LABORATORY ASPECT

IN LIVER DISEASES

Edwin Darmawan
Tutor: dr. I Putu Adi S, Sp.PK
 Liver Disease
• Injured hepatocytes  potentially
reversible accumulation of fat and
bilirubin (cholestasis) or irreversible by
necrosis or apoptosis
– Necrosis: commonly seen following hepatic
injury caused by hypoxia and ischemia.
– Apoptotic: predominates in viral,
autoimmune, and drug- and toxin-induced
hepatitides.
• Major primary diseases: viral hepatitis,
alcoholic liver disease, nonalcoholic fatty
liver disease (NAFLD), and hepatocellular
carcinoma (HCC).
• Secondarily in a variety of common
disorders, such as cardiac disease,
disseminated cancer, and extrahepatic
infections.
• Spectrum: mild to severe, diffuse liver
disease, life-threatening consequences.
 • The most severe clinical
consequence of liver disease is
LIVER FAILURE
↓
ACUTE, CHRONIC, &
ACUTE-ON-CHRONIC
 Acute Liver Failure
• liver disease that produces hepatic
encephalopathy within 6 months of the
initial diagnosis
– fulminant liver failure: encephalopathy develops
within 2 weeks
– subfulminant liver failure: encephalopathy develops
within 3 months
• US  accidental ingestion of acetaminophen
almost 50%, autoimmune hepatitis, other drugs
and toxins, and acute hep A and B infections
• Asia  acute hep B and E predominate
Chronic Liver Failure and Cirrhosis

• Diffuse transformation of the liver into

regenerative parenchymal nodules
surrounded by fibrous bands.
• Leading causes: chronic hepatitis B,
chronic hepatitis C, non-alcoholic fatty
liver disease (NAFLD), and alcoholic liver
disease.
 Acute-on-Chronic Liver Failure

• Chronic disease suddenly develop signs

of acute liver failure.
• Established cirrhosis with extensive vascular
shunting, or large volumes of functioning
liver parenchyma with a borderline vascular
supply  vulnerable to superimposed,
potentially lethal insults.
• The short-term mortality of patients with this
form of liver failure is around 50%
• Hepatic insults that cause sudden
decompensation:
– hepatitis D superinfection in those with chronic
hepatitis B
– emergence of resistance to medical therapy in
those with viral hepatitis
– development of ascending bacterial cholangitis in
patients with primary sclerosing cholangitis
– replacement of liver parenchyma by primary or
metastatic carcinoma.
• Systemic disorder: sepsis, acute cardiac
failure or a superimposed toxic injury that tips
a well-compensated cirrhotic patient into
liver failure.
Approach in Patient with
JAUNDICE
 Definition
• French word jaune, which means “yellow”
• One of the oldest known pathologic conditions
reported, described by Hippocratic physicians.
• Yellow discoloration of the skin, eyes, and mucous
membranes  From the retention of bilirubin or
other substances.
• Usually apparent first in the sclera.
• Not noticeable to the naked eye until bilirubin
levels reach 3.0 to 5.0 mg/dL.
• Icterus (Latin)  most commonly used
in the clinical laboratory to refer to a
serum or plasma sample with a yellow
discoloration due to an elevated bilirubin
level.
Pseudojaundice
• Skin color changes in conditions other
than hyperbilirubinemia:
– Addison disease, anorexia nervosa,
ingestion of beta carotene–rich foods
(carotenemia), or use of spray-tanning
products.
 Epidemiology
A retrospective study of more than 700
individuals:
• Most cases (55%) in adults are caused
by intrahepatic disorders: viral
hepatitis, alcoholic liver disease, and
drug-induced liver injury.
• Remaining are extrahepatic: gallstone
disease, hemolysis, and malignancy
 Pathophysiology
• Approximately 250 mg of bilirubin per
day is produced by an average adult
through the catabolism of the heme
molecule.
• Bilirubin is a product of the hemolysis of red blood
cells (RBCs) and the breakdown of hemoglobin.
Jaundice or hyperbilirubinemia is
not itself a disease but rather is a sign.
These disorders are classified in three
groups:
1. PREHEPATIC
2. HEPATIC
3. POSTHEPATIC
 Prehepatic jaundice
• Results from excessive destruction of
red blood cells and is characteristic of
hemolytic anemias or transfusion
reactions.
• Liver function is normal but unable to
handle additional bilirubin.
 Intrahepatic jaundice
• Occurs in individuals with liver disease
• Impaired uptake of bilirubin from the blood and
decreased conjugation of bilirubin
• E.g. Hepatitis, Cirrhosis
Other:
• Gilbert's disease, Crigler-Najjar syndrome, and
physiologic jaundice of the newborn 
elevations in unconjugated bilirubin.
• Dubin-Johnson and Rotor's syndrome a
elevations in conjugated bilirubin.
Gilbert's syndrome
• Benign autosomal recessive hereditary disorder
• Genetic mutation UGT1A1 that produces the enzyme uridine
diphosphate glucuronosyltransferase
• Located on chromosome 2, and other mutations of this same gene 
Crigler-Najjar syndrome
• Usually manifests during adolescence or early adulthood.
• Total serum bilirubin usually fluctuates between 1.5 and 3.0 mg/dL,
and it rarely exceeds 4.5 mg/dL.

Crigler-Najjar syndrome
• First described by Crigler and Najjar in 1952
• Syndrome of chronic nonhemolytic unconjugated hyperbilirubinemia.
• Inherited disorder of bilirubin metabolism defect within the gene
involved with bilirubin conjugation.
• Divided into two types:
– type 1: a complete absence of enzymatic bilirubin conjugation
– type 2: causing a severe deficiency of the enzyme for conjugation
• Rare and is a more serious disorder that may result in death.
Dubin-Johnson syndrome
• Rare autosomal recessive inherited disorder
• Deficiency of the canalicular multidrug resistance/multispecific
organic anionic transporter protein (MDR2/cMOAT)
• So much of the conjugated bilirubin circulates bound to albumin 
delta bilirubin  problem in lab. because the delta bilirubin
fraction reacts as conjugated bilirubin  measured as direct
bilirubin.
• Dark-stained granules (pigmented lysosomes) on a liver biopsy
• Relatively mild in nature with an excellent prognosis.

Rotor's syndrome
• Clinically similar to Dubin-Johnson, but the defect is not known
 hypothesized due to reduction in activity of intracellular
binding proteins such as ligandin.
• A liver biopsy does not show dark pigmented granules.
• Seen less commonly; relatively benign condition and carries
an excellent prognosis
 Posthepatic jaundice
• Caused by obstruction of bile flow into the gallbladder or
duodenum and subsequent backup of bile into the blood.
• Liver cell itself is functioning bilirubin is effectively
conjugated  unable to be properly excreted from the
liver.
• Since bile is not being brought to the intestines, stool loses
its source of normal pigmentation and becomes clay-
colored.
• Cause: congenital atresia of the bile ducts, obstruction
caused by cholelithiasis, inflammation of the liver, or
tumors.
 Physiologic jaundice of the newborn
• Common 2 to 3 days after birth.
• Nonpathologic jaundice, caused by normal neonatal
changes in bilirubin metabolism  increased
bilirubin production, decreased bilirubin
clearance, and increased enterohepatic
circulation.
1. Bilirubin production is 2-3 higher than in adults.
 newborns have more RBC, shorter life span
2. Bilirubin clearance is decreased, deficiency of the
enzyme (UGT1A1). UGT activity in term infants at
seven days of age is approximately 1 percent until
14 weeks
3. Increase in the enterohepatic circulation,
 History Taking & Physical Examination
History Taking
• A detailed alcohol and drug use history  alcoholic liver
disease, viral hepatitis, chronic liver disease, or drug-induced
liver injury.
• Fever and prodromal viral symptoms  acute viral hepatitis,
underlying sepsis
• Weight loss  underlying malignancy.

Physical Examination
• Encephalopathy  asterixis and mental status changes
• Signs of chronic liver disease bruising, spider
angiomas, palmar erythema, and gynecomastia
• Complete abdominal examination  hepatomegaly,
splenomegaly, right upper quadrant tenderness, and
ascites
Laboratory
Evaluation
• If etiology is unknown after the initial lab.
 additional tests: hepatitis panels
and autoimmune panels, e.g., ANA-test,
SMA and Anti-LKM.
 Imaging
• USG or CT is usually the first-line option 
obstruction, cirrhosis, and vessel patency,
• MR cholangiopancreatography  visualization of
the intra- and extrahepatic biliary tree
• Endoscopic retrograde
cholangiopancreatography  therapeutic options,
i.e. biliary stent placement relieve obstruction.
• Endoscopic ultrasonography + endoscopic
retrograde cholangiopancreatography  CBD
obstructions caused by mass or stone.
 Liver Biopsy
• It should be performed only if
– diagnosis is unclear after the initial history
and physical examination, laboratory
studies, and imaging
– results are required to determine treatment
and prognosis
• Alter care in only about one-third of
cases.
CIRRHOSIS
 CIRRHOSIS
• Condition that results in
parenchymal fibrosis and
hepatocytic nodular
regeneration.
• Caused by alcoholism
(macronodular or Laennec’s
cirrhosis), panhepatic hepatitis,
chronic active hepatitis, toxins
and drugs, and diseases of the
biliary tract, such as primary and
secondary biliary cirrhosis.
Clinical Features
• Jaundice and icterus
• Pruritus (itching)  risk repeated bouts of
potentially life-threatening infection. In some
patients, severe pruritus is the primary
indication for liver transplantation.
• Hepatic encephalopathy,
• Elevated ammonia levels
• Coagulopathy.  source of a number of
coagulation factors that decline  easy bruising
and bleeding  DIC due to failure to remove
activated factors.
• Portal hypertension  diminished flow through
the portal venous system because of obstruction
at the prehepatic, intrahepatic, or posthepatic level
• Hepatorenal syndrome  renal failure occurring
in individuals with liver failure
• Hyperestrogenemia  can give rise to palmar
erythema (a reflection of local vasodilatation) and
spider angiomas of the skin, also leads to
hypogonadism and gynecomastia.
• Hypogonadism  disruption of hypothalamic-
pituitary axis functioning
• Major clinical
consequences of
portal hypertension in
the setting of
cirrhosis, shown for
the male.
• In females,
oligomenorrhea,
amenorrhea, and
sterility are frequent
as a result of
hypogonadism.
 Diagnosis
• Although liver biopsy remains the
“imperfect” diagnostic standard (because
of sampling error), the degree of fibrosis
can be estimated by measurement of
biomarkers, such as type I and type III
collagen, laminin, and hyaluronic acid.
• Degree of fibrosis can also be estimated
using clinical indices, such as a
combination of transaminase
measurements, platelet count, and age.
 MELD System
• The purpose is to compute the
probability of survival for patients with
liver disease.
• The score uses serum bilirubin, INR,
and serum creatinine to compute a
score based on these values.
• As an illustration of the use of this formula
in guiding treatment  considered to be
candidates for TIPS
• The best outcomes for this procedure are
for patients with MELD scores under 14.
• Not recommended for patients with MELD
scores of over 24.
• For scores between 14 and 24, clinical
evaluation of the risks and benefits is
required.

transjugular intrahepatic portosystemic shunt (TIPS)

 Child-Turcotte-Pugh Score
Classified as
category
A: 5 to 6 points
B: 7 to 9 points
C: 10 to 15 points

Projected 2-year
survival
A, 85%;
B, 57%;
C, 35%.
TUMORS
Tumors of the liver may also be classified as benign
or malignant.
• Benign tumors of the liver include
– Hepatocellular adenoma (a condition occurring almost
exclusively in females of childbearing age)
– Hemangiomas (masses of blood vessels with no known
etiology).
• Malignant tumors of the liver include
– Hepatocellular carcinoma (HCC) (a.k.a hepatocarcinoma,
and hepatoma) the most common malignant tumor of the
liver
– Bile duct carcinoma.
– Hepatoblastoma is an uncommon hepatic malignancy of
children.
Cancers of the liver are classified as
primary or metastatic.
• Primary liver cancer is cancer that begins
in the liver cells while metastatic cancer
occurs when tumors from other parts of the
body spread (metastasize) to the liver.
• Metastatic liver cancer is much more
common than primary liver cancer;
– 90% to 95% of all hepatic malignancies are
classified as metastatic.
– Cancers that commonly spread to the liver
include colon, lung, and breast cancer.
• Approximately 80% of cases
worldwide are attributable to HBV and
HCV
• Estimated 4-year survival rate is 85%
and the recurrence-free survival rate
is 92%.
• Whether primary or metastatic, any
malignant tumor in the liver is a
serious finding and carries a poor
prognosis, with survival times
measured in months.
Diagnostic and Laboratory Findings
• Isolated increases in the two
enzymes LD and ALP.
• Most commonly, LD5  produced by
the liver
• May be produced by tumors  LD is
greater than 500 to 1000 IU/L and
ALP is greater than 500 IU/L.
• If a malignant tumor spreads widely through
the liver, mild elevation in the
aminotransferases may be seen, along with
hyperbilirubinemia due to bile duct
obstruction, and low protein and albumin.

• Serodiagnostic tests
– serum levels of AFP are elevated in
hepatocellular carcinoma.
– Angiosarcomas can be diagnosed using
specific antibodies to mutated ras-p21
protein.
 Clinical Question
• Is measurement of serum α-fetoprotein
(AFP) levels better than imaging when
screening symptomatic patients with
hepatitis C virus (HCV) infection for
hepatocellular carcinoma?
• American Association for the Study of
Liver Diseases:
USG for patients with HCV and cirrhosis every
six to 12 months, and AFP measurement only
when USG is not available

• Based on fair-quality evidence, National

Cancer Institute:
screening would not decrease mortality from
hepatocellular carcinoma, and could result in
rare but serious adverse effects from
diagnostic testing.
 DRUG- AND TOXIN-
INDUCED LIVER INJURY
• As the major drug metabolizing
and detoxifying organ 
subject to injury from an
enormous array of therapeutic
and environmental chemicals.
Drug reactions may be predictable
(intrinsic) or unpredictable
(idiosyncratic).
Both classes of injury may be immediate
or take weeks to months to develop .
Predictable drug or toxin reactions
• Affect all individuals in a dose-dependent
fashion.
• A classic, predictable hepatotoxin is
acetaminophen, now the most common
cause of acute liver failure necessitating
transplantation in the US.
• The toxic agent is not acetaminophen itself
but rather toxic metabolites produced by the
cytochrome P-450 system.
• The damage begins in centrilobular
hepatocytes but extends to encompass
entire lobules in the most severe cases.
Unpredictable Reactions
• depend on idiosyncrasies of the host,
particularly the propensity to mount an
immune response to the antigenic
stimulus or the rate at which the agent
can be metabolized.
– Chlorpromazine, an agent that causes
cholestasis in patients who are slow to
metabolize it
– Halothane and its derivatives, which can
cause a fatal immunemediated hepatitis after
repeated exposure.
 ALCOHOLIC AND
NONALCOHOLIC FATTY
LIVER DISEASE
• Alcohol is a well-known cause of fatty
liver disease in adults and can manifest
histologically as steatosis,
steatohepatitis, and cirrhosis.
• In recent years, it has become evident
that another entity, so-called
“nonalcoholic fatty liver disease
(NAFLD),” can mimic the entire
spectrum of hepatic changes associated
with alcohol abuse.
Toxic byproducts of ethanol and its metabolites:
1. Acetaldehyde (a major metabolite of ethanol)  lipid
peroxidation and acetaldehyde-protein adduct
formation  disrupt cytoskeleton and membrane
function.
2. Alcohol  affects mitochondrial function and
membrane fluidity.
3. Reactive oxygen species generated during
oxidation of ethanol by the microsomal ethanol
oxidizing system react with and damage membranes
and proteins. Also are produced by neutrophils, which
infiltrate areas of hepatocyte necrosis.
 Alcoholic Liver Disease
• Excessive ethanol consumption causes more
than 60% of chronic liver disease in Western
countries and accounts for 40% to 50% of
deaths due to cirrhosis.
• Among the most important adverse effects of
chronic alcohol consumption are the overlapping
forms of alcohol-related fatty liver disease:
1. HEPATIC STEATOSIS
2. ALCOHOLIC HEPATITIS
3. FIBROSIS AND CIRRHOSIS
• Short-term ingestion of as much as 80 g
of ethanol per day (5–6 beers or 8–9
ounces of 80-proof liquor) generally
produces mild reversible hepatic changes,
such as fatty liver.
• Chronic intake of 40 to 80 g/day is
considered a borderline risk factor for
severe injury.
• Cirrhosis typically develops after more
than 10 years of heavy drinking, but only
occurs in a small proportion of chronic
alcoholics.
• The multiple pathologic effects of
alcohol include changes in lipid
metabolism, decreased export of
lipoproteins, and cell injury caused by
reactive oxygen species and metabolites
of alcohol.
 Nonalcoholic Fatty Liver Disease
• Common condition in which fatty liver disease develops in
individuals who do not drink alcohol.
• Three types of changes (steatosis, steatohepatitis, and
cirrhosis)  less prominent than in alcoholic liver disease.
 Pathogenesis
• The exact mechanism of NAFLD is unknown
but involves insulin resistance, steatosis,
the release of inflammatory cytokines, and
oxidative stress,  lead to fibrosis and
cirrhosis.
• These factor combine  increase
mobilization of free fatty acids from adipose
tissue, taken up by hepatocytes  stimulate
the synthesis of fatty acids within hepatocytes
NAFLD
associated with
insulin resistance,
central adiposity,
increased BMI,
hypertension, and
hyperlipidemia,
which collectively
are features of
metabolic
syndrome.
 Diagnosis
• Screening for nonalcoholic fatty liver
disease is not recommended in the
general population
• Considered after an incidental
discovery of unexplained elevation of
liver enzyme levels or when hepatic
steatosis is noted on imaging i.e USG
 HISTORY TAKING
• Often asymptomatic, symptoms may include
RUQ pain, jaundice, and pruritus.
• Alcohol and drug history, must be excluded.
• Explore diet, physical activity, change in weight
(usually an increase, such as 40 lb [18 kg] over
two to three years)
• Associated conditions  diabetes,
hypertension, hyperlipidemia, obesity, sleep
apnea
• Risk factors for viral hepatitis  IV drug use,
blood transfusion, and sexual activities.
 PHYSICAL EXAMINATION
• Often is unremarkable, but may include
elevated blood pressure, central obesity,
and hepatosplenomegaly. 
 LABORATORY STUDIES
• May be used to examine factors for insulin
resistance and metabolic syndrome, to
evaluate liver injury, and to exclude other
causes of liver disease.
• Measures of insulin resistance include the
– Homeostasis Model Assessment (normal
value < 3.99)
– Quantitative Insulin Sensitivity Check Index
(normal value > 0.35)
• No single laboratory test is diagnostic for
nonalcoholic fatty liver disease.
• Liver enzyme levels have low sensitivity and
specificity, and do not predict clinical
outcomes.
 IMAGING
• Assess liver and spleen anatomy, and the presence of
hepatic steatosis.
• Exclude other diseases.
• Cannot detect inflammation or fibrosis.
Ultrasonography
• Qualitative evaluation and detection of moderate to
high amounts of fat in the liver,
• Limitation:
– Intraobserver reproducibility and interobserver variability &
accuracy and reliability also may be reduced by a patient's
body habitus.
– Cannot differentiate between fibrosis and steatosis.
 NONINVASIVE TESTS FOR LIVER
FIBROSIS
• In response to inflammatory cytokines
and liver injury, collagen deposition
occurs in the liver and results in fibrosis.
• Noninvasive tests for fibrosis may
reduce the need for liver biopsy in
patients with nonalcoholic fatty liver
disease.
 Prognosis
• Hepatic steatosis rarely progresses to
cirrhosis
– 15% to 30% of patients with nonalcoholic
steatohepatitis progress to advanced fibrosis
– 12% to 35% with advanced fibrosis progress
to cirrhosis.
• Patients with cirrhosis should be
monitored for signs of portal hypertension,
disease progression, and hepatocellular
carcinoma.
THANK
YOU
Mechanisms of
hyperbilirubinemia.
(A)Normal bilirubin
metabolism,
(B)hemolytic
jaundice,
(C)Gilbert's
disease,
(D)physiologic
jaundice,
(E)Dubin-Johnson
syndrome, and
(F)intrahepatic or
extrahepatic
obstruction
 EXERCISE AND WEIGHT LOSS
• A healthy diet, weight loss, and exercise are first-line therapeutic measures to
reduce insulin resistance in patients with nonalcoholic fatty liver disease. 2
 Although there is no established treatment, a healthy low-fat diet may have
benefits independent of weight loss. A modest weight loss of 5% to 10% can
result in normalizationof AST levels.2 A meta-analysis of 49 randomized
controlled trials found that weight loss was safe in patients with nonalcoholic
fatty liver disease, and it improved liver histology. 30 Patients should be
encouraged to increase physical activity and exercise, because these have
been shown to reduce steatosis and improve liver enzyme levels independent
of weight loss.2 Vigorous physical activity may be more effective in improving
liver function but should be avoided until cardiovascular disease is assessed
because patients with nonalcoholic fatty liver disease are at increased
cardiovascular risk.13 
• Orlistat (Xenical) is effective for short-term weight loss and is associated with
improvement in AST levels, ALT levels, and liver histology. 13,30 
• A Cochrane review found insufficient evidence to assess the benefits or harms
of bariatric surgery for the treatment of nonalcoholic steatohepatitis.
• It is estimated that over half of the lipid
found in hepatocytes in NAFLD is
derived from adipose tissue, with most
of the remainder coming from de novo
synthesis in liver cells.
• Precisely how the accumulation of lipid
in hepatocytes predisposes to the
development of NASH is not known and
may involve several interrelated
mechanisms
• Excessive intrahepatic lipids and their
metabolic intermediates enhance insulin
resistance in the liver and sensitize
hepatocytes to the toxic effects of
inflammatory cytokines, which are
produced in increased amounts in the
setting of the metabolic syndrome.
• In addition, hepatocytes in patients with NASH
show evidence of inflammasome activation,
possibly due to direct or indirect effects of
particular lipids, leading to local release of the pro-
inflammatory cytokine IL-1.
• Other products of lipid metabolism appear to be
directly toxic to hepatocytes; proposed
mechanisms include increased production of
reactive oxygen species, induction of ER stress,
and disruption of mitochondrial function.
• Liver injury resulting from these various insults
causes stellate cell activation, collagen deposition,
and hepatic fibrosis, which along with ongoing
hepatocyte damage lead to full-blown NASH.
 Clinical Features
• Most common cause of incidental
elevation of serum transaminases.
• Most individuals with steatosis are
asymptomatic; patients with active
steatohepatitis or fibrosis may also be
asymptomatic, but some may have
fatigue, malaise, right upper-quadrant
discomfort, or more severe symptoms of
chronic liver disease.
• Liver biopsy is required to identify NASH and
distinguish it from uncomplicated NAFLD.
• Fortunately, the frequency of progression from
steatosis to active steatohepatitis and then from
active steatohepatitis to cirrhosis is low
• Nevertheless, NAFLD is considered to be a
significant contributor to the pathogenesis of
“cryptogenic” cirrhosis.
• Because they share common risk factors, the
incidence of CAD also is increased in patients with
NAFLD.
Physiologic jaundice of the newborn

• result of a deficiency in the enzyme UDPGT,

one of the last liver functions to be activated in
prenatal life since bilirubin processing is
handled by the mother of the fetus.
• Premature infants may be born without
UDPGT, the enzyme responsible for bilirubin
conjugation.
• This deficiency results in the rapid buildup of
unconjugated bilirubin, which can be life
threatening.
Mechanisms of
hyperbilirubinemia.
(A)Normal bilirubin
metabolism,
(B)(B) hemolytic
jaundice,
(C)(C) Gilbert's
disease, (D)
physiologic
jaundice, (E)
Dubin-Johnson
syndrome, and
(F) intrahepatic
or extrahepatic
obstruction
Unconjugated Hyperbilirubinemia

• INCREASED BILIRUBIN
PRODUCTION
• IMPAIRED BILIRUBIN
CONJUGATION
 INCREASED BILIRUBIN
PRODUCTION
• Result of too much bilirubin presented to the
conjugating machinery (from increased red
blood cell destruction).
• RBC membrane disorders, enzyme disorders,
hemoglobin disorders, autoimmune destruction,
or some cancers.
• The excess turnover of red blood cells results in
increased heme metabolism, producing large
amounts of bilirubin that overwhelm the
conjugating machinery, leading to decreased
excretion and clinical jaundice.
IMPAIRED BILIRUBIN CONJUGATION
• Deficiencies in the same conjugating machinery may also lead to
jaundice in individuals with normal red blood cell turnover.
• Gilbert syndrome involves a deficiency in uridine diphosphate-
glucuronosyltransferase, and it affects 10% of the white
population.
• This is a benign condition that may be exacerbated by physical or
emotional stress such as illness, strenuous exercise, or fasting.
• Crigler-Najjar syndrome is a more severe variant of the same
enzyme deficiency.
• Patients with impaired conjugation due to low levels of the
bilirubin-UGT enzyme are particularly susceptible to jaundice from
medications that inhibit this enzyme, such as protease inhibitors.
Conjugated Hyperbilirubinemia
• INTRAHEPATIC DISORDERS:
HEPATOCELLULAR DAMAGE AND
INTRAHEPATIC CHOLESTASIS
• EXTRAHEPATIC DISORDERS:
CHOLESTASIS
 INTRAHEPATIC DISORDERS:
HEPATOCELLULAR DAMAGE AND
INTRAHEPATIC CHOLESTASIS
• The largest worldwide contributor to liver disease is viral hepatitis,
mostly from hepatitis C.
• Viral hepatitis causes increased oxidative stress within
hepatocytes, leading to cell death, scarring, and diminished liver
mass available for normal function.
• Chronic alcohol consumption can cause various hepatic disorders,
including steatosis or fatty liver disease with minimal symptoms and
often no jaundice; alcoholic hepatitis with acute onset jaundice and
more severe symptoms; and cirrhosis, which is often associated
with decompensation and liver failure in the setting of jaundice.
• Jaundice in persons with alcoholic liver disease can occur via
multiple mechanisms, such as direct hepatocellular damage caused
by ethanol metabolites or from alcohol’s effect on bile acid uptake
and secretion contributing to cholestasis.
• Approximately 30% to 40% of patients with nonalcoholic
fatty liver disease progress to nonalcoholic
steatohepatitis, and approximately 40% to 50% of these
patients develop fibrosis or cirrhosis that may lead to
hyperbilirubinemia.
• Although the exact mechanism is poorly understood,
liver lipid deposition may trigger inflammation and
fibrosis, particularly when coupled with type 2 diabetes.
• Sepsis may also induce hyperbilirubinemia as circulating
acute phase reactants and bacterial endotoxins disrupt
bilirubin transport, leading to cholestasis and elevated
bile salt levels.
• Drug-induced liver injury has multiple potential mechanisms, including
direct hepatocellular toxicity and activation of an immune response that
advances the inflammatory cascade, inhibiting bilirubin transport into
canaliculi, which causes cholestasis.
• Wilson disease, a rare genetic disorder, is associated with a loss of
function of a cellular transporter responsible for moving dietary copper
into liver canaliculi.
• Elevated liver copper levels affect hepatic lipid metabolism, which leads
to steatosis and cholestasis.
• Additional causes of intrahepatic hyperbilirubinemia include
autoimmune disorders, such as autoimmune hepatitis and the rare
autoimmune condition primary biliary cirrhosis, which occurs most
commonly in middle-aged women.
• Both conditions are associated with inflammation, which disrupts the
transport of bilirubin within the liver
 EXTRAHEPATIC DISORDERS:
CHOLESTASIS
• Conjugated hyperbilirubinemia may also arise from
extrahepatic obstruction. Patients with biliary
obstruction may present with multiple signs and
symptoms, including fever, pruritus, abdominal pain,
weight loss, muscle wasting, dark urine, and pale
stools. Choledocholithiasis is the most common non-
neoplastic cause of biliary obstruction, accounting for
14% of all new cases of jaundice.2 An estimated 20
million Americans have gallstones, and risk factors
for choledocholithiasis include female sex, older age,
increasing body mass index, and rapid weight loss
• Gallstones may cause jaundice by obstructing the
biliary tree (typically the common bile duct) or by
inducing a biliary stricture.
• Less commonly, stones in the gallbladder or cystic
duct may mechanically compress the common
hepatic duct causing jaundice, and, rarely, stones
may cause the formation of a biliary-vascular fistula
with accompanying jaundice.
• Biliary stricture causing postoperative jaundice is a
rare complication of cholecystectomy (0.6% of
cases).
• Jaundice may be caused by surgeries such
as liver transplantation and the Whipple and
Billroth procedures, which both involve the
creation of a choledochojejunostomy. Chronic
pancreatitis may cause biliary strictures and
jaundice, as may different forms of
cholangitis.
• In children, biliary atresia and choledochal
cysts are the main causes of extrahepatic
biliary obstruction.
• Neoplasms are associated with 6.2% of new-onset cases of jaundice.2
Cholangiocarcinoma may affect the proximal or distal portions of the
biliary tree by causing biliary strictures. Five-year survival for persons
who have resection is 20% to 40%; survival in unresectable disease is
less than one year.
• Primary sclerosing cholangitis confers a 1,500-fold increased risk of
cholangiocarcinoma, but more than 80% of cases have no risk factors
for disease.
• Gallbladder cancer, although rare, is the most common biliary tract
malignancy; risk factors include gallstones, infection (Salmonella typhi),
and female sex. Median survival is six to 12 months, depending on the
stage at diagnosis.
• Ampullary cancers and bile duct compression from lymphadenopathy,
or external tumors such as pancreatic cancer, may also cause
obstruction.
• When unconjugated bilirubin builds up in
the neonate, it cannot be processed and
it is deposited in the nuclei of brain and
degenerate nerve cells, causing
kernicterus. Kernicterus often results in
cell damage and death in the newborn,
and this condition will continue until
UDPGT is produced.
Inflammation and immunologic reactions are
involved in many forms of liver disease.
• Systemic inflammation alters the metabolic and
biosynthetic activities of the liver, leading to
increased secretion of acute-phase reactants such
as C-reactive protein, serum amyloid A protein (a
precursor of some forms of amyloid) and hepcidin,
(a key regulator of iron metabolism).
• Adaptive immune cells play a critical role in viral
hepatitis, with CD4+ and CD8+ T cells being
particularly important in the eradication of virus-
infected hepatocytes and, in chronic disease, liver
injury.
 Reye's Syndrome
• Reye's syndrome is a term used to describe a group of disorders caused by infectious,
metabolic, toxic, or drug-induced disease found almost exclusively in children, although adult
cases of Reye's syndrome have been reported. 20 Although the precise cause of Reye's
syndrome is unknown, it is often preceded by a viral syndrome such as varicella,
gastroenteritis, or an upper respiratory tract infection such as influenza. 21 , 22 , 23 Although
not described as the precise cause of Reye's syndrome, studies have demonstrated a strong
epidemiologic association between the ingestion of aspirin during a viral syndrome and the
subsequent development of Reye's syndrome. 24,25 As a result, the Centers for Disease
Control and Prevention (CDC) cautioned physicians and parents to avoid salicylate use in
children with a viral syndrome, and the U.S. Surgeon General mandated that a warning label
be added to all aspirin-containing medications, beginning in 1986. 26,27 Reye's syndrome is
an acute illness characterized by noninflammatory encephalopathy and fatty degeneration of
the liver, with a clinical presentation of profuse vomiting accompanied with varying degrees
of neurologic impairment such as fluctuating personality changes and deterioration in
consciousness. The encephalopathy is characterized by a progression from mild confusion
(stage 1) through progressive loss of neurologic function to loss of brain stem reflexes (stage
5). The degeneration of the liver is characterized by a mild hyperbilirubinemia and threefold
increases in ammonia and the aminotransferases (aspartate aminotransferase [AST] and
alanine aminotransferase [ALT]). Without treatment, rapid clinical deterioration leading to
death may occur.
• Fractionated bilirubinemia  conjugated and
unconjugated hyperbilirubinemia.
• CBC  hemolysis, anemia of chronic disease and
thrombocytopenia (common in decompensated cirrhosis)
• Elevated ALT & AST  hepatocellular damage, smay be
normal in chronic liver disease (e.g., cirrhosis).  there may
not be enough normal liver parenchymal tissue to release
elevated levels of these enzymes.
• Elevated ALP  biliary obstruction and parenchymal liver
disease, pathologic processes in bone, kidney, intestine,
and placenta.
• Elevated GGT  biliary obstruction and hepatocellular
damage, as well as pancreatic disorders, myocardial
infarction, renal disease, and diabetes mellitus.
• Low levels of protein, albumin, or elevated PT or INR 
decreased synthetic function and hepatic decompensation.
 Reye's Syndrome
• Reye's syndrome is a term used to describe a group of disorders caused by infectious,
metabolic, toxic, or drug-induced disease found almost exclusively in children, although adult
cases of Reye's syndrome have been reported. 20 Although the precise cause of Reye's
syndrome is unknown, it is often preceded by a viral syndrome such as varicella,
gastroenteritis, or an upper respiratory tract infection such as influenza. 21 , 22 , 23 Although
not described as the precise cause of Reye's syndrome, studies have demonstrated a strong
epidemiologic association between the ingestion of aspirin during a viral syndrome and the
subsequent development of Reye's syndrome. 24,25 As a result, the Centers for Disease
Control and Prevention (CDC) cautioned physicians and parents to avoid salicylate use in
children with a viral syndrome, and the U.S. Surgeon General mandated that a warning label
be added to all aspirin-containing medications, beginning in 1986. 26,27 Reye's syndrome is
an acute illness characterized by noninflammatory encephalopathy and fatty degeneration of
the liver, with a clinical presentation of profuse vomiting accompanied with varying degrees
of neurologic impairment such as fluctuating personality changes and deterioration in
consciousness. The encephalopathy is characterized by a progression from mild confusion
(stage 1) through progressive loss of neurologic function to loss of brain stem reflexes (stage
5). The degeneration of the liver is characterized by a mild hyperbilirubinemia and threefold
increases in ammonia and the aminotransferases (aspartate aminotransferase [AST] and
alanine aminotransferase [ALT]). Without treatment, rapid clinical deterioration leading to
death may occur.
 INFECTIOUS DISORDERS
Viral Hepatitis
• The terminology for acute and chronic viral hepatitis can be confusing,
because the same word, hepatitis, can be used to describe several
different entities; careful attention to context can clarify its meaning in
any situation.
• Firstly, hepatitis is the name applied to viruses (hepatitis A, B, C, D, and
E virus) that are hepatotropic, that is, have a specific affinity for the
liver.
• Secondly, hepatitis is applied to patterns of acute and chronic hepatic
injuries that are produced not only by hepatotropic viruses, but also by
damage produced by other viruses such as EBV, CMV , and yellow
fever as well as autoimmune reactions, drugs, and toxins.
• In this section, we will focus on the main features of hepatotropic
viruses, which are summarized in Table 16.2, and we will then discuss
the clinicopathologic characteristics of acute and chronic viral hepatitis.
Viral Hepatitis
 Hepatitis A Virus (HAV)
• HAV usually is a benign self-limited infection that does not cause chronic hepatitis
and rarely (in about 0.1% of cases) produces fulminant hepatitis.
• HAV is a small, nonenveloped, positive-strand RNA picornavirus that occupies its
own genus, Hepatovirus.
• incubation period of 3-6 weeks.
• It is typically cleared by the host immune response, so it does not establish a carrier
state.
• Overall, HAV accounts for about 25% of clinically evident acute hepatitis worldwide.
• The receptor for HAV is HAVcr-1, a membrane glycoprotein that also may serve as a
receptor for Ebola virus.
• HAV is spread by ingestion of contaminated water and food and is shed in the stool
for 2 to 3 weeks before and 1 week after the onset of jaundice.
• Thus, close personal contact with an infected individual or fecal-oral contamination
accounts for most cases and explains outbreaks in institutional settings such as
schools and nurseries, as well as water-borne epidemics in places where people live
in overcrowded, unsanitary conditions.
• HAV can also be detected in serum and saliva of infected individuals.
• Acute HAV tends to cause a febrile illness
associated with jaundice and nonspecific
symptoms such as fatigue and loss of
appetite.
Temporal
changes in
serologic
markers in
acute hepatitis
A
infection.HAV,
Hepatitis A
virus.
 Hepatitis B Virus (HBV)
• The outcome of HBV infection varies widely,
from (1) acute hepatitis with recovery and
clearance of the virus; (2) nonprogressive
chronic hepatitis; (3) progressive chronic
disease ending in cirrhosis; (4) fulminant
hepatitis with massive liver necrosis; and (5)
an asymptomatic “healthy” carrier state.
• HBV-induced chronic liver disease is also an
important precursor for the development of
HCC.
• Potential outcomes of hepatitis B infection in adults,
with their approximate frequencies in the United
States.
*Spontaneous HBsAg clearance occurs during chronic
HBV infection at an estimated annual incidence of 1%
to 2% in Western countries.
 Hepatitis C Virus (HCV)
• HCV is a major cause of liver disease, with
approximately 170 million individuals affected
worldwide.
• Approximately 4.1 million Americans (1.6% of
the population) have chronic HCV infection.
• Persistent infection and chronic hepatitis are
the hallmarks of HCV infection, despite the
generally asymptomatic nature of the acute
illnes.
• Life cycle of hepatitis C.
Viral entry, replication,
assembly, and budding
are shown, emphasizing
steps that can be
effectively targeted with
anti-viral drugs.
• In the alphabet of hepatotropic viruses, some easy mnemonic
devices may be useful:
– The vowels (hepatitis A and E) never cause chronic hepatitis, only AcutE
hepatitis.
– Only the consonants (hepatitis B, C, D) have the potential to cause
chronic disease (C for consonant and for chronic).
– Hepatitis B can be transmitted by blood, birthing, and “bonking” (as they
say in the United Kingdom).
– Hepatitis C is the single virus that is more often chronic than not (almost
never detected acutely; 85% or more of patients develop chronic hepatitis,
20% of whom will develop cirrhosis).
– Hepatitis D, the delta agent, is a defective virus, requiring hepatitis B
coinfection for its own capacity to infect and replicate.
– Hepatitis E is endemic in equatorial regions and frequently epidemic.
• The inflammatory cells in both acute and chronic viral hepatitis are
mainly T cells; it is the pattern of injury that is different, not the
nature of the infiltrate.
• Patients with long-standing HBV or HCV infections are at
increased risk for development of HCC.
 Bacterial, Parasitic, and Helminthic
Infections
• A multitude of organisms can infect the liver and
biliary tree, including bacteria, fungi, helminths and
other parasites, and protozoa. Infectious organisms
can reach the liver through several pathways:
– Ascending infection, via the gut and biliary tract
(ascending cholangitis)
– Vascular seeding, most often through the portal system
via the gastrointestinal tract
– Direct invasion, from an adjacent source (e.g., bacterial
cholecystitis)
– Penetrating injury
• Schistosomiasis, most commonly found in Asia, Africa, and South
America, is one of the most common causes of noncirrhotic portal
hypertension worldwide. Adult worms in the gut produce numerous
eggs, some of which find their way into the portal circulation, where
they lodge and induce a granulomatous reaction associated with
marked fibrosis.
• Entamoeba histolytica, an important cause of dysentery sometimes
ascends to the liver through portal circulation and produces
secondary foci of infection that can progress to large necrotic areas
called amebic liver abscesses. Amebic abscesses are more common
in the right lobe of the liver. The abscess cavity contains necrotic
liver cells, but unlike pyogenic abscesses, neutrophils are absent.
• Liver fluke infection, most common in Southeast Asia, is
associated with a high rate of cholangiocarcinoma. Responsible
organisms include Fasciola hepatica, Opisthorcis species, and
Clonorchis sinensis.
• Echinococcal infections may cause the formation of intrahepatic
hydatid cysts that produce symptoms due to pressure on
surrounding structures or following rupture.
 AUTOIMMUNE HEPATITIS
• Autoimmune hepatitis is a chronic, progressive
hepatitis with all the features of autoimmune
diseases in general: genetic predisposition,
association with other autoimmune diseases, the
presence of autoantibodies, and therapeutic
response to immunosuppression.
• Risk for autoimmune hepatitis is associated with certain
HLA alleles, such as the DRB1* allele in Caucasians,
but as in other autoimmune disorders the mechanistic
basis for this relationship is unclear. Triggers for the
immune reaction may include viral infections or drug or
toxin exposures.
 Clinicopathologic Features
• The annual incidence is highest among white northern
Europeans at 1.9 in 100,000, but all ethnic groups are
susceptible.
• There is a female predominance (78%). Autoimmune hepatitis is
classified into two types, based on the patterns of circulating
antibodies.
• Type 1, more common in middle-age and older individuals, is
characterized by the presence of antinuclear (ANA), anti–smooth
muscle actin (SMA), antimitochondrial (AMA), and anti–soluble
liver antigen/ liver-pancreas antigen (anti-SLA/LP) antibodies.
• Type 2, usually seen in children and teenagers, is chararcterized
by the presence of anti–liver kidney microsome-1 antibodies and
anti–liver cytosol-1 antibodies.
• There are two primary types of autoimmune hepatitis:
• Type 1 autoimmune hepatitis is most often seen in middleage
women and is characteristically associated with antinuclear and
anti–smooth muscle antibodies.
• Type 2 autoimmune hepatitis is most often seen in children or
teenagers and is associated with anti–liver kidney microsomal
autoantibodies.
• Autoimmune hepatitis may either develop with a rapidly
progressive acute disease or follow a more indolent path; if
untreated, both are likely to lead to liver failure.
• Plasma cells are a prominent and characteristic component of
the inflammatory infiltrate in biopsy specimens showing
autoimmune hepatitis.
• The following features are typical of
autoimmune hepatitis:
• Necrosis and inflammation, indicated by
extensive interface hepatitis or foci of confluent
(perivenular or bridging) necrosis or
parenchymal collapse
• Plasma cell predominance in the mononuclear
inflammatory infiltrates
• Hepatocyte “rosettes” in areas of marked
activity
DRUG- AND TOXIN-INDUCED LIVER
INJURY
• As the major drug metabolizing and
detoxifying organ in the body, the
liver is subject to injury from an
enormous array of therapeutic and
environmental chemicals.
 ALCOHOLIC AND NONALCOHOLIC
FATTY LIVER DISEASE
• Alcohol is a well-known cause of fatty
liver disease in adults and can
manifest histologically as steatosis,
steatohepatitis, and cirrhosis.
 INHERITED METABOLIC LIVER
DISEASES
• Hemochromatosis
• Wilson Disease
• α1-Anti-Trypsin Deficiency
CHOLESTATIC SYNDROMES
• CHOLESTATIC SYNDROMES
• Bilirubin and Bile Formation
• Pathophysiology of Jaundice
• Defects in Hepatocellular Bilirubin Metabolism
• Cholestasis
• Neonatal Cholestasis
• Biliary Atresia
• Autoimmune Cholangiopathies
CIRCULATORY DISORDERS
• Impaired Blood Flow Into the Liver
• Hepatic Artery Compromise
• Portal Vein Obstruction and Thrombosis
CIRCULATORY DISORDERS
• 1. Impaired Blood Flow Into the Liver
• A. Hepatic Artery Compromise
• B. Portal Vein Obstruction and Thrombosis
• 2. Impaired Blood Flow Through the Liver
• 3. Hepatic Venous Outflow Obstruction
• A. Hepatic Vein Thrombosis
• 4. Passive Congestion and Centrilobular
Necrosis
 NODULES AND TUMORS
• Focal Nodular Hyperplasia
• Benign Neoplasms
• Hepatocellular Adenomas
• Malignant Neoplasms
• Hepatocellular Carcinoma (HCC)
The fundamental patterns of laboratory
findings in liver function abnormalities are
summarized and are encapsulated in Table 8-
5.
• In this section, the major hepatic disorders
are discussed, with emphasis on laboratory
evaluations that enable diagnoses to be
made, often without the need to perform
invasive procedures such as liver biopsies.
 DIAGNOSIS OF LIVER DISEASES

• HEPATITIS
• Alcoholic Hepatitis
• Chronic Hepatitis
• CIRRHOSIS
 HEPATITIS
• Alcoholic Hepatitis
• Chronic Hepatitis
CHRONIC PASSIVE CONGESTION
 CIRRHOSIS
• Diagnosing and Following Cirrhosis,
Fibrosis, and Necroinflammation of the
Liver Noninvasively Using Serum Analytes
• Computed Indices Used to Predict Survival
of Patients with Extensive Liver Disease
• MELD System
• Child-Turcotte-Pugh Score
• Biochemical and Clinical Correlations of
Cirrhosis
POSTHEPATIC BILIARY
OBSTRUCTION
SPACE-OCCUPYING LESIONS
FULMINANT HEPATIC FAILURE
Typical time course for appearance of viral antigens and antiviral antibodies in hepatitis A viral (HAV) infection.
• The appearance of the hepatitis A antigen, HAAg, occurs early on; it is no longer present during the acute phase, during which
time jaundice may develop. During the incubation period (which averages 2 to 3 weeks), HAV RNA is replicating, and viral
particles can be detected in stool by immune electron microscopy. Viral RNA is also detectable during this time by real-time
polymerase chain reaction (PCR). The most effective diagnostic determination of hepatitis A acute infection is the detection of
anti-HAV immunoglobulin (Ig)M. Also shown in this figure is the rise of the aminotransferases, aspartate aminotransferase (AST)
and alanine aminotransferase (ALT), which occurs at the beginning of the early acute phase and lasts for several weeks to 1 to 2
months. The patient ceases to be infectious after anti-HAV IgM falls to undetectable levels in 3 to 6 months post early phase.
Permanent anti-HAV IgG rises over several months and lasts for many years, conferring immunity on the exposed or infected
individual.
Typical time course for appearance of viral antigens and antiviral antibodies in hepatitis B viral (HBV) infection. In the early acute phase, the
HBV surface antigen (HBsAg) (red curve) appears and lasts for several months. Detection of this antigen signifies acute HBV infection.
Between the time the titer of HBsAg falls and the titer of anti-HBV immunoglobulin (Ig)G (dark blue curve), which confers immunity, rises, there
is a gap of about 6 months. In this time period, the titers of anti-HBV core antigen (anti-HBc) IgM (purple curve) and IgG (black curve) rise,
indicating acute HBV infection. This is the so-called core window. IgG anti-HBV e antigen (anti-HBe) (cyan or light blue curve) also rises
during this core window period. Permanent immunity is conferred by anti-HBsAg IgG (anti-HBs) (dark blue curve). It is difficult to determine the
time at which the patient is no longer infectious. Generally, an individual is considered noninfectious when no HBsAg or HBeAg, and no anti-
HBcAg IgM, can be detected, and the anti-HBsAg IgG has plateaued. Also shown in this figure is the pattern of aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) elevations. These occur in the early acute phase, slightly after HBsAg rises. AST and ALT levels
may remain elevated for several weeks to several months, after which time they decline. In HBV chronic active hepatitis, HBsAg is present
continuously. AST and ALT generally remain elevated, although they can oscillate throughout the course of the disease. (
• Different groups of tests are
recommended for three different clinical
situations as follows:
1. Acute HBV hepatitis: HBsAg, IgM anti-
HBc
2. Chronic HBV hepatitis: HBsAg, IgG anti-
HBc, IgG anti-HBs
3. Monitoring chronic HBV infection: HBs,
HBeAg, IgG anti-HBs, IgG anti-HBe, and
ultrasensitive quantitative PCR
• A diagnosis of drug or toxin-induced liver
injury may be made on the basis of a
temporal association of liver damage with
drug or toxin exposure, recovery (usually)
upon removal of the inciting agent, and
exclusion of other potential causes.
• Exposure to a toxin or therapeutic agent
should always be included in the
differential diagnosis of any form of liver
disease.
• Hepatocellular steatosis is caused by alcohol
through several mechanisms. First, metabolism of
ethanol by alcohol dehydrogenase and
acetaldehyde dehydrogenase generates large
amounts of nicotinamide-adenine dinucleotide
(NADH), which increases shunting of substrates
away from catabolism and toward lipid
biosynthesis. Second, ethanol impairs the
assembly and secretion of lipoproteins. The net
effect is to cause the accumulation of intracellular
lipids.
• For unknown reasons, cirrhosis develops
in only a small fraction of chronic
alcoholics. With complete abstinence, at
least partial regression of scarring
occurs, and the micronodular liver
transforms though parenchymal
regeneration into a macronodular
cirrhotic organ (see Figure 16.6); rarely,
there is regression of cirrhosis altogether.
 Clinical Features
• Alcoholic steatosis may be innocuous or
give rise to hepatomegaly with mild
elevations of serum bilirubin and alkaline
phosphatase. Severe hepatic
compromise is unusual. Alcohol
withdrawal and the provision of an
adequate diet are sufficient treatment.
Drug- and Alcohol-Related Disorders

• Drug-induced liver disease is a major

problem in the United States, accounting
for one-third to one-half of all reported
cases of acute liver failure.
• The liver is a primary target organ for adverse drug
reactions because it plays a central role in drug
metabolism. Many drugs are known to cause liver
damage, ranging from very mild transient forms to
fulminant liver failure.
• Drugs can cause liver injury by a variety of
mechanisms, but the most common mechanism of
toxicity is via an immune-mediated injury to the
hepatocytes. 30 In this type of mechanism, the drug
induces an adverse immune response directed against
the liver itself and results in hepatic and/or cholestatic
disease.
• Of all the drugs associated with hepatic
toxicity, the most important is ethanol. In very
small amounts, ethanol causes very mild,
transient, and unnoticed injury to the liver;
however, with heavier and prolonged
consumption, it can lead to alcoholic
cirrhosis. While the exact amount of alcohol
needed to cause cirrhosis is unknown, a
small minority of people with alcoholism
develop this condition. 3
• Approximately 90% of the alcohol absorbed
from the stomach and small intestines is
transported to the liver for metabolism. Within
the liver, the elimination of alcohol requires
the enzymes alcohol dehydrogenase and
acetaldehyde dehydrogenase to convert
alcohol to acetaldehyde and subsequently to
acetate. The acetate can then be oxidized to
water and carbon dioxide, or it may enter the
citric acid cycle.
• Long-term excessive consumption of alcohol can result in a
spectrum of liver abnormalities that may range from
alcoholic fatty liver with inflammation (steatohepatitis) to
scar tissue formation, as in hepatic fibrosis, to the
destruction of normal liver structure seen in hepatic
cirrhosis. Alcohol-induced liver injury may be categorized
into three stages: alcoholic fatty liver, alcoholic hepatitis,
and alcoholic cirrhosis. The risk for the development of
cirrhosis increases proportionally with the consumption of
more than 30 g (the equivalent of 3 to 4 drinks) of alcohol
per day, with the highest degree of risk seen with the
consumption of greater than 120 g (the equivalent of 12 to
16 drinks) per day.
• Unconjugated bilirubin is lipid soluble and passes easily
through cell membranes to bind to albumin in serum,
whereas free (unbound) bilirubin is taken up by liver
hepatocytes and converted to conjugated bilirubin.
• Conjugated bilirubin is water soluble and is transported
from liver hepatocytes into the biliary tract system where
it passes to the intestines and is excreted into the stool.
Some conjugated bilirubin is reabsorbed in the intestines
and is excreted by the kidneys as urobilinogen.
• Jaundice occurs when there are disruptions along this
metabolic pathway, causing an increase in unconjugated
bilirubin (e.g., from increased red blood cell destruction or
impaired bilirubin conjugation) or conjugated bilirubin
(e.g., from hepatocellular damage or biliary tract
obstructions).
• Alcoholic fatty liver represents the mildest category where very few changes in liver function are measurable.
This stage is characterized by slight elevations in AST, ALT, and γ-glutamyltransferase (GGT), and on biopsy,
fatty infiltrates are noted in the vacuoles of the liver. This stage tends to affect young to middleaged people with
a history of moderate alcohol consumption. A complete recovery within 1 month is seen when the drug is
removed. Alcoholic hepatitis presents with common signs and symptoms including fever, ascites, proximal
muscle loss, and far more laboratory evidence of liver damage such as moderately elevated AST, ALT, GGT, and
alkaline phosphatase (ALP) and elevations in total bilirubin greater than 5 mg/dL. The elevations in AST are
more than twice the upper reference of normal but rarely exceed 300 IU/mL. The elevations in ALT are
comparatively lower than AST, resulting in an AST/ALT ratio (De Ritis ratio) greater than 2. Serum proteins,
especially albumin, are decreased and the international normalized ratio (INR, which is a ratio of coagulation
time in the patient compared with a normal coagulation time) is elevated. Prognosis is dependent on the type
and severity of damage to the liver, and when serum creatinine levels begin to increase, it is a threatening sign,
which may precede the onset of hepatorenal syndrome and death. 34 There are a variety of scoring systems
that have been used to assess the severity of alcoholic hepatitis and to guide treatment including the Maddrey's
discriminant function, 35 the Glasgow score, 36 and the Model for End-Stage Liver Disease (MELD) score. 37
All three scoring systems use bilirubin, INR, creatinine, age, white cell counts, blood urea nitrogen, and albumin
levels to stage and guide treatment. The last and most severe stage is alcoholic cirrhosis. The prognosis
associated with alcoholic cirrhosis is dependent on the nature and severity of associated conditions such as a
gastrointestinal bleeding or ascites; however, the 5-year survival rate is 60% in those who abstain from alcohol
and 30% in those who continue to drink. This condition appears to be more common in males than in females,
and the symptoms tend to be nonspecific and include weight loss, weakness, hepatomegaly, splenomegaly,
jaundice, ascites, fever, malnutrition, and edema. Laboratory abnormalities include increased liver function tests
(AST, ALT, GGT, ALP, and total bilirubin), decreased albumin, and a prolonged prothrombin time. A liver biopsy is
the only method by which a definitive diagnosis may be made.
• Other drugs, including tranquilizers, some
antibiotics, antineoplastic agents, lipid-lowering
medication, and anti-inflammatory drugs, may
cause liver injury ranging from mild damage to
massive hepatic failure and cirrhosis. One of
the most common drugs associated with
serious hepatic injury is acetaminophen. When
acetaminophen is taken in massive doses, it is
virtually certain to produce fatal hepatic
necrosis unless rapid treatment is initiated.
• Infants with this type of jaundice are usually treated with phototherapy to destroy the bilirubin as
it passes through the capillaries of the skin.
• Since it was first described in 1958, phototherapy has been effectively used as a relatively
inexpensive and noninvasive method of treating neonatal hyperbilirubinemia through photo
oxidation. Conventional phototherapy lowers serum bilirubin levels by using halogen or
fluorescent lights to transform bilirubin into watersoluble isomers that can be eliminated without
conjugation in the liver.
• During phototherapy, the baby is undressed so that as much of the skin as possible is exposed
to the light, his/her eyes are covered to protect the nerve layer at the back of the eye (retina)
from the bright light, and the bilirubin levels are measured at least once a day. Alternatively,
fiberoptic phototherapy is also available via a blanket, called a bili-blanket, that consists of a
pad of woven fibers used to transport light from a light source to the baby's back. The light
generated through the bili-blanket breaks down the bilirubin through photo oxidation. The dose
of phototherapy is a key factor in how quickly it works and the dose is determined by the
wavelength of the light, the intensity of the light (irradiance), the distance between the light and
the baby, and the body surface area exposed to the light. Commercially available phototherapy
systems include those that deliver light via fluorescent bulbs, halogen quartz lamps,
lightemitting diodes, and fiberoptic mattresses. In extreme cases of hyperbilirubinemia, an
exchange transfusion may be used as the second-line treatment when phototherapy fails. An
exchange transfusion involves removing aliquots of blood and replacing it with donor blood in
order to remove abnormal blood components and circulating toxins while maintaining adequate
circulating blood volume. Because hyperbilirubinemia is so serious in newborns, bilirubin levels
are carefully and frequently monitored so the dangerously high levels of unconjugated bilirubin
(approximately 20 mg/dL) can be detected and treated appropriately.
 LIVER FUNCTION ALTERATIONS
DURING DISEASE
• Jaundice
• Cirrhosis
• Tumors
• Reye's Syndrome
• Drug- and Alcohol-Related Disorders
 Introduction
• The normal adult liver weighs 1400 to 1600 gm.

Circulatory:
• portal vein providing 60% to 70% of hepatic blood flow,
hepatic artery supplying the remaining 30% to 40%.
↓
• Portal vein and the hepatic artery enter the inferior
aspect of the liver through the hilum, or porta hepatis.
• branches of the portal veins, hepatic arteries, and bile
ducts travel in parallel within portal tracts, ramifying
variably through 10 to 12 orders of branches.
Hepatic microarchitecture:
• lobular model: drawn as
hexagonal structures, divides
the liver into lobules 1- to 2-
mm in diameter that are
centered on a terminal
tributary of the hepatic vein
and demarcated by portal
tracts at their periphery.
• triangular acini: divides the
liver based on position of
hepatocytes relative to their
blood supply. nity of the
terminal hepatic vein are
called centrilobular; those near
the portal tract are periportal.
• Within the lobule, hepatocytes are organized into anastomosing sheets or
“plates” extending from portal tracts to the terminal hepatic veins.
• Between the trabecular plates of hepatocytes are vascular sinusoids. Blood
traverses the sinusoids and exits into the terminal hepatic veins through
numerous orifices in the vein wall. Hepatocytes are thus bathed by well-mixed
portal venous blood on one side and hepatic arterial blood on the other.
• The sinusoids are lined by a fenestrated endothelium that overlies a
perisinusoidal space (the space of Disse) into which abundant hepatocyte
microvilli protrude.
• Attached to the luminal face of the sinusoids are scattered Kupffer cells,
specialized long-lived tissue macrophages that arise early in embryogenesis.
• Another specialized cell type, the hepatic stellate cell, is found in the space of
Disse and has a role in the storage of vitamin A.
• Between abutting hepatocytes are bile canaliculi, channels 1 to 2 μm in
diameter that are formed by grooves in the plasma membranes of adjacent
hepatocytes and are separated from the vascular space by tight junctions.
These channels drain successively into the intralobular canals of Hering,
periportal bile ductules, and finally into the terminal bile ducts within the portal
tracts.
• Inflammation and immunologic reactions are involved in
many forms of liver disease.

• Systemic inflammation alters the metabolic and

biosynthetic activities of the liver, leading to increased
secretion of acute-phase reactants such as C-reactive
protein, serum amyloid A protein (a precursor of some
forms of amyloid) and hepcidin, a key regulator of iron
metabolism).

• Adaptive immune cells play a critical role in viral hepatitis,

with CD4+ and CD8+ T cells being particularly important
in the eradication of virus-infected hepatocytes and, in
chronic disease, liver injury.
• Although the terms jaundice and icterus
are used interchangeably, the term
icterus is most commonly used in the
clinical laboratory to refer to a serum or
plasma sample with a yellow
discoloration due to an elevated bilirubin
level.
• Jaundice is most commonly classified based on the site of the
disorder: prehepatic jaundice, hepatic jaundice, and posthepatic
jaundice.
• This classification is important because knowing the classification
of jaundice will aid health care providers in formulating an
appropriate treatment or management plan.
• Prehepatic and posthepatic jaundice, as the names imply, are
caused by abnormalities outside the liver, either before, as in
“prehepatic,” or after, as in “posthepatic.” In these conditions, liver
function is normal or it may be functioning at a maximum to
compensate for abnormalities occurring elsewhere.
• This is not the case with hepatic jaundice, where the jaundice is
due to a problem with the liver itself—an intrinsic liver defect or
disease.
 Prehepatic Jaundice
• Occurs when the problem causing the jaundice occurs prior to liver
metabolism.
• It is most commonly caused by an increased amount of bilirubin being
presented to the liver such as that seen in acute and chronic hemolytic
anemias.
• Hemolytic anemia causes an increased amount of red blood cell
destruction and the subsequent release of increased amounts of bilirubin
presented to the liver for processing.
• The liver responds by functioning at maximum capacity; therefore, people
with prehepatic jaundice rarely have bilirubin levels that exceed 5.0 mg/dL
because the liver is capable of handling the overload. This type of jaundice
may also be referred to as unconjugated hyperbilirubinemia because the
fraction of bilirubin increased in people with prehepatic jaundice is the
unconjugated fraction. This fraction of bilirubin (unconjugated bilirubin) is
not water soluble, is bound to albumin, is not filtered by the kidneys, and is
not seen in the urine.
 Hepatic jaundice
• occurs when the primary problem causing the jaundice
resides in the liver (intrinsic liver defect or disease).
• This intrinsic liver defect or disease can be due to disorders
of bilirubin metabolism and transport defects (Crigler-Najjar
syndrome, Dubin-Johnson syndrome, Gilbert's disease, and
neonatal physiologic jaundice of the newborn) or due to
diseases resulting in hepatocellular injury or destruction.
Gilbert's disease, Crigler-Najjar syndrome, and physiologic
jaundice of the newborn are hepatic causes of jaundice that
result in elevations in unconjugated bilirubin. Conditions
such as Dubin-Johnson and Rotor's syndrome are hepatic
causes of jaundice that result in elevations in conjugated
bilirubin
 Gilbert's syndrome
• Gilbert's syndrome, first described in the early twentieth
century, is a benign autosomal recessive hereditary
disorder that affects approximately 5% of the US
population.
• Gilbert's syndrome results from a genetic mutation in
the UGT1A1 gene that produces the enzyme uridine
diphosphate glucuronosyltransferase, one of the
enzymes important for bilirubin metabolism. The
UGT1A1 gene is located on chromosome 2, and other
mutations of this same gene produce Crigler-Najjar
syndrome, a more severe and dangerous form of
hyperbilirubinemia. 6
 Gilbert's syndrome
• Of the many causes of jaundice, is the most common cause, and
interestingly, it carries no morbidity or mortality in the majority of those
affected and carries generally no clinical consequences. It is characterized
by intermittent unconjugated hyperbilirubinemia, underlying liver disease
due to a defective conjugation system in the absence of hemolysis. The
hyperbilirubinemia usually manifests during adolescence or early
adulthood. Total serum bilirubin usually fluctuates between 1.5 and 3.0
mg/dL, and it rarely exceeds 4.5 mg/dL. The molecular basis of Gilbert's
syndrome (in whites) is related to the UDPGT superfamily, which is
responsible for encoding enzymes that catalyze the conjugation of bilirubin.
The UGT1A1 (the hepatic 1A1 isoform of UDPGT) contributes substantially
to the process of conjugating bilirubin. The UGT1A1 promoter contains the
sequence (TA)6TAA. The insertion of an extra TA in the sequence, as seen
in Gilbert's syndrome, reduces the expression of the UGT1A1 gene to 20%
to 30% of normal values. That is, the liver's conjugation system in Gilbert's
syndrome is working at approximately 30% of normal. 7,8
 Crigler-Najjar syndrome
• was first described by Crigler and Najjar in 1952 as a
syndrome of chronic nonhemolytic unconjugated
hyperbilirubinemia. 9 Crigler-Najjar syndrome, like Gilbert's
syndrome, is an inherited disorder of bilirubin metabolism
resulting from a molecular defect within the gene involved
with bilirubin conjugation. Crigler-Najjar syndrome may be
divided into two types: type 1, where there is a complete
absence of enzymatic bilirubin conjugation, and type II,
where there is a mutation causing a severe deficiency of
the enzyme responsible for bilirubin conjugation. Unlike
Gilbert's syndrome, Crigler-Najjar syndrome is rare and is a
more serious disorder that may result in death. 10
• While Gilbert's disease and Crigler-Najjar syndrome are characterized as primarily
unconjugated hyperbilirubinemias, Dubin-Johnson syndrome and Rotor's syndrome are
characterized as conjugated hyperbilirubinemias. DubinJohnson syndrome is a rare
autosomal recessive inherited disorder caused by a deficiency of the canalicular
multidrug resistance/multispecific organic anionic transporter protein (MDR2/cMOAT). In
other words, the liver's ability to uptake and conjugate bilirubin is functional; however,
the removal of conjugated bilirubin from the liver cell and the excretion into the bile are
defective. This results in accumulation of conjugated and, to some extent, unconjugated
bilirubin in the blood, leading to hyperbilirubinemia and bilirubinuria. DubinJohnson is a
condition that is obstructive in nature, so much of the conjugated bilirubin circulates
bound to albumin. This type of bilirubin (conjugated bilirubin bound to albumin) is
referred to as delta bilirubin. An increase in delta bilirubin poses a problem in laboratory
evaluation because the delta bilirubin fraction reacts as conjugated bilirubin in the
laboratory method to measure conjugated or direct bilirubin. A distinguishing feature of
Dubin-Johnson syndrome is the appearance of dark-stained granules (thought to be
pigmented lysosomes) on a liver biopsy sample. Usually, the total bilirubin concentration
remains between 2 and 5 mg/dL, with more than 50% due to the conjugated fraction.
This syndrome is relatively mild in nature with an excellent prognosis. People with
Dubin-Johnson syndrome have a normal life expectancy, so no treatment is necessary
 Rotor's syndrome
• is clinically similar to Dubin-Johnson syndrome, but the
defect causing Rotor's syndrome is not known.
• It is hypothesized to be due to a reduction in the
concentration or activity of intracellular binding proteins such
as ligandin.
• Unlike in Dubin-Johnson syndrome, a liver biopsy does not
show dark pigmented granules. Rotor's syndrome is seen
less commonly than Dubin Johnson syndrome; it is a
relatively benign condition and carries an excellent
prognosis, and therefore, treatment is not warranted.
• However, an accurate diagnosis is required to aid in
distinguishing it from more serious liver diseases that require
treatment
 Posthepatic jaundice
• results from biliary obstructive disease, usually from
physical obstructions (gallstones or tumors) that
prevent the flow of conjugated bilirubin into the bile
canaliculi. Since the liver cell itself is functioning,
bilirubin is effectively conjugated; however, it is unable
to be properly excreted from the liver. Since bile is not
being brought to the intestines, stool loses its source of
normal pigmentation and becomes clay-colored. The
laboratory findings for bilirubin and its metabolites in
the abovementioned types of jaundice are summarized
in Table 25.1. Mechanisms of hyperbilirubinemia may
be found in Figure 25.6.
Jaundice or hyperbilirubinemia is
not itself a disease but rather is a sign.
These disorders are classified in three
groups:
1. prehepatic
2. hepatic
3. posthepatic
 Prehepatic jaundice
• Results from excessive destruction of red
blood cells and is characteristic of hemolytic
anemias or transfusion reactions.
• Liver function is normal but unable to handle
additional bilirubin.
• Physiologic jaundice of the newborn is common
2 to 3 days after birth.
• Increased hemolysis of red blood cells
combined with the immature infant liver leads to
a transient mild hyperbilirubinemia.
 Intrahepatic jaundice
• Occurs in individuals with liver disease,
such as hepatitis or cirrhosis.
• Related to impaired uptake of bilirubin
from the blood and decreased
conjugation of bilirubin by the
hepatocytes
• Cause: disorders of bilirubin metabolism
and transport defects or due to diseases
resulting in hepatocellular injury or
destruction.
• Gilbert's disease, Crigler-Najjar
syndrome, and physiologic jaundice of
the newborn  elevations in
unconjugated bilirubin.
• Dubin-Johnson and Rotor's syndrome
a elevations in conjugated bilirubin
 Gilbert's syndrome
• Benign autosomal recessive hereditary disorder that
affects approximately 5% of the US population.
• Genetic mutation in the UGT1A1 gene that produces the
enzyme uridine diphosphate glucuronosyltransferase, one
of the enzymes important for bilirubin metabolism.
• UGT1A1 gene is located on chromosome 2, and other
mutations of this same gene produce Crigler-Najjar
syndrome
• The hyperbilirubinemia usually manifests during
adolescence or early adulthood.
• Total serum bilirubin usually fluctuates between 1.5 and
3.0 mg/dL, and it rarely exceeds 4.5 mg/dL.
 Crigler-Najjar syndrome
• First described by Crigler and Najjar in 1952 as a syndrome
of chronic nonhemolytic unconjugated hyperbilirubinemia.
• Inherited disorder of bilirubin metabolism resulting from a
molecular defect within the gene involved with bilirubin
conjugation.
• Divided into two types:
– type 1: a complete absence of enzymatic bilirubin conjugation,
and
– type 2: mutation causing a severe deficiency of the enzyme
responsible for bilirubin conjugation.
• Rare and is a more serious disorder that may result in
death.
 Dubin-Johnson syndrome
• Rare autosomal recessive inherited disorder
• Deficiency of the canalicular multidrug resistance/multispecific
organic anionic transporter protein (MDR2/cMOAT) 
accumulation of conjugated and unconjugated bilirubin in the
blood, leading to hyperbilirubinemia and bilirubinuria.
• Obstructive in nature, so much of the conjugated bilirubin
circulates bound to albumin  delta bilirubin  an increase
poses a problem in laboratory evaluation because the delta
bilirubin fraction reacts as conjugated bilirubin in the laboratory
method to measure conjugated or direct bilirubin.
• Dark-stained granules (thought to be pigmented lysosomes)
on a liver biopsy sample.
• Relatively mild in nature with an excellent prognosis.
 Rotor's syndrome
• Clinically similar to Dubin-Johnson syndrome,
but the defect causing Rotor's syndrome is not
known.
• It is hypothesized to be due to a reduction in the
concentration or activity of intracellular binding
proteins such as ligandin.
• Unlike in Dubin-Johnson syndrome, a liver
biopsy does not show dark pigmented granules.
• Seen less commonly; relatively benign condition
and carries an excellent prognosis
Physiologic jaundice of the newborn

• Result of a deficiency in the enzyme

UDPGT, one of the last liver functions to
be activated in prenatal life since bilirubin
processing is handled by the mother of the
fetus.
• Premature infants may be born without
UDPGT, the enzyme responsible for
bilirubin conjugation.
• Results in the rapid buildup of unconjugated
bilirubin, which can be life threatening 
When builds up in the neonate, deposited in
the nuclei of brain and degenerate nerve
cells  kernicterus.
• Kernicterus often results in cell damage and
death in the newborn, and this condition will
continue until UDPGT is produced.
• Treated with phototherapy to destroy the
bilirubin as it passes through the capillaries
of the skin.
 Posthepatic jaundice
• Caused by obstruction of bile flow into the gallbladder
or duodenum and subsequent backup of bile into the
blood.
• Since the liver cell itself is functioning, bilirubin is
effectively conjugated; however, it is unable to be
properly excreted from the liver.
• Since bile is not being brought to the intestines, stool
loses its source of normal pigmentation and becomes
clay-colored.
• Cause: congenital atresia of the bile ducts, obstruction
caused by cholelithiasis, inflammation of the liver, or
tumors.