In liver tissue, over 5,000 genetically-determined metabolic pathways have been described. This article will concentrate on the diagnosis and management of metabolic disorders in which the principal clinical features are hepatic and for which effective treatment is available. Liver disease associated with alpha- 1 antitrypsin deficiency is described to exemplify the need for up-to-date information in genetic counselling. There is no treatment for this disorder short of complete liver grafting. Metabolic storage disorders are not considered.
The earliest possible recognition of such metabolic disorders is essential for three reasons
1. Early appropriate treatment may prevent permanent damage to vital organs such as the brain or liver.
2. Precise genetic counselling with antenatal diagnosis may be possible.
3. Where no treatment is available, complications may be minimized if a precise diagnosis is known.
DISORDERS PRESENTING IN EARLY INFANCY WITH LIVER DYSFUNCTION
The two most common features of liver dysfunction in infancy are jaundice with urine that is not colorless and spontaneous bleeding. Less commonly, failure to thrive, edema, ascites and hypoglycemia may be presenting symptoms. Clinical examination commonly reveals a liver that is palpable more than 2 cm below the costal margin, and is firm. There may be splenomegaly. Biochemical tests of liver function will be abnormal. The essential immediate test is the prothrombin time.
Regardless of the cause of liver damage there may be Vitamin K malabsorption leading to a severe coagulopathy which can be complicated by intracranial hemorrhage. Intravenous Vitamin K will frequently correct this complication. The patient should receive no galactose or fructose until hereditary galactosemia and hereditary fructosemia have been excluded.
Infants with metabolic disorders are frequently septicemic. After obtaining urine and blood for culture such infants may require intravenous antibiotics while awaiting culture results and final diagnosis.
The endocrine deficiency states (Table 1), galactosemia, fructosemia and tyrosinosis must be excluded in every case, since with appropriate replacement or dietary treatment die prognosis is vastly improved. Cystic fibrosis and alpha- 1 antitrypsin deficiency must be excluded since they are numerically important causes of this type of liver injury in the US and Europe.
If there is consanguinity or if similar cases occur in a family the other metabolic disorders listed in Table 1 must be excluded. In the absence of such history, these diagnoses should be pursued if other clinical features suggest the diagnosis and particularly if liver biopsy or bone marrow aspirate findings are suggestive.
Galactosemia is a rare disorder in which deficiency of the enzyme galactose- 1-phosphate uridyl transferase is inherited in an autosomal, recessive fashion. Galactose cannot be incorporated into carbohydrate metabolism. It accumulates in all the body tissues together with metabolites which may be toxic. Galactosuria may occur following the ingestion of lactose.
Since all milks contain lactose, signs of the disease appear early, particularly in the breast-fed infant since human milk has a very high lactose content. As well as the features described above, some patients may present with mild failure to thrive and features of cirrhosis which become evident at 2 to 6 months of age. Rarely, cases may present with mental retardation and/or cataracts and following investigation, are found to have evidence of liver disease.
METABOLIC DISORDERS PRESENTING WITH LIVER DAMAGE IN EARLY INFANCY
Treatment and Prognosis
Following the institution of a galactose-free diet, there should be rapid improvement in the infant's condition with regression of the jaundice, gastrointestinal symptoms, bleeding and renal abnormalities. In patients in whom hepatic damage has been severe before the diet is instituted, a progressive course is followed. Infants with less severe damage may go on to develop cirrhosis later in life.
The majority do improve and have no subsequent hepatic problems. Cataracts are stabilized and may regress slightly with treatment. Brain damage is irreversible. Long-term follow-up of adequately treated galactosemic children shows their mental development is often impaired and they have a slightly increased incidence of psychological disturbance.
Factors to be Considered in Genetic Counselling
If galactosemia is diagnosed at birth in a subsequent sibling and a galactose-free diet is immediately instituted the major effects of galactosemia are avoided but the child's IQ may be much lower than expected for the family background. It has been suggested that these infants may have brain damage due to galactose crossing the placenta and such damage might be prevented by a galactose-free diet for the mother during pregnancy. An alternative hypothesis is that galactose is required for proper synthesis of brain glycoprotein. In view of lack of evidence on this point, parents may consider prenatal diagnosis by measurement of enzymatic activity in cells cultured from the amniotic fluid in early pregnancy.
Fructosemia (Hereditary Fructose Intolerance)
Hereditary frustose intolerance arises from an autosomal, recessively inherited deficiency of fructose- 1- phosphate aldolase. If fructose is ingested there are profound secondary effects on carbohydrate and nucleotide metabolism, particularly within the liver cells. Affected individuals develop an extreme aversion to fructose-containing foods.
Symptoms start as soon as fructose is ingested. Classically this occurs when breast milk is substituted by a milk containing fructose, sucrose or honey. The features are as described above. Alternatively it may present as a feeding difficulty when a fructose-containing food is offered to a child who is old enough to appreciate that the food causes malaise. Tragically the disease may also present in older children and in adults when given intravenous fructose during an illness. Some patients tolerate a small amount of sucrose but this usually provokes progressive liver damage, abdominal distension and ultimately cirrhosis.
A detailed dietary history is essential. Withdrawal of the fructose from the diet causes regression of vomiting almost immediately and there is a gradual improvement in the coagulation abnormalities over a few days. Confirmation of die diagnosis is made by demonstrating low enzymatic activity in liver or intestinal mucosal biopsy.
A fructose-sucrose free diet must be maintained for life; vitamin C supplements must be provided. For acute liver failure exchange transfusions, plasma/blood infusions, intravenous glucose must be considered. With the institution of a fructose-free diet, hepatomegaly gradually regresses and liver function tests return to normal. The fatty liver diminishes but never completely clears. Antenatal diagnosis is not possible, and subsequent siblings should be regarded as suffering from fructosemia until the diagnosis has been excluded.
Tyrosinemia (Fumarylacetoacetate Fumaryl-Hydrolase Deficiency)
In the last 3 years deficiency of the above enzyme appears to have been established as a biochemical basis of tyrosinemia with activity at 2% of normal values. Diagnosis may be established by measuring the enzymatic activity in fibroblasts or by detecting accumulation of succinyl acetone in the urine. Values are generally between 20 and 100 times normal.
Two forms of the disease occur. The acute form presents in the first 2 to 6 months of life with vomiting, diarrhea, edema, ascites, hepatosplenomegaly and a bleeding diathesis with marked failure to thrive. Jaundice occurs in only about onethird of infants. Thirty percent die in the first year of life. The chronic form presents in infancy or early childhood with features of cirrhosis and a renal tubular defect (Fanconi syndrome) which causes rickets. Hypoglycemia may occur in both forms of the disease.
A dietary restriction of phenylalanine, tyrosine and methionine is necessary. Regular estimation of serum amino acids to maintain a profile as near normal, should be the aim. Secondary metabolic problems such as hypoglycemia, alkalosis and rickets require specific treatment.
With such therapy there is an improvement in symptoms and complications but it has yet to be shown that dietary treatment influences the long-term outcome. There is a very high incidence of hepatoma in such patients.
Antenatal diagnosis by measuring the concentration of succinylacetone in the amniotic fluid or measuring enzymatic activity should be possible.
ALPHA-I ANTITRYPSIN DEFICIENCY (PROTEASE INHIBITOR TYPE ZZ:PIZZ)
This deficiency state serves as an example of a recently defined but as yet, untreatable disorder in which diagnosis has many implications. The subject emphasizes the point that genetic counselling requires the most up-to-date information which may not be available in the standard textbooks.
Genetic deficiency of this glycoprotein is inherited in an autosomal co-dominant fashion. The deficiency state, PiZZ, predisposes to emphysema in early adult life in up to 60% of subjects, and to liver disease which usually starts in early infancy. Fifty percent have abnormal biochemical tests of liver function throughout early childhood; at least 12% have symptoms of liver disease. The diagnosis is important in that cases presenting with jaundice frequently have clinical, biochemical and liver biopsy findings which may be indistinguishable from the surgically correctable disorder, extrahepatic biliary atresia. The prognosis for such children is poor, much worse than for idiopathic hepatitis of infancy. At least 50% will have cirrhosis, often leading to death by 10 years of age but up to 30% seem to grow into adult life with insignificant liver damage. The outcome is as yet undetermined in the remainder.
CLINICAL FEATURES OF GLYCOGEN STORAGE DISEASES WITH SIGNIFICANT HEPATIC PROBLEMS
Although spectacular advances have been made in our knowledge of the biochemistry of alpha- 1 antitrypsin, its exact physiological role remains uncertain and what causes liver injury and determines its severity remains to be solved.
The main products of the urea cycle, together with a currently recognized enzymatic defect and its relationship to pyridimine biosynthesis and the acetic acid cycle are shown in the Figure. Hyperammonemia is a constant feature but the degree depends on the protein intake. Glutamine, alanine and aspartate may also rise. Orotic aciduria is a feature of Types 3 to 7. Ornithine, citrulline, argininosuccmic acid or arginine accumulate depending on the enzymatic defect. Blood urea and urinary urea are normal.
Diagnosis is made on the basis of the above features, together with the demonstration of deficient enzymatic activity. This can be assayed in fibroblasts, leukocytes or red cells and in amniotic cells for prenatal diagnosis in all except disorders 2 and 3 which require liver tissue.
For the severely ill neonate exchange transfusion, peritoneal dialysis and a high carbohydrate/protein-free diet with gut sterilization by oral antibiotics is essential. Thereafter, it may be possible to maintain the patient on a low protein intake of between 0.5 and 1.5g protein/kg/day, with the addition of essential amino acids depending on the serum amino acid response. Meals should be small. The addition of arginine ( 1 to 2g/day) may prevent hyperammonemia in Type 5. In the other disorders alpha- keto analogues of the essential amino acids may have a useful role. Intercurrent bacterial and viral infection and surgery greatly aggravate the disorders and a high carbohydrate and minimal protein intake is mandatory during such episodes.
In a study of 47 families with two or more PiZ - individuals, we derived a risk of severe liver disease in the second PiZ- child in a family with a previously severely affected child, to be 80%. Families with a child with severe liver disease may thus opt for termination of a subsequent PiZ -pregnancy. However, at present antenatal diagnosis of the Pi status can only be done by fetal blood sampling and classical Pi phenotyping at 17 or 18 weeks gestation, which is much later than desirable. With synthetic oligonucleotides which can distinguish the PiZ - from the PiM - (normal) alpha- 1 antitrypsin in chorionic villous tissue, diagnosis much earlier in pregnancy can confidently be expected.
DISORDERS PRESENTING WITH PREDOMINANTLY NEUROLOGICAL FEATURES
Urea Cycle Disorders (Hyperammonemic Syndromes)
Although the majority of children with these disorders have hepatomegaly and raised serum transaminase activity, the principal clinical features are neurological irritability, convulsions, coma, ataxia and mental retardation. Vomiting is a common symptom.
GLYCOGEN STORAGE DISEASE
Type 1 and Type O (glycogen synthetase deficiency) Glycogen Storage Disease may present in the newborn period with tachypnea and hypoglycemic seizures.
Although 8 of the 13 currently well-defined forms of glycogen storage disease affect the liver, only four will be considered in this review. In the others the clinical and metabolic effects of liver involvement is minimal, the prognosis is good and no treatment is required.
The diagnosis of glycogen storage disease in late infancy or childhood may frequently be made on the basis of the clinical features (Table 2), the striking contrast between the distended abdomen and the thin limbs with poor muscle bulk and the chubby cheeks. The diagnosis is confirmed by demonstrating the decreased or absent enzymatic activity appropriate for the disorder. In types 1 and lb this requires liver tissue, but the other disorders can be diagnosed in leukocytes or fibroblasts.
Type O may respond to very frequent feeds with a high protein intake. Type 1 and lb requires treatment with a diet high in oligosaccharide which is given as a high starch diet at very frequent intervals while awake and by nasogastric tube during nighttime sleep. The goal of such treatment is to maintain blood glucose levels at between 70 and 100 mg/dl. Cold, uncooked, corn starch given 6-hourly in a dose of 2G/ kg may have a similar effect. Such a dietary regimen corrects the metabolic abnormalities and promotes normal growth. It is uncertain whether it prevents adenoma formation.
The management of Type III has to be tailored to each patient. A high protein diet during the day with continuous nocturnal intragastric feeding of a high protein diet at night may be beneficial. One of our patients responded most satisfactorily to the regimen designed for Type 1 Glycogen Storage Disease. Patients severely affected with the above diseases have received liver transplants. Whether this would be appropriate for Type IV Glycogen Storage Disease for which there is no dietary treatment, is speculative in view of the accumulation of abnormal carbohydrates in the brain in this disorder. It is uncertain whether this is secondary or primary.
Wilson's disease is an autosomally recessive inherited disorder of copper metabolism which is characterized by tissue damage caused by the deposition of copper in the liver, brain, red blood cells, kidney and eyes. Delay in diagnosis still results in death or unnecessary morbidity in Wilson's disease, 30 years after the introduction of effective therapy.
The age of onset ranges from the second year to the sixth decade. It must therefore be considered in any atypical or chronic hepatic disorder presenting after the age of 2 years. Asymptomatic hepatomegaly or cirrhosis, hepatomegaly with vague gastrointestinal symptoms, subacute hepatitis, fulminant hepatitis, gastrointestinal hemorrhage due to portal hypertension, jaundice with edema and ascites and the clinical and laboratory syndrome of chronic active hepatitis are well-documented hepatic presentations.
Neurological presentations in childhood usually take the form of deteriorating school performance but classical features of extra-pyramidal involvement may also appear. Neurological abnormalities are more common in the adolescent age group.
Patients may present with a hemolytic anemia with minimal biochemical evidence of hepatic involvement.
Renal tubular abnormalities with significant proteinuria, hematuria and edema and Vitamin D resistant rickets have been described. Occasionally, asymptomatic patients are found with Kayser-Fleischer rings. Arthralgia, abdominal pain, fever are non-specific symptoms.
Kayser-Fleischer rings are present in approximately 50% of children with Wilson's disease and must be sought by slitlamp examination. The affected cases are virtually all over 6 years of age. Serum ceruloplasmin is low in 90% to 95% of cases. The urinary copper is well above the upper limit of normal (less than 40 µg/24 hrs), with values usually in excess of 800 µg/day. The liver copper is invariably elevated. If Wilson's disease is diagnosed, it is absolutely essential to screen asymptomatic siblings to exclude the disorder.
The mainstay of treatment is the chelating agent D-penicillamine. This is given in a dose of 20 µg/kg/24 hrs in four divided doses taken before meals. Occasionally, a dose twice as high as this will be required to obtain effective chelation, but this has the risk of increasing side effects. For patients who develop side effects with penicillamine, triethylene tetraamine hydrochloride or unithiol (dimercaptopropane) may be effective. Large oral doses of zinc appear to increase fecal excretion of copper and may prove to be an effective long-term treatment.
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METABOLIC DISORDERS PRESENTING WITH LIVER DAMAGE IN EARLY INFANCY
CLINICAL FEATURES OF GLYCOGEN STORAGE DISEASES WITH SIGNIFICANT HEPATIC PROBLEMS