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Abstract
A 74-year-old woman presented to the neurology clinic with worsening of her longstanding peripheral neuropathy of unknown cause. There was below knee loss of spinothalamic sensation, reduced joint position of toes, absent below hips vibration sensation and absent ankle jerks. Neurophysiology studies showed further progression of her axonal sensory neuropathy. Urine and blood analysis previously carried out in Australia suggested elevated levels of arsenic. After abstinence from seafood, a random urine sample was collected and this confirmed the elevation in urine arsenic (622.1 nmol/L, reference range <534 nmol/L). The household water was found to be uncontaminated and the patient had no occupational or environmental exposure to arsenic. On questioning the patient admitted to taking fish oils, omega-3 oils and glucosamine sulphate dietary supplements in excess of the recommended dosage. These supplements were identified as possible sources of arsenic and the patient was asked to stop all supplements. One month later the urine arsenic had reduced to 57.5 nmol/L. There was an improvement in patient wellbeing, she no longer required Gabapentin for pain relief and the neurophysiology studies also showed improvement. Clinicians should consider heavy metal toxicity as a cause of peripheral neuropathy of unknown cause. A detailed patient history including all dietary supplements is essential to help elucidate the source of heavy metal toxicity.
Introduction
Arsenic is toxic to humans with chronic exposure affecting multiple organs including the nervous system. Alternative medicines are a known cause of toxicity from arsenic being an ingredient or contaminant; however, reports are also now showing commercial dietary supplements may also contain heavy metals. We describe here an unusual case of peripheral neuropathy suspected to be caused by arsenic toxicity from the excessive consumption of dietary supplements.
Case presentation
A 74-year-old woman presented to the Neurology clinic with worsening of her longstanding peripheral neuropathy of unknown cause, burning dysaesthesia in her feet and increasing fatigue. Her medical history included attendance at Rheumatology seven years previously with chronic back pain, unsteadiness and loss of toe sensation. Biochemistry investigations were unremarkable; however, neurophysiology studies showed axonal sensory neuropathy in her legs. Five years later she had two lumber spine operations and neurophysiology studies at this time showed further progression of her axonal sensory motor neuropathy. There was no family history of neurological disease. She was a non-smoker, with a moderate alcohol intake (<14 units/week), taking Gabapentin for pain relief and various vitamin/mineral supplements. General physical examination was unremarkable. Neurological examination found abnormalities confined to her legs, with below knee loss of spinothalamic sensation, reduced joint position sensation of toes, absent vibration sense below the hips, distal wasting without weakness, absent ankle jerks and absent plantar reflexes. Neurophysiology studies showed further progression of her axonal sensory motor neuropathy.
Prior to referral the patient had visited family in Australia, who recommended she consult a toxicologist. The toxicology report suggested elevated levels of urine and blood arsenic (results unavailable). On her return home she was referred to Neurology in order to confirm and elucidate the cause for the elevated arsenic levels. After dietary abstention of fish and shellfish for five days, random urine samples were collected from the patient and her husband, who had not been previously tested as he was fit and well. The patient's urine arsenic was found to be elevated at 622.1 nmol/L and her husband's was within the reference range at 225.0 nmol/L (reference range <534 nmol/L). The patient confirmed she had stopped eating fish and shellfish as directed. Drinking water contaminated by naturally high arsenic-containing soil or by industrial pollution is a well-known cause of chronic arsenic toxicity worldwide.1 This together with Cornwall having a rich industrial mining heritage, the house water supply was tested and was found not contaminated. Occupational exposure was also excluded, as the patient was retired and no other environmental sources could be identified.
With all the main potential sources of arsenic excluded, careful in-depth questioning of the patient's drug history including alternative medicines was carried out. It became apparent that the ‘various vitamin/mineral supplements’ noted in the patient's drug history were Gingo biloba, fish oil, omega-3 and glucosamine sulphate supplements. Furthermore, she also admitted to exceeding the recommended dosage. As marine organisms are known to accumulate arsenic,1,2 the fish oil supplements and the omega-3 supplements (also derived from fish oil) were identified as possible arsenic sources. Furthermore, on reading the ingredients label of the glucosamine sulphate supplements it was discovered that the main compound was derived from ground shellfish shells, thus these supplements too were another potential arsenic source. The patient was advised to immediately stop all her supplements. One month later, a repeat random urine sample was collected and the arsenic level was now found to be 57.5 nmol/L, less than 10% of what it had been originally and now well within the reference range. Five months after stopping all supplements, the patient was reviewed in clinic. She described an improved sense of wellbeing, that sensation was returning and she no longer required any Gabapentin for pain relief. Anecdotally her clinician noted, ‘she looked a completely different person’ compared with the previous clinic. Her clinical examination was unchanged; however, neurophysiology studies now showed some recovery in motor function.
Arsenic exposure
Arsenic is absorbed in the small intestine and on entering the circulation undergoes hepatic metabolism to produce less toxic forms of arsenic (monomethylarsonic acid and dimethylarsinic acid). Approximately 50% of ingested arsenic is excreted via the kidneys in 3–5 days. In chronic exposure arsenic accumulates in the heart, kidneys, liver and lungs, with smaller amounts in the gastrointestinal tract, muscles, nervous system and spleen. After two weeks of chronic exposure deposits also occur in the hair and nails.1
Exposure can be divided into industrial, drinking water, dietary and medicinal. Environmental arsenic is found in the earths crust and is liberated via the natural action of volcanoes and erosion; and by human interventions of mining, smelting and coal combustion. The released arsenic is mainly inorganic and accumulates in the soil by binding to organic arsenic.2 Industrial use of arsenic includes the production of fungicides, herbicides, insecticides, pesticides, paints, wood preservatives, lasers, transistors and semiconductors.1 Industrial exposure to arsenic can therefore be occupational or from contaminated drinking water. Also drinking water can be contaminated by soil and rock naturally high in arsenic due to the geology of the area.1–3 This is the leading cause of arsenic toxicity worldwide, with over 30 countries reporting this form of contamination,3 with major effected regions including Bangladesh and West Bengal, India.1–3 Without industrial exposure or contaminated drinking water, diet forms the main source of intake.1,2,4 Fish, shellfish and seaweed provided the highest dietary sources,1,2,5 as marine organisms accumulate high amounts of organic arsenic (e.g. arsenobetaine, arsenocholine, arsenosugars), believed to be non-toxic.1,5 However, in 2004 the UK Food Standards Agency issued an advisory warning on Hijiki seaweed (Hijikia fusiforme), a health food at the time, as unusually it was found to contain high levels of toxic inorganic arsenic.4,5 Human studies later performed in Japan concluded that Hijiki ingestion produced inorganic arsenic exposure equivalent to drinking contaminated water.5 Crops grown in high arsenic-containing soil areas will also provide a dietary arsenic source.1,2
Arsenic has been used in medicine since the ancient Greeks right up to the present-day. In the 1900s, a 1% arsenic trioxide solution (Fowler's solution) was used to treat dermatitis, eczema and leukaemia; and a 30% solution (Arsphenamine) was used intravenously in World War 2 to treat syphilis.1 Today, Arsenic trioxide (Trisenox)6 is used to treat promyelocytic leukaemia1,6 as it induces cell apoptosis.1 Arsenic can also be found in alternative/traditional medicinal remedies either as an intentional ingredient or contaminant.1,2,7,8 For example, a case was reported of a 12-year-old-boy in India who developed weakness, parathesisae, Mees lines and hyperpigmentation. The investigation concluded arsenic toxicity from a homemade vitalizer, made to a traditional recipe that included arsenic as an ingredient. After cessation for 18 months, there was a clinical improvement in skin and neurophysiology studies.7 Dietary supplement consumption has increased in popularity, and these too have been identified as potential arsenic sources2,8 either via studies analysing the heavy metal content of supplements produced commercially1,8 or case reports.2 In 2007, a case of chronic arsenic poisoning from the excessive ingestion of Icelandic Kelp supplements was reported. The patient presented with alopecia and memory loss, which progressed over the next few months. She then developed diarrhoea, nausea, vomiting, headaches, weakness and debilitating fatigue to the extent that she had to move from full-time to part-time work. Investigations found an elevated urine arsenic level and the Kelp supplements identified as the source. Within one month of stopping the supplements, urine arsenic returned to the reference range and the patient recovered enough to return to full-time work.2 The above case has many similarities with our reported case, particularly the excessive use of dietary supplements identified as the potential arsenic source and the clinical improvement on cessation. Lastly, arsenic has been used as a murder weapon due to its properties of being odourless, tasteless and resembling sugar.1
Arsenic toxicity
Inorganic arsenic is considered toxic to humans and is mostly found as arsenite (trivalent form) and arsenate (pentavalent form),1,3 with the former being 60 times more toxic.1 Organic arsenic is considered non-toxic.1,5 Arsenic exerts its toxicity by the inactivation of 200 enzymes, including those involved in cellular energy pathways, DNA replication and repair, as well as substituting itself for the phosphate group in ATP and similar compounds. Unbound arsenic produces reactive oxygen intermediates that damage DNA and induces lipid peroxidation.1,7
Acute poisoning usually occurs from the accidental or intentional ingestion of insecticides and pesticides.1 Patients primarily present with nausea, vomiting, abdominal pain, profuse diarrhoea, excessive salivation, acute psychosis, diffuse skin rash, cardiomyopathy and seizures.1,7 Neurological features include peripheral neuropathy and encephalopathy. Pulmonary oedema, haematological abnormalities, respiratory failure and renal failure are also common. Dependent on the amount consumed death can occur within 24 h to four days, primarily due to the massive fluid loss from the gut leading to circulatory collapse.1
In contrast, the symptoms of chronic arsenic toxicity have an insidious onset,3 with a large interpatient variation in its manifestation,1–3 even within families.3 The amount and length of time exposure also has great bearing.1–3 The nervous system is a major target of heavy metals including arsenic; with chronic exposure leading to peripheral neuropathy, paraesthesiae, muscle weakness, fatigue, behavioural changes, confusion, memory loss,1–3,7 sleep disturbances and headaches.3 Dermatological changes include characteristic hyperpigmentation with palmer and solar keratosis,1,3,7 with nails becoming brittle and exhibiting Mees lines.2,7 Gastrointestinal symptoms mainly occur in acute poisoning; even so, chronic patients may have recurrent episodes of diarrhoea often accompanied with vomiting. Additionally, there is an increased incidence of respiratory disease,1,3 diabetes mellitus, haematological abnormalities3 and malignancy (bladder, kidney, ureter, liver, lung and skin).1–3
What is your patient really taking?
Our case highlights the importance of a detailed drug history, including a full breakdown of all dietary supplements (or any other supplements and alternative medicines) in the investigation of a patient. Surveys in the UK have reported 35% of adults having used a herbal medicine9 and in the USA dietary supplements usage is reported as 52%10,11 to as high as 75%.10 Not all patients will consider it important to inform their clinician of any supplements consumption,8–10 with a survey showing this may be a high as 22%.9 Furthermore, supplements are known to interact with other medicines; however patients are often unaware of this,8–10 particularly as they perceive supplements as safe because they are natural.9
Our patient admitted to taking the dietary supplements in excess of the recommended dosage. Excessive consumption of dietary supplements has been reported before 2,10 and was highlighted in the Icelandic Kelp supplement case (see above) as the patient of her our accord continuously increased her intake in order to try and relieve her symptoms.2 Symptoms of supplement toxicity can be non-specific (e.g. abdominal pain, headache, nausea, diarrhoea),8 so the patient may not consider the supplement as the cause for their illness 2,8,9 and even when the clinician is aware of supplement consumption, it can be hard to attribute it to the patient's illness.8 As a result less than 1% of adverse events associated with dietary supplements are reported to the Food and Drug Administration (FDA) in the USA.10 In our case, the cessation of supplement consumption produced a reduction in urinary arsenic, the improvement of patient wellbeing (including cessation of Gabapentin) and neurophysiology studies showing some recovery in motor function.
Conclusions
Given that the patient had peripheral neuropathy of unknown cause, the finding of elevated urine arsenic concentration, suggested that arsenic toxicity was perhaps the cause. With the usual sources of arsenic excluded, the regular and high consumption of fish oil, omega-3 and glucosamine sulphate supplements; all derived from fish/shellfish origins, were identified as possible sources. The dramatic fall in urine arsenic on stopping the supplements combined with the neurophysiological improvement in motor function; suggests a diagnosis of peripheral neuropathy secondary to chronic arsenic exposure from excessive dietary supplements. The urine arsenic report only gave a total level and did not give a breakdown of organic verses inorganic. Similarly, the case of arsenic toxicity from excessive intake of Icelandic Kelp supplements only reported a total urine arsenic level and even the analysis of the supplements did not elucidate the form(s) of arsenic found.2 Although seafood contains large amounts of organic arsenic, toxicity from excessive intake would be unusual as it is considered the least toxic form.1,5 Inorganic arsenic toxicity is more likely due to the patient presentation. Furthermore, the reports on Hijiki seaweed have shown that high levels of inorganic arsenic can be identified in seafood.4–5 We believe this is the first case of arsenic toxicity from dietary supplements reported in the UK literature. This unusual case highlights the importance of a detailed drug history including any dietary supplements and that clinicians need to consider heavy metal toxicity when investigating idiopathic peripheral neuropathy.
Contributorship
AB wrote and submitted the article. BM reviewed the article, made annotations and obtained patient consent. All authors agreed the final version.
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