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Cutaneous and Ocular Toxicology

ISSN: 1556-9527 (Print) 1556-9535 (Online) Journal homepage: http://www.tandfonline.com/loi/icot20

AGE-RELATED MACULAR DEGENERATION ANDCUTANEOUS SIGNS OF MERCURY TOXICITY

Paul I. Dantzig

To cite this article: Paul I. Dantzig (2005) AGE-RELATED MACULAR DEGENERATION ANDCUTANEOUS SIGNS OF MERCURY TOXICITY, Cutaneous and Ocular Toxicology, 24:1, 3-9, DOI:10.1081/CUS-200046177

To link to this article: http://dx.doi.org/10.1081/CUS-200046177

Published online: 10 Oct 2008.

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AGE-RELATED MACULAR DEGENERATION ANDCUTANEOUS SIGNS OF MERCURY TOXICITY

Paul I. DantzigDepartment of Dermatology, Columbia University School of Medicine,New York, USA

Objective. The objective of this study is to determine the relationship between age-related

macular disease, and cutaneous signs of mercury toxicity. Methods. Fourteen patients

with macular degeneration, 14 patients with Grover’s disease, 14 control patients over the

age of 52 with no signs of Grover’s disease, and nine control patients over age 57 with

measurable blood mercury levels but no evidence of macular degeneration were randomly

selected. All patients had physical exam, skin biopsies where applicable, and blood mercury

levels checked. Results. Of the 14 patients with macular degeneration, 11 patients had

Grover’s disease, two had spongiotic papules as reported by Dantzig, and 13 had measurable

blood mercury levels. Of the 14 patients with Grover’s disease, all 14 patients had measur-

able blood mercury levels and three of the patients were treated with diet and chelation with

excellent response. Conclusions. Grover’s disease may represent a cutaneous marker for

age-related macular degeneration, and low levels of mercury may represent an etiology

for both age-related macular degeneration and Grover’s disease. If these findings are corro-

borated and proven to be true, then both diseases could potentially be drastically reduced or

eradicated through strict environment controls.

Keywords: Age-related macular degeneration; Grovers disease; Mercury; Signs of mercury toxicity

Age-related macular degeneration is the leading cause of blindness in the world.It is estimated that 100 million people are afflicted with the disease and it is predictedthat the incidence will quadruple in the next 10 years. The incidence has increaseddramatically over the past 3 decades and now accounts for vision loss in as manyas 18% of the population over the age of 85. It is rarely seen in people under 50and is more common in women and people who smoke. The disease is devastatingbecause it progressively destroys central vision, thus making it impossible to performdaily functions such as reading, driving, and recreation. The cause is unknown andthe treatment is only supportive with some minor improvement noted in recent mod-alities including laser and photodynamic therapy. Antioxidants and nutritional sup-plements have been used with varying degrees of success (1–3).

Grover’s disease (transient acantholytic dermatosis) is a chronic cutaneouseruption also with an unknown etiology. Like macular degeneration, the inci-dence has increased over the past 3 decades and distribution is also more common

Address correspondence to Paul I. Dantzig, M.D., Department of Dermatology, Columbia Univer-

sity School of Medicine, 30 East 60th Street Suite 705, New York, NY 10022, USA. E-mail: pidmd@

aol.com

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Cutaneous and Ocular Toxicology, 24: 3–9, 2005

Copyright # Taylor & Francis Inc.

ISSN: 0731-3829 print=1532-2505 online

DOI: 10.1081/CUS-200046177

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in industrialized nations. It is also seen predominantly in people over 50 but has beenreported to be more common in men. Pruritus can be mild to severe and thedisease can last for years. Treatment is frequently symptomatic and the disease isoften resistant to therapy, including oral and tropical steroids, isotrentinoin, andphototherapy (4,5).

Recently, a new cutaneous sign of mercury toxicity was described by Dantzig(6). It consists of a generalized or localized erythematous papular eruption with onlymild pruritus and is usually seen in people under the age of 50. Due to the similaritiesbetween this eruption and Grover’s disease, it was postulated that Grover’s may rep-resent a variant of this mercury eruption in older people and since the incidence ofmacular degeneration, Grover’s disease, and mercury pollution have paralleledthemselves very closely, it was decided to see if there was any relationship betweenmacular degeneration and cutaneous signs of mercury toxicity.

MATERIALS AND METHODS

Fourteen patients with age-related macular degeneration (ages 57–97) wererandomly recruited via radio advertisements. All patients were diagnosed with macu-lar degeneration by an ophthalmologist using the following criteria: 1) blurred cen-tral vision, 2) positive test with Amsler grid, and 3) visual macular retinopathyincluding signs of Drusen formation. All 14 patients gave verbal consent for physicalexam of chest, abdomen, and back, a shave biopsy of a cutaneous lesion and bloodtest for mercury. Seven were women and seven were men.

Fourteen patients with Grover’s disease (age 55–85) were randomly selectedfrom a private dermatology practice. All patients were diagnosed using the followingcriteria: 1) complaints of pruritic eruption of the chest, abdomen or back, 2) physicalexam showing discreet small (<2mm) scattered erythematous scaly or crustedpapules of chest, abdomen, or back; and 3) biopsy showing a superficial perivascularinfiltrate of lymphocytes, suprabasal clefts, and acantholytic cells (Figs. 1 and 2). Allpatients gave verbal consent for a shave biopsy of a skin lesion and a blood test formercury. Two were women and 12 were men.

Two control groups were randomly selected. Group 1 consisted of 14 patientswithout any signs or symptoms of Grover’s disease or macular degeneration. Therewere four women and 10men and ages ranged from 52 to 93. A random bloodmercurywas drawn on each patient and compared with the 14 patients with Grover’s disease.

Control group 2 consisted of nine patients with detectable blood mercury butno signs of macular degeneration. There were two women and seven men and agesranged from 56 to 93. These patients were examined for signs of Grover’s disease andcompared with the 14 patients with macular degeneration.

Blood mercury levels were measured in all patients by inductively coupledplasma mass spectrometry by Nichols Laboratory (7).

RESULTS

Of the 14 patients with macular degeneration, all patients had at least oneerythematous papule or crusted papule of the chest, abdomen, or back, but no

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patient had more than 20. None of the patients complained of pruritus or wasaware of any skin problem. A skin biopsy of each patient revealed Grover’sdisease (acantholytic epidermal cells) in 11 patients, a spongiotic papule asdescribed by Dantzig in two patients, and a nonspecific biopsy in one patient.(Note: since this patient had more than one lesion , physician error in diagnosingand biopsing the wrong lesion cannot be ruled out.) Thirteen of the 14 patientshad measurable blood mercury (mean 4.5 u=Liter). The one patient who had anegative reading still gave a history of fish consumption (the major source ofmethyl mercury exposure) so an error in quantitative analysis cannot be ruledout (Table 1).

Of the nine control patients with measurable blood mercury levels (mean12 u=Liter) and no macular degeneration, none showed signs of Grover’s diseaseon physical examination.

Of the 14 patients with Grover’s disease, all had measurable blood mercury(mean 10 u=Liter). All patients complained of pruritus and were aware of skinlesions. All 14 patients were treated with topical steroids without improvement.However, three patients were treated with diet (no seafood) and chelation with suc-cimer (200–300mg TID� 1–2 months) with clearing of the eruption, thus lendingcredence to mercury as the cause of the disease.

Of the 14 patients in the control group for Grover’s disease, 12 had no detect-able blood mercury and two had blood mercury levels of 10 and 16 micrograms=Liter (Table 2).

Figure 1 Skin biopsy from patient number 5 showing characteristic signs of Grover’s disease, including

suprabasal clefts, acantholytic cells, and superficial perivascular infiltrate of lymphocytes.

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Figure 2 Photograph of patient with Grover’s disease, showing small discreet erythematous papules and

crusted papules of the back.

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DISCUSSION

Mercury pollution is becoming a major ecological problem due to the contami-nation of water and seafood (8). Mercury is present in coal and oil and when theseare burned, it vaporizes, eventually falling with precipitation into water and farm-land. Atmospheric mercury also occurs from the inappropriate disposal of industrialproducts including medical waste, lights, computers, and thermostats. In water, mer-cury is picked up by lower forms of life where it is methylated (its most toxic form)and works its way up the food chain to larger fish and humans. Mercury is extremelytoxic with an affinity for neural tissue. It combines with the sulfide bonds in mito-chondria, robbing the cell of energy and causing cell death (9). Since mercury depos-its itself intracellularly, only a small amount is free in the serum and filterablethrough the kidneys. Much of the mercury is excreted through the intestines andis therefore recycled, which accounts for its half-life in the body of at least 2 months.Because of this, only small amounts of mercury consumption can lead to a residualreservoir in the body. However, there is a paucity of studies linking low levels of

Table 1 Patients with macular degeneration and cutaneous signs of mercury toxicity

Patient Age Sex Skin sign Blood mercury Approx. no. of cutaneous lesion

1. JS 57 M Spongiotic papule 5 2–4

2. LW 68 M Grover’s 3 2–4

3. SR 72 F Grover’s 7 2

4. GH 78 M Grover’s 8 10–20

5. AM 70 F Grover’s 10 5–8

6. EC 82 F Grover’s 0 2

7. SM 60 M Spongiotic papule 8 5–8

8. RS 97 M Grover’s 3 2–4

9. SK 79 F Grover’s 1.3 2.4

10. RM 64 M Grover’s 1.7 2.4

11. NE 82 M Grover’s 3 5–8

12. MB 78 F Grover’s 3 5–8

13. SR 83 F None on biopsy 3 2–4

14. MM 60 F Grover’s 10 5–8

Table 2 Comparison of patients with macular degeneration and Grover’s disease to controls

Mean blood

mercury

Skin symptoms

pruritus

Skin signs

(number of papules)

1. Patients with macular degeneration

and Grover’s Disease

4.5 (13=14) none <10

2. Patients with detectable blood

mercury and no signs of macular

degeneration (Control Group)

12 (9=9) none none

3. Patients with Grover’s Disease 10 (14=14) moderate to severe many

4. Patients without macular

degeneration or Grover’s

disease (Control Group)

2 (2=14) none none

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mercury toxicity to any diseases. Most studies center around acute cases of mercurypoisoning, and therefore it is believed that blood levels under 15 or 20 u=Liter aresafe (10). However, in the eruption reported by Dantzig, blood levels as low as5–6 u=Liter were shown to be toxic to the body and in this study, levels as low as1–2 u=Liter were associated with disease activity.

In this study, it was shown that even very low levels of mercury are found inpatients with Grover’s disease and age-related macular degeneration and at leastin Grover’s disease, seem to be directly related to the etiology. The fact that threepatients cleared with treatment points to mercury as the causative agent. Also, theblood levels in most cases correlated with the severity of symptoms and the numberof lesions, which also lends credence to this theory. Electron microscopic studies ofGrover’s disease have shown a loss of intercellular and intracellular proteins, sug-gesting an interference with cell metabolism and protein synthesis, which would beconsistent with the toxic effects of mercury. Electron microscopy in macular degener-ation likewise shows an abnormal protein patter (11–12).

This study suggests that Grover’s disease may represent a cutaneous marker forage-related macular degeneration and may share common etiology with it. What can-not be deduced from this study is why some people are affected and others are not, asshown by the control groups, but it may point to the basement membrane of the skinand retina as the focal point. Both the skin and retina are separated by a basementmembrane, which with age degenerates, creating gaps and possibly allowing the cross-ing of toxins such as mercury (13–14). This point needs to be studied further to seewhy some people are affected by mercury contamination and others are not.

This study is important because: 1) it links for the first time low levels of bloodmercury to 2 diseases; 2) it suggests that Grover’s disease may be a marker for age-related macular degeneration, though patients with Grover’s disease and no signs ofmacular degeneration need to be followed for the development of retinopathy toconfirm this; and 3) for the first time it suggests that a specific toxin, mercury,may play an etiological role in the development of age-related macular degeneration.Since this series of patients is relatively small, corroboration with larger studies isnecessary. However, if mercury proves to be the cause of macular degenerationand Grover’s disease, then both diseases could potentially be greatly reduced or era-dicated through strict environmental controls, and novel treatments with diet andchelation may prove to be helpful for existing newly diagnosed patients.

REFERENCES

1. O’Shea JG. Age-related macular degeneration. Postgraduate Medical Journal 1988; 74:203–207.

2. Koh AH, Ang CL. Age related macular degeneration: what’s new. Annals Academy ofMedicine Singapore 2002; 31:399–404.

3. Bartlett H, Eperjes F. Age related macular degeneration and nutritional supplementation:a review of randomized controlled trials. Ophthalmic Physiology 2003; 23:383–399.

4. Davis MD, Dinneen AM, Landa N, Gibson LE. Grover’s disease: clinicopathologicreview of 72 cases. Mayo Clinic Proceedings 1999; 74:229–234.

5. French LE, Piletta PA, Etienne A, Salomon D, Saurat JH. Incidence of transient acantho-lytic dermatosis (Grover’s disease) in a hospital setting. Dermatology 1999; 198:410–411.

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6. Dantzig PI. A new cutaneous sign of mercury poisoning. Journal of the AmericanAcademy of Dermatology 2003; 49:1109–1111.

7. Chan S, Gerson B, Reitz R, Sadjadi S. Technical and clinical samples. Clinics in Labora-tory Medicine 1998; 18(4):615–630.

8. FDA Consumer Advisory. An important message for pregnant women and women ofchild bearing age who may become pregnant about the risks of mercury in fish. 2001.

9. Shanker BJ, Guo TL, Shapiro IM. Low level methyl mercury exposure cause human T cellto undergo apoptosis: evidence of mitochondrial dysfunction. Environmental Research1998; 77:149–159.

10. McNeil NI, Issler C, Olver RE, Wrong OM. Domestic metallic mercury poisoning. Lancet1984; 41:269–271.

11. Hashimoto K, Fujiwara K, Tada J, Harada M, Setoyama, M, Eto H. Desmosomaldissolution in Grover’s disease, Hailey-Hailey Disease and Daviers Disease. Journal ofCutaneous Pathology 1979; 22(6):488–501.

12. Anderson DH, Talaga KC, Rivest AJ, Barron E, Hagemen GS, Johnson LV. Character-ization of beta amiloid assemblies in drusen: the deposits associated with aging and agerelated macular degeneration. Exp Eye Res 2004; 78:243–256.

13. Gilchrest B. Aging Skin in Dermatology in General Medicine. Fitzpatrick, T. McGraw-Hill, 1993:150–156.

14. Zarbin MA. Age related macular degeneration: review of pathogenesis. European Journalof Ophthalmology 1998; 4:199–206.

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