Clinical and forensic signs related to ethanol abuse: a mechanistic approach.

http://informahealthcare.com/txm ISSN: 1537-6516 (print), 1537-6524 (electronic) Toxicol Mech Methods, 2014; 24(2): 81–110 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15376516.2013.869782

REVIEW ARTICLE

Ricardo Jorge Dinis-Oliveira1,2,3,4, Teresa Magalha˜es2,3,5,6, Roxana Moreira1, Jorge Brandaõ Proença1, Helena Pontes4, Agostinho Santos2,3,5, Jose´ Alberto Duarte7, and Fe´lix Carvalho4 1

IINFACTS – Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences – North, CESPU, CRL, Gandra, Portugal, 2Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal, 3Center of Forensic Sciences (CENCIFOR), Coimbra, Portugal, 4REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal, 5National Institute of Legal Medicine and Forensic Sciences, I.P., North Branch, Portugal, 6Biomedical Sciences Institute ‘‘Abel Salazar’’, University of Porto, Porto, Portugal, and 7CIAFEL, Faculty of Sport, University of Porto, Porto, Portugal Abstract

Keywords

For good performance in clinical and forensic toxicology, it is important to be aware of the signs and symptoms related to xenobiotic exposure since they will assist clinicians to reach a useful and rapid diagnosis. This manuscript highlights and critically analyses clinical and forensic imaging related to ethanol abuse. Here, signs that may lead to suspected ethanol abuse, but that are not necessarily related to liver disease are thoroughly discussed regarding its underlying mechanisms. This includes flushing and disulfiram reactions, urticaria, palmar erythema, spider telangiectasias, porphyria cutanea tarda, ‘‘paper money skin’’, psoriasis, rhinophyma, Dupuytren’s contracture, multiple symmetrical lipomatosis (lipomatosis Lanois– Bensaude, Madelung’s disease), pancreatitis-related signs, black hairy tongue, gout, nail changes, fetal alcohol syndrome, seborrheic dermatitis, sialosis and cancer.

Ethanol, black hairy tongue, Dupuytren’s contracture, fetal alcohol syndrome, porphyria cutanea tarda, psoriasis, rhinophyma, spider telangiectasias

Introduction Ethanol use has been part of human culture since the beginning of recorded history. Its abuse represents a serious cause of morbidity and mortality in our society and it is implicated in multiple health conditions. In a very interesting study, Rehm et al. (2009) concluded that ethanol abuse is one of the major avoidable risk factors, and actions to reduce burden and costs associated with ethanol should be urgently raised. Ethanol abuse–related disorders are one of the leading causes of mortality and morbidity worldwide, and are ranked in the top five causes of disease burden by the World Health Organization (2009), and the third highest cause of disability when expressed in terms of disability-adjusted life years (DALYs) (World Health Organization, 2009). Data for Eastern Europe indicate that deaths resulting from ethanol abuse could be as high as 1 in 7 (Rehm et al., 2009). These figures are greater than deaths caused by HIV/AIDS, violence or tuberculosis (World Health Organization, 2011). Disease burden is closely related to average volume of ethanol consumption, and, for every unit of exposure, is strongest in Address for correspondence: Ricardo Jorge Dinis-Oliveira, Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Jardim Carrilho Videira, 4050-167 Porto, Portugal. Tel: +351 222073850. E-mail: [email protected]

History Received 12 October 2013 Revised 30 October 2013 Accepted 8 November 2013 Published online 23 January 2014

poor people and in those who are marginalized from society (World Health Organization, 2009). The costs associated with ethanol, amount to more than 1% of the gross national product in high-income and middle-income countries, with the costs of social harm constituting a major proportion in addition to health costs (Rehm et al., 2009). The pattern of ethanol misuse varies globally. The lowest consumption levels are in Africa and the Eastern Mediterranean (World Health Organization, 2009). Worldwide, ethanol causes more harm to males (6.0% of deaths, 7.4% of DALYs) than females (1.1% of deaths, 1.4% of DALYs) reflecting differences in drinking habits, both in quantity and pattern of drinking. Alcoholism is a chronic, progressive, and potentially lethal disease characterized by ethanol dependence and multi-organ dysfunction. It is characterized by the loss of self-control and by a continuous ethanol intake. Genetic, environmental, and psychosocial factors can play a very important role in its development (Morse & Flavin, 1992; Sanchez, 1999). Almost all societies that consume ethanol show related health and social problems. The industrialization of production and globalization of marketing and promotion of alcoholic drinks have increased both the amount of worldwide consumption and the harms associated with it. These developments have led to several resolutions by the World Health Assembly and World Health Organization Regional

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Clinical and forensic signs related to ethanol abuse: a mechanistic approach


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Committees, outlining the public health problems caused by ethanol (World Health Assembly, 2005) and possible strategies to reduce the harmful use of ethanol (World Health Assembly, 2008). Ethanol is a water and lipid-soluble molecule, and it spreads into all tissues of the body affecting most vital functions. It contributes to more than 60 types of disease and injury, and it is a contributing cause in 200 others, including hepatic failure by cirrhosis or cancer, neurological damage, epilepsy, hematological disorders, and nutritional deficiencies, mouth, oropharynx oesophagus, colon and rectum cancers, ischemic heart disease, diabetes mellitus, prematurity and low birth weight, to name just few. In addition, ethanol may be implicated in a wide range of social problems namely traffic accidents, injuries, violence, domestic violence, abuse, crime, suicide, poor performance at work, high unemployment rates, debt, housing problems, etc. (World Health Organization, 2009). Ethanol is metabolized primarily (92–95%) by the cytosolic (namely hepatic) alcohol dehydrogenase (ADH1B) into acetaldehyde (bioactivation reaction), a mutagen and animal carcinogen that causes DNA damage and has other cancerpromoting effects (Brooks & Theruvathu, 2005; Seitz & Stickel, 2007). Cytochrome P450 subenzyme 2E1 (CYP2E1) and, to a much lesser extent, catalase can also catalyze the same reaction (Klaassen, 2013). Acetaldehyde is subsequently detoxified to acetate, mainly by the mitochondrial enzyme aldehyde dehydrogenase (ALDH2) (Crabb et al., 2004). Genetic variants are known for both enzymes (ADH, ALDH), which coincide with significantly different enzyme activities (‘‘rapid’’ and ‘‘slow’’ variants) (Druesne-Pecollo et al., 2009). The variant ADH1B*2, as well as homozygote mutations in the methylenetetrahydrofolate reductase, are known to increase acetaldehyde levels (Lewis & Smith, 2005). In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys) (Yoshida et al., 1984). The Glu allele (also designated ALDH2*1) encodes a protein with normal catalytic activity, whereas the Lys allele (ALDH2*2) encodes an inactive protein. As a result, Lys/Lys homozygotes have no detectable ALDH2 activity resulting in a significant increase in serum acetaldehyde triggered by ethanol drinking. Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold (Crabb et al., 2004). For good performance in clinical and forensic toxicology, it is important to know the signs and symptoms related to xenobiotic exposure (Dinis-Oliveira et al., 2009, 2010a,b,c, 2012a,b,c). The suspicion is an extremely important preanalytical step since it allows the clinician to rapidly implement an appropriate therapy until toxicological results become available to corroborate (or not) the initial suspicion. In addition, for the toxicologist, the suspicion also acquires importance for the correct selection of biological matrices to be analyzed since when erroneously done it can introduce bias to the obtained analytical result (Dinis-Oliveira et al., 2010b, 2012a,b). In this manuscript, we highlight and discuss suggestive clinical and forensic images related to ethanol

Toxicol Mech Methods, 2014; 24(2): 81–110

that can further orientate toxicological analysis. For this purpose, clinical and forensic cases related to ethanol abuse were reviewed. Flushing and disulfiram reactions, urticaria, palmar erythema, spider telangiectasias, porphyria cutanea tarda (PCT), ‘‘paper money skin’’, psoriasis, rhinophyma, Dupuytren’s contracture, multiple symmetrical lipomatosis (lipomatosis Lanois–Bensaude, Madelung’s disease), pancreatitis-related signs, black hairy tongue, gout, nail changes, fetal alcohol syndrome (FAS), seborrheic dermatitis, sialosis and cancer, are some signs that may lead to suspect ethanol abuse, which are thoroughly discussed in the following sections of this manuscript regarding its underlying mechanisms.

Methods Besides contributions with personal forensic and clinical cases, articles written in English, German, French, Spanish and Portuguese were searched for macroscopic signs and symptoms related to ethanol abuse, using the National Library of Medicine’s PubMed MedLine database and the Web of Knowledge (WOK). This study was carried out in accordance with published ethical guidelines (Declaration of Helsinki) for medical research involving human subjects. Vascular dermatologic manifestations Although the cutaneous manifestations are not specific of ethanol exposure, they may be the earliest noticeable consequence, presenting with distinctive ‘‘stigmata’’ and may serve as clues to the disease. Understanding the cutaneous manifestations of substance abuse allows for earlier intervention and treatment. The majority of cutaneous manifestations associated with ethanol abuse are indirectly mediated through the impairment of various organ systems. Most of them are induced by liver toxicity, by an inappropriate diet or by various organ dysfunctions (Chou et al., 1996; Higgins & du Vivier, 1994a,b; Kostovic & Lipozencic, 2004; Smith & Fenske, 2000; Vogl et al., 2005). Flushing and disulfiram reactions Hypersensitivity reactions to ethanolic drinks are common (Vally & Thompson, 2002, 2003). Although manifestations and mechanisms of these reactions are heterogeneous, an immunologically mediated hypersensitivity to ethanol itself is unlikely. Flushing describes episodic attacks of non-elevated intense erythema of the skin together with a sensation of warmth or burning (Hillson & Hockaday, 1984), mainly located in the face, neck and, less frequently, the upper trunk and abdomen. The transient nature of the attacks, distinguishes flushing from the persistent erythema of photosensitivity or acute contact reactions. Repeated flushing over a prolonged period can lead to telangiectasia and occasionally to rosacea of the face. Ethanol (particularly in heavy drinkers) is clearly the cause of some flushing syndrome and it is the most common cutaneous adverse reaction to ethanol. Typically develops within minutes after drinking small amounts of ethanol and the intensity of flushing increases with the amount of ethanol consumed (Groop et al., 1984; Hillson & Hockaday, 1984; Waldhausl, 1984). Symptoms peak at 30 to 40 min and


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usually subside for 1 to 2 h. Subjective feelings like nausea, dizziness, anxiety, headache, lightheadedness, as well as vomiting and sleepiness are often associated with both flushing entities, whereas wheezing and conjunctivitis are only seen in orientals (Waldhausl, 1984). This represents a metabolically based intolerance and not a true immunological hypersensitivity (Zeiner et al., 1979). Two major clinical groups of ethanol-related flushing syndromes can be distinguished and they represent acquired or genetic alterations of ethanol metabolism (Vasiliou et al., 1986). The first type of flushing can occur after the administration of certain drugs (e.g. disulfiram, metronidazole, griseofulvin and ketoconazole) concomitantly with ethanol and is therefore called drug-ethanol flushing (Vasiliou et al., 1986). The second group is termed ‘‘simple ethanol flushing’’ since it is not related to any drug-intake. Simple ethanol flushing affects 3–29% of occidentals, but as it can be found in 47–85% of orientals (predominantly Asian) it is also referred to as ‘‘oriental flushing’’ and it results from genetic deficiency of ALDH2 (Tsuritani et al., 1995; Yokoyama et al., 1997). Symptoms are usually less severe in drug-ethanol flushing than in simple ethanol flushing. ALDH2 deficiency leads to increased serum acetaldehyde levels (Matsuse et al., 2001; Rilliet et al., 1980). Wilkin and Fortner (1985) patch-tested with primary alcohols and aldehydes, in three East Asian patients who reported facial flushing with oral ethanol intake. All three had positive erythematous immediate reactions to primary alcohols and aldehyde, leading the authors to conclude that ALDH2 deficiency and subsequent acetaldehyde buildup might have been causing flushing in these patients (Umulis et al., 2005). However, ethanolic drinks are extremely complex, consisting of many hundreds of components besides ethanol. These components play an important role in determining the flavor and character of these drinks and some of these components have also been linked with the triggering of adverse responses (Vally & Thompson, 2003). Indeed, intolerance to metabisulphites and salicylates of wine, brewer’s yeast, hops and barley contained in beer have been implicated in episodic urticarial reactions, rhinitis, asthma and anaphylaxis with most of these studies focusing on individuals with preexisting asthma (Fernandez-Anaya et al., 1999; Gall et al., 1996; Jamieson et al., 1985; Vally & Thompson, 2001). More recent evidence using double-blind placebo-controlled challenges suggests that intolerance to these chemicals is directly responsible for only a relatively small number of cases of adverse reactions (Armentia, 2008; Vally et al., 2007). Decreased activity of the histamine-degrading enzyme, monoamine oxidase, has been proposed in certain individuals as a mechanism of intolerance to the histamine that is contained in red wine (Wantke et al., 1994). Interestingly, oral sensitization to Hymenoptera venom, known to contaminate the wine during its preparation, has recently been implicated as a cause of reactions in certain subjects (Armentia, 2008). Blocking ALDH2 results in the accumulation of acetaldehyde, which is toxic, and leads to a series of aversive symptoms that deter ethanol consumption (Fuller et al., 1986). Disulfiram is a pharmacologic agent that has been used with variable success to reduce the likelihood of relapse in patients with ethanol dependence (Fuller et al., 1986; Hughes

Imaging in ethanol abuse

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& Cook, 1997). It functions as an ‘‘aversive drug’’ and serves as a negative reinforcement to ethanol ingestion. Disulfiram causes irreversible inhibition of ALDH2. When ethanol is consumed and metabolized, the resultant acetaldehyde accumulates, causing the classic ‘‘disulfiram-ethanol reaction’’. The symptoms begin as soon as 5 min after ingestion, peak at 15–20 min, and may last hours. The intensity of the reaction varies from person to person but in general is proportional to the dose of both ethanol and disulfiram. There is a striking ‘‘rash’’ moderate-to-intense erythema of the face, proximal upper extremities, and torso-that can be part of the disulfiramethanol reaction. More severe reactions, producing hypotension, dysrhythmias, severe respiratory depression, seizures, and even death, can occur when blood ethanol levels rise above 100 mg/dL. Bourcier et al. (2013) reported a case of a life-threatening shock mimicking successively anaphylactic, cardiogenic, and septic shock, which was finally related to disulfiram ethanol reaction. Indeed, disulfiram-ethanol reaction is known to provoke unpleasant symptoms through vasodilatation in various organs, namely flushing, headache, nausea, vomiting, vertigo, abdominal discomfort, palpitations and diaphoresis. These effects may be explained by the inhibition of dopamine b-hydroxylase by disulfiram, with consequent reduction of noradrenaline levels (Schroeder et al., 2010). Moreover, acetaldehyde is also thought to cause flushing by stimulating release of histamine, which also possesses a well-known vasodilator effect. In line with this effect, reactions, such as exacerbation of bronchial asthma can also be consequence of consumption of alcoholic drinks (Dahl et al., 1986; Vidal & Gonzalez-Quintela, 1995; Vally & Thompson, 2002, 2003). In European Caucasian subjects certain antigens, preservatives, or both which are present in alcoholic beverages have been implicated in asthma exacerbation (Nihlen et al., 2005; Vally et al., 2000). Acetaldehyde is also a well-known cause of bronchoconstriction in the Japanese population (Shimoda et al., 1996). In vitro, acetaldehyde stimulation induces bronchoconstriction and degranulation of human mast cells and stimulates human airway mast cells to release histamine, which may be involved in bronchial smooth muscle contraction following ethanol consumption (Kawano et al., 2004). Since ADH1B and ALDH2 exist systemically, including the skin (Goedde et al., 1979), the skin-patched ethanol is converted into acetaldehyde. Acetaldehyde is not detoxified in individuals with low ALDH2 activity and causes larger skin erythema caused by vasodilatation compared with individuals with normal ALDH2 activity. Brooks et al. described facial flushing in a 22-year-old patient (Figure 1A) due to an inherited deficiency in the ALDH2 (Brooks et al., 2009). On the basis of this phenomenon, the ALDH2 activity can be determined by using the ethanol patch-test (Higuchi et al., 1987). Similar reactions can also occur from inadvertent use of ethanol-containing products such as over-the-counter cough syrups. Pimecrolimus and tacrolimus, topical calcineurin inhibitors, are approved for the treatment of atopic dermatitis. Intolerance has recently been described after topical application of these drugs associated with ethanol (Figure 1B) (Lubbe & Milingou, 2004; Ogunleye & James, 2008). The mechanism for this flushing reaction is unknown but has been

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postulated to be associated with ALDH2 inhibition at the site of topical calcineurin inhibitor application (Ogunleye & James, 2008). Management of the disulfiram-related reaction/ toxicity is largely supportive. Interventions include intravenous hydration, anti-emetics, and cardiac monitoring. Urticaria


Although rare (mainly described in isolated case reports) immediate manifestations such as urticaria/angioedema and even shock may be related to ethanol itself and exhibits


different mechanisms and clinical implications from flushing syndromes (Alcoceba Borras et al., 2007; Mallon & Katelaris, 1997; Sbornik et al., 2007; Sticherling & Brasch, 1999; Sticherling et al., 1995). Maibach and Johnson (1975) presented an extensive list of urticarial causative agents, including ethanol. Urticarial reactions can be restricted to the area of direct contact with ethanol or may occur systemically after either local contact (following percutaneous absorption) or ingestion of ethanol (Wong et al., 2011). Anaphylactoid reactions represent systemic and sometimes even lifethreatening events resulting from exposure only to small

(A)

(B)

Figure 1. Facial flushing after ethanol exposure. (A) – Before and after drinking ethanol. (B) – Before and 12 min after ethanol exposure in a women treated with tacrolimus ointment. Reproduced from (A) – (Brooks & Theruvathu, 2005) and (B) – (Lubbe & Milingou, 2004), with permission to authors.



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amounts of ethanol (Fernando & Clarke, 2009). Within minutes after intake, erythema with an urticarial aspect evolves on the upper trunk and may rapidly spread to include oral and bronchial mucous membranes followed by asthma, hypotension, and loss of consciousness. These manifestations closely resemble systemic (anaphylactic) manifestations of immunoglobulin-E (IgE)-mediated allergy, but they are commonly termed anaphylactoid since an IgE-mediated mechanism is unlikely in these cases. Ethanol is a lowweight molecule and should act as a hapten after binding to a protein in order to induce a specific immune response (Hicks, 1968). Nevertheless, ethanol-specific IgE was never demonstrated in cases of suspected ethanol allergy (Boehncke & Gall, 1996; Przybilla & Ring, 1983; Sticherling et al., 1995). Circulating IgE antibodies to adducts of acetaldehyde and protein have been detected in subjects with ethanol hypersensitivity reactions (Israel et al., 1992). These findings, are not consistent among different studies and their significance is unknown (Ehlers et al., 2002). Positive skin prick tests against acetic acid have been observed in some cases of anaphylactoid reactions to ethanolic drinks, and therefore they appear to be IgE-mediated responses to acetic acid, rather than to ethanol itself (Boehncke & Gall, 1996; Przybilla & Ring, 1983; Sticherling et al., 1995). Responses to ethanol are invariably negative (Boehncke & Gall, 1996; Nakagawa et al., 2006; Ophaswongse & Maibach, 1994; Wilkin & Fortner, 1985). Wong et al. (2011) described a 30-year-old East Asian American nurse with sensitivity to ethanol-based hand sanitizers, which she frequently uses at work. Patch-test results revealed large wheal and flare from 100% acetaldehyde and 100% ethanol within 5 min of occlusion on the ALDH2 deficiency patient’s arm (Figure 2A). It is pertinent to note that food chemicals such as metabisulphites, salicylates, and grapes are absent in gin, vodka and whisky (Swain et al., 1985), and this may heighten

(A)

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the speculation that ethanol is the inciting factor in patients who develop an urticarial or anaphylactic reaction to these spirits if consumed neat (Fernando & Clarke, 2009). Santos et al. (2007) described a disfiguring edema of the face and eyelids in an alcoholic patient leading to a huge impaired the vision due to closure of the eyes (Figure 2B). Palmar erythema Palmar erythema, or ‘‘liver palms,’’ is another vascular finding associated with ethanol abuse. It is characterized by warm, florid, light-red patches usually on the palms of the hands and fingertips (Figure 3A and B) (Kostovic & Lipozencic, 2004; Vogl et al., 2005). The soles may similarly be affected. It has been attributed to a disruption of the body’s androgen balance that causes local vasodilatation and erythema. Blanching occurs with pressure, and an increase in the intensity of the erythema may occur with the arterial pulse. Patients may complain of associated throbbing or a tingling sensation. Although related to ethanol exposure, palmar erythema may also be seen in pregnancy, leukemia, and as a familial trait without underlying liver disease. Spider telangiectasias One of the most characteristic vascular changes associated with ethanol abuse is spider telangiectasias (or angiomas, arterial spider, spider nevus, or nevus araneus) given that name because of their appearance (Liu et al., 2010). Clinically, they are characterized by a pinpoint erythematous macule, representing a central arterivascular ole, surrounded by radiating efferent arterioles (Figure 4A–D). Pulsation of the vessels and blanching may be seen by diascopy or pressure. Active blood flow is required for pulsation presence since spider nevi are noted to fade after death. The classic distribution includes the face, V area of the neck, upper chest,

(B)

Ethanol 100%

Acetaldehyde 100%

Figure 2. (A) – Patch-test resulting in a large wheal and flare from 100% acetaldehyde and 100% ethanol within 5 min of occlusion on the aldehyde dehydrogenase deficiency patient’s arm. (B) – Ethanol-related massive eyelid edema. Reproduced from (A) – (Wong et al., 2011) and (B) – (Santos et al., 2007), with permission to authors.

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arms, hands, and, rarely, the mucous membranes, abdomen, and legs (Kostovic & Lipozencic, 2004; Vogl et al., 2005). The etiology of the vascular changes is not clear, although decreased metabolism of estrogen (typically of the alcoholic cirrhotic patients) has been implicated. However, spider nevi can appear and disappear regardless of changes in serum estradiol (Sarkany, 1988). Therefore, other hypothesis such as ethanol-induced direct vasodilatation of dermal arterioles, alteration of central vasomotor control mechanisms (Malpas et al., 1990) and vascular proliferative syndromes (Capron et al., 1981) have also been described. It is important to recognize that many of these vascular changes can occur secondary to liver disease from any cause and are not specific for alcoholic liver disease. In addition, small numbers of spider angiomas are seen in healthy children and adults. They are more common in women, especially during pregnancy, as female hormone, estrogen, influences them.

(A)



(B)

Porphyria cutanea tarda

Figure 3. Palmar erythema. Reproduced from (A) – (Kumar et al., 2007) and (B) – (Lotti & D’Erme, 2010), with permission to authors.

Porphyrias are a clinically and genetically heterogeneous group of metabolic diseases, which arise from a predominantly inherited dysfunction of specific enzymes in the heme biosynthetic pathway (Puy et al., 2010). PCT is the most common type of porphyria worldwide (Frank & PobleteGutierrez, 2010). It is the only type of porphyria that is not exclusively hereditary, since an acquired form can be distinguished. Whether acquired or inherited, PCT results from a deficiency in one of the hepatic enzymes involved in

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(B)

(C) (D)

Figure 4. Spider telangiectasias. Reproduced from (A) – (Liu et al., 2010), (B) – (Lee et al., 2007), (C) – (Lotti & D’Erme, 2010), (D) – (Caseiro & da Costa, 2012), with permission to authors.



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porphyrin metabolism, specifically uroporphyrinogen decarboxylase (UROD), the fifth enzyme in heme biosynthesis that catalyzes the conversion of uroporphyrinogen to coproporphyrinogen (Higgins & du Vivier, 1992, 1994b; McColl et al., 1981; Smith & Fenske, 2000). As a consequence, impaired UROD activity leads to an accumulation of uroporphyrin and other highly carboxylated porphyrins in various organs, including the skin and liver (Lambrecht et al., 2007; Puy et al., 2010). The resultant upstream accumulation of these photoreactive porphyrin precursors renders the skin extremely photosensitive (Smith & Fenske, 2000). Ethanol inhibits the activity of porphobilinogen synthase, UROD, corproporphyrinogen oxidase and ferrochelatase (McColl et al., 1980), whereas it induces the first and rate-limiting enzymes in the pathway of heme synthesis, -aminolevulinic acid synthase and porphobilinogen deaminase (Louis et al., 1998), leading to the accumulation of photoreactive porphyrin compounds (Higgins & du Vivier, 1992, 1994b; McColl et al., 1981). However, the doubt persists regarding the relevance of ethanol exposure in the clinical expression of PCT since -aminolevulinic acid synthase is increased in patients with hepatic cirrhosis without porphyria (Rodrı´guez et al., 1983). The cutaneous characteristics of an acute PCT attack include skin blistering, erosions, scarring, crusts, milia, scleroderma, hyperpigmentation and increased hair growth (hypertrichosis on the upper cheeks, ears and arms) on sunexposed areas (and therefore subjected to repeated trauma) such as face and back of the hands (Figure 5A–E) (Higgins & du Vivier, 1992, 1994b; Smith & Fenske, 2000). Another rare skin symptom is a purplish red (‘‘heliotrope’’) suffusion of the central part of the face, particularly involving the periorbital areas, which may bear a striking resemblance to the plethora seen in polycythemia rubra vera (Grossman et al., 1979; Lambrecht et al., 2007). Skin symptoms show seasonal variations, with an obvious greater intensity in the summer and autumn than in other seasons. At least two different types of PCT exist, although clinically indistinguishable: the acquired type, also referred to as sporadic or type I PCT, in which the enzymatic deficiency is only limited to the liver; and an autosomal dominantly inherited type, also known as familial or type II PCT, in which there is a decrease of enzymatic activity in all tissues (Lambrecht et al., 2007; Puy et al., 2010). In patients with type I PCT, there is a significant association with liver disease that can be triggered by genetic but also environmental factors, such as ethanol abuse (the most frequent factor), iron overload, hemochromatosis, polychlorinated hydrocarbons, and hepatitis C virus infection (Lambrecht et al., 2007; Puy et al., 2010). The diagnosis of PCT can be made based on the skin symptoms, a characteristic urinary porphyrin excretion profile and color (Figure 6A and B), and the detection of isocoproporphyrin in the feces. ‘‘Paper money skin’’ First described by Bean (1974), ‘‘paper money skin’’ skin (or dollar-paper markings) is a rare variant of spider telangiectasias that refers to the similarity of threadlike dilated blood vessels in skin to silk threads of dollar bills (Sarkany, 1988; Satoh et al., 2002). These represent multiple minimally

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dilated venules that may be present diffusely and have coalesced to form a network on the skin surface, normally covering the upper body, and often in association with spider telangiectasias. Also disappear on diascopy, but rarely pulsate (Smith & Fenske, 2000). Similarly to spider telangiectasias, the vasodilator estrogen (Pirovino et al., 1988) or the hyperdynamic blood flow in liver cirrhosis (Witte et al., 1975) have been implicated in the pathogenesis of these lesions. This condition may improve with hemodialysis, perhaps due to elimination of free estrogen (Maruyama et al., 1991; Satoh et al., 2002). Psoriasis Psoriasis is a chronic inflammatory autoimmune, multisystem disorder that has a complex multifactorial pathogenesis resulting from the interaction between genetic and environmental factors. It is characterized by epidermal hyperproliferation (Farkas et al., 2003; Higgins & du Vivier, 1994b). The immunopathogenesis of the disease is associated with a T-helper (Th)1 and Th17 response, with overproduction of proinflammatory cytokines, including interleukin (IL)-2, IL-12, IL-17, IL-21, IL-22, IL-23, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha. Several factors have been implicated in the pathogenesis of psoriasis, such as physical and psychological stresses, metabolic factors, smoking, drugs, infections, and traumas. Extensive evidence demonstrates a link between ethanol abuse and psoriasis (Figure 7A–C) (Higgins & du Vivier, 1992, 1994b; Poikolainen et al., 1990; Qureshi et al., 2010). The amount of ethanol consumed and the type of alcoholic beverage have both been shown to confer higher risk for development and/or exacerbation of plaque psoriasis (Qureshi et al., 2010). In the presence of appropriate genetic predisposition, ethanol exposure also results in more extensive psoriasis (including erythrodermic) and treatment resistant disease (Gupta et al., 1993; Higgins & du Vivier, 1994a; Smith & Fenske, 2000). Moreover, heavy drinking reduces options for treatment of psoriasis, as some medicines are contraindicated if the drinking has led to liver disease (methotrexate) or to high levels of triglyceride (acitretin). Interestingly, the cutaneous distribution of psoriasis in heavy drinkers tends to be predominantly acral, involving the dorsum of the hands and digits (Figure 7A), resembling that seen in immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection (Higgins & du Vivier, 1992; Smith & Fenske, 2000) This distribution highlights the potential role of ethanol induced immunosuppression in the development of psoriasis. The exact molecular mechanisms by which ethanol triggers or exacerbates psoriasis are yet to be fully elucidated. One theory is that ethanol abuse may induce immune dysfunction with resultant relative immunosuppression (Higgins & du Vivier, 1994b; Smith & Fenske, 2000). Ethanol may also enhance the production of inflammatory cytokines and cell cycle activators, such as cyclin D1 and Keratinocyte Growth Factor, which could lead to epidermal hyperproliferation (Farkas et al., 2003; Ockenfels et al., 1996; Smith & Fenske, 2000). Additionally, increased susceptibility to superficial infections commonly observed in alcoholics, such as those caused by Streptococcus and trauma, has also been postulated


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(C) (F)

Figure 5. Porphyria cutanea tarda. (A and B) – Purplish macules, erosions, milia, bullae, and scars on the dorsum of the hands after minor trauma. (C) – Hypertrichosis. (D and E) – Erosions, hyperpigmentation and hypopigmented scars on the forehead. (F) – Sclerodermoid changes in the neck. Reproduced from (A and C) – (Cruz et al., 2010), (B and D) – (Fevang et al., 2008) and (E and F) – (Frank & Poblete-Gutierrez, 2010), with permission to authors.

to have implications in the development of psoriasis (Farkas et al., 2003). Important reviews on this subject could be found in (Cassano et al., 2011; Farkas & Kemeny, 2010a,b). Rhinophyma Rosacea is a common inflammatory disease of the elderly with a predominance of facial manifestations. There are four primary subtypes – ‘‘erythematotelangiectatic’’ (i.e. vascular), inflammatory, phymatous, and ocular – and several variants – granulomatous, pyoderma faciale, and perioral dermatitiss (Jansen & Plewig, 1997). Phyma is the result of hyperplasia and fibrosis of the sebaceous glands in the presence of rosacea (Macdonald & Nguyen, 2012). Although rhinophyma is by far the most common pattern in cases of phyma, metophyma (swelling of the forehead), otophyma (swelling of the ear), and gnathophyma (swelling of the chin) can also be observed. The lesions can become large, causing significant social stigmatization and posing a challenge in the management of patient care. In rhinophyma (‘‘drinker’s nose’’; Figure 8A–C), the skin of the nose becomes slightly swollen and smoother. Pores become more apparent as

keratinous debris accumulate and glandular tissue swells. Gradually, a lumpy surface develops. Histologically, the process is initially one of sebaceous overgrowth. As rhinophyma becomes more established, accompanying fibrosis develops (Webster, 2009). Patients with ethanol abuse had an increased level of collagen III propeptide, a marker of enhanced collagen metabolism that may play a role in the mechanism of hyperplasia of connective and sebaceous tissues such as rhinophyma, observed in grade IV rosacea. Although it is thought to be related to ethanol abuse, results are contradictory since other factors were also documented, namely gender, caffeine intake, occupational environment, or education level between rosacea patients and controls (Curnier & Choudhary, 2004; Abram et al., 2010). Dupuytren’s contracture Dupuytren’s contracture is a deforming, fibrotic condition of the palmar fascia which has confounded clinicians and scientists since the early descriptions by a French military surgeon, Guillaume Dupuytren in 1831 (Elliot, 1999; van Dijk et al., 2013). The disease is described as a type of


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Figure 6. Patient’s urine with porphyria cutanea tarda. (A) – Pink fluorescence color under a Wood’s lamp, suggesting the presence of uroporphyrin. (B) – The same two urine samples under ultraviolet-A light. Reproduced with permission from (Chan & Lin, 2011). (C)

fibromatosis in the fascia of the palms characterized by nodular and/or distributed aggregates of immature fibroblasts dispersed in dense collagen, a finding consistent with localized ischemia (Tomasek et al., 1999). During ischemia, adenosine triphosphate (ATP) is converted to hypoxanthine and xanthine, and endothelial xanthine dehydrogenase to its real form (xanthine oxidase), and ethanol has also been shown to mediate these changes (Oei et al., 1982, 1986). The progressive and irreversible flexion contractures of the phalangeal joints of the hand (namely the small and ring finger), pulling the fingers into a contracted position is the hallmark of the disease (Figure 9). Proliferation of myofibroblasts in the fascia of the hand represents the underlying mechanism. It predominantly affects elderly, male Caucasians and it has a genetic predisposition since it is common in some northwestern European populations, especially those of Viking or Celtic progeny (Loos et al., 2007). Lifestyle, occupational factors and comorbid conditions may also increase the risk of developing Dupuytren’s contracture, namely diabetes, ethanol consumption, cigarette smoking and HIV infection (Geoghegan et al., 2004; Ling, 1963; Noble et al., 1992; Su & Patek, 1970). Several other studies also reported positive associations between Dupuytren’s disease and ethanol intake (Attali et al., 1987; Bradlow & Mowat, 1986; Godtfredsen et al., 2004; Noble et al., 1992).

Figure 7. Psoriatic plaques associated with ethanol abuse. Reproduced from (A) – (Di Lernia & Guareschi, 2010), (B and C) – (Aronson & Malick, 2010), with permission to authors.

Multiple symmetrical lipomatosis (lipomatosis of Lanois–Bensaude, Madelung’s disease) Madelung’s disease (also known as multiple symmetric lipomatosis or Launois–Bensaude syndrome) was first described in detail by Madelung (1888) and Launois and

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Figure 8. Rhinophyma. Multilobulated sebaceous nodule protruding from the nasal tip. Reproduced from (A) – (Macdonald & Nguyen, 2012), (B) – (Lotti & D’Erme, 2010) and (C) – (Faris et al., 2013), with permission to authors.

Bensaude (1898) and since then, several cases have been published in the literature (Meningaud et al., 2007). The disease is more frequently diagnosed in males, with a maleto-female ratio ranging from 15:1 (Zhang et al., 2008) to 30:1 (Enzi et al., 2002) and predominantly affects males between the ages of 30 and 60 years (Landis et al., 2009). The highest incidence is reported in the Mediterranean population and a strong association between the disease and mild-to-excessive ethanol abuse exists (Morinaka et al., 1999). Madelung’s disease is characterized by the presence of massive multiple asymptomatic and symmetrical non-encapsulated fat accumulations involving in the face, neck, occipital region, back of the head, upper arms, abdomen, back, upper leg and supraclavicular fossa (Figure 10A–D) in a very specific pattern or distribution (Parmar & Blackburn, 1996). It is different from simple obesity, which is characterized by the presence of well-distributed total body fat (Mevio et al., 2012). Fat deposits around the cervical region form a ‘‘buffalo hump’’ and a ‘‘horse collar’’, while, fat deposits around the parotid region may also appear as ‘‘hamster cheek’’. Although aesthetic alterations are the typical concerns, fat can penetrate deeply in the surrounding tissues,

involving vessels, nerves, and muscles and compress trachea and esophagus resulting in dyspnea and/or dysphagia. Two different clinical forms of this disease have been described. Type I is characterized by fat masses around the neck, the upper back, the shoulders and upper arms, giving a pseudoathletic appearance. In Madelung’s type II, the fatty deposits are re-diffusely distributed over the entire body surface, resembling simple obesity (Verna et al., 2008). Metabolic and endocrine disturbances including impaired glucose tolerance, excessive secretion of insulin, insulin resistance, hyperuricemia, renal tubular acidosis, alteration in liver enzyme levels, hypercholesterolemia, degenerative bone diseases including arthrosis and pathologic fractures, and abnormal function of thyroid, adrenal glands, hypophysis and testicles have been described (Gonzalez-Garcia et al., 2004). The etiology of Madelung’s disease is still unknown, but several hypotheses have been postulated. One is that an enzymatic defect or an alteration in the membrane receptors causes a reduction in adrenergically mediated lipolysis. Further, the sympathetic denervation of the brown fat adipocytes may lead to their hypertrophy. Mutations or deletions of mitochondrial DNA are also discussed as


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Figure 9. Dupuytren’s contracture in an alcoholic patient.

possible causes (Ramos et al., 2010). A strong association (up to 90% of cases) of Madelung’s disease and ethanol consumption has been described, but contradictory results also exists (Mevio et al., 2012; Morinaka et al., 1999; Verna et al., 2008). Ethanol could function as a cofactor in any of the above-mentioned hypothesis, because it reduces not only the number but also the activity of b-adrenergic receptors, promoting lipogenesis (Ramos et al., 2010).

Ethanol is a risk factor for the development of pancreatitis with skin manifestations, accounting for approximately 65% of cases (Hughes et al., 1975). Cullen’s sign and GreyTurner’s sign develop in 3% of patients with acute pancreatitis and predict a high mortality, while subcutaneous fat necrosis occurs less frequently (Bem & Bradley, 1998). Cullen’s and Grey-Turner’s signs are both ecchymotic signs that develop most commonly in conjunction with acute necrotizing pancreatitis, although they can be observed in any process characterized by retroperitoneal blood accumulation or hemoperitoneum (Mookadam & Cikes, 2005). These signs develop approximately 1–3 d after the onset of pancreatitis and may help the diagnosis of acute pancreatitis necrosis with retroperitoneal or intra-abdominal bleeding. It is thought that one or both (since they may co-exist) signs may be present in 1–3% of patients with acute pancreatitis (Bem & Bradley, 1998; Bosmann et al., 2009; Dickson & Imrie, 1984). Cullen’s sign it is a periumbilical ecchymosis (Figure 11A–D) due to hemorrhage that diffuses through the retroperitoneum along the round ligament to the umbilicus (Bosmann et al., 2009). The portal of entry to the round ligament complex from the retroperitoneum is via the gastrohepatic ligament to the falciform ligament at the inferior-posterior liver edge (Mabin & Gelfand, 1974). In turn, the falciform ligament contributes to the connective tissue tube covering the round ligament (obliterated left umbilical vein) as it passes to the umbilicus. The discoloration around the peri-umbilical region can vary in color (from green/yellow to purple) according to the stage of breakdown of the red blood cells. Pancreatic enzymes have been implicated in the discoloration of the abdominal wall adipose tissue, but peri-umbilical ecchymosis presenting in the absence of pancreatitis is also observed (Dickson & Imrie, 1984; Marinella, 1999; Marinella & Baumann, 2008). A wide range of causes of Cullen’s sign have been documented in the literature, namely pancreatitis, ruptured ectopic pregnancy, perforated duodenal ulcer, percutaneous liver biopsy, ruptured abdominal aortic aneurysm, metastatic thyroid cancer, ruptured common bile duct, hepatocellular carcinoma and pancreatic/abdominal trauma. An excellent review on this subject could be found in (Rahbour et al., 2012). Grey-Turner’s sign was first described in 1920 (Turner, 1920). It is a flank ecchymosis (Figure 12A–C) occurring after hemorrhagic spread from the posterior pararenal space to the lateral edge of the quadratus lumborum muscle, where a defect in the transversalis fascia permits access to the abdominal wall musculature and subsequently tissue of the flank (Bem & Bradley, 1998; Bosmann et al., 2009). It usually signifies a retroperitoneal hemorrhage, although it has been reported to occur without bleeding as well. It is associated with acute pancreatitis, ectopic pregnancy, perforated duodenal ulcers, portal hypertension and splenic rupture. Di Bisceglie and Richart (2006) described a 46-year-old woman with a prolonged history of ethanol abuse and cirrhosis who developed ecchymosis of right flank. Panniculitis is defined as an inflammation and necrosis of subcutaneous fat layer underlying the epidermis of the skin. Enzymatic or pancreatic panniculitis is a type of panniculitis that results from the saponification or necrosis of fat,


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Figure 10. Madelung’s disease. Large symmetrical lipid deposits of soft and spongy in the neck (A), back (B), thorax (C) and arms (D). (A) – Courtesy from Professor Emilio Mevio-(Mevio et al., 2012). (B–D) Reproduced from (Gomes da Silva et al., 2011), with permission to authors.

secondary to the action of liberated pancreatic enzymes in pancreatic diseases (Dahl et al., 1995). Pancreatic panniculitis affects 2–3% of all patients with diseases of the pancreas (Chee, 2009). In 40% of the cases associated with pancreaticinduced subcutaneous fat necrosis, skin lesions were observed (Saag et al., 1992). The most common pancreatic disorders associated with pancreatic panniculitis are acute or chronic pancreatitis, especially ethanol related (Colantonio & Beecker, 2012; Mourad et al., 2001), and pancreatic carcinoma (usually acinar cell carcinoma, less frequently islet cell carcinoma) (Millns et al., 1979). Acute panniculitis is classified as ‘‘panniculitis without systemic disease’’ usually due to trauma or exposure to cold and ‘‘panniculitis with systemic disease’’ usually due to collagen vascular diseases, pancreatic diseases and lymphoproliferative disorders (Johnson et al., 2005). It consists of tender erythematous red-brown nodules 1–2 cm in size that may coalesce into larger plaques (Figure 13A–C), commonly located in the distal parts of the lower extremities (around the ankles and pretibial regions of the legs) and only occasionally on the arms, buttocks, abdomen, chest, scalp and trunk (GarciaRomero & Vanaclocha, 2008). In milder cases, the nodule can be single (Sanchez et al., 1996) and can resolve itself without ulceration. In other cases, the nodules may be fluctuant and may evolve into sterile necrotic abscesses which

spontaneously ulcerate exuding a thick brown oily material (Figure 13D), due to liquefaction, fat necrosis containing free and esterified cholesterol, neutral fats, free fatty acids, and soaps. The pathogenesis is still unknown, but released pancreatic enzymes, such as trypsin lipase, phosphorilase, and amylase, may increase the permeability of the microcirculation and lymphatic channels (van der Zeev et al., 2004). Zellman (1996) suggested that some damage to the blood vessels via inflammation, edema, or altered immunity may act as the initiating factor. Lipase or amylase then causes subcutaneous fat necrosis in the lobules, which results in the liberation of free fatty acids that combine with calcium to form soap (Johnson et al., 2005). Fat saponification combined with secondary pannicular inflammation results in ‘‘lobular panniculitis’’, characteristic of pancreatic panniculitis. The diagnosis of panniculitis frequently requires deep skin biopsy. The most important histological characteristic is the location of the inflammatory process. Inflammation, primarily in the fibrous septa is designated as septal panniculitis and it is usually present at a very early stage, whereas inflammatory cells, primarily in the fat lobules designate lobular panniculitis (Ball et al., 1996). However, some patients manifest normal serum lipase levels, which have led to alternative hypotheses. Possibly, phospholipase A may destroy phospholipids in cell membranes, or an inhibitor of lipolysis may


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Figure 11. Intra-abdominal hemorrhage – Cullen’s sign (periumbilical ecchymosis). Reproduced from (A) – (Rahbour et al., 2012), (B) – (Chauhan et al., 2008), (C) – (Mookadam & Cikes, 2005) and (D) – (Bonani et al., 2008), with permission to authors.

be deficient in these patients (Bem & Bradley, 1998). Association with chronic alcoholism has been reported to occur in 47% of cases (Hughes et al., 1975). Recently, Rani & Kaka (2013) described a case of a 62-year-old man with chronic hepatitis C virus infection and ethanol-induced cirrhosis with pancreatic panniculitis. Black hairy tongue Black hairy tongue (also known as lingua villosa nigra) it is a common benign, asymptomatic disorder (Nisa & Giger, 2011), presenting as a black coating usually on the tongue’s dorsum, anterior to the circumvallate papillae

(Figure 14A–C). It usually begins on the posterior tongue near the foramen cecum and then spreads laterally and anteriorly. Black hairy tongue appearance is diagnosed when filiform papillae are hyperplasic and elongated more than 3 mm due to accumulation of keratin and lack of desquamation (Avcu & Kanli, 2003). Usually, it does not affect the tip or the sides of the tongue and other colorations have been described (brown, yellow, and green). Although aesthetic alterations are the typical concerns, symptoms such as nausea, halitosis, dysgeusia, and unattractive appearance of the tongue have been described (Korber & Dissemond, 2006). The main differential diagnosis of hairy tongue consists of some forms of acanthosis nigricans (which usually involves the lips),

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Figure 12. Intra-abdominal hemorrhage – Turner’s sign (ecchymosis on the abdominal flank). Reproduced from (A) – (Chauhan et al., 2008), (B) – (Mookadam & Cikes, 2005) and (C) – (Bonani et al., 2008), with permission to authors.

hairy oral leukoplakia (white lesions), and black staining over a normal tongue (bismuth, food colorings) (Refaat et al., 2008). Predisposing factors include ethanol abuse (Nisa & Giger, 2011), history of smoking, poor oral hygiene, status after radiation therapy, poor feeding, oral infections, and therapeutic use of drugs such as bismuth, tetracycline, linezolid, and olanzapine (Refaat et al., 2008; Vano-Galvan & Jaen, 2008). Although the etiology of black hairy tongue is not well understood, secondary infection of Candida albicans and/or Bacillus subtilis varietas niger can frequently be involved (Kobayashi et al., 2010). Gout Gout is the most common inflammatory arthritis in men (Roubenoff et al., 1991). The association between ethanol abuse and increased risk of gout has long been suspected (Choi et al., 2004); however, the association has not been prospectively confirmed. Metabolic studies have shown that hyperuricemia (not gout per se) can be induced by ethanol loading (Drum et al., 1981; Faller & Fox, 1982, 1984; Yu et al., 1957). Furthermore, hyperuricemia has been proposed

as a marker for ethanol ingestion (Drum et al., 1981; Whitehead et al., 1978). These findings provided the basis that ethanol might eventually cause gout through hyperuricemia. A number of mechanisms have been implicated in the pathogenesis of ethanol-induced hyperuricemia, including both decreased urate excretion and increased production (Faller & Fox, 1982, 1984). The former is via conversion of ethanol to lactic acid, which reduces renal uric acid excretion by competitively inhibiting uric acid secretion by the proximal tubule (Beck, 1981; Gibson et al., 1983; Yu et al., 1957). The confounding effect of fasting, often associated with heavy drinking has been implicated as the cause of decreased urinary excretion, via induction of acetoacetic and b-hydroxybutyric acidaemia (Gibson et al., 1983). Additionally, ethanol administration has been shown to increase uric acid production as consequence of ATP metabolism to adenosine monophosphate, a uric acid precursor (Faller & Fox, 1982). Moreover, and as described above, ethanol promotes ATP conversion to hypoxanthine and xanthine, and endothelial xanthine dehydrogenase to xanthine oxidase (Oei et al., 1982, 1986). Then, xanthine oxidase


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Figure 13. Pancreatic panniculitis. (A) – Tender erythematous plaques and nodules (arrows) on the ankle, on the pretibial regions of both legs and along the medial aspect of the dorsum of the right foot. (B) – Lobular panniculitis. (C) – Nodules. (D) – Ulcerated subcutaneous nodules on the lower leg exuding an oily brownish-yellow fluid. Reproduced from (A) – (Johnson et al., 2005), (B) – (Rani & Kaka, 2013), (C) – (Masferrer et al., 2011) and (D) – (Colantonio & Beecker, 2012), with permission to authors.

catalyzes the oxidation of hypoxanthine to xanthine and uric acid. This process was later shown to involve acetate conversion to acetyl CoA in the metabolism of ethanol (Puig & Fox, 1984). Factors not related to uric acid, but also implicated in the pathogenesis of ethanol-associated gout, include the frequent coexistence in heavy drinkers of other inducing factors, such as concurrent trauma and hypothermia of the lower extremities (Vandenberg et al., 1994). These factors may explain why alcoholic gouty patients tend to have lower

concentrations of urate in serum than non-alcoholics during acute attacks of gout (Vandenberg et al., 1994). Risk of gout could conceivably vary depending on type of alcoholic beverage: beer confers a larger risk than spirits, whereas moderate wine drinking does not increase the risk. Results of a case-control study suggest that certain nonalcoholic components that vary across these alcoholic beverages play an important role in the incidence of gout (Choi et al., 2004). One candidate for this nonalcoholic component is the variation in purine contents among the individual

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Figure 14. Black hairy tongue. Reproduced from (A) – (Nisa & Giger, 2011), (B) – (Guhl & Diaz Ley, 2011), (C) – (Sheikh et al., 2011), with permission to authors.

alcoholic beverages (Gibson et al., 1984). Beer is the only alcoholic beverage acknowledged to have a large purine content, which is predominantly guanosine (Gibson et al., 1984). Guanosine is more readily absorbed than other nucleosides, nucleotides, or bases (Gibson et al., 1983, 1984) and is metabolized to xanthine by guanine deaminase (Jorgensen, 1956). Thus, the effect of ingested purine in beer on uric acid in blood might be sufficient to augment the hyperuricemic effect of ethanol itself, producing a greater risk of gout than spirits or wine (Gibson et al., 1983, 1984). If different alcoholic beverages have different effects on risk of gout, this fact would have practical implications for gout prevention and management. Nail changes It is important for the clinicians to understand and examine carefully the nails for color, texture, thickness and curvature to reach a prompt and early diagnosis since it may suggest an underlying systemic disease. Onycholysis, clubbing, and koilonychia are some of the most common changes in the morphology of the nail. Red lunula is one of the most common changes in the color of the nail. Several nail changes are associated to ethanol abuse, namely clubbing, koilonychia, leukonychia, Terry’s nails, and Muercke nails. Most of these are non-specific and can be found in normal persons and in patients with diseases not involving the liver. Digital clubbing (also known as ‘‘Hippocratic fingers’’, watch-glass nails and drumstick fingers) is a clinically descriptive term of the soft tissue thickening beneath the proximal nail plate that results in sponginess of the proximal

plate and thickening in that area of the digit (Myers & Farquhar, 2001). The fingernails curve over the rounded fingertips, bulges out instead of dipping in slightly before it meets the skin at the root of the nail, resembling a club (Figure 15A–D). The angle between the nail plate and proximal nail fold (called the Lovibond angle), is normally less than 180 (indicating a dip and rise where the nail and skin meet), increases in clubbing (Salerno et al., 2010). The angle between the finger proximal to the nail and the proximal nail plate is straightened, creating the ‘‘Schamroth sign,’’ which is an obliteration of the normally diamondshaped space formed when dorsal sides of the distal phalanges of corresponding right and left digits are opposed. Although digital clubbing was recognized as long ago as 400 BC, when Hippocrates described the phenomenon in a patient with empyema (Hippocrates, 2002), the diagnosis remains controversial (Spicknall et al., 2005). It has been postulated that it may result from megakaryocytes and platelet clumps that have escaped filtration in the pulmonary bed and have entered the systemic circulation. Platelets and hepatocytes then may release platelet-derived growth factor and hepatocyte growth factor, respectively, at the nail bed, causing periosteal changes (Fatourechi et al., 2002). Clubbing is associated with a number of diseases and a comprehensive work-up should be performed when a patient presents with digital clubbing (Roy et al., 2013). It occurs specially in patients with neoplastic diseases, particularly those of the lung and pleura. It also may accompany other pulmonary diseases, including bronchiectasis, lung abscess, empyema, pulmonary fibrosis, and cystic fibrosis (Castori et al., 2005; Koulaouzidis & Said, 2007).


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Figure 15. Digital clubbing. Schamroth’s sign in clubbing (B). Reproduced from (A) – (Wu & Shih, 2008), (B) – (Nayak et al., 2012), (C) – (Spicknall et al., 2005) and (D) – (Salem et al., 2010), with permission to authors.

Arteriovenous malformations or fistulas have also been associated with clubbing, as have celiac disease, cirrhosis, and inflammatory bowel disease. Ethanol related liver disease has been considered a relevant factor (Goossens et al., 2011; Koulaouzidis & Said, 2007). It was suggested that clubbing in cirrhosis is not because of hypertrophic osteo-arthropathy, but rather an increase in peripheral blood flow with dilatation of arteriovenous anastomasis in the fingers (Dickinson, 1993). Clubbing also may occur in patients with congenital heart disease and endocarditis. Koilonychia is the opposite of nail clubbing. Instead of bulging out, the nail plate is flat or sunken in (concave or spoon-shaped) (Figure 16A and B). It is more common in fingernails, but it is occasionally seen in toenails. It is primarily recognized as a manifestation of chronic iron deficiency (with or without resultant anemia), which may result from a variety of causes, such as malnutrition, gastrointestinal blood loss, worms, gastrointestinal malignancy, celiac disease and hemochromatosis (Barnett et al., 1991; Fawcett et al., 2004; Kumar et al., 2007). Other causes of koilonychia are high altitude, trauma, and exposure to petroleum products, and it can even be hereditary (Fawcett et al., 2004; Prathap & Asokan, 2010). Rao (2004) described spoon-shaped nails in alcoholic patients and therefore should prompt an evaluation for possible iron deficiency. Alcoholism has also been associated to leukonychia. A Muehrcke1 nail is 1 of 3 leukonychia forms (the other are Lindsay’s and Terry’s nails) caused by abnormalities in nail bed vascularization typically observed in alcoholics. It appears as white bands (usually occurring in pairs and extending across all nail) running parallel to the lunula (moon of the nail) with normal pink nail between the bands (Figure 17). This sign may be due to low protein in the blood (hypoalbuminemia) and to an increase in subungual connective tissue leading to compression of capillaries (Muehrcke,

1956). They may occur in several diseases, namely nephrotic syndrome, glomeruionephritis, liver disease, malnutrition, and those who have undergone chemotherapy (D’Alessandro et al., 2001; Muehrcke, 1956). Terry’s nails present with an opaque white nail plate, with the exception of the distal part (last 2 mm), which retains its normal pink color (Figure 18 A–C). It was the most common finding in liver cirrhosis patients (80%), reported by several authors (Smith & Fenske, 2000; Terry, 1954). It is presumed to result from reduced capillary blood flow to the nail bed secondary to an increased growth of connective tissue. Jensen (1981) reported the presence of typical white nails associated with patients complaining of hepatocellular damage due to ethanol abuse. Nevertheless, Terry’s nails were also attributed to congestive heart failure and diabetes mellitus with adult onset, iron-deficiency anemia, chemotherapy, an overactive thyroid and malnutrition (Holzberg & Walker, 1984). The lunula or half-moon of a fingernail is pale cream subungual tissue visible through the nail plate, most evident in the thumb and radial digits, and rarely seen in the little finger. The nail bed exhibits an accentuation of the depth of pink to red color in a transverse band just proximal to the margin of separation of the nail bed and plate, known as the onychocorneal band. Changes in the color of the lunula can be revealing. In patients with Wilson’s disease, the area takes on a blue coloration, a phenomenon called azure lunula. Silver poisoning will turn the nail itself a blue-gray color. Excessive fluoride ingestion can turn nails brown or black and tetracycline therapy can turn it yellow. The pale color can alter to red in a range of conditions, while retaining a moderately clear margin of demarcation with the nail bed distally. Erythronychia is a term that covers a range of pathological patterns of red discoloration of the subungual tissues. Red lunulae (Figure 19) are associated with

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Figure 16. Koilonychia or concave or spoon-shaped. Reproduced from (A) – (Kumar et al., 2007) and (B) – (Takahashi et al., 2010).

Fetal alcohol syndrome

Figure 17. Muehrcke nails. Reproduced from (Morrison-Bryant & Gradon, 2007), with permission.

rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, cardiac failure, hepatic cirrhosis, lymphogranuloma venereum, psoriasis, carbon monoxide poisoning, certain medicines exposure, twenty-nail dystrophy, and reticulosarcoma (Ghetti et al., 2003; Lesher et al., 2004; Tunc et al., 2007; Wollina et al., 1999). Wilkerson and Wilkin (1989) described two patients with red lunulae as consequence of alcoholism. It was proposed that the vasculature of the matrix has differential vasodilatation, possibly due to local inflammatory changes of the connective tissue at the adjacent distal interphalangeal joint (de Berker, 2012). An alternative explanation is a change in optical properties of the overlying nail so that normal blood vessels become more apparent.

Ethanol is one of the most common and important substances that affect the developing fetal brain, and its abuse during pregnancy can produce a wide range of cognitive, behavioral and physical anomalies. The FAS represents one end of the spectrum of ethanol-related congenital defects and neurodevelopmental abnormalities, which is encompassed by the term fetal alcohol spectrum disorder (FASD). FAS occurs in children born to women who drank heavily during pregnancy. FAS is the leading known cause of mental retardation in the Western world (Abel & Sokol, 1986, 1987) and is one of the only known to be completely preventable. Among women described as alcoholic, the risk for FAS has been reported to be as high as 44% (Jones et al., 1974). Due to a variety of impediments to identifying all children with this condition, the true prevalence of FAS and FASD is not known. However, current estimates suggest that 0.5–2 per 1000 children born in the United States have the full-blown syndrome. However, in some groups where heavy drinking is prevalent, and cases of FAS have been actively ascertained, estimates have been as high as 9.8 per 1000 (May & Gossage, 2001a,b; May et al., 2007, 2008; Viljoen et al., 2005). The neurobehavioral and neurodevelopmental consequences of FAS are the most frequent debilitating feature of the disorder. The principal features of the disorder include growth retardation, e.g. low birth weight, lack of weight gain over time, disproportional low weight relative to height; a characteristic pattern of minor malformations which is made up of subtle but distinct facial features (Figure 20A–C) including short palpebral fissures, small head size at birth, maxillary hypoplasia, and a long smooth philtrum with a thin smooth vermilion border of the upper lip; and alterations in neurobehavioral development, such as structural brain abnormalities, impaired fine motor skills, poor eye–hand coordination, neurosensory hearing loss, etc. The


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Figure 18. Terry’s finger and toenails. Reproduced from (A and B) – (Albuquerque et al., 2012) and (C) – (Smith & Fenske, 2000), with permission to authors.

characteristic pattern of facial features, growth deficiency and neurodevelopmental deficits constitute the criteria for making the diagnosis of FAS. Other structural abnormalities including heart defects, oral clefts, renal anomalies, ocular defects, and skeletal abnormalities are seen more frequently in children born to women who drank heavily during pregnancy. As with every known teratogen, the prenatal consequences of ethanol span a spectrum of effects, with full-blown FAS at one end of the continuum. Many more children exhibit only some features of FAS and others may exhibit only other ethanolrelated birth defects.

Figure 19. Red lunulae.

Although a variety of disorders share some features in common with FAS, the only apparent phenocopy is fetal toluene embryopathy which occurs in some children born to mothers who abuse the solvent toluene as a recreational drug. In a series of 18 infants who were evaluated following prenatal exposure, 83% had craniofacial features similar to those characteristic of FAS, over half exhibited pre- or postnatal growth deficiency and postnatal microcephaly, and there was an 80% incidence of developmental delay (Pearson et al., 1994). The exact developmental pathogenesis of FAS and FASD is unknown. In particular, the mechanisms underlying abnormal development of the central nervous systems have not been clearly defined. Experimental evidence has shown that ethanol interferes with many molecular, neurochemical and cellular events that are taking place during brain development (Guerri, 2002). Some brain areas are more affected than others and, even within a given region, some cell populations are more vulnerable than others. The neocortex, hippocampus and cerebellum are especially susceptible to ethanol and have been associated with the behavioral deficits. For example, ethanol exposure during the development of neocortex increases natural apoptosis and induces cell necrosis. These effects may be associated with ethanol-induced alterations in both neurotrophic support, and the expression of cell adhesion molecules, which may affect cell–cell interactions and cell survival. Experimental evidence also shows that ethanol disrupts radial glial and astroglial development which may lead to alterations in cell migration and neuronal survival and differentiation. Impairment of several neurotransmitter systems and/or their receptors, as well as changes in the endocrine environment during brain development, are also important factors involved in the neurodevelopmental liabilities observed after in utero ethanol exposure. Seborrheic dermatitis Although seborrheic dermatitis is common among nonalcoholics, evidence suggest that excess ethanol consumption can both precipitate or exacerbate this disease (Walker et al.,

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Figure 20. Facial alterations in fetal alcohol syndrome. A and B are courtesy of Dr. Gummel from Karolinska Institutet, Stockholm – Sweden (Gummel & Ygge, 2013), (C) – (Sokol et al., 2003), with permission to authors.

1973), especially in patients who are debilitated with hepatic disease, nutritional deficiencies, and pancreatitis. In one study (Rosset & Oki, 1971), 11% of patients with alcoholism were found in one study to have seborrheic dermatitis (Parish & Fine, 1985). Other researchers (Rosset & Oki, 1971) found a slightly lower prevalence (7%), but this was still twice the expected rate (Welton & Greenberg, 1961a,b), and again, a significant number of the drinkers surveyed linked deterioration of their skin disease to ethanol. A large number of patients (10%) were also found to have seborrheic dermatitis of the scalp and 7% had facial or body seborrheic dermatitis (Rosset & Oki, 1971). At the time, this was considered to be secondary to poor hygiene, but now evidence would

suggest that it is in fact a facet of ethanol-induced immunodysfunction facilitating colonization by, and reactivity to the causal agent: the pityrosporum yeast. Higgins et al. (1993) shown 16% of patients had pityrosporum-related dermatoses. Unlike studies of bacteria, Pitryosporum ovale was not found to produce acetaldehyde in the presence of ethanol (Hook-Nikanne et al., 1995). Sialosis Sialosis (or sialadenosis, or sialadenosis) is the chronic, bilateral, diffuse, non-inflammatory, non-neoplastic painless (asymptomatic) swelling of the parotid glandule (Figure 21A



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and B) associated with hypertrophy of acinar cells (Mandel & Surattanont, 2002). It was first discussed in the most comprehensive series published so far, in which 50 patients were evaluated (Duggan & Rothbell, 1957). Seventy-two percent had chronic liver disease (namely cirrhosis), and several of the remainder were obese, or had hyperglycemia, or both. Sialosis mainly affects the major salivary glands, particularly the parotid glands, but occasionally affects the submandibular glands and rarely, the minor salivary glands (Mignogna et al., 2004). Several causes have been recorded (Scully et al., 2008), most of which are associated with nutrition (e.g. malnutrition, gastrointestinal disease, pellagra, beriberi, vitamin A deficiency) metabolic/endocrine (e.g. acromegaly, alcoholism, diabetes insipidus, diabetes mellitus, hypothyroidism, cirrhosis of the liver and uremia), or drugs exposure (e.g. lead, antihypertensives, , thiocyanate, thiouracil, valproic acid, naproxen). In the pathogenesis of sialosis, a neuropathic process (manifesting itself as a demyelinating polyneuropathy) that affects the autonomic innervation of the salivary glands has been suggested (Fairburn & Cooper, 1984; Guggenheimer et al., 2009). The parotid gland has both a parasympathetic and a sympathetic supply. The parasympathetic innervation is primarily concerned with fluid and electrolyte secretion. The sympathetic supply is involved with intracellular protein synthesis and secretion (Chilla, 1981). With a disturbance in the autonomic sympathetic innervation, dysregulation of protein levels occurs. Cytoplasmic swelling develops from engorgement by intracytoplasmic zymogen granules and clinically visible glandular hypertrophy ensues (Chilla, 1981). In addition, there was evidence of axonal and myoepithelial cell degeneration with swelling of the axon fibers and vacuolization (Donath & Seifert, 1975). Autonomic neuropathies develop in patients with alcoholic as well as non(A)

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Figure 21. Sialosis. Reproduced from (A) – (Scully et al., 2008) and (B) – (Guggenheimer et al., 2009), with permission.

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alcoholic liver disease, cirrhosis, and diabetes (Bajaj et al., 2003; Oliver et al., 1997). Changes in salivary aquaporin water channels may also be involved (Mandic et al., 2005). Scully et al. (2008), examining 35 patients whose persistent swelling of the parotid was diagnosed as sialosis, showed that alcoholism was particularly involved. Incidence estimates of 30–86% have been described (Guggenheimer et al., 2009). Cancer Since eighties, ethanol has been associated with an increased risk of a number of cancers (Rothman, 1980) and several epidemiological studies have shown an important correlation between ethanol intake and cancer (Testino, 2011). Particularly relevant are the cases of the cancer of the mouth, pharynx and larynx, esophagus (Allen et al., 2009; Longnecker, 1995), intestine (Chen et al., 1994; Cho et al., 2004; Su & Arab, 2004), liver (Voigt, 2005), stomach (Benedetti et al., 2009), pancreas, ovaries (Bagnardi et al., 2001a,b), endometrium (Tinelli et al., 2008), gallbladder (Yagyu et al., 2008), prostate (Bagnardi et al., 2001a,b) and breasts (Roth et al., 1994). Nearly 3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of ethanol (Boffetta et al., 2006). However, the effect of a given ethanol intake on absolute risk of cancer depends not only on the direct mutagenic effect of ethanol and metabolites, and on the ethanol-related impairment of DNA repair, but also on the prevalence of other risk factors (ethanol-related immunosuppression, nutritional deficiency, smoking, exposure to other mutagenic agents, etc.) (Longnecker, 1995; Ogden & Wight, 1998; Wight & Ogden, 1998). The main metabolite of ethanol, acetaldehyde, has been reported as the predominant responsible for ethanol associated mutagenesis and carcinogenesis. Acetaldehyde binds to DNA and proteins, depletes folate and results in secondary hyperproliferation (Poschl & Seitz, 2004; Seitz & Becker, 2007; Seitz & Stickel, 2007). Other mechanisms by which ethanol stimulates carcinogenesis include (1) the induction of cytochrome P-4502E1, which is associated with an enhanced production of free radicals and enhanced activation of various procarcinogens such as tobacco. These ROS together with polyamines (also increased in alcoholics, especially those who smoke) lead to the generation of DNA adducts, for example, mutagene 1, N2-propanodeoxyguanosin (Theruvathu et al., 2005), or etheno adducts (Bartsch & Nair, 2005), which are highly reactive and modify DNA and proteins (including enyzmes) (Bartsch & Nair, 2005; Theruvathu et al., 2005); (2) alterations in cell cycle behavior such as cell cycle duration leading to hyperproliferation; (3) nutritional deficiencies, such as methyl-, vitamin E-, folate-, pyridoxal phosphate-, zinc- and selenium deficiencies; (4) alterations of the immune system eventually resulting in an increased susceptibility to certain virus infections such as hepatitis B virus and hepatitis C virus; (5) ethanol-induced tissue injury such as cirrhosis of the liver, which is linked to the development of hepatocellular carcinoma; and (6) ethanol-mediated increase of estradiol, which may be at least in part responsible for breast cancer risk (Poschl & Seitz, 2004; Testino, 2011). In some studies, no significant association between smoking, ethanol consumption, and nonmelanoma skin cancer was found (Kune et al., 1992; Sahl et al., 1995).


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Ethanol does appear, however, to increase the carcinogenic risk of tobacco, and women who smoke cigarettes have been found to have a 50% higher risk of cutaneous squamous cell carcinomas (Grodstein et al., 1995; Smith & Fenske, 1996). In alcoholics, basal cell carcinomas are more prone to be invasive (Oram et al., 1995). One study found the risk of melanoma to be increased 2.5 times in women who drank 20 g of ethanol or more, whereas other studies have not uncovered an association (Kirkpatrick et al., 1994). In another study, high ethanol intake has been associated with the development of malignant melanoma (Millen et al., 2004). Patients with alcoholic cirrhosis have a greater susceptibility than the general population to develop porokeratosis (keratinization disorder of clonal origin that presents as a linear configuration of white scaly papules that coalesce into plaques throughout the body) (Ibbotson, 1996; Kono et al., 2000). These lesions can completely resolve when liver function improves (Park et al., 1997). However, these lesions can also transform into squamous cell carcinoma, a cancer with high risk of widespread metastases (Murata et al., 2001). Frequent and heavy consumption of ethanol, along with tobacco and human papillomavirus infection are associated with an increased risk of squamous cell carcinoma of the head and neck, especially cancers of the oral cavity (Figure 22A–F), oropharynx, hypopharynx, and larynx (Gandini et al., 2008; Hashibe et al., 2006, 2007). In a recent study including 177 individuals who developed head and neck cancer, the proportion of head and neck cancer cases attributed to ethanol was 14.7% (Hashibe et al., 2013). Ryerson et al. (2008) have reported that drinking ethanol is one of the risk factors most frequently cited for oral cavity and pharynx cancer. Moreover, people who use both tobacco and ethanol are at a greater risk of developing these cancers than people who use either tobacco or ethanol alone (Tuyns et al., 1988). Typical symptoms of head and neck cancers include a lump or sore (e.g. in the mouth and lips) that does not heal, a sore throat that does not go away, bleeding of the mouth, swellings, difficulty swallowing, and a change or hoarseness in the voice (Fronie et al., 2013). Leukoplakia (presence of white patches), erythroplakia (presence of red patches) and lichen planus (presence of rashes, papules or plaques in the buccal mucosa) are examples of oral clinical lesions that have been associated to ethanol consumption and which carry an increased risk to undergo malignant transformation (Rajkumari et al., 2013). The total amount and the duration of ethanol abuse seem to be more important factors than the type or constitution of the alcoholic beverage consumed. The pathological mechanism of chronic ethanol consumption might be the local production of carcinogenic acetaldehyde from ethanol by oral microbes. Although ethanol is normally metabolized in the liver, bacteria in the oral cavity possess ADH and are capable of oxidizing ethanol, resulting in the accumulation of acetaldehyde levels in the saliva, which exceed blood levels by 100-fold (Homann et al., 2000). Although normal human saliva does not contain measurable levels of acetaldehyde (Balbo et al., 2012), mutagenic concentrations of acetaldehyde are found in saliva during and after ingestion of ethanol as well as smoking (Balbo et al., 2012; Timmons et al., 2002). Indeed, cigarette smoke has acetaldehyde as a chemical constituent and, besides that, it


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Figure 22. Squamous cell carcinoma of the buccal (A) mucosa and lip (B and C). Reproduced from (A) – (Ray et al., 2013), (B and C) – (Tuncali et al., 2005), and (D and E) – (Jane-Salas et al., 2012), with permission to authors.



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modifies the oral flora, leading to an increased alcohol oxidation and high acetaldehyde levels in mouth (Salaspuro & Salaspuro, 2004). A spectrum of microbes, including oral streptococci, Candida and Neisseria spp., has been shown to be capable of producing significant levels of acetaldehyde (Marttila et al., 2013). Besides the increased risk for oral cancer due to its conversion to the carcinogenic compound acetaldehyde, chronic alcohol consumption interferes with the appetite and to the normal absorption in the intestine, leading to a deficiency of many nutrients, namely vitamins. This deficiency, in its turn, is also associated to poor oral health and increased cancer risk (Muro et al., 2010; Zidenberg-Cherr et al., 1990). The esophagus is one of the organs in which the direct contact of ethanol is exerting an immediate damage to the epithelial lining (Figure 23A–B). Smoking and ethanol consumption are considered the major risk factors for the development of squamous cell cancers, and the molecular pathways leading from these environmental exposures to carcinogenesis are still being established. It was first reported in 1962 (Schwartz et al., 1962) that excessive ethanol intake is related with a higher incidence of esophageal cancer. This was further confirmed by further case-control and cohort studies (Franke et al., 2006). Up to 50–75% of esophageal cancer cases in both men and women are attributable to the consumption of ethanol (Rothman, 1980). The risk of developing esophageal cancer increases by 30% with every daily drink (equivalent to 10g ethanol) and there is no threshold under which there is no increase in the risk of cancer (Franke et al., 2006). A strong link between the risk of esophageal squamous cell carcinoma (Brooks & Theruvathu, 2005) and ethanol consumption in low-activity ALDH2 heterozygotes has been identified (Yokoyama et al., 1996). The relative hazard for future upper aerodigestive tract cancers (oral cavity, pharynx, larynx, and esophagus) in lowactivity ALDH2 heterozygotes is approximately 12 times higher than in individuals with active ALDH2 (Yokoyama et al., 2006). This is probably due to a higher increase of the amount of mutagenic acetaldehyde-derived DNA adducts in white blood cells than in individuals with active ALDH2 (Matsuda et al., 2007). It is important to note that ALDH2 deficiency does not influence esophageal cancer risk in nondrinkers (Lewis & Smith, 2005). Ethanol is impairing the mucosal barrier of the gastric epithelium, thus, inducing an inflammatory response with liberation of ROS and proinflammatory cytokines. Chronic inflammation and an enhanced absorption of nitrosamines – due to impaired barrier function – are regarded as possible factors leading to gastric cancer (Haas et al., 2012). Ethanol has been extensively studied as a cause of stomach cancer but there is no conclusive evidence that it increases the risk. In more than 40 epidemiologic studies, no association between gastric carcinoma and chronic ethanol consumption was found (even for amounts of ethanol higher than 200 g daily and independently of the type of alcoholic beverage and its concentration) (Franke et al., 2006). However, ethanol has been identified as a risk factor for pre-cancerous lesion of gastric cancer (Wu et al., 2013). Another recent study showed that ethanol is a risk factor for gastric cardia cancer (Sun et al., 2013). Results from at least three studies suggest that

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Figure 23. Squamous cell carcinoma of the esophagus. Reproduced from (A) – (Nakamura et al., 2012), (B) – (Brooks et al., 2009), with permission to authors.

heavy ethanol consumption may increase the risk of stomach cancer in heavy smokers (Chen et al., 2000; Inoue et al., 1994; Sjodahl et al., 2007). Finally, Helicobacter pylori is accepted to be central to the development of duodenal ulcers and subsequent gastric cancer (Vakil & Go, 2000). As peptic ulceration is more frequent among drinkers this could provide a common link between ethanol and gastric cancer. Drinking ethanol may be a cause of earlier onset of colorectal cancer (Zisman et al., 2006) in men at consumption levels above 30 g of absolute ethanol daily. Those who drank more than 45 g of ethanol increased their bowel cancer risk by around 45% (Seitz & Becker, 2007; Seitz & Stickel, 2007). A study concluded that for every additional drink regularly consumed per day, the incidence of rectal cancer increases by 1 per 1000 (Allen et al., 2009). A Japanese study concluded that one fourth of colorectal cancer cases in men were attributable to an ethanol intake of 23 g/d (Mizoue et al., 2008). Ethanol is also propagating the development of colon polyps, a preneoplastic stage mandatory in the canonic development of colorectal cancer (Haas et al., 2012). Ethanol is a risk factor for breast cancer in women (Roth et al., 1994). A study concluded that for every additional drink regularly consumed per day, the incidence of breast cancer increases by 11 per 1000 (Allen et al., 2009). Moreover, moderate to heavy consumption of alcoholic beverages


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(at least three to four drinks per week) is associated with a 1.3-fold increased risk of the recurrence of breast cancer (Kwan et al., 2010). The specialty of alcoholic carcinogenesis in the liver is both the lipid peroxidation, hybrid adducts, and the activation of stem cells (Setshedi et al., 2010). Ethanol is a risk factor for liver cancer, through cirrhosis (Donato et al., 2002; Poschl & Seitz, 2004). Approximately 5% of people with cirrhosis develop liver cancer (Persson et al., 2012). Worldwide, more than 80% of all primary liver malignancies are represented by hepatocellular carcinoma (Figure 24A–C), which is the fifth most common malignancy. Ethanol abuse of more than 80 g/d increases the risk for hepatocellular carcinoma by a factor of five, and 1–2% of patients with decompensated alcoholic liver cirrhosis develop hepatocellular carcinoma (Morgan et al., 2004). One possible mechanism (besides those presented above) is by lowering the levels of folate, as ethanol is known to interact with the absorption and extraction of folate. Chronic ethanol consumption has been shown to cause low levels of folate, which becomes more pronounced with advancing tumor stage (Morgan et al., 2004). Circulating folate is important in methionine synthesis and lower levels of folate can lead to inhibition of this synthesis, which may increase the likelihood of gene mutation or modify gene expression progressing to cancer (Morgan et al., 2004).


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Concluding remarks Ethanol abuse has been related to several characteristic symptoms and signs (of diverse in etiology), some of which were resumed and discussed in this review. This work may provide appropriate counseling and education for preventive measures to be taken by ethanol abusers and also for new therapeutic or forensic measures to be followed when the mentioned clinical and forensic signs develop upon ethanol abuse. These findings are also particularly important in clinical and forensic toxicology to guide toxicological analysis. One of the main difficulties when performing toxicological analysis is the complete absence of suspicion regarding the xenobiotic involved in the intoxication. Knowing the non-biological or biological signs related to the exposure of drugs of abuse is particularly important to allow an oriented and thus more successful toxicological analysis (Dinis-Oliveira et al., 2010b, 2012a,b). It should be taken into account that these are not specific pathognomonic signs and therefore a differential diagnosis should be considered. Only toxicological analysis may provide the definite information that supports or refutes the diagnosis of any xenobiotic exposure (Dinis-Oliveira et al., 2010b, 2012a,b). As highlighted in this manuscript, flushing and disulfiram reactions, urticaria, palmar erythema, spider telangiectasias, PCT, ‘‘paper money skin’’, psoriasis, rhinophyma, Dupuytren’s contracture, multiple symmetrical lipomatosis (lipomatosis Lanois–Bensaude, Madelung’s disease), pancreatitis-related signs, black hairy tongue, gout, nail changes, fetal alcohol syndrome, seborrheic dermatitis and cancer, are some findings that may lead to the suspect of ethanol abuse. Other signs and symptoms related of ethanol abuse, particularly those that are direct consequence of liver toxic effects, such as cirrhosis, steatosis, jaundice, caput

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Figure 24. Hepatocellular carcinoma. Reproduced from (A) – (Kuwabara et al., 2011), (B) – (Ochiai et al., 2010), (C) – (Heinke et al., 2008), (D) – (Manipadam et al., 2007), with permission to authors.

medusa, ascites, petechiae and ecchymoses, gynecomastia, nutritional deficiency hemochromatosis, and others, will be subject of another manuscript. Finally, many questions remain unanswered and deserve further investigations, namely those concerning the molecular

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and pathophysiological mechanisms involved in: flushing, namely the influence of polymorphisms; Dupuytren’s contracture; the direct mutagenic effect of ethanol and metabolites and the influence of smoking; the influence in the number but also the activity of b-adrenergic receptors, promoting lipogenesis; immune dysfunction as consequence of ethanol exposure leading to psoriasis; and the fetal alcohol syndrome, specifically the neurochemical and cellular events that are taking place during brain development.


Acknowledgements The authors confirm appropriate permissions were obtained to publish all figures cited from other publications, and acknowledge sole responsibility for use of the figures.

Declaration of interest Ricardo Dinis-Oliveira acknowledges FCT for Investigator Grant (IF/01147/2013). The authors report no conflicts of interests. The authors alone are responsible for the content and writing of this article.

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Clinical and forensic signs related to chemical burns: a mechanistic approach.

Gender differences in drug abuse in the forensic toxicological approach.

Parricide: a forensic approach.

A mechanistic approach to modeling respiratory sensitization.

The late clinical and forensic symptoms and signs of sulfur mustard.

Dismemberment and disarticulation: A forensic anthropological approach.

Approach of forensic medicine to gossypiboma.

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Physical signs of sexual abuse in children.

A videotape approach to teaching interpretation of Amerind signs.

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Forensic and clinical toxicology.

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Refractory hyperkalemia related to heparin abuse.

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