2.2.1 Acne vulgaris

The double strands of DNA that carry the genes we inherit from our parents determine whether or not we are likely to suffer from acne, which kind, and probably how bad it can be. If you have acne, the genes had to come from somebody, and even if you figure out who gave you the acne genes, it is too late to change your parents now. You must do the best you can with the genes you were dealt. It is just like playing poker.

On the other hand, if you do not have acne, that does not mean you do not have the genes. The problem is that some genes are fully expressed in all the people who have them (like brown eyes), while other genes (like for freckles) only show up (are “fully expressed”) if the conditions are right. For freckles, you need to add sun exposure.

For acne, you need to add hormones. And if you add the hormones without having the genes for acne, you will not get acne. Lucky you! So let’s get a little deeper into this.

If neither of your two parents had acne, it does not mean that they are not your parents. The rules of heredity are complicated, and if your mother had just enough acne genes to give you a “half dose,” then she could easily have had no acne as a teen. The same may be true with your father, but with two half doses, one from each parent, you could get a single full dose of the genes required to give you acne. You just got unlucky. To use an analogy that you will see again, you were born with a loaded gun. You will need to avoid anything that wants to pull the trigger. A recent study from Italy rates the risk of acne, if one has affected first-degree relatives, at 3.41. So if you have one parent or sibling with acne, the risk of getting acne is almost 3 1/2 times that of the rest of the population who is your age but does not have affected relatives [2].

Just about every patient I see with acne vulgaris has a positive family history. Acne is not always present in other family members, but when the family history is positive, it is both variable and complex. For instance, I am aware of a family with two daughters. One of them has never been troubled by acne. The other one had acne that was so bad at age 11 that she required a course of isotretinoin. The father and his side of the family have almost no acne, and the mother also had very little. The girls’ maternal uncle, on the other hand, suffered terribly with acne on his face and back as a teenager, and still has problems as a senior. Although their mother was not affected, she seems to have carried the gene, whatever it (or they) might be, through to the younger daughter.

There are some very good studies on genetics and acne, the best being those that studied twins. It’s not a surprise to me that there is a relationship, but it is worth noting that the expression of some genes rests upon environmental exposures long after the genes are provided by the parents. New babies are born with unfreckled skin but, under the influence of sunlight, one will develop freckles later, and another will not. There are related markers, such as red hair, that can predict which one will likely develop freckles, but there’s no guarantee. There are redheads who have flawless “peaches and cream” complexions that never freckle. This is a very rough illustration of the direct influence of our environment on the actual expression of our genes. It is simple and straightforward activation of the genes that were set at the time of conception.

There is another, more complicated influence that needs consideration, a more subtle process that is hidden in the background, and about which we are only now learning. This is the problem of our genes’ exposure to various chemical and other influences after conception, during gestation (pregnancy), during early life, and during the process of sexual development and maturity. This field of study is called epigenetics. More about that in Section 2.3.

Meanwhile, for clarification, the “instruction set” that you are born with, located in the DNA within your genes, is called your genotype. What those instructions actually turn out as a product (what you actually look like) is called the phenotype (from the Greek word pheno meaning “to show, to appear, or to display”).

A genotypic freckled redhead (someone who has the genes to make red hair and freckles) who is never exposed to the sun will never be troubled with freckles. His or her genotype will not be expressed as a freckled phenotype unless there is a certain environmental exposure, in this case sunlight, but the red hair will be there whether there is sunlight or not.

I raise this point because some people simply do not seem capable of getting acne. While this makes life a lot easier for them than their pimply brothers and sisters, it does make life difficult for researchers experimenting on the cause of acne. Some study subjects are simply incapable of developing acne. Including such individuals in a study designed to trigger acne would give inaccurate results, because the results of the studies would always be negative in such persons. Only persons who can get acne should be included in dietary studies on acne, for instance.

Lucky people with flawless complexions just won’t get acne. This is a small percentage of our Western population, but other populations may be different. Over a decade ago, Loren Cordain described two tribes on different sides of the world that did not have acne, both tribes in their aboriginal habitat. One group inhabits the island of Kitava, one of the Trobriand Islands in Papua New Guinea’s archipelago. The other, the Aché, live in the jungles of Paraguay. Both groups are hunter-gatherers with predominantly vegetarian diets. The Trobriander people have been thoroughly studied by social anthropologists and human ethnologists, but medical reports have been few. As isolated groups, the tribes’ genetics were stable and the environmental influences from person to person within the tribe were likewise pretty much the same, particularly their diet.

Lindeberg et al. reported, “The residents of Kitava lived exclusively on root vegetables (yam, sweet potato, taro, tapioca), fruit (banana, papaya, pineapple, mango, guava, water melon, pumpkin), vegetables, fish and coconuts. Less than 0.2% of the caloric intake came from Western food, such as edible fats, dairy products, sugar, cereals, and alcohol” [3]. In eastern Paraguay, the Aché tribal diet contains wild, foraged foods; locally cultivated foods; and 8% Western foods (mainly pasta, flour, sugar, yerba tea, and bread). Cordain’s study reported that members of these tribes had no problems with acne whatsoever [4].

The diets, very low in processed food and generally presenting a low glycemic load [5], were given credit for this lack of acne. At the time, the paper was criticized for attributing the lack of acne to the diet because it was thought that these populations might have been genetically incapable of developing acne. It was even suggested that these populations be subjected to a Western diet to see whether or not they would develop acne [6], a reasonable scientific approach in an ethics-free world. Following up this question in discussion with Prof. Cordain, I learned that some of these individuals, when exposed to a so-called Western diet, do indeed develop acne, which certainly suggests that some of them really do harbor the acne genotype. That certainly has been the pattern in other previously isolated groups. Further testing with dietary challenges would be needed to determine the frequency of the gene(s) for acne in that population, work that would challenge ethnologic ethics.

There are other populations that had essentially no acne before the advent of the Western diet. Acne is now endemic among the previously clear-skinned Inuit in the Canadian Arctic [7]. The Japanese and others have been the subjects of several papers [8]. It seems, therefore, that the genetic tendency toward acne is present in most human populations, probably all of them.

The likelihood is that the genetic background is expressed only when the FPSUs are challenged by a specific stimulus, and it is generally accepted that a change in the hormonal environment has that effect. This theme and its mechanism will be fully developed elsewhere. (See Section 2.8.)

It is not only aboriginal populations that develop acne when genes and diets meet. The multicenter study in Italy quoted above [2] has shown acne positively correlated not only with family history, but also with dairy intake and mild obesity. In the population studied, three factors stood out. In addition to an increased risk of 3.41 times triggered by a family history of acne in parents or siblings, being overweight increased the risk of acne by 1.3 to 3.3 times. Third, milk consumption (three 250 mL glasses or more per week) increased risk in the entire population by 1.78 times for any kind of milk and 2.20 times for skim milk [2]. There was no significant correlation to menses and a negative correlation to one serving of fish per week.

It is important to consider that these dietary risks apply to the entire population studied. That includes, at one end of the curve, the subjects who may have no genetic risk of acne at all. They bring down the risk artificially because they have no innate risk of developing acne no matter what diet they consume. At the other end of the curve are those whose acne will be triggered by only small amounts of milk. Remember these results when you get to Section 2.8.

2.2.2 Acne rosacea

The discussion above relates mainly to acne vulgaris, the acne that is common among 85–90% of North American teenagers. With regard to acne rosacea, many of my rosacea patients report that their parents, in their middle and later years, also had acne rosacea. There is little doubt in my mind that this is also genetically influenced, but early work done on this facet of this disease is only beginning to surface.

It is said that “genes rule.” While there is little doubt that they load the gun, there are many different influences that can pull the trigger. One study suggests that of the numerous inflammatory mediators that are active in acne, some are heritable as single genes that often control enzymes, neuroendocrine transmitters, and cytokines found in the pathways that lead to acne rosacea’s signs and symptoms [9]. A specific genetically determined defect in the skin’s ability to handle reactive oxygen species (small, chemically active substances that cause damage) has been correlated with rosacea [10]. On the other hand, in a study of twins, only one of a pair of homozygous (identical) twins developed acne rosacea, suggesting that a nonheritable variable made the difference and was the trigger [11].

It would certainly be no surprise to learn that, ultimately, heredity and environment interact. Just like the freckles and the sun we started with.

2.2.3 Acne inversa/hidradenitis suppurativa (AI/HS)

That this disorder is hereditary to some degree is accepted. A positive family history occurs in 35–40% via autosomal dominant inheritance. That means that each child has a 50:50 chance of inheriting the disorder, and that if you had 100 children then 50 of them would likely inherit the gene (provided only one parent is a carrier). But Mother Nature can be a devious parent at times and it is possible to have four to six involved (or uninvolved) children in a row. Explanations other than random selection and luck are lacking. The family history in AI is often less well defined than in acne vulgaris because family members do not always report the existence of their disease. It is somewhat hidden from view, it is often undiagnosed, and its existence is often denied. Indeed, without the trigger, the genotype would not show up as the phenotype. Nevertheless, I have treated many mother–daughter (and even one granddaughter) groups with this disorder, and a few father–daughter families have shown up over the years. Interestingly, the father–daughter pairs shared a very disfiguring and scarring nodular form of facial acne as well as the acne inversa. And last year a mother showed up with her four-and-a-half-year-old son, who has a history of small “boils” on his buttocks. The mother has mild AI/HS herself. So did her father. And his father. Four generations.

Details of the molecular genetics are emerging. For example, two novel mutations of the nicastrin gene have been associated with the disorder in two Chinese families [12], but it will be a while before we know exactly how they are related to expression of the disorder. Meanwhile it appears that this same problem is not common among AI patients. How the pieces of this giant puzzle fit together remains a mystery.

2.2.4 The scottish twins

I met Meghan when she was 28. She had had acne since she was 12, and was getting more than a little tired of it. Although there was some variation with her periods, the problem persisted and was active pretty much all the time. She was not sexually active, had never been on any hormonal contraceptives, and was generally content with her life, with minimal stress.

She presented during the early years of my practice when I was collecting dietary data. Meghan had moderately severe nodular acne involving both cheeks, particularly the jawline and under the chin. She had tried numerous treatments; had been on antibiotics, particularly tetracycline, for years; and was pretty fed up. During the “family history,” she told me that she was an identical twin, and her sister had never had so much as a single “spot” for as long as she had known her. When I got to asking her about her dietary intake, and in particular her dairy intake, her face lit up. Her eyes widened, and she said to me, “Oh, my goodness, it must be the cream in the milk.”

She told me that when she grew up in Scotland, the milk arrived on the doorstep in bottles, and was not homogenized. That meant that the cream had separated, was sitting on top of the milk, and would pour off first when the lid was removed from the milk bottle. She told me that she always wanted to be the first to bring in the milk bottles in the morning, because she loved to use the cream from the top of the bottle. Her sister, quite to the contrary, would drink milk only when forced, and only from the bottom of the bottle.

Meagan agreed to continue with her standard therapy, which at that time consisted of oral tetracycline and topical retinoic acid cream, but to discontinue all dairy products. She started to clear within 2 months, at the end of 6 months she was able to discontinue the tetracycline, but it took a full year before I could convince her to let go of the retinoic acid. I did not ask her to return to her dairy, and I never saw her again as a patient.

She was one of my first successes in dietary management involving twins. Fortunately, it was not necessary to “double blind” the study, because her identical twin sister had already served as a control. Asking a pair of twins to decide which one of them should go off dairy and which should stay on dairy presents problems not only in interpersonal relationships but also in ethics. This is especially true in private practice, where patients present themselves for the best care possible, and are not expecting to be “guinea pigs.”

• Lesson learned: Twin studies are valuable even with just one set of twins!

2.3.1 The farmer’s boys

My father was a dermatologist, and I joined his practice when I completed my training. He had been caring for a patient from upstate New York, a farmer’s son, with terrible acne. At that time, there was a “digestant” on the market in Canada that contained bromide salts and there is a disorder called bromoderma that looks like acne. My father had seen a couple of cases, and he wondered whether there might be a link between bromides and this teenage boy’s acne. As it happened, there had been some contamination of the well on the farmer’s property, and methyl bromide was at fault. It had been used in the agricultural process of soil fumigation and had gotten into the well. Suspecting that this was the cause of the acne, and being unable to obtain blood levels of bromine at that time, my father attempted to “wash out” the bromide by the pragmatic prescription of sodium chloride tablets to tolerance. Achieving no significant results after a month of this, he asked me for some assistance with the case.

I had just begun working with milk and other dairy products as a possible cause of acne, and I went through this young man’s dietary history for a few minutes. It turns out that the farm was a dairy farm, and the lad consumed roughly two quarts of unpasteurized whole milk daily. He was 17 at the time, and was accompanied to the visit by his 15-year-old brother as well as their parents. The younger brother was likewise involved with acne, over his face, neck, shoulders, and trunk. He was also a very aggressive consumer of his cows’ product. At that time, isotretinoin was just becoming available but these young lads were from over the border in New York State, and so I could not prescribe it for them. Instead, I simply asked them to discontinue their entire intake of dairy products, continue on the tetracycline that was the standard at that time, reduce it if possible, and check back in a few months. Winter intervened, but they did show up the following spring, and their active lesions were essentially clear.

A couple of years later, I got a telephone call from the boys’ mother. Their 11-year-old brother was now 13, and he was starting to develop acne. What should she do? Could she bring him over to see me? I was surprised to learn that, despite the fairly solid relationship between dairy withdrawal and her older sons’ clearance, the youngest son was still drinking lots of raw farm milk. I suggested that this be discontinued, she agreed, and that was the end of the story. Some years later, the mother saw me for an unrelated problem and confirmed that once the youngest brother stopped the dairy, they never needed my services.

• Lesson learned: Even the apparently obvious lessons need reinforcement.

2.5.1 Onwards and downwards

The follicular part of the FPSU is classically called the infundibulum, and there is no reason to change that. It is basically a tube made up of layers of concentric maturing cells. If you cut it in cross-section, it looks like the layers of an onion or the rings of growth in a tree. The actively growing cells start in the outside basal cell layer and move inwards. With time and as a result of metabolic changes, they turn into thin flattened ductal keratinocytes. These are pretty much the same as normal skin cells on the surface of the skin, the thin, flat, layered little fellows called epidermal keratinocytes. Their last living function is to separate from each other, a process called terminal differentiation. Once these cells are fully differentiated, which is a complex metabolic process, the links between them are dissolved by a protease and they separate from each other and are then free to move in the duct. Together with the hair and the sebum, they flow up the central hollow channel to the surface.

This hollow cellular tube is wrapped in a closely fitted layer of supporting tissues. The first layer just outside the basal cells is actually the extension of the basement membrane. That is the thin layer of tissue between the epidermis and the dermis of our surface skin. Beneath the epidermis, its job is to anchor the bottoms of the basal cells of the epidermis above to the dermis below (Figure 2.3). It then extends down from the epidermis and wraps around the various components of the “pilosebaceous unit,” now the FPSU. The horizontal surface basement membrane turns and extends downwards to become the vertical glassy or vitreous layer that wraps around the follicle and the rest of the FPSU. It is continuous because both are produced under the influence of the keratinocyte basal cells above them (Figure 2.4). This glassy or vitreous layer, although it is generally equivalent to the basement membrane, is thicker where it wraps around the pilar unit, lending support. It has a somewhat glassy appearance, hence its name. It is visible on light microscopy with the usual stains but is best demonstrated by using a special technique, the periodic acid–Schiff (PAS) stain. This makes certain substances show up a bright pink (PAS-positive) under the microscope. It makes them easy to see and allows us to estimate or measure the thickness of the basement membrane and its relatives.

The glassy or vitreous basement membrane layer merges into the fibrous root sheath. It is also PAS + and is composed of thick collagen bundles. This sheath wraps around and contains the follicular portion of the FPSU like a vinyl glove, and extends down to wrap around the pilar and the sebaceous parts as well.

This layer performs two very important jobs. First, the tightness of the wrap provides very significant support to the otherwise weak tubular cellular structures. This wrap limits their expansion and under normal conditions prevents them from overexpanding or simply bursting. The thickness of the wrap is particularly obvious in the eccrine sweat glands and their ducts—they are only one cell thick and would easily burst without this support (Figure 2.5). They have very prominent PAS + basement membranes. The same is true of the apocrine sweat glands and their ducts (Figure 2.6).

Second, the membrane provides a semipermeable barrier that provides physical separation between the body’s “inside” and its “outside.” Remember that the basement membrane under the epidermis separates the epidermis, which is considered “non-self,” from the underlying dermis, which is considered “self.” Material that is enclosed within the glassy membrane is a downward extension of the “non-self” epidermis (Figure 2.7). If you can think of the relationship between these two compartments as “self-inside” and “non-self-outside,” it gives you some idea why there is such an inflammatory reaction when the duct bursts, releasing “non-self” materials under the skin into the “self” dermis. If you ever had an ingrown hair, you can now understand why the body reacts to this foreign material. This material, your own hair, is considered by the part of your body beneath the epidermis to be something that was not supposed to ever be in the dermis. It was supposed to be out on the surface of the skin, well beyond the basement membrane and its extensions. This is important in understanding why the immune systems (both innate and adaptive) do what they do. More on that later.

2.5.2 What is going on inside the FPSU?

The three parts of the FSPU are all designed to grow. Each produces its special product, ductal lining cells, hair, or sebum. The growth and replacement of new ductal lining cells, as well as the production of hair and sebum, are turned on by hormones.

Androgens (the male hormones) turn on beard hairs (in both sexes). They also turn on oil glands. And they turn on the ductal lining cells, the keratinocytes that line the central canal of the follicular part of the FPSU. Adding more stimulus (androgens and other hormones) to the system, and then adding more time for the reaction to occur, leads to an increase in production of these ductal lining cells. That increase in production results in effects well beyond what was supposed to happen in nature. That is why excess androgen effects produce moustaches and facial hair in women with certain hormonal disorders. And that is why excess androgen effects cause the acnes.

Normal levels of androgen working on the follicular part of the FPSU yield a well-regulated production, growth, and elimination of the keratinocytes lining the duct. A finely tuned process called terminal differentiation [17] regulates the speed at which new cells, once produced, fulfill their destiny as detached keratinocytes and are lost up the follicular duct.

We know that some human populations that are not exposed to the acnegens in our Western diet do not have acne. That is the baseline I choose to use in providing a rational explanation of acne’s development. When androgens and other hormonal acnegens are at normal levels, uninfluenced by unnatural hormone sources, no acne is produced. When the level of acnegenic activity exceeds the threshold of our individual tolerance, increased amounts of hair or sebum or ductal lining keratinocytes are produced.

Increased hair may be a social problem, but hair doesn’t generally get stuck in the pores or become ingrown as a result of increased androgens. The reason is simple—pressure from below, from growth in the hair bulb, pushes the hair shaft to the surface. Likewise, increased sebum production may have sent an earlier generation of women to mirrors to powder their noses, but sebum does not get stuck in the pores. Sebum is a slippery oily liquid at body temperature, and it simply percolates up the follicular canal of the FPSU and onto the surface of the skin. Even when the follicular canal is so choked with keratinous material that a very “tightly inspissated” comedo results, sebum finds its way to the surface [18]. Never in years of “acne surgery” have I ever come across a pool of free sebum “trapped under the skin.” “Trapped sebum” as a cause of acne is a misconception that has inappropriately blamed sebum as a cause of acne for well over 50 years. Sebum is a bystander in the process of acnegenesis. An innocent bystander as far as comedo formation is concerned, sebum is not innocent of all blame. It feeds the commensal organisms and likely acts like hydraulic fluid in transmitting intraductal pressure—more on that later.

To be clear, there is a disease in which sebum is trapped under the skin. It is rare, usually runs in families, and has the wonderful name of steatocystoma multiplex. But it is not acne, it is not caused by hormones, and it does not respond to the medications that are effective in treating the acnes, not any one of them, not even isotretinoin.

So it is not hair from the pilar area that is plugging the follicular canal—indeed, the hair normally prevents such plugging. And it is not oil from the sebaceous gland plugging up the canal—it is a liquid and doesn’t plug anything. That leaves only one other source of trouble. No matter which acne we are discussing, the source of the problem is the little lining cells that are supposed to simply flake off into the canal and disappear up to the surface.

When the ductal keratinocytes don’t flake off, they plug the duct, and they cause acne, whether acne vulgaris, acne rosacea, or acne inversa.

So why has this simple and easily observed physical feature not been more widely understood? And why has it not been recognized as the real cause of acne? I think we can blame the “scientific method” in this case. Very early in their investigative lives, scientists learn that they must measure what they wish to study. Thus, for almost 50 years, acne investigators have been measuring what they could measure. They could measure sebum production on the surface, or they could count lesions. There are hundreds of papers written about the skin surface lipids and the amount of oil produced by the FPSU. And there are hundreds of acne papers in which comedones have been counted. Nobody has measured the weight or volume of the keratinous material caught in the lumen of the FPSU. There were some visually impressive studies done with cyanoacrylate adhesives that demonstrated the plugs to a certain degree, but no assay was ever developed to quantify the weight or volume of the comedo or the microcomedo. Anyone who has ever performed acne surgery or comedo extraction knows the challenge of extracting material of a certain diameter through an orifice with a much smaller diameter. With no ability to accurately and reproducibly measure the keratinous content of the duct, there was no technique to measure the effect of various therapies on the quantity of material trapped in the follicular canal. To do so would have required numerous small biopsies of the pilosebaceous units before, during, and after therapies.

To measure sebum output, a simpler chore, cigarette paper is applied to the study site, held in place for a defined time period, and then removed and weighed to measure absolute weight and so calculate the rate of sebum production. It is sufficiently difficult to recruit study subjects just to wrap cigarette paper onto their greasy foreheads; doing serial biopsies would be a monumental undertaking. It is no wonder that this area has remained uninvestigated, and so it is no wonder that we have remained in the dark. That means that our only option until now has been to observe, postulate, consider, suggest, review, and reconsider the possible mechanisms involved in the development of these tiny early lesions. But perhaps now, with the availability of confocal microscopy, automated serial cross-sectional photography, accurate marker-driven pore location, and almost instantaneous computerized calculation, a system could be designed to quantify comedonal volume. Four matched cohorts of patients previously cleared with isotretinoin could be provided with a zero-dairy, low-glycemic-load diet as a control and three experimental diets: one would be a full-dairy, low-glycemic-load diet; a second would be a zero-dairy, high-glycemic-load diet; and the third, a full-dairy, low-glycemic-load diet. I offer that suggested protocol to better financed and more technologically capable colleagues than I. But I offer one caveat—an attempt to recruit volunteers into such a study, one that involved introducing dairy to a blinded population of patients cleared with Roaccutane attracted only two recruits in 14 months.

So, while we wait for the technical capacity and backing to quantify what we already know, let’s look a little deeper into the pore.

Remember the tight PAS + wrapping around the whole FPSU? It fits like a thin, tight, and tough vinyl glove on your hand and fingers. It holds the whole unit firmly together. As the FPSU produces its various products (hair and sebum and ductal keratinocytes), it expands a bit, resistance is created, and just enough pressure is generated to force the contents of the canal, both sebum and keratinocytes, along the path of least resistance toward the surface. If it were not for the glassy membrane and the fibrous root sheath, the whole FPSU would simply expand like the comedones in Favre–Racouchot syndrome. Remember that hair doesn’t need any constrictive pressure to head to the surface; it is growing out on its own, pushed from below by the power of cellular reproduction in the hair papilla and the walls of the pilar unit. The same power of cellular reproduction operates within the follicular unit, but the push is centripetal (toward the center). When the center of the tubular structure is filled up and more cells are added, the intraductal pressure must rise, the intraductal keratinocytes become compressed and folded, the duct expands to the circumferential limit imposed by the glassy membrane and root sheath, and there is “pushback” against the constraints of the follicular walls [19]. The pressures are so great that the keratinocytes can be folded back on themselves, as illustrated (Figure 2.8) years ago using electron microscopy [20]. This is the source of the pressure that eventually weakens, splits, and ruptures those walls.

That brings us to the very basic question—what leads to the “tipping point” where the ductal keratinocytes stop flaking off and start to form the tiny structure that Plewig called the “follicular filament” [18]? This filament (Figure 1.1a) is the earliest sign of the microscopic keratinocytic plug, just before the formation of the microcomedo. It grows to form the keratinous plug that accumulates within the follicular canal. What starts the life of the plug that slowly grows and expands within the canal until it becomes a force to be reckoned with, a force that can burst that vinyl glove, releasing all that “outside the body” non-self-material into the “inside the body” environment where it causes such trouble? Before we get into the mechanism behind all that, we need to take a further look at the anatomy of the follicular portion of the FPSU as it occurs in acne.

So let’s step back a short distance for another look at what we know so far. We have a closed system that has a limit to how much it can expand. We have contents that normally are produced at a steady rate and that can exit the system at the same steady rate, so that there is no real strain on the container’s walls. So what can go wrong to challenge the container’s walls and lead to their rupture? The first problem worth considering is the increase in output of “product.” We know the hair is not part of the problem. Terminal hair is basically a “constant,” passing through the canal, always the same diameter, never getting stuck. Even the tiny vellus hairs, supple and soft as they are, normally reach the surface with little or no difficulty. And we know that sebum simply flows out of the follicular canal onto the skin, producing the oily skin we all know is part of acne vulgaris and acne rosacea. Oily skin is not such a constant feature in AI/HS, but there is a reason for that—more later. So that leaves us with the plug in the follicular canal, the distinguishing feature of all the acnes, even when it is invisible.

That leads logically to the next subject, physiology, which gives us an idea of the mechanisms driving the increased amount of material in the follicular canal.

2.6.1 Hair first

Of the three functional units of the FPSU, the pilar unit has the least to do with acne. The area of the body most thickly covered with hair, the scalp, develops true comedones only exceptionally rarely. Each hair is produced on a cyclic schedule, growing under the combined influence of (female) estrogens and (male) androgens. The timing is still a bit of a mystery.

The hair starts in the papilla (hair bulb), the deepest part of the pilar unit. It picks up whatever color its owner’s DNA is coded for, from special cells in the papilla and bulb, and then it heads north. Forced upwards from below by new hair cells being continually produced, it is pushed from the pilar unit through the follicular unit on the way to the surface. It starts out in the pilar unit wrapped in two layers called the inner and outer root sheathes, but it separates from them at the top of the pilar unit. At that point, the now-independent hair shaft acquires a thin and ever-renewing coat of protective and lubricating sebum as sebocytes dissolve around it before the hair heads to the outside world.

2.6.2 Oil second

The sebum that layers onto the hair is produced by the sebaceous glands (Figure 2.9) that are attached to the lower end of the follicular unit at the sebofollicular junction. These glands are narrow-necked structures that look like sacks full of dozens of boring, mostly round, but tightly packed thin-walled cells that are almost all fat-laden cytoplasm with only a tiny nucleus. These sebocytes start life as basal cells inside a protective sack of the same basement membrane material that is wrapped around the other two parts of the FPSU.

The basal cells are stimulated into action mainly by androgens, the male hormones, but other hormones and growth factors are all part of the push to grow. When conditions are right (and nobody really knows for sure what the trigger is), a basal cell will divide into two daughter cells. One will stay behind as a basal cell, and the other (now a sebocyte) will be pushed into the body of the gland. There, the sebocytes grow, fill with various lipids (fats, waxes, and oils), and are gradually pushed up to the neck of the gland, near the hair and the follicle. They head toward the ductus seboglandularis (sebaceous gland duct). The sebaceous cells are actually pushed toward the exit like people leaving a theatre, jostling for the next free space, but each maintains its walls intact until it actually reaches the “door.” As soon as it gets through the sebaceous duct, up against the hair, the sebocyte’s wall dissolves, and the oil is released onto the hair in the follicular unit. Even on a microscopic level, there is no “pool” of sebum in the sebaceous duct or anywhere under the skin. The sebocyte remains intact until it actually reaches the hair it is meant to lubricate (Figure 2.10).

Much of the best research in acne has been directed at figuring out what hormone and enzyme systems provide the push to the basal cells to make them produce either many or few daughter cells (sebocytes), and so regulate the oiliness on the skin surface. This complex subject is coming up in the next couple of sections.

2.6.3 Last but definitely not least: the follicle

The same hormones that push the hair up from the pilar unit and push the sebocytes up to the junction of the follicular unit, where they can burst and lubricate the hair shaft, also have serious work to do in the follicular unit. In fact, they are the cause, and this is the location, of the first sign of trouble in all the acnes. As the hormones turn on the basal cells that lie just inside the glassy membrane of the follicular unit, daughter cells are again produced, but this time they turn into keratinocytes instead of sebocytes. And instead of heading randomly to the exit, they normally follow a very strict and formal path toward the center of the follicular duct.

When all is going according to plan, each keratinocyte gradually matures from a cuboidal cell to a gradually flattened cell and eventually becomes pancake-shaped as the center of the duct is approached. Internal chemical processes gradually use up the energy provided by the fats and complex sugars. This energy fuels the formation of special proteins that make keratin for the keratinocyte and also forms the protein and complex lipid and sugar junctions between the cells, all needed to complete the maturation and terminal differentiation of the keratinocytes. Residual energy sources then produce proteases that dissolve the junctions between the fully differentiated keratinocytes until they are fully separated into squames. These are the residual flat flakes of keratin that normally separate from each other, flake off into the central duct, and mix with the sebum. Suitably lubricated, they slide up to the surface in the space between the follicular wall and the hair shaft, if there is one.

That is how it is supposed to work, and that is how it does work until too much stimulus is added to the system.

2.6.4 Looking deeperspan>

The chemical processes that run in the background, making the physiology work, run through highly complex biochemical reactions that produce equally complex and varied products. Each of the basal keratinocytes and basal hair root cells and basal sebocytes uses its own specialized set of enzymatic reactions, chosen from the huge set of possible reactions the cellular genome can produce on demand.

Just think for a moment—back to the embryology section (Section 2.4). Those few fetal cells that made the buds that formed on the underside of the fetal skin can go on to produce a full beard, or a greasy scalp, or a face and back full of inflammatory acne, or a perineum full of draining acne inversa lesions, or Farrah Fawcett’s glorious mane of hair. DNA and hormones are a potent combination.