Ketosis and Ketoacidosis

Ketosis is a metabolic state in which the bodies energy supply comes from ketone bodies in the blood in contrast to a state of glycolysis in which there is adequate glucose breakdown. In most cases, ketosis results from a high metabolism of fatty acids which are converted to ketone bodies. Ketone bodies are formed from ketogenesis when liver glycogen stores are depleted. Most cells in the body utilize both ketone bodies and glucose for energy, and while in ketosis the body works to maintain normal metobolism so it ramps up gluconeogenesis. Gluconeogenesis is glucose synthesis used to go through glycolysis.

Most of the time ketosis is a short interval of time, although long-term ketosis may be a result of fasting or a dietary insufficiency of carbohydrates. In glycolysis, high levels of insulin are released which promotes storage of fat and delayed release of fat from adipose tissue. In ketosis, fat reserves are readily available and are consumed. For this reason, ketosis has become one of the more recent diet fads as a way to burn fat quickly and lose weight.


Although similar, ketosis is not ketoacidosis. Ketoacidosis is a physiological life-threatening situation due to insulin deficiency. Ketone bodies are acidic, and acid-base homeostasis in the blood is normally maintained through bicarbonate buffering, respiratory compensation, and renal compensation. Prolonged excess of ketone bodies can overwhelm the normal compensatory mechanisms and cause a state of acidosis when the blood pH falls below 7.35.

There are multiple precipitating factors that leads to ketoacidosis, which is most prevalent in patients with type 1 diabetes. Ketoacidosis in the case of a patient with type 1 diabetes is deemed diabetic ketoacidosis (DKA). In established type 1 diabetes, patients often forget to take insulin, with non-compliance being the bigger issue. This does not rule out other causes of ketoacidosis, as those are still prevalent. Acute major illnesses such as a myocardial infarction, cerebrovascular accident, sepsis, or pancreatitis. Certain drugs that affect carbohydrate metabolism such as glucocorticoids, diuretics, or anti-psychotic agents can cause ketoacidosis. General malnutrition associated with physiological problems can also lead to ketoacidosis. Such disorders lead to psychological starvation, which leads to ketone production and if prolonged ketoacidosis.


Clinical Presentation

The clinical presentation of DKA is a two headed monster. The earliest symptoms of marked hyperglycemia is polyuria, polydipsia, and unexplained weight loss. As the duration of hyperglycemia continues neurological symptoms, including lethargy, focal signs and obtundation develop. Further progression can lead to a coma. The other head is the extent of the metabolic acidosis due to the excess ketone bodies. As the acidemia worsens accompanied with it is abdominal pain which can sometimes be severe. The electrolyte imbalance and metabolic acidosis causes delayed gastric emptying and an ileus (obstruction of the bowel). Vomiting and nausea are common.

Diagnostic Evaluation

The initial laboratory evaluation of patients with suspected DKA should include a serum glucose to establish whether or not the patient is hyperglycemic or not. Its helpful to measure the serum electrolytes and calculate the anion gap, BUN, plasma creatinine, and a plasma osmolality. This gives a broad picture of the metabolic state of the patient. Urinalysis is commonly performed along with urine ketones measured by dipstick method. Serum ketones are also measured to assess whether or not the patient is undergoing ketogenesis. An arterial or venous blood gas can be helpful to determine whether the serum bicarbonate is substantially reduced, which presumptively leads to metabolic acidosis. This also aids in determining hypoxia if it is present.


Hyperglycemia and hyperosmolality are the two primary laboratory findings in patients with DKA. Patients with DKA have a high anion gap metabolic acidosis. Serum glucose often times exceeds 350-500 mg/dL. Three ketone bodies are produced and accumulate in DKA; acetoacetic acid, beta-hydroxybutyric, and acetone. Acetoacetic acid is the only true ketoacid. A serum ketone measurement gives levels of beta-hydroxybutyric, while a urine dipstick measures the presence of acetoacetic acid using the nitroprusside method.

Other findings that may or may not be present are leukocytosis, and lipidemia. The majority of patients with hyperglycemic emergencies present with leukocytosis, which is proportional to the degree of ketonemia. Patients with DKA also present with marked hyperlipidemia. Lipolysis, primarily caused from insulin deficiency, and to a lesser extent elevated levels of lipolytic hormones including catecholamines, GH, ACTH, and glucagon. Lipolysis releases glycerol and free fatty acids into circulation which causes insulin resistance and serves as the substrate for ketoacid generation in the hepatocyte mitochondria.

To recap, ketosis is a dietary manipulation that if done right can lead to results. Ketoacidosis is a life-threatening metabolic state that requires immediate medical care.

This discussion will be continued with the next article focusing on ketoacid generation.


Acid-Base Balance

An acid is any compound that can donate H+ when dissolved in water. A base is any compound that can donate OH- ions. A buffer system is a combination of a weak acid or base and its salt or conjugate that resists changes in pH. The human body has incredible mechanisms to maintain an acid-base balance. Changes in pH put the body in different physiological states that can cause an array of problems. Acidosis is when the pH falls below the reference range of 7.34. Alkalosis is when the pH increases above the reference range of 7.44.


The most important buffer system in the body is the bicarbonate (HCO3)/carbonic acid (H2CO3) system. Carbonic acid works to allow the human body to rid of toxic CO2 via respiration to maintain a normal pH of 7.4. There normally is a 20:1 ratio of bicarbonate to carbonic acid.

The red cells pick up CO2 from tissues and throughout its travel through the blood vessel its converted to carbonic acid. That carbonic acid is then broken down into bicarbonate and hydrogen. The excess hydrogen ions are buffered by hemoglobin. Bicarbonate leaves the red cell and goes into circulation. Bicarbonate enters the plasma through an exchange mechanism with chloride to maintain a state of electroneutrality in the cell. When the red cells reach the lung the hemoglobin will release the excess hydrogen ions by the binding of oxygen to hemoglobin. The excess hydrogen ions bind to bicarbonate to form carbonic acid. Carbonic acid then dissociates into H20 and CO2 which is expelled.

As mentioned above, an individual can be in a state of acidosis or alkalosis. This can be caused by ventilation and is called respiratory acidosis or respiratory alkalosis or it can either be caused by HCO3-. This is called metabolic acidosis or alkalosis.

Respiratory acidosis is an increase in PCO2. Conversely respiratory alkalosis is a decrease in PCO2. Metabolic acidosis is a loss of HCO3- or an addition of H+. Metabolic alkalosis is a loss of H+ or an increase of HCO3-. The body will naturally compensate for the pH changes. Some of the compensatory mechanisms are increasing respiration in metabolic acidosis. Hyperventilation increases the amount of CO2 that is expelled and raising the pH. In respiratory acidosis the kidney will increase its reabsorption of HCO3-.

Metabolic acidosis can be caused by multiple different disease states. Excessive loss of HCO3- by diarrhea can cause metabolic acidosis. Diabetic ketoacidosis can cause it. Other causes are ingestion of acids or renal tubular failure where there is no renal reabsorption of HCO3-.

Metabolic alkalosis is caused by excess or an overdose of HCO3-. Excessive vomiting causes a loss of hydrochloric acid with the stomach contents. Vomiting also results in hypokalemia and hyponatremia which are both positively charged ions (acids) leading to an increase in the pH. Excessive diuretic use can sometimes initially cause an increase in chloride, but most commonly results in hyponatremia and causing a contractile alkalosis.

Respiratory acidosis is most commonly caused by CO2 retention usually due to ventilation failure. Decreased cardiac output and hypotension also cause acidosis. Less blood is pumped to the heart so less CO2 is getting transported to the lungs to be expelled. Chronic lung conditions such as COPD result in an inability to ventilate properly and to expel CO2. Certain drugs cause depression of the respiratory center in the brain and can cause respiratory acidosis. Some of these drugs are barbiturates, opiates and ethanol (alcohol).

Respiratory alkalosis is primarily caused by hyperventilation (increased alveolar ventilation). This results in a decreased arterial PCO2. Any condition which decreases pulmonary compliance causes a sensation of dyspnea. Dyspnea is not a single sensation and there are at least three distinct sensations including air hunger, work/effort, and chest tightness. These sensations cause a state of hypoxia which is caused by the hyperventilation.