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Hepatitis 153
Table 4.4 Serological markers of hepatitis B infection
HBsAg anti-HBc anti-HBs IgM anti-HBc
Susceptible to infection Negative Negative Negative Negative
Immune due to natural
infection
Immune due to
hepatitis B vaccination
Acutely infected
Chronically infected
anti-HBc, anti-hepatitis B core antibody; anti-HBs, anti-hepatitis B surface antibody;
HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.
ALT and HBV DNA ≤2000 IU/mL) who are at low risk for progressive liver
disease. Patients who lie outside these categories may require treatment if
significant inflammation or necrosis is found in the liver biopsy or if there are
increases in serum ALT.
All patients need long-term follow-up with annual assessment of hepatitis
B serology and liver biochemistry, as transition to an active phase is common.
The lifetime risk of malignancy is increased in all HBsAg-positive patients.
Negative Positive Positive
Negative Negative Positive
Positive Positive Negative
Positive Positive Negative
Negative
Negative
Positive
Negative
Antiviral agents
The aim of therapy is to prevent disease progression and, ideally, to eliminate
HBsAg.
• Interferon is an immunostimulator which induces an immune response
leading to prolonged remission after discontinuation of therapy.
Pegylated interferon-α-2a is most often used in patients who are
HBeAg-positive with active disease. Younger patients with higher serum
ALT and lower viral loads respond best to treatment. A proportion of
patients with active disease (high ALT, increased HBV DNA) convert to
inactive disease, and response can be assessed by an early decline
in HBsAg. Adverse effects of treatment include an acute influenzalike illness 6–8 hours after the first injection. Malaise, headaches and
myalgia are common; depression, reversible hair loss and bone marrow
depression and infection may also occur.
• Oral nucleotides (e.g. entecavir and tenofovir) suppress viral replication
and are used for a prolonged period of time. Long-term viral suppression
has been shown to reverse fibrosis and even patients with cirrhosis
respond with reversion of the fibrosis. Resistance is rarely seen with
these agents, and older, more resistance-prone drugs like lamivudine
are no longer recommended. A small proportion of patients develop
154 Liver, biliary tract andpancreatic disease
an immune response leading to loss of HBeAg and, very rarely, loss of
HBsAg. However, the majority of patients who commence oral antiviral
agents will require very prolonged treatment, perhaps for life. Entecavir
and tenofovir are the drugs of choice for HBV, and both agents are
associated with very few side effects and an excellent response.
Hepatitis B and HIV co-infection
Routes of infection are similar for HBV and the human immunodeficiency
virus (HIV) and rates of co-infection are 10%–20%. All patients with chronic
HBV infection should have a test for HIV antibody and vice versa. Testing
should be repeated if there is ongoing risk of HIV, particularly before antiviral
treatment for HBV is contemplated. HIV infection makes it more likely that an
individual exposed to HBV will develop chronic infection and this will progress
to more severe liver disease. Treatment of co-infection is complex and best
managed in a specialist unit.
Prophylaxis
The avoidance of high-risk factors (needle sharing, sex workers and multiple
male homosexual partners) and counselling of patients who are potentially
infective are key aspects of prevention. Active immunization with a recombinant yeast vaccine is universal in most developed countries. In the UK it
is only recommended for those at increased risk, e.g. healthcare workers,
homosexual and bisexual men, sex workers, intravenous drug users, people
with haemophilia, haemodialysis patients, partners and household contacts
of infected individuals. The immunity that develops after active immunization
lasts for over 10 years. Combined prophylaxis (i.e. active immunization and
passive immunization with specific antihepatitis B immunoglobulin) is given
to non-immune individuals after high-risk exposure, e.g. needle-stick injury
from a carrier, newborn babies of HBsAg-positive mothers and HBV-negative
sexual partners of HBsAg-positive patients.
Hepatitis D (delta or δ agent)
This is caused by the hepatitis D virus (HDV) which is an incomplete RNA
particle enclosed in a shell of HBsAg and belongs to the Deltaviridae family.
It is unable to replicate on its own but is activated by the presence of HBV.
Diagnosis is by finding HDV RNA or anti-HDV IgM in the serum. It is common
in some parts of the world including Eastern Europe (Romania, Bulgaria),
North Africa and the Brazilian rainforest. Hepatitis D viral infection can occur
as a co-infection with HBV. It is clinically indistinguishable from an acute
icteric HBV infection but a biphasic rise of serum aminotransferases may
be seen. Superinfection results in an acute flare-up of previously quiescent
chronic HBV infection. A rise in serum AST or ALT may be the only indication
of infection. Diagnosis is by finding HDV RNA or serum anti-HDV IgM at the
same time as IgG anti-hepatitis B core antibody (anti-HBc). Active HBV DNA
Hepatitis 155
synthesis is reduced by delta superinfection and patients are usually negative
for HBeAg with low HBV DNA. Acute hepatic failure can follow both types of
infection but is more common after co-infection.
Chronic hepatitis D is an infrequent chronic hepatitis but spontaneous
resolution is rare. Between 60% and 70% of patients will develop cirrhosis
more rapidly than with HBV infection alone. In 15% of cases, the disease is
rapidly progressive with development of cirrhosis in a few years. Treatment
for patients with active liver disease is with pegylated α-2a interferon for
12months, although response rates are very low.
Hepatitis C
The prevalence rate of infection ranges from 0.4% in Europe to 1%–3% in
Southern Europe (possibly linked to intramuscular injections of vaccines or
other medicines), 6% in Africa, and in Egypt the rates are as high as 19% due
to parenteral antimony treatment for schistosomiasis. The virus is transmitted
by blood and blood products and was common in persons with haemophilia
treated before screening of blood products was introduced. The incidence
in intravenous drug users is high (50%–60%). The low rate of HCV infection
in high-risk groups such as men who have sex with men, sex workers and
attendees at sexually transmitted infection (STI) clinics suggests a limited
role for sexual transmission. Vertical transmission from a healthy mother
to child can occur, but is rare (~ 5%). Other routes of community-acquired
infection (e.g. close contact) are extremely rare. In 20% of cases the exact
mode of transmission is unknown. An estimated 240 million people are
infected worldwide.
Hepatitis C virus
HCV is a single-stranded RNA virus of the Flaviviridae family with six genotypes which differ in geographical distribution. Genotypes 1a and 1b account
for 70% of cases in the USA and 50% in Europe.
Most acute infections are asymptomatic, with about 10% of patients having
a mild flu-like illness with jaundice and a rise in serum aminotransferases.
Some 85%–90% of asymptomatic patients develop chronic liver disease.
A higher percentage of symptomatic patients ‘clear’ the virus with only
48%–75% going on to develop chronic liver disease.
Chronic hepatitis C infection
Patients with chronic hepatitis C infection are usually asymptomatic, the
disease being discovered only following a routine biochemical test when
mild elevations in the aminotransferases (usually ALT) are noticed (50%). The
elevation in ALT may be minimal and fluctuating while some patients have
a persistently normal ALT (25%), the disease being detected when checking
for HCV antibodies (e.g. in blood donors). Non-specific malaise and fatigue
are common in chronic infection and often reverse following viral clearance.
156 Liver, biliary tract andpancreatic disease
Extrahepatic manifestations may be present and include arthritis,
cryoglobulinaemia with or without glomerulonephritis and porphyria cutanea
tarda. There is a higher incidence of diabetes and association with lichen
planus, sicca syndrome and non-Hodgkin’s lymphoma.
Chronic HCV infection causes slowly progressive fibrosis. After 20 years of
infection, 16% of patients would have developed cirrhosis. Factors associated
with rapid progression of HCV fibrosis include excessive alcohol consumption,
co-infection with HIV, obesity, diabetes and infection with genotype 3. Once
cirrhosis has developed, some 3%–4% per year will develop decompensated
cirrhosis and approximately 1% will develop HCC.
Diagnosis is through the detection of HCV antibody in the serum. A small
proportion of patients with spontaneous clearance will have undetectable
HCV RNA in serum (measured by polymerase chain reaction [PCR]) but most
patients who are antibody positive will be viraemic and the level of viraemia
varies from a few thousands to several millions. Disease progression is not
influenced by the viral load but treatment outcome is less effective in those
with high levels of viraemia.
The HCV genotype should be characterized in patients who are to be given
treatment and assessment of fibrosis (either by liver biopsy or non-invasive
methods) is important. The aim of treatment is to eliminate HCV RNA from the
serum in order to stop the progression of active liver disease and prevent the
development of HCC. A clinical cure is determined by a sustained virological
response (SVR), defined by a negative HCV RNA using PCR, 6 months after
the end of therapy.
Treatment for HCV infection is now based on direct-acting antiviral agents
administered orally. These drugs target enzymes in the virus – usually the
polymerase, NS5a protein or NS3/4 protease – and therapy usually uses a
combination of different drugs (e.g. a nucleotide inhibitor of the polymerase
[sofosbuvir] combined with an NS5a inhibitor). All of the treatment regimens
eliminate virus in more than 95% of patients; in the very few who do not
respond to therapy a ‘rescue’ treatment involving sofosbuvir/velpatasvir and
the pan-genotypic protease inhibitor voxilaprevir is licensed and eliminates
virus in over 90% of patients. Following viral clearance, liver fibrosis
progression is halted and may even reverse, but in patients with cirrhosis the
risk of liver cancer persists (albeit at a reduced level). Patients who do not
have cirrhosis can be discharged from follow-up after successful therapy,
defined as undetectable virus 12 weeks after discontinuation of treatment.
The extraordinary effectiveness of the oral antiviral regimens against
HCV, combined with their excellent safety programme, has led to campaigns
to identify and treat all patients with HCV, and the World Health Organization
has a goal of eliminating HCV by 2030.
Hepatitis E
Hepatitis E virus (HEV) is an RNA virus which causes enteral (epidemic
or water-borne) hepatitis, similar to hepatitis A, particularly in developing
Hepatitis 157
countries (see Table 4.3). In recent years it has become clear that HEV infec-
tion is common in many domestic animals, particularly pigs. Contamination of
meat is not uncommon and acute infection with HEV is now the most common
cause of acute viral hepatitis in the UK and many EU countries. The infection
with animal-derived HEV is usually less aggressive than the water-borne infections in the Indian subcontinent and the symptoms and outcomes are similar
to those of hepatitis A infection. A large proportion of the adult population in
England have evidence of infection with hepatitis E, suggesting that subclinical
infection is common. In patients who are immunocompromised, HEV infection
may lead to chronic infection. Diagnosis is by detection of IgG and IgM antihepatitis E virus (anti-HEV) in the serum or HEV RNA in serum or stools.
Acute hepatic failure
This is defined as hepatic failure with encephalopathy, a neuropsychiatric
condition which develops as a consequence of liver disease. It develops in
less than 2 weeks in a patient with a previously normal liver or in patients
with an acute exacerbation of underlying liver disease. Cases that evolve
at a slower pace (2–12 weeks) are called subacute hepatic failure. It is an
infrequent complication of acute liver damage from any cause (see Fig. 4.5)
and occurs as a result of massive liver cell necrosis. In the UK, viral hepatitis
and paracetamol overdose are the most common causes. Presentation is
with hepatic encephalopathy (Table 4.5) of varying severity, accompanied by
severe jaundice and a marked coagulopathy. The complications include cerebral oedema, hypoglycaemia, bacterial and fungal infections, hypotension
and renal failure (hepatorenal syndrome). Most patients should be managed
with supportive treatment in a specialist liver unit (Table 4.6). Emergency
liver transplantation may offer life-saving treatment, depending on the cause.
Without transplantation, 80% of patients with grade 4 encephalopathy might
otherwise die.
Table 4.5 Clinical grading of hepatic encephalopathy
Grade Neurological findings
0 No alteration in consciousness, intellectual function, personality
1 Daytime somnolence, short attention span, mild asterixis*
2 Lethargic, drowsiness, disorientated usually in time, inappropriate
3 Asleep but rousable, confusion, incomprehensible speech
4 Coma
*Asterixis (liver flap), involuntary flapping movements of the hand when the arm is
extended and wrist held in a backward position.
or behaviour
behaviour, obvious asterixis*
158 Liver, biliary tract andpancreatic disease
Table 4.6 Transfer criteria for patients with acute liver injury
tospecialized units
INR >3.0
Presence of hepatic encephalopathy
Hypotension after resuscitation with fluid
Metabolic acidosis
Prothrombin time (seconds) > interval (hours) from overdose (paracetamol cases)
INR, international normalized ratio.
Alcohol use
In the UK, approximately one in five male admissions to acute medical
wards is directly or indirectly the result of alcohol. Over the past 20 years,
admissions to psychiatric hospitals for the treatment of alcohol-related
problems have increased 25-fold. Excessive alcohol use is the leading cause
of preventable hypertension with increased risk of myocardial infarction and
stroke. There is a steady rise in recorded alcohol consumption in developing
countries but these data are also likely to conceal heavy drinking in some
localities and among populations. Associated with this is an increase in
alcohol-related problems including trauma, violence, various cancers and
alcohol-associated organ damage.
Alcohol dependence is defined by a physical dependence on or addiction
to alcohol. The key feature of alcohol dependence is a lack of control over
alcohol use, demonstrated by a compulsive need to drink and the inability
to cut down or stop drinking. Guidelines for safe drinking limits are 14 units
weekly for both males and females. Units of alcohol in a drink are calculated
by a simple equation:
Units of alcohol in a drinkvolume (1)
e.g. a 0.75-L bottle of whisky which is 40% ABV contains 30 units of alcohol.
In general, 1 unit = a measure of spirits, a glass of wine or half a pint of
standard-strength beer.
=
%alcohol by volume (
× AABV)
Screening for problem drinking
An elevated serum γ-GT and raised red cell mean corpuscular volume (MCV)
are useful screening tests for excessive alcohol use and are helpful in monitoring progress. Blood and urine alcohol levels are sometimes measured to
demonstrate high intake.
Consequences of alcohol use and dependence
Physical complications. These usually occur after a long period of heavy
drinking, e.g. 10 years. Problems are generally seen earlier in women than in
Hepatitis 159
men. Damage is the result of direct tissue toxicity and the effects of malnutrition
and vitamin deficiency which often accompany excessive alcohol use:
• Cardiovascular: a direct toxic effect on the heart leads to a
cardiomyopathy and arrhythmias.
• Neurological: acute intoxication leads to ataxia, falls and head injury with
intracranial bleeds. Long-term complications include polyneuropathy,
myopathy, cerebellar degeneration, dementia and epilepsy.
• Wernicke’s encephalopathy (WE) is the result of vitamin B1
(thiamine) deficiency. It can also occur in severe starvation and
prolonged vomiting. The classic triad of WE (confusion, ataxia and
ophthalmoplegia) occurs in a minority of patients. Mental changes
are the most common (acute confusion, drowsiness, coma), whereas
ataxia and ophthalmoplegia occur in less than one-third of patients.
The diagnosis is clinical. A high index of suspicion and a low threshold
for making presumptive diagnosis is necessary. Treatment is with
urgent intravenous administration of B-complex vitamins which
may reverse some of the early changes. Inappropriately managed,
WE is fatal in 20% of patients. Many survivors will develop longterm brain damage (Korsakoff’s syndrome) with a gross defect of
short-term memory associated with confabulation. Patients at risk
of WE (malnourished patients with alcohol withdrawal symptoms
requiring hospital admission) should be treated prophylactically with
intravenous B vitamins daily followed by oral B vitamins on discharge.
Administration of glucose may exacerbate the acute loss of thiamine
and it is essential that thiamine is given before glucose.
• Gastrointestinal: liver damage, acute and chronic pancreatitis,
oesophagitis and an increased incidence of oesophageal carcinoma.
• Haematological: thrombocytopenia (alcohol inhibits platelet maturation
and release from bone marrow), a raised MCV and anaemia caused by
dietary folate deficiency.
• Psychiatric complications: there is an increased incidence of depression
and deliberate self-harm among patients with alcohol dependence.
• Social complications: marital and sexual difficulties, employment
problems, financial difficulties and homelessness.
Alcohol withdrawal. Most heavy drinkers will experience some form of
withdrawal symptoms if they attempt to reduce or stop drinking. No patient
should ever be advised to stop drinking immediately in view of the potentially
life-threatening complications of alcohol withdrawal without appropriate
detoxification:
• Mild, early features occur within 6–12 hours and include tremor, nausea
and sweating. Treatment is with a reducing dose of benzodiazepines or
chlordiazepoxide (Emergency Box 4.1).
• Major features usually occur later, within 2–3 days, but may take up to
2weeks.
• Generalized convulsions.
160 Liver, biliary tract andpancreatic disease
Emergency Box 4.1 Management of alcohol withdrawal
in hospital
• Prevent or treat Wernicke’s encephalopathy by administration of
intravenous vitamin B complex. Give before administration of glucosecontaining intravenous fluids.
• Correct dehydration and electrolyte imbalance. Hypophosphataemia and
hypomagnesaemia are common.
• Benzodiazepines (e.g. diazepam) or chlordiazepoxide are routinely used in
the UK to treat the symptoms of alcohol withdrawal.
• Local protocols should be followed at all times. This may include a
symptom-triggered regimen involving treatment tailored to the individual
patient’s needs, determined by the severity of the symptoms and signs.
The patient is regularly assessed using a designated questionnaire such
as the Clinical Institute Withdrawal Assessment of Alcohol Scale, revised
(CIWA-Ar). This is a validated 10-item assessment tool that can be used
to assess the severity of the alcohol withdrawal.
• Alcohol withdrawal seizures should be treated with benzodiazepines as
the first-line agent.
• Delirium tremens is a potentially fatal severe alcohol withdrawal
syndrome. There is fever, marked tremor, tachycardia, agitation and
visual hallucinations (‘pink elephants’). Treatment must be given urgently
(see Emergency Box 4.1).
Alcohol detoxification is usually carried out in the community under
the care of a specialist team. The patient attends daily for medication and
monitoring. Exclusion criteria for community detoxification are inadequate
social support, severe liver disease, concurrent medical or psychiatric illness
or a previous history of delirium tremens or alcohol withdrawal fits.
After alcohol withdrawal, it is essential that relapse is prevented. This
involves local alcohol services, specialist psychiatry and the alcohol nurse
specialist. ‘Brief interventions’ refers to 10–15 minutes of counselling, with
feedback about drinking, advice, goal setting, and follow-up contact (one or
more discussions lasting 10–15 minutes with a clinician or specialist nurse). Oral
acamprosate, a γ-aminobutyric acid (GABA) analogue, reduces relapses by 50%.
Autoimmune hepatitis
This is a progressive inflammatory liver condition with a female preponderance. Approximately 40% of patients with autoimmune hepatitis (AIH) have
a family history of autoimmune disease (e.g. pernicious anaemia, thyroid
disease, coeliac disease) and at least 20% have concomitant autoimmune
disease or develop it during follow-up.
Non-Alcoholic Fatty Liver Disease 161
Aetiology
The pathogenesis of AIH is incompletely understood, although increasing evidence suggests that genetic susceptibility, molecular mimicry and impaired
immunoregulatory networks contribute to the initiation and perpetuation of
the autoimmune process. Liver damage is thought to be mediated primarily
by T-cell-mediated events (CD4+ T cells) against liver antigens, producing
a progressive necroinflammatory process leading to fibrosis and cirrhosis.
Clinical features
The onset is often insidious, with anorexia, malaise, nausea and fatigue.
Twenty-five per cent of cases present as an acute hepatitis, with rapidly
progressive liver disease. The signs of chronic liver disease are often present, with palmar erythema, spider naevi, hepatosplenomegaly and jaundice.
Features of other autoimmune diseases may be present.
Investigations
Circulating autoantibodies (antinuclear, smooth muscle, soluble liver antigen,
liver/kidney microsomal antibodies) are present in most patients. There is
hypergammaglobulinaemia (particularly IgG), and serum bilirubin and aminotransferases are elevated. Liver histology will show the non-specific changes
of chronic hepatitis with interface hepatitis and often cirrhosis.
Treatment
Prednisolone is given for at least 2 weeks, followed by a gradual dose reduction to a maintenance dose of 5–15 mg daily. Azathioprine should be added
as a steroid-sparing agent, and in some as sole long-term maintenance
therapy. Levels of thiopurine methyltransferase should be obtained. Other
agents that have been used in resistant cases include budesonide (in noncirrhotic patients), mycophenolate, ciclosporin and tacrolimus.
Prognosis
Steroid and azathioprine therapy induces remission in over 80% of cases.
This response indeed forms part of the diagnostic criteria. Treatment is lifelong in most cases although withdrawal may be considered after 2–3 years
of biochemical remission. Liver transplantation is performed if treatment
fails, although the disease may recur. Hepatocellular carcinoma occurs less
frequently than in viral-induced cirrhosis.
NON-ALCOHOLIC FATTY LIVER DISEASE
NAFLD is now the commonest cause of chronic liver disease in many
developed countries. It is often detected on routine abdominal ultrasound
examination with steatosis found in up to a third. NAFLD is a spectrum of
liver diseases composed of non-alcoholic fatty liver (NAFL) and non-alcoholic
162 Liver, biliary tract andpancreatic disease
steatohepatitis (NASH). Whereas NAFL has negligible risk of progression,
10%–30% of NASH patients may develop cirrhosis or HCC. NAFL and NASH
have traditionally been considered as two separate clinical entities. However,
patients with both NAFL and NASH have the potential to develop progressive
liver disease, suggesting that NAFL, NASH and fibrosis progression are a
continuum rather than separate diagnoses.
Risk factors for NAFLD are obesity, hypertension, type 2 diabetes and
hyperlipidaemia and NAFLD is considered the liver component of the
metabolic syndrome. Most patients are asymptomatic but hepatomegaly may
be present. Mild increases in serum aminotransferases and/or γ-GT (with ALT
> AST) are frequently the sole liver biochemistry abnormalities. Elastography
is used to evaluate the degree of fibrosis but may not be technically possible
in the morbidly obese and liver biopsy may be necessary.
All NAFLD patients require lifestyle advice aimed at weight loss, increased
physical activity, and attention to cardiovascular risk factors. A reduction
in body weight >7%–9% has been associated with reduced steatosis,
hepatocellular injury and hepatic inflammation. Medications such as orlistat,
pioglitazone or vitamin E may be considered. Weight loss following bariatric
surgery leads to reduced steatosis, steatohepatitis and fibrosis.
The yearly cumulative incidence of HCC is 2.6% in patients with NASH
cirrhosis and US surveillance should be performed 6-monthly.
CIRRHOSIS
Cirrhosis results from necrosis of liver cells followed by fibrosis and nodule
formation. The end result is impairment of liver cell function and gross distortion of the liver architecture leading to portal hypertension.
Aetiology
The causes of cirrhosis are shown in Table 4.1. Alcohol is the most common
cause in the Western world but hepatitis B and C are more common causes
worldwide.
Pathology
Histologically, two types are described:
• Micronodular cirrhosis: uniform, small nodules up to 3 mm in diameter. This
type is often caused by ongoing alcohol damage or biliary tract disease.
• Macronodular cirrhosis: nodules of variable size and normal acini may be
seen within large nodules. This type is often seen following chronic viral
hepatitis.
There is also a mixed type, with both small and large nodules.
Clinical features
These are secondary to portal hypertension and liver cell failure (see Fig.4.1).
Cirrhosis with the complications of encephalopathy, ascites or variceal