Ketoacidosis is a metabolic state caused by uncontrolled production of
ketone bodies that cause a
metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
. While
ketosis refers to any elevation of blood
ketones, ketoacidosis is a specific pathologic condition that results in changes in
blood pH
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
and requires medical attention. The most common cause of ketoacidosis is
diabetic ketoacidosis
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 ...
but can also be caused by
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
, medications, toxins, and rarely, starvation.
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.
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.
Altered mental status is more common in diabetic than alcoholic ketoacidosis.
Causes
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
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
.
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
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 ...
and is characterized by
hyperglycemia
Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...
,
dehydration and metabolic acidosis. Other electrolyte disturbances such as
hyperkalemia
Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
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
Acetyl-CoA (acetyl coenzyme A) 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 (Krebs cycle) to be oxidized fo ...
, some of which is diverted to
ketogenesis
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, und ...
. This raises ketone levels significantly above what is seen in normal physiology.
Alcohol
Alcoholic ketoacidosis
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 generall ...
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
Ethanol, an alcohol found in nature and in alcoholic drinks, is metabolized through a complex catabolic metabolic pathway. In humans, several enzymes are involved in processing ethanol first into acetaldehyde and further into acetic acid and acety ...
further impairs
gluconeogenesis. This can reduce glucose availability and lead to
hypoglycemia
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 belo ...
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
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
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.
Starvation
Starvation is a rare cause of ketoacidosis, usually instead causing
physiologic ketosis without ketoacidosis.
Ketoacidosis from starvation most commonly occurs in the setting of an additional metabolic stressor such as pregnancy, lactation, or acute illness.
Medications
Certain medications can also cause elevated ketones, such as
SGLT2 inhibitors
SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that modulate sodium-glucose transport proteins in the nephron (the functional units of the kidney), unlike SGLT1 inhibitors that perform a similar function in the int ...
causing
euglycemic ketoacidosis. Overdose of
salicylates
Salicylic acid is an organic compound with the formula HOC6H4CO2H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of aspirin (acetylsalicylic acid). It is a plant hormone, and has been listed by the EPA Toxic Substanc ...
or
isoniazid
Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For lat ...
can also cause ketoacidosis.
Toxins
Ketoacidosis can be the result of ingestion of
methanol,
ethylene glycol
Ethylene glycol ( IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an odo ...
,
isopropyl alcohol, and
acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscible wi ...
.
Pathophysiology
Ketones are primarily produced from free fatty acids in the
mitochondria of
liver cells
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
. 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
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
. Insulin deficiency can also enhance ketone production and inhibit peripheral use of ketones.
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).
Acetoacetic acid
Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta- keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite sta ...
and
β-hydroxybutyrate
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-Hydroxyb ...
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.
Management
Treatment depends on the underlying cause of the ketoacidosis.
Diabetic ketoacidosis
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 ...
is resolved with insulin infusion, intravenous fluids, electrolyte replacement and supportive care.
Alcoholic ketoacidosis is treated with intravenous
dextrose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
and supportive care and usually does not require insulin.
Starvation ketoacidosis can be resolved with intravenous dextrose with attention to electrolyte changes that can occur with
refeeding syndrome
Refeeding syndrome is a metabolic disturbance that occurs as a result of reinstitution of nutrition in people and animals who are starved, severely malnourished, or metabolically stressed because of severe illness. When too much food or liquid nu ...
.
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.
Prolonged heavy alcohol use is a risk of ketoacidosis, especially in people with poor nutrition or a concurrent illness.
Pregnant women have high levels of hormones including glucagon and
human placental lactogen that increase circulating free fatty acids which increases ketone production.
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.
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.
See also
*
Alcoholic ketoacidosis
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 generall ...
*
Diabetic ketoacidosis
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 ...
*
Ketosis
*
Kussmaul breathing
*
Metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
*
Type I diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
References
{{Water-electrolyte imbalance and acid-base imbalance
Acid–base disturbances