Glucose-6-Phosphatase Deficiency

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Background

Glycogen is the stored form of glucose and serves as a tissue reserve for the body's glucose needs. It is composed of polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4-10 residues. Glycogen is formed in periods of dietary carbohydrate surplus and is broken down during starvation or periods of high glucose demand. Several inborn errors of glycogen metabolism have been described, and they result from mutations in genes that code for proteins involved in various steps of glycogen synthesis, degradation, or regulation. These disorders result in abnormal storage of glycogen, and hence the phrase glycogen storage diseases (GSDs).[1]

Glucose-6-phosphatase (Glc-6-Pase) deficiency, also termed GSD type I or von Gierke disease, is a rare form of GSD. The hydrolysis and transport of glucose 6-phosphate requires a hydrolase and microsomal transporters, pyrophosphate and glucose. Type Ia results from a deficiency in the glucose 6-phosphate hydrolase activity, and makes up more than 80% of cases. Types Ib (glucose-6-phosphate transporter deficiency), Ic, and Id are allelic defects in the translocase associated with glucose-6-phosphatase.[2]

Pathophysiology

Between meals, most tissues depend on glucose generated predominantly in the liver and kidney and distributed via the blood. The liver and the kidney are the primary organs responsible for blood glucose homeostasis in between meals. As alluded to earlier, glucose homeostasis is dependent upon the activity of the glucose-6-phosphatase (Glc-6-Pase)1 complex, which is composed of a glucose-6-phosphate transporter (Glc-6-PT) and a Glc-6-Pase catalytic unit. Glc-6-PT is a single copy gene (3–5) that is expressed ubiquitously.

Glycogenolysis results in the production of glucose-6-phosphate, which must then be dephosphorylated by Glc-6-Pase to yield free glucose that can be used by the body. In those with GSD the deficit can either be in the catalytic subunit (type Ia; von Gierke disease) or the G6P transporter (type Ib). In the former, enzyme is not expressed in liver, kidney, and intestine cells. This results in impaired generation of glucose from glycogen, thus resulting in fasting hypoglycemia, the prototype biochemical manifestation of this disease.

Glycogen and glucose-6-phosphate accumulate in the liver in GSD patients, as there is no effective alternative route for their metabolism, while glycogen synthesis continues normally in the postabsorptive stage. This results in characteristic hepatomegaly and on a diagnostic liver biopsy, sheets of swollen hepatocytes could be seen, typically arranged in a mosaic pattern with centrally placed nuclei. These cells have a clear cytoplasm as a result of all the glycogen within the cell being leached out by the process of fixation (using aqueous formalin).

Repetitive episodes of hypoglycemia leads to up-regulation of synthesis and transport of counterregulatory (stress) hormones, such as glucagon, cortisol, catecholamines, and growth hormone, with predictable metabolic effects. Muscle glycolysis is often up-regulated, resulting in high levels of pyruvate, lactate,[3] and free fatty acid (FFA) being released into systemic circulation. In the liver, FFA partly undergoes conversion to acetyl CoA, which then enters the oxidative tricarboxylic (Krebs) acid cycle. Also, the fatty acids generated circulate as FFA or as triacylglycerol and may manifest as high serum levels of nonesterified fatty acid, triglyceride, or both.

Prolonged plasma retention of triglyceride-rich lipoproteins also promotes lipid deposition in lean tissue, such as liver, skeletal muscle, cardiac muscle, and pancreatic (islets of Langerhans) tissue, resulting in lipotoxicity, with deleterious tissue effects (steato-hepatitis, insulin resistance, cardiac contractile dysfunction, and pancreatic beta cell failure/insulin deficiency).

Hyperuricemia results from overproduction and underexcretion. Excessive urate is produced during the production of adenosine triphosphate (ATP) from adenosine 5'-diphosphate in a reaction that involves deamination of adenosine monophosphate to inosine, with resultant conversion to uric acid. This hyperuricemia is worsened by the excess lactate that competes with the uric acid for excretion by a common renal anion transporter.[3]

Epidemiology

Frequency

United States

The incidence of GSD I is 1 per 100,000 live births and inheritance is autosomal recessive.[4] The glucose 6-phosphatase gene (G6PC) that encodes the hydrolase resides at 17q21 and that encoding glucose 6-phosphate translocase (G6PT) at 11q23 and mutations responsible for GSD I have been described in both type Ia and Ib patients.

International

Incidence in non-Ashkenazi Jews from North Africa may be as high as 1 case in 5420 persons.

Mortality/Morbidity

Prior to the advent of therapies such as continuous feeding and the use of cooked cornstarch, most individuals with GSD died young, usually as a result of hypoglycemia and other metabolic derangements. However, with prompt recognition of this condition in the perinatal period, effective therapy could be planned thus ensuring that most affected individuals are increasingly living up to adulthood.

Race

Sex

Age

History

It is usually diagnosed in first year of life. However, long-term care requires repeated documentation of symptoms to assess glycemic control and screen for complications.

Physical

In a report from the collaborative European Study on Glycogen Storage Disease Type I, patients (GSD Ia and GSD Ib) presented at a median age of 6 months (range 1 d to 12 y) and 4 months (range 1 d to 4 y), respectively.[6] This study reported the following features, from most to least common:

Hepatomegaly is often the first clue to diagnosis and in the first year of life; asymptomatic hepatomegaly may be the only finding. Typically, no associated jaundice, ascites, or splenomegaly is present. The liver enlargement may be massive, with the lower border extending down to the pelvis in older patients. Hepatic adenomas are frequent and should be specifically sought during palpation. When present, they may give the liver a lumpy texture. They may even be tender, especially if any recent hemorrhage has occurred within the mass. The absence of palpable adenomas does not exclude their presence; it simply underlines the importance of hepatic imaging tests. Documenting the size of the liver and adenomas over time is important. This information can prove to be a good indicator of therapeutic response and can indicate the need for further investigation and management.

Height and growth velocity are usually subnormal, and pubertal development is usually delayed. This is thought to be a consequence of chronic disease and a chronic catabolic state similar to malnutrition. Usually, bone age is delayed and insulinlike growth factor 1 levels are subnormal. Abnormal growth patterns may be ameliorated by good, long-term compliance and control with treatment regimens. Serial documentation of height and pubertal stage may be used as surrogate markers for overall disease control.

Patients may have a tendency toward central adiposity (rounded abdomen). Following blood pressure levels regularly is key to the early diagnosis of renal insufficiency.

Physical signs of hyperlipidemia may be present, especially as xanthomas, which may be seen over the elbows, knees, shins, and possibly as eruptions over the buttocks.

Joint examination may reveal signs of hyperuricemia, including acute gouty arthritis or tophaceous gouty deposits. Spinal examination may document the presence of a deformity or pain over any of the vertebral bodies as a clue to potential osteoporotic fracture.

Some patients have an increased tendency to bruising or bleeding. The presence of recurrent bacterial skin infections may be a clue to the diagnosis of GSD type Ib, which is otherwise clinically identical to GSD type Ia.

Cardiac examination may reveal signs of pulmonary hypertension, including high jugular venous pressure, loud P2, right ventricular heave, tricuspid regurgitation, or right-sided S3.[7]

Causes

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Histologic Findings

Even following resection of hepatic adenomas, the presence of tumor necrosis may make differentiating a malignant and nonmalignant hepatic tumor difficult.

Medical Care

Surgical Care

Consultations

Diet

Dietary therapy is the cornerstone of managing GSD. The goal is to provide a diet that supplies a constant amount of glucose during the day and night, while also providing all the essential nutrients for normal growth. At the same time, avoid overfeeding and possible excessive weight gain.

Dietary therapy usually begins in the hospital and requires expert help from an experienced dietitian. The diet may require frequent modification to maximize compliance and metabolic control, while taking the changing nutritional requirements of the growing child into account.

Activity

Medication Summary

Medication therapy should be primarily directed toward controlling hyperlipidemia and hyperuricemia. However, note that most literature in this area consists of case reports. No randomized controlled trials, aside from dietary therapy, have been performed.

Allopurinol (Zyloprim)

Clinical Context:  Inhibits xanthine oxidase, which is responsible for conversion of xanthine to uric acid.

Class Summary

Used in the treatment of hyperuricemia, gout, and uric acid nephrolithiasis.

Fenofibrate (Tricor, Triglide)

Clinical Context:  Lowers LDL-C better than older fibrate drugs do and increases high density lipoproteins (HDL). Presently used for triglyceride reduction and mixed dyslipidemias. Significantly decreases total cholesterol, LDL cholesterol, total triglycerides, apolipoprotein B, and triglyceride rich lipoprotein (VLDL). Increases plasma catabolism and clearance of TG-rich particles by lipoprotein lipase induction and suppression of hepatic production of apo C-III through activation of PPARs. Activates acyl CoA and other enzymes, which increases fatty acid oxidation. TG production is also decreased via inhibition of acetyl-CoA carboxylase and fatty acid synthase. Clinically, a marked reduction in plasma TGs and VLDL is observed, as is an increase in HDL-C levels. When triglyceride levels fall, the size and composition of LDL change from small dense particles (thought to be atherogenic), to large buoyant particles, which are catabolized rapidly through cholesterol receptors, improving lipid profiles.

Niacin (vitamin B-3)

Clinical Context:  Suppresses hepatic synthesis of very low-density lipoprotein and LDL cholesterol, subsequently lowering triglyceride and total cholesterol levels.

Gemfibrozil (Lopid)

Clinical Context:  Lowers serum triglyceride and total cholesterol levels while increasing HDL cholesterol levels. Mechanism of action is thought to be decreased hepatic lipogenesis.

Class Summary

Hyperlipidemia, especially hypertriglyceridemia, is thought to be a risk factor for acute pancreatitis and contributes to the development of atherosclerotic vascular disease.

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications

Transfer

Deterrence/Prevention

Complications

Prognosis

Author

Vasudevan A Raghavan, MBBS, MD, MRCP(UK), Director, Cardiometabolic and Lipid (CAMEL) Clinic Services, Division of Endocrinology, Scott and White Hospital, Texas A&M Health Science Center College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Bernard Corenblum, MD, FRCP(C), Professor of Medicine, Director, Endocrine-Metabolic Testing and Treatment Unit, Ovulation Induction Program, Department of Internal Medicine, Division of Endocrinology, University of Calgary, Canada

Disclosure: Nothing to disclose.

Gregory A Kline, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Richmond Road Diagnostic Centre, University of Calgary, Canada

Disclosure: Nothing to disclose.

Specialty Editors

Frederick H Ziel, MD, Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Disclosure: Nothing to disclose.

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

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