The Ketogenic Diet is Linked to a Very Specific Kind of Itchy Rash
The ketogenic diet is gaining increasing attention and popularity in the mainstream. The name and concept, unknown to most only a few years ago, is now well-recognized in many North American households. Medical literature, however, dates back as far as the Hippocratic era investigating the therapeutic efficacy of dietary interventions that induce ketosis.1 While varying degrees of clinical evidence supports this nutritional modification in conditions such as epilepsy,2 Parkinson’s and Alzheimer’s,3 brain tumours,4 and obesity,5 the ketogenic diet risks being used as a panacea by some practitioners. While it is important to critically evaluate the potential efficacy of this treatment, the safety of the ketogenic diet is another consideration practitioners must take into account when recommending it to patients. The most common reported adverse events in the medical literature regarding a ketogenic diet are: fatigue, lethargy, hypoglycemia, and a transient flu-like syndrome (muscle weakness, headache, brain fog, nausea, body pain).6 Kidney stones, impacts on cardiovascular health and a disruption of the microbiome have been cited as potential long-term risks of the diet, as well, but require further study. As the popularity of this diet grows, another potential adverse effect, known as the “keto rash,” is increasingly reported.
Prurigo pigmentosa (PP) is a rare form of inflammatory dermatitis that was first documented in the 1970s.7 It is also known as Nagashima’s disease. The morphology of the lesions can vary, depending on the stage of the presentation, but specific to this condition is the reticular (meshed network) pattern of the rash.8 It most commonly affects Asian women,8 but it has been documented in other races and in men,9 as well. A number of systemic conditions have been associated with PP, including atopy,10 Sjogren’s Syndrome11 and H. pylori infection.12 One of its strongest associations is in conditions in which ketosis is produced, such as fasting, restrictive diets and poorly-controlled diabetes mellitus.13,8 The early presentation is characterized by intense pruritis with the development of urticarial plaques. Pathology of the lesions will show perivascular neutrophilic infiltration. As the condition progresses, the lesions will become papulo-vesicular with crust formation and erythema. Histologically, intercellular edema will then be present with necrotic keratinocytes. In the later stages, the lesions become smooth and macular with hyperpigmentation, as lymphocytes and melanophages infiltrate the papillary dermis.8 For treatment, antibiotics have been used successfully, possibly due to an anti-inflammatory effect and immunomodulatory effects on the intestinal flora,14 however, in patients with underlying ketosis, metabolic correction with insulin or increasing carbohydrate consumption will resolve the issue.15 This is, of course, undesirable in the setting of using the ketogenic diet for therapeutic purposes. What causes PP is still not well understood, but one theory suggests that dysbiosis of the GI microflora could contribute to its evolution, based on the connection between the immune system and the human microbiome. The fact that certain antibiotics have been shown to successfully treat this condition lends some support to this theory in that the alterations to the microflora from treatment might modulate immune responses.
With an increasing number of patients on ketogenic diets (either self-prescribed or practitioner-recommended), the incidence of this adverse effect is likely to become more common. As such, it is important for all clinicians to have a better understanding of prurigo pigmentosa, including its diagnosis, management and long-term implications if left untreated.
A recent case study by Wong et al,16 published in the Hawai’i Journal of Public Medicine and Health, reported 2 cases of PP associated with ketogenic diet intervention that resolved with increased carbohydrate intake. Of particular relevance was that in 1 of these cases resolution of the rash was possible without discontinuing ketosis. This may offer hope for patients who benefit from therapeutic ketogenic diets and do not want to stop ketosis, but experience this adverse event.
The first case involved a 43 year old Asian-American woman who had initiated a ketogenic diet on her own for weight management. Her daily macronutrient intake averaged 20 g carbohydrates, 105 g protein and unrestricted fat consumption. The PP first presented as erythematous papules 3 weeks after initiating the dietary change. The rash improved after 1 week, but continued to cycle through periods of relapse and remission. Exercise and hot water showers were noted to aggravate the condition. A number of treatments were attempted to resolve the issue, including oral diphenhydramine and loratadine, topical steroids, elimination of potential environmental allergens (changing shampoo) and the elimination of potential food allergens (like nuts). None of these interventions were successful at resolving the rash. The condition immediately corrected when the patient increased her dietary carbohydrate intake and there was no reported relapse 12 months after while continuing to consume a higher carbohydrate intake in her diet.
The second case involved an 18 year old Japanese man who used a ketogenic diet for intractable seizures. This patient’s diet was overseen by an RDN who prescribed a 2:1 fat to carbohydrate and protein ratio (170 g/day fat, 16 g/day carbohydrates, 70 g/day protein). Urinary ketones were measured to confirm ketosis. Nine days after beginning the dietary intervention, he developed a pruritic rash consistent with PP and by day 14, the lesions had worsened with an increase in erythema. The patient’s diet was adjusted to a .75:1 ratio (increased daily carbohydrates to 90 g, increased daily protein to 95 g, and daily fat was reduced to 146 g). This resulted in significant improvement in pruritis and erythema within 1 day. The patient’s urinary ketones did decrease from the levels at the beginning of the intervention, but were still present in an appreciable amount to confirm ketosis was still maintained. The rash resolved and remained in remission for 8 months at the time of reporting. No seizures occurred throughout this time, despite the changing of the macronutrient ratios.
In summary, PP is an uncommon but potential adverse effect of ketogenic diets that clinicians should be familiar with and should also inform their patients of when discussing the procedure, alternatives, risks and questions (PARQ). The condition is most common in Asian woman (though not exclusive) and has not been reported in pre-pubescent children as a result of a ketogenic diet.8 The rash evolves through 3 stages and may appear similar to contact dermatitis, urticaria, erythema multiforme, drug reactions, and confluent and reticulated papillomatosis. PP is differentiated from these other conditions by its reticulated pattern and intense pruritis (especially at onset). It generally presents in a symmetrical distribution on the back, neck and chest.8 Histo-pathological analysis of biopsied lesions may help confirm diagnosis. Increasing carbohydrate intake seems to be the most efficient way to resolve the condition. Antibiotics, such as minocycline, doxycycline and dapsone may also be effective treatments. Colchicine has also been used.17 Antihistamines and steroids do not appear to be effective. Ketosis may still be able to be preserved in these patients, by carefully increasing carbohydrate intake dosing and adjusting the ratio of macronutrients in the diet. Addressing dysbiosis of the gut through other treatments may theoretically benefit this condition, but further research into this proposed mechanism of action of pathogenesis still needs to be explored. The long-term implications of PP if left untreated are not well-defined, but it would seem to be self-limiting and posing little risk to the patient other than the discomfort and cosmetic aspects of the rash. There have been reported cases of long-standing PP that have left hyperpigmentation of the skin even after the condition has been treated and resolved.17 With many dermatological conditions, especially accompanied by pruritis, there is an increased risk of infection due to mechanical irritation and potentially subsequent scarring. These risks should be taken into consideration if a patient and provider agree to continue a ketogenic diet, despite the development of prurigo pigmentosa.
- Todman D. Epilepsy in the Graeco-Roman World: Hippocratic Medicine and Asklepian Temple Medicine Compared. J Hist Neurosci. 2008;17(4):435-441. doi:10.1080/09647040701426088
- Hwang S, Stevens S, Fu A, Proteasa S. Intractable Generalized Epilepsy: Therapeutic Approaches. Curr Neurol Neurosci Rep. 2019;19(4). doi:10.1007/s11910-019-0933-z
- Włodarek D. Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease). 2019;11(1):169. doi:10.3390/nu11010169
- Schwartz K, Chang H, Nikolai M et al. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab. 2015;3(1). doi:10.1186/s40170-015-0129-1
- Mohorko N, Černelič-Bizjak M, Poklar-Vatovec T et al. Weight loss, improved physical performance, cognitive function, eating behavior, and metabolic profile in a 12-week ketogenic diet in obese adults. Nutrition Research. 2019;62:64-77. doi:10.1016/j.nutres.2018.11.007
- Goday A, Bellido D, Sajoux I et al. Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus. Nutr Diabetes. 2016;6(9):e230-e230. doi:10.1038/nutd.2016.36
- Nagashima M. PRURIGO PIGMENTOSA. J Dermatol. 1978;5(2):61-67. doi:10.1111/j.1346-8138.1978.tb01049.x
- Beutler B, Cohen P, Lee R. Prurigo Pigmentosa: Literature Review. Am J Clin Dermatol. 2015;16(6):533-543. doi:10.1007/s40257-015-0154-4
- Gur-Toy G, Gungor E, Artuz F, Aksoy F, Alli N. Prurigo pigmentosa. Int J Dermatol. 2002;41(5):288-291. doi:10.1046/j.1365-4362.2002.01356_2.x
- Cota C, Donati P, Amantea A. Prurigo Pigmentosa Associated with an Atopic Diathesis in a 13‐Year‐Old Girl. Pediatric Dermatology. 2007;24(3):277-279.
- Togawa Y, Shinkai H, Utani A. Prurigo pigmentosa in a patient with primary biliary cirrhosis and Sjögren syndrome. The Journal of Dermatology. 2004;31(10):815-819.
- ErbagcizI Z. Prurigo pigmentosa in association with Helicobacter pylori infection in a Caucasian Turkish woman. Acta Dermato-venereologica. 2002;82(4):302-303.
- Oh Y, Lee M. Prurigo pigmentosa: a clinicopathologic study of 16 cases. Journal of the European Academy of Dermatology and Venereology. 2011;26(9):1149-1153. doi:10.1111/j.1468-3083.2011.04263.x
- Gironi L, Farinelli P, Giacalone A, Colombo E. The efficacy of minocycline in inflammatory dermatoses: a case of prurigo pigmentosa of prepubescent onset in Western world. Dermatol Ther. 2015;28(4):239-242. doi:10.1111/dth.12216
- Yokozeki M, Watanabe J, Hotsubo T, Matsumura T. Prurigo Pigmentosa Disappeared Following Improvement of Diabetic Ketosis by Insulin. J Dermatol. 2003;30(3):257-258. doi:10.1111/j.1346-8138.2003.tb00385.x
- Wong M, Lee E, Wu Y, Lee R. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawai’i Journal of Public Medicine and Health. 2018: 77(5).
- An I, Ucmak D, Ibiloglu I, Demir V, Akdeniz S. Colchicine may be of therapeutic benefit in prurigo pigmentosa. Pediatr Dermatol. 2018;35(3):e202-e203. doi:10.1111/pde.13480