Von Gierke disease is a hereditary pathology that is caused by a deficiency of liver enzymes that transform glucose-6-phosphate into glucose. It proceeds with disorders of carbohydrate and lipid metabolism, is characterized by hypoglycemia, accumulation of glycogen in the liver and kidneys. Symptoms include weakness, headaches, convulsions, nausea, vomiting, hypotension, shortness of breath, fever, decreased blood clotting. Diagnostics is carried out by laboratory methods, including biochemical blood analysis, provocative tests, biopsy and cytological examination of the liver. The treatment is based on diet therapy, which provides round-the-clock glucose flow into the bloodstream.
E74.0 Glycogen storage diseases
Von Gierke disease has a number of synonymous names: glycogenosis type I, glucose-6-phosphatase deficiency, glucose-6-phosphattranslase defect. The eponymous name is associated with the surname of a doctor from Germany, Edgar von Gierke, whose research in 1929 led to the discovery of the synthesis of type I glycogen. He described in detail the biochemical changes and the clinical picture of glycogenosis I. The enzyme defect was discovered in 1952. The prevalence of the syndrome is small ‒ 1:200 thousand newborns. At the same time, the disease is the most frequent among glycogenoses. The frequency is the same among male and female representatives, the diagnosis is established at the age of 1 year, usually up to 3-5 months.
The disease belongs to hereditary metabolic pathologies, is transmitted from generation to generation by an autosomal recessive mechanism. The cause of the disease is mutations of genes that encode a liver enzyme that triggers the process of converting glycogen into free glucose. With a change in the G6PC gene, the production of glucose-6-phosphatase is disrupted, with a change in the structure of the SLC37A4 gene, the synthesis of glucose–6-phosphattranslase is disrupted.
For the development of glycogenesis, it is necessary that the child receives the mutated gene from the mother and from the father. Pathology develops in the presence of a pair of altered recessive genes, and if only one defective gene is present, the child remains healthy, but is a carrier of the disease and is able to pass it on to his future children. Thus, the probability of illness in a newborn, both parents of which are carriers of the mutation, is 25%.
In von Gierke disease, liver cells are unable to produce enzymes that cause the processes of glycogenolysis (cleavage of glycogen to glucose) and gluconeogenesis (formation of glucose from non-carbohydrate compounds). The conversion of glucose from food into glycogen, as well as its deposition in the liver and other tissues remains intact. Glycogen accumulates, but is not wasted on the needs of the body, the liver increases. In between meals, hypoglycemia develops due to the inability to use energy reserves.
Persistent hypoglycemia provokes a constant increased production of glucagon, which is a stimulant of glycogenolysis. This process is interrupted by a lack of enzymes, only its initial stages are realized, and hypoglycemia persists. The content of glucose-6-phosphate, an intermediate product of glycogenolysis, increases in cells. Due to the feedback, glycogen remains in the kidneys and liver, this is manifested by structural changes in organs and an increase in their size. Renal and hepatic insufficiency is formed. The concentration of lactic acid in the bloodstream increases, acidosis occurs.
By the nature of the course, Girke’s disease can be acute and chronic. The acute form develops more often in the first year of a child’s life, manifests itself with pronounced symptoms: vomiting, muscle cramps, shallow frequent breathing, which is accompanied by a feeling of lack of air. The chronic form is characterized by gradual progression of renal and hepatic insufficiency, stunting, delayed puberty. According to the initial enzyme defect , two types of glycogenosis are distinguished:
- Type Ia. In this variant, the production of glucose phosphatase is disrupted. It proceeds in a milder form than glycogenosis Ib. Accounts for 80% of cases of the disease.
- Type Ib. The insufficiency of phosphate translocase is determined. Neutropenia develops, the risk of infectious complications increases.
The symptoms of the disease most often unfold at 3-4 months of life, less often – from the period of newborn. The most pronounced manifestations of lactic acidosis and hypoglycemia are: babies are sluggish, sleepy, suck poorly on the breast or the nipple of the bottle, often cry, do not calm down for a long time. Sleep is restless, with frequent awakenings, the day and night regime is not set, blood pressure is reduced. There may be involuntary muscle twitching on the arms, legs, and eyelids. By 3 months, seizures develop. All these symptoms are more noticeable in children who are on artificial feeding and receive food “by the hour”, and not on demand. With frequent feedings, glucose enters the body almost continuously, hypoglycemia is weakly expressed.
The features of the child’s appearance change: the face becomes “doll-like”, rounded, the cheeks and abdomen are enlarged, the limbs are relatively thin. As they grow up, stunting, poor physical development, and late puberty are determined. Adipose tissue is distributed in a special way: the arms and legs are thin, seem even thinner against the background of a large face and torso. The large size of the abdomen is associated with both the accumulation of subcutaneous fat and pathological enlargement of the liver.
Xanthomas are formed – focal fatty neoplasms under the skin, located on the elbows, knees, hips, buttocks. Shortness of breath appears, the temperature often remains at the level of subfebrile values of 37-37.5C. Reduced platelet activity is manifested by nasal bleeding, bruising. Some children have diarrhea periodically. Insufficiency of kidney function develops with a prolonged severe course of the disease.
With inadequate treatment, non-compliance with doctor’s prescriptions, attacks of severe hypoglycemia negatively affect the work of the higher departments of the central nervous system, lead to oligophrenia. Some patients have serious liver damage: by the age of 20-30, adenomas develop that can transform into a malignant tumor – carcinoma. Other possible complications of von Gierke disease include hyperuricemic gout, pancreatitis, chronic renal failure, amyloidosis, Fanconi-Bikkel syndrome, hypocalcemia, distal tubular acidosis.
The disease is diagnosed in the first months after birth. The examination of children is carried out by pediatricians, endocrinologists, geneticists. Suspicion of von Gierke disease occurs with characteristic clinical signs, the detection of an increased content of lipid compounds and lactate in the results of a blood test. A number of laboratory studies are carried out to confirm the alleged diagnosis, differentiate different types of glycogenoses, exclude syphilis, toxoplasmosis, cytomegaly, tumors and liver steatosis:
- Blood test. With type 1 glycogenosis, the amount of glucose after 4 hours of hunger is no more than 2.2 mmol / l, after 5-7 hours without food – less than 1.10 mmol / l. Elevated levels of lactic and uric acids, triglycerides, cholesterol, AsAT and AlAT enzymes are determined. The high content of fatty substances makes the serum cloudy, milky in color.
- Laboratory provocative tests. In order to differentiate glycogenoses of various types and to determine the defect of enzymes, the level of metabolites and hormones is measured on an empty stomach, and then after a carbohydrate load. For glycogenosis of the first type, it is characteristic that after loading with glucose, the lactate level decreases, the curve has a diabetoid form – a high peak of sugar rise and a slow decrease.
- Glucagon test. Glucagon is administered intramuscularly or intravenously after a 4-6-hour period of hunger, lactate and glucose levels are monitored at regular intervals. With von Gierke disease, glucagon does not contribute to an increase in glucose concentration or increases it slightly, high lactate levels continue to grow.
- Examination of liver biopsy material. For an accurate diagnosis of an enzyme defect, whole and destroyed liver microsomes are examined, the activity of glucose-6-phosphatase is determined. A differential sign of glycogenesis Ia is a decrease in enzyme activity in microsomes of any type by 10%. In the Ib variant of the disease, it is active in damaged microsomes, and in whole ones it is absent or little functional. A high glycogen content with a standard molecular structure is also detected.
Therapy is aimed at compensation of hypoglycemia, elimination of secondary metabolic disorders. At the early beginning of treatment – during the periods of newborn and infancy – it is often enough to use methods of diet therapy. When a child grows up, hyperuricemia and hyperlipoproteidemia increase, the functioning of the kidneys and liver deteriorates, which requires medication, and sometimes surgical intervention. The full range of therapeutic measures includes:
To compensate for the inability of the enzymatic system to release glucose, a dietary nutrition system is used, which ensures the continuity of glucose intake for 24 hours. In medical practice, two methods are used to supply the body with carbohydrates around the clock:
- Probe administration of glucose. The infusion of nutrient solutions is carried out through the nasogastric pathway, less often through a gastrostomy. The mode of procedures is selected individually. Most children need to install a probe at night, as this allows them not to disturb sleep.
- The use of corn starch. During the day, children are given high-carb food. Regular feeding with raw corn starch is widely used. Glucose is released from it gradually, within a few hours, thanks to which normoglycemia is maintained.
Drug correction of metabolic disorders
By adulthood, additional measures are needed to normalize the level of uric acid and lipids (diet therapy is not enough). With hyperuricemia, the xanthine oxidase inhibitor allopurinol is prescribed, with hyperlipidemia – fibrates, statins. At the first signs of impaired renal function, ACE inhibitors and citrates are used.
Treatment of neutropenia
With the development of glycogenosis of subtype Ib, accompanied by a decrease in the number of granulocytes, the introduction of colony-stimulating factors is shown: granulocytic and granulocytic-macrophage. They prevent the development of neutropenia and reduce its severity, resulting in a reduction in the frequency of infectious diseases.
Treatment of liver neoplasms
Patients with volumetric liver adenomas are treated with percutaneous ethanol injections (CIE). In case of malignant tumors, the recommendation of orthotopic liver transplantation is possible.
Prognosis and prevention
Patients who do not receive the necessary treatment die during the newborn, infancy or early childhood from severe hypoglycemia and acidosis. With adequate therapy, the disease is successfully compensated, and the severity of hypoglycemia decreases with age. In adults, the activity of another enzyme that promotes the formation of glucose, amyl–1,6-glucosidase, increases. As a result, the ratio of the rate of production and utilization of glucose becomes more balanced. Preventive measures should be carried out during planning and in the early stages of pregnancy. Married couples from risk groups need to consult a geneticist to calculate the probability of the disease. Prenatal diagnosis allows you to identify the presence of pathology in the fetus.