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Disorders of Fructose Metabolism

Fructose metabolism is a complex cascade involving several enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. The enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes may be deficient or cause abnormal processing and disease. Essential fructosuria, hereditary fructose intolerance, and intestinal fructose intolerance are 3 of the distinct disorders. The presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor may range from asymptomatic to complaints of vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, bloating Bloating Constipation, flatulence, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea. Management is varied and often focuses on dietary modification. Severe complications such as kidney failure and even death may occur in hereditary fructose intolerance.

Last updated: 14 May, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Fructose metabolism is an enzymatic cascade, which causes a breakdown of fructose, a monosaccharide, for energy production. The complex process relies upon a series of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (absent in some individuals) and may cause 3 distinct disorders: essential fructosuria, hereditary fructose intolerance, and intestinal fructose intolerance.

Normal fructolysis

Fructolysis is the 1st portion of fructose metabolism:

  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance transporter 2 ( GLUT2 GLUT2 A glucose transport facilitator that is expressed primarily in pancreatic beta cells; liver; and kidneys. It may function as a glucose sensor to regulate insulin release and glucose homeostasis. Digestion and Absorption) and glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance transporter 5 ( GLUT5 GLUT5 A hexose transporter that mediates fructose transport in skeletal muscle and adipocytes and is responsible for luminal uptake of dietary fructose in the small intestine. Digestion and Absorption) absorb fructose (as a monosaccharide or disaccharide) from the lumen of the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy.
  • GLUT2 GLUT2 A glucose transport facilitator that is expressed primarily in pancreatic beta cells; liver; and kidneys. It may function as a glucose sensor to regulate insulin release and glucose homeostasis. Digestion and Absorption brings fructose into hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy.
  • Fructose is converted into fructose-1- phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes by fructokinase (also known as ketohexokinase). 
  • Fructose-1- phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes cannot be transported out of the cell.
  • Fructose-1- phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes is split by aldolase Aldolase Becker Muscular Dystrophy B (also known as fructoaldolase) into dihydroxyacetone phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (DHAP) and glyceraldehyde.
  • DHAP and glyceraldehyde continue along the metabolic cascade to glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis.
Normal metabolism of fructose

Normal metabolism of fructose:
Fructose is metabolized in hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy to produce dihydroxyacetone phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (DHAP) and glyceraldehyde, which are funneled into glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis.

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Epidemiology

  • Essential fructosuria: 
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 per 130,000 live births 
    • Difficult to report because asymptomatic
  • Hereditary fructose intolerance:
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 per 20,000 live births
  • Intestinal fructose intolerance:
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 per 10 live births
    • Common

Pathophysiology

Essential fructosuria (fructokinase deficiency):

Hereditary fructose intolerance ( aldolase Aldolase Becker Muscular Dystrophy B/fructoaldolase deficiency):

  • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance (heterozygotes are often asymptomatic)
  • Fructose-1- phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes cannot be split into DHAP and glyceraldehyde.
  • Fructose-1- phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes accumulation inhibits glycolytic and gluconeogenic pathways.

Intestinal fructose intolerance (deficiency/reduced activity of fructose carriers Carriers The Cell: Cell Membrane of the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy ( GLUT5 GLUT5 A hexose transporter that mediates fructose transport in skeletal muscle and adipocytes and is responsible for luminal uptake of dietary fructose in the small intestine. Digestion and Absorption)):

  • Fructose cannot be absorbed into enterocytes and remains in the small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy lumen.
  • Normal GI bacterial flora breaks down fructose.
  • Byproducts of bacterial metabolism include methane and hydrogen.

Clinical Presentation

Essential fructosuria

Essential fructosuria is asymptomatic.

Hereditary fructose intolerance

Symptoms appear when fructose is introduced into the diet.

  • Systemic: 
    • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
    • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • GI:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
    • Hepatomegaly
  • Neurologic:
    • Convulsions Convulsions Seizures, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Endocrine:  hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia

Intestinal fructose intolerance

Symptoms are most evident after ingestion of a fructose load (e.g., juice, fruit).

  • GI:
    • Bloating Bloating Constipation
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Abdominal distention Abdominal distention Megacolon

Diagnosis

Essential fructosuria

  • Incidental diagnosis: usually during another investigation
  • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat: reducing sugars present
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies: mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in KHK gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics

Hereditary fructose intolerance

  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies:
  • Blood chemistry:
    • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Elevated uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis
  • A liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is required if blood testing is inconclusive or not available.

Intestinal fructose intolerance

Hydrogen breath testing detects hydrogen produced by GI bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology.

Management

Essential fructosuria

Hereditary fructose intolerance

  • Acute management of symptoms, especially if life-threatening (e.g., seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, decreased level of consciousness)
  • Immediate initiation of fructose- and sucrose-free diet:
    • Exercise particular caution in the case of sorbitol Sorbitol A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. Laxatives infusion.
    • Sorbitol Sorbitol A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. Laxatives and fructose are metabolized by a similar process and can result in the same symptomatology Symptomatology Scarlet Fever.
  • For young children, supplement vitamins in fruits and vegetables.

Intestinal fructose intolerance

  • Dietary changes: 
    • Avoid fructose.
    • Avoid sorbitol Sorbitol A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. Laxatives.
    • Avoid disaccharides Disaccharides Oligosaccharides containing two monosaccharide units linked by a glycosidic bond. Basics of Carbohydrates and oligosaccharides Oligosaccharides Carbohydrates consisting of between two (disaccharides) and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. Basics of Carbohydrates (e.g., mannitol Mannitol A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. Osmotic Diuretics, xylitol).
  • Xylose isomerase, which converts fructose into glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance, may be supplemented. 
  • Because GLUT2 GLUT2 A glucose transport facilitator that is expressed primarily in pancreatic beta cells; liver; and kidneys. It may function as a glucose sensor to regulate insulin release and glucose homeostasis. Digestion and Absorption transports glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance and fructose into the enterocytes independent of GLUT5 GLUT5 A hexose transporter that mediates fructose transport in skeletal muscle and adipocytes and is responsible for luminal uptake of dietary fructose in the small intestine. Digestion and Absorption, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can tolerate sucrose.

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

Only patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hereditary fructose intolerance have clinically significant complications:

  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and renal disease are common in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship unable to adhere to restrictions.
  • If individuals do not adhere to a strict diet, death may result.

Clinical Relevance

  • Inflammatory bowel disease (IBD): a general term describing disorders involving chronic inflammation Chronic Inflammation Inflammation of the digestive tract, including both Crohn’s disease and ulcerative colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis. The etiology of IBD is multifactorial; environmental, genetic, and immune factors are implicated. Symptomatology Symptomatology Scarlet Fever includes diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, GI pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery. A definitive cure for IBD is not available. The goal of management is to control symptoms and induce remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches. Surgical intervention to remove severely damaged segments of the bowel is sometimes necessary.
  • Hepatomegaly: an abnormal enlargement of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy found on physical examination or imaging. The etiology is varied, but many cases are attributed to infection, malignancy Malignancy Hemothorax, or metabolic disorders such as hereditary fructose intolerance. Accurate diagnosis is important and work-up should include both blood work and imaging to find the underlying cause of the enlarged liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy. Treatment is aimed at the underlying cause of the disease. 
  • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly: abnormal enlargement of the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy. Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly can be attributed to numerous causes such as infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, infiltrative processes (e.g., acute leukemia/ lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum), and various outflow obstructions of portal vein Portal vein A short thick vein formed by union of the superior mesenteric vein and the splenic vein. Liver: Anatomy drainage. Aside from risks associated with the underlying pathology, enlargement of the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy puts individuals at increased risk for splenic rupture Splenic rupture Splenic rupture is a medical emergency that carries a significant risk of hypovolemic shock and death. Injury to the spleen accounts for nearly half of all injuries to intra-abdominal organs. The most common reason for a rupture of the spleen is blunt abdominal trauma, specifically, motor vehicle accidents. Rupture of the Spleen. A splenic rupture Splenic rupture Splenic rupture is a medical emergency that carries a significant risk of hypovolemic shock and death. Injury to the spleen accounts for nearly half of all injuries to intra-abdominal organs. The most common reason for a rupture of the spleen is blunt abdominal trauma, specifically, motor vehicle accidents. Rupture of the Spleen is a significant medical emergency and may require surgical intervention.

References

  1. Gaughan, S., Ayres, L., Baker, P.R. (2015). Hereditary Fructose Intolerance. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK333439/
  2. Hannou, S., … , McKeown, N.M., Herman, A.H. (2018). Fructose metabolism and metabolic disease. J Clin Invest. Doi: 10.1172/JCI96702.
  3. Yasawy, M.I., Folsch, U.R., Schmidt, W.E., Schwend, M. (2009). World J Gastroenterol. PMID: 19452588.
  4. Ali, M., Rellos, P., Cox, T.M. (1998). Hereditary fructose intolerance. J Med Genet. PMID: 9610797.

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