Investigative algorithms for disorders affecting plasma manganese concentration: a narrative review

Introduction

Background

Manganese is a trace element, used as a cofactor for various enzymatic processes, such as gluconeogenesis and chondroitin sulphate synthesis (1). Furthermore, it is utilised in dopamine, glutamate and macronutrient metabolism. Manganese is acquired dietarily from nuts, grains and tea. Manganese is also involved in making steel, dry-cell batteries, and various chemicals (2), and it serves as a contrast agent for magnetic resonance imaging (MRI) scans and is included in intravenous (IV) nutrition. Abnormal plasma manganese concentrations are uncommon in routine laboratory testing, but when present, they are clinically significant (2). Elevated levels can lead to manganism, a Parkinson’s-like neurotoxic syndrome involving the basal ganglia, and have been described in association with liver disease, parenteral nutrition, and occupational or environmental exposure (3-5). Conversely, manganese deficiency, though rare, can cause impaired glucose tolerance, skeletal demineralisation, infertility, and dermatological changes (3,6).

Rationale and knowledge gap

Despite these established associations, several barriers limit timely and accurate diagnosis of abnormal manganese concentrations. These include the limited availability of highly sensitive detection instruments, inter-laboratory variability in reference ranges, and the risk of sample contamination due to the use of stainless-steel needles or inappropriate containers (7-9). Furthermore, suboptimal sample handling, haemolysis, and delayed processing can lead to falsely elevated results, complicating clinical interpretation (7,8). As a result, many cases of true manganese imbalance may go undetected or misclassified, delaying recognition and appropriate management.

Although several reviews have examined manganese neurotoxicity, imaging findings, or inherited transporter disorders, none provide a unified diagnostic framework for both high and low plasma manganese concentrations. Existing literature is largely confined to specific domains such as toxicology, occupational exposure, or genetics, and lacks integration of biochemical, clinical, and pre-analytical considerations into a single structured pathway. Reviews by Mattison et al. [2024] (10) and Magro et al. [2025] (11) focus on manganese-induced neurotoxicity, while others, such as Majewski et al. [2024] (12) and Kulshreshtha et al. [2021] (13), address only neurological or imaging aspects. To our knowledge, no published review has presented practical diagnostic algorithms encompassing the full spectrum of hypermanganesemia and hypomanganesemia.

Objective

This paper aims to provide laboratory-based diagnostic algorithms to assist clinicians in evaluating patients with low or high manganese concentrations of unknown cause. The review integrates physiological, environmental, and analytical factors that influence manganese status and aims to improve diagnostic accuracy and recognition of disordered manganese homeostasis. We present this article in accordance with the Narrative Review reporting checklist (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-25-36/rc).

Methods

Relevant literature was identified by searching PubMed (Medline), Google Scholar, and Online Mendelian Inheritance in Man (OMIM), as well as by reviewing seminal reference texts and key bibliographies published between January 1989 and June 2025.

Search terms included combinations of “manganese”, “trace element”, “plasma”, “serum”, “diagnosis”, “deficiency”, “toxicity”, “ICP-MS”, and “biomarker”. Only human studies and reviews published in English were included. Animal or in vitro studies were referenced selectively when mechanistic insight was relevant.

The inclusion criteria were studies describing manganese homeostasis, analytical methodology, genetic transport disorders, clinical manifestations of manganese imbalance, or diagnostic interpretation. Studies were screened manually for relevance by the authors.

The diagnostic algorithms were developed inductively based on themes emerging from the literature and refined to prioritise laboratory tests and approaches that are widely available in clinical practice. Table 1 portrays details of our literature search.

Testing influences on manganese concentration

Manganese levels are usually measured in the blood, with fasting samples preferred. An absolute minimum blood sample of 300 µL has been provided as a baseline (2). Serum manganese levels, along with lymphocyte manganese superoxide dismutase activity, are considered strong biomarkers for tracking manganese intake. Inductively coupled plasma mass spectrometry (ICP-MS) is the favoured testing method due to its exceptionally high sensitivity, precision, and ability to detect trace manganese concentrations as low as 0.001 µmol/L. ICP-MS allows multi-element analysis from small sample volumes with minimal interference compared to atomic absorption spectroscopy (14,15). However, its high acquisition and maintenance costs, as well as the need for highly trained operators, limit its widespread availability to specialist laboratories. Another option is to use a plastic cannula or an already established line in the patient instead.

Blood samples are usually collected in all-plastic lithium heparin non-gel tubes or Sarstedt 2 mL paediatric lithium heparin tubes and then subjected to acid digestion, commonly with high-purity nitric acid via microwave-assisted digestion, to break down organic material (2). The digested sample is nebulised into an argon plasma, where manganese atoms are ionised. These ions are separated based on their mass-to-charge ratio within a mass spectrometer and quantified against calibration standards (2). Blood arginase activity may also serve as an indicator (16). Collection, storage and technique advice is included in Table 2 to provide clarity on particular factors affecting concentration of manganese in laboratory-tested specimens and how to avoid inaccurate results.

In addition to contamination from collection materials, several pre-analytical factors can influence manganese results. Improper centrifugation, prolonged storage, or repeated freeze-thaw cycles may cause cell lysis and release of intracellular manganese, leading to falsely elevated concentrations. Samples should be centrifuged promptly, stored at 4 ℃ if analysed within 24 hours, or frozen at −20 ℃ for longer-term storage to maintain integrity (2,7,14). To evaluate manganese overexposure, brain MRI scans and neuro-functional assessments are commonly used.

Stainless-steel needles contain manganese; thus, venesection can falsely cause high manganese readings (18). To minimise falsely elevated manganese readings, take other blood samples first through that needle and fill the manganese bottle last, or discard the first 5 mL of blood to avoid contamination (8), or plastic cannulas should be used to take the blood instead. To avoid haemolysis, which may also falsely elevate results, samples should be handled gently, processed promptly, and mixing should be gentle (9). It does not seem to matter when on the day one tests for manganese (21).

Manganese homeostasis

Manganese is mainly absorbed in the small intestine by active transport via the divalent metal transporter divalent metal transporter 1 (DMT1), with absorption efficiency typically below 10% under normal dietary conditions (22). If manganese intake is high, some manganese may diffuse passively (22). Manganese is stored in the liver, with 10–20% in bone, and only a small concentration in the plasma bound to transport proteins, e.g., albumin, transferrin, alpha 2 macroglobulin (23) (Figure 1). Manganese is excreted down concentration gradients in bile to faeces, with only a minor excretory role of the kidney (22,24). The SLC39A8 is the transport protein which takes manganese into cells (25).

Figure 1 Homeostasis of manganese, author’s own, created in https://BioRender.com/2905sut. DMT1, divalent metal transporter 1.

Average manganese concentrations in humans vary widely in studies, so whilst below is a guide, one should follow the local laboratory’s range as it will be validated for the methods they are using to measure manganese and the local population (2,7):

• 4–15 mcg/L in whole blood.
• 2 mcg/L in serum.
• 0.4–0.85 mcg/L in plasma.

Physiological regulation of absorption

Beyond the basic homeostatic pathways described above, several dietary and metabolic factors finely regulate manganese absorption and distribution. The efficiency of intestinal uptake depends strongly on the nutrient environment and interactions with other trace metals. As iron and manganese share transport proteins, manganese absorption has been shown to decrease as the iron content of an ingested meal increases (26-28). Additionally, iron supplementation has been associated with decreased manganese concentrations (26,28). It appears as though iron and manganese have an inverse correlation; small studies have shown that both low iron and ferritin concentrations, respectively, are associated with high manganese (28). Calcium and magnesium also compete for intestinal uptake and can reduce manganese bioavailability (29,30).

Certain foods are higher in manganese than others, but seafood, grains and tea are amongst the highest (Table 3). However, dietary content alone does not determine manganese absorption, as intestinal uptake is tightly regulated by competitive interactions and physiological state. Table 4 depicts what constitutes adequate dietary intake for manganese, based on the physiological stage. Dietary fibre, oxalates, and phytates form insoluble complexes that inhibit absorption, whereas certain organic acids such as citrate and ascorbate may chelate manganese and enhance its solubility and absorption efficiency (23,29). These regulatory interactions explain why foods like tea, despite their high manganese content (see Table 3), contribute relatively little to systemic manganese status due to low bioavailability (5,31). Dietary supplements vary in how much manganese they provide, if any, and data on the relative bioavailability of the chelated or inorganic forms is lacking (6). Manganese concentration in water sources varies as seawater is usually between 0.4–10 mcg/L, freshwater is between 1–200 mcg/L, but can be much higher depending on the industry around the area (5).

Physiological stage effects

Manganese absorption and plasma concentrations vary with age, sex, and physiological condition. Infants and young children exhibit higher fractional absorption and plasma manganese concentrations than adults, likely due to immature biliary excretion and increased metabolic demand for growth (7,32). Whole-blood manganese concentrations in neonates are often two to three times those in adults (32). The elderly may show lower absorption and altered distribution because of reduced dietary intake, gastrointestinal transport efficiency, or concurrent micronutrient deficiencies (5). Manganese concentrations in breast milk typically range from 3–10 µg/L, whereas cow’s-milk-based formulas contain about 30–100 µg/L and soy-based formulas 200–300 µg/L (31). Despite the lower absolute concentrations, manganese from human milk is absorbed more efficiently (8.2%) than from cow’s milk (3.1%) or soy formula (0.7%), due to favourable solubility and the presence of binding ligands such as lactoferrin (33,34). Therefore, although breast milk contains less manganese, it provides a more physiologically appropriate and bioavailable source for infants.

Gender and reproductive stages also influence manganese handling. Premenopausal women generally have higher plasma manganese concentrations than men, possibly reflecting lower iron stores (28). During pregnancy, manganese concentrations in whole blood rise considerably—on average up to threefold higher than in non-pregnant adults—and newborns exhibit similarly elevated levels. This rise likely reflects both enhanced fetal transport and the inverse correlation between manganese and iron levels (35,36). For pregnant women receiving iron supplementation, the increase is less pronounced. These life-stage differences underscore the need for careful interpretation of plasma manganese results, as apparent abnormalities may reflect physiological adaptation rather than true dysregulation.

Hypermanganesemia

The most commonly described features of manganese toxicity are a Parkinson’s-like presentation of bradykinesia, tremor and rigidity. Damage typically involves the globus pallidus and other basal ganglia structures (3,37). MRI scans during exposure may show high signal intensities in these areas, which normalise after cessation of exposure, while symptoms may persist (3). Diagnosis of manganese-induced Parkinsonism can be complicated due to overlapping symptoms with Parkinson’s disease (PD), including bilateral symptoms and early mental changes. MRI and positron emission tomography (PET) scans can aid in differentiation; while PD shows abnormal fluorodopa uptake, manganese-induced Parkinsonism may present normal results despite significant neurological symptoms (3). Key distinguishing features include the age of onset (younger in manganese cases), the presence of kinetic tremor, and a lack of response to levodopa therapy (3).

When investigating causes of high manganese, the presence of symptoms of hypermanganism (see Table 5) would suggest true toxicity, whereas their absence would indicate spurious results (18). Once one has ruled out false elevation of manganese from needle contamination and haemolysis, then elevation of manganese usually results from high intake, failure of excretion, or a combination of the two.

Manganese is excreted in bile, so any biliary pathology may affect homeostasis, particularly in the setting of increased manganese uptake, like total parenteral nutrition, where no bile is being excreted (38). Therefore, those with cholestasis have impaired manganese excretion, and both primary sclerosing cholangitis and primary biliary cirrhosis have been shown to increase manganese levels (38). Therefore, those with partially or poorly functioning bowels are at risk of manganism, particularly if they already have too much manganese in their diet, and excess levels of manganese have even been described in cases of drinking too much tea (31). Biliary obstruction will cause a buildup of manganese, as described in a cohort of patients with biliary atresia (39).

Manganism can also occur in hospitalised patients with chronic liver disease (40) and is also believed to play a role in the hepatic encephalopathy seen in liver cirrhosis (41). However, data regarding alcohol related cirrhosis and whether there is an elevation of manganese is conflicting. Of course, manganese intake may be low if nutrition is poor (5). One study of cirrhotics demonstrated that manganese levels were threefold higher in those with liver failure than controls (10 mcg/L c.f. 30 mcg/L) (42). Higher manganese concentration has also been noted in the plasma of those with non-alcoholic fatty liver disease. However, there is debate as to whether it is causative, associated, or related to poorer excretion, and the differences were small and overlapping (34,40).

Otherwise, of course, taking too much manganese, either as purposeful or accidental poisoning, can cause fatal manganism, as seen in an oral ingestion of a large quantity of Epsom salts for a liver-cleansing diet (43). For decades now, there has been the realisation that manganese content in artificial feeding bags must be controlled to prevent toxicity (4,6).

Excessive dietary intake of manganese can lead to problems, including a report of someone developing a Huntington’s chorea-type presentation as a consequence of high manganese after excessive tea drinking (44). Some batteries contain manganese, and the first reported case in a child had the conclusion that the patient’s death, one week after battery ingestion, was partially driven by manganese toxicity (45). Synthetic stimulant methcathinone (also known as m-cat, meow meow, or white magic) contains manganese dioxide as a by-product from production, and so regular intravenous use can cause manganism (46).

Certain occupations present a risk of manganese exposure (47). Ferroalloy plants, ore mining, various welding rods, and the battery industry all represent possible causes of manganism (6,47,48). Inhalation of welding fumes can result in manganese entering the blood, as manganese is a key component of many welding alloys (49,50). Following exposure to high concentrations of welding fumes, manganese has been shown to accumulate in the globus pallidus, as demonstrated in brain MRIs (50). Children living near a manganese refinery also developed symptoms (51). As alluded to earlier, the potential manganese concentration in water surrounding industrial sites may be much higher than average concentrations (52). Percutaneous absorption of manganese can occur with contact with the gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT) (34).

As iron and manganese share transport proteins, low iron and ferritin concentrations, respectively, are associated with high manganese concentrations (27,36). Therefore, iron deficiency anaemia can be a cause of disproportionately increased manganese concentrations in the blood (27). There is also a possibility that polymorphism in one’s iron-handling proteins may also indirectly affect manganese status.

There are rare genetic causes of manganese excess, i.e., mutations in SLC30A10 (ZNT10) and SLC39A14 (ZIP14) (53). Both of them reduce manganese excretion via slightly different methods, hence leading to higher manganese concentrations and subsequent toxicity. The following algorithm provides a suggestion for those encountering abnormal results unexpectedly or whilst investigating symptoms that could indicate manganism (see Figure 2).

Figure 2 Diagnostic algorithm for hypermanganesemia. Created in https://BioRender.com/14zxrk7. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TTG, tissue transglutaminase.

Hypomanganesaemia

Manganese deficiency can cause a long list of nonspecific symptoms (6).

Hypomanganesaemia is rare in the UK for those with usual dietary habits. Causes of hypomanganesaemia may include genetic mutations. A heterozygous or compound homozygous mutation in the SLC39A8 gene on chromosome 4q24 causes the glycosylation type IIn (CDG2N) congenital disorder (54). The pathology indicates renal wasting as conveyed by low concentrations of manganese and zinc in blood but high concentrations in urine. This disorder is marked by delayed psychomotor development noticeable from infancy, along with hypotonia and a range of other possible symptoms, including short stature, seizures, vision impairment, and cerebellar atrophy (54). Leigh syndrome, another genetic condition caused by mutations in SLC39A8, is a neurodegenerative condition with severe manganese deficiency (55). Diagnosis of these genetic conditions relies on accessible first-line tests, with biopsy or genetic analysis reserved for definitive confirmation where necessary.

Systemic conditions may also contribute to low levels of manganese, including autoimmune diseases (e.g., Crohn disease, ulcerative colitis, coeliac disease) (56), chronic liver disease and bone disorders, each with characteristic clinical features and diagnostic protocols (22). Inflammatory bowel disease and coeliac disease can result in malnutrition and thus, low manganese levels. Initial investigations typically involve blood tests, imaging, endoscopy, biopsy and condition-specific markers such as C-reactive protein, tissue transglutaminase, stool calprotectin, and serologies. Inborn errors like phenylketonuria and metabolic conditions such as diabetes can also impact manganese levels (22).

Anaemia can also be a cause of disproportionately increased manganese concentrations in the blood, as iron and manganese share transport proteins (27). One study also showed adding calcium to milk seemed to reduce manganese absorption (29). Processed foods are low in manganese, so people are at higher risk of hypomanganasemia in developed nations where they are more widely consumed (57,58). Magnesium has also been shown to compete with manganese for absorption, in a similar manner to iron (30).

Discussion

Accurate recognition of manganese imbalance is constrained by several analytical, pre-analytical, and biological factors. Analytical availability is limited: the preferred platform, ICP-MS, offers very low detection limits and multi-element capability but is expensive to purchase and maintain and requires specialist expertise, restricting access to reference or regional laboratories (14,15). Pre-analytical vulnerabilities include contamination from stainless-steel needles or inappropriate containers (7,18), haemolysis from suboptimal venepuncture or mixing (9), and procedural issues such as delayed or improper centrifugation, prolonged storage, or multiple freeze-thaw cycles that can release intracellular manganese and artifactually elevate results (16). Between-laboratory variability in reference intervals and the use of different matrices (whole blood, serum, plasma) complicate interpretation and comparison across sites (2,6,7). Biological confounders—notably iron status, pregnancy-related shifts, age, diet, and environmental/occupational exposures—can alter circulating manganese independent of disease (3,5,23,27,28,32). Imaging/clinical interpretation may also be challenging: T1 hyperintensity in the globus pallidus can normalise after exposure cessation even when symptoms persist, and clinical overlap with PD complicates attribution (3,37). Finally, genetic heterogeneity (SLC30A10, SLC39A14, SLC39A8) produces divergent biochemical signatures that are not captured by a single test (25,53,55).

Future research directions should include: (I) multicentre prospective validation of the diagnostic algorithms presented here, including outcome-linked thresholds; (II) harmonisation of pre-analytical protocols and external quality assessment for manganese with matrix-specific, age/sex/pregnancy-specific reference intervals (2,6,16); (III) head-to-head analytical studies comparing ICP-MS against alternative platforms in clinically relevant ranges, with cost-effectiveness analyses (14,15); (IV) evaluation of adjunct biomarkers (e.g., MnSOD activity, blood arginase) for diagnostic and monitoring performance (16,26); (V) standardised MRI reporting criteria for manganese exposure and correlation with clinical outcomes (3,37); (VI) integration of iron status and genetic testing (SLC30A10, SLC39A14, SLC39A8) into reflex pathways (25,28,53,55); and (VII) development of low-volume sampling and stable storage solutions to expand access in community and resource-limited settings (16). Table 6 provides information on the symptoms that occur when manganese levels become too low.

This is a narrative review that synthesises diverse literature across toxicology, neurology, nutrition, genetics, and laboratory medicine; as such, it is susceptible to selection and publication bias and does not include a formal risk-of-bias assessment. Several topics rely primarily on observational data, small experimental studies, or case reports, which limits certainty and generalisability: examples include the dietary absorption modifiers (27,29,57), manganese and NAFLD associations with small, overlapping effect sizes (42), and older occupational cohorts or mechanistic imaging studies (37,48,50). Evidence for some adjunct biomarkers is preliminary (16,26). Pre-analytical recommendations are based on best practice documents and stability studies rather than large clinical trials (7,8,16). Finally, the diagnostic algorithms were intentionally designed around widely available tests; they have not yet been prospectively validated across multiple centres, and thresholds may require refinement for different matrices (whole blood vs. serum vs. plasma) and physiological states (e.g., pregnancy). These constraints should be considered when applying our proposed pathways in clinical practice.

Conclusions

Because of the dual risks of toxicity and deficiency, manganese, a trace element necessary for many enzymatic and physiological processes, holds a special place in clinical medicine. Due to the nonspecificity of presenting symptoms and the relative rarity of severe deviations in plasma concentrations, manganese homeostatic disturbances are frequently overlooked, despite their importance. In order to help physicians assess patients with abnormal plasma manganese concentrations, this review compiles recent research and offers useful diagnostic frameworks. Using investigations that are accessible in practice, the diagnostic algorithms presented are intended to be both thorough and applicable in a range of clinical settings. Although there are many different causes of manganese derangements, such as genetic mutations, nutritional deficiencies, impaired excretion, and environmental exposures, a methodical evaluation can help with prompt and precise diagnoses. Maintaining a high index of suspicion is crucial, especially when atypical causes like iatrogenic exposure or congenital glycosylation disorders are identified. Future work should focus on validating these diagnostic algorithms in clinical practice, developing more reliable biomarkers of manganese status, and elucidating the interplay between genetic variants, environmental exposure, and clinical outcomes. This article seeks to improve diagnostic accuracy and guide appropriate management by providing healthcare professionals with organised, evidence-based guidance.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Sukhbir Kaur) for the series “Trace Elements and Vitamins” published in Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-36/rc

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-36/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-36/coif). The series “Trace Elements and Vitamins” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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