**4. Modern copy-cats**

Pellagra demonstrates that a disorder that mimicked many neurodegenerative conditions, as now classified, can have a single and simple dietary cause even when there is evidence for (epi-) genetic involvement, dysbiotic microbiomes, mitochondrial and oxidative stress, and proteinopathy (**Figure 1**). This is not surprising as NAD is so central to metabolism in a "NAD" world (**Figure 2**) [20–23]. Dietary nicotinamide backed-up by the degradation of tryptophan on the kynurenine and "immune tolerance" pathway are the precursors to NAD. NAD(H) is critical to mitochondrial energetics as NADH, other dehydrogenase reactions, anabolism (as NADP), and NAD consumer pathways [24]. Stress from chemical or microbial toxins, requiring DNA or tissue repair by poly ADP ribose polymerases (PARPs) and Sirtuins could have the same pathological result by consuming NAD.

Some cancer and age-related antagonistic pleiotropy-type or somatic mutations clearly interact with NAD metabolism and may respond to nicotinamide supplementation or restriction later in life [25–27]. Others such as high energy neurones in the frontal cortex or in dopaminergic neurones may suffer if there

#### **Figure 1.**

*Pellagra's penumbras. Classical pellagra encompassed multi-organ involvement and disturbed symbiotic and social relationships in the context of poverty. NAD deficiency may involve an even wider multifactorial phenotype and involve excess consumption and nicotinamide overload.*

#### **Figure 2.**

*NAD is so central to our metabolism and our relationships with the outside milieu that it is appropriate to call this perspective an "NAD world" with many opportunities for lost homeostasis that could lead to the prevention of at the least many diseases of poverty.*

are "too many mouths to feed" and need supplements [28–30]. Epigenetic developmental origins of health and disease (DOHaD) or somatic mutations may also be helped by a steady satisfactory dose of nicotinamide throughout lives and across generations avoiding various trade-offs such as poor repair or "disposable soma's" to allow high fertility and unite downstream mechanisms: such as reactive oxygen species, mitochondrial failure, DNA methylation and protein misfolding or physiological and immune collapse with the beneficial effects of calorie restriction, ketogenic diets and exercise [31–37]. Pellagra probably used all these mechanisms although this is best documented for mitochondrial, oxidative stress, and amyloidosis.

#### **5. Test and trace**

Pellagra may be being missed even with classical presentations let alone "pellagra sine pellagra" and when hidden in the pellagra penumbra where NAD deficiency may exacerbate other conditions. Alcoholism is a known risk factor and some cases treated rightly for thiamine deficiency with multivitamins may be obscuring cases with a pellagrous element contributing to lack of awareness of the condition. Pellagra may be endemic in the millions in poverty who are meat and milk deprived masquerading as Kwashiorkor ("juvenile pellagra") or "environmental enteropathy" or as poor cognition or general ill-health and susceptibility to adverse effects of infection or trauma. A community screening test that would not be difficult to develop should be a priority and where found family and other contacts should be traced as they will be at risk [38–40].

#### **6. TB known cons but some surprising pros**

Tuberculosis, common diarrhoeal illnesses and very high death rates from acute infections, such as smallpox and measles, decrease markedly as societies modernise and increase their meat and nicotinamide intake. Nicotinamide and its analogues, such as Isoniazid, are TB antibiotics and many bacterial toxins (including TB's), interact with NAD-consumer pathways so being NAD replete would improve host

#### *Poverty and Pellagra's Penumbras DOI: http://dx.doi.org/10.5772/intechopen.100001*

resistance making this less of a mystery [41–47]. Intriguingly this is more complex as TB excretes nicotinic acid (used as a test for pathogenic forms for many years), suggesting that when diet is poor, but not too poor, a low population of TB can act as a helpful symbiont, as may some gut organisms in stark contrast to acute infections [48–53]. High dietary dosage, as much as improved hygiene and less crossinfection, will lead to an "absence of TB", and other "Old Friends". TB and even BCG vaccination have important roles in educating the immune system particularly the T cell population and reducing the over-reaction to otherwise harmless antigens characteristic of auto-immune and allergic disease [54].
