Ketone Bodies

Introduction

Ketone bodies are water-soluble molecules produced in the liver from fatty acids during periods of prolonged fasting or low carbohydrate intake. They are used as an alternative source of energy when glucose is not available, such as during prolonged exercise, fasting, or in conditions like diabetes.

Overview

•  Structure
  • two types
    • acetoacetate
    • β-hydroxybutyrate
      • β-hydroxybutyrate + NAD+ → acetoacetate + NADH
      • ↑ NADH:NAD+ ratio results in ↑ β-hydroxybutyrate:acetoacetate ratio 
  • 1 ketone body = 2 acetyl-CoA
• Function
  • produced by the liver
    • brain can use ketones if glucose supplies fall
      • >1 week of fasting
  • can provide energy to body in prolonged energy needs
    • prolonged starvation
      • glycogen and gluconeogenic substrates are exhausted
  • can provide energy if citric acid cycle unable to function
    • diabetic ketoacidosis
      • cycle component (oxaloacetate) consumed for gluconeogenesis
    • alcoholism
      • ethanol dehydrogenase consumes NAD+ (converts to NADH)
      • ↑ NADH:NAD+ ratio in liver reduces pyruvate and oxaloacetate levels available for gluconeogenesis (both are products of reactions where NAD+ is required for as cofactor)
  • RBCs cannot use ketones as they lack mitochondria
• Synthesis
  • occurs in hepatocyte mitochondria
    • liver cannot use ketones as energy
      • lacks β-ketoacyl-CoA transferase (thiophorase) which converts acetoacetate to acetoacetyl
  • under normal conditions acetoacetate = β-hydroxybutyrate
  • HMG CoA synthase is rate limiting enzyme
• Clinical relevance
  • ketoacidosis
    • pathogenesis
      • ↑ ketone levels
      • caused by
        • poorly controlled type I diabetes mellitus
          • liver ketone production exceeds ketone consumption in periphery
        • possible in type II diabetes mellitus but rare
        • alcoholism
          • chronic hypoglycemia results in ↑ ketone production
    • presentation
      • β-hydroxybutyrate > acetoacetate
        • due to ↑ NADH:NAD+ ratio
      • acetone gives breath a fruity odor
      • polyuria
      • ↑ thirst
    • tests
      • ↓ plasma HCO₃
      • hypokalemia
        • individuals are initially hyperkalemic (lack of insulin + acidosis) because K leaves the cells
        • overall though the total body K is depleted
          • glucosuria results in osmotic diuresis, K+ loss
          • replete K in these patients once the hyperkalemia begins to correct
      • nitroprusside urine test for ketones may not be strongly +
        • does not detect β-hydroxybutyrate
          • state favored by ↑ NADH:NAD+ ratio
• should use a test specific for β-hydroxybutyrate

Symptoms

High levels of ketone bodies in the blood, a condition known as ketosis, can cause a range of symptoms. Some of the symptoms associated with ketosis include:

• Fruity breath odor: When ketone bodies are produced in excess, they are released into the breath, causing a distinct fruity or acetone odor.
• Increased thirst and dry mouth: Ketosis can cause dehydration due to increased urination and loss of fluids from the body.
• Fatigue and weakness: The body may feel weak and tired due to a lack of glucose, which is the primary energy source for the brain.
• Nausea and vomiting: High levels of ketones in the blood can cause gastrointestinal distress, including nausea and vomiting.
• Dizziness and confusion: Ketosis can cause a state of confusion and dizziness due to the altered metabolic state.

Imaging

Ketone bodies can be imaged using various imaging techniques, including positron emission tomography (PET) and magnetic resonance spectroscopy (MRS).

PET is a non-invasive imaging technique that uses radioactive tracers to visualize metabolic processes in the body. PET can be used to image the brain and other tissues to determine the levels of glucose and ketone body utilization. PET imaging using a ketone tracer, such as [11C]acetoacetate, has been used to study brain metabolism during fasting and in conditions like epilepsy and Alzheimer’s disease.

MRS is a non-invasive imaging technique that uses magnetic fields and radio waves to detect and measure the concentrations of various metabolites, including ketone bodies. MRS can be used to quantify the levels of ketone bodies in different tissues, including the brain, liver, and muscle. MRS studies have shown that ketone body concentrations in the brain increase during prolonged fasting and in conditions like Alzheimer’s disease.

Treatment

Ketone bodies are naturally produced by the body during periods of prolonged fasting or low carbohydrate intake. In most cases, ketosis is a normal metabolic process and does not require treatment. However, in some cases, high levels of ketone bodies can lead to a condition called ketoacidosis, which requires immediate medical attention.

Treatment for ketoacidosis typically involves hospitalization and the administration of fluids, insulin, and electrolytes to correct the metabolic imbalance. In severe cases, patients may require admission to the intensive care unit for close monitoring and supportive care.

Ketone bodies have gained popularity in recent years as a potential weight loss tool and for their potential therapeutic benefits in conditions like epilepsy and neurodegenerative diseases. However, more research is needed to fully understand the long-term effects and potential risks of sustained ketosis.

Complications

High levels of ketone bodies in the blood, a condition known as ketosis, can lead to a range of complications. Some of the potential complications associated with ketosis include:

• Ketoacidosis: High levels of ketone bodies can lead to a condition called ketoacidosis, which can be life-threatening. Ketoacidosis is a metabolic state characterized by elevated blood acidity levels and can cause symptoms such as abdominal pain, nausea, vomiting, and confusion.
• Dehydration: Ketosis can cause dehydration due to increased urination and loss of fluids from the body.
• Electrolyte imbalances: Ketosis can lead to imbalances in electrolytes, such as sodium, potassium, and magnesium, which can lead to muscle weakness, cramping, and irregular heart rhythms.
• Increased risk of kidney stones: A high-fat, low-carbohydrate diet, which is often used to induce ketosis, can increase the risk of kidney stones.
• Nutrient deficiencies: A diet that is very low in carbohydrates and high in fat can lead to nutrient deficiencies, particularly in vitamins and minerals that are found in carbohydrate-rich foods.