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Hepatocellular adenomatosis associated with hereditary haemochromatosis

Abstract

A young healthy man presented with abdominal pain following an accidental fall. Imaging studies and laparoscopy revealed multiple yellowish well-defined hepatic lesions. Liver biopsies showed hepatic adenomas and iron overload. Laboratory investigation confirmed a diagnosis of hereditary haemochromatosis. To our knowledge this represents the first report of an association of hepatic adenomatosis and primary haemochromatosis.

  • liver
  • adenomatosis
  • haemochromatosis

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Hepatocellular adenomatosis is a rare disease characterised by the presence of more than four adenomas. It represents an entity which is distinct from hepatocellular adenoma and its pathogenesis continues to be unknown.1 2 Isolated cases of hepatic adenoma and secondary iron overload have been described.3 4Hereditary haemochromatosis is known to be complicated by hepatic cirrhosis and carcinoma but not adenomas.

Case report

A 26-year-old man presented to the emergency room 7 years ago with abdominal pain following an accidental fall. On examination, he was found to have tenderness throughout the right upper quadrant and a palpable lower liver edge. A presumptive diagnosis of liver injury was made and the patient was admitted for observation. A computed tomography (CT) scan at the time demonstrated multiple intrahepatic lesions of variable sizes ranging from less than 1 cm to 5 cm, with no suggestion of intra-abdominal haemorrhage or injury (figure 1). The differential diagnosis based on the CT scan included multiple haemangiomas and the possibility of metastatic disease. In view of the liver function tests, carcinoembryonic antigen and alpha-feto protein markers were assayed and were within normal range. A liver biopsy was performed and revealed hepatic adenoma with parenchymal iron overload.

Figure 1

Enhanced CT scan taken at the level of the splenic artery shows multiple low attenuation lesions. The largest lesion anteriorly measures 5.0 cm and shows inhomogeneity

The patient's condition stabilised and he was discharged to annual follow-up by clinical and radiological examination. He presented again in 1995 with abdominal discomfort. Laboratory tests showed the following results: haemoglobin 151 g/l; haematocrit 0.424; red blood cell count 4.72 × 1012/l; white blood cell 8.8 × 109/l; bilirubin 6 mmol/l; aspartate transaminase 30 IU/l (normal range 0–18 IU/l); alanine transaminase 26 IU/l (0–22 IU/l); serum iron 36 mmol/l (13–33 mmol/l); total iron-binding capacity 81 mmol (41–63 mmol); saturation 47% (25–56%); ferritin 437 μg/l (24–250 μg/l). There was no history of transfusions, intramuscular injection of iron, haemolysis, chronic illness or alcoholism. Laparoscopy showed multiple well-defined hepatic lesions. Biopsies were taken from three lesions and hepatic parenchyma. HLA typing was performed and revealed HLA Type A3 B7. Blood work performed on family members showed a sibling with the same HLA type, high serum iron, ferritin and saturation index. However, ultrasound of the parents and four siblings revealed no hepatic lesions.

Both the initial and the most current liver biopsy samples showed similar changes. There were lesions clearly distinguishable from the adjacent liver parenchyma. They were composed of three or more cell thick cords of benign appearing hepatocytes with uniform nuclei and pale, vacuolar cytoplasm due to marked fatty changes (figure 2A). Portal tracts were absent, but several medium sized vessels were present within the lesions.

Figure 2

(A) Hepatic adenoma with fatty changes and evident vascularity; (B) adjacent parenchyma shows iron overload

The adjacent normal appearing parenchyma revealed massive deposition of haemosiderin pigments in hepatocytes (grade 3 & 4 by the modified Scheuer histologic grading method for iron),5 and bile duct cells with mild portal fibrosis and no evidence of cirrhosis (figure 2B). The adenomas were completely devoid of haemosiderin pigments. Hepatic iron assayed on paraffin-fixed tissue was 115.7 μmol/l and hepatic iron index was 4.45.

Discussion

Hepatocellular adenomatosis is a very uncommon disease, is characterised by the presence of numerous adenomas (more than four) within an otherwise normal parenchyma.1 Since the description of the disease in 1985, 16 cases have been reported in the literature, excluding those present in association with glycogen storage disease, oral contraceptives or androgenic steroids.1 2 It is recognised as an entity distinct from hepatocellular adenoma.6 Hepatocellular adenomas are usually single or occasionally multiple, arise in women of child-bearing age, with strong relation to prolonged use of oral contraceptive, anabolic/androgenic steroids, non-contraceptive oestrogen, danazol, virilising and feminising ovarian tumours, type I glycogen disease and diabetes mellitus.1 The prevalence of hepatic adenomatosis is equal in men and women. In men, the tumour has been associated with anabolic corticosteroids.7 The patient under discussion was asymptomatic until his accident with the diagnosis becoming apparent after a CT scan and a needle liver biopsy, followed by thorough clinical and biochemical examination.

The pathogenesis of hepatocellular adenomatosis remains unknown. This is the first case report of hepatic adenomatosis with primary haemochromatosis, and it is possible that this may be an incidental finding. However, adenomas have been described with iron overload. Review of the world literature reveals two case reports of single hepatic adenomas described in patients with secondary haemochromatosis, complicating thalassaemia.3 4 Genetic haemochromatosis is an autosomal recessive disorder that is associated with HLA-A3, B7 and B14 MHC antigens, and a putative defect on the short arm of chromosome 6.8 The precise cytopathological mechanisms by which iron induces neoplastic transformation is unknown, but may be due in part to induction of hepatic damage with resultant hepatocyte regeneration. Iron has been demonstrated to be directly mutagenic, possibly by peroxidative damage to DNA.9 The pathogenesis of hepatic adenomatosis in iron overload is not clear. The lack of iron in these lesions is an indication that these adenomas function independently from the rest of the liver and suggest that a neoplastic process is involved in their formation.

Summary points

  • hepatic adenomatosis is defined by the presence of multiple adenomas of an uncertain aetiology

  • the natural history and treatment of liver adenomatosis are not yet well defined hence clinical and radiological follow-up is mandatory, as the risk of malignant changes is not known

  • a conservative surgical approach is advocated for symptomatic large lesions

  • this entity is rare but should be considered in the differential of multiple hepatic lesions

This case presents a dilemma as to future management. There is a potential risk of developing cirrhosis and hepatocellular carcinoma in a patient with haemochromatosis. Intratumoural bleeding causing abdominal pain and haemoperitoneum has been reported in adenomatosis.1 Therapeutic manoeuvres include removal of iron, monitoring of liver function tests and radiological follow-up to determine if the lesions change. The patient is young and otherwise healthy and needs to be considered for hepatic transplantation should cirrhosis or malignant transformation occur. However, the outcome of liver transplantation in patients with haemochromatosis is rather poor. Survival of patients with haemochromatosis after transplantation is decreased compared to other recipients, due to cardiac, infectious and malignant complications which account for excess morbidity and mortality in these patients.9 A conservative surgical approach with resection of large or symptomatic lesions and observation of smaller lesions has been advocated.10

References

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