Protective altruistic phlebotomy: hereditary haemochromatosis presenting as hepatocellular carcinoma in a non-cirrhotic 83-year-old man

Abstract

Hereditary haemochromatosis is a multisystem disorder of iron metabolism. Hepatic manifestations include hepatomegaly, cirrhosis and hepatocellular carcinoma. Hepatocellular carcinoma is almost always preceded by cirrhosis. We present a case of an 83-year-old man without history of liver disease or iron overload who presented with abdominal pain. Workup revealed mildly elevated transaminases, ferritin of 3996 and a solitary liver tumour. Biopsy was consistent with hepatocellular carcinoma in a background of haemosiderosis without cirrhosis. He was diagnosed with hereditary haemochromatosis and hepatocellular carcinoma. He underwent a partial hepatectomy and was started on routine phlebotomy and surveillance imaging. He has improved and has not had signs of recurrence or new complications of haemochromatosis. We suggest a possible reason for his unique and late presentation.

Background

Hereditary haemochromatosis (HH) caused by homozygous C282Y mutation is a disease of abnormal iron metabolism with variable penetrance. Hepatic manifestations can range from hepatomegaly to cirrhosis. A small proportion of patients with HH develop hepatocellular carcinoma (HCC), which is almost always preceded by cirrhosis.

Case presentation

An 83-year-old man with a remote history of smoking and a paternal family history notable for liver disease, pancreatic cancer and diabetes presented with 6 months of vague abdominal pain.

Investigations

He had mildly elevated transaminases (aspartate transaminase (AST) 47; Alanine transaminase (ALT) 53), alpha-fetoprotein (AFP) 3, ferritin 3995 and iron 196; the unsaturated iron binding capacity was <17 µg/dL, hence transferrin saturation could not be calculated. Abdominal ultrasound scan revealed increased liver echotexture and a 5 mm echogenic focus that grew to 7×8 mm 6 months later on a surveillance scan. Correlative CT scan showed diffusely increased attenuation in the liver and a 1.5 cm arterial phase enhancing lesion in segment 6 that became hypodense on delayed phases (figure 1). Tissue sample obtained from CT-guided liver biopsy showed moderately differentiated HCC in a background of haemosiderosis (3–4+/4 iron) with periportal fibrosis (figure 2). He was homozygous for the HFE C282Y mutation.

Figure 1.

(A) Ultrasound scan showing a new echogenic lesion in the liver which prompted the follow-up multiphase CT scan. (B) CT image of the abdomen without contrast showing increased liver density at 95 hounsfield units, the portal vasculature is lower in attenuation than the liver parenchyma and there are no features of cirrhosis. The lesion (arrow) is hypodense compared to the liver. (C) Arterial phase CT image demonstrating hyperenhancement of the lesion (arrow). Portal venous (D) and delayed (E) phase imaging showing subsequent washout of HCC.

Figure 2.

(A) Background of iron-laden liver (blue; blue arrow) and hepatocellular carcinoma (HCC) (red arrow) (Prussian blue stain). (B) Interface between iron-laden liver (blue) and HCC (Prussian blue stain). (C) Background of iron-laden non-cirrhotic liver (cytoplasmic brown iron pigment) and HCC (H&E stain) (D) Small area of background liver (cytoplasmic brown iron pigment, blue arrow) and HCC (red arrow) (H&E stain). Original magnification: (A) ×40 (B) ×400, (C) ×40 and (D) ×200.

Outcome and follow-up

Genetic testing confirmed the diagnosis of HH. He was stated on weekly phlebotomy and underwent a partial hepatectomy with negative margins. As of 8 months following the hepatectomy, he has had no recurrence of HCC and no other manifestations of HH.

On further interview, he reported that he regularly donated blood for over 20 years beginning in his mid-20s, but was later told that he could no longer donate because his blood was ‘too heavy’.

Discussion

HH can present with a wide variety of symptoms/complications such as arthralgia, fatigue, impotence and liver dysfunction. In those patients who develop HCC, it is almost always preceded by cirrhosis. HCC without cirrhosis is rare. Our review of the literature reveals only 17 cases of HCC in non-cirrhotic patients with HH.^1–7 In published cases where histories are provided, a diagnosis of iron overload or symptoms such as arthralgia or fatigue preceded the diagnosis of HCC. In a large cohort study of Australian Caucasians, C282Y homozygotes developed iron overload disease by a mean age of 65 years.⁸ Our case is unique for three reasons: (1) he is the oldest person reported in the literature to present with HCC in the absence of cirrhosis; (2) his is the only case where HCC was the initial manifestation of HH and (3) at 83 years, he presents much later.

In HH, dysfunctional regulation of intestinal iron absorption causes increased iron deposition in the liver and other organs. Iron generates free radicals which damage lipids, proteins, DNA and other macromolecules.⁹ For reasons that are not well understood, many HFE C282Y homozygotes remain asymptomatic with normal iron laboratories while others will develop progressive liver fibrosis leading to cirrhosis. In one cohort study, only 28% of male and 1% of female C282Y homozygotes developed iron overload disease.⁸ In another study, only 14% of C282Y homozygote patients who underwent liver biopsy were found to have cirrhosis.¹⁰ The current therapy is based on the observation that therapeutic phlebotomy removes iron and limits oxidative damage. We believe our patient's unique presentation was due to the protective effects of frequent and sustained blood donation early in life. We cannot, however, exclude the possibility that our patient possesses some protective factor other than his history of phlebotomy.

Our patient's discordant manifestations—HCC without other disease—may offer clues to the pathogenesis of HH. It may suggest that phlebotomy confers greater protection from liver fibrosis and extrahepatic manifestations of iron overload than it does from cancer. Our case supports the idea that iron overload has direct carcinogenic effects in addition to its fibrotic effects.¹¹ Given our patient's age, other mechanisms, for example those underlying cellular senescence may also play a role in carcinogenesis. This case also suggests that iron loss early in life in males modulates the disease course analogous to the protective effects of menstruation in females with HH.

Patient's perspective.

• ‘I am extremely pleased at how things turned out and I am very happy with the care that I received. I guess I got lucky. After I was diagnosed, I found out that other people in my family have my disease. I told my son that he should be tested for the gene. I think he has but I do not know if he was positive’.

Learning points.

• Hereditary haemochromatosis (HH) should be suspected in patients with elevated ferritin and increased liver echotexture or attenuation on ultrasound scan or CT scan, respectively.

• While cirrhosis usually precedes hepatocellular carcinoma without cirrhosis has been reported.

• In HH, iron deposits cause liver damage; processes that reduce iron stores—such as menstruation or phlebotomy—can reduce the toxic effects of iron.