Rare cases of severe life-threatening lead poisoning due to accident or chronic occupational exposure to lead and manganese: Diagnosis, treatment, and prognosis

Abstract

Background:

Chronic long-term, low-dose environmental and occupational exposure to lead (Pb) has been extensively studied in large cohorts worldwide among general populations, miners, smelters, or battery workers. However, studies on severe life-threatening Pb poisoning due to accidental or chronic occupational exposure to Pb and manganese (Mn) were rarely reported.

Methods:

We present one case of acute severe Pb poisoning and compare it with another severe chronic occupational exposure case involving Pb and Mn. A 27-year-old woman mistakenly took a large quantity of pure Pb powder as an herbal remedy; she developed abdominal colic, severe nausea, vomiting, fatigue, and cutaneous and sclera icterus. Laboratory tests showed her blood lead level (BLL) of 173.5 μg dL⁻¹ and urinary lead level (ULL) of 1240 μg dL⁻¹. The patient was diagnosed with acute Pb poisoning and acute liver failure. In another chronic exposure case, a 56-year-old man worked in a Pb and Mn smelting factory for 15 years. He was brought to the emergency room with severe nausea, vomiting, and paroxysmal abdominal colic, which was intolerable during the onset of pain. His BLL was 64.8 μg dL⁻¹ and ULL was 38 μg dL⁻¹, but his blood and urinary Mn levels were normal. The patient was diagnosed with chronic Pb poisoning. Both patients received chelation therapy with calcium disodium ethylene-diamine-tetraacetate (CaNa₂EDTA). The woman with acute severe Pb intoxication recovered well and was discharged from the hospital after treatment, and the man who survived severe Pb poisoning was diagnosed with lung cancer.

Conclusion:

Clinical manifestations of acute and chronic severe Pb poisoning are different. Chelation therapy with CaNa₂EDTA is proven to be an effective life-saving therapy in both cases by reducing BLL. Occupational exposure to both Pb and Mn does not appear to increase Mn neurotoxicity; however, the probability that co-exposure to Mn may increase Pb toxicity in the same patient cannot be excluded.

Introduction

Lead (Pb) has been extensively used in modern industry for several centuries. Aside from occupational exposure, severe Pb poisoning indeed occurs from time to time in daily life. The early signs and symptoms of Pb poisoning can be nonspecific, including abdominal pain, pale appearance, headaches, fatigue, and irritability. For these nonspecific clinical presentations that are not unique to Pb toxicity, the diagnosis of Pb poisoning in clinics can be over-looked, delaying clinical intervention and leading to a life-threatening outcome. Thus, accurate identification of clinical indications, considering unusual sources of exposure, and detailed occupational history are essential for clinical treatment of Pb toxicity.

Manganese (Mn) and Pb are two of the most ubiquitous metals (Guilarte, 2015; Neal and Guilarte, 2013; Wennberg, 1994). Previous studies have established the association between exposure to individual metals and neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease (Cowan et al., 2009; Jiang et al., 2008; O’Neal and Zheng, 2015; Weisskopf et al., 2010). However, the report on the clinical toxicity due to mixed exposure to both Pb and Mn remains are rare. Thus, reporting clinical cases with synergistic toxicities resulting from a combined exposure are highly desirable.

Here, we report one clinical case with acute life-threatening Pb exposure and another with chronic exposure to both Pb and Mn. The diagnosis, treatment, and prognosis of two cases are discussed.

Case presentation

Case 1

A 27-year-old healthy woman had complained of frequent abdominal pain during menstrual periods with a small number of blood clots. She visited a private clinic and was prescribed an herbal medicine, which was mistakenly replaced with 12 g of Pb powder. Two hours after taking the powder, the patient complained of severe abdominal pain, nausea, vomiting, and tiredness. Twenty-four hours later, the symptoms worsened, accompanying with cutaneous and sclera icterus and brownish urine color. The patient was admitted to the emergency room (ER) 36 h after initial intoxication.

Clinical presentations included icterus of the sclera and skin throughout the body (Figure 1), slight pale lips and nails, and the liver region with tenderness (+) and tapping (+). Laboratory test revealed a moderate microcytic hypochromic anemia with hemoglobin (Hb) of 8.9 g dL⁻¹ (12–15.5 g dL⁻¹; the range expressed in the parentheses are normal values, same below), hematocrit (HCT) of 25.3% (40–50%), mean corpuscular volume of 69.7 fL (82–100 fL) and increased fragmented red cells, basophilic stippling of erythrocytes, and reticulocytes of 1.2%, 3%, and 6.14%, respectively. Her urine color was brown; urine routine test showed red blood cells (RBCs) (++), urobilinogen (+++), and urine bilirubin (++). Other tests revealed the increased levels of liver transaminases: alanine-aminotransferase (ALT) of 4707 U L⁻¹ (10–40 U L⁻¹), aspartate-aminotransferase (AST) of 5363 U L⁻¹ (10–40 U L⁻¹), lactate dehydrogenase (LDH) of 2988 U L⁻¹ (100–190 U L⁻¹), conjugated hyperbilirubinemia with total bilirubin (TBIL) of 371.4 μmol L⁻¹ (5–21 μmol L⁻¹), direct bilirubin (DBIL) of 184.3 μmol L⁻¹ (0–6.8 μmol L⁻¹), indirect bilirubin (IBIL) of 187.1 μmol L⁻¹(3.4–11.7 μmol L⁻¹), and total bile acid (TBA) of 272.4 μmol L⁻¹ (0–10 μmol L⁻¹). Her coagulation function was abnormal with prothrombin time of 30.7 s (9.6–13 s), prothrombin time activity percentage of 27% (80–120%), prothrombin time ratio of 2.58 (0.80–1.20), international normalized ratio of 2.74 (0.80–1.20), activated partial thromboplastin time of 43.4 s (21–34 s), fibrinogen of 155.3 μg dL⁻¹ (170–400 μg dL⁻¹), thrombin time of 21 s (14–21 s), and d-dimer of 9.2 mg L⁻¹ (≤0.55 mg L⁻¹). Blood lead level (BLL) was 173.5 μg dL⁻¹, while urinary lead level (ULL) was 1240 μg dL⁻¹; the latter was 177 times higher than the normal value (≤7 μg dL⁻¹). Bone marrow proliferation was active. Granulocyte, erythroid, and lymphocyte lines accounted for 49.0%, 16.5%, and 28.5% of bone marrow, respectively. The basophilic dotted RBCs and megakaryocytes were rare. An abdominal computerized tomography (CT) scan showed that the density of the liver was diffusely reduced with small intestinal dilatation and fluid accumulation (Figure 2). Based on these clinical and laboratory findings, the patient was diagnosed as acute severe Pb poisoning accompanying with acute severe toxic hepatopathy, acute hemolysis, and severe hemolytic anemia.

Figure 1.

Case-1 patient admitted to the ER showed cutaneous and sclera icterus, severe vomit, and weak extremities. The patient complains nausea, stomach ache/colic, dizziness, and lack of energy. Picture shows a released sclera icterus after EDTA treatment. ER: emergency room; EDTA: ethylene-diamine-tetraacetate.

Figure 2.

Case-1 patient underwent CT scanning after her admission to Chaoyang Hospital. Abdominal CT shows the density of the liver was diffusely reduced. CT: computerized tomography.

In the first 2 days, plasmapheresis therapy was immediately used after patient admission. On day 3, a homotypic-suspended RBC (2U) solution was iv-infused to improve anemia, followed by, on days 4 and 5, infusion of 400 mL freshly frozen plasma to improve the coagulation function. The chelation therapy with calcium disodium ethylene-diaminetetraacetate (CaNa₂EDTA) was started on the second day of admission with a 3-day-on and 4-day-off CaNa₂EDTA regimen as one course, for seven courses. CaNa₂EDTA treatment significantly reduced BLL from 170 μg dL⁻¹ at day 1 to 10 μg dL⁻¹ at the end of the seven-course treatment, and the Hb level also returned to normal (Figure 3). Other parameters associated with liver function and bilirubin level (Figure 4(a) and (b)) were also returned to normal. Anemia, icterus, and all gastrointestinal symptoms disappeared by the end of chelation therapy.

Figure 3.

Time course of BLL and Hb in case-1 patient following EDTA and other clinical interventions. The patient received EDTA chelation therapy with a regimen of 3 days on/4 days off of EDTA as one course, for seven courses. Blood chemistry was monitored prior to EDTA treatment and at the end of each course. BLL: blood lead level; Hb: hemoglobin; EDTA: ethylene-diamine-tetraacetate.

Figure 4.

Time course of liver function parameters in case-1 patient following EDTA and other clinical treatments. The EDTA chelation was the same as those described in Figure 3. Changes of liver panel (a) and bile acid and bilirubin levels (b) were monitored prior to EDTA treatment and at the end of each course. EDTA: ethylene-diamine-tetraacetate.

Case 2

A 56-year-old man worked in a Pb and Mn smelter from 2002 to 2016. He was engaged in removing the slag from smelting furnaces where ores were burned to produce crude Pb and Mn at high temperature. The factory produces about 2 tons of crude Pb and 50–60 tons of crude Mn in a working day. The patient worked 3–4 days week⁻¹, 12 h a day wearing work clothes, gloves, and dust masks. The workshop was about 100 m² in size and the dust removal equipment was installed at the top of the workshop.

The patient was brought to the ER with severe vomiting, paroxysmal abdominal colic, which was intolerable during the onset of pain, rendering the patient rolling over on the floor. The patient looked exhausted with pale skin at admission. He complained of right shoulder pain, malaise, and tiredness. Clinical examination revealed a visible Pb line on the gums (Figure 5) but without signs of dehydration, fever, and sclera. He had tenderness elicited by abdominal palpation without peritoneal signs; the remaining examination was normal. Before visiting the ER, the patient had complained of nausea, vomiting, abdominal colic accompanied with headache, dizziness, increased irritability, and memory decline for more than 1 year; these symptoms had become more frequent, although his abdominal pain in the past year was intermittent and not persistent.

Figure 5.

Case-2 patient admitted to the ER showed intolerable pain in stomach, severe vomit, and dizziness. Pb line (indicated by a red circle) was clearly identified alongside the gum. ER: emergency room; Pb: lead.

Routine blood test before any treatment showed RBC of 2.54 × 10¹² L⁻¹, HGB of 7.1 g dL⁻¹ (13.5–17.5 g dL⁻¹), and HCT of 22% (40–50%). BLL and ULL were 64.8 μg dL⁻¹ and 38.3 μg dL⁻¹, respectively. The test on Mn, however, showed that blood and urinary Mn levels were 0.1 μg dL⁻¹ (≤82 μg dL⁻¹) and 2.4 μg dL⁻¹ (1–3 μg dL⁻¹). Blood levels of AST, ALT, LDH, hydroxybutyrate dehydrogenase, TBIL, DBIL, IBIL, and TBA were all normal.

The patient received the same CaNa₂EDTA chelation regimen as described above on the first day of admission. After three courses of CaNa₂EDTA chelation, his symptoms of nausea, vomiting, abdominal pain, headache, dizziness, and irritability were alleviated; BLL decreased and Hb increased (Figure 6), although the pain in the right shoulder was persistent and further aggravated. High-resolution CT scan indicated a right-lung cancer (Figure 7) and this was confirmed by fiberbonchoscope biopsy as a squamous cell carcinoma (Figure 8). For his evident lung cancer, the patient was discharged and transferred to the Oncology Unit in a Cancer Hospital for further treatment.

Figure 6.

Time course of BLL and Hb in case-2 patient following EDTA and other clinical interventions. The patient received EDTA chelation therapy with a regimen of 3 days on/4 days off of EDTA as one course, for three courses. Blood chemistry was monitored prior to EDTA treatment and at the end of each course. BLL: blood lead level; Hb: hemoglobin; EDTA: ethylene-diamine-tetraacetate.

Figure 7.

Case-2 lung HRCT scan. (a) and (b) Mediastinum-typed lung cancer with mediastinal lymph node metastasis. HRCT: high-resolution computed tomography.

Figure 8.

Case-2 fiberbronchoscope exam. (a) and (b) Lesions in the lower trachea, carina, the right and left main bronchus, and the right upper lobe were identified.

This study was approved by the Medical Ethical Committee and the patients have provided informed consent for publication of the cases.

Discussion

Chronic, long-term exposure to Pb has been reported frequently and extensively in the literature (Haider and Qureshi, 2013; Weisskopf et al., 2004); yet reported cases of severe, life-threatening Pb poisoning are rare. Here, we reported two unique cases of severe Pb poisoning via either ingestion or inhalation exposure. The woman in case 1 was mistakenly provided with pure Pb powder as an herbal medicine; the patient was nearly at the edge of death upon admission to the ER. The man in case 2 was clearly occupationally exposed to Pb and Mn over 15 years and had reached a critical life-threatening point of Pb poisoning. Table 1 summarizes the general information of the two patients, and Table 2 lists the signs, symptoms, and complications observed in clinics.

Table 1.

Information on two cases of severe Pb intoxication.

	Case 1	Case 2
Age	27 years old	56 years old
Gender	Female	Male
Occupation	Housewife	Smelting worker
Exposure way	Ingestion	Inhalation
Previous health	Good	Good
Diagnosis	Acute	Chronic
Severity	Severe	Severe
Treatment	EDTA; plasmapheresis	EDTA
Prognosis	Cure	Relief

EDTA: ethylene-diamine-tetraacetate.

Table 2.

Summary of clinical manifestations/complications of two cases of severe Pb intoxication.

		Case 1		Case 2
Clinical manifestations/complications		Before treatment	After treatment	Before treatment	After treatment
Nervous system	Headache	−	−	+	−
	Dizziness	−	−	+	−
	Disturbance of consciousness	−	−	−	−
	Irritability	−	−	+	−
Respiratory system	Cough	−	−	+	+
	Short of breath	−	−	−	−
	Dyspnea	−	−	−	−
Digestive system	Nausea	++	−	++	−
	Vomiting	++	−	++	−
	Abdominal pain	+++	−	+++	−
	Liver dysfunction	++++	−	−	−
Blood system	Hemolysis	++	−	−	−
	anemia	++	−	++	+
Sclera and skin	Icterus	+++	−	−	−
Systemic	Tiredness	++	−	+	−
Local	Pb lines	−	−	++	±
	shoulder pain	−	−	+	+

Pb: lead.

Pb poisoning exhibits a variety of signs and symptoms in clinics, varying widely among individuals depending upon the degree and time of exposure. Two patients reported here, while having entirely different routes of exposure and strikingly dissimilar exposure scenarios and durations, shared similar anemia symptoms. They also displayed similar gastrointestinal symptoms, such as nausea, vomiting, and abdominal pain. The anemia appearance observed in these two severe Pb poisoning cases is consistent with previous reports (White, 1975; White and Selhi, 1975). Pb poisoning has been shown to cause the abnormal Hb synthesis, as when Pb was used as treatment for cancer (Gould et al., 1937). In a seminal occupational safety survey among shipbreaking yards in the British coast, Mccallum and colleagues (1969) reported that 36% of workers suffered from anemia; the authors believed that airborne Pb burning through Pb painted metal with a high-temperature flame was the cause. A more recent mechanistic study suggested a direct interaction of Pb on erythrocyte membranes by inhibiting the activity of Na+-K+-ATPase (Ahyayauch et al., 2013).

The cases of abdominal pain due to oral exposure to Pb have been reported previously (Shiri et al., 2007; Vossoughinia et al., 2016). Noticeably, aside from Pb, oral exposure to other metals can also cause nonspecific abdominal pain, which is thought to be due to the direct interaction between metals and the gastrointestinal tract, such as metal-induced alterations in sodium transport in the small-intestinal mucosa and/or metal-induced interstitial pancreatitis (Janin et al., 1985). Interestingly, in case 2, the chronic Pb exposure was mainly through inhalation. Thus, the abdominal colic appears to be distinct in severe Pb poisoning, no matter by which route Pb enters the body. The current observation supports the hypothesis that the abdominal colic in severe cases of Pb exposure is caused by changes in visceral smooth muscle tone secondary to the action of Pb on the visceral autonomic nervous system (Janin et al., 1985).

The differences in clinical manifestations between these two cases are apparent. The oral ingestion of Pb powder in acute case 1 caused a severe liver injury, which was absent in case 2, whereas chronic inhalation exposure to airborne Pb in case 2 yielded a characteristic “Pb line” in the patient’s teeth. The bioavailability of Pb in adults is 10–27% (40–50% in children) (Maddaloni et al., 1998). During the absorption process, Pb entering the liver may produce free radicals and increase the expression of apoptotic protein and deplete antioxidants (Matovic et al., 2015), leading to the destruction of hepatocyte structure and ultimately toxic liver disease. While rare, clinical cases have indeed been reported in the literature on acute and severe liver injury caused by accident Pb ingestions that threaten human life (Beattie et al., 1979; Verheij et al., 2009). Verheij et al. (2009) and colleagues reported on a 40-year-old man who was admitted to the hospital with severe abdominal pain, abnormal liver function tests, and normocytic anemia, which was similar to case 1 reported here. A liver biopsy on that patient revealed active hepatitis together with extensive steatosis, cholestasis, and lymphocytic cholangitis. In Verheij’s case, chelating therapy also showed a positive response with hepatic enzymes returning to normal. Our case 1 with acute Pb exposure also supports the view that the Pbinduced acute liver injury is reversible after Pb is removed by chelation therapy.

It is important to note that the case-2 subject was exposed not only to airborne Pb but also Mn. Mn is known to induce syndromes clinically similar but not identical to Parkinson’s disease (O’Neal et al., 2014). There is a possibility that the mixed exposure to Pb and Mn may exacerbate each other’s toxicity. However, our neurological examination in case 2 with a focus on the motor system did not reveal any movement disorders following chronic, long-term exposure to both metals. Thus, it is difficult to conclude that Pb exposure may initiate or enhance the Mn-induced motor dysfunction. Nonetheless, our recent study among Mn-exposed Chinese workers indicates that the Mn level in bone, as determined by a transportable in vivo neutron activation analysis system, is significantly associated with a decline in cognitive function (Rolle-McFarland et al., 2019). Since occupational Pb exposure is also known to cause neurological and cognitive disturbances (Bleecker et al., 2007), it is possible that exposure to both metals in case 2 may potentiate each other’s neurotoxicity, particularly the neurobehavioral dysfunction.

Considering the normal blood level of Mn in case 2, it would become puzzling how the normal Mn status in blood may aggravate the Pb toxicity. Data from Dr Zheng’s group have shown that Mn has a short half-life in blood but a prolonged half-life in bone (equivalent to about 8–9 years in human bone), which results from an extensive Mn accumulation in bone (O’Neal et al., 2014; Zheng et al., 2000, 2011). Thus, a slow release of Mn from the bone tissue makes it possible for Mn to interact with Pb. In fact, animal studies with combined exposures to both Pb and Mn have shown that brain Pb levels are significantly higher in combined exposure than exposure to Pb alone, in both adult (Chandra and Shukla, 1981) and developmentally exposed animals (Chandra et al., 1983). While the human studies on combined exposures to Pb and Mn are scarcely seen in the literature. A published cohort study has indeed shown evidence of synergism between Pb and Mn. It suggested that Pb toxicity was increased when co-exposure with Mn among children, particularly during potentially sensitive developmental stages such as early childhood (Claus Henn et al., 2012).

The case-2 patient with chronic exposure developed an evident lung cancer; this could be due to the inhalation exposure to Pb as well as to Mn. A study by Lundstrom and his colleagues on the mortality and cancer incidence of long-term Pb smelter workers revealed a significant association between Pb exposure and incidence of lung cancer (Lundstrom et al., 1997). Lung injuries have also been reported among welders who were exposed to welding fumes containing a high amount of Mn (Antonini et al., 2004). Therefore, it is reasonable to infer that co-exposure to mixed airborne Pb and Mn in working place may increase the risk of developing lung cancer.

Recommendations

Clinical indications of Pb poisoning are broad; yet patients presenting in the ER with unexplained and severe multisystem symptoms, especially of the gastrointestinal and CNS characters, are suggested to have blood and urinary Pb tests taken, which likely directly support or reject the diagnosis of Pb toxicity. In acute case 1, the mistakenly provided pure Pb powder as an herbal medicine is an unexpected source of Pb exposure. It is, therefore, incumbent upon the physician to consider unconventional sources of Pb exposure when confronting those cases without an apparent etiology.

In case 2 with chronic occupational exposure, the working history and pertinent clinical tests are of significant importance to identify Pb poisoning. Mn is known to accumulate in bone having a long bone half-life. Such a long existence of Mn in the body makes it possible for Mn to interact with Pb.

Chelation therapy with EDTA, which has been registered in the “WHO Model list of Essential Medicines” (WHO, 2017) and also recently verified by a clinical study (Sakthithasan et al., 2018), is an effective strategy for treatment of Pb poisoning. Importantly, clinical interventions must be accompanied by aggressive environmental prevention for workplace Pb exposure.