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CHRONIC HEPATITIS
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, drug-induced 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 even
occasionally in patients with alcoholic liver injury. Although all types of chronic hepatitis share
certain clinical, laboratory, and histopathologic features, chronic viral and chronic autoimmune
hepatitis are sufficiently distinct to merit separate discussions.
CLASSIFICATION OF CHRONIC HEPATITIS
Common to all forms of chronic hepatitis are histopathologic distinctions based on localization
and extent of liver injury. These vary from the milder forms, previously labeled chronic
persistent hepatitis and chronic lobular hepatitis, to the more severe form, formerly called
chronic active hepatitis. When first defined, these designations were felt to have prognostic
implications, which have been challenged by more recent observations. Compared to the time
three decades ago when the histologic designations chronic persistent, chronic lobular, and
chronic active hepatitis were adopted, much more information is currently available about the
causes, natural history, pathogenesis, serologic features, and therapy of chronic hepatitis.
Therefore, categorization of chronic hepatitis based primarily upon histopathologic features has
been replaced by a more informative classification based upon a combination of clinical,
serologic, and histologic variables.
Classification of chronic hepatitis is based upon
1) its cause,
2) its histologic activity, or grade,
3) its degree of progression, or stage.
Thus, neither clinical features alone nor histologic features—requiring liver biopsy—alone are
sufficient to characterize and distinguish among the several categories of chronic hepatitis.
Classification by Cause
Clinical and serologic features allow the establishment of a diagnosis of chronic viral hepatitis,
caused by hepatitis B, hepatitis B plus D, hepatitis C, or potentially other unknown viruses;
autoimmune hepatitis, including several subcategories, types 1, 2, and 3, based on serologic
distinctions; drug-associated chronic hepatitis; and a category of unknown cause, or cryptogenic
chronic hepatitis. These are addressed in more detail below.
Clinical and Laboratory Features of Chronic Hepatitis
Type of Hepatitis
Diagnostic Test(s)
Autoantibodies
Chronic hepatitis B HBsAg, IgG anti-HBc, HBeAg, Uncommon
HBV DNA
Chronic hepatitis C Anti-HCV, HCV RNA
Anti-LKM1a
Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg,
IgG anti-HBc
Autoimmune
ANAb (homogeneous), antihepatitis
LKM1(±), hyperglobulinemia
Drug-associated
—
Cryptogenic
All negative
Anti-LKM3
ANA, anti-LKM1,
anti-SLAc
Uncommon
None
Therapy
IFN-α, lamivudine
PEG-IFN-α plus
ribavirin
IFN-α (?)
Prednisone,
azathioprine
Withdraw drug
Prednisone (?),
azathioprine (?)
a
Antibodies to liver-kidney microsomes type 1 (autoimmune hepatitis type II and some cases of
hepatitis C).
b
Antinuclear antibody (autoimmune hepatitis type I).
c
Antibodies to soluble liver antigen (autoimmune hepatitis type III).
Note: HBsAg, hepatitis B surface antigen; IFN-α, interferon α; PEG-IFN-α, pegylated interferon
α.
Classification by Grade
Grade, a histologic assessment of necroinflammatory activity, is based upon examination of the
liver biopsy. An assessment of important histologic features includes the degree of periportal
necrosis and the disruption of the limiting plate of periportal hepatocytes by inflammatory cells
(so-called piecemeal necrosis or interface hepatitis); the degree of confluent necrosis that links
or forms bridges between vascular structures—between portal tract and portal tract or even more
important bridges between portal tract and central vein—referred to as bridging necrosis; the
degree of hepatocyte degeneration and focal necrosis within the lobule; and the degree of portal
inflammation. Several scoring systems that take these histologic features into account have been
devised, and the most popular is the numerical histologic activity index (HAI), based on the
work of Knodell and Ishak Technically, the HAI, which is primarily a measure of grade, also
includes an assessment of fibrosis, which is currently used to categorize stage of the disease, as
described below. Based on the presence and degree of these features of histologic activity,
chronic hepatitis can be graded as mild, moderate, or severe.
TABLE Histologic Activity Index (HAI) (Knodell-Ishak Score) in Chronic Hepatitis
HAIa
Histologic Feature
Severity
1. Perioportal necrosis, None
including piecemeal Mild PN
necrosis (PN)
Moderate PN
and/or bridging
Marked PN
necrosis (BN)
Moderate PN + BN
Marked PN + BN
Multilobular necrosis
Modified HAIb
ScoreSeverity
0
1
3
4
5
6
10
None
Mild
Mild/moderate
Moderate
Severe
Score
0
1
2
3
4
2. Intralobular necrosisNone
Mild
Moderate
Marked
0
1
3
4
3. Portal inflammation None
Mild
Moderate
Moderate/marked
Marked
4. Fibrosis
None
Portal fibrosis—some
Portal fibrosis—most
Bridging fibrosis—few
Bridging fibrosis—many
Incomplete cirrhosis
Cirrhosis
Maximum score
0
1
3
3
4
0
1
1
3
3
3
4
22
a
b
Confluent None
Focal
Zone 3 some
Zone 3 most
Zone 3 + BN few
Zone 3 + BN multiple
Panacinar/multiacinar
Focal None
≤ 1 focus/10× field
2–4 foci/10× field
5–10 foci/10× field
>10 foci/10× field
0
1
2
3
4
5
6
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
5
6
Grade 18/Stage 6
“Knodell Score,” Hepatology 1:431, 1981
“Ishak Score,” Hepatology 24:289, 1996
Classification by Stage
The stage of chronic hepatitis, which reflects the level of progression of the disease, is based on
the degree of fibrosis. When fibrosis is so extensive that fibrous septa surround parenchymal
nodules and alter the normal architecture of the liver lobule, the histologic lesion is defined as
cirrhosis. Staging is based on the degree of fibrosis as categorized by one of several numerical
scales.
Reconciliation between Histologic Classification and New Classification
For historic purposes, and to provide the basis for navigating several decades worth of literature
on chronic hepatitis, the histologic categories of chronic persistent hepatitis, chronic lobular
hepatitis, and chronic active hepatitis are correlated with their contemporary counterparts in .
When the early classification was devised, chronic persistent and lobular hepatitis were felt to
have a good prognosis, while chronic active hepatitis was considered a progressive disorder with
a poor prognosis. The prognostic value of these histologic distinctions, however, was found to be
limited, and this classification scheme has been supplanted by distinctions in grade and stage.
TABLE Correlation Between Earlier and Contemporary Nomenclature of Chronic
Hepatitis
Contemporary Classification
Old Classification
Grade (Activity)
Stage (Fibrosis)
Chronic persistent hepatitisa
Chronic lobular hepatitisb
Chronic active hepatitisc
Minimal or mild
Mild or moderate
Mild, moderate, or severe
None or mild
Mild
Mild, moderate, or severe
a
Inflammatory infiltrate localized to, and confined within, portal tracts.
Portal inflammation confined within portal tracts plus foci of necrosis and inflammation in the
liver lobule, resembling slowly resolving acute hepatitis.
c
Erosion of the limiting plate of periportal hepatocytes by inflammatory cells (“piecemeal
necrosis” or “interface hepatitis”), usually with periportal connective tissue septa extending into
the liver lobule. More severe instances involve hepatocellular dropout and collapse spanning
liver lobules (“bridging necrosis”), and, in the most severe form, multilobular collapse, bridging
necrosis, and collapse of lobules are extensive and associated with rapid clinical deterioration.
b
CHRONIC VIRAL HEPATITIS
The term hepatitis describes inflammation of the liver. Hepatitis may be caused by alcohol,
drugs, autoimmune diseases, metabolic diseases, and viruses. Viral infection accounts for more
than half the cases of acute hepatitis in the United States.
The term viral hepatitis is often thought to be synonymous with diseases caused by the known
hepatotropic viruses, including hepatitis viruses A, B, C, D, and E. However, the term
hepatotropic is itself a misnomer. Infections with hepatitis viruses, especially hepatitis viruses B
and C, have been associated with a wide variety of extrahepatic manifestations. Infrequent
causes of viral hepatitis include adenovirus, cytomegalovirus, Epstein-Barr virus, and, rarely,
herpes simplex virus infection. Newly discovered pathogens (eg, virus SEN-V) may account for
additional cases of non-A/non-E hepatitis.
Epidemiology of viral hepatitis
Hepatitis A virus (HAV); hepatitis B virus (HBV); hepatitis C virus (HCV); hepatitis D virus
(HDV), which requires coexisting HBV infection; and hepatitis E virus (HEV) cause 95% of
cases of acute viral hepatitis observed in the United States. Whether hepatitis G virus (HGV) is
pathogenic in humans remains unclear. HAV is the most common cause of acute hepatitis in the
United States; HCV is the most common cause of chronic hepatitis. Typical patterns of virus
transmission are as follows, with + symbols indicating the frequency of transmission (ie, more +
symbols = higher frequency):
1. Fecal-oral transmission
 HAV (+++)
 HEV (+++)
2. Parenteral transmission
 HBV (+++)




HCV (+++)
HDV (++)
HGV (++)
HAV (+)
3. Sexual transmission
 HBV (+++)
 HDV (++)
 HCV (+)
4. Perinatal transmission
 HBV (+++)
 HCV (+)
 HDV (+)
5. Sporadic (unknown) transmission
 HBV (+)
 HCV (+)
Natural history of chronic viral hepatitis
Approximately 90-95% of cases of acute hepatitis B in neonates, 5% of cases of acute hepatitis B
in adults, and as many as 85% of cases of acute hepatitis C demonstrate histologic evolution to
chronic hepatitis. Some patients with chronic hepatitis remain asymptomatic for their entire
lives. Other patients report fatigue (ranging in severity from mild to severe) and dyspepsia.
Approximately 20% of patients with chronic hepatitis B or hepatitis C eventually develop
cirrhosis, histologically. While some patients with cirrhosis are asymptomatic, others develop
life-threatening complications. The clinical illnesses of chronic hepatitis and cirrhosis may take
months, years, or decades to evolve.
HEPATITIS B

Hepatitis B virus
HBV is a member of the Hepadnaviridae family. It is a 3.2-kb partially doubled-stranded DNA
virus. Its positive strand is incomplete. The complete negative strand has 4 overlapping genes.
Gene S codes for HBsAg, also known as surface antigen, a viral surface polypeptide. Gene C
codes for HBcAg, also known as core antigen, the nucleocapsid protein. It also codes for
HBeAg, whose function is unknown. Gene P codes for a DNA polymerase that has reverse
transcriptase activity. Gene X codes for the X protein that has transcription-regulating activity.
The viral core particle consists of a nucleocapsid, HBcAg, which surrounds HBV DNA, and
DNA polymerase. The nucleocapsid is coated with HBsAg. The intact HBV virion is known as
the Dane particle. Dane particles and spheres and tubules containing only HBsAg are found in
the blood of infected patients. In contrast, HBcAg is not detected in the circulation. It can be
identified by immunohistochemical staining of infected liver tissue.
Eight genotypic variants of the HBV (genotypes A-H) are described. Although preliminary
studies suggest that particular HBV genotypes may predict the virus' response to therapy or may
be associated with more aggressive disease, incorporating HBV genotype testing into clinical
practice is premature.
 Mechanism of hepatocyte necrosis in HBV infection
HBV may be directly cytopathic to hepatocytes. However, immune system–mediated
cytotoxicity plays a predominant role in causing liver damage. The immune assault is driven by
human leukocyte antigen class I–restricted CD8 cytotoxic T lymphocytes that recognize HBcAg
and HBeAg on the cell membranes of infected hepatocytes.
 Epidemiology of HBV
Infection with HBV is defined by the presence of HBsAg. Approximately 5% of the world's
population (ie, 300 million people) is chronically infected with HBV. More than 10% of people
living in sub-Saharan Africa and in East Asia are infected with HBV. Maintenance of a high
HBsAg carriage rate in these parts of the world is partially explained by the high prevalence of
perinatal transmission and by the low rate of HBV clearance by neonates.
Of cases of chronic HBV infection, 20% progress to cirrhosis or hepatocellular carcinoma
(HCC), resulting in 1-2 million deaths each year. This makes hepatitis B the ninth leading cause
of death in the world.
Approximately 200,000 new cases of HBV infection occur each year in the United States.
Approximately 250-350 patients die from HBV-associated FHF each year.
 Transmission of HBV
HBV is readily detected in serum. It is seen at very low levels in semen, vaginal mucus, saliva,
and tears. The virus is not detected in urine, stool, or sweat. HBV can survive storage at -20°C (4°F) and heating at 60°C (140°F) for 4 hours. It is inactivated by heating at 100°C (212°F) for 10
minutes or by washing with sodium hypochlorite (bleach).
1. Perinatal transmission of HBV
The vast majority of HBV cases around the world result from perinatal transmission. Infection
appears to be due to contact with a mother's infected blood at the time of delivery, as opposed to
transplacental passage of the virus. Neonates infected via perinatal infection are usually
asymptomatic. Although breast milk can contain HBV virions, the role of breastfeeding in
transmission is unclear.
2. Sexual transmission of HBV
HBV is transmitted more easily than HIV or HCV. Infection is associated with vaginal
intercourse, genital-rectal intercourse, and oral-genital intercourse. An estimated 30% of sexual
partners of patients infected with HBV also contract HBV infection. However, HBV cannot be
transmitted through kissing, hugging, or household contact such as sharing towels, eating
utensils, or food. Sexual activity is estimated to account for as many as 50% of HBV cases in the
United States.
3. Parenteral transmission of HBV
HBV was once a common cause of posttransfusion hepatitis. Screening of US blood donors for
HBcAb, beginning in the early 1970s, dramatically reduced the rate of HBV infection associated
with blood transfusion. Currently, approximately 1 HBV transmission occurs per 250,000
individuals transfused.
4. Sporadic cases of hepatitis B
The cause of HBV infection is unknown in approximately 27% of cases. Some these cases, in
fact, may be due to sexual transmission or contact with blood.

Natural history of HBV
The incubation period of HBV is 40-150 days, with an average of approximately 12 weeks. As
with HAV, the clinical illness associated with acute HBV infection may range from mild disease
to a disease as severe as FHF (<1% of patients).
After acute hepatitis resolves, 95% of adult patients and 5-10% of infected infants ultimately
develop anti-HBV antibody, clear HBsAg (and HBV virions), and fully recover. Five percent of
adult patients and 90-95% of infected infants develop chronic infection.
 Inactive carrier state
With the development of chronic infection (as marked by a positive HBsAg finding), 70-90% of
HBsAg carriers enter the inactive carrier state (previously known as the healthy carrier state).
They have no symptoms, normal liver chemistry test results, and normal or minimally abnormal
liver biopsy results. Blood test evidence of HBV replication should be nonexistent or minimal,
with a serum HBV DNA level in the range of 0-30,000 copies (genomes)/mL. Inactive carriers
remain infectious to others through parenteral or sexual transmission.
Inactive carriers may ultimately develop HBsAb and clear the virus. However, some inactive
carriers develop chronic hepatitis, as determined by liver chemistry results, liver biopsy findings,
and HBV DNA levels. Inactive carriers remain at risk, albeit low, to develop HCC. At this point,
no effective antiviral therapies are available for patients in an inactive carrier state.
Chronic hepatitis B
Of HBsAg carriers, 10-30% develop chronic hepatitis. These patients are often symptomatic.
Fatigue is the most common symptom of chronic HBV infection. Patients may occasionally
experience an acute flare of their disease, with symptoms and signs similar to those of acute
hepatitis. Patients also may have extrahepatic manifestations of their disease, including
polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis.
Chronic hepatitis B patients have abnormal liver chemistry results, blood test evidence for active
HBV replication, and inflammatory or fibrotic activity on liver biopsy specimens. Patients with
chronic hepatitis may be considered either HBeAg-positive or HBeAg-negative.
Ultimately, approximately 20% of HBsAg carriers (approximately 1% of all adult patients
infected acutely with HBV) go on to develop cirrhosis or HCC.
Patients with HBeAg-positive chronic hepatitis have signs of active viral replication with an
HBV DNA level greater than 105 copies (genomes)/mL. HBV DNA levels may be as high as
1011 copies/mL.
Patients with HBeAg-negative chronic hepatitis were presumably infected with wild-type virus
at some point. Over time, they acquired a mutation in either the precore or the core promoter
region of the viral genome. In such patients with a precore mutant state, HBV continues to
replicate but HBeAg is not produced. Patients with a core mutant state appear to have downregulated HBeAg production. HBeAg-negative patients typically have lower HBV DNA levels
than HBeAg-positive patients. More than half are noted to have an HBV DNA level less than
105 copies/mL.
Diagnosis of chronic HBV infection
HBsAg may remain detectable for life in many patients. Individuals who have positive findings
for HBsAg are termed carriers of HBV; they may be inactive carriers or they may have chronic
hepatitis. Anti-HBc is present in all patients with chronic HBV infections. HBeAg and HBV
DNA may or may not be present. If present, they reflect a state of active viral replication and a
high level of infectivity. Anti-HBs are usually absent in patients with chronic infection. If antiHBs are present in a patient who has positive HBsAg findings, it reflects the presence of a low
level of antibody that was unsuccessful at inducing viral clearance.
Pathologic findings of HBV infection
Inactive carriers of HBV have no or minimal histologic abnormalities detected on liver biopsy
specimens.
Patients with chronic hepatitis B may have a number of classic histologic abnormalities.
Inflammatory infiltrates composed of mononuclear cells may either remain contained within the
portal areas or disrupt the limiting plates of portal tracts, expanding into the liver lobule
(interface hepatitis). Periportal fibrosis or bridging necrosis (between portal tracts) may be
present. The presence of bridging necrosis places the patient at increased risk for progression to
cirrhosis. Ground-glass cells may be seen. This term describes the granular homogeneous
eosinophilic staining of cytoplasm caused by the presence of HBsAg. Sanded nuclei reflect the
presence of an overload of HBcAg. Special immunohistochemical stains may help detect HBsAg
and HBcAg.
Treatment of chronic hepatitis B
The key goal of antiviral treatment of HBV is the inhibition of viral replication, as marked by the
loss of HBeAg and HBV DNA. Secondary goals are to reduce symptoms, if any, and to prevent
or delay the progression of chronic hepatitis to cirrhosis or HCC.
Antiviral therapy infrequently leads to viral eradication, as marked by the loss of HBsAg.
Currently, no antiviral therapy is available for inactive carriers who do not have actively
replicating virus.
Candidates for antiviral therapy must have evidence of active HBV infection. This is generally
defined as the presence of HBV DNA greater than 105 copies/mL in patients who are positive
for HBeAg or HBV DNA greater than 104 copies/mL in patients who are negative for HBeAg.
Patients tend to have abnormal liver chemistry findings. Treatment may be offered to patients
with a normal alanine aminotransferase (ALT) level, but it may be less efficacious. Although
performing a liver biopsy is not mandatory prior to treatment, the author recommends it. Liver
biopsy is helpful for confirming the clinical diagnosis of chronic hepatitis B and for documenting
the severity of liver disease.
 Interferon alfa treatment for chronic hepatitis B
Interferons have both antiviral and immunomodulatory effects. Treatment with interferon alfa is
appropriate for some patients with chronic hepatitis B.
The most commonly used dose of interferon alfa-2b is 5 million U/d subcutaneously for at least
16 weeks. Alternatively, 10 million units may be injected subcutaneously 3 times per week for at
least 16 weeks. Pegylated interferon alfa may also be used once per week by subcutaneous
injection.

Lamivudine for chronic hepatitis B
Lamivudine (Epivir, GlaxoSmithKline; Research Triangle Park, NC) is the negative enantiomer
of 2'3'-dideoxy-3'-thiacytidine. This synthetic nucleoside analogue inhibits DNA polymerase–
associated reverse transcriptase and can suppress HBV replication. Treatment with a dose of 100
mg/d orally for 1 year result in loss of HBeAg in 32% of patients. Treatment also induces
histologic improvement and a statistically significant reduction in the rate of development of
hepatic fibrosis.

HBV vaccine
Plasma-derived and recombinant HBV vaccines use HBsAg to stimulate the production of antiHBs in noninfected individuals. The vaccines are highly effective, with a greater than 95% rate
of seroconversion. Vaccine administration is recommended for all infants and for adults at high
risk of infection (eg, those on dialysis, health care workers).
The recommended vaccination schedule for infants is an initial vaccination at the time of birth
(ie, before hospital discharge), repeat vaccination at 1-2 months, and another repeat vaccination
at 6-18 months. The recommended vaccination schedule for adults is an initial vaccination, a
repeat vaccination at 1 month, and another repeat vaccination at 6 months.
HEPATITIS C

Hepatitis C virus
HCV is a Flavivirus. It is a 9.4-kb RNA virus with a diameter of 55 nm. It has one serotype and
multiple genotypes. HCVs have profound genetic variability throughout the world. At least 6
major genotypes and more than 80 subtypes are described, with as little as 55% genetic sequence
homology. Genotype 1b is the genotype most commonly seen in the United States, Europe,
Japan, and Taiwan. Genotypes 1b and 1a (also common in the United States) are thought to be
less responsive to interferon therapy than other HCV genotypes. The genetic variability of HCV
hampers the efforts of scientists to design an effective anti-HCV vaccine.
Epidemiology of hepatitis C
Hepatitis C is prevalent in 0.5-2% of populations in nations around the world. An estimated 4
million Americans are infected with HCV. In the 1980s, as many as 180,000 new cases of HCV
infection were described each year in the United States. Currently, approximately 28,000 new
cases are documented each year. The decreasing incidence of HCV is explained by a decline in
the number of cases of transfusion-associated hepatitis (because of improved screening of blood
products) and by a decline in the number of cases associated with intravenous drug use.
1. Transmission of HCV via blood transfusion
Screening of the US blood supply has dramatically reduced the incidence of transfusionassociated HCV infection. Prior to 1990, 37-58% of cases of acute HCV infection (then known
as NANB) were attributed to the transfusion of contaminated blood products. Now, only
approximately 4% of acute cases are attributed to transfusion. HCV is estimated to contaminate
0.01-0.001% of units of transfused blood. Acute hepatitis C remains an important issue in
dialysis units, where patients' risk for HCV infection is approximately 0.15% per year.
2. Transmission of HCV via intravenous and intranasal drug use
Intravenous drug use remains an important mode of transmitting HCV. Intravenous drug use and
the sharing of paraphernalia used in the intranasal snorting of cocaine and heroin account for
approximately 60% of new cases of HCV infection. More than 90% of patients with a history of
intravenous drug use have been exposed to HCV.
3. Transmission of HCV via occupational exposure
Occupational exposure to HCV accounts for approximately 4% of new infections. On average,
the chance of acquiring HCV after a needle stick injury involving an infected patient is 1.8%
(range, 0-7%). Importantly, reports of HCV transmission from health care workers to patients are
extremely uncommon.
4. Transmission of HCV via sexual contact
Approximately 20% of cases of hepatitis C appear to be due to sexual contact. In contrast to
hepatitis B, approximately 5% of the sexual partners of those infected with HCV contract
hepatitis C. Currently, the US Public Health Service recommends that persons infected with
HCV be informed of the potential for sexual transmission. Sexual partners should be tested for
the presence of anti-HCV. Safe sex precautions are recommended for patients with multiple sex
partners. Current guidelines do not recommend the use of barrier precautions for patients with a
steady sexual partner. However, it is recommended that patients avoid sharing razors and
toothbrushes with others. Additionally, contact with patients' blood should be avoided.
5. Transmission of HCV via perinatal transmission
Perinatal transmission appears to be uncommon. It is observed in fewer than 5% of children born
to mothers infected with HCV. The risk of perinatal transmission of HCV is higher, estimated at
18%, in children born to mothers co-infected with HIV and HCV. Available data show no
increase in HCV infection in babies who are breastfed. The US Public Health Service does not
advise against pregnancy or breastfeeding for women infected with HCV.
 Natural history of chronic hepatitis C
Approximately 15% of patients acutely infected with HCV lose virologic markers for HCV.
Thus, approximately 85% of newly infected patients remain viremic and may develop chronic
liver disease. In chronic hepatitis, patients may or may not be symptomatic, with fatigue being
the predominant reported symptom. Aminotransferase levels may fluctuate from the reference
range (<40 U/L) to 300 U/L. However, no clear-cut association exists between aminotransferase
levels and symptoms or risk of disease progression.
 Natural history of cirrhosis induced by hepatitis C
An estimated 20% of patients with chronic hepatitis C experience progression to cirrhosis. This
process may take 10-40 years to evolve. Importantly, patients who are newly diagnosed with
well-compensated cirrhosis must be counseled regarding their risk of developing symptoms of
liver failure (ie, decompensated cirrhosis). Only 30% of patients with well-compensated cirrhosis
are anticipated to decompensate over a 10-year follow-up period.
Patients with HCV-induced cirrhosis are also at increased risk for the development of HCC,
especially in the setting of HBV co-infection. In the United States, HCC arises in 3-5% of
patients with HCV-induced cirrhosis each year. Accordingly, routine screening (eg, ultrasound
and AFP testing every 6 mo) is recommended in patients with HCV-induced cirrhosis to rule out
the development of HCC.
End-stage liver disease caused by HCV leads to 8000-10,000 deaths each year.

Extrahepatic manifestations of hepatitis C
Patients with chronic hepatitis C are at risk for extrahepatic complications. In essential mixed
cryoglobulinemia, HCV may form immune complexes with anti-HCV (IgG) and with
rheumatoid factor. The deposition of immune complexes may cause small-vessel damage.
Complications of cryoglobulinemia include rash, vasculitis, and glomerulonephritis. Other
extrahepatic complications of HCV infection include focal lymphocytic sialadenitis, autoimmune
thyroiditis, porphyria cutanea tarda, lichen planus, and Mooren corneal ulcer.

Pathologic findings of hepatitis C
Lymphocytic infiltrates, either contained within the portal tract or expanding out of the portal
tract into the liver lobule (interface hepatitis), are commonly observed in patients with chronic
hepatitis C. Portal and periportal fibrosis may be present. Other classic histologic features of the
disease include bile duct damage, lymphoid follicles or aggregates, and macrovesicular steatosis.
Pathologists who interpret liver biopsy specimens frequently use a histologic scoring system
introduced by Batts and Ludwig in 1995, which is displayed in the Table. The METAVIR
scoring system (developed by the French METAVIR Cooperative Study Group) uses similar
methodology.
Histologic Grading for Hepatitis C–Induced Liver Disease
Grade
1 - Minimal
2 - Mild
3 - Moderate
4 - Severe
Portal
Inflammation
Mild
Mild
Moderate
Marked
Interface
Hepatitis
Scant
Mild
Moderate
Marked
Lobular
Necrosis
None
Scant
Spotty
Confluent
The histologic staging for hepatitis C–induced liver disease is as follows:
Stage 1 - Portal fibrosis
Stage 2 - Periportal fibrosis
Stage 3 - Septal fibrosis
Stage 4 - Cirrhosis
Diagnosis of hepatitis C
The most common tests used in the diagnosis of hepatitis C include liver chemistries, serologic
tests, HCV RNA tests, and liver biopsies.

Diagnosis of hepatitis C using liver chemistry testing
Elevations of the aspartate aminotransferase (AST) and ALT merely indicate the presence of
liver injury. Patients with chronically elevated aminotransferase values should undergo a workup
to exclude the possibility of chronic liver disease.
 Diagnosis of hepatitis C using serologic tests for HCV
Structural and nonstructural regions of the HCV genome have been synthesized. These can be
recognized by human IgG anti-HCV. Recombinant HCV antigens are used in enzyme-linked
immunoabsorbent assays (ELISAs) to detect anti-HCV in patients' sera.

Diagnosis of hepatitis C using HCV RNA tests
PCR assays and branched DNA assays have been used since the early 1990s to detect HCV RNA
in serum. In contrast to ELISA and RIBA testing, HCV RNA testing can confirm the presence of
active HCV infection.

Diagnosis of hepatitis C using liver biopsy
Liver biopsy is an important diagnostic test in possible cases of chronic hepatitis C. Biopsy can
help confirm the diagnosis and can help exclude other diseases that might have an impact on
antiviral therapy, such as autoimmune hepatitis or hemochromatosis. Furthermore, liver biopsy
offers the most reliable assessment of the severity of disease.
Patients with minimal inflammatory or fatty changes on biopsy specimens may elect to not
receive antiviral therapy. Such patients may return for repeat biopsy in 3-4 years to rule out
progression of liver disease. Patients with previously unsuspected cirrhosis on biopsy specimens
should be monitored to ensure they do not develop large esophageal varices or HCC.
Furthermore, knowledge of the severity of histologic changes may influence the patient and the
physician to be more aggressive or less aggressive in the pursuit of effective antiviral therapy.
Patients with advanced histologic findings may seek experimental therapies should they not
respond to standard antiviral therapy.
Treatment of HCV infection
Antiviral therapy has a number of major goals. These include (1) to decrease viral replication or
eradicate HCV, (2) to prevent progression of disease, (3) to decrease the prevalence of cirrhosis,
(4) to decrease the frequency of HCC as a complication of cirrhosis, (5) to ameliorate symptoms
such as fatigue and joint pain, and (6) to treat extrahepatic complications of HCV infection such
as cryoglobulinemia or glomerulonephritis.
Interferons are a class of naturally occurring compounds that have both antiviral and
immunomodulatory effects. Currently, they are the backbone of antiviral strategies used against
HCV infection. Future medications may target the enzymes responsible for HCV replication and
may have activity against viral helicases, proteases, and polymerases.

Treatment of chronic hepatitis C
Interferon alfa-2b, dosed at 3 million units subcutaneously 3 times per week, was approved by
the FDA in 1991 for the treatment of chronic HCV infection. Patients treated with this interferon,
and with subsequently introduced interferon alfa-2a and consensus interferon, had only an 1112% chance of obtaining a sustained virologic response (ie, a persistently undetectable HCV
RNA level).
The combination of ribavirin, a nucleoside analog, with interferon significantly improved
patients' responses to treatment. The sustained virologic response after 48 weeks of treatment
improved from 13% in patients treated with interferon alfa-2b alone to 38% in patients treated
with interferon alfa-2b in combination with ribavirin at 1000-1200 mg/d orally. So-called
combination therapy received approval from the FDA in 1998.

Limitations of antiviral therapy
Not all patients with chronic hepatitis C are appropriate candidates for therapy with interferon
and ribavirin. First, the medications have well-known adverse effects, which lead to drug
discontinuation in approximately 15% of patients. Interferon can induce fatigue, joint pain,
depression, alopecia, neutropenia, and thrombocytopenia. Interferon has been known to induce
the development of thyroid disease or exacerbate an underlying immune-mediated disease (eg,
psoriasis, sarcoidosis). Ribavirin commonly produces a hemolytic anemia and can induce a rash.
Patients with baseline thrombocytopenia (eg, platelet count <70,000/mL) are not anticipated to
tolerate interferon administration. Patients with underlying psychiatric disorders must be
screened carefully before receiving a drug that has the potential to worsen underlying depression
or schizophrenia or even induce suicidal ideation.
HEPATITIS D
 Hepatitis D virus
HDV is a single-stranded, 1.7-kb RNA virus. The viral particle is 36 nm in diameter and contains
HDAg and the RNA strand. It uses HBsAg as its envelope protein. Thus, HBV co-infection is
necessary for the packaging and release of HDV virions from infected hepatocytes.
 Epidemiology of HDV
HDV is believed to infect approximately 5% of the world's 300 million HBsAg carriers. The
prevalence of HDV infection in South America and Africa is high. Italy and Greece are areas of
intermediate endemicity and are well studied. The sharing of contaminated needles in
intravenous drug use is thought to be the most common means of transmitting HDV. Persons
who use intravenous drugs who are also positive for HBsAg have been found to have HDV
prevalence rates ranging from 17-90%. Sexual and perinatal transmission also are described. The
prevalence of HDV in prostitutes in Greece and Taiwan is high.
 Natural history of HDV co-infection
Simultaneous introduction of HBV and HDV into a patient results in the same clinical picture as
acute infection with HBV alone. The resulting acute hepatitis may be mild or severe. Similarly,
the risk of developing chronic HBV and HDV infection after acute exposure to both viruses is
the same as the rate of developing chronic HBV infection after acute exposure to HBV
(approximately 5% in adults). However, chronic HBV and HDV disease tends to progress more
rapidly to cirrhosis than chronic HBV infection alone.
 Natural history of HDV superinfection
Introduction of HDV into an individual already infected with HBV may have dramatic
consequences. Superinfection may give HBsAg-positive patients the appearance of a sudden
worsening or flare of hepatitis B. HDV superinfection may result in FHF.
 Pathologic findings of HDV infection
Pathologic abnormalities associated with HBV/HDV infection are the same as those observed in
patients infected with HBV alone.
 Diagnosis of HDV infection
A serologic diagnosis of HDV infection is made by using IgM anti-HDV and IgG anti-HDV
tests. HBcAb IgM should be used to help distinguish between co-infection (HBcAb IgM–
positive) and superinfection (HBcAb IgM–negative). Detecting HDV RNA in serum is also
possible.
 Treatment of hepatitis D
Patients co-infected with HBV and HDV are less responsive to interferon therapy than patients
infected with HBV alone. To date, lamivudine appears to be ineffective against HBV/HDV coinfection.
HEPATITIS E
 Hepatitis E virus
HEV is a Calicivirus. It is a 7.5-kb single-stranded RNA virus and is 32-34 nm. The virus has an
incubation period of 2-9 weeks.
 Epidemiology of HEV
HEV is transmitted via the fecal-oral route. HEV appears to be endemic in some parts of the
lesser-developed countries. Anti-HEV antibodies are observed in as many as 60% of Indian
children younger than 5 years. Sporadic infections are observed in persons traveling from
western countries to these regions.
 Natural history of HEV
HEV primarily infects adults and young adults. Acute infection is generally less severe than
acute HBV infection and is characterized by fluctuating aminotransferase levels. However,
pregnant women, especially when infected during the third trimester, have up to a 25% risk of
mortality associated with acute HEV infection. HEV does not appear to cause chronic liver
disease.
 Pathologic findings of HEV infection
The classic pathological findings include infiltration of portal tracts by lymphocytes and
polymorphonuclear leukocytes, ballooned hepatocytes, acidophilic body formation, and the
intralobular necrosis of hepatocytes. Submassive and massive hepatic necrosis may be observed
in severe cases.
 Diagnosis of HEV infection
The serologic diagnosis is made by using IgM anti-HEV and IgG anti-HEV. HEV RNA can be
detected in the serum and stool of infected patients.
 Treatment of hepatitis E
The treatment of those infected with HEV is supportive in nature.
HEPATITIS G
HGV is similar to viruses in the Flaviviridae family, which includes HCV. The HGV genome
codes for 2900 amino acids. The virus has 95% homology (at the amino acid level) with the GB
virus (ie, GBV-C), a previously described virus. HGV has 26% homology (at the amino acid
level) with HCV.
HGV can be transmitted by blood transfusion. HGV co-infection is observed in 6% of chronic
HBV infections and in 10% of chronic HCV infections. However, whether HGV is actually
pathogenic in humans remains unclear.
AUTOIMMUNE HEPATITIS
During the past 30 years, remarkable advances have occurred in the understanding of the
epidemiology, natural history, and pathogenesis of chronic hepatitis. The development of viral
serologic tests has permitted hepatologists to differentiate chronic viral hepatitis from other types
of chronic liver disease, including autoimmune hepatitis. Autoimmune hepatitis is now accepted
as a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation
and necrosis, which tends to progress to cirrhosis. Immune serum markers frequently are present,
and the disease often is associated with other autoimmune diseases. Autoimmune hepatitis
cannot be explained based on chronic viral infection, alcohol consumption, or exposure to
hepatotoxic medications or chemicals.
In 1950, Waldenstrom first described a form of chronic hepatitis in young women. This
condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked
hypergammaglobulinemia. Kunkel, in 1950, and Bearn, in 1956, described other features of the
disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented
abdominal striae, obesity, arthritis, and amenorrhea. In 1955, Joske first reported the association
of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis. This
association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956.
Researchers currently know that no direct link exists between systemic lupus erythematosus
(SLE) syndrome and autoimmune hepatitis; thus, lupoid hepatitis is not associated with SLE.
Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and
females of all ages. This condition can coexist with other liver diseases (eg, chronic viral
hepatitis) and also may be triggered by certain viral infections (eg, hepatitis A) and chemicals
(eg, minocycline).
The histopathologic description of autoimmune hepatitis has undergone several revisions over
the years. In 1992, an international panel last codified the diagnostic criteria. The term
autoimmune hepatitis was selected to replace terms such as autoimmune liver disease and
autoimmune chronic active hepatitis. The panel waived the requirement of 6 months of disease
activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and
reaffirmed the nonviral nature of the disease. The panel also designated incompatible histologic
features, such as cholestatic histology, the presence of bile duct injury, and ductopenia.
Frequency
In the US: The frequency of autoimmune hepatitis among patients with chronic liver disease
ranges from 11-23%.
Internationally: The frequency of autoimmune hepatitis among patients with chronic liver
disease in North America is 11-23%. Incidence in Western Europe is 0.69 cases per 100,000
persons per year; this statistic can be applied to other ethnically similar populations. Prevalence
is greatest among northern European/Caucasian groups with a high frequency of HLA-DR3 and
HLA-DR4 markers.
Women are affected more often than men (70-80% of patients are women).
Autoimmune hepatitis usually is detected in the third to fifth decades of life, but young children
and older adults also are affected. Men are affected more commonly than women in older age
groups.
Causes
Autoimmune hepatitis is a chronic disease of unknown etiology.
Pathophysiology
Evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cellmediated immunologic attack. This attack is directed against genetically predisposed
hepatocytes. Aberrant display of human leukocyte antigen (HLA) class II on the surface of
hepatocytes facilitates the presentation of normal liver cell membrane constituents to antigenprocessing cells. These activated cells, in turn, stimulate the clonal expansion of autoantigen-
sensitized cytotoxic T lymphocytes. Cytotoxic T lymphocytes infiltrate liver tissue, release
cytokines, and help to destroy liver cells.
The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic
factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection), and chemical
agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid).
The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed
as the triggering autoantigens.
Some patients appear to be genetically susceptible to developing autoimmune hepatitis. This
condition is associated with the complement allele C4AQO and with the HLA haplotypes B8,
B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of
autoimmune hepatitis in younger patients. HLA DR3-positive patients are more likely than other
patients to have aggressive disease, which is less responsive to medical therapy; these patients
are younger than other patients at the time of their initial presentation. HLA DR4-positive
patients are more likely to develop extrahepatic manifestations of their disease.

Evidence for an autoimmune pathogenesis includes the following:
1. Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells
2. Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal,
soluble liver antigen, hepatic lectin)
3. Association with hypergammaglobulinemia and the presence of a rheumatoid factor
4. Association with other autoimmune diseases
5. Response to steroid and/or immunosuppressive therapy
The autoantibodies described in these patients include the following:

Antinuclear antibody (ANA), primarily in a homogenous pattern

Anti–smooth muscle antibody (ASMA) directed at actin

Anti–liver-kidney microsomal antibody (anti–LKM-1)

Antibodies against soluble liver antigen (anti-SLA) directed at
cytokeratins types 8 and

Antibodies to liver-specific asialoglycoprotein receptor or hepatic
lectin

Antimitochondrial antibody (AMA) - The sine qua non of primary
biliary cirrhosis (PBC) but may be observed in the so-called overlap syndrome
with autoimmune hepatitis

Antiphospholipid antibodies
Based on autoantibody markers, autoimmune hepatitis is recognized as a heterogeneous disorder
and has been subclassified into 3 types. The distinguishing features of these types are noted in
the Table.
Clinical Features
Diagnostic
autoantibodies
Age
Women (%)
Clinical Characteristics of Autoimmune Hepatitis
Type 1
Type 2
Type 3
Anti-LKMP-450
IID6Synthetic core
Soluble liver-kidney
ASMA
motif peptides 254- antigenCytokeratins 8
ANAAntiactin
271
and 18
Bimodal (10-20 y
Pediatric (2-14
and 45-70 y)
y)Rare in adults
Adults (30-50 y)
78
89
90
Concurrent
immune disease
(%)
Gamma globulin
elevation
Low IgA*
HLA association
Steroid response
Progression to
cirrhosis (%)
*Immunoglobulin A
41
34
58
+++
No
B8, DR3, DR4
+++
+
Occasional
B14, Dr3, C4AQO
++
++
No
Uncertain
+++
45
82
75
CLINICAL
History
Clinical features of autoimmune hepatitis
Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established
cirrhosis.
Approximately one third of patients present with symptoms of acute hepatitis marked by fever,
hepatic tenderness, and jaundice. In some patients, the acute illness may appear to resolve
spontaneously; however, patients invariably develop signs and symptoms of chronic liver
disease. Other patients experience rapid progression of the disease to acute liver failure, as
marked by coagulopathy and jaundice. Ascites and hepatic encephalopathy also may ensue.
Clinicians must consider the diagnosis of autoimmune hepatitis when confronted with a patient
who has acute hepatitis or acute liver failure (defined by the new onset of coagulopathy). The
workup of such patients should include testing for serum ANA, ASMA, serum protein
electrophoresis (SPEP), and quantitative immunoglobulins. Urgent liver biopsy, transjugular if
appropriate, may help to confirm the clinical suspicion of acute autoimmune hepatitis. Rapid
institution of treatment with high-dose corticosteroids may rescue patients whose disease
ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Other patients
continue to deteriorate in spite of immunosuppressant therapy. Accordingly, a low threshold
should exist for transferring patients with acute liver failure to tertiary care hospitals that are
capable of performing emergent liver transplantation.
The chronic hepatitis associated with autoimmune hepatitis may range in severity from a
subclinical illness without symptoms and with abnormal results on liver chemistries to a
disabling chronic liver disease. Symptoms and physical examination findings may stem from the
various extrahepatic diseases associated with autoimmune hepatitis.
Common symptoms include the following:









Fatigue
Upper abdominal discomfort
Mild pruritus
Anorexia
Myalgia
Diarrhea
Cushingoid features
Arthralgias
Skin rashes (including acne)





Edema
Hirsutism
Amenorrhea
Chest pain from pleuritis
Weight loss and intense pruritus (unusual)
Without therapy, most patients die within 10 years of disease onset. Treatment with
corticosteroids has been shown to improve the chances for survival significantly. Indeed, the life
expectancy of patients in clinical remission is similar to that of the general population.
Many patients have histologic evidence of cirrhosis at the onset of symptoms. This is true both
for patients with an initial presentation of acute hepatitis and for patients with chronic hepatitis.
Thus, subclinical disease often precedes the onset of symptoms.
As many as 20% of patients present initially with signs of decompensated cirrhosis. In other
patients, chronic hepatitis progresses to cirrhosis after years of unsuccessful immunosuppressant
therapy marked by multiple disease relapses. Patients with cirrhosis may experience classic
symptoms of portal hypertension, namely variceal bleeding, ascites, and hepatic encephalopathy.
Patients with complications of cirrhosis should be referred for consideration of liver
transplantation.
Disease associations: Autoimmune hepatitis, especially type 2, is associated with a wide variety
of other disorders. Involvement of other systems may present at disease onset or may develop
during the course of active liver disease. These conditions, most of which are immunologic in
origin, include the following:
 Hematologic complications
 Hematologic manifestations of hypersplenism
 Autoimmune hemolytic anemia
 Coombs-positive hemolytic anemia
 Pernicious anemia
 Idiopathic thrombocytopenic purpura
 Eosinophilia
 Gastrointestinal complications
 The hepatitis C connection
The hepatitis C virus (HCV) has several important associations with autoimmune hepatitis. The
prevalence rate of HCV infection in patients with autoimmune hepatitis is similar to that in the
general population.
Although autoimmune hepatitis and chronic HCV have similar histologic features, moderate-tosevere plasma cell infiltration of the portal tracts is more common in patients with autoimmune
hepatitis. Portal lymphoid aggregates, steatosis, and bile duct damage are more common in
patients with chronic HCV.
Overlap syndromes
Patients with autoimmune hepatitis may present with features that overlap those classically
associated with patients with PBC and PSC. Patients with disease that overlaps with PBC may
have detectable AMA (usually in low titer), histologic findings of bile duct injury and/or
destruction, and the presence of hepatic copper. These patients may improve with steroid
therapy. Patients with disease that overlaps with PSC usually have concurrent inflammatory
bowel disease, and the liver biopsy findings reveal bile duct injury. Findings from
cholangiograms are abnormal. Such patients usually have mixed hepatocellular and cholestatic
liver chemistries and typically are resistant to steroid therapy.
Autoimmune cholangitis is characterized by mixed hepatic and cholestatic liver chemistries,
positive ANA and/or ASMA, negative AMA, antibodies to carbonic anhydrase, and histology
that resembles PBC. Patients may have an unpredictable response to therapy with steroids or
ursodeoxycholic acid.

Cryptogenic autoimmune hepatitis is characterized by a clinical
picture that is indistinguishable from autoimmune hepatitis. ANA, ASMA, and
anti–LKM-1 are negative at disease onset and may appear late in the disease
course, as might anti-SLA. The disease usually is responsive to steroid therapy.
Physical
Common findings on physical examination are as follows:
 Hepatomegaly (83%)
 Jaundice (69%)
 Splenomegaly (32%)
 Spider angiomata (58%)
 Ascites (20%)
 Encephalopathy (14%)
All of these findings may be observed in patients with disease that has progressed to the point of
cirrhosis with ensuing portal hypertension; however, hepatomegaly, jaundice, splenomegaly, and
spider angiomata also may be observed in patients who do not have cirrhosis.
Lab Studies
1. Autoantibodies
Autoimmune hepatitis is characterized by positive findings on autoantibody tests. Autoimmune
hepatitis type 1 is characterized by positive test results for ASMA and ANA. Type 2 disease is
observed infrequently in the United States, but it is well characterized in Europe. Type 2 disease
is marked by a positive test result for anti–LKM-1 antibody. Type 3 disease also is observed
infrequently in the United States. Type 3 is marked by a positive test result for anti-SLA
antibody.
2. Serum protein electrophoresis and quantitative immunoglobulins
An immunoglobulin G (IgG)–predominant polyclonal hypergammaglobulinemia is a common
finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range
from 3-4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome
secondary to high IgG levels are reported. Autoimmune hepatitis is an unlikely diagnosis in
patients who have acute hepatitis without hypergammaglobulinemia.
The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease
responsiveness to therapy.
3. Aminotransferases
Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase
[ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300
U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however,
values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.
Continued elevation of the aminotransferases in the face of ongoing therapy is a reliable marker
for ongoing inflammatory activity in the liver. Normalization of the aminotransferase levels
during therapy is an encouraging sign, but active liver inflammation is present in more than 50%
of patients with normalized liver chemistries. Indeed, biochemical remission may precede true
histologic remission by 3-12 months; thus, patients should be treated for at least 1 year after
documentation of normal liver chemistries. Liver biopsy then may be employed to determine
whether the patient is in histologic remission. Drug withdrawal may be attempted at this time.
Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in
remission may signal a resurgence of disease activity.
4. Other liver chemistries
Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80-90%
of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmune
disease might reflect the development of PSC or the onset of hepatocellular carcinoma as a
complication of cirrhosis.
Hypoalbuminemia and prolongation of prothrombin time are markers of severe hepatic synthetic
dysfunction, which may be observed in active disease or decompensated cirrhosis.
5. Other common laboratory abnormalities
 Mild leukopenia
 Normochromic anemia
 Coombs-positive hemolytic anemia
 Thrombocytopenia
 Elevated sedimentation rate
 Eosinophilia (uncommon but counts ranging from 9-48% are described)
Autoimmune hepatitis even has been described as the sole presenting feature of idiopathic
hypereosinophilic syndrome.
Imaging Studies
Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune
hepatitis; however, the presence of heterogeneous echotexture on abdominal ultrasound or
abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active
inflammation or necrosis. The appearance of an irregular nodular liver may confirm the presence
of cirrhosis. Furthermore, these imaging studies may be used to rule out the presence of
hepatocellular carcinoma, a potential complication of autoimmune hepatitis–induced cirrhosis.
Procedures
 Liver biopsy
Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis.
This procedure can be performed percutaneously, with or without ultrasound guidance, or by the
transjugular route. The latter is preferred if the patient has coagulopathy or severe
thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present or if
the liver is small, shrunken, and difficult to reach percutaneously. Liver biopsy routinely is
performed in the outpatient setting to investigate abnormal liver chemistries. Liver biopsy should
be performed as early as possible in patients with acute hepatitis who are thought to have
autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early
stage in the disease process.
The role of biopsy in patients presenting with well-established cirrhosis secondary to
autoimmune hepatitis is less clear. As an example, the initiation of treatment in a patient with
cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not
expected to influence the disease outcome.

Endoscopic retrograde cholangiopancreatography
Occasionally, a patient with autoimmune hepatitis and ulcerative colitis may require endoscopic
retrograde cholangiopancreatography (ERCP) to rule out coexisting PSC.
 Histologic Findings
Autoimmune hepatitis is characterized by a chronic inflammatory cell infiltrate. Plasma cells are
the prominent cell type. Biopsies may show evidence for interface hepatitis (ie, piecemeal
necrosis), bridging necrosis, and fibrosis. Lobular collapse, best identified by reticulin staining,
is a common finding.
Interface hepatitis does not predict a progressive disease course. By contrast, a strong likelihood
exists that cirrhosis will develop when bridging necrosis is present. The presence or absence of
cirrhosis on liver biopsy is an important determinant of the patient's prognosis.
Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic HCV
infection, alcohol-induced hepatitis, drug-induced liver disease, PBC, and PSC.
TREATMENT
 Diet
Patients with acute autoimmune hepatitis and symptoms of nausea and vomiting may require
intravenous fluids and even total parenteral nutrition; however, most patients can tolerate a
regular diet. A high caloric intake is desirable.
Patients with cirrhosis secondary to autoimmune hepatitis may develop ascites. A low-salt diet
(generally <2000 mg of sodium per d) is mandatory in these individuals. Patients should
continue to consume protein (ie, >1.1 g protein per kg body weight) given the catabolic nature of
the disease and patients' high risk for developing muscle wasting.
 Activity
Most patients do not need hospitalization, although this may be required for clinically severe
illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restricted
physical activity.
 Medical Care
For more than 3 decades, prednisone and azathioprine have been the mainstays of drug therapy
for patients with autoimmune hepatitis.
Albert Czaja (1995) recently published his treatment recommendations for autoimmune hepatitis,
which are as follows:
Absolute indications for treatment
 Incapacitating symptoms
 Relentless clinical progression
 AST greater than 10 times the reference range
 AST greater than 5 times the reference range and IgG greater than 2 times the
reference range
 Bridging necrosis on histology
 Multilobular necrosis on histology
Relative indications for treatment
 Mild or no symptoms
 AST 3-9 times the reference range


AST greater than 5 times the reference range and IgG less than 2 times the
reference range
Periportal hepatitis on histology
No indication for treatment
No symptoms
Previous intolerance to prednisone or azathioprine
AST less than 3 times the reference range
Severe cytopenia
Inactive cirrhosis or mild portal hepatitis on histology
Decompensated cirrhosis with variceal bleeding
Czaja's guidelines for single-drug therapy are as follows:


Prednisone - 60 mg/d for 1 week, 40 mg/d for 1 week, 30 mg/d for 2 weeks, and
20 mg/d until reaching the treatment end point
Recommendations for combination drug therapy - Prednisone 30 mg/d for 1
week, 20 mg/d for 1 week, 15 mg/d for 2 weeks, and 10 mg/d until reaching the
treatment endpoint with azathioprine 50 mg/d until reaching the treatment end
point
Treatment endpoints: Patients may achieve 1 of 4 treatment endpoints.
1. Complete remission is indicated by the absence of symptoms, a serum AST level less than 2
times the reference range, and histologic improvement to normal or minimal activity.
2. Treatment failure is defined as a deterioration in patient condition during therapy.
3. An incomplete patient response is defined as an improvement that is insufficient to satisfy
remission criteria.
4. Drug toxicity may occur.
Patients with severe disease have a high short-term mortality rate if they fail to show
normalization of at least 1 laboratory parameter or if pretreatment hyperbilirubinemia fails to
improve during a 2-week treatment trial. In contrast, patients who improve by these parameters
have an excellent immediate survival rate, and their treatment should be continued.
Histologic remission tends to lag behind clinical and laboratory remission by 3-6 months.
Follow-up liver biopsies can optimize management by avoiding medication withdrawal in
patients who are not yet in histologic remission.
Surgical Care
 Liver transplantation
This procedure is an effective form of therapy for patients with decompensated cirrhosis caused
by autoimmune hepatitis. This procedure also may be used to rescue patients who present with
fulminant hepatic failure secondary to autoimmune hepatitis.
The long-term outlook after liver transplantation is excellent, with 5-year survival rates reported
at 90% or more. Positive autoantibodies and hypergammaglobulinemia tend to disappear within
2 years of transplantation.
Recurrence of autoimmune hepatitis is uncommon after liver transplantation. It has been reported
primarily in inadequately immunosuppressed patients and HLA DR3-positive recipients of HLA
DR3-negative donors.
CIRRHOSIS
Cirrhosis represents the final common histologic pathway for a wide variety of chronic liver
diseases. The term cirrhosis was first introduced by Laennec in 1826. It is derived from the
Greek term scirrhus and is used to describe the orange or tawny surface of the liver seen at
autopsy.
Many forms of liver injury are marked by fibrosis. Fibrosis is defined as an excess deposition of
the components of extracellular matrix (ie, collagens, glycoproteins, proteoglycans) within the
liver. This response to liver injury potentially is reversible. In contrast, cirrhosis is not a
reversible process.
Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and the
conversion of normal liver architecture into structurally abnormal nodules. The progression of
liver injury to cirrhosis may occur over weeks to years. Indeed, patients with hepatitis C may
have chronic hepatitis for as long as 40 years before progressing to cirrhosis.
Often a poor correlation exists between histologic findings and the clinical picture. Some
patients with cirrhosis are completely asymptomatic and have a reasonably normal life
expectancy. Other individuals have a multitude of the most severe symptoms of end-stage liver
disease and have a limited chance for survival. Common signs and symptoms may stem from
decreased hepatic synthetic function (eg, coagulopathy), decreased detoxification capabilities of
the liver (eg, hepatic encephalopathy), or portal hypertension (eg, variceal bleeding).
Epidemiology
Chronic liver disease and cirrhosis result in 26,000-35,000 deaths each year in the United States.
Cirrhosis is the ninth leading cause of death in the United States and is responsible for 1.2% of
all US deaths. Many patients die from the disease in their fifth or sixth decade of life. Each year,
2000 additional deaths are attributed to fulminant hepatic failure (FHF). FHF may be caused
viral hepatitis (eg, hepatitis A and B), drugs (eg, acetaminophen), toxins (eg, Amanita phalloides,
the yellow death-cap mushroom), autoimmune hepatitis, Wilson disease, and a variety of less
common etiologies. Cryptogenic causes are responsible for one third of fulminant cases. Patients
with the syndrome of FHF have a 50-80% mortality rate unless they are salvaged by liver
transplantation.
Etiology
Causes of cirrhosis












Hepatitis C (26%)
Alcoholic liver disease (21%)
Hepatitis C plus alcoholic liver disease (15%)
Cryptogenic causes (18%)
Hepatitis B, which may be coincident with hepatitis D (15%)
Autoimmune hepatitis
Primary biliary cirrhosis
Secondary biliary cirrhosis (associated with chronic extrahepatic bile duct
obstruction)
Primary sclerosing cholangitis
Hemochromatosis
Wilson disease
Alpha-1 antitrypsin deficiency
Pathophysiology of hepatic fibrosis
The development of hepatic fibrosis reflects an alteration in the normally balanced processes of
extracellular matrix production and degradation. Extracellular matrix, the normal scaffolding for
hepatocytes, is composed of collagens (especially types I, III, and V), glycoproteins, and
proteoglycans. Stellate cells, located in the perisinusoidal space, are essential for the production
of extracellular matrix. Stellate cells, which were once known as Ito cells, lipocytes, or
perisinusoidal cells, may become activated into collagen-forming cells by a variety of paracrine
factors. Such factors may be released by hepatocytes, Kupffer cells, and sinusoidal endothelium
following liver injury. As an example, increased levels of the cytokine transforming growth
factor beta1 (TGF-beta1) are observed in patients with chronic hepatitis C and those with
cirrhosis. TGF-beta1, in turn, stimulates activated stellate cells to produce type I collagen.
Increased collagen deposition in the space of Disse (the space between hepatocytes and
sinusoids) and the diminution of the size of endothelial fenestrae lead to the capillarization of
sinusoids. Activated stellate cells also have contractile properties. Both capillarization and
constriction of sinusoids by stellate cells contribute to the development of portal hypertension.
Future drug strategies to prevent fibrosis may focus on reducing hepatic inflammation, inhibiting
stellate cell activation, inhibiting the fibrogenic activities of stellate cells, and stimulating matrix
degradation.
Main manifistetion of cirrhosis
PORTAL HYPERTENSION
Causes
The normal liver has the ability to accommodate large changes in portal blood flow without
appreciable alterations in portal pressure. Portal hypertension results from a combination of
increased portal venous inflow and increased resistance to portal blood flow. Patients with
cirrhosis demonstrate increased splanchnic arterial flow and, accordingly, increased splanchnic
venous inflow into the liver. Increased splanchnic arterial flow is explained partly by decreased
peripheral vascular resistance and increased cardiac output in the patient with cirrhosis. Nitric
oxide appears to be one of the major driving forces for this phenomenon. Furthermore, evidence
for splanchnic vasodilation exists. Putative splanchnic vasodilators include glucagon, vasoactive
intestinal peptide, substance P, prostacyclin, bile acids, tumor necrosis factor-alpha (TNF-alpha),
and nitric oxide.
Clinically, increased resistance across the sinusoidal vascular bed of the liver may be a more
important factor in the development of portal hypertension. Factors that increase resistance to
blood flow include disruption of hepatic architecture and compression of hepatic venules by
regenerating nodules, increased collagen deposition in the space of Disse, and increased
intrahepatic levels of locally acting vasoconstricting chemicals. As an example, endothelin,
which is produced by hepatocytes, may bind to receptors on stellate cells. This, in turn, may lead
to stellate cell contraction and vasoconstriction of the hepatic sinusoid.
Intrahepatic causes of portal hypertension are divided into
1. presinusoidal,
2. sinusoidal,
3. postsinusoidal conditions.
1. The classic form of presinusoidal disease is caused by the deposition of Schistosoma oocytes
in presinusoidal portal venules, with the subsequent development of granulomata and portal
fibrosis. Schistosomiasis is the most common noncirrhotic cause of variceal bleeding worldwide.
Schistosoma mansoni infection is described in Puerto Rico, Central and South America, the
Middle East, and Africa. Schistosoma japonicum is described in the Far East. Schistosoma
hematobium, observed in the Middle East and Africa, can produce portal fibrosis but more
commonly is associated with urinary tract deposition of eggs.
2. The classic sinusoidal cause of portal hypertension is cirrhosis.
3. The classic postsinusoidal condition is an entity known as venoocclusive disease. Obliteration
of the terminal hepatic venules may result from ingestion of pyrrolizidine alkaloids in Comfrey
tea or Jamaican bush tea and following the high-dose chemotherapy that precedes bone marrow
transplantation.
Posthepatic causes of portal hypertension may include chronic right-sided heart failure and
tricuspid regurgitation and obstructing lesions of the hepatic veins and inferior vena cava.
ASCITES
Ascites is defined as an accumulation of excessive fluid within the peritoneal cavity and may be
a complication of both hepatic and nonhepatic diseases.
The 4 most common causes of ascites in North America and Europe are cirrhosis, neoplasm,
congestive heart failure, and tuberculous peritonitis.
In the past, ascites was classified as being a transudate or an exudate. In transudative ascites,
fluid was said to cross the liver capsule because of an imbalance in Starling forces. In general,
ascites protein was less than 2.5 g/dL. Classic causes of transudative ascites are portal
hypertension secondary to cirrhosis and congestive heart failure.
In exudative ascites, fluid was said to weep from an inflamed or tumor-laden peritoneum. In
general, ascites protein was greater than 2.5 g/dL. Examples included peritoneal carcinomatosis
and tuberculous peritonitis.
The role of portal hypertension in the pathogenesis of cirrhotic ascites
The formation of ascites in cirrhosis depends on the presence of unfavorable Starling forces
within the hepatic sinusoid and on some degree of renal dysfunction. Patients with cirrhosis are
observed to have increased hepatic lymphatic flow.
Fluid and plasma proteins diffuse freely across the highly permeable sinusoidal endothelium into
the space of Disse. Fluid in the space of Disse, in turn, enters the lymphatic channels that run
within the portal and central venous areas of the liver.
Because the transsinusoidal oncotic gradient is approximately zero, the increased sinusoidal
pressure that develops in portal hypertension increases the amount of fluid entering the space of
Disse. When the increased hepatic lymph production observed in portal hypertension exceeds the
ability of the cisterna chyli and thoracic duct to clear the lymph, fluid crosses into the liver
interstitium. Fluid may then extravasate across the liver capsule into the peritoneal cavity.
The role of renal dysfunction in the pathogenesis of cirrhotic ascites
Patients with cirrhosis experience sodium retention, impaired free water excretion, and
intravascular volume overload. These abnormalities may occur even in the setting of a normal
glomerular filtration rate. To some extent, these abnormalities are due to increased levels of
renin and aldosterone. Why the renin-angiotensin-aldosterone system is stimulated in cirrhosis
remains unknown.
The underfill hypothesis postulates that the formation of ascites leads to decreased effective
intravascular volume and to stimulation of the renin-angiotensin system. The hypothesis is
supported by the fact that head-out-of-water immersion of the patient with cirrhosis results in
plasma redistribution and a decrease in renin, aldosterone, antidiuretic hormone, and
norepinephrine levels. The hypothesis is contradicted by the presence of increased intravascular
volume in patients with cirrhosis.
The overflow hypothesis states that in cirrhosis, intrahepatic mechanoreceptors sense decreased
hepatocyte perfusion with portal blood. This event stimulates sodium and water retention. A
subsequent increase in plasma volume then results in an overflow of fluid into the peritoneal
cavity.
The peripheral arterial vasodilation hypothesis states that splanchnic arterial vasodilation,
perhaps driven by nitric oxide and glucagon, leads to intravascular underfilling. This leads to
stimulation of the renin-angiotensin system, the sympathetic nervous system, and antidiuretic
hormone release. This is followed by an increase in sodium and water retention, an increase in
plasma volume, and the overflow of fluid into the peritoneal cavity.
Clinical features of ascites
Ascites is suggested by the presence of a number of findings upon physical examination, which
are abdominal distention, bulging flanks, shifting dullness, and elicitation of a "puddle sign" in
patients in the knee-elbow position. A fluid wave may be elicited in patients with massive tense
ascites. However, physical examination findings are much less sensitive than performing
abdominal ultrasonography, which can detect as little as 30 mL of fluid. Furthermore, ultrasound
with Doppler can help assess the patency of hepatic vessels. Factors associated with worsening
of ascites include excess fluid or salt intake, malignancy, venous occlusion (eg, Budd-Chiari
syndrome), progressive liver disease, and spontaneous bacterial peritonitis (SBP).
Patients with massive ascites may experience abdominal discomfort, depressed appetite, and
decreased oral intake. Diaphragmatic elevation may lead to symptoms of dyspnea. Pleural
effusions may result from the passage of ascitic fluid across channels in the diaphragm.
Umbilical and inguinal hernias are common in patients with moderate and massive ascites. The
use of an elastic abdominal binder may protect the skin overlying a protruding umbilical hernia
from maceration and may help prevent rupture and subsequent infection. Timely large-volume
paracentesis also may help to prevent this disastrous complication. Umbilical hernias should not
undergo elective repair unless patients are significantly symptomatic or their hernias are
irreducible. As with all other surgeries in patients with cirrhosis, herniorrhaphy carries multiple
potential risks such as intraoperative bleeding, postoperative infection, and liver failure because
of anesthesia-induced reductions in hepatic blood flow. However, these risks become acceptable
in patients with severe symptoms from their hernia. Urgent surgery is necessary in the patient
whose hernia has been complicated by bowel incarceration.
Paracentesis in the diagnosis of ascites
Paracentesis is essential in determining whether ascites is caused by portal hypertension or by
another process. Ascites studies also are used to rule out infection and malignancy. Paracentesis
should be performed in all patients with either new onset of ascites or worsening ascites.
Medical treatment of ascites
Therapy for ascites should be tailored to the patient's needs. Some patients with mild ascites
respond to sodium restriction or diuretics taken once or twice per week. Other patients require
aggressive diuretic therapy, careful monitoring of electrolytes, and occasional hospitalization to
facilitate even more intensive diuresis.

Sodium restriction
Salt restriction is the first line of therapy. In general, patients begin with a diet containing less
than 2000 mg sodium per day. Some patients with refractory ascites require a diet containing less
than 500 mg sodium per day. However, ensuring that patients do not construct diets that might
place them at risk for calorie and protein malnutrition is important. Indeed, the benefit of
commercially available liquid nutritional supplements (which often contain moderate amounts of
sodium) often exceeds the risk of slightly increasing the patient's salt intake.
 Diuretics
Diuretics should be considered the second line of therapy.
1. Spironolactone (Aldactone) blocks the aldosterone receptor at the distal tubule. It is dosed at
50-300 mg once per day. Although the drug has a relatively short half-life, its blockade of the
aldosterone receptor lasts for at least 24 hours. Adverse effects of spironolactone include
hyperkalemia, gynecomastia, and lactation. Other potassium-sparing diuretics, including
amiloride and triamterene, may be used as alternative agents, especially in patients complaining
of gynecomastia.
2. Furosemide (Lasix) may be used as a solo agent or in combination with spironolactone. The
drug blocks sodium reuptake in the loop of Henle. It is dosed at 40-240 mg per day in 1-2
divided doses. Patients infrequently need potassium repletion when furosemide is dosed in
combination with spironolactone.
Aggressive diuretic therapy in hospitalized patients with massive ascites can safely induce a 0.5to 1-kg weight loss per day, providing that patients undergo careful monitoring of renal function.
The author's practice is to administer intravenous furosemide following intravenous infusion of
albumin at 25 g twice per day, in addition to ongoing therapy with spironolactone. Diuretic
therapy should be held in the event of electrolyte disturbances, azotemia, or the induction of
hepatic encephalopathy.

The ability of intravenous albumin to promote diuresis in some patients
with cirrhosis and ascites is well known.
Albumin also may protect against the development of renal insufficiency. One recent report
supports the use of intravenous albumin in patients with SBP. Patients receiving cefotaxime and
albumin at 1 g/kg/day experienced a lower risk of renal failure and a lower in-hospital mortality
rate than patients treated with cefotaxime and conventional fluid management.

Large-volume paracentesis
Aggressive diuretic therapy is ineffective in controlling ascites in approximately 5-10% of
patients. Such patients with massive ascites may need to undergo large-volume paracentesis in
order to receive relief from symptoms of abdominal discomfort, anorexia, or dyspnea. The
procedure also may help reduce the risk of umbilical hernia rupture.
Large-volume paracentesis was first used in ancient times. It fell out of favor from the 1950s
through the 1980s with the advent of diuretic therapy and following a handful of case reports
describing paracentesis-induced azotemia. In 1987, Gines and colleagues demonstrated that
large-volume paracentesis could be performed with minimal or no impact on renal function. This
and other studies showed that 5-15 L of ascites could be removed safely at one time. Large-
volume paracentesis is thought to be safe in patients with peripheral edema and in patients not
currently treated with diuretics. Debate exists whether colloid infusions (eg, with 5-10 g albumin
per 1 L ascites removed) are necessary to prevent intravascular volume depletion in patients who
are receiving ongoing diuretic therapy or in patients with mild or moderate underlying renal
insufficiency.
Peritoneovenous shunts
LeVeen shunts and Denver shunts are devices that permit the return of ascites fluid and proteins
to the intravascular space. Plastic tubing inserted subcutaneously under local anesthesia connects
the peritoneal cavity to the internal jugular vein or subclavian vein via a pumping chamber.
These devices are successful at relieving ascites and reversing protein loss in some patients.
However, serious complications are observed in 10% of the recipients of these devices.
Complications include peritoneal infection, sepsis, disseminated intravascular coagulation, and
congestive heart failure. Shunts may clot and require replacement in an additional 30% of
patients. However, peritoneovenous shunts may be a reasonable form of therapy for patients with
refractory ascites who are not candidates for TIPS or liver transplantation.
Portosystemic shunts and transjugular intrahepatic portosystemic shunts
The prime indication for portocaval shunt surgery is the management of refractory variceal
bleeding. However, since 1945, the medical field has recognized that portocaval shunts, by
decompressing the hepatic sinusoid, may improve ascites. The performance of a side-to-side
portocaval shunt for ascites management must be weighed against the approximate 5% mortality
rate associated with this surgery and the chance (as high as 30%) of inducing hepatic
encephalopathy.
TIPS is an effective tool in managing massive ascites in some patients. Ideally, TIPS placement
produces a decrease in sinusoidal pressure and a decrease in plasma renin and aldosterone levels,
with subsequent improved urinary sodium excretion. In one study, 74% of patients with
refractory ascites achieved complete remission of ascites within 3 months of TIPS placement.
However, patient selection for the procedure is important. Creation of a TIPS has the potential to
worsen preexisting hepatic encephalopathy and exacerbate liver dysfunction in patients with
severe underlying liver failure. In the author's opinion, TIPS use should be reserved for patients
with Child class B cirrhosis or patients with Child class C cirrhosis without severe coagulopathy
or encephalopathy. Furthermore, shunt stenosis is observed in half the cases within 1 year of
placement, necessitating angiographic revision. Thus, patients must be willing to return to the
hospital for Doppler and angiographic follow-up of TIPS patency.
Liver transplantation
Patients with massive ascites have a less than 50% 1-year survival rate. Liver transplantation
should be considered as a potential means of salvaging the patient prior to the onset of
intractable liver failure or hepatorenal syndrome.
HEPATIC ENCEPHALOPATHY
Hepatic encephalopathy is a syndrome observed in some patients with cirrhosis that is marked by
personality changes, intellectual impairment, and a depressed level of consciousness. The
diversion of portal blood into the systemic circulation appears to be a prerequisite for the
syndrome. Indeed, hepatic encephalopathy may develop in patients who do not have cirrhosis
who undergo portocaval shunt surgery.
Pathogenesis
A number of theories have been postulated to explain the pathogenesis of hepatic
encephalopathy in patients with cirrhosis. Patients may have altered brain energy metabolism
and increased permeability of the blood-brain barrier. The latter may facilitate the passage of
neurotoxins into the brain. Putative neurotoxins include short-chain fatty acids, mercaptans, false
neurotransmitters (eg, tyramine, octopamine, and beta-phenylethanolamines), ammonia, and
gamma-aminobutyric acid (GABA).
 The ammonia hypothesis
Ammonia is produced in the GI tract by bacterial degradation of amines, amino acids, purines,
and urea. Normally, ammonia is detoxified in the liver by conversion to urea and glutamine. In
liver disease or portosystemic shunting, portal blood ammonia is not converted efficiently to
urea. Increased levels of ammonia may enter the systemic circulation because of portosystemic
shunting.
Ammonia has multiple neurotoxic effects, including altering the transit of amino acids, water,
and electrolytes across the neuronal membrane. Ammonia also can inhibit the generation of both
excitatory and inhibitory postsynaptic potentials. Therapeutic strategies to reduce serum
ammonia levels tend to improve hepatic encephalopathy. However, approximately 10% of
patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many
patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy.

The gamma-aminobutyric acid hypothesis
GABA is a neuroinhibitory substance produced in the GI tract. When GABA crosses the
extrapermeable blood-brain barrier of a patient with cirrhosis, it interacts with supersensitive
postsynaptic GABA receptors. The GABA receptor, in conjunction with receptors for
benzodiazepines and barbiturates, regulates a chloride ionophore. Binding of GABA to its
receptor permits an influx of chloride ions into the postsynaptic neuron, leading to the generation
of an inhibitory postsynaptic potential. Administration of benzodiazepines and barbiturates to
patients with cirrhosis increases GABA-ergic tone and predisposes patients to depressed
consciousness. The GABA hypothesis is supported by the clinical observation that flumazenil (a
benzodiazepine antagonist) transiently can reverse hepatic encephalopathy in patients with
cirrhosis.
Clinical features of hepatic encephalopathy
The symptoms of hepatic encephalopathy may range from mild to severe and may be observed in
as many as 70% of patients with cirrhosis. Symptoms are graded on the following scale:
Grade 0 - Subclinical; normal mental status, but minimal changes in memory, concentration,
intellectual function, coordination
Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to
perform mental tasks, irritability, disorder of sleep pattern (ie, inverted sleep cycle)
Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious
personality changes, inappropriate behavior, intermittent disorientation (usually for time)
Grade 3 - Somnolent but arousable, unable to perform mental tasks, disorientation to time and
place, marked confusion, amnesia, occasional fits of rage, speech is present but
incomprehensible
Grade 4 - Coma, with or without response to painful stimuli
Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-term
memory and concentration on mental status testing. Findings upon physical examination include
asterixis and fetor hepaticus.
Laboratory abnormalities in hepatic encephalopathy
An elevated arterial or free venous serum ammonia level is the classic laboratory abnormality
reported in patients with hepatic encephalopathy. This finding may aid in the assignment of a
correct diagnosis to a patient with cirrhosis who presents with altered mental status. However,
serial ammonia measurements are inferior to clinical assessment in gauging improvement or
deterioration in patients under therapy for hepatic encephalopathy. No utility exists for checking
the ammonia level in a patient with cirrhosis who does not have hepatic encephalopathy.
Some patients with hepatic encephalopathy have the classic but nonspecific
electroencephalogram (EEG) changes of high-amplitude low-frequency waves and triphasic
waves. EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental
status when ruling out seizure activity may be necessary.
CT scan and MRI studies of the brain may be important in ruling out intracranial lesions when
the diagnosis of hepatic encephalopathy is in question.
Common precipitants of hepatic encephalopathy
Some patients with a history of hepatic encephalopathy may have normal mental status when
under medical therapy. Others have chronic memory impairment in spite of medical
management. Both groups of patients are subject to episodes of worsened encephalopathy.
Common precipitants of hyperammonemia and worsening mental status are diuretic therapy,
renal failure, GI bleeding, infection, and constipation. Dietary protein overload is an infrequent
cause of worsening encephalopathy. Medications, notably opiates, benzodiazepines,
antidepressants, and antipsychotic agents, also may worsen encephalopathy symptoms.
Treatment of hepatic encephalopathy
1. Lactulose is helpful in patients with the acute onset of severe encephalopathy symptoms and
in patients with milder, chronic symptoms. This nonabsorbable disaccharide stimulates the
passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production.
Initial lactulose dosing is 30 mL orally once or twice daily. Dosing is increased until the patient
has 2-4 loose stools per day. Dosing should be reduced if the patient complains of diarrhea,
abdominal cramping, or bloating. Higher doses of lactulose may be administered via either a
nasogastric tube or rectal tube to hospitalized patients with severe encephalopathy. Other
cathartics, including colonic lavage solutions that contain polyethylene glycol (PEG) (eg, GoLytely), also may be effective in patients with severe encephalopathy.
2. Neomycin and other antibiotics (eg, metronidazole, oral vancomycin, paromomycin, oral
quinolones) serve as second-line agents. They work by decreasing the colonic concentration of
ammoniagenic bacteria. Neomycin dosing is 250-1000 mg orally 2-4 times daily.
Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-aspartate
(available in Europe) and sodium benzoate.
3. Low-protein diets were recommended routinely in the past for patients with cirrhosis. High
levels of aromatic amino acids contained in animal proteins were believed to lead to increased
blood levels of the false neurotransmitters tyramine and octopamine, with resulting worsening of
encephalopathy symptoms. In this author's experience, the vast majority of patients can tolerate a
protein-rich diet (>1.2 g/kg/d) including well-cooked chicken, fish, vegetable protein, and, if
needed, protein supplements. Although protein restriction may play a role in the management of
the patient with an acute flare of hepatic encephalopathy, it rarely is necessary in patients with
chronic encephalopathy symptoms. Furthermore, many patients with cirrhosis have proteincalorie malnutrition at baseline. The routine restriction of dietary protein intake increases their
risk for worsening malnutrition.
Other manifestations of cirrhosis; assessment of severity of cirrhosis
All chronic liver diseases that progress to cirrhosis have in common the histologic features of
hepatic fibrosis and nodular regeneration. However, patients' signs and symptoms may vary
depending on the underlying etiology of liver disease.
As an example, patients with end-stage liver disease caused by hepatitis C might develop
profound muscle wasting, marked ascites, and severe hepatic encephalopathy, with only mild
jaundice.
In contrast, patients with end-stage primary biliary cirrhosis might be deeply icteric, with no
evidence of muscle wasting. These patients may complain of extreme fatigue and pruritus and
have no complications of portal hypertension.
In both cases, medical management is focused on the relief of symptoms. Liver transplantation
should be considered as a potential therapeutic option, given the inexorable course of most cases
of end-stage liver disease.
1. Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle wasting.
2. Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin telangiectasias
(termed “paper money skin” by Dame Sheila Sherlock), palmar erythema, white nails,
disappearance of lunulae, and finger clubbing, especially in the setting of hepatopulmonary
syndrome.
3. Patients with cirrhosis may experience increased conversion of androgenic steroids into
estrogens in skin, adipose tissue, muscle, and bone.
Males may develop gynecomastia and impotence. Loss of axillary and pubic hair is noted in both
men and women. Hyperestrogenemia also may explain spider angiomata and palmar erythema.
4. Hematologic manifestations
Anemia may result from folate deficiency, hemolysis, or hypersplenism. Thrombocytopenia
usually is secondary to hypersplenism and decreased levels of thrombopoietin. Coagulopathy
results from decreased hepatic production of coagulation factors. If cholestasis is present,
decreased micelle entry into the small intestine leads to decreased vitamin K absorption, with
resulting reduction in hepatic production of factors II, VII, IX, and X. Patients with cirrhosis also
may experience fibrinolysis and disseminated intravascular coagulation.
5. Pulmonary and cardiac manifestations
Patients with cirrhosis may have impaired pulmonary function. Pleural effusions and the
diaphragmatic elevation caused by massive ascites may alter ventilation-perfusion relations.
Interstitial edema or dilated precapillary pulmonary vessels may reduce pulmonary diffusing
capacity.
Assessment of the severity of cirrhosis
The most common tool for gauging prognosis in cirrhosis is the Child-Turcotte-Pugh (CTP)
system. Child and Turcotte first introduced their scoring system in 1964 as a means of predicting
the operative mortality associated with portocaval shunt surgery. Pugh's revised system in 1973
substituted albumin for the less specific variable of nutritional status. More recent revisions use
International Normalized Ratio (INR) in addition to prothrombin time.
Recent epidemiologic work shows that the CTP score may predict life expectancy in patients
with advanced cirrhosis. A CTP score of 10 or greater is associated with a 50% chance of death
within 1 year.
TREATMENT OF CIRRHOSIS
Specific medical therapies may be applied to many liver diseases in an effort to diminish
symptoms and prevent or forestall the development of cirrhosis. Examples include prednisone
and azathioprine for autoimmune hepatitis, interferon and other antiviral agents for hepatitis B
and C, phlebotomy for hemochromatosis, ursodeoxycholic acid for primary biliary cirrhosis, and
zinc and penicillamine for Wilson disease. These therapies become progressively less effective if
chronic liver disease evolves into cirrhosis. Once cirrhosis develops, treatment is aimed at the
management of complications as they arise. Certainly variceal bleeding, ascites, and hepatic
encephalopathy are among the most serious complications experienced by patients with
cirrhosis. However, attention also must be paid to patients' chronic constitutional complaints.
Nutrition
Many patients complain of anorexia, which may be compounded by the direct compression of
ascites on the GI tract. Care should be taken to assure that patients receive adequate calories and
protein in their diets. Patients frequently benefit from the addition of commonly available liquid
and powdered nutritional supplements to the diet. Only rarely can patients not tolerate proteins in
the form of chicken, fish, vegetables, and nutritional supplements. Institution of a low-protein
diet in the fear that hepatic encephalopathy might develop places the patient at risk for the
development of profound muscle wasting.
Adjunctive therapies
Zinc deficiency commonly is observed in patients with cirrhosis. Treatment with zinc sulfate at
220 mg orally twice daily may improve dysgeusia and can stimulate appetite. Furthermore, zinc
is effective in the treatment of muscle cramps and is adjunctive therapy for hepatic
encephalopathy.
Pruritus is a common complaint in both cholestatic liver diseases (eg, primary biliary cirrhosis)
and in noncholestatic chronic liver diseases (eg, hepatitis C). Although increased serum bile acid
levels once were thought to be the cause of pruritus, endogenous opioids are more likely to be
the culprit pruritogens. Mild itching complaints may respond to treatment with antihistamines.
Cholestyramine is the mainstay of therapy for the pruritus of liver disease. Care should be taken
to avoid coadministration of this organic anion binder with any other medication, to avoid
compromising GI absorption. Other medications that may provide relief against pruritus include
ursodeoxycholic acid, naltrexone (an opioid antagonist), rifampin, and ondansetron.
Patients with cirrhosis may develop osteoporosis. Supplementation with calcium and vitamin D
is important in patients at high risk for osteoporosis, especially patients with chronic cholestasis,
patients with primary biliary cirrhosis, and patients receiving corticosteroids for autoimmune
hepatitis. The discovery of decreased bone mineralization upon bone densitometry studies also
may prompt institution of therapy with an aminobisphosphonate (eg, alendronate sodium).
Surgery in the patient with cirrhosis
Surgery and general anesthesia carry increased risks in the patient with cirrhosis. Anesthesia
reduces cardiac output, induces splanchnic vasodilation, and causes a 30- to 50%-reduction in
hepatic blood flow. This places the cirrhotic liver at additional risk for decompensation. Surgery
is said to be safe in the setting of mild chronic hepatitis. Its risk in patients with severe chronic
hepatitis is unknown. Patients with well-compensated cirrhosis have an increased but acceptable
risk of morbidity and mortality. A study of nonshunt abdominal surgeries demonstrated a 10%
mortality rate for patients with Child class A cirrhosis as opposed to a 30% mortality rate for
patients with Child class B cirrhosis and a 75% mortality rate for patients with Child class C
cirrhosis. Thus, unless absolutely necessary, surgery should be avoided in the patient with
cirrhosis. Although cholecystectomy was among the riskier surgeries noted, several recent
reports have described the successful performance of laparoscopiccholecystectomy in patients
with Child class A and B cirrhosis.
Monitoring the patient with cirrhosis
Patients with cirrhosis should undergo routine follow-up monitoring of their complete blood
count, renal and liver chemistries, and prothrombin time. The author's policy is to monitor stable
patients 3-4 times per year. The author performs routine diagnostic endoscopy to determine
whether the patient has asymptomatic esophageal varices. Follow-up endoscopy is performed in
2 years if varices are not present. If varices are present, treatment is initiated with a nonselective
beta-blocker (eg, propranolol, nadolol), aiming for a 25% reduction in heart rate, and a longacting nitrate medication (eg, isosorbide-5-mononitrate). Such therapy offers effective primary
prophylaxis against the new onset of variceal bleeding.
This author encourages the screening of patients to rule out the interval development of HCC.
The author's practice is to perform abdominal ultrasonography and alpha-fetoprotein testing
twice yearly, although the clinical utility and cost-effectiveness of this strategy remains
controversial. Patients with suspected HCC should undergo ultrasound or liver biopsy guided by
CT scan. If HCC is confirmed, the physician may elect to treat the patient with resection surgery,
percutaneous injection therapy with ethanol or acetic acid, thermal ablation, or
chemoembolization. Appropriate patients without evidence of extrahepatic disease, as
determined by chest and abdominal CT scan and by bone scan, may require an accelerated
course to liver transplantation.
LIVER TRANSPLANTATION
Liver transplantation has emerged as an important strategy in the management of patients with
decompensated cirrhosis. Patients should be referred for consideration of liver transplantation
after the first signs of hepatic decompensation, as marked by a score of 7 or greater using the
CTP scoring system. The United Network for Organ Sharing states that this score is the
minimum required to permit entry of a patient's name onto the national transplant waiting list.
Other less common indications for liver transplantation include detection of HCC, recurrent
biliary sepsis in the setting of primary sclerosing cholangitis, and hepatic osteodystrophy.
Contraindications for liver transplantation include severe cardiovascular or pulmonary disease,
active drug or alcohol abuse, malignancy outside the liver, sepsis, or psychosocial problems that
might jeopardize patients' abilities to follow their medical regimens after transplant. The
presence of HIV in the bloodstream also is a contraindication to transplant. However, successful
liver transplantations are now being performed in patients with no detectable HIV viral load due
to antiretroviral therapy. Additional clinical study is required before liver transplantation can be
offered routinely to such patients.
Advances in surgical technique, organ preservation, and immunosuppression have resulted in
dramatic improvements in postoperative survival over the last 2 decades. In the early 1980s, the
percentage of patients surviving 1 year and 5 years after liver transplant was only 70% and 15%,
respectively. Now, patients can anticipate a 1-year survival rate of 85% and a 5-year survival rate
of higher than 70%. Quality of life after liver transplant is good or excellent in most cases.
HEPATIC FAILURE
Acute liver failure (ALF) is a broad term that refers to both fulminant hepatic failure (FHF) and
subfulminant hepatic failure (or late-onset hepatic failure). The latter term is reserved for patients
with liver disease for up to 26 weeks prior to the development of hepatic encephalopathy. Some
patients with previously unrecognized chronic liver disease decompensate and present with liver
failure; although this technically is not FHF, discerning this at the time of presentation may not
be possible (eg, Wilson disease).
FHF is a term used to describe the development of coagulopathy and encephalopathy as a result
of acute hepatic decompensation within 8 weeks from the onset of illness. FHF may result from a
variety of hepatic disease processes. Viral hepatitis and hepatotoxic drugs are the most common
causes of FHF. Treatment of the underlying process is essential, but the common factor
underlying the severity of illness is loss of hepatic function.
Frequency
Incidence of FHF appears to be low, with approximately 2000 cases annually occurring in the
United States.
Acetaminophen or paracetamol overdoses are prominent causes of FHF in Europe and, in
particular, Great Britain. In the developing world, acute hepatitis B virus (HBV) infection
dominates as a cause of FHF because of the high prevalence of HBV. Hepatitis delta virus
(HDV) superinfection is much more common in developing countries than in the United States
because of the high rate of chronic HBV infection. Hepatitis E virus (HEV) is associated with a
high incidence of FHF in women who are pregnant and is of concern in pregnant patients living
in or traveling through endemic areas. These regions include, but are not limited to, Mexico and
Central America, India and the subcontinent, and the Middle East.
Several factors contribute to morbidity and mortality. The etiologic factor leading to hepatic
failure and the development of complications is key. In general, the best prognoses occur in the
absence of complications. Spontaneous bacterial peritonitis, adult respiratory distress syndrome,
hepatorenal syndrome, bleeding, cerebral edema, and sepsis pose challenges that reduce the
probability of survival.
Viral hepatitis: In patients with FHF due to hepatitis A virus (HAV), survival rates are greater
than 50-60%. These patients account for a substantial proportion (10-20%) of the pediatric liver
transplants in some countries despite the relatively mild infection that is observed in many
children infected with HAV. The outcome for patients with FHF as the result of other causes of
viral hepatitis is much less favorable.
Causes
Numerous causes of FHF exist, but viral hepatitis and acetaminophen overdoses are the most
common.
The cause remains unknown in as many as 15% of patients.
Viral hepatitis is a common cause of hepatic failure.
Pathophysiology
The development of cerebral edema distinguishes FHF from portosystemic encephalopathy,
although certain mechanisms appear to be common to both clinical entities.
Briefly, hyperammonemia may be involved in the development of cerebral edema. Another
consequence of FHF is multisystem organ failure, which often is observed in the context of a
hyperdynamic circulatory state that mimics sepsis (low systemic vascular resistance); therefore,
circulatory insufficiency and poor organ perfusion possibly either initiate or promote
complications of FHF.
Many hemodynamic features of FHF may be mediated by elevated systemic concentrations of
nitric oxide, which acts as a potent vasodilator. However, in this setting, cytokine profiles are
deranged, and a distinct possibility exists that neurohumoral effects mediate extrahepatic organ
dysfunction, with the circulatory manifestations simply representing epiphenomena. Elevated
serum concentrations of bacterial endotoxin, tumor necrosis factor-a, and interleukin-1 and
interleukin-6 have been found in FHF, but the specific roles of these inflammatory mediators are
unclear.
The development of liver failure represents the final common outcome of a wide variety of
potential causes, as the broad differential diagnosis suggests. A complete discussion is beyond
the scope of this article, and the reader is directed to consult the literature dealing specifically
with these underlying etiologic factors. However, mechanisms of acetaminophen hepatotoxicity
are worth discussing briefly.
As with many drugs that undergo hepatic metabolism (in this case, by cytochrome P-450), the
oxidative metabolite of acetaminophen is more toxic than the drug. An active metabolite, Nacetyl-p-benzoquinoneimine (NAPQI), appears to mediate much of the damage to liver tissue by
forming covalent bonds with cellular proteins. Therefore, the presence of highly reactive free
radicals following acetaminophen ingestion poses a threat to the liver parenchyma, but it usually
is addressed adequately by intrahepatic glutathione reserves. The reduced glutathione quenches
the reactive metabolites and acts to prevent nonspecific oxidation of cellular structures that may
result in severe hepatocellular dysfunction.
This mechanism fails in 2 different yet equally important settings. The first is an overdose
(accidental or intentional) of acetaminophen. This simply overwhelms the hepatic stores of
glutathione, allowing reactive metabolites to escape. The second and less obvious scenario
occurs with a patient who consumes alcohol regularly. This does not necessarily require a history
of alcohol abuse or alcoholism. Even a moderate or social drinker who consistently consumes 12 drinks daily may sufficiently deplete intrahepatic glutathione reserves. This results in
potentially lethal hepatotoxicity from what is otherwise a safe dose of acetaminophen (below the
maximum total dose of 4 g/d) in an unsuspecting individual.
Histologic Findings. Biopsy findings may be nonspecific, but in general, they depend on the
underlying etiology. Panlobular necrosis generally is observed as a result of idiosyncratic
medication-induced hepatitis leading to FHF. Centrilobular necrosis is typical of acetaminopheninduced FHF, but panlobular injury also may be observed. Viral hepatitis typically shows a
panlobular injury and may be difficult to distinguish from medication-induced hepatitis. The
presence of microvesicular steatosis suggests certain medications as a cause for FHF (valproic
acid, salicylates in Reye syndrome) but also is observed in acute fatty liver of pregnancy.
CLINICAL
History
Clinical features may be self-evident and lead to a rapid diagnosis of ALF.
History is valuable for guiding appropriate interventions.
If the patient is incapacitated, closely question family members and friends.
Detail the date of onset of jaundice and encephalopathy, alcohol use, medication use
(prescription and illicit or recreational), herbal or traditional medicine use, family history of liver
disease (Wilson disease), exposure risk factors for viral hepatitis (travel, transfusions, sexual
contacts, occupation, body piercing), and toxin ingestion (mushrooms, organic solvents,
phosphorus contained in fireworks).
Determine if any complications have developed.
Physical
By definition, findings include jaundice and encephalopathy. The latter may be demonstrated to
a varying degree.
In contrast to the typical patient with hepatic encephalopathy, hallucinations are somewhat more
prevalent.
Development of cerebral edema ultimately may give rise to manifestations of increased
intracranial pressure (ICP), including papilledema, hypertension, and bradycardia.
Patients may demonstrate massive ascites and anasarca due to fluid redistribution following the
development of hypoalbuminemia.
Patients may not exhibit this initially if deterioration has been rapid, particularly if no fluid
resuscitation has been performed.
Hematemesis or melena may complicate the presentation of FHF as a result of upper
gastrointestinal bleeding.
This pattern is indistinguishable from septic shock. While this may be intrinsic to hepatic failure,
considering the possibility of a superimposed infection (especially spontaneous bacterial
peritonitis) is important.
Lab Studies
CBC count: Results may indicate thrombocytopenia.
These tests are used to determine the presence or severity of coagulopathy.
They are sensitive markers of hepatic synthetic failure but rarely in the setting of suspected FHF.
Hepatic enzymes
Levels of the transaminases often are elevated dramatically as a result of severe hepatocellular
necrosis.
Procedures:
 Liver biopsy
A percutaneous liver biopsy is contraindicated in the setting of a coagulopathy. However, a
transjugular biopsy can be performed in this setting if clinically indicated.
 Intracranial pressure monitoring
When establishing a diagnosis of intracranial hypertension or cerebral edema, this approach is
frequently necessary and has value in guiding management.
Typically, extradural catheters are safer than intradural catheters. Intradural catheters are
somewhat more accurate and, in the hands of a neurosurgeon experienced with their use, may be
equally safe.
TREATMENT
Diet
Patients are, by necessity, nothing by mouth (NPO). They may require large amounts of
intravenous glucose to avoid hypoglycemia.
When enteral feeding via a feeding tube is not feasible (eg, as in a patient with paralytic ileus),
institute total parenteral nutrition (TPN).
Restricting protein (amino acids) to 0.6 g/kg body weight per day was previously routine in the
setting of hepatic encephalopathy, but this may not be necessary.
Activity: Recommend bedrest.
Medical Care
The most important aspect of treatment is to provide good intensive care support. Recognizing
the condition promptly and understanding its potential to require transplantation are essential.
Monitoring for complications and instituting appropriate therapy are critical.
Use the standard method to manage portosystemic encephalopathy. Administer lactulose and/or
neomycin to reduce ammoniagenesis
The most important issue is to consider, detect, and appropriately manage cerebral edema.
As a result of severe coagulation deficits, patients with FHF are prone to intracranial
hemorrhages and subdural hematomas that must be considered in the evaluation.
Management of increased ICP is as follows:
Management is not unique to FHF, and the situation requires monitoring.
Use mannitol for primary treatment; however, it is contraindicated in renal failure. In this setting,
consider treating with a barbiturate coma. However, try to avoid using sedatives because they
impair accurate assessment of the patient's progress.
The exception may be in a patient with raised ICP who is extremely agitated (this further raises
ICP). Raise the head of the bed 10-20° and avoid agitating the patient (noise, intratracheal
suctioning).
Manage renal failure as follows:
Hemodialysis may significantly lower the mean arterial pressure such that cerebral perfusion
pressure is compromised.
Continuous arteriovenous hemofiltration is preferred.
Manage coagulopathy as follows:
Patients with FHF may bleed from any percutaneous access site or minor abrasion, and extensive
internal hemorrhage may occur.
Requirements for fresh frozen plasma and platelet replacements may be substantial, and this
requires close monitoring, especially during planned procedures (eg, ICP monitor placement).