Serum Mineral Dynamics in Periparturient Dairy Cows and Their Association With Fatty Liver Disease

Fatty liver disease is a frequently encountered nutritional–metabolic disorder in high-yielding dairy cows, particularly during the periparturient period. It is primarily defined by excessive lipid accumulation within hepatocytes, and despite advances in metabolic profiling, liver biopsy remains the only definitive diagnostic method^1,2. From a clinical perspective, this limitation underscores the importance of understanding the metabolic and nutritional factors that predispose cows to fatty liver, especially during early lactation. 

Metabolic Challenges During the Periparturient Period 

Fatty liver most commonly develops within the first four weeks after calving, coinciding with the period of maximum metabolic stress in dairy cows². During early lactation, energy requirements for milk synthesis exceed dietary energy intake, leading to a pronounced negative energy balance (NEB). To compensate, large quantities of fatty acids are mobilized from adipose tissue and released into circulation as non-esterified fatty acids (NEFA)^3,4,5,. 

Although NEFA serve as an alternative energy source, excessive mobilization overwhelms hepatic metabolic capacity, resulting in triglyceride accumulation within the liver. Studies have further shown that elevated fatty acid concentrations negatively affect antioxidant capacity, thereby increasing oxidative stress and metabolic dysfunction in cows⁶. Oxidative stress, in turn, exacerbates liver damage and impairs lipid metabolism. 

Importance of Macroelements and Microelements in Liver Health 

Macroelements and microelements play indispensable roles in maintaining energy metabolism, antioxidant defense, and overall metabolic homeostasis in dairy cows^2,7. Deficiencies in these nutrients during the periparturient period can intensify NEB and predispose cows to metabolic diseases such as fatty liver. 

Calcium (Ca) is closely involved in glucose metabolism, and dietary Ca deprivation has been shown to abolish the physiological increase in gluconeogenesis in cows. Magnesium (Mg) is a critical regulator of Ca homeostasis and energy metabolism. Increasing dietary Mg around parturition helps prevent hypocalcaemia and reduces circulating NEFA concentrations. Potassium (K), along with Ca and Mg, is essential for rumen motility and feed intake; deficiencies suppress intake and reduce rumen peristalsis, further aggravating NEB^2,8,9. 

Among trace elements, boron (B) supplementation has been reported to reduce lipolysis and lower NEFA concentrations. Selenium (Se) plays a vital role in lipid metabolism, antioxidant defense, and immune function, particularly in transition cows^2,10,11,12. These findings highlight the need for timely monitoring of mineral status to reduce the risk of fatty liver in dairy herds. 

Alterations in Serum Mineral Profiles in Fatty Liver Cows 

To clarify the relationship between mineral metabolism and fatty liver, dynamic monitoring of nine macroelements and microelements in serum was conducted in healthy and fatty liver cows postpartum using inductively coupled plasma mass spectrometry. Cows were selected with comparable parity, age, and body condition score to minimize confounding factors². 

The analysis revealed that serum concentrations of Ca, K, Mg, Sr, Se, Mn, B, and Mo were significantly lower in cows with fatty liver compared with healthy controls, whereas Cu concentrations were significantly higher. These mineral concentrations also showed marked fluctuations from calving to 28 days postpartum². 

Multivariate statistical analyses, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), demonstrated clear separation between healthy and fatty liver cows, indicating distinct mineral metabolic patterns. Strong correlations were observed among Ca, K, Mg, Sr, Se, Mn, B, and Mo. Receiver operating characteristic (ROC) curve analysis and variable importance values further identified Ca, Se, K, B, and Mo as particularly relevant diagnostic indicators for postpartum fatty liver². 

Mineral Deficiency, Oxidative Stress, and Disturbed Glucolipid Metabolism 

Both group comparisons and multiple regression analyses suggested that fatty liver occurrence is closely associated with deficiencies in Ca, K, Mg, Mo, B, Se, Sr, and Mn. Consistent with earlier reports, cows with fatty liver exhibited elevated serum NEFA and γ-glutamyl transferase (GGT) levels and reduced blood glucose concentrations, reflecting impaired glucolipid metabolism and increased oxidative stress². 

Abnormal mineral metabolism has been linked to disorders of lipid and glucose metabolism in both humans and animals^2,13. Although the precise molecular role of Mn in fatty liver remains unclear, cohort studies have suggested that higher blood Mn concentrations may exert a protective effect against fatty liver development ^14,15. Additionally, increased triglyceride concentrations have been associated with reduced blood Ca and Mg levels. Supplementation with B and Mo has been shown to reduce hepatic fat accumulation and lower fatty liver risk². 

Feed intake during the transition period is a major determinant of NEB. Blood Ca and K concentrations influence dry matter intake, and appropriate supplementation of these minerals can alleviate the severity of NEB in dairy cows. Although a uniform conclusion regarding mineral–fatty liver relationships has not been established, accumulating evidence suggests that alterations in macroelement and microelement status contribute to disease development². 

Mitochondrial Dysfunction and the Role of Minerals 

Following parturition, fatty acid concentrations rise sharply in both serum and liver tissues to meet energy demands. However, excessive fatty acids exert lipotoxic effects on hepatocytes. Reduction of fatty acid–induced hepatic lipotoxicity depends on improved mitochondrial function, decreased reactive oxygen species (ROS) production, and enhanced fatty acid oxidation². 

Macroelements and microelements are fundamental to mitochondrial activity and lipid metabolism. Deficiencies can result in mitochondrial dysfunction and oxidative stress, both of which have been demonstrated in cows with fatty liver. Experimental data from mice indicate that mineral-rich deep seawater containing Mg, Ca, and K enhances antioxidant capacity and inhibits fatty acid biosynthesis, showing strong preventive effects against fatty liver². 

In dairy cows, mineral supplementation has been shown to improve antioxidant status. Specifically, Se and B supplementation increases antioxidant enzyme activity and reduces the incidence of fatty liver and other metabolic disorders. Mn and Cu are integral components of superoxide dismutase (MnSOD and Cu/Zn SOD), and adequate supplementation helps reduce mitochondrial oxidative stress and improve ROS scavenging capacity. Copper also promotes mitochondrial biogenesis and fatty acid oxidation through regulation of AMP-activated protein kinase activity². 

In the present findings, elevated serum Cu levels in fatty liver cows may reflect increased mobilization of Cu in response to oxidative stress. Cu metabolism is strongly influenced by Mo status, and Mo deficiency can enhance Cu absorption, leading to elevated serum Cu concentrations. Furthermore, fatty acid overload and intrahepatic lipid accumulation can induce endoplasmic reticulum stress, which has been associated with reduced Sr levels, consistent with the Sr deficiency observed in fatty liver cows². 

Clinical Implications and Conclusions 

Fatty liver disease in periparturient dairy cows is closely linked to oxidative stress, impaired lipid metabolism, and disrupted mineral homeostasis. Current evidence suggests that deficiencies in Ca, K, Mg, Se, B, Mo, Mn, and Sr may contribute to hepatic lipid accumulation and disease progression. 

From a clinical and herd-management perspective, routine monitoring of serum macroelements and microelements during the transition period, combined with targeted mineral supplementation and nutritional management, may offer a practical strategy for reducing the incidence and severity of fatty liver in dairy cows. 

References 

1. Giannuzzi D, Tessari R, Pegolo S, Fiore E, Gianesella M, Trevisi E, et al. Associations between ultrasound measurements and hematochemical parameters for the assessment of liver metabolic status in Holstein-Friesian cows. Sci Rep. 2021;11:16314. https://doi.org/10.1038/s41598-021-95538-x. 

2. Zhang KX, Li K, Li ZH, Liu XC, Li MM, Jiang S, Fan RF, Yan ZG. Serum macroelements and microelements levels in periparturient dairy cows in relation to fatty liver diseases. BMC veterinary research. 2024 Jul 6;20(1):295. https://doi.org/10.1186/s12917-024-04121-9 

3. Fang Z, Liu G, Zhu M, Wang S, Jiang Q, Loor JJ, et al. Low abundance of mitophagy markers is associated with reactive oxygen species overproduction in cows with fatty liver and causes reactive oxygen species overproduction and lipid accumulation in calf hepatocytes. J Dairy Sci. 2022;105:7829–41. https://doi.org/10.3168/jds.2021-21774. 

4. Dong J, Loor JJ, Zuo R, Chen X, Liang Y, Wang Y, et al. Low abundance of mitofusin 2 in dairy cows with moderate fatty liver is associated with alterations in hepatic lipid metabolism. J Dairy Sci. 2019;102:7536–47. https://doi.org/10.3168/jds.2019-16544. 

5. Shen Y, Chen L, Yang W, Wang Z. Exploration of serum sensitive biomarkers of fatty liver in dairy cows. Sci Rep. 2018;8:13574. https://doi.org/10.1038/s41598-018-31845-0. 

6. Zhang C, Shao Q, Liu M, Wang X, Loor JJ, Jiang Q, et al. Liver fibrosis is a common pathological change in the liver of dairy cows with fatty liver. J Dairy Sci. 2023;106:2700–15. https://doi.org/10.3168/jds.2022-22021. 

7. Yasui T, Ehrhardt RM, Bowman GR, Vazquez-Anon M, Richards JD, Atwell CA, et al. Effects of trace mineral amount and source on aspects of oxidative metabolism and responses to intramammary lipopolysaccharide challenge in midlactation dairy cows. Animal. 2019;13:1000–8. https://doi.org/10.1017/S1751731118002525. 

8. Leno BM, LaCount SE, Ryan CM, Briggs D, Crombie M, Overton TR. The effect of source of supplemental dietary calcium and magnesium in the peripartum period, and level of dietary magnesium postpartum, on mineral status, performance, and energy metabolites in multiparous Holstein cows. J Dairy Sci. 2017;100:7183–97. https://doi.org/10.3168/jds.2017-12773. 

9. Goff JP, Hohman A, Timms LL. Effect of subclinical and clinical hypocalcemia and dietary cation-anion difference on rumination activity in periparturient dairy cows. J Dairy Sci. 2020;103:2591–601. https://doi.org/10.3168/jds.2019-17581. 

10. Somagond YM, Alhussien MN, Dang AK. Repeated injection of multivitamins and multiminerals during the transition period enhances immune response by suppressing inflammation and oxidative stress in cows and their calves. Front Immunol. 2023;14:1059956. https://doi.org/10.3389/fimmu.2023.1059956. 

11. Basoglu A, Baspinar N, Tenori L, Vignoli A, Gulersoy E. Effects of Boron Supplementation on Peripartum Dairy Cows’ Health. Biol Trace Elem Res. 2017;179:218–25. https://doi.org/10.1007/s12011-017-0971-9. 

12. Xiao J, Khan MZ, Ma Y, Alugongo GM, Ma J, Chen T, et al. The Antioxidant Properties of Selenium and Vitamin E; Their Role in Periparturient Dairy Cattle Health Regulation. Antioxidants (Basel). 2021;10. https://doi.org/10.3390/antiox10101555. 

13. Steinbrenner H, Duntas LH, Rayman MP. The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities. Redox Biol. 2022;50: 102236. https://doi.org/10.1016/j.redox.2022.102236. 

14. Zhang D, Wu S, Lan Y, Chen S, Wang Y, Sun Y, et al. Blood manganese and nonalcoholic fatty liver disease: A cohort-based case-control study. Chemosphere. 2022;287: 132316. https://doi.org/10.1016/j.chemosphere.2021.132316. 

15. Nasr P, Ignatova S, Lundberg P, Kechagias S, Ekstedt M. Low hepatic manganese concentrations in patients with hepatic steatosis - A cohort study of copper, iron and manganese in liver biopsies. J Trace Elem Med Biol. 2021;67: 126772. https://doi.org/10.1016/j.jtemb.2021.126772.