A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.6-10
Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.
Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.11 The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.11 In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.11
Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.12,13 Teraki et al13 observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.12,13
Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.14 Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.14 This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.
Middleton and Norris15 observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.
We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.