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Epidemiology
• Cancer is considered an acquired genetic disease
produced by exposure to environmental carcinogens.
• Exposure to environmental carcinogens is a constant
and cumulative process.
• Gut epithelia are dynamic tissues that constantly
undergo proliferation and renewal. No single gene is
so critical to the process that a mutation in it will
result in cancer.
• Each mutation or genetic alteration involved in
carcinogenesis produces a new cell that has a slight
survival advantage over the previous ones.
Molecular genetic events in evolution of colon cancer
Genetic alterations in progression to colorectal cancer
Carcinoma within a polyp
Risk factors
Risk factors
• Industrialized nations are at greatest risk.
• Large epidemiologic studies have examined the
role of diet in cancer.
- The relative risk among daily eaters of beef, pork
or lamb
- Eating fish or skinned chicken was associated
with lower risk
- The Western diet is relatively deficient in fiber
compared with the diet of non-Western
populations and this may be important in the
pathogenesis of colon cancer
Macronutrient considerations
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Meat and fat
Serum cholesterol
Dietary fat
Dietary fiber
Micronutrient considerations
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Calcium
Selenium
Vitamins A, C and E
Dietary folate and hypomethylation of DNA
Other micronutrient anticarcinogens
Role of Aspirin in colorectal cancer
Aspirin
• It has been appreciated by epidemiologists for some time
that aspirin takers suffer fewer cancers than the rest of
the population.
• In animal models of colorectal cancer, aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the
development of tumors.
• The mechanism of action by which aspirin and NSAIDs
protect against tumor formation in the digestive tract
remains an issue of speculation and includes many
possibilities.
- modifications in the production of prostaglandins in the
gastrointestinal tract
- may induce programmed cell death (apoptosis) in some
early adenomatous cells but not in carcinoma cells
Etiology
• Colorectal cancer development through
multistep carcinogenesis
• Caretaker and gatekeeper genes
• The adenomatous polyposis coli gene is a
gatekeeper for the colorectal adenoma
• K- ras gene mutations are associated with the
progressive growth of adenomas
• The p53 gene is a gatekeeper for the transition
from adenoma to carcinoma
• Genetic alterations in cancers complicating
ulcerative colitis (aneuploidy, mutagenesis)
Classification
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adenocarcinomas
squamous cell carcinomas
adenosquamous carcinomas
lymphomas
endocrine tumors
• Rectal cancer is a distinct
disease from colon cancer in
its epidemiology, in its
pathogenesis and in the way
we treat it.
Macroscopic
• Colon cancers develop within preexisting foci
of adenomatous tissue.
• This occurs usually, but not always, in a
polypoid lesion.
• Adenomatous change may occur in flat
mucosa and a cancer may develop in this
setting.
Macroscopic
• Colon cancers
characteristically begin
as round mass lesions,
but deviations from the
ideal shape occur as a
result of the
asymmetric sloughing
of cells and the
emergence of clones
with rapid growth
capacity.
Macroscopic
• If the resected colon is
opened, a cancer
typically has an
elevated advancing
edge and the lumenal
aspect usually is
ulcerated and irregular.
• After the diameter of a
cancer approaches the
circumference of the
colon, the opposite edges
of the tumor converge,
creating the characteristic
apple-core lesion
described by radiologists.
• This most often occurs in
the sigmoid colon, which
has the smallest
circumference.
Macroscopic
• It is not rare to find multiple primary colorectal cancers.
• synchronous lesions and metachronous lesions
• Synchronous colorectal cancers occur in 3% to 6% of de
novo colon cancer diagnoses..
• The lesions may be either near one another or located in
different portions of the colon.
• Multiple primary neoplastic lesions occur often enough
that total colonoscopy is an essential part of the workup if
a neoplastic lesion is found at a more limited examination.
• This permits the removal of synchronous polyps and the
detection of synchronous cancers, which will modify the
surgical approach.
Microscopic
• Most colonic adenocarcinomas are moderately or welldifferentiated tumors and there are few morphologic
features of prognostic significance among them.
• About 20% of adenocarcinomas are poorly differentiated
or undifferentiated tumors and these two types are well
known to be associated with a poorer outcome.
• About 10% to 20% of tumors may be described as
mucinous or colloid carcinomas on the basis of a more
prodigious production of mucin. These tumors are
associated with a poorer 5-year survival rate than
nonmucinous tumors.
The classification of tumor invasion was
first undertaken by Dukes for rectal
carcinoma
• Carcinoma in situ (also called high-grade dysplasia) is intramucosal
carcinoma that does not penetrate the muscularis mucosae.
• Stage A tumors invade through the muscularis mucosae into the
submucosa but do not penetrate the next layer, the muscularis
propria.
• Stage B1 tumors invade into the muscularis propria and B2 lesions
completely penetrate the smooth muscle layer to the serosa but go
no further. Some use B3 to describe a lesion that invades an
adjacent organ.
• Stage C lesions encompass any degree of apparent invasion but are
defined by regional lymph node involvement. Some studies
subdivide Stage C lesions based on the number of lymph nodes
involved, with C1 lesions having one to three (or four) involved, and
C2 having more positive nodes.
• Stage D lesions include all those with distant metastases
In an attempt to create more uniform pathological categories for clinical
studies, the American Joint Commission on Cancer and the Union
Internationale Contre le Cancer have classified many tumors by a tumornode-metastasis (TNM) system
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Tis refers to carcinoma in situ.
T1 indicates submucosal invasion (i.e., Dukes stage A)
T2 indicates invasion of the muscularis propria (Dukes B1)
T3 indicates invasion through the muscularis propria into the
subserosa or perirectal tissues (Dukes B2)
T4 indicates invasion into adjacent organs or tissues (B3).
N0 indicates no involved lymph nodes
N1, one to three regional lymph node metastases (as in Dukes C1)
N2, more than three regional lymph node metastases
(Dukes C2)
N3, a nodal metastasis along the course of a major blood vessel.
M0 (no distant metastasis)
M1 (metastasis present)
Clinical manifestations
• grow at a slow, somewhat unpredictable rate
• It is difficult to make any estimates of growth
rates because colorectal tumors are rarely left
in place for observation.
• Some information from the precolonoscopy
era suggests that about 11.4 years may elapse
before polyps with mild atypia become
malignant, although polyps containing severe
dysplasia become malignant in 3.6 years
Clinical manifestations
• changes in bowel habits may be a sign of
distal colorectal cancer, even if the symptoms
have developed over a period as long as 1
year
• As a colon cancer grows, it may give rise to
one or more of four different groups of
symptoms
First, the colonic lumen may be obstructed,
relatively or completely, and
produce corresponding symptoms
• Obstruction may produce abdominal distention,
pain, or, in its most extreme degree, nausea and
vomiting.
• Gastrointestinal obstruction suggests the presence of
a large tumor and is anominous symptom; it is
associated with a significant adverse effect on
survival.
Second, as colonic tumors expand into the
bowel lumen, they tend to bleed
1. because of the presence of abnormal
vasculature
2. because of trauma from the fecal stream
• less than 6 mL of blood per day
Bleeding
• If a tumor is located near the anus, the blood may be
deposited on the surface of the stool and may be
grossly visible to the patient.
• More typically, the blood is mixed in with the stool
and evades detection.
• Tumors in the proximal colon tend to grow larger
without producing obstructive symptoms; thus, they
may bleed longer and present with iron deficiency
anemia.
• Tumors in the sigmoid colon or rectum are more likely
to produce hematochezia or give rise to a positive fecal
occult bleeding test (FOBT).
An invasive tumor eventually penetrates
the muscularis propria and invades
adjacent tissues
• Local invasion may produce tenesmus in the
rectum, urinary symptoms (including
pneumaturia) in the bladder, nonspecific
symptoms in the pelvic organs or an acute
abdomen from colonic perforation
• Invasion by rectal cancers into the perirectal
fat may be associated with rapid extension
and can produce ureteral obstruction.
Invasion …
• Tumor may extend through the mesentery and
compromise a vascular structure or, rarely, create
a fistula between the colon and the small
intestine or stomach.
• A metastatic lesion also may produce local
symptoms because of its expansive or
penetrating qualities.
• In these instances, the clinician may be drawn to
the liver or bony site because of pain and later
find a primary tumor in the colon that has
produced a minimum of symptoms.
Finaly …
• Some tumors produce a wasting syndrome that is out
of proportion to the size of the tumor, and normal
resting energy expenditure, despite excessive
metabolic activity of the tumor itself.
• Cancer cachexia is characterized clinically by a loss of
appetite, weight and strength.
• Cancer cachexia is common in patients with any
gastrointestinal malignancy and affected patients may
experience a more profound loss of subcutaneous fat
than that caused by an equivalent degree of benign
inflammatory disease, accounting for the characteristic
general appearance of a cancer patient.
Three of the four symptom complexes
usually are indications of advanced stages
of disease.
• The only exception is occult gastrointestinal bleeding.
• Of patients with colorectal cancer who present with
symptoms at the time of diagnosis, most will have
advanced disease and probably will die of their cancer.
• Early forms of colorectal cancer lose blood at rates that are
only minimally greater than normal rates of blood loss.
• It has been difficult to develop accurate and sensitive tests
for early diagnosis.
• No substance has been detected in the serum that
correlates with the presence of early cancer.
Familiality and Colorectal Cancer
• Key issues are the number of affected people in a
family, the age at the time of tumor development, the
number of first-degree relatives who did not develop
cancer (a point often overlooked) and associated
syndromic features.
• This issue is best understood first by considering
syndromic familial cancer syndromes in which the
genetic basis is understood, with the realization that
much of the weaker forms of familiality may represent
variations on these themes.
Family …
• Familial Adenomatous Polyposis and Gardner
Syndrome
• Familial Adenomatous Polyposis and Gardner
Syndrome
• Nonsyndromic Familiality for Colorectal
Cancer
• Juvenile Polyposis Syndromes and PeutzJeghers Syndrome
Other Clinical Associations
• Colon Cancer and Cholecystectomy
• Endocrine Abnormalities
• Skin Tags - the presence of acrochordons suggests the
simultaneous presence of colonic polyps
• Colon Cancer and Streptococcus bovis
• Breath Methane - Several laboratories reported that
colon cancer patients are more likely to be breath
methane excreters than the general population,
presumably reflecting a difference in the anaerobic
flora; methane excretion is strongly affected by the
use of laxatives or antibiotics and must be interpreted
with caution.
Differential diagnosis
• Symptomatic colon cancers may present in several
ways: as a partial or complete lower gastrointestinal
obstruction; as overt gastrointestinal bleeding (i.e.,
hematochezia); as a locally invasive or expanding
tumor with invasion of the perirectal tissue, bladder, or
other pelvic organs; as a fistulous connection with
another portion of the gastrointestinal tract; as a
locally expanding metastatic lesion in the liver, bone, or
other site; and, less commonly, as a systemic wasting
disease (i.e., cancer cachexia).
• All these symptoms carry a substantial list of
possibilities in the differential diagnosis
Do not panic until is absolutely
necessary …
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diverticulitis
inflammatory masses
postinflammatory or ischemic strictures
volvulus
hemorrhoids
anal fissure
inflammatory bowel disease
certain entities may give rise to an ambiguous biopsy,
including colitis cystica profunda, which may occur at a
surgical anastomosis, and endometriosis.
Diagnosis
• Laboratory
• Investigations
• Estimating risk for colorectal cancer
• Digital examination of the anus and distal
rectum
Laboratory
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HLG
Biochemical
Tumoral markers
Occult blood tests - The presence of a guaiacpositive stool increases the suspicion of
colorectal neoplasia, but a negative test does
not exclude it.
Invesigations
• Colonoscopy - the most accurate and sensitive
diagnostic modality available and it permits the biopsy
of suspicious mucosal lesions.
• Barium X-ray - a barium enema may provide important
complementary information not available using
colonoscopy, especially if there is a colonic stricture or
obstruction or when an extrinsic lesion is involved.
• Abdominal ultrasound
• CT
• RM
• Scintigraphy
Screening
• screening refers to testing patients in the
absence of specific symptoms
• Two modalities have been evaluated for
efficacy as screening tests for colorectal
cancer:
1. testing of feces for occult blood
2. endoscopic examination of the bowel.
• Both modalities are effective in reducing
cancer mortality, but each has limitations.
Fecal Occult Bleeding Tests
• The Hemoccult card test has been developed so
that patients can take it home, modify their diets,
collect two samples per day from a stool on each
of 3 consecutive days and return the cards for
developing.
• Because the basis of the guaiac test is the
oxidation of an indicator substance (guaiac), the
presence of strong antioxidants (e.g., 1 to 2 g/day
of ascorbic acid) produces a spuriously negative
guaiac test.
Fecal Occult Bleeding Tests
Role of Colonoscopy in Screening
for Colon Cancer
• The magnitude of protection is substantially
greater than that derived from FOBTs,
presumably because it is possible not only to
detect early-stage lesions but also to remove
premalignant lesions and interrupt neoplastic
progression early in its long natural history.
• Virtual colonoscopy refers to the use of an
imaging procedure such as a computed
tomography (CT) or magnetic resonance imaging
of the colon
Screening Recommendations for
Asymptomatic Populations
• annual FOBT
• Screening sigmoidoscopy is substantially more
effective in preventing cancer mortality, but
only the distal bowel is examined.
Blood tests
• A complete blood count is needed because of
the possibility of iron deficiency anemia
• CEA
Colonoscopy
• inspection of the entire colon
• 5% risk for a second primary cancer
Mucocutaneous pigmentation in Peutz-Jeghers syndrome
©Copyright Science Press Internet Services
Flexible sigmoidoscopic view of the distal rectum
©Copyright Science Press Internet Services
Barium enema
• may suffice if there is difficulty advancing the
colonoscope proximal to the index lesion
Colonic poliposis
Thoracic X-ray (MTS)
CT scan
• to search for metastatic neoplastic disease
Scintigraphy/+CT= PET CT
• Radionuclide scanning with a monoclonal
antibody directed against co-lorectal tumor
antigens is available, but does not routinely
add to the information gained from a CT scan.
• This modality is more valuable in localizing
pelvic or abdominal recurrence, which may be
difficult to find on CT.
Prognosis
CHRONIC HEPATITIS
DEFINITION
• a series of liver disorders of varying causes
and severity in which hepatic inflammation
and necrosis continue for at least 6 months
• chronic viral hepatitis
• drug-induced chronic hepatitis
• autoimmune chronic hepatitis
Risk factors
• Strength of association varies
• Include:
– male gender
– advanced age
– excessive alcohol use
– duration of infection
– HIV coinfection
– nonalcoholic steatohepatitis
– porphyria cutanea tarda
Classification
• By cause
• By grade
• By stage
Physical exam
Telangiectasia / spider naevi
Physical exam
• Skin
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jaundice
hipopilosity
ginecomastia
Xantelasmas, xantomas
• INSPECTION
Physical exam
• PALPATION
Physical exam
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LIVER PALPATION
Physical exam
PERCUTION
-UPPER
MARGIN
- V ic space - mid axilar line
-VII ic space- anterior axilar line
-X ic – space scapular line.
Physical exam
• ASCULTATION – hepatic artery murmer in liver
cancer
Hepatomegaly
• lower margin mid clavicular line
• : costal rib upper margin
• : percusion 5th intercostal space mdi clavicular
line
• 8th ic space mid axila
Hepatomegaly
• Inflammation – acute hepatitis, chronic hepatitis autoimune
hepatitis, alcoholic liver disease, tuberculosis, liver abces, liver
cirrhosis,
• Metabolic disorders – steatosis,
• Biliarry diseases primary billiary cholangitis, biliarry
obstruction
• Vascular disorders heart failure, chronic pericarditis
• Tumors, liver metastasis
• Congenital disorders hemocromatosis, Wilson disease,
glicogenosis
• Hematological disorders chornic leukemia, lymphomas
Hepatomegaly
• Liver cirrhosis: not painful, high consistency,
nodular
• Liver tumors: painful, irregular
• Heart failure: painful, regular, mobile, hepatojugular reflex
Laboratory
• Hepatitis B surface antigen (HBsAg) for hepatitis B
• Antibody to hepatitis C virus (anti-HCV) and HCVRNA for hepatitis C
• Antimitochondrial antibody for primary biliary
cirrhosis
• Serum ceruloplasmin (reduced) and urinary
copper (elevated) for Wilson's disease
• Serum α1-antitrypsin for α1-antitrypsin deficiency
• α-Fetoprotein for hepatocellular carcinoma
Hepatic tests
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Tests for Liver Injury
Tests for Cholestasis
Tests of Hepatic Synthetic Capacity
Other laboratory tests
Tests for Liver Injury
• Aminotransferases
• Lactate dehydrogenase
Tests for Cholestasis
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Bilirubin
Unconjugated hyperbilirubinemia
Conjugated hyperbilirubinemia
Bilirubinuria
Alkaline phosphatase
γ-Glutamyl transpeptidase (GGT)
Tests of Hepatic Synthetic Capacity
• PT and INR
• Serum proteins
- Serum albumin
Other Laboratory Tests
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Ammonia
Serum immunoglobulins
Antimitochondrial antibodies
Other antibodies:
Autoimmune hepatitis: Smooth muscle antibodies against actin,
antinuclear antibodies (ANA) that provide a homogenous (diffuse)
fluorescence, and antibodies to liver-kidney microsome type 1
(anti-LKM1) are often present.
- Primary biliary cirrhosis: Antimitochondrial antibody is key to the
diagnosis.
- Primary sclerosing cholangitis: p-ANCA can help raise the index of
suspicion.
• α-Fetoprotein (AFP)
Imaging techniques
Ultrasonography
Imaging techniques
• Radiology
• CT
• MRI
• scintigraphy (Tc99).
Hepatic arteriography
Chronic viral hepatitis
Splenoportography
ERCP
CT
Helical CT scan of a multi-focal
hepatocellular carcinoma in a 30year-old patient with unrecognized
hepatitis B e antigen-positive
chronic hepatitis B. Palliative
treatment was initiated with no
response. The patient died 8 weeks
after diagnosis.
chronic hepatitis C virus infection
MRI
Scintigraphy
Liver biopsy/fine needle aspiration
Chronic viral hepatitis B
• Infection at birth is associated with a clinically
silent acute infection but a 90% chance of
chronic infection, while infection in young
adulthood in immunocompetent persons is
typically associated with clinically apparent
acute hepatitis but a risk of chronicity of only
approximately 1%.
• histologic features are of prognostic
importance
• Inactive Carrier: Inactive HBsAg carrier state is defined as the presence of
HBsAg in serum, no detectable HBeAg, low levels of HBV DNA (less than
100,000 copies per milliliter), and persistently normal ALT levels for periods of
longer than 6 months. These patients are often described as immunotolerant
and remain at risk for HBV DNA integration into hepatocyte nuclear DNA with
the attendant risk for liver cancer at a later point in life.
• Reactivation: occurs when a person is in the inactive HBsAg carrier state
and develops an elevation of liver enzyme levels and a rise in HBV viral
DNA levels. The HBeAg can become positive in such patients. The liver
biopsy typically has an hepatic activity index score of 4 or greater.
• Resolved Infection: is defined as serologic tests showing HBsAg negative
and HBV DNA negative in a person with a history of acute or chronic HBV
infection and currently normal levels of liver enzymes. These patients may
remain anti-HBc positive for 5 to 10 years or longer and are at risk for
transmitting disease on rare occasions (such as the donation of solid organ
tissue) or of reactivating HBV disease if treated with immunosuppressive
medications.
• Co-infectionwith hepatitis delta virus (HDV), hepatitis C virus (HCV) and
human immu nodeficiency virus (HIV) is defined as the presence of active
viral replication with one or more of the previously defined viruses by
molecular assays.
Elementary lesions
Severe chronic viral hepatitis B. Area of
multilobular lytic necrosis in phase of
postnecrotic collapse and early fibrosis,
with several small islands of surviving
hepatocytes, appearing swollen and
pale, and sometimes arranged in tubular
fashion (‘hepatitic-type liver cell
rosettes’). (H&E)
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spotty necrosis
confluent lytic necrosis
portal inflammation
interface hepatitis
fibrosis
cirrhosis
Transmission
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vertical transmission
nosocomial and occupational exposure
sexually transmitted disease
blood transfusion is a very unlikely source of HBV in
Western countries, where effective screening of blood
takes place
• About 20% to 35% of individuals with adult acquired
HBV infection in the United States have no known risk
factor or easily identifiable risk factor. Possible
transmission through sexual contact, medical or dental
treatment, sharing household utensils, and blood
exposure in an occupational etting must be considered.
Clinical features
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Asymptomatic, clinically silent for years
Fatigue
Jaundice
Malaise
Anorexia
Symptoms of complications (e.g.: cirrhosisascites, edema, bleeding gastroesophageal
varices, hepatic encephalopathy, coagulopathy, or
hypersplenism.
Extrahepatic manifestations
• membranous glomerulonephritis
• polyarteritis nodosa
• cryoglobulinaemia
Laboratory findings
• Aminotransferase elevations tend to be modest for
chronic hepatitis B but may fluctuate in the range of
100 to 1000 units.
• Levels of alkaline phosphatase activity tend to be
normal or only marginally elevated.
• In severe cases, moderate elevations in serum bilirubin
[51.3 to 171 mol/L (3 to 10 mg/dL)] occur.
• Hypoalbuminemia and prolongation of the
prothrombin time occur in severe or end-stage cases.
• Hyperglobulinemia and detectable circulating
autoantibodies are distinctly absent in chronic
hepatitis B (in contrast to autoimmune hepatitis).
Laboratory
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prolonged International Normalized Ratio
low cholesterol
high ammonia
creatinine levels
proteinuria
QoL
• Patients with chronic HBV infection may have
a normal to moderately reduced quality of life
compared with those without HBV infection.
• Patients with end-stage liver disease have a
markedly reduced quality of life, although this
is true for all patients with advanced liver
disease and is not specific to HBV infection.
Complications
serious risks for all HBV carriers:
• hepatocellular carcinoma
• hepatoma
• primary liver cancer
Differential diagnosis
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fatty liver
medication toxicity
elevated iron
HDV and HCV infection
alcohol abuse
Hepatitis D virus
• Patients with acute co-infection have a very high rate of
viral clearance of both HBV and HDV.
• When HDV infection is superimposed on chronic HBV
infection, the disease commonly accelerates to cirrhosis in
a much shorter time.
• Patients with HDV and HBV co-infection, compared with
patients with chronic HBV infection alone, may also be at
greater risk for liver cancer, probably because cirrhosis
develops as a higher rate.
• The diagnosis of chronic hepatitis D is readily made when
HDAg is detected by immunohistochemistry in the nucleus
of hepatocytes of the liver biopsy specimen.
Virus C hepatitis
• Chronic hepatitis C virus (HCV) infection has
reached pandemic proportions, with an
estimated 170 million individuals infected
worldwide
• Chronic hepatitis C is the most common chronic
blood-borne infectious disease in the United
States
• Infection with HCV has no boundaries and affects
individuals from all walks of life, ranging from
children to elderly people
Transmission
• blood transfusion
• injection drug use
• other known exposures (occupational,
hemodialysis, household, perinatal)
• In up to 10% of individuals with chronic HCV
infection, no recognized source of infection can
be identified
• sexual transmission up to 20% of patients
• vertical transmission is low
Histopathology
• chronic hepatitis C does not have
characteristic pathognomic features and
demonstrates wide variation of pathologic
findings
• numeric scoring systems
• Biopsies are graded in four categories:
periportal necrosis, intralobular necrosis,
portal inflammation, and fibrosis
Microscopy
• Chronic viral hepatitis C.
Low-power view of two
joined portal tracts with
dense mononuclear cell
infiltration, forming a
lymphoid aggregate and a
lymph follicle. The portal–
parenchymal interface is
irregular (moderate degree
of interface hepatitis). A few
scattered macrovesicular
steatosis vacuoles are
visible in the lobular
parenchyma. (H&E)
Screening
• A test for anti-HCV should be performed if an elevated
ALT level is found or a positive history of risk factors for
HCV infection or physical findings suggest the presence
of chronic liver disease.
• A qualitative polymerase chain reaction (PCR) test for
HCV RNA is warranted in patients who test positive for
anti-HCV, particularly those with normal ALT levels or
no HCV risk factors, to confirm HCV infection and rule
out a false-positive test or recovery from past HCV
infection. Serologic tests for anti-HCV are probably the
best screening tests for dialysis patients.
Screening
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Chronic HCV infection may be a multisystem disease
serum cryoglobulins
serum creatinine
urinalysis
standard liver panel
complete blood cell count
prothrombin time
tests for co-infection with HBV or HIV
antinuclear antibody to exclude coexistent autoimmune
hepatitis
- alpha-fetoprotein level
- abdominal ultrasound
Diagnosis
1. serologic tests or assays that detect anti-HCV
2. molecular tests or assays that detect,
quantify and characterize HCV RNA
Serologic tests
• screening tests for anti-HCV, such as the
enzyme immunoassay (EIA)
• supplemental tests, such as the recombinant
immunoblot assay (RIBA)
Serum HCV RNA
• provides evidence of active HCV infection and
is useful as a confirmatory test
• HCV RNA assays using PCR at present have a
sensitivity of less than 100 copies/mL
Clinical findings
• Chronic HCV infection develops in as many as
85% of patients after acute infection.
• Most patients with chronic infection have
asymptomatic elevation of aminotransferase
levels and lack physical findings suggestive of liver
disease.
• Fatigue is the most common symptom reported
• Vague and intermittent right upper quadrant
pain
• low-grade fever, nausea, vomiting, myalgia,
arthralgia
Hepatitis C–Related Cirrhosis
• Several studies have now confirmed that
chronic HCV infection demonstrates minimal
clinical progression in the initial two decades
after infection.
• Chronic infection with HCV leads to cirrhosis in
at least 20% to 25% of immunocompetent
patients within 20 years of the onset of
infection.
Extrahepatic clinical manifestations
• Autoantibodies (Antinuclear antibody, anti–smooth-muscle antibody, and
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antithyroid antibody are detectable in 40% to 65% of patients with chronic HCV
infection)
Renal disorders (proteinuria, microscopic hematuria, nephrotic syndrome, or
acute renal failure)
Endocrine disorders (insulin resistance, autoimmune thyroiditis)
Rheumatologic disorders (mixed cryoglobulinemia, vasculitis, sicca
symptoms, myalgia, arthritis, and fibromyalgia)
Cutaneous and mucosal lesions (cutaneous lichen planus or oral lichen
planus)
Cardiac dysfunction (hypertrophic cardiomyopathy or dilated
cardiomyopathy)
• Miscellaneous extrahepatic manifestations (polyarteritis nodosa–type
systemic vasculitis, colonic vasculitis, idiopathic thrombocytopenic purpura, celiac sprue,
Sjögren syndrome, polymyositis, multiple myeloma)
Chronic C hepatitis ultrasound
Outcomes of drug metabolism
Epidemiology
• Drug-induced hepatotoxicity is a frequent
cause of acute liver injury of exceptional
severity, comprising more than 50% of all
cases of acute liver failure (ALF) in the United
States .
• Hepatotoxicity has been described for a large
number of drugs, although the number of
cases is quite low, given the number of
prescriptions written.
Metabolism
• Most drugs and xenobiotics cross the intestinal brush border
because they are lipophylic.
• Biotransformation is the process whereby lipophilic therapeutic
agents are rendered more hydrophilic by the hepatocyte, resulting
in drug excretion in urine or bile.
• Foremost is an oxidative pathway (e.g., hydroxylation) mediated by
the cytochromes P450 (CYPs). This is typically followed by
esterification to form sulfates and glucuronides, which results in
addition of highly polar groups to the hydroxyl group.
• These two enzymatic steps are referred to as phase I (P450
oxidation) and phase II (esterification).
• Other important metabolic pathways involve glutathione Stransferase, acetylating enzymes, and alcohol dehydrogenase, but
the principal metabolic pathways for most pharmacological agents
involve P450 and subsequent esterification.
Mechanism - the best example is
acetaminophen
• The exact details of the pathogenesis of liver injury remain unclear
for most drugs.
• Acetaminophen taken in large quantities causes profound
centrilobular necrosis
• The metabolic pathway for acetaminophen involves both phase I
and phase II reactions, glutathione detoxification, and the
formation of reactive intermediates .
• Glucuronidation and sulfation occur as the initial detoxifying step
since the parent compound contains a hydroxyl group.
• Since glucuronidation and sulfation capacity greatly exceeds daily
needs, even patients with far-advanced liver disease continue to
have adequate glucuronidation capacity, which explains why no
obvious enhancement of toxicity is observed in patients with
cirrhosis taking acetaminophen
CLASSIFICATION OF HEPATOTOXIC
AGENTS
• Intrinsic (Dose-Dependent) Agents
• Idiosyncratic Reactions
Drugs that induce the P-450 enzymes
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Phenobarbital
Phenytoin
Carbamazepine
Primidone
Ethanol
Glucocorticoids
Rifampin
Griseofulvin
Quinine
Omeprazole - Induces P-450 1A2
Drugs that inhibit the P-450 enzymes
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Amiodarone
Cimetidine
Erythromycin
Grape fruit
Isoniazid
Ketoconazole
Metronidazole
Sulfonamides
Quinidine
Omeprazole - Inhibits P-450 2C8
Clinical manifestations
• highly variable, ranging from asymptomatic
elevation of liver enzymes to fulminant
hepatic failure
• the injury may suggest a hepatocellular injury,
with elevation of aminotransferase levels as
the predominant symptom, or a cholestatic
injury, with elevated alkaline phosphatase
levels (with or without hyperbilirubinemia)
being the main feature
Extrahepatic manifestations of druginduced hepatotoxicity
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Chlorpromazine, phenylbutazone, halogenated anesthetic agents, sulindac Fever, rash, eosinophilia
Dapsone - Sulfone syndrome (ie, fever, rash, anemia, jaundice)
INH, halothane - Acute viral hepatitis
Chlorpromazine, erythromycin, amoxicillin-clavulanic acid - Obstructive jaundice
Phenytoin, carbamazepine, phenobarbital, primidone - Anticonvulsant
hypersensitivity syndrome (ie, triad of fever, rash, and liver injury)
Para-amino salicylate, phenytoin, sulfonamides - Serum sickness syndrome
Clofibrate - Muscular syndrome (ie, myalgia, stiffness, weakness, elevated creatine
kinase level)
Procainamide - Antinuclear antibodies (ANAs)
Gold salts, propylthiouracil, chlorpromazine, chloramphenicol - Marrow injury
Amiodarone, nitrofurantoin - Associated pulmonary injury
Gold salts, methoxyflurane, penicillamine, paraquat - Associated renal injury
Tetracycline - Fatty liver of pregnancy
Contraceptive and anabolic steroids, rifampin - Bland jaundice
Aspirin - Reye syndrome
Sodium valproate - Reyelike syndrome
Diagnosis
• History: History must include dose, route of administration, duration,
previous administration, and use of any concomitant drugs, including
over-the-counter medications and herbs. Knowing whether the patient
was exposed to the same drug before may be helpful. The latency period
of idiosyncratic drug reactions is highly variable; hence, obtaining a history
of every drug ingested in the past 3 months is essential.
– Onset: The onset is usually within 5-90 days of starting the drug.
– Exclusion of other causes of liver injury/cholestasis: Excluding other causes of
liver injury is essential.
• Dechallenge: A positive dechallenge is a 50% fall in serum transaminase
levels within 8 days of stopping the drug. A positive dechallenge is very
helpful in cases of use of multiple medications.
• Track record of the drug: Previously documented reactions to a drug aid in
diagnosis.
• Rechallenge: Deliberate rechallenge in clinical situations is unethical and
should not be attempted; however, inadvertent rechallenge in the past
has provided valuable evidence that the drug was indeed hepatotoxic.
Differential diagnosis
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Acute viral hepatitis
Autoimmune hepatitis
Shock liver
Cholecystitis
Cholangitis
Budd-Chiari syndrome
Alcoholic liver disease
Cholestatic liver disease
Pregnancy-related conditions of liver
Malignancy
Wilson disease
Hemochromatosis
Coagulation disorders
Hepatic function tests
• Bilirubin (total) - To diagnose jaundice and assess severity
• Bilirubin (unconjugated) - To assess for hemolysis
• Alkaline phosphatase - To diagnose cholestasis and infiltrative
disease
• AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose
hepatocellular disease and assess progression of disease
• ALT/serum glutamate pyruvate transaminase (SGPT) - ALT relatively
lower than AST in persons with alcoholism
• Albumin - To assess severity of liver injury (HIV infection and
malnutrition may confound this.)
• Gamma globulin - Large elevations suggestive of autoimmune
hepatitis, other typical increase observed in persons with cirrhosis
• Prothrombin time after vitamin K - To assess severity of liver
disease
• Antimitochondrial antibody - To diagnose primary biliary cirrhosis
• ASMA - To diagnose primary sclerosing cholangitis
Imaging studies
• Ultrasonography: is inexpensive compared with CT
scanning and MRI and is performed in only a few
minutes. Ultrasonography is effective to evaluate the
gall bladder, bile ducts, and hepatic tumors.
• CT scanning: can help detect focal hepatic lesions 1 cm
or larger and some diffuse conditions. It can also be
used to visualize adjacent structures in the abdomen.
• MRI: provides excellent contrast resolution. It can be
used to detect cysts, hemangiomas, and primary and
secondary tumors. The portal vein, hepatic veins, and
biliary tract can be visualized without contrast
injections.
Liver biopsy
• Histopathologic evaluation remains an
important tool in diagnosis.
• A liver biopsy is not essential in every case,
but a morphologic pattern consistent with the
expected pattern provides supportive
evidence.
AUTOIMMUNE HEPATITIS
• When first described autoimmune hepatitis (AIH) was
thought to be a potentially fatal form of chronic
hepatitis which predominately affected young women.
• It is now recognized that this disease may affect all age
groups and men are affected in a ratio to women of
1:4.
• All racial groups are at risk of AIH.
• Its prevalence in Europe is about 1.9 per 100,000.
• Spontaneous remission may occur, but subsequent
relapse is usual; only rarely is the disease curable.
Pathogenesis
• Certain human leukocyte antigen (HLA) class II alleles
are associated with both disease “susceptibility” and
treatment responsiveness.
• AIH may be associated with low serum complement
levels and a null allotype at the C4A or C4B gene
location (a silent C4AQ+0 gene is identified in such
patients).
• This C4A gene deletion is associated with both relapse
on therapy and increased mortality.
• Immunoglobulin levels are elevated two- to threefold
in active AIH, indicating marked B-cell activation, the
cause being multifactorial
Clinical manifestations
• Presentation symptoms :
- At first presentation the diagnosis of AIH may be
missed as the symptoms of a mild self-limiting, acute
hepatitis are very nonspecific.
- As with most chronic liver diseases fatigue is the most
common symptom; jaundice is a presenting symptom
in more than half. Other gastrointestinal complaints
include anorexia, diarrhea, sometimes pruritus and
occasionally right upper quadrant discomfort.
- Associated autoimmune diseases include thyroiditis,
inflammatory bowel disease and rheumatoid
arthritis.
Physical examination
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hepatomegaly
jaundice
the spleen may be palpable (50%)
spider nevi
ascites (20%)
hepatic encephalopathy (14%)
bleeding varices (8%)
Laboratory
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elevation in the serum aminotransferase levels
conjugated hyperbilirubinemia
hypoalbuminemia
Infection with hepatitis A, hepatitis B, and
hepatitis C must be ruled out through serological
testing.
• Other viruses may affect the liver as part of a
systemic infection, (e.g., Epstein-Barr, adenovirus,
parvovirus, and Cytomegalovirus)
• testing for serum ANA and SMA should be
requested
Histology
• Even when the clinical presentation is acute,
it is common for patients to have evidence of
chronic liver disease, possibly even
established cirrhosis.
• The composite histological picture is 81%
specific and the positive predictive value is
68% of AIH when compared with tissue from
individuals with viral hepatitis and cryptogenic
cirrhosis.
Autoimmune hepatitis. Lobular
inflammation and focal necrosis.
DIFFERENTIAL DIAGNOSIS
• Wilson disease
• There are several drugs that may cause the
clinical, biochemical, serologic, and
histological features typical of AIH
(minocycline and nitrofurantoin)
• viral hepatitis
• cryptogenic cirrhosis
Clinical manifestations of hereditary hemochromatosis
Clinical manifestations of Wilson's disease
Common physical findings in hereditary hemochromatosis
Findings
Occurrence, %
Hepatomegaly
60–85
Cirrhosis
50–95
Skin pigmentation
40–80
Arthritis (second and third metacarpophalangeal joints) 40–60
Clinical diabetes
10–60
Splenomegaly
10–40
Loss of body hair
10–30
Testicular atrophy
10–30
Dilated cardiomyopathy
0–30
Diagnosis Wilson D
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Serum ceruloplasmin
Urinary copper
Hepatic copper
Hepatic histology
Glucosuria
Hemolysis
Alcoholic liver disease
• Ethanol is rapidly absorbed from the
gastrointestinal tract.
• Is largely metabolized in liver to acetaldehyde
by alcohol dehydrogenase (ADH) in the cytosol
and the cytochrome P450IIE1 (CYP2E1) in
microsomes.
Three major stages of alcoholic liver
injury
• alcoholic fatty liver
• alcoholic hepatitis
• cirrhosis
Clinical manifestations
• The spectrum of ALD ranges from asymptomatic
hepatomegaly to hepatocellular failure from alcoholic
hepatitis or end-stage cirrhosis
• Occasionally, patients with fatty liver will present with right
upper quadrant discomfort, tender hepatomegaly, nausea
and jaundice.
• Fever, spider nevi, jaundice and abdominal pain simulating
an acute abdomen represent the extreme end of the
spectrum, while many patients will be entirely
asymptomatic.
• Differentiation of alcoholic fatty liver from nonalcoholic
fatty liver is difficult unless an accurate drinking history is
ascertained.
Laboratory findings
• macrocytosis is common in alcoholics and its presence in
an otherwise healthy person suggests occult alcohol abuse.
• this may be due to either thick macrocytes caused by folate
deficiency or thin, target cell macrocytes due to a toxic
effect of alcohol on the bone marrow or changes in the
lipid composition of the red cell membrane in cirrhosis or
cholestasis.
• spur cell anemia is seen in patients with severe ALD.
• the red cells of these patients have increased free
cholesterol, form multiple irregular projections, and are
cleared from the circulation by the spleen.
• hemolytic anemia
Biochemistry
Complications
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Metabolic disorders
Infections
Altered Neurological Status
Renal Dysfunction (hepatorenal syndrome)
Worsening Liver Disease