What is up with this keto rash?

Estimated reading time: 15 minutes

This article is going to talk about something called a keto rash, which can happen in some people initiating a ketogenic diet. We are going to review some articles shared with me by Marco Medeot. If you are on LinkedIn and do not follow Marco, let me assure you that you are missing out. He really does share some of the best articles about ketogenic diets, and he is a wealth of knowledge on the topic. He shares so much good research, I sincerely can’t keep up! But when I tell him that in the comments of his LinkedIn posts, he tells me to just keep going! So here we are.

Introduction

First, let’s talk about what this rash is. It actually has a name and is called Prurigo Pigmentosa (PP).

In the article “Prurigo Pigmentosa – A Multi-institutional Retrospective Study,” published in the Journal of the American Academy of Dermatology, researchers conducted a retrospective analysis of 30 patients diagnosed with Prurigo Pigmentosa. The study revealed that 40% of these patients were on a ketogenic diet before the onset of symptoms, which primarily included pruritus and hyperpigmentation, predominantly affecting the back and chest. Histopathological examination typically showed mild spongiosis and a lymphoplasmacytic infiltrate, with neutrophils and eosinophils being infrequent findings.

Let’s define some of those terms.

• mild spongiosis – A swelling or fluid buildup between the skin cells in the outer layer of the skin
• lymphoplasmacytic infiltrate – Immune cells that have gathered in a specific area of the tissue. This is often a response to some form of inflammation, infection, or other immune stimulus.
• neutrophils – Often the first immune cells to arrive at a site of infection or injury. They respond quickly to signals of an invasion by bacteria, viruses, or other pathogens. One of their main functions is phagocytosis, where they engulf and digest invading microorganisms.
• eosinophils – A component of the immune system and are involved in the body’s defense mechanisms. They are less numerous than other types of white blood cells, like neutrophils, but they are important in combating parasitic infections and in allergic responses.

The article goes on to say that the most effective treatment for PP was found to be oral antibiotics, which led to complete resolution in all treated patients, whereas topical corticosteroids provided only temporary relief. It underscored the diverse triggers and presentations of PP, highlighting its prevalence across different ages and genders, with a notable female predominance. And it points out that not all cases are associated with a ketogenic diet.

But isn’t that interesting that there is so much acute activity in immune cells? Make note of that, because I will share a hypothesis around that as part of this article. Keep reading!

Case Study 1

In the article “Prurigo Pigmentosa Following a Keto Diet and Bariatric Surgery,” a case study is presented of a 25-year-old woman who developed a skin condition known as Prurigo Pigmentosa (PP) after undergoing gastric sleeve surgery and following a ketogenic diet. This condition, characterized by a rash that started as small red papules and progressed to larger plaques, is not uncommon among individuals on ketogenic diets. Interestingly, the patient had previously experienced a similar rash during an earlier attempt at a ketogenic diet. In both instances, the rash improved significantly when she reintroduced carbohydrates into her diet. After the surgery, the rash initially improved with the use of oral minocycline, a type of antibiotic, and an increase in carbohydrate intake, but it did not completely disappear until she consistently maintained a higher carbohydrate diet. This case highlights the potential link between dietary changes, particularly those leading to ketosis, and the development of PP, while also emphasizing the effectiveness of dietary adjustments in resolving the condition. The rash typically cleared up over a period of a month once a normal, carbohydrate-rich diet was resumed.

This presentation could be suggestive of a
stronger relationship between PP and the metabolic state of the body.

Alkhouri, F., Alkhouri, S., & Potts, G. A. (2022). Prurigo Pigmentosa Following a Keto Diet and Bariatric Surgery. Cureus, 14(4), e24307. https://doi.org/10.7759/cureus.24307

Case Study 2

the article “Remission of Prurigo Pigmentosa after Breaking Ketogenic Diet and Resuming Regular Diet,” it is clear that the patient, a 21-year-old woman, was indeed advised to discontinue the ketogenic diet and take minocycline for her Prurigo Pigmentosa (PP). However, she chose to resume a regular diet without taking the medication. Following this change in her diet, her skin lesions resolved within two months, leaving only light-brown post-inflammatory pigmentation. There was no recurrence of PP after 12 months of follow-up since she resumed a higher carbohydrate diet. This case highlights the potential for dietary modifications alone to be effective in resolving PP, particularly when associated with a ketogenic diet.

An otherwise healthy 21‑year‑old woman
presented with itchy skin lesions over
the chest and neck evolving for 2 weeks.
The rash occurred 1 week after starting a
carbohydrate‑restricted KD.

Daneshpazhooh, M., Nikyar, Z., Kamyab Hesari, K., Rostami, E., Taraz Jamshidi, S., & Mohaghegh, F. (2022). Remission of prurigo pigmentosa after breaking ketogenic diet and resuming regular diet. Advanced Biomedical Research, 11, 70. https://doi.org/10.4103/abr.abr_138_21

Case Study 3

In the case report titled ‘Prurigo Pigmentosa Post-Bariatric Surgery,’ a 25-year-old Saudi male patient experienced a unique instance of Prurigo Pigmentosa following bariatric surgery, diverging from the condition’s typical demographic. Notably, 18 days post-surgery, he developed a pruritic, erythematous rash over his trunk, upper abdomen, and chest. Pathological findings from skin biopsies revealed a focal interface reaction, scattered necrotic keratinocytes, dilated hair follicles filled with bacteria, and a mildly acanthotic dermis with perivascular lymphocytes, eosinophils, and extravasated red blood cells. These findings suggest an enhanced immune response, with the immune system potentially targeting previously unresolved issues in the skin. The patient’s rash resolved completely within two weeks of treatment with topical and oral medication, although post-inflammatory hyperpigmentation persisted. This case highlights the potential for PP to manifest in diverse populations and scenarios, and underscores the role of an activated immune system in response to changes in the body’s metabolic state.

Nowadays, Prurigo pigmentosa (PP) cases are being reported from all around the world, including cases of PP that appeared following bariatric surgery for weight loss without ketogenic dietary modification.

Jazzar, Y., Shadid, A. M., Beidas, T., Aldosari, B. M., & Alhumidi, A. (2023). Prurigo pigmentosa post-bariatric surgery: a case report. AME Case Reports, 7, 43. https://dx.doi.org/10.21037/acr-23-45

Case Study 4

In the study “Ketogenic Diet-induced Prurigo Pigmentosa (the ‘Keto Rash’): A Case Report and Literature Review,” published in The Journal of Clinical and Aesthetic Dermatology, a 21-year-old Hispanic man experienced a significant dermatological reaction after adhering to a ketogenic diet. He developed Prurigo Pigmentosa (PP), characterized by a pruritic rash on his chest and upper back, which persisted for three weeks. The rash appeared after two months on the diet, during which he lost 20 pounds. Clinical examination revealed erythematous to hyperpigmented papules coalescing into reticulated thin plaques. A skin biopsy confirmed the diagnosis of PP, showing spongiosis and a superficial perivascular infiltrate of eosinophils, lymphocytes, and rare neutrophils. The patient’s treatment involved oral doxycycline and discontinuation of the ketogenic diet, leading to the resolution of pruritus within two weeks and the gradual transformation of the erythematous plaques into asymptomatic, hyperpigmented patches. This case highlights the potential skin complications associated with dietary changes, particularly the ketogenic diet and its role in triggering PP.

dermatologists should review dietary habits of all patients presenting with
a pruritic erythematous papular reticulated
rash on the trunk, and consider Prurigo Pigmentosa (PP) at the top
of their differential for any patient presenting with a cutaneous eruption after initiating a ketogenic diet.

Xiao, A., Kopelman, H., Shitabata, P., & Nami, N. (2021). Ketogenic Diet-induced Prurigo Pigmentosa (the “Keto Rash”): A Case Report and Literature Review. The Journal of Clinical and Aesthetic Dermatology, 14(12 Suppl 1), S29–S32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903224/

Case Study 5

In the case study titled ‘A Rare Case of Prurigo Pigmentosa in a Danish Sibling Couple,’ two healthy Danish siblings, aged 16 and 18, developed PP approximately two weeks after starting a ketogenic diet. The histopathological examination of their skin revealed distinct features. The 18-year-old’s biopsy showed incrustation, spongiosis, and focal lichenoid changes with predominantly eosinophilic and some neutrophilic granulocytes in the dermis. The 16-year-old’s biopsy displayed mild hyperkeratosis, mild epidermal hyperplasia with a few necrotic keratinocytes, and a sparse dermal infiltrate of lymphocytes and melanophages. These findings highlight the complex dermatological changes associated with PP, particularly in the context of a ketogenic diet.

Let me clarify in plain language what the biopsy found. They found crusty, local bumpy, and sometimes itchy skin that was holding on to more fluid than it should due to inflammation. And when they looked at what kind of cells and changes were causing this, they found, like in the other case studies, neutrophils and eosinophils. Suggesting the body was reacting to something related to the rash.

Most patients with PP do not have ketosis or diabetes, and our cases raise the question whether certain tissue types (e.g., HLA types) nevertheless possess a different threshold to ketone bodies in the blood and thereby a higher likelihood of developing PP.

Danielsen, M., Pallesen, K., Riber-Hansen, R., & Bregnhøj, A. (2023). A Rare Case of Prurigo Pigmentosa in a Danish Sibling Couple. Case Reports in Dermatology, 15, 26–30. https://doi.org/10.1159/000528422

So, what the heck is going on here? I don’t know. I am not any kind of immune system expert. But I have a common sense hypothesis that will hopefully depathologize this common response that some people have to the ketogenic diet.

The Intricate Interplay Between Ketogenic Diets and Immune System Modulation

So everybody knows, at this point, that the ketogenic diet is a high-fat, moderate protein, and low-carbohydrate way of eating that initiates and maintains a profound metabolic shift in the human body, leading to a state of ketosis.

If you follow this blog at all, you know that this state, characterized by the elevated production of ketone bodies such as β-hydroxybutyrate (BHB), acetoacetate, and acetone, is not merely a metabolic alternative to glucose-based energy production; it represents a significant reprogramming of cellular and systemic functions. There are many articles on this blog discussing the effects on the brain’s immune response and how that modulates neuroinflammation.

Neuroinflammation and depression

But because this blog is mostly focused on your noggin, we really haven’t gotten into the far-reaching implications of ketogenic diets for the immune system in general.

At the cellular level, ketone bodies, particularly BHB, exert a regulatory influence on key immune pathways. BHB is known to inhibit the NLRP3 inflammasome, a multiprotein complex within neutrophils that plays a pivotal role in the innate immune response and inflammation. The NLRP3 inflammasome’s activation leads to the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which are crucial in combating infections but can also contribute to pathological inflammation. By modulating the activity of the NLRP3 inflammasome, BHB can potentially mitigate excessive inflammatory responses, suggesting a balancing effect on the immune system.

If Your Brain Were a City: Understanding Oxidative Stress and Neuroinflammation

Furthermore, the ketogenic diet’s impact extends to the gut microbiome, a critical component of the immune system. The gut microbiota is a complex ecosystem that influences systemic immunity. Dietary changes profoundly affect the composition and function of this microbiome, thereby altering the immune landscape. A ketogenic diet can lead to a gut microbiota that favors anti-inflammatory states, potentially enhancing the body’s ability to manage autoimmune conditions and inflammatory responses.

β-HB regulates the activation of the NLRP3 inflammasome in neutrophils and macrophages. The trajectory of caspase-1 is essential for the cleavage of precursors of several proteins and an important factor in the immune system. K+ efflux prevention resulting from β-HB inhibits the activation of the NLRP3 inflammasome. Ketone bodies activate HCA2 receptors and inhibit the assembly of the NLRP3 inflammasome.

Ansari, M. S., Bhat, A. R., Wani, N. A., & Rizwan, A. (2022). Antiepileptic Mechanisms of Ketogenic Diet. Current Neuropharmacology, 20(11), 2047-2060. DOI: 10.2174/1570159X20666220103154803

But what’s going on in this keto rash? Isn’t a ketogenic diet supposed to reduce inflammatory responses? Well yes! But…

In the context of skin health and conditions like Prurigo Pigmentosa (PP), the ketogenic diet’s immunomodulatory effects become particularly relevant. The skin, an active immune organ, is home to various immune cells, including neutrophils and eosinophils. These cells are integral to the innate immune response, acting as first responders to infection and inflammation. In PP, the influx of neutrophils and eosinophils to skin lesions is indicative of an active immune response. The ketogenic diet, through its systemic and local effects, might influence this response. By altering immune cell metabolism and modulating inflammatory pathways, the diet could contribute to an enhanced or rebalancing of immune presence in the skin.

Where do I get this humble hypothesis? Why the scientific literature, of course. This hypothesis is further supported by research into ketogenic diets in other contexts, such as cancer therapy. Cancer research has revealed that ketogenic diets can affect tumor growth and immune surveillance. While the mechanisms are complex and multifaceted, one aspect is the modulation of immune responses, enhancing the body’s ability to target and destroy cancer cells. This suggests that ketogenic diets have the potential to significantly influence immune function, not just in cancer but in other conditions where immune responses are critical.

What other factors could be going on? Well, I don’t know! But based on what I understand about the ketogenic diet and immune response? I am guessing some of these!

Hypothesis: Ketogenic Diet and Immune System Modulation
Metabolic Shift and Immune Cell Function

Let’s go through some of the possible layers involved in the increased immune response we see with Keto Rash.

Metabolic shifts matter in immune function

The ketogenic diet induces a metabolic shift from glucose to ketone bodies for energy. This shift can influence immune cells, as different energy sources can modulate their function. For example, ketone bodies might alter the activation and function of immune cells like neutrophils and eosinophils, which are often seen in PP lesions. Ketone bodies have been shown to inhibit the NLRP3 inflammasome, a component of the immune system involved in inflammation. This could potentially reduce chronic inflammation but might also enhance the body’s response to acute stressors, such as pathogens or damaged cells.

β-HB regulates the activation of the NLRP3 inflammasome in neutrophils and macrophages

Kumar, A., Kumari, S., & Singh, D. (2022). Insights into the Cellular Interactions and Molecular Mechanisms of Ketogenic Diet for Comprehensive Management of Epilepsy. Preprints, 2022120395. https://doi.org/10.20944/preprints202212.0395.v1

Gut Microbiome and Immune Response

The ketogenic diet significantly alters the gut microbiome. Since a large portion of the immune system is located in the gut, changes in the microbiome composition can have profound effects on immune responses.
A healthier gut microbiome, often associated with ketogenic diets, might enhance the body’s ability to fight infections and could explain an upregulated immune response in the skin.

Ketogenic Diets and Gut Microbiome

Reduction in Inflammation

Ketogenic diets are known to reduce systemic inflammation. This reduction could paradoxically allow the immune system to focus more effectively on localized issues, such as skin conditions in PP. A decrease in systemic inflammatory signals might “unmask” previously subclinical conditions, leading to an apparent increase in immune activity in specific areas like the skin.

Oxidative Stress and Immune Surveillance

It is really well known in the scientific literature, that ketogenic diets can influence oxidative stress levels in the body. A balance in oxidative stress is crucial for optimal immune function. Reduced oxidative stress might enhance immune surveillance, allowing the immune system to more effectively identify and respond to pathogens or abnormal cells, which could be seen in the skin reactions of PP.

Hormonal and Cytokine Changes

Ketogenic diets can alter hormone levels and cytokine production. These changes can have wide-ranging effects on the immune system, potentially enhancing its responsiveness or altering its targets. For example, changes in insulin levels and insulin-like growth factors can influence inflammation and immune cell activity.

So, I humbly put forth the hypothesis that the ketogenic diet’s impact on metabolism, the gut microbiome, inflammation, oxidative stress, and hormonal balance can collectively modulate the immune system. This modulation might manifest as an enhanced or more targeted immune response in specific conditions like PP, where we see an increase in immune cells such as neutrophils and eosinophils in the skin.

Conclusion

None of this sounds scary to me. It sounds like the righting of a wrong. Not a disruptor, but a restorer of immune balance. Not an alarm, but a recalibration of immune health. And certainly not a pathological emergency requiring antibiotics or a fatal discontinuation of the diet providing metabolic therapy for the patient.

In conclusion, the ketogenic diet represents a significant intervention in human metabolism with profound effects on the immune system. Its ability to modulate key immune pathways, alter the gut microbiome, and influence systemic and local immune responses suggests a potential mechanism behind the enhanced immune activity observed in conditions like PP. This enhanced or rebalanced immune response could be a reflection of the body’s adaptation to a new metabolic state, with implications for various health conditions, including skin disorders, autoimmune diseases, and even cancer.

In my work with patients, I have not had someone for whom this rash has not gone away with patience and, possibly, a much slower transition down in carbohydrate consumption. I have certainly not, in my capacity as a health coach, suggested anyone seek out antibiotics. Because of my clinical experience, I already know that antihistamines and cortisol creams or gels are not going to do the trick. I tell my patients that this rash might be a good sign that their immune system is rebalancing or upregulating. I know I had it off and on for several months when I transitioned into my ketogenic diet. Sometimes it was super itchy and uncomfortable, but it eventually went away. And I shudder to think if I would have freaked out and gone off my ketogenic diet as a response to it, because I assure you, my brain would not be working as well as it is today in order to write you this article.

I am not in your itchy, keto-rash body. So, what you do and how you choose to respond is certainly up to you. No judgment exists on my part, I assure you. I want you to feel good.

But I want you to know there can be an explanation for it happening that is not a “pathological response” as the average dermatologist or non-ketogenic trained MD or functional medicine practitioner may imply or assume. If it really bothers you, go up in your carbs about 5 or 10 grams and work with your dietician or nutritionist. See if that does the trick. But it still might happen to some extent when you get down low carb enough that the metabolic magic starts to happen.

Here is what modern medicine doesn’t tell you. Because it is so focused on symptom management instead of root cause healing, I don’t think it knows. But healing is messy. It is uncomfortable. But it is wise. Your body is likely putting things to right and making adjustments in ways that you and/or your medical professional, or even myself as someone super interested in this topic, could never ever begin to understand.

I encourage you to expand what you are willing to explore and tolerate in your goal of healing. Keep going if you can. And see what is possible for you.

References

Alkhouri, F., Alkhouri, S., & Potts, G. A. (n.d.). Prurigo Pigmentosa Following a Keto Diet and Bariatric Surgery. Cureus, 14(4), e24307. https://doi.org/10.7759/cureus.24307

Daneshpazhooh, M., Nikyar, Z., Kamyab Hesari, K., Rostami, E., Taraz Jamshidi, S., & Mohaghegh, F. (2022). Remission of Prurigo Pigmentosa after Breaking Ketogenic Diet and Resuming Regular Diet. Advanced Biomedical Research, 11, 70. https://doi.org/10.4103/abr.abr_138_21

Danielsen, M., Pallesen, K., Riber-Hansen, R., & Bregnhøj, A. (2023). A Rare Case of Prurigo Pigmentosa in a Danish Sibling Couple. Case Reports in Dermatology, 15(1), 26–30. https://doi.org/10.1159/000528422

Effinger, D., Hirschberger, S., Yoncheva, P., Schmid, A., Heine, T., Newels, P., Schütz, B., Meng, C., Gigl, M., Kleigrewe, K., Holdt, L.-M., Teupser, D., & Kreth, S. (2023). A ketogenic diet substantially reshapes the human metabolome. Clinical Nutrition, 42(7), 1202–1212. https://doi.org/10.1016/j.clnu.2023.04.027

Jazzar, Y., Shadid, A. M., Beidas, T., Aldosari, B. M., & Alhumidi, A. (2023). Prurigo pigmentosa post-bariatric surgery: A case report. AME Case Reports, 7(0), Article 0. https://doi.org/10.21037/acr-23-45

Kumar, A., Kumari, S., & Singh, D. (2022). Insights into the Cellular Interactions and Molecular Mechanisms of Ketogenic Diet for Comprehensive Management of Epilepsy. Current Neuropharmacology, 20(11), 2034–2049. https://doi.org/10.2174/1570159X20666220420130109

Murakami, M., & Tognini, P. (2022). Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet. Nutrients, 14(4), Article 4. https://doi.org/10.3390/nu14040782

Nutrients | Free Full-Text | Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet. (n.d.). Retrieved November 12, 2023, from https://www.mdpi.com/2072-6643/14/4/782

Shen, A., Cheng, C. E., Malik, R., Mark, E., Vecerek, N., Maloney, N., Leavens, J., Nambudiri, V. E., Saavedra, A. P., Hogeling, M., & Worswick, S. (2023). Prurigo pigmentosa: A multi-institutional retrospective study. Journal of the American Academy of Dermatology, 89(2), 376–378. https://doi.org/10.1016/j.jaad.2023.03.034

Srivastava, S., Pawar, V. A., Tyagi, A., Sharma, K. P., Kumar, V., & Shukla, S. K. (2023). Immune Modulatory Effects of Ketogenic Diet in Different Disease Conditions. Immuno, 3(1), Article 1. https://doi.org/10.3390/immuno3010001

Talib, W. H., Al-Dalaeen, A., & Mahmod, A. I. (2023). Ketogenic diet in cancer management. Current Opinion in Clinical Nutrition and Metabolic Care, 26(4), 369–376. https://doi.org/10.1097/MCO.0000000000000944

Tzenios, N., Tazanios, M. E., Poh, O. B. J., & Chahine, M. (2022). The Effects of Ketogenic Diet on the Immune System: A Meta-Analysis (2022120395). Preprints. https://doi.org/10.20944/preprints202212.0395.v1

Xiao, A., Kopelman, H., Shitabata, P., & Nami, N. (2021). Ketogenic Diet-induced Prurigo Pigmentosa (the “Keto Rash”): A Case Report and Literature Review. The Journal of Clinical and Aesthetic Dermatology, 14(12 Suppl 1), S29–S32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903224/ Zhu, H., Bi, D., Zhang, Y., Kong, C., Du, J., Wu, X., Wei, Q., & Qin, H. (2022). Ketogenic diet for human diseases: The underlying mechanisms and potential for clinical implementations. Signal Transduction and Targeted Therapy, 7(1), Article 1.