Commentary

Blackfoot Disease and Chronic Arsenism inSouthern Taiwan

HsiN-Su Yu, M.D.

From the Department of Dermaloiogy,Kaohsiung Medical College,Kaohsiung, Taiwan

An endemic peripheral vascular disorder named"blackfoot disease," seen in a limited area on the south-ern coast of Taiwan, results in gangrene of the ex-tremities, especially the feet (Fig. 1). Since the first casewas reported in 1954, this disease has been anepidemiologic problem in Taiwan. The total populationof this endemic area is approximately 100,000. Theoverall prevalence rate of blackfoot disease in 1968 was8.9/1000. It has been noted that biackfoot disease islimited to people using deep-well water for drinking,which shows a variable high concentration of arsenic(0.10-1.81 ppm).

Clinical Signs

Clinically, the symptoms and signs of biackfoot dis-ease are similar to those of Buerger's disease. Yeh andHow reported that blackfoot disease can be divided intotwo distinct pathologic reaction groups: thromboangiitisobliterans and arteriosclerosis obliterans.^ Erythematousswelling and stabbing pain are present in the involvedlimbs in the early stage of the disease. The mainpathologic features of the affected skin are vascularchanges, including thickening and fibrinoid degenera-tion of the blood vessel wall, and perivascular smallround cells infiltration (Fig. 2). These reactions wereprominent at the middle and lower dermis. A skinspecimen obtained from the gangrenous limbs showednecrosis of the epidermis, proliferation, and dilatation ofthe dermal vessels with stasis of the erythrocytes. But the

Address for reprints: Hsin-Su Yu, M.D., Department of Dermatol-ogy, Kaohsiung Medical College, Kaohsiung, Taiwan 800, Republicof China.

most important reaction was at the subcutaneous ar-terioles: The arteriole demonstrated occluding lumenwith thrombosis and proliferation of its vasa vasorum(Fig. M

Among the inhabitants of this endemic area, a re-markable percentage of chronic arsenism—manifestedas hyperpigmentation, keratosis, and cancer—was ob-served. The overall prevalence rates for hyper-pigmentation, keratosis, and skin cancer in 1968 were183.5, 71.0, and 10.6 per 1000 persons, respectively.'Characteristic of arsenic pigmentation is the presence ofhypomelanosislike raindrops within a field of diffusehyperpigmentation. Punctate hyperkeratosis frequentlyis observed on the palms and soles (Fig. 4). Arsenicalskin cancers in the blackfoot disease area are usuallymultiple lesions. One characteristic of arsenical skincancer in this endemic area is the preponderance ofintraepidermal carcinoma (58.40%). The intraepidermalcarcinoma includes classical Bowen's disease (50.84%)and type B arsenical keratosis (7.56%). Other types ofcarcinoma are epidermoid carcinoma (19.32%), basalcell carcinoma {15.1 2%), and combined form (7.14%).^

Etiology

The association of blackfoot disease and chronic arse-nism is significantly high. Arsenical cancer was as-

FiG. 1. Blackfoot disease.

258

No. 4 BLACKFOOl DISEASE AND ARSENISM • Yu 259

A

FIC;. 2. Fibrinoid degeneration ond thickening (it the d<'rni<il bloodvessels.

FIG. 4, Right palm; punctate hyperkeratosis. Leitdisease wilh basal (ell carcinoma (arrow).

Bowen s

sociated with blackfoot disease patients in 15.3%, andthat blackfoot disease was seen in 32.83% of patientswith arsenical cancer.

Many doctors in Taiwan believe that the high concen-tration of arsenic in endemic artesian well water is the

cause of blackfoot disease and chronic arsenism; how-ever, besides this endemic area, gangrene of the limbswas not reported in olher literature on arsenic contami-nation. Apparently, arsenic is not the only explanationfor both peripheral vascular disturbances and chronicarsenism.

In 1975, Lu et al reported that fluorescent substances(FC) were found in artesian well water in the same area.'*FC is heat-stable and bonded tightly to arsenic. Underultraviolet light irradiation, FC reveals green fluores-cence (Fig. 5). Its maximum excitation spectrum is at the325 ± 5 nm level, and the maximum emission spectrumis at the 435 ± 5 nm level. The structure of FC still is notknown, but Lu et al believe that it is similar to ergotalkaloid. Lu et al also reported that FC had the propertiesof teratogenicity, inhibition of DNA synthesis in cultured

PFIG. 3. Thrombosis ol Ihe bubculaneous drteriol. FIG. 5. Right: FC in artesian well water. Loft: Distilled water.

260 INTERNATIONAL JOURNAL OF DERMATOLOGY May 1984 Vol. 23

HeLa cells. When FC was intraperitoneally injected intoa mouse, thrombosis occurred in arterioles of its tail.Other properties we found are: (1} inhibition ofhistamine-induced capillary permeability; (2) inhibitionof platelet aggregation and its release reaction; (3)mutagenicity (noticed during Ames' test; (4) enhancedincorporation of tritiated thymidine in low-protein, cul-tured fibroblast.^

Conclusion

FC is the main substance affecting the capillary endo-thelium and blood coagulation through which it has animportant effect on blackfoot disease. Other results of FCinclude mutagenicity and increased DNA synthesis.When these are combined with arsenic, chronic arse-nism is prevalent. The exact roles of FC and arsenic on

the endothelial and epidermal cells still are not defined.It is certain that FC has a great effect on blackfootdisease.

References

1. Tseng WP, Chu HM, How SW, Fong |M, Lin CS, Yeh S: Preva-lence of skin cancer in an endemic area of chronic arsenicismin Taiwan. ) NatI Cancer Inst 40:453, 1968

2. Yeh S, How SW: A pafhological study on the blackfool disease inTaiwan. Reports, Institute of Pathology, National Taiwan Uni-versity, 14:25, 1963

3. Yeh S, How SW, Lin CS: Arsenical cancer of skin. Cancer 21:312,1968

4. Lu F|, Yang CK, Ling KH: Physico-chemical characteristics ofdrinking water in biackfoot disease endemic areas in Chia-1 andTainan Hsiens. ) Formosan Med Assoc 74:596, 1975

5. Yu HS: Studies on c hronic arsenism at blackfoot disease endennicarea in southern Taiwan. Proceedings of the 33rd. Middle lapanDermatological Meeting, 1982, p 25

The Tools of Microbiology

The seventies and eighties of the 19th century saw the introduction of an entire series of technicalimprovements that were to further materially the progress of bacteriology. Not only was the micro-scope improved, but bacteriology discovered methods of its own. The first epoch-making discoveriesof Pasteur had resulted from experiments in which the apparatus employed had been borrowedchiefly from chemistry. Not until later did he and his pupils begin to concern themselves with theproblems of nutritive media, and methods of filtration (porcelain candle of C. E. Chamberland). Themethods of bacterial filtration date from the work of the Swiss, E. Tiegel, who, in 1871, filtered anthraxfluids through a porous cylinder of unburnt clay. This method was also used by Eberth in 1872 inexperiments on diphtheria. In 1877 Pasteur and loubert used plaster of Paris to separate anthrax bacillifrom the fluids containing them, and it was not until 1884 that Chamberland first introduced hiscandle-shaped filter. In 1873 Klebs introduced the warm stage for the observation, at body tempera-ture, of fluids containing bacteria. Bacteriological methodology was repeatedly enriched byneighbouring sciences. Then came the methods developed by Koch.

A further technical development was the introduction of aniline dyes and their use in the staining ofbacteria. In this field, Weigert and Ehriich played important parts.

The useof stains for the study of bacteria grew out of the staining methods employed in histology. In1849 Goeppert and Cohn first used carmine, but this method first came into prominence throughGerlach (1858). Hermann Hoffmann (1819-91), professor of botany at Giessen was the first to try tostain bacteria, using aqueous solutions of carmine and fuchsin. The staining of bacteria, however,really dates from the work of Weigert in 1875, when he successfully stained cocci in tissues by meansof methyl violet. Koch greatly improved the methods of staining (1877), and technical progress in thefollowing decades was very rapid owing chiefly to the epochal researches of Paul Ehriich (1854-1915) on the staining of blood cells by aniline dyes.—Leikind MC: The discovery of pathogenicgerms. CIBA Symp 2:748, 1941