Pruritus mul interna! diseases Pruritus an Ullportant symptom of interna[ d-iseases V. Peharda, F. Gruber, M . Kaštelan, I. Brajac and L. čabrijan SUMMARY Pruritus is a common unpleasant sensation, accompanied frequently by scratching. This symptom can be caused by numerous cutaneous diseases and by interna! disorders. Pruritus is mediated by histamine, proteases, prostaglandins, and substance P. The biochemical, cellular mechanisms and the neuroanatomical pathway which determine the outbreak of pruritus in different interna! diseases are described. The exact diagnosis is important for choosing an appropriate treatment. Introduction Pruritus is one of the most prominent and disturbing symptoms of skin and other diseases, which was already known to the physicians in the Old Age, including Hippocrates who wrote about it (1). Despite its common use, the word pmritus is not easy to defrne. A simple description is that pruritus is an unpleasant cutaneous sensation that provokes a desire to scratd1. This desire is the most remarkable d1aracteristic of itch or pruritus in its differentiation from other similar sensations. In the seventeen century Hafenreffer, already described it as "tristis sensatio, desideri scalpendi excitans" (2). Although it seems simple, this attempt to define pruritus can be in1precise; recently Savin noted that the "word unpleasant means different things to different people" , and patients suffering from itch do not always want to scratch (3). Pruritus can be a physiological sensation if the con- secutive scratching removes a potentially harmful agent, or pathological, if associated with skin and interna! diseases, and psychic disorders, or caused by some drugs. We will use tl1e terms pruritus and itch as synonyms, but some authors use the term itch if there are skin lesions expressed, and pruritus if there are no primary skin alterations "pruritus sine materia" (4,5). The present article reviews some aspects of itch caused by interna! diseases based on new investiga- tions obtained by immunohistochemical, clinical, Revi ,ew 92 Acta Dermatoven APA Vol 9, 2000, No 3 Pruritus and interna! diseases neurophysiological, electrostirnubtive ancl molecubr stuclies. General clinical aspects Pruritus can be experienced only on the skin , beca- use of the unique neural rnechanisrns present in it, and they also permit a precise localization. Pruritus bas to be distinguished from pain , burning, tickling, touch and other sensations. It shoulcl be stre- ssed that pruritus is a symptom and nota disease. It is a subjective sensation, but sometirnes it can be accom- paniecl by excoriations, crusts, hyperpigmentation, li- chenification with thickening, increasecl skin creasing, ancl burnished nails. It can also lead to pyodermization. Pruritus affects patients of ali ages and both sexes. The intensity can be miki, moderate, severe or distressing with sleep clisturbances, loss of weight, discomfort, increased irritability, problems in claily activities, ancl even stress. It may be acute or long lasting, and it can be localized on the scalp, anal and genital area, back, legs or generalizecl. Chronic itch triggers psychic res- ponses but the psyche can also influence itch. Pruritus may present a cliagnostic and therapeutic challenge to the clinician, a dermatologist, family physician, internist, pecliatrician or psychiatrist. Some point in the patient's histo1y can be helpful. Etiopathogenesis and mediators Pruritus can be provoked by many different exo- genous agents (weak mechanical stimuli, electrical, thermal and chemical excitation) or by endogenous causes or stimuli. Although our knowledge of some aspects of the pathogenesis of pruritus is stili incomplete, it has greatly increased in recent years. Incornplete data concerning the prima1y cause of pruritus are in part resulting from the fact that this subjective sensation is, unfortunately, bard to measure , as well as from the Jack of a good animal model. Much has been deduced from investigations concerning pain, and from intraderrnal injection of pruritogenic substances. Recently, the intensity of pruritus was measured by instruments that measured the movement of scratching, or by an infrared video camera that acted also during sleep (6,7). A number ofpathological processes can lead to pru- ritus: inflammation, hypersensitivity, degenerative changes, malignant tumors, and even psychic abnor- malities. To understand the pathogenesis of pruritus, it is necessa1y to review briefly the neuroanatomical basis of pruritus, which is relatively well known, and the mediators of the itch. Itch originates in free nerve endings near the dermo-epidermal junction and is 94 concluctecl centripetally by afferent nerves entering the spina! cord via the dorsal roots. The sensitive nerves for pruritus are small , non-myelinated C fibers with a slow conduction rate. The celi bodies of these no- ciceptive prima1y neurons are located in the clorsal root ganglion. After entering into the spina! cord the prima1y neurons syna pse seconda1y neurons whose axons cross to the opposite side, ancl then by the tractus spino- thalamicus reach the laminar nuclei of the thalanrns. Finally, these nuclei relay to the cere bral cortex, i.e. the senso1y area in postcentral gyrus. Here we note the location, the nature, the intensity and other quality of this sensation. Recent investigation by positron emission tomography dernonstratecl the activation of the pre- motor area and of the inferior parietal !obule, a region, which propose movement, after intracutaneous injec- tions of histamine (8). Probably there are synaptic connections to the motor area of the cortex, which prepare scratching. For a long tirne it was thought that itch represents a weak pain, ancl there was a debate whether the same nerves conduct itch ancl pain. Now we believe that itch anc.l pain are clifferent ancl inclepenclent sensory moc.la- lities, even if local anesthesia or cutting of the sensitive nerves can abolish both. Following observations confirm the opinion that receptors for itch and pain cliffer: - itch elicits scratching, while pain a withdrawal response, - morphine relieves pain but can produce pruritus , - the heating of the skin to 41 °C relieves itch but not pain, - removal of the epidermis ancl upper dermis abolishes pruritus, but not pain. Recent studies suggest the existence of specific C fibers for pruritus (9,10). In a well-designed study, Schmelz ancl collaborators using a microneurographic and histamine iontophoretic method clemonstrated the existence of specific ve1y thin C fibers w ith low con- duction velocity (0,5m /s) which seem to be the recep- tors for itch in humans (10). Gradually, investigators established that a number of chemical substances provoke or enhance pruritus. These releasecl substances are mediators, which act peripherally on receptors , on cells or nerves. The most known are histamine , proteinases, prostaglandins, neuropeptides, cytokines anc.l bile salts. Some of the substances can act clirectly on the free nerve endings, other act indirectly through mastocytes or other cells. Histamine , an imidazolethylamine, was the first ancl most important recognized pruritogenic substance but it does not account for ali the types of pruritus. This biogenic amine is present in the numerous meta- chromatic granules in mast cells, and when releasecl acts on tl1e Hl receptors, eliciting itch (11,12). Intere- stingly, histamine applied intraepidermally or at the Rev i ew Acta Dermatoven APA Vol 9, 2000, No 3 Review basal membrane, causes itch, while when released cleeply in the clermis causes pain and edema (angio- edema). Itch provoked by histamine is generally associatecl with flare ancl wheal. It acts on neurons by elevating the concentration of c AMP. Some experiments clemonstratecl that serotonine (5-hyclroxytryptamine, 5- HT), only scantly present in the skin, and injected intra- clermally, can also cause pruritus ancl pain (13). Among prostaglanclins, PGE2 cloes not itself elicit itch, but lo- wers the thresholcl ancl potentiates the itch provoked by histamine (14). PGE is a vasoclilatator present in hea- ling wouncls. It causes inflammation ancl itch after solar exposition. Antihistamines can partially alleviate the pru- ritus inclucecl by this substance. Substance P (SP), a proinflammat01y neuropeptide, consisting of eleven aminoacicls, is proclucecl in the clorsal ganglia ancl then transported to the periphe1y by nociceptive nerves A ancl C (15). SP can release hista- mine from the mast celi granules ancl so provoke itch. In the skin, SP can also cause erythema, edema and neurogenic inflammation releasing histamine, IL -1, prostaglanclins ancl lysosomal enzymes but is quickly degraclecl in the dermis (16). The prior oral admini- stration of antihistamines inhibits the pruritus caused by SP. Capsaicin obtainec.l from hot pepper appliecl locally clepletes SP from cutaneous nerves, and so diminishes pruritus. Among other cytokines, interleukine 2, given intradermally or i.v. causes itch (17). Proteases and pepticlases such as papain, trypsin, chymotrypsin, kallikrein injectecl in the skin also cause pruritus (18). Furthermore, these substances could incluce pruritus in histamine clepletecl skin. It is worthy to say that Shelley ancl Arthur were the first to demonstrate, in their classic experiments with spicules from the itch producing plant of cowhage (mucuna pruriens), that the itch is causecl by an endopepticlase (papain) present in the specules (19). It is well known that in cases with obstructive jaundice, bile salts and bile acids probably cause Table 1. Conditions associated with pruritus - Chronic renal failure - Sclerosis multiplex - Patients on hemodialysis - Stroke - Intrahepatic cholestasis - Psychogenic states - Posthepatic cholestasis - Delusion of parasitosis - Pregnancy -Lymphoma - Drug-induced cholestasis - Mastocytosis - Polycythemia vera - Brain tumors - Iron-cleficiency anemia -AIDS - Hyperthyroiclism - Systemic parasitosis -Mixoeclema - Sjogren's syndrome - Diabetes mellitus - Drug eruptions - I-Iyperparathyroiclism Acta Dermatoven APA Vol 9, 2000, No 3 Pruritus and internat diseases pruritus. Recent research has shown that in addition to these substances, opioicls such as ~-enclorphin, met- enkephalin, anc.l leu-enkephalin, can play an important role in causing itch, acting centrally or peripherally (20, 21). On the other hand, scratching the skin stimulates inhibito1y reflexes which break circuits in the spina! corcl or centrally ancl so abolishes or alleviates pruritus. This is in agreement with the "Gate theo1y" proposecl by Melzak and Wall (22). Stuclies on volunteers demonstratecl that cooling the skin from 32.8°C to 29.7°C or the application of menthol on histamine inc.lucecl pruritus can recluce its intensity. These findings suggest a central inhibito1y effect of colcl on activation of A - delta fibers (23). Classtfication ojpruritus Huet has classifiecl the causes of pruritus in three groups (24): • predisposing causes, that inclucle genetic ancl allergic factors as well as endogenous and exogenous into- xications; • fortuitous that inclucle environmental factors like temperature , lrnmic.lity, wincl, emotions; • cletermining causes, such as physical agents, chemical agents, infections, infestations ancl others. It is important to distinguish the localizecl from the generalizecl pruritus, which can be cliviclecl traclitionally into: 1. Pruritus clue to a variety of cutaneous cliseases in which various mecliators act on free nerve enclings; 2. Pruritus associated with interna! diseases; 3. Idiopathic or "pruritus of uncletermined origin" (PUO) (25), if no cause can be iclentifiecl. The most frequent interna! cliseases associatecl with generalized pruritus are shown in Table l. Dry skin (asteatosis, xerosis) as well as excessive bathing may provoke pruritus, especially in old inclivicluals. In such cases the itch can be triggerecl by mechanical or osmotic mechanisms (26,27). Prurit:1.1s is a frequent ancl important symptom of various systemic clisorclers (28-30) . Skin disorders characterizecl by itching are beyond the scope of this review. Uremic pruritus Pruritus uraemicus or renal itch is a common and often intolerable symptom of chronic renal insufficiency (31), being presentin about 13 % ofthe cases; seconda1y 97 Prurirus and iruernal diseases skin lesions due to scratching can be seen. It is even more common (50-90%) in patients undergoing peritoneal dialysis or hernodialysis (32); it can be loca- lized (about 50 % ofthe cases), or generalized. Itching is not present in acute renal failure. The pathogenesis ofthis pruritus is poorlyunderstood. The cause can be asteatosis , iron deficiency, seconc.la1y hyperparathy- reoic.lism, hypervitaminosis A, proliferation of mast cells in the skin, release of histamine, allergic reactions to the mate rial used for c.lialys is , uremic neuropathy affecting motor, senso1y anc.l autonomic ne1ves, changes in the calcium-phosphate proc.luct, endogenous opioicls and others (33). Probably the cause is multifactorial. Severa! stuclies do not indicate that plasma histamine concentration is implicatec.l in renal pruritus (34,35) and antihistamines are rarely beneficial. The treatment of renal pruritus is basec.l on intensive anc.l efficient c.lialysis to remove pruritogenicsubstances from the blooc.l, anc.l on the use of non-complement-activating membranes. One can also use UV therapy, emollient o intments , activatec.l charcoal, cholestyramine (4 grams twice a day), phosphate binding agents. Sometimes parathyroi- dectomy is necessary. Recently, erythropoietin (100 units/kg IV or S.C) demonstrated an antipruritic effect in these patients (36,37). Improvement occurs after transplantation. Cholestatic pruritus Pruritus is a well-recognized manifestation among patients with !iver diseases ancl intrahepa tic or posthepatic cholestasis. I-Iepatic diseases leac.ling to prmitus include primary bilia1y cirrhosis, B and C vira! hepatitis, primary sclerosing cholangitis, carcinoma of bile ducts, alcoholic cirrhosis, autoimmune hepatitis and others. The pruritus is generalized and more intense on hancls, feet anc.l arouncl tight-fitting clothes, while face, neck and genital area are rarely involved (38). The pathogenesis is stili poorly understoocl, as the precise substance responsible for it is not known. Some authors believe it is caused by the bile acids in the blood (cho- lemia) or skin (39, 40), but there is a poor correlation between the skin concentration ofbile salts and intensity of pruritus. Recently, an elevation of enc.logenous opio- ids was found in the blood of these patients C 41), and treatment with the opiate antagonist naloxone improved pruritus. The itch in patients with cholemic pruritus can be lessened by treatment with cholestyramine, photo- therapy, plasmapheresis which lower or remove the unknown circulating pruritogen; antihistamines can be used as adjuvants. Ursodeoxycholic acid has been used (10-15 mg/kg) w ith gooc.l success. Interestingly, some serotonin subtype-3-receptor antagonists like ondan- setron, given intravenously, have been helpful in the treatment of cholestatic prnritus C 42). On the other hand, drugs like testosterone, chlorpromazine, oral 98 contraceptive pills, e1ythromycin, allopurinol, rifampicin can also provoke cholestatic jaunclice and pruritus C 43, 44). Pruritus in pregnancy Generalized pruritus is present in 1-8% of pregnant wom en (45). This pruritus graviclarum mu s t be clifferentiatec.l from pruritic dermatoses in pregnancy, such as pemphigoicl gestationis (herpes gestationis), papular anc.l pruritic clermatosis of pregnancy and others (46). Pruritus gravidarum was describecl together w ith jaunclice by Kehrer in 1907 (47). It manifests without any rash mostly in the third trimester of pregnancy, but it may also appear earlier, firstly on the abdomen ancl then becomes generalized. This symptom usually tencls to be worse at night and disappears after delive1y ( within 1-4 weeks). Probably it is associated with intrahepatic cholestasis , as there is an increase of gamma GT ancl alkaline phosphatase, and sometimes also of direct bilirubin leve! in these patients. Pruritus is more frequent in nrnltiple pregnancies and can recur in subsequent pregnancies or cluring the use of oral contraceptives (48). Severe pruritus can be treated with urso- cJeoxycholic acicJ or by induction of delive1y at 38 weeks (49). Pruritus in hematologic disease Some hematological c.lisorc.lers are known to be associatecl with pruritus. In polycythemia rnbra vera with overprodu ction of ali three hematopoietic celi lines, patients typically experience severe itch located on the trunk , but sparing the face, hands and feet, a few minutes after contact w ith warm water. \'v'ater-inclucecl itching (aquagenic prmitus, or bath itch) can be present in 70% of the patients (50). The itch can last for about 15 minutes to one hour, ancl be so severe that the patients refuse to bathe. It is caused by release of histamine (51) or other substances from an increasec.l number of basophils in blood; antihistamines do not relieve this symptom, anc.l currently the most effective methocl to treat it is the use of salicylates, photoche- mothera py or interferon alfa (52). In patients with hypochromic anemia, localizecl or generalizec.l pruritus is also common (53). It seems that iron cleficiency is the cause, and treatment w ith iron abolishes the symptom. In older patients the cause can be a malignant tumour leading to anemia. Interestingly, in patients with hemochromatosis in which the leve! of iron in blood and tissues is elevatec.l the pruritus may also be present (54). In the last decades pruritus has been described in patients with graft versus host reactions after bone marrow transplantation. R ev iew Acta Dermatoven APA Vol 9, 2000, No 3 Review Endocrine pruritus Pruritus can be a symptom of endocrine disorders. It is present occasionally in diabetic patients. In 1927 Greenwood, studying 500 patients with diabetes, found pruritus in 7% ofthem (55). The itch can be generalized or more frequently localized in the anogenital area. The pruritus can be linked to neuropathy, candida infections, d1y skin, and drug aclministration. Pruritus vulvae in diabetic women is often associated with poor diabetes control, i. e. elevatecl glycosylated hemoglobin leve! in blood. Treatment consists in regulation of diabetes, topical antifungal drugs. In some cases of localized pruritus topical capsaicin can be helpful. Pruritus associated with hyperthyreosis was known from the beginning of the 20th centu1y (56). The mechanism of this pruritus is unclear, perhaps an increase in bloocl tlow ancl consecutively in skin temperature may be a causative factor. Toclay, pruritus in patients with mixoedema is rare; if present, it may be relatecl to the d1y skin. Pruritus ancl even chronic urticaria may be associatecl with the presence of thyroicl autoimmunity ancl antibodies against severa! thyroid components such as are thyreoglobulin, and TSH receptor. In such cases appropriate treatment is levothyroxin O.OS mg/day. Patients with abnormal parathyroid gland activity can also have pruritus. This suggests that secondary incre- ased PTH during renal diseases can have a role in uremic itch, but intradermal injection ofthis hormone failecl to trigger itch (57). D1y skin and cutaneous candidosis probably cause pruritus in patients with primary hypoparathyreoiclism (58). Vulvar pruritus can be linked to hormona! deficit in women in the postmenopausal period (59). Pruritus and malignancy A number of malignant tumors can cause pruritus (prnritus paraneoplasticus). Carcinoma of the Jung, stomach, colon, prostata, breast and pancreatic can rarely be associated with generalized pruritus (60,61). Treatment consists in the surgical removal of the tumor and, in inoperable cases in the use of paroxetine, a serotonin re-uptake inhibitor, or of topisetron, a sero- tonin antagonist. Lymphomas such as mycosis iimgoides and Hodgkin's disease are frequently associated with itch. Goldman and Koh founcl pruritus in 35% of patients suffering from Hodgkin's disease (62). In Hodgkin lymphoma, pruritus can be for a long tirne the only symptom before the disease becomes apparent, and it improves aft:er radiation therapy or chemotherapy. In these diseases and in leukemia severe pruritus and exco- riations can indicate a poorer prognosis and pruritus may precede recurrences. Pruritus can be the initial symptom of Sezary syndrome, but is rare in leukemia Acta Dermatoveh APA Vol 9, 2000, No 3 Pruritus and interna/ diseases (63,64). It is an important symptom in patients with clifferent form of mastocytosis: solitary mastocytoma, urticaria pigmentosa, teleangiectasia macularis eruptiva perstans, systemic mastocytosis (65). Mast cells (MC) in human 's skin are mostly of the MC-te type, i.e. containing t1yptase and chymase, while in the alveoli and gastrointestinal nrncosa they are of the MC-c type. This distinction can help to differentiate the skin mastocytoses from the systemic ones (66,67). In carci- noid syndrome pruritus is sometimes associated with tlushing. The pruritus is elicited by serotonin, produced in the enterochromaphine cells of the tumor (68). Treatment with antiserotonin drugs alleviates the symptom. Andreev and Petkov have found frequent (17%) associations of pruritus with brain tumors. Interestingly, nasal pruritus was present in about half of the cases (69). The reason of annoying pruritus in patients with tumors is not always understood. It may be triggered by immunological mechanisms, tumor metabolites, iron deficiency, dry skin and other causes. Antihistamines do not relieve it, but it is known that the eradication of the tumor can diminish or abolish itch. In patients with MEN syndrome (Multiple Endocrine Neoplasmas) 2A (Sipple synclrome) a unilateral pruritus over the sca pular region, linked to deposition of amyloid can be present (70). Drugs given for chemotherapy (plant alkaloids, alkylating agents, antimetabolites), and irradiation can also produce pruritus that is generally self-limiting (71- 73). Neurogenic pruritus In patients with brain diseases (stroke, sclerosis multiplex, brain tumors, abscesses, Creutzfelclt-Jacobi disease and others) severe generalized or localized pruritus sometimes occurs (7 4-76). Characteristically, the itch occurs in paroxysms and can be unilateral. It is probable that in such cases the pathologic processes provoke an interruption of the descending inhibitoty tracts. This is partly confirmed by the treatment with amitriptyline, which is blocking the up take of serotonin, increases the conduction in the medulla, and alleviates itch (77). Patients with neuropathies complain rather of paresthesias than of pruritus. Psychogenic pruritus Psychological factors, such as anxiety, depression, and psychoses, can be the cause of pruritus. In more than 10% of the adults with generalized pruritus is triggered by psychological causes (78,79). A particular form is present in patients with Ebkom syndrome or delusion of parasitosis. In 1937, Ebkom described the 99 Pruritus and interna/ diseases syndrome calling it "Dermatozoenwahn"; it appears typically in elderly people, usually women (80). Zbey often complain about itch and believe that they are infestecl with some parasites, such as lice, ants, flies, and scratch the skin to eradicate them (81,82). Therapy with pimozicle (phenilbutyl piperazine) 2mg/day, an antipsychotic drug, seems to be effective, but psychiatric aclvise is neeclecl. Conclusion All the anatomical strnctures involved: the skin , peripheral nerves, central nerve system and various mediators can be intluenced by treatment. The therapy can be topical or systemic, symptomatic ancl causal. In many cases it is necessa1y to avoid excessive bathing, irritative fabrics, vasoclilatation caused by alcoholic beverages , hot liquicls or foods, stress, etc. Drug-induced pruritus Internally, one can use antihistamines, sedating or not. The non-seclating include loratadine, astemizole, terfenacline and others. The classic seclating anti- histamines are difenhidramin ancl clorpheniramin, which induce side effects like sedation, slowing the motor skill and somnolence. Phototherapy, chole- styramine, capsaicine ancl other clrugs can be of value, as well as the specific treatment of the interna! disease. Useful is also tbe tricyclic antidepressant doxepin used topically or systemically. Finally, the use of some drugs can induce prnritus acting directly on skin strnctures, or inclirectly through iatrogenic hepatotoxicity, or nephrotoxicity. Morphine and opioids were cited above; other known drngs are angiotensine converting enzyme inhibitors, analgetics, vitamin A, contrast media, gole!, chloroquine and sulfonamicles (83-84). There are a few reports on pruritus caused by infusions ofhydroxyethylstarch, used to treat sucklen hearing loss. The drug remains for a long tirne in the dermal macrophages (85). The use of antihistamines is not helpful, so one may assume that histamine does not play a role. In conclusion, pruritus is a symptom, which should never be unclerestimatecl. EFE E l. The genuine works of Hippocrates. (Trans! F. Adams) vol I, London, New Sydenham Society 1849: 753. 2. Haffenrefer S. 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Paroxysmal itching in multiple sclerosis. Br J Dermatol 1976; 95: 555-8 77. Sheehan-Dare RA, Henderson MJ, CotterillJA. Anxiety and depression in patients with chronic urticaria and generalized pruritus. Br J Dermatol 1990; 123: 769-74. 78. Musaph H. Psychogenic pruritus. Sem Dermatol 1983; 2: 217-22. 79. Beare JM. Generalized pruritus: A study of 43 cases. Ciin Exp Dermatol 1976; 1: 343-352. 80. Ekbom K. Der praesenile Dermatozoenwahn. Acta Psychiat Neurol 1938; 13: 227-59. 81. Arrese JE, Pierard-Franchimont C, Hougardy G, Pierard GE. Le delire de la parasitose ou syndrome d' Ekbom. Rev Med Lie 1993; 48: 631-4. 82. Ceccarini M, Falleni M. La sindrome tli Ebkom o delirio da parassitosi: presentazione tli tre casi clinici. Chron Derm 1994; 4: 857-866. 83. Bircher AJ. Arzneimittelallergie und Haut. Stuttgart-New York, G Thieme 1996: 97-9. 84. de Shazo RD, Kemp SF. Allergic reaction to drugs and biologic agents. JAMA 1997; 278: 1895-1906. 85. Leunig A, Szemies RM, Wilmes E, Gutman R, Stolz W, FeyhJ. Klinische und elektronenmikroskopische Untersuchungen zur Horsturztherapie mit der Kombination 10% BES / 0.5 mg Pentoxy - phillin. Laryngorhinootologie 1995; 74: 135-40. Vesna Peharda MD, Department oj Dermatovenerology, Clinical Hospital Centre, J(rešimirova 42, 51000 Rijeka, Croatia. Franjo Gruber MD, PhD, projessor and chairman, same address Marijal(aštelan, MD, PhD, dermatologist, same address Ines Brajac MD, dermatologist, same address Leo ČabrijanMD, dermatologist, same address Review Acta Dermatoven APA Vol 9, 2000, No 3