dermatologic lesions in diabetes mellitus

EPIDEMIOLOGY OF SKIN LESIONS INDIABETES MELLITUS

Numerous skin lesions are associated with either type1 or type 2 diabetes mellitus, specific chroniccomplications of the disease, use of antidiabetic drugs,and certain endocrine and metabolic disorders thatcause secondary diabetes mellitus.

CLASSIFICATION OF DERMATOLOGICLESIONS IN DIABETES MELLITUS

There is considerable uncertainty about thepathogenesis of the many cutaneous conditionsaffecting diabetic patients in no small part because ofour inadequate understanding of the metabolic basis ofdiabetes mellitus itself.

There is no strict classification of skin lesions relatedto diabetes mellitus, therefore grouping them underthe following headings will give us an idea aboutvarious types of skin lesions occurring in diabetes. So,one would know what are the dermatologic conditionsoccurring in a diabetic (1).

Dermatologic lesions associated with but notspecific for diabetes mellitus (disease markers)

• Pruritus

• Necrobiosis lipoidica diabeticorum

• Granuloma annulare

• Diabetic dermopathy

• Scleroderma-like syndrome

• Acanthosis nigricans

• Diabetic bullae

Skin alterations due to diabetic complications

• Diabetic foot

• Cutaneous infections associated with diabetes

- furunculosis- carbuncle- pyodermas- candidiasis- dermatophytosis

• Erythrasma

• Xanthomatosis

• Xanthelasma

• Pycomycetes

• Malignant otitis media

Dermatologic changes associated withneurovascular complications

• Macroangiopathy

147Diabetologia Croatica 31-3, 2002

1 Pathuri Skin Hospital,Near Gokawaram Bus StandRajahmundryAndhra Pradesh, India

2 Vuk Vrhovac Institute, University Clinic for Diabetes,Endocrinology and Metabolic Diseases,Dugi dol 4a, HR-10000 Zagreb, Croatia

Review

DERMATOLOGIC LESIONS IN DIABETES MELLITUS

Chilukuri Sreedevi1, Nikica Car2, Ivana Pavliæ-Renar2

• Microangiopathy

• Diabetic neuropathy

Dermatologic complications of diabetestreatment

• with oral hypoglycemic drugs

• with insulin

Endocrine syndromes with skin alterations anddiabetes mellitus

• Migratory necrolytic erythema in glucagonoma

Dermatoses that are more common in diabetesmellitus

• Perforating dermatosis

• Vitiligo

• Lichen planus

• Eruptive xanthomas

• Kaposi’s sarcoma

• Bullous pemphigoid

• Dermatitis herpetiformis

• Psoriasis

VARIOUS TYPES OF DERMATOLOGICLESIONS IN DETAIL

Dermatologic lesions associated with but notspecific to diabetes mellitus (disease markers)

Pruritus

Generalized pruritus was once considered a typicalsymptom of diabetes but its frequency is unknown.Studies have failed to provide a statistical basis for thisbelief (2,3). A higher rate of pruritus is found in liverdiseases, uremia, parasitic infestation, endocrinedisorders (thyroid), malignant diseases, hemotologicand metabolic diseases, and as a side effect of somedrugs. Generalized pruritus is associated with diabetescomplications of chronic renal insufficiency,occasionally neuropathy (irritation of nerve endings canbe the cause). High levels of urea in the blood cause

the skin to itch. Candidiasis or dermatophytosis mayunderlie pruritus in diabetic patients. Anogenitalpruritus is often caused by candidiasis in diabeticpatients (4).

Some fungal infections most commonly occurring indiabetics are jock itch, athlete’s foot and ringworm.Jock itch appears as a red, itchy area that will spreadfrom genitals outward over the inside of the thighs.Jock itch is more common in men than in women.When athlete’s foot occurs the skin between the toeswill become itchy and sore. It may also crack, peel orblister. Ringworm is identified by ring-shaped, red scalypatches that can itch or blister. Ringworm can appearon the feet, groin, trunk, scalp or nails. Itching in thelegs in elderly diabetics is not a feature ofhyperglycemia but rather a manifestation of xerosis.Simple lubricants and low potency corticosteroidapplication should prove helpful.

Necrobiosis lipoidica diabeticorum

The disease is very rare, occurring in 7% of diabeticpatients (5). These relatively asymptomatic lesionsare three times more common in women than in men.It is one of the cutaneous markers of diabetes. At thetime of diagnosis 10% of the people will developdiabetes within 5 years or have abnormal glucosetolerance or history of the disease in at least one parent(6). The condition occurs at any age but it generallyfavors young adults at a mean age of 34 years. In insulinusers, the onset is considered to occur much earlierthan in type 2 diabetics or nondiabetics (7). Thelesions are characteristically found on the anterior andlateral surfaces of lower legs, i.e. in the pretibial andmedial malleolar region. They may also be present onthe face, arms and trunk. There may be one or severallesions, either unilateral or bilateral. The lesion beginsas a small, dusky-red elevated nodule with a sharplycircumscribed border. It slowly enlarges to turn into aplaque of irregular outline, flattened, and eventuallydepressed as the dermis becomes more atrophic.

The color turns more brownish-yellow except for theborder, which may remain red. Coalescing or enlarginglesions may in time encompass the entire anteriortibial area. The epidermis is smooth or slightly scalyand atrophic. Delicate vessels can be seen through thesurface. The lesions may be anesthetic or havereduced sensation to pin prick and to fine touch due todestruction of cutaneous nerves (8).

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C. Sreedevi, N. Car, I. Pavliæ-Renar / DERMATOLOGIC LESIONS IN DIABETES MELLITUS

The chronic lesions of necrobiosis lipoidicadiabeticorum (NLD) are indolent; shallow, oftenpainful ulcers frequently appear in long-standinglesions. In the early stages, NLD may resemblegranuloma annulare or sarcoid, but a well-developedplaque is characteristic and easily recognized. Theprimary pathologic changes are in the lower dermis,where collagen is markedly altered with focal areas ofloss of normal structure, swelling, basophilia, anddistortion of the bundles (necrobiosis). Cross-striationsand diameters of collagen fibers are irregular. Althoughthe amount of collagen is actually decreased, therelative proportions of types I and III are preserved.Fibroblasts cultured from skin lesions have beenreported to produce less collagen. There is also theloss and fragmentation of elastic fibers. There isincreased collagenase in the lesional skin. In theseareas, there are aggregations of inflammatory cells. Thelate appearance of foam cells accounts for thedesignation ’lipoidica’.

The vasculature is always involved, with endothelialproliferation and occlusion of the lumina of arteriolesand venules (9,10). Capillary walls are thickened withfocal deposits of PAS-positive material that may alsobe present in the lumen. The nature of the associationwith diabetes and its pathogenesis remains unclear.Because NLD occurs in both IDDM and NIDDM, itspathogenesis cannot be related to genetic factors,underlying autoimmune disease, or other causes ofdiabetes. It can be reasonably assumed that thegranulomatous response is secondary to alterations indermal collagen. It is not clear whether this issecondary to an underlying vascular disease ordevelops independently. The latter would ascribe thechanges in dermal collagen and vasculature to someprimary disorder of connective tissue (as yetunknown). However, the invariable presence ofarteriolar changes deep into and within the areas ofcollagen degeneration suggests an interrelationbetween the two components of NLD (11). It has beenhypothesized that increased platelet aggregation maybe a trigger factor in vascular changes (12).Immunoglobulins, complement (C3 and C4) (13), andfibrinogen are present in blood vessels in lesional and,in some cases, nonlesional skin (14). These findingsare in concordance with the presence of inflammatorychanges in adjacent clinically normal skin. Thetreatment of NLD is not very satisfactory. Progressionof lesions does not correlate with normalization of

hyperglycemia. Local therapy with topical applicationof glucocorticoids under occlusion or by intralesionalinjection may afford some improvement of activelesions. There have been some enthusiastic reports onthe use of aspirin and dipyridamole, but these werenot confirmed in a rigorous double-blind trial (15).Favorable effects were obtained with very small dosesof aspirin: 3.5 mg/kg every 48 to 72 h (16). Otherhelpful agents are clofazimine, nicotinamide, andpentoxifylline. Ultraviolet light treatment has beenfound to control this condition when it is flaring.

Granuloma annulare

It is a benign necrobiotic condition associated withlesions similar to NLD, the only difference being theabsence of epidermal atrophy. This is a skin diseaseusually seen in children and young adults. It isoccasionally associated with diabetes. Skin signs arecharacterized by red spots in the initial stages thatexpand outwards in a ring-like fashion. The hands,especially the fingers, on dorsal or lateral aspect of thehands and elbows (forearms), are commonly affected.When granuloma annulare is widespread it may beassociated with underlying diabetes mellitus. The skinlesions may precede the symptoms and signs ofdiabetes mellitus. Patients with widespread granulomaannulare need to be screened for diabetes mellitus.Mostly it is asymptomatic and resolves spontaneously.

Diabetic dermopathy

It is the most common skin lesion occurring indiabetics (17). It is prominent in males who are morethan 50 years of age (18). It is seen even in euglycemic,endocrine diseases and also in healthy individuals. Thepresence of small blood vessel changes has led to theterm diabetic dermopathy (17).The lesions areasymptomatic, irregularly shaped patches occurringprimarily over the anterior lower legs; their surfaces aredepressed and they have a light brown color. Thepigmentation is due to deposition of hemosiderin inhistiocytes and extravasated superficial erythrocytes.These lesions can occur on upper arms, thighs, and anybony prominences. Lesions appear in crops andgradually resolve over 12 to 18 months. The disorder isasymptomatic requiring no treatment except forprotecting the area from any trauma and secondaryinfection. Use of bio-occlusive dressing is recom-mended.



Scleroderma-like syndrome, reduced joint mobi-lity, waxy skin syndrome

These terms are synonymous denoting one and thesame skin disorder (17,19). As many as one third ofdiabetic patients (both IDDM and NIDDM) havetight, thickened waxy skin over the dorsum of thehands. Reduced joint motion probably is the earliestcomplication of diabetes mellitus, a characteristicfinding in children and adolescents after only 10 yearsof diabetes duration. The metacarpophalangeal andproximal intraphalangeal joints are usually firstinvolved. Reduced extension, initially active, then alsopassive, is observed. Flexion may for long remaincompletely preserved. Clinical signs include impossibleextension of the palm on the table and impossibleclasping hands as in prayer. Restriction of passiveextension of the interphalangeal and metacarpo-phalangeal joints is most important from the diagnosticpoint of view (20,21). The skin becomes thickened,with a waxy appearance, in about one third of patients(22). Such skin resembles sclerodermic skin.Histologically, dermal collagen thickening and elasticfiber reductions are observed (23,24). This cutaneousmanifestation can accompany MODY and is consideredto be associated with poor prognosis in terms ofprediction of retinopathy and nephropathy (25,26).However, there are no substantial evidence supportingthe above concept (27).

Acanthosis nigricans

This disorder is characterized by velvetypapillomatous hyperplasia of the disease, and diabetes.Mild forms also occur in obesity without evidentendocrine disorder. It appears likely that a commonpathogenetic mechanism accounts for acanthosisnigricans linked to endocrinopathy. Studies of patientsshowed the epidermis with intense hyperpigmen-tation, which was most pronounced in the axillary,inguinal, and inframammary folds, and in the creases ofthe neck.

In more severe forms it may be more generalized andaccompanied by verrucous patches on knuckles andother extensor surfaces, hyperkeratosis of the palmsand soles, and other hyperplastic lesions. Acanthosisnigricans is associated with two types of disorders. Themore severe form is usually found in patients withadvanced malignant disease. The more limited form ismore frequently found in association with a variety of

endocrinopathies (28), including acromegaly, Cushing’ssyndrome, and polycystic ovary. A variety of endocrinediseases and acanthosis nigricans suggest that insulinresistance is a common denominator even in theabsence of overt diabetes. It was first shown to beassociated with insulin resistance in patients with therare syndrome of lipoatrophic diabetes (29). Subse-quently, acanthosis nigricans has been associated withall three types of insulin resistance:

- type A, in which insulin resistance is due to receptordefects resulting in decreased insulin binding;

- type B, in which insulin resistance is conferred byeffects of circulating antireceptor antibodies; and

- type C, in which postreceptor defects includingabnormalities in signal transduction such asautophosphorylation of the receptor and activation oftyrosine kinase inhibit insulin action (1,30). Histologic examinations reveal markedhyperkeratosis and papillomatous lesions (31),although the epidermis is mildly acanthotic, i.e.thickened (32). The use of keratolytic agents such assalicylic acid can improve the appearancecosmetically, if desired.

Diabetic bullae

Diabetic bullae are very rare but characteristic ofdiabetes mellitus. They occur in adult males. Thebullae appear spontaneously, commonly in the dorsumand sides of the lower legs, especially feet. Sometimesthey are associated with similar lesions on the forearmand hands. Bullae may range from millimeters to fewcentimeters. The lesions are often bilateral, containingclear sterile fluid. There is no surrounding erythema.Generally, the bullae heal in several weeks withoutsignificant scarring, although they may recur (33).These blisters are not the result of trauma or infection(34). The bullae are subepidermal, and ultrastructuralstudies have demonstrated the plane of separation tobe in the basement membrane zone above the basallamina. In some cases the distribution of lesions in lightexposed areas suggests porphyria cutanea tarda, butabnormalities of porphyrin metabolism have not beenfound. Neither trauma nor immune mechanisms havebeen implicated. The cause of this rare manifestationof diabetes is unknown. At least 75 percent of patientshave significant diabetic retinopathy, and in one seriesof three patients dermopathy and cutaneous angio-pathy were present (17). The localization of the planeof separation suggests that weakness in the basement

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membrane zone is an underlying factor. That this maybe the case is suggested by the presence of a reducedthreshold to formation of suction blisters on theforearms of insulin-dependent diabetics (35). Usuallythey do not require any treatment apart fromprevention of secondary infection which can be done bythe application of bio-occlusive dressings.

Skin alterations due to diabetic complications

Neurovascular and ischemic changes and footulceration (diabetic foot)

Diabetic foot is a serious complication which resultsfrom confluence of multifactorial pathogenicmechanisms. Neuropathy (motor, sensory andautonomic) and diabetic angiopathy are thecontributing factors for its development, theneuropathy being the major factor. Laceration whichmay be complicated with necrosis, gangrene andosteomyelitis, accentuated plantar arches and hammertoes with interdigital maceration leading to bacterialand fungal infections, and loss of the ankle jerk andvibration sensation are the features of the diabetic foot.Because of its serious nature it requires specialattention. Prevention is by far more relevant than cure.Hence care of the foot must become a routine indiabetic patients.

Cutaneous infections associated with diabetes

Poorly controlled or undiagnosed diabetics have agreater susceptibility to bacterial and fungal infectionsof the skin. The most frequently encounteredinfections are staphylococcal pyodermas such asfurunculosis and carbuncles, candidiasis, erythrasmaand dermatophytosis.

Furunculosis (boils). The word ’boil’ has been derivedfrom the German language and refers to ’swelling’,There is extended involvement of the hair follicleincluding the perifollicular region in the dermis andsubcutaneous tissue, i.e. there is folliculitis as well asperifolliculitis. It is caused by Staphylococcus (S.) aureus.Boils are common during adolescence and early adultage. In India these are more common during the rainyseason. Isolated furuncles appear, and many lesionsmay develop together. In other cases crops of lesionskeep appearing. Generally, the subjects are healthy buthave poor hygiene or are carriers of S. aureus. Factors

like diabetes mellitus, exfoliative dermatitis and intakeof systemic steroids may be responsible for theirincreased frequency and greater severity.

A furuncle usually begins as a tender area, whichrapidly develops into an inflammatory induratednodule of 2 to 3 cm in diameter. Within the next fewdays the area becomes necrotic and discharges pus froma point at the follicular opening. Those furuncles,which do not discharge on the surface are called ’blindboils’.

Carbuncle. A carbuncle may be said to be a group ofboils which show deep infection of contiguous follicleswith S. aureus. The infection spreads from one follicleto the other usually not via the surface but through thesubcutaneous tissue. The lesion starts as a painful,tender, firm to hard indurated lump with a coursesimilar to but more protracted than that of a furuncle.It is associated with intense inflammatory changes inthe surrounding and underlying tissues. Pus isdischarged not necessarily through the follicularopenings but from any point. The common sites are theback of the neck, shoulders, hips and thighs. It isfrequently associated with diabetes mellitus. If theunderlying conditions are controlled and appropriatetherapy instituted, healing takes place leaving a scar,otherwise toxemia and even death may follow.

Pyodermas. The advent of antibiotics and tightercontrol of diabetes has markedly reduced the incidenceand morbidity of pyodermas which were formerlyconsidered as serious complications. Lower extremitiesconstitute a particular hazard for the diabetic patient.The associated atherosclerosis and peripheral neuro-pathy lead to ulceration and gangrene as well as poorwound healing.

Candidiasis (monoliasis). Candida albicans is a commoncomplication in poorly controlled diabetics (36). Theyshow considerable improvement when diabetes iscontrolled. Candidal infections of the skin mayresemble those caused by other dermatophytes but aremost common where the skin is moist and in contactwith itself, e.g. groins, perineum, breasts, axillae. Nailinfections start at the base, forming ridges, oftenaccompanied by paronychia. Paronychia is the infectionof the web space between the middle and fourth finger.In the mouth, white curd-like patches are seen, whichcan be scraped away leaving a bleeding base (37).Atrophy of the gums and angular stomatitis arecommon in the elderly.



Vulvovaginal candidiasis. It commonly presents withitching, soreness, and a thick creamy white discharge.In severe cases, there is beefy red erythema of thevaginal mucosa and vulval skin with curdy white flecksof discharge. The lesion may spread to the perineumand groins. The perianal area is often affected.Candidal vulvovaginitis may be chronic and recurrent.Factors that predispose to candidal vaginitis includepregnancy, diabetes mellitus, oral contraceptive orantibiotic administration, and occlusive tight fittinggarments (38).

Balanitis or balanoposthitis. Balanitis is common amongthe elderly and uncircumcised patients. Balano-posthitis usually presents with itching, pain, erosions,cracks and whitish scales on the terminal portion of theprepuce. Diabetes mellitus is often the underlyingdisease. In diabetic or immunosuppressed patients, asevere edematous, ulcerative balanitis may occur.Phimosis has been observed as a common complaint indiabetic men and recurring candidal infection is usuallythe cause.

Investigations: The yeast may be identified micro-scopically or by culture from swabs or scrapings fromthe lesions, and be cultured from the blood in systemicdisease. Underlying local or systemic defects should besought.

Management: Most important is to correct or controlthe underlying predisposition. Cutaneous candidiasis istreated with a topical azole ointment. Mucosalinfection usually responds well to lozenges orsuspension of nystatin or amphotericin. Persistentinfections and nail infections require oral fluconazole oritraconazole. Systemic infections should be treatedwith intravenous amphotericin or with amphotericinplus flucytosine.

Dermatophytosis (tinea infections) ringworm infections. It isencouraged by the sharing of wash places and ringwormis due to the infection by dermatophyte fungi. Thereare three main genera: Trichophyton (skin, hair, and nailinfections); Microsporum (skin and hair), and Epuler-mophyton (skin and nails).

Clinical features: These depend upon the site and thespecies of fungus involved.

Tinea pedis (athlete’s foot). This is the most commontype of fungal infection in humans. The sharing of washplaces and swimming pools encourages it. Infrequentwashing of socks and the use of occlusive footwear

encourage relapses. It may present in three main ways:soggy interdigital scaling, diffuse powdery scaling ofthe soles (which is often unilateral and which picks outskin creases), and recurrent bouts of vesiculation of thesoles. The organisms involved are usually T. rubrum, T.mentagrophytes var. interdigitale and E. floccosum.

Tinea unguium (tinea of the nails). Toe nail infection ismore common than finger nail infection and is oftenaccompanied by tinea pedis. Usually only a few nailsare infected. The changes first occur at the free edgeof the nail, which becomes yellow and crumbly.Thickening of the nail and separation of the nail fromthe nail bed may follow. T. rubrum is a frequent cause.

Tinea manuum (tinea of the hands). It is usuallyasymmetric and involves the palms (dry, powderyscaling picking out the creases) more often than thebacks of the hands.

Tinea cruris (tinea of the groin). It affects men more thanwomen and causes well-demarcated redness andperipheral scaling of the groins and upper thighs. A fewvesicles or pustules are usually seen within the lesions.The eruption is often unilateral or asymmetric, anditchy.

Tinea corporis (tinea of the trunk). It is the archetypal’ringworm’ eruption. Erythematous scaly plaquesexpand slowly and clear in the center, leaving a ring-like pattern. Peripheral scaling, a few vesicles andpustules are characteristic.

Erythrasma

As the name suggests the initial lesions are reddish(in fact, reddish-brown) but as the disease isasymptomatic, patients are not generally observed atthis stage. After a period of time, the lesions becomebrownish-black (like a silver nitrate stain) withirregular but very well defined borders. They aresmooth but later appear creased and even finely scaly.The sites of predilection of clinical disease are thegenitocrural folds, axillae and submammary regions.The Coryneforms causing erythrasma are seen in largesections of the population in the interdigital webspaces where they produce only mild scaling. Thelesions fluoresce coral-red under Wood’s light orultraviolet-A (UVA) light, due to coproporphyrin IIIproduction by the bacteria. If the patient has recentlytaken a bath, the fluorescence may not be observed asthe porphyrin is soluble in water.

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Xanthomatosis

Eruptive xanthomas are a characteristic butuncommon complication of diabetes mellitus asso-ciated with a more sustained hyperlipidemia affectingplasma triglycerides and cholesterol more thanphospholipids, and hyperglycemia with glycosuria. Thedecreased lipoprotein lipase activity in insulin-dependent diabetics results in the accumulation ofserum triglycerides, whose levels are occasionallyhighly elevated to produce eruptive xanthomas.

Cutaneous xanthomas result from deposition of lipidin the histiocytes in the dermis or subcutaneous tissue.Xanthomas tend to appear rapidly in crops as multiple,small, reddish-yellow nodules of up to 0.5 cm indiameter. They present in clusters primarily on theextensor surfaces and buttocks. The lesions are muchsmaller and more inflammatory than tendinous andtuberous xanthomas, which are associated withhypercholesterolemia and may be pruritic initially.Rapid regression of these lesions occurs whenhyperlipidemia is brought under control.

Xanthelasma

It occurs in most hyperlipidemic states includingdiabetes. It does not regress with therapy for diabetes.A yellowish discoloration of the skin of the palms, solesand nasolabial folds due to the deposition of carotenepresent in excess quantities in plasma may beassociated with hyperlipidemia even in the absence ofxanthomatosis in diabetes.

Phycomycetes infection

Sometimes hyperglycemia may permit organisms thatare nonpathogenic to produce infection in traumatizedskin, which may lead to gangrene and loss of the limb.There are various factors, which help thephycomycetes establish and lead to the infection.These factors include pre-exsisting leg ulcers,nonhealing surgical wounds, deep seated fungalinfections, etc. Treatment must be aggressive,consisting of correcting acid-base balance, debride-ment of devitalized tissue, and intravenous antifungaltherapy. Patients with uncontrolled diabetes mellitusand ketosis may be predisposed to deep fungalinfections or rhinocerebral mucormycosis of theturbinates, septum, palate, maxillary and ethmoidsinuses (38).

Malignant otitis media

It is caused by Pseudomonas aeruginosa. It is anuncommon but a very serious infection. Initially thereis purulent discharge and pain in the external ear canal.It occurs commonly in diabetic men. It begins as acellulitis and can progress to chondritis, ostomyelitis,and infective cerebritis. It usually has fatal outcome.So, the treatment includes the use of antipseudomonasantibiotics and debridement of devitalized tissue ifnecessary (38).

Dermatologic changes associated withneurovascular complications of diabetes

Macroangiopathy

Patients with diabetes mellitus have a slightly higherincidence and prevalence of large-vessel diseasecompared with control subjects (39). In patients withIDDM or NIDDM, both low-density lipoproteincholesterol and VLDL triglycerides are risk factors(40). Atherosclerosis of the arteries of the legs resultsin skin atrophy, hair loss, coldness of the toes, naildystrophy, pallor on elevation, and mottling ondependence (33). A reliable sign of large vessel diseaseis dependent rubor with delayed return of color (>15seconds) after pressure has been applied to the skin(41).

Microangiopathy

The role of diabetic microangiopathy is notcompletely understood. The signs include diabeticdermopathy, pigmented purpura, erysipelas such aserythema, NLD, periungual telangiectases, anddiabetic foot (42). Other signs of microangiopathyinclude cutaneous reactive hyperemia and reducedcapillary flow on cold or warm challenges of patientswith IDDM and those with NIDDM, as measured bylaser Doppler flowmetry (43-47).

The thickening of the vessel walls, perivasculardeposition of material reactive with periodic acid-Schiff stain, and clumping of the elastic fibers in thepapillary dermis are produced by a combination ofintimal hyperplasia and increased deposition of type IVcollagen within and around the vessel wall. The spacebetween the pericytes and the endothelial cells iswider, and the cytoplasmic process that formed thecontact point between them is longer and thinner thannormal, suggesting a possible explanation for increased



permeability (48). The capillary leakage leads to theloss of albumin and water, and the platelets have ahigher tendency to aggregate. As a result, increasedwhole blood and plasma viscosity creates a sluggishmicrocirculation (41).

Diabetic rrubeosis is a peculiar rosy reddening of the face,sometimes of the hands and feet, which may beobserved in longstanding diabetics. It has beenattributed to diabetic microangiopathy or a decreasedvascular tone.

Diabetic neuropathy

Elderly patients in whom the onset of diabetes isinsidious are especially at risk of developing diabeticneuropathy. A common neuropathy in diabetes mellitusis a distal, symmetric, mixed polyneuropathy involvingboth the motor and the sensory nerves (49).

The skin manifestations of autonomic neuropathy indiabetes mellitus are disturbances in sweating andperipheral hyperemia with erythema, edema, andatrophy. Motor neuropathy of the feet leads toimbalance between flexor and extensor muscles,displacement of fat pads, and subluxation of digits(50).

Typical signs of sensory neuropathy in diabetesmellitus are paresthesias with the loss of temperatureand pain sensation, as well as aching and burning of thelegs that are worse at night. The combination of motorand sensory neuropathy along with mechanical factorsand microangiopathy plays a major role in thedevelopment of the diabetic foot (42).

Immunohistochemical studies of nerves in diabeticskin have demonstrated depletion of neuropathies.The antidepressant drugs such as desipramine andamitriptyline that inhibit the membrane pumpmechanism for the reuptake of neuropeptides haveproved effective in diabetic peripheral neuropathy(50).

Dermatologic complications due to the treatmentof diabetes

Oral hypoglycemic drugs

The cutaneous complications of oral hypoglycemicagents are few. They occur more commonly with firstgeneration sulphonylureas such as chlorpropamide and

tolbutamide, and usually develop in the first twomonths of treatment. They may be either toxic orallergic in nature.

Phototoxic reactions presenting as excessive sunburnafter exposure to sunlight occur in a few patients (52).Allergic skin reactions are uncommon and are similarfor all hypoglycemic drugs belonging to thesulphonylurea group. They are usually mild and self-limited. Patients may present with intermittent orpersistent pruritus or a maculopapular rash. Othercutaneous reactions which may occur occasionallyinclude urticaria and erythema multiforme, which mayprogress to the Stevens-Johnson syndrome. Other rareskin manifestations include erythema nodosum andpurpura as well as exacerbation of porphyria cutaneatarda and generalized hypersensitivity reactions.

The chlorpropamide alcohol flush occurs in patientstaking this drug. The reaction usually begins within 15min after ingestion of alcohol. It causes flushing,headache, tachycardia and dyspnea that graduallysubsides after an hour. Second generation sulpho-nylureas, which are now widely used, produce fewercutaneous side effects. The allergic skin reactions tosuphonylureas often disappear while the patient isreceiving a maintenance drug regimen.

Insulin

Cutaneous complications due to insulin therapy usedto be common before the advent of newer insulins.Allergic reactions to insulin may be immediate ordelayed. Serious generalized reactions such as urticariaand anaphylaxis are rare. The immediate local reactionis probably IgE-mediated. It starts as erythema,becomes urticarial within 30 min and subsides withinan hour. The delayed reaction is the most commonreaction. It is due to delayed hypersensitivity. About 2weeks after the initiation of insulin therapy, a pruriticnodule develops within 1 or 2 days at the site ofinjection, lasts for days and heals with hyper-pigmentation and scarring. Localized induration,ulceration and scar formation, cutaneous abscessformation and development of keloids may result fromfaulty injection techniques. Idiosyncratic reactions arevery rare and include pigmentation and occasionallykeloid formation. Skin reaction resembling acanthosisnigricans has been reported.

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Lipoatrophy. Insulin lipoatrophy and lipohypertrophy,which are the complications of insulin injection, arerare after the introduction of newer insulins.Lipoatrophy presents as circumscribed atrophicplaques showing atrophy of the subcutaneous fat at thesite of insulin injection, and rarely shows completeresolution. It may be due to a local immune response toinsulin injection (53).

Lipohypertrophy. It presents as a soft dermal nodule.The overlying skin appears normal at the site ofinjection. It may be due to the lipogenic action ofinsulin.

Insulin edema. Edema of the abdomen and legs is amore common and usually a self-limiting complicationwhich appears shortly after starting or increasing thedose of insulin. It is commonly seen in women (54) andis unrelated to cardiac or renal disease. Thepathogenesis is unclear. Ephedrine is the drug of choice(55).

Endocrine syndromes with skin alterations anddiabetes mellitus

Glucagonoma

It is the most characteristic endocrine syndromemanifesting with skin alterations and diabetes mellitus.This syndrome is often diagnosed late and mostly by adermatologist. The dermatosis is the presenting clue.The syndrome is usually caused by tumors of the alpha-cell, glucagon secreting portion of the pancreas. It hasfour components:

- hypersecretion of glucagon,

- diabetes that is usually mild,

- weight loss, and

- necrolytic migratory erythema.

The chronic, fluctuating dermatosis is characterizedby an annular and figurative erythema that forms bullaeand erosions. The periphery of these lesions extendswith vesiculopustules. The lesions tend to coalescebefore healing which starts within weeks, as they arereplaced by new ones. They commonly occur in theintertriginous areas, perioral regions and on ex-tremities. Histologically, they resemble pustular pso-riasis, with features of intracellular edema in the upperepidermis, acanthosis and subcorneal pustulosis (56).

Necrolytic migratory erythema resolves after ex-tirpation of the pancreatic tumor, which in the majorityof cases is the treatment of choice (57).

Dermatoses reported to be more common indiabetics than in nondiabetics

Kaposi’s sarcoma

It is a multiple idiopathic hemorrhagic sarcoma,which manifests primarily as multiple vascular nodulesin the skin and other organs. It predominantly affectsmales. The lesions begin in the legs as multiple, purplemacules, nodules or plaques. Later, other areas of theskin, mucous membranes and internal organs may beinvolved. Edema of the legs is frequent and may evenbe a prodrome. Histologic picture reveals accumulationof spindle cells forming vascular slits containingerythrocytes (58). Diabetes mellitus has been reportedwith greater than expected frequency in classicKaposi’s sarcoma, however, confirmation is still needed(59).

Perforating dermatosis

There are several acquired cutaneous disordershaving as a common histologic denominator thetransepidermal elimination of degenerative material,chiefly collagen and elastic fibers. Many are seen inpatients with chronic renal failure, particularly those ondialysis and with IDDM or NIDDM. The size of thesepapules ranges from 2 to 10 mm in diameter, often witha keratotic plug. They favor the extensor surface of thetrunk and extremities, and are itchy with littletendency to spontaneous resolution. Most patients aremiddle aged, often black, and more often men thanwomen. Improvement of itchy lesions is not achievedeasily but topical retinoic (60) and ultraviolet therapy(61) has been useful.

Vitiligo

It is a disease with a diminished or absent function ofmelanocytes resulting in macular depigmentation. It isfound mostly in periorifacial regions and also on theextensor aspect of the extremities. It is asymptomaticbut emotionally stressful, particularly in people withdark skin. Vitiligo occurs with a greater incidence thanexpected (4.8%) in patients with maturity onsetdiabetes (62) and type 2 diabetes (63). It has also been



reported in association with IDDM and otherautoimmune disorders of the adrenal and thyroid orgastric parietal cells.

Lichen planus

An increased incidence of diabetes mellitus andabnormal insulin response to glucose challenge havebeen claimed in patients with lichen planus (64). Thisseems particularly so in adults, especially those withthe erosive oral form (65). There were various studiesof lichen planus and its relationship with diabetesmellitus, which have led to a conclusion that there aretwo types of lichen planus, i.e. the immunogenic typeand the metabolic defect type, both being associatedwith diabetes mellitus (66,67).

Yellow nails

The lesion involves distal hallux and is quite commonin diabetic individuals (68). It is one of the importantmarkers of diabetes mellitus. The earliest sign is yellowor brown color of the distal part of the hallux nail plate.Later, a canary-yellowish discoloration occurs on thenails. It can involve finger nails and other toe nailsduring the later stage of the disease.

Eruptive xanthomas

They commonly occur in hyperlipidemic status.Frequently, the underlying problem is uncontrolleddiabetes. The eruptions are multiple, firm, yellowish incolor, waxy papules ranging from 1 to 4 mm in diameter,appearing in crops. They are mostly located on theextensor surfaces. The firm nontender papules arepresent on the knees, elbows, back, buttocks and trunk(69). These lesions are itchy, sometimes tender,surrounded by erythematous halo. They showKoebner’s phenomena (70). The unifying factor in

hyperlipidemic status is decreased lipoprotein lipaseactivity or increased LDL, making chylomicrons lessable to compete LDL for lipoprotein lipase. The netresult is an increase in plasma chylomicrons (71).There is some evidence that eruptive xanthomas indiabetics result from macrophages incorporatingplasma lipoprotein forming foam and xanthoma cells(71). With correction of hyperlipidemia andhyperglycemia, the lesions involute, sometimes withpostinflammatory hyperpigmentation and occasionallyscars.

Bullous pemphigoid

There are very few studies relating bullouspemphigoid and diabetes. The relationship betweenthe two awaits for confirmation. Theoretically, theirassociation may be due to the lower threshold ofdiabetes in traumatically induced blisters or on thebasis of antigenic changes at the level of lamina lucidabecause of enzymatic glycosylation. Steroids andsometimes even immunosuppressive drugs may beappropriate.

Dermatitis herpetiformis

The HLA association of diabetes and dermatitisherpetiformis may be a possible explanation for the twodiseases appearing together more frequently thanexpected (72).

Psoriasis. It is a multifactorial disease of unknownorigin. There is a distinct pattern of associated diseasesexisting in patients with psoriasis. Systemic disorderssuch as hypertension and diabetes are often seen inthese patients. The reasons for these diseases to occurin psoriasis patients have been related to nutritionalfactors of hypercaloric dietary habits (73).

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