the fontan procedure is used to separate the systemic and pulmonary circulations in patients with various forms of functionally univentricular hearts . in the fontan circulation
, systemic venous return is sent to the pulmonary arteries without passage through a ventricle .
the fontan procedure can result in various late complications , including central venous hypertension , diminished oxygen delivery , reduced cardiac output , venous thrombosis , and arrhythmia ( 1,2 ) .
these complications caused by central venous hypertension lead to parenchymal injury , fibrosis , and cirrhosis of the liver ( 2,3 ) .
cardiac cirrhosis is a serious late complication of congenital heart disease and can cause hepatocellular carcinoma ( hcc ) ( 4,5 ) .
however , the prevalence and risk factors of cirrhotic changes and hccs have not been clearly identified .
furthermore , non - invasive diagnostic tools for hepatic fibrosis and the management of hcc in patients after undergoing the fontan procedure have not yet been clearly established .
a 29-year - old woman with a history of a univentricular heart had undergone a fontan operation 10 years of age .
she was followed - up at the department of pediatric cardiology in our hospital , and regularly underwent blood examinations without alpha - fetoprotein ( afp ) at 2- or 3-month intervals .
a routine follow - up day , she experienced slight abdominal discomfort and received abdominal ultrasonography ( us ) .
b - mode conventional us showed a 15 mm hypoechoic mass in liver segment 4 ( s4 ) ( fig .
1a ) , and an 18 mm hyperechoic mass in liver segment 2 ( s2 ) ( fig .
furthermore , the liver parenchyma had a coarsened appearance consistent with cirrhosis , and ascites and splenomegaly were observed ( fig .
b - mode conventional ultrasonography showed a 15 mm hypoechoic mass in liver segment 4 ( s4 ) ( a ) , the liver parenchyma had a coarsened appearance consistent with cirrhosis , and ascites and splenomegaly were observed ( b , c).ceus using sonazoid showed a homogeneously enhanced mass in the arterial dominant phase ( d ) , a hypoechoic mass relative to the adjacent liver parenchyma during the portal dominant phase ( e ) , and a contrast defect with a clear border in the postvascular phase ( f ) .
b - mode conventional ultrasonography showed an 18 mm hyperechoic mass in liver segment 2 ( s2 ) ( a ) ; and ceus showed a homogeneously enhanced mass in the arterial dominant phase ( b ) , isoechoic mass relative to the adjacent liver parenchyma during the portal dominant phase ( c ) , and no defects in the postvascular phase ( d ) .
we next performed contrast - enhanced us ( ceus ) using a bolus injection of 0.015 ml / kg sonazoid ( perfluorobutane ; daiichi - sankyo , tokyo , japan ) .
the mass lesion in s4 was homogeneously enhanced in the arterial dominant phase ( from 10 to 30 seconds ) ( fig .
the lesion became progressively hypoechoic relative to the adjacent liver parenchyma during the portal dominant phase ( from 30 to 120 seconds ) ( fig .
1e ) , and provided a contrast defect with a clear border in the postvascular phase ( 10 minutes later ) ( fig .
the mass lesion in s2 was homogeneously enhanced in the arterial dominant phase ( fig .
the lesion became isoechoic mass relative to the adjacent liver parenchyma during the portal dominant phase ( fig .
2c ) and provided no defects in the postvascular phase ( 10 minutes later ) ( fig .
we subsequently performed magnetic resonance imaging ( mri ) with conventional t1-and t2-weighted imaging ( wi ) before and after contrast media administration , including diffusion imaging .
the contrast media used was hepatocyte - specific primovist [ gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid ( gd - eob - dtpa ) ; bayer schering pharma , berlin , germany ] .
there was radiographic evidence of liver cirrhosis with portal hypertension , including a nodular surface , a coarse texture , ascites , and splenomegaly on mri ( fig .
there was radiographic evidence of liver cirrhosis with portal hypertension , including a nodular surface , a coarse texture , ascites , and splenomegaly on mri ( a , b ) .
gd - eob - dtpa mri showed a 15 mm s4 mass with a moderately low intensity in t1-wi ( c ) , moderately high intensity in t2-wi ( d ) , moderately high intensity in diffusion ( e ) , homogeneous arterial enhancement ( b , f ) , and complete washout in the hepatobiliary phase ( g ) .
this imaging revealed a mass lesion in s4 with a moderately low intensity in t1-wi ( fig .
3b and f ) , and washout in the portal phase at 70 seconds and interstitial phase at 180 seconds . at 20 minutes ( hepatobiliary phase ) after the contrast uptake the lesion showed washout ( fig .
in addition , mri imaging revealed a mass lesion in s2 with a moderately high intensity in t1-wi ( fig .
4a and e ) , an isoenhancement relative to the adjacent liver parenchyma in the portal and interstitial phases , and a high intensity in the hepatobiliary phase ( fig .
gd - eob - dtpa mri showed an 18 mm s2 mass with a moderately high intensity in t1-wi ( b ) , moderately low intensity in t2-wi ( c ) , moderately low intensity in diffusion ( d ) , homogeneous arterial enhancement ( a , e ) , and high intensity in the hepatobiliary phase ( f ) .
her liver function was well preserved with the child - pugh classification a , and her international normalized ratio was low ( the patient was on warfarin for atrial arrhythmia ) .
other lab findings included a high afp level [ normal less than 40 nanograms / milliliter ( ng / ml ) ] , high lens culinaris agglutinin - reactive fraction of afp ( afp - l3 ) ( normal less than 10% ) , low platelet count ( normal greater than 150,000/microliter ) , high hyaluronic acid ( normal less than 50 ng / ml ) , and high type iv collagen 7s ( normal less than 6.0 ng / ml ) .
the patient had no other significant medical problems and no other risk factors for cirrhosis , as she expressed negativity for viral and autoimmune markers , no alcoholic consumption , no hepatotoxic drugs ( such as amiodarone ) , and no metabolic factors such as diabetes mellitus , obesity ( her body mass index was 17.7 ) , or fatty liver in us . following the reversal of her warfarin therapy , an ultrasound - guided needle biopsy of the s2 lesion was performed .
histological findings revealed that bridging fibrosis in the liver section , and the parenchymal cells did not display cellular or structural atypia ( fig .
wbc : white blood cells , rbc : red blood cells , hb : hemoglobin , hct : hematocrit , plt : platelets , pt : prothrombin time , inr : international normalized ratio , tp : total protein , alb : albumin , che : cholinesterase , t.bil : total bilirubin , d.bil : direct bilirubin , ast : aspartate aminotransferase , alt : alanine aminotransferase , ldh : lactate dehydrogenase , alp : alkaline phosphatase , -gtp : -glutamyltranspeptidase , ztt : zinc sulfate turbidity test , ttt : thymol turbidity test , bun : blood urea nitrogen , cr : creatinine , crp : c - reactive protein , icg - r : indocyanine green retention , hbsag : hepatitis b surface antigen , hbsab : hepatitis b surface antibody , hbcab : hepatitis b core antibody , hcv : hepatitis c virus antibody , ana : antinuclear antibodies , ama - m2 : anti - mitochondrial m2 antibody , afp : alpha - fetoprotein , afp - l3 : lens culinaris agglutinin - reactive fraction of afp , cea : carcinoembryonic antigen , ca : carbohydrate antigen a histological specimen was obtained by an ultrasound - guided needle biopsy of the s2 lesion .
the parenchymal cells did not display cellular or structural atypia [ hematoxylin and eosin staining ( a ) , and silver impregnation ( b ) with a low - power field ] .
the patient underwent a curative operation , involving partial hepatectomy of s4 in the liver .
macroscopically , sections of the specimen revealed a yellowish - white encapsulated solid tumor measuring 15 mm in size ( fig .
6a ) . a macroscopic appearance of the resected s4 specimen revealed a yellowish - white encapsulated solid tumor measuring 15 mm in size ( a ) .
microscopically , the growth pattern of the s4 liver tumor showed expansive growth with extracapsular invasions [ b , hematoxylin and eosin ( h&e ) staining with a low - power field ] .
tumor cells had an increased nuclear / cytoplasmic ratio , polymorphic , and chromatin - rich nuclei , and the pathological diagnosis was poorly differentiated hcc ( c , h&e staining with a high - power field ) .
the growth pattern of the liver tumor showed expansive growth with extracapsular invasions ( fig .
the tumor cells had an increased nuclear / cytoplasmic ratio , polymorphic , and chromatin - rich nuclei , and the pathological diagnosis was poorly differentiated hcc ( fig .
the non - cancerous area of the resected specimen revealed that bridging fibrosis was observed without fat deposition , and the patient was diagnosed with liver cirrhosis ( fig .
fibrosis was observed in both the portal and pericellular areas , the sinusoidal structure was maintained , but no signicant inflammation was observed ( fig .
the noncancerous area of the resected specimen revealed bridging fibrosis without fat deposition , and the patient was diagnosed with liver cirrhosis [ silver impregnation ( a ) ] .
fibrosis was observed in both the portal and pericellular areas , the sinusoidal structure was maintained , and signicant inammation was not seen [ silver impregnation ( b , c ) with a high - power field ] .
after discharge from the hospital , the patient was followed - up at 3-month intervals . at the 1-year follow - up , her afp level was 2.7 ng / ml , afp - l3 was less than 0.5% , and the tumor markers remained normal .
in the present case , there were no known etiological factors such as hepatitis viral infection , alcoholic liver disease , autoimmune liver diseases , autoimmune hepatitis , primary biliary cirrhosis , metabolic liver diseases [ such as non - alcoholic steatohepatitis ( nash ) ] , or medication with hepatotoxic drugs ( such as amiodarone ) .
moreover , significant hepatic inflammation or fat deposition was not seen as a result of processes such as hepatitis viral infection or nash .
on histology in the present case , hepatic sinusoidal fibrosis extending from centrilobular areas toward the portal tract without inflammation were observed .
schwarz et al . discussed that hepatic fibrosis after the fontan procedure was a mixed disease that affects both the portal and centrilobular areas in liver biopsy and autopsy specimens ( 6,7 ) .
sinusoidal fibrosis is believed to result from an increase in central venous pressure transmitted to hepatic cells that surround the central veins , because the extent of cirrhosis is strongly correlated with elevated hepatic venous pressures and a low cardiac index in patients after undergoing the fontan procedure ( 8) .
after fontan palliation , a significant liver disease can result in central venous congestion and hypoxia resulting from a low cardiac output , however , little is known regarding fibrogenic mechanisms independent of the inflammation - mediated pathway in congestive liver disease ( cld ) . in cld ,
mechanotransduction associated with stretching and compression of hepatic stellate cells may be a potent inducer of hepatic fibrosis ( 9,10 ) . using a newly characterized murine cld model , sinusoidal thrombosis and mechanical stretching of adjacent hepatic stellate cells caused by sinusoidal dilatation
was shown to induce the release of fibronectin by hepatic stellate cells , and both fibrin and stretching stimulated fibronectin fibril assembly through a 1-integrin and actin - dependent mechanism ( 11 ) .
in addition , hepatic complications after the fontan procedure are associated with the duration of follow - up ( 8,12 ) .
progression to cirrhosis may even be observed within 10 years after the initial fontan procedure ( 13 ) . in 34 patients with a median follow - up of 11.5 years after the fontan procedure
, 30% experienced abnormal transaminases , 61% abnormal -gtp , 32% abnormal bilirubin , and 58% coagulopathy ( 14 ) .
as compared to a duration of 0 - 5 years , the odds ratio of hepatic complications was 4.4 for a post - fontan duration of 11 - 15 years and 9.0 for a duration of 16 - 20 years , respectively ( 12 ) .
liver cirrhosis is a potential prerequisite for hcc , however , the prevalence and progression of cirrhotic changes in the fontan population have not been clearly identified .
non - invasive diagnostic tools for hepatic fibrosis are needed , because a liver biopsy , the golden standard for diagnosing liver cirrhosis , is difficult to perform in fontan patients due to prophylactic anticoagulation .
similar to the present case , a radiological assessment of liver fibrosis using various methods such as us , ct , or mri may be useful .
as shown in table 2 , a recent pubmed search identified 12 cases of hccs among published reports .
the publications described the use of surgical resection , transcatheter arterial chemoembolization , radioembolization , local ablation , or sorafenib therapy ( 15 - 22 ) .
in previous reports , two patients were treated with surgical resection ( 20,21 ) . for early stage
hcc , surgical resection provides curative treatment with a long - time survival , however , hepatectomy is rarely performed following the fontan procedure because it is difficult to detect early stage hccs . although the present patient did not receive periodic surveillance for hcc , such as us and afp , it is fortunate that early stage hcc was incidentally detected .
hcc detected after the onset of symptoms has a poor prognosis ( 5-year survival rate of 0 - 10% ) .
in contrast , early stage hccs detected by surveillance can be cured with both surgical resection and liver transplantation ( 5-year disease - free survival rate > 50% ) ( 23 ) .
f : female , m : male , nd : not described , tace : transarterial chemoembolization , tae : transarterial embolization thus , surveillance for hcc may be necessary in patients with cld who undergo the fontan procedure because cirrhosis is a high - risk factor for hcc .
however , the screening interval for liver disease after the fontan procedure has not yet been established .
surveillance is based on an ultrasound examination , and the recommended screening interval is 6 months according to the american association for the study of liver diseases ( aasld ) practice guidelines on the management of hcc ( 24 ) .
( 25 ) , all patients with high - risk risk factors for hcc are advised to undergo periodic surveillance with us and laboratory work ups , including afp and protein induced by vitamin k absence or antagonists - ii ( pivka - ii ) , every 6 months . however ,
similar to the present case , pivka - ii is not useful in most patients after the fontan procedure because prophylactic antiplatelet with anticoagulation therapies , such as warfarin administration , are necessary to prevent thromboembolic events , which are one of the major causes of morbidity and mortality ( 26 ) . following the fontan procedure , patients face a risk of hcc and require a lifelong follow - up with not only a pediatric cardiologist , but also a hepatologist experienced in the care of patients with liver cirrhosis .
we herein described a patient with hcc who was able to safely undergo liver resection following the fontan procedure under a preserved cardiac and hepatic function .
 a 29-year - old woman who underwent the fontan procedure at 10 years of age had an incidental finding of liver masses on abdominal ultrasonography . 
 subsequent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid magnetic resonance imaging showed a 15 mm hypervascular mass with washout in the hepatobiliary phase in liver segment 4 ( s4 ) , and an 18 mm hypervascular mass without washout in the hepatobiliary phase in liver segment 2 ( s2 ) . 
 the s2 liver mass was pathologically diagnosed to be a regenerative nodule by an ultrasound - guided needle biopsy , and the s4 liver mass was pathologically diagnosed as a poorly differentiated hepatocellular carcinoma after partial hepatectomy . 
Introduction
Case Report
Discussion
The authors state that they have no Conflict of Interest (COI).