Alcohol induced changes in the skin

Dr C.HSU

(Fetal Alcohol Syndrome, Dupuytren’s disease, Launois Bensaude disease, lichenoid dermatitis and conditions aggravated by alcohol not included)

Alcohol induced changes

Due to organ dysfunction (digestive tract)

–Liver

–Porphyria Cutanea Tarda

–Cirrhosis

–Jaundice

–Pruritus

–Pancreas

–Pancreatitis

Generalized

–Acute changes

-Urticaria

–Infections

–Chronic changes

–Malnutrition

–Skin Aging

–Neoplasia

Porphyria Cutanea Tarda

All porphrias are hereditary except PCT type I

PCT type I also as symptomatic protoporphria

-Epidemiology:affects males from 40 onwards, often with a history of alcohol abuse

-Three categories

-PCT I: symptomatic protoporphyria, non hereditary, 80% of PCTs, deficit in uroporphrinogen decarboxylase (only in hepatocytes)

-PCT II: : autosomal dominant, less than 20% of PCTs), the deficit in uroporphyrinogen decarboxylase is also present in red blood cells.

-PCT III: similar to PCTI in the sense that uroporphrinogen decarboxylase is only present in the hepatocyte (less than 5% of PCTs), but hereditary

-Clinically

-skin hyperfragility

-serous-hemorrhagic bullae and erosions on dorsum of hands following minimal trauma

-actinic bullosis: light-coloured bullae appearing after sun exposition. Then erosions form leaving scars with milia.

-hypertrichosis: mostly in malar area

-chronic actinic dermatosis: premature aging of the skin=diffuse brownish pigmentation, losangeal skin on the nape of the neck (nuchae rhomboidalis), diffuse elastoma and elastosis with cysts, comedones on the face.

-in 1/3 of cases, scleroderma-like lesions appear lately on the face, neck, torso, trunk and scalp (scarring alopecia beginning from the hairline). In the preauricular area, these lesions calcify (microliths) and the ulcers they create only heal after they disappear.

-Diagnosis

–dark urine (dark beer or Coca Cola) intensely fluorescing under wood’s light due to high porphyrin content. Uroporphrin is the mostly present followed by heptacarboxylic porphyrin and coproporphyrin.

–stools: isocoproporphyrin which is not present in other porphyries except the hepato-erythropoietic porphyria.

–labs also show elevated liver function tests (transmaninases), elevated iron and ferritin levels. Not unfrequently, elevated glycaemia.

-Histology

-the hyperfragility bulla is sub-epidermal in the papillary dermis. On the floor, the papillae are conserved and have a saw-toothed appearance. There is no inflammatory reaction. Elastosis often present.

-immunofluoresence shows IgG4 and IgM and C3 thick deposits in the dermo-epidermal junction.or around superficial dermal vessels.

-Cause

the diminution of 50% of the the activity of

uroporphyrinogen-decarboxylase. The cause of

the increase ofof iron is not known…

–Treatment

–alcohol withdrawal

-no hepatotoxic substances

-balanced diet: rich in proteins and phospholipids, poor in cholesterol.

-photoprotection (UVB and UVA)

–blood letting:300-500cm 3 of blood every week for a volume of 2-4 litres. Satisfying results in a few weeks. The mode of action is unknown and it also normalizes iron levels (iron diminishes the activity of UDase). Surprisingly the usage of deferoxamine mesilate is less effective.

–chloroquine: 100mg twice weekly (136 g of chloroquine sulfate) enables control achieved with higher doses but no side effects.

-alcalinisation of urine=not any more

Cirrhosis

§-Spider naevi:

-present in 75% of the time

-on the face and trunk

-rarely unilateral of the naevoid type, which abundance would correlate with the existence of oesophageal varicosities (Foutch et al),

§-Nails

-total apparent leuconychia (Terry’s nails): 80% of patients with cirrhosis. Proximal 2/3 white, presumed to result from reduced blood flow due to overgrowth of connective tissue.

-flat nails, koilonychia or clubbing (10-15%)

-red lunulae: due to arteriolar increased blood flow or venodulatation

-Endocrine changes

–hypogonadism: reduced facial hair growth, Soft texture. Sign of atrophy

–hyperestrogenism: gynaecomastia, spider naevi, changes in fat distribution, loss of body hair and change of pubic hair. Palmar erythrosis.

–Pseudo Cushing: Moon facies, truncal obesity, proximal muscle wasting, buffalo hump, abdomen striae, hypertension, osteoporosis. -Women may have signs of virilisation, breast atrophy or menstrual irregularities

-Other skin changes

-melanoderma (pigmented cirrhosis):

-Suspect familial haemochromatosis.

-due to excess melanin in giant melanosomes in the epidermis

-cause….

-blotchy circumscribed areas of hyperpigmentation, freckling, areolar, perioral, periorbital pigmentation.

-linear pigment in the finger creases

-purpura (thromopenia or hypoprothrombinaemia)

-Other visible changes

-Gynecomastia

-testicular atrophy (both due relative hyperestrogenaemia)

-caput medusae (due to collateral vein development)

-bilateral parotidial swelling

-icterus (cholestasis)

Jaundice

-due to the deposition of billirubin, product of the breakdown of heme: accumulation in the liver due toimpaired hepatic conjugation. It subsequently binds tissues with a special affinity to elastin.

–detectable with serum levels above 2,5 mg/dL

-The ocular sclera are often the first to turn yellow.

-DD prehepatic, hepatic, posthepatic

-Rx abstinence resolves jaundice provided there is residual hepatic function.

Pruritus

-It may appear up to 2 years before the onset of cirrhosis

-40% of alcohol abusers with liver disease are estimated to have severe pruritus

-generalized but with predilection to extensor extremities, upper trunk, palms and soles,

-chemical mediators (Bile acids) are thought to directly depolarize nerve endings or release pruritogenes (histamine).

-Treatment with bile acid-binding resins (cholestyramine) relieves the pruritus in 80% of cases, but malabsorption of ADEK. Also methyltestosterone or norethandrolone, UVA and UVB photoherapy. Phenobarbital (3mg/KG), intravenous albumin, extracorporeal photophoresis, diets rich in polyunsaturated acids.

-Poor correlation with bile-levels/pruritus though.

Pancreatitis

–Due to alcohol abuse in 65% of cases

-Clinically

-Panniculitis

-also called nodular cystosteatonecrosis or cutaneous nodular adiponecrosis: mechanism thought to be due to the liberation of enzymes in the circulation directly or through lymphatic channels

-found in the male between 40 and 70 years old

-clinically: -dermohypodermic inflammatory plaques predominantlylocated in the fingers and lower limbs with pain

-can lead to fistulisation and leakage of molten fat

-evolves in to cup-like depressions

-accompanied with fever, arthralgia, distal bone pain (due to cystosteatonecrosis of the bone medulla.

-lab findings: elevation of serum amylase and lipase levels.

-histology: foci of adipocyte necrosis, beginning in the centrolobular area. The content of the adipocytes disappears and only the cypoplasmic membranes of these “ghost cells”. Finally formation of a lipophagic granuloma.

Urticarial and anaphylactoid reactions

-reported to occur minutes after alcohol intake. May occur with anaphylactic symptoms

-reproductible with oral challenge with ethyl alcohol

-may have genetic intolerance with defects in alcohol-metabolizing enzymes (Oriental flushing syndromes). Many though develop a reaction after red or white wine intake suggesting the preservative, not the alcohol are responsible.

-DD cholinergic urticaria

-Alcohol and urticaria

1.

§Nakagawa Y, Sumikawa Y, Nakamura T, Itami S, Katayama I, Aoki T.

§Urticarial reaction caused by ethanol.

§Allergol Int. 2006 Dec;55(4):411-4

§urticarial reaction after drinking alcohol beverages. The patient was a 47-year-old man suffering urticarial and anaphylactoid reaction to alcohol for two years. These reactions were observed at every alcohol beverages intake.

§Prick test with diluted ethanol, alcohol beverages and their metabolites (acetaldehyde, acetic acid). Only acetic acid showed a positive result.

§Oral challenge test with diluted-ethanol caused pruritus and swelling of his lips. An oral challenge test with 8% diluted Shochu (Japanese distilled alcohol from rice or wheat) caused wheals on his upper back.

§Only acetic acid, a metabolite of alcohol, induced a positive prick test in the patient with alcohol-induced urticaria.

–This result was not observed in normal volunteers. An oral challenge test with diluted-alcohol or Shochu showed a positive wheal reaction in a dose dependent-manner which suggests that urticaria seen in this patient might be induced by alcohol-intolerance.

2.

§Sticherling M, Brasch J, Brüning H, Christophers E.

§Urticarial and anaphylactoid reactions following ethanol intake

§Br J Dermatol. 1995 Mar;132(3):464-7

§three patients who presented with recurrent generalized urticaria, which developed within minutes of consumption of small amounts of ethyl alcohol.

§Common causes of chronic recurrent urticaria were excluded by case history, physical examination and laboratory investigations, and by comprehensive allergy testing.

§All patients produce positive prick tests with acetic acid, and developed urticaria after oral challenge with small amounts of highly purified ethyl alcohol. The symptoms are most probably caused by an intolerance to ethyl alcohol or its metabolites, whereas an allergy sensu strictu seems unlikely

3.

§Ehlers I, Hipler UC, Zuberbier T, Worm M

§Ethanol as a cause of hypersensitivity reactions to alcoholic beverages.

§Clin Exp Allergy. 2002 Aug;32(8):1231-5

§In search of possible pathomechanisms all patients were analysed by skin prick testing and sulfidoleukotriene production of peripheral leucocytes using ethanol and its metabolites.

§METHODS: Food challenges with a cumulated amount of 30 mL ethanol were performed in 12 adult patients with a positive history of adverse reactions after consumption of different alcoholic beverages.

Skin prick tests and measurement of sulfidoleukotriene production were performed using different concentrations of ethanol and acetaldehyde from 50 to 1000 mm.

§RESULTS: Oral challenges with pure ethanol were positive in 6 out of 11 patients. All 6 challenge-positive patients, but also 4 (out of 5) challenge-negative patients, showed an increased sulfidoleukotriene production in-vitro compared with healthy controls. Skin prick tests using alcoholic beverages, ethanol, acetaldehyde and acetic acid were negative in all patients (12/12).

§CONCLUSION: Our study shows that ethanol itself is a common causative factor in hypersensitivity reactions to alcoholic beverages. These reactions occur dose-dependent and a non-IgE-mediated pathomechanism is likely, because skin prick tests were negative in all cases. Increased sulfidoleukotriene production was determined in some patients, but is no reliable predictor. Therefore oral provocation tests remain indispensable in making the diagnosis of ethanol hypersensitivity.

Infections

§Ness KJ, Fan J, Wilke WW, Coleman RA, Cook RT, Schlueter AJ

§Chronic ethanol consumption decreases murine Langerhans cell numbers and delays migration of Langerhans cells as well as dermal dendritic cells

§Alcohol Clin Exp Res. 2008 Apr;32(4):657-68. Epub 2008 Jan 28

§Dendritic cells (DC) migrate from peripheral locations to lymph nodes (LN) to initiate adaptive immunity against infection.

§METHODS: Mice received 20% EtOH in the drinking water for up to 35 weeks. Baseline Langerhans cell (LC) and dermal DC (dDC) numbers were enumerated by immunofluorescence (IF). LC repopulation after inflammation was determined following congenic bone marrow (BM) transplant and ultraviolet (UV) irradiation. Net LC loss from epidermis was determined by IF following TNF-alpha or CpG stimulation. LC and dDC migration into LN was assessed by flow cytometry following epicutaneous FITC administration.

§RESULTS: Chronic EtOH consumption caused a baseline reduction in LC but not dDC numbers. Net loss of LC from epidermis following inflammation was greatly reduced in EtOH-fed mice versus controls. Ethanol consumption for at least 4 weeks led to delayed LC migration into LN, and consumption for at least 8 weeks led to delayed dDC migration into LN following epicutaneous FITC application.

§CONCLUSIONS: Chronic EtOH consumption causes decreased density of epidermal LC, which likely results in decreased epidermal immunosurveillance. It also results in altered migratory responsiveness and delayed LC and dDC migration into LN, which likely delays activation of adaptive immunity. Decreased LC density at baseline appears to be the result of an alteration in the skin environment rather than an intrinsic LC defect. These findings provide novel mechanisms to at least partially explain why chronic alcoholics are more susceptible to infections, especially those following skin penetration

Malnutrition

-Zinc

Clinically:

-erythematous crusting erosive sometimes bullous dermatitis

-periorificial: buccal, nasal, palpebral, anal, vulval, genital, flexural

-progressive alopecia

-diagnosis and treatment: reduced Zn and alkaline phosphatase, sometimes also reduced non esterified essential fatty acids (linoleic and arachidonic acid). IV or oral by zinc salts (gluconate, sulfate) leads to spectacular cures.

-Essential Fatty Acids

-sometimes associated with Zinc deficiency

-Clinically: leads to dry ichthyotic skin or eczema craquele and is associated with growth retardation.

-diagnosis and treatment: blood dosage. Treatment can be topical, IV or oral.

-Vitamin PP

-composed of nicotinic acid (niacin) and nicotinic amide (nicotinamide)

-its precursor is tryptophane

-its metabolism needs the vitaminic coenzymes B1, B2 and B6.

-Clinically = pellagra

-dermatitis: dusky red erythema appearing quickly on exposed skin accompanied with edema, fine cracked skin followed by bullous hemorrhagic sloughings slowly resolving leaving behind thin, pigmented skin.

-diarrhea: often preceeded by stomatitis and glossitis.

-dementia: apathic, depression. Sensorial deficiency is present in severe cases

-diagnosis and treatment: PP dosage can sometimes be normal despite symptoms. Treatment by Nictinamide 500mg/d IV. Skin signs are the first to disappear, followed by the neurological and digestive ones.

-Vitamin B6 (pyridoxin):

-Clinically = peri-orificial seborrhoeic dermatitis.

-diagnosis: charge test with tryptophane (measurement of urinary xanthurenic acid): efficient. Treatment with Vitamin B6 orally or IV (1g/d) leads to healing in a few months.

-Vitamin B2 (riboflavin)

-Clinically :

-oral: fissural cheilitis and perleche, angular stomatitis, glossitis, conjunctivitis

-genital: peri-orificial erythema

-ocular: blepharitis and conjunctivitis

-diagnosis: riboflavin dosage can’t be relied on. Only Riboflavin IV (20-40mg/d) treatment followed by rapid improvement confirms the diagnosis

-Vitamin A

-Clinically

-rough dry scaly wrinkled skin

-hypohidrosis and sebaceous atrophy

-follicular hyperkeratosis (non specific)(=phrynoderma) of limbs, nape of neck, shoulders, trunk

-other systems: diminished night vision

-diagnosis and treatment: diagnosis by dosage of vitamin A or by proof treatment with vitamin A 50000 units/d (cured in a few months).

-Vitamin C (ascorbic acid) (scurvy)

-plays a role in collagen, iron, sulfur, tyrosine and folic acid metabolism

-Clinical features of scurvy:

-follicular keratosis

-corkscrew hairs

-perifollicular hemorrhage

-extensive polychrome purpura with a sclerodermiform oedema. Sometimes hemorrhagis hypodermitis.

-glossitis

-hypertrophic and hemorrhagic gingivitis

-teeth fall

-Diagnosis and treatment: Intraleucocyte dosage of Vit C can be normal in the beginning. Treatment with ascorbic acid orally or IV 1-2g/d

-Vitamin K

-plays a role in the synthesis of coagulation factors II VII IX X.

-Clinically: purpura

-Treatment: intramuscular Vit K injection is sometimes followed by an inflammatory eczema-like reaction which can evolve to scleroderma-like plaques and necroses.

-Iron (excess by intoxication=hemochromatosis):

-Clinically: melanoderma ; if diffuse associated with atrophic skin, hypopilosity, thin hair, leuconychia, koilonychias should lead to the suspicion of familial Hemochromatosis. Acquired ichtyosis in that case could be paraneoplastic.

Skin Aging

§von Wurmb-Schwark N, Ringleb A, Schwark T, Broese T, Weirich S, Schlaefke D, Wegener R, Oehmichen M.

§The effect of chronic alcohol consumption on mitochondrial DNA mutagenesis in human blood.

§Mutat Res. 2008 Jan 1;637(1-2):73-9. Epub 2007 Jul 21.

§The 4977bp deletion of mitochondrial DNA (mtDNA) is known to accumulate with increasing age in post mitotic tissues. Recently, studies came out detecting this specific alteration also in fast replicating cells, e.g. in blood or skin tissue, often in correlation to specific diseases or — specifically in skin — external stressors such as UV radiation.

§In this study, we investigated mitochondrial mutagenesis in 69 patients with a chronic alcoholic disease and 46 age matched controls with a moderate drinking behavior. Two different fragments, specific for total and for deleted mtDNA (dmtDNA) were amplified in a duplex-PCR. A subsequent fragment analysis was performed and for relative quantification, the quotient of the peak areas of amplification products specific for deleted and total mtDNA was determined. Additionally, a real time PCR was performed to quantify mtDNA copy number.

§The relative amount of 4977bp deleted mtDNA in alcoholics was significantly increased compared to controls. On the other hand, no difference regarding the mtDNA/nuclear DNA ratio in both investigated groups was detected. Additionally, no age dependence could be found nor in alcoholics, neither in the control group.

§These findings indicate that mtDNA mutagenesis in blood can be influenced by stressors such as alcohol. Ethanol seems to be a significant factor to alter mitochondrial DNA in blood and might be an additional contributor for the cellular aging process.

Skin Cancer

-by immunosuppression

-by associated nutritional deficiencies which alter mucosal integrity

-by impairing detoxification

-promotion: eg ENT Scc, oral

-for BCC incidence increased as well as infiltrative

-unclear for malignant melanoma.

§Tan W, Bailey AP, Shparago M, Busby B, Covington J, Johnson JW, Young E, Gu JW.

§Chronic alcohol consumption stimulates VEGF expression, tumor angiogenesis and progression of melanoma in mice.

§Cancer Biol Ther. 2007 Aug;6(8):1211-7. Epub 2007 May 8.

§We used the immunocompetent mice implanted with B16F10 cells to evaluate the effects of physiologically relevant EtOH intake on tumor growth and angiogenesis of melanoma.

§Six-wk-old male mice (C57BL/6J) were given 1% EtOH in drinking water for 12-hrs during the night which was then replaced with regular water during the remaining 12-hrs each day for 4 wks (n = 10).

§In the second week, all mice were inoculated subcutaneously on the right proximal dorsal with 5 x 10(5) B16F10 cells.

§In the end, the tumors were isolated for measuring tumor size, average microvascular density (AMVD) using CD31 immunohistochemistry, and the expression of VEGF and its receptor (Flt-1) using Northern blot, ELISA, and immunohistochemistry.

§EtOH intake caused a 2.16-fold increase in tumor weight over the control (4.81 +/- 0.39 vs. 2.23 +/- 0.48 g; n = 10; p = 0.003), a 2.02-fold increase in AMVD (60.63 +/- 5.56 vs. 30.01 +/- 7.41/mm(2); p = 0.0014), and a significant increase in VEGF mRNA and protein expression plus Flt-1 protein levels in melanoma compared to the control group (p < 0.01).

§These results suggest that progression of melanoma growth and angiogenesis may be mediated by upregulation of VEGF and Flt-1, especially under the influence of EtOH.