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Sunday 18 October 2015

Breastfeeding on a low carb diet - is there an increased risk of ketoacidosis?

[Disclaimer: I have never breast fed a baby and thus have no practical experience of this subject. This blog post details the insights into this problem that can be found in the medical literature and is not intended as medical advice.]

Any disaster that may overtake him, even to the extent of

ground moles getting in his lawn, will be blamed on his "red
meat" diet.
                - Blake Donaldson, Strong Medicine 1961 (download here)

Lactation ketoacidosis is a rare event in humans, and the authors of a 2012 case study could only find four previous cases in the literature.[1]
Non-diabetic ketoacidosis outside of breastfeeding related to diet is also rare, with 3 cases (including one unexplained death) attributed to the Atkins diet. It will be seen from the example given here the role that fluid and electrolyte loss from vomiting can play in the condition.[2]

What all these cases seem to have in common is rapid weight loss; they also (where information is available) tend to involve illness with loss of appetite, fasting, or deliberate undereating. There are also cases involving recent or historical gastric bypass surgery. I am unable to find a case of diet-related ketoacidosis in a male, or of either lactation or LCHF diet-related ketoacidosis in anyone with type 2 diabetes, type 1 diabetes, or gestational diabetes (however diabetic ketoacidosis is an infrequent complication of pregnancies in gestational diabetes). On the other hand, anorexia and bulimia are associated with diabetic ketoacidosis in insulin-dependent diabetics.
The Association of British Clinical Diabetologists states that diagnosis of ketoacidosis should only be confirmed with a concomitant blood glucose over 11.1 mmol/l or known diabetes, and significant acidosis (arterial pH below 7.3 or venous bicarbonate below 15 mmol/l). Thus the non-lactation case in ref [2] qualifies, despite normal HbA1c, but the lactation ketoacidosis cases do not because blood glucose in these cases is at normal or lower than normal levels.
Recently two cases of lactation ketoacidosis in Sweden have been given wide publicity. The first of these is discussed by Andreas Eenfeldt here on his diet doctor blog, and can clearly be attributed to inability to eat for a prolonged period, unrelated to the diet - the woman concerned now says that she continues to breastfeed at 10 months on an LCHF diet; if the diet composition was the cause of the ketoacidosis the risk would have increased as the child's milk requirement grew.
The second case might give us more prima facie reason to suspect a mechanism related to diet composition.

"A 32-year-old white woman presented to our county hospital with a history of nausea, vomiting, heart palpitations, trembling and extremity spasms. She had started a strict LCHF diet, with an estimated carbohydrate intake of less than 20g per day, 10 days before admittance, lost 4 kilograms and had felt growing malaise. She was breastfeeding her son of 10 months of age.
An arterial blood gas was taken. It revealed pH 7.20, base excess (BE) −19, partial pressure of carbon dioxide (pCO 2 ) 2.8 kPa, glucose 3.8mmol/l and lactate 1.0mmol/l. Her blood ketones were 7.1mmol/l (reference 0 to 0.5mmol/l). The primary diagnosis was thought to be ketoacidosis due to starvation induced by the LCHF diet."[3]

The authors concluded "A lactating woman has a high demand of substrate to produce milk. A LCHF diet limits the amount of substrate and results in a negative energy balance. This kind of diet should thus be avoided during lactation."

This is vague. What is the substrate(s), and are they limited by the LCHF diet itself, or by negative energy balance, which is something that can occur on any weightloss diet or as a result of undereating for any reason? There is a case study of lactation ketoacidosis occurring in someone eating a normal diet with a healthy appetite (the possible triggers were feeding twins, albeit with some formula feeding, and gastric bypass surgery some 5 years previously).[4] What aspects of LCHF if any would counsel avoidance during lactation, and what if anything can be done to modify these, given that ketogenic LCHF will be some mothers' choice of a natural treatment for potentially serious medical conditions, and not only a way to regain one's original silhouette?

The substrates for milk production are amino acids for protein synthesis, triglycerides (fatty acids and glycerol) and glucose for fat synthesis, and glucose (or other sugars) and glycerol for lactose synthesis. In the carbohydrate-fed state all lactose (a disaccharide formed by joining one molecule of glucose and one molecule of galactose) can be made from glucose, in the fasting state glycerol is the substrate for the majority of the galactose portion, but not the glucose.[5] If galactose is present in the diet it will be incorporated into lactose in the breast (rather than being converted to glucose in the liver).

Lactation ketoacidosis is sometimes called "bovine" ketoacidosis because it is similar to the ketoacidosis seem in milking cows. However there is an important difference as acetate is the main substrate in ruminants. Hexoneogenesis involves the interconversion of glucose or glycerol to glucose or galactose via the normal glycolytic or pentose-phosphate pathways, so does not require the removal of oxaloacetate from the TCA cycle, whereas generation of glucose and galactose from acetate in ruminants involves removing oxaloacetate from the TCA cycle, increasing the rate of ketogenesis.
In starvation and carbohydrate restriction, ketogenesis from fatty acid oxidation in the liver is in large part a byproduct of gluconeogenesis - when there is little glucose in the diet, the liver needs to make glucose from amino acids and glycerol. Removal of oxaloacetate from the TCA cycle to form glucose means that all the acetyl-CoA yielded from fatty acid beta-oxidation cannot enter the TCA cycle by condensing to citrate, and some is converted to ketone bodies which are exported from the liver instead.
It is the removal of blood glucose for breast milk production and compensatory production of extra glucose by the liver that may have the potential to raise ketones above the level usually seen on ketogenic diets. The removal of glycerol for fasting breast milk production also means that this substrate for hexoneogenesis, which also supplies oxaloacetate to the TCA cycle and is the main substrate for fasting hepatic glucose production, needs to be plentiful in the LCHF diet (i.e. by keeping fat intake high).
Because blood glucose may be unusually low, insulin sensitivity is high and insulin is low. Whereas ketoacidosis is reversed with glucose and insulin. This may explain why lactation ketoacidosis and diet-related ketoacidosis isn't seen (as far as I can tell from the literature) in people with type 2 diabetes, in whom high insulin and high glucose will continue to suppress ketosis.

Ref [3] may also indicate that the period of ketoadaptation presents a increased risk of lactation ketoacidosis (or it may not, given how rare such cases are).

Ketoacidosis is unlikely in a fat-adapted person, because ketone and non-hepatic FFA clearance has increased, electrolytes are back in balance, and stress hormones have normalised. Perhaps trying to ketoadapt while lactating is like trying to ketoadapt while running a marathon.

In the case of lactation, the doubled demand for glucose GNG could cause a sudden rise in ketones during ketoadaptation - making it too easy to get into deep ketosis before the body has fully adapted to utilize ketones or regulate ketogenesis.  Meanwhile, the loss of electrolytes during ketoadaptation (due to the diuretic effects of glycogen loss), especially in someone who doesn't eat enough salt, could result in a decreased ability to buffer serum ketoacids. Electrolytes are also being incorporated into the milk and have been contributing to fetal growth before that.
It seems to me that in a woman who has already adapted to the LCHF diet, especially if she has a hyperinsulinaemic condition as her reason for LCHF eating, the conditions that predispose to ketoacidosis are reduced, especially if sudden weight loss is avoided.
On the other hand lactation, by diverting sugars into milk, will also increase glucose tolerance, and breastfeeding decreases a woman's future risk of type 2 diabetes.[6]

A comment (by greensleeves21) on the Diet Doctor blog includes the following observation:

"The old Atkins community group heard Dr. Atkins once caution against this theoretically possible scenario & ever since their official recommendation was that breastfeeding moms should never fast, get 3 square meals a day & eat 60-70 carbs a day to avoid it. So I guess there is some validity to that old recommendation to avoid such rare cases."

If one was to take this advice, what food source of carbohydrate would be best for the extra 30-50g? It seems to me from the studies I've read that cow's milk would be ideal, at least for part of it, IYTI. In the first place, the galactose in milk, 50% of its carbohydrate content, will be directly incorporated into breast milk with little effect on blood sugar (this is likely true of glucose as well, as when a fat-adapted athlete sips a glucose gel in the middle of an endurance event, and the sugar is skimmed off the top into the muscles and does not interfere with fat adaptation).[7] Milk also supplies glycerol and short- and medium-chain fats, and as short-chain and medium-chain fats are not present in large amounts in body stores and are synthesised by the breast, with glycerol and glucose as potential substrates, including them in the diet by eating full fat dairy foods seems prudent.[8, 9] Galactose is also present in appreciable amounts in non-starchy leaf and root vegetables, especially beetroot and celery.

Mahommad, Sunemag and Haymond have provided most of the experimental research into the metabolic pathways involved in lactation and its adaptation to fasting and low carb diets that I have drawn on. They have tested the effect of a hypocaloric low carb high fat diet (1800 kcal, 31%E or 137 g/d CHO) on weight loss and milk composition during lactation in a short crossover study (n=7).[10]
The high fat diet included eggs, butter, cheese and cream. The average infant in this study consumed 486 kcal of milk, including 44g lactose, 11g protein, and 29g fat per day, on the low-carb diet (this was not significantly different from the milk in the high carb arm).

There are other considerations when using low carb purely for weightloss that are discussed on this La Leche League post.[link] In particular the warning to avoid sudden weight loss because of potential mobilization of persistent environmental toxins stored in body fat makes me speculate whether this effect played a role in the sickness that stopped some of the subjects in the case studies from eating. We'll never know of course.

Some of the foods commonly eaten on LCHF diets, such as fermented meats, shellfish, pre-packed salads and some cheeses, present a listeria risk during pregnancy and need to be avoided.  There is a list of these foods here.

To summarise - 

- Ketoacidosis can occur on rare occasions due to sudden weight loss or inability to eat while breastfeeding on a variety of diets - undereating should thus be avoided. 

- The increased demand for sugars for milk lactose synthesis may play a role in the strict LCHF cases but this need is small (the Atkins recommendation of 60-70g/day would cover it). 

- Sugars from milk and some non-starchy vegetables and medium-chain fats from full-fat dairy can be incorporated into human milk with minimal effects on glucose tolerance.

- No cases of LCHF ketoacidosis or lactation ketoacidosis in type 2 diabetics (or any diabetics) could be found, possibly because type 2 diabetics have higher blood glucose and glycerol and higher fasting insulin than non-diabetics.

- Adapting to a very low carbohydrate ketogenic diet is best done when physiological and emotional stresses in one's life are minimal, 
if this is at all possible. Adaptation to other degrees of carbohydrate restriction that are effective for weight control and metabolic health presents minimal challenges.

From a Mexican science paper - look what your dietary guidelines have done America.

[1] Learning from errors. A severe case of iatrogenic lactation ketoacidosis. Szulewski A, Howes D, Morton AR. BMJ Case Reports 2012; doi:10.1136/bcr.12.2011.5409

[2] Ketoacidosis during a Low-Carbohydrate Diet. Shah, P, Isley, WL. N Engl J Med 2006; 354:97-98 January 5, 2006; doi:10.1056/NEJMc052709 

[3] Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. von Geijer L, Ekelund M. Journal of Medical Case Reports (2015) 9:224 doi: 10.1186/s13256-015-0709-2

[4] A Case of Lactation "Bovine" Ketoacidosis. Heffner AC, Johnson DP. The Journal of Emergency Medicine, Vol. 35, No. 4, pp. 385–387, 2008. doi:10.1016/j.jemermed.2007.04.013
[5] Precursors of hexoneogenesis within the human mammary gland. Mohammad MA, Maningat P, Sunehag AL, Haymond MW. Am J Physiol Endocrinol Metab 308: E680–E687, 2015. doi:10.1152/ajpendo.00356.2014

[6] Lactation Intensity and Postpartum Maternal Glucose Tolerance and Insulin Resistance in Women With Recent GDM. The SWIFT cohort. Gunderson AP et al.  Diabetes Care January 2012 vol. 35 no. 1 50-56. doi: 10.2337/dc11-1409

[7] Galactose promotes fat mobilization in obese lactating and nonlactating women.
Mohammad MA, Sunehag AL, Rodriguez LA, Haymond MW. Am J Clin Nutr. 2011 Feb;93(2):374-81. doi: 10.3945/ajcn.110.005785. Epub 2010 Dec 1.
[8] De novo synthesis of milk triglycerides in humans. Mohammad MA, Sunehag AL, Haymond MW. Am J Physiol Endocrinol Metab. 2014 Apr 1; 306(7): E838–E847.  doi:  10.1152/ajpendo.00605.2013

[9] Acute effects of dietary fatty acids on the fatty acids of human milk.
Francois CA, Connor SL, Wander RC, Connor WE. Am J Clin Nutr. 1998 Feb;67(2):301-8.

[10] Effect of dietary macronutrient composition under moderate hypocaloric intake on maternal adaptation during lactation. Mohammad MA, Sunehag AL, Haymond MW. Am J Clin Nutr June 2009 vol. 89 no. 6 1821-1827. [link]

Tuesday 6 October 2015

Do moderate ketone levels from low carb protect against symptomatic hypoglycemia in type 1 diabetes? A relevant case study.

Before many can know something, one must know it. 
- Dr Stockmann, in Ibsen's An Enemy of the People.

One of the benefits of a very low carbohydrate diet for type 1 diabetes is a much lower rate of hypoglycemic episodes, because of the need for less insulin, lower insulin doses and longer acting insulin overall (a greater proportion of the insulin used is basal dose). This is predicted by the laws of small numbers.
It is also reported anecdotally that hypoglycemia, when it does occur by the meter, is often non-symptomatic. The milder symptoms aren't easily ignored, and severe hypoglycaemia can lead to seizures, unconsciousness, and death. This is because the brain requires glucose at a steady rate. The brain can also use ketone bodies, which are generated by the liver from the incomplete combustion of fatty acids and some amino acids on a low carb diet. On the Bernstein diet carbohydrate intake is around 30g/day and this would provide deep ketosis if the protein intake were not high. As it is, the ketone level in someone on the Bernstein diet has been reported as 2 mmol/L.

Is this enough to protect against symptoms in insulin-induced hypoglycaemia? Does an oversupply of insulin suppress ketogenesis in the absence of carbohydrate?

These questions are impossible to test in someone with Type 1 Diabetes, no ethics committee would approve the experiment.

Luckily a case study has just been published that seems to answer them. Thanks to Bill Lagakos @caloriesproper for tweeting this.

Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage. 
Maiorana, A, Manganozzi, L, Barbetti, F, Bernabei, S, Gallo, G, Cusmai, R, Caviglia, S, Dionisi-Vici, C. Orphanet Journal of Rare Diseases 2015, 10:120  doi:10.1186/s13023-015-0342-6

The subject is a child with congenital hyperinsulinism, that is, she has chronic high insulin levels (without apparent insulin resistance) and eating carbohydrate to relieve hypoglycaemia causes a further increase in insulin.

In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae.
A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs.We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life.

Note the points that a) insulin suppresses ketogenesis by suppressing lipolysis, b) neurologists know that lactate is a cerebral energy substrate.

At the age of 3 years laboratory tests were performed and showed hypoglycemia with hyperinsulinemia (blood glucose 1.95–2.3 mmol/L; plasma insulin 5.5–10.2 μUI/ml).

 A further association with slow-release carbohydrate to drugs did not elicit any clinical improvement, and the patient continued to present hypoglycemic episodes (0.5–1.6 mmol/L), seizures and absence epilepsy regardless of glycemic values, that required frequent hospitalizations.

Furthermore, at the age of 10 years the patient quickly gained 11.5 kg within 12 months, becoming mildly obese (BMI z-score: >97 th centile). Overall, her quality of life was very poor. The lack of response to drug therapy with risk of permanent and severe brain sequelae made us to consider a near-total pancreatectomy, that was discussed with parents with the warning of no guarantee to achieve normoglycemia and of the increased hazard of secondary diabetes. At parents’ request to avoid surgery, we then proposed a trial with KD, explaining that it was aimed to prevent neuroglycopenic epilepsy and to improve neurological status by providing ketone bodies as an alternative energy source for neurons, as seen in GLUT1 deficiency.

Six months after KD was started, maintenance of blood ketones between 2–5 mmol/L (Fig. 1, panel a) fully resolved neuroglycopenic signs with parallel disappearance of both epileptic crisis and absence epilepsy, despite blood glucose levels permanently below 5.5 mmol/L even after meal, and close to 2.2–2.7 mmol/L most of time (Fig. 1, panel b). EEG improved and became normal within the first year on KD, showing no alteration even during episodes of hypoglycemia (Fig. 2). During the first 6 months of KD the patient lost 9 kg and her BMI normalized. Psychological evaluation revealed a strengthening of social, cognitive and verbal capacities (Fig. 3). The child and her family reported an improvement of physical and psychosocial well-being, reduction of fear of hypoglycemic symptoms and awareness of a lower risk of neurological injury, with an overall amelioration of the quality of life related to the management of disease. Diazoxide was discontinued, and currently the patient is given octreotide, reduced to 25 μg/kg/day, without any neuroglycopenic symptoms. KD was well tolerated over a period of 24 months, with no side-effects and no changes in laboratory tests.

Thus we see some relevant findings - excessive levels of insulin doesn't suppress ketogenesis completely on a ketogenic diet (but I would really like to know what the insulin levels were on the KD). Ketones rise steadily proportionate to the ketogenic ratio, there is no cut-off. Ketones can replace glucose in insulin-induced hypoglycaemia, as expected - and were still present in sufficient amounts to do so. Insulin doesn't cause weight gain in the absence of carbohydrate.
An interesting question is whether the insulin resistance that is supposed to be caused by a high-fat diet played a role in this child's recovery by increasing lipolysis, as shown by the weight loss.

This is a neat study that confirms the anecdotal accounts that hypoglycemic episodes in type 1 diabetes are less symptomatic on a very low carb diet (that they are much fewer is already confirmed). Of course we would like more information about this, but this young girl's ordeal, and her convincing recovery, is compelling evidence that we haven't been barking up the wrong tree, given the difficultly of gathering any evidence at all about what happens in this situation.

For support and information about the Bernstein Diet for type 1 diabetes, join the TypeOneGrit group on Facebook. For Dr Bernstein's book, look here. For more information, see Dr Bernstein's YouTube Channel "Dr Bernstein's Diabetes University".

Before many can know something, one must know it.