1

Diseases of Subcutaneous Fat. Endocrine Diseases.

Ben Adams

KCOM

5-11-05

2

Diseases of Subcutaneous Fat

• Panniculitis

• May appear similar due to depth

• Two broad categories:– Septal (classically E.N.)– Lobular (Vascular)

3

Erythema Nodosum

Acute Erythema Nodosum– Crops of bilateral, deep, tender, 1-10 cm diameter, red

nodules, on pretibial area (or other). – Lesions resolve over several days or weeks, leaving a

bruise like area. (erythema contusiforme) which resolves without scarring.

– Fever, malaise, leg edema, arthritis and other systemic symptoms may be present

– Associated states (reactive process)• W>>M, TB, Streptococcal inf., Mycoplasma,

Coccidioidomycosis, Yersinia, Salmonella, deep fungal infections, Sarcoidosis, drug (oral contraceptives). Pregnancy. Many others.

– Idiopathic 35-55% of cases

4

Erythema Nodosum

5

Erythema Nodosum

•

                   

6

Findings suggestive of a systemic cause for Erythema Nodosum

• Synovitis

• Diarrhea

• Abnormal chest X-ray

• Preceding upper respiratory tract infection

• Elevated anti-Dnase B

• Positive tuberculin skin test

7

Erythema Nodosum

Chronic Erythema Nodosum• Distinguishing features:

– Older women– Unilateral, Single lesion which spreads centrifugally to form

annular plaques. Sometimes bilateral.– No systemic symptoms ( Possibly arthralgia )– Less tender– No underlying disease– Prolonged course of months / years.

• Key to diagnosis: Pretibial, no systemic complaints. Biopsy seldom required.

• DDX: erythema induratum (post. Calf), syphilitic gummas (unilateral). Subcutaneous fat necrosis assoc with pancreatits etc. – systemic.

8

Erythema Nodosum• Histologic Features

– Septal infiltrate of neutrophils (early), other mononuclear cells. Histiocytes and Multinucleated Giant cells may predominate older lesions. Some foamy histiocytes may be seen.

– Meischer’s radial granulomas: Aggregates of histiocytes around stellate clefts is characteristic not diagnostic.

9

Erythema Nodosum

Septa are widened and edematous, and infiltrated by lymphocytes and neutrophils

10

Erythema Nodosum

Miescher's microgranulomas within septa.

11

Erythema Nodosum

• Treatment:– Treat underlying causes.– NSAIDS, bed rest / reduced activity– Potassium Iodide: Increase to control.

• Watch for hypothyroidism.

• Reports of EN triggered by SSKI

– Intralesional / systemic Steroids– Refractory cases: anti-malarials, colchicine.– Most cases resolve in 3-6 wks.

12

Nodular Vasculitis• AKA: Erythema Induratum• Tender subcutaneous nodules of calves of middle

aged, thick – legged women. Bilateral, often ulcerate and recur over years.

• Pathology: Arteritis, venulitis of septal vessels with substantial necrosis of lobular adipocytes resulting in suppuration and perforation. Granulomatous inflammation.

• DDX: Erythema induratum. TB testing, PCR of affected tissue for mycobacterium.

• Treatment: SSKI (50% effective). Other agents used in E.N.

13

Nodular Vasculitis

• Nodular lesions on the lower leg with evidence of ulceration

14

Sclerosing Panniculitis(Lipodermatosclerosis)

• Presentation: Development of woody induration of lower calves (esp. left) with appearance of inverted champagne bottle. Induration begins near ankles and slowly progresses proximally. Most common W > 40 years. May be painful.

• Pathogenesis: venous insufficiency with hypoxia of center of fat lobule. May not be apparent venous disease.

• Histopathology: Necrosis of fat lobules with ghost cells (pale cells no nuclei). Foamy histiocytes, inflammatory cells and septal thickening with fat microcyst.

• Biopsy should be avoided. Heals poorly. Venous eval.

• TX - Treat venous insufficiency. – Compression stockings (may be painful). – Stanozolol decreases perivascular fibrin, decreases pain in 3 wks

and induration in 8 wks.

15

Sclerosing Panniculitis

16

Sclerosing Panniculitis

Lipomembranous change, consisting of cystic formation with elaborate papillary configurations

17

Physical Panniculitis

Sclerema Neonatorium• Presentation: Gravely ill, premature neonate’s skin

begins to harden on buttocks and LE and rapidly spreads to involve entire body except palms, soles and genitalia. – Mobility affected by induration.– Rapidly fatal.– Child is very ill.

• Histopathology: Enlarged adipocytes filled with needle like clefts in radial array.

• TX: treat underlying disease.

18

Sclerema Neonatorium

Needle-shaped clefts within lipocytes, in the absence of inflammation.

19

Subcutaneous Fat Necrosis of the Newborn.

• Presentation: Asymptomatic, firm, rubbery nodules on upper back, buttocks, cheeks and proximal extremities. May fuse into plaques which resolve over several months without scarring.

– Occurs during first 4 weeks of life.– Child is otherwise healthy– Associated with perinatal

hypothermia, asphyxia and difficult labor and maternal drug use.

– Rarely, hypercalcemia occurs during the episode.

• Histopathology: Lobular panniculitis with radial needle clefts in adipocytes.

• Fine needle aspiration has been used to DX.

20

Subcutaneous Fat Necrosis of the Newborn.

Indurated plaques on the trunk

21

Subcutaneous Fat Necrosis of the Newborn.

Needle-shaped clefts in radial configuration are present within giant cells.

22

Cold Panniculitis• Synonyms: Popsicle / equestrian

panniculitis.• Presentation: Within several

days of cold exposure, affected skin becomes mildly erythematous with nontender firm Sub-Q nodules. Face, thighs and scrotum.

• Typical patients: (Hx of cold exposure).– Infants and young children.

Black > Whites.– Scrotal disease: prepubertal,

9-14 yr old male who is over weight. Bilateral, painful, no transillumination.

• Resolves in several days to weeks without TX.

23

Cold Panniculitis

Erythematous, violaceous plaques on the thighs in a case of equestrian cold panniculitis.

24

Post Steroid Panniculits• Firm sub-Q nodules form within one month of

rapid withdraw from high dose systemic steroids. • Predominantly children.• Most cases resolve. May have to restart steroids

and wean more slowly.

Traumatic Panniculitis• Trauma, often not recalled, induces a firm mildly

tender lipoma like sub-Q mass.• Heals with fibrosis of septa.

25

Factitial Panniculitis• Factitial injection of foreign substances into

the skin. Medical personal are common patients.

• DX: – Careful HX. Fits no other pattern.– Healing injection site, biopsy revealing foreign

material, polarized light micro, Mass spectroscopy in difficult cases is suspicion is high.

26

Sclerosing Lipogranuloma• Granulomatous and fibrotic reaction from intentional,

often cosmetic, injection of mineral oils, silicon or guayacol (Mexico).

• Presentation: Up to ten years after implantation, skin becomes erythematous, hyperpigmented and indurated with a lumpy quality of sub-q. Due to migration of material, features may extend beyond the implantation site.

• 66% autoimmune finding (+) ANA, Raynauds, Sjogrens ect. 10% connective tissue disease usually scleroderma.

• Histologically: Swiss cheese appearance of panniculus. Histiocytes with ingested material. Fibrosis.

27

Sclerosing Lipogranuloma

2nd to Cosmetic Paraffin injections

28

Sclerosing Lipogranuloma

Oil granuloma. Numerous vacuolated spaces, in this case due to grease gun injury.

29

Pancreatic Panniculitis• Fat necrosis 2nd to Pancreatitis or pancreatic

carcinoma. May be first sign of malignancy (40%). Digestive enzymes cause damage.

• Presentation: Tender or painless, erythematous Sub-q nodules 1-5 cm. In diameter. Lower leg is affected 90%. Lesions typically number <10 (may be 100s). Involutes with scarring. – Assoc findings: abd pain (sometimes), arthritis (FFA in

synovial fluid), pulm. infiltrates.

• DX: pancreatic workup amylase, lipase.– Peripheral eosinophila in Pancreatic CA.

• Histology: fat necrosis, Ghost cells. Finely stippled Basophilic material (Calcium) with rim of necrotic cells. Inflammatory infiltrate at periphery.

30

Pancreatic Panniculitis

31

Pancreatic Panniculitis

Neutrophilic inflammation, cellular necrosis, and deposition of homogeneous basophilic material due to saponification of fat by calcium salts.

32

Alpha-1 Antitrypsin Deficiency Panniculitis

• 1:2500 of European decent have homozygous deficiency of enzyme which inhibits neutrophil elastase. The genetic defect results in a molecule that cannot be released from its production sites in hepatocytes.

• AAT is 1 of the 3 most common lethal genetic diseases among whites.

• Presentation: After minor trauma, painful nodules appear on extremities and trunk. Lesions may form draining sinuses.

• M=F, 20-40 years.

• Histopathlogy: Dissolution of septae. Islands of normal fat floating in spaces of destroyed septae.

33

Alpha-1 Antitrypsin Deficiency Panniculitis

Purpuric nodules on the ankle

34

Alpha-1 Antitrypsin Deficiency Panniculitis

• DX– Constellation of Liver dysfunction and

Pulmonary dysfunction with skin lesions– Serum AAT levels– AAT function analysis

• TX– Replace enzyme (prolastin)– Dapsone, doxycycline

35

Cytophagic Histiocytic Panniculitis• Multi-system disease with widespread, painful sub-q

nodules which may break down and form ulcerations.– Progressive febrile illness with heptomegaly, pancytopenia, HTG.

• Etiology: Proliferation of histiocytes. Triggered by viral infection or 2nd to lymphomas.

– Benign: (-) EBV

– Malignant (+) EBV, B or T cell Lymphoma.

– HIV assoc.

• Histopathology: Infiltration of fat lobules with histiocytes with fat necrosis. Bean bag cell stuffed with RBC.

– Clonal B or T cell proliferation = malignant.

• TX: Benign - cyclosporine induces permanent remissions. Malignant - Chemo or bone marrow.

36

Cytophagic Histiocytic Panniculitis

Subcutaneous nodules with purpura

37

Cytophagic Histiocytic Panniculitis

Macrophages engaged in cytophagic activity. Some of them have the appearance of ‘bean bag cells’

38

Misc. Panniculitis

• Eosinophilic Panniculitis– Prominent infiltration with eosinophils assoc

with arthropod bites, parasites, contact derm, Well’s, bacteria, injections.

• Gouty Panniculitis– Uric acid in Sub-Q leading to fat necrosis.

39

Lipoatrophies

• Total

• Partial

• Centrifugal

• Semicircular

• Lipoatrophia Annularis

• Localized

• HIV associated

40

Total Lipodystrophy2 types: Congenital vs Acquired.

Both are assoc. with D.M. (lipoatrophic diabetes)

1.) Beradinelli - Seip (congenital)• Autosomal recessive. Hypermetabolic state.• General: Paucity of fat at birth with voracious appetite,

increased height velocity, muscular hypertrophy, genital enlargement, mild MR, protuberant abdomen, HTG. Hypertrophic cardiomyopathy, pul stenosis. DM resistant to therapy.

• Cutaneous: AN (often generalized), Hypertrichosis with abundant curly scalp hair.

• Death in young adulthood from DM, cardiac, liver dx.

• TX: fenfluramine reduces hypermetabolic state.

41

Beradinelli - Seip (congenital)

42

Congenital Total

Lipodystrophy

AN and Loss of Bichat’s fat pad

43

Total Lipodystrophy

2.) Seip - Lawrence (acquired)

• Begins <15 yrs old, often <5yrs (not at birth)

• Well defined illness precedes 30 % of cases.

• Presentation: As in congenital, but less striking. AN with DM is common. Severe liver involvement is more common (death). Loss of fat may begin local and generalize or start generalized.

• TX: etretinate has helped AN in some.

44

Seip - Lawrence (acquired)

45

Partial Lipodystrophy(Inherited Forms)

Kobberling-Dunnigan syndrome • Autosomal dominate.• At puberty adipose tissue is lost from extremities, gluteal and

truncal areas with fat accumulation on the neck and face.• DM with AN, HTG, hirsutism, PCOS after age of 20 years.

Other inherited forms:• Onset early infancy with adipose tissue loss localized to the

face and buttocks. Rieger anomaly: tooth and eye abnormalities: hypoplasia of the iris and iris strands to the peripheral cornea.

• Bone age and dentition are retarded. • DM late. No AN.

46

Partial Lipodystrophy(Acquired Forms)

Progressive Partial Lipo. (Barraquer-Simons)• W > M, Present first or second decade.• After a febrile illness, diffuse and progressive loss

of fat beginning on face and scalp and progressing downward to iliac crest. Sparing of LE.

• No discomfort or inflammation.• Low C3 levels are assoc. and proteinuria occurs in

in 50% of these cases. • 3rd trimester intrauterine death may occur.

47

Progressive Partial Lipo.

Loss of buccal fat and AN.

48

Lipoatrophies

• Centrifugal– One type is seen primarily in infants from Japan. 90 %

are under 5 years.• Centrifugally spreading loss of abdominal fat over 3- 8 years

with regional lymphadenopathy.• Resolves completely after progression stops.

• Semicircular– Adult women affected with single or multiple,

asymptomatic, symmetric depressions of anterolateral thigh.

– Often after trauma. Resolves in several years.

• Annular Atrophic panniculitis– 10cm band of atrophy, bilaterally, around the ankles of

children and young adults. Rare.

49

Lipoatrophies

Lipoatrophia Annularis– Bracelet like constrictions of upper extremities 1-2 cm wide

on women following a period of swelling and erythema of extremity.

– Arthralgias and Pain of affected extremity– Persist up to 20 years.

Localized lipodystrophy– 2nd to injection of medications esp. insulin.

HIV assoc. Lipodystrophy.– Occurs in effectively Treated Aids Patients with reverse

transcriptase inhibitors and protease inhibitors.– Fat redistribution from face, buccal, buttocks and limbs is

lost to neck , upper back and inter abdominal areas.

50

Localized lipodystrophy

Insulin injection lipodystrophy

51

HIV assoc. Lipodystrophy

Loss

52

Endocrine diseases

53

Acromegaly• Hypersecretion of growth hormone.

– 2nd to adenoma

• Changes:• Diffuse hypertrophy of skin. Reddening and wrinkling of

forehead.

• Cutis verticis gyryata in 30%

• Enlargement of hands and feet and tongue. Drum-stick fingers.

• Hypertrichosis, hyperpigmentation, hyperhydrosis.

• TX: transpenoidal microsurgery. Irradiation. Octreotide inhibits GH if surgery is not an option.– 50% of patients completely normalize with TX.

54

Acromegaly

55

Cushing’s Syndrome• Hyperfunctioning of adrenocortical

tissue1. Cushing disease : microadenoma

of pituitary. 10%2. Hyperfunctioning

adrenals/adenomas or other tumors account for remainder.

• Non – Iatrogenic: W > M. Peak age 20-30s.

• Features:– Obesity of face, neck and trunk.

Buffalo trunk. Moon face– Cutaneous: hypertrichosis,

dryness, fragility, acne, dermatphyte/pityrosporum infections, flushing, striae of abdomen and thighs. Thinning of skin.

– Systemic: HTN, weakness, reduced bone density, DM, atherosclerosis, osteoporosis.

56

Cushing’s Syndrome

57

Cushing’s Syndrome

Stria rubra

58

• Diffuse hyperpigmentation, which persisted into autumn months, in a 11-year old boy with Addison’s disease.

• Adrenal insufficiency

• Increased Pituitary POMC leads to increased ACTH and melanocyte stim. hormone.

• Cutaneous signs: – Diffuse hyperpigmentation

• Most prominent in sun exposed areas and sites of recent trauma

• Axillae, perineum and nipples.

• Darkening of palmar, scars, hair and nails.

Addison’s Disease

59

Addison’s Disease

60

Panhypopituitarism

Diminished axillary hair is an early sign

•Loss of pituitary hormones 2nd to infections (syphilis and TB), tumor, postpartum hemorrhage.

•Loss of melanin 2nd to decreased ACTH/MSH.

•Cutaneous signs: Thin dry skin. Diffuse loss of body hair. Thin, opaque, slow growing nails. Light skin susceptible to sunburn. Decrease in facial folds.

Fine facial wrinkles and light skin

61

Hypothyroidism

– Generalized myxedema in adult hypothyroidism. Face is puffy with a dull expression and the hair is dry.

• Cretinism– Insufficient thyroid hormone in

fetal life– Cool, dry, white to yellow

skin. Patchy alopecia. Hypohydrosis. Brittle nails. Thick protuberant lips. Enlarged tongue. Wide face.

• Myxedema– Systemic mucinosis– Rough, dry, dull skin over

areas of swelling, esp the face. (lips, tongue and nose)

– Diffuse hair loss and shedding of outer third of eyelashes occurs

– Brittle, coarse nails.

62

Hypothyroidism

Cretinism

Pretibial Myxedema with peau d’ orange of mucin deposition

63

Hypothyroidism• Mild Hypothyroidism

– Harder to detect

– Coldness of hands and feet in absence of vascular disease, cool intolerance, hypohydrosis, weight gain, excessive sleeping, constipation.

– Palmoplantar keratoderma may occur and resolves with TX.

64

Hypothyroidism

65

Hypothyroidism

Palmoplantar keratoderma

66

Hyperthyroidism• Cutaneous changes:

– Warm, moist, smooth textured skin. – Thin, downy hair with possible non-scarring alopecia. – Diffuse pigmentary changes - ‘melanoderma’. may

result in melasma.– Plummers’s nails – concave with distal onycholysis.

• Graves disease (F>M, onset 20-30 years.)– Thyroid Acropachy ( 1% of graves patients)

• Digital clubbing, diaphyseal proliferation in acral and distal bones.

• Frequently accompanies exophthalmos and pretib. myxedema• May be seen in euthyroid and hypothyroid pt on occasion.

Acromegally, Pul. osteoperiostitis.• Radiographic findings are pathognomonic.

67

Thyroid Acropachy

68

Hyperthyroidism• Pretibial Myxedema

– 4% of graves patients. Also, during Hashimoto’s thyroiditis and primary hypothyroidism.

– Bilateral, localized accumulations of glycosaminoglycans assoc with thyroid stimulating antibodies.

– Exophthalamous and acropachy assoc.

– TX: • intralesional steroids,

clobetasol under occlusion. (not systemic)

• IVIG• Vitiligo – 7 % assoc with graves.

69

Hyperthyroidism

70

Hypo-parathyroidism• Cutaneous:

– Poor dentition if during development.– Dry scaly skin. – Scanty hair. Absence of axillary and pubic

hair.– Brittle malformed nails with onycholysis.– 15 % of idiopathic cases develop candidisis.– APECED syndrome:

• Autoimmune PolyEndocrinopathy, Candidasis, External Dystrophy - syndrome.

• Hypoparathroidism most common endo. Dysfunction with this syndrome.

71

Pseudo - hypoparathyroidism• Autosomal dominate or X-linked.• End organ unresponsiveness to PTH.• Elevated PTH and phosphorus. Low calcium.• Clinical findings:

– Short stature, obesity, round face, prominent forehead, low nasal bridge, attached ear lobes, short neck, short wide nails, delayed dentition, mental deficiency, blue sclera and cataracts. Sub-Q calcifications

– Shortened long bones 2nd to premature epiphyseal closure.• Short stubby toes with metacarpophalangeal dimpling (Albright’s sign).

– Albright’s hereditary osteodystrophy• Includes Pseudo-hypoparathyroidism and Pseudo-pseudo PH.• Defect in G protein pathway leads to resistance to agents acting

through adenylate cyclase pathway.

72

Albright’s Hereditary Osteodystrophy

Features of Albright Hereditary Osteodystrophy (AHO). [A] Young woman with short stature (~ 3rd centile), disproportionate shortening of the limbs, generalized obesity, and round, flattened face. [B] Radiograph of the hand showing the shortened 4th and 5th metacarpals. [C] Fist with the characteristic 'dimples' over the 3rd, 4th, and 5th digits replacing the knuckles formed by the distal head of normally sized metacarpal bones (Archibald sign). [D] Brachydactyly of the hand, with the short 4th and 5th digits, the greatly foreshortened terminal 1st digit, and very short, wide thumbnail (potter's thumb). (Reproduced from Levine, 2000, with permission).

73

Hyper-Parathyroidism• Multiple endocrine neoplasia (MEN-I)

– Tumors of Parathyroid, pancreas, pituitary, thyroid and adrenal glands.

– Most common abnormality is hypercalcemia from the tumors of the parathyroids.

– Autosomal dominate. Presents in 4th decade.– Assoc. with multiple angiofibromas,

collaganomas, café au lait macules, lipomas, confetti like hypopigmentation and gingival macules.

– Tumors arise 2nd to abnormal tummor suppresor genes

74

Hyper-Parathyroidism and MEN-I

Angiofibromas

Collagenomas

Gingival papules

75

Acanthosis Nigricans• Hyperpigmentation and

papillary hypertrophy in a symmetrical distribution.

• Any area of the body may be involved including conjunctiva, lips and buccal mucosa. Palms may show hyperkeratosis.

• Type I : Malignancy associated.– Preceeds(18%),

accompanies(60%), follow(22%) malignancy

– Adenocarcinoma most associated. Esp G.I.

• Nonobese male >40 yrs old.

76

Malignant Acanthosis Nigricans

77

Acanthosis Nigricans– Tripe Palms – thickened velvety palms with

demoglyphics. • 95 % assoc with cancer. • 77% occurs with AN. • If only palms were only presenting sign then lung

CA most common.• If palms and AN then gastric cancer most common.

• Type II : Familial Acanthosis Nigricans.– Present at birth or early childhood.– No cancer assoc.– Accentuated at Puberty.

78

Tripe Palms

79

Acanthosis Nigricans• Type III: DM assoc.

– Most common– Grayish, velvety thickening of neck, axillae and

groin. – Occurs in obesity and with endocrine disorders

such as DM, acromegaly, Stein – Leventhal, Cushing, Addisons, thyroid d/o. Renal transplant pts. Many others.

– Insulin resistance either clinical or subclincal.– Drugs: nicotinic acid, glucocorticoids,

diethylstilbestrol, trizineate, BCP.

80

Acanthosis Nigricans

81

Acanthosis Nigricans• Histopathology: papillomatosis,

hyperkeratosis and slight hyperpigmentation. Without thickening of the Malpighian layer.– Darkening of skin 2nd to

hyperkeratosis.Treatment

– Address malignancy, endocrinopathy

– Weight Loss– Lipodystrophic DM

improves with fish oil.– Etretinate and tretinoin.

82

The End