When NEFAs from adipose tissue are mobilized beyond the liver's capacity for lipid oxidation and secretion, the result is the accumulation of TAG in the liver (30). Due to the increased sensitivity of adipose tissue to lipolytic chemicals and decreased sensitivity to lipogenic compounds, cows with fatty livers have larger adipose stores and mobilize more TAG, which raises plasma NEFAs concentrations. Additionally, as demonstrated by decreased plasma apolipoprotein and lipid concentrations and decreased serum lecithin-cholesterol acyltransferase (LCAT) activity, cows with fatty livers have decreased fatty acid oxidation, hepatic apolipoprotein synthesis, and lipid secretion (31). Cows with fatty livers also have challenges with glucose metabolism in addition to problems with lipid metabolism. According to De Koster and Opsomer (32), cows with fatty livers are either hypoinsulinemic hypoglycemic or hyperinsulinemic-hyperglycemic because of decreased hepatic gluconeogenesis or decreased insulin and glucagon secretion, which indicates insulin resistance. Furthermore, there is a drop in plasma amino acids. In conclusion, cows with fatty livers have less glucose, amino acids, and lipids available for peripheral tissues. Fatty liver can form within 24 h after an animal stops eating. This usually occurs around the time of calving. Until the cow achieves a positive energy balance, which may take more than 10 weeks after calving, especially if the fatty liver is severe, the amount of fat in the liver does not decrease once it has been deposited. The risk of fatty liver disease is significantly higher in overweight cows (Body Condition Score > 3.5). In the case of energy deficiency, stored fat is released in the form of free fatty acids, which can be used as a source of energy or oxidized to triglycerides in the liver, where they are accumulated or transported as very-low-density lipoproteins (VLDL). Due to the limited possibilities of synthesis of triglycerides and their transport as VLDL, a large amount of released fat results in fatty liver as fat accumulates in liver cells. Serum fatty acid levels increase from about 2 weeks before calving, peaking up to 2 days after calving, and return to normal levels in the 3^rd week of lactation (33). A fatty liver is associated with a negative energy balance, which is normal during the first few weeks after calving. Fatty liver occurs when metabolism cannot be adjusted to meet the requirements of the body. Under normal physiological conditions, the level of fat in the liver rises a few weeks before calving to approximately 20% in the 1^st week after calving, and slowly decreases to < 5% by week 26 post-partum. However, the difference can range from almost 0% to 70% in the 1^st week after calving. Fat mobilization begins 2–3 weeks before calving and is most likely initiated by hormonal changes caused by parturition, not by energy deficiency. Liver changes are functional, reversible, and dependent on metabolic requirements during late pregnancy and early lactation. In cows with experimentally induced fatty livers, the intensity of liver glycogenesis during the perinatal period is higher than that in cows without steatosis. Low glucagon content leads to low blood glucose concentrations, low insulin levels, and high fatty acid mobilization, causing severe fatty liver disease. Figure 2 illustrates the etiology of fat cow syndrome.

The syndrome has no unique clinical signs; however, a distinctive indication is an overly fat cow. Other disease characteristics include the presence of inappetence, depression, and low milk production, excessive loss of body condition, progressive debilitation, and general body weakness. However, there is a severe incidence of milk fever, ketosis, clinical mastitis, and retained fetal membranes. Blood test results that show elevated levels of NEFAs concentrations and increased ketones.

Blood and liver tissue samples obtained from cows following abdominal surgery, during a skin biopsy of the liver, or in the abattoir immediately after slaughter have been used to characterize the biochemical alterations linked to fatty liver disease. Depending on the fatty liver, different biochemical indicators are present. With a higher fat content in the liver, it's activity increases (27). Blood tests, particularly for liver enzyme levels, are necessary to evaluate the state of the liver. According to Gerspach and Ruetten (34), the activity of these enzymes increases when steatosis damages the liver cells. Decreases in blood glucose, total protein, albumin, globulin, cholesterol, triglycerides, and urea are caused by decreased enzyme production in the liver with a substantial fatty liver. Furthermore, the secretory capacity of the hepatocytes is diminished, which increases blood levels of bile acids, ammonia, and total bilirubin (35). According to Andrews et al. (29), there is a drop in leukocyte levels, glucose, cholesterol, albumin, magnesium, insulin, and free fatty acids and an increase in bilirubin and AST. In a study involving 59 cows, gamma-glutamyltransferase (GGT), (AST), succinate dehydrogenase (SDH), and total bilirubin levels were at least twice the normal range, indicating fatty liver in 50% of the cows and the need for treatment for secondary ketosis in 50% of them. To determine the fatty liver and triglyceride contents, a liver biopsy can be performed. This is the most accurate way to define this illness. In healthy cows, the percentage of triacylglycerols in the liver ranges between 10% and 15%. Biochemical or histological techniques can be used to determine the lipid content of liver tissue by biopsy. Both offer trustworthy results for liver fat content (28). The following categories are distinguished: normal liver or mild steatosis (0%−20% lipids), moderate fatty liver (20%−40%), and severe fatty liver (>40%) based on the level of degeneration and fat infiltration in the hepatocytes. Owing to damage to the cell membrane, fatty liver causes hepatocytes to degenerate, releasing cytoplasmic enzymes (AST, GGT, and LDH) and increasing their total activity in the bloodstream (35).

There is practically no satisfactory outcome when treating cows with clinically severe fatty liver syndrome. Several treatment plans have been suggested, as is the case for the majority of illnesses for which there is no proven cure. Treatment during a crisis, treating the diseased liver, and preventing further occurrences will be the three areas of therapeutic approach that will be discussed.

For disease prevention, potential risk factors of the disease must be reduced or eliminated. Early diagnosis and treatment that affects voluntary feed intake in late pregnancy and shortly after calving are essential for reducing fat mobilization to cover the energy requirements during periods of negative energy balance and to maintain or increase liver glycogenesis. To prevent fatty liver, it is imperative to promptly address conditions such as ketosis, abomasum displacement, retained placenta, mastitis, hypocalcemia, and down cow syndrome. A restricted diet throughout the dry season is the primary component of prevention to guarantee a suitable body condition for calving, that is, BCS of 2.5–3.0 Preventing the breakdown of fat and fatty liver would involve ensuring that cows are calving at the appropriate body condition. A calf's optimal body condition score is in the range of 2.5 to 3.0. At this point, cows should be dried off and their weight should be maintained during the dry season. Reducing stress is crucial to avoid fatty liver disease. Avoiding abrupt changes in surroundings is recommended. For instance, alterations to diet, housing, temperature, and herd mates may result in a decrease in the amount of feed consumed and initiate catecholamine-mediated increases in the mobilization of fat.

Clinical ketosis and subclinical ketosis are metabolic disorders primarily caused by NEB in dairy cows during early lactation. This occurs when the energy demands for milk production surpass the energy intake from the diet, leading to the mobilization of body fat reserves. The liver metabolizes these fats into ketone bodies, such as BHBA, acetoacetate, and acetone, which accumulate in the blood, urine, and milk. Subclinical ketosis is characterized by elevated ketone levels (BHBA 1.2–3.0 mmol/L) without overt clinical signs, while clinical ketosis presents with visible symptoms such as reduced milk yield, weight loss, and neurological abnormalities, alongside higher ketone concentrations (BHBA > 3.0 mmol/L). Subclinical ketosis in cows involves ketone body accumulation with no obvious symptoms. Blood ketone levels rise, the liver faces metabolic stress as fatty acid processing is disrupted, and there are subtle performance impacts. In clinical ketosis, hypoglycemia, severe liver impairment, and increased depression occur, with body defenses against negative energy balance severely compromised. Key risk factors include poor dry period management, over conditioning, inadequate transition diets, and stressors such as overcrowding or concurrent diseases like mastitis or metritis. Genetic predisposition may also influence susceptibility. Effective prevention focuses on optimizing nutrition, monitoring ketone levels, and ensuring proper herd management during the transition period (47, 48).

During early lactation, the amount of energy required for the maintenance of body tissues and milk production exceeds the amount of energy obtained from dietary sources. Therefore, cows must utilize body fat as an energy source. There is a limit to the quantity of fatty acids that the liver tricarboxylic acid cycle can completely oxidize or export as very-low-density lipoproteins. When this threshold is crossed, acetyl-coenzyme A, which is not integrated into the tricarboxylic acid cycle, is transformed into acetoacetate and beta-hydroxybutyrate, and triglycerides build up inside hepatocytes, hindering their ability to operate. These ketone bodies are indicative of ketosis and may be observed in the blood, milk, and urine. They typically appear clinically between 10 days and 3 weeks after calving. Hypoglycemia is the outcome of poor gluconeogenesis. Cows experience increased depression, which lowers milk output and feed intake. The capacity of an over conditioned cow's liver to oxidize fatty acids is more constrained than that of a leaner animal (49). When the body's natural defenses against a negative energy balance are compromised, cows develop ketosis (50). While inadequate feedback control of non-esterified fatty acid release from adipose tissue is a likely contributing factor to ketosis, failure of hepatic gluconeogenesis to deliver sufficient glucose for lactation and body demands may be a cause of ketosis (50). After calving, all dairy cows typically undergo a phase of negative energy balance and fat mobilization; however, not all animals develop hyperketonemia, and even fewer develop clinical ketosis. Different animals respond differently to negative energy balance in their metabolism. Nevertheless, insufficient metabolic adaptability appears to be linked to the onset of ketosis, rather than the severity of low-energy status alone. Ketosis can develop during the early stages of lactation for various reasons. Early-lactating cows are more susceptible to ketosis if they have a high body condition score (greater fat storage) and significant fat mobilization around parturition (51–53). The likelihood of peripartum diseases causing cows to consume less feed raises the possibility of ketosis. For instance, there is a link between an increased risk of disease, lameness (54), and milk fever (55). Environmental variables contribute to the genesis of ketosis in addition to several “cow factors”. The increased demand for glucose during peak lactation or the initial stages of milk production in high-yielding animals restricts oxaloacetate availability for metabolic reactions. This leads to decreased tricarboxylic acid cycle activity, which in turn lowers the rate of acetyl-CoA catabolism and energy production. Increased breakdown of depot fats due to restricted energy production results in increased acetyl-CoA synthesis. Ketone body production is the target of extra acetyl-CoA. The blood ketone content increases, resulting in ketonemia, and ketone bodies are present in the urine, causing ketonuria due to the decreased ability of extra-hepatic tissues to catabolize acetyl CoA. The combined condition of ketonemia and ketonuria is known as ketosis. The composition and quality of animal feedstuff may play a role in the development of ketosis. Figure 3 shows the etiology of ketosis in cows.

Ketosis manifests in two distinct phases: the subclinical or latent phase, and the clinical phase characterized by apparent symptoms. Subclinical ketosis in dairy cows refers to the occurrence of ketone bodies in the bloodstream without any observable symptoms of ketosis (56). Subclinical ketosis, also known as the latent phase, is characterized by non-specific disruptions in metabolic balance. The symptoms of this disorder encompass imbalanced milk production, a propensity to experience weight loss despite a normal appetite and functioning rumen, as well as occasional cases of mild ketonuria. A cow exhibiting subclinical ketosis may not always display thinness, as shown in cases of fat cow syndrome. Milk production imbalance is defined as substantial daily fluctuations in milk amount without any discernible explanation (57). Subclinical ketosis is characterized by low blood sugar levels (hypoglycemia) and the presence of ketones in the blood (ketonemia) from a biochemical perspective (58). Subclinical ketosis remains latent until the level of ketones in the blood exceeds the level of glucose, and the level of urinary protein also changes (59). Subclinical ketosis is of great practical and economic relevance because of its hidden progression and large impact on production losses. The occurrence of subclinical ketosis in dairy cows during the early lactation period varies between 7.5% and 14%. Cows experiencing subclinical ketosis have a 4.9-fold increased likelihood of having metritis, a 6.1-fold increased likelihood of developing displaced abomasum, and a 1.98-fold increased likelihood of developing hoof diseases (60). The clinically manifested phase occurs when the level of ketones in the blood exceeds the level of glucose, however it may potentially occur sooner if hormonal control is ineffective. Initially, the clinical presentation is mainly characterized by non-specific symptoms of impaired energy balance and indigestion syndrome. As a result, early lactation leads to rapid weight loss, lower milk output, reduced fertility, increased veterinary expenses, and eventually a higher percentage of cows being culled. Body temperature can vary, ranging from normal to lowered, mostly as a result of diminished oxidative processes in the body. Bradycardia and bradypnea can manifest (61). The majority of animals display lethargy, experiences a decrease or fluctuation in appetite, and may demonstrate aberrant behavior. The normal functioning of the rumen is disrupted, resulting in either acidity or blockage. Animals have the ability to release a scent of acetone, particularly in their breath and milk, which also has a taste that is bitter. In instances of extreme severity, the entire herd may have an acetone odor (62, 63). These symptoms arise due to an elevation in ketone levels in the bloodstream, rumen contents, and urine. The content of ketones in the blood can increase by 5 to 10 times compared to the normal level, while in urine, it can rise by 10 to 100 times (56). If ketone bodies are detected in the urine on the 21^st day of the disease, and appropriate preventative measures and treatment protocols have been implemented prior to that, it is recommended to euthanize such a cow (64). In situations that are more severe and progressed, ketosis may be accompanied by symptoms of metabolic acidosis, dehydration, and central nervous system abnormalities. Acidosis occurs due to the buildup of acidic metabolic by-products and a decrease in alkaline reserves. Depletion of sodium ions results in loss of water from the body (45). Dehydration is characterized by an increase in the concentration of blood components and a relative increase in protein levels. The skin's elasticity is diminished, and the eyes appear to be sunken. Central nervous system symptoms occur as a result of decreased oxidative processes in the nervous system caused by a lack of carbohydrates, as well as the harmful effects of metabolic by-products, particularly acetoacetic acid. In acute cases, distinct signs of nervous system disorders manifest, including agitation, paralysis, abnormal sensations, and hyperesthesia. Animals engage in behaviors such as chewing without any food, grinding their teeth, making loud sounds, displaying a crazy expression, and having saliva dripping from their lips. Post-partum ketosis, a condition comparable to puerperal paresis, can develop after calving. The symptoms are identical to puerperal paresis, except that the pupillary reflex remains intact, and treatment with calcium is not beneficial (65). Animals in advanced stages experience a state of stupor, which eventually progresses into a coma. The prognosis and outcome of the illness are significantly influenced by symptoms emanating from the liver. According to Djoković et al. (66), moderate episodes of ketosis often do not exhibit clinical or biochemical indications of liver damage. Severe and advanced cases of liver disease, particularly if it is a long-term condition, may exhibit an enlarged liver that is somewhat sensitive to touch and may be detected by percussion and palpation. This is typically noticed in the area beyond the right final rib (67). From a histological perspective, the liver exhibits fatty degeneration, also known as steatosis. In more severe instances, cirrhosis may develop.

Subclinical cases of ketotic diseases may alone be identified through systematic tests of urine and milk to detect the presence of ketone bodies. Animals in a herd or flock are chosen for testing based on a clinical assessment and statistics on milk production. An imbalance in milking over the whole lactation period often suggests a disruption in metabolic equilibrium (68). The gold standard for diagnosing subclinical ketosis in the laboratory is by measuring the concentration of BHBA in the blood and doing a liver biopsy (69). Subclinical ketosis is diagnosed when the blood concentration of BHBA exceeds 0.85 mmol/L. Studies have demonstrated that around 15% of herds exhibit ketosis, with a threshold of 10% considered to be important (70). The blood content of BHBA rises after eating, and samples should be collected at intervals of 4 to 5 h following the initial meal. The sample should comprise 12 randomly selected cows from a population of 50 cows. If one or two samples provide positive results, showing high levels of BHBA, it means that the herd's condition is in a critical state. If two or more cows in a group of twelve test positive, the herd sample is classified as positive for ketosis (43). The blood (and maybe milk and urine) can be analyzed to assess the levels of acetoacetic acid (71). Subclinical ketosis is defined as having an acetoacetic acid concentration over 0.36 mmol/L, whereas clinically exhibited ketosis occurs when the concentration of acetoacetic acid surpasses 0.5 mmol/L (72). Acetoacetic acid is an unsuitable laboratory measure for detecting ketosis due to its inherent instability, leading to its fast decomposition into acetone and carbon dioxide (73). The ketone bodies in milk have a concentration that is around 50% less than the concentration in blood. On the contrary, the concentration of ketone bodies in urine is many times larger than that in blood (74). An elevation in the levels of ketone bodies in the bloodstream corresponds with a reduction in the concentration of blood glucose. The typical blood glucose concentration in cattle varies from 2.3 to 4.1 mmol/L. If the concentration falls below 2.3 mmol/L, the animal is diagnosed as ketosis (75). Another significant indicator is NEFA. The NEFAs threshold value in cows 2 to 14 days before to calving and 4 to 5 h after the first meal of the day is >0.4 mEq/L (76). Proper storage of samples is essential, requiring them to be kept at a low temperature or even frozen from the time of collection until they are delivered to the laboratory. The presence of ketone bodies in urine may be identified by utilizing sodium nitroprusside, which is the approved test according to Kumar (77). The presence of ketones in urine is detected by observing a color shift, which can range from pink (+) to pink/purple (++) or dark purple (+++), depending on the concentration of ketones. Currently, there are several efficient techniques available for promptly identifying ketones in milk and urine, often referred to as dipstick tests. These tests enable the direct detection of acetone and acetoacetic acid in milk and urine (69).

Ketosis in cows is a prevalent metabolic disorder that demands well-thought-out treatment strategies. The most common and effective treatment is oral administration of 250–400 g propylene glycol (drenched) every 24 h for 3 to 5 days. Extra treatment is advised in instances of hypoglycemia, such as vitamin B12 (1.25 mg, IM, every 24 h for 3 days) and bolus glucose treatment (500 mL of 50% dextrose solution, IV, as a single bolus) in neurologic patients. Restoring normoglycemia and lowering blood ketone body concentration are the goals of ketosis treatment. Another popular treatment is bolus glucose, which involves intravenous injection of 500 mL of 50% dextrose solution (78, 79). It is important to ensure that this solution is administered IV because it is highly hyperosmotic and causes severe tissue swelling and irritation if administered perivascularly. When type I ketosis (around peak lactation) occurs, bolus glucose therapy usually produces a quick, transient recovery. However, relapses are frequent and the benefits are typically fleeting. While dextrose administration is advised in cases of nervous ketosis, it may not be required or even beneficial in all cases of ketosis. As there is minimal evidence of benefits and some indications of risk, the administration of glucocorticoids is not advised. Propylene glycol functions as a precursor for glucose and treating ketosis with oral drenching (250–400 g [8–14 oz], PO, every 24 h for 3–5 days) is beneficial. Propylene glycol overdosing leads to CNS depression. In addition, oral propylene glycol drenching is supported when used in conjunction with vitamin B12 (1.25 mg, IM) for 3 days, especially in ketotic and hypoglycemic cows. Type II ketosis, which develops in the first 2 weeks post-partum, is often more resistant to treatment than type I ketosis, which develops closer to the peak of lactation. Frequently, a recurrent 5-day oral propylene glycol immersion regimen, frequently in conjunction with vitamin B12, appears to address these persistent ketosis issues (80). Although there is not much evidence to support this hypothesis, some studies have proposed that, in certain situations, a long-acting insulin preparation (150–200 U, IM, every 24 h for 5 days) would be helpful. Insulin should be administered in conjunction with glucose or a glucocorticoid to prevent hypoglycemia since it inhibits both adipose mobilization and ketogenesis. It is not authorized to use insulin in this manner.

Hypocalcemia or insufficient calcium in the blood serum is the cause of milk fever. At the end of the dry season, the metabolism of dairy cows quickly shifts from a resting phase to a high-performance phase. During the dry season, cows do not require as much Ca.

The need for calcium nearly doubles when lactation begins because colostrum synthesis requires a large amount of calcium (2.3 g/L). Typically, bones or food supplies calcium. Mobilization frequently fails to be initiated rapidly enough in elderly cows. Because there is not enough calcium from the feed and bones, the body takes what is needed from the muscles. This causes overstimulation of the nervous system and paralysis (Figure 4). Hypocalcemia first results in hyperexcitability of the neurological system, which usually leads to paresis and weaker contractions of the muscles (23). Cows of any age can develop parturient paresis, although high-producing dairy cows that start their third or later lactation are more likely to experience parturient paresis. Breeds, such as Guernsey and Jersey, have higher incidence rates.

Recumbency around the time of parturition and hyperexcitability that leads to flaccid paralysis are possible signs. The majority of parturient paresis occurrences occur within the first 3 days following parturition. Hypocalcemia not only causes parturient paresis but can also lead to metritis, abomasal displacement, retained fetal membranes, dystocia, and mastitis. There are three distinct phases of parturient paresis.

Stage 1 cows exhibit clinical signs of hypersensitivity and excitability, although they remain mobile and upright. They may show signs of head swaying and ear twitching, as well as minor ataxia and tiny tremors over the flanks and triceps. Cows may snort, look agitated, or shuffle their feet. Cows will probably move on to a more severe stage 2 if calcium treatment is not initiated during stage 1.

Cows with stage 2 parturient paresis are paretic to the point where they cannot stand. Their musculoskeletal control is adequate to sustain sternal recumbency. They usually have cold extremities, dry snouts, subnormal body temperatures, and obtundation and they are also anorectic. Owing to compromised cardiac contractility, auscultation demonstrates tachycardia and a decrease in the loudness of the heart sounds. Weak peripheral pulse may be observed. Gastrointestinal stasis, which can cause bloating, inability to pass gas, and loss of anal sphincter tone, is caused by smooth muscle paralysis (88). Rectal examination may reveal a dilated bladder as a sign of an inability to urinate. Asymmetry of the cervical musculature may result in an S-shaped curvature of the neck may develop, indicating muscle weakness, if the cow can extend its head.

Cows with stage 3 parturient paresis progressively lose consciousness to the point of coma. They cannot lie flat on their sides or sustain sternal recumbency (85). They can have considerable bloats and extremely flaccid muscles, and may not respond to stimulation. Peripheral pulses may become undetectable and the heart rate may approach 120 bpm as the cardiac output deteriorates. Cows in stage 3 may not survive for more than a few hours without treatment.

Prior to therapy, it is imperative to get a blood sample in order to validate the diagnosis by the identification of a reduced calcium level in the serum. Cows with blood calcium levels below 8.0 mg/dL are classified as hypocalcemia. For optimal results, it is recommended to collect the blood sample from the cow 12 to 24 h after giving birth. It is also important to collect at least 12 samples in order to obtain reliable data (89). If three to five samples have a serum calcium value below 8.0 mg/dL, they are deemed to have reached a critical threshold. If six or more cows out of a group of twelve test positive, the sample is considered positive, indicating that the herd is experiencing hypocalcemia (90). Urine pH has demonstrated efficacy as a diagnostic technique for dietary cation-anion balancing DCAD verification, as blood pH is expected to be about 7.0. For diagnostic reasons, a minimum of eight urine samples from cows is required, and it is recommended to do testing on a weekly basis, or even more regularly. The process is simple, as it just requires the use of a standard pH indicator paper (91).

The treatment involves administering calcium borogluconate intravenously at a dosage of 1 gram of calcium per 45 kilograms of the animal's body weight. For the management of big cows that produce a significant amount of milk, an extra dose of the medication might be given by injecting it under the skin (92). Due to the cardiotoxic nature of calcium, it is important to deliver the medicine at a very slow rate, taking 10 to 20 min, while closely monitoring the heart's activity using auscultation (93). If bradycardia or arrhythmia is observed, cessation of therapy is necessary, and resumption should only occur gradually until the heart's activity returns to normal. Administering calcium intravenously is not advisable for the treatment of hypocalcemic cows that are still able to stand. Administering calcium intravenously promptly elevates blood calcium levels, posing a possible risk (93). Elevated concentrations of calcium in the bloodstream can lead to life-threatening cardiac problems and inhibit the movement of calcium in cows during crucial periods (94). Due to compromised peripheral absorption, the subcutaneously injected drug is not recommended as the sole option. Administering calcium subcutaneously restores blood calcium levels to normal after 6 h of injection (92). According to Miltenburg et al. (95), giving cows with low calcium levels oral calcium supplements is the most effective option, especially if the cows are still able to stand. According to Oetzel (96), cows that show a positive response to intravenous calcium therapy and are able to regain consciousness and able to swallow should also be provided with oral calcium supplements 12 h following the treatment. Table 2 provides a comprehensive comparison.

Implementing measures to prevent milk fever is financially advantageous for dairy farmers as it leads to decreased losses in production, mortality, and veterinary costs related to milk fever. Various nutritional strategies have been employed to regulate hypocalcemia and facilitate calcium release from dairy cattle. These strategies include administration of anionic salts, diets low in calcium ions, and supplementation with vitamin D (97, 98). Prior to conception, consuming diets deficient in calcium enhances the secretion of parathyroid hormone. This process activates osteoclasts within the bone, enhances the absorption of calcium within the bone, encourages the renal tubules to reabsorb calcium from urine, and initiates the production of 1,25-dihydroxyvitamin D. Consequently, after the onset of lactation, calcium regulatory pathways become activated and can avoid low levels of calcium in the blood (88). According to Goff and Koszewski (99), one technique for reducing milk fever in cows is to provide diets that are low in calcium throughout the dry period. This can be accomplished by consuming < 50 grams each day. Consequently, forage that is high in calcium, such as alfalfa, should be eliminated from the animal's diet. Regular feeding of corn silage and grass hay throughout the dry months is recommended to reduce calcium levels effectively (100). Bhanugopan and Lievaart (101) discovered that all farmers employed hay, straw, and grain as a comprehensive nutritional regimen throughout the dry period. Grain feeding facilitates rapid adaptation of the rumen to high-energy meals provided after post-partum, and grains also possess low calcium content.

When the body's absorption of dietary magnesium is insufficient to meet the needs for breastfeeding (120 mg/kg milk) and maintenance (3 mg/kg body weight), hypomagnesemic tetany results from a decrease in the plasma magnesium concentration. This might happen when cows graze short grass-dominant pastures with < 0.2% magnesium on a dry matter basis, during transit, or when they reduce their food intake due to bad weather. During breastfeeding, live weight loss occurs when there is insufficient herbage availability (< 1,000 kg dry matter/hectare). The body mobilizes its magnesium stores to support lactation more than it actually needs to, leading to reduced plasma magnesium levels (107).

Secondary hypomagnesemia stems from dietary variables that hinder Mg absorption, such as excessive K and N concentrations or low Na levels (103, 108). Fertilizers containing nutrients such as nitrogen (N), potassium (K), and phosphorus (P) can enhance forage production. However, they may reduce the bioavailability of magnesium (Mg) in the rumen, as illustrated in Figure 5 (103, 108). High N content in fast-growing grasses (ranging from 4.2% to 6.3%, equivalent to 26%−39% crude protein) leads to high ammonium ion concentrations in the rumen, increasing pH and decreasing Mg bioavailability (109). Until blood calcium concentrations are also lowered to < 0.8 mg/dL (0.35 mmol/L), which frequently happens in cattle grazing green cereal crops, cows frequently do not exhibit clinical symptoms of hypomagnesemic tetany. A decrease in calcium intake, calcium absorption, or both can lead to hypocalcemia. Cattle raised in lush grass pastures or green cereal crops are more likely to have metabolic alkalosis (urine pH > 8.5), which can lead to a reduced supply of ionized calcium and magnesium, thereby raising the risk of hypocalcemia and hypomagnesemia. In cows with hypomagnesemia, urine magnesium concentrations are undetectable and yet serve as good indicators of magnesium status (107).

Hypomagnesemia in cows' manifests in several distinct ways. Neurologically, lactating cows, especially those grazing on lush grass pastures or green cereal crops, are at risk (107, 110). They often exhibit hyperexcitability, with sudden head-throwing, loud bellowing, and erratic galloping. Muscular spasms are common, and in severe cases, seizures occur. During seizures, cows may display paddling motions, chomping jaws, frothy salivation, and eyelid fluttering. In extreme situations, respiratory distress sets in, potentially leading to collapse and death. Digestively, affected cows show a significant reduction in appetite, either refusing to eat or consuming only small amounts of feed. This can lead to weight loss and malnutrition. Diarrhea, with thin or watery feces, is also a prevalent digestive symptom (111). Reproductively, the deficiency of magnesium ions impacts the cows' breeding capacity, disrupting normal physiological processes and causing a decline in their overall reproductive function (107).

Clinical symptoms emerge abruptly in acute cases. Affected animals exhibit unease, stop eating and remain wary. These symptoms are associated with muscular twitching. The animal may seem terrified or “agitated”. Faltering gait can lead to falls and spastic limb movements in the unwell animal. Clinical symptoms can cause death within 4.0 h. A rapid increase in body temperature may occur after a tetanic event. The pulse and respiration increase. In sub-acute situations, progressive appetite loss leads to unpredictable conditions. Research indicates a 22–55 kg body weight reduction in pregnant animals and a 27% decline in milk supply in nursing animals.

Clinical signs of hypomagnesemic tetany in sheep occur when hypomagnesemia (plasma total magnesium [tMg] < 0.5 mg/dL [0.2 mmol/L]) occurs concomitantly with hypocalcemia (plasma total calcium [tCa] < 8.0 mg/dL [2.0 mmol/L]). The disease in lactating ewes occurs under essentially the same conditions and has the same clinical signs as those of cattle. Treatment response is typically used to confirm the diagnosis, followed by confirmation of pre-treatment sample hypomagnesemia. The reference range for total magnesium in sheep is 2.2–2.8 mg/dL (0.9–1.15 mmol/L) and in cattle is 1.8–2.4 mg/dL (0.75–1.0 mmol/L). In sheep and cattle, tetany typically develops when plasma tMg is < 0.5 mg/dL (0.2 mmol/L) and < 1.2 mg/dL (0.5 mmol/L). Hypocalcemia frequently occurs concurrently with other conditions. In cows with hypomagnesemic tetany, magnesium is typically not detected in the urine (107). Mg concentrations in dead animals may be normal due to muscle damage and leakage from intracellular pools. Mg concentrations < 1 mg/dL (0.4 mmol/L) from the CSF within 12 h of death or from the vitreous humor of the eye within 24–48 h after death are indicative of hypomagnesemic tetany, provided environmental temperatures have remained below 23°C (107).

Clinical cases are treated with intravenous, subcutaneous, or oral Magnesium solutions. Recommended intravenous Mg dosage: 2.0–4.0 g. Alternatively, 200.0–400.0 mL of 25% Magnesium sulfate (MgSO₄7H₂O) can be subcutaneously injected at 100 mL each location. The animals in coma fail treatment. Oral Mg salts can maintain plasma Mg levels for longer and lower the incidence of aspiration pneumonia once the animal has recovered esophageal reflexes (112). Oral administration of Mg is not recommended as an initial therapy due to its slow absorption. Intraruminal gavage with an aqueous solution comprising 100.0 g MgO, 100 g CaCl₂, and 50 g NaCl may be more effective in hypocalcemia with hypomagnesemia. Na boosts ruminal Magnesium absorption. Because it is better absorbed than MgO, 200 ml of 50% MgSO₄7H₂O intraruminal restores blood Mg levels faster (112). When an animal exhibits clinical symptoms, it must be treated immediately with calcium and magnesium solutions, ideally administered slowly intravenously while the heart is being watched. Because it takes longer to recover magnesium levels in the cerebrospinal fluid (CSF), animals with hypomagnesemic tetany respond to treatment more slowly than animals with hypocalcemia alone. Stimulation of the animal while receiving treatment can produce lethal seizures. A mature cow needs 1.5–2.25 g of elemental magnesium (107). This equates to 15–22.5 g of Mg sulfate solution or 30.0–45.0 ml of a 50% Mg sulfate solution because Mg sulfate is only 9.7% elemental Mg. Mg is present in several commercial intravenous formulations as a solution of hypophosphite, borogluconate, and chloride. A standard course of treatment involves slow intravenous injection of 400.0 ml of 40% calcium borogluconate and 50.0 ml of 25% magnesium sulfate. If possible, cows should be relocated off the tetany-prone pasture after treatment and given time to respond naturally. The illness can return within 36.0 h following the first treatment if the animals are not given hay treated with 60.0 g of magnesium oxide every day.

Prevention of hypomagnesemia in cows mainly lies in the rational adjustment of the diet structure. During the periods prone to the disease, such as winter or when cows are pregnant and lactating, it is essential to ensure an adequate supply of magnesium in the diet (110, 113). Research shows that starting to supplement high—magnesium mineral feed at least 30 days before calving is significantly effective. Cows need to consume 4.0 ounces of a mineral mixture containing 12% magnesium per day. For example, an appropriate amount of magnesium oxide (MgO) can be added to grains to ensure the magnesium intake of cows. However, magnesium oxide has a bitter taste and poor palatability. To improve the cows' feeding enthusiasm, it can be mixed with palatable ingredients such as molasses and concentrate (110, 113, 114).

In terms of pasture management, fertilization should be carried out reasonably according to the results of soil testing, and excessive application of potassium fertilizer should be avoided. Because the potassium content in lush spring forage is too high, which will hinder the absorption of magnesium by cows (115). In addition, during the periods when cows are prone to hypomagnesemia, some targeted measures can be taken. For example, providing hay for cows or limiting the grazing time to 2.0–3.0 h per day can slow down the passage of food through the digestive tract and promote the absorption of magnesium (116, 117). At the same time, for pastures with a high risk, animals that are less likely to be affected (such as heifers, dry cows, and fattening cattle) should be given priority for grazing. Some studies point out that 60.0 grams of magnesium oxide can be supplemented to cows daily for prevention during the dangerous period. The magnesium content in forage can also be increased by spreading magnesium oxide powder (500 grams per cow) on hay or spraying a 2% magnesium sulfate solution every 1.0–2.0 weeks. However, it should be noted that if the rainfall exceeds 40.0–50.0 mm within 2.0–3.0 days after spraying, the treatment needs to be carried out again.