Hyperketonemia is an elevated concentration of ketone bodies (acetone, acetoacetate, beta-hydroxybutyrate) in the blood. Hyperketonemia often occurs without the presence of clinical signs, whereas ketosis is a clinical disorder associated with more severe hyperketonemia. Key clinical signs of ketosis are vague but include anorexia, decreased milk production, noticeable loss of body condition, firm dry feces, and, occasionally, neurological signs (nervous ketosis). Cows with elevated ketone bodies can be identified via routine testing using appropriate cowside tests of blood (hyperketonemia), milk (hyperketolactia), or urine (hyperketonuria). The most efficacious treatment for hyperketonemia is oral drenching of propylene glycol.
Ketosis is the clinical expression of severe hyperketonemia and is a common disease of adult cattle. It typically occurs in dairy cows in early lactation and is most consistently characterized by hyporexia and decreased milk production. Rarely, it occurs in cattle in late gestation, at which time it resembles pregnancy toxemia of ewes.
In addition to inappetence, clinical signs of nervous dysfunction occasionally occur, including pica, abnormal licking, incoordination and abnormal gait, bellowing, and aggression. Ketosis is worldwide in distribution; however, it is most common where dairy cows are bred and managed for high production.
Etiology and Pathogenesis of Hyperketonemia in Cattle
The pathogenesis of bovine hyperketonemia is incompletely understood; however, it requires the combination of intense adipose mobilization and high glucose demand. Both of these conditions are present in early lactation, at which time energy deficit leads to adipose mobilization and milk synthesis creates a high glucose demand.
Adipose mobilization is accompanied by high serum concentrations of nonesterified fatty acids (NEFAs). During periods of intense gluconeogenesis, a large portion of serum NEFAs is directed to ketone body synthesis in the liver. Thus, the main clinicopathological characterization of ketosis, the clinical manifestation of severe hyperketonemia, includes a sequence of high serum concentrations of NEFAs and ketone bodies (acetone, acetoacetate, and beta-hydroxybutyrate [BHB]) and low concentrations of glucose.
A secondary, although much less common, etiology of ketosis arises from ingestion of silage that has undergone clostridial fermentation to produce high concentrations of butyric acid.
Pathogenesis of hyperketonemia cases occurring in the immediate postpartum period is thought to differ slightly from that of cases occurring closer to the time of peak milk production. Cases of hyperketonemia in the immediate postpartum period, such as the first week after calving, are usually associated with fatty liver. Both fatty liver and hyperketonemia are part of a spectrum of conditions associated with intense fat mobilization in cattle.
Hyperketonemia cases occurring close to the time of peak milk production (usually around 4–6 weeks after parturition but sometimes as early as 2 weeks after parturition) are associated with underfed cattle experiencing a metabolic shortage of gluconeogenic precursors rather than with excessive fat mobilization. This can be due to high-producing dairy cows expending immense energy in the production of milk or due to their nutritional energy needs not being met.
The exact pathogenesis of the clinical signs associated with ketosis is not known. The development of the clinical syndrome of ketosis is not directly associated with serum concentrations of either glucose or ketone bodies. For example, cows with ketosis always have severe hyperketonemia, but not all cows with severe hyperketonemia develop ketosis. Development of ketosis may be due to metabolites of ketone bodies. In contrast to many other species, cattle with hyperketonemia do not have concurrent acidemia.
Hyperketonemia is defined as elevated serum ketone body concentrations, which can occur with clinical signs (ketosis) or without them. Cows that develop hyperketonemia in early lactation are at increased risk of ketosis, metritis, and displaced abomasum and are also less fertile than cows with normal serum ketone body concentrations. Furthermore, they have decreased milk production and are at increased risk of culling in early lactation.
Distinction between clinical and subclinical hyperketonemia is unimportant in practical terms. Both are part of the same disease syndrome, with impacts increasing as ketone body concentrations increase. Determination of serum or whole blood BHB concentration is considered the best way to detect and monitor hyperketonemia; however, urine or milk cowside tests can also be used in on-farm monitoring programs to detect hyperketonuria and hyperketolactia, respectively.
Concentrations ranging from 1.0 mmol/L (10.4 mg/dL) to 1.4 mmol/L (14.6 mg/dL) of blood, serum, or plasma BHB are considered diagnostic of hyperketonemia. The standard threshold used for blood is 1.2 mmol/L (12.5 mg/dL), which corresponds to thresholds of 100 mcmol/L for milk and 15 mg/dL (or "small" on a dipstick) for urine.
Given that hyperketonemia is a costly disease and that treatment is efficacious, on-farm monitoring programs are cost-effective for most farms with moderate to high prevalence. Two outcomes of monitoring programs are treatment of individual hyperketonemic cows and evaluation of prevalence, focusing on cows within 3 to 9 days in milk, to determine effectiveness of prevention strategies at the herd level.
Sudden or prolonged elevation in herd prevalence of hyperketonemia indicates a herd-level problem and should prompt a review of nutritional and cow management.
Many farms use handheld BHB meters to test all cows in early lactation. Cows with hyperketonemia are treated with oral drenching of propylene glycol. Such an approach is labor-intensive but has been demonstrated to decrease blood BHB concentrations in hyperketonemic animals and to improve milk production in treated animals.
Sound nutritional management procedures are also important.
Routine milk ketone body tests are available in some countries from dairy herd improvement companies. These tests can be used to classify herd risk before considering on-farm testing programs or as the sole source of monitoring in herds with very low prevalence (< 10%) of the disease.
Epidemiology of Hyperketonemia in Cattle
All dairy cows in early lactation (the first 6 weeks after parturition) are at risk of hyperketonemia, with most cases occurring in the first 2 weeks of lactation.
Hyperketonemia occurs in cows of all parities, but the risk increases with increasing parity. Historically, the clinical manifestation of hyperketonemia, ketosis, was thought not to have a genetic predisposition other than being associated with dairy breeds; however, specific genetic markers have been associated with ketosis risk, suggesting moderate heritability. Cows with excessive adipose stores (body condition score ≥ 3.75 on a 5-point scale) at calving are at greater risk of hyperketonemia than those with lower body condition scores.
Lactating cows with hyperketonemia are also at a greater risk of developing clinical ketosis and displaced abomasum than cows with lower blood BHB concentrations. Most cases of displaced abomasa are associated with hyperketonemia. Cows with hyperketonemia are less likely to become pregnant on the first insemination and are at increased risk of being culled in early lactation.
As a result of these impacts, and because treatment and prevention substantially decrease these risks, hyperketonemia is considered a gateway disease of early lactation (meaning that prevention of hyperketonemia can prevent other diseases or problems).
Clinical Findings of Hyperketonemia in Cattle
In cows maintained in confinement stalls, decreased feed intake is usually the first clinical sign of severe ketonemia (ketosis). If rations are offered in components, cows with ketosis often refuse grain before forage.
In group-fed herds, decreased milk production, lethargy, and an empty-appearing abdomen are usually the first clinical signs of ketosis. On physical examination, cows are afebrile and may be slightly dehydrated. Rumen motility is variable, being hyperactive in some cases and hypoactive in others. In many cases, there are no other physical abnormalities.
In some cases, CNS disturbances are evident (nervous ketosis). Neurological signs include abnormal licking and chewing, and sometimes incessant chewing on pipes and other objects (pica). Incoordination and gait abnormalities occasionally occur, as do aggression and bellowing. These clinical signs occur in a minority of cases; however, because the disease is so common, encountering patients with these clinical signs is not unusual (see videos of flank sucking and licking in nervous ketosis).
Diagnosis of Hyperketonemia in Cattle
Cowside tests of blood, milk, or urine
Blood BHB measurement via a cowside meter
The gold standard test for hyperketonemia in dairy cows is an enzymatic laboratory test based on spectrophotometry. However, these tests are inconvenient and costly, and tests that can be conducted on-farm are the preferred method of diagnosis.
Cowside tests that measure ketone body concentrations in blood, milk, or urine are critical for diagnosis. Handheld instruments designed to monitor the concentration of ketone bodies in the blood of human diabetic patients are available. These and newer handheld instruments designed specifically for cows quantitatively and accurately measure blood BHB concentration (see cowside test images, blood and milk).
Courtesy of Dr. Todd Duffield.
Courtesy of Dr. Todd Duffield.
It is important to use accurate instruments validated for use in cows and operate these instruments according to manufacturer instructions with periodic calibration. Cold temperatures can affect the measurement capacity of both BHB instruments and BHB test strips.
Dipstick tests that measure acetoacetate and acetone concentrations in urine are reasonably accurate when interpreted within 5–10 seconds; however, delayed interpretation can cause a higher rate of false-positive reactions.
Milk dipstick tests that measure BHB concentration are also reasonably accurate but typically take 1–2 minutes to react.
These dipstick urine and milk tests are read by observation of a particular color change and are semiquantitative. Care should be taken to allow the appropriate time for color development as specified by the test manufacturer, with particular attention to the recommended temperature and volume of liquid tested (see dipstick urine test image).
In the absence of clinical signs (eg, hyporexia), elevated ketone body concentrations are a marker of energy deficit. Increasing ketone body concentration above the positive threshold for the test indicates increased severity of the deficit regardless of whether clinical signs have been observed.
In early lactation cows, lactation initiates an energy deficit. Cows with chronic clinical signs of disease, during which their milk production has dropped substantially for a period of time, will often have normal ketone body concentrations. This generally provides a poorer prognosis for a cow's retention in the herd.
Diagnosis of clinical ketosis is based on the presence of risk factors (eg, early lactation), clinical signs, and elevated ketone body concentrations in blood, urine, or milk. When ketosis is diagnosed, a thorough physical examination should be performed, given that ketosis frequently occurs concurrently with other peripartum diseases. Especially common concurrent diseases include displaced abomasum, retained fetal membranes, and metritis. Rabies and other CNS diseases are important differential diagnoses in cases involving neurological signs (nervous ketosis).
Treatment of Hyperketonemia in Cattle
Oral administration (drench) of propylene glycol
Vitamin B12 supplementation in cases of concurrent hypoglycemia
Bolus glucose treatment in cases of nervous ketosis
Treatment of hyperketonemia is aimed at reestablishing normoglycemia and decreasing serum ketone body concentrations.
Propylene glycol acts as a glucose precursor, and oral drenching (250–400 g [8–14 oz] per cow, PO, every 24 hours for 3–5 days) is effective as a hyperketonemia treatment. Overdosing propylene glycol reportedly leads to CNS depression in other species, but this has not been clinically recognized in cattle.
Pearls & Pitfalls
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There is also support for the use of vitamin B12 (1.25–5 mg per cow, IM, every 24 hours for 3–5 days) as an adjunct treatment with oral drenching of propylene glycol, particularly in hyperketonemic cows that are also hypoglycemic.
Bolus glucose treatment (500 mL of 50% dextrose solution, IV, as a single bolus) is also common but does not affect the time to hyperketonemia resolution, subsequent disease development, or milk production. This solution is very hyperosmotic and must be administered IV to avoid adverse effects of perivascular administration. Bolus glucose treatment generally results in a rapid temporary recovery due to immediate decreases in blood BHB concentrations; however, the effect is transient and relapses are common.
Dextrose administration is recommended for cases of nervous ketosis but may not be beneficial in every case. Administration of glucocorticoids is not recommended.
Clinical ketosis cases occurring within the first 1–2 weeks after parturition are often refractory. In many cases, a repeated 5-day course of oral drenching of propylene glycol often combined with vitamin B12 seems to resolve these refractory ketosis problems. However, some cows remain clinically hyporectic.
Other treatments that might be of benefit in refractory ketosis cases are continuous IV glucose infusion and tube feeding (see Fatty Liver Disease of Cattle). In addition, limited research has demonstrated that decreasing milking frequency from twice a day to once daily will lower ketone body concentration and improve the chances of a cure, although at the expense of decreased milk production. The welfare aspects of once-a-day milking in early postparturient cows experiencing udder engorgement have not yet been assessed.
Prevention and Control of Hyperketonemia in Cattle
Prevention of hyperketonemia is via nutritional and cow management. Hyperketonemia risk increases with age at first calving and is elevated in cows that have a prolonged interval from calving to conception.
Body condition of cows should be managed in late lactation, when cows frequently become too fat. Modifying the diets of late lactation cows to increase the energy supply from digestible fiber and decrease the energy supply from starch may aid in partitioning dietary energy toward milk and away from body fattening. The dry period is generally too late to decrease body condition score. Decreasing body condition in the dry period, particularly in the late dry period, may even be counterproductive, resulting in excessive adipose mobilization prepartum.
A critical area in hyperketonemia prevention is maintaining and promoting feed intake. This includes attention to diet but also to the management of the cows and management of feeding. Cows tend to decrease feed consumption in the last 3 weeks of gestation. Stressors such as empty feed bunks, cow movement disrupting the social order, overcrowding, heat stress, and isolation can all inhibit feed intake.
Nutritional management should be aimed at minimizing this decrease in feed intake. Controversy exists regarding the optimal dietary characteristics during this period. It is likely that optimal energy and fiber concentrations in rations for cows in the last 3 weeks of gestation vary from farm to farm. Feed intake should be monitored and rations adjusted to meet but not greatly exceed energy requirements throughout the entire dry period. For Holstein cows of typical adult body size, the typical energy requirement (expressed as net energy for lactation [NEL]) throughout the dry period is between 14 and 16 Mcal every 24 hours. See Nutritional Requirements of Dairy Cattle.
After calving, diets should promote rapid and sustained increases in feed and energy consumption. Early lactation rations should be relatively high in nonfiber carbohydrate concentration but contain enough fiber to maintain rumen health and feed intake. Neutral-detergent fiber concentrations should usually be in the range of 28%–30%, with nonfiber carbohydrate concentrations in the range of 38%–41%. Dietary particle size will influence the optimal proportions of carbohydrate fractions.
Some feed additives, including niacin, yeast products, and rumen-protected choline, might be helpful aids in the management of hyperketonemia. To be effective, these supplements should be fed in the last 2–3 weeks of gestation, as well as during the period of hyperketonemia susceptibility.
In some countries, monensin sodium is approved for use in preventing hyperketonemia and its associated diseases. Where approved, it is recommended at the rate of approximately 300 mg/cow, every 24 hours throughout the transition period.
Key Points
Hyperketonemia is a common and costly disease in dairy cattle that increases the risk of other diseases and of impaired production and reproduction.
Hyperketonemia can be diagnosed with cowside blood, milk, or urine tests; the most accurate method is blood measurement of beta-hydroxybutyrate (BHB) concentration.
Hyperketonemia is treated with oral drenching of propylene glycol (300 g per cow, PO, every 24 hours for 3 days in mild cases and extended for 5 days in severe cases).
Vitamin B12 (1.25–5 mg/cow, IM) is administered as an adjunct with propylene glycol drench to promote gluconeogenesis.
Ketosis is the clinical manifestation of hyperketonemia.
For More Information
Mann S, McArt JAA. Hyperketonemia: A marker of disease, a sign of a high-producing dairy cow, or both? Vet Clin N Am - Food Anim. 2023;39:307-324.
McArt JAA, Nydam DV. Hyperketonemia in dairy cattle (ketosis). In: Smith BP, ed.Large Animal Internal Medicine. 5th ed. Mosby; 2019:1408-1414.
