What is ketosis? why do we worry about it?
We commonly see ketosis as an energy disorder of the modern dairy cow, a telltale that things are not going well, and one that hints at poor fertility, reduced lactation performance, and an increased risk for the development of early lactation diseases. In practice, ketosis is diagnosed by the measurement of betahydroxy butyrate (BHB), one of two major ketones, that becomes elevated in blood, urine, and milk of fresh cows. In this way, ketosis is used as a cow-side test for identifying sick cows, and as means to direct our efforts to “problem cows” (for example with propylene glycol administration) before it is too late. Despite our efforts for ketosis prevention and treatment over the last 5-7 decades, our understanding of ketosis as a disease, as well as our ability to reverse it and to prevent the arrival of other associated disorders (for example displaced abomasum, infection, fatty liver, milk fever), remain limited. Today, ketosis is commonly observed in 40-60% of cows entering lactation, with estimated costs of ~$375 and ~$256 per case for first lactation and multiparous cows, respectively¹.
“...relying on ketosis alone may be insufficient to effectively address the big challenges faced by the early-lactation dairy cow.“
The short answer is yes. Ketones constitute a normal response of dairy cows to the energy shortage (commonly known as negative energy balance) of early lactation. At this moment, milk production is a high priority, and large amounts of glucose (a key blood sugar) are funneled to the mammary gland to allow milk synthesis. At the same time, when the mammary gland is using most of the available glucose to produce milk, the liver is copiously making ketones from body fat stores (i.e., NEFA) to support the demand of other tissues (e.g., muscle and brain) and keep the system running. In this way, ketones can be understood as very important sources of energy for the lactating dairy cow. Beyond their importance as a fuel to sustain bodily functions, ketones may also act to promote good health by other means. For example, research in rodents and humans indicates that ketones can be helpful in controlling pain and inflammation associated with several metabolic diseases ranging from gout to non-alcoholic fatty liver²⁻⁵. Unfortunately, whether these molecules may be also playing any positive roles in cow health is currently unknown.
Understanding the origins of diseases in animals can sometimes be a complicated task. We do not know “what is hurting”, and so we have to rely on indicators of cow behavior, production, or even animal-side tests. In the case of ketosis, most of our knowledge about this so-called metabolic disorder comes from some studies that find high ketones in cows that experience difficulties around calving, becoming sick, and displaying poor performance. Nowadays, ketones are even used to indicate or predict that a cow is or will become sick when the levels BHB in blood are 1.2mmmol/L (we call this subclinical ketosis). To complicate things even more, new research indicates that ketones may also be elevated in healthy fresh cows with normal lactation performance and fertility. This would indicate that ketones are not always bad news. When we focus on ketosis and milk production, we see that although some show reduced milk yield in cows with high ketones, others show that cows diagnosed with hyperketonemia sustain higher milk production (Figure 1).
These contradictions are best exemplified by a handful of studies that show a paradoxical relationship between ketones and performance outcomes. A study from the Netherlands⁷ including over 23 dairies and ~1700 dairy cows, showed that cows with increased ketones at the first DHI test in the second week postpartum had a higher milk yield and a predicted higher 305-d milk yield. Furthermore, the authors reported ketones of 2.0 mml/L (higher than the subclinical threshold) appeared to be optimal in terms of milk production. Although this does not mean that more ketones can result in increased milk production, at the very least, it runs contrary to the expected negative association between ketosis and lactation performance. Similarly, a study conducted at the University of Wisconsin-Madison⁸ reported that hyperketonemic cows (BHB 1.2mmmol/L) consistently exhibited higher milk yield during the first month of lactation, relative to cows with normal/lower blood ketone concentrations. In both cases, however, it is important to note that these results are still consistent with the idea that higher producing cows are more likely to experience ketosis.
When we think about ketones and reproductive performance, the usual expectation is that ketosis will be associated with reduced fertility in the early days of lactation, as cows strive to cope with a state of energy deficiency (i.e., negative energy balance) and may fail to sustain optimal productivity and reproductive function. In contrast, a new study from the University of Minnesota⁹ reported that cows with moderate to high milk yield had better reproductive performance than low-milk-producing cows regardless of whether they were experiencing ketosis or not. This does not necessarily exonerate ketones, however, as the authors also reported that the group with the poorest overall reproductive performance was that of low-producing cows experiencing ketosis. In this way, it appears we should place increased attention on those animals that fail to adapt to energy shortages, and try to understand which other factors may cause simultaneous low milk yield and ketosis. Are these animals fighting an infection? is their appetite normal? Ideally, we would want to identify these cows as early as possible, hopefully with better predictors and well before calving. That is our challenge.
Given the above, it is worth asking whether dairy cows get sick because of or despite ketones. If anything, these recent studies highlight the fact that we must still work to unveil how and when ketosis is related to cow health and performance. After all, the responses that dairy cows display to deal with the challenge of lactation (namely utilizing body fat and making ketones to obtain energy) are in essence normal and necessary. While it would seem that some cows are able to sustain normal health and performance while on ketosis, others start heading into negative health trajectories when ketones are increased (see summary in Figure 2). This might mean that relying on ketosis alone may be insufficient to effectively address the big challenges faced by the early-lactation dairy cow, and we will need to pick up on other factors as we move forward. Closer monitoring of cows for other early cues that underlie increased risk for metabolic disorders (for example activity, appetite, and rumination) may help us better identify animals heading in negative trajectories even before ketones become elevated. Similarly, the proper management of fresh cows may need the identification of lower -yielding dairy cows with ketosis, as this helps us focus on —and treat— those animals that actually carry the highest risk for health complications.
Solving the puzzle of ketosis will require some work. For this reason, our research group at the University of Maryland is currently working to improve our understanding of the “good and the bad” of ketones and ketosis. We anticipate that new research can help us to develop better management strategies at the farm that in turn help prevent other metabolic diseases associated with ketosis, and lessen their negative impacts on cow performance and the sustainability of dairy farms.
- McArt J, Oetzel G. A stochastic estimate of the economic impact of oral calcium supplementation in postparturient dairy cows. Journal of dairy science. 2015;98(10):7408-18.
- Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD. β-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell reports. 2017;18(9):2077-87.
- Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'agostino D, Planavsky N, Lupfer C, Kanneganti TD. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature medicine. 2015;21(3):263-9.
- Yamanashi T, Iwata M, Kamiya N, Tsunetomi K, Kajitani N, Wada N, Iitsuka T, Yamauchi T, Miura A, Pu S. Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Scientific reports. 2017;7(1):1-11.
- Møller N. Ketone Body, 3-Hydroxybutyrate: Minor Metabolite-Major Medical Manifestations. The Journal of Clinical Endocrinology & Metabolism. 2020;105(9):2884-92.
- Benedet A, Manuelian CL, Zidi A, Penasa M, De Marchi M. Invited review: β-hydroxybutyrate concentration in blood and milk and its associations with cow performance. Animal. 2019 Aug;13(8):1676-89.
- Vanholder T, Papen J, Bemers R, Vertenten G, Berge AC. Risk factors for subclinical and clinical ketosis and association with production parameters in dairy cows in the Netherlands. Journal of dairy science. 2015 Feb 1;98(2):880-8.
- Rathbun FM, Pralle RS, Bertics SJ, Armentano LE, Cho K, Do C, Weigel KA, White HM.Relationships between body condition score change, prior mid-lactation phenotypic residual feed intake, and hyperketonemia onset in transition dairy cows. Journal of dairy science. 2017. May 1;100(5):3685-96.
- Rodriguez Z, Wynands E, Shepley E, Baumgard LH, Cramer G, Caixeta LS. Exploring the role of milk yield in the first week of lactation on the association between hyperketonemia and reproductive performance in dairy cattle. JDS Communications. 2022 Jan 1;3(1):7-12
This article appears on June 16, 2022, Volume 3, Issue 2 of the Maryland Milk Moos newsletter.
Maryland Milk Moos is a quarterly newsletter published by the University of Maryland Extension that focuses on dairy topics related to Nutrition and Production, Herd Management, and Forage Production. To subscribe to this newsletter, click the button below to enter your contact information.