Cutaneous manifestation in Endocrinology

WARAYUWADEE AMORNPINYO ATHIBORDEE MEESINGHA JULY8 2011

Scope
Diabetes Hyper/Hypoparathyroidism Xanthomatoses Acromegaly GH deficiency Androgen excess / Hirsutism Hypo / Hyperthyroidism Cushing syndrome Addisons disease

Diabetes
METABOLIC ABNORMALITIES IN GLUCOSE&INSULIN 2. N E U R O P A T H Y , V A S C U L O P A T H Y , A N D I M M U N E DYSFUNCTION 3. U N K N O W N P A T H O G E N E S I S

1.

Diabetes
1. Metabolic abnormalities in glucose&insulin
Acanthosis nigricans Diabetic thick skin Limited joint mobility Eruptive xanthomas

2. Neuropathy, vasculopathy, immune dysfn

Foot ulcers Cutaneous infections

3. Unknown pathogenesis :
Necrobiosis lipoidica Granuloma annulare Diabetic dermopathy Acquired perforating dermatosis Bullosis diabeticorum

Acanthosis nigricans

-Brown to gray-black papillomatous cutaneous thickening in the flexural areas, symmetrically -The affected skin has a dirty, velvety texture

 Posterolateral neck ** Axillae, groin, and abdominal folds

Oral, esophageal, pharyngeal, laryngeal, conjunctival, and anogenital mucosal surfaces may be involved

Palms,rugated tripe palms asso. malignancy

Conditions associated
Obesity Insulin resistance Drugs Familial Race Tumor
Mutations in fibroblast GFR-3 EGFR IGF-1 receptor

release TGF-B

Hyperinsulinemia

Excess GF stimulation aberrant keratinocyte&fibroblast proliferation

Treatment
Ineffective treatment Topical treatment calcipotriol,salicylic acid, urea, systemic and topical retinoids Weight reduction Offend drug Treat underling disease Look for T2DM

Diabetic thick skin

: Alteration in dermal collagen and MPS 1. Limited joint mobility and scleroderma-like syndrome 2. Sclerederma diabeticorum (Scleredema of diabetes)

Prayer sign

nonpitting, woody, peau d'orange

Eruptive xanthoma
1-4 mm, reddish-yellow

papules Buttocks & extensor surfaces of extremities

Asso : TG > 1000 Resolve in 6-8 wk after

lowering glucose

Hypertriglyceridemia (>4000)
Lipemia retinalis

Pale pink to white

retinal arterioles and venules. Milky fundus Abdominal pain, hepatosplenomegaly, pancreatitis, or dyspnea

Bacterial infections
Gr B streptococcal infection (S. agalactiae)

30 fold , skin soft tissue and bone infection 3.7 fold , soft tissue infection

Gr A streptococcal infection

Staphylococcal infection controversy Malignant External Otitis

P.aeruginosa purulent discharge, unilateral facial swelling, hearing loss, and granulation tissue in the ear canal, no fever Intracranial involvement Surgical debridement

Necrotizing Fasciitis Polymicrobial organisms

Fungal and yeast infections

Candida Dermatophyte Rhinocerabral mucormycosis 75% in DM Zygomycetes (Mucor and Rhizopus sp.) Headache, fever, and lethargy, nasal congestion and facialocular pain and swelling

Mucormyco -sis

Diabetic ulcers
Peripheral neuropathy,

pressure, and trauma 10-30 fold amputation Prevention is the most important
Glycemic control Foot examination Soft shoes Treat T.pedis Stop smoking

3. Unknown pathogenesis :
Necrobiosis lipoidica Granuloma annulare Diabetic dermopathy Acquired perforating dermatosis Bullosis diabeticorum

Necrobiosis lipodica (NL)

Sharply demarcated yellow-brown plaques

Flatten, atrophic central yellow or orange area, telangiectasias

"glazed-porcelain" sheen

Treatment
Early : potent topical glucocorticoid ( slow progress) Few case report : Systemic glucocorticoids Aspirin and dipyridamole Topical retinoids Topical PUVA Topical fumaric a Surgical excision and STSG

Granuloma Annulare (GA)

Erythematous to violaceous domed-shaped papules in an annular configuration

Granuloma Annulare (GA)

2 forms Localized : most common, children & young adult , dorsum of hands /ankles and feet, <10 lesions ,W>M self limited Generalized : older adult , chronic and relapsing , 100-1000 of 1-2mm flesh-colored papulesform small annular plaques , abdomen/chest/thigh/extensor elbow Treatment : potent topical or intralesional glucocorticoids

Diabetic dermopathy ( Shin spot)

< 1 cm, atrophic, pink to brown, scar-like macules on the pretibial areas

Diabetic dermopathy ( Shin spot)

asymptomatic , clear within 1 - 2 years antecedent trauma 33% in T1DM, 39% in T2DM Correlated : retinopathy, nephropathy, neuropathy

Acquired Perforating disorders

pruritic, keratotic

papules with central plug Extensor surface of ext., trunk , face Asso : DM CKD Treatment :
Retinoic acid Topical steroid PUVA

-Kyrle disease -Reactive perforating collagenosis -Perforating folliculitis -Elastosis perforans serpiginosa

Abrupt onset of bullae on the lower extremities

Histo : separation varying from intraepidermal to subepidermal, IF neg

Heal 2-5 wk , non scarring Rx :Wound care

Bullosis Diabeticorum

DM

Limit joint

Bullosis diabeticorum

NLD ,Diabetic dermopathy

DM

AG Scleredema

Otitis externa

Eruptive xanthoma

GA Ulcer

Parathyroid hormone
PTH STIMULATES THE ACTIVITY OF THE 1-HYDROXYLASE ENZYME IN THE KIDNEY, RESULTING IN INCREASED PRODUCTION OF CALCITRIOL, THE BIOLOGICALLY ACTIVE FORM OF VITAMIN D3. INCREASED CALCITRIOL PRODUCTION RESTORES NORMAL SERUM CALCIUM LEVELS IN THREE DIFFERENT WAYS: 1) BY ACTIVATING THE VITAMIN DDEPENDENT TRANSPORT SYSTEM IN THE SMALL INTESTINE, INCREASING THE ABSORPTION OF DIETARY CALCIUM; 2) BY INCREASING THE MOBILIZATION OF CALCIUM FROM BONE INTO THE CIRCULATION; AND 3) BY INCREASING THE REABSORPTION OF CALCIUM BY THE KIDNEYS. PTH IS ALSO REQUIRED TO INCREASE CALCIUM MOBILIZATION FROM BONE AND CALCIUM REABSORPTION BY THE KIDNEYS. HOWEVER, PTH IS NOT REQUIRED FOR THE EFFECT OF CALCITRIOL ON THE INTESTINAL ABSORPTION OF CALCIUM.

Metabolism

Hyperparathyroidism
Primary hyperparathyroidism Pseudohyperparathyroidism (PTHrP) Secondary hyperparathyroidism
Renal disease**, OCP, long term furosemide therapy Resistance of end organs to PTH PTH, Ca, PO4

Tertiary hyperparathyroidism (Autoactivated)

Osteomalacia despite hypercalcemia

Hypoparathyroidism
Primary hypoparathyroidism Secondary hypoparathyroidism

Skin in Parathyroid disease

Resulting from calcium dysregulation site of PTH action Keratinocytes express PTHrP keratinocyte growth and differentiation normal wound healing squamous cell carcinomas

Calcinosis cutis
Subcutaneous

calcifications, skin color

Symmetric overlying large joints or linear arrayed papules and plaques Pruritic Chronic urticaria

Calciphylaxis

- results from calcium deposition in the walls of small- to medium-sized vessels vascular occlusion and skin necrosis - Mottled violaceous patches ,indurated & painful, ulceration and eschar formation tissue gangrene - Histo : calcification in the media of small- and medium-sized vessels, subcutaneous calcium deposits and fat necrosis

Early stage of calciphylaxis showing the mottled and reticulated dusky erythema

Progressive necrosis of the calciphylaxis lesions

symmetric reticulated violaceous erythema, nodules, and puched out ulcers with central black eschars

Parathyroidectomy and aggressive management of wounds and infections

Calciphylaxis : Poor prognosis Mortality rate 80% (from infection)

Hypoparathyroidism
familial PGA type 1 chronic mucocutaneous candidiasis (CMC) and adrenal failure dental enamel hypoplasia, vitiligo pseudohypoparathyroidism or PTH-resistant

hypoparathyroidism Albright's hereditary

short stature, obesity, rounded facies, dental hypoplasia, and shortened bones of the hands and feet shortening 4th MCB Albright's sign

Albright hereditary osteodystrophy with short stature, round facies, short neck Brachydactyly Shortening of the 4th, 5th metacarpals

Treatment
Hyperparathyroidism Parathyroidectomy Hypoparathyroidism Normalized Ca , PO4

Xanthomatoses

Lipid metabolism

The exogenous pathway transports dietary lipids to the periphery and the liver

The endogenous pathway transports hepatic lipids to the periphery

Xanthoma
Abnormal lipid deposition and foam cells Histo : Foam cells (macrophages contained lipid) Local factors such as heat, movement, and friction Present in 4 major form Eruptive Tuberous Tendinous Planar(generalized)
xanthelasma

palpebrarum, xanthoma striatum palmare, arcus

cornealis

Classification of Genetic Hyperlipidemias

Frederickson type Classification Familial lipoprotein lipase Deficiency (hyperchylomicronemia, hypertriglyceridemia) (FLD) Familial hypercholesteralnemia (FH) Familial combinded hyperlipidemia (FCHL) Familial dysbetalipidemia (remnant particle disease) (FD) Familial hypertriglyceridemia (FHTG) Familial combinded Hypertriglyceridemia (FHT) Lipid Profile TG++ , C normal , CM++ , HDL -/normal

IIa IIb III IV V

TG normal , C+ , LDL+

TG+ , C+ , LDL+ , VLDL+

TG+ , C+ , IDL+ ,CMremnant+

TG+ , C norm/+, LDL++ , VLDL++ TG+ , C+ , VLDL++ , CM++

Eruptive Xanthoma

Suddenly appering Papule : dome-shaped, discrete, initially red, then

yellow center with red holo If confluent form nodular tuberoeruptive Typically on buttock, elbows, forearm, knee A sign of FHT , FD, FLD (rare), DM poor control Rx : react favorable to low-calorie and low-fat diet

Eruptive xanthoma

dome-shaped papule, yellow center with red holo

Eruptive xanthoma

Tuberous Xanthoma

Nodule or plaque : yellowish Typically on elbows and knee A sign of FD, FHT, FH In homozygous FH present with flatter and

skin colored Rx : underlying condition

Tuberous xanthoma

yellowish-colored skin plaque lesions on the knee

Tuberous xanthoma

nodular or plaques; extensor surfaces of large joints, hands, buttocks, heels, flexures

Tuberous xanthoma

Skin color to yellowish nodule and plaque

Tendinous xanthoma

Subcutaneous tumor : yellow or skin-colored

move with extensor tendon A sign of FH In homozygous : xanthoma appear in early childhood and have early cardiovascular complication Rx : low Chol and saturated fat diet , statin

Tendinous xanthomas
Firm,smooth,nodular At achilles tendon or

extensor tendon of the hands,knee or elbow Almost always a clue to underlying disorder

Tendinous Xanthoma

Plane xanthoma

Generalized : yellowish-red elevated plaque

commonly on upper trunk, neck Normolipid pt. with monoclonal gammopathy, MM, lymphoma Less common in FHT

Xanthelasma palpebrarum

Most common of xanthoma Papule or plaque : yellow-orange , localized to upper and lower eyelids If isolated finding most unlelated to hyperlipidemia Associated with FH and FD Rx : laser, excision, application of trichloroacetic acid

Normolipidemia 50% or FH,FD

Screening : young

with xanthelasma, strong family history of hyperlipidemia

Xanthoma stiatum palmaris

Flat or elevated infiltrative

lesion : yellow-orange typically at volar crease of palm and fingers Pathognomonic for FD (type III) Rx : FD

low-calorie and low-fat diet

if necessary use statin

Plane xanthoma

Intertrigenous plane

xanthoma(antecubital fossae or web space of finger) Pathognomonic for homozygous familial hypercholesterolemia

Familial hypercholesteralnemia (FH)

A genetic deficiency of LDL receptor Devided into 2 form

Homozygous Heterozygous

In homozygous

1:1,000,000 No or very low LDL recptor >> very high LDL 800-1,000 mg/dl Develop cardiovascular complication before teenage Severs xanthoma : tuberous, periosteal, tendon, elevated xanthomatous plaque Rx : bile-sequestrant and HMG-COA inhibitor have little benefit Liver transplantation

Familial hypercholesteralnemia (FH)

In Heterozygous

More common 1:500 LDL level are twice normal Develop cardiovascular complication in 5-6 decade Xanthoma : tendon xanthoma are common , rare tuberous form Rx : statin is effective drug , combind with bile-sequestrant

Growth hormone
1. GIGANTISM / ACROMEGALY 2. GH DEFICIENCY

Acromegaly is caused
by pituitary tumors secreting GH or rarely by extrapituitary disorders. The disease is characterized by elevated levels of GH and IGF-I with resultant signs and symptoms of hypersomatotropism.

Etiology of Acromegaly
Excess GH Pituitary adenoma (98%)
Mixed

Ectopic

Excess GHRH Ectopic

Carcinoid

GH Other syndromes

GH&PRL (25%) Pure GH

bronchus, GI/Pancreas Pancreatic islet cell tumor Small cell carcinoma Adrenal adenoma

The Insidious Nature Of Onset Of Symptoms

Cutaneous findings in acromagaly

Enlargement of hands and feet with a doughy texture Increased ring, glove, shoe, and hat size Jaw enlargement with separation of teeth (prognathism) Macroglossia Cutis vertices gyri Acanthosis nigricans Hirsutism Hyperhidrosis Brittle thick nails

Frontal bossing Hyperostosis frontalis

Prognathia

Prominent brow

Wided triangular nose Macronathia

Cutis vertices gyri

- Wide space teeth - Deep & hollow sounding voice - Thick and protude lip

Acral enlargement
-increased head,

hand, and foot size

-increasing shoe,

ring, glove, or hat size Spade-like hand with sausageshaped finger (Spaturate finger)

Acanthosis nigricans

Skin tag

GI popyp malignancy

GH deficiency
Solitary GH deficiency : reduce skin thickness and collagen Abnormal short stature (in Children) decreased lean body mass, decreased strength and exercise capacity in part due to decreased sweating, loss of general vitality (in Adult) Panhypopituitary : fine wrinkling of the skin, decreased pigmentation, and decreased to absent pubic and axillary hair
(clinical of hypothyroidism)

Androgenic hormone

HPA / HPG axis

Androgen excess
Women :

acne, hirsutism, virilization, androgenetic alopecia, increase muscle mass, menstrual irregularities, clitoromegaly. Man : increase muscle mass, acne, hyperpigmentation, hypertrophy of penis.

Ferriman-Gallway Scoring

GRAVES DISEASE AND HYPERTHYROIDISM

GRAVES DISEASE
3 major manifestations Hyperthyroidism with diffuse goiter Ophthalmopathy Dermopathy Do not occur together Independent of each other

Dermopathy
Pretibial myxedema Early lesions bilateral,asymmetric, firm, nonpitting nodules and plaques that are pink, skin-colored, or purple Late lesions confluence of early lesions, which symmetrically involve the pretibial regions

Pretibial myxedema

Fingers
Acropachy (osteoarthropathy) Diaphyseal proliferation of the periosteum and

clubbing

GD ophthalmopathy
Spastic stare lid lag lid retraction Mechanical Proptosis Ophthalmoplegia Congestive oculopathy Chemosis Conjuctivitis Periorbital swelling Complications of corneal ulceration Optic neuritis Optic atrophy

Exophthalmic ophthalmoplegia ocular muscle weakness with inward gaze, convergence, strabismus, diplopia

GD ophthalmopathy

Management
Ophthalmopathy Symptomatic treatment in mild cases Severe cases: prednisone 100120 mg/d initially, tapering to 5 mg/d Orbital radiation Orbital decompression

Management
Dermopathy Topical glucocorticoid preparations under plastic occlusion for several months are usually effective. Low dose oral glucocorticoids (prednisone 5 mg/d) Intralesional triamcinolone 35 mg/mL for smaller lesions

HYPOTHYROIDISM AND MYXEDEMA

HYPOTHYROIDISM
Hypothyroidism may be Thyroprivic (e.g.congenital, primary idiopathic,postablative) Goitrous (e.g., heritable biosynthetic defects, maternally transmitted, iodine deficiency, druginduced or chronic thyroiditis) Trophoprivic (e.g., pituitary) Hypothalamic [e.g., infection (encephalitis),neoplasm]

HYPOTHYROIDISM
Early symptoms of myxedema fatigue, lethargy, cold intolerance constipation, stiffness and cramping of muscles carpal tunnel syndrome,menorrhagia slowing of intellectual and motor activity decline in appetite increase in weight, and deepening of voice.

 There is a dull, expressionless facies with puffiness

of eyelids. Skin appears swollen, cool, waxy, dry, coarse, and pale with increased skin creases Palms and soles are yellow-orange due to carotenemia The hair is dry, coarse, and brittle Thinning of he scalp, beard and sexual areas Eyebrows: alopecia of the lateral one-third Nails brittle and slow growing. Large, smooth, red, and clumsy tongue Management is by replacement therapy.

carotenemi a

ADDISON DISEASE

ADDISON DISEASE
Insidious

Characterized by Progressive generalized brown hyperpigmentation, Slowly progressive weakness, fatigue, anorexia, nausea,and, frequently, GI symptoms (vomiting and diarrhea)

ADDISON DISEASE
Skin Generalized brown hyperpigmentation 1. Normal areas habitually or UV-induced around the eyes, face, dorsa of hands,nipples,in the linea nigra (abdomen), Axillae, and anogenital areas in males and females (the intensity of the pigmentation is related to skin phototype)

Normal areas linea nigra

ADDISON DISEASE
2.In new areas Gingival or buccal mucosa, creases of palms bony prominences New scars following surgery

CUSHING SYNDROME AND HYPERCORTICISM

CUSHING SYNDROME
Excess adrenocorticosteroids of endogenous or

exogenous source
Skin lesions: A plethoric obese person with a clasic

habitus that results from the redistribution of fat: moon facies buffalo hump,truncal obesity, and thin arms

CUSHING SYNDROME
Purple striae, mostly on the abdomen and trunk Atrophic skin with easy bruising and telangiectasia Facial hypertrichosis with pigmented hairs Acne of recent onset (without comedones)

Buffalo hump Moon face

Purple striae

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