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Abstract
A 38-year-old man presented at the emergency department with abdominal pain, vomiting, generalised weakness and altered consciousness. He had been ingesting opioids for over 5 years and had several past hospital admissions for abdominal pain. His investigations showed deranged liver function tests, anaemia and basophilic stippling on the peripheral blood smear. Further investigations revealed a significant increase in the serum lead level. We started chelation with peroral penicillamine 250 mg every 6 hours for 2 days and switched to intramuscular dimercaprol 4 mg/kg every 12 hours and intravenous calcium ethylenediamine tetraacetic acid 50 mg/kg in two divided doses daily for the next 5 days. We then discharged him home; he had become clinically stable by that time. We repeated his lead level and followed him up in the clinic. In this report, we emphasise the consideration of lead toxicity in opioid abusers and bring to attention a rare way of lead chelation in resource-limited settings.
- exposures
- adult intensive care
- toxicology
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Background
Lead is an environmental pollutant with no physiological role in the human body. According to the Agency for Toxic Substances and Disease Registry 2019 Priority List of Hazardous Substances,1 it is the second most lethal after arsenic. Although Center for Disease Control and Prevention (CDC) adopted a serum lead level of <5 micrograms/decilitre (µg/dL) as a reference range for children, it has no physiological role in the body.2
Lead spreads to all parts, including the brain, liver, kidney and bones, and accumulates in the teeth and bones. Blood lead level (BLL) measures lead levels in the body. Lead affects all organ systems and generally presents with abdominal pain and neurological signs and symptoms.3 Lead encephalopathy occurs at a very late stage in lead intoxication.4 Encephalopathy is altered consciousness for more than 24 hours, including change in behaviour, lethargy and irritability. Encephalopathy can have magnitude of underlying reasons, including septic, metabolic and toxic. Each aetiology has a different management plan; hence, it is essential to diagnose the cause early on the disease’s course to decrease the mortality.5
According to the Institute for Health Metrics and Evaluation, there were 1.06 million deaths in 2017 due to lead intoxication. According to the WHO, the highest burden of lead intoxication is in low-income and middle-income countries, and its neurological and mental impacts are supposed to be irreversible.6 Patients are generally exposed through their occupation or environment. Case studies from Iran showed high levels of lead in opioid addicts.7–9 This case report reinforces the possibility of lead intoxication in opioid abusers in Pakistan. As no such case has been reported before in Pakistan, diagnosis is missed by missing out on the risk factor. The report also discusses a rare way of lead chelation in resource-limited settings leading to a successful outcome.
Case presentation
A 38-year-old man presented at the emergency department of a private hospital in Pakistan with abdominal pain for one and a half months, generalised body weakness for 10 days and an altered level of consciousness for 1 day. He had a background history of undocumented weight loss in the last few months. Also, there were 2–3 episodes of vomiting containing food particles and one episode of fresh per-rectal bleeding in the previous month. He had no fever, seizure, headache or haematemesis. The patient had been admitted thrice with abdominal pain at different hospitals, but the complaint persisted. He worked as a transporter and delivered goods to other cities. He had been ingesting opioids for over 5 years and was a recent cannabis abuser.
The patient had blood pressures of 160/70 mm Hg on presentation, heart rate of 113 beats per minute and respiratory rate of 20 breaths per minute and was afebrile and maintaining O2 saturation on room air. He was pale, irritable and agitated and had phlebitis on his left hand on general physical examination. He was disoriented with a Glassgow Coma Scale (GCS) of 13/15 (E4V3M6). The pupils were bilaterally equal and reactive to light, and there was no sign of meningism. Cardiovascular, chest and abdominal examinations were unremarkable.
Investigations
On admission, the patient had the following lab results (shown in table 1)
Lab investigations at the time of admission
He had a high retic count of 12.66 (N: 0.6%–2.4%) and a negative Coombs test. Urine toxicology showed positive benzodiazepines (>900 ng/mL, cut-off value=200 ng/mL) and opioids (>3800 ng/mL, cut-off value=2000 ng/mL).
At the time of presentation, his blood sugars were 116 mg/dL (glucose random—GLUR). He had fasting glucose (glucose fasting) of 62 mg/dL the next day. The sugar level increased during the intensive care unit (ICU) stay with GLUR reaching up to 252 mg/dL. He had high anion gap metabolic acidosis with a lactic acid level of 7.7 mmol/L (normal: 0.5–2.2 mmol/L).
MRI of the brain showed no meningeal enhancement, haemorrhage or tuberculoma. His cerebrospinal fluid (CSF) analysis came up normal as well. Electroencephalogram showed a mild slow posterior dominant rhythm (alpha intermixed with theta activity).
For abdominal pain, endoscopy from another hospital a month ago showed internal haemorrhoids. The stool for occult blood was positive. There was no intestinal obstruction on X-ray abdomen. Abdominal ultrasonography showed fatty infiltration of the liver. We discussed his peripheral blood smear, which showed basophilic stippling (figure 1).
Basophilic stippling in the peripheral blood smear of patient.
The patient developed a fever during hospitalisation, and we sent pan-cultures for this. Tracheal culture and sensitivity showed Aspergillus fumigatus. β-D-Glucan (BDG) and galactomannan levels were within the normal range.
The patient’s BLL was sent, which got reported on the day 13th of admittance. It was significantly high with a level of 148 µg/dL. It took 13 days to get the BLL, mainly due to the initial delay in diagnosis. We first managed the patient for opioid withdrawal and did not expect lead intoxication. Therefore, we sent the BLL for testing very late. Hospital’s laboratory runs the test for BLL only once a week, which caused an additional delay. The biochemistry lab reported it after 3 days, as per protocol, further delaying the results.
Differential diagnosis
Owing to the patient’s altered level of consciousness, we kept drug withdrawal syndrome and meningoencephalitis as the primary differentials and consulted neurology and psychiatry teams.
After consulting the gastroenterology and general surgery teams, we ruled out intestinal obstruction and haemorrhoids.
We consulted the haematology team about anaemia, and the team recommended testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency, acute porphyria and lead poisoning. BLL came out to be elevated to 148 µg/dL, so lead poisoning became the principal diagnosis. We then consulted the toxicology team to propose a plan for lead chelation therapy.
Treatment
On admission, the patient was disoriented and very agitated. He was not responding to any sedatives, so the Emergency Response (ER) team intubated and shifted him to the medical ICU. In the ICU, he had uncontrolled blood sugar levels and high anion gap metabolic acidosis, so diabetic ketoacidosis (DKA) protocol was followed. We consulted the psychiatry team about opioid withdrawal. The team recommended tablet lorazepam 1 mg every 6 hours and tablet quetiapine 37.5 mg every 12 hours. Feed was given through a nasogastric tube.
He had low haemoglobin of 7 g/dL, so we transfused him two packed cells. We consulted gastroenterology and general surgery teams for mild coffee ground nasogastric aspirate and a history of an episode of per-rectal bleed. Omeprazole infusion was started. As there was no further drop in haemoglobin, both teams advised no intervention. The patient was extubated after 4 days, stabilised and shifted to the internal medicine ward.
He had a fever during the stay, so we consulted the infectious disease team and sent pan-cultures. Piperacillin/tazobactam 4.5 g every 8 hours was empirically started. Tracheal culture and sensitivity results showed Aspergillus fumigatus, so 1,3-β-d-glucan and Galactomannan (BDG-GALA) was sent, which came out negative, so no antifungal was initiated.
The haematology team was consulted, which advised retic count, Coombs test,and BLL. After getting his BLL, we consulted the hospital’s toxicology team to plan lead chelation.
We initially gave peroral penicillamine 250 mg every 6 hours for 2 days and switched to intramuscular dimercaprol 4 mg/kg every 12 hours and intravenous calcium Ethylenediamine tetraacetic acid (EDTA) 50 mg/kg in two divided doses for the next 5 days. Each dose of dimercaprol was given before the dose of EDTA. Considering peripheral neuropathy, pregabalin was started to treat bilateral lower extremity pain. The patient improved and remained clinically and haemodynamically stable. He was discharged home after the completion of the chelation with a total hospital stay of 20 days.
Outcome and follow-up
We followed up with the patient in the clinic after 2 weeks. His serum lead level had decreased to 19.5 µg/dL, and he was haemodynamically stable. His abdominal pain had subsided. He still complained of bilateral lower limb pain, for which we prescribed him mefenamic acid 500 mg 8 hourly on an as-needed basis and pregabalin 75 mg twice daily. His liver function tests had improved. Alanine transaminase had got down from 162 IU/L to 53 IU/L. We advised him to follow up again after 3 weeks.
Discussion
This case introduces the consideration of lead encephalopathy in an adult opioid abuser presenting with symptoms like abdominal pain and an altered level of consciousness. As lead poisoning can have hepatic, gastrointestinal, neurological and haematological involvement, these systemic manifestations should alarm one to think of it as a possible diagnosis. This report discusses how lead intoxication can present to us and how we can manage it.
Lead intoxication is rare in adults,10 and it is even rarer due to opioid abuse. Hence, before considering opioids as the primary lead source, it is essential to rule out other more frequent sources. We factored these out on the history. Our patient worked as a transporter and thus had exposure to vehicle exhaust fumes. He had no significant exposure to paints, lead chips, lead pipes, ammunition or any other possible lead source. So, we suspected vehicle fumes and opioids to be the potential sources. Though vehicle fumes could be thought of as the primary source, more than half of the Pakistani population is exposed to high air pollution, and cases of lead poisoning are not that common. Opioid ingested by our patient was tested, which showed 0.15% lead in it (figure 2). A study in 2017 found raised BLLs in opioid addicts.7 8 Though it is not precisely known how opium gets contaminated with lead, it is suggested that lead is added to opium by smugglers to increase its weight and improve sales. According to the WHO, 25 µg/kg body weight is tolerable lead per week. A person ingesting 3–5 g of opium a day could have consumed about 10 000–17 000 µg of lead.9
Lead level in opioid consumed by the patient.
Normal BLLs are less than 10 µg/dL, and if raised to more than 40, it can cause lead poisoning. Lead encephalopathy usually occurs when BLLs rise over 100 or, in some cases, over 70.11 Further, lead encephalopathy is more common in the paediatric population than in adults.12 The neurotoxic effects of lead occur due to its ability to inhibit the regulatory effect of calcium on brain cells and alter the presynaptic release of neurotransmitters. This leads to the disturbance in the brain’s regulatory and homoeostatic mechanisms.13 MRI findings, though, can be present but are not necessary. Results of the research done by Haghighi-Morad showed that there is no correlation between MRI findings and BLLs in encephalopathy following ingestion of lead-contaminated opium.14 Our patient also had no significant changes on MRI.
As lead encephalopathy is rare in adults, it is essential to first exclude all other possible causes that could lead to the encephalopathic state. These include metabolic and septic causes, drug withdrawal and meningitis. We first ruled out meningitis by CSF analysis. As our patient was severely agitated, he was intubated and shifted to the ICU. He had an episode of hyperglycaemia at the ICU, due to which we followed DKA protocol making sure not to miss the metabolic cause. We stopped it once the anion gap improved. The patient was not a previously known diabetic and had no further hyperglycaemic episodes during the hospital stay. We consulted the psychiatry team for drug withdrawal, which advised tablet lorazepam and quetiapine. His agitation improved, and therefore, we extubated him. His encephalopathy still persisted, and the patient did not follow commands. We did not suspect sepsis as the patient had no history of fever on presentation. We later tested his opioid, which showed lead, so encephalopathy due to chronic lead poisoning became our principal diagnosis, and chelation was started.
Chelation can be oral or parenteral. The main properties of a good chelating agent are its high affinity for toxic metal and low affinity for essential metals, ability to form non-toxic products, good distribution in the body and efficient elimination. Main chelating agents for lead poisoning include intramuscular dimercaprol, intravenous CaNa2EDTA (Calcium Disodium Ethylenediamine tetraacetic acid), oral D-penicillamine and succimer. Studies have shown that dimercaprol and EDTA are the most efficient chelating agents. Dimercaprol is usually given for 5 days at a dose of 2.5–5 mg/kg body weight every 4 hours for the first 2 days, every 6 hours for the next 2 days and then every 6–12 hours. EDTA is given at 50–75 mg/kg in two divided doses per day for 3–5 days. Oral D-penicillamine can be given 0.5–1.5 g/day in three to four divided doses for 5 days. D-Penicillamine is not United States Food and Drug Administration (FDA)-approved for the treatment of lead poisoning. Succimer is given at a dose of 10–30 mg/kg/day in three divided doses for the first 1 week, and then, the dose is gradually decreased in the following 2 weeks.15
This case report highlights the alternative treatment options for the resource-limited setting. Ideally, lead encephalopathy should be treated with dimercaprol and EDTA as chelating agents. In Pakistan, we only have EDTA available. Giving EDTA alone carries a risk of worsening encephalopathy as lead leaches out of the bone and may raise the CNS concentration of the lead that’s why it should be given in combination with dimercaprol. Another option, if the patient can tolerate orally, is succimer and D-penicillamine. Succimer is also not available in Pakistan. While we were trying to arrange dimercaprol, we decided to give D-penicillamine first, and once dimercaprol was arranged, we gave it in combination with EDTA.
Although there are risks of severe side effects with D-penicillamine,16 a case series in Iran described the successful treatment of 63 patients with D-penicillamine with a median BLL of 106 µg/dL.17
A multidisciplinary approach involving haematology, gastroenterology, neurology and toxicology teams is always the best way to reach this rare diagnosis. Chelation therapy should start as soon as the level is reported high, and the patient should then be regularly followed up in the clinic.
Patient’s perspective
I was feeling unwell for a long time but never thought to quit opioids. I went to a number of physicians but was not improving. That day, I was very irritable and all of sudden became drowsy. And then, I couldn’t recall anything that what was going on with me. After the treatment, which I got there in hospital, I got improved, and now, I am feeling better day by day. Thanks to the Almighty for everything. I was thinking how opioid slowly made me sick; therefore, I got it checked from laboratory, and it showed that small amount of lead in opioids causes this devastating effect on someone’s health.
Learning points
Lead poisoning is an important differential of abdominal pain; therefore, several hospital admissions with unresolved abdominal pain should alert the doctors to think about this.
Heavy metal poisoning should be thought of being a possible diagnosis in opioid abusers.
Lead poisoning can manifest with hepatic, gastrointestinal, neurological and haematological problems.
Multidisciplinary team involvement is always the best approach to solve a case.
Ethics statements
Patient consent for publication
Footnotes
Contributors AA was the primary internal medicine consultant managing the patient while he was admitted in the hospital and also followed him in clinic once he was discharged. Patient was admitted under his care. He has provided a critical review on manuscript draft, took consent from the patient for reporting the case, asked for the patient’s perspective, and acts as the guarantor of the study. KSS was the internal medicine team resident, managing the patient while he was admitted in the hospital. She provided intellectual input while preparing the manuscript draft and also reviewed it. FFS was the internal medicine team intern, managing the patient while he was admitted in the hospital. She analysed the data and prepared the manuscript draft. NUK reviewed the patient from toxicology point of view, suggesting the required treatment in lead poisoning. He also provided a critical review on manuscript draft. US reviewed the patient’s haematology and provided his opinion on the patient’s peripheral smear. He also provided the picture of peripheral smear slide for submission in the case report manuscript. All authors had full access to the study data, and all of them approved the final manuscript before it was submitted to BMJ.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.