Fructose Intolerance Case File

Fructose Intolerance Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 24

A 3-year-old boy is brought to the emergency department after several episodes of vomiting and lethargy. His pediatrician has been concerned about his failure to thrive and possible hepatic failure along with recurrent episodes of the vomiting and lethargy. After a careful history is taken, you observe that these episodes occur after ingestion of certain types of food, especially high in fructose. His blood sugar was checked in the emergency department and was extremely low.

◆ What is the most likely diagnosis?

◆ What is the biochemical basis for the clinical symptoms?

◆ What is the treatment of the disorder?

ANSWERS TO CASE 24: FRUCTOSE INTOLERANCE

Summary: A 3-year-old boy with failure to thrive and possible hepatic failure. He presents with hypoglycemia and recurrent episodes of nausea and vomiting after ingestion of foods high in fructose.

◆ Diagnosis: Fructose intolerance.

◆ Biochemical basis of disorder: Because of a genetic disorder, the hepatic aldolase B enzyme is defective, and functions normally in glycolysis but not in fructose metabolism. Glucose production is inhibited by elevated fructose 1-phosphate. When fructose is ingested, severe hypoglycemia results.

◆ Treatment: Avoid dietary fructose.

CLINICAL CORRELATION

Individuals with a deficiency in aldolase B have the condition known as fructose intolerance. As with most enzyme deficiencies, this is an autosomal recessive disease; it does not cause difficulty as long as the patient does not consume any foods with fructose or sucrose. Frequently, children with fructose intolerance avoid candy and fruit, which should raise some eyebrows! Likewise, they usually do not have many dental caries. However, if chronically exposed to fructose-containing foods, infants and small children may have poor weight gain and abdominal cramping or vomiting.

APPROACH TO DISACCHARIDE METABOLISM

Objectives

1. Know about the metabolism of disaccharides, specifically fructose.

2. Know about the role of aldolase B in fructose metabolism.

Definitions

Disaccharide: Two sugar molecules (monosaccharides) linked together by a glycosidic bond. The major disaccharides obtained in the diet are maltose [4-(α-D-glucosido)-D-glucose], sucrose [β-D-fructofuranosyl-α-Dglucopyranoside], and lactose [4-(β-D-galactosido)-D-glucose].

Essential fructosuria: A rare, benign genetic condition in which fructose spills over to the urine because the liver, kidney, and intestine lack the enzyme fructokinase.

Fructokinase: An enzyme present in the liver, kidney, and intestine that will phosphorylate fructose to fructose 1-phosphate at the expense of an ATP.

Fructose intolerance: A genetic deficiency in the liver enzyme aldolase B. The absence of this enzyme leads to a build up of fructose 1-phosphate and depletion of liver ATP and phosphate stores.

GLUT 5: A facilitative glucose transporter isoform present in the small intestine and other tissues that will transport fructose (and glucose to a lesser extent) across the plasma membrane.

β-Glycosidase: A bifunctional, membrane-bound enzyme located on the brush-border membrane of the small intestine. This single polypeptide enzyme has two activities, lactase and glycosylceramidase, located in different domains of the protein. It will hydrolyze lactose to glucose and galactose.

SGLT1: A sodium-dependent glucose transporter located on the luminal side of the intestinal epithelial cells. It will transport glucose and galactose across the intestinal cell using a sodium ion gradient.

SGLT2: A sodium-dependent glucose transporter that has a high specificity for glucose and is specific to the kidney.

Sucrase-isomaltase complex: An enzyme complex comprised of two enzyme units. Both units have high α-1,4-glucosidase activity and will hydrolyze maltose and maltotriose to glucose. The sucrase unit will also hydrolyze sucrose to fructose and glucose, whereas the isomaltase unit will hydrolyze α-1,6 bonds found in isomaltose and the limit dextrins of starch.

DISCUSSION

The major disaccharides obtained in the diet are maltose, sucrose, and lactose. Maltose is primarily obtained from the consumption of the plant storage polysaccharide starch. Starch is degraded to glucose and small branched oligosaccharides called limit dextrins by exhaustive digestion by α-amylase. The limit dextrins are further enzymatically hydrolyzed to a branched tetrasaccharide by glucoamylase and to maltotriose and maltose and ultimately to glucose by the sucrase-isomaltase complex. Both of these enzyme complexes are located on the brush-border membrane of the small intestine. Sucrose, or table sugar, is hydrolyzed to glucose and fructose by the sucrase subunit of the sucrase-isomaltase complex. Lactose, or milk sugar, is enzymatically converted to glucose and galactose by β-glycosidase, also located on the brushborder membrane of the small intestine. This membrane-bound enzyme is a single polypeptide that has lactase and glycosylceramidase activities located in different domains of the protein.

Glucose and galactose are absorbed from the lumen of the intestine by the sodium-dependent glucose transporter, SGLT1, which is located on the luminal side of the intestinal epithelial cells. Fructose absorption is not dependent on a sodium gradient. It is transported into the intestinal cell by facilitative diffusion by a glucose transporter isoform, GLUT 5. Fructose transport is less rapid than glucose transport, and GLUT 5 does not have a high capacity. Thus, in most individuals, ingestion of fructose in amounts greater than 0.5 to 1.0 g/kg body weight can result in malabsorption. Fructose enters the bloodstream, along with glucose and galactose, via the GLUT 2 transporter. Fructose is taken up by the liver by the same GLUT 2 transporter, along with glucose and galactose. There is a large gradient between the extracellular and intracellular concentrations of fructose in the liver cells, indicating that the rate for fructose uptake by the hepatocyte is low.

In the liver, kidney, and intestine, fructose can be converted to glycolytic/ gluconeogenic intermediates by the actions of three enzymes—fructokinase, aldolase B, and triokinase (also called triose kinase)—as shown in Figure 24-1. In these tissues, fructose is rapidly phosphorylated to fructose 1-phosphate (F1P) by fructokinase at the expense of a molecule of adenosine triphosphate (ATP). This has the effect of trapping fructose inside the cell. A deficiency in this enzyme leads to the rare but benign condition known as essential fructosuria. In other tissues such as muscle, adipose, and red blood cells, hexokinase can phosphorylate fructose to the glycolytic intermediate fructose 6-phosphate (F6P).

Fructose 1-phosphate is further metabolized to dihydroxyacetone phosphate (DHAP) and glyceraldehyde by the hepatic isoform of the enzyme aldolase, which catalyzes a reversible aldol condensation reaction. Aldolase is present in three different isoforms. Aldolase A is present in greatest concentrations in the skeletal muscle, whereas the B isoform predominates in the liver, kidney, and intestine. Aldolase C is the brain isoform. Aldolase B has similar activity for either fructose 1,6-bisphosphate (F16BP) or F1P; however, the A or C isoforms are only slightly active when F1P is the substrate.

Glyceraldehyde may be converted to the glycolytic intermediate, glyceraldehyde 3-phosphate (GAP), by the action of the enzyme triokinase. This enzyme phosphorylates glyceraldehyde at the expense of another molecule of ATP. The GAP can then enter into the glycolytic pathway and be further converted to pyruvate, or recombine with DHAP to form F16BP by the action of aldolase.

Figure 24-1. The metabolic pathway for the entrance of fructose into the glycolytic pathway. Fructokinase rapidly converts fructose to fructose 1-phosphate, which in the liver is cleaved by aldolase B to dihydroxyacetone phosphate (DHAP) and glyceraldehyde.

A deficiency in aldolase B leads to the condition known as fructose intolerance. This inherited condition is benign as long as the patient does not consume any foods with fructose or sucrose. Patients with this condition usually develop an aversion to sweets early in life and as a result frequently are without any caries. However, infants and small children if chronically exposed to fructose-containing foods usually exhibit periods of vomiting and poor feeding, as well as a failure to thrive. A defect in the aldolase B gene results in a decrease in activity that is 15 percent or less than that of normal controls. This results in a buildup of F1P levels in the hepatocyte. Because the maximal rate of fructose phosphorylation by fructokinase is so high (almost an order of magnitude greater than that of glucokinase), intracellular levels of both ATP and inorganic phosphate (Pi) are significantly decreased. The drop in ATP concentration adversely affects a number of cellular events, including detoxification of ammonia, formation of cyclic AMP (cAMP), and ribonucleic acid (RNA) and protein synthesis. The decrease in intracellular concentrations of Pi leads to a hyperuricemic condition as a result of an increase in uric acid formation. AMP deaminase is inhibited by normal cellular concentrations of Pi. When these levels drop, the inhibition is released and AMP is converted to IMP and, ultimately, uric acid (Figure 24-2).

The toxic effects of F1P can also be exhibited in patients that do not have a deficiency in aldolase B if they are parenterally fed with solutions containing fructose. Parenteral feeding with solutions containing fructose can result in blood fructose concentrations that are several times higher than can be achieved with an oral load. Since the rate of entry into the hepatocyte is dependent on the fructose gradient across the cell, intravenous loading results in increased entry into the liver and increased formation of F1P. Since the rate of formation of F1P is much faster than its further metabolism, this can lead to hyperuricemia and hyperuricosuria by the mechanisms described above.

Figure 24-2. The inhibition of AMP deaminase by inorganic phosphate (Pi). A decrease in [Pi] increases the activity of AMP deaminase and leads to increased production of uric acid.

COMPREHENSION QUESTIONS

[24.1] A 22-year-old soldier collapses from dehydration during maneuvers in the desert and is sent to a military hospital. Prior to enlisting, a physician observed a high level of glucose in his urine during an examination. At first, he was not allowed to enlist because he was suspected of being a diabetic. Further tests, however, determined that his insulin level was normal. A glucose tolerance test exhibited a normal pattern. Laboratory tests following his dehydration episode repeat the previous findings, but further testing of the urine reveals that only D-glucose is elevated. Other sugars were not elevated. 

This patient’s elevated urinary glucose and his dehydration episode are caused by a deficiency in which of the following?

A. GLUT 2

B. GLUT 4

C. Insulin receptor

D. SGLT1

E. SGLT2

[24.2] Your patient is a 7-month-old baby girl, the second child born to unrelated parents. She did not respond well to breast-feeding and was changed entirely to a formula based on cow’s milk at 4 weeks. Between 7 and 12 weeks of age, she was admitted to the hospital twice with a history of screaming after feeding, but was discharged after observation without a specific diagnosis. Elimination of cow’s milk from her diet did not relieve her symptoms; her mother reported that the screaming bouts were worse after the child drank juice and that she frequently had gas and a distended abdomen. Analysis of a liver needle biopsy did not reveal any liver enzyme deficiencies. Overall, the girl is thriving (weight greater than 97th percentile) with no abnormal findings on physical examination.

If a biopsy of intestinal tissue were obtained from your patient and analyzed, which of the following would most likely be deficient or defective?

A. GLUT 2

B. GLUT 5

C. Isomaltase

D. Lactase

E. SGLT1

[24.3] A 24-year-old African-American female presents with complaints of intestinal bloating, gas, cramps, and diarrhea following a meal including dairy products. A lactose-tolerance test confirms your suspicion that she had a deficiency of lactase in her intestine. Which of the following dairy products could you recommend that would be least likely to cause her difficulties in the future?

A. Condensed milk

B. Cottage cheese

C. Ice cream

D. Skim milk

E. Yogurt

Answers

[24.1] E. The patient has normal levels of blood insulin and exhibits a normal glucose tolerance test. This indicates that glucose absorption from the intestine is normal as is clearance of glucose from the blood. The presence of glucose in the urine is most likely a kidney problem. Because the defect seems to involve only D-glucose and no other sugar, this points to a transporter with high specificity. The kidney has the GLUT 2, SGLT1, and SGLT2 transporters. GLUT 2 and SGLT1 are present in other tissues, and a defect in these would be expected to result in more serious sequelae. SGLT2 is a sodiumdependent glucose transporter specific to the kidney that has a high specificity for glucose. The glucose is present in the urine because of a failure to reabsorb it as a consequence of a defect in SGLT2. This leads to a loss of water also, because it is reabsorbed with glucose.

[24.2] B. Because the patient’s liver enzymes are normal and her symptoms seem to correlate with her intake of fruit juices, most likely her problem stems from an inability to absorb fructose. Since removal of cow’s milk from her diet did not eliminate the problem, a lactase deficiency can be ruled out. GLUT 5 is the primary transporter of fructose in the intestine and a deficiency in this transporter would lead to an inability to absorb fructose in the gut, making it a substrate for bacterial metabolism that produces various gases, including hydrogen, as well as organic acids.

[24.3] E. The microorganisms that convert milk to yogurt (Streptococcus salivarius thermophilus and Lactobacillus delbrueckii bulgaricus) metabolize most of the lactose in the milk, thus removing the source of this patient’s intestinal disquietude. Yogurt is also a good source of dietary calcium.

BIOCHEMISTRY PEARLS

❖ The major disaccharides obtained in the diet are maltose, sucrose, and lactose.

❖ Sucrose, or table sugar, is hydrolyzed to glucose and fructose.

❖ Lactose, or milk sugar, is enzymatically converted to glucose and galactose by β-glycosidase, also located on the brush-border membrane of the small intestine.

❖ A deficiency in aldolase B leads to the condition known as fructose intolerance.

References

Gitzelmann R, Steinmann B, Van den Berghe G. Disorders of fructose metabolism. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York: McGraw-Hill, 1995. 

Semenza G, Auricchio S. Small-intestinal disaccharidases. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York: McGraw-Hill, 1995. 

Ludueña RF. Learning Biochemistry: 100 Case-Oriented Problems. New York: Wiley-Liss, 1995.

HomeCase FilesFructose Intolerance Case File