Each day, approximately 0.1-2 mg of lead enters the human body through ingestion (75%), inhalation and skin contact (25%). Once lead is absorbed and enters the bloodstream, it is distributed and deposited in various types of soft tissue in the human body. Lead accumulates in the bone, followed by the liver, kidney, neurons, and spleen9.
In the blood, 95% of lead binds to erythrocytes and has a mean half-life of 35 days. There are various ranges of normal BLL depending on an individual’s age and environmental exposure to lead. BLLs of 25-40 μg/dl in adults and 5-10 μg/dL in children are considered to be normal reference levels in the nonlead-exposure population, while a BLL of 40-60 μg/dl is an acceptable normal value among occupational lead-exposure workers10. The diagnosis of chronic lead poisoning is based on BLL regardless of the presence of signs or symptoms.
To date, there are few studies about hepatotoxicity from lead poisoning. Most of these studies were case reports of participants with acute lead poisoning symptoms and abnormal liver chemistry tests; the ranges of the liver enzymes for SGOT and SGPT were 63-66 mg/dL and 75-256 mg/dL, respectively5-7, 11-16. No liver failure was reported. There were only four analytical studies that focused on hepatotoxicity among occupational lead-exposed workers4-6, 17. Every study found that there was a mild elevation of liver enzymes. Two of the studies showed significant differences in the levels of liver enzymes between occupational lead-exposed workers and healthy control participants6, 7. However, in the other two studies, there were no differences in the levels of liver enzymes between the people who were exposed to lead and those in the control group5, 17. In our study, the majority of participants had normal levels of liver enzymes. However, approximately 20% of the participants had elevated SGOT and/or SGPT levels without any known causes. Bilirubin and ALP levels were also normal. These findings were in concordance with previous reports4-6,17. Lead accumulates in the liver among workers who are constantly exposed to lead. Therefore, we recommend that further investigations exploring chronic toxicity from chronic lead poisoning be conducted.
Our study found that GSH levels were markedly elevated and that BLL decreased after chelation therapy. This might imply that lead depleted antioxidants, which was consistent with findings from animal studies10,18. Lead-induced oxidative stress was the main mechanism of lead poisoning according to the animal models; there was a decrease in GSH reserve and an increase in reactive oxygen species (ROS). Lead inactivates GSH by binding to sulfhydryl groups and inhibits GSH synthesis9, 18. In addition, lead destabilizes the cell membrane by inducing lipid peroxidation, changes the membrane’s biophysical properties and causes cell damage18. Our study was the first human study that supported findings from animal studies demonstrating that GSH depletion contributed to liver injury in individuals with chronic lead poisoning.
The results from our study supported the systemic inflammation theory. We showed that after chelation therapy, the BLL and the levels of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 were reduced. Lead exposure could enhance the production of various proinflammatory cytokines, such as IL-1β, IL-6, IL-8, IFN-γ and TNF-α. Overall, lead causes tissue damage by inducing inflammation and inhibits anti-inflammatory mechanisms19-23.
The liver is one of the major organs that accumulates lead. We hypothesized that sustained lead exposure contributed to chronic inflammation, which predisposed individuals to hepatic fibrosis. Histopathological findings from animal experiments23, 24 and two human case reports of acute lead poisoning with unexplained hepatitis demonstrated extensive microvesicular and macrovesicular steatosis, portal and intralobular lymphocytic infiltrate, disrupted liver parenchymal architecture and pericellular fibrosis12, 24. Our study used LS as a noninvasive parameter that represented the degree of liver fibrosis. Although the mean LS in our study was within the normal range, 26.7% of the participants had LS values above the significant fibrosis cut-off level. Notably, 82.6% of the participants with significant fibrosis had nonsevere steatosis; thus, significant liver fibrosis might be a consequence of lead poisoning. Our study found that the duration of lead exposure was the major factor associated with the development of liver fibrosis. This finding supported our hypothesis that liver injury occurred as a result of chronic lead poisoning.
After chelation therapy, we found that the degree of LS and levels of inflammatory cytokines were significantly reduced and that there was an increase in GSH. These findings suggested that liver fibrosis was associated with lead poisoning. Although the change in the degree of LS was not significantly altered in proportion to a change in any single biomarker, we postulated that each cytokine exerted small effects in concert, rather than a single cytokine resulting in hepatic fibrosis.
Evidently, chronic liver inflammation from chronic lead poisoning not only leads to hepatic fibrosis but also induces various pathways that contribute to the development of hepatic steatosis. Animal studies have revealed that lead-intoxicated rats had altered gene expression of hepatic enzymes involved in cholesterol and triglyceride homeostasis7,25-27. Few studies have found significant hypertriglyceridemia and hypercholesterolemia among lead-exposed workers28,29 with scant histological reports of macrovesicular steatosis12. The mean CAP in our study was 225.1 + 49.3 dB/m, which was considered to indicate mild steatosis (S1). Notably, 54.7% of our participants had significant steatosis. However, we did not find a significant correlation between the degree of steatosis and lead-associated parameters, such as the duration of exposure and BLL. Obesity might overcome the effects of chronic lead poisoning. We observed a strong significant correlation between the degree of steatosis and BMI as well as WC.
Regarding the change in the degree of liver steatosis, we did not find a significant reduction in the level of CAP after treatment. In terms of inflammatory marker analysis, only TNF-α levels changed and were significantly negatively correlated with CAP changes. It should be noted that the mean prechelation CAP level was rather low and within the normal reference range. It is possible that the sample size was too small to allow for the detection of a change in CAP after therapy. Thus, we cannot confidently conclude that there was no relationship between lead toxicity and steatosis.
Our study has some limitations. First, the lack of a control group in our study might compromise the strength of the conclusion of the efficacy of chelation therapy in regard to changes in the degree of liver fibrosis, levels of inflammatory mediators and GSH. Regarding liver fibrosis and steatosis detection, we did not use the gold standard of histopathology to detect liver fibrosis and steatosis. Due to ethical and safety concerns, we opted to use a noninvasive technique, FibroScan®, which has been validated by other investigators. FibroScan® has shown good accuracy in evaluating the degree of fibrosis and can even replace liver biopsy30. Another limitation was that the chelation regimen might be insufficient because the mean posttreatment BLL was still above the normal level, and the follow-up time might have been too short to detect any change after treatment.