Q J Med 2004; 97: 365-376
QJM vol. 97 no. 6 © Association of Physicians 2004; all rights reserved.
Masterclasses in medicine |
An unusual cause for ketoacidosis
From the 1Nephrology Unit and Department of Internal Medicine, University of Stellenbosch, Cape Town, South Africa, 2Division of Nephrology, University of Vermont, Burlington, USA, 3Department of Nutrition, Case Western Reserve University, Cleveland, USA, and 4Division of Nephrology, St Michael's Hospital, University of Toronto, Toronto, Canada
 |
Summary |
|---|
 Top Summary IntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
A 22-year-old male developed a severe degree of metabolic acidosis (plasma pH 7.20, bicarbonate 8 mmol/l), with a large increase in the plasma anion gap (26 mEq/l). Ketoacidosis was suspected because of the odour of acetone on his breath and a positive qualitative test for acetone in plasma (to a 1:4 dilution). Later, his plasma ß-hydroxybutyrate concentration was found to be 4.5 mmol/l. After receiving an infusion of 1 l of half-isotonic saline and 1 l of 5% dextrose in water over 24 h, as well as curtailing his large oral intake of sweetened beverages, all blood tests became normal. Diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketosis and hypoglycaemic ketoacidosis were all ruled out, and his toxin screen was negative for salicylates. Finding another possible cause for ketoacidosis became the focus of this case.
|
Introduction |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
In our continuing series on the application of principles of integrative physiology at the bedside, once again the central figure is an imaginary consultant, the renal and metabolic physiologist, Professor McCance, who deals with data from a real case. On this occasion his colleague Sir Hans Krebs, an expert in the field of glucose and energy metabolism, assists him in the analysis. Their emphasis is on concepts that depend on an understanding of physiology that crosses subspecialty boundaries. To avoid overwhelming the reader with details, key facts are provided, but only when necessary. The overall objective of this teaching exercise is to demonstrate how application of simple principles of integrative physiology at the bedside can be extremely helpful for clinical decision-making (Table 1).
|
|
The consultation |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
The housestaff were stumped by this perplexing case (more complete information is provided in Appendix 1 and Table 2). They were evaluating a patient who had metabolic acidosis accompanied by a large increase in the plasma anion gap (Table 3). Because of the odour of acetone on his breath and a positive test for plasma ketones, he appeared to have ketoacidosis. However, try as they might, the data did not fit into any of the entities in their differential diagnosis of ketoacidosis (Table 3). The next step was obvious: seek a consultation with Professor McCance.
|
|
As the intern began to present the patient's history and physical findings, Professor McCance stopped her. He wanted only the most important data to begin his analysis and asked his younger colleagues to formulate their questions with precision.
The intern summarized their puzzling case succinctly—the patient had two major laboratory findings—the plasma pH was 7.20 and the concentration of bicarbonate in plasma (PHCO3) was 8 mmol/l. As usual, Professor McCance began by considering any potential threats to the patient and he therefore asked the group, ‘Why might a patient with metabolic acidosis die suddenly?’
Question 1. Why might a patient with metabolic acidosis be likely to die suddenly?
Physiology principle 1. A high H+ concentration per se is seldom life-threatening.
If subjects who have more severe metabolic acidosis than this patient survive, it is difficult to believe that a high H+ concentration is a direct cause of death. The best example of this principle is that the arterial pH may be <7.00 at the end of a 10 second sprint, yet every runner survives.1
Return to the bedside: Professor McCance concluded that the threat to survival is probably due to something related to the basis for the acidosis, rather than in the pH per se. Therefore, he examined the list of causes of metabolic acidosis provided by the medical housestaff, and briefly pointed out the possible threats to the patient in each of these categories (Table 5). In his usual methodical fashion, he then proceeded to the next question.
|
|
Question 2. What is the most likely basis of metabolic acidosis in this patient?
Physiology principle 2. One can deduce that H+ ions have been added when new anions appear in the body and/or in excreted fluids.
Return to the bedside: There are two types of metabolic acidosis: a gain of acids and/or a loss of NaHCO3. Therefore if one suspects a gain of acids, one must hunt for the presence of new anions by finding their ‘chemical or electrical shadow’. The simplest clinical tool used to detect new anions is a rise in the anion gap in plasma. The rationale is as follows. When an acid is added and dissociates, the H+ ions formed react with HCO3– ions and remove an equimolar amount of this anion. The conjugate base of this acid takes the electrical place of HCO3– ions in the extracellular fluid (ECF) compartment (Figure 1). This 1:1 stoichiometry in mEq/l causes many clinicians to expect that the surplus of new anions (reflected by the rise in the anion gap in plasma) will equal the deficit in HCO3– (reflected by the (PHCO3). This is only correct if there is no change in the ECF volume. McCance emphasized that in diabetic ketoacidosis or alcoholic ketoacidosis, this assumption is incorrect. A recent example that illustrates this point can be found in reference 2.
|
Question 3. What clues are useful to identify the nature of the acid that was retained in the body?
Physiology principle 3. Identify the acid by considering the properties of the anion.
There are several aspects to consider (Table 1, Principle 3), but we shall first examine the rate of new acid production, as the metabolic acidosis seemed to develop over 24 h.
Return to the bedside: There are only two explanations for a rapid gain of H+—ingestion of acids, and L-lactic acidosis, where the cause is an inadequate supply of oxygen to meet tissue demands. Our patient did not have a history of ingestion of the usual toxins, nor was his plasma osmolal gap elevated. There were no clues suggesting L-lactic acid overproduction: blood pressure and circulation were normal, cyanosis was not evident, and he did not have a history of previous bouts of L-lactic acidosis. The only factor that might have suggested rapid production of L-lactic acid was that the patient was extremely agitated. This possibility, however, was ruled out when the plasma L-lactate concentration was measured—it was not elevated.
Having ruled out the largest group in the differential diagnosis of metabolic acidosis, Professor McCance moved on to consider renal failure as a possible cause.
Question 4. Why do patients with renal insufficiency develop metabolic acidosis accompanied by an increase in the plasma anion gap?
Physiology principle 4. Metabolic acidosis develops when the kidney fails to add new HCO3– to the body—this is the result of a low rate of excretion of ammonium (NH4+)3.
Electroneutrality must be present, so the kidney must make NH4+ with an organic anion. In biochemical terms, this anion is 2-oxoglutarate2–, a component of the Krebs cycle, which is metabolized further to yield HCO3– ions that are added to the blood. In summary, the net effect of all these tubular functions is to replace Cl– in the blood with HCO3–, and to excrete NH4+ and Cl– in the urine (Figure 2).
|
‘But if the kidney fails to add new HCO3– to the blood, why does the plasma anion gap rise?’ asked a curious medical student. McCance responded to this excellent question by pointing out that it was all due to the ongoing dietary acid load (mainly from the oxidation of sulphur-containing amino acids, producing sulphuric acid). The concentration of sulphate anions in plasma rises when the GFR is depressed. A reduction in the GFR also results in a fall in renal NH4+ production4 and a low rate of excretion of NH4+. Therefore with less HCO3– added to the body, there is an increased anion gap type of acidosis. The intern volunteered that the plasma creatinine and urea were in the normal range, and that they had ruled out renal insufficiency as the basis of the metabolic acidosis.
Metabolic acidosis with a large increase in the plasma anion gap has a well-defined list of causes (Table 3).5–8 In a young male with no evidence of renal insufficiency, hypoxia, nutritional (e.g. B vitamins) deficiency, or toxin ingestion, the differential diagnosis centres on ketoacidosis9 or organic acid over-production by the gastrointestinal (GI) tract.10
Question 5. What might suggest that there was no overproduction of organic acids by the gastrointestinal tract?
The absence of antibiotic use, which might change the GI bacterial flora, or low gastrointestinal motility and/or a blind loop of bowel, makes D-lactic acidosis unlikely as a sole or major cause of the metabolic acidosis.10
Question 6. Could this be ketoacidosis?
Physiology principle 5. Ketoacids are brain fuels, produced when there is insufficient insulin action for a protracted period.
There will be a low insulin level if we lack a stimulus for its release (hypoglycaemia), if an inhibitor for insulin release is present, or if there is major damage to pancreatic islets.
Return to the bedside: The usual differential diagnosis of ketoacidosis is listed in Table 3. Nevertheless, the team could not assign their patient to one of the known categories. In more detail, being well aware of Principle 5, they had quickly confirmed that the patient had a normal plasma glucose level (PGlu), that he had not taken alcohol or any drugs that inhibited insulin release, and that he was not diabetic. In addition, he had a complete recovery in 24 h, and had had several similar episodes in the past (later, they would also learn that his plasma insulin was in the normal range). Therefore they were very reluctant to make a diagnosis of ketoacidosis from any of the usual causes.
Despite the obvious difficulty in assigning the patient to one of the usual causes (Table 3), Professor McCance was not prepared to simply dismiss the data in hand. Because acetone was detected in the exhaled air and in serial dilutions of plasma, he was convinced that ketoacidosis remained the most likely diagnosis. Just then the Chemical Pathology registrar called to confirm that there was an elevated plasma ß-hydroxybutyrate (ß-HB) concentration (4.5 mmol/l). Professor McCance was delighted. Perhaps they were on the brink of adding a new cause of ketoacidosis to the list. The medical team shared his excitement—could they apply the principles of physiology they had learnt, and suggest a novel basis for ketoacidosis? Recognizing the need for the advice of an expert on intermediary metabolism, McCance suggested that they adjourn the round, read more about this subject, and call on an old friend, Sir Hans Krebs. They would reconvene tomorrow morning and continue their exploration of this fascinating case.
The following day, over a steaming cup of tea, Sir Hans led the way. ‘So what are the conditions within the liver that are required to develop ketoacidosis?’ he began.
Physiology principle 6. Ketoacids are produced in the liver from acetyl-CoA, usually derived from fatty acids.
Ketoacidosis is not simply due to an oversupply of the regular precursors of acetyl-CoA to the liver. There must also be a low net insulin level, feedback inhibition of the TCA cycle related to the need to regenerate ATP, and inhibition of fatty acid synthesis. At this point it appeared that Professor Krebs lapsed into silence, appearing deep in thought, and almost oblivious to their presence. His colleagues waited anxiously, wondering what new insights might emanate from this reverie. They were not disappointed. Apologizing when he noticed the silence, he leapt to his feet, grabbed a piece of chalk and started scribbling furiously on the blackboard. He had a new emphasis concerning the regulation of ketoacid formation that he could not wait to share with the group. ‘When large amounts of acetyl-CoA are formed in hepatic mitochondria, inhibition of fatty acid synthesis should become the most important metabolic alteration in the liver that leads to ketoacid overproduction, because this pathway has a large capacity for acetyl-CoA removal’ he declared. The next step is to appreciate the hormonal setting required for this inhibition, namely low insulin and high glucagon. It is also important to consider how rapidly ketoacids can be made, because this hormonal profile ‘gives permission’ for, but does not set the upper limit on the rate of, ketogenesis. To understand this upper limit, we must return to the physiology of ketoacids during prolonged fasting.11
In this setting, ketoacids, with their resultant H+ load, can be harmful if their rate of synthesis exceeds their rate of removal by a large amount (Figure 4). Such an imbalance is prevented because the rates of oxygen consumption in the brain and the liver are poised to achieve this effect. In quantitative terms, the rate of ketogenesis has its maximum limit set by hepatic ATP turnover (Figure 4).12 The net result is that the rate of ketoacid production in the liver is close to 1 mmol/min. The oxygen consumption of the brain dictates that if ketoacids were the only fuel oxidized in this organ, the brain would remove close to 0.5 mmol of ketoacids per minute.13 In addition, the kidney removes 
0.25 mmol of ketoacids per minute, 60% by oxidation and 40% by urine excretion.14 The remainder of the ketoacids is oxidized by the intestinal tract15 and by conversion to acetone, detected on the patient's breath. Ketoacidosis develops when this normal physiology is perturbed. At this point, Professor Krebs proceeded to look at the components of ketoacid physiology in more detail.
|
|
Production of acetyl-CoA: There are two major physiologic substrates for acetyl-CoA formation in the liver, pyruvate (from glucose) or fatty acids (from adipose tissue triglycerides). One cannot develop ketoacidosis when there is a high rate of carbohydrate oxidation, because when acetyl-CoA rises, it is a potent inhibitor of its own formation via inhibition of pyruvate dehydrogenase.16 Ketoacids may be formed when fatty acids are oxidized, if two conditions are met. First, fatty acids can gain entry into mitochondria (Figure 3, top right) and second, the conversion of acetyl-CoA to fatty acids must be inhibited (Figure 3, bottom right). The hormonal setting for both of these effects is a relative lack of insulin. At this point, Professor Krebs stopped and again appeared deep in thought. What could he be thinking about, they wondered? He then asked a provocative question—‘Can there be an appreciable amount of acetyl-CoA precursors other than glucose or fatty acids?’
Question 7. Can there be an appreciable amount of acetyl-CoA precursors other than glucose or fatty acids?
Physiology principle 7. Acetyl-CoA can be produced from the metabolism of ethanol or acetic acid. In both cases, the usual sites of regulation of ketogenesis are bypassed.
While a low level of insulin is usually needed for the production of ketoacids, this is not true if something else inhibits acetyl-CoA carboxylase (Figure 5). When ethanol is the substrate, acetyl-CoA is produced and the control is by the rate of removal of one of the byproducts (NADH) that leads to ATP generation (Figure 6, top left). The upper limit of ketogenesis from ethanol is also controlled by hepatic ATP turnover, and the rate is similar to that seen when fatty acids provide the acetyl-CoA.17
|
|
One can also make hepatic acetyl-CoA directly from acetic acid when this acid is delivered to the liver. The usual source of acetic acid is from bacterial metabolism in the gastrointestinal tract.18 In quantitative terms,
200 mmol of acetic acid are produced daily by this route. With this substrate, the only form of regulation of ketoacid formation is inhibition of fatty acid synthesis (Figure 6, lower left).
Physiology principle 8. Bacteria in the gastrointestinal tract produce many useful products.
Propionate is useful for synthesizing oxaloacetate, a TCA cycle intermediate. Butyrate is an important fuel for the colon.19 Producing organic acids by fermentation in the gastrointestinal tract from sugars such as fructose diminishes the supply of hexoses that the liver must extract in a single pass, and thereby helps diminish the rise in the PGlu and plasma fructose concentration during the accelerated phase of sugar absorption.
The production of acetic acid is dependent on how much fuel is delivered to intestinal bacteria and the properties of these bacteria in the colon. Therefore, Professor Krebs asked the group whether there was any unusual intake in the patient that could have supplied a precursor of acetic acid to these intestinal bacteria. The intern who had taken the history replied that the patient drank extraordinarily large volumes of sweetened soft drinks, but that there were no unusual sugars ingested. Professor Krebs reminded the group that fructose is the principal sugar in fruits—hence the name, fructose (Table 6). Nevertheless, there are no specific intestinal transporters for fructose, which makes it a poorly absorbed sugar.20 Moreover, fructose has a sweeter taste than glucose or sucrose, and it is not surprising that soft drinks are particularly rich in fructose to tempt the consumer. This patient could therefore have had a very large delivery of acetic acid to his liver (Figure 7).
|
|
The synthesis of long-chain fatty acids should be inhibited in states with low insulin levels, and in states with high levels of hormones with actions that oppose those of insulin (including adrenaline). ‘Now I recall you saying that the patient was exceedingly agitated’ said Krebs and he put forward his hypothesis. If the extreme agitation and anxiety could produce a high adrenergic state, this could inhibit the first committed step for fatty-acid synthesis in the liver, via acetyl-CoA carboxylase (Figure 5). The combination of too much acetyl-CoA and an inability to remove it for fatty-acid synthesis would cause the acetyl-CoA levels to rise remarkably and drive the synthesis of ketoacids, even in the presence of insulin.
Professor Krebs raised two other interesting points. First he considered the removal of ketoacids, reminding his colleagues that half of the ketoacids produced are removed by the brain and one quarter by the kidneys (Figure 4). ‘Did this patient have any CNS problem or was he on a sedative that reduced normal brain metabolism?’ Sir Hans asked. The intern answered that the patient had cerebral palsy due to a birth injury and suggested that perhaps this diminished his capacity to burn ketoacids in his brain. He was also on medications for control of anxiety and depression. With respect to his kidneys, he had normal renal function, and therefore no reason to have a low rate of ketoacid oxidation by the kidney. The second issue concerned the possibility of a C-5 ketoacid being made from acetyl-CoA and propionyl-CoA in the liver.21 This latter ketoacid would be very interesting, because it could supply propionate, a precursor of oxaloacetate the 4-carbon catalyst in the Krebs cycle, to organs such as the heart. This is particularly useful to the heart when it needs to regenerate this component of the Krebs cycle. At this point, the chief medical registrar mentioned that he had learned at the cardiology rounds that propionyl carnitine was mentioned as a possible adjunct in therapy in the treatment of heart failure. Perhaps it was not just the carnitine that conferred benefit, but also propionate if it was converted to oxaloacetate in the heart.
|
Request for newer information |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
Before drawing this issue of inhibited lipogenesis (fatty-acid synthesis) to a close, Professor Krebs asked if there was any new information that might require a change in his metabolic analysis. The endocrine fellow rose to the challenge, and said that there were a few major surprises concerning hepatic lipogenesis, based on the use of new techniques using labelled water (2H2O).22 First, there appears to be very little de novo lipogenesis in the liver, even when the diet is supplemented with carbohydrates such that subjects consumed 1500 extra kcal for 5 days.23 Second, the metabolism of a 24 g dose of ethanol did not lead to an appreciable rate of hepatic fatty acid synthesis. Rather, the major metabolic fate of this ethanol was the release of acetic acid from the liver.24
Professor Krebs said he was very surprised, because hepatocytes have both acetyl-CoA carboxylase and fatty acid synthetase activities. Upon reflection, he knew that one does not know actual fluxes in metabolic pathways, because of regulatory influences that could change substrate availability and/or enzyme activity. Moreover, he recognized how accurate these new techniques could be. Nevertheless, he added a caution—the data cited refer only to the condition of study. Accordingly, he felt compelled to re-examine his conclusions in a quantitative fashion. He asked, ‘While we have qualitative information about the presence of ketoacidosis (odour of acetone, serum qualitative test for acetone plus acetoacetic acid, rise in the anion gap and fall in the HCO3- concentration in plasma), what was the measured Pß-HB?’ The housestaff said that his Pß-HB was 4.5 mmol/l. All eyes turned to Professor McCance, anticipating his quantitative analysis.
Professor McCance expressed concern, because the concentration of ß-hydroxybutyrate in plasma was only 4.5 mmol/l, yet the plasma anion gap was elevated by 14 mEq/l. He wondered aloud whether there was another organic anion present. His first thought was that there was an unusually high concentration of acetoacetate because the conversion of acetate to acetyl-CoA does not generate NADH. Accordingly, the lower NADH/NAD+ ratio in hepatocytes would lead to higher acetoacetate– and lower ß-HB– formation rates. He also wondered whether there could be a mixture of short-chain fatty acids produced by bacterial fermentation, including acetic acid, butyric acid and/or propionic acid, because they are the common ones made by our normal bacterial flora. Moreover, if these products of bacterial fermentation were oxidized in the brain or the kidneys, less ketoacid would be oxidized. Hence the degree of ketoacidosis might be even larger than expected.
|
Additional questions |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
The Renal Fellow asked if Professor Krebs would be willing to answer a few additional questions. On receiving a positive reply, he asked, ‘In your description of the biochemistry of the prolonged fasted state (Figure 4), might the excretion of ketoacids serve a useful purpose?’
Question 8. In the prolonged fasted state, might the excretion of ketoacids serve a useful purpose?
Physiology principle 9. The volume of urine when vasopressin acts is directly proportional to the number of effective osmoles in the urine, and inversely proportional to the concentration of effective osmoles in the urine (equation 1).
 | (1) |
‘Why is fructose so poorly absorbed when it was the main dietary sugar in prehistoric times?’ continued the Renal Fellow.
Question 9. Why is fructose so poorly absorbed when it was the main dietary sugar in prehistoric times?
Professor Krebs guessed that when fibre from grain was not yet a dietary staple, ingesting fruit rich in fructose would deliver sugar to intestinal bacteria to produce the valuable short-chain organic acids described above. Moreover, the small amount of absorbed fructose would cause the hepatocytes to produce more glucokinase in the liver,26 increasing the ability of the liver to lower the PGlu (Figure 7). At this point, one of the medical students asked, ‘Can we ever have very slow intestinal absorption of glucose?’
Question 10. Can we ever have very slow intestinal absorption of glucose?
Acarbose is used to inhibit the digestion of starch,27 said the intern. By inhibiting the digestion of starch, glucose absorption might be decreased and result in more fuel reaching the distal intestine where bacterial fermentation could occur. ‘Might this conceivably predispose to ketoacidosis under certain circumstances?’, she wondered.
Professor Krebs added a final concept to end this portion of the discussion—fermentation will come to a stop when luminal pH falls too low, so the use of drugs decreasing gastric acid or the presence of gastric achlorhydria might increase the production of organic acids in the patient receiving acarbose or those ingesting fructose or sorbitol.
|
Concluding remarks |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
Because all the common causes for ketoacidosis had been ruled out, a novel hypothesis was required to explain why ketoacidosis might have developed in this patient (Figure 7). The combination of a very large carbohydrate (fructose) load, prolonged agitation releasing adrenaline to block fatty acid synthesis in the liver, and reduced CNS metabolism of ketoacids, could all act in concert to produce a mixture of ketoacidosis and acidosis due to short-chain fatty-acid accumulation. The likely source of the fructose was the sweetened soft drinks. After bacterial fermentation of fructose, a large amount of acetic acid would be delivered to the liver. The fact that everything resolved after stopping his intake of fructose and lessening of his anxiety was supportive, but not proof for this hypothesis. Perhaps this combination of events could be present in other patients who have decreased absorption of sugars in their GI tract, especially if combined with antacid therapy that could increase organic acid production by bacterial fermentation.
|
Appendix 1: Index case |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
A 22-year-old male had a past medical history of cerebral palsy. The defects were relatively modest, in that he had no mental retardation and could stand and walk for a reasonable period, but preferred being in a wheelchair. He suffered from repeated episodes of anxiety, during which he became extremely agitated and depressed. In the most recent episode, his symptoms were severe—he had not slept for 3 days before admission. He denied the intake of any drugs, including salicylates and ethanol (blood tests for ethanol were negative and the plasma osmolal gap was not increased on the two days he came to the hospital during this current episode). His only symptom was crampy, intermittent lower abdominal pain. There was no history of diabetes mellitus or suggestive symptoms—his haemoglobin A1C was 4.4%. He was not starved, because he consumed a very large carbohydrate load in the form of sweetened soft drinks— > 6 cans/day, 31 g sugar/355 ml. He was on venlafaxine and diphenhydramine for long-term control of depression and anxiety. On physical examination, his ECF volume was thought to be normal, but there was a strong odour of acetone on his breath.
One day before he was admitted, he had a milder degree of acidosis, as evidenced by a PHCO3 of 18 mmol/l and a plasma anion gap of 19 mEq/l. There was no evidence of ethanol in his plasma. He was discharged without treatment from the Emergency Department. At the time of admission, laboratory testing revealed that his plasma was positive for ketones in a 1:4 dilution. He had metabolic acidosis (pH 7.20, PHCO3 8 mmol/l) with an anion gap of 26 mEq/l, and a normal plasma K concentration (4.2 mmol/l) (Table 2). The plasma concentration of ß-HB was 4.5 mmol/l—AcAc was not measured. His plasma insulin level in overnight fasted serum (PGlu 4 mmol/l (74 mg/dl)) was just above the normal range when measured 24-hours later (29 µI units/ml, normal range 6–27 µI units/ml).
Hospital course: Therapy consisted of stopping the oral carbohydrate intake and infusing 1 l of half isotonic saline plus 1 L of D5W. All the laboratory abnormalities returned to normal values within 24 h.
|
Footnotes |
|---|
Address correspondence to Professor M.L. Halperin, St. Michael's Hospital Annex, Lab #1, Research Wing, 38 Shuter Street, Toronto, Ontario, M5B 1A6, Canada. e-mail: mitchell.halperin{at}utoronto.ca
|
References |
|---|
|
TopSummaryIntroductionThe consultationRequest for newer informationAdditional questionsConcluding remarksAppendix 1: Index caseReferences |
|---|
1. Cheetham M, Boobis L, Brooks S, Williams C. Human muscle metabolism during sprint running. J Appl Physiol 1986; 61:54–60.
2. Napolova O, Urbach S, Davids MR, Halperin ML. How to assess the degree of extracellular fluid volume contraction in a patient with a severe degree of hyperglycemia. Nephrol Dial Trans 2003; 18:2674–7.
3. Halperin ML. How much ‘new’ bicarbonate is formed in the distal nephron in the process of net acid excretion? Kidney Int 1989; 35:1277–81.[Web of Science][Medline]
4. Halperin ML, Jungas RL, Pichette C, Goldstein MB. Quantitative analysis of renal ammoniagenesis and energy balance: a theoretical approach. Can J Physiol Pharmacol 1982; 60:1431–5.[Web of Science][Medline]
5. Emmett M, Narins RG. Clinical use of the anion gap. Medicine 1977; 56:38–54.[Medline]
6. Gabow PA, Kaehny WD, Fennessey DV, Goodman SI, Gross PA, Shrier RW. Diagnostic importance of an increased anion gap. N Engl J Med 1980; 303:854–8.[Web of Science][Medline]
7. Gabow PA. Disorders associated with an altered anion gap. Kidney Int 1985; 27:472–83.[Web of Science][Medline]
8. Oh MS, Carroll HJ. The anion gap. N Engl J Med 1979; 297:814–17.
9. Halperin ML, Cherney DZI, Kamel KS. Ketoacidosis. In: Hamm LL, ed. Acid-Base and Electrolyte Disorders: a companion to Brenner and Rector's The Kidney. Philadelphia, WB Saunders, 2002:67–82.
10. Halperin ML, Kamel KS. Turning sugar into acids in the gastrointestinal tract. Kidney Int 1996; 49:1–8.[Web of Science][Medline]
11. Cahill GFJ. Starvation in man. N Engl J Med 1970; 282:668–75.[Medline]
12. Flatt JP. On the maximal possible rate of ketogenesis. Diabetes 1972; 21:50–3.[Web of Science][Medline]
13. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GFJ. Brain metabolism during fasting. J Clin Invest 1967; 46:1589–95.[Web of Science][Medline]
14. Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF, Jr. Liver and kidney metabolism during prolonged starvation. J Clin Invest 1969; 48:574–83.[Web of Science][Medline]
15. Windmueller HG, Spaeth AE. Intestinal metabolism of glutamine from the lumen as compared to glutamine from the blood. Archiv Biochem Biophys 1975; 171:662–72.[CrossRef][Web of Science][Medline]
16. Harris RA, Huang B, Wu P. Control of pyruvate dehydrogenase kinase gene expression. Adv Enzyme Regul 2001; 41:269–88.[CrossRef][Web of Science][Medline]
17. Halperin ML, Hammeke M, Josse RG, et al. Metabolic acidosis in the alcoholic: A pathophysiologic approach. Metabolism 1983; 32:308–15.[CrossRef][Web of Science][Medline]
18. Cummings JH, MacFarlane GT. Role of intestinal bacteria in nutrient metabolism. J Parent Ent Nutr 1997; 21:357–65.
19. Roediger WEW. The colonic epithelium in ulcerative colitis: an energy-deficiency disease? Lancet 1980; ii:713–15.
20. Corpe CP, Basaleh MM, Affleck J, Gould G, Jess TJ, Kellett GL. The regulation of GLUT5 and GLUT2 activity in the adaptation of intestinal brush-border fructose transport in diabetes. Pflugers Arch 1996; 432:192–201.[CrossRef][Web of Science][Medline]
21. Leclerc J, des Rosiers C, Montgomery JA, Brunet J, Ste-Marie L, Reider MW, et al. Metabolism of R-ß-hydroxypentanoate and of ß-ketopentanoate in conscious dogs. Am J Physiol 1996; 268:E446–52.
22. Hellerstein MK. In vivo measurement of fluxes through metabolic pathways: The missing link in functional genomics and pharmaceutical research. Annu Rev Nutr 2003; 23:379–402.[CrossRef][Web of Science][Medline]
23. Sidossis LS, Wolfe RR. Glucose and insulin-induced inhibition of fatty acid oxidation: the glucose-fatty acid cycle revisited. Am J Physiol 1996; 270:E733–8.
24. Siler SQ, Neese RA, Hellerstein MK. De novo lipogenesis, lipid kinetics, and whole body lipid balances in humans after acute alcohol consumption. Am J Clin Nutrition 1999; 70:928–36.
25. Kamel KS, Lin S-H, Cheema-Dhadli S, Marliss EB, Halperin ML. Prolonged total fasting: a feast for the integrative physiologist. Kidney Int 1998; 53:531–9.[CrossRef][Web of Science][Medline]
26. Vandercammen A, Van Schaftingen E. Competitive inhibition of liver glucokinase by its regulatory protein. Eur J Biochem 1991; 200:545–51.[Web of Science][Medline]
27. Chaisson J-L, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359:2072–7.[CrossRef][Web of Science][Medline]
28. DeMars C, Hollister K, Tomassoni A, Himmelfarb J, Halperin ML. Citric acidosis: A life-threatening cause of metabolic acidosis. Ann Emerg Med 2001; 38:588–91.[CrossRef][Web of Science][Medline]
29. Pitt JJ, Hauser S. Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects. Clin Chem 1998; 44:1497–503.
30. Jungas RL. Lectures on gastrointestinal physiology and the hormonal regulation of energy metabolism. Farmington CT, University of Connecticut Health Center, 2002.
31. Halperin ML. The ACID truth and BASIC facts—with a Sweet Touch, an enLYTEnment, 6th ed. Stirling, Canada, RossMark Medical Publishers, 2003.
32. McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 1977; 60:265–70.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||