“Silent” Tyrosinemia Presenting as Hepatocellular Carcinoma in a 10‐year‐old Girl

Abstract

INTRODUCTION Hepatocellular carcinoma (HCC) is rare in the pediatric population, with an incidence of 0.5 to 1.5 cases per million (1–3). Children with HCC, unlike adults, are less likely to have an underlying disease. An underlying disease is found in only 25% to 38% of children with HCC (1,3,4). HCC is seen in children with hepatitis B, biliary atresia, tyrosinemia type 1, progressive familial intrahepatic cholestasis type 1, Wilson disease, hepatitis C, neonatal iron storage disease, prolonged parenteral nutrition, glycogen storage disease type 1a, and other causes of cirrhosis (2,5–9). Tyrosinemia type 1 is an autosomal recessive inborn disease of the tyrosine pathway in which the enzyme fumarylacetoacetate hydrolase (FAH) is deficient (10). It usually presents in 1 of 2 ways: before 6 months of age with severe liver disease or after 6 months of age with renal dysfunction, mild liver disease, rickets, and/or growth failure (11). In patients with tyrosinemia and known liver disease, hepatocarcinoma is usually a long-term complication. We report the case of a 10-year-old girl who presented with HCC as the initial manifestation of tyrosinemia type 1. CASE REPORT A previously well 10-year-old girl was brought to our attention in June 2005 with a few days' history of abdominal pain and vomiting. She had been born to nonconsanguineous parents of Italian and Lebanese origin. Her growth and development were entirely normal, and she had never experienced hepatic, renal, neurological, or bone problems, except for a traumatic fracture of the femur. Physical examination revealed a firm, tender, enlarged liver; an enlarged spleen; and clubbing. Abdominal Doppler ultrasound showed a heterogenous nodular liver and ascites. Splenomegaly and hepatofugal flow in both the portal vein and the superior mesenteric vein suggested severe portal hypertension. Initial investigations revealed normal levels of serum aminotransferases, bilirubin, γ-glutamyltransferase, and albumin. Complete blood count showed mild microcytic anemia (hemoglobin 114 g/L and mean corpuscular volume 67.5 fL) and mild thrombocytopenia (platelets 137 × 109/L). Coagulation studies were normal. Serologic results for hepatitis B and C were negative. Results for antinuclear, anti–smooth muscle, antimitochondrial, anti–liver kidney microsomes, and antibodies to liver cytosol were negative. Gammaglobulins, α-1-antitrypsin, ceruloplasmin, and ferritin were normal. Sweat test results and 24-hour urinary copper were also normal. No Kayser-Fleischer rings or sunflower cataracts were found on ophthalmological examination. α-Fetoprotein (AFP) was markedly elevated at 314 160 μg/L (normal 0.0–9.1). Computed tomography of the abdomen showed a heterogenous liver with hypodense, occasionally calcified macronodules. Also present were ascites, splenomegaly, multiple venous collaterals, and suspicion of portal vein thrombosis. 67Gallium and sulfur-colloid scintigraphies were compatible with a multicentric hepatocarcinoma of the right lobe. Magnetic resonance imaging confirmed the multinodular cirrhosis and revealed an enhancing nodule, 5.4 × 5.3 × 5.2 cm, in segment VIII, highly suggestive of HCC (Fig. 1). Open liver biopsy revealed an inactive macronodular cirrhosis. In some areas the liver architecture was altered (Fig. 2), with broad trabeculae, nuclear hyperchromasia, anisocytosis, frequent mitoses, and tumoral vascular invasion (Fig. 3). No tumoral cells were seen in the peritoneal tissue. The final diagnosis was moderately differentiated HCC grade II/IV (Edmondson-Steiner). Computed tomography of the thorax showed no pulmonary metastases. An upper endoscopy indicated esophageal varices stage I/IV and mild hypertensive gastropathy.FIG. 1: MRI showing multiple liver nodules from 1 to 8 cm and a larger enhanced infradiaphragmatic mass in segment VIII, suggestive of hepatocellular carcinoma.FIG. 2: Liver biopsy showing a hepatocytic tumor with broad trabeculae, giving an altered architecture.FIG. 3: Liver biopsy showing the tumoral intravascular invasion following the portal axes.The high level of AFP prompted further investigation for tyrosinemia, an inherited metabolic disease known to present with elevated AFP. Urinary and plasmatic succinylacetone were both elevated (2196 nmol/mmol creatinine [normal 0–28] and 60 nmol/L [normal 0–21], respectively). These results were pathognomonic of tyrosinemia even in the presence of normal plasmatic tyrosine levels. Serum levels of FAH showed a normal quantitative result, but enzyme activity was not assayed and could be presumed to be abnormal. Unsurprisingly, the usual French-Canadian mutations were absent, and complete gene sequencing is pending as of this writing. Our patient had normal glomerular filtration rate, normal urinalysis, and no aminoaciduria. She demonstrated no evidence of neurological involvement and no sign of rickets (normal alkaline phosphatase, phosphorus, and calcium). Osteodensitometry was not performed. The results of screening of her siblings for tyrosinemia were negative. Because tyrosinemia type 1 is particularly prevalent in French Canadians (12), it is included in the Québec provincial newborn screening program with use of succinylacetone levels. Our patient was born in Québec, and we confirmed that her newborn screening results had been negative for tyrosinemia type 1. The patient was not considered an eligible candidate for surgery or liver transplantation because of the size of the tumor and the documented vascular involvement. Tumor embolization could not be considered because there was portal vein thrombosis. Palliative chemotherapy was initiated with doxorubicin and cisplatin. After discussion with the family, no dietary restriction and no treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione were instituted, in view of the poor prognosis and the fact that treatment is meant to improve liver and kidney function (which were normal at diagnosis) and prevent the development of HCC (which had already developed). At this writing, she has been receiving chemotherapy for more than 10 months with no regression of the tumor. DISCUSSION The worldwide incidence of tyrosinemia is estimated to be 1/100,000. However, it is more common in the province of Québec, with an incidence of 1/16,000 live births, and particularly in the Saguenay-Lac St-Jean region, with an incidence of 1/1846 live births (13). Consequently, in the province of Québec, neonatal screening has been performed for tyrosinemia type 1 on every newborn since the 1970s. Tyrosinemia type 1 usually presents with high AFP, high tyrosine levels, deficient FAH, and a pathognomonic elevated urinary succinylacetone. It also presents in either an acute or a chronic form. The acute form consists of liver failure and coagulopathy early in infancy. The chronic form of the disease presents in childhood with renal disease (Fanconi), hypophosphatemic rickets, failure to thrive, porphyria-like neurologic crisis, and cirrhosis (13–15). In our patient's case, extensive evaluation initially suggested the diagnosis of cryptogenic cirrhosis; it was only the extremely elevated level of AFP that led to the investigation for tyrosinemia. A few cases of tyrosinemia type 1 have been reported in children who lacked some of the usual clinical features, such as rickets or tubular dysfunction (16), but to our knowledge there are no other reported cases of tyrosinemia type 1 diagnosed on the basis of a diagnosis of hepatocarcinoma, in a patient who otherwise had none of the usual findings of chronic tyrosinemia type 1 (normal liver function, normal kidney function, no evidence of rickets, and normal growth). In the pediatric population, HCC is not common. In most cases, the disease is advanced at the time of diagnosis, with large extrahepatic tumor extension and/or vascular invasion. (3,4) These 2 factors are known to carry a poor prognosis, with a mean 5-year survival of 10% to 28% in all pediatric HCC patients. (1–4). HCC usually presents with high levels of AFP, from 400 to more than 500,000 μg/L, with cases reported to be as elevated as 1.4 million and 1.77 million ng/mL (2–4,6,8). The level of AFP in our patient was consistent with HCC, but the elevated urinary succinylacetone confirmed the diagnosis of tyrosinemia. CONCLUSIONS In children without hepatitis, HCC is rare. Underlying causes associated with chronic liver disease may predispose to this condition; tyrosinemia is particularly recognized as one of them. Although the presentation of tyrosinemia type 1 usually includes hepatic failure, coagulopathy, neurological crisis, renal dysfunction, and/or rickets, our case suggests that tyrosinemia type 1 should be suspected as a cause of HCC even in otherwise asymptomatic children. Tyrosinemia should also be considered in the investigation of cryptogenic cirrhosis, especially when AFP levels are highly elevated. The common mutation in French Canadians is associated with the acute neonatal form of tyrosinemia, but clinicians everywhere must remember that the acute neonatal form of tyrosinemia is not the only mode of presentation. With the current trend to expand newborn screening programs to include a wide range of inborn errors of metabolism detectable by tandem mass spectrometry, newborn screening for tyrosinemia will become more and more widespread. Our case demonstrates that a normal newborn screening result does not rule out a diagnosis of tyrosinemia type 1 in a patient with suggestive findings (like nonhepatitis hepatocarcinoma), especially if the clinical presentation seems atypical.