Diabetes and the Skin

Abstract

Skin manifestations of diabetes mellitus are frequent. Symptoms vary from mild cosmetic concerns to disabling conditions. The skin signs are not always recognized though they can be a presenting symptom of diabetes mellitus or a marker of advanced disease. In this chapter different skin manifestations and their pathogenesis are discussed, some of them are more specific for type 1 diabetes mellitus, others for type 2, or both. Cutaneous side effects of medications used to treat diabetes mellitus are discussed as well. Several clinical and histopathological images are included.

FormalPara Chapter Objectives

• There are several skin manifestations in diabetes mellitus; some of them occur frequently.

• Some of these are specific for type 1 diabetes mellitus, others for type 2, and some occur in both.

• Medications used to treat diabetes mellitus may also cause skin adverse effects.

Introduction

Many diabetes mellitus patients develop skin manifestations during the course of the disease, and children are no exception [1, 2]. Prevalence rates range from 30% to 80% [2, 3]. However we should keep in mind that diabetes is a highly prevalent disease and therefore should remain critical toward studies trying to determine a direct relationship without being aware of possible confounding factors. Our skin is a large organ of the human body and is directly visible to the outside world. Because of this patients tend to care a lot about their skin, sometimes more than clinicians realize [4].

Skin manifestations of diabetes mellitus are diverse and range from cosmetic concerns to severe conditions more frequently seen in long-standing disease. Recognizing these is a rewarding clinical skill to master, since some of them may be important diagnostic clues as well as markers of advanced disease [5]. Some diabetes-related skin defects can be a port of entry for later infections. Several medications can affect the skin shortly after intake. Some skin manifestations are more specific for diabetes than others. Besides evaluating the skin for establishing a diagnosis of diabetes, it can also be a help for evaluating treatment success, study results, and glucose levels.

Pathogenesis

Pathogenesis of the skin involvement in diabetes mellitus can be seen as a collaborative phenomenon of biochemical, vascular, neurological, immune-mediated, and metabolic changes with long-standing hyperglycemia as its key player. Diabetics with hemoglobin A1c values <8 mmol/ml tend to have less cutaneous involvement than those with hemoglobin A1c values >8 mmol/ml [2].

Increased oxidative stress and chronic high levels of circulating glucose lead to a nonenzymatical chemical reaction between glucose and proteins, lipids, and nucleic acids. The chemical reactions between amino acids and the carbonyl group of glucose are called a Maillard reaction. First reversible Schiff’s bases are formed followed by the conversion to stable products. Finishing transforming chemical reaction lead to the formation of advanced glycation end products (AGE) which bind to specific receptor on many cell surfaces initiating numerous intracellular signaling cascades leading to diabetic complications [6]. Due to formation of AGE and oxidative stress, vascular damages appear [7]. Neuropathy leads to hypo- or even anhidrosis, vascular dilation causing erythema, and hyposensation. Vascular and neurological changes are responsible for loss of sensation, impaired blood supply, and failure of homeostatic regulatory mechanism in end organs such as the skin.

Hyperglycemia increases the flux through to polyol and hexosamine pathways with activation of protein kinase C, NF-kappa b, mitogen-activated protein kinase (MAPK), and others [8]. Consequently this leads to endothelial proliferation and basement membrane thickening with deposition of periodic acid-Schiff stain positive (PAS+) material with narrowing of arterioles, capillaries, and venules.

Keratinocyte function is frequently altered which leads to an impaired epidermal barrier function and delayed wound healing [9,10,11]. Decreased hydration might play a role. pH values of the skin are higher than in nondiabetic patients leading to an increase in bacterial colonization.

Skin Manifestations of Diabetes Mellitus

Certain skin manifestations are specific for type 1 diabetes mellitus, others for type 2, and some occur in both. In the following text, diseases appear in alphabetical order. Whether they occur predominantly in type 1 diabetes mellitus, 2, or both will be mentioned.

Acanthosis Nigricans

Acanthosis nigricans consists of velvety hyperpigmented plaques in the intertriginous areas of the skin. Frequently skin tags are found within these lesions. Most patients are asymptomatic although maceration, malodor, and discomfort have been reported. It is the most frequent skin condition in diabetes; almost all type 2 diabetic patients develop acanthosis nigricans to a certain extent. It is more frequently seen in Hispanics and native as well as African Americans; men and women are equally affected. Besides diabetes, acanthosis nigricans can also appear in obese individuals, patients with insulin resistance (both independently associated), and less frequently in patients with acromegaly, Cushing syndrome, and leprechaunism. It is sometimes observed in malignancies (especially those of the stomach) and associated with certain medications, for example, nicotinic acid, corticosteroids, and rarely repetitive insulin injections. Lastly it can appear in healthy individuals as well [12, 13].

Histopathology of the affected skin reveals hyperkeratosis, papillomatosis, mild acanthosis, and sometimes hyperpigmentation of the basal layer. There is usually no dermal inflammation. The hyperkeratosis causes the darkened aspect, and papillomatosis causes accentuation of skin markings. High levels of circulating insulin bind the tyrosine kinase growth factor receptors (e.g., insulin-like growth factor 1receptor) on fibroblasts and keratinocytes. This stimulates these cells to grow, causing the typical skin manifestations.

People with extensive acanthosis nigricans seem to have higher fasting plasma insulin levels [14, 15].

Weight reduction, exercise, and if necessary glucose-lowering treatment in combination with lipid-lowering drugs may reduce insulin resistance and improve acanthosis nigricans. If patients experience discomfort, ointments containing salicylic acid, urea, lactic acid, or retinoids may reduce the hyperkeratotic lesions. Systemic retinoids have been used in severe cases. Recurrence is often seen after discontinuation of therapy (Figs. 57.1 and 57.2).

Fig. 57.1

Acanthosis nigricans

Fig. 57.2

Acanthosis nigricans . Acanthosis nigricans: the lesion shows hyperkeratosis and papillomatosis usually without dermal inflammation

Acrochordon

Acrochordon , also called fibroma molle , fibroepithelial polyp, or skin tag, is a soft pedunculated flesh colored papule in the axillae, neck, eyelids, and in the inframammary region. Patients are asymptomatic apart from possible cosmetic concerns and rarely experience pain or irritation when the fibroma contains nerve endings.

There is a slight female predisposition and prevalence increases with age. The association between acrochordon and obesity is well established, but they are also an independent marker for diabetes, especially type 2 [16]. Skin tags have been detected in 23% of diabetic patients compared to 8% in a healthy control group. Though there is some controversy regarding the total amount of skin tags per individual and the associated risk of diabetes, current literature seems to show that the higher the number, the higher the risk for diabetes mellitus. Patients with over 30 skin tags are especially at risk. A positive correlation has also been found between the total number of skin tags and mean fasting plasma glucose [17, 18] making skin tags an even more sensitive cutaneous marker for diabetes than acanthosis nigricans. Clinicians should be aware of this association when taking note of multiple acrochordons. As mentioned earlier, high levels of circulating insulin stimulate keratinocytes to grow, which could help explain the higher prevalence of skin tags in diabetics. Treatment is not necessary, but if patients want them to be removed, they can be excised. Electrodessication and cryotherapy are two valid alternatives (Figs. 57.3 and 57.4).

Fig. 57.3

Acrochordon in the right axilla

Fig. 57.4

Acrochordon or fibroepithelial polyp : the papules show a fibrovascular core covered by the epidermis showing hyperplasia sometimes resembling seborrheic keratosis. The stroma often shows loosely arranged collagen, an increased number of blood vessel and (in larger lesions) fat cells

Acquired Perforating Dermatosis

Acquired perforating dermatosis presents with scaly highly pruritic follicular hyperkeratotic dome-shaped papules and nodules, often with central umbilication or a central keratotic plug on the extensor surfaces of the lower extremities and in some cases also on the face, trunk, and dorsal area of the hands.

This chronic disease is rare but more frequently seen in Afro-Americans with diabetes (both type 1 and 2) and chronic kidney disease or hemodialysis (as high as 10%). However it can also occur in diabetics with normal kidney function [19,20,21].

Skin conditions to be included in the differential diagnosis are prurigo nodularis, folliculitis, arthropod bites, multiple keratoacanthomas, psoriasis vulgaris, and lichen planus. Pathologic examination shows a hyperplastic invaginating epidermis containing parakeratosis, degenerated connective tissue, and cellular debris, following the transepidermal elimination of dermal collagen and elastin.

The cause is probably a multifactorial interplay between glycation of collagen, Koebner phenomenon, microvasculopathy, and inflammatory reaction to altered dermal collagen or deposition of substances which are not removed by dialysis. It is unclear whether the abnormality appears first in the dermis or epidermis; pruritus is probably rather the cause of these changes than the effect. Acquired perforating dermatosis is difficult to treat. Treating the pruritus is the main goal. Coexisting disease should be treated according to current standards though dialysis does not improve the disease course. Topical glucocorticoids, antihistamines, topical and systemic retinoids, doxycycline, allopurinol, cryotherapy, and phototherapy are all used for symptom relief (Figs. 57.5, 57.6, and 57.7).

Fig. 57.5

Acquired perforating dermatosis

Figs. 57.6 and 57.7

Acquired perforating dermatosis . The lesion shows an invaginating epidermis containing a parakeratotic plug with degenerated connective tissue fibers and cellular debris

Bullosis Diabeticorum

Patients suffering from bullosis diabeticorum present with uni- to bilateral spontaneous tense noninflammatory bullae on normal appearing skin of the dorsolateral sides of the lower extremities and sometimes of the hands. Though it is thought to be a distinct marker for diabetes, it is the rarest skin manifestation in diabetes occurring in 0.5% of all diabetic patients. No large population studies have confirmed this, so its frequency might be higher. It does occur more in men with long-standing poorly controlled type 1 diabetes mellitus with peripheral neuropathy [22, 23].

There are three known subtypes. In the first, “classic” type the cleavage level of the bullae is intraepidermal [24], the fluid in these bullae is clear and sterile, and the surrounding epidermis shows spongiosis. There is no pain. These bullae resolve spontaneously without scars in a few weeks, but recurrence is possible. Histopathological examination shows a subepidermal blister with early reepithelialization. The second type consists of bullae filled with hemorrhagic fluid. The cleavage level lies below the dermoepidermal junction. Healing comes with scarring and atrophy. The third type appears on tanned skin, and its cleavage level lies within the lamina lucida of the dermoepidermal junction. Healing leaves no scars. The differential diagnosis of bullosis diabeticorum includes primary autoimmune blistering such as pemphigus, bullous pemphigoid, erythema multiforme, epidermolysis bullosa acquisita, and porphyria cutanea tarda. Immunofluorescence tests are negative. Bullosis diabeticorum is associated with high blood glucose levels, but venous pressure elevation may also play a role. Microangiopathic vessels offer less blood to the skin which then becomes more prone to acantholysis and thus blister formation. Other possible causes are autoimmune phenomena, exposure to UV light, and alterations in calcium and magnesium levels [22, 25, 26]. Spontaneous resolution is seen within 2–5 weeks [27]. No treatment is needed besides the prevention of complications, e.g., chronic ulcers and bacterial infections. In cases of major discomfort, aspiration can be considered. Nevertheless recurrence of bullae is frequent.

Diabetic Cheiroarthropathy (Diabetic Stiff Hand or Limited Joint Mobility Syndrome)

People with diabetic cheiroarthropathy have a thickened waxy skin and bilateral limited joint mobility of the hands and fingers leading to flexion contractures (e.g., Dupuytren’s disease). This process starts at the fifth digit and progresses radially. It can extend to the wrists, elbows, ankles, knees, toes, and cervicothoracic spine. Clinical examination can reveal a prayer sign, which is the inability to approximate the palmar surfaces of the hands and fingers. Some patients have Huntley papules, which are multiple tiny papules grouped on the dorsal sides of the fingers or periungally. On histologic examination, a hyperkeratotic epidermis and dermal papillary hypertrophy are noticed. Up to 30% of diabetics have diabetic cheiroarthropathy. Incidence increases with disease duration but not with diabetes control. Although it is more common in patients with type 1 and type 2 diabetes mellitus than in other individuals, the disease can occur in people without diabetes. If presenting in diabetic patients, it is a predictor of other complications (especially retinopathy and nephropathy). In children with type 1 diabetes, it is the earliest clinically apparent long-term complication [1].

Differences in the collagen household of the skin such as increased glycosylation of collagen lead to irreversible cross-linking of collagen and other proteins and decreased collagen degradation. Other possible contributing factors are microangiopathy, neuropathy [28, 29], and accumulation of AGE which, after binding their receptors, would stimulate inflammatory and fibrogenic growth factor receptors and cytokines via protein kinase C.

Diabetic cheiroarthropathy is not yet treatable, but control of diabetes and physiotherapy are likely to be helpful. Phototherapy, radiotherapy, prostacyclin, penicillin, cyclosporin, factor XIII, and sorbinil have been applied without spectacular results. Research in animals is currently underway, investigating drugs blocking the protein cross-linking or blocking interactions between AGE and their receptors in the early stages of the disease.

Diabetic Dermopathy

Lesions of diabetic dermopathy or so-called shin spots are dynamic; various stages can present in the same patient at the same time. They are usually asymmetrical, 0,5 to 1 cm large red to brown hyperpigmented spots ranging from atrophic macules to plaques. Plaques are more frequently recognized. These appear bilateral on the extensor parts of the legs but can rarely occur elsewhere and are usually asymptomatic. It is one of the most common skin manifestations in diabetes (type 1 and 2) with a prevalence up to 70%, although it is rare in children [1]. It is more frequent in men aged 50 and over and patients with poorly controlled diabetes. Although the association is strong, it is not entirely specific for diabetes mellitus since 20% on nondiabetic people have similar lesions [3]. Patients presenting with this dermopathy should be screened for diabetes especially if they present with four or more shin spots because they are thought to represent postinflammatory hyperpigmentation and cutaneous atrophy in the setting of poor vascular supply and microtrauma [30].

Shin spots may precede abnormal glucose metabolism but may also be a marker for microangiopathic complications such as retinopathy, nephropathy, and neuropathy as well as macroangiopathic complications, especially coronary artery disease [30, 31]. Differential diagnosis with dermatophytosis should be made. Diabetic dermopathy should be a clinical diagnosis, and there is no need for skin biopsy. If performed, a specific histopathologic findings are seen such as hyperpigmentation of the epidermal basal layer, hemosiderin, and melanin in the dermis and thickening of the arteriolar basement membrane. There is no effective treatment, but some lesions resolve spontaneously in 18–24 months on average though atrophic hypopigmented scars are seen afterward. Infection prevention can be indicated and new lesions may always arise.

Disseminated Granuloma Annulare

Granuloma annulare is a rare benign inflammatory disease. The main efflorescences are erythematous papules which slowly expand centrifugally and resolve centrally to reveal annular plaques with superficial scaling. The back of the hands and arms is usually affected. Patients are usually asymptomatic but can experience pruritus. The disease can occur at any age but is mostly seen in children and adolescents. Multiple subtypes exist. Its relation to diabetes has been the subject of many discussions over the years, and now only the disseminated form is believed to be associated with diabetes, and even this correlation is only based on retrospective studies, and currently no case control studies are available [32, 33]. Generalized granuloma annulare can also be seen in malignancies, thyroid dysfunction, hepatitis B and C, and HIV infections [34,35,36,37,38]. Histology reveals a granulomatous reaction pattern showing palisading of histiocytes (and sometimes giant cells) and lymphocytes surrounding an area of necrobiotic/collagenolytic collagen (complete type). The necrobiotic areas show deposition of mucin. The incomplete type shows interstitial inflammation with histiocytes (sometimes admixed with giant cells) and lymphocytes, and also mucin deposition can be found (incomplete/interstitial form). Pathologists sometimes have difficulties differentiating this disease from necrobiosis lipoidica because both present with infiltrating palisaded histiocytes and collagen degeneration in the dermis. In the disseminated form, inflammation may be mild, and the areas of inflammation are often found in the papillary dermis as seen in lichen nitidus. Also, necrobiosis and mucin deposition might be less profound. Not only pathologists have a hard time differentiating these diseases, they are also clinically resembling and might even coexist. Some authors suggest that generalized granuloma annulare is an early phase of necrobiosis lipoidica [39], although in the former, no epidermal atrophy or yellow discoloration is seen.

In contrast to localized forms, generalized granuloma annulare only rarely resolves spontaneously. A protracted and relapsing course is usually seen with often therapy-resistant lesions. Many different types of treatment have been used including cryotherapy, topical, intralesional or systemic corticosteroids, phototherapy (UVA1 and PUVA), chlorambucil, pentoxifylline, cyclosporine, fumaric acid ester derivatives, potassium iodide, niacinamide, etanercept, infliximab, adalimumab, efalizumab, hydroxychloroquine, and dapsone (Figs. 57.8 and 57.9).

Fig. 57.8

Disseminated granuloma annulare

Fig. 57.9

Disseminated granuloma annulare . Granuloma annulare: areas of necrobiosis are surrounded by palisading histiocytes and lymphocytic inflammation. Although the histopathological features can be identical to classical granuloma annulare, disseminated granuloma annulare often shows a mild infiltrate located in the papillary dermis

Eruptive Xanthomas

Eruptive xanthomas are small (1–2 mm) yellow papules with erythematous border appearing in weeks to months, mostly asymptomatic but sometimes tender. They appear most frequently on the extensor surfaces of the limbs and the buttocks. Lesions often occur as a result of Koebner phenomenon on pressure sites. The yellow discoloration is due to foamy macrophages in the dermal inflammatory infiltrate of lymphocytes and neutrophils. They are associated with elevated eruptive triglycerides in the blood of patients with poorly controlled diabetes (especially type 2), in familial hypertriglyceridemia, and in patients using excessive amounts of alcohol. Insulin stimulates the activity of lipoprotein lipase and plays a role in the metabolism of triglycerides. This leads to a decreased clearance of very low-density lipoproteins and chylomicrons. This can be aggravated further by polyphagia caused by glycosuria [20, 40]. Clinicians should be aware of a significantly elevated risk of pancreatitis [41]. Only 0.1% of patients with diabetes will develop eruptive xanthomas. The main treatment objective is controlling the hypertriglyceridemia and to be aware of other problems related to this condition. Control of diabetes and hyperlipidemia leads to swift disappearance of the xanthomas. Local therapeutic options are application of trichloroacetic acid, excision, curettage, and CO2 laser therapy.

Infections

Recurrent skin infections may be the presenting feature of diabetes. Bacterial and fungal infections appear more frequently, more severe, and atypical. Skin infections occur in 20–50% of diabetic patients, more frequently in type 2, and are associated with poor glycemic control. Patients with well-controlled diabetes are not at higher risk of infections. Viral infection on the contrary is not more frequent. For further details we refer to Chap. 66, Infections.

Lichen Planus

Lichen planus is a chronic inflammatory disease of the skin, mucous membranes, scalp, and nails. Lesions are pruritic and present as flat-topped polygonal violaceous papules. Wickham striae can be visible on oral mucosa only and consist of a fine reticular network of white arborizing lines, but lichen planus can also affect genital mucosa. Four P’s (pruritic, purple, polygonal, and papules or plaques) can be used as a mnemonic. The exact pathogenesis of lichen planus is not clear, but it has been postulated to be a T-cell-mediated autoimmune process, resulting in damage of keratinocytes [42,43,44]. Microscopic examination of a skin specimen reveals specific changes consisting of a lichenoid lymphocytic infiltrate with liquefactive degeneration. Half of the patients with lichen planus have impaired glucose metabolism, and approximately 25% suffer from diabetes. The reverse relationship has been examined much less, and the association is still controversial. Prevalence ranges from 0.9% to 1.4% in the general population vs. 2–4% in patients with either type 1 or 2 diabetes [45,46,47]. Although the disease is usually self-limiting, patients are frequently treated. Topical corticosteroids should be tried first. If necessary other options include oral corticosteroids, oral retinoids, cyclosporine, and phototherapy which have all shown efficacy (Figs. 57.10 and 57.11).

Fig. 57.10

Lichen planus : the lesion shows hyperkeratosis, acanthosis, and a lichenoid interface dermatitis with scattered apoptotic cells along the basement membrane

Fig. 57.11

Lichen planus : an interface dermatitis is noted with scattered apoptotic keratinocytes along the basal layer

Necrobiosis Lipoidica

Necrobiosis lipoidica is a chronic inflammatory skin disorder of collagen degeneration with a granulomatous response, thickening of the blood vessel walls, and fat deposition [48]. A small clinical study determined that patients with necrobiosis lipoidica had a higher proportion of natural antibodies against such as actin, myosin, keratin, and desmin when compared to patients with type 1 diabetes mellitus and healthy control subjects [49, 50]. The disease is typically seen in patients in the third to fourth decade. Normally patients are asymptomatic though pain and pruritus can occur. Necrobiosis lipoidica starts with bilateral non-scaling red papules mostly seen on the pretibial regions though other regions can be involved. Red-brown rims may indicate disease activity. There is a centrifugal spreading pattern. Red papules slowly turn into atrophic lesions with central yellow discoloration possibly due to underlying dermal fibrosis and lipid excess in the dermis or due to the formation of advanced glycation end products, especially 2-(2-furoyl)-4[5]-(2-furanyl)-1H-imidazole which has a yellow hue. Telangiectasia can be seen through the translucent plaque. In advanced disease large plaques can be seen, and 35% of the lesions show ulceration. It should be known that chronic ulceration is a risk factor for the development of squamous cell carcinomas. Necrobiosis lipoidica is thought to be the best recognized skin associated disease of diabetes although it is rare. Prevalence ranges from 0,3 to 1,2% of all diabetics to 2–3% in the insulin-dependent subtype and even higher rates in female patients. Patients with type 1 diabetes develop the disease earlier than those with type 2 diabetes. Diabetes usually proceed the onset of necrobiosis lipoidica by 10 years, although simultaneous and reverse patterns can be seen [51]. The association is less strong if the skin disease presents on other body parts than the legs. Whether the severity of diabetes and the activity of necrobiosis lipoidica are correlated is still uncertain. Its presence is worth mentioning given the higher prevalence of retino- and nephropathy. Histology shows a dermal infiltrate which usually affects the entire thickness of the dermis. The infiltrate tends to be horizontally orientated showing intervening layers of granulomatous inflammation and horizontal layers of layers of necrobiosis (sandwich), in areas showing palisading of histiocytes surrounding necrobiosis . The deep dermis often shows admixture with lymphocytes and plasma cells. Whether microangiopathy, neuropathy, trauma, immunoglobulin deposition causing vasculitis, or a combination of these forms, the origin of the collagen matrix destruction is still under discussion. Necrobiosis lipoidica is very hard to treat, but sometimes slow healing occurs. No positive effect of glycemic control has been demonstrated so far [52, 53]. Topical steroids (if necessary under occlusion) are a therapeutic option but can also worsen the atrophy. If an active border is seen, intralesional steroids may be of help. Topical calcineurin inhibitors and compression therapy might be effective. Systemic treatment is possible with chloroquine, fumaric acid ester derivatives, mycophenolate mofetil, cyclosporine, anti-TNF-alpha, and psoralen with ultraviolet As radiation (PUVA). Lesions tend to relapse with therapy cessation. Spontaneous resolution is seen in 13–19% of patients after 6–12 years [20] (Figs. 57.12 and 57.13).

Fig. 57.12

Necrobiosis lipoidica

Fig. 57.13

Necrobiosis lipoidica . The infiltrate shows horizontal “sandwich” layering (a) of granulomatous inflammation and necrobiosis (b) and fibrosis. The deep dermis often shows a surrounding lymphocytic infiltrate admixed with plasma cells (c)

Psoriasis Vulgaris

Psoriasis is a chronic immune-mediated inflammatory disease of the skin. Patients present with erythematous scaly papules and plaques occurring most frequently in areas of friction [50]. It is common, the prevalence worldwide is estimated to be 1–3% [54]. The association between these two diseases has been made, but up until now, no consensus was made. Patients with diabetes may present with a more edematous inflammatory course of psoriasis as well as more therapy-resistant psoriasis [55]. Treatment consists of topical (e.g., calcipotriol, corticosteroids, and tacrolimus) or systemic immunomodulators as well as UV light [50] (Fig. 57.14).

Fig. 57.14

Psoriasis vulgaris

Pruritus, Xerosis Cutis, and Keratosis Pilaris

Xerosis cutis , xeroderma, or dry skin is one of the earliest and most frequent skin signs in diabetes, found in almost half the diabetic population. Dry mucous membranes, for example, laryngitis scleroticans sicca can be observed as well. Xerosis can be demonstrated in diabetics by measuring transepidermal water loss and high-frequency conductance of the forearm [51]. We should keep in mind that both xerosis cutis and diabetes mellitus are very common. The presence of xerosis cutis increases the risk of complications, including infection and ulceration [50]. Pruritus is the main complaint patients present with. In atopic patients, the prevalence of xerosis cutis is higher.

Xerosis cutis is believed to result from sympathetic and sensory neuropathy and also vasculopathy. Sweat gland dysfunction starts with thermoregulatory dysfunction of the extremities and later on the entire body (global anhidrosis) although the reverse can occur (e.g., postprandial gustatory sweating on the face, neck, and chest). Chronic generalized pruritus can be a sign of undiagnosed diabetes as well as truncal pruritus, burning feet syndrome, pruritus vulvae, and anogenital pruritus although the latter may be secondary to candidiasis or streptococci infection. Clinicians should keep in mind that underlying illness and drug reactions also cause pruritus. Regular use of emollients helps to prevent this skin problem.

Keratosis pilaris consists of rough follicular papules and variable erythema on the extensor surfaces of the extremities and sometimes on the face, buttocks, and trunk. It flares up in wintertime. 11.7% of children with type 1 diabetes have keratosis pilaris, but it is very common in nondiabetic patients as well. Xerosis cutis certainly plays a role in this disease. Treatment is difficult and not strictly necessary, but emollients as well as keratolytic agents, retinoids, and topical corticosteroids of low potency can be helpful.

Rubeosis Faciei: Palmar Erythema and Periungual Telangiectasia

Acral erythema is an erysipelas-like erythema of the hands (especially the thenar and hypothenar region) and feet and has a mostly patchy distribution due to microangiopathy [56]. It differs from physiological erythema caused by warmth, emotional state, hand elevation, and external pressure in its distribution and aspect of the erythema .

Rubeosis faciei is a relatively common chronic flushed appearance of the face, neck, and upper extremities. It is more easily to notice in Fitzpatrick skin types one and two.

These two asymptomatic skin signs both result from small vessel occlusive disease with compensatory hyperemia of superficial blood vessels or from decreased vascular tone. Described prevalence in patients with type 1 and 2 diabetes range from less than 10% to over 60% [57,58,59,60]. This might be due to confounding factors such as Fitzpatrick skin type (Table 57.1), severity of disease, and inpatient status. It is associated with vessel engorgement which contributes to visual impairment in diabetics. The erythema is directly related to disease duration. Improvement is seen with adequate control of blood sugar levels, but these phenomena flare up with concomitant use of vasodilating therapies or vasodilators such as caffeine and alcohol.

Table 57.1 Fitzpatrick scale of skin phototypes [61]. Different skin types are divided based on skin color and response to ultraviolet irradiation

Periungual telangiectasia is clinically visible dilated capillary veins due to loss of capillary loops and dilation of other surrounding capillaries. It is seen in 40–50% of all patients with diabetes. It can also be seen in connective tissue diseases such as scleredema and dermatomyositis. It is highly likely that nail folds show erythema and that cuticles are ragged (this should not be confused with paronychia caused by infection). Some patients are asymptomatic, while others experience discomfort in their fingertips. No treatment is necessary [50] (Fig. 57.15).

Fig. 57.15

Erythema

Skin Thickening and Scleredema Diabeticorum

Skin thickening and scleredema diabeticorum are associated with long-term disease progression and diabetic neuropathy (P < 0.05) [62] and are a cutaneous marker for other microvascular complications.

There are three subtypes of skin thickening. The first subtype there is a benign asymptomatic thickening which is only measurable with ultrasonography. This type is seen in nearly 25% of all diabetic patients. The second type of skin thickening is clinically noticeable. Phenotypes range from Huntley papules to diabetic hand syndrome in 8–50% of diabetic patients [63, 64]. The initial complaints in diabetic hand syndrome consist of stiffness and progresses to limited joint mobility and possibly Dupuytren’s contracture (caused by shortening of skin anchoring ligaments).

Scleredema diabeticorum is a rare asymptomatic diffuse ill-defined erythematous induration of the upper back and neck possibly extending to the deltoid and lumbar region. Acral regions are spared. The skin can have a peau d’orange aspect. Reduced elasticity of the skin can result in reduced joint mobility and thus stiffness frequently coexists. Two and a half to fourteen percent of patients with diabetes suffer from this condition. Men and obese patients with long-lasting type 2 diabetes are at higher risk. Pathology reports show an unaffected epidermis and a homogenous thickened dermis with activated fibroblasts and enlarged collagen bundles separated by mucin deposition. It is import to take a full-thickness excisional biopsy. An excess of blood glucose leads to collagen synthesis by fibroblasts and retarded collagen degradation and glycosaminoglycan depositions. Scleredema is also seen in rheumatoid arthritis, hyperparathyroidism, Sjögren’s syndrome, and seldom in IgG paraproteinemia or malignancy.

Scleredema diabeticorum and classic scleredema are clinically difficult to distinguish but appear to have distinct light and electron microscopic features [65]. Scleredema diabeticorum does not improve with glycemic control although this measure is believed to be an important preventive tool. Treatment is often difficult and includes UVA (psoralen UVA as well as UVA1) and systemic therapy such as oral corticosteroids, cyclosporine, and cyclophosphamide. In severe cases radiotherapy could give some relief [66,67,68,69].

Ulcers

See Chap. 65, foot complications.

Vitiligo

In vitiligo depigmented maculae are seen which are slowly progressive. The extent of affected skin ranges from localized to generalized and even universal and is mostly seen on the face, hands, and genitals. Histopathology shows the absence of melanocytes in the basal layer after Melan A staining. It is possible that some melanocytes are seen around the hair follicles. The depigmentation is the result of immune-mediated melanocyte loss or function loss, and tyrosinase is the main antigen recognized. One in three patients has a positive family history of vitiligo . One to seven percent of insulin-dependent diabetics suffer from vitiligo [2] compared to a 0.2–1% prevalence in the global population making it the most common depigmenting disorder [5]. Due to the high number of type 2 diabetics, these patients will be seen more often with vitiligo, though it is relatively more prevalent in type 1 diabetes. The combination of type 1 diabetes and vitiligo is suggestive for polyglandular autoimmune syndrome. This is a rare immune-mediated endocrinopathy with at least two affected endocrine glands. In these cases vitiligo is often more difficult to treat. Patients should avoid sun exposure. Topical corticosteroids of high potency can give satisfying results if applied early on (with or without narrowband ultraviolet B). Topical calcineurin inhibitors have shown some benefit. PUVA and 8-methoxypsoralen lotion can be used as well. In generalized vitiligo, treatment with ultraviolet B light may be an option as well. Camouflage therapy is an option if patients have cosmetic concerns (Figs. 57.16, 57.17, and 57.18).

Fig. 57.16

Vitiligo

Fig. 57.17

Vitiligo: absence of melanocytes (HE stain)

Fig. 57.18

Vitiligo: absence of melanocytes (Melan A stain)

Yellow Skin

The yellow skin of some diabetic patients consists of an orange to yellow discoloration of the skin, most obvious on the palms and soles. The sclerae are spared in contrast to patients suffering from jaundice. Yellow nails affects up to 40% of diabetic patients, especially the elderly. The yellow color is best visible at the distal part of the nails, and these discolored nails have a slower growth rate and appear more curved due to poor vascularization of the nail matrix. Differential diagnosis includes physiological processes in the elderly, onychomycosis, yellow nail syndrome, yellow nails due to lymphedema, or respiratory tract disease [70].

The relationship of both discolorations to diabetes mellitus is questionable. Some believe that diabetic patients are exposed to higher levels of carotene in their diet rich of fruits and vegetables, which together with an impaired hepatic conversion leads to carotenemia and thus yellow discoloration of skin and nails. Differential diagnosis of carotenemia includes jaundice hypothyroidism, hypogonadism, hypopituitarism, bulimia, and anorexia nervosa [12].

Another possibility is the formation of advanced glycation end products, especially 2-(2-furoyl)-4[5]-(2-furanyl)-1H-imidazole which has a yellow hue as mentioned before. There is currently no treatment available (Fig. 57.19).

Fig. 57.19

Yellow nails

Side Effects of Medication

Side Effects of Insulin

Insulin Lipodystrophy

Atrophy and hypertrophy of the skin might both occur although they are less frequently seen since the use of more pure insulins and synthetic analogues. Hypertrophy used to be present in two thirds of insulin-dependent patients, but this number has been reduced to 1–2%. It is characterized by a localized hypertrophy of subcutaneous fat. In these hypertrophic areas, insulin absorption is delayed; therefore, patients should rotate the injection site. Hypertrophy resolves spontaneously.

Atrophy at the insulin injection sites is due to an immunological reaction including IgM, IgE, and C3 in dermal blood vessels initiating a signal cascade that inhibits adipocyte differentiation [71]. Duration of exposure and depot formation play a role in the onset of atrophy. Substitution with fast-acting insulin has been suggested as therapy [3]. It is unknown why women are more likely to develop atrophy and why men suffer from lipohypertrophy more often.

Continuous subcutaneous insulin infusion with the latest type of infusion materials does not frequently induce local infections, although allergy to tape and certain tubing constituents can be seen.

Allergic reactions to insulin are seen in approximately 2.4% of insulin-dependent diabetics. They can be classified into four categories (immediate local, generalized, delayed, and biphasic). Immediate local reactions range from erythema to urticaria and are assumed to be IgE mediated. Peak intensity is reached in 15–30 minutes and resolves within the hour. The immediate local reaction may progress to generalized erythema and urticaria. Anaphylaxis is rare. Delayed forms (4–24 hours after injection appearing 2 weeks after the start with insulin therapy [3, 10] present most frequently with itchy nodules at the injection site. Biphasic reactions are rare and consist of a combination of an immediate and a delayed local reaction in a patient with symptoms resembling serum sickness. Treatment with topical corticosteroids is almost always successful.

Oral Hypoglycemic Medication

A wide range of quit frequently appearing cutaneous drug reactions to oral antidiabetic agents have been described ranging from pruritus, photosensitivity, allergic reactions, erythema multiforme, erythema nodosum, urticarial, and pruritus to lichenoid and morbilliform eruptions.

• Sulfonylurea has the most skin-related side effects, as approximately 1–5% of patients develop cutaneous reactions within 2 months of treatment. Maculopapular eruptions are the most common. Other cutaneous side effects include erythema, urticaria, erythema multiforme, exfoliative dermatitis, erythema nodosum, pemphigus vulgaris, psoriasiform, and lichenoid drug eruptions. Most sulfonylureas can induce photosensitivity. Even with a negative patch, test oral antidiabetic therapies should be switched.

  Approximately 20% develop an alcohol flush with symptoms of redness, warmth, headache, tachycardia, and seldom dyspnea within 15 minutes after alcohol consumption and disappearing within the hour. Second-generation sulfonylureas present with less cutaneous side effects.

• Meglitinides or glinides rarely cause cutaneous reactions (<0.01%). If present they usually consist of pruritus, rash, urticaria, or generalized reactions such as anaphylaxis shock.

• Biguanides such as metformin cause cutaneous side effects ranging from psoriasiform drug eruptions and leukocytoclastic vasculitis to phototoxic reactions and erythema multiforme.

• Thiazolidinediones glitazones can seldom cause edema.

• Dipeptidyl peptidase IV inhibitors give dose-dependent necrotic skin lesions in monkeys. Increased rates of angioedema are noted only if they are used together with ace inhibitors due to inhibition of the degradation of bradykinin and substance P. Case reports show severe skin reactions such as bullous pemphigoid, Stevens-Johnson syndrome, and toxic epidermal necrosis.

• Alpha glucosidase inhibitors like acarbose have been responsible for acute generalized exanthematous pustulosis and erythema multiforme.

• Injection of glucagon-like peptide-1 receptor agonist (or incretinomimetics) can cause local granulomatous reactions (e.g. eosinophilic sclerosing lipogranulomas).

Concluding Remarks

The skin is often involved in diabetes mellitus as well as in side effects of medications used to treat diabetes. Some of those skin diseases are more specific for diabetes than others, and some are more frequent in type 1, others in type 2, or both types of diabetes mellitus.

The intensity ranges from mild to severe. Recognizing these skin conditions may be of great value since they can be the presenting symptom in diabetes mellitus, port of entry for infection or sign of advanced disease.

Multiple-Choice Questions

• 1. Which statement is false?

  • (a) Circa 10% of all patients with diabetes mellitus develop skin manifestations.

    False, 30–80% of all patients with diabetes mellitus develop skin manifestations.

  • (b) Patients care a lot about the appearance of their skin.

  • (c) Disseminated granuloma annulare can be observed in diabetes mellitus patients, malignancies, thyroid dysfunction, hepatitis B and C, and HIV infections.

  • (d) Skin manifestations of diabetes mellitus can be present before the diagnosis of diabetes mellitus.

  • (e) Some of the skin manifestations of diabetes mellitus are linked to neuropathy and angiopathy.

• 2. What is true about acanthosis nigricans ?

  • (a) Acanthosis nigricans can only occur in patients with diabetes mellitus.

  • (b) Acanthosis nigricans is highly disabling.

  • (c) Acanthosis nigricans occurs in the intertriginous areas

    Correct, especially in the neck, armpits, and groins.

  • (d) After treatment no recurrence is possible.

  • (e) It occurs more often in the Caucasian race.

• 3. Acquired perforating dermatosis is (Fig. 57.20)

  • (a) Easy to treat

  • (b) A frequently appearing dermatosis

  • (c) Is most frequently seen on the flexor areas of the lower extremities

  • (d) A highly pruritic skin disease

    Correct. It presents with scaly highly pruritic follicular hyperkeratotic papules and nodules.

  • (e) More frequently seen in Caucasian people

• 4. Which statement about bullosis diabeticorum is false ?

  • (a) There are three known subtypes.

  • (b) All subtypes heal without scarring.

    False, the cleavage level of the second subtype lies below the dermoepidermal junction, so healing leaves scars.

  • (c) It occurs more frequently in men with long-standing poorly controlled type 1 diabetes.

  • (d) No treatment is needed.

  • (e) Primary autoimmune blistering should be excluded.

• 5. Diabetic dermopathy is

  • (a) A synonym for shin spots

    Correct, these are asymmetric red to brown hyperpigmented spots.

  • (b) A synonym for diabetic stiff hands

  • (c) No reason to screen for diabetes mellitus

  • (d) A skin manifestation that never precedes diabetes mellitus

  • (e) A unilateral appearing dermatosis

• 6. Which statement concerning eruptive xanthomas is false?

  • (a) Patients with eruptive xanthomas are usually asymptomatic.

  • (b) There is a correlation with elevated blood triglycerides.

  • (c) There is an elevated risk of pancreatitis.

  • (d) Systemic treatment is indicated.

    False, the main treatment objective is controlling the hypertriglyceridemia. Local therapeutics can be used.

  • (e) 10% of all diabetes mellitus patients develop eruptive xanthomas.

• 7. Which statement on granuloma annulare is false?

  • (a) Granuloma annulare is a rare benign inflammatory disease.

  • (b) This disease usually occurs on the hands and arms.

  • (c) All forms occur more frequently in patients with diabetes mellitus.

    False, only the disseminated form occurs more frequently in diabetes mellitus patients.

  • (d) It is sometimes histopathologically difficult to distinguish from necrobiosis lipoidica.

  • (e) Multiple subtypes exist.

• 8. Which statement on lichen planus is true?

  • (a) Lichen planus is a chronic inflammatory disease due to overactivity of the B-cells.

  • (b) Lichen planus only occurs on the oral mucous membrane.

  • (c) The relationship to diabetes mellitus is completely clear.

  • (d) Lichen planus only occurs on the skin.

  • (e) Four P’s can be used as a mnemonic.

    Correct, it stands for pruritic, purple, polygonal, papules, or plaques.

• 9. What is true about necrobiosis lipoidica ?

  • (a) It is important to diagnose.

    Correct, prevalence of retinopathy and nephropathy is higher in this subgroup of patients.

  • (b) Never precedes diabetes mellitus.

  • (c) Occurs in the first and second decade.

  • (d) This skin condition never heals.

  • (e) This skin condition is easy to treat.

• 10. Which statement on vitiligo is false?

  • (a) Patients with vitiligo should avoid sun exposure.

  • (b) After melan A staining, no melanocytes are observed on histopathological examination.

  • (c) It occurs more often in type 2 diabetes.

    False, vitiligo occurs more frequently in type 1 diabetes. Both are autoimmune diseases.

  • (d) Ultraviolet B light may be of help in the treatment of this disease.

  • (e) Topical corticosteroids and calcineurin inhibitors are used in the treatment of vitiligo.

Fig. 57.20

Acquired perforating dermatosis

Correct Answers

• 1. (a) Circa 10% of all patients with diabetes mellitus develop skin manifestations

  False, 30–80% of all patients with diabetes mellitus develop skin manifestations

• 2. (c) Acanthosis nigricans occurs in the intertriginous areas

  Correct, especially in the neck, armpits, and groins

• 3. (d) A highly pruritic skin disease

  Correct. It presents with scaly highly pruritic follicular hyperkeratotic papules and nodules.

• 4. (b) All subtypes heal without scarring

  False, the cleavage level of the second subtype lies below the dermoepidermal junction, so healing leaves scars

• 5. (a) A synonym for shin spots

  Correct, these are asymmetric red to brown hyperpigmented spots

• 6. (d) Systemic treatment is indicated

  False, the main treatment objective is controlling the hypertriglyceridemia. Local therapeutics can be used

• 7. (c) All forms occur more frequently in patients with diabetes mellitus

  False, only the disseminated form occurs more frequently in diabetes mellitus patients

• 8. (e) Four P’s can be used as a mnemonic

  Correct, it stands for pruritic, purple, polygonal, papules, or plaques

• 9. (a) It is important to diagnose

  Correct, prevalence of retinopathy and nephropathy is higher in this subgroup of patients

• 10. (c) It occurs more often in type 2 diabetes

  False, vitiligo occurs more frequently in type 1 diabetes. Both are autoimmune diseases

Glossary

Atrophy

a loss of tissue from the epidermis, dermis, or subcutaneous tissues. There may be fine wrinkling and increased translucency if the process is superficial.

Erythema

redness of the skin produced by vascular congestion or increased perfusion.

Koebner phenomenon

the onset of new inflammatory skin lesions after minor trauma such as scratching.

Macula

a circumscribed alteration in the color of the skin.

Nodule

a solid mass in the skin, which can be observed as an elevation or can be palpated. It is more than 0.5 cm in diameter. It may involve the epidermis and dermis, dermis and subcutis, or subcutis alone. It may consist of fluid, other extracellular material (e.g., amyloid), inflammatory, or neoplastic cells.

Papule

a circumscribed palpable elevation, less than 0.5 cm in diameter. By careful examination, it is often possible to determine whether the thickening involves predominantly the epidermis or the dermis and what type of pathological process is concerned. The only distinction between a papule and a nodule is the size, and this is artificial; some lesions characteristically occur at the smaller size of a papule, whereas others typically enlarge from a papule to become a nodule. Recording a finite size is more useful.

Plaque

an elevated area of the skin, usually defined as 2 cm or more in diameter. It may be formed by the extension or coalescence of either papules or nodules as in psoriasis and granuloma annulare, respectively. Small plaque is sometimes used for such lesions 0.5–2 cm in diameter.

Sclerosis

diffuse or circumscribed induration of the subcutaneous tissues. It may also involve the dermis, when the overlying epidermis may be atrophic. It is characteristically seen in scleroderma but may occur as a sequel to or in association with many different processes.

Ulcer

a loss of the dermis and epidermis, often with loss of the underlying tissues.

Vesicles and bullae

visible accumulation of fluid within or beneath the epidermis. Vesicles are small (less than 0.5 cm in diameter) and often grouped. Bullae, which may be of any size over 0.5 cm, should be subdivided as multilocular (due to coalesced vesicles, typically in eczema) or unilocular [72].