Chapter 088. Hepatocellular Carcinoma (Part 2) pot

Chapter 088. Hepatocellular
Carcinoma
(Part 2)

Epidemiology
Endemic hot spots occur in areas of China and sub-Saharan Africa, which
are associated with both high endemic hepatitis B carrier rates and mycotoxin
contamination of foodstuffs, stored grains, drinking water, and soil. Environmental
factors are important; Japanese in Japan have a higher incidence than those living
in Hawaii, who in turn have a higher incidence than those living in California.
Etiologic Factors
Chemical Carcinogens
Probably the best-studied and most potent ubiquitous natural chemical
carcinogen is a product of the Aspergillus fungus, called aflatoxin B
1
. This mold
and aflatoxin product can be found in stored grains in hot, humid places, where
peanuts and rice are stored in unrefrigerated conditions. Aflatoxin contamination
of foodstuffs correlates well with incidence rates in Africa and to some extent in
China. In endemic areas of China, even farm animals such as ducks have HCC.
The most potent carcinogens appear to be natural products of plants, fungi, and
bacteria, such as bush trees containing pyrrollizidine alkaloids as well as tannic
acid and safrole. Pollutants such as pesticides and insecticides are known rodent
carcinogens.
Hepatitis
Both case-control and cohort studies have shown a strong association
between chronic hepatitis B carrier rates and increased incidence of HCC. In
Taiwanese male postal carriers who were hepatitis B surface antigen (HBsAg)-
positive, a 98-fold greater risk for HCC was found compared to HBsAg-negative
individuals. The incidence of HCC in Alaskan natives is markedly increased
related to a high prevalence of HBV infection. HBV-based HCC may arise from

rounds of hepatic destruction with subsequent proliferation and not necessarily
from frank cirrhosis. The increase in Japanese HCC incidence rates in the past
three decades is thought to be from hepatitis C. A large-scale intervention study
sponsored by the World Health Organization (WHO) is currently underway in
Asia involving HBV vaccination of the newborn. HCC in African blacks is not
associated with severe cirrhosis but is poorly differentiated and very aggressive.
Despite uniform HBV carrier rates among the South African Bantu, there is a
ninefold difference in HCC incidence between Mozambicans living along the
coast and inland. These differences are attributed to the additional exposure to
dietary aflatoxin B
1
and other carcinogenic mycotoxins. A typical interval between
HCV-associated transfusion and subsequent HCC is ~30 years. HCV-associated
HCC patients tend to have more frequent and advanced cirrhosis, but in HBV-
associated HCC, only half the patients have cirrhosis; the remainder have chronic
active hepatitis (Chap. 300).
Other Etiologic Conditions
The 75–85% association of HCC with underlying cirrhosis has long been
recognized, more typically with macronodular cirrhosis in Southeast Asia but also
with micronodular cirrhosis (alcohol) in Europe and the United States (Chap. 302).
It is still not clear whether cirrhosis itself is a predisposing factor to the
development of HCC or whether the underlying causes of the cirrhosis are actually
the carcinogenic factors. However, ~20 % of U.S. patients with HCC do not have
underlying cirrhosis. Several underlying conditions are associated with an
increased risk for cirrhosis-associated HCC (Table 88-2), including hepatitis,
alcohol abuse, autoimmune chronic active hepatitis, cryptogenic cirrhosis, and
nonalcoholic steatohepatitis (NASH). A less common association is with primary
biliary cirrhosis and several metabolic diseases, including hemochromatosis,
Wilson's disease, α
1

-antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda,
glycogenesis types 1 and 3, citrullinemia, and orotic aciduria. The etiology of
HCC in those 20% of patients who have no cirrhosis is unclear, and their HCC
natural history not well-defined.
Table 88-2 Risk Factors for Hepatocellular Carcinoma

Common Unusual
Cirrhosis from any cause Primary biliary cirrhosis
Hepatitis B or C chronic infection Hemochromatosis
Ethanol chronic consumption α
1
Antitrypsin deficiency

Nonalcoholic steatohepatitis (NASH)

Glycogen storage diseases

Aflatoxin B
1
or

other mycotoxins Citrullinemia

Porphyria cutanea tarda
Hereditary tyrosinemia
Wilson's disease