BOOK 1

STUDENTS GUIDANCE
MODUL

HEPATITIS, CIRRHOSIS AND ITS

COMPLICATIONS
(Course Period : 6th Semester)

Contributors :
Dr. Supriono, SpPD-KGEH
Dr. Bogi Pratomo, SpPD-KGEH
Prof. DR. Dr. Harijono Achmad, SpPD-KGEH

MEDICAL FACULTY OF BRAWIJAYA UNIVERSITY

SAIFUL ANWAR HOSPITAL MALANG
2013
0

Level of Competencies
No.

Diseases

1
2
3
4
5
6
7
8
9
10
11
12
13
14

Fatty liver
Hepatitis A
Uncomplicated Hepatitis B
Amoebic liver abscess
Hepatitis in pediatric patient
Cirrhosis
Acute cholecystitis
Active Hepatitis C
Cirrhosis hepatis
Liver failure
Hydrops of gall bladder
Chole(docho)lithiasis
Empyema of gall bladder
Pancreatitis

15

Amoebiasis intestinal

Level of Competencies
Indonesian Medical Medical faculty of
Council 2006
Brawijaya - University
4
3-A
4
4
3-A
4
3-A
3-A
Modul-4
3-A
3-A
3-A
3-A
2
2
2
2
2
2
2
2
2
2
2
3-B
2
3-B (acute)
3-A (chronic)
Modul-2
-

Description
Module name

MODUL-: LIVER
BOOK-1 :

Learning Methods

Equipment
Time

- Hepatitis
- Cirrhosis
- Complications of cirrhosis

Self-Directed Learning (SDL)/Module task

Small-class Discussion/Tutorial
Cooperative Learning (CL)
Lectures (Teaching Learning Process)
Small classroom, Computer, LCD and Screen
- 2 x 120 minute : module task (SDL)
- 2 x 120 minute : small class discussion
1. Hepatitis, acute liver failure, cirrhosis and its complication
2. NAFLD, Liver abscess, gall-bladder disorder and pancreatitis
- 8 x 50 minute : expert lecture (teaching session)
1. Hepatitis
2. Acute Liver Failure
3. Cirrhosis
4. Complications of cirrhosis
5. NAFLD
6. Liver Abscess

Lecture Description

Lecturer
Evaluation
Suggested Refferences

This module is a part of Module on Gastrointestinal Disorders,

integratedly designs for medical student of 6 rd semester. This part of
module will facilitate the student to understand the hepato-bilier disorders
and pancreatitis.
Lecturer or lecturers taken from list of the doctors from Gastrointestinal
Block, as scheduled
Post test after teaching session
-

Harrison
Gayton

Contents
Level of Competencies

..

Description of the module

..

Contents

..

A. Objective of the module

B. Topic and Topic Tree
C. Module overview

..
..
.

4
5
7

Book-1
1. Hepatitis
a. Hepatitis A Virus (HAV) infection
b. Hepatitis B Virus (HBV) infection
c. Hepatitis C Virus (HCV) infection
2. Acute liver failure (ALF)
3. Cirrhosis and its Complications

...

7
9
12
15
18

20

Book-2
4. Non-alcoholic Fatty Liver Diseases (NAFLD)
5. Liver Abscess (amoebic and pyogenic)
6. Disorder of Gall-bladder and biliary tract
7. Pancreatitis

D. References and suggested further reading

A. OBJECTIVE OF THE MODULE

This module is a part of Module on Gastrointestinal Disorders, integratedly designs for medical
student of 7rd semester. This part of module will facilitate the student to understand the hepatobilier disorders and pancreatitis. To achieve the student level competencies, this module
contains description of scientific in simple overview and integrated with 10 tasks for student.
The objective of 10 tasks for the student to know:
1.
2.
3.
4.
5.
6.
7.

The etiology of acute hepatitis

The pathogenesis and management of HAV infection.
The risk factors of HBV infection and the route transmission of HBV infection.
The markers of acute and chronic HBV infection
The pathogenesis of chronic HCV infection
The causes of acute liver failure
The clinical manifestations of liver cirrhosis and the Child-Pugh classification of liver
cirrhosis!
8. The complications of liver cirrhosis
9. The pathogenesis of ascites in cirrhotic patient.
10. The management of liver cirrhosis complications!

B. TOPIC AND TOPIC TREE

Hepatocellular
Carcinoma (HCC)

Liver cirrhosis and its

complications
Clinical skill
supporting the
diagnosis

CHRONIC HEPATITIS

The complications of
liver cirrhosis:
- Ascites
- Variceal bleeding
- SBP
- HRS
- HE

The clinical
manifestations

Except HAV

The prevention and

management

ACUTE HEPATITIS

The etio-pathogenesis of
hepatitis

Figure-1: the Topic Tree of Hepatitis, cirrhosis

The anatomy of the liver
Clinical skill
supporting the
diagnosis

The prevention and

management

The physiology of the liver

The etiologies:
- Viral : hep A, B, C, etc
- Metabolic : fatty liver
- Alcoholic
and
its complications
- Drug induced
- Afatoxins

Amoebic Liver Abscess

The clinical
manifestations

AMOEBIASIS
INTESTINAL

The etio-pathogenesis of
amoebiasis intestinal

The anatomy of the

Intestine

The physiology of the

intestine

The etiology:
Entamoeba hystolitica

Figure-2: The Topic Tree of Amoebic Liver Abscess

5

Clinical skill
supporting the
diagnosis

The initial
management

Disorders of gall bladder

and biliary tract:
- Acute cholecystitis
- Chole(docho)lithiasis
- Hydrop of gall bladder
- Emphysema of gall
bladder

The clinical
manifestations

The prevention

The etio-pathogenesis of
disorders of gall bladder and
biliary tract

The anatomy and

physiology of biliary
system

The metabolism of the

bilirubin

The risk factors of disorders of

gall bladder and biliary tract

Figure-3: The Topic Tree of Gall Bladder and Biliary Tract Disorders

Clinical skill
supporting the
diagnosis

The initial
management

The clinical
manifestations

PANCREATITIS
- Acute Pancreatitis
- Chronic Pancreatitis

The prevention

The etio-pathogenesis of
pancreatitis

The anatomy of
pancreas

The physiology of
pancreas

The risk factors of

pancreatits

Figure-4: The Topic Tree of Pancreas Disorders

C. MODULE OVERVIEW
1. HEPATITIS
Hepatitis is a systemic infection or inflammation predominantly affecting the liver. It is
most often caused by viruses (viral hepatitis) that are hepatotropic and other viral
infections. Many abnormalities of metabolic and autoimmune result in inflammation in
hepatocyte.
Module task:

1. What is the etiology of acute hepatitis?

a. HEPATITIS A VIRUS (HAV) INFECTION
Hepatitis A virus (HAV) is an RNA-containing virus of the Picornaviridae family. HAV
infection is self-limiting and does not require treatment; contacts should be
vaccinated (particularly in low incidence areas). There is no chronic infection; HAV
infection induces lifelong immunity.
There are an estimated 1.5 million cases of acute HAV annually worldwide, or
depending on local endemicity, around 150 per 100,000. Most of these occur in
areas with poor hygiene and a poor sanitation infrastructure. The prevalence and
incidence of HAV infection are directly related to socio-economic conditions.
Infection occurs predominantly in childhood.
HAV is found in the feces of individuals with acute HAV in the pre-symptomatic and
early phases of the disease. HAV is usually spread between individuals by oral
contact with something that has been contaminated by fecal matter from an HAVinfected person (fecaloral transmission).The risk groups/circumstances for HAV:
Children living in poor sanitation and in areas with low hygiene
Children living in areas with a high incidence of HAV
Poor sanitation
Consumers of high-risk foods (e.g., raw shellfish)
Day-care employees and family of children in day care
People traveling to endemic areas
Once HAV is ingested and survives gastric acid, it traverses the small intestinal
mucosa and reaches the liver via the portal vein. The precise mechanism of hepatic
uptake in humans is unknown.
Module task:

2. Please explain the pathogenesis and management of HAV infection?

Clinical manifestations
The onset of the icteric phase is heralded by dark urine (conjugated bilirubinuria)
before jaundice becomes apparent. The nonspecific and gastrointestinal symptoms
often subside but may persist. The duration of jaundice is quite variable. Abnormal
physical examination findings apart from jaundice occurred in approximately half the
patients or fewer. Disease duration, not unexpectedly, varied with the duration of
jaundice. This relatively short duration may reflect their younger age.
As with the clinical symptoms and signs, there are no pathognomonic findings in the
laboratory investigations that distinguish HAV from other hepatotrophic viruses. The
maximum elevation of alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) can be substantially higher than that observed in acute
hepatitis B, but there is a wide range. In general the degree of aminotransferase
elevation roughly correlates with the severity of the acute hepatitis A in that
asymptomatic cases have lower aminotransferase levels. The overall severity of the
infection, however, is demonstrated by the bilirubin level as well as the prothrombin
time. Most cases of hepatitis A have a bilirubin of 10 mg/dl in the absence of
hemolysis, an indication that hepatitis A is usually not severe.
Diagnosis of HAV infection
All forms of acute viral hepatitis have the same initial presentation. Hepatitis A
cannot be definitively diagnosed without a blood test that measures various
serologic markers for HAV. HAV virus is reliably diagnosed by anti-HAV
immunoglobulin M (IgM); the presence of anti-HAV immunoglobulin G indicates a
previous infection. Persistent anti-HAV IgM can sometimes be detected in patients
with autoimmune hepatitis.
The following table displays the serologic tests available and what their results
mean.
Marker
Anti-HAV IgM

Anti-HAV IgG

Anti-HAV Total
HAV viral antigen
tests

Definition and diagnostic use

Diagnostic for acute hepatitis A infection.
False positive tests are rare. Anti-HAV IgM is detectable in virtually
every case at their first clinical examination.
Remains positive for 3-6 months, but can be positive for up to a
year.
Occasionally positive in adults up to two weeks after receiving
hepatitis A vaccine.
Not diagnostic for acute hepatitis A infection.
Indicates past infection and immunity.
Useful to determine immune status of the patient.
Positive test results not routinely investigated.
Not diagnostic for acute hepatitis A infection.
Useful to determine immune status of the patient.
Positive test results not routinely investigated.
Does not differentiate between IgM and IgG antibodies
Detects the presence of antigen in stool.
Viral shedding typically completed before the patient seeks medical
attention.

PCR

- Test has little routine value.

- Not recommended for diagnostic use.

Prevention
Improving sanitation and water supplies are the most important goals in the
prevention of HAV infection (as well as many other infections).
There are a number of inactivated vaccines on the market. Vaccination for preexposure prophylaxis (for example, with VAQTA or Havrix) provides long-term
protection for up to 20 years. Vaccination for post-exposure prophylaxis should be
given as early as possible.

b. HEPATITIS B VIRUS (HBV) INFECTION

HBV is a DNA-containing virus of the Hepadnaviridae family. The virus is present in
most body fluids in individuals with acute or chronic hepatitis and in inactive
carriers. The World Health Organization (WHO) estimates that over 5 million cases
of acute hepatitis B infection occur annually. The incidence of HBV infection and
patterns of transmission vary greatly throughout the world, depending on local
endemicity, with rates between 0.1 and 120 per 100,000. HBV infection is a global
health problem. Two billion people have been infected worldwide; 360 million are
chronically infected; over 520,000 die each year (50,000 of acute hepatitis B and
470,000 of cirrhosis or liver cancer).
Module task:

3. What are the risk factors of HBV infection? ; Please describe the route
transmission of HBV infection.
Pathogenesis and Natural History of HBV Infection
The observation that many HBV carriers are asymptomatic with minimal liver injury,
despite extensive and continuing intrahepatic replication of the virus, supports the
concept that HBV is not directly cytotoxic to hepatocytes. The severity of

hepatocellular injury is modulated by the strength of host immune responses. In

patients with fulminant HBV infection, rapid viral clearance is achieved after severe
liver injury as a result of a vigorous host immune response. However, in neonates
with an immature immune system, exposure to HBV often results in minimal acute
liver injury but high rates of chronic infection (up to 90%).
The outcome of acute HBV infection depends on age and immune competence at
the time of infection. For example, chronic HBV infection will develop in as many as
90% of infected neonates and infants but only in 1% to 5% of immunocompetent
adults (excluding those with acute exacerbations of chronic HBV infection). Children
aged 1 to 5 years have an intermediate risk (approximately 30%).
Fulminant hepatitis occurs in 0.1% to 0.5% of those with acute HBV infection and
often demonstrates no evidence of HBV replication because of the massive
immunemediated lysis of infected hepatocytes. Persons infected as children may
present in adulthood with clinical manifestations similar to those of acute hepatitis if
they have acute exacerbation of chronic HBV infection. These exacerbations
frequently may be associated with elevated levels of IgM antibody to hepatitis B
core antigen, which may lead to misdiagnosis of acute HBV infection, and an
increase in the serum -fetoprotein concentration, which may raise concerns for the
presence of hepatocellular carcinoma (HCC).
Module task

4. Please describe the markers of acute and chronic HBV infection.

Clinical manifestation of HBV Infection

HBV infection has variable manifestations. During the acute stage, HBV infection
can manifest as anicteric (subclinical) hepatitis, icteric hepatitis, or, rarely, acute
fulminant hepatitis. Chronic HBV infection can be asymptomatic (the HBV surface
antigen carrier state), or it can be manifested by symptoms and signs of cirrhosis or
hepatocellular carcinoma or both. Extrahepatic manifestations, including serum
sickness, polyarteritis nodosa, essential mixed cryoglobulinemia, membranous
glomerulonephritis, and aplastic anemia, have been reported in patients with HBV
infection.
The incubation period of HBV ranges from 2 weeks to 4 months. Initially, patients
complain of fatigue, malaise, anorexia, right upper quadrant discomfort, or flu-like
symptoms (coryza, photophobia, headache, and myalgia); then jaundice becomes
apparent, usually within 10 days of the onset of symptoms. Low-grade fever,
jaundice, and mildly tender hepatomegaly are the most common signs.
In the acute phase, ALT and AST levels rise, sometimes to values above 1,000 IU/L.
In icteric hepatitis, bilirubin levels also rise, usually after the ALT level does.
Although the peak ALT level reflects the hepatocellular injury, it has no prognostic
value. With recovery, ALT levels normalize in 1 to 4 months. Acute fulminant
hepatitis B occurs in 0.1% to 0.5% of patients. Patients typically present with rapidly
progressive acute hepatitis characterized by signs of liver failure, such as
coagulopathy, encephalopathy, and cerebral edema.

10

Chronic hepatitis B is usually diagnosed as a result of a workup for abnormal liver

function tests or as a result of screening patients at risk for HBV infection. Many
patients with chronic hepatitis B have no symptoms or have nonspecific symptoms
such as fatigue or right upper quadrant discomfort.
Acute exacerbations due to HBeAg sero-reversion (ie, in which HBeAg reappears)
occasionally occur in patients with chronic hepatitis B. Most of these exacerbations
are asymptomatic, but occasionally an acute hepatitis-like clinical picture with
detectable IgM antibody against the core antigen occurs, leading to misdiagnosis of
acute HBV infection in patients not previously known to have chronic HBV infection.
In chronic hepatitis B, liver enzyme levels can be normal, even in patients with wellcompensated cirrhosis. ALT levels may range from normal to five times higher than
normal. Thrombocytopenia, hypoalbuminemia, direct hyperbilirubinemia, and
prolonged prothrombin time suggest cirrhosis. Findings of chronic hepatitis B on
liver biopsy range from minimal inflammation to cirrhosis. The most characteristic
histologic feature of chronic HBV infection is the ground-glass hepatocyte, which is
due to intracellular accumulation of HBsAg.
In late cases, signs of cirrhosis such as jaundice, ascites, splenomegaly, pedal
edema, encephalopathy, or variceal bleeding can be present. Hepatocellular
carcinoma should be suspected in cirrhotic patients with new-onset right upper
quadrant pain, rapidly developing ascites, a palpable liver mass or hepatic
encephalopathy. Other nonspecific features of hepatocellular carcinoma include
watery diarrhea, hypoglycemia, and certain cutaneous manifestations such as
acanthosis nigricans and the Leser-Trelat sign (multiple pruritic seborrheic
keratoses of sudden onset).
Diagnosis of HBV infection
The diagnosis of acute hepatitis B is based on the detection of HBsAg and anti-HBc
(IgM). During the initial phase of infection, markers of HBV replication, HBeAg and
HBV DNA, are also present. Recovery is accompanied by the disappearance of
detectable HBV DNA, HBeAg seroconversion to anti-HBe, and subsequently
clearance of HBsAg with seroconversion to anti-HBs with anti-HBc (IgG). All this
should take place within 3 months of the diagnosis.
The differential diagnosis of HBsAg-positive acute hepatitis includes exacerbations
of chronic hepatitis B, which may occur at any time in any individual who is
chronically infected (at these times, reversion back to anti-HBc IgM may occur).
Acute hepatitis may occur following withdrawal from immunosuppressive therapy or
through superinfection of a person chronically infected with hepatitis B with either
hepatitis C and/or D virus. Superimposed acute hepatitis due to drugs and other
toxins administered to someone who has silent chronic hepatitis B infection may
also present as acute hepatitis. A precipitating factor is sometimes not identified.
Management of HBV infection
Spontaneous recovery occurs after acute infection with HBV occurs in 9599% of
previously healthy adults. Antiviral therapy is not therefore likely to improve the rate
of recovery and is not required unless there are indications. Before any form of HBV
therapy is started, and optimally at the time of first presentation, the patient needs to
be provided with information about the natural history of chronic hepatitis B infection
and the fact that most infections remain entirely without symptoms even in those

11

with severe disease, so that there is a need for regular lifelong monitoring, and this
information should be discussed with the patient.
The aims of treatment of chronic hepatitis B are to achieve sustained suppression of
HBV replication and remission of liver disease. The ultimate goal is to prevent
cirrhosis, hepatic failure and HCC. Parameters used to assess treatment response
include normalization of serum ALT, decrease in serum HBV DNA level, loss of
HBeAg with or without detection of anti-HBe, and improvement in liver histology.
Currently, six therapeutic agents (Lamivudine, Telbivudine, Adefovir, Entecavir,
Tenofovir and IFN/Peginterferon alfa) have been approved for the treatment of
adults with chronic hepatitis B in the United States. While interferons (IFNs) are
administered for predefined durations, NAs are usually administered until specific
endpoints are achieved. The difference in approach is related to the additional
immune modulatory effects of IFN. For HBeAg-positive patients, viral suppression
with currently approved treatments can be sustained in 50%-90% patients if
treatment is stopped after HBeAg seroconversion is achieved. For HBeAg-negative
patients, relapse is frequent even when HBV DNA has been suppressed to
undetectable levels by PCR assays for more than a year; thus, the endpoint for
stopping treatment is unclear.
Prevention
A program for universal vaccination (available since the early 1980s) of all
newborns is a key step toward effective control of HBV infection throughout the
world. Hepatitis B vaccination is highly cost-effective, in that it prevents infection
with HBV and thus reduces the incidence of chronic hepatitis, cirrhosis, and HCC in
the vaccinated population.

c. HEPATITIS C VIRUS (HCV) INFECTION

Since 1970, when non-A non-B hepatitis viruses were first recognized, until the
early 90s, when Houghton et al successfully cloned Hepatitis C virus (HCV),
different interpretations regarding evolution and prognosis of HCV infection existed.
HCV is an RNA-containing virus of the Flaviviridae family.
The global incidence of hepatitis C is currently unknown. Preliminary estimates of
the incidence of HCV suggest that 6,400,000 HCV infections may occur each year.
The incidence of new symptomatic infections has been estimated to be one to three
cases per 100,000 persons annually, but rates of more than 20 per 100,000 have
been reported. The actual incidence of new infections is obviously much higher (the
majority of cases being asymptomatic).
Risk factors and transmission
Transmission is from blood to blood. As a blood-borne infection, HCV may
potentially be transmitted sexually, mainly in individuals with other sexually
transmitted diseases. The perinatal transmission rate is around 5%, much lower
than the rates for HIV and HBV. Breastfeeding does not pose a risk. Health-care
workers are at risk; mostly due to nosocomial transmission (needlestick injury
carries a 3% HCV risk). Also at risk are individuals in prisons and persons born in
countries with high rates of endemic disease.
High risk of HCV infection is associated with:

12

Any history of injection drug use

Contaminated blood or blood products or organ transplantation
Needlestick or sharp injuries
Procedures (e.g., injection, vaccination, surgery, transfusion, ceremonial rituals)
involving reuse or sharing of contaminated equipment in parts of the world with
high HCV prevalence
Nonsterile contaminated tattooing or body piercing equipment
Receiving hemodialysis
Sharing personal items contaminated with blood with an HCV-infected person
(e.g., razors, nail clippers, toothbrush)
Sharing contaminated intranasal cocaine equipment
Hepatitis B virus or HIV infection
Children born to mother with HCV infection

Module task

5. Please explain the pathogenesis of chronic HCV infection

Clinical manifestation of HCV infection
The incubation period varies from 14 to 160 days, with a mean of 7 weeks. Most
acute and chronic infections are asymptomatic. If symptoms occur, they usually last
212 weeks. Unlike the other forms of acute viral hepatitis, acute HCV is very likely
to become chronic.
Most infected people (60%75%) do not experience symptoms when acutely
infected. For those with symptomatic acute infections, the manifestations are similar
to those of hepatitis A or B virus infection: malaise, fatigue, lethargy, anorexia,
abdominal pain, jaundice, mild hepatosplenomegaly, maculopapular rash and
arthralgia. These symptoms may last for 212 weeks. Fulminant hepatitis is very
rare in the acute infection stage. This is because the vast majorities of acute HCV
cases is asymptomatic or have only mild flu-like symptoms with little or no jaundice.
Some patients with chronic infection experience malaise, nausea, abdominal pain
and pruritis. Fluctuating ALT levels are characteristic.

13

Typical course of a case of acute HCV infection

14

Diagnosis of HCV infection

Diagnosis of hepatitis C is based on serological assays which detect HCV-specific
antibodies (anti-HCV) and on molecular assays which detect HCV RNA. Current
enzyme immunoassays (EIAs) are highly sensitive as well as specific and represent
the primary diagnostic tool. HCV RNA detection by real-time RT-PCR is now
standardized, reliable and reproducible, and offers a broad dynamic quantitation
range. HCV becomes positive by RT-PCR as early as 12 weeks after infection and
46 weeks before anti-HCV seroconversion. HCV RNA testing is used to confirm
active infection in anti-HCV-positive individuals and to diagnose acute hepatitis C or
chronic hepatitis C in the rare immunocompromised patients that do not develop
anti-HCV antibodies. However, the principal role of HCV RNA testing is in the
tailoring and monitoring of antiviral therapy. Determination of HCV genotype is
important for the selection of the optimal antiviral regimen.
Management
The main aim of treating patients with chronic hepatitis C virus infection is to
prevent progressive hepatic fibrosis by eradicating viral RNA. Sustained virological
clearance is defined as the absence of hepatitis C virus RNA as judged by a
sensitive polymerase chain reaction assay 24 weeks after the end of treatment. The
potential long term benefits of sustained virological clearance include normalisation
of serum aminotransferase levels, improvement in hepatic necroinflammation and
fibrosis, improvement in health related quality of life measures, survival benefits,
and reduction in risk of developing hepatocellular carcinoma. Although all patients
should be considered for treatment, balancing the risks of progressive disease with
potential side effects of current therapy remains a major challenge for healthcare
providers. Thus patients with mild disease activity should be given the option of
deferring therapy.
Current standard therapy of chronic hepatitis C consists of pegylated interferon-
(PEG-IFN-), administered once weekly by subcutaneous injection, combined with
ribavirin, which is taken orally on a daily basis. Both drugs operate through
incompletely understood, likely direct antiviral and immunomodulatory mechanisms.
There are a number of contraindications, and adverse effects, sometimes serious,
are frequent. Standard treatment duration is 48 weeks for HCV genotype 1 and 24
weeks for genotypes 2 and 3. With this treatment, 4050% of genotype 1- and
about 80% of genotype 2- and 3-infected patients achieve a sustained virological
response (SVR). Current efforts are aimed at tailoring doses and treatment duration
to the individual patient based on baseline parameters (e.g., genotype, viremia,
fibrosis stage) and on-treatment viral kinetics (viremia at 4, 12 and 24 weeks).
Hence, therapy may be abbreviated in selected patients with favorable baseline
parameters and a rapid virological response (i.e., negative HCV RNA after 4 weeks
of treatment) while others may benefit from prolonged treatment.
Prevention
Because no effective vaccine and no effective postexposure prophylaxis against
HCV infection are available, a major effort should be placed on counseling both
HCV-infected patients and those at risk for HCV infection. In addition, adequate
sterilization of medical and surgical equipment is mandatory.

15

6. ACUTE LIVER FAILURE

Acute liver failure (ALF) is a rare condition in which rapid deterioration of liver function
results in altered mentation and coagulopathy in previously normal individuals. The
most prominent causes include drug-induced liver injury, viral hepatitis, autoimmune
liver disease and shock or hypoperfusion; many cases (~20%) have no discernible
cause. Acute liver failure often affects young persons and carries a high morbidity and
mortality.
The most widely accepted definition of ALF includes evidence of coagulation
abnormality, usually an international normalized ratio (INR) 1.5, and any degree of
mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an
illness of 26 weeks duration. A number of other terms have been used including
fulminant hepatic failure and fulminant hepatitis or necrosis. Acute liver failure is a better
overall term that should encompass all durations up to 26 weeks. Terms used signifying
length of illness such as hyperacute (7 days), acute (7-21 days) and subacute ( 21
days and 26 weeks) are not particularly helpful since they do not have prognostic
significance distinct from the cause of the illness. For example, hyperacute cases may
have a better prognosis but this is because most are due to acetaminophen toxicity.
Module task

6. What are the causes of acute liver failure?

Diagnosis and Initial Evaluation of ALF
All patients with clinical or laboratory evidence of moderate to severe acute hepatitis
should have immediate measurement of prothrombin time and careful evaluation for
subtle alterations in mentation. If the prothrombin time is prolonged by ~4-6 seconds or
more (INR 1.5) and there is any evidence of altered sensorium, the diagnosis of ALF is
established and hospital admission is mandatory. Since the condition may progress
rapidly, with changes in consciousness occurring hour-by-hour, early transfer to the
intensive care unit (ICU) is preferred once the diagnosis of ALF is made.
History taking should include careful review of possible exposures to viral infection and
drugs or other toxins. If severe encephalopathy is present, the history may be provided
entirely by the family or may be unavailable. In this setting, limited information is
available, particularly regarding possible toxin/drug ingestions. Physical examination
must include careful assessment and documentation of mental status and a search for
stigmata of chronic liver disease. Jaundice is often but not always seen at presentation.
Right upper quadrant tenderness is variably present. Inability to palpate the liver or
even to percuss a significant area of dullness over the liver can be indicative of
decreased liver volume due to massive hepatocyte loss. An enlarged liver may be seen
early in viral hepatitis or with malignant infiltration, congestive heart failure, or acute
Budd-Chiari syndrome.
Initial laboratory examination must be extensive in order to evaluate both the etiology
and severity of ALF. In addition to coagulation parameters, early testing should include
routine chemistries (especially glucose as hypoglycemia may be present and require
correction), arterial blood gas measurements, complete blood counts, blood typing,
acetaminophen level and screens for other drugs and toxins, viral hepatitis serologies

16

(most prominently A and B), tests for Wilson disease, autoantibodies (anti-nuclear and
anti-smooth muscle antibodies) and a pregnancy test in females. Plasma ammonia,
preferably arterial, may also be helpful. A liver biopsy may be indicated when certain
conditions such as autoimmune hepatitis, metastatic liver disease, lymphoma, or
herpes simplex hepatitis are suspected.
As the evaluation continues, several important decisions must be made: whether to
admit the patient to an ICU, whether to transfer the patient to a transplant facility, and (if
already at a transplant center) whether and when to place the patient on the list for
transplantation. For patients in a non-transplant center, the possibility of rapid
progression of ALF makes early consultation with a transplant facility critical. Specific
prognostic indicators may point toward the need for transplantation. For patients with
acetaminophen-related ALF in particular, an arterial pH of 7.3 should prompt
immediate consideration for transfer to a transplant center and placement on a
transplant list.
Patients with altered mentation should generally be admitted to an ICU. Planning for
transfer to a transplant center should begin in patients with grade I or II encephalopathy
because they may worsen rapidly. Early transfer is important as the risks involved with
patient transport may increase or even preclude transfer once stage III or IV
encephalopathy develops. Evaluation for transplantation should begin as early as
possible. In these critically ill patients with potential for rapid deterioration it is necessary
to make treatment plans promptly. Social and financial considerations are unavoidably
tied to the overall clinical assessment where transplantation is contemplated. It is
important to inform the patients family or other next of kin of the potentially poor
prognosis and to include them in the decision-making process.
Management of ALF
Optimal medical management in the ICU is one of the most important determinants of
outcome. The outcomes also varied based on the etiology of disease. Transplant free
survival was highest (50%) for patients with acetaminophen overdose, hepatitis A
virus, ischemic hepatitis or pregnancy-related disease. Notably, fewer than 10% of
patients with acetaminophen toxicity, the most common cause of ALF, underwent liver
transplantation.
Fluid management and renal failure
Most patients with ALF arrive in the ICU with varying degrees of intravascular volume
depletion (due to inadequate fluid intake caused by obtundation or gastrointestinal
bleeding), which may lead to renal insufficiency. Therefore, volume resuscitation is an
important aspect of initial management. However, excess administration of intravenous
volume may have detrimental effects in the setting of ALF. In particular, overloading the
vascular space may lead to increased brain edema, herniation and death. Therefore,
volume resuscitation is best done judiciously to prevent these problems. Renalreplacement therapy (RRT) should be provided early in the course of acute renal failure
to prevent its attendant complications of acidosis and volume overload.
N-acetylcysteine (NAC)
N-acetylcysteine (NAC) is a proven effective therapy for acetaminophen hepatotoxicity
and its use in this clinical scenario is widely recognized. In addition, some studies
suggest that NAC may have beneficial effects on ALF from other causes (in addition to
acetaminophen). NAC may improve circulatory dysfunction and impaired oxygen
delivery found in all forms of acute hepatic failure. Early intervention with NAC may

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prevent progressive decompensation in patients with nonacetaminophen-induced ALF.

In summary, NAC is an innocuous and easily administered medication and may be
administered in all forms of ALF (acetaminophen and nonacetaminophen), although a
survival benefit has only been demonstrated with acetaminophen toxicity.
Treatment of cerebral edema
The cause of cerebral edema in ALF is not fully understood. However, evidence
suggests that the following mechanisms play a contributing role: loss of vascular
cerebral autoregulation, inflammatory mediators and increased neural glutamine
content caused by elevated arterial ammonia. Simple interventions may have some
benefit such as elevation of the head of the bed to 30 degrees, avoidance of stimulation
and the administration of intravenous sedation. The selection of a specific sedative is
an important consideration. In general, the use of benzodiazepines should be avoided
primarily due to their protracted sedating effects in patients with ALF.
Lactulose may also be beneficial in improving mental status, but there are very few data
to support its use. Theoretically, lactulose may reduce intracranial pressure (ICP) by
decreasing arterial ammonia levels which are associated with increased ICP and
cerebral herniation.
Mannitol is an osmotic diuretic commonly used in the ICU to treat intracranial
hypertension. In a controlled trial, mannitol was effective in reducing intracranial
hypertension caused by ALF and improved survival. However, there is no indication for
its prophylactic use and long-term administration of mannitol is complicated by
hypernatremia and volume overload.
Corticosteroids are commonly used in the treatment of intracranial hypertension due to
intracranial trauma or bleeding. However, a controlled trial failed to show any
improvement in survival or ICP in patients with ALF and, therefore, corticosteroids are
not a recommended therapy.
Coagulopathy
Severe coagulopathy in ALF is a common problem, because these patients are
frequently thrombocytopenic and have marked elevation in the INR. However, the
administration of fresh frozen plasma (FFP) is not encouraged for the following reasons:
even with substantial infusion of FFP, the improvement in INR is modest and shortlived, administration of FFP increases the intravascular volume which may increase
cerebral edema and FFP has been shown to be ineffective in a controlled study. For
similar reasons, the prophylactic infusion of platelets is not recommended. The only
exception to this rule is the correction of coagulopathy for invasive procedures or
clinically significant bleeding.
Recombinant activated factor VII is effective in correcting coaguloapathy and has the
advantage of its rapid onset of action and absence of volume load to the patient. Its
major drawbacks are its extreme cost, short-term effect and theoretical concerns of
thrombosis, which have been borne out in case reports. The most effective use of
activated factor VII in ALF is the rapid correction of INR before an invasive procedure.
Infection
Infection accompanied by multiorgan system failure is one of the most common causes
of death in ALF. In addition, the success of liver transplantation is significantly
jeopardized by systemic infection. Therefore, investigators have studied the effects of
prophylactic antibiotics through systemic intravenous administration as well as gut
decontamination with oral nonabsorbed antibiotics. Unfortunately, there is no survival

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advantage with either approach, although parenteral antibiotics may reduce the
incidence of infection. As a result, prophylactic antibiotics are not recommended in ALF.
However, as with any ICU patient, careful monitoring for infection is warranted and
antibiotics should be administered in patients with early clinical signs of infection.
Liver transplantation
Liver transplantation is the only effective therapy for ALF patients who fail to recover
spontaneously. The most critical decision for liver transplant candidates with ALF is
whether spontaneous recovery will occur and when to abandon hope for recovery and
proceed with transplantation.
7. CIRRHOSIS AND ITS COMPLICATIONS
Cirrhosis and chronic liver failure are leading causes of morbidity and mortality in the
United States, with the majority of preventable cases attributed to excessive alcohol
consumption, viral hepatitis, or nonalcoholic fatty liver disease. Cirrhosis often is an
indolent disease; most patients remain asymptomatic until the occurrence of
decompensation, characterized by ascites, spontaneous bacterial peritonitis, hepatic
encephalopathy, or variceal bleeding from portal hypertension.
Physical examination of patients with cirrhosis may reveal a variety of findings that
necessitate a hepatic- or gastrointestinal-based work-up to determine the etiology.
Some patients already may have had laboratory or radiographic tests that incidentally
uncovered signs of cirrhosis and its co-morbidities. No serologic or radiographic test
can accurately diagnose cirrhosis. A significant correlation has been demonstrated
between persistently elevated liver function tests and biopsy-proven underlying hepatic
disease; thus, a more targeted serologic work-up is indicated in patients whose liver
function test results are persistently abnormal. Referral for liver biopsy should be
considered only after a thorough, noninvasive serologic and radiographic evaluation
has failed to confirm a diagnosis of cirrhosis; the benefit of biopsy outweighs the risk;
and it is postulated that biopsy will have a favorable impact on the treatment of chronic
liver disease.
Although numerous pathophysiologic mechanisms of injury exist, the final common
pathway is persistent wound healing resulting in hepatic parenchymal fibrosis.
Parenchymal fibrosis represent a continuous disease spectrum characterised by an
increase in total liver collagen and other matrix proteins which disrupt the architecture of
the liver and impair liver function. Fibrosis results from sustained wound healing in the
liver in response to chronic or iterative injury. The wound healing response is an integral
part of the overall process of inflammation and repair: it is dynamic and has the
potential to resolve without scarring. When complications of cirrhosis occur, they
typically are related to impaired hepatic function or actual physical disruption and
reorganization of the liver parenchyma.
Module task

7. What are the clinical manifestations of liver cirrhosis? Pleases describe the
Child-Pugh classification of liver cirrhosis!
Laboratory Evaluation

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No serologic test can diagnose cirrhosis accurately. The term liver function tests are
a misnomer because the assays in most standard liver panels do not reflect the
function of the liver correctly. When a liver abnormality is suspected or identified, a
liver panel, a complete blood count (CBC) with platelets, and a prothrombin time
test should be performed. Common tests in standard liver panels include the serum
AST, ALT, alkaline phosphatase (ALP), and -glutamyltransferase (-GT); total,
direct, and indirect serum bilirubin; and serum albumin.
Additional serologic studies should be pursued in such circumstances to evaluate
for various etiologies of cirrhosis. If clinical suspicion for liver disease is high, then
further serologic work-up is warranted within six months. If a patient has a
persistently increased ALT level, viral hepatitis serologies (HBsAg and anti HCV)
should be assayed.
Ultrasonography
Abdominal ultrasonography with Doppler is a noninvasive, widely available modality
that provides valuable information regarding the gross appearance of the liver and
blood flow in the portal and hepatic veins in patients suspected to have cirrhosis.
Ultrasonography should be the first radiographic study performed in the evaluation
of cirrhosis because it is the least expensive and does not pose a radiation
exposure risk or involve intravenous contrast with the potential for nephrotoxicity as
does Computed Tomography (CT). Nodularity, irregularity, increased echogenicity,
and atrophy are ultrasonographic hallmarks of cirrhosis. In advanced disease, the
gross liver appears small and multinodular, ascites may be detected, and Doppler
flow can be significantly decreased in the portal circulation. The discovery of hepatic
nodules via ultrasonography warrants further evaluation because benign and
malignant nodules can have similar ultrasonographic appearances.
CT and MRI
CT and magnetic resonance imaging (MRI) generally are poor at detecting
morphologic changes associated with early cirrhosis, but they can accurately
demonstrate nodularity and lobar atrophic and hypertrophic changes, as well as
ascites and varices in advanced disease. Although MRI sometimes differentiates
among regenerating or dysplastic nodules and hepatocellular carcinoma, it is best
used as a follow-up study to determine whether lesions have changed in
appearance and size. CT portal phase imaging can be used to assess portal vein
patency, although flow volume and direction cannot be determined accurately.
Although used rarely, magnetic resonance angiography (MRA) can assess portal
hypertensive changes including flow volume and direction, as well as portal vein
thrombosis.
Liver Biopsy
Referral for liver biopsy should be considered after a thorough, noninvasive
serologic and radiographic evaluation has failed to confirm a diagnosis of cirrhosis;
the benefit of biopsy outweighs the risk; and it is postulated that biopsy will have a
favorable impact on the treatment of chronic liver disease. The sensitivity and
specificity for an accurate diagnosis of cirrhosis and its etiology range from 80 to
100 percent, depending on the number and size of the histologic samples and on
the sampling method.
Module task

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8. What are the complications of liver cirrhosis?

9. Please explain the pathogenesis of ascites in cirrhotic patient.

MANAGEMENT OF LIVER CIRRHOSIS

Generally, liver damage from cirrhosis cannot be reversed, but treatment could stop
or delay further progression and reduce complications. A healthy diet is encouraged,
as cirrhosis may be an energy-consuming process. Close follow-up is often
necessary. Antibiotics will be prescribed for infections, and various medications can
help with itching. Laxatives, such as lactulose, decrease risk of constipation; their
role in preventing encephalopathy is limited.
Module task

10. Please describe the management of liver cirrhosis complications!

D. References and suggested further reading

-

Harrisons Textbook of Internal Medicine

Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed
Diagnosis of Hepatitis A Virus Infection: a Molecular Approach; CLINICAL
MICROBIOLOGY REVIEWS, Jan. 2006, P. 6379
Hepatitis A: Old and New; CLINICAL MICROBIOLOGY REVIEWS,Jan. 2001, p. 3858
Hepatitis B Virus Biology; MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS,
Mar. 2000, p. 5168
Hepatitis B; World Gastroenterology Organisation Practice Guideline ;September 2008
Acute Hepatitis C Virus Infection: Diagnosis, Pathogenesis, Treatment; J
Gastrointestin Liver Dis; September 2006 Vol.15 No.3, 249-256
Hepatitis C: a review for primary care physicians; CMAJ 2006;174(5):649-59
Cirrhosis and Chronic Liver Failure: (Am Fam Physician 2006;74:756-62
Stigmata of chronic liver diseases; Hospital Physician, july 2003
Management of complications of cirrhosis in patients awaiting liver transplantation;
Journal of Hepatology 42 (2005) S124S133

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