What is the etiopathogenesis of hidradenitis suppurativa in a young adult female with a history of acne and obesity?

Etiopathogenesis of Hidradenitis Suppurativa

Hidradenitis suppurativa is primarily a disease of follicular occlusion, beginning with infundibulofolliculitis and follicular hyperkeratosis, followed by follicular rupture that triggers a robust inflammatory cascade involving both innate and adaptive immunity. 1

Primary Pathogenic Event: Follicular Occlusion

The initiating event in HS is follicular hyperkeratosis and occlusion of the hair follicle infundibulum, not primary apocrine gland pathology as historically believed 1. Histopathological studies demonstrate:

• Follicular hyperplasia and hyperkeratosis with spongiform infundibulofolliculitis as the earliest detectable change 1
• Follicular dilatation and rupture releasing keratin and follicular contents into the dermis 1
• Secondary involvement of apocrine glands occurs after the initial follicular event 2
• Formation of keratin-containing cysts, abscesses, sinus tracts, granulomas, and eventual fibrosis 1

This follicular occlusion mechanism explains why the term "acne inversa" may be more pathogenetically accurate 2.

Genetic Susceptibility

Up to 42% of patients report a family history, with autosomal dominant inheritance patterns observed in some kindreds 1. Key genetic findings include:

• Heterozygous mutations in γ-secretase genes (NCSTN, PSEN1, PSENEN) underlie familial cases 1
• These γ-secretase alterations in animal models directly result in follicular occlusion, linking genetic defects to the primary pathogenic mechanism 1
• Higher β-defensin copy numbers have been associated with HS in small cohorts 1
• Single nucleotide polymorphisms in TNF and IL-12RB1 genes have been identified, though genetic testing has no current clinical role 1

Immune Dysregulation

The disease involves hyperactivation of both innate and adaptive immunity, with the innate system predominating in early disease and adaptive responses amplifying chronic inflammation 3:

Innate Immunity

• Elevated pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-17A 1
• Macrophage activation within visceral adipose tissue contributes to systemic cytokine elevation 1
• Biofilm formation in sinus tracts may perpetuate inflammation, though bacteria appear to be secondary colonizers rather than primary causative agents 1, 4

Adaptive Immunity

• T-cell predominance in the lymphocytic infiltrate of early lesions 2
• High percentage of HLA-DR positive lymphocytes with inverse relationship to Leu-8 positive cells 2
• Sharp decline in T-helper/suppressor ratio after disease initiation 2
• The significant response to anti-TNF agents (particularly adalimumab) supports aberrant immunity as a key pathogenic driver 1

Hormonal Influences

Female predominance (3:1 ratio), post-pubertal onset, premenstrual flares, and pregnancy-related changes strongly implicate hormonal factors, though exact mechanisms remain unclear 1, 5, 6:

• Disease typically manifests between ages 20-30 years, after puberty 5
• Clinical improvement often observed during pregnancy 1
• Exacerbations correlate with menstrual cycles in many women 6
• Three-fold increased risk of polycystic ovarian syndrome (up to 9% prevalence) 1
• Androgen influences are suggested by response to antiandrogen therapies in some patients 1

Extrinsic Contributing Factors

Smoking

Approximately 70-75% of patients with HS are active smokers 1:

• Nicotine induces epidermal hyperplasia and follicular plugging 1
• Association with disease severity, duration, and treatment failure in some studies 1
• Smoking cessation has resulted in complete remission in documented cases 1

Obesity

Prevalence of overweight/obesity exceeds 75% in HS patients 1:

• Obesity increases mechanical friction at flexural sites, potentially damaging follicular outlets 1
• Increases sweat retention in intertriginous areas 1
• Visceral adipose tissue secretes pro-inflammatory cytokines (IL-1β, TNF-α) systemically 1
• Odds ratio of 33 for HS compared to controls 5
• Weight loss >15% has been associated with disease improvement or remission in case series 1

Microbiome Alterations

• Mixed normal flora and skin commensals are cultured from suppurative discharge, with gram-negative organisms abundant in some lesions 1, 4
• Biofilms present in most HS skin samples, especially sinus tracts, though their pathogenic role versus secondary colonization remains unclear 1, 4
• Short courses of antibiotics do not alter flare natural history, suggesting bacterial involvement is secondary 1
• Antibiotic benefits likely derive from anti-inflammatory rather than antimicrobial properties 1

Clinical Context for Young Adult Female with Acne and Obesity

In this specific patient population, the pathogenesis involves convergence of multiple risk factors:

• Follicular occlusion tendency shared with acne vulgaris (part of follicular occlusion tetrad) 1, 5
• Hormonal influences from post-pubertal androgen activity and potential PCOS 1, 6
• Obesity-mediated mechanical stress and pro-inflammatory cytokine elevation 1, 5
• Increased friction in intertriginous areas from body habitus 1
• Potential genetic predisposition requiring family history assessment 1

The combination of these factors creates a perfect storm: follicular occlusion initiates the process, obesity amplifies mechanical and inflammatory contributions, and hormonal fluctuations trigger flares, all occurring in a patient with likely genetic susceptibility to follicular disorders 1, 5, 7.