Ketoacidosis

Last updated
Ketoacidosis
Ketone-group-2D-skeletal.svg
Ketone bodies
Specialty Endocrinology
Symptoms nausea, vomiting, pain, weakness, unusual breath odor, rapid breathing
Causesmedications, alcoholic beverages

Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes in blood pH and requires medical attention. The most common cause of ketoacidosis is diabetic ketoacidosis but can also be caused by alcohol, medications, toxins, and rarely, starvation.

Contents

Signs and symptoms

The symptoms of ketoacidosis are variable depending on the underlying cause. The most common symptoms include nausea, vomiting, abdominal pain, and weakness. [1] [2] Breath may also develop the smell of acetone as it is a volatile ketone that can be exhaled. Rapid deep breathing, or Kussmaul breathing, may be present to compensate for the metabolic acidosis. [1] Altered mental status is more common in diabetic than alcoholic ketoacidosis. [2]

Causes

Legend: Muscle fiber Amino acids Liver Fatty acids Glucagon Blood vessel Process: Lack of insulin leads to the release of amino acids from the muscle fiber. Amino acids are released from the muscle fiber, which get converted into glucose in the liver. The glucose produced becomes abundant in the bloodstream. Fatty acids and glycerol are released from the adipose tissue, which get converted into ketones in the liver. Along with the fatty acids and glycerol, the glucose produced from the lack of insulin also gets converted into ketones in the liver. The ketones produced become abundant in the bloodstream. Diabetic Ketoacidosis Model.svg
Legend:
  1. Muscle fiber
  2. Amino acids
  3. Liver
  4. Fatty acids
  5. Glucagon
  6. Blood vessel
Process:
  1. Lack of insulin leads to the release of amino acids from the muscle fiber.
  2. Amino acids are released from the muscle fiber, which get converted into glucose in the liver.
  3. The glucose produced becomes abundant in the bloodstream.
  4. Fatty acids and glycerol are released from the adipose tissue, which get converted into ketones in the liver.
  5. Along with the fatty acids and glycerol, the glucose produced from the lack of insulin also gets converted into ketones in the liver.
  6. The ketones produced become abundant in the bloodstream.

Ketoacidosis is caused by the uncontrolled production of ketone bodies. Usually the production of ketones is carefully controlled by several hormones, most importantly insulin. If the mechanisms that control ketone production fail, ketone levels may become dramatically elevated and cause dangerous changes in physiology such as a metabolic acidosis. [3] [4]

Diabetes

The most common cause of ketoacidosis is a deficiency of insulin in type 1 diabetes or late-stage type 2 diabetes. This is called diabetic ketoacidosis and is characterized by hyperglycemia, dehydration and metabolic acidosis. Other electrolyte disturbances such as hyperkalemia and hyponatremia may also be present. A lack of insulin in the bloodstream allows unregulated fatty acid release from adipose tissue which increases fatty acid oxidation to acetyl CoA, some of which is diverted to ketogenesis. This raises ketone levels significantly above what is seen in normal physiology. [1]

Alcohol

Alcoholic ketoacidosis is caused by complex physiology that is usually the result of prolonged and heavy alcohol intake in the setting of poor nutrition. Chronic alcohol use can cause depleted hepatic glycogen stores and ethanol metabolism further impairs gluconeogenesis. This can reduce glucose availability and lead to hypoglycemia and increased reliance on fatty acid and ketone metabolism. An additional stressor such as vomiting or dehydration can cause an increase in counterregulatory hormones such as glucagon, cortisol and growth hormone which may further increase free fatty acid release and ketone production. Ethanol metabolism can also increase blood lactic acid levels which may also contribute to a metabolic acidosis. [2]

Starvation

Starvation is a rare cause of ketoacidosis, usually instead causing physiologic ketosis without ketoacidosis. [5] Ketoacidosis from starvation most commonly occurs in the setting of an additional metabolic stressor such as pregnancy, lactation, or acute illness. [5] [6]

Medications

Certain medications can also cause elevated ketones, such as SGLT2 inhibitors causing euglycemic ketoacidosis. [7] Overdose of salicylates or isoniazid can also cause ketoacidosis. [4]

Toxins

Ketoacidosis can be the result of ingestion of methanol, ethylene glycol, isopropyl alcohol, and acetone. [4]

Pathophysiology

Ketones are primarily produced from free fatty acids in the mitochondria of liver cells. The production of ketones is strongly regulated by insulin and an absolute or relative lack of insulin underlies the pathophysiology of ketoacidosis. Insulin is a potent inhibitor of fatty acid release, so insulin deficiency can cause an uncontrolled release of fatty acids from adipose tissue. Insulin deficiency can also enhance ketone production and inhibit peripheral use of ketones. [3] This can occur during states of complete insulin deficiency (such as untreated diabetes) or relative insulin deficiency in states of elevated glucagon and counter-regulatory hormones (such as starvation, heavy chronic alcohol use or illness). [4]

Acetoacetic acid and β-hydroxybutyrate are the most abundant circulating ketone bodies. Ketone bodies are acidic; however, at physiologic concentrations, the body's acid/base buffering system prevents them from changing blood pH. [3]

Management

Treatment depends on the underlying cause of the ketoacidosis. Diabetic ketoacidosis is resolved with insulin infusion, intravenous fluids, electrolyte replacement and supportive care. [1] Alcoholic ketoacidosis is treated with intravenous dextrose and supportive care and usually does not require insulin. [2] Starvation ketoacidosis can be resolved with intravenous dextrose with attention to electrolyte changes that can occur with refeeding syndrome. [5]

Epidemiology

Certain populations are predisposed to develop ketoacidosis including people with diabetes, people with a history of prolonged and heavy alcohol use, pregnant women, breastfeeding women, children, and infants.

People with diabetes that produce very little or no insulin are predisposed to develop ketoacidosis, especially during periods of illness or missed insulin doses. This includes people with type 1 diabetes or ketosis prone diabetes. [1]

Prolonged heavy alcohol use is a risk of ketoacidosis, especially in people with poor nutrition or a concurrent illness. [2]

Pregnant women have high levels of hormones including glucagon and human placental lactogen that increase circulating free fatty acids which increases ketone production. [6] Lactating women also are predisposed to increased ketone production. These populations are at risk of developing ketoacidosis in the setting of metabolic stressors such as fasting, low-carbohydrate diets, or acute illness. [8]

Children and infants have lower glycogen stores and may develop high levels of glucagon and counter-regulatory hormones during acute illness, especially gastrointestinal illness. This allows children and infants to easily produce ketones and although rare, can progress to ketoacidosis in acute illness. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

The following is a glossary of diabetes which explains terms connected with diabetes.

<span class="mw-page-title-main">Diabetic ketoacidosis</span> Medical condition

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of consciousness. A person's breath may develop a specific "fruity" smell. The onset of symptoms is usually rapid. People without a previous diagnosis of diabetes may develop DKA as the first obvious symptom.

<span class="mw-page-title-main">Ketone bodies</span> Chemicals produced during fat metabolism

Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA —which then enters the citric acid cycle and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate.

<span class="mw-page-title-main">Ketosis</span> Using body fats as fuel instead of carbohydrates

Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional energy source for the brain in the form of ketones. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.

<span class="mw-page-title-main">Diabetic coma</span> Medical condition

Diabetic coma is a life-threatening but reversible form of coma found in people with diabetes mellitus.

<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is an ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Ketogenesis</span> Chemical synthesis of ketone bodies

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

<span class="mw-page-title-main">Alcoholic ketoacidosis</span> Medical condition

Alcoholic ketoacidosis (AKA) is a specific group of symptoms and metabolic state related to alcohol use. Symptoms often include abdominal pain, vomiting, agitation, a fast respiratory rate, and a specific "fruity" smell. Consciousness is generally normal. Complications may include sudden death.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

Ketotic hypoglycemia refers to any circumstance in which low blood glucose is accompanied by ketosis, the presence of ketone bodies in the blood or urine. This state can be either physiologic or pathologic; physiologic ketotic hypoglycemia is a common cause of hypoglycemia in children, often in response to stressors such as infection or fasting. Pathologic ketotic hypoglycemia is typically caused by metabolic defects, such as glycogen storage disorders.

<span class="mw-page-title-main">Ketonuria</span> Medical condition

Ketonuria is a medical condition in which ketone bodies are present in the urine.

β-Hydroxybutyric acid Chemical compound

β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).

<span class="mw-page-title-main">High anion gap metabolic acidosis</span> Medical condition

High anion gap metabolic acidosis is a form of metabolic acidosis characterized by a high anion gap. Metabolic acidosis occurs when the body produces too much acid, or when the kidneys are not removing enough acid from the body. Several types of metabolic acidosis occur, grouped by their influence on the anion gap.

Complications of diabetes are secondary diseases that are a result of elevated blood glucose levels that occur in diabetic patients. These complications can be divided into two types: acute and chronic. Acute complications are complications that develop rapidly and can be exemplified as diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia. Chronic complications develop over time and are generally classified in two categories: microvascular and macrovascular. Microvascular complications include neuropathy, nephropathy, and retinopathy; while cardiovascular disease, stroke, and peripheral vascular disease are included in the macrovascular complications.

Pseudohypoxia refers to a condition that mimics hypoxia, by having sufficient oxygen yet impaired mitochondrial respiration due to a deficiency of necessary co-enzymes, such as NAD+ and TPP. The increased cytosolic ratio of free NADH/NAD+ in cells (more NADH than NAD+) can be caused by diabetic hyperglycemia and by excessive alcohol consumption. Low levels of TPP results from thiamine deficiency.

Glucagon receptor agonists are a class of drugs under development for the treatment of obesity, non-alcoholic fatty liver disease, and congenital hyperinsulinism.

References

  1. 1 2 3 4 5 Misra, Shivani; Oliver, Nick S (2015-10-28). "Diabetic ketoacidosis in adults". BMJ. 351: h5660. doi:10.1136/bmj.h5660. hdl: 10044/1/41091 . ISSN   1756-1833. PMID   26510442.
  2. 1 2 3 4 5 McGuire, L. C.; Cruickshank, A. M.; Munro, P. T. (June 2006). "Alcoholic ketoacidosis". Emergency Medicine Journal. 23 (6): 417–420. doi:10.1136/emj.2004.017590. ISSN   1472-0213. PMC   2564331 . PMID   16714496.
  3. 1 2 3 Oster, James R.; Epstein, Murray (1984). "Acid-Base Aspects of Ketoacidosis". American Journal of Nephrology. 4 (3): 137–151. doi:10.1159/000166795. ISSN   1421-9670. PMID   6430087.
  4. 1 2 3 4 Cartwright, Martina M.; Hajja, Waddah; Al-Khatib, Sofian; Hazeghazam, Maryam; Sreedhar, Dharmashree; Li, Rebecca Na; Wong-McKinstry, Edna; Carlson, Richard W. (October 2012). "Toxigenic and Metabolic Causes of Ketosis and Ketoacidotic Syndromes". Critical Care Clinics. 28 (4): 601–631. doi:10.1016/j.ccc.2012.07.001.
  5. 1 2 3 Owen, Oliver E.; Caprio, Sonia; Reichard, George A.; Mozzoli, Maria A.; Boden, Guenther; Owen, Rodney S. (July 1983). "Ketosis of starvation: A revisit and new perspectives". Clinics in Endocrinology and Metabolism. 12 (2): 359–379. doi:10.1016/s0300-595x(83)80046-2. ISSN   0300-595X.
  6. 1 2 Frise, Charlotte J.; Mackillop, Lucy; Joash, Karen; Williamson, Catherine (March 2013). "Starvation ketoacidosis in pregnancy". European Journal of Obstetrics & Gynecology and Reproductive Biology. 167 (1): 1–7. doi:10.1016/j.ejogrb.2012.10.005. ISSN   0301-2115. PMID   23131345.
  7. ↑ Modi, Anar; Agrawal, Abhinav; Morgan, Farah (2017). "Euglycemic Diabetic Ketoacidosis: A Review". Current Diabetes Reviews. 13 (3): 315–321. doi:10.2174/1573399812666160421121307. ISSN   1875-6417. PMID   27097605.
  8. ↑ Gleeson, Sarah; Mulroy, Eoin; Clarke, David E. (Spring 2016). "Lactation Ketoacidosis: An Unusual Entity and a Review of the Literature". The Permanente Journal. 20 (2): 71–73. doi:10.7812/TPP/15-097. ISSN   1552-5775. PMC   4867828 . PMID   26909776.
  9. ↑ Fukao, Toshiyuki; Mitchell, Grant; Sass, Jörn Oliver; Hori, Tomohiro; Orii, Kenji; Aoyama, Yuka (July 2014). "Ketone body metabolism and its defects". Journal of Inherited Metabolic Disease. 37 (4): 541–551. doi:10.1007/s10545-014-9704-9. ISSN   0141-8955. PMID   24706027.

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