Case Report
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Apr 7, 2013; 19(13): 2110-2113
Published online Apr 7, 2013. doi: 10.3748/wjg.v19.i13.2110
Hepatocellular carcinoma in a non-cirrhotic patient with Wilson's disease
Raphael Thattil, Jean-François Dufour
Raphael Thattil, Jean-François Dufour, Department of Hepatology, University Clinic of Visceral Surgery and Medicine, Inselspital University Hospital Bern, CH-3010 Bern, Switzerland
Jean-François Dufour, Division of Hepatology, Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland
Author contributions: Thattil R acquired data; Dufour JF analysed the case; Thattil R and Dufour JF wrote the paper.
Correspondence to: Dr. Jean-François Dufour, Professor, Department of Hepatology, University Clinic of Visceral Surgery and Medicine, Inselspital University Hospital Bern, CH-3010 Bern, Switzerland.
Telephone: +41-31-638026 Fax: +41-31-6329765
Received: July 22, 2012
Revised: December 3, 2012
Accepted: December 15, 2012
Published online: April 7, 2013


We report the exceptional case of hepatocellular carcinoma in a non-cirrhotic patient, whose Wilson’s disease was diagnosed at the unusual age of 58 years. The liver histology revealed macrovesicular steatosis with fibrosis, but no cirrhosis. The disease was treated with D-penicillamine for 3 years until acute discomfort in the right upper quadrant led to detection of multifocal hepatocellular carcinoma, which was successfully resected. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Hepatocellular carcinoma is rare in Wilson’s disease, especially in the absence of cirrhosis. The literature’s 28 published cases are reviewed and the contributory role of copper in the hepatocarcinogenic process is discussed.

Key Words: Wilson’s disease, Hepatocellular carcinoma, Hepatocarcinogenesis, Copper, Liver, Fibrosis, Cirrhosis


Wilson’s disease is an autosomal recessive disorder of copper metabolism. Wilson’s disease has a worldwide prevalence between 1 in 30 000 and 1 in 100 000[1]. The responsible gene ATP7B is located on chromosome 13 and encodes a copper transporter. In Wilson’s disease, the copper transporter is mutated and its function is impaired[1]. Wilson’s disease has hepatic, neurological, psychiatric and ophthalmic manifestations. Hepatic manifestations are characterized histologically by steatohepatitis, which evolves into cirrhosis if left untreated. Because most cases of Wilson’s disease are diagnosed and treated early, hepatocellular carcinoma is a rare sequela. We report the unusual case of a Wilson’s disease patient diagnosed at an advanced age and who developed hepatocellular carcinoma in a non-cirrhotic liver.


The patient underwent cholecystectomy due to symptomatic gallstones at 51 years of age. Liver biopsies showed macrovesicular steatosis. The circulating levels of gamma-glutamyltransferase remained chronically elevated and the ALT levels were at the upper limit of the normal. A computed tomography (CT) scan performed 5 years later revealed the presence of a 3 cm subcapsular lesion in liver segment VI as well as several ≤ 1 cm lesions. All lesions displayed a discrete enhancement during the arterial phase without washout during the portal phase. Radiological controls over the next 2 years revealed no evolution of these lesions. The biopsy of the largest lesion showed fibrotic remodelling corresponding to Metavir F3 or a modified Ishak score of 4 without evidence of cirrhosis, a 25% macrovascular steatosis, a moderate chronic hepatic inflammation and an area with small cell dysplasia. A broad clinical examination was negative for neurological and ophthalmic (Kayser-Fleischer-rings) signs of Wilson’s disease. However ceruloplasmin levels below the limit of detection (0.1 g/L) and urinary copper excretion was elevated. A genetic test confirmed a frameshift-mutation in exon 14 and 2 missense-mutations in exons 18 and 21 of the ATP7B gene. The patient was treated with D-penicillamine and pyridoxal-phosphate. This treatment was well tolerated. An magnetic resonance imaging with hepatocellular specific contrast confirmed the known lesions, which were stable in size and interpreted as regeneration nodules.

The patient worked as a mechanic, never smoked and consumed less than 10 g alcohol per day. His mother had metastatic breast carcinoma and died of a cerebral haemorrhage. His father suffered from an undefined psychiatric condition. His 2 brothers and 1 sister are in good health. He has no children.

At the age of 61 years, the patient presented with acute pain in the right upper quadrant, which was preceded for several weeks by discomfort. Contrast-enhanced CT revealed 4 hepatic lesions showing enhancement during the arterial phase and washout during the portal phase. Two lesions of 3.7 cm and 2.1 cm were in segment IV, 1 lesion of 3.2 cm was in the segment V and the largest lesion of 9.7 cm was in segments VI and VII. A curative resection was performed. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Moreover, there was a mild iron hepatocellular accumulation (Rowe 1), which was absent on the previous biopsy.


All the published cases of hepatocellular carcinoma occurring in patients with Wilson’s disease are listed in Table 1. As expected for hepatocellular carcinoma, males predominate whereas female constitute a lower than expected percentage (14%) of this group. Females constitute 30% of overall hepatocellular carcinoma cases. The reason may be that cirrhosis initiated by Wilson’s disease is less carcinogenic than that linked to other cirrhotic conditions and that male gender provides additional susceptibility to initiate hepatocarcinogenesis. Because it is uncertain from the information in previous reports whether other risk factors had been considered and excluded[2-6], it is not possible to fully assess whether common features could link them to the hepatocarcinogenic process in our male patient with longstanding, untreated Wilson’s disease. However, our patient was exceptional in that he was non-cirrhotic, whereas all previous cases of hepatocellular carcinoma in Wilson’s disease occurred in cirrhotic livers (Table 1).

Table 1 Synopsis of patients with hepatocellular carcinoma and Wilson’s disease.
Ref.SexWD-age (yr)HCC-age (yr)CirrhosisMedical therapyInvasive therapyStatus
Guan et al[2]Female2327YesPenicillaminHepatic resectionAlive
Iwadate et al[3]Male1723YesPenicillamin, low copper diet-Dead
Lowette et al[4]---YesPenicillaminTransplantAlive
Ikegawa et al[5]Male2837YesPenicillamin, zinc acetate dehydrateRadiofrequency ablationAlive
Kumagi et al[6]Male2666YesPenicillamin, transplantTranscatheter arterial chemoembolisationDead
Kumagi et al[6]Male2736YesPenicillamin, transplant-Dead
Kumagi et al[6]Male2746YesPenicillamin-Alive
Lygren et al[15]Male1516Yes--Dead
Girard et al[16]Male2241YesPenicillamin-Dead
Kamakura et al[17]Male2632YesPenicillamin-Dead
Terao et al[18]Male2940YesPenicillamin, dimercaprol potassium sulfate-Dead
Wilkinson et al[19]Male3141YesPenicillamin-Dead
Buffet et al[20]Male4557YesPenicillamin-Dead
Imhof et al[21]Male1840-PenicillaminHepatic resectionAlive
Madden et al[22]Male6161YesPenicillamin-Dead
Polio et al[23]Male3233YesPenicillamin, low copper dietChemotherapyDead
Cheng et al[24]Female3972YesPenicillamin, dimercaprol potassium sulfate-Dead
Agret et al[25]Male7373Yes--Dead
Walshe et al[26]Male846YesPenicillaminTransplantAlive
Walshe et al[26]Male1142YesPenicillamin-Dead
Kumagi et al[27]Male6666Yes-Transcatheter arterial chemoembolisationDead
Ozçay et al[28]Male-13YesPenicillaminTransplantAlive
Aydinli et al[29]Male2222Yes-Radiofrequency ablation, transplantAlive
Xu et al[30]Male2929Yes-Transcatheter arterial chemoembolisation, transplantAlive
Reyes et al[31]Male5959Yes--Dead
Emlakçioglu et al[32]Female3050-PenicillaminTranscatheter arterial chemoembolisationAlive
Ikubo et al[33]Female2854YesPenicillamin, pyridoxal-phosphateHepatic resectionAlive
Savas et al[34]Male612YesPenicillamin, low copper dietTransplantAlive

Long-Evans cinnamon rats, which have a mutated ATP7B gene and are therefore an experimental model for Wilson’s disease, develop hepatocellular carcinoma spontaneously. However, these animals accumulate iron in addition to copper, and an iron-deficient iron diet can abrogate the development of liver tumors[7]. This was attributed to the role of iron in promoting reactive oxygen species and DNA strand breaks[8]. Copper can assume a similar role. Mice receiving copper develop hepatocellular carcinoma, preventable by the concurrent administration of thiamine, which reduces the production of reactive oxygen species in the mitochondria[9]. In addition, copper stabilizes hypoxia-inducible factor-1α (HIF-1α)[10-12] by restraining the activity of the HIF-1α-inhibition factor[10], thereby ensuring the formation of the HIF-1α transcriptional complex[11,12] and the expression of target genes important for angiogenesis, such as vascular endothelial growth factor (VEGF)[10]. Indeed, Martin showed that copper increases VEGF in human hepatoma cells[12]. Another potential carcinogenic property of copper is its ability to stimulate fibroblast growth factor-2[13]. Treatment with D-penicillamine promotes hepatocellular iron accumulation[14]. It is possible that the D-penicillamine treatment of our patient contributed to the oxidative stress through and increase in iron.

When our case is combined with the 28 published cases of hepatocellular carcinoma (Table 1), the mean age at diagnosis of Wilson’s disease was 31 ± 18 years: 30 ± 7 years for women and 32 ± 19 years for men. The diagnosis of this genetic disease at such an advanced age suggests that longstanding, untreated Wilson’s disease may represent a risk factor for hepatocellular carcinoma. This notion is supported by the observation that the mean age at diagnosis of hepatocellular carcinoma was younger than that observed in patients with other underlying liver diseases (43 ± 18 years).

In conclusion, this case report illustrates that hepatocellular carcinoma does occur in patients with Wilson's disease and that those with longstanding, untreated disease may be particularly vulnerable. Therefore, the importance of determining the fibrosis stage of Wilson's disease patients and of enrolling them in a surveillance program when cirrhotic can only be emphasized.


P- Reviewer Elena V S- Editor Gou SX L- Editor A E- Editor Xiong L

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