Histamine, narcolepsy and “idiopathic” hypersomnia

Histamine is critical for maintaining arousal and wakefulness. The sole source of histamine in the brain is a region called the TMN (tuberomammillary nucleus) in the posterior hypothalamus. The hypothalamus is also where orexin comes from in the brain. Like orexin, neurons which make histamine (called histaminergic neurons) have far-reaching projections in the brain. Because of this, again, like orexin, these neurons are implicated in many different physiological states including sleep-wake control, learning, emotional status, and memory formation.

Most of us have experienced the histamine wakefulness-promoting effect when we have taken anti-histamines (Benadryl, etc.). The #1 side effect that most people notice is drowsiness. This is due to the fact that anti-histamines bind and antagonize histamine receptors (H1 receptors). Anti-histamines block histamine signaling in the brain.

In health, histominergic neuron activity is highest during wakefulness, and is becomes nearly undetectable during sleep (REM and NREM).

It has been shown previously that  people with narcolepsy have low CSF histamine. In addition, the lower the corresponding orexin levels, the lower the histamine levels; indicating that proper orexin signaling in the brain is crucial for proper histaminergic signaling. The same trend has been shown for those with idiopathic hypersomnia.

Mouse models have also demonstarted a link between histamine and sleep impairment. Histamine deficient (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, a condition that sounds intriguingingly similar to narcolepsy. Moreover, sex differences in histamine deficiency have been demonstated in mice: female HDC KO mice demonstrated “hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention.”

Currently, it has been hypothesized that histaminergic neuron activity of the TMN may be reduced in individuals with narcolepsy.

Somewhat unexpectedly, researchers have also recently discovered an increase in the number of histaminergic neurons in people with narcolepsy. And, they didn’t find just a modest increase – they found narcoleptics had up to 94% more histaminergic neurons! They also confirmed their human findings using orexin knock-out mice, which displayed a similar increase.  It has now been suggested that this drastic increase in histaminergic neurons may be a compensatory effect of orexin loss.
It was recently demonstrated that, contrary to expectation, individuals with narcolepy may have more histaminergic neurons in the TMN.

It was recently demonstrated that, contrary to expectation, individuals with narcolepy may have more histaminergic neurons in the TMN.

It is important to note that just because there are more histaminergic neurons, does not mean that there is more histamine. This previously mentioned study has been incorrectly represented in mainstream media already. As mentioned before, we already know that narcoleptics have lower CSF histamine.
Histamine has been implicated in neuroinflammation. Experimentally, histamine has been demonstrated to be neuromodulatory/regulatory in multiple sclerosis (“EAE” is the murine experimental version of the human disease MS).  Unlike individuals with narcolpesy, people with active multiple sclerosis have higher levels of CSF histamine, although it is probable that elevated histamine is a feature of neuroinflammation in general.  If narcolepsy is a true neurological autoimmune disease, one would expect elevated CSF histamine. It’s important to note that how CSF histamine changes over time in narcolepsy is not known.
Histamine has also been implicated in neurogenesis. I’ve already discussed this concept to some degree here (although I should point out that was discussing a different region of adult neurogenesis).  This has been demonstrated largely in the subventricular zone (SVZ), which is a known area of adult neurogenesis and has implications for repair following injury. The image below shows the respective regions (SVZ) in relation to the hypothalamus (where orexin neurons are).CaptureWhat does it mean for narcolepsy?  Why would narcoleptics have low histamine and a compensatory increase in the number of histmaine-containing neurons?

Link between Hashimoto’s thyroiditis and lichen planus.

Today I am reviewing an article about my FAVORITE subject! Autoimmune associations!

The article, titled: Possible link between Hashimoto’s thyroiditis and oral lichen planus: a novel association found, was published in May of this year in the journal Clinical Oral Investigations.

Why I like this article:
In addition to narcolepsy, I also struggle with Hashimoto’s thyroiditis and lichen planus. (My lichen planus is predominantly on my ankles, however, and not in my mouth as it is for many people, including those covered in this article). The lichen planus appeared before I was formally diagnosed with Hashimoto’s, however, it is difficult to know when I developed Hashimoto’s, and it isn’t unreasonable to assume that I may have had the Hashimoto’s for quite some time prior to developing lichen planus.
What they found: 
The authors found that more people with oral lichen planus (OLP) had a higher incidence of Hashimoto’s thyroiditis (HT) than those that did not. In fact, 14.3% of people with LP had Hashimoto’s (13% more than the general population, which has a 1% occurrence of HT). They also found that in 93.3% of the cases where Hashimoto’s and LP presented together, the Hashimoto’s thyroiditis came first, suggesting a causal role for circulating anti-thyroid antibody in lichen planus.
Though novel, the finding isn’t altogether surprising.  In fact, lichen planus is associated with many other autoimmune diseases, including Sjrogen’s syndrome and lupus, and is considered a common skin rash among autoimmune patients.
What is interesting about the association between Hashimoto’s and skin disorders such as lichen planus, however, is that keratinocytes (skin cells) have been shown to express receptors for thyroid hormones, thus potentially serving as an extra-thyroid site of organ specific autoimmune attack.  This is speculative, as of yet, but it will be interesting to see if these antigens are upregulated in lichen planus lesions of individuals with Hashimoto’s thyroiditis.

Hashimoto’s disease, lichen planus, and lupus

While many autoimmune diseases are known to be associated with one another (take celiac disease and type I diabetes, for example), few reports exist in the literature documenting what is termed “Multiple Autoimmune Syndrome,” whereby an individual patient manifests three or more autoimmune diseases at the same time.  In fact, it is commonly asserted, though not conclusively shown (in my humble opinion), that multiple autoimmune syndrome is rare. 

I do not believe that this is accurate. In my limited experience, it seems to me that multiple autoimmunity is actually quite common, particularly in individuals with documented food sensitivities, such as celiac disease/gluten intolerance. When gluten, and other food, sensitivities exist, the gut becomes leaky and allows foodstuffs, bacteria, and other pathogens to pass the intestinal barrier, where they can be detected by the immune system.  While everyone likely harbors “self-reactive” immune cells, not everyone mounts an autoreactive immune response, like people with autoimmune disease do.  Pathogen (food, bacteria, or otherwise) encounter by the immune system in the gut delivers inflammatory signals, that may then lead to the activation and response of autoreactive immune cells.  In fact, current data suggests that all autoimmune diseases may begin in the gut.

Because of the supposed rarity of multiple autoimmune syndrome, my favorite articles are case studies of individuals with multiple autoimmunity. In the case reported here, a 24-year-old female presents with lichen planus (a suspected autoimmune disease), lupus (a known autoimmune disease), and hashimoto’s thyroiditis (also called autoimmune hypothyroidism), and to date, it is the first association of it’s kind.