Secondary Logo

Journal Logo

Life-Threatening Lactation or “Bovine” Ketoacidosis: A Case Report

Greaney, David J. FRCA, FCAI, MRCPI, MSc; Benson, Pat FFARCSI, FJFICMI, DABA

doi: 10.1213/XAA.0000000000000350
Case Reports: Case Report
Free

Lactation or “bovine” ketoacidosis is a rare cause of raised anion gap metabolic acidosis whereby a perfect storm of negative calorie balance (starvation/glucose preferentially used for milk production) and insulin resistance (counter regulatory stress hormone release/infection) leads to a dysregulated ketogenic state. We present a case of life-threatening lactation-related ketoacidosis in a patient 9 weeks postpartum, who presented to the emergency department with an arterial pH of 6.88, HCO3 of 5.8 mmol/L and blood ketone level of 5.8 mmol/L. Treatment consists of aggressive glucose loading, triggering supraphysiologic endogenous insulin release, and subsequent inhibition of ketone body formation.

From the Department of Anaesthesia and Critical Care, St. Vincent’s University Hospital, Dublin, Ireland.

Accepted for publication March 17, 2016.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to David J. Greaney, FRCA, FCAI, MRCPI, MSc, St. Vincent’s University Hospital, Elm Park, Merrion Rd, Dublin 4, Ireland. Address e-mail to drdavidgreaney@gmail.com.

Lactation or “bovine” ketoacidosis is a rare cause of raised anion gap metabolic acidosis precipitated by a starvation-induced reversal of the normal glucagon:insulin ratio with ongoing obligate caloric loss from breastfeeding. We present a case of life-threatening lactation-related ketoacidosis in a patient 9 weeks postpartum. Although uncommonly reported in the literature, the few reports of lactation ketoacidosis have mirrored the rising popularity of low-carbohydrate dieting postpartum. Appropriate therapy rapidly reverses the hormonal and metabolic derangements when the condition is correctly recognized and treated.

Back to Top | Article Outline

CASE REPORT

A 36-year-old woman presented to the emergency department with a 24-hour history of general malaise, myalgia, and 3 episodes of small-volume nonbilious vomiting. She was 9 weeks postpartum having delivered a healthy baby girl at 39 weeks of gestation by spontaneous vaginal delivery. She sustained a third-degree tear that was repaired uneventfully under spinal anesthesia 2 hours after delivery. Her puerperium was otherwise uneventful, and she exclusively breastfed her baby. She had been previously fit and healthy with no medical comorbidities. She drank wine on occasion socially and was a nonsmoker. She weighed 85 kg, and her body mass index was 28 kg/m2.

On presentation to the emergency department, she was tachycardic with a heart rate of 110 beats/min and tachypneic with a respiratory rate of 24 breaths/min. She was normotensive at 135/85 mm Hg, afebrile, and alert with no neurologic deficits. Point-of-care blood glucose on admission was 6.1 mmol/L. Clinical examination was otherwise unremarkable. Notably, her abdomen was soft, nontender, and there were no signs of intra-abdominal, intrapelvic, or other obvious focus of infection. Electrocardiogram revealed a sinus tachycardia, and chest radiograph was unremarkable. Laboratory tests revealed a leukocytosis of 17 × 109/L, Na+ was 137 mmol/L, K+ was 4.3 mmol/L, Cl was 106 mmol/L, Mg2+ was 0.95 mmol/L, PO43− was 0.79 mmol/L, urea and creatinine were 4.2 and 76 mmol/L, respectively, and serum bicarbonate was 6 mmol/L. Arterial blood gas following this confirmed a severe metabolic acidosis: her pH was 6.88, standardized bicarbonate 5.8 mmol/L, Paco2 17 mm Hg (2.27 kPa), and lactate 1.0 mmol/L. Anion gap was calculated at −29 mmol/L. She was rehydrated with 2000 mL compound sodium lactate solution and empirically administered 1.2 g IV co-amoxiclav with no improvement in her clinical or biochemical parameters. A repeat arterial blood gas showed that pH remained at 6.91, standardized bicarbonate 5.8 mmol/L, and glucose of 5.7 mmol/L. Interim urinalysis tested positive for trace protein, leukocytes, and strongly positive for ketones. Blood ketones (3-hydroxybutyrate point-of-care ketone meter) were markedly elevated at 5.8 mmol/L. A broader history enquiring of potential causes of raised anion gap acidosis such as methanol, ethylene glycol, or salicylate ingestion revealed no obvious precipitant. A provisional diagnosis of euglycemic ketoacidosis of uncertain etiology was assumed with the hypothesis that marked insulin resistance was precipitating a ketoacidotic state. She was transferred to the high-dependency unit, and 1000 mL of 5% dextrose was administered over 30 minutes. Her measured ketones improved to 4.5 mmol/L, and her pH increased to 7.06. She was started on an IV infusion of 20% dextrose after which her ketone levels were decreased to 0.1 mmol/L and her pH normalized over the next 8 hours (Figure 1).

Figure 1.

Figure 1.

Concomitantly, her symptomatology steadily improved over the same timeframe. Subsequent questioning revealed that she frequently skipped meals to lose weight while exclusively breastfeeding her 9-week-old child who was undergoing a growth spurt. What meals she had been consuming tended to be high protein and low carbohydrate to facilitate weight loss.

Back to Top | Article Outline

DISCUSSION

Lactation ketoacidosis is a rare metabolic disturbance whereby a perfect storm of negative calorie balance (starvation/glucose preferentially used for milk production)1 and insulin resistance (counter regulatory stress hormone release/infection) leads to a raised glucagon:insulin ratio and subsequent ketogenic state (Figure 2).

Figure 2.

Figure 2.

In additional to glycogen depletion, there is an obligate energy loss of approximately 500 kcal/d2 more than nonlactating women as a result of breastfeeding. The historical title “bovine ketoacidosis” comes from the first 2 case reports3,4 that likened it to the phenomenon that occurs in frequently lactating cattle. In approximately 20% of cattle, the metabolic and glucose demands of milk secretion exceed the cow’s carbohydrate and glycogen stores.5 Early ketosis and inhibition of gluconeogenesis reflect both glucose- and protein-sparing mechanisms that enable lactation yet preserve lean body mass.5 However, the term is a misnomer, because the phenomenon in cattle is usually a ketosis rather than ketoacidosis. The ketotic state only progresses to ketoacidosis once usual physiologic-buffering mechanisms are exceeded. In humans, the condition has been only been described 9 times in the literature; however, 4 of these have been in the last calendar year.3,4,6–12

Back to Top | Article Outline

Biochemistry

Ketone bodies are produced by the liver and used peripherally in the heart, brain, and renal cortex as an energy substrate when glucose is not readily available. Human brain cells are ill equipped to utilize free fatty acids when blood glucose levels become compromised and instead rely on ketone bodies that can provide over half the energy substrate during periods of starvation.13

Acetoacetate is the main ketone body with 3-hydroxybutyrate and acetone forming from the reduction and decarboxylation of acetoacetate, respectively. In times of carbohydrate deficiency, the glycolytic product pyruvate diminishes leading to a deficiency of oxaloacetate in the citric acid cycle.13 Beta-oxidation of free fatty acids is stimulated by the rising levels of the counterregulatory stress hormones adrenaline and glucagon, leading to a large accumulation of acetyl coenzyme A (CoA). The high levels of acetyl CoA and low levels of oxaloacetate precipitate shunting of the excess acetyl CoA down the ketogenic pathways. Three enzymes are critical in the activation of ketone body formation: hormone sensitive lipase, acetyl CoA carboxylase, and 3-hydroxy-3-methylglutaryl-CoA synthase. All 3 promote ketone formation in the setting of a high glucagon:insulin ratio as occurs in times of stress and starvation.14 Once ketone bodies form, they pass freely across cell membranes via monocarboxylate transporters. They are strong ions and fully dissociate at physiological pH14 and are comfortably buffered in times of rest by the body’s usual physiologic-buffering mechanisms.

Back to Top | Article Outline

Differential of Ketoacidosis

There are a number of recognized causes of ketoacidosis, all of which are intuitive based on the knowledge of these biochemistry pathways (Table).

Table.

Table.

Having tested positive for ketones in blood and urine, the likely cause of her raised anion gap metabolic acidosis was ketoacidosis. We sequentially ruled out competing causes of ketoacidosis clinically and biochemically. The patient had no history of diabetes or gestation diabetes, had normal serum glucose concentrations, and had a DCCT HbA1c of 5.8% making euglycemic diabetic ketoacidosis highly unlikely. She was not chronically malnourished, had an above average body mass index, and denied any toxin ingestion on direct questioning. It is also possible to identify a delayed initial presentation of an inherited metabolic disorder by a gene panel and urinary organic acid analysis. However, given her initial response to treatment and subsequent maintained clinical improvement, these tests were not performed.

As often seen in diabetic ketoacidosis, the calculated anion gap of −29 mmol/L considerably exceeded that directly accountable by ketone bodies alone. The cause of this is likely 2-fold. First, blood ketone meters traditionally check β-hydroxybutyrate only and exclude the contribution of acetoacetate and acetone. Second, the low-molecular-weight intermediary bodies of metabolism such as isocitrate, malate, d-lactate, and α-ketoglutarate may also be raised in ketoacidotic states. Because these are not routinely tested, they are not included when calculating the anion gap.15

Back to Top | Article Outline

Clinical Implications

The key to inhibiting a ketogenic state is to reverse the raised glucagon-to-low-insulin ratio. Because she had no history of diabetes and had a normal blood sugar level, it was intuitive that our patient’s pancreas retained the capacity to secrete enough insulin to suppress ketogenesis and hopefully prevent rebound hyperglycemia. The amount of insulin secreted per gram carbohydrate shows significant interindividual variation. Thus, she was started on a 20% glucose infusion that was titrated between 10 and 20 mL/h. As seen in Figure 1, her pH steadily increased to 7.41 over a 10-hour time, and her bicarbonate increased correspondingly to 24 mmol/L with ketones falling from 5.9 to 0.1 mmol/L. Although some case reports used 8.4% sodium bicarbonate and/or IV insulin empirically as part of initial therapy,7,8,10,12 we managed to correct her similarly profound acidemia with supplementary glucose alone.

All other cases reported have advocated the cessation of breastfeeding, yet our patient expressed a strong desire to continue breastfeeding. Our clinical nutrition department drafted a suitable frequent carbohydrate dietary regime that enabled her to continue breastfeeding. She continued to successfully breastfeed her baby without any adverse events postdischarge.

Of interest, this is the fifth case of lactation ketoacidosis this calendar year,9–12 and all cases related to maternal weight loss in the setting of lactation with additional physiologic stress. A survey from the Royal College of Midwives of 1105 new mothers found that 82% felt weight gain after pregnancy affected their self-esteem and 38% considered a fad diet before enrolling in a managed weight loss program.16 There have also been numerous case reports of ketoacidosis associated with very low carbohydrate diets,17,18 the safety of which remains controversial.19 The safety of these diets in the setting of lactation is unknown, and 85% of new mothers described the overall care from midwives regarding healthy eating and weight management while lactating as neutral, poor, or very poor in the same college of midwives survey.16

Back to Top | Article Outline

CONCLUSIONS

Lactation ketoacidosis is a potentially life-threatening state that appears to be occurring in increasing frequency in lactating women when the metabolic demands of breastfeeding, marked nutritional deficiency, and an abnormal glucagon:insulin ratio lead to a severe ketoacidotic state. Potentially significant morbidity and mortality can be prevented with early recognition and appropriate glucose and electrolyte administration. Breastfeeding mothers should be appropriately educated about the risks associated with carbohydrate avoidance while lactating.

Back to Top | Article Outline

REFERENCES

1. Mohammad MA, Sunehag AL, Chacko SK, Pontius AS, Maningat PD, Haymond MW. Mechanisms to conserve glucose in lactating women during a 42-h fast. Am J Physiol Endocrinol Metab 2009;297:E87988.
2. Tigas S, Sunehag A, Haymond MW. Metabolic adaptation to feeding and fasting during lactation in humans. J Clin Endocrinol Metab 2002;87:3027.
3. Chernow B, Finton C, Rainey TG, O’Brian JT. “Bovine ketosis” in a nondiabetic postpartum woman. Diabetes Care 1982;5:479.
4. Altus P, Hickman JW. Severe spontaneous ‘bovine’ ketoacidosis in a lactating woman. J Indiana State Med Assoc 1983;76:3923.
5. Holtenius P, Holtenius K. New aspects of ketone bodies in energy metabolism of dairy cows: a review. Zentralbl Veterinarmed A 1996;43:57987.
6. Heffner AC, Johnson DP. A case of lactation “bovine” ketoacidosis. J Emerg Med 2008;35:3857.
7. Sandhu HS, Michelis MF, DeVita MV. A case of bovine ketoacidosis in a lactating woman. NDT Plus 2009;2:2789.
8. Szulewski A, Howes D, Morton AR. A severe case of iatrogenic lactation ketoacidosis. BMJ Case Rep 2012;2012:.
9. Monnier D, Goulenok T, Allary J, Zarrouk V, Fantin B. Starvation ketosis in a breastfeeding woman. Rev Med Interne 2015;36:8548.
10. von Geijer L, Ekelund M. Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. J Med Case Rep 2015;9:224.
11. Wuopio J, Schiborr R, Charalampakis G. Severe ketoacidosis in breastfeeding woman with low energy and carbohydrate intake. Lakartidningen 2015;112:.
12. Hudak SK, Overkamp D, Wagner R, Häring HU, Heni M. Ketoacidosis in a non-diabetic woman who was fasting during lactation. Nutr J 2015;14:117.
13. Davids MR, Segal AS, Brunengraber H, Halperin ML. An unusual cause for ketoacidosis. QJM 2004;97:36576.
14. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15:41226.
15. Forni LG, McKinnon W, Lord GA, Treacher DF, Peron JM, Hilton PJ. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care 2005;9:R5915.
16. Carolyn P. Most New Mums Have Low Self-esteem and Feel Under Pressure to Lose Baby Weight. October 13, 2013. Accessed December 8, 2015Royal College of Midwives, Available at: https://www.rcm.org.uk/content/most-new-mums-have-low-self-esteem-and-feel-under-pressure-to-lose-baby-weight-survey-shows.
17. Shah P, Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006;354:978.
18. Chen TY, Smith W, Rosenstock JL, Lessnau KD. A life-threatening complication of Atkins diet. Lancet 2006;367:958.
19. Manninen AH. Metabolic effects of the very-low-carbohydrate diets: misunderstood “villains” of human metabolism. J Int Soc Sports Nutr 2004;1:711.
Copyright © 2016 International Anesthesia Research Society