Defects in Metabolism of Carbohydrates

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Chapter 81 Defects in Metabolism of Carbohydrates

Carbohydrate synthesis and degradation provide the energy required for most metabolic processes. The important carbohydrates include 3 monosaccharides—glucose, galactose, and fructose—and a polysaccharide, glycogen. The relevant biochemical pathways of these carbohydrates are shown in Figure 81-1. Glucose is the principal substrate of energy metabolism. A continuous source of glucose from dietary intake, gluconeogenesis, and glycogenolysis of glycogen maintains normal blood glucose levels. Metabolism of glucose generates adenosine triphosphate (ATP) via glycolysis (conversion of glucose or glycogen to pyruvate), mitochondrial oxidative phosphorylation (conversion of pyruvate to carbon dioxide and water), or both. Dietary sources of glucose come from ingesting polysaccharides, primarily starch and disaccharides, including lactose, maltose, and sucrose. Oral intake of glucose is intermittent and unreliable. Glucose made de novo from amino acids, primarily alanine (gluconeogenesis), contributes to maintaining the euglycemic state, but this process requires time. The breakdown of hepatic glycogen provides the rapid release of glucose, which maintains a constant blood glucose concentration. Glycogen is also the primary stored energy source in muscle, providing glucose for muscle activity during exercise. Galactose and fructose are monosaccharides that provide fuel for cellular metabolism; their role is less significant than that of glucose. Galactose is derived from lactose (galactose + glucose), which is found in milk and milk products. Galactose is an important energy source in infants, but it is 1st metabolized to glucose. Galactose (exogenous or endogenously synthesized from glucose) is also an important component of certain glycolipids, glycoproteins, and glycosaminoglycans. The dietary sources of fructose are sucrose (fructose + glucose, sorbitol) and fructose itself, which is found in fruits, vegetables, and honey.

Defects in glycogen metabolism typically cause an accumulation of glycogen in the tissues, hence the name glycogen storage disease (Table 81-1). Defects in gluconeogenesis or the glycolytic pathway, including galactose and fructose metabolism, do not result in an accumulation of glycogen (see Table 81-1). The defects in pyruvate metabolism in the pathway of the conversion of pyruvate to carbon dioxide and water via mitochondrial oxidative phosphorylation are more often associated with lactic acidosis and some tissue glycogen accumulation.

81.1 Glycogen Storage Diseases

The disorders of glycogen metabolism, the glycogen storage diseases (GSDs), result from deficiencies of various enzymes or transport proteins in the pathways of glycogen metabolism (see Fig. 81-1). The glycogen found in these disorders is abnormal in quantity, quality, or both. GSDs are categorized by numeric type in accordance with the chronological order in which these enzymatic defects were identified. This numeric classification is still widely used, at least up to number VII. The GSDs can also be classified by organ involvement and clinical manifestations into liver and muscle glycogenoses (see Table 81-1).

There are more than 12 forms of glycogenoses. Glucose-6-phosphatase deficiency (type I), lysosomal acid α-glucosidase deficiency (type II), debrancher deficiency (type III), and liver phosphorylase kinase deficiency (type IX) are the most common that typically present in early childhood; myophosphorylase deficiency (type V, McArdle disease) is the most common in adolescents and adults. The frequency of all forms of GSD is ≈1/20,000 live births.

Liver Glycogenoses

The GSDs that principally affect the liver include glucose-6-phosphatase deficiency (type I), debranching enzyme deficiency (type III), branching enzyme deficiency (type IV), liver phosphorylase deficiency (type VI), phosphorylase kinase deficiency (type IX, formerly termed GSD VIa), glycogen synthetase deficiency (type 0), and glucose transporter-2 defect. Because hepatic carbohydrate metabolism is responsible for plasma glucose homeostasis, this group of disorders typically causes fasting hypoglycemia and hepatomegaly. Some (type III, type IV, type IX) can be associated with liver cirrhosis. Other organs can also be involved and may manifest as renal dysfunction in type I, myopathy (skeletal and/or cardiomyopathy) in types III and IV, as well as in some rare forms of phosphorylase kinase deficiency, and neurological involvement in types II (the brain, anterior horns cells), III (peripheral nerves), and IV (some patients can present with diffuse central and peripheral nervous system dysfunction).

Type I Glycogen Storage Disease (Glucose-6-Phosphatase or Translocase Deficiency, Von Gierke Disease)

Type I GSD is caused by the absence or deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestinal mucosa. It can be divided into two subtypes: type Ia, in which the glucose-6-phosphatase enzyme is defective; and type Ib, in which a translocase that transports glucose-6-phosphate across the microsomal membrane is defective. The defects in both type Ia and type Ib lead to inadequate hepatic conversion of glucose-6-phosphate to glucose through normal glycogenolysis and gluconeogenesis and make affected individuals susceptible to fasting hypoglycemia.

Type I GSD is an autosomal recessive disorder. The structural gene for glucose-6-phosphatase is located on chromosome 17q21; the gene for translocase is on chromosome 11q23. Common mutations responsible for the disease are known. Carrier detection and prenatal diagnosis are possible with the DNA-based diagnosis.

Clinical Manifestations

Patients with type I GSD may present in the neonatal period with hypoglycemia and lactic acidosis; they more commonly present at 3-4 mo of age with hepatomegaly, hypoglycemic seizures, or both. These children often have doll-like faces with fat cheeks, relatively thin extremities, short stature, and a protuberant abdomen that is due to massive hepatomegaly; the kidneys are also enlarged, whereas the spleen and heart are normal.

The biochemical hallmarks of the disease are hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Hypoglycemia and lactic acidosis can develop after a short fast. Hyperuricemia is present in young children; gout rarely develops before puberty. Despite marked hepatomegaly, the liver transaminase levels are usually normal or only slightly elevated. Intermittent diarrhea may occur in GSD I. In patients with GSD Ib, the loss of mucosal barrier function due to inflammation, which is likely related to the disturbed neutrophil function, seems to be the main cause of diarrhea. Easy bruising and epistaxis are common and are associated with a prolonged bleeding time as a result of impaired platelet aggregation and adhesion.

The plasma may be “milky” in appearance as a result of a striking elevation of triglyceride levels. Cholesterol and phospholipids are also elevated, but less prominently. The lipid abnormality resembles type IV hyperlipidemia and is characterized by increased levels of very low density lipoprotein, low-density lipoprotein, and a unique apolipoprotein profile consisting of increased levels of apo B, C, and E, with relatively normal or reduced levels of apo A and D. The histologic appearance of the liver is characterized by a universal distention of hepatocytes by glycogen and fat. The lipid vacuoles are particularly large and prominent. There is little associated fibrosis.

All these findings apply to both type Ia and type Ib GSD, but type Ib has additional features of recurrent bacterial infections from neutropenia and impaired neutrophil function. Gut mucosa ulceration culminating in GSD enterocolitis is also common. Exceptional cases of type Ib without neutropenia and type Ia with neutropenia have been reported.

Although type I GSD affects mainly the liver, multiple organ systems are involved. Puberty is often delayed. Virtually all females have ultrasound findings consistent with polycystic ovaries; other features of polycystic ovary syndrome (acne, hirsuitism) are not seen. Nonetheless, fertility appears to be normal, as evidenced in several reports of successful pregnancy in women with GSD I. Increased bleeding during menstrual cycles, including life-threatening menorrhagia, has been noted and could be related to the impaired platelet aggregation. Symptoms of gout usually start around puberty from long-term hyperuricemia. Secondary to the lipid abnormalities, there is an increased risk of pancreatitis. The dyslipidemia, together with elevated erythrocyte aggregation, predisposes these patients to atherosclerosis. Premature atherosclerosis has not yet been clearly documented except for rare cases. Impaired platelet aggregation and increased antioxidative defense to prevent lipid peroxidation may function as a protective mechanism to help reduce the risk of atherosclerosis. Frequent fractures and radiographic evidence of osteopenia are common; bone mineral content is reduced even in prepubertal patients.

By the 2nd or 3rd decade of life, most patients with type I GSD exhibit hepatic adenomas that can hemorrhage and, in some cases, become malignant. Pulmonary hypertension has been seen in some long-term survivors of the disease.

Renal disease is another complication, and most patients with type I GSD who are >20 yr of age have proteinuria. Many also have hypertension, renal stones, nephrocalcinosis, and altered creatinine clearance. Glomerular hyperfiltration, increased renal plasma flow, and microalbuminuria are often found in the early stages of renal dysfunction and can occur before the onset of proteinuria. In younger patients, hyperfiltration and hyperperfusion may be the only signs of renal abnormalities. With the advancement of renal disease, focal segmental glomerulosclerosis and interstitial fibrosis become evident. In some patients, renal function has deteriorated and progressed to failure, requiring dialysis and transplantation. Other renal abnormalities include amyloidosis, a Fanconi-like syndrome, hypocitraturia, hypercalciuria, and a distal renal tubular acidification defect.


Treatment is designed to maintain normal blood glucose levels and is achieved by continuous nasogastric infusion of glucose or oral administration of uncooked cornstarch. Nasogastric drip feeding can be introduced in early infancy from the time of diagnosis. It can consist of an elemental enteral formula or contain only glucose or a glucose polymer to provide sufficient glucose to maintain normoglycemia during the night. Frequent feedings with high-carbohydrate content are given during the day.

Uncooked cornstarch acts as a slow-release form of glucose and can be introduced at a dose of 1.6 g/kg every 4 hr for infants <2 yr of age. The response of young infants is variable. As the child grows older, the cornstarch regimen can be changed to every 6 hr at a dose of 1.75-2.5 g/kg of body weight. New starch products, which are currently being developed, are thought to be longer acting, better tolerated, and more palatable. A short-term double-blind crossover pilot study comparing uncooked, physically modified cornstarch to traditional cornstarch showed that the majority of GSD patients treated with the new starch had better short-term metabolic control and longer duration of euglycemia; however, more extensive studies replicating these results are necessary at this time. Because fructose and galactose cannot be converted directly to glucose in GSD type I, these sugars are restricted in the diet. Sucrose (table sugar, cane sugar, other ingredients), fructose (fruit, juice, high fructose corn syrup), lactose (dairy foods), and sorbitol should be avoided or limited. Due to these dietary restrictions, vitamins and minerals such as calcium and vitamin D may be deficient and supplementation is required to prevent nutritional deficiencies. Dietary therapy improves hyperuricemia, hyperlipidemia, and renal function, slowing the development of renal failure. This therapy fails, however, to normalize blood uric acid and lipid levels completely in some individuals, despite good metabolic control, especially after puberty. The control of hyperuricemia can be further augmented by the use of allopurinol, a xanthine oxidase inhibitor. The hyperlipidemia can be reduced with lipid-lowering drugs such as HMG-CoA reductase inhibitors and fibrate (Chapter 80). Microalbuminuria, an early indicator of renal dysfunction in type I disease, is treated with angiotensin-converting enzyme (ACE) inhibitors. Citrate supplements can be beneficial for patients with hypocitraturia by preventing or ameliorating nephrocalcinosis and development of urinary calculi. Growth hormone should be used with extreme caution and limited to only those with a documented growth hormone deficiency. Even in those cases, there should be close monitoring of metabolic parameters and presence of adenomas.

In patients with type Ib GSD, granulocyte and granulocyte-macrophage colony–stimulating factors are successful in correcting the neutropenia, decreasing the number and severity of bacterial infections, and improving the chronic inflammatory bowel disease.

Orthotopic liver transplantation is a potential cure of type I GSD, but the inherent short- and long-term complications leave this as a treatment of last resort, usually for patients with liver malignancy, multiple liver adenomas, metabolic derangements refractory to medical management, and/or liver failure. Large adenomas (>2 cm) that are rapidly increasing in size and/or number may require partial hepatic resection. Smaller adenomas (<2 cm) can be treated with percutaneous ethanol injection or transcatheter arterial embolization. A challenge is the recurrence of liver adenomas with potential for malignant transformation in these patients, ultimately requiring a liver transplant. Bone marrow transplantation has been reported to correct the neutropenia of type Ib.

Before any surgical procedure, the bleeding status must be evaluated and good metabolic control established. Prolonged bleeding times can be normalized by the use of intensive intravenous glucose infusion for 24-48 hr before surgery. Use of 1-deamino-8-D-arginine vasopressin (DDAVP) can reduce bleeding complications. Lactated ringer solution should be avoided because it contains lactate and no glucose. Glucose levels should be maintained in the normal range throughout surgery with the use of 10% dextrose.

Type III Glycogen Storage Disease (Debrancher Deficiency, Limit Dextrinosis)

Type III GSD is caused by a deficiency of glycogen debranching enzyme activity. Debranching enzyme, together with phosphorylase, is responsible for complete degradation of glycogen. When debranching enzyme is defective, glycogen breakdown is incomplete and an abnormal glycogen with short outer branch chains and resembling limit dextrin accumulates. Deficiency of glycogen debranching enzyme causes hepatomegaly, hypoglycemia, short stature, variable skeletal myopathy, and variable cardiomyopathy. The disorder usually involves both liver and muscle and is termed type IIIa GSD. In approximately 15% of patients, the disease appears to involve only liver and is classified as type IIIb.

Type III glycogenosis is an autosomal recessive disease that has been reported in many different ethnic groups; the frequency is relatively high in Sephardic Jews from North Africa. The gene for debranching enzyme is located on chromosome 1p21. More than 30 different mutations are identified; 2 exon 3 mutations (17delAG and Q6X) are specifically associated with glycogenosis IIIb. Carrier detection and prenatal diagnosis are possible using DNA-based linkage or mutation analysis.

Clinical Manifestations

During infancy and childhood, the disease may be indistinguishable from type I GSD, because hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation are common (Fig. 81-2). Splenomegaly may be present, but the kidneys are not enlarged. Remarkably, hepatomegaly and hepatic symptoms in most patients with type III GSD improve with age and usually resolve after puberty. Progressive liver cirrhosis and failure can occur. Hepatocellular carcinoma has also been reported, more typically in patients with progressive liver cirrhosis. The frequency of adenomas in individuals with GSD III is far less, compared to GSD I. Furthermore, the relationship of hepatic adenomas and malignancy in GSD III is unclear. A single case of malignant transformation at the site of adenomas has been noted. In patients with muscular involvement (type IIIa), muscle weakness can present in childhood but can become severe after the 3rd or 4th decade of life, as evidenced by slowly progressive weakness and wasting. Because patients with GSD III can have decreased bone density, they are at an increased risk of potential fracture. Myopathy does not follow any particular pattern of involvement; both proximal and distal muscles are involved. Electromyography reveals a widespread myopathy; nerve conduction studies are often abnormal. Ventricular hypertrophy is a frequent finding, but overt cardiac dysfunction is rare. There have been some reports of life-threatening arrhythmia and need for heart transplant in some GSD III patients. Hepatic symptoms in some patients may be so mild that the diagnosis is not made until adulthood, when the patients show symptoms and signs of neuromuscular disease. The initial diagnosis has been confused with Charcot-Marie-Tooth disease. Polycystic ovaries are common; some patients can develop hirsutism, irregular menstrual cycles, and other features of polycystic ovarian syndrome. Fertility does not appear to be reduced; successful pregnancies in patients with GSD III have been reported.

Hypoglycemia and hyperlipidemia are common. In contrast to type I GSD, elevation of liver transaminase levels and fasting ketosis are prominent, but blood lactate and uric acid concentrations are usually normal. Serum creatine kinase levels can be useful to identify patients with muscle involvement; normal levels do not rule out muscle enzyme deficiency. The administration of glucagon 2 hr after a carbohydrate meal provokes a normal increase in blood glucose; after an overnight fast, glucagon may provoke no change in blood glucose level.

Type IV Glycogen Storage Disease (Branching Enzyme Deficiency, Amylopectinosis, or Andersen Disease)

Deficiency of branching enzyme activity results in accumulation of an abnormal glycogen with poor solubility. The disease is referred to as type IV GSD or amylopectinosis because the abnormal glycogen has fewer branch points, more α 1-4 linked glucose units, and longer outer chains, resulting in a structure resembling amylopectin.

Type IV GSD is an autosomal recessive disorder. The glycogen branching enzyme gene is located on chromosome 3p21. Mutations responsible for type IV GSD have been identified, and their characterization in individual patients can be useful in predicting the clinical outcome. Some mutations are associated with a good prognosis and lack of progression of liver disease.

Phosphorylase Kinase Deficiency Limited to Heart

These patients present with cardiomyopathy in infancy and rapidly progress to heart failure and death. Phosphorylase kinase deficiency is demonstrated in the heart with normal enzyme activity in skeletal muscle and liver. Studies have questioned the existence of cardiac-specific primary phosphorylase kinase deficiency because they did not find any mutations in the 8 genes encoding the phosphorylase kinase subunits.

Glycogen Synthetase Deficiency (GSD 0)

Deficiency of hepatic glycogen synthetase (GYS2) activity leads to a marked decrease of glycogen stored in the liver. The disease appears to be very rare in humans, and in the true sense, this is not a type of GSD because the deficiency of the enzyme leads to decreased glycogen stores.

The patients present in infancy with early-morning (before eating breakfast) drowsiness, pallor, emesis, and fatigue and sometimes convulsions associated with hypoglycemia and hyperketonemia. Blood lactate and alanine levels are low, and there is no hyperlipidemia or hepatomegaly. Prolonged hyperglycemia, glycosuria, and elevation of lactate with normal insulin levels after administration of glucose or a meal suggest a possible diagnosis of deficiency of glycogen synthetase. Definitive diagnosis requires a liver biopsy to measure the enzyme activity or identification of mutations in the liver glycogen synthetase gene, located on chromosome 12p12.2. Treatment consists of frequent meals, rich in protein, and nighttime supplementation with uncooked cornstarch. Most children with GSD 0 are cognitively and developmentally normal. Short stature and osteopenia are common features. The prognosis seems good for patients who survive to adulthood, including resolution of hypoglycemia, except during pregnancy.

Hepatic Glycogenosis with Renal Fanconi Syndrome (Fanconi-Bickel Syndrome)

This rare autosomal recessive disorder is caused by defects in the facilitative glucose transporter 2 (GLUT-2), which transports glucose in and out of hepatocytes, pancreatic β cells, and the basolateral membranes of intestinal and renal epithelial cells. The disease is characterized by proximal renal tubular dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in liver and kidney.

The affected child typically presents in the 1st yr of life with failure to thrive, rickets, and a protuberant abdomen from hepatomegaly and nephromegaly. The disease may be confused with type I GSD because a Fanconi-like syndrome can develop in type I disease patients.

Laboratory findings include glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting, hypophosphatemia, increased serum alkaline phosphatase levels, and radiologic findings of rickets. Mild fasting hypoglycemia and hyperlipidemia may be present. Liver transaminase, plasma lactate, and uric acid levels are usually normal. Oral galactose or glucose tolerance tests show intolerance, which could be explained by the functional loss of GLUT-2 preventing liver uptake of these sugars.

Tissue biopsy results show marked accumulation of glycogen in hepatocytes and proximal renal tubular cells, presumably owing to the altered glucose transport out of these organs. Diffuse glomerular mesangial expansion along with glomerular hyperfiltration and microalbuminuria similar to nephropathy in GSD Ia and diabetes have been reported.

Fanconi-Bickel syndrome is rare. Seventy percent of patients with a detectable GLUT-2 mutation have consanguineous parents. Most patients are homozygous for the disease-related mutations; some patients are compound heterozygotes. The majority of mutations detected thus far predict a premature termination of translation. The resulting loss of the C-terminal end of the GLUT-2 protein predicts a nonfunctioning glucose transporter with an inward-facing substrate-binding site.

There is no specific treatment. Growth retardation persists through adulthood. Symptomatic replacement of water, electrolytes, and vitamin D; restriction of galactose intake; and a diet similar to that used for diabetes mellitus presented in frequent and small meals with an adequate caloric intake may improve growth.

Muscle Glycogenoses

The role of glycogen in muscle is to provide substrates for the generation of ATP for muscle contraction. The muscle GSDs are broadly divided into 2 groups. The 1st group is characterized by hypertrophic cardiomyopathy, progressive skeletal muscle weakness and atrophy, or both, and includes deficiencies of acid α-glucosidase, a lysosomal glycogen degrading enzyme (type II GSD), and deficiencies of lysosomal-associated membrane protein 2 (LAMP2) and AMP-activated protein kinase γ2 (PRKAG2). The 2nd group comprises muscle energy disorders characterized by muscle pain, exercise intolerance, myoglobinuria, and susceptibility to fatigue. This group includes myophosphorylase deficiency (McArdle disease, type V) and deficiencies of phosphofructokinase (type VII), phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase. Some of these latter enzyme deficiencies can also be associated with compensated hemolysis, suggesting a more generalized defect in glucose metabolism.