ACADEMIC

AND
ACUTE VIRAL HEPATITIS

A. Definition
Acute viral hepatitis is a systemic infection affecting the liver predominantly. Almost
all cases of acute viral hepatitis are caused by one of five viral agents: hepatitis A
virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the HBV-associated delta
agent or hepatitis D virus (HDV), and hepatitis E virus (HEV).
Other transfusion-transmitted agents (e.g., "hepatitis G" virus and "TT" virus, have
been identified but do not cause hepatitis). All these human hepatitis viruses are
RNA viruses, except for hepatitis B, which is a DNA virus.
Although these agents can be distinguished by their molecular and antigenic
properties, all types of viral hepatitis produce clinically similar illnesses. These range
from asymptomatic and inapparent to fulminant and fatal acute infections common
to all types, on the one hand, and from subclinical persistent infections to rapidly
progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma,
common to the bloodborne types (HBV, HCV, and HDV), on the other.

B. Virology and Etiology

1. HEPATITIS A
o Hepatitis A virus is a nonenveloped 27-nm, heat-, acid-, and ether-resistant RNA
virus in the Hepatovirus genus of the picornavirus family.
o Its virion contains four capsid polypeptides, designated VP1 to VP4, which are
cleaved posttranslationally from the polyprotein product of a 7500-nucleotide
genome. Inactivation of viral activity can be achieved by boiling for 1 minute, by
contact with formaldehyde and chlorine, or by ultraviolet irradiation.
o Hepatitis A has an incubation period of 4 weeks. Its replication is limited to the
liver, but the virus is present in the liver, bile, stools, and blood during the late
incubation period and acute preicteric phase of illness. Despite persistence of
virus in the liver, viral shedding in feces, viremia, and infectivity diminish rapidly
once jaundice becomes apparent.
o Antibodies to HAV (anti-HAV) can be detected during acute illness when serum
aminotransferase activity is elevated and fecal HAV shedding is still occurring.
This early antibody response is predominantly of the IgM class and persists for
several months, rarely for 6-12 months. During convalescence, however, anti-HAV
of the IgG class becomes the predominant antibody

2. HEPATITIS B
o Hepatitis B virus is a DNA virus with a remarkably compact genomic structure;
despite its small, circular, 3200-bp size, HBV DNA codes for four sets of viral
products with a complex, multiparticle structure.
o Once thought to be unique among viruses, HBV is now recognized as one of a
family of animal viruses, hepadnaviruses (hepatotropic DNA viruses), and is
classified as hepadnavirus type 1.
o The envelope protein expressed on the outer surface of the virion and on the
smaller spherical and tubular structures is referred to as hepatitis B surface
antigen (HBsAg).
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o The antigen expressed on the surface of the nucleocapsid core is referred to as
hepatitis B core antigen (HBcAg), and its corresponding antibody is anti-HBc.
o A third HBV antigen is hepatitis B e antigen (HBeAg), a soluble, nonparticulate,
nucleocapsid protein that is immunologically distinct from intact HBcAg but is a
product of the same C gene.
o After a person is infected with HBV, the first virologic marker detectable in serum
within 1-12 weeks, usually between 8-12 weeks, is HBsAg. Circulating HBsAg
precedes elevations of serum aminotransferase activity and clinical symptoms by
2-6 weeks and remains detectable during the entire icteric or symptomatic phase
of acute hepatitis B and beyond. In typical cases, HBsAg becomes undetectable 1-
2 months after the onset of jaundice and rarely persists beyond 6 months. After
HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum
and remains detectable indefinitely thereafter.
o Because HBcAg is intracellular and, when in the serum, sequestered within an
HBsAg coat, naked core particles do not circulate in serum and, therefore, HBcAg
is not detectable routinely in the serum of patients with HBV infection. By
contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1-2
weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs
by weeks to months
o Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first six months
after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc
beyond six months.

ACU
TE
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o Departing from the pattern typical of acute HBV infections, in chronic HBV
infection, HBsAg remains detectable beyond six months, anti-HBc is primarily of
the IgG class, and anti-HBs is either undetectable or detectable at low levels
o During early chronic HBV infection, HBV DNA can be detected both in serum and
in hepatocyte nuclei, where it is present in free or episomal form. This replicative
stage of HBV infection is the time of maximal infectivity and liver injury; HBeAg is
a qualitative marker and HBV DNA a quantitative marker of this replicative phase,
during which all three forms of HBV circulate, including intact virions. Over time,
the replicative phase of chronic HBV infection gives way to a relatively
nonreplicative phase. This occurs at a rate of 10% per year and is accompanied by
seroconversion from HBeAg-positive to anti-HBe-positive. In most cases, this
seroconversion coincides with a transient, acute hepatitis-like elevation in
aminotransferase activity, believed to reflect cell-mediated immune clearance of
virus-infected hepatocytes.

CH
RO
NI
C

o Hepatitis B antigens and HBV DNA have been identified in extrahepatic sites,
including lymph nodes, bone marrow, circulating lymphocytes, spleen, and
pancreas. Although the virus does not appear to be associated with tissue injury
in any of these extrahepatic sites, its presence in these "remote" reservoirs has
been invoked (but is not necessary) to explain the recurrence of HBV infection
after orthotopic liver transplantation.
 ACADEMIC
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3. HEPATITIS D
o The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a
defective RNA virus that coinfects with and requires the helper function of HBV
(or other hepadnaviruses) for its replication and expression.
o HDV can either infect a person simultaneously with HBV (co-infection) or
superinfect a person already infected with HBV (super-infection); when HDV
infection is transmitted from a donor with one HBsAg subtype to an HBsAg-
positive recipient with a different subtype, the HDV agent assumes the HBsAg
subtype of the recipient, rather than the donor. Because HDV relies absolutely on
HBV, the duration of HDV infection is determined by the duration of (and cannot
outlast) HBV infection.

4. HEPATITIS C
o Hepatitis C virus, which, before its identification was labeled "non-A, non-B
hepatitis," is a linear, single-strand, positive-sense, 9600-nucleotide RNA virus,
the genome of which is similar in organization to that of flaviviruses and
pestiviruses; HCV is the only member of the genus Hepacivirus in the family
Flaviviridae.

HEPATITIS C VIRUS GENOME

5. HEPATITIS E
o Previously labeled epidemic or enterically transmitted non-A, non-B hepatitis,
HEV is an enterically transmitted virus that occurs primarily in India, Asia, Africa,
and Central America; in those geographic areas, HEV is the most common cause
of acute hepatitis.
o There is no genomic or antigenic homology, however, between HEV and HAV or
other picornaviruses; and HEV, although resembling caliciviruses, is sufficiently
distinct from any known agent to merit a new classification of its own as a unique
genus, Hepevirus, within the family Hepeviridae.
o The virus has been detected in stool, bile, and liver and is excreted in the stool
during the late incubation period; immune responses to viral antigens occur very
early during the course of acute infection. Both IgM anti-HEV and IgG anti-HEV
can be detected, but both fall rapidly after acute infection, reaching low levels
 ACADEMIC
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within 9-12 months. Currently, serologic testing for HEV infection is not available
routinely.

Table 304-1 Nomenclature and Features of Hepatitis Viruses

Hepatiti Classification Antigen(s) Antibodie Remarks
s Type s
HAV Hepatovirus HAV Anti-HAV - Early fecal shedding
- Diagnosis: IgM anti-HAV
- Previous infection: IgG anti-HAV
HBV Hepadnavirus HBsAg Anti-HBs - Bloodborne virus; carrier state
HBcAg Anti-HBc - Acute diagnosis: HBsAg, IgM anti-HBc
HBeAg Anti-HBe - Chronic diagnosis: IgG anti-HBc, HBsAg
- Markers of replication: HBeAg, HBV DNA
- Liver, lymphocytes, other organs
HBcAg Anti-HBc - Nucleocapsid contains DNA and DNA polymerase
HBeAg Anti-HBe - Present in hepatocyte nucleus;
- HBcAg does not circulate
- HBeAg (soluble, nonparticulate) and HBV DNA circulate-correlate
with infectivity and complete virions

HBsAg Anti-HBs - HBsAg detectable in >95% of patients with acute hepatitis B

- Found in serum, body fluids, hepatocyte cytoplasm
- Anti-HBs appears following infection-protective antibody
HCV Hepacivirus HCV Anti-HCV - Bloodborne agent, formerly labeled non-A, non-B hepatitis
C100-3 - Acute diagnosis: anti-HCV (C33c, C22-3, NS5), HCV RNA
C33c - Chronic diagnosis: anti-HCV (C100-3, C33c, C22-3, NS5) and HCV
C22-3 RNA; cytoplasmic location in hepatocytes
NS5
HDV Resembles HBsAg Anti-HBs - Defective RNA virus, requires helper function of HBV
viroids and HDV Anti-HDV (hepadnaviruses)
plant satellite antigen - HDV antigen present in hepatocyte nucleus
viruses - Diagnosis: anti-HDV, HDV RNA; HBV/HDV coinfection-IgM anti-HBc
and anti-HDV; HDV superinfection-IgG anti-HBc and anti-HDV

HEV Hepevirus HEV Anti-HEV - Agent of enterically transmitted hepatitis

antigen - Rare in USA; occurs in Asia, Mediterranean countries, Central
America
- Diagnosis: IgM/IgG anti-HEV (assays not routinely available); virus
in stool, bile, hepatocyte cytoplasm
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C. Pathogenesis
1. HEPATITIS B
o For HBV, the existence of inactive hepatitis B carriers with normal liver histology
and function suggests that the virus is not directly cytopathic. The fact that
patients with defects in cellular immune competence are more likely to remain
chronically infected rather than to clear HBV supports the role of cellular immune
responses in the pathogenesis of hepatitis B-related liver injury.
o Nucleocapsid proteins (HBcAg and possibly HBeAg), present on the cell
membrane in minute quantities, are the viral target antigens that, with host
antigens, invite cytolytic T cells to destroy HBV-infected hepatocytes.
o Under the influence of the potent immunosuppressive agents required to
prevent allograft rejection, HBV may have a direct cytopathic effect on liver cells,
independent of the immune system.
o Although the precise mechanism of liver injury in HBV infection remains elusive,
studies of nucleocapsid proteins have shed light on the profound immunologic
tolerance to HBV of babies born to mothers with highly replicative (HBeAg-
positive), chronic HBV infection. This, in turn, may explain why, when infection
occurs so early in life, immunologic clearance does not occur, and protracted,
lifelong infection ensues.
o An important distinction should be drawn between HBV infection acquired at
birth and infection acquired in adulthood. Infection in the neonatal period is
associated with the acquisition of immunologic tolerance to HBV, absence of an
acute hepatitis illness, but the almost invariable establishment of chronic, often
lifelong infection. Neonatally acquired HBV infection can culminate decades later
in cirrhosis and hepatocellular carcinoma.
o In contrast, when HBV infection is acquired during adolescence or early
adulthood, the host immune response to HBV infected hepatocytes tends to be
robust, an acute hepatitis-like illness is the rule, and failure to recover is the
exception. After adulthood acquired infection, chronicity is uncommon, and the
risk of hepatocellular carcinoma is very low.
o Based on these observations, some authorities categorize HBV infection into an
"immunotolerant" phase, an "immunoreactive" phase, and an "inactive" phase.
o Even among those with neonatally acquired HBV infection, in whom immunologic
tolerance is established definitively, intermittent bursts of hepatic
necroinflammatory activity punctuate the period during the early decades of life
during which liver injury appears to be quiescent (labeled by some as the
"immunotolerant" phase).
o In addition, even when clinically apparent, liver injury and progressive fibrosis
emerge during later decades (the so-called immunoreactive, or
immunointolerant phase), the level of immunologic tolerance to HBV remains
substantial.
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o More accurately, in patients with neonatally acquired HBV infection, a dynamic
equilibrium exists between tolerance and intolerance, the outcome of which
determines the clinical expression of chronic infection.
o Those individuals who are infected as neonates tend to have a relatively higher
level of immunologic tolerance during the early decades of life and a relatively
lower level (but only rarely a loss) of tolerance in the later decades of life.

2. HEPATITIS C
o Cell-mediated immune responses and elaboration by T cells of antiviral cytokines
contribute to the containment of infection and pathogenesis of liver injury
associated with hepatitis C. Perhaps HCV infection of lymphoid cells plays a role
in moderating immune responsiveness to the virus, as well.
o Intrahepatic HLA class I restricted cytolytic T cells directed at nucleocapsid,
envelope, and nonstructural viral protein antigens have been demonstrated in
patients with chronic hepatitis C; however, such virus-specific cytolytic T cell
responses do not correlate adequately with the degree of liver injury or with
recovery.
o Yet, a consensus has emerged supporting a role in the pathogenesis of HCV-
associated liver injury of virus-activated CD4 helper T cells that stimulate, via the
cytokines they elaborate, HCV-specific CD8 cytotoxic T cells.
o Although attention has focused on adaptive immunity, HCV proteins have been
shown to interfere with innate immunity by resulting in blocking of type 1
interferon responses and inhibition of interferon signaling and effector molecules
in the interferon signaling cascade.
o Also shown to contribute to limiting HCV infection are natural killer cells of the
innate immune system that function when HLA class 1 molecules required for
successful adaptive immunity are underexpressed. Of note, the emergence of
substantial viral quasispecies diversity and HCV sequence variation allow the virus
to evade attempts by the host to contain HCV infection by both humoral and
cellular immunity.
o Finally, cross-reactivity between viral antigens (HCV NS3 and NS5A) and host
autoantigens (cytochrome P450 2D6) has been invoked to explain the association
between hepatitis C and a subset of patients with autoimmune hepatitis and
antibodies to liver-kidney microsomal (LKM) antigen (anti-LKM)

D. Extrahepatic Manifestation
Immune complex-mediated tissue damage appears to play a pathogenetic role in the
extrahepatic manifestations of acute hepatitis B. The occasional prodromal serum
sickness-like syndrome observed in acute hepatitis B appears to be related to the
deposition in tissue blood vessel walls of HBsAg-anti-HBs circulating immune
complexes, leading to activation of the complement system and depressed serum
complement levels.
In patients with chronic hepatitis B, other types of immune-complex disease may be
seen. Glomerulonephritis with the nephrotic syndrome is observed occasionally;
HBsAg, immunoglobulin, and C3 deposition has been found in the glomerular
basement membrane.
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While generalized vasculitis (polyarteritis nodosa) develops in considerably fewer

than 1% of patients with chronic HBV infection, 20-30% of patients with polyarteritis
nodosa have HBsAg in serum. In these patients, the affected small- and medium-size
arterioles contain HBsAg, immunoglobulins, and complement components.
Another extrahepatic manifestation of viral hepatitis, essential mixed
cryoglobulinemia (EMC), was reported initially to be associated with hepatitis B. The
disorder is characterized clinically by arthritis; cutaneous vasculitis (palpable
purpura); and, occasionally, with glomerulonephritis and serologically by the
presence of circulating cryoprecipitable immune complexes of more than one
immunoglobulin class. Many patients with this syndrome have chronic liver disease,
but the association with HBV infection is limited; instead, a substantial proportion
has chronic HCV infection, with circulating immune complexes containing HCV RNA.
Immune-complex glomerulonephritis is another recognized extrahepatic
manifestation of chronic hepatitis C.

E. Pathology
The typical morphologic lesions of all types of viral hepatitis are similar and consist of
panlobular infiltration with mononuclear cells, hepatic cell necrosis, hyperplasia of
Kupffer cells, and variable degrees of cholestasis.
Hepatic cell regeneration is present, as evidenced by numerous mitotic figures,
multinucleated cells, and "rosette" or "pseudoacinar" formation.
The mononuclear infiltration consists primarily of small lymphocytes, although
plasma cells and eosinophils occasionally are present.
Liver cell damage consists of hepatic cell degeneration and necrosis, cell dropout,
ballooning of cells, and acidophilic degeneration of hepatocytes (forming so-called
Councilman or apoptotic bodies).
Large hepatocytes with a ground-glass appearance of the cytoplasm may be seen in
chronic but not in acute HBV infection; these cells contain HBsAg and can be
identified histochemically with orcein or aldehyde fuchsin. In uncomplicated viral
hepatitis, the reticulin framework is preserved.
In hepatitis C, the histologic lesion is often remarkable for a relative paucity of
inflammation, a marked increase in activation of sinusoidal lining cells, lymphoid
aggregates, the presence of fat (more frequent in genotype 3 and linked to increased
fibrosis), and, occasionally, bile duct lesions in which biliary epithelial cells appear to
be piled up without interruption of the basement membrane.
Occasionally, microvesicular steatosis occurs in hepatitis D. In hepatitis E, a common
histologic feature is marked cholestasis. A cholestatic variant of slowly resolving
acute hepatitis A also has been described.
A more severe histologic lesion, bridging hepatic necrosis, also termed subacute or
confluent necrosis or interface hepatitis, is observed occasionally in acute hepatitis.
"Bridging" between lobules results from large areas of hepatic cell dropout, with
collapse of the reticulin framework. Characteristically, the bridge consists of
condensed reticulum, inflammatory debris, and degenerating liver cells that span
adjacent portal areas, portal to central veins, or central vein to central vein. This
lesion had been thought to have prognostic significance; in many of the originally
described patients with this lesion, a subacute course terminated in death within
several weeks to months, or severe chronic hepatitis and cirrhosis developed;
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however, the association between bridging necrosis and a poor prognosis in patients
with acute hepatitis has not been upheld.
In massive hepatic necrosis (fulminant hepatitis, "acute yellow atrophy"), the striking
feature at postmortem examination is the finding of a small, shrunken, soft liver.
Histologic examination reveals massive necrosis and dropout of liver cells of most
lobules with extensive collapse and condensation of the reticulin framework.

F. Global Features

Table 304-2 Clinical and Epidemiologic Features of Viral Hepatitis

Feature HAV HBV HCV HDV HEV
Incubation 15-45, mean 30 30-180, mean 60-90 15-160, mean 50 30-180, mean 60-90 14-60, mean
(days) 40
Onset Acute Insidious or acute Insidious Insidious or acute Acute
Age preference Children, young Young adults (sexual Any age, but more Any age (similar to Young adults
adults and percutaneous), common in adults HBV) (20-40 years)
babies, toddlers
Transmission
Fecal-oral +++ - - - +++
Percutaneous Unusual +++ +++ +++ -
Perinatal - +++ + -
Sexual ++ ++ -
Clinical
Severity Mild Occasionally severe Moderate Occasionally severe Mild
Fulminant 0.1% 0.1-1% 0.1% 5-20% 1-2%e
Progression to None Occasional (1-10%) Common (85%) Common None
chronicity (90% of neonates)
Carrier None 0.1-30% 1.5-3.2% Variable None
Cancer None +(Neonatal infection) + None
Prognosis Excellent Worse with age, Moderate Acute, good Good
debility Chronic, poor
Prophylaxis IG, inactivated HBIG, recombinant None HBV vaccine (none Vaccine
vaccine vaccine for HBV carriers)
Therapy None Interferon Pegylated interferon Interferon None
Lamivudine plus ribavirin
Adefovir telaprevir
Pegylated interferon boceprevir
Entecavir
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Telbivudine
Tenofovir

G. Clinical Manifestation
Acute viral hepatitis occurs after an incubation period that varies according to the
responsible agent. Generally, incubation periods for hepatitis A range from 15-45
days (mean, 4 weeks), for hepatitis B and D from 30-180 days (mean, 8-12 weeks), for
hepatitis C from 15-160 days (mean, 7 weeks), and for hepatitis E from 14-60 days
(mean, 5-6 weeks).

The prodromal symptoms of acute viral hepatitis are systemic and quite variable.
Constitutional symptoms of anorexia, nausea and vomiting, fatigue, malaise,
arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza may
precede the onset of jaundice by 1-2 weeks.
o The nausea, vomiting, and anorexia are frequently associated with alterations in
olfaction and taste.
o A low-grade fever between 38 and 39C (100-102F) is more often present in
hepatitis A and E than in hepatitis B or C, except when hepatitis B is heralded by a
serum sickness-like syndrome; rarely, a fever of 39.5-40C (103-104F) may
accompany the constitutional symptoms.
o Dark urine and clay-colored stools may be noticed by the patient from 1-5 days
before the onset of clinical jaundice.

With the onset of clinical jaundice, the constitutional prodromal symptoms usually
diminish, but in some patients mild weight loss (2.5-5 kg) is common and may
continue during the entire icteric phase.
o The liver becomes enlarged and tender and may be associated with right upper
quadrant pain and discomfort.
o nfrequently, patients present with a cholestatic picture, suggesting extrahepatic
biliary obstruction.
o Splenomegaly and cervical adenopathy are present in 10-20% of patients with
acute hepatitis.
o Rarely, a few spider angiomas appear during the icteric phase and disappear
during convalescence.
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During the recovery phase, constitutional symptoms disappear, but usually some
liver enlargement and abnormalities in liver biochemical tests are still evident. The
duration of the posticteric phase is variable, ranging 2-12 weeks, and is usually more
prolonged in acute hepatitis B and C.

Complete clinical and biochemical recovery is to be expected 1-2 months after all
cases of hepatitis A and E and 3-4 months after the onset of jaundice in three-
quarters of uncomplicated, self-limited cases of hepatitis B and C (among healthy
adults, acute hepatitis B is self-limited in 95-99% while hepatitis C is self-limited in
only 15%). In the remainder, biochemical recovery may be delayed. A substantial
proportion of patients with viral hepatitis never become icteric.

Infection with HDV can occur in the presence of acute or chronic HBV infection; the
duration of HBV infection determines the duration of HDV infection. When acute
HDV and HBV infection occur simultaneously, clinical and biochemical features may
be indistinguishable from those of HBV infection alone, although occasionally they
are more severe.
As opposed to patients with acute HBV infection, patients with chronic HBV infection
can support HDV replication indefinitely. This can happen when acute HDV infection
occurs in the presence of a nonresolving acute HBV infection. More commonly, acute
HDV infection becomes chronic when it is superimposed on an underlying chronic
HBV infection. In such cases, the HDV superinfection appears as a clinical
exacerbation or an episode resembling acute viral hepatitis in someone already
chronically infected with HBV. Superinfection with HDV in a patient with chronic
hepatitis B often leads to clinical deterioration.
In addition to superinfections with other hepatitis agents, acute hepatitis-like clinical
events in persons with chronic hepatitis B may accompany spontaneous HBeAg to
anti-HBe seroconversion or spontaneous reactivation (i.e., reversion from
nonreplicative to replicative infection).

H. Laboratory Features
The serum aminotransferases aspartate aminotransferase (AST) and ALT (previously
designated SGOT and SGPT) show a variable increase during the prodromal phase of
acute viral hepatitis and precede the rise in bilirubin level. The acute level of these
enzymes, however, does not correlate well with the degree of liver cell damage. Peak
levels vary from 400-4000 IU or more; these levels are usually reached at the time
the patient is clinically icteric and diminish progressively during the recovery phase of
acute hepatitis. The diagnosis of anicteric hepatitis is based on clinical features and
on aminotransferase elevations.

Jaundice is usually visible in the sclera or skin when the serum bilirubin value is >43
mol/L (2.5 mg/dL). When jaundice appears, the serum bilirubin typically rises to
levels ranging from 85-340 mol/L (5-20 mg/dL). The serum bilirubin may continue to
rise despite falling serum aminotransferase levels. In most instances, the total
bilirubin is equally divided between the conjugated and unconjugated fractions.
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Bilirubin levels >340 mol/L (20 mg/dL) extending and persisting late into the course
of viral hepatitis are more likely to be associated with severe disease.

Neutropenia and lymphopenia are transient and are followed by a relative

lymphocytosis. Atypical lymphocytes (varying between 2 and 20%) are common
during the acute phase. Measurement of the prothrombin time (PT) is important in
patients with acute viral hepatitis, for a prolonged value may reflect a severe hepatic
synthetic defect, signify extensive hepatocellular necrosis, and indicate a worse
prognosis. Occasionally, a prolonged PT may occur with only mild increases in the
serum bilirubin and aminotransferase levels.

Prolonged nausea and vomiting, inadequate carbohydrate intake, and poor hepatic
glycogen reserves may contribute to hypoglycemia noted occasionally in patients
with severe viral hepatitis.

Serum alkaline phosphatase may be normal or only mildly elevated, while a fall in
serum albumin is uncommon in uncomplicated acute viral hepatitis. In some
patients, mild and transient steatorrhea has been noted as well as slight microscopic
hematuria and minimal proteinuria.

A diffuse but mild elevation of the globulin fraction is common during acute viral
hepatitis. Serum IgG and IgM levels are elevated in about one-third of patients during
the acute phase of viral hepatitis, but the serum IgM level is elevated more
characteristically during acute hepatitis A. In hepatitis C and D, antibodies to LKM
may occur; however, the species of LKM antibodies in the two types of hepatitis are
different from each other as well as from the LKM antibody species characteristic of
autoimmune hepatitis type 2. The autoantibodies in viral hepatitis are nonspecific
and can also be associated with other viral and systemic diseases. In contrast, virus-
specific antibodies, which appear during and after hepatitis virus infection, are
serologic markers of diagnostic importance.

As described above, serologic tests are available with which to establish a diagnosis
of hepatitis A, B, D, and C. Tests for fecal or serum HAV are not routinely available.
Therefore, a diagnosis of hepatitis A is based on detection of IgM anti-HAV during
acute illness . Rheumatoid factor can give rise to false-positive results in this test.

A diagnosis of HBV infection can usually be made by detection of HBsAg in serum.

Infrequently, levels of HBsAg are too low to be detected during acute HBV infection,
even with contemporary, highly sensitive immunoassays. In such cases, the diagnosis
can be established by the presence of IgM anti-HBc. Another serologic marker that
may be of value in patients with hepatitis B is HBeAg. Its principal clinical usefulness
is as an indicator of relative infectivity. Because HBeAg is invariably present during
early acute hepatitis B, HBeAg testing is indicated primarily during follow-up of
chronic infection.

Anti-HBs is rarely detectable in the presence of HBsAg in patients with acute hepatitis
B, but 10-20% of persons with chronic HBV infection may harbor low-level anti-HBs.
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This antibody is directed not against the common group determinant, a, but against
the heterotypic subtype determinant (e.g., HBsAg of subtype ad with anti-HBs of
subtype y).

After immunization with hepatitis B vaccine, which consists of HBsAg alone, anti-HBs
is the only serologic marker to appear.

Tests for the detection of HBV DNA in liver and serum are now available. Like HBeAg,
serum HBV DNA is an indicator of HBV replication, but tests for HBV DNA are more
sensitive and quantitative.

In patients with hepatitis C, an episodic pattern of aminotransferase elevation is

common. A specific serologic diagnosis of hepatitis C can be made by demonstrating
the presence in serum of anti-HCV. When contemporary immunoassays are used,
anti-HCV can be detected in acute hepatitis C during the initial phase of elevated
aminotransferase activity.

Assays for HCV RNA are the most sensitive tests for HCV infection and represent the
"gold standard" in establishing a diagnosis of hepatitis C. HCV RNA can be detected
even before acute elevation of aminotransferase activity and before the appearance
of anti-HCV in patients with acute hepatitis C.

The presence of HDV infection can be identified by demonstrating intrahepatic HDV

antigen or, more practically, an anti-HDV seroconversion (a rise in titer of anti-HDV or
de novo appearance of anti-HDV). Circulating HDV antigen, also diagnostic of acute
infection, is detectable only briefly, if at all. Because anti-HDV is often undetectable
once HBsAg disappears, retrospective serodiagnosis of acute self-limited,
simultaneous HBV and HDV infection is difficult. Early diagnosis of acute infection
may be hampered by a delay of up to 30-40 days in the appearance of anti-HDV.

Liver biopsy is rarely necessary or indicated in acute viral hepatitis, except when the
diagnosis is questionable or when clinical evidence suggests a diagnosis of chronic
hepatitis.

A diagnostic algorithm can be applied in the evaluation of cases of acute viral

hepatitis. A patient with acute hepatitis should undergo four serologic tests, HBsAg,
IgM anti-HAV, IgM anti-HBc, and anti-HCV.

The presence of HBsAg, with or without IgM anti-HBc, represents HBV infection. If
IgM anti-HBc is present, the HBV infection is considered acute; if IgM anti-HBc is
absent, the HBV infection is considered chronic. A diagnosis of acute hepatitis B can
be made in the absence of HBsAg when IgM anti-HBc is detectable.

A diagnosis of acute hepatitis A is based on the presence of IgM anti-HAV. If IgM anti-
HAV coexists with HBsAg, a diagnosis of simultaneous HAV and HBV infections can be
 ACADEMIC
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made; if IgM anti-HBc (with or without HBsAg) is detectable, the patient has
simultaneous acute hepatitis A and B, and if IgM anti-HBc is undetectable, the
patient has acute hepatitis A superimposed on chronic HBV infection.

The presence of anti-HCV supports a diagnosis of acute hepatitis C. Occasionally,

testing for HCV RNA or repeat anti-HCV testing later during the illness is necessary to
establish the diagnosis. Absence of all serologic markers is consistent with a diagnosis
of "non-A, non-B, non-C" hepatitis, if the epidemiologic setting is appropriate.

Table 304-5 Commonly Encountered Serologic Patterns of Hepatitis B Infection

HBsAg Anti-HBs Anti-HBc HBeAg Anti- Interpretation
HBe
+ - IgM + - Acute hepatitis B, high infectivity
+ - IgG + - Chronic hepatitis B, high infectivity
+ - IgG - + Late acute or chronic hepatitis B, low infectivityHBeAg-negative
("precore-mutant") hepatitis B (chronic or, rarely, acute)
+ + + +/- +/- 1 HBsAg of one subtype and heterotypic anti-HBs (common)
2 Process of seroconversion from HBsAg to anti- HBs (rare)
- - IgM +/- +/- 1 Acute hepatitis B
2 Anti-HBc "window"
- - IgG - +/- 1 Low-level hepatitis B carrier
2 Hepatitis B in remote past
- + IgG - +/- Recovery from hepatitis B
- + - - - 1 Immunization with HBsAg (after vaccination)
2 Hepatitis B in the remote past (?)
3 False-positive

Table 304-6 Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis
Serologic Tests of Patient's Serum
HBsAg IgM Anti-HAV IgM Anti-HBc Anti-HCV Diagnostic Interpretation
+ - + - Acute hepatitis B
+ - - - Chronic hepatitis B
+ + - - Acute hepatitis A superimposed on chronic hepatitis B
+ + + - Acute hepatitis A and B
- + - - Acute hepatitis A
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- + + - Acute hepatitis A and B (HBsAg below detection threshold)

- - + - Acute hepatitis B (HBsAg below detection threshold)
- - - + Acute hepatitis C

In patients with chronic hepatitis, initial testing should consist of HBsAg and anti-HCV.
Anti-HCV supports and HCV RNA testing establishes the diagnosis of chronic hepatitis
C.
If a serologic diagnosis of chronic hepatitis B is made, testing for HBeAg and anti-HBe
is indicated to evaluate relative infectivity. Testing for HBV DNA in such patients
provides a more quantitative and sensitive measure of the level of virus replication
and, therefore, is very helpful during antiviral therapy.
In patients with chronic hepatitis B and normal aminotransferase activity in the
absence of HBeAg, serial testing over time is often required to distinguish between
inactive carriage and HBeAg-negative chronic hepatitis B with fluctuating virologic
and necroinflammatory activity.
In persons with hepatitis B, testing for anti-HDV is useful in those with severe and
fulminant disease, with severe chronic disease, with chronic hepatitis B and acute
hepatitis-like exacerbations, with frequent percutaneous exposures, and from areas
where HDV infection is endemic.

I. Prognosis
Virtually all previously healthy patients with hepatitis A recover completely with no
clinical sequelae. Similarly, in acute hepatitis B, 95-99% of previously healthy adults
have a favorable course and recover completely. Certain clinical and laboratory
features, however, suggest a more complicated and protracted course.
Patients of advanced age and with serious underlying medical disorders may have a
prolonged course and are more likely to experience severe hepatitis. Initial
presenting features such as ascites, peripheral edema, and symptoms of hepatic
encephalopathy suggest a poorer prognosis. In addition, a prolonged PT, low-serum
albumin level, hypoglycemia, and very high-serum bilirubin values suggest severe
hepatocellular disease.
In the case of HDV superinfection of a person with chronic hepatitis B, the likelihood
of fulminant hepatitis and death is increased substantially. Although the case fatality
rate for hepatitis D has not been defined adequately, in outbreaks of severe HDV
superinfection in isolated populations with a high hepatitis B carrier rate, the
mortality rate has been recorded in excess of 20%.

J. Treatment
In hepatitis B, among previously healthy adults who present with clinically apparent
acute hepatitis, recovery occurs in 99%; therefore, antiviral therapy is not likely to
improve the rate of recovery and is not required. In rare instances of severe acute
hepatitis B, treatment with a nucleoside analogue at oral doses used to treat chronic
hepatitis B has been attempted successfully.
Most authorities would recommend institution of antiviral therapy with a nucleoside
analogue for severe, but not mild-moderate, acute hepatitis B.
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In typical cases of acute hepatitis C, recovery is rare, progression to chronic hepatitis

is the rule, and meta-analyses of small clinical trials suggest that antiviral therapy
with interferon alfa monotherapy (3 million units SC three times a week) is beneficial.
Many authorities now opt for a 24-week course (beginning within 2-3 months after
onset) of the best regimen identified for the treatment of chronic hepatitis C, long-
acting pegylated interferon plus the nucleoside analogue ribavirin, although the
value of adding ribavirin has not been demonstrated.
Forced and prolonged bed rest is not essential for full recovery, but many patients
will feel better with restricted physical activity. A high-calorie diet is desirable, and
because many patients may experience nausea late in the day, the major caloric
intake is best tolerated in the morning. Intravenous feeding is necessary in the acute
stage if the patient has persistent vomiting and cannot maintain oral intake. If severe
pruritus is present, the use of the bile salt-sequestering resin cholestyramine is
helpful. Glucocorticoid therapy has no value in acute viral hepatitis, even in severe
cases associated with bridging necrosis, and may be deleterious, even increasing the
risk of chronicity (e.g., of acute hepatitis B).
Hospitalized patients may be discharged following substantial symptomatic
improvement, a significant downward trend in the serum aminotransferase and
bilirubin values, and a return to normal of the PT. Mild aminotransferase elevations
should not be considered contraindications to the gradual resumption of normal
activity.
In fulminant hepatitis, the goal of therapy is to support the patient by maintenance
of fluid balance, support of circulation and respiration, control of bleeding, correction
of hypoglycemia, and treatment of other complications of the comatose state in
anticipation of liver regeneration and repair. Protein intake should be restricted, and
oral lactulose or neomycin administered. Glucocorticoid therapy has been shown in
controlled trials to be ineffective. Meticulous intensive care that includes
prophylactic antibiotic coverage is the one factor that does appear to improve
survival. Orthotopic liver transplantation is resorted to with increasing frequency,
with excellent results, in patients with fulminant hepatitis.
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BILIRUBIN METABOLISM
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JAUNDICE
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A. Pre Hepatic Jaundice
Pre-hepaticular jaundice is caused by anything which causes an increased rate of
hemolysis (breakdown of red blood cells).
Unconjugated bilirubin comes from the breakdown of the heme pigment found in red
blood cells' hemoglobin. The increased breakdown of red blood cells leads to an increase
in the amount of unconjugated bilirubin present in the blood and deposition of this
unconjugated bilirubin into various tissues can lead to a jaundiced appearance.
In tropical countries, severe malaria can cause jaundice in this manner. Certain genetic
diseases, such as sickle cell anemia, spherocytosis, thalassemia, pyruvate kinase
deficiency, and glucose 6-phosphate dehydrogenase deficiency can lead to increased red
cell lysis and therefore hemolytic jaundice. Commonly, diseases of the kidney, such as
hemolytic uremic syndrome, can also lead to coloration.
In jaundice secondary to hemolysis, the increased production of bilirubin leads to the
increased production of urine-urobilinogen. Bilirubin is not usually found in the urine
because unconjugated bilirubin is not water-soluble, so, the combination of increased
urine-urobilinogen with no bilirubin (since, unconjugated) in urine is suggestive of
hemolytic jaundice.

B. Hepatocellular/Hepatic Jaundice
Hepatocellular (hepatic) jaundice can be caused by acute or chronic hepatitis,
hepatotoxicity, cirrhosis, drug-induced hepatitis and alcoholic liver disease.
Cell necrosis reduces the liver's ability to metabolize and excrete bilirubin leading to a
buildup of unconjugated bilirubin in the blood. Other causes include primary biliary
cirrhosis leading to an increase in plasma conjugated bilirubin because there is
impairment of excretion of conjugated bilirubin into the bile. The blood contains an
abnormally raised amount of conjugated bilirubin and bile salts which are excreted in the
urine.
Jaundice seen in the newborn, known as neonatal jaundice, is common in newborns as
hepatic machinery for the conjugation and excretion of bilirubin does not fully mature
until approximately two weeks of age. Rat fever (leptospirosis) can also cause hepatic
jaundice.
Bilirubin transport across the hepatocyte may be impaired at any point between the
uptake of unconjugated bilirubin into the cell and transport of conjugated bilirubin into
biliary canaliculi. In addition, swelling of cells and oedema due to inflammation cause
mechanical obstruction of intrahepatic biliary tree.
Hence in hepatocellular jaundice, concentration of both unconjugated and conjugated
bilirubin rises in the blood. In hepatocellular disease, there is usually interference in all
major steps of bilirubin metabolismuptake, conjugation and excretion. However,
excretion is the rate-limiting step, and usually impaired to the greatest extent. As a result,
conjugated hyperbilirubinaemia predominates.
The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual
way. This conjugated bilirubin is then returned to the blood, probably by rupture of the
congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver.
Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the
unconjugated type, and this conjugated bilirubin which did not go to intestine to become
urobilinogen gives the urine the dark color.
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C. Post Hepatic Jaundice
Post-hepatic jaundice, also called obstructive jaundice, is caused by an interruption to
the drainage of bile containing conjugated bilirubin in the biliary system.
The most common causes are gallstones in the common bile duct, and pancreatic
cancer in the head of the pancreas. Also, a group of parasites known as "liver flukes"
can live in the common bile duct, causing obstructive jaundice. Other causes include
strictures of the common bile duct, biliary atresia, cholangiocarcinoma, pancreatitis,
cholestasis of pregnancy, and pancreatic pseudocysts. A rare cause of obstructive
jaundice is Mirizzi's syndrome.
In complete obstruction of the bile duct, no urobilinogen is found in the urine, since
bilirubin has no access to the intestine and it is in the intestine that bilirubin gets
converted to urobilinogen to be later released into the general circulation. In this
case, presence of bilirubin (conjugated) in the urine without urine-urobilinogen
suggests obstructive jaundice, either intra-hepatic or post-hepatic.
The presence of pale stools and dark urine suggests an obstructive or post-hepatic
cause as normal feces get their color from bile pigments. However, although pale
stools and dark urine are a feature of biliary obstruction, they can occur in many
intra-hepatic illnesses and are therefore not a reliable clinical feature to distinguish
obstruction from hepatic causes of jaundice.
Patients also can present with elevated serum cholesterol, and often complain of
severe itching or "pruritus" because of the deposition of bile salts.

Function test Pre-hepatic jaundice Hepatic jaundice Post-hepatic jaundice

Total bilirubin Normal / increased Increased (++) Increased (+++)

Conjugated bilirubin Normal Increased Increased

Unconjugated bilirubin Normal / increased Increased Normal

Urobilinogen Normal / increased Decreased Decreased / negative

Urine color Normal Dark Dark

Stool color Normal Normal/pale Pale

Alkaline phosphatase levels Increased (+) Increased (+++)

Alanine transferase and Normal

Increased (+++) Increased (+)
aspartate transferase levels

Conjugated bilirubin in urine Not present Present

Urine bilirubin Negative Negative (may increase) Increased

Urine urobilinogen Increased Normal Decreased/Negative

Splenomegaly Present Present Absent

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CHRONIC HEPATITIS

A. Introduction
Chronic hepatitis represents a series of liver disorders of varying causes and severity
in which hepatic inflammation and necrosis continue for at least 6 months.
Milder forms are nonprogressive or only slowly progressive, while more severe forms
may be associated with scarring and architectural reorganization, which, when
advanced, lead ultimately to cirrhosis.
Several categories of chronic hepatitis have been recognized. These include chronic
viral hepatitis, druginduced chronic hepatitis, and autoimmune chronic hepatitis.
In many cases, clinical and laboratory features are insufficient to allow assignment
into one of these three categories; these "idiopathic" cases are also believed to
represent autoimmune chronic hepatitis. Finally, clinical and laboratory features of
chronic hepatitis are observed occasionally in patients with such
hereditary/metabolic disorders as Wilson's disease (copper overload) and
nonalcoholic fatty liver disease and even occasionally in patients with alcoholic liver
injury

B. Classification

Table 306-1 Clinical and Laboratory Features of Chronic Hepatitis

Type of hepatitis Diagnostic test(s) Autoantibodies Therapy
Chronic hepatitis B HBsAg, IgG anti-HBc, Uncommon IFN-, PEG IFN-
HBeAg, HBV DNA lamivudine adefovir entecavir telbivudine tenofovi
r
Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1 PEG IFN- ribavirin Telaprevir
Boceprevir
Chronic hepatitis D Anti-HDV, HDV RNA, Anti-LKM3 IFN-, PEG IFN-
HBsAg, IgG anti-HBc
Autoimmune hepatitis ANA (homogeneous), ANA, anti-LKM1 Prednisone, azathioprine
anti-LKM1 () anti-SLA
Hyperglobulinemia
Drug-associated - Uncommon Withdraw drug
Cryptogenic All negative None Prednisone (?), azathioprine (?)

C. Chronic Hepatitis B
The likelihood of chronicity after acute hepatitis B varies as a function of age.
Infection at birth is associated with 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%. Most cases of chronic hepatitis B among adults,
however, occur in patients who never had a recognized episode of clinically apparent
acute viral hepatitis.
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The degree of liver injury (grade) in patients with chronic hepatitis B is variable,
ranging from none in inactive carriers to mild to moderate to severe. Among adults
with chronic hepatitis B, histologic features are of prognostic importance.
More important to consider than histology alone in patients with chronic hepatitis B
is the degree of hepatitis B virus (HBV) replication.
In HBeAg-reactive chronic hepatitis B, two phases have been recognized based on the
relative level of HBV replication. The relatively replicative phase is characterized by
the presence in the serum of HBeAg and HBV DNA levels well in excess of 105-106
virions/mL, by the presence in the liver of detectable intrahepatocyte nucleocapsid
antigens [primarily hepatitis B core antigen (HBcAg)], by high infectivity, and by
accompanying liver injury.
In contrast, the relatively nonreplicative phase is characterized by the absence of the
conventional serum marker of HBV replication (HBeAg), the appearance of anti-HBe,
levels of HBV DNA below a threshold of 103 virions/mL, the absence of
intrahepatocytic HBcAg, limited infectivity, and minimal liver injury.
Those patients in the replicative phase tend to have more severe chronic hepatitis,
while those in the nonreplicative phase tend to have minimal or mild chronic
hepatitis or to be inactive hepatitis B carriers.
Inactive carriers are patients with circulating hepatitis B surface antigen (HBsAg),
normal serum aminotransferase levels, undetectable HBeAg, and levels of HBV DNA
that are either undetectable or present at levels 103 virions/mL. This serologic profile
can occur not only in inactive carriers but also in patients with HBeAg-negative
chronic hepatitis B during periods of relative inactivity; distinguishing between the
two requires sequential biochemical and virologic monitoring over many months.
The spectrum of clinical features of chronic hepatitis B is broad, ranging from
asymptomatic infection to debilitating disease or even end-stage, fatal hepatic
failure. As noted above, the onset of the disease tends to be insidious in most
patients, with the exception of the very few in whom chronic disease follows failure
of resolution of clinically apparent acute hepatitis B.
Fatigue is a common symptom, and persistent or intermittent jaundice is a common
feature in severe or advanced cases. Intermittent deepening of jaundice and
recurrence of malaise and anorexia, as well as worsening fatigue, are reminiscent of
acute hepatitis; such exacerbations may occur spontaneously, often coinciding with
evidence of virologic reactivation; may lead to progressive liver injury; and, when
superimposed on well-established cirrhosis, may cause hepatic decompensation.
Complications of cirrhosis occur in end-stage chronic hepatitis and include ascites,
edema, bleeding gastroesophageal varices, hepatic encephalopathy, coagulopathy, or
hypersplenism. Occasionally, these complications bring the patient to initial clinical
attention.
Extrahepatic complications of chronic hepatitis B, similar to those seen during the
prodromal phase of acute hepatitis B, are associated with deposition of circulating
hepatitis B antigen-antibody immune complexes. These include arthralgias and
arthritis, which are common, and the more rare purpuric cutaneous lesions
(leukocytoclastic vasculitis), immune-complex glomerulonephritis, and generalized
vasculitis (polyarteritis nodosa).
Laboratory features of chronic hepatitis B do not distinguish adequately between
histologically mild and severe hepatitis. Aminotransferase elevations tend to be
 ACADEMIC
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modest for chronic hepatitis B but may fluctuate in the range of 100-1000 units. As is
true for acute viral hepatitis B, alanine aminotransferase (ALT) tends to be more
elevated than aspartate aminotransferase (AST); however, once cirrhosis is
established, AST tends to exceed ALT. Levels of alkaline phosphatase activity tend to
be normal or only marginally elevated.
In severe cases, moderate elevations in serum bilirubin [51.3-171 mol/L (3-10
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).

Table 306-3 Comparison of Pegylated Interferon (Peg IFN), Lamivudine, Adefovir, Entecavir, Telbivudine, and
Tenofovir Therapy for Chronic Hepatitis B
Feature PEG IFN Lamivudin Adefovir Entecavir Telbivudine Tenofovir
e
Route of administration Subcutaneous Oral Oral Oral Oral Oral
Injection
Duration of therapyc 48-52 weeks 52 weeks 48 weeks 48 weeks 52 weeks 48 weeks

Tolerability Poorly Well Well tolerated; Well Well Well tolerated

tolerated tolerated creatinine tolerated tolerated creatinine
monitoring monitoring
recommended recommended
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Table 306-4 Recommendations for Treatment of Chronic Hepatitis B

HBeAg Clinical HBV DNA ALT Recommendation
status (IU/ml)
HBeAg- b >2 x104 <2 x ULN No treatment; monitor. In patients >40, with family history
reactive of hepatocellular carcinoma, and/or ALT persistently at the
high end of the twofold range, liver biopsy may help in
decision to treat
Chronic hepatitis >2 x 104d >2 x ULN Treat
Cirrhosis >2 x 103 < or > ULN Treat with oral agents, not PEG IFN
compensated
<2 x 103 >ULN Consider treatment
Cirrhosis Detectable < or > ULN Treat with oral agents, not PEG IFN; refer for liver
decompensated transplantation
Undetectabl < or > ULN Observe; refer for liver transplantation
e
HBeAg- b 2 x 103 ULN Inactive carrier; treatment not necessary
negative
Chronic hepatitis >103 1->2 x ULN Consider liver biopsy; treat if biopsy shows moderate to
severe inflammation or fibrosis
Chronic hepatitis >104 >2 x ULN Treat
Cirrhosis >2 x 103 < or > ULN Treat with oral agents, not PEG IFN
compensated
<2 x 103 >ULN Consider treatment
Cirrhosis Detectable < or > ULN Treat with oral agents, not PEG IFN; refer for liver
decompensated transplantation
Undetectabl < or > ULN Observe; refer for liver transplantation
e

Table 306-5 Pegylated Interferon versus Oral Nucleoside Analogues for the Treatment of Chronic Hepatitis B
PEG IFN Nucleoside Analogues
Administration Weekly injection Daily, orally
Tolerability Poorly tolerated, intensive Well tolerated, limited monitoring
monitoring
Duration of therapy Finite 48 weeks 1 year, indefinite in most patients
 ACADEMIC
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Maximum mean HBV DNA suppression 4.5 log10 6.9 log10

Effective in high-level HBV DNA ( 109 IU/ml) No Yes
HBeAg seroconversion
During 1 year of therapy 30% 20%
During >1 year of therapy Not applicable 30% (year 2)50% (year 5)
HBeAg-negative
posttreatment HBV DNA suppression 17% @ 5 years 7% @ 4 years (lamivudine)
HBsAg loss
During 1 year of therapy 3-4% 0-3%
During >1 year of therapy Not applicable 3-6% @ 2 years of therapy
After 1 year of therapy-HBeAg-negative 12% @ 5 years 3.5% @ 5 years
Antiviral resistance None Lamivudine: 30% year 1, 70% year 5
Adefovir: 0% year 1, 30% year 5
Telbivudine: up to 4% year 1, 22% year 2
Entecavir: 1.2% through year 5
Tenofovir: 0% through year 3
Use in cirrhosis, transplantation, No Yes
immunosuppressed
Cost, 1 year of therapy ++++ + to ++

D. Chronic Hepatitis C
Regardless of the epidemiologic mode of acquisition of hepatitis C virus (HCV)
infection, chronic hepatitis follows acute hepatitis C in 50-70% of cases; chronic
infection is common even in those with a return to normal in aminotransferase levels
after acute hepatitis C, adding up to an 85% likelihood of chronic HCV infection after
acute hepatitis C.
In patients with chronic hepatitis C followed for 20 years, progression to cirrhosis
occurs in about 20-25%. Such is the case even for patients with relatively clinically
mild chronic hepatitis, including those without symptoms, with only modest
elevations of aminotransferase activity and with mild chronic hepatitis on liver
biopsy.
Most cases of hepatitis C are identified initially in asymptomatic patients who have
no history of acute hepatitis C (e.g., those discovered while attempting to donate
blood, while undergoing lab testing as part of an application for life insurance, or as a
result of routine laboratory tests).
Approximately one-third of patients with chronic hepatitis C have normal or near-
normal aminotransferase activity; although one-third to one-half of these patients
have chronic hepatitis on liver biopsy, the grade of liver injury and stage of fibrosis
tend to be mild in the vast majority.
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Despite this substantial rate of progression of chronic hepatitis C, and despite the
fact that liver failure can result from end-stage chronic hepatitis C, the long-term
prognosis for chronic hepatitis C in a majority of patients is relatively benign.
Although death in the hepatitis group is more likely to result from liver failure, and
although hepatic decompensation may occur in 15% of such patients over the course
of a decade, the majority (almost 60%) of patients remain asymptomatic and well
compensated, with no clinical sequelae of chronic liver disease.
Overall, chronic hepatitis C tends to be very slowly and insidiously progressive, if at
all, in the vast majority of patients, while in approximately one-fourth of cases,
chronic hepatitis C will progress eventually to end-stage cirrhosis.
In fact, because HCV infection is so prevalent, and because a proportion of patients
progress inexorably to endstage liver disease, hepatitis C is the most frequent
indication for liver transplantation.
Despite the relatively benign nature of chronic hepatitis C over time in many
patients, cirrhosis following chronic hepatitis C has been associated with the late
development, after several decades, of HCC; the annual rate of HCC in cirrhotic
patients with hepatitis C is 1-4%, occurring primarily in patients who have had HCV
infection for 30 years or more.
Perhaps the best prognostic indicator in chronic hepatitis C is liver histology; the rate
of hepatic fibrosis may be slow, moderate, or rapid. Patients with mild necrosis and
inflammation as well as those with limited fibrosis have an excellent prognosis and
limited progression to cirrhosis.
Clinical features of chronic hepatitis C are similar to those described above for
chronic hepatitis B. Generally, fatigue is the most common symptom; jaundice is rare.
Immune complex-mediated extrahepatic complications of chronic hepatitis C are less
common than in chronic hepatitis B (despite the fact that assays for immune
complexes are often positive in patients with chronic hepatitis C).
In addition, chronic hepatitis C has been associated with extrahepatic complications
unrelated to immune-complex injury. These include Sjogren's syndrome, lichen
planus, porphyria cutanea tarda, type-II diabetes mellitus and the metabolic
syndrome (including insulin resistance and steatohepatitis).
Laboratory features of chronic hepatitis C are similar to those in patients with chronic
hepatitis B, but aminotransferase levels tend to fluctuate more (the characteristic
episodic pattern of aminotransferase activity) and to be lower, especially in patients
with long-standing disease.
For the treatment of chronic hepatitis C, standard IFNs have now been supplanted by
PEG IFNs. These have elimination times up to sevenfold longer than standard IFNs
(i.e., a substantially longer half-life), and achieve prolonged concentrations,
permitting administration once (rather than three times) a week. Instead of the
frequent drug peaks (linked to side effects) and troughs (when drug is absent)
associated with frequent administration of short-acting IFNs, administration of PEG
IFNs results in drug concentrations that are more stable and sustained over time.
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CIRRHOSIS

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

Table 308-1 Causes of Cirrhosis

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

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

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

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

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

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

PORTAL HYPERTENSION

A. Introduction
Portal hypertension is an increase in the blood pressure within a system of veins
called the portal venous system. Veins coming from the stomach, intestine, spleen,
and pancreas merge into the portal vein, which then branches into smaller vessels
and travels through the liver.
If the vessels in the liver are blocked due to liver damage, blood cannot flow properly
through the liver. As a result, high pressure in the portal system develops. This
increased pressure in the portal vein may lead to the development of large, swollen
veins (varices) within the esophagus, stomach, rectum, or umbilical area (belly
button). Varices can rupture and bleed, resulting in potentially life-threatening
complications.

B. Causes
The most common cause of portal hypertension is cirrhosis of the liver. Cirrhosis is
scarring which accompanies the healing of liver injury caused by hepatitis, alcohol, or
other less common causes of liver damage. In cirrhosis, the scar tissue blocks the
flow of blood through the liver.
Other causes of portal hypertension include blood clots in the portal vein, blockages
of the veins that carry the blood from the liver to the heart, a parasitic infection
called schistosomiasis, and focal nodular hyperplasia, a disease seen in people
infected with HIV, the virus that may lead to AIDS. Sometimes the cause is unknown.

C. Symptoms
Gastrointestinal bleeding marked by black, tarry stools or blood in the stools, or
vomiting of blood due to the spontaneous rupture and hemorrhage from varices
Ascites (an accumulation of fluid in the abdomen)
Encephalopathy or confusion and forgetfulness caused by poor liver function
Reduced levels of platelets, blood cells that help form blood clots, or white blood
cells, the cells that fight infection
Splenomegaly

D. Pathogenesis
The pathophysiology of portal hypertension is indicated by increasing vascular
resistance via different etiologies, additionally stellate cells and myofibroblasts are
activated. Liver disease that decreases the portal vascular radius produces a dramatic
increase in portal vascular resistance. In cirrhosis, the increase occurs at the hepatic
microcirculation (sinusoidal portal hypertension). Increased hepatic vascular
resistance in cirrhosis is not only a mechanical consequence of the hepatic
architectural disorder; a dynamic component also exists due to the active contraction
of myofibroblasts, activated stellate cells, and vascular smooth-muscle cells of the
intrahepatic veins.
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ASCITES

A. Pathogenesis in Cirrhosis
Ascites in patients with cirrhosis is the result of portal hypertension and renal salt
and water retention.
Portal hypertension signifies elevation of the pressure within the portal vein.
According to Ohm's law, pressure is the product of resistance and flow. Increased
hepatic resistance occurs by several mechanisms. First, the development of hepatic
fibrosis, which defines cirrhosis, disrupts the normal architecture of the hepatic
sinusoids and impedes normal blood flow through the liver. Second, activation of
hepatic stellate cells, which mediate fibrogenesis, leads to smooth muscle
contraction and fibrosis. Finally, cirrhosis is associated with a decrease in endothelial
nitric oxide synthetase (eNOS) production, which results in decreased nitric oxide
production and increased intrahepatic vasoconstriction.
The development of cirrhosis is also associated with increased systemic circulating
levels of nitric oxide (contrary to the decrease seen intrahepatically) as well as
increased levels of vascular endothelial growth factor and tumor necrosis factor that
result in splanchnic arterial vasodilatation. Vasodilatation of the splanchnic
circulation results in pooling of blood and a decrease in the effective circulating
volume, which is perceived by the kidneys as hypovolemia. Compensatory
vasoconstriction via release of antidiuretic hormone ensues, thereby leading to free
water retention and activation of the sympathetic nervous system and renin
angiotensin aldosterone system, leading in turn to renal sodium and water retention.

B. Causes
Cirrhosis accounts for 84% of cases of ascites. Cardiac ascites, peritoneal
carcinomatosis, and "mixed" ascites resulting from cirrhosis and a second disease
account for 10 to 15% of cases. Less common causes of ascites include massive
hepatic metastasis, infection (tuberculosis, Chlamydia), pancreatitis, and renal
disease (nephrotic syndrome). Rare causes of ascites include hypothyroidism and
familial Mediterranean fever.

C. Diagnosis
Once the presence of ascites has been confirmed, the etiology of the ascites is best
determined by paracentesis. Paracentesis is a bedside procedure in which a needle
or small catheter is passed transcutaneously to extract ascitic fluid from the
peritoneum. The lower quadrants are the most frequent sites for paracentesis.
Occasionally, an infraumbilical approach is used. The left lower quadrant is preferred
because of the greater depth of ascites and thinner abdominal wall.
Once ascitic fluid has been extracted, its gross appearance should be examined.
Turbid fluid can result from infection or tumor cells within the fluid. White, milky
fluid indicates the presence of triglycerides in levels >200 mg/dL (and often >1000
mg/dL), which is the hallmark of chylous ascites. Chylous ascites results from
lymphatic disruption that may occur with trauma, cirrhosis, tumor, tuberculosis, or
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certain congenital abnormalities. Dark brown fluid can reflect a high bilirubin
concentration and indicates biliary tract perforation. Black fluid may indicate the
presence of pancreatic necrosis or metastatic melanoma.
The ascitic fluid should be sent for measurement of the albumin and total protein
levels, cell and differential counts, and, if infection is suspected, Gram's stain and
culture, with inoculation of the fluid into blood culture bottles at the patient's
bedside to maximize the yield. In addition, a serum albumin level should be sent
simultaneously to permit calculation of the serum-ascites albumin gradient (SAAG).

D. Treatment
The initial treatment of cirrhotic ascites is restriction of sodium intake to 2 g/d. When
sodium restriction alone is inadequate to control ascites, oral diuretics, typically the
combination of spironolactone and furosemide, are used. Spironolactone is an
aldosterone antagonist that inhibits Na+ resorption in the distal convoluted tubule of
the kidney. Use of spironolactone may be limited by hyponatremia, hyperkalemia,
and painful gynecomastia. If the gynecomastia is distressing, amiloride, 5-40 mg/d,
may be substituted for spironolactone. Furosemide is a loop diuretic that is generally
combined with spironolactone in a ratio of 40:100; maximal daily doses of
spironolactone and furosemide are generally 400 mg and 160 mg, respectively.
Refractory cirrhotic ascites is defined by the persistence of ascites despite sodium
restriction and maximal (or maximally tolerated) diuretic use. Refractory ascites can
be managed by serial large volume paracentesis (LVP) or a transjugular intrahepatic
peritoneal shunt (TIPS), a radiologically placed portosystemic shunt to decompress
the hepatic sinusoids. TIPS is superior to LVP in reducing the reaccumulation of
ascites but is associated with an increased frequency of hepatic encephalopathy with
no difference in mortality rates.
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HEPATIC ENCEPHALOPATHY

A. Introduction
Hepatic encephalopathy is a syndrome observed in patients with cirrhosis. Hepatic
encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in
patients with liver dysfunction, after exclusion of brain disease.
Hepatic encephalopathy is characterized by personality changes, intellectual
impairment, and a depressed level of consciousness.

B. Causes
The exact cause of hepatic encephalopathy is unknown. Hepatic encephalopathy is
brought on by disorders that affect the liver. These include:
o Conditions that reduce liver function (such as cirrhosis or hepatitis)
o Conditions in which blood circulation does not enter the liver

An important job of the liver is to make toxic substances in the body harmless. These
can include substances made by the body as well things that you take in (such as
medicines). However, when the liver is damaged, these "poisons" can build up in the
bloodstream. Ammonia, which is produced by the body when proteins are digested,
is one of the substances normally made harmless by the liver. Other toxins may also
build up. These things can cause damage to the nervous system.

C. Symptoms
Early symptoms may be mild and include:
o Breath with a musty or sweet odor
o Change in sleep patterns
o Changes in thinking
o Confusion that is mild
o Forgetfulness
o Mental fogginess
o Personality or mood changes
o Poor concentration
o Poor judgment
o Worsening of handwriting or loss of other small hand movements

More severe symptoms may include:

o Abnormal movements or shaking of hands or arms
o Agitation, excitement, or seizures (occur rarely)
o Disorientation
o Drowsiness or confusion
o Strange behavior or severe personality changes
o Slurred speech
o Slowed or sluggish movement
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NON ALCOHOLIC FATTY LIVER DISEASE

A. Fatty Liver
A fatty liver is the result of the excess fat in liver cells. Fatty tissue slowly builds up in
the liver when a persons diet exceeds the amount of fat his or her body can handle.
A person has a fatty liver when fat makes up at least 5% of the liver. Simple fatty liver
can be a completely benign condition and usually does not lead to liver damage.
However, once there is a buildup of simple fat, the liver becomes vulnerable to
further injury, which may result in inflammation and scarring of the liver

B. Non-Alcoholic Fatty Liver Disease

NAFLD is a progressive complex of liver disease which starts with fat accumulation in
the liver without excessive alcohol consumption. It is strongly associated with
metabolic syndrome (obesity + insulin resistance + dyslipidemia)

C. Causes
Nonalcoholic fatty liver disease occurs when your liver has trouble breaking down
fats, causing fat to build up in your liver tissue.
The most common cause of fatty liver disease in Canada is obesity. Besides obesity,
nutritional causes of fatty liver disease are:
o starvation and protein malnutrition,
o long term use of total parenteral nutrition (a feeding procedure that involves
infusing nutrients directly into the blood stream),
o intestinal bypass surgery for obesity,
o rapid weight loss.

Certain conditions often accompany and may contribute to fatty liver disease:
o diabetes mellitus,
o hyperlipidemia (elevated lipids in the blood),
o insulin resistance and high blood pressure.

Other causes include:

o genetic factors,
o drugs and chemicals such as alcohol, corticosteroids, tetracycline and carbon
tetrachloride.

D. Symptoms
Nonalcoholic fatty liver disease usually causes no signs and symptoms. When it does,
they may include:
Fatigue
Pain in the upper right abdomen
Weight loss
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E. Stages
1. Stage 1: simple fatty liver (steatosis)
o Hepatic steatosis is stage 1 of the condition. This is where excess fat builds up in
the liver cells, but is considered harmless. There are usually no symptoms, and
you may not even realise you have it until you receive an abnormal blood test
result.

2. Stage 2: non-alcoholic steatohepatitis (NASH)

o Only a few people with simple fatty liver go on to develop stage 2 of the
condition, called non-alcoholic steatohepatitis (NASH).
o NASH is a more aggressive form of the condition, when the liver has become
inflamed. Inflammation is part of the body's response to injury, which suggests
that cells in the liver are being damaged and that some liver cells are dying.
o A person with NASH may have a dull or aching pain in the top right of their
abdomen (over the lower right side of their ribs), although there may be no
symptoms at all.

3. Stage 3: fibrosis
o Some people with NASH go on to develop fibrosis, which is where persistent
inflammation in the liver results in the generation of fibrous scar tissue around
the liver cells and blood vessels.
o This fibrous tissue replaces some of the healthy liver tissue, but there is still
enough healthy tissue for the liver to function normally.

4. Stage 4: cirrhosis
o This is the most severe stage, where bands of scar tissue and clumps of liver cells
develop. The liver shrinks and becomes lumpy (known as cirrhosis).
o Cirrhosis tends to occur after the age of 50-60, following many years of liver
inflammation associated with the early stages of the disease. However, this can
happen much earlier in some people.
o People who have type 2 diabetes are at the greatest risk of developing cirrhosis
of the liver caused by NAFLD.
o The damage caused by cirrhosis is permanent and can't be reversed. Cirrhosis
progresses slowly, over many years, gradually causing your liver to stop
functioning. NAFLD can also lead to primary liver cancer (hepatocellular
carcinoma). This is what is known as liver failure. Learn more about cirrhosis of
the liver, including the warning signs.

F. Diagnosis
Blood tests. Liver function tests, including tests of liver enzymes, may help your
doctor make a diagnosis.
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Imaging procedures. Imaging procedures used to diagnose fatty liver disease include
ultrasound, computerized tomography (CT) scan and magnetic resonance imaging
(MRI).
Liver tissue testing. If it's suspected that you have a more serious form of
nonalcoholic fatty liver disease, your doctor may recommend a procedure to remove
a sample of tissue from your liver (liver biopsy). The tissue sample is examined in a
laboratory to look for signs of inflammation and scarring.
G. Treatment
Currently, there is no medication proven to effectively treat fatty liver disease, if the
main causes are related to obesity, diabetes and dyslipidemia. The treatment is
based in lifestyle modification, weight loss, and physical activity in order to reduce
the amount of fat in the liver. Patients who are obese are advised to achieve a
gradual and sustained weight loss through proper nutrition and exercise.
Summary of treatment:
o Losing weight and exercise
o Stop smoking
o Medication
o Avoid alcohol

HEPATOCELLULAR CARCINOMA

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

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

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

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

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

A. Pathogenesis
Gallstones are formed because of abnormal bile composition. They are divided into
two major types: cholesterol stones account for more than 80% of the total, with
pigment stones comprising less than 20%.
Cholesterol gallstones usually contain >50% cholesterol monohydrate plus an
admixture of calcium salts, bile pigments, and proteins. Pigment stones are
composed primarily of calcium bilirubinate; they contain <20% cholesterol and are
classified into "black" and "brown" types, the latter forming secondary to chronic
biliary infection.

B. Cholestrol stones and biliary sludges

Cholesterol is essentially water insoluble and requires aqueous dispersion into either
micelles or vesicles, both of which require the presence of a second lipid to solubilize
the cholesterol. Cholesterol and phospholipids are secreted into bile as unilamellar
bilayered vesicles, which are converted into mixed micelles consisting of bile acids,
phospholipids, and cholesterol by the action of bile acids. If there is an excess of
cholesterol in relation to phospholipids and bile acids, unstable, cholesterol-rich
vesicles remain, which aggregate into large multilamellar vesicles from which
cholesterol crystals precipitate
There are several important mechanisms in the formation of lithogenic (stone-
forming) bile. The most important is increased biliary secretion of cholesterol. This
may occur in association with obesity, the metabolic syndrome, high-caloric and
cholesterol-rich diets, or drugs (e.g., clofibrate) and may result from increased
activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-
limiting enzyme of hepatic cholesterol synthesis, and increased hepatic uptake of
cholesterol from blood.
In patients with gallstones, dietary cholesterol increases biliary cholesterol secretion.
This does not occur in non-gallstone patients on high-cholesterol diets. In addition to
environmental factors such as high-caloric and cholesterol-rich diets, genetic factors
play an important role in gallstone disease.
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To summarize, cholesterol gallstone disease occurs because of several defects, which

include (1) bile supersaturation with cholesterol, (2) nucleation of cholesterol
monohydrate with subsequent crystal retention and stone growth, and (3) abnormal
gallbladder motor function with delayed emptying and stasis.

C. Pigment stones
Black pigment stones are composed of either pure calcium bilirubinate or polymer-
like complexes with calcium and mucin glycoproteins. They are more common in
patients who have chronic hemolytic states (with increased conjugated bilirubin in
bile), liver cirrhosis, Gilbert's syndrome, or cystic fibrosis. Gallbladder stones in
patients with ileal diseases, ileal resection, or ileal bypass generally are also black
pigment stones.
Enterohepatic recycling of bilirubin in ileal disease states contributes to their
pathogenesis. Brown pigment stones are composed of calcium salts of unconjugated
bilirubin with varying amounts of cholesterol and protein. They are caused by the
presence of increased amounts of unconjugated, insoluble bilirubin in bile that
precipitates to form stones.
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Deconjugation of an excess of soluble bilirubin mono- and diglucuronides may be

mediated by endogenous -glucuronidase but may also occur by spontaneous
hydrolysis. Sometimes, the enzyme is also produced when bile is chronically infected
by bacteria, and such stones are brown. Pigment stone formation is especially
prominent in Asians and is often associated with infections in the gallbladder and
biliary tree
ACUTE AND CHRONIC CHOLECYSTITIS

A. Acute cholecystitis
Acute inflammation of the gallbladder wall usually follows obstruction of the cystic
duct by a stone. Inflammatory response can be evoked by three factors: (1)
mechanical inflammation produced by increased intraluminal pressure and
distention with resulting ischemia of the gallbladder mucosa and wall, (2) chemical
inflammation caused by the release of lysolecithin (due to the action of
phospholipase on lecithin in bile) and other local tissue factors, and (3) bacterial
inflammation, which may play a role in 50-85% of patients with acute cholecystitis.
The organisms most frequently isolated by culture of gallbladder bile in these
patients include Escherichia coli, Klebsiella spp., Streptococcus spp., and Clostridium
spp.

Acute cholecystitis often begins as an attack of biliary pain that progressively

worsens. Approximately 60-70% of patients report having experienced prior attacks
that resolved spontaneously. As the episode progresses, however, the pain of acute
cholecystitis becomes more generalized in the right upper abdomen. As with biliary
colic, the pain of cholecystitis may radiate to the interscapular area, right scapula, or
shoulder.

Peritoneal signs of inflammation such as increased pain with jarring or on deep

respiration may be apparent. The patient is anorectic and often nauseated. Vomiting
is relatively common and may produce symptoms and signs of vascular and
extracellular volume depletion. Jaundice is unusual early in the course of acute
cholecystitis but may occur when edematous inflammatory changes involve the bile
ducts and surrounding lymph nodes.

A low-grade fever is characteristically present, but shaking chills or rigors are not
uncommon. The RUQ of the abdomen is almost invariably tender to palpation. An
enlarged, tense gallbladder is palpable in 25-50% of patients. Deep inspiration or
cough during subcostal palpation of the RUQ usually produces increased pain and
inspiratory arrest (Murphy's sign). Localized rebound tenderness in the RUQ is
common, as are abdominal distention and hypoactive bowel sounds from paralytic
ileus, but generalized peritoneal signs and abdominal rigidity are usually lacking, in
the absence of perforation.

The diagnosis of acute cholecystitis is usually made on the basis of a characteristic

history and physical examination. The triad of sudden onset of RUQ tenderness,
fever, and leukocytosis is highly suggestive. Typically, leukocytosis in the range of
10,000-15,000 cells per microliter with a left shift on differential count is found. The
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serum bilirubin is mildly elevated [<85.5 mol/L (5 mg/dL)] in fewer than half of
patients, while about one-fourth have modest elevations in serum aminotransferases
(usually less than a fivefold elevation). Ultrasound will demonstrate calculi in 90-95%
of cases and is useful for detection of signs of gallbladder inflammation including
thickening of the wall, pericholecystic fluid, and dilation of the bile duct. In view of
the natural history of the disease, acute cholecystitis is best treated by early surgery
whenever possible.

B. Chronic cholecystitis
Chronic inflammation of the gallbladder wall is almost always associated with the
presence of gallstones and is thought to result from repeated bouts of subacute or
acute cholecystitis or from persistent mechanical irritation of the gallbladder wall by
gallstones.
The presence of bacteria in the bile occurs in >25% of patients with chronic
cholecystitis. The presence of infected bile in a patient with chronic cholecystitis
undergoing elective cholecystectomy probably adds little to the operative risk.
Chronic cholecystitis may be asymptomatic for years, may progress to symptomatic
gallbladder disease or to acute cholecystitis, or may present with complications

CHOLEDOCHAL CYST

Cystic dilatation may involve the free portion of the CBD (common bile duct), i.e.,
choledochal cyst, or may present as diverticulum formation in the intraduodenal
segment.
In the latter situation, chronic reflux of pancreatic juice into the biliary tree can
produce inflammation and stenosis of the extrahepatic bile ducts leading to
cholangitis or biliary obstruction.
Because the process may be gradual, 50% of patients present with onset of
symptoms after age 10.
The diagnosis may be made by ultrasound, abdominal CT, MRC, or cholangiography.
Only one-third of patients show the classic triad of abdominal pain, jaundice, and an
abdominal mass. Ultrasonographic detection of a cyst separate from the gallbladder
should suggest the diagnosis of choledochal cyst, which can be confirmed by
demonstrating the entrance of extrahepatic bile ducts into the cyst.
Surgical treatment involves excision of the "cyst" and biliary-enteric anastomosis.
Patients with choledochal cysts are at increased risk for the subsequent development
of cholangiocarcinoma.

CHOLEDOCHOLITHIASIS (GALLSTONES IN BILE DUCTS)

Passage of gallstones into the CBD occurs in 10-15% of patients with cholelithiasis.
The overwhelming majority of bile duct stones are cholesterol stones formed in the
gallbladder, which then migrate into the extrahepatic biliary tree through the cystic
duct.
Primary calculi arising de novo in the ducts are usually pigment stones developing in
patients with (1) hepatobiliary parasitism or chronic, recurrent cholangitis; (2)
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congenital anomalies of the bile ducts (especially Caroli's disease); (3) dilated,
sclerosed, or strictured ducts; or (4) an MDR3 (ABCB4) gene defect leading to
impaired biliary phospholipids secretion (low phospholipid-associated cholelithiasis).
Common duct stones may remain asymptomatic for years, may pass spontaneously
into the duodenum, or (most often) may present with biliary colic or a complication.

CHOLANGITIS (INFLAMMATION OF BILE DUCTS)

Cholangitis may be acute or chronic, and symptoms result from inflammation, which
usually is caused by at least partial obstruction to the flow of bile. Bacteria are
present on bile culture in 75% of patients with acute cholangitis early in the
symptomatic course.
The characteristic presentation of acute cholangitis involves biliary pain, jaundice,
and spiking fevers with chills (Charcot's triad). Blood cultures are frequently positive,
and leukocytosis is typical.
Nonsuppurative acute cholangitis is most common and may respond relatively
rapidly to supportive measures and to treatment with antibiotics. In suppurative
acute cholangitis, however, the presence of pus under pressure in a completely
obstructed ductal system leads to symptoms of severe toxicity-mental confusion,
bacteremia, and septic shock. Response to antibiotics alone in this setting is relatively
poor, multiple hepatic abscesses are often present, and the mortality rate
approaches 100% unless prompt endoscopic or surgical relief of the obstruction and
drainage of infected bile are carried out. Endoscopic management of bacterial
cholangitis is as effective as surgical intervention. ERCP with endoscopic
sphincterotomy is safe and the preferred initial procedure for both establishing a
definitive diagnosis and providing effective therapy.