Leukonychia Totalis: An Underreported Sign of Chronic Arsenicosis

Arsenic, a toxic heavy metal, is ubiquitously present in the environment. Its colourless, odourless, and tasteless nature renders it a preferred choice for poisoning. Indeed, arsenic has earned the monikers “king of poisons” and “poison of kings” due to its potency and the clandestine methods employed in its administration, particularly in the context of eliminating members of the ruling class during the Middle Ages and Renaissance. It exists in two primary forms: the less toxic organic compounds and the more toxic inorganic compounds. Organic arsenic is commonly found in seafood, poultry, mushrooms, and rice, while the inorganic form is prevalent in groundwater and medicinal preparations [1].

Arsenic poisoning typically results from prolonged exposure to sublethal doses through ingestion, inhalation, or direct skin contact. Various sources of exposure, including natural, industrial, and medicinal, are known. Cutaneous and neurological manifestations are the earliest and most common presentations, enabling early diagnosis. Arsenic has an affinity for sulfhydryl groups present in keratin filaments, leading to its accumulation in skin, hair, nails, and mucous membranes, resulting in visible changes. Estimation of arsenic levels using appropriate samples and methods is essential to establish a diagnosis. Atomic absorption spectrophotometry (AAS) is the most commonly used method for the analysis of arsenic. Other methods include inductively coupled plasma atomic emission spectrometry and inductively coupled plasma mass spectrometry, both of which have lower detection limits than AAS [2, 3]. Arsenic exposure over the past 9 months is reflected in hair and nail arsenic levels, while urine levels of arsenic indicate more recent exposure, whereas blood is not favoured for estimation due to its short serum half-life of arsenic (2–4 h). Using AAS, the normal arsenic levels in hair, nails, and urine have been reported to be 0.02–0.2 mg/kg, 0.02–0.5 mg/kg, and <0.1 mg/L, respectively [2]. The recommended level of arsenic in food and dietary supplements is <10 ppb (0.01 mg/kg) [3]. The WHO-recommended maximum permissible limit of arsenic in drinking water is 0.01 mg/L [3].

Leukonychia refers to the white discolouration of nails and can be classified as true, apparent, or pseudoleukonychia, based on the underlying cause. True leukonychia stems from nail plate abnormalities, while apparent leukonychia results from nail bed alterations. True leukonychia occurs due to abnormal keratinisation in the matrix, causing desquamation of parakeratotic cells, which get trapped within the nail plate, imparting it a white colour. It can also occur due to the deposition of keratinophilic metals and drugs within the nail plate, as is the case in arsenic poisoning. The morphological subtypes of leukonychia include leukonychia totalis, subtotalis, partialis, transversalis, striata, punctata, and variegata. It can be genetic, idiopathic, or associated with numerous dermatological and non-dermatological disorders. However, leukonychia totalis due to chronic arsenicosis is exceedingly rare [4, 5].

A 27-year-old male presented with whitish discolouration of all nails for 2 years, along with tingling and numbness of bilateral extremities for 6 months. The patient did not have any other disease and was not on any medication. None of the family members had white nails or paraesthesias. However, he has been taking a herbal supplement for 3.5 years, as advised by his gym trainer.

On examination, there was complete whitening of all fingernails and toenails, which was more prominent in fingernails (Fig. 1). The rest of the general physical, mucocutaneous, and systemic examinations did not reveal any abnormalities. There was neither any peripheral nerve thickening nor any sensory or motor deficit.

The electrophysiologic studies revealed a reduction in compound muscle action potential as well as sensory nerve action potential amplitudes with a slightly slow conduction velocity, suggestive of symmetric sensorimotor polyneuropathy with more distal impairment. Blood levels of lead and mercury were within normal limits. Hair, nail, urine, water, and herbal supplement samples were collected to estimate arsenic levels using AAS. Hair and nail samples were analysed after acid digestion. About 0.02–0.05 g of the sample were combined with 4 mL of concentrated nitric acid (HNO₃) and 2 mL of 30% (v/v) hydrogen peroxide (H₂O₂) in a 25 mL beaker. The mixture was heated on a hot plate at 80–90° C with periodic supplementation of a known volume of concentrated HNO₃ until the colour of the solution changed from deep brown to pale yellow. After reaching a volume of about 1 mL, heating was stopped. Following cooling, 2–3 mL of water was added, and the solution was filtered using a Millipore filter. The volume was then adjusted to 5 mL for further analysis [2]. Arsenic levels in the water, urine, herbal supplement, and biological samples (hair and nails) after acid digestion were analysed using AAS. The arsenic levels in hair, nails, and herbal supplements were 2,720 mg/kg, 9,390 mg/kg, and 7.2 mg/kg, respectively, which was much higher than the safe upper limit. The urinary and water levels of arsenic were within normal limits. Other haematological and biochemical parameters were within normal limits. A plain radiograph of the chest and electrocardiogram did not reveal any abnormalities. Nail matrix biopsy did not reveal any abnormality (Fig. 2).

A diagnosis of leukonychia totalis with early peripheral neuropathy due to chronic arsenicosis was made, and the patient was advised to stop the use of herbal supplements. He was referred to a neurologist for management of peripheral neuropathy.

Chronic arsenic exposure can affect any organ of the human body. The most common source of exposure is drinking water. The time period between the onset of arsenic exposure and clinical manifestation is variable and depends on the amount of arsenic intake. The average reported duration ranges from 6 months to 2 years [6, 7]. The initial signs of acute arsenic poisoning consist of vomiting, abdominal pain, and diarrhoea, followed by sensations of numbness and tingling in the limbs, muscle cramps, and, in severe instances, fatality [3]. The most commonly reported cutaneous manifestations of chronic arsenic poisoning are pigmentary changes and palmoplantar keratosis, which have been reported in 100% and 69% of patients, respectively, in a study from Bangladesh [6]. Pigmentary changes include diffuse hyperpigmentation, spotty melanosis, leukomelanosis, dyschromatosis, and mucosal pigmentation [6, 7]. The characteristic appearance of spotty depigmented macule on the background of diffuse hyperpigmentation involving the trunk is known as “raindrops on a dusty road” appearance. Arsenic keratosis, a premalignant dermatosis, is considered an early and sensitive marker of arsenic toxicity. Hair changes may present as diffuse, non-scarring alopecia. Mees line is a well-recognised nail manifestation of arsenic exposure which is usually seen in acute arsenic poisoning. It is characterised by a 1–2 mm wide transverse white band involving all nails. Other less commonly reported nail changes are melanonychia, nail dystrophy, and Beau’s line [6, 7]. Uede and Furukawa [8] reported leukonychia totalis in 7 patients after 3 months of acute arsenic poisoning. However, leukonychia totalis as the sole cutaneous manifestation of chronic arsenicosis, as seen in the present case, has not been reported previously. The restoration of the normal appearance of nails usually takes a long time following the cessation of exposure. Apart from skin cancer, prolonged exposure to arsenic can lead to bladder and lung cancers. Additionally, chronic ingestion of inorganic arsenic may result in various health issues including developmental disorders, diabetes, and pulmonary and cardiovascular complications. Arsenic-induced myocardial infarction, in particular, can significantly contribute to increased mortality rates. Furthermore, arsenic exposure has been associated with adverse outcomes during pregnancy and increased infant mortality rates, with lasting effects on child health. Exposure during gestation and early childhood has been linked to increased mortality rates in young adults due to various cancers, pulmonary effects, myocardial infarction, and kidney failure. Multiple studies have demonstrated the detrimental effects of arsenic exposure on cognitive development, intelligence, and memory [3].

Leukonychia can be inherited and acquired. In inherited cases, it can occur in isolation or as part of an inherited syndrome. Various inherited syndromes with skin or skin appendage abnormalities have been linked to leukonychia. True hereditary leukonychia, for instance, is associated with autosomal dominant Bart-Pumphrey syndrome, which also features koilonychia, palmoplantar keratoderma, and sensorineural hearing loss. True leukonychia has also been reported in association with pili torti, severe keratosis pilaris, and LEOPARD syndrome. Acquired leukonychia totalis is exceedingly rare and has been reported with reflex sympathetic dystrophy. When no identifiable cause is found, it is referred to as idiopathic leukonychia totalis [9].

Neuropathy associated with chronic arsenicosis may remain subclinical or mild for a long time before the development of overt manifestations of sensorimotor peripheral neuropathy, as seen in our case. This is unlike acute arsenic poisoning, where the neurological involvement is prominent and can be life-threatening. Neurotoxicity primarily involves sensory fibres within peripheral nerves compared to motor fibres in the form of axonal degeneration involving small myelinated and unmyelinated nerve fibres [10]. To date, there are no effective treatments for chronic arsenicosis. Management strategy mainly focuses on preventive measures and symptomatic management.

The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The subject has given his written informed consent to publish the case (including the publication of images). Institutional Ethical Review Board approval was not required for this study in accordance with national guidelines.

The authors have no conflicts of interest to declare. None of the authors report any form of support or financial involvement. There are no nonfinancial relationships (personal, political, or professional) that may potentially influence the writing of the manuscript.

The authors did not receive any funding.

All authors contributed equally to the concept, design, and definition of intellectual content, data acquisition, and data analysis. Dr. Anil Kumar Bhoi prepared the first draft of the manuscript. Dr. Vishal Gaurav and Dr. Sunil Kushwaha did manuscript editing and review. Dr. Vishal Gaurav shall act as guarantor.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.