Each day, about 0.1-2 mg of lead enters the human body through ingestion (75%), inhalation and skin contact (25%). Once the lead is absorbed and enters the blood stream, it is distributed and deposited in various types of soft tissue in the human body. The lead accumulates in the bone, followed by the liver kidney, neuron, and spleen8.
In the blood, 95% of lead binds to the erythrocytes and has a mean half-life of 35 days. There are various ranges of normal BLL depending on the age and environmental exposure to lead. The BLL of 25-40 μg/dl in adults and 5-10 μg/dL in children are considered to be normal reference levels in non-lead exposure population while BLL of 40-60 μg/dl is an acceptable normal value among occupational lead-exposure workers9. The diagnosis of chronic lead poisoning is based on the BLL regardless of the presence of signs or symptoms.
To date, there were few literatures about hepatotoxicity from lead poisoning. Most 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, respectively4-6, 10-15. 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 the liver enzymes. Two of the studies showed significant differences in the level of the liver enzyme between occupational lead-exposed workers and healthy control participants.5, 6 However, in the other two studies, there were no differences in the level of liver enzymes in the people who were exposed to lead versus the control group4, 16. In our study, majority of participants have normal levels of liver enzymes. However, approximately 20% of the participants had elevated SGOT and/or SGPT levels without any explainable causes. Bilirubin and ALP levels were also normal. These findings were in concordance with the previous reports4-6,17. Lead is accumulated in the liver among workers who are constantly exposed to lead. Therefore, we recommend that further investigations of the chronic toxicities from chronic lead poisoning be conducted.
Our study found GSH level was markedly elevated and that BLL dropped after chelation therapy. This indicated that lead depleted antioxidants which was consistent with findings from animal studies10,18. Lead-induced oxidative stresses were the main mechanisms 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 the sulfhydryl groups and inhibits GSH synthesis8, 17. Besides this, lead destabilizes the cell membrane by inducing lipid peroxidation and changes the membrane’s biophysical properties and causes cell damage17. Our study was the first human study that confirmed findings from animal studies that GSH depletion contributed to liver injury in individuals with chronic lead poisoning.
Results from our study supported the systemic inflammation theory. We showed that after chelation therapy, BLL and the levels of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 were reduced. Lead exposures could enhance production of various pro-inflammatory 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 mechanisms18-22.
Liver is one of the major organs that collects lead. We hypothesized that sustained lead exposure contributed to chronic inflammation which predisposed 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, disrupt liver parenchymal architecture and pericellular fibrosis11, 23. Our study used LS as a non-invasive parameter that represented the degree of liver fibrosis. Although the mean LS in our study was within normal range, 26.7% of the participants had LS values above the significant fibrosis cut-off level. As of note, 82.6% of the participants with significant fibrosis had non-severe steatosis, thus the significant liver fibrosis might be the consequences from lead poisoning. Our study found that duration of lead exposure was the major factor that contributed to the development of liver fibrosis. This finding supported our hypothesis that liver injury came from 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 elevation of GSH. These findings suggested that liver fibrosis was associated with lead poisoning. Although the change in degree of LS did not significantly alter in proportion to the change in any single biomarker, we postulated that each cytokine exerted small effects in concert, rather than a single cytokine that contributed to hepatic fibrosis.
Evidently, chronic liver inflammation from chronic lead poisoning does not only lead to hepatic fibrosis, but it also induces various pathways that contribute to the development of hepatic steatosis. Animal studies found that lead-intoxicated rats had altered-gene expressions of hepatic enzymes in cholesterol and triglyceride homeostasis7,25-27. Few literatures observed significant hypertriglyceridemia and hypercholesterolemia among lead-exposed workers28, 29 with scant histological reports of macrovesicular steatosis11. The mean CAP in our study was 225.1 ± 49.3 dB/m which was considered to be mild steatosis (S1). Noticeably, 54.7% of our participants had significant steatosis. However, we did not find a significant correlation between degree of steatosis and lead-associated parameters such as duration of exposure and BLL. Obesity might overcome the effect of chronic lead poisoning. We saw that there was a strong significant correlation between degree of steatosis and BMI as well as WC.
Regarding the change in 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 level changed which was significantly negatively correlated with CAP change. It should be noted that the mean pre-chelation CAP level was rather low and within normal reference range. It is possible that the sample size was small so that we could not detect 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. We did not use the gold standard of histopathology in detecting liver fibrosis and steatosis. Due to ethical and safety concerns, we opted to use a non-invasive technique, the FibroScan®, which has been validated by other investigators. Not only that, but it has shown good accuracy in evaluating the degree of fibrosis. It can even replace liver biopsy30. Another limitation was the chelation regimen that might be insufficient because the mean post-treatment BLL was still above the normal level and the follow-up time might have been too short to detect any change after treatment.