A Scoping Review Examining the Association between Lead Exposure and Non-Alcoholic Fatty Liver Disease

1. Introduction

Non-Alcoholic Fatty Liver Disease (NAFLD), now recognized as Metabolic-Associated Fatty Liver Disease (MAFLD), has emerged as a burgeoning global health concern characterized by hepatic fat accumulation in the absence of significant alcohol consumption [1]. Its prevalence has risen precipitously, paralleling shifts in lifestyle and dietary patterns [2,3,4]. The complex etiology of NAFLD/MAFLD encompasses a spectrum of genetic, metabolic, and environmental factors. In this context, the role of environmental exposures in contributing to NAFLD/MAFLD pathogenesis warrants meticulous exploration.

NAFLD/MAFLD is increasingly acknowledged as a complex interplay between genetic predisposition and environmental factors, prompting investigations into the potential influence of environmental contaminants such as lead [5,6]. Lead has long been recognized for its adverse health effects, particularly on the hepatic system. The hepatotoxic properties of lead and its capacity to disrupt metabolic processes provide a rationale for examining its potential association with NAFLD/MAFLD. Experimental evidence and epidemiological observations underscore the plausibility of lead exposure influencing metabolic pathways and hepatocellular function [7,8,9], warranting a comprehensive review of the existing literature.

Therefore, we conducted a scoping review to explore the available literature on the association between lead exposure and NAFLD/MAFLD. The primary objective of this review was to discern the extent to which lead exposure has been posited as a determinant or risk factor for NAFLD/MAFLD.

2. Materials and Methods

We performed a scoping literature review following the framework proposed in the seminal paper by Arksey and O’Malley [10,11] and according to the recommendations from the Joanna Briggs Institute. Moreover, the review was reported according to the PRISMA extension for scoping reviews (the PRISMA-ScR) [12].

2.1. Review Question

This scoping review was performed to summarize the evidence about the relationship between lead exposure and NAFLD/MAFLD. To this end, we framed a prognostic question specifying the types of Participants, types of Index prognostic factor, and types of outcomes as follows: Participants: general population; Index prognostic factor: lead exposure; Outcomes: NAFLD/MAFLD onset and outcomes. Thus, the review answered the following question:

What information and empirical data have been reported concerning the association between lead exposure and its impact on the onset and outcomes of Non-Alcoholic Fatty Liver Disease (NAFLD)/Metabolic Associated Fatty Liver Disease (MAFLD)?

2.2. Inclusion/exclusion Criteria

All peer-reviewed published literature describing or analyzing the relationship between lead exposure and NAFLD/MAFLD were considered eligible for inclusion. We included observational studies (cohorts, case-control, and cross-sectional studies) that analyzed human populations of any age and investigated the association between lead exposure/blood lead levels and risk of NAFLD/MAFLD. We excluded review articles, case reports, and studies performed on animals.

2.3. Types of Participants

Because we were interested in learning about lead exposure effects on the risk of NAFLD/MAFLD in humans, we did not restrict the inclusion criteria to a particular population of interest. Instead, studies with population-based data (i.e., surveys) or those performed in populations with a baseline higher risk of lead exposure (i.e., industrial workers or people living near industrial zones) were considered appropriate for inclusion.

2.4. Exposure of Interest

Lead was the exposure of interest. The principal sources of lead exposure are paints, water, soil, dust, cooking and baking utensils, and leaded gasoline. Industrial emissions can also be responsible for population exposure to lead.

For this review, we included studies where lead exposure was objectively defined by quantifying blood lead levels (BLL) in the individuals analyzed. Although BLL ≥ 5ug/dL is considered elevated, we did not restrict the BLL to a particular cut-off value. Instead, we extracted data on the exposure of interest using the cut-off values reported on each study and by exposure quartiles, if available.

2.5. Concept, Context, and Outcomes

The association between lead exposure and NAFLD/MAFLD onset and outcomes was the core concept of this scoping review. This concept was explored in observational studies examining the effect of lead exposure on the following outcomes of interest: 1. Hepatic steatosis, and 2. Liver fibrosis. These outcomes were not pre-defined; we included and extracted outcome data according to the definitions reported in each study.

2.6. Search Methods

Electronic database searches were performed in MEDLINE (through OVID), EMBASE, and SCOPUS from inception to November 15/2023. Search strategies were designed to include words related to the condition of interest (NAFLD, MAFLD) and the exposure of interest (lead exposure). For example, the search strategy in MEDLINE was: (exp Lead/ OR exp Lead Poisoning/ OR lead exposure.mp. OR lead toxicity.mp. OR “blood lead levels”.mp. OR “lead levels”.mp.) AND (exp Non-alcoholic Fatty Liver Disease/ OR nafld.mp. OR metabolic associated fatty liver disease.mp. OR MAFLD.mp. OR exp Fatty Liver/ OR non-alcoholic steatohepatitis.mp.).

2.7. Study Selection

The records found in the electronic search strategies were imported into Ryyan. Then, two authors independently screened titles and abstracts according to the inclusion criteria previously described. Finally, relevant articles identified in this phase were retrieved as full texts and reviewed by two authors, who selected the articles to be included in the scoping review.

2.8. Data Extraction and Synthesis of the Literature

The articles selected, based on the inclusion/exclusion criteria, were then reviewed to collect information relevant to the review research question. The data was extracted into a data collection form and included: author, year and country of publication, data sources (i.e., national survey data, large observational studies, among others), number of individuals analyzed, demographic and clinical characteristics, the definition of lead exposure and method for its quantification, and definition of outcomes (NAFLD/MAFLD). Also, the estimates of the effect of lead exposure in NAFLD/MAFLD were extracted as reported in each study. When available, adjusted effect estimates by quartile of lead exposure were collected.

All the data was extracted as reported in the primary source (peer-reviewed article) and summarized descriptively to chart the available literature.

3. Results

Figure 1 provides the flow diagram for the screening and selection of the studies included in the review. A total of 62 documents were retrieved from MEDLINE, SCOPUS, and EMBASE searches. Twenty-two of these documents were duplicates. Thereby leaving 40 articles for screening. After applying the review inclusion/exclusion criteria, ten articles were included [7,9,13,14,15,16,17,18,19,20]. See Table 1 for a general overview of the studies included in the review

The ten articles included in this scoping review were published between 2010 and 2022. Eight articles were secondary analyses of population Health surveys (NANHES=4, Korean National Environmental Health Survey=1, Korean National Health and Nutrition Examination Survey=1, Survey on Prevalence in East China for Metabolic Diseases and Risk Factors=2). In addition, one was a cross-sectional study with data from workers of a battery manufacturing factory, and one was a prospective cohort study from Mexico. All studies examined the relationship between Lead exposure (measured in BLL) and NAFLD/MAFLD.

Six studies reported positive risk-adjusted associations between BLL and the odds of NAFLD. One study reported positive correlations between BLL and indexes reflecting fatty liver and fibrosis. Another one reported a positive correlation between the duration of lead exposure and the degree of liver fibrosis. Finally, two studies found no associations between lead exposure and NAFLD/MAFLD.

Table 2 shows the results from multivariable regression analyses showing the risk-adjusted odds of NAFLD/MAFLD across quartiles of blood lead levels.

4. Discussion

This scoping review summarized the evidence around the association between lead exposure and the likelihood of NAFLD/MAFLD. The most obvious finding to emerge from this study was a noticeable pattern in which higher levels of lead exposure induced greater odds of NAFLD/MAFLD, more evident in the BLL 4th quartile, where positive associations were more often reported, reflecting a plausible dose-response relationship consistent across studies. Indeed, the study by Zhai et al.[15] reported a considerably rising prevalence at each BLL quartile. The NAFLD/MAFLD prevalence went from 35% and 34% in the first BLL quartile to 47% and 48% in the Q4 for males and females, respectively.

Although continued efforts are needed to unravel the cause-effect relationship between lead exposure and NAFLD/MALFD, the data synthesized herein provides a compelling argument favoring a plausible association exhibiting attributes of causation. First, the association was consistent across studies, in line with Hill’s concept of consistency, including different persons, places, contexts, and times [21]. Second, it displayed a biological gradient as the outcome odds increased with increasing exposure doses (See Table 2). Third, the associations reported were strong. Moreover, the association between lead and NAFLD/MAFLD is supported by biologically plausible mechanisms. Lead triggers a chain reaction starting with lipid peroxidation, cell membrane destabilization, and cell death. It is well-known from histological examinations that exposure to lead nanoparticles increases hepatic glucose levels and induces fatty liver accumulation in rats [22]. Chronically, lead induces fatty liver changes with periportal inflammation.

In humans, lead exposure demonstrated by elevated blood lead levels induces pathological liver changes that can be indirectly measured using non-invasive imaging tests [23]. Indeed, two of the ten articles diagnosed NAFLD/MAFLD using vibration-controlled transient elastography (VCTE). Spaur et al. [7] defined liver steatosis as a CAP260 dB/m and significant liver fibrosis as a liver stiffness value higher than 7kPa. They found that higher levels of BLL were related to an increased likelihood of VCTE abnormal results. Similarly, Teerasarntipan [14]found that more extended periods of lead exposure were positively correlated with the degree of liver impairment on transient elastography, potentially increasing the chance of more advanced liver disease at diagnosis. Therefore, individuals with prolonged periods of exposure (i.e., those living for many years in industrial areas with a proven higher likelihood of lead exposure) should be prioritized when implementing programs for the early detection of NAFLD/MAFLD.

Continued improvement of non-invasive imaging techniques in assessing fatty liver and liver fibrosis holds key to truly advancing NAFLD/MAFLD early detection in special populations at higher risk of the condition. Current EASL guidelines recommend calculating the FIB-4 score in patients at risk of metabolic-associated chronic liver disease and evaluating liver stiffness by transient elastography [24]. Patients with LS≥8 on elastography should undergo liver biopsy if the hepatologist considers it a reasonable approach. Of course, these recommendations have to be placed in context. Thus, as we have demonstrated an association between lead exposure and higher risk-adjusted odds of NAFLD, individuals exposed to sources of lead (i.e., individuals living near industrial zones and workers of battery-manufacturing factories) should undergo a medical evaluation including the assessment of liver health using non-invasive tools, either serological or imagining tests. Given its practicality and the fact that it can be performed at the bedside, transient elastography may be an efficient alternative for NAFLD/MAFLD screening in populations with a higher risk of lead toxicity.

However, studies are still needed to evaluate whether a vibration-controlled transient elastography screening strategy improves liver-related outcomes. These studies should also assess the cost-effectiveness of such strategies. Currently, the LiverScreen project [25], a multicenter European research study, is testing the hypothesis that implementing a screening program using transient elastography may increase the detection of asymptomatic patients with advanced liver fibrosis, thereby increasing the likelihood of early interventions, which may result in better outcomes. Suppose the population-based data from the LiverScreening project indicates that transient elastography is accurate and effective. In that case, it is rational to posit that such a strategy may have significant implications for evaluating liver health when the baseline risk is higher, such as in the case of the population explored in this review: those with evidence of lead exposure. In the meantime, at least the Fib-4 score should be calculated among individuals with risk factors for environmental lead toxicity.

5. Conclusions

Our scoping review reveals a consistent pattern linking higher lead exposure, particularly in the fourth blood lead level quartile, to increased odds of Non-Alcoholic Fatty Liver Disease/Metabolic-Associated Fatty Liver Disease (NAFLD/MAFLD). This observed association aligns with established criteria for causation, supported by a biological gradient and strong reported associations across diverse studies. The biological plausibility of lead-induced processes further supports this link. Notably, non-invasive imaging tools, especially vibration-controlled transient elastography, emerge as valuable in assessing liver health in lead-exposed individuals. While awaiting further validation of screening strategies, routine medical evaluations, including Fib-4 score calculations, seem pragmatic for those with potential lead exposure, highlighting the importance of ongoing research for early NAFLD/MAFLD detection in at-risk populations.