ekrynowe u pacjentów z hiperpotliwością wyglądają normalnie pod względem wielkości i liczby w porównaniu do osób bez tego zaburzenia. Jednakże zwoje współczulne u tych pacjentów są zwykle większe. Potwierdza to teorię, że hiperpotliwość jest zaburzeniem nadmiernej stymulacji cholinergicznej, a nie problemem z gruczołami ekrynowymi.¹²³

Droga neuronowa w hiperpotliwości

Dla hiperpotliwości sugerowana jest centralna droga eferentna sudomotoryczna z następującymi połączeniami:

Kora mózgowa do podwzgórza
Podwzgórze do rdzenia przedłużonego
Włókna krzyżujące się w rdzeniu przedłużonym i biegnące do bocznego rogu rdzenia kręgowego
Boczny róg do zwojów współczulnych
Zwoje współczulne do gruczołów potowych jako pozazwojowe włókna C¹²

Głównym neuroprzekaźnikiem w połączeniu neuroglangularnym włókien pozazwojowych jest acetylocholina, w przeciwieństwie do większości zakończeń nerwowych, gdzie neuroprzekaźnikiem jest noradrenalina. Różne bodźce, takie jak aktywność fizyczna, gorące otoczenie, niepokój i stres, aktywują okolicę przedwzrokową podwzgórza, która poprzez stymulację współczulną uwalnia acetyloocholinę w połączeniu neuroglandularnym, zwiększając odpowiedź w gruczole potowym i generując wsteczny bodziec do podwzgórza poprzez drogi aferentne (ujemne sprzężenie zwrotne).¹

Równowaga między drogami aferentnymi i eferentnymi utrzymuje homeostazę w organizmie. U osób z hiperpotliwością system ten wydaje się być w ogniskowej nierównowadze, z amplifikacją bodźców eferentnych.¹

Czynniki genetyczne w hiperpotliwości

Większość badań epidemiologicznych wykazała istnienie rodzinnej cechy pierwotnej hiperpotliwości, ponieważ 44% do 66% pacjentów ma pozytywny wywiad rodzinny. Najnowsze badania wykazały również dowody na transmisję genetyczną.¹²

Badania genetyczne sugerują, że hiperpotliwość pierwotna jest dziedziczona w sposób autosomalny dominujący ze zmiennym stopniem penetracji i jest cechą niezależną od płci.¹²

Przeprowadzając analizę genomu z wykorzystaniem polimorficznych markerów DNA, szczegółowa analiza haplotypów ujawniła, że loci pierwotnej hiperpotliwości dłoniowej (PPH) są zlokalizowane na 14q11.2-q13 w interwale między D14S1070 a D14S990. Jednakże inne sprzeczne badanie ujawniło locus hiperpotliwości na chromosomie 2q31.1, dostarczając silnych dowodów na różne warianty genetyczne.¹

Zmiany biochemiczne i molekularne

Badania wykazały podwyższone poziomy tlenku azotu w osoczu u pacjentów z hiperpotliwością w porównaniu do grupy kontrolnej, co potwierdza inną hipotezę, że uszkodzenie oksydacyjne spowodowane zwiększoną produkcją reaktywnych form tlenu z niewystarczającą zdolnością mechanizmów antyoksydacyjnych może być zaangażowane w patogenezę choroby.¹

Proces komórkowy w gruczołach potowych jest kontrolowany przez gen ITPR2, który koduje receptor 2 inozytolo-1,4,5-trifosforanu (InsP3R2) i jest związany z ludzką chorobą zwaną anhidrozą (niezdolność do pocenia się). Gen FoxA1, kodujący czynnik transkrypcyjny Forkhead, odgrywa znaczącą rolę w regulacji pocenia poprzez kanał anionowy bestrofiny 2 i kotransporter NaKCl.¹

Lin i współpracownicy odkryli, że receptor typu 1 aktywiny A (ACVR1) jest nadekspresjonowany w gruczołach potowych pacjentów z pierwotną hiperpotliwością pachową w porównaniu do osób z grupy kontrolnej. Ponadto nadekspresja podjednostki alfa-1 nikotynowego receptora cholinergicznego (CHRNA1) jest typową cechą gruczołów potowych u pacjentów z pierwotną ogniskową hiperpotliwością.¹

Hiperpotliwość pierwotna i wtórna

Hiperpotliwość można sklasyfikować jako pierwotną (idiopatyczną) lub wtórną w zależności od przyczyny występowania nadmiernego pocenia.¹²

Hiperpotliwość pierwotna

Pierwotna hiperpotliwość to zaburzenie, w którym nie zidentyfikowano wyraźnej przyczyny nadmiernego pocenia. Charakteryzuje się symetrycznym, ogniskowym, nadmiernym poceniem najczęściej obejmującym pachy, dłonie, stopy lub okolice twarzy i głowy. Zwykle rozpoczyna się w dzieciństwie lub okresie dojrzewania i utrzymuje się w wieku dorosłym.¹²³

Grupa ekspertów zaproponowała następujące kryteria diagnostyczne dla pierwotnej hiperpotliwości ogniskowej: ogniskowe, widoczne, nadmierne pocenie trwające co najmniej sześć miesięcy bez widocznej przyczyny.¹

U osób z pierwotną hiperpotliwością występuje wyższy niż normalny podstawowy poziom produkcji potu oraz zwiększona odpowiedź na normalne bodźce, takie jak stres emocjonalny lub fizyczny.¹²

Hiperpotliwość wtórna

Hiperpotliwość wtórna może być ogniskowa lub uogólniona i jest spowodowana chorobą podstawową lub stosowaniem leków. Najczęstszą przyczyną wtórnej hiperpotliwości jest hiperpotliwość wywołana lekami.¹²³

Różne choroby podstawowe mogą prowadzić do wtórnej hiperpotliwości, w tym:

Zaburzenia endokrynologiczne (np. nadczynność tarczycy, cukrzyca)
Infekcje
Nowotwory
Choroby neurologiczne
Ciąża lub menopauza u kobiet¹²

Leki, które mogą powodować hiperpotliwość, działają na szlaki związane z regulacją temperatury ciała i zwiększają transmisję acetylocholiny. Tabela 1 przedstawia przykłady leków, które mogą powodować hiperpotliwość oraz proponowane mechanizmy:¹

Grupa leków	Przykłady	Proponowany mechanizm
Inhibitory acetylocholinoesterazy	Galantamina, Rywastygmina	Hamowanie cholinoesterazy prowadzące do zwiększenia poziomu acetylocholiny
Opioidy	Kodeina, Fentanyl, Morfina, Oksykodon, Tramadol	Uwalnianie histaminy, a następnie acetylocholiny
Selektywne inhibitory wychwytu zwrotnego serotoniny	Citalopram, Escitalopram, Fluoksetyna, Paroksetyna	Wpływ serotoninergiczny na podwzgórze lub rdzeń kręgowy
Inhibitory wychwytu zwrotnego serotoniny i noradrenaliny	Wenlafaksyna	Wpływ serotoninergiczny na podwzgórze lub rdzeń kręgowy
Trójpierścieniowe leki przeciwdepresyjne	Amitryptylina, Klomipramina, Doksepina, Imipramina	Hamowanie wychwytu zwrotnego noradrenaliny i stymulacja obwodowych receptorów adrenergicznych
Leki wpływające na funkcje endokrynne	Deksametazon, Hydrokortyzon, Prednizon, Lewotyroksyna	Uwalnianie różnych hormonów wpływających na pętle sprzężenia zwrotnego

Zaburzenia mechanizmów regulacyjnych

Nieprawidłowości w układzie współczulnym

Hiperpotliwość obejmuje nadaktywność układu współczulnego, powodującą nadmierne uwalnianie acetylocholiny z zakończeń nerwowych. Uważa się, że mechanizm ujemnego sprzężenia zwrotnego do podwzgórza może być upośledzony, powodując, że organizm produkuje więcej potu niż jest to konieczne do ochłodzenia ciała.¹²

Badania elektrofizjologiczne wykazują podwyższoną odpowiedź skórną współczulną u pacjentów z hiperpotliwością dłoni w porównaniu do zdrowych osób. Niedawne badanie dotyczące odzyskiwania pobudliwości somatosympatycznej odpowiedzi skórnej u pacjentów z hiperpotliwością i w grupie kontrolnej wykazało istotne różnice. Pacjenci z hiperpotliwością wykazali zwiększone odzyskiwanie pobudliwości, co sugeruje nadpobudliwy somatosympatyczny szlak polisynaptyczny.¹²

Rola układu przywspółczulnego

Interesujące jest, że kilka badań wykazało, że dysregulacja w pierwotnej hiperpotliwości jest zgodna z dysregulacją w innych zaburzeniach autonomicznych, w tym zaburzeniach sudomotorycznych, baroreceptorowych i wazomotorycznych.¹

W badaniu poziomu katecholamin w osoczu u pacjentów przed i po sympatektomii piersiowej stwierdzono, że przedoperacyjne poziomy noradrenaliny i adrenaliny były prawidłowe. Po sympatektomii poziom noradrenaliny spadł, ale adrenalina pozostała bez zmian. Wyciągnięto więc wniosek, że pierwotna hiperpotliwość jest bardziej prawdopodobnie spowodowana nadaktywnością współczulną w górnych zwojach grzbietowych.¹

Co ciekawe, nie zaobserwowano różnic między grupami w paśmie niskiej częstotliwości, które reprezentuje współczulne unerwienie serca, ale pasmo wysokiej częstotliwości reprezentujące unerwienie przywspółczulne wykazywało różnice. Wyniki te skłoniły badaczy do zasugerowania, że pierwotna hiperpotliwość może obejmować bardziej złożoną dysfunkcję układu autonomicznego niż wcześniej sądzono, w tym różnice w szlaku przywspółczulnym.¹

Centralny mechanizm kontroli pocenia

Podwzgórze kontroluje wydzielanie potu poprzez uwalnianie neurotransmiterów do autonomicznego układu nerwowego, które aktywują gruczoły potowe. Hiperpotliwość może być zatem spowodowana albo dysfunkcją neuronalną regulacji autonomicznego układu nerwowego prowadzącą do nadaktywności układu współczulnego, albo nieprawidłowym centralnym przetwarzaniem emocji.¹

Pierwotny defekt u pacjentów z hiperpotliwością może być związany z nadwrażliwością podwzgórza na bodźce emocjonalne z kory mózgowej. U pacjentów z hiperpotliwością występuje wyższy niż normalny podstawowy poziom produkcji potu oraz zwiększona odpowiedź na normalne bodźce.¹²

W przypadku pierwotnej hiperpotliwości mózg wysyła sygnały, które aktywują gruczoły potowe, nawet jeśli warunki, które wymagałyby chłodzącego działania potu, nie są obecne.¹

Zmiany histologiczne i funkcjonalne

Gruczoły potowe w hiperpotliwości

Gruczoły potowe u pacjentów z hiperpotliwością nie różnią się histopatologicznie od gruczołów u pacjentów bez tego zaburzenia, ani nie występuje zwiększenie liczby lub wielkości gruczołów. Stan ten jest spowodowany nadczynnością gruczołów potowych, a nie ich hipertrofią.¹²

Co istotne, zwiększone wydzielanie potu u pacjentów z hiperpotliwością nie jest spowodowane nieprawidłowościami w samych gruczołach potowych, ale procesami regulacyjnymi, które wpływają na produkcję potu przez gruczoły.¹

Chociaż Du i współpracownicy nie znaleźli znaczących różnic w cechach morfologicznych lub liczbie gruczołów potowych między pacjentami z hiperpotliwością pachową a zdrowymi osobami, autorzy wykryli znacznie większą liczbę ziarnistości wydzielniczych u pacjentów, którzy wykazywali nadmierne wydzielanie gruczołów potowych pachowych.¹

Zmiany w zwojach współczulnych

Kilka badań wykazało zmiany strukturalne i histochemiczne w zwojach współczulnych, najbardziej zauważalne w wielkości i liczbie zwojów.¹

Zwoje współczulne są rozmieszczone podłużnie po obu stronach kręgosłupa i są połączone drogami międzyzwojowymi. Zwykle identyfikuje się trzy zwoje szyjne (górne, środkowe i dolne), dziesięć do dwunastu piersiowych, dwa do pięciu lędźwiowych, cztery do pięciu krzyżowych i jeden w kości ogonowej.¹

Region czaszkowo-szyjny jest unerwiony przez pregangionalne włókna sudomotoryczne pochodzące z pierwszego do piątego segmentu kręgosłupa piersiowego. Ponadto włókna sudomotoryczne kończyny górnej pochodzą z segmentów od drugiego do ósmego, a włókna kończyn dolnych od dziesiątego segmentu piersiowego do drugiego segmentu lędźwiowego.¹

Mechanizmy działań terapeutycznych

Leki antycholinergiczne

Oksybutynina jest lekiem antycholinergicznym o pojawiającej się roli w leczeniu hiperpotliwości. Badania wykazały, że lek skutecznie zmniejsza pocenie i jest doskonałym wyborem w leczeniu ogniskowej pierwotnej hiperpotliwości.¹

Podawanie oksybutyniny wiąże się z niskim wynikiem HDSS (Hyperhidrosis Disease Severity Scale), zmniejszeniem częstości zaburzeń funkcjonowania psychospołecznego i poprawą jakości życia. Oksybutynina blokuje receptory acetylocholiny, szczególnie receptory muskarynowe M1, M2 i M3. Poprzez ten efekt antymuskarynowy zmniejsza pocenie, ograniczając rolę acetylocholiny na gruczoły potowe.¹

Systematyczny przegląd przeprowadzony przez Cruddas i współpracowników wykazał, że terapia antycholinergiczna nie wywołuje tachyfilaksji, co potwierdza skuteczność oksybutyniny w długotrwałym stosowaniu. Jednak istnieje obawa dotycząca oksybutyniny, ponieważ jest ona związana z działaniami niepożądanymi na ośrodkowy układ nerwowy, które są faworyzowane przez zdolność do przechodzenia przez barierę krew-mózg.¹

Toksyna botulinowa

Toksyny botulinowe (BoNT) blokują uwalnianie acetylocholiny i szeregu innych neurotransmiterów z pęcherzyków presynaptycznych poprzez dezaktywację białek SNARE. Cztery typy BoNT są zatwierdzone przez FDA do zastosowań klinicznych w USA: onabotulinumtoksynaA (A/Ona, Botox), incobotulinumtoksynaA (A/Inco, Xeomin), abobotulinumtoksynaA (A/Abo, Dysport) i rimabotulinumtoksynaB (B/Rima, Myobloc).¹²

Toksyna botulinowa typu A (BoNTA) wywiera swoje właściwości przeciwpotowe poprzez czasową blokadę neuronów cholinergicznych w gruczołach potowych ekrynowych, które uwalniają acetyloocholinę. Toksyna botulinowa typu B (BoNTB) również blokuje uwalnianie acetylocholiny z neuronów cholinergicznych.¹

Efekt zmniejszający pocenie toksyny botulinowej A został po raz pierwszy zaobserwowany u bezobjawowych ochotników. Zastrzyki toksyny botulinowej są bezpieczne i skuteczne oraz często poprawiają jakość życia pacjentów z hiperpotliwością.¹²

Jonoforeza

Jonoforeza to procedura, w której prąd elektryczny przepuszczany jest przez skórę namoczoną w wodzie z kranu (nie w wodzie destylowanej), normalnej soli fizjologicznej (0,9%) lub roztworze zawierającym lek antycholinergiczny, co pozwala zjonizowanym (naładowanym) cząsteczkom na przejście przez normalną barierę skórną. Jest bezpieczna, skuteczna i niedrogą metodą.¹

Dokładny mechanizm działania jonoforezy w redukcji pocenia nie jest w pełni poznany. Pot powstaje w odpowiedzi na gradient elektryczny wytwarzany przez aktywność nerwów współczulnych na komórkach gruczołu potowego. Istnieje kilka teorii wyjaśniających, w jaki sposób zmiana gradientu elektrycznego zmniejsza produkcję potu:¹

Jony wytwarzane przez jonoforezę mogą fizycznie blokować przewody potowe w warstwie rogowej naskórka.
Zewnętrzny prąd elektryczny może zakłócać normalną transmisję nerwu współczulnego.
pH w gruczole potowym spada z powodu nagromadzenia jonów wodorowych.¹²

Sympatektomia

Endoskopowa sympatektomia piersiowa jest ostatecznością w leczeniu hiperpotliwości dłoni, pach i twarzy. Działa poprzez przerwanie włókien zwojów współczulnych.¹

W przypadku wykonania uszkodzenia zwojów piersiowych T2, T3 i T4, bodziec eferentny przekazywany do zwojów współczulnych zostałby wzmocniony do obwodu przez utratę ujemnego bodźca do podwzgórza przez drogi aferentne. Ponieważ wzmocnione bodźce nie docierają do obszarów poddanych sympatektomii, może wystąpić zwiększone pocenie w innych regionach.¹

Wydaje się, że istnieje korelacja między nasileniem pocenia kompensacyjnego a zakresem resekcji, gdy zwój jest częścią procedury. Ryzyko trwałej dysfunkcji seksualnej ogranicza użyteczność sympatektomii lędźwiowej w leczeniu hiperpotliwości stóp.¹²

Hiperpotliwość kompensacyjna

Hiperpotliwość kompensacyjna jest formą neuropatii. Spotyka się ją u pacjentów z mielopatią, chorobą piersiową, chorobą naczyniowo-mózgową, urazem nerwu lub po operacjach. Dokładny mechanizm tego zjawiska jest słabo poznany. Przypisuje się go percepcji w podwzgórzu (mózgu), że temperatura ciała jest zbyt wysoka. Pocenie jest wywołane w celu zmniejszenia ciepła ciała.¹

Hiperpotliwość kompensacyjna to nieprawidłowe funkcjonowanie współczulnego układu nerwowego. Jedyne badanie oceniające całkowite pocenie ciała przed i krótko po sympatektomii doszło do wniosku, że pacjenci produkują więcej potu po operacji, tylko nie tak dużo w obszarach leczonych przez operację.¹

Termin 'kompensacyjny’ jest w dużej mierze mylący, ponieważ wskazuje, że istnieje mechanizm kompensacyjny, który zaczyna działać po sympatektomii, w którym ciało 'przekierowuje’ pocenie się z dłoni lub twarzy do innych obszarów ciała. Pocenie po operacji współczulnej jest cyklem odruchowym między układem współczulnym a przednią częścią podwzgórza. Pocenie odruchowe nie nastąpi, jeśli pocenie się dłoni można zatrzymać bez przerywania napięcia współczulnego do ludzkiego mózgu.¹

Najlepszym podejściem do hiperpotliwości kompensacyjnej byłoby unikanie jej wywoływania w pierwszej kolejności. Wskazania do leczenia hiperpotliwości powinny być ostrożne, a pacjent powinien być poinformowany o wynikach operacji, jej powikłaniach i fakcie, że idealna technika chirurgiczna nie jest obecnie dostępna.¹

Nowe kierunki badań i leczenia

Najnowszy systematyczny przegląd na temat etiologii pierwotnej hiperpotliwości opisuje trzy główne kierunki przyszłych badań w celu określenia patofizjologii pierwotnej hiperpotliwości: genetyka, obserwacje histologiczne i badania enzymatyczne. Zarysowują one, że etiologia pierwotnej hiperpotliwości może być związana z dziedziczną cechą genetyczną z patologicznymi allelami w niektórych chromosomach lub zmianami histologicznymi obserwowanymi w komórkach zwojów współczulnych.¹

Sofpironium bromide jest innowacyjnym i obiecującym związkiem stosowanym głównie w leczeniu pierwotnej hiperpotliwości pachowej. Mechanizm działania sofpironium bromide opiera się na jego funkcji jako miękkiego środka antycholinergicznego, który specyficznie celuje w gruczoły potowe, aby zmniejszyć ich aktywność, a tym samym zmniejszyć pocenie.¹

Sofpironium bromide, gdy jest stosowany miejscowo, selektywnie wiąże się z receptorami muskarynowymi na gruczołach potowych w okolicy pach, skutecznie blokując działanie acetylocholiny. Ta inhibicja zapobiega aktywacji gruczołów potowych, zmniejszając w ten sposób produkcję potu.¹

Brella to nowa klasa leczenia tego stanu. Ciepło generowane przez arkusz sodowy jest wysoce zlokalizowane, mikrocele gruczołów potowych w celu znacznego zmniejszenia produkcji potu. Jest to pierwsze kliniczne zastosowanie tej zasady jako urządzenia medycznego, używanego do zmniejszenia nadmiernego pocenia.¹

Istnieją również metody leczenia wykorzystujące kontrolowaną technologię mikrofalową do niszczenia nadaktywnych gruczołów potowych bez potrzeby operacji, ale mogą one nie być odpowiednie dla każdego pacjenta.¹

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Primary focal hyperhidrosis – UpToDate
https://www.uptodate.com/contents/primary-focal-hyperhidrosis
Hyperhidrosis is the secretion of sweat in amounts greater than physiologically needed for thermoregulation. It is most commonly a chronic idiopathic (primary) condition; however, secondary medical conditions or medications should be excluded. Idiopathic hyperhidrosis localized to certain areas of the body is called primary focal hyperhidrosis. Primary focal hyperhidrosis usually affects the axillae, palms, and soles. The condition may also affect other sites, such as the face, scalp, inguinal, and inframammary areas. […] A consensus panel suggested the following diagnostic criteria for primary focal hyperhidrosis: Focal, visible, excessive sweating of at least six months duration without apparent cause.
#1 Hyperhidrosis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459227/
Hyperhidrosis is a disorder of excessive sweating due to the overstimulation of cholinergic receptors on eccrine glands. This disorder is characterized by sweating beyond what the body uses for homeostatic temperature regulation. […] The acetylcholine negative feedback loop is likely impaired in these patients, which may help explain how a physiologic response can become pathologic. […] Hyperhidrosis involves hyperactivity of the sympathetic nervous system, causing excessive release of acetylcholine from the nerve endings. It is believed that the negative feedback mechanism to the hypothalamus may be impaired, causing the body to sweat more than what is needed to cool the body. This pathologic reaction can be triggered by medications that increase the release of acetylcholine from the neuron or systemic medical disorders, which also upregulate a sympathetic response.
#1 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://www.mdpi.com/2072-6651/5/4/821
It is believed the hypothalamic sweat center, which is in charge of the palms, soles, and in some individuals the axilla, is distinct from the other hypothalamic sweat centers and is actually under exclusive control of the cortex, with no input from the thermosensistive elements. Because emotional sweating does not occur during sleep or sedation, one of the criteria for primary hyperhidrosis is that the individual does not experience sweating during sleep. Sympathetic cholinergic nerves activate both thermoregulatory and emotional sweating and are controlled by different central nervous system neurons. It is possible that Primary hyperhidrosis is due to abnormal central control of emotional sweating given that it affects the same body areas as those affected in emotional sweating (hands, feet, and axillae).
#1 Hyperhidrosis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459227/
On histologic examination, eccrine glands appear normal in size and number compared to those without the disorder. However, the sympathetic ganglia in these patients are usually larger. This supports the theory that hyperhidrosis is a disorder of excessive cholinergic stimulation instead of a problem with the eccrine glands.
#1 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://www.mdpi.com/2072-6651/5/4/821
Hyperhidrosis occurs as a primary process of autonomic neuronal dysfunction. This dysfunction tends to occur in areas where there is a higher concentration of eccrine glands such as the palms, soles, and axillae, which are sweat-producing glands. The nerves that innervate sweat glands are sympathetic, postganglionic and have acetylcholine as their primary neurotransmitter. A central sudomotor efferent pathway is suggested for hyperhidrosis with the following connections: (1) cerebral cortex to hypothalamus; (2) hypothalamus to medulla; (3) fibers crossing in the medulla oblongata and travelling to the lateral horn of the spinal cord; (4) the lateral horn to sympathetic ganglia; and (5) sympathetic ganglia to sweat glands as postganglionic C fibers. Because the sympathetic fibers arising from the hypothalamus cross mostly at the level of the pons, and most of this crossing is completed in the medulla oblongate, lesions in the medulla may cause altered sweating, such as the ipsilateral anhidrosis seen in Hornerâs syndrome.
#1 SciELO Brazil – Palmar hyperhidrosis: clinical, pathophysiological, diagnostic and therapeutic aspects Palmar hyperhidrosis: clinical, pathophysiological, diagnostic and therapeutic aspects
https://www.scielo.br/j/abd/a/wWFVwn5VLVswDWrMpzMrscw/
Palmar hyperhidrosis evolves from a localized hyperactivity of the sympathetic autonomic system and can be triggered by stressful events. […] No histopathological finding was identified in individuals with palmar hyperhidrosis, nor the increase in the amount of sweat glands. This data suggests that there is a complex disorder of the autonomic nervous system involving the sympathetic and parasympathetic pathways, and it can be inferred that PH is primarily a neurological disease with exuberant cutaneous manifestation. […] Electrophysiological studies show high skin sympathetic response in patients with palmar hyperhidrosis compared with healthy subjects. […] The main neurotransmitter of the neuroglandular junction of postganglionic fibers is the acetylcholine, unlike what happens in most of the nerve endings, whose neurotransmitter is the noradrenaline. Various stimuli, such as physical activity, hot environment, anxiety and stress, activate the preoptic area of the hypothalamus that, by sympathetic stimulation, release acetylcholine in the neuroglandular junction, increasing the response in the sweat gland and generating a retrograde stimulus to the hypothalamus through the afferents pathways, the negative feedback. The balance between the afferent and efferent pathways maintains homeostasis in the body. In individuals with PH, this system appears to be in focal imbalance, with amplification of efferent stimuli.
#1 Pathophysiology of hyperhidrosis – Choe – Shanghai Chest
https://shc.amegroups.org/article/view/5204/html
Primary hyperhidrosis is a pathologic condition that is characterized by excessive sweating beyond the physiological needs required for thermoregulation. […] The exact pathophysiology of primary hyperhidrosis remains unclear, but the prevailing theory of pathogenesis appears to be neurogenic hyper-excitability of the sympathetic nervous circuits innervating eccrine glands. […] Most epidemiological studies have shown the existence of a familial trait for primary hyperhidrosis, as 44% to 66% of patients share a positive family history. […] Recent studies have also demonstrated evidence for genetic transmission. […] The most probable explanation is neurogenic over-activity of the reflex circuits innervating the eccrine glands. Increased nervous impulses in the central nervous system can release excessive amounts of acetylcholine, which then increases sudoral response.
#1
https://journals.lww.com/jfmpc/fulltext/2023/12120/primary_hyperhidrosis__from_a_genetics_point_of.4.aspx
Primary hyperhidrosis is a disorder of profuse sweating which negatively influences a patient’s quality of life and is caused because of over-activation of the sympathetic nervous system. […] It has been found that people with a positive family history of primary hyperhidrosis are likely to suffer from this condition, suggesting a strong genetic basis. Genetic analysis has revealed a dominant autosomal pattern of inheritance with a variable degree of penetrance and is a sex-independent trait. […] The exact origin of hyperhidrosis is still unclear. It is proposed to result from the over-activation of the sympathetic nerves. […] The strong patterns of inheritance suggest the genetic basis of hyperhidrosis and therefore considered to be hereditary in nature. Family history of hyperhidrosis plays a fundamental role in the onset of hyperhidrosis.
#1
https://journals.lww.com/jfmpc/fulltext/2023/12120/primary_hyperhidrosis__from_a_genetics_point_of.4.aspx
Hyperhidrosis is a genetically transmitted disorder. However, it is still unclear whether primary hyperhidrosis is a single gene defect or a multi-factorial disorder. […] From the genetic analysis, Ro et al. argued that primary hyperhidrosis is hereditary in nature with a variable degree of penetrance and is a sex-independent condition. […] Another study revealed a positive family history of hyperhidrosis in 62% of patients, and the trait had skipped a generation, signifying either autosomal dominant transmission with reduced disease penetrance or an autosomal recessive disease with a high disease allele frequency. […] To identify the disease locus, genome-wide DNA polymorphic markers were used, and haplotype detailed analysis revealed primary palmer hyperhidrosis (PPH) loci which are positioned at 14q11.2-q13 to an interval between D14S1070 and D14S990.
#1 Pathophysiology of hyperhidrosis – Choe – Shanghai Chest
https://shc.amegroups.org/article/view/5204/html
Another study found higher plasma nitric oxide levels in patients with hyperhidrosis in comparison to the control group, which supports another hypothesis that oxidative damage from increased reactive oxygen species production with deficient capacity of antioxidation mechanisms may be involved in the pathogenesis of the disease. […] Specifically, in axillary hyperhidrosis, several studies have shown an abnormal regeneration of sympathetic nerves or an increase in the number or distribution of eccrine glands from hyperstimulation. […] A recent systematic review on the etiology of primary hyperhidrosis describe three main lines for future research, in order to delineate the pathophysiology of primary hyperhidrosis: genetics, histological observations and enzymatic studies. […] They outline that the etiology of primary hyperhidrosis may be related to a hereditary genetic trait with pathological alleles in some chromosomes, or histological changes observed in the sympathetic ganglion cells.
#1
https://journals.lww.com/jfmpc/fulltext/2023/12120/primary_hyperhidrosis__from_a_genetics_point_of.4.aspx
The putative gene mapped by Higashimoto et al. may be the major gene, but because of the genetically heterogeneous nature, the existence of other gene loci surely modifies the expression pattern of the identified gene. […] Another contradictory study revealed a hyperhidrosis locus on chromosome 2q31.1, providing strong evidence of different genetic variants. […] The cellular process in sweat glands is controlled by ITPR2 gene, which codes for 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) and is associated with human disease known as anhidrosis (inability to sweat). […] FoxA1 gene, which codes for Forkhead transcription factor, plays a significant role in sweat regulation through bestrophin 2 anion channel and NaKCl cotransporter. […] Understanding the relationship between anxiety and hyperhidrosis-causing genes will help to devise better anxiolytics, which in turn helps in controlling the condition by breaking the vicious hyperhidrosis sweat cycle. […] Further research is required to provide evidence characterizing the exact mechanism of pathogenesis and to identify the putative gene or network of genes causing primary hyperhidrosis.
#1
https://link.springer.com/article/10.1007/s13555-022-00885-w
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. […] However, while Du et al. 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. […] Lin et al. found that activin A receptor type 1 (ACVR1) is upregulated in the sweat glands of patients with primary axillary HH compared to control subjects. […] Upregulation of the cholinergic receptor nicotinic alpha-1 subunit (CHRNA1) is a typical feature of sweat glands in patients with primary focal HH.
#1 Hyperhidrosis: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/1073359-overview
Generalized hyperhidrosis may be the consequence of autonomic dysregulation, or it may develop secondary to a metabolic disorder, febrile illness, or malignancy. […] In its localized form, hyperhidrosis may result from a disruption followed by abnormal regeneration of sympathetic nerves or a localized abnormality in the number or distribution of the eccrine glands, or it may be associated with other (usually vascular) abnormalities. […] Essential hyperhidrosis, a disorder of the eccrine sweat glands, is associated with sympathetic overactivity. […] Essential hyperhidrosis does not appear to be a generalized disorder involving vascular endothelium. […] Palmoplantar hyperhidrosis may be inherited in an autosomal dominant manner.
#1 Hyperhidrosis: Management Options | AAFP
https://www.aafp.org/pubs/afp/issues/2018/0601/p729.html
Hyperhidrosis is excessive sweating that affects patients’ quality of life, resulting in social and work impairment and emotional distress. Primary hyperhidrosis is bilaterally symmetric, focal, excessive sweating of the axillae, palms, soles, or craniofacial region not caused by other underlying conditions. Secondary hyperhidrosis may be focal or generalized, and is caused by an underlying medical condition or medication use. […] The cause of primary hyperhidrosis is not well understood. Eccrine sweat glands distributed throughout the body, but heavily concentrated on the palms, soles, axillae, and face are innervated by postganglionic autonomic nerve fibers and stimulated by the neurotransmitter acetylcholine. It is thought that increased or aberrant sympathetic stimulation of the eccrine sweat glands is responsible for the increased sweating rather than an increased number or size of the glands. […] Persons with primary hyperhidrosis have a higher-than-normal basal level of sweat production and an increased response to normal stimuli, such as emotional or physical stress.
#1 Excessive sweating
https://www.mayoclinic.org/symptoms/excessive-sweating/basics/causes/sym-20050780
If excessive sweating has no underlying medical cause, it’s called primary hyperhidrosis. It happens when excess sweating is not triggered by a rise in temperature or physical activity. Primary hyperhidrosis may be at least partly hereditary. […] If the excess sweating is due to an underlying medical condition, it’s called secondary hyperhidrosis. […] Health conditions that might cause excessive sweating include: Acromegaly, Diabetic hypoglycemia, Fever of undetermined cause, Hyperthyroidism (overactive thyroid) also known as overactive thyroid, Infection, Leukemia, Lymphoma, Malaria, Medication side effects, such as sometimes experienced when taking some beta blockers and antidepressants, Menopause, Neurologic disease, Pheochromocytoma (a rare adrenal gland tumor), Tuberculosis. […] Causes shown here are commonly associated with this symptom. Work with your doctor or other health care professional for an accurate diagnosis.
#1 MEDSAFE
https://www.medsafe.govt.nz/profs/PUArticles/December2024/Medicines-that-make-you-sweat-drug-induced-hyperhidrosis.html
Drug-induced hyperhidrosis is the most common cause of secondary hyperhidrosis. […] The thermoregulatory pathway maintains body temperature, and involves the hypothalamus, spinal thermoregulatory centres, sympathetic ganglia and the eccrine-neuroeffector junction. Acetylcholine is an important mediator in the regulation of body temperature and sweating. Medicines that act on these pathways and increase acetylcholine transmission may increase sweating. […] Table 1 provides examples of medicines that can cause hyperhidrosis and the proposed mechanisms. […] Acetylcholinesterase inhibitors Galantamine Rivastigmine Cholinesterase inhibition leading to increased levels of acetylcholine Opioids Codeine Fentanyl Morphine Oxycodone Tramadol Release of histamine and subsequently acetylcholine Selective serotonin reuptake inhibitors Citalopram Escitalopram Fluoxetine Paroxetine Serotonergic effect on hypothalamus or spinal cord Serotonin and noradrenaline reuptake inhibitors Venlafaxine Serotonergic effect on hypothalamus or spinal cord Tricyclic antidepressants Amitriptyline Clomipramine Dosulepin Imipramine Noradrenaline reuptake inhibition and stimulation of peripheral adrenergic receptors. […] Medicines that affect endocrine function Dexamethasone Hydrocortisone Prednisone Levothyroxine Release of various hormones that influence regulatory feedback loops.
#1 Pathophysiology of hyperhidrosis – Choe – Shanghai Chest
https://shc.amegroups.org/article/view/5204/html
Exact specifics and nature linking this neurogenic over-activity to primary hyperhidrosis are still unclear. […] Interestingly, several studies showed that dysregulation in primary hyperhidrosis is consistent with dysregulation in other autonomic disorders, including sudomotor, baroreceptor and vasomotor disorders. […] Eccrine glands have previously been found to be both histologically and functionally normal in individuals with hyperhidrosis, which supports the theory on the dysfunction of the thermoregulation capacity of the sympathetic component of the autonomic nervous system. […] Nonetheless, it is evident that the sympathetic chain at T2 and T3 level is the direct pathway between the hypothalamus and the end organ effector cells, which are the eccrine glands. […] Furthermore, several studies have shown structural and histochemical changes in the sympathetic ganglia, most notably in the size and number of ganglia.
#1 Pathophysiology of Excessive Sweating – International Hyperhidrosis Society | Official Site
https://www.sweathelp.org/about-hyperhidrosis/pathophysiology-of-normal-sweating.html
If there is generalized sympathetic overactivity in primary hyperhidrosis, catecholamine levels in patients could be predicted to be elevated. However, a study of plasma catecholamine levels in patients before and after thoracic sympathectomy found preoperative norepinephrine and epinephrine levels to be normal. After sympathectomy, the norepinephrine level fell, but epinephrine was unchanged. It was thus concluded that primary hyperhidrosis is more likely due to sympathetic overactivity in the upper dorsal ganglia. […] Interestingly, there were no differences between groups in the low-frequency band that represents sympathetic cardiac innervation, but the high-frequency band representative of parasympathetic innervation did show differences. These results led the investigators to suggest that primary hyperhidrosis may involve a more complex dysfunction of the autonomic nervous system than previously thought, involving parasympathetic pathway differences as well. […] In summary, although the exact pathophysiology of primary hyperhidrosis is yet to be determined, there is much evidence for abnormalities in autonomic nervous system function.
#1
https://link.springer.com/article/10.1007/s13555-022-00885-w
Hyperhidrosis (HH) is a central nervous dysfunction characterized by abnormally increased sweating due to a central dysregulation of sweat secretion. […] The central nervous system controls sweat secretion through the release of neurotransmitters into the autonomous nervous system (ANS) that activate the sweat glands. […] HH may thus be due to either a neuronal dysfunction of ANS regulation leading to a hyperactivity of the sympathetic nervous system, or to abnormal central processing of emotions. […] Various pathogenic mechanisms have been proposed to be involved in pathological sweat secretion in HH, ranging from structural changes within the ANS to increased expression of aquaporin 5 and upregulation of activin A receptor type 1 in eccrine sweat glands. […] 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.
#1 Palmoplantar Hyperhidrosis: A Therapeutic Challenge | AAFP
https://www.aafp.org/pubs/afp/issues/2004/0301/p1117.html
Excessive sweating from the palms and soles, known as palmoplantar hyperhidrosis, affects both children and adults. […] The primary defect in patients with hyperhidrosis may be hypothalamic hypersensitivity to emotional stimuli from the cerebral cortex. […] The underlying mechanism of iontophoresis is not fully understood. According to one hypothesis, iontophoresis may induce hyperkeratosis of the sweat pores and obstruct sweat flow and secretion (although no plugging of the pores has been found). […] Injections of botulinum toxin type A (Botox) are safe and effective, and often improve quality of life in patients with hyperhidrosis. The toxin inhibits the release of acetylcholine at the neuromuscular junction and affects the post-ganglionic sympathetic innervation of the sweat glands. […] Sympathectomy involves the surgical destruction of the second and third thoracic sympathetic ganglia for the palms. The risk of permanent sexual dysfunction limits the usefulness of lumbar sympathectomy for the treatment of plantar hyperhidrosis.
#1 Botox injections one way to treat hyperhidrosis sweating | UCLA Health
https://www.uclahealth.org/news/article/botox-injections-one-way-treat-hyperhidrosis-sweating
Hyperhidrosis is a disorder in which the sweat glands become overactive. The reason this disorder occurs is not fully understood. However, it is believed to be linked to a glitch in the workings of the sympathetic nervous system, which oversees the body’s fight-or-flight response and acts as its thermostat. […] It appears that when someone has primary hyperhidrosis, the brain is sending signals that activate the sweat glands, even though the conditions that would require the cooling effects of sweat are not present. […] Nerve impulses associated with sweating can also be muted with the use of Botox. The treatment works by blocking the nerve signals that instruct the sweat glands to become active.
#1 Pathophysiology of Excessive Sweating – International Hyperhidrosis Society | Official Site
https://www.sweathelp.org/about-hyperhidrosis/pathophysiology-of-normal-sweating.html
Sweat glands in patients with hyperhidrosis are not histopathologically different from those in normal patients, nor is there an increase in the number or size of glands. The condition is caused by hyperfunction of the sweat glands rather than hypertrophy. […] One of the underlying mechanisms for a lowered threshold and exaggerated response in hyperhidrosis patients may be excessive sympathetic activity. […] This study suggested that increased sympathetic activity through the T2-T3 ganglia causes palmar hyperhidrosis. […] A recent study of recovery of excitability of the sympathetic sudomotor skin response in patients with hyperhidrosis and in normal controls found significant differences. Patients with hyperhidrosis had enhanced recovery of excitability, implying a hyperexcitable somatosympathetic polysynaptic pathway.
#1 SciELO Brazil – Palmar hyperhidrosis: clinical, pathophysiological, diagnostic and therapeutic aspects Palmar hyperhidrosis: clinical, pathophysiological, diagnostic and therapeutic aspects
https://www.scielo.br/j/abd/a/wWFVwn5VLVswDWrMpzMrscw/
The sympathetic ganglia are distributed longitudinally on each side of the spine and are connected by interganglionar pathways. Usually, three cervical ganglia (upper, middle and lower), ten to twelve thoracic, two to five lumbar, four to five sacral, and one at coccyx, are identified. […] The craniocervical region is innervated by preganglionic sudomotor fibers originating from the first to the fifth segment of the thoracic spine. Moreover, sudomotor fibers of the upper limb originate from the second to the eighth segments; and those of the lower limbs from the tenth thoracic segment to the second lumbar segment. […] When the lesion of the thoracic ganglia T2, T3 and T4 is performed, the efferent stimulus transmitted to sympathetic ganglia would be amplified to the periphery by the loss of the negative stimulus to the hypothalamus by afferent pathways. Because the amplified stimuli do not reach the sympathectomized areas, there may be increased sweating in other regions. […] There seems to be a correlation between the severity of CH and the extension of resection, as the ganglion approached in the procedure.
#1
https://duradry.com/blogs/hyperhidrosis/oxybutynin-for-the-treatment-of-hyperhidrosis?srsltid=AfmBOorRzHNnHW2P3I-rcM9-NH8FKzTWB7WTYT4FrPZZfvZeYke_fljg
Oxybutynin is an anticholinergic drug with an emerging role in the treatment of hyperhidrosis. Studies have shown that the drug is effective in reducing sweating and is an excellent choice for treating focal primary hyperhidrosis. […] Although the exact cause of primary hyperhidrosis is unknown, the prevalence of the condition is likely to be greater than previously thought. The disorder is characterized by excessive sweating that is caused by increased sympathetic stimulation. The primary cause of the condition is still unknown, but it may be related to an increased response to normal stimuli and increased basal sweat production. The condition is easily treatable and can improve a patient’s quality of life. […] Oxybutynin has been shown to be effective in many clinical trials in both generalized and focal forms of hyperhidrosis. However, its tolerability and long-term compliance may be an issue.
#1
https://link.springer.com/article/10.1007/s00403-023-02587-5
Sweating is a physiologic mechanism of human thermoregulation. Hyperhidrosis is defined as a somatic disorder where the sweating is exaggerated in an exact area because the sweat glands are hyperfunctioning. […] The acetylcholine negative feedback loop is likely impaired in these patients, which can clarify how a physiologic response can change into pathological. […] Oxybutynin administration is associated with a low HDSS score, a decrease in the incidence of psychosocial functioning impairment, and an improvement in quality-of-life score. These effects contribute to the actual action of oxybutynin as it plays on the underlying mechanisms of HH. It contra verse acetylcholine receptors, especially muscarinic receptors M1, M2, and M3. By this antimuscarinic effect, it reduces sweating by limiting the role of acetylcholine on sweat glands.
#1
https://link.springer.com/article/10.1007/s00403-023-02587-5
A systematic review conducted by Cruddas et al. reported that anticholinergic therapy does not induce tachyphylaxis, which supports the effectiveness of oxybutynin in long-term usage. […] However, there is dreadful concern regarding oxybutynin since it is associated with CNS events that are favored by the ability to pass through the bloodbrain barrier.
#1 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://pmc.ncbi.nlm.nih.gov/articles/PMC3705293/
BoNTs block the release of acetylcholine and a number of other neurotransmitters from presynaptic vesicles by deactivating SNARE proteins. Four types of BoNTs are approved by FDA for clinical use in the USA: onabotulinumtoxinA (A/Ona, Botox), incobotulinumtoxinA (A/Inco, Xeomin), abobotulinumtoxinA (A/Abo, Dysport) and rimabotulinumtoxinB (B/Rima, Myobloc). These toxins use different presynaptic proteins for their site of action. The sweat reducing effect of BoNT-A was first observed in asymptomatic volunteers.
#1 Examining Hyperhidrosis: An Update on New Treatments
https://www.ajmc.com/view/examining-hyperhidrosis–an-update-on-new-treatments
Recent studies indicate that the prevalence of Americans affected by hyperhidrosis is higher than originally determined. […] The exact mechanism causing primary hyperhidrosis is not well understood. It is thought that increased or uncontrollable sympathetic stimulation (via acetylcholine) of the eccrine sweat glands may be responsible for the excessive sweating. […] Furthermore, it is known that individuals with primary hyperhidrosis have a higher-than-normal basal level of sweat production and an increased response to normal stimuli such as stress. […] Botulinum toxin type A (BoNTA) exerts its antisweat properties through the temporary blockade of cholinergic neurons in eccrine sweat glands that release acetylcholine. […] Botulinum toxin type B (BoNTB) also blocks acetylcholine release from cholinergic neurons.
#1 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://www.mdpi.com/2072-6651/5/4/821
BoNTs block the release of acetylcholine and a number of other neurotransmitters from presynaptic vesicles by deactivating SNARE proteins. Four types of BoNTs are approved by FDA for clinical use in the USA: onabotulinumtoxinA (A/Ona, Botox), incobotulinumtoxinA (A/Inco, Xeomin), abobotulinumtoxinA (A/Abo, Dysport) and rimabotulinumtoxinB (B/Rima, Myobloc). These toxins use different presynaptic proteins for their site of action. For instance, for A/Abo the protein is Synaptin 25. For B/Rima it is synaptobrevin, also known as vesicle-associated membrane protein (VAMP). The sweat reducing effect of BoNT-A was first observed in asymptomatic volunteers.
#1 Iontophoresis
https://dermnetnz.org/topics/iontophoresis
Iontophoresis is a procedure in which an electrical current is passed through skin soaked in tap water (not distilled water), normal saline (0.9%), or a solution containing an anticholinergic medication, which allows ionised (charged) particles to cross the normal skin barrier. It reduces sweating and enhances the delivery of drugs and macromolecules into and through the skin. It is safe, effective and inexpensive. […] The mechanism of action of iontophoresis in reducing sweating is not completely understood. Sweat forms in response to an electrical gradient produced by sympathetic nerve activity on the cells of the sweat gland. There are several theories as to how a change in the electrical gradient reduces sweat production. […] Ions produced by iontophoresis may physically block the sweat ducts in the stratum corneum. […] The external electrical current may disrupt normal sympathetic nerve transmission. […] The pH drops in the sweat gland due to an accumulation of hydrogen ions.
#1 Hyperhidrosis and bromhidrosis A guide to assessment and management
https://www.racgp.org.au/afp/2013/may/hyperhidrosis-and-bromhidrosis
Hyperhidrosis can be either generalised or focal. Generalised hyperhidrosis may be primary and idiopathic or secondary to systemic disease. […] Focal hyperhidrosis is usually primary and responds to topical measures. Specialist referral for botulinum toxin A, iontophoresis or sympathectomy should be considered for severe cases. […] The main mechanism of action is the inhibition of acetylcholine release from the sympathetic nerves that innervate the eccrine sweat glands. […] There is long term data on the safety and efficacy of anticholinergic use in focal hyperhidrosis. […] The dosage required to control hyperhidrosis invariably results in generalised anticholinergic effects, including dry mouth and eyes, urinary retention and headaches. […] Endoscopic thoracic sympathectomy is the last resort for the treatment of palmar, axillary and craniofacial hyperhidrosis. It works by interrupting the fibres of the sympathetic ganglia.
#1 Compensatory hyperhidrosis – Wikipedia
https://en.wikipedia.org/wiki/Compensatory_hyperhidrosis
Compensatory hyperhidrosis is a form of neuropathy. It is encountered in patients with myelopathy, thoracic disease, cerebrovascular disease, nerve trauma or after surgeries. The exact mechanism of the phenomenon is poorly understood. It is attributed to the perception in the hypothalamus (brain) that the body temperature is too high. The sweating is induced to reduce body heat. […] Compensatory hyperhidrosis is aberrant sympathetic nervous system functioning. The only study evaluating the total body sweat prior and shortly after sympathectomy concluded that patients produce more sweat after the surgery, just not so much in the areas treated by the surgery. […] The term 'compensatory’ is largely misleading, as it indicates that there is a compensatory mechanism that takes effect after sympathectomy, in which the body 'redirects’ the sweating from the palms or face to other areas of the body. Sweating after sympathetic surgery is a reflex cycle between the sympathetic system and the anterior portion of the hypothalamus. Reflex sweating will not happen if hand sweating can be stopped without interrupting sympathetic tone to the human brain.
#1 SciELO Brazil – Current treatment options for craniofacial hyperhidrosis Current treatment options for craniofacial hyperhidrosis
https://www.scielo.br/j/jvb/a/NzhgXmPsykFQ9r3JPDBTrVb/
In FH, sweat is visible on the forehead and face. […] Criteria exist for identifying primary hyperhidrosis and to facilitate correct diagnosis. […] The first step is to differentiate between primary (focal) and secondary hyperhidrosis. […] In contrast with secondary hyperhidrosis, primary hyperhidrosis occurs in healthy individuals. […] The sympathetic tone efferent to the hypothalamus would then induce sweating through synapses in the sympathetic ganglia, triggering a negative sympathetic stimulus afferent to the hypothalamus after the synapse. […] In cases of sympathectomy at the T2 or T3 level, the efferent sympathetic stimulus is amplified, because there is interruption of the afferent fibers into the hypothalamus, and there is no sympathetic negative stimulus. […] Therefore, compensatory sweating is apparently a reflex mechanism mediated by the hypothalamus and is not fully understood. […] The best approach to CH would be avoid causing it in the first place. Indications for treatment of hyperhidrosis should be cautious, and the patient should be informed about the results of surgery, its complications, and the fact that a perfect surgical technique is not currently available.
#1 What is the mechanism of Sofpironium Bromide?
https://synapse.patsnap.com/article/what-is-the-mechanism-of-sofpironium-bromide
Sofpironium bromide is an innovative and promising compound used primarily in the treatment of primary axillary hyperhidrosis, a condition characterized by excessive underarm sweating. The mechanism of action of sofpironium bromide revolves around its function as a soft anticholinergic agent, specifically targeting sweat glands to reduce their activity and thus decrease perspiration. […] Sweat production is primarily controlled by the sympathetic nervous system through the release of acetylcholine, a neurotransmitter. This neurotransmitter binds to muscarinic receptors on eccrine sweat glands, which triggers a cascade of intracellular events leading to the secretion of sweat. Sofpironium bromide intervenes in this process by acting as an antagonist to the muscarinic receptors. When applied topically, it selectively binds to these receptors on the sweat glands in the underarm area, effectively blocking the action of acetylcholine. This inhibition prevents the activation of the sweat glands, thereby reducing sweat production.
#1 Doris Day, MD, Discusses Primary Axillary Hyperhidrosis and Brella SweatControl Patch
https://www.dermatologytimes.com/view/doris-day-md-discusses-primary-axillary-hyperhidrosis-and-brella-sweatcontrol-patch
Brella is a new class of treatment for this condition. […] The heat generated by the sodium sheet is highly localized, microtargeting sweat glands to significantly reduce sweat production. […] It is the first clinical application of this principle as a medical device, used to reduce excessive sweating.
#1 Hyperhidrosis Treatment Reading – Causes, Symptoms & Treatments | Derma
https://www.dermareading.co.uk/hyperhidrosis
There are also treatments that use controlled microwave technology to destroy the overactive sweat glands without the need for surgery, but they may not be appropriate for every patient. […] In some rare cases in patients with severe hyperhidrosis, surgery is necessary to treat the condition, but this would only performed when all other avenues have been exhausted.
#2 Hyperhidrosis and Its Impact on Those Living With It
https://www.ajmc.com/view/hyperhidrosis-and-its-impact–on-those-living-with-it
Hyperhidrosis is the term used to describe a condition of excessive sweating beyond what is physiologically necessary. It can be either systemic or localized, based on the distribution of sweat, and is also classified as primary or secondary, based on the cause of sweating. Systemic hyperhidrosis describes sweating over the entire body; localized sweating affects only certain parts of the body. Primary focal hyperhidrosis presents as local sweating, such as in the axillae (underarms), palms (hands), soles (feet), and craniofacial regions. Other areas include, but are not limited to, inframammary, groin, and gluteal folds. These sites on the body are primarily affected because of the presence of large numbers of sweat glands. There is no difference in morphology, number, or size between the sweat glands of a patient with hyperhidrosis and an individual without hyperhidrosis. In patients with hyperhidrosis, the sweat glands are overstimulated by ACh that is released by the sympathetic nervous system. These patients appear to have a reduced threshold for emotional sweating, despite having normal responses to thermoregulatory sweating.
#2
https://link.springer.com/article/10.1007/s00403-023-02587-5
Sweating is a physiologic mechanism of human thermoregulation. Hyperhidrosis is defined as a somatic disorder where the sweating is exaggerated in an exact area because the sweat glands are hyperfunctioning. […] The acetylcholine negative feedback loop is likely impaired in these patients, which can clarify how a physiologic response can change into pathological. […] Oxybutynin administration is associated with a low HDSS score, a decrease in the incidence of psychosocial functioning impairment, and an improvement in quality-of-life score. These effects contribute to the actual action of oxybutynin as it plays on the underlying mechanisms of HH. It contra verse acetylcholine receptors, especially muscarinic receptors M1, M2, and M3. By this antimuscarinic effect, it reduces sweating by limiting the role of acetylcholine on sweat glands.
#2 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://pmc.ncbi.nlm.nih.gov/articles/PMC3705293/
It is believed the hypothalamic sweat center, which is in charge of the palms, soles, and in some individuals the axilla, is distinct from the other hypothalamic sweat centers and is actually under exclusive control of the cortex, with no input from the thermosensistive elements. Because emotional sweating does not occur during sleep or sedation, one of the criteria for primary hyperhidrosis is that the individual does not experience sweating during sleep. Sympathetic cholinergic nerves activate both thermoregulatory and emotional sweating and are controlled by different central nervous system neurons. It is possible that Primary hyperhidrosis is due to abnormal central control of emotional sweating given that it affects the same body areas as those affected in emotional sweating (hands, feet, and axillae).
#2 Pathophysiology of hyperhidrosis – Choe – Shanghai Chest
https://shc.amegroups.org/article/view/5204/html
Exact specifics and nature linking this neurogenic over-activity to primary hyperhidrosis are still unclear. […] Interestingly, several studies showed that dysregulation in primary hyperhidrosis is consistent with dysregulation in other autonomic disorders, including sudomotor, baroreceptor and vasomotor disorders. […] Eccrine glands have previously been found to be both histologically and functionally normal in individuals with hyperhidrosis, which supports the theory on the dysfunction of the thermoregulation capacity of the sympathetic component of the autonomic nervous system. […] Nonetheless, it is evident that the sympathetic chain at T2 and T3 level is the direct pathway between the hypothalamus and the end organ effector cells, which are the eccrine glands. […] Furthermore, several studies have shown structural and histochemical changes in the sympathetic ganglia, most notably in the size and number of ganglia.
#2 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://pmc.ncbi.nlm.nih.gov/articles/PMC3705293/
Hyperhidrosis occurs as a primary process of autonomic neuronal dysfunction. This dysfunction tends to occur in areas where there is a higher concentration of eccrine glands such as the palms, soles, and axillae, which are sweat-producing glands. The nerves that innervate sweat glands are sympathetic, postganglionic and have acetylcholine as their primary neurotransmitter. A central sudomotor efferent pathway is suggested for hyperhidrosis with the following connections: (1) cerebral cortex to hypothalamus; (2) hypothalamus to medulla; (3) fibers crossing in the medulla oblongata and travelling to the lateral horn of the spinal cord; (4) the lateral horn to sympathetic ganglia; and (5) sympathetic ganglia to sweat glands as postganglionic C fibers. Because the sympathetic fibers arising from the hypothalamus cross mostly at the level of the pons, and most of this crossing is completed in the medulla oblongate, lesions in the medulla may cause altered sweating, such as the ipsilateral anhidrosis seen in Horners syndrome.
#2
https://link.springer.com/article/10.1007/s13555-022-00885-w
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. […] Overall, findings in genetics suggest considerable heterogeneity in the disorder, and it is likely that HH is a multifactorial disorder.
#2
https://journals.lww.com/jfmpc/fulltext/2023/12120/primary_hyperhidrosis__from_a_genetics_point_of.4.aspx
Hyperhidrosis is a genetically transmitted disorder. However, it is still unclear whether primary hyperhidrosis is a single gene defect or a multi-factorial disorder. […] From the genetic analysis, Ro et al. argued that primary hyperhidrosis is hereditary in nature with a variable degree of penetrance and is a sex-independent condition. […] Another study revealed a positive family history of hyperhidrosis in 62% of patients, and the trait had skipped a generation, signifying either autosomal dominant transmission with reduced disease penetrance or an autosomal recessive disease with a high disease allele frequency. […] To identify the disease locus, genome-wide DNA polymorphic markers were used, and haplotype detailed analysis revealed primary palmer hyperhidrosis (PPH) loci which are positioned at 14q11.2-q13 to an interval between D14S1070 and D14S990.
#2 Primary focal hyperhidrosis – UpToDate
https://www.uptodate.com/contents/primary-focal-hyperhidrosis
Hyperhidrosis is the secretion of sweat in amounts greater than physiologically needed for thermoregulation. It is most commonly a chronic idiopathic (primary) condition; however, secondary medical conditions or medications should be excluded. Idiopathic hyperhidrosis localized to certain areas of the body is called primary focal hyperhidrosis. Primary focal hyperhidrosis usually affects the axillae, palms, and soles. The condition may also affect other sites, such as the face, scalp, inguinal, and inframammary areas. […] A consensus panel suggested the following diagnostic criteria for primary focal hyperhidrosis: Focal, visible, excessive sweating of at least six months duration without apparent cause.
#2 Hyperhidrosis: Management Options | AAFP
https://www.aafp.org/pubs/afp/issues/2018/0601/p729.html
Hyperhidrosis is excessive sweating that affects patients’ quality of life, resulting in social and work impairment and emotional distress. Primary hyperhidrosis is bilaterally symmetric, focal, excessive sweating of the axillae, palms, soles, or craniofacial region not caused by other underlying conditions. Secondary hyperhidrosis may be focal or generalized, and is caused by an underlying medical condition or medication use. […] The cause of primary hyperhidrosis is not well understood. Eccrine sweat glands distributed throughout the body, but heavily concentrated on the palms, soles, axillae, and face are innervated by postganglionic autonomic nerve fibers and stimulated by the neurotransmitter acetylcholine. It is thought that increased or aberrant sympathetic stimulation of the eccrine sweat glands is responsible for the increased sweating rather than an increased number or size of the glands. […] Persons with primary hyperhidrosis have a higher-than-normal basal level of sweat production and an increased response to normal stimuli, such as emotional or physical stress.
#2 Examining Hyperhidrosis: An Update on New Treatments
https://www.ajmc.com/view/examining-hyperhidrosis–an-update-on-new-treatments
Recent studies indicate that the prevalence of Americans affected by hyperhidrosis is higher than originally determined. […] The exact mechanism causing primary hyperhidrosis is not well understood. It is thought that increased or uncontrollable sympathetic stimulation (via acetylcholine) of the eccrine sweat glands may be responsible for the excessive sweating. […] Furthermore, it is known that individuals with primary hyperhidrosis have a higher-than-normal basal level of sweat production and an increased response to normal stimuli such as stress. […] Botulinum toxin type A (BoNTA) exerts its antisweat properties through the temporary blockade of cholinergic neurons in eccrine sweat glands that release acetylcholine. […] Botulinum toxin type B (BoNTB) also blocks acetylcholine release from cholinergic neurons.
#2 MEDSAFE
https://www.medsafe.govt.nz/profs/PUArticles/December2024/Medicines-that-make-you-sweat-drug-induced-hyperhidrosis.html
Drug-induced hyperhidrosis is the most common cause of secondary hyperhidrosis. […] The thermoregulatory pathway maintains body temperature, and involves the hypothalamus, spinal thermoregulatory centres, sympathetic ganglia and the eccrine-neuroeffector junction. Acetylcholine is an important mediator in the regulation of body temperature and sweating. Medicines that act on these pathways and increase acetylcholine transmission may increase sweating. […] Table 1 provides examples of medicines that can cause hyperhidrosis and the proposed mechanisms. […] Acetylcholinesterase inhibitors Galantamine Rivastigmine Cholinesterase inhibition leading to increased levels of acetylcholine Opioids Codeine Fentanyl Morphine Oxycodone Tramadol Release of histamine and subsequently acetylcholine Selective serotonin reuptake inhibitors Citalopram Escitalopram Fluoxetine Paroxetine Serotonergic effect on hypothalamus or spinal cord Serotonin and noradrenaline reuptake inhibitors Venlafaxine Serotonergic effect on hypothalamus or spinal cord Tricyclic antidepressants Amitriptyline Clomipramine Dosulepin Imipramine Noradrenaline reuptake inhibition and stimulation of peripheral adrenergic receptors. […] Medicines that affect endocrine function Dexamethasone Hydrocortisone Prednisone Levothyroxine Release of various hormones that influence regulatory feedback loops.
#2 Hyperhidrosis Treatment Reading – Causes, Symptoms & Treatments | Derma
https://www.dermareading.co.uk/hyperhidrosis
Some conditions that commonly cause secondary hyperhidrosis are; Infection, Pregnancy or menopause in women, Problems relating to the thyroid gland, Low blood sugar, Diabetes, Some types of cancer, Conditions relating to the nervous system, Heart attack. […] Your appointment will begin with an examination and discussion of your medical history, followed by the dermatologists recommended treatment options. […] Some people with hyperhidrosis may respond to prescription antiperspirants or to other types of topical treatment, whereas others may need to undergo routine injections of botulinum toxin, which prevents the nerves from activating the sweat glands. […] It may also be possible to have Iontophoresis, which involves passing a current through the skin in a way that is painless, to try and stop the sweating.
#2 Hyperhidrosis – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/hyperhidrosis/symptoms-causes/syc-20367152
Hyperhidrosis is caused by faulty nerve signals that trigger eccrine sweat glands to become overactive. […] Primary hyperhidrosis is caused by faulty nerve signals that trigger eccrine sweat glands to become overactive. […] Eccrine sweat glands are involved in hyperhidrosis, though apocrine glands may play a role as well.
#2 Pathophysiology of Excessive Sweating – International Hyperhidrosis Society | Official Site
https://www.sweathelp.org/about-hyperhidrosis/pathophysiology-of-normal-sweating.html
Sweat glands in patients with hyperhidrosis are not histopathologically different from those in normal patients, nor is there an increase in the number or size of glands. The condition is caused by hyperfunction of the sweat glands rather than hypertrophy. […] One of the underlying mechanisms for a lowered threshold and exaggerated response in hyperhidrosis patients may be excessive sympathetic activity. […] This study suggested that increased sympathetic activity through the T2-T3 ganglia causes palmar hyperhidrosis. […] A recent study of recovery of excitability of the sympathetic sudomotor skin response in patients with hyperhidrosis and in normal controls found significant differences. Patients with hyperhidrosis had enhanced recovery of excitability, implying a hyperexcitable somatosympathetic polysynaptic pathway.
#2 Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins
https://www.mdpi.com/2072-6651/5/4/821
BoNTs block the release of acetylcholine and a number of other neurotransmitters from presynaptic vesicles by deactivating SNARE proteins. Four types of BoNTs are approved by FDA for clinical use in the USA: onabotulinumtoxinA (A/Ona, Botox), incobotulinumtoxinA (A/Inco, Xeomin), abobotulinumtoxinA (A/Abo, Dysport) and rimabotulinumtoxinB (B/Rima, Myobloc). These toxins use different presynaptic proteins for their site of action. For instance, for A/Abo the protein is Synaptin 25. For B/Rima it is synaptobrevin, also known as vesicle-associated membrane protein (VAMP). The sweat reducing effect of BoNT-A was first observed in asymptomatic volunteers.
#2 Palmoplantar Hyperhidrosis: A Therapeutic Challenge | AAFP
https://www.aafp.org/pubs/afp/issues/2004/0301/p1117.html
Excessive sweating from the palms and soles, known as palmoplantar hyperhidrosis, affects both children and adults. […] The primary defect in patients with hyperhidrosis may be hypothalamic hypersensitivity to emotional stimuli from the cerebral cortex. […] The underlying mechanism of iontophoresis is not fully understood. According to one hypothesis, iontophoresis may induce hyperkeratosis of the sweat pores and obstruct sweat flow and secretion (although no plugging of the pores has been found). […] Injections of botulinum toxin type A (Botox) are safe and effective, and often improve quality of life in patients with hyperhidrosis. The toxin inhibits the release of acetylcholine at the neuromuscular junction and affects the post-ganglionic sympathetic innervation of the sweat glands. […] Sympathectomy involves the surgical destruction of the second and third thoracic sympathetic ganglia for the palms. The risk of permanent sexual dysfunction limits the usefulness of lumbar sympathectomy for the treatment of plantar hyperhidrosis.
#2 Examining Hyperhidrosis: An Update on New Treatments
https://www.ajmc.com/view/examining-hyperhidrosis–an-update-on-new-treatments
The mechanism of action of aluminum chloride is 2-fold: obstruction of the eccrine sweat glands and destruction of the secretory cells. […] Iontophoresis is the process by which an ionized substance (eg, water) is passed through the skin via direct electrical current. The exact mechanism of action is not known, but theories include the clogging of eccrine sweat glands due to ion deposition, blockade of sympathetic nerve transmission, a decrease in pH due to accumulation of hydrogen ions, and a complex mechanism that involves changes in the reabsorption of ductal sodium.
#3 Hyperhidrosis | Excess Sweating Causes | Night Sweats
https://www.skymd.com/conditions/hyperhidrosis
Hyperhidrosis, spelled phonetically as hi-pur-hi-DROE-sis, is excessive sweating, and affects 1%-3% of the population. […] The mechanism of sweating is controlled by the sympathetic nervous system which manages our bodies’ reactions to stress, fight-or-flight reflexes, and similar emergencies. Our sympathetic nervous system uses the chemical acetylcholine to activate the sweat glands, and people with hyperhidrosis are especially sensitive to this chemical signal, making them produce several times more sweat than normal. […] To understand what causes excessive sweating, we need to talk about the two types of hyperhidrosis: primary and secondary. Primary hyperhidrosis is a result of your body excessively sweating on its own. Secondary hyperhidrosis is a result of medical conditions or medications.
#3 Pathophysiology of Excessive Sweating – International Hyperhidrosis Society | Official Site
https://www.sweathelp.org/about-hyperhidrosis/pathophysiology-of-normal-sweating.html
Sweat glands in patients with hyperhidrosis are not histopathologically different from those in normal patients, nor is there an increase in the number or size of glands. The condition is caused by hyperfunction of the sweat glands rather than hypertrophy. […] One of the underlying mechanisms for a lowered threshold and exaggerated response in hyperhidrosis patients may be excessive sympathetic activity. […] This study suggested that increased sympathetic activity through the T2-T3 ganglia causes palmar hyperhidrosis. […] A recent study of recovery of excitability of the sympathetic sudomotor skin response in patients with hyperhidrosis and in normal controls found significant differences. Patients with hyperhidrosis had enhanced recovery of excitability, implying a hyperexcitable somatosympathetic polysynaptic pathway.
#3 Hyperhidrosis, or excessive perspiration | Ducray
https://www.ducray.com/en/hyperhidrosis-excessive-perspiration
Sweating is a natural physiological phenomenon. It allows our body to not only regulate its temperature but also eliminate waste. Sometimes the mechanism spirals out of control and produces sweat in excess. We call this hyperhidrosis, excessive perspiration or oversweating. […] We use the term hyperhidrosis when more sweat is secreted than required to regulate body temperature. […] When the causes of excessive perspiration are not identified, we call this primary hyperhidrosis. It concerns 90% of cases. It is usually genetic and can begin in childhood or adolescence. Although its causes are not identified, primary hyperhidrosis can become worse under the influence of various factors, including stress. […] We use the term secondary hyperhidrosis when it is induced by a disease or on taking certain medicinal treatments.
#3 Drug-induced hyperhidrosis
https://dermnetnz.org/topics/drug-induced-hyperhidrosis
Hyperhidrosis is excessive sweating due to the overstimulation of the eccrine sweat glands by a neurotransmitter, acetylcholine. […] Drug-induced hyperhidrosis is the most common cause of secondary hyperhidrosis. Drugs can act on the hypothalamus or at spinal thermoregulatory centres, at sympathetic ganglia or at the eccrine-neuroeffector junction. […] It results from the release of acetylcholine by medications that block the action of acetylcholinesterase, an enzyme that breaks down the neurotransmitter. […] Acetylcholine exerts its effect via receptors found on sweat glands. Due to impaired negative feedback to the hypothalamus, acetylcholine causes the body to sweat more than is needed for core temperature to reach homeostasis. […] Drug-induced hyperhidrosis is diagnosed clinically. Other causes of secondary hyperhidrosis should be excluded, such as an underlying infection, malignancy, neurological, or endocrine conditions.