An ordinary day in the medicine OPD. A woman in her mid-40s enters the doctor's cabin, her walk slow and tired and her skin unusually dark in certain places. As soon as she sat down in front of you, the history-taking began. She complained of persistent diarrhea for the past few months, the weakness that seemed to worsen by the day, and a strange rash on her neck and arms. On closer inspection the rash revealed itself, wrapped around the woman's neck, with dark symmetrical patches and a leathery texture.
Clue 1: The Necklace
Cassal's Necklace - a characteristic finding of a vitamin deficiency that's rare these days yet extremely dangerous. But you’re not ready to make any conclusions yet. You need more clues.
Clue 2: Gastrointestinal distress
Her diarrhea, as she describes it, is relentless. Watery, occurring multiple times a day, without any obvious triggers. No recent history of infections, no suspicious food intake. At this point, your mind is wandering. Could this be a malabsorption syndrome? Celiac disease? Inflammatory bowel disease? No definite diagnosis comes to mind yet.
Clue 3: Dietary Habits
You shift your line of questioning and ask about her diet. She says, “Mostly maize-based,” and your ears perk up. “We’ve had a bad harvest recently, and it’s all we’ve been able to afford.
There it is—the vital clue that ties everything together.
The Puzzle Fits: A Diagnosis Emerges
A maize-heavy diet, without adequate supplementation, is a known risk factor for niacin (vitamin B3) deficiency. Corn, unless treated with lime (a process called nixtamalization), contains niacin in a bound form that the body cannot easily absorb. People on a strict maize-based diet thus develop a deficiency of this important vitamin and if this deficiency is severe enough, it leads to pellagra, a disease marked by the "three Ds": diarrhea, dermatitis, and dementia as seen in the case above. Congratulations Dr. Sherlock Holmes, you've solved yet another one of your cases.
Niacin or Vitamin B3, is a nutrient found in food components like meat, fish, grains, and vegetables. It is synthesized endogenously from the essential amino acid tryptophan primarily in the liver [1]. Approximately 60 mg of dietary tryptophan is needed to produce 1 mg of niacin with the help of other vitamins namely Vitamin B2 and B6. The primary biological function of Niacin indirectly contributing to other essential roles in our body is the generation of nicotinamide adenine dinucleotide (NAD+) through a series of metabolic pathways out of which the salvage pathway stands out as the main contributor [2]. NAD+ is reduced to form NADH, which is then utilized in the electron transport chain (ETC) situated at the inner mitochondrial membrane for the generation of ATP via 4 enzyme complexes and the enzyme ATP Synthase [3].
NAD+ also acts as a substrate for other important enzymes including Sirtuins and poly (ADP-ribose) polymerases (PARPs). Sirtuins are famously referred to as the family of anti-aging proteins involved in processes such as free radical mediated damage inhibition, metabolism at the cellular level and inflammation [4]. PARPs on the other hand is the first responder molecule needed for DNA repair signaling [5]. Studies also highlight the decreased retinal levels of NAD+ observed with age and its association with retinal pathologies such as glaucoma proving niacin deficiency as an important contributor towards age related macular degeneration [6].
The primary receptor for niacin is Hcar2, an inhibitory G protein coupled receptor (GPCR). Once bound with a ligand such as niacin, Hcar2 undergoes a conformational change. In adipocytes, this stimulates a cascade inhibiting lipolysis thus reducing the release of free fatty acids into the bloodstream [7]. On the other hand, in immune cells such as macrophages, dendritic cells, and neutrophils, the activation of Hcar2 by niacin has immunomodulatory effects [8]. Niacin also plays a significant role in cholesterol homeostasis by promoting cholesterol efflux and increased macrophage dependent phagocytosis [9] These properties of niacin have been researched extensively and proven to play a significant role of neuroprotection in diseases like Multiple Sclerosis, Alzheimer's and Parkinsons [7].
Dr. Ford Brewer, a preventive medicine physician based in Kentucky, US talks about the pros and cons of Niacin on his YouTube channel extensively. He said,
Niacin is the only thing that decreases LDL and triglycerides and increases HDL. You just don't find other things like thatDr. Ford Brewer, MD, MPH
The above case of Pellagra reminds us that even basic vitamins like niacin can play a crucial role in an individual’s overall health. Even though it's easily preventable through balanced diet and/or supplementation, niacin deficiency is often misdiagnosed or ignored by patients leading to debilitating consequences in those who are left untreated. Early diagnosis and awareness of symptoms through community healthcare efforts are therefore key to ensure optimal health and prevent long-term complications.
[1] Zhou, Y., Yang, C., & Li, S. (2020). Metabolism of amino acids in the brain and their roles in regulating food intake. In Nutritional Neuroscience. Springer.
[2] She, J., Sheng, R., & Qin, Z. H. (2021). Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors. Aging and disease, 12(8), 1879–1897.
[3] Xiao, W., Wang, R. S., Handy, D. E., & Loscalzo, J. (2018). NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. Antioxidants & redox signaling, 28(3), 251–272.
[4] Vassilopoulos, A., Fritz, K.S., Petersen, D.R. et al. The human sirtuin family: Evolutionary divergences and functions. Hum Genomics 5, 485 (2011).
[5] Pandey N, Black BE. Rapid detection and signaling of DNA damage by PARP-1. Trends Biochem Sci. 2021;46(9):744–57.
[6] Cimaglia, G., Votruba, M., Morgan, J. E., André, H., & Williams, P. A. (2020). Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration. Nutrients, 12(9), 2871.
[7] Thaler, A., Giladi, N., & Mirelman, A. (2023). The Promise of Niacin in Neurology. Neurotherapeutics, 20, 1332–1342.
[8] Graff, E. C., Fang, H., Wanders, D., & Judd, R. L. (2016). Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism: clinical and experimental, 65(2), 102–113.
[9] Yvan-Charvet, L., Kling, J., Pagler, T., Li, H., Hubbard, B., Fisher, T., Sparrow, C. P., Taggart, A. K., & Tall, A. R. (2010). Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arteriosclerosis, thrombosis, and vascular biology, 30(7), 1430–1438.