Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear … · Hepatocellular Carcinoma in...
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Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of AFP Willem G. van Ginkel, BSc a , Annette S.H. Gouw, MD, PhD b , Eric J. van der Jagt, MD, PhD c , Koert P. de Jong, MD, PhD d , Henkjan J. Verkade, MD, PhD e , Francjan J. van Spronsen, MD, PhD a abstract Patients with hereditary tyrosinemia type 1 have an elevated risk of developing hepatocellular carcinoma, especially if initiation of treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed. Hepatocellular carcinoma can usually be suspected when there are increased a 1 -fetoprotein levels and characteristic imaging features. The present case shows that a lack of a clear increase in a 1 -fetoprotein should still lead to consideration of liver transplantation when imaging features change. Hereditary tyrosinemia type 1 (HT1; McKusick 276700) is a metabolic disease in the catabolic pathway of tyrosine. HT1 is based on functional fumarylacetoacetate hydrolase deficiency, causing liver failure, hepatocellular carcinoma (HCC), renal tubulopathy, glomerular disease, heart disease, and neurologic problems. Treatment of HT1 patients with 2-(2- nitro-4-trifluoro-methylbenzoyl)-1,3- cyclohexanedione (NTBC) inhibits the upstream enzyme 4-hydroxy- phenylpyruvate dioxygenase, thereby preventing the formation of the toxic metabolites fumarylacetoacetate and succinylacetoacetate. Liver failure, renal disease, heart disease, and neurologic problems are resolved with treatment. 1,2 Since the introduction of NTBC in 1992, the incidence of HCC in HTI patients treated with NTBC has dramatically decreased compared with reports in patients treated without this agent. 1–4 However, NTBC-treated patients with HTI are at increased risk of developing HCC. 5,6 Patients with a late initiation of NTBC due to delayed diagnosis or unavailability of NTBC, a slow decrease of a 1 -fetoprotein (AFP), or an AFP level that remains just above the normal range of 0 to 10 mg/L have an increased risk of developing HCC. 3,5–7 In HTI, early detection of HCC is based on routine follow-up of AFP levels and liver imaging. An increase in AFP after the start of NTBC suggests the development of HCC. To our knowledge, the present case report is the first analysis of a patient with HTI in whom HCC was found without a clear increase in AFP levels and with hepatic lesions that were not suspicious for HCC. CASE REPORT A white female child presented with delay in gross motor development at 14 months of age. 6 She had hypotonia, an enlarged abdomen due to hepatosplenomegaly, and rickets. Laboratory investigations showed a blood tyrosine level of 335 mmol/L, an AFP level of 528 568 mg/L, and a urinary succinylacetone concentration of 148 mg/mmol of creatinine. DNA analysis revealed homozygosity for the common mutation (IVS12+5[g.a]). NTBC was initiated at a dose of 1.2 mg/kg with a diet restricted in phenylalanine and Sections of a Metabolic Diseases, and e Pediatric Gastroenterology, Beatrix Children’ s Hospital; Section of d Hepatobiliary Surgery, and Departments of b Pathology and c Radiology, University Medical Center of Groningen, University of Groningen, Groningen, Netherlands Mr van Ginkel completed the initial version of the manuscript and revised the manuscript; Dr Gouw was responsible for the histopathologic examination of the patient’ s liver and critically reviewed the manuscript; Dr van der Jagt performed the radiologic follow-up of the patient and critically reviewed the manuscript; Dr de Jong performed the patient’ s liver transplantation and critically reviewed the manuscript; Dr Verkade critically reviewed the manuscript; and Dr van Spronsen was responsible for the diagnosis of hereditary tyrosinemia type 1, performed the treatment and monitoring of the patient, drafted the initial version of the manuscript, and cowrote the manuscript. All authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2014-1913 DOI: 10.1542/peds.2014-1913 Accepted for publication Nov 26, 2014 Address correspondence to Francjan J. van Spronsen, MD, PhD, University Medical Center of Groningen, Hanzeplein 1, 9700 RB Groningen, Netherlands. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2015 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr van Spronsen has consulted for and received grants from SOBI, but this relationship began after completing the present study; the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: Dr van Spronsen has received research grants, advisory board fees, and speaker honoraria from Merck Serono and Nutricia Research; the other authors have indicated they have no potential conflicts of interest to disclose. PEDIATRICS Volume 135, number 3, March 2015 CASE REPORT by guest on January 24, 2020 www.aappublications.org/news Downloaded from
Transcript of Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear … · Hepatocellular Carcinoma in...
Hepatocellular Carcinoma inTyrosinemia Type 1 Without ClearIncrease of AFPWillem G. van Ginkel, BSca, Annette S.H. Gouw, MD, PhDb, Eric J. van der Jagt, MD, PhDc, Koert P. de Jong, MD, PhDd,Henkjan J. Verkade, MD, PhDe, Francjan J. van Spronsen, MD, PhDa
abstractPatients with hereditary tyrosinemia type 1 have an elevated risk ofdeveloping hepatocellular carcinoma, especially if initiation of treatment with2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed.Hepatocellular carcinoma can usually be suspected when there are increaseda1-fetoprotein levels and characteristic imaging features. The present caseshows that a lack of a clear increase in a1-fetoprotein should still lead toconsideration of liver transplantation when imaging features change.
Hereditary tyrosinemia type 1 (HT1;McKusick 276700) is a metabolicdisease in the catabolic pathway oftyrosine. HT1 is based on functionalfumarylacetoacetate hydrolasedeficiency, causing liver failure,hepatocellular carcinoma (HCC), renaltubulopathy, glomerular disease, heartdisease, and neurologic problems.Treatment of HT1 patients with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC) inhibits theupstream enzyme 4-hydroxy-phenylpyruvate dioxygenase, therebypreventing the formation of the toxicmetabolites fumarylacetoacetate andsuccinylacetoacetate. Liver failure,renal disease, heart disease, andneurologic problems are resolved withtreatment.1,2
Since the introduction of NTBC in1992, the incidence of HCC in HTIpatients treated with NTBC hasdramatically decreased compared withreports in patients treated without thisagent.1–4 However, NTBC-treatedpatients with HTI are at increased riskof developing HCC.5,6 Patients witha late initiation of NTBC due to delayeddiagnosis or unavailability of NTBC,a slow decrease of a1-fetoprotein(AFP), or an AFP level that remains just
above the normal range of 0 to 10 mg/Lhave an increased risk of developingHCC.3,5–7
In HTI, early detection of HCC is basedon routine follow-up of AFP levels andliver imaging. An increase in AFP afterthe start of NTBC suggests thedevelopment of HCC. To ourknowledge, the present case report isthe first analysis of a patient with HTIin whom HCC was found withouta clear increase in AFP levels and withhepatic lesions that were notsuspicious for HCC.
CASE REPORT
A white female child presented withdelay in gross motor development at14 months of age.6 She had hypotonia,an enlarged abdomen due tohepatosplenomegaly, and rickets.Laboratory investigations showeda blood tyrosine level of 335 mmol/L,an AFP level of 528 568 mg/L, anda urinary succinylacetoneconcentration of 148 mg/mmol ofcreatinine. DNA analysis revealedhomozygosity for the commonmutation (IVS12+5[g.a]). NTBC wasinitiated at a dose of 1.2 mg/kg witha diet restricted in phenylalanine and
Sections of aMetabolic Diseases, and ePediatricGastroenterology, Beatrix Children’s Hospital; Section ofdHepatobiliary Surgery, and Departments of bPathology andcRadiology, University Medical Center of Groningen,University of Groningen, Groningen, Netherlands
Mr van Ginkel completed the initial version of themanuscript and revised the manuscript; Dr Gouw wasresponsible for the histopathologic examination ofthe patient’s liver and critically reviewed themanuscript; Dr van der Jagt performed the radiologicfollow-up of the patient and critically reviewed themanuscript; Dr de Jong performed the patient’s livertransplantation and critically reviewed themanuscript; Dr Verkade critically reviewed themanuscript; and Dr van Spronsen was responsiblefor the diagnosis of hereditary tyrosinemia type 1,performed the treatment and monitoring of thepatient, drafted the initial version of the manuscript,and cowrote the manuscript. All authors approved thefinal manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2014-1913
DOI: 10.1542/peds.2014-1913
Accepted for publication Nov 26, 2014
Address correspondence to Francjan J. vanSpronsen, MD, PhD, University Medical Center ofGroningen, Hanzeplein 1, 9700 RB Groningen,Netherlands. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).
Copyright © 2015 by the American Academy ofPediatrics
FINANCIAL DISCLOSURE: Dr van Spronsen hasconsulted for and received grants from SOBI, but thisrelationship began after completing the present study;the other authors have indicated they have no financialrelationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr van Spronsenhas received research grants, advisory board fees,and speaker honoraria from Merck Serono andNutricia Research; the other authors have indicatedthey have no potential conflicts of interest to disclose.
PEDIATRICS Volume 135, number 3, March 2015 CASE REPORT by guest on January 24, 2020www.aappublications.org/newsDownloaded from
tyrosine. The patient’s condition wasstable during the following years. HerAFP levels decreased slowly, bloodand urinary succinylacetoneconcentrations remained within thenormal range, and NTBCconcentrations were continuouslywithin the therapeutic range(60–80 mmol/L), except for 2occasions when concentrations wereslightly lower (40–50 mmol/L).Regular, 4 times yearly, ultrasound/computed tomography (CT) scanswere conducted and revealed nohepatic nodules suspicious for HCC.
After ∼4 years of NTBC treatment,a hepatic lesion of 8 3 6 mm wasfound on ultrasound and interpretedas a hemangioma. At that time, AFPconcentrations had stabilized around24 mg/L (Fig 1), wheras a furtherdecrease was expected.6 Morespecific characterization of the lesionwas performed by using multiphasecontrast-enhanced CT scanning. Thescans revealed 2 lesions (15 315 mm each), with no arterialenhancement and with hypodensityin the venous phase. Based on thesecharacteristics, the lesions wereconsidered to be hyperplastic nodulesrather than foci of HCC. An ultrasoundof the liver revealed no increase inthe number or size of the lesions;treatment with NTBC was againmonitored closely to exclude thepossibility of nonoptimal treatment.After 10 months, MRI was performed
as a more objective follow-upmeasurement. The lesions were stillvisible in contrast to ultrasound andMRI, now, 6 focal lesions witha diameter up to 15 mm were found;there was no arterial enhancement,portal venous washout, or differentretention in the hepatic phase. On thebasis of these characteristics, the lesionswere interpreted as hyperplasticnodules (Fig 2). At the time of theMRI, AFP levels had not decreased tonormal values (0–10 mg/L) and wererecorded as 27.7 mg/L (Fig 1).
The patient was listed for livertransplantation due to the followingreasons: (1) a new lesionrepresenting a hemangioma at thisage is curious; (2) the AFP levels hadnot decreased further; and (3) wewere unable to exclude the possibilityof HCC on imaging. After a 3-monthwait time, the liver transplantationwas performed; the patient was 6.5years of age. At the time oftransplantation, the serum AFPconcentration was 26 mg/L (Fig 1).The removed liver showed cirrhosiswith 7 distinguishable focal lesions.The lesion first considered asa hemangioma was now interpretedas “a lesion compatible with earlyHCC” (not shown), whereas thesecond lesion, first noted on the CTscan, was diagnosed as HCC (Fig 3).Both lesions were 9 mm in diameter.The other 5 lesions, all witha diameter of 3 to 10 mm, were
interpreted as focal lesions displayingsmall cell dysplasia. During the 8-yearfollow-up after liver transplantation,there were no signs of metastases,and AFP concentrations remainedwithin the normal range.
DISCUSSION
HT1 is associated with an increasedrisk of developing HCC.5,6 Signssuggestive of HCC in the individualHT1 patient are a slow decrease tonormal in AFP values; AFP notreaching normal values; an increasein AFP levels; and/or a new lesionfound on imaging.3,5–7 In otherdiseases with a high risk ofdeveloping HCC (eg, hepatitis B andC), up to 44% of patients diagnosedwith HCC show no clear increase inAFP levels.8,9 Until now, all reportedHT1 patients with proven HCC hadexhibited a well-defined rise in AFPlevels and a clear lesion atimaging.1,5,6 Therefore, AFP in HTIhas always been considered a reliablemarker for HCC development.However, the present report is basedon 1 patient. In addition, we do notknow what would have happened ifwe had chosen a “wait and see”approach. It is possible that .1 yearafter the first detection, the AFPlevels would eventually have startedto rise given the pathologic report ofearly-stage HCC.
Theoretically, the malignancy couldalso have been a hepatoblastoma,which may present without increasedAFP levels10 and has been reported atleast once in HTI.11 The pathology ofthe explanted liver, however, clearlyshowed HCC.12
In the present case report, AFP levelsat the time of HT1 diagnosis at age14 months was 528 568 mg/L. AFPlevels may be high in infancy evenwhen the child is healthy,13,14 but thisscenario especially refers to neonatalage and the first 6 months of life.Indeed, AFP levels at diagnosis in thispatient may have been very high forher age. However, until now, it has
FIGURE 1Course of AFP from diagnosis until 1 year after liver transplantation. After an initial decline in AFP,levels stabilized at ∼25 mg/L. After liver transplantation, AFP levels further decreased to normalvalues. This finding is in contrast with the reference patients who almost immediately reachednormal values (ie, 0–10 mg/L).
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been unclear whether there isa relation between the AFP level attime of HT1 diagnosis and the risk of
HCC development and whether AFPat time of diagnosis may be a usefuladditional sign suggesting an
increased risk of HCC development inthe individual HT1 patient.
Imaging, especially CT and/or MRIwith contrast, plays a key role in the(early) diagnosis of HCC.15 In general,HCC has a characteristic pattern invarious imaging modalities, althoughdifferentiating HCC from other lesionsremains challenging.15,16 In thepresent case, for example, both CTand MRI results suggestedhyperplastic nodules rather than HCC.
CONCLUSIONS
We present a case illustrating thatAFP levels, ultrasound, CT, and MRImay fail to detect early HCC inpatients with HT1. Based on the data
FIGURE 2MRI of the liver. A and C, The lesion in segment 5 is slightly lower in intensity on T1 (arrow); B, the lesion is not visible on the T2 half-Fourier single-shotturbo spin-echo sequence; D, the lesion shows no arterial enhancement; E, the lesion is not visible in the portal venous phase; and F, the lesion is slightlylower in intensity in the parenchymal phase after administration of the liver-specific contrast agent.
FIGURE 3HCC in the native liver removed at liver transplantation. A, Prominent fibrotic septum separatingHCC (left) and cirrhotic liver (right). B, Cellular detail of HCC showing enlarged hepatocytes ina trabecular pattern, pleomorphic nuclei, prominent nucleoli, and swollen cytoplasm due tobilirubinostasis.
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of this patient, we conclude that a newhepatic lesion during adequate NTBCtreatment should be considered highlysuspicious for HCC even when imagingtechniques do not show a profilecharacteristic of HCC and there are noclear increases in AFP levels.Moreover, the additional value of otherparameters for early detection of HCCin HTI should be investigated.Baumann et al17 reported promisingresults with lens culinaris agglutinin-Afor HT1, but other markers such asdes-g-carboxy (abnormal)prothrombin, glypican-3, andsquamous cell carcinoma antigen-Irequire further investigation.8,9,18
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DOI: 10.1542/peds.2014-1913 originally published online February 9, 2015; 2015;135;e749Pediatrics
Henkjan J. Verkade and Francjan J. van SpronsenWillem G. van Ginkel, Annette S.H. Gouw, Eric J. van der Jagt, Koert P. de Jong,
AFPHepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of
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DOI: 10.1542/peds.2014-1913 originally published online February 9, 2015; 2015;135;e749Pediatrics
Henkjan J. Verkade and Francjan J. van SpronsenWillem G. van Ginkel, Annette S.H. Gouw, Eric J. van der Jagt, Koert P. de Jong,
AFPHepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of
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