Instructor: Hi, y'all.
In this lecture, we'll be discussing the epidemiology
of liver cancer.
Our goals for this module are to review anatomy
and function of the liver, to describe the global burden
of liver cancer and to define hepatocellular carcinoma
or HCC and its major risk factors.
We'll also look at epidemiologic patterns
of HCC and studies of HCC risk,
as well as looking at primary prevention of HCC.
We'll also look at the other major form
of liver cancer, cholangiocarcinoma
and we'll describe its risk factors.
So to begin with, looking at the anatomy of the liver,
we see that the liver receives
a dual blood supply consisting
of the hepatic portal vein
and the hepatic arteries.
Supplying approximately 75%
of the liver's blood supply,
the hepatic portal vein carries venous blood drain
from the spleen, gastrointestinal tract
and its associated organs.
The hepatic arteries supply the remainder
of the blood flow, approximately 25%, to the liver.
We see that there's two separate
and distinctly different forms of primary liver cancer.
The first is called hepatocellular carcinoma
and then it arises from the cells of the liver, per se,
which we call hepatocytes.
There's also cholangiocarcinoma or biliary cancer,
which arises from the epithelial lining
of the gallbladder or of the biliary ducts.
Hepatocellular carcinoma is much more common
than biliary cancer, accounting
for approximately 93% of all primary liver cancers
and each type has its own set of epidemiologic parameters.
When we look at the incidence of hepatocellular carcinoma,
we see it's the fifth most common malignancy in the world
and the third most common cause of death due to cancer.
Liver cancer has an extremely poor prognosis
and nearly as many people die
from the disease as are diagnosed
and most hepatocellular carcinomas are non-resectable
at the time of diagnosis
and the disease is usually fatal within three to six months.
Rates are highest in sub-Saharan Africa,
your Eastern and southeastern Asia, and Melanesia,
which is the South Pacific Islands north of Australia.
Approximately 84% of new cases occur
in low and middle income countries
in areas where oncogenic liver viruses,
like hepatitis B virus and hepatitis C virus are endemic.
More than half of new cases are diagnosed in China.
Chronic exposure to aflatoxins from multigrains
and chronic alcohol abuse are also independent risk factors
that can synergistically interact
with oncogenic hepatitis viruses
to markedly heighten the risk.
Hepatocellular carcinoma shows
two main epidemiologic patterns,
the predominant one being in China,
sub-Saharan Africa, Southeast Asia, and the Amazon Basin.
In these regions, liver viruses are endemic
and the initial infection usually occurs
during the perinatal period.
In the populations of these regions,
hepatocellular carcinomas are diagnosed early in life,
sometimes during adolescence
and their peak incidence occurs before the age of 50.
A less common pattern
of late onset is evident in North America
and Western Europe.
In the populations of these regions,
the onset of hepatocellular carcinoma occurs late in life,
usually after the age of 60.
This pattern is primarily a consequence
of sustained damage to liver cells
from chronic alcohol abuse or late onset viral hepatitis.
In the US, liver cancer accounts
for less than 1% of all primary cancers, and it's associated
with chronic infectious and inflammatory processes
in the liver.
There's a peak incidence
at 60 to 65 years when it's 60 per 100,000 people.
Looking at the 2020 statistics in the US,
the incidence rate was 9.5 per 100,000 people
and the rate in men was 14.1 per 100,000 people.
In women, there's an instance
of 5.2 cases per 100,000 people.
In regards to mortality,
there's an overall mortality rate of 8.7 per 100,000 people
with a rate of 12.9 in men and 4.8 per 100,000 in women.
When we look at the pathogenesis
of hepatocellular carcinoma,
we see that there's a couple different mechanisms at play.
So hepatocellular carcinoma is initiated
and promoted by sustained recursive damage
to hepatocytes due to infection by oncogenic liver viruses,
chronic exposure to alpha toxins, chronic alcohol abuse
or a combination of these factors.
Cellular mechanisms involved
in the pathogenesis include early fatty change,
chronic inflammation and cell necrosis,
wound healing and regeneration of hepatocytes
and late stage fibrosis leading
to the eventual formation of fibrotic nodules.
This is also referred to as cirrhosis of the liver.
So as I just mentioned,
some risk factors include alcohol use, cirrhosis,
viral hepatitis caused by hepatitis B
and hepatitis C viruses, aflatoxin B1,
and then there's also some infectious etiology
by liver flukes.
Also, environmental causes,
exposure to polycyclic aromatic hydrocarbons and metastasis.
That is the metastasizing of cancer
from a distant site in the body to the liver.
So first, to turn to liver viruses.
We see that in high-risk areas where hepatitis B virus
and hepatitis C virus are endemic, 10 to 20%
of young individuals become chronic carriers of HPV or HCV.
Among those who suffer from chronic viral hepatitis,
the annual incidence rates per 100,000 range from 400 to 800
for men and 120 to 180 for women.
Among such individuals,
the cumulative risk at developing hepatocellular carcinoma
by age 65 years is nearly 35% in men and 10% in women.
Hepatitis A, B and C all cause inflammation, necrosis
and cirrhosis of the liver.
Their signs and symptoms
are abdominal pain, jaundice, SCTs, and relapsing fever.
Risk factors for these viruses
are exposure to contaminated blood,
maternal fetal placental transmission
and sexually transmitted causation.
The diagnosis of these viruses is by antibodies,
increased liver enzymes, jaundice, SCTs, or imaging studies
and the treatment is diet, alcohol abstinence, palliation
and liver transplant.
So the relative risk of developing liver cancer is increased
by more than 20 fold for those chronically infected
with either HPV or HCV compared
to non-infected individuals and more than a hundredfold
for those infected by both viruses.
Approximately 50 to 55%
of hepatocellular carcinomas are caused by HPV
and 20 to 25% by HCV.
Since HPV causes far more infections than HCV,
particularly in younger generations,
the global pattern of chronic HPV infections
roughly simulates the global distribution of liver cancer.
So to turn to discuss hep B virus a little bit more.
We see it's a virus.
It affects humans and chimpanzees,
and there is an effective vaccine available.
There's also blood-to-blood transmission of the virus
and as we've discussed, it causes liver inflammation,
liver cirrhosis, and hepatocellular carcinoma.
I would encourage you all to look
at the slide notes for more information
about the history and biology of hep B virus.
We also see that there are differing rates
of hep B virus in different countries,
largely due to preventive factors uptake
of hep B vaccines probably being the primary determinant
of rates of transmission.
So as I just mentioned,
there's several methods of primary prevention.
The key method really being the hepatitis B virus vaccine.
So there's widespread immunization
against HPV in children globally,
and this widespread immunization led to a 49% decrease
in hepatocellular carcinoma in birth cohorts in Taiwan
and a 42% decrease in hepatocellular carcinoma
in birth cohorts in Korea.
These vaccines target the viral envelope
and provide long-term immunity against HPV infection,
as well as protection against liver carcinogenesis.
Turning to hepatitis C virus, we see that there's 150
to 200 million people worldwide infected.
It also infects humans in chimpanzees, however,
no vaccine is available.
We see that one key prevention technique
that has limited the spread
of hepatitis C virus has been the screening
of donor blood because hepatitis infection
from blood transfusion used to be more common.
We also see the seroprevalence of HCV.
That is the number of individuals infected
with hepatitis C virus is highest
in certain countries of Africa, Asia, and South America.
It's also interesting
that Egypt has the highest seroprevalence, 20%,
which may have resulted from accidental transmission
in a now discontinued mass campaign
of paternal treatment of schistosomiasis.
Schistosomiasis is a key neglected tropical disease caused
by schistosomes, a kind of parasite
that completes its lifecycle in reverse snails.
So in many areas of Egypt where communities live close
to the Nile and swim or bathe in the Nile,
it's common to see schistosomiasis infection.
So Egypt led this mass campaign against schistosomiasis.
However, did not sterilize the needles completely
and this campaign unfortunately led to the spread
of hepatitis C virus when blood
from infected persons contaminated the needles
that were then used to vaccinate other people
against schistosomiasis.
So as I just mentioned,
the areas that have the highest rates
of hepatitis C virus are spread around the world.
So there's some South American countries,
some African countries
and some East Asian countries that have high burdens
of hepatitis C virus.
We also see that approximately 30%
of HIV infected patients in the US are also infected
with hepatitis C virus.
HIV and HCV co-infection is due
to blood-borne transmission of both viruses with IV drug use
and/or unprotected sex with multiple partners.
Survival has improved for HIV-infected individuals due
to highly active antiretroviral therapy.
But nevertheless, patients coinfected with HIV
and HCV have more rapid progression of liver cirrhosis
and are at increased risk of liver failure
and hepatocellular carcinoma compared to those infected
by only HCV.
Hepatocellular carcinoma has become the leading cause
of non AIDS-related death among co-infected individuals.
We also see that aflatoxins
or mycotoxins produced by certain species
of fungus are a key risk factor
for hepatocellular carcinoma.
So these fungi readily colonizing contaminated grain
before harvest, and during storage
in areas and times of high humidity.
We see this effects of wide variety
of crops, including cereals, oil seeds, spices
and tree nuts.
Humans are primarily exposed to these toxins
by consuming multi-grains and exposure rates are highest
in populations with high rates of hepatocellular carcinoma,
particularly in the nations of sub-Saharan Africa
and in certain provinces of southern China.
Other risk factors for hepatocellular carcinoma,
include chronic alcohol consumption, which leads
to a replacement of necrotic liver tissue
by fibrosis and severe alcoholic liver cirrhosis.
So we see that when looking
at the progression of non-alcoholic fatty liver disease,
this disease first becomes non-alcoholic steatohepatitis
or NASH, then continues onto fibrosis and finally, resulting
in cirrhosis, which as previously mentioned,
leads to an elevated risk of hepatocellular carcinoma.
So we also see
that there are some inherited genetic disorders related
to hepatocellular carcinoma risk:
cigarette smoking, obesity, other comorbidities,
as well as exposure to vinyl chloride,
which is a compound used in the plastics industry.
This can cause a rare form
of liver cancer called hepatic angiosarcoma
that appears many years after exposure.
Finally, turning to cholangiocarcinoma.
It is an uncommon malignancy.
It affects the epithelial lining of the gallbladder
or bile ducts, and it's an intrahepatic disease,
which affects the gallbladder and ducts within the liver.
It also can cause an extra hepatic disease
affecting the biliary ducts outside the liver.
So really we see these two manifestations.
Though it's important to note that this is uncommon.
When we're looking at the global epidemiology
of cholangiocarcinoma, we see
it's a relatively rare malignancy
but the incidence is highest
in certain regions of Southeast Asia.
That's attributable to endemic liver parasites there.
The annual incidence in Northern Thailand is 135
per 100,000 in men, and 43 per 100,000
in women compared to only one to two cases per 100,000
in the US.
We also see that mortality rates
largely mirror incidence rates,
especially in areas where infection
with liver flukes are common.
Risk factors for cholangiocarcinoma include gallstones,
chronic alcohol abuse, hepatitis, cirrhosis,
HIV infection, liver stones
and congenital liver abnormalities.
We also see that in high income countries,
like the US, an important risk factor
for the development of cholangiocarcinoma
is the presence of primary sclerosing cholangitis,
which is an inflammatory disease of the bile ducts
that arises in patients with ulcerative colitis.
Finally, it's important to note
that the liver is the most common site of metastasis
of primary malignancies at other anatomic sites.
This is due to the hepatic portal system of blood flow
and these other malignancies largely
have poor survival rates
when they metastasize to the liver.