Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention

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HFE gene and protein

HH was identified in the 1970s as a disorder linked to a genetic locus on the short arm of chromosome 6 and inherited in an autosomal-recessive fashion [8]. Feder et al [9] subsequently identified a novel gene called HFE in the HLA region of chromosome 6. This gene encodes a major histocompatibility complex class 1–like protein that binds to β2-microglobulin (like other major histocompatibility complex class 1 molecules) and interacts with TfR-1 [10], [11], [12], [13]. Several missense

Pathophysiology of hemochromatosis

The primary defect in HFE-related HH is an increase in intestinal iron absorption relative to body iron stores [14], [15], [18], [19]. The villus enterocytes of the duodenum (Fig. 1) are responsible for iron absorption. Luminal ferric iron is reduced to ferrous iron by the ferric reductase, duodenal cytochrome b [20], and is then transported across the apical membrane by a protein called divalent metal transporter-1 (DMT-1) [21], [22]. Iron is subsequently exported from the basolateral cell

Clinical features of hereditary hemochromatosis

In the past, HH was recognized by a constellation of symptoms and physical findings related to significant iron loading in the liver, pancreas, heart, skin, and pituitary [38]. Recently, most patients are asymptomatic, and phlebotomy treatment can be started before the development of significant disease manifestations [3]. This is the result of screening blood tests obtained during a routine health physical, and identification of HFE mutations in individuals during family screening.

Diagnosis of hemochromatosis

The inclusion of iron studies during routine health physicals coupled with the availability of HFE genotyping for familial and population studies has facilitated the detection of HH [2], [3]. It has also led to identification of C282Y homozygotes that lack phenotypic expression. In the past, liver biopsy provided important information for the diagnosis of HH; liver biopsy is no longer essential for the diagnosis. Nonetheless, it still provides an important assessment of liver fibrosis and a

Treatment of hemochromatosis

Once the diagnosis is confirmed, the therapeutic approach for HH is relatively simple but effective. Weekly therapeutic phlebotomy is performed to remove 250 mg of iron with each phlebotomy (each unit of blood contains between 200 and 250 mg of iron depending on the hemoglobin content) [3]. Phlebotomy is to be continued weekly until the patient's serum ferritin level is less than 50 ng/mL and the transferrin saturation is less than 50%.

Family screening for hemochromatosis

Once a proband has been identified and treated, all first-degree relatives should be screened for this familial disorder [2], [3], [45]. Generally, these relatives are screened by measuring fasting transferrin saturation and ferritin levels. Genetic testing can also be performed. If elevated iron studies are detected, or if any relatives are C282Y-C282Y or C282Y-H63D, therapeutic phlebotomy can be initiated, using the previously mentioned guidelines. Children of a proband are often evaluated

Population screening for hemochromatosis

After the discovery of HFE, it was suggested that population screening with genetic testing might be ideal for HFE-related HH. This was because the disorder is common, has a long latent phase before the development of disease manifestations, has simple and effective treatment, and has simple tests for phenotypic markers. Not all C282Y homozygotes, however, have phenotypic expression; this raises questions about the advisability of large-scale population screening. In fact, studies using HFE

Secondary iron overload

Abnormal serum iron studies are common in patients with porphyria cutanea tarda, nonalcoholic steatohepatitis, chronic hepatitis C, and alcoholic liver disease [54], [55], [56], [57], [58], [59]. Up to 50% of patients with these disorders have abnormal serum iron studies. The hepatic iron concentration is typically normal or slightly increased [3], [38]. A detailed discussion of these clinical entities is beyond the scope of this article but has been previously outlined [60].

Relationship of hemochromatosis with hepatocellular carcinoma

HCC occurs in 19% to 24% of HH [61]. Kowdley et al [62] detected HCC in 27% of patients undergoing liver transplantation for hemochromatosis. In fact, this rate increased to 43% when including either dysplasia or HCC. Early studies reported that the likelihood of developing HCC in the setting of HH was increased more than 200-fold [4], [5]. Recent data from a Swedish cohort suggest that the increased risk is closer to 20-fold, however, with an adjusted risk of liver cancer at 10 years of

Risk factors for hepatocellular carcinoma

Most HH patients developing HCC are male, more than 50 years old, and have cirrhosis. Indeed, a review of the literature revealed only 13 cases of HCC in hemochromatosis patients without cirrhosis [68], [69], [70], [71], [72], [73], [74], [75]. The higher the amount and the longer the duration of iron overload the higher the risk of developing cirrhosis and of HCC [76]. Other risk factors for HCC include concomitant infection with hepatitis B or hepatitis C virus [77], and alcoholism and

Clinical presentation and natural history of hepatocellular carcinoma associated with hemochromatosis

Most patients with HH developing HCC are cirrhotic. Unfortunately, the prevalence of cirrhosis in several population cohort studies ranges from 20% to 69% [4], [6], [63]. Among a cohort of Italian patients with HH and cirrhosis, the cumulative survival rates were 75% at 5 years and 47% at 10 years [7]. HCC was responsible for death in 45% of these patients. HCC typically occurs in males in the fifth or sixth decade of life [65], [79], [80]. Up to 36% of cirrhotic HH patients develop HCC during

Pathogenesis of hepatocellular carcinoma associated with hemochromatosis

The principles of hepatic carcinogenesis in the setting of hepatic iron overload are debated. The transformation from normal tissue to neoplasia is a dynamic, multifaceted process that is believed to begin with an initiator or carcinogen that results in altered nuclear base pairs and resultant genetic changes. With cell division, these mutations are propagated and result in potential neoplastic proliferation. Iron may be a direct carcinogen that initiates this sequence of events.

Epidemiologic

Screening-diagnosis of hepatocellular carcinoma

The prognosis of HCC is dismal unless detected at an early stage. Unfortunately, most patients have advanced disease at diagnosis [78], [79], [95], precluding them from potentially curative surgery. Although prospective, randomized trials demonstrating a survival benefit from screening for HCC do not exist, new technology is allowing for the detection of HCC at a much earlier stage.

Historically, screening strategies for HCC have included serologic testing for alpha fetoprotein. The sensitivity

Treatment of hepatocellular carcinoma associated with hereditary hemochromatosis

Surgical intervention, whether partial hepatotectomy or liver transplantation, is the only established curative therapy. Other modalities are considered palliative. Unfortunately, most patients with cirrhosis and HCC are not surgical candidates. Current surgical treatment strategies are based on tumor size, number, and location; presence of vascular invasion; extrahepatic metastasis; overall patient condition; and comorbidity. In general, liver transplantation is the best treatment option for

Prevention of hepatocellular carcinoma in hemochromatosis

Strategies to prevent or detect early HCC in HH patients are being evaluated. Early diagnosis and treatment of HH can significantly reduce the risk of HCC. Although HCC can rarely occur in noncirrhotic patients, most HH patients with HCC have cirrhosis. Every effort should be made to diagnose and treat HH patients with phlebotomy before the development of cirrhosis. Hemochromatosis patients with normal aspartate aminotransferase, age less than 40 years, serum ferritin level less than 1000

Summary

HH is a common inherited disorder of iron metabolism affecting about 1 out of 250 individuals of Northern European decent. Many of these patients do not have evident phenotypic expression and do not develop significant iron loading. Some patients, however, develop progressive iron overload and cirrhosis. These individuals are at risk of developing HCC. Cirrhotics with hemochromatosis should undergo regular screening for HCC. If HCC is identified early, treatment with either resection or liver

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      Hereditary hemochromatosis is an autosomal recessive disorder characterized by excessive dietary iron absorption and subsequent deposition in the parenchymal cells of the liver, pancreas, heart, joints, and pituitary gland. Iron overload may eventually lead to cirrhosis and HCC [138]. Early studies reported that the likelihood of developing HCC among persons with hereditary hemochromatosis was increased more than 200-fold [139,140].

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