The Nephropathy of Type I Tyrosinemia after Liver Transplantation

Abstract

Type I tyrosinemia (HTI) is an autosomally recessively inherited disease caused by deficiency of fumarylacetoacetate hydrolase. The disease manifests with liver failure, renal tubular defects, and neurologic crises. Currently orthotopic liver transplantation (OLT) enables patients to survive. However, renal fumarylacetoacetate hydrolase deficiency is not corrected by OLT, and the long-term prognosis of the nephropathy is not known. We investigated tyrosine metabolism, GFR, renal tubular function, and histopathology before and 18-36 mo after OLT in eight patients with HTI. Progressive renal dysfunction was not documented despite continuing, although diminished, urinary succinylacetone excretion in all patients. The mean GFR was 82 mL/min/1.73 m 2 before and 102 mL at 18 mo and 93 mL at 36 mo after OLT. All patients showed tubular dysfunction before OLT. At 18 mo, glucosuria occurred in one, amino aciduria and phosphaturia in three, and hypercalciuria in six patients. Only hypercalciuria was seen at 36 mo. Renal biopsies showed mild Type I tyrosinemia is an autosomally recessively inh erited disease caused by FAR deficiency (1). FAR catalyzes the last step of tyrosine metabolism, and the deficiency leads to the accumulation of maleyl-and fumaryl acetoacetate and to the appearance of SA and SAA. Increased urinary excretion of SA and SAA occurs only in tyrosinemia and is diagnostic for the disease. The gene coding for FAR has been assigned to chromosome 15q23-q25 (2). Seven separate disease-inducing mutations of the gene have been described (3-6).Clinically type I tyrosinemia can be divided into two forms. The acute form of the disease is ch aracterized by signs of severe liver failure-ascites, bleeding tendency, and hypoglycemia-from the first months of life , and previously the patients died in early infancy. The chronic form is milder, and liver function less abnormal. However, the risk of hepatocellular carcinoma is increased, and carcinoma has been estimated

Renal function in tyrosinaemia type I after liver transplantation: A long‐term follow‐up

“…This finding is in accordance with the report of Laine and Krogerus (1995). At the same time, tubulopathy persisted in some patients.…”

“…In 1995, Laine showed that, 3 years after liver transplantation, hypercalciuria was the only sign of tubular dysfunction in 3 out of 8 patients (Laine et al 1995). The most recent study on this issue (Paradis 1996) showed that renal function may already be at risk before liver transplantation, even to such a degree that liver-kidney transplantation should be considered.…”

Treatment of two children with hereditary tyrosinaemia type I and long‐standing renal disease with a 4‐hydroxyphenylpyruvate dioxygenase inhibitor (NTBC)

“…Further improvement might be obtained by liver transplantation, although production of toxic metabolites and decreased renal function may persist (Tuchman et al 1987;Shoemaker et al t992;Laine et al 1995).…”

Kidneys of Mice With Hereditary Tyrosinemia Type I Are Extremely Sensitive to Cytotoxicity

“…Although cancer of the kidney is no feature of the mouse Fah Ϫ/Ϫ phenotype and has not been reported or found in patients with HT1 (F.J. van Spronsen Groningen University Medical Centre, personal communication 2005), it cannot be ruled out that renal cancer may eventually develop in HT1 patients who underwent liver transplantation and do not receive NTBC treatment after OLT. These patients continue to excrete low amounts of succinylacetone in the urine (6,10) due to the persistence of the enzyme defect in the kidneys (1,9). Their kidneys are, therefore, constantly exposed to FAA that is produced locally and may acquire resistance to cell death, as has been found for Fah Ϫ/Ϫ mice.…”

“…OLT has a beneficial effect on the tubular dysfunction of some HT1 patients (1,6), but patients who continued to have renal problems after successful OLT have also been reported (7)(8)(9)(10). Since 1992, HT1 patients have been treated with NTBC in combination with a diet low in phenylalanine and tyrosine (11).…”