Januari 2012
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include transient thrombocytopenia, neutropenia, itching, burning, photophobia, corneal opacities
and erosions.
2,9
During treatment regular monitoring of metabolites (blood and urine), adverse effects, NTBC blood
levels and renal function in addition to abdominal imaging are advised.
2,10
Long-term effects of treatment with NTBC is yet unknown, therefore detailed follow-up, preferably
in a study protocol, is of great importance.
Diet
Dietary restriction of phenylalanine and tyrosine are also necessary during Nitisinon therapy. (The
total amount of natural protein should be restricted to keep blood phenylalanine and tyrosine
levels within target range being >35 μmol/L, and 200-400 μmol/L, respectively) A supplement of
tyrosine/phenylalanine-free amino acids is usually given to meet protein requirements.
Supplement should be given in divided doses at meals. Vitamin and mineral supplements, if not
sufficiently provided with the amino acid supplement, are usually needed because of the general
restrictions in normal food intake.
9
Liver transplantation
Liver transplantation should be reserved for those children with non-response to NTBC, risk of
malignancy and/or poor quality of life related to dietary restriction and frequency of blood
sampling.
11
Hepatic encephalopathy is an urgent indication for liver transplantation.
10
Transplant recipients require lifelong immunosuppression and face a considerable mortality rate
(10-15%).
Children with tyrosinemia, in whom transplantation can be performed on a
nonemergency basis, tend to have a good postoperative course
11
.
Liver transplant cures the hepatic and neurologic complications of tyrosinemia. Since
succinylaceton is also generated in renal tissue progressive renal dysfunction may remain after
liver transplantation. Therefore the use of low-dose NTBC might be considered after liver
transplantation to prevent progression of tubular and glomerular dysfunction.
12
Annual follow-up
of renal function (with isotopic glomerular filtration) is another option.
10
Complications
Liver failure
Liver dysfunction occurs in virtually all patients with tyrosinemia. Synthetic functions are most
affected, most prominent in the prolonged bleeding times (non-responsive to vitamin K).
Acute hepatic crisis consisting of ascites, jaundice, irritability and gastrointestinal bleeding. These
crisis can be precipitated by infections or catabolic stress and may resolve spontaneously or
progress to complete liver failure and hepatic encephalopathy. Acute hepatic complications have
not been reported to occur following treatment with NTBC.
Chronic liver disease, including liver cirrhosis, is common in untreated children with tyrosinemia
and dramatically increases the risk of hepatocellular carcinoma.
10
Hepatocellular carcinoma (HCC)
Untreated children who survive acute onset liver failure are at high risk of developing
hepatocellular carcinoma. The results of an international NTBC study suggest a decreased risk of
HCC in patients who started treatment at an early age; however the later NTBC is started the less
effective in this respect it seems to be.
8,10,13
Increased AFP levels may be a reflection of insufficient metabolic control; however further
examinations to exclude HCC are usually warranted.
9
Renal involvement
Renal tubular dysfunction is most common in tyrosinemia, although glomerular dysfunction can
occur as a consequence of long-lasting tubular dysfunction. Loss of phosphate, amino acids and
glucose and renal tubular dysfunction are due to dysfunction of the proximal tubulus.
Hypophosphatemic rickets is the principal clinical sign of renal tubular dysfunction. Therapy (diet
and NTBC) usually improves renal tubular function to some extent.