Changes of serum macro and trace element in hyperketonemic goats

[Alterações dos macro e oligoelementos séricos em cabras hipercetonémicas]

ABSTRACT

In this trial, changes in macro and trace element concentrations and the relationships between these changes and glucose (Glu), β-hydroxybutyrate (βHB) and non-esterified fatty acid (NEFA) parameters were evaluated in hyperketonemic goats. Goat blood serum submitted to the laboratory for routine metabolic profile test were used as the study material. Serum with βHB concentrations >0.8mmol/L constituted the hyperketonemia group and those with concentrations <0.8mmol/L constituted the control group. Trace element concentrations of serum samples were measured using inductively coupled plasma mass spectrometry (ICP-MS). Hyperketonemia group goats had significantly higher levels of βHB, NEFA and aspartate transaminase (AST) and lower levels of Glu, triglyceride (TG) and alkaline phosphatase (ALP) compared to control group goats (p range: 0.05-0.001). Serum calcium (Ca), magnesium (Mg), copper (Cu), zinc (Zn), nickel (Ni) and chromium (Cr) levels were lower, and cobalt (Co) levels were higher in the hyperketonemic group (p<0.05). In addition, some elements had significant correlations with βHB, NEFA and Glu, the main metabolic markers of ketosis (p<0.05). The results of this study showed that hyperketonemia induced significant changes in blood element hemostasis in goats and this process may be closely related to energy metabolism.

Keywords:
elements; hyperketonemia; metabolic energy

RESUMO

Neste ensaio, foram avaliadas as alterações nas concentrações de macro e oligoelementos e as relações entre estas alterações e os parâmetros de glicose (Glu), β-hidroxibutirato (βHB) e ácidos gordos não esterificados (NEFA) em cabras hipercetonémicas. Foram utilizados como material de estudo soros de sangue de cabra enviados para o laboratório para o teste de rotina do perfil metabólico. Os soros com concentrações de βHB > 0,8 mmol/L constituíram o grupo de hipercetonemia e os soros com concentrações < 0,8 mmol/L constituíram o grupo de controlo. As concentrações de oligoelementos nas amostras de soro foram medidas por espetrometria de massa com plasma indutivamente acoplado (ICP-MS). Os caprinos do grupo de hipercetonemia apresentaram níveis significativamente mais elevados de βHB, NEFA e aspartato transaminase (AST) e níveis mais baixos de Glu, triglicéridos (TG) e fosfatase alcalina (ALP) em comparação com os caprinos do grupo de controlo (intervalo de p: 0,05-0,001). Os níveis séricos de cálcio (Ca), magnésio (Mg), cobre (Cu), zinco (Zn), níquel (Ni) e crómio (Cr) foram inferiores e os níveis de cobalto (Co) foram superiores no grupo hipercetonémico (p<0,05). Para além disso, alguns elementos apresentaram correlações significativas com βHB, NEFA e Glu, os principais marcadores metabólicos da cetose (p<0,05). Os resultados deste estudo mostraram que a hipercetonemia induziu alterações significativas na hemostasia dos elementos sanguíneos em caprinos e este processo pode estar intimamente relacionado com o metabolismo energético.

Palavras-chave:
elementos; hipercetonemia; energia metabólica

INTRODUCTION

Hyperketonemia is a metabolic disorder characterized by elevated ketone bodies in the blood, which is quite common in ruminants (Pichler et al., 2014). High ketone levels in the blood bring about several clinical problems such as lethargy, incoordination, tremors, loss of weight, a depression in productivity, and even death (Souza et al., 2020; Marutsova et al., 2024). It is commonly observed in periods of transition, when the intake of feed by the animal is not sufficient to maintain its energy requirement. It occurs as a result of negative energy balance (NEB). This is primarily caused by insufficient dry matter intake, especially in ruminants under high lactation demands or stressful conditions. In response, ruminants initiate gluconeogenesis to produce glucose from non-carbohydrate substances. This results in increased and then accumulated ketone bodies during metabolism (Sordillo and Raphael, 2013; Karimi et al., 2015; Nayak et al., 2021). The resultant disease caused hyperketonemia is categorized into subclinical or clinical ketosis depending on the blood levels of ketone bodies β-hydroxybutyrate (βHB) and presence of clinical signs among ruminants (Pichler et al., 2014; Kozat and Yüksek, 2017; Kivrak et al., 2023).

Hyperketonemia is characterized by an elevation of acetone, acetoacetate, and the ketone bodies called βHB in the blood (Davies, 2007; Pichler et al., 2014; Kozat and Yüksek, 2017; Marutsova et al., 2024). Of all these substances, the measurement of serum levels of βHB is considered the most reliable diagnostic for hyperketonemia (Puppel et al., 2019; Sahar et al., 2020; Marutsova et al., 2024). The level of βHB is usually colourmetrically or enzymatically determined in veterinary practice and has been one of the most used indicators for metabolic status assessment of high-yielding dairy animals (Chapinal et al., 2011). In ruminants, high βHB concentration is the clearest indicator of the presence of subclinical (usually from 0.8 to 1.6 mmol/L) or clinical ketosis (usually >1.6 mmol/L) (McArt et al., 2013; Li et al., 2021). Early detection and monitoring of blood βHB levels are important for effective treatment and prevention, for cow with ketosis, goat and sheep with pregnancy toxemia. (Ghanem et al., 2017).

Sheep and goats with multiple pregnancies struggle to meet high energy demands, making them dependent on the gluconeogenesis pathway. Therefore, small ruminants are highly susceptible to ketosis (Campbell et al., 2015; Simpson et al., 2019; Nayak et al., 2021). Besides, poor rearing conditions that raise stress, including feed restriction, sudden dietary changes, and changes in the environment, are known to contribute to susceptibility to ketosis in small ruminants by disrupting energy balance (Jeffrey and Higgins, 1992; Junkuszew et al., 2020).

Minerals and trace elements are inorganic structures that participate in the structure of enzymes necessary for all physiological reactions such as reproduction, lactation and growth (Yatoo et al., 2013; Uslu et al., 2017; Singh et al., 2021). In earlier studies, a deficiency of certain macro and trace elements has been associated with ketosis in ruminants (Karimi et al., 2015; Kozat and Yüksek, 2017). Macrominerals Ca, Mg and phosphorus P have important roles in glucose and energy metabolism, and it is known that deficiency of these minerals increases the risk of ketosis (Goff, 2006). Trace elements like Cu, selenium (Se), and Zn are important inorganic substances involved in various physiological processes within metabolism. Imbalances in blood and tissue concentrations of these essential trace elements have been reported to have negative effects on the health of animals (Stewart et al., 2018; Singh et al., 2019; Nayak et al., 2021). Cu trace element has important roles in energy metabolism and antioxidant defense (Saylor and Leach, 1980). Therefore, it is one of the most important trace elements associated with hyperketonemia in ruminants and several studies have reported that decreases in blood Cu levels increase susceptibility to ketosis in ruminants (Maalouf et al., 2007; Sousa et al., 2012). The trace element Se is essential for the regulation of the antioxidant system, thyroid gland and energy metabolism. Since there are studies showing that Se deficiency in dairy cows increases susceptibility to ketosis (Karimi et al., 2015; Kozat and Yüksek, 2017; Jin et al., 2023), it is likely that a similar situation exists in small ruminants. In addition, in studies on the metabolic functions of other essential trace elements Zn, manganese (Mn) and Co, it is known that Zn plays a critical role in insulin signalization and carbohydrate metabolism, while Mn and Co play critical roles in energy production and red blood cell production, respectively (Zhang et al., 2010; Karimi et al., 2015). Understanding the changes in elemental homeostasis caused by hyperketonemia in ruminants is important for elucidating the pathophysiology of ketosis. In this study, we aimed to determine the macro and trace element changes between hyperketonemic and healthy goats and to investigate the relationship between these changes and energy profile parameters.

MATERIALS AND METHODS

In this study, goat blood serum that came to Bornova Veterinary Control Institute Directorate Biochemistry laboratory for routine metabolic profile tests were used. The goats were of various breeds, with different pregnancy statuses (pregnant or non-pregnant), and ages ranging from (2-6). In the metabolic profile test, serum with βHB (beta-hydroxybutyrate) concentration <0.8 mmol/L constituted the control group and serum with βHB (beta-hydroxybutyrate) concentration >0.8 mmol/L constituted the hyperketonemia group (Türk and Keleş 2024). Serum samples received for metabolic profile were accepted to the laboratory after examination for quantity, hemolysis and lipemia and analyzed on the same day. Serum separated for trace element determination were stored at -20°C until analysis.

For Cu, Zn, Se, Mn, Co, Ni, Cr, arsenic (As), cadmium (Cd) and lead (Pb) analysis, 2 ml of serum samples were digested in a microwave digestion unit (Berghof, Eningen, Germany) by adding 5 ml of 65% nitric acid (Merck Suprapur® 65% HNO3 Darmstadt-Germany) and diluted with ultrapure water. Trace element concentrations in the solutions obtained from this process were determined using ICP-MS (7700 series; Agilent Technologies, Tokyo, Japan).

Levels of βHB and NEFA in serum samples were determined using the Biosystems A15 (Spain) autoanalyzer device, while levels of Glu, TG, total cholesterol (T-Chol), AST, alanine transaminase (ALT), ALP, γ-glutamyl transferase (GGT), lactate dehydrogenase (LDH), total proteins (TP), albumin (ALB), urea (UR), Ca, Mg, and inorganic phosphate (P) were determined using commercial test kits on the Mindray BS-240 (China) autoanalyzer through spectrophotometric methods.

The data obtained were analyzed using SPSS 26.0 software. The normality of the data was tested using the Shapiro-Wilk test. Differences in measured parameters between ketotic and control groups were determined using Student's t-test. The Pearson test was used to calculate the correlation coefficients between the hyperketonemic group findings. The significance of the differences between the groups was accepted as p<0.05.

RESULTS

As a result of the metabolic profile test, βHB, NEFA and AST (p<0.05) levels were significantly higher (p<0.001), while Glu, TG and ALP levels were lower (p<0.05) in the hyperketonemia group compared to the control group. No changes were observed in other metabolic profile parameters (p>0.05) (Table 1).

Table 1
Comparison of metabolic profile parameters among control, and hyperketonemia in goat.

Metabolic Profiles
Measurand	Control (n=32)	Hyperketonemia (n=19)	p-value
βHB (mmol/L)	0.5±0.1	3.0±2.9	p<0.001
NEFA (mmol/L)	0.2±0.1	0.6±0.2	p<0.001
Glu (mg/dL)	61.1±17.8	44.8±12.5	p<0.05
TG (mg/dL)	27.5±15.0	16.8±11.8	p<0.05
T-Chol (mg/dL)	77.1±21.8	75.2±14.4	p>0.05
AST (U/L)	85.1±31.7	108.4±35.9	p<0.05
ALT (U/L)	19.3±7.3	16.1±2.4	p>0.05
ALP (U/L)	88.4±30.8	58.6±62.2	p<0.05
GGT (U/L)	52.6±12.4	42.7±5.4	p>0.05
LDH (U/L)	219.2±136.4	263.8±82.1	p>0.05
TP (g/L)	70.5±14.5	64.7±8.3	p>0.05
ALB (U/L)	26.6±4.7	25.1±2.8	p>0.05
UR (mg/dL)	19.1±5.9	18.2±3.9	p>0.05

• βHB-β-hydroxybutyrate, NEFA- non-esterified fatty acid, ALT - Alanine Transaminase, AST - Aspartate Transaminase, ALP - Alkaline Phosphatase, GGT - Gamma-Glutamyl Transferase, LDH - Lactate Dehydrogenase, GLU - Glucose, TG - Triglycerides, TC - Total Cholesterol, TP - Total Proteins, ALB - Albumin, Urea - Urea

In the elemental analysis of goat serum samples, Ca, Mg, Cu, Zn, Co, Ni and Cr levels were lower in the hyperketonemia group compared to the control group, but Co levels were higher (p<0.05). However, no significant difference was observed in Mn, Se, Ar, Cd and Pb levels between the two groups (p>0.05) (Table 2). In addition, significant correlations were observed between elements and Glu, NEFA and βHB parameters which are important markers of ketosis in hyperketonemic goats (Table 3).

Table 2
Comparison of trace and macro element profile parameters among control, and hyperketonemia in goat

Elements
Measurand	Control (n=32)	Hyperketonemia (n=19)	p-value
Cu (ppb)	927.8±281.7	759.2±241.7	p<0.05
Zn (ppb)	944.9±337.1	707.7±214.8	p<0.05
Se (ppb)	73.1±22.0	68.6±11.1	p>0.05
Mn (ppb)	9.7±2.6	9.9±1.9	p>0.05
Co (ppb)	12.1±28.8	19.7±13.5	p<0.05
Ni (ppb)	25.7±16.9	15.6±6.72	p<0.05
Cr (ppb)	21.5±19,7	14.6±10.0	p<0.05
As (ppb)	1.12±0.33	1.37±0.54	p>0.05
Cd (ppb)	ND	ND	p>0.05
Pb (ppb)	ND	ND	p>0.05
Ca (mg/dL)	9.9±1.7	8.1±0.6	p<0.05
Mg (mg/dL)	2.9±0.5	2.1±0.3	p<0.05
P (mg/dL)	5.3±2.0	5.3±1.4	p>0.05

• Cu - Copper, Zn - Zinc, Se - Selenium, Mn - Manganese, Co - Cobalt, Ni - Nickel, Cr - Chromium, As - Arsenic, Cd - Cadmium, Pb - Lead, Ca - Calcium, Mg - Magnesium, P - Phosphorus

Table 3
Correlation of serum Glu, NEFA and βHB with macro and trace elements in hyperketonemic goats

Elements r-value	Glu	NEFA	βHB
Cu	.311	-.613*	-.646*
Zn	.499*	-.354	-.573*
Se	-.269	-.049	.053
Mn	.244	-.126	-.111
Co	-.577*	-.126	.413
Ni	.212	-.536*	-.479
Cr	-.238	-.121	.189
As	-.073	.102	.145
Ca	.217	-.671*	-.509*
Mg	.157	-.475	.463
P	.024	.202	.241

• ^*
  Correlation is significant at the P<0.05 level.

DISCUSSION

In ruminants entering NEB due to their inability to meet their high energy needs, mobilization of triglycerides from adipose tissue to compensate for the energy deficit and consequently blood NEFA concentration increases (McArt et al., 2013; Tessari et al., 2020). As a result of partial oxidation of NEFAs that cannot be sufficiently esterified in the liver, ketone body concentrations increase in the blood. The most practical determination of ketone level in ruminants is done by measuring serum ΒHB levels (Pichler et al., 2014; Mann et al., 2016). Animals with serum ΒHB levels higher than 0.8 mmol/L are considered hyperketonemic (Mann et al., 2016; Ghanem et al., 2017; Puppel et al., 2019; Lisuzzo et al., 2022). Therefore, in the present study, goat serum with βHB levels >0.8 mmol/L constituted the hyperketonemic group (n=19) and those with lower levels constituted the control group (n=32).

The high (p<0.001) NEFA (normal range: < 0.4 mmol/L) and βHB concentrations we measured in the hyperketonemic goat group are the most important differential diagnosis of ketosis in ruminants (Puppel et al., 2019) and are consistent with the findings of similar studies in small ruminants (Lisuzzo et al., 2022; Dinçer and Tümer, 2023). At the same time, higher NEFA concentrations (p<0.001) compared to the control group indicate that hyperketonemia group goats enter NEB and there is an increase in triglyceride mobilization in these goats (McArt et al., 2013; Marutsova et al., 2024). High NEFA levels mostly result in elevated βHB levels as in our study. This is because increased NEFAs in the blood cannot be completely esterified due to oxalacetate deficiency in the liver and are converted into ketone bodies (acetone, acetoacetate and βHB). This is in parallel with the present study in the literature (Scalia et al., 2006; McArt et al., 2013; Lisuzzo et al., 2022; Mustafa et al., 2023). In contrast, the hyperketonemic group had significantly lower Glu and TG concentrations (p<0.05). This low level is consistent with the results of studies reporting that impaired carbohydrate and lipid metabolism due to fat accumulation in hepatocytes of ruminants entering NEB (Lima et al., 2012; Mustafa et al., 2023; Aydoğdu et al., 2023; Marutsova et al., 2024). Also, higher AST and lower ALP concentrations compared to the control group are another indication of liver dysfunction in hyperketonemia group goats due to lipid deposits in hepatocytes (Davies, 2007; Ghanem et al., 2017; Simpson et al., 2019).

In the present study, we measured lower Ca and Mg macro element levels in the hyperketonemic group (p<0.05). This result is in line with previous studies reporting that hyperketonemia status impairs Ca and Mg homeostasis in ruminants and affects the clinical course of ketosis (McCoy et al., 2002; DeGaris and Lean, 2008; Sahar et al., 2020). This has been associated with many factors in the literature, such as inadequate nutrient or mineral intake due to hyperketonemia and impairments in bone resorption mechanisms (Ghanem et al., 2017; Marutsova et al., 2024). At the same time, in this study, the negative correlation between Ca and NEFA (r=-0.671) and βHB (r=-0.509) concentration changes in goats in the hyperketonemia group supports this relationship. Because NEB in ruminants is known to disrupt many physiological processes and make ruminants more sensitive to metabolic disorders (McArt et al., 2013; Dervishi et al., 2020).

The results of trace element analysis showed a significant decrease in serum Cu, Zn, Ni and Cr trace element levels and an increase in Co levels in hyperketonemic goats. However, there was no significant change in Mn, Se, Ar, Cd and Pb levels. The lower Cu and Zn levels in the present study compared to the control group are similar to the results of previous studies in small ruminants characterized by hyperketonemia (Saylor and Leach, 1980; Sousa et al., 2012; Stewart et al., 2018). Cu trace element is known to have many roles such as energy metabolism and antioxidant defense mechanism (Celi et al., 2008; Ghanem et al., 2017). In addition, Cu acts as a cofactor for key enzymes of carbohydrate and lipid metabolism such as cytochrome-C oxidase and superoxide dismutase. Therefore, a decrease in Cu levels impairs the activation of these enzymes, which prevents ruminants from utilizing glucose efficiently and causes them to turn to alternative energy sources such as ketone bodies as an energy source (Manto, 2014; Karimi et al., 2015; Ghanem et al., 2017). Similarly, Mbassa and Poulsen (1993) reported that deficiency in Cu levels increased the risk of ketosis in dairy cows. Therefore, the low Cu levels in the present study may have contributed to NEB and high ketone levels in the hyperketonemic group of goats. At the same time, the negative correlation of low Cu levels with NEFA (r=-0.613) and βHB (r=-0.646) in this group proves this speculation. It is known in the literature that Zn trace element is involved in many processes such as insulin signaling, carbohydrate and lipid metabolism in ruminants (Zhang et al., 2010; Karimi et al., 2015). There are studies reporting that Zn deficiency in ruminants impairs glucose hemostasis and increases susceptibility to ketosis (Zhang et al., 2010; Ghanem et al., 2017). The fact that Zn levels in the hyperketonemic group, which we measured at lower levels, were positively correlated with Glu (r=0.499) and negatively correlated with βHB (r=-0.573) could be a proof the studies reporting that this element has an important role in the pathogenesis of ketosis.

Studies conducted in non-ruminant species have reported that Cr plays a role in glucose and lipid metabolism (Khan and Awan, 2014; Sijko et al., 2021). The lower serum Cr levels in the present study compared to the control group may be due to the involvement of Cr in a protective mechanism against hyperketonemia-induced metabolic disorders. Also, Ni results, which were both lower than the control group and negatively correlated with NEFA (r=-0.536) levels in our study, were surprising. In the literature, we did not find any studies on the relationship between these two trace elements and hyperketonemia in ruminants. However, our Cr and Ni element results in the hyperketonemic group led us to think that more research should be done on the possible relationship of these elements with energy balance in ruminants. In addition, serum Co levels were higher in the hyperketonemia group compared to the control group (p<0.05). Co is an essential component of vitamin B12 (cobalamin), which is required for fatty acid metabolism and gluconeogenesis (Yatoo et al., 2013; Scharf et al., 2014; Dinçer and Tümer, 2023). We suggest that the increase in serum Co levels in hyperketonemic goats in this study may be related to impaired liver function due to hyperketonemia or increased mobilization of body vitamin and mineral stores to meet metabolic demands. At the same time, the negative correlation between Co and Glu (r=-0.577) supported this idea. Kozat and Yüksek (2017) reported that Se levels decreased in dairy cattle with ketosis. There are also many studies reporting that this element plays role in thyroid function and energy metabolism (Drutel et al., 2013; Jin et al., 2023; Rezaei et al., 2019). However, in the present study, the levels of Mn, Se, As, Cd and Pb measured in goat serum did not show a significant difference between the two groups. This result suggested that the relationship between these elements and energy hemostasis and ketosis in goats may be limited.

CONCLUSION

In conclusion, this study revealed significant alterations in various serum macro and trace element levels in hyperketonemic goats compared to healthy goats. The elevated βHB and NEFA levels, along with decreased glucose and triglyceride levels, confirmed the metabolic alterations indicative of ketosis. Additionally, the lower levels of Cu, Zn, Ca, and Mg, and the higher levels of Co in hyperketonemic goats highlight that imbalances in element homeostasis may contribute to the pathogenesis of ketosis in ruminants, while also showing a close relationship with the energy profile. Therefore, monitoring serum element levels may assist in the early diagnosis and management of hyperketonemia. However, further research is needed in this area.

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Publication Dates

• Publication in this collection
  14 July 2025
• Date of issue
  Jul-Aug 2025

History

• Received
  06 Nov 2024
• Accepted
  07 Jan 2025