Symptoms may begin early in infancy due to rapidly progressive
liver failure and may include vomiting, diarrhea, jaundice, hypoglycemia,
edema, ascites, and especially bleeding. The symptoms may also progress
slowly over many years and may include failure to thrive, hepatosplenomegaly,
tendency to bleed, and hypophosphatemic rickets due to renal tubular dysfunction
of the Fanconi type. Mental retardation is not a feature. Acute
attacks of peripheral neuropathy, resembling acute porphyria, with
severe abdominal pain, vomiting, paralytic ileus, extensor hypertonus,
and muscular weakness may occur. Late-presenting individuals can
remain undiagnosed, but all types of tyrosinemia type 1 have a high
risk for developing hepatocellular carcinoma.1
Deficiency of the last enzyme in tyrosine catabolism, fumarylacetoacetate
hydrolase (FAH), leads to the accumulation of fumarylacetoacetate
and possibly maleylacetoacetate, two cellular toxins that cause
hepatic and renal cellular damage (see Fig. 135-1).
Secondary inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPD)
leads to elevated concentrations of tyrosine, and accumulating tyrosine
metabolites such as 4-hydroxyphenylpyruvate, -lactate, and -acetate
are excreted in urine, a phenomenon known as tyrosyluria.
Fumarylacetoacetate can be reduced to succinylacetoacetate, which
is decarboxylated to succinylacetone. The latter is a strong inhibitor
of porphobilinogen synthase and thus causes secondary acute intermittent porphyria2 (see
Chapter 167). Complete absence of FAH leads to early infantile disease, whereas
late-presenting cases usually have some residual activity.3