Endgames Case Report

Anaemia and unexplained abdominal pain: looking for a lead

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e2996 (Published 02 May 2012) Cite this as: BMJ 2012;344:e2996
  1. Dimitris A Tsitsikas, specialist registrar in haematology,
  2. Michelle Emery, consultant endocrinologist,
  3. Suzanne Pomfret, core trainee year 2 in medicine,
  4. Jasmeen Kaur Mehta, foundation year 2 trainee in medicine,
  5. Shaista Mufti, foundation year 2 trainee in medicine,
  6. Alireza Rezaeinia, biomedical scientist,
  7. Roger J Amos, consultant haematologist
  1. 1Homerton University Hospital NHS Foundation Trust, London E9 6SR, UK
  1. Correspondence to: D A Tsitsikas dimitristsitsikas{at}hotmail.com

A 37 year old man, originally from India, presented with a five month history of worsening colicky abdominal pain, associated with nausea and vomiting. He had also been experiencing irritability, mood swings, and sleep disturbance over the past three months and erectile dysfunction for two months. Clinical examination showed mildly reduced power in both legs, with absence of the left knee jerk, while the right one could be elicited only after reinforcement. He had a normochromic normocytic anaemia with a haemoglobin of 96 g/L (reference range 130-170). The rest of his full blood count was normal. Iron studies, vitamin B12, and folate were all within normal ranges, and there was no evidence of haemolysis. His peripheral blood morphology showed mild basophilic stippling but was otherwise unremarkable. He had been diagnosed as having type 2 diabetes six months previously, for which he was taking traditional (ayuverdic) remedies that had been sent from India. He underwent extensive investigations, including computed tomography of his abdomen and pelvis as well as upper and lower gastrointestinal endoscopy, all of which failed to identify a cause for his abdominal symptoms. A porphyria screen showed a urine 5-aminolevulinic acid (5-ALA) of 24.2 μmol/mmol (<3.8) with normal urine porphobilinogen. Urine coproporphyrin III and eythrocyte zinc protoporphyrin were subsequently found to be markedly raised.

Questions

  • 1 How would you interpret the porphyria screen results?

  • 2 What is the diagnosis?

  • 3 What is the underlying cause?

  • 4 What is the treatment?

Answers

1 How would you interpret the porphyria screen results?

Short answer

These results suggest disruption of the haem synthetic pathway at the level of ALA dehydrase.

Long answer

The porphyrias constitute a heterogeneous group of disorders that affect haem synthesis and should be considered in patients with atypical neuropsychiatric symptoms and unexplained abdominal pain. A characteristic pattern of accumulation of porphyrin precursors arises that can help identify which enzyme is affected (figure). Initial testing for urine 5-ALA and porphobilinogen can be used as a screening tool. The combination of raised 5-ALA with normal porphobilinogen is characteristic of a blockage at the level of ALA dehydrase; in all other porphyrias both 5-ALA and porphobilinogen are raised. Inherited 5-ALA dehydrase deficiency is described but is exceedingly rare; however, an identical clinical and biochemical picture can be produced in the context of lead poisoning (plumboporphyria), which causes inhibition of 5-ALA dehydrase. In 5-ALA dehydrase deficiency or inhibition, urinary coproporphyrin III and erythrocyte zinc protoporphyrin are also raised. Estimation of porphobilinogen deaminase, faecal porhyrins, and plasma porhyrins can help differentiate between the more common inherited acute porphyrias (table).1 2

Figure1

Biosynthetic pathway of haem. *Deficient in 5-ALA dehydrase deficiency, lead poisoning, and tyrosinaemia type 1; †deficient in acute intermittent porphyria; ‡deficient in hereditary coproporphyria; § deficient in variegate porphyria

Characteristic porphyrin detection profiles in the different types of acute porphyria

View this table:

2 What is the diagnosis?

Short answer

Lead poisoning.

Long answer

The lack of any previous episodes of a similar nature suggests that our patient did not have an inherited disorder. His blood concentration of lead was greatly increased at 932 μg/L (upper acceptable limit for adult men 100 μg/L, equivalent to 4.8 μmol/L). Lead can be absorbed through inhalation or ingestion. Absorption is enhanced by fasting, malnutrition, and deficiencies in calcium, iron, or zinc.3 In the blood, 95-99% of lead is sequestered in red cells and is mainly bound to haemoglobin, whereas overall, the largest proportion is accumulated in the skeleton.4 Lead is neurotoxic; several mechanisms have been implicated, including generation of reactive oxygen species, which results in “oxidative stress.”5 Usual symptoms include abdominal pain, irritability, and memory impairment. Peripheral motor neuropathy is also a feature. In infants and young children, lead exposure has been associated with impaired cognitive development.6 It has been shown that each 10 μg/L (0.48 μmol/L) increase in lead is associated with a 4.6 point decrease in IQ.7 Fatigue is common, mainly because of anaemia. A “lead line” can sometimes be seen at the gingival-tooth border in cases of chronic heavy exposure. Chronic exposure can also lead to interstitial nephritis and hypertension. The anaemia of lead poisoning is caused not only by impaired haem synthesis but also by inhibition of intracellular iron delivery to ferrochelatase; this results in increased incorporation of zinc into protoporphyrin, which explains the high concentrations of zinc protoporphyrin.8 Although it is not sensible to screen all cases of unexplained anaemia for lead intoxication,9 the presence of other relevant symptoms such as abdominal pain should raise suspicion. Basophilic stippling is the result of lead induced inhibition of the enzyme 5′-nucleotidase and intracellular accumulation of pyrimidine nucleotides resulting from RNA degradation.10 Skeletal lead burden can be measured in vivo using x ray fluorescence and may be a better predictor of toxicity than blood lead levels.11

3 What is the underlying cause?

Short answer

Ingestion of traditional drugs with a high lead content.

Long answer

The most likely source in this patient is consumption of traditional remedies contaminated with lead. Our suspicion was confirmed when biochemical analysis of his tablets showed them to contain 5.8-6.2% lead per dry weight. Lead exposure can come from occupational or environmental sources. Occupational exposure may occur in workers involved in bridge renovation, foundry work or smelting, work on iron and steel structures, casting, lead abatement, battery manufacturing, cleaning of petrol storage tanks that once contained leaded petrol, and other occupations. Strict regulation of industry and the removal of lead from petrol, food cans, and paint have greatly reduced lead exposure.12 Even though occupational exposure has steadily decreased over time, the number of cases with a non-occupational cause has remained relatively steady and is reported to range between 11% and 75% of cases with blood lead levels of 600 μg/L or greater.13 Heavy metal contamination has been identified in many commercially available herbal supplements and remedies. Around 20.7% of ayuverdic remedies have been reported to contain detectable lead, mercury, or arsenic, especially if prepared according to the ancient practice of rasa shastra, which combines herbs, metals, minerals, and gems (for example, pearls).14 In a survey of 6712 women, those using herbal supplements had lead levels 10% higher than non-users; women using ayuverdic remedies had blood lead levels 24% higher than non-users.15 About 80% of India’s population use ayuverdic remedies.16 With recent increases in travel, migration, and the availability of these products in health food stores and over the internet, heavy metal poisoning as a result of ingestion of contaminated products also occurs in the Western world. A high index of suspicion is therefore needed to identify cases of lead poisoning as a result of such remedies, particularly because patients may not readily admit their use.

4 What is the treatment?

Short answer

Identification and removal of the source of lead exposure and treatment with chelating agents.

Long answer

The most important step in the management of lead poisoning is to identify the source of exposure and remove it. A detailed occupational and drug history is essential, with particular emphasis on aspects that may not be readily apparent, such as use of non-prescription remedies. Patients may have poisoning with other heavy metals such as arsenic or mercury as well, and that possibility should be excluded. Close contacts such as family members may also be exposed, and it is often a good idea to measure their blood lead levels too. The use of chelating agents in adults is not well studied and treatment recommendations are based on experience and common sense. It seems reasonable to treat patients with symptoms and those with blood levels in excess of 500 μg/L.17 CaNa2EDTA (calcium disodium ethylenediaminetetraacetic acid) is the most commonly used chelating agent, but it has to be given intravenously. Lead displaces calcium from the chelate and the Pb-EDTA complex is excreted, leaving calcium behind. DMSA (meso-2,3-dimercaptosuccinic acid) is a derivative of dimercaprol which has the added benefit that it can be given orally in the outpatient setting. A reduction in the blood lead level after initial chelation is often followed by a rebound increase owing to redistribution from storage areas such as the skeleton.18

Patient outcome

Our patient improved symptomatically and his anaemia resolved within two months of discontinuing the ayuverdic remedies. Because his blood lead level was very high, and after we sought advice from the National Poisons Information Service, he received DMSA at a dose of 30 mg/kg for five days. His blood lead dropped from a pretreatment level of 782 μg/L to 287 μg/L. He remains under close follow-up.

Notes

Cite this as: BMJ 2012;344:e2996

Footnotes

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References