Introduction

Acne vulgaris is most commonly found in adolescents aged 10-14, regressing by the ages of 20-25. Acne develops due to the hypersensitivity of the sebaceous glands, found on the hair follicles, which secrete an oily substance called sebum. Acne affects regions rich in sebaceous glands, such as the face, neck, upper trunk, and back. Acne can start from being non-inflammatory to inflammatory lesions, which form scars once healed.¹

Nodular acne is a severe inflammatory type of acne vulgaris, similar to papular acne, another inflammatory acne. It is caused by the blockage of pores by bacteria, excess oil, and dead skin cells. Blackheads or whitehead comedones can manifest nodular acne when it gets underneath the surface of the skin and becomes red and swollen. They are usually located on the chin or the jawline. 

The association between acne and genetics has been extensively studied due to the release of certain hormones in certain individuals, which make them more susceptible to the occurrence of acne vulgaris.

Pathophysiology of nodular acne

The four primary pathogenic mechanisms involved in the formation of acne and its progression from a non-inflammatory lesion to an inflammatory lesion include:² 

1. Increased sebum production
2. Follicular Hyperkeratinization
3. Cutibacterium acnes
4. Inflammation

Increased sebum production

Androgen is a hormone secreted by the adrenal gland that plays a role in sebum activity in hair follicles. Sebaceous glands can produce their androgens by converting a hormone precursor called dehydroepiandrosterone (DHEA) into testosterone, and the enzyme 5-alpha-reductase converts testosterone into dihydrotestosterone (DHT). Their receptors have an affinity for DHT and testosterone, which stimulates the sebaceous glands’ growth and secretory function, leading to seborrhea, the excess secretion of sebum, and the formation of acne. So, in turn, there’s an increase in levels of free fatty acids, squalene, and squalene oxide, which are all oily substances. 

Follicular hyperkeratosis

Androgens not only regulate the sebaceous gland function, but they also have an important role in the development of hyperkeratosis in the infundibulum, a funnel-shaped cavity or organ. Increased androgens cause an increased expression of tenascin, an extracellular matrix glycoprotein that interacts with cells and alters them to adhere, migrate, and proliferate, which is associated with the development of acne lesions. Additionally, the modified lipid composition can also lead to the process of keratinization. Inflammation that occurs after keratinization can also contribute to keratinization by releasing the pro-inflammatory cytokine IL-1a.

Propionibacterium and cutibacterium acne

The excessive secretion of sebum provides the perfect environment for Cutibacterium and Propionibacterium acne, which play an important role in the worsening of a non-inflammatory acne lesion into an inflammatory acne lesion. C. acne consumes the sebum and hydrolyses the triglycerides into free fatty acids and glycerol. Another bacterium species, P. acne, also contributes to the pathophysiology of inflammatory acne by initiating propionic and acetic acid to metabolise the sebaceous triglycerides into fatty acids, producing a strong inflammatory response and causing follicular damage, rupture, and the release of germs, fatty acids and lipids into the dermis layer.

Inflammation

The free fatty acids produced by P. acnes and C. acnes are toxic to the hair follicle’s wall cells and so cause the release of pro-inflammatory mediators like reactive oxygen species (ROS) and cytokines, which activate an immune response. Pro-inflammatory mediators like IL-1a and EGF cause the disorganisation of keratinocytes in hair follicles, leading to membrane rupture and resulting sebum entering the dermis and causing the development of inflammation. Keratinocytes and sebocytes also have receptors like TLRs, CD14, and CD1d involved in the innate immune response, which releases cytokines to activate the adaptive immune response and further exacerbate the inflammation of the sebaceous gland.

Genetic factors in acne development

A study done in the UK (2002) compared the family history of 220 twins with acne and 1358 twins with no acne and found that 47% of acne twins had a family history of acne. The heritability of acne has been extensively studied, and many studies have concluded that genes do play a role in the occurrence and severity of acne. Particularly, genes that produce proteins play a role in inflammation, cell division, and hormone production. 

Selectin-L (SELL), damage-specific DNA binding protein 2 (DDB2), and tumour protein 63 (TP63)

Li He et al. (2014) performed a genome-wide association study (GWAS) by looking at the genes of 1860 acne and 3660 healthy subjects of the Chinese population in China for single nucleotide polymorphisms (SNPs), a genomic variant at a single nucleotide base of the DNA, which has some association with the disease. They found three SNPs associated with acne, which are SELL, DDB2, and TP63. Selectin encodes the cell surface adhesion molecules, regulating homeostasis and cutaneous inflammation and facilitating leukocyte migration into the secondary lymphoid organs and site of inflammation. DDB2 has been found to induce or inhibit apoptosis upon DNA damage, and TP63 is essential for ectodermal development and for the maintenance of the basal cell population found in the lower epidermis and terminal differentiation of the stratified epithelia, a type of epithelium.

TGFβ-pathway

Another GWAS done in the UK by Navarini et al. (2014) found three more additional SNPs linked to the TGFβ pathway associated with the occurrence of acne, which are OVOL1, FST, and TGFβ2. Studies have found that the TGFβ pathway inhibits keratinocyte hyperproliferation, decreases sebaceous glands’ lipid production, and modulates the innate immune response due to P. acnes colonisation. Navarini and colleagues also discovered that TGFβ2 and OVOL1 levels were significantly decreased in fresh inflammatory acne papules. OVOL1 is expressed in hair follicles and interfollicular epidermis and encodes a transcription factor that downregulates the TGFβ/BMP7-Smad4 signalling pathway, which regulates the growth of keratinocytes. The FST gene produces follistatin, a regulator of the TGFβ pathway, which binds and neutralises TGFβ-binding proteins like activin.

Interleukin 1-alpha (IL-1a) and Interleukin 6 (IL-6)

It’s known that pro-inflammatory cytokines contribute to the initiation of inflammatory acne lesions, and IL-1a is highly expressed in sebaceous glands. Furthermore, the development of comedones can be provoked by increased IL-1a immunoreactivity. In a study (1996), isolated pilosebaceous units treated with the IL-1a protein could express comedonal features like hyperproliferation and abnormal differentiation. Genetic variation in IL-1a can result in an imbalance in cellular homeostasis and could underlie susceptibility to acne vulgaris. Additionally, the study did find that SNP variation in the IL-1a and IL-6 genes is correlated with the severity of inflammatory acne vulgaris.³

The association of acne and environmental and biological factors

Gender

An epidemiological study in Singapore showed that 69% of males suffer more from adolescent acne than 31% of females, but more females suffer from post-adolescent acne. This phenomenon could be due to the menstrual cycle, as a study by Stoll et al. (2001) and another study by Shrestha et al. (2018) showed that hormonal alteration in females with adult acne had a significant association with irregular menstruation.

Diet

There’s a large consensus that a high-glycemic diet is a risk factor for the occurrence and severity of acne. A study looking at high school students and their diet (2009) found a significantly positive association with acne. The mechanism could be because a high glycaemic diet causes a rise in blood glucose levels, and elevated insulin levels lead to increased secretion of insulin-like growth factors (IGF-1), which has been linked to increased androgen levels, promoting sebum secretion. Furthermore, greasy, fatty foods can also contribute to the occurrence of acne in people; they release free fatty acids by triglycerides, which, under the action of P. acnes, could promote the development of acne. However, some say spicy foods are also a risk factor for acne, but research on the association between the two hasn’t been properly established and needs to be further explored.

Temperature and humidity

An Indian study (2019) reported a seasonal variation in the severity level of acne. They found that 82 (47.95%) out of the 171 acne patients had more aggravated acne issues in the summer compared to the rainy and winter seasons. Williams et al. (1973) found that sebum excretion rate varied with local temperature; sebum excretion rate increased by 10% for every 1-degree increase in temperature. Additionally, according to a meta-analysis in China (2017), the prevalence of acne in southern China was higher than in northern China because the southern part was more humid and warmer.⁴ 

Psychological factors and stress

The skin and the nervous system have a close and neat relationship due to the fact that both structures originate from the same primordial embryonic structure, namely the ectoderm, the outermost layer of cells during embryonic development. Psychological factors like stress can induce the release of neuropeptides and hormones, which activate cells to participate in the acne tissues. A study done in North East China (2010), found that psychological stress and depression were the main risk factors for acne among college students. The mechanism of stress on acne is the weakening of the protective function of the hydrolipid mantle, which is made up of sebaceous gland secretions, which leads to a greater susceptibility to inflammation and injury. To replenish lipid deficiencies causes the increased production of sebum and increases the risk of acne lesions. Stress also releases cortisol, which influences the rate of cell metabolism, which affects the function of sebaceous glands and inhibits the synthesis of collagen and other proteins. Furthermore, stress can also affect the circadian rhythm, which overall has a debilitating effect on the immune system and promotes skin susceptibility to infection.

Summary

Nodular acne is a severe inflammatory form of acne that is caused by the release of androgens and excessive production of sebum, which causes the keratinization of the sebaceous gland. This environment provides a good medium for the growth of Propionibacterium and Cutibacterium acne, which in turn activates the immune response and causes inflammation. The factors presented above have some effect on the mechanism of acne formation, like IL-1a and IL-6 regulating inflammation, cytochrome P450 converting and producing hormones that influence sebaceous gland activity, and TP63 maintaining the cell layer of the skin tissue. Moreover, biological and environmental risk factors can exacerbate the occurrence and severity of acne, as listed above.