Neonatal Presentation of a rare metabolic liver disease

The first typical case of hepato-renal tyrosinemia, including characteristic clinical and biochemical features, was described by Saki et al1 in 1957. Reports from the Indian subcontinent are sparse and most are without an enzyme assay confirmation. The worldwide prevalence of tyrosinemia is estimated at 1/100,000 to 1/120,000.[1] We describe the case of this rare disorder in a neonate.

Case Report

A 15-day-old male infant born of 2nd degree consanguineous marriage with a normal and uneventful birth history and average birth weight was admitted with progressive abdominal distension involving both flanks, associated with progressive jaundice and scrotal swelling. He did not have any bleeding diathesis or decreased urine output. The mother did not have symptoms of the TORCH group of illnesses and family history of similar illness was lacking. There was no prior fetal loss or early neonatal death.

On examination, the neonate had mild pallor with deep icterus. Vital parameters were normal. There was absence of lymphadenopathy or skin lesions like rash, petechiae and ecchymosis. He had abdominal distension, pedal oedema and scrotal swelling (diagnosed as hydrocele). On abdominal examination, there was firm hepatomegaly (4 cm) without splenomegaly. The neonate was drowsy without any focal neurological deficits. The remaining systemic examination was normal.

Investigations revealed leukocyte count of 14000/mm3, with 78% polymorphs, 20% lymphocytes and 2% eosinophils. Liver function tests revealed an elevated total serum bilirubin (3 mg/dL). Serum albumin was low (2.3 mg/dL), while globulin was elevated (4.1 mg/dL). Liver enzymes were normal (SGOT and SGPT- 54 IU and 15 IU, respectively). Prothrombin time was mildly deranged (19 seconds for control of 11 seconds). Serum alkaline phosphatase was raised (1982 IU). The serum electrolytes were normal and random blood sugar was 68 mg/dL. Ascitic fluid demonstrated a protein level of 2 g/dL with a total of 850 cells with 86% polymorphs and 16% lymphocytes. The viral markers for hepatitis were negative. Urine tested positive for reducing substances with proteins (1+) and Benedict’s test positive (3+). The Butler’s assay was normal. The galactose-1-phosphate uridyltransferase showed normal activity. The ultrasound Doppler of abdomen showed a nodular liver with coarse echotexture (suggestive of liver parenchymal disease) with gross ascites. Abdominal CT angiography revealed a nodular liver with normal portal and hepatic veins and inferior vena cava. CT scan of the brain was normal. On fundus examination, there was absence of cataract or corneal opacity. The TORCH titres were negative. The serum iron studies were normal. á-fetoprotein was significantly elevated to 4,42,640 ng/mL (normal range 150-450 ng/mL). The urine aminoacidogram and plasma aminoacidogram showed elevated spot in the tyrosine region and methionine. The liver biopsy detailed signs of cirrhosis with no evidence of PAS positive granules. Clinically we arrived at differential diagnoses of galactosemia, a neonatal iron storage disease, alpha-1 antitrypsin deficiency and hereditary fructose intolerance. With the urine aminoacidogram showing elevated spot in the tyrosine region and liver biopsy demontrating cirrhosis, the infant was diagnosed as Type I (hereditary) tyrosinemia with cirrhosis. The patient was readmitted with encephalopathy at 8 weeks of age and died.

Discussion

Tyrosine is obtained from ingested proteins and is synthesized endogenously from phenylalanine.1 Hypertyrosinemia is observed with deficiencies of tyrosine aminotransferase, 4-hydroxy phenylpyruvate dioxygenase (4-HPPD) or fumarylacetoacetate hydrolase (FAH).[1] Tyrosinemia type I is a rare autosomal recessive disorder with clinical and pathological manifestations involving mainly the liver, kidney and peripheral nerves. Hereditary infantile tyrosinemia or tyrosinemia type I is a completely different disease from those of types II and III. These patients have a peculiar (cabbage like) urine odour, renal tubular dysfunction (Fanconi’s syndrome) and survive less than 12 months if untreated. Fulminant onset of liver failure can occur in the first few months of life.2 Tyrosinemia type II presents with herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms and soles, as well as mental retardation. Tyrosinemia type III is an extremely rare cause of intermittent ataxia, without hepatorenal involvement or skin lesions.[2]

Rarely will the infant with tyrosinemia type I become symptomatic before 2 weeks of age, the usual presentation is between 2 and 6 months of age.[1] The earlier the presentation, poorer is the prognosis. Our patient presented on day 15 of life. Below 1 year of age the mortality is 60%, while it is 4% when symptoms develop beyond 6 months of age. [1] Our patient had liver involvement in the form of hepatic crisis withencephalopathy and hepatomegaly with ascites. Ascites and oedema are known to occur in these patients.[2] Some patients may present with bruising and nose bleeds whereas intracranial haemorrhage is usually not observed as the initial clinical presentation of the bleeding diathesis.[4]

In tyrosinemia type I, children older than 6 months of age may present with renal involvement usually in the form of Fanconi’s-like syndrome with normal anion gap metabolic acidosis, hyperphosphaturia, hypophosphatemia and vitamin–D resistant rickets. [1] Peripheral neuropathy can occur in 40% patients characterised by severe leg pain associated with hypertonic posturing of the head and trunk, vomiting, paralytic ileus and occasionally self induced injuries. Mechanical ventilation may be required if there is marked weakness and paralysis. [1]

Markedly raised plasma á-fetoprotein (442640 ng/mL) was noted in our patient. Typical laboratory findings of raised plasma á-fetoprotein, plasma and urine tyrosine, methionine, proline, alanine and lysine are strongly indicative of this disorder.[5,6] Laboratory evaluation in these patients includes a markedly prolonged prothrombin time, with only mild elevation of liver enzymes and conjugated bilirubin.[3,6] Liver biopsy specimens are notable for hepatocellular inflammation and necrosis, fatty infiltration, pseudoacinar formation and marked nodular regeneration. [3,6 Our patient’s liver histopathology showed changes of cirrhosis. Galactosemia was ruled out with a normal galactose-1-phosphate uridyltransferase. A very high á-fetoprotein level, with urine aminoacidogram showing tyrosine spot and liver showing cirrhosis were all in favour of tyrosinemia in our patient. CT scan shows the progression of liver disease from cirrhosis, to macronodular disease and finally hepatocellular carcinoma.[4]

The medical therapy of tyrosinemia is aimed at treating the acute hepatic decompensation and coagulopathy along with dietary restriction of tyrosine and phenylalanine. Nutritional treatment aims to minimise phenylalanine tyrosine load.[3] If untreated the disorder is known to result in liver failure within 6 to 8 months.[2] Medical management is with NTBC i.e. nitro trifluoromethyl benzene (Nitisinone) which inhibitshydroxyphenylpyruvate dioxygenase preventing hepatic and neurologic crisis. The compound NTBC was developed as an insecticide, however, on the basis of its structural similarity to tyrosine, was later found to be a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase. [2] Hepatic imaging should be performed on an annual basis after initiating nitisinone therapy and any exploratory nodules should be evaluated for hepatocellular carcinoma. Nitisinone related adverse effects in an international study showed eye-related changes like photophobia and corneal opacities erosions. [3] The therapeutic use of NTBC in tyrosinemia does not normalise hepatic collagen metabolism and the already fibrosed liver which remains vulnerable to further structural damage. [3] Liver transplantation for both acute and chronic disease can successfully and almost virtually correct the metabolic disease.[4] If liver transplantation is considered before the development of hepatocellular carcinoma, transplantation appears to have a salutary effect on both renal and liver disease. [4] Prenatal diagnosis of tyrosinemia is possible by assay of succinyl acetoacetate in amniotic fluid and by assay of fumaryl acetoacetate hydrolase and molecular analysis in aminocytes or chorionic villi and direct genetic molecular analysis.[6] Prenatal diagnosis based on elevation of amniotic fluid succinyl acetone had a sensitivity of approximately 94% and a specificity of 100% in a study of 64 pregnancies. [2] Succinyl acetone which is not detected by the current screening methods is the metabolite used preferably.[1] Cord blood can be tested to see increased level of á-fetoprotein which indicates intrauterine liver damage. [1]

To conclude, our patient was a 15-days-old neonate who presented with hepatic manifestations of tyrosinemia type I with extremely high á-fetoprotein level, urine aminoacidogram showing spot in tyrosine region and liver biopsy showing evidence of cirrhosis. He died very early.

Key Points

1. In tyrosinemia type I, earlier presentation predicts poorer prognosis.

2. The main clinical features are progressive liver disease and renal tubular abnormalities.

3. The impact of nitisinone depends on the stage of disease at which drug treatment is instituted.

4. Liver transplantation can be successful (for both acute and chronic disease) and virtually corrects the metabolic disease.

Acknowledgement

The authors thank Dr.SN Oak, Dean, TN Medical College & BYL Nair Hospital, Mumbai for granting permission to publish this manuscript.

References

1. Mitchell GA, Rezvani I. Tyrosine. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (editors). Nelson Textbook of Pediatrics, 18th edition (Vol 1). Philadelphia: WB Saunders, 2007:pp 532-3.

2. Teckman JH, Perlmutter DH. Metabolic Disorders of the liver. In: Willie R, Hyams JS (editors). Pediatric Gastrointestinal Disease- Pathophsiology, Diagnosis, Management, 2nd edition. Philadelphia: W.B.Saunders Company (a Division of Harcourt Brace & Company), 1999:pp 579-99.

3. Roth K.S. Tyrosinemia. http//www.e medicine.com. Accessed on 01-04-2008.

4. Sherlock S, Dooley J. Hereditary Tyrosinemia in Nutritional and Metabolic disease of the liver. In: Diseases of the Liver and Biliary System, 11th edition. Oxford (UK): Blackwell Science, 2002:pp 445-6.

5. Karnik D, Thomas N, Eapen CE, Jana AK, Oommen A. Tyrosinemia type 1: a clinico-laboratory case report. Indian J Pediatr. 2004;71:929-32.

6. Bijarnia S, Puri RD, Ruel J, Gray GF, Jenkinson L, Verma IC. Tyrosinemia type I- Diagnostic issues and prenatal diagnosis. Indian J Pediatr. 2006;73:163-5.