HEPATOCELLULAR CARCINOMA

A. Introduction
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver
and occurs predominantly in patients with underlying chronic liver
disease and cirrhosis.

B. Causes
Hepatocellular carcinoma accounts for most liver cancers. This type of
cancer occurs more often in men than women. It is usually diagnosed
in people age 50 or older.
Hepatocellular carcinoma is not the same as metastatic liver cancer,
which starts in another organ (such as the breast or colon) and spreads
to the liver.
In most cases, the cause of liver cancer is long-term damage and
scarring of the liver (cirrhosis). People with hepatitis B or C are at high
risk of liver cancer, even if they do not develop cirrhosis.

C. Symptoms
Abdominal pain or tenderness, especially in the upper-right part
Easy bruising or bleeding
Enlarged abdomen
Yellow skin or eyes (jaundice)
Unexplained weight loss

D. Pathogenesis

E. Diagnosis
AFP is a marker that is useful if it is markedly elevated. At levels >20
sensitivity is 41-65% and specificity is 80-94%. However, at levels
>200 sensitivity is 31, specificity is 99%
Ultrasound (US) is often the first imaging and screening modality used.
On US, HCC often appears as a small hypo-echoic lesion with poorly
defined margins and coarse irregular internal echoes.
 When the tumor grows, it can sometimes appear heterogeneous with
fibrosis, fatty change, and calcifications. This heterogeneity can look
similar to cirrhosis and the surrounding liver parenchyma.
A systemic review found that the sensitivity was 60 percent (95% CI
44-76%) and specificity was 97 percent (95% CI 95-98%) compared
with pathologic examination of an explanted or resected liver as the
reference standard. The sensitivity increases to 79% with AFP
correlation.
In people with a higher suspicion of HCC (such as rising alpha-
fetoprotein and des-gamma carboxyprothrombin levels), the best
method of diagnosis involves a CT scan of the abdomen using
intravenous contrast agent and three-phase scanning (before contrast
administration, immediately after contrast administration, and again
after a delay) to increase the ability of the radiologist to detect small or
subtle tumors. Triple phase helical CT improves the detection of these
tumors.
Due to the increased vascularity of hepatocellular carcinoma, the
classic finding on CT imaging is hypervascularity in the arterial phase
with washout in the portal and delayed phases. A pseudocapsule, a
mosaic pattern and both calcifications and intralesional fat may be
appreciated. A systemic review found that the sensitivity was 68
percent (95% CI 55-80%) and specificity was 93 percent (95% CI 89-
96%) compared with pathologic examination of an explanted or
resected liver as the reference standard. With triple phase helical CT,
the sensitivity 90% or higher, but this data has not been confirmed
with autopsy studies

F. Treatment
Liver transplantation to replace the diseased liver with a cadaveric liver
or a living donor graft has historically low survival rates (20%-36%). If
the liver tumor has metastasized, the immuno-suppressant post-
transplant drugs decrease the chance of survival. Considering this
objective risk in conjunction with the potentially high rate of survival,
some recent studies conclude that: "LTx can be a curative approach for
patients with advanced HCC without extrahepatic metastasis". For
those reasons, and others, it is considered nowadays that patient
selection is a major key for success.
A receptor tyrosine kinase inhibitor, Sorafenib, approved by the US FDA
in December 2005 and in Europe in July 2006, may be used in patients
with advanced hepatocellular carcinoma. Sorafenib is a small molecule
that inhibits tumor-cell proliferation and tumor angionesis. It also
increases the rate of apoptosis in other tumor models. The results
indicated that single-agent sorafenib might have a beneficial
therapeutic effect.
Surgical resection to remove a tumor together with surrounding liver
tissue while preserving enough liver remnant for normal body function.
This treatment offers the best prognosis for long-term survival, but
only 10-15% of patients are suitable for surgical resection. This is often
because of extensive disease or poor liver function.
CIRRHOSIS

A. Introduction
Cirrhosis is a condition that is defined histopathologically and has a
variety of clinical manifestations and complications, some of which can
be life-threatening. In the past, it has been thought that cirrhosis was
never reversible; however, it has become apparent that when the
underlying insult that has caused the cirrhosis has been removed,
there can be reversal of fibrosis. This is most apparent with the
successful treatment of chronic hepatitis C; however, reversal of
fibrosis is also seen in patients with hemochromatosis who have been
successfully treated and in patients with alcoholic liver disease who
have discontinued alcohol use.
Regardless of the cause of cirrhosis, the pathologic features consist of
the development of fibrosis to the point that there is architectural
distortion with the formation of regenerative nodules. This results in a
decrease in hepatocellular mass, and thus function, and an alteration
of blood flow. The induction of fibrosis occurs with activation of hepatic
stellate cells, resulting in the formation of increased amounts of
collagen and other components of the extracellular matrix.
Clinical features of cirrhosis are the result of pathologic changes and
mirror the severity of the liver disease. Patients who have cirrhosis
have varying degrees of compensated liver function, and clinicians
need to differentiate between those who have stable, compensated
cirrhosis and those who have decompensated cirrhosis.
Patients who have developed complications of their liver disease and
have become decompensated should be considered for liver
transplantation. Portal hypertension is a significant complicating
feature of decompensated cirrhosis and is responsible for the
development of ascites and bleeding from esophagogastric varices,
two complications that signify decompensated cirrhosis. Loss of
hepatocellular function results in jaundice, coagulation disorders, and
hypoalbuminemia and contributes to the causes of portosystemic
encephalopathy. The complications of cirrhosis are basically the same
regardless of the etiology.
Nonetheless, it is useful to classify patients by the cause of their liver
disease; patients can be divided into broad groups with alcoholic
cirrhosis, cirrhosis due to chronic viral hepatitis, biliary cirrhosis, and
other, less-common causes such as cardiac cirrhosis, cryptogenic
cirrhosis, and other miscellaneous causes.

Table 308-1 Causes of Cirrhosis

Alcoholism Chronic viral hepatitis
Cardiac cirrhosis Inherited metabolic liver disease
Hepatitis B Hemochromatosis
Hepatitis C Wilson's disease
Autoimmune hepatitis 1 Antitrypsin deficiency
 Nonalcoholic steatohepatitis Cystic fibrosis
Biliary cirrhosis Cryptogenic cirrhosis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune cholangiopathy

B. Cirrhosis due to Chronic Viral Hepatitis B or C

1. Introduction
o Of patients exposed to the hepatitis C virus (HCV), approximately
80% develop chronic hepatitis C, and of those, about 20-30% will
develop cirrhosis over 20-30 years. Many of these patients have had
concomitant alcohol use, and the true incidence of cirrhosis due to
hepatitis C alone is unknown.
o HCV is a noncytopathic virus, and liver damage is probably immune-
mediated. Progression of liver disease due to chronic hepatitis C is
characterized by portal-based fibrosis with bridging fibrosis and
nodularity developing, ultimately culminating in the development of
cirrhosis.
o In cirrhosis due to chronic hepatitis C, the liver is small and
shrunken with characteristic features of a mixed micro- and
macronodular cirrhosis seen on liver biopsy. In addition to the
increased fibrosis that is seen in cirrhosis due to hepatitis C, an
inflammatory infiltrate is found in portal areas with interface
hepatitis and occasionally some lobular hepatocellular injury and
inflammation.
o Similar findings are seen in patients with cirrhosis due to chronic
hepatitis B. Of patients exposed to hepatitis B, about 5% develop
chronic hepatitis B, and about 20% of those patients will go on to
develop cirrhosis.
o Special stains for hepatitis B core (HBc) and hepatitis B surface
(HBs) antigen will be positive, and ground-glass hepatocytes
signifying hepatitis B surface antigen (HBsAg) may be present.

2. Clinical features
o Patients with cirrhosis due to either chronic hepatitis C or B can
present with the usual symptoms and signs of chronic liver disease.
Fatigue, malaise, vague right upper quadrant pain, and laboratory
abnormalities are frequent presenting features.
o Diagnosis requires a thorough laboratory evaluation, including
quantitative HCV RNA testing and analysis for HCV genotype, or
hepatitis B serologies to include HBsAg, anti-HBs, HBeAg (hepatitis
B e antigen), anti-HBe, and quantitative HBV DNA levels.

3. Treatment
o Management of complications of cirrhosis revolves around specific
therapy for treatment of whatever complications occur, whether
 they be esophageal variceal hemorrhage, development of ascites
and edema, or encephalopathy.
o In patients with chronic hepatitis B, numerous studies have shown
beneficial effects of antiviral therapy, which is effective at viral
suppression, as evidenced by reducing aminotransferase levels and
HBV DNA levels, and improving histology by reducing inflammation
and fibrosis. Currently available therapy includes lamivudine,
adefovir, telbivudine, entecavir, and tenofovir. Interferon can also
be used for treating hepatitis B, but it should not be used in
cirrhotics.
o Treatment of patients with cirrhosis due to hepatitis C is a little more
difficult because the side effects of pegylated interferon and
ribavirin therapy are oftentimes difficult to manage.

C. Cirrhosis due to Alchohol Consumption

1. Introduction
o Excessive chronic alcohol use can cause several different types of
chronic liver disease, including alcoholic fatty liver, alcoholic
hepatitis, and alcoholic cirrhosis. Furthermore, use of excessive
alcohol can contribute to liver damage in patients with other liver
diseases, such as hepatitis C, hemochromatosis, and those patients
who have fatty liver disease related to obesity.
o Chronic alcohol use can produce fibrosis in the absence of
accompanying inflammation and/or necrosis. Fibrosis can be
centrilobular, pericellular, or periportal. When fibrosis reaches a
certain degree, there is disruption of the normal liver architecture
and replacement of liver cells by regenerative nodules. In alcoholic
cirrhosis, the nodules are usually <3 mm in diameter; this form of
cirrhosis is referred to as micronodular. With cessation of alcohol
use, larger nodules may form, resulting in a mixed micronodular and
macronodular cirrhosis.

2. Pathogenesis
o Ethanol is mainly absorbed by the small intestine and, to a lesser
degree, through the stomach. Gastric alcohol dehydrogenase (ADH)
initiates alcohol metabolism. Three enzyme systems account for
metabolism of alcohol in the liver. These include cytosolic ADH, the
microsomal ethanol oxidizing system (MEOS), and peroxisomal
catalase. The majority of ethanol oxidation occurs via ADH to form
acetaldehyde, which is a highly reactive molecule that may have
multiple effects. Ultimately, acetaldehyde is metabolized to acetate
by aldehyde dehydrogenase (ALDH).
o Intake of ethanol increases intracellular accumulation of
triglycerides by increasing fatty acid uptake and by reducing fatty
acid oxidation and lipoprotein secretion. Protein synthesis,
glycosylation, and secretion are impaired.
o Oxidative damage to hepatocyte membranes occurs due to the
formation of reactive oxygen species; acetaldehyde is a highly
reactive molecule that combines with proteins to form protein-
acetaldehyde adducts. These adducts may interfere with specific
enzyme activities, including microtubular formation and hepatic
protein trafficking.
o With acetaldehyde-mediated hepatocyte damage, certain reactive
oxygen species can result in Kupffer cell activation. As a result,
profibrogenic cytokines are produced that initiate and perpetuate
stellate cell activation, with the resultant production of excess
collagen and extracellular matrix. Connective tissue appears in both
periportal and pericentral zones and eventually connects portal
triads with central veins forming regenerative nodules. Hepatocyte
loss occurs, and with increased collagen production and deposition,
together with continuing hepatocyte destruction, the liver contracts
and shrinks in size. This process generally takes from years to
decades to occur and requires repeated insults.
 3. Clinical Manifestation
o The diagnosis of alcoholic liver disease requires an accurate history
regarding both amount and duration of alcohol consumption.
Patients with alcoholic liver disease can present with nonspecific
symptoms such as vague right upper quadrant pain, fever, nausea
and vomiting, diarrhea, anorexia, and malaise. Alternatively, they
may present with more specific complications of chronic liver
disease, including ascites, edema, or upper gastrointestinal (GI)
hemorrhage. Many cases present incidentally at the time of autopsy
or elective surgery. Other clinical manifestations include the
development of jaundice or encephalopathy.
On physical examination, the liver and spleen may be enlarged, with the liver
edge being firm and nodular. Other frequent findings include scleral icterus,
palmar erythema, spider angiomas, parotid gland enlargement, digital
clubbing, muscle wasting, or the development of edema and ascites. Men
may have decreased body hair and gynecomastia as well as testicular
atrophy, which may be a consequence of hormonal abnormalities or a direct
toxic effect of alcohol on the testes. In women with advanced alcoholic
cirrhosis, menstrual irregularities usually occur, and some women may be
amenorrheic. These changes are often reversible following cessation of
alcohol.