Inherited Metabolic Liver Diseases
Inherited metabolic liver diseases are a group of metabolic defects that typically lead to early chronic liver involvement. Most are due to defective metabolic pathways caused by an enzyme deficiency. The liver is the most important organ where metabolism, a process by which the absorbed nutrients are converted to energy through chemical reactions through enzymes. In the absence of a particular enzyme, the chemical reactions do not function normally and there is a toxic build-up of chemicals in the body leading up to organ damage.
Fortunately, inherited metabolic disorders are quite rare in the general population. Considered all together, inherited metabolic disorders may affect about 1 in 1,000 to 2,500 new-borns.
- Poor appetite
- Abdominal pain due to enlarged liver
- Bloated abdomen due to accumulation of fluid
- Nausea and vomiting
- Failure to grow normally/thrive
- Developmental delays/milestone delays
- High colored urine
- Low blood glucose level
- Enlarged liver detected by ultrasound imaging
- Growth delay
- Jaundice, yellowish coloration to the skin and whites of eyes
- Eating many small meals that are low in sugar can help keep blood sugar levels normal while preventing excess glycogen storage in the liver.
- Carbohydrate solutions may be given continuously during the night to prevent a drop in blood glucose level during sleep, but this carries more risk of severe hypoglycemia compared to using uncooked cornstarch around the clock.
- Enzyme replacement therapy and gene therapy is being evaluated
- Infants with tyrosinemia and cancer of the liver will need a liver transplant to survive.
- Gene therapy and enzyme replacement therapies are being evaluated.
The symptoms of genetic metabolic disorders vary widely depending on the metabolism disorder present. The symptoms may come on suddenly or progress slowly. Sometimes the symptoms may be brought on by foods, certain medications, state of dehydration, and even minor illnesses. Symptoms begin to appear within a few weeks after birth in most conditions. Some symptoms of inherited metabolic disorders include:
Inherited metabolic disorders are present at birth, and some are detected by routine screening. And in some cases only diagnosed once the symptoms appear. Once symptoms develop, specific blood or DNA tests are available to diagnose most genetic metabolic disorders.
Few of the inherited metabolism disorders in the pediatric population responsible for early chronic liver diseases are described here:
Glycogen Storage Disease
In glycogen storage disease (GSD), an enzyme needed for glycogen metabolism is missing or unable to function properly. Glycogen metabolism involves the process of converting glucose to be stored as glycogen in the liver and muscles, which is once again converted to glucose by enzymes when energy is required by the body. Therefore, in GSD, the body is not able to store or break down the glycogen as it should. This can lead to low blood glucose levels
Many different enzymes are used by the body to process glycogen. As a result, there are many types of GSDs that have been identified and most of the types adversely affect the liver. The most common type of GSD is GSD Type 1 (90%).
GSDs occur when the defective gene is passed down from parents to children. In most cases, in order to have the GSD, a child must get a bad gene from both parents. Just because both parents have the gene does not always mean they will both pass it on to their children.
Four parameters that might cause suspicion for a type of GSD that affects the liver include:
Confirmatory test is a liver tissue biopsy which involves taking a tissue sample directly from the liver for analysis in the laboratory for glycogen levels and defective enzymes. Gene testing will also confirm a GSD.
Treatment varies depending on the type of GSD. For types of GSD that involve the liver, treatment is aimed at keeping the right level of glucose in the blood. Recent advancements in therapy provide treatment options that are very effective in managing the types of glycogen storage disease that affect the liver. GSD type I was considered a fatal disorder until 1971, when it was discovered that providing a continuous source of glucose could relieve the metabolic disturbances associated with the disorder.
Treatment since 1982 consists of taking regular doses of uncooked cornstarch and/or nutrition supplements dramatically improving quality of life enabling affected persons to lead full and normal lives
GSDs that are not treated properly can lead to problems such as liver failure, heart failure, and lung failure.
GSD Type IV (Andersen’s disease) occurs in 1: 600,000 births and causes scarring (cirrhosis) of the liver leading up to liver failure. If diagnosed within the first months of life with failure to thrive and hepatomegaly evolving to cirrhosis with portal hypertension, a liver transplantation is required.
Type I tyrosinemia is the most severe form of genetic tyrosinemia and is the only one that causes a severe liver involvement. It is a very rare disorder with an incidence of 1 : 100,000 births. It occurs due to deficiency of an enzyme called fumaryl acetoacetic hydrolase, which causes increase in blood and urine level of succinyl acetone (diagnostic golden standard) and high levels of tyrosine, methionine, and phenylalanine in the blood.
If left untreated, patients will progress to liver failure at about one year with kidney dysfunction. Untreated patients die within the first decade of liver failure or of early liver cancer.
A drug called NTBC and a special tyrosine-restricted diet can completely revert symptoms of tyrosinemia and help the liver and kidney tissue to return to normal. Liver transplantation was used in the past since it provided a better long-term outcome than diet alone, but treatment with NTBC is more effective with a 90% survival
Galactosemia is a rare hereditary disease that can lead to cirrhosis in infants, if not diagnosed quickly. It is inherited from both parents and occurs in about 1 in 20,000 live births. This disease is caused by increased levels of galactose (a sugar in milk) in the blood resulting from a deficiency of the liver enzyme galactose-1-phosphate uridyl transferase required for its metabolism (breakdown).
The symptoms usually appear in the first few days of life following the ingestion of breast milk or formula. Galactosemia should be considered in any jaundiced infant because of beneficial effects of early dietary restriction.
Up to 70% of infants can die if not diagnosed and treated early. One of the common causes of early death in these children is sepsis from bacterial infections. Galactosemia can be diagnosed through blood and urine tests.
Treatment is based on the elimination of galactose from the diet done in the early neonatal period by stopping breast feeding and by the administration of diets which contain no lactose or galactose, to be strictly followed, and continued for years, and possibly for life.