Specific diseases Endocrine/metabolic		There are a number of endocrine and metabolic disorders that can rarely cause cholestasis. Their importance lies not with their frequency of occurrence but in the fact that all are treatable and, as such, should be looked for early in the diagnostic workup. Tyrosinemia type I typically presents with acute liver failure < 6 months of age, characterized by severe coagulopathy. LFTs are only slightly abnormal, but alpha-fetoprotein levels are hugely elevated. This phase may progress to development of cirrhosis, ascites, jaundice and GI bleeding. There often is a characteristic odor of "boiled cabbage". Those diagnosed less than 2 months of age have a 75% mortality by age 2; if diagnosed between 2 and 6 months, mortality is 70% by age 6. More information on the clinical aspects, genetic defect and an exciting new therapy are available here. Hereditary fructose intolerance (HFI) can be life-threatening as well. It is caused by an absence of aldolase B in the liver, kidney and small intestine. This enzyme catalyzes the conversion of fructose-1-phosphate to the triosephosphates. There is a buildup of fructose-1-phosphate with resultant sequestering of inorganic phosphorus. This causes decreased ATP formation and hypoglycemia, both from disordered gluconeogenesis and failure of glycogenolysis. Patients with HFI are entirely asymptomatic until they ingest fructose or sucrose. Then symptoms develop beginning with poor feeding, vomiting and failure to thrive and progressing to hypoglycemia, coagulopathy, hepatomegaly and lactic acidosis. Liver and kidney failure and ultimately death can ensue. The course may be chronic and the symptoms intermittent. Chronic liver disease with hepatomegaly and cirrhosis may be seen. Classic galactosemia is due to a deficiency of galactose-1-phosphate uridyl transferase (GALT). This enzyme catalyzes the conversion of galactose-1-phosphate to UDP galactose. As with HFI, absence of this enzyme leads to a sequestering of inorganic phosphorus, resulting in low ATP levels, energy depletion and metabolic collapse. Most cases are now diagnosed by newborn screening, and are often asymptomatic. Some cases, though, present early with vomiting, irritability or lethargy and hypotonia. There is a high incidence of E. coli sepsis with galactosemia. In fact, it is recommended that galactosemia be ruled out in any baby with E. coli sepsis. If galactose ingestion continues, jaundice, acidosis and acute metabolic collapse may occur with liver and kidney failure ending in death. Some infants have a more chronic course characterized by feeding intolerance, growth failure and cirrhosis. Mental retardation is the rule in survivors. Cataracts are common later in infancy in patients not on a restricted diet. Both galactosemia and HFI can be diagnosed by enzyme assay. In galactosemia, the gene locus is 9p13 and RBCs should be used for the assay; with HFI, the gene locus is 9q22.3 and liver tissue is preferred. Both diseases have non-glucose reducing substances in the urine. Fructose tolerance test can confirm the diagnosis of HFI, showing increased plasma uric acid and magnesium and decreased phosphorus and glucose following a fructose load. In both diseases the treatment is dietary restriction. In HFI, all known sources of fructose, sucrose and sorbitol must be eliminated. With treatment, recovery is complete with normalization of hepatic functon and histology. Treatment of galactosemia involves restriction of dietary galactose. For infants this means no breast milk, only galactose-free formula. The treatment will allow recovery from the acute metabolic syndrome, reverse liver and kidney failure and prevent development of cataracts. However the dietary treatment of galactosemia does not prevent the mental retardation nor the ovarian dysfunction seen in females. The reasons for this are not known. Some patients detected by neonatal screening have the Duarte variant associated with decreased but not absent GALT levels and they may be able to tolerate galactose. The triad of hypoglycemia, nystagmus and cholestasis is strongly suggestive of hypopituitarism. Typically there is an absent septum pellucidum and septo-optic dysplasia. The mechanism appears to be decreased BAIF leading to cholestasis. The usual cholestatic features (acholic stools, hepatomegaly) are present. Although neonatal hypothyroidism much more commonly presents with indirect hyperbilirubinemia, it may also be associated with decreased BAIF resulting in cholestasis. Return to top of page