Hepatology

Hepatology overview
Background anatomy, physiology and histology
Anatomy
The liver is separated into four lobes (left, right, caudate, quadrate) or 8
segments that each have a branch of the hepatic portal vein and hepatic artery
supplying it.
Functional units of the liver
Sinusoids carry blood away from the portal triads, into the hepatic vein from the
portal vein/hepatic artery. Canaliculi carry bile produced by hepatocytes and duct
cells towards the biliary tree. The space between the sinusoids and canaliculi is
known as the perisinosoidal space (the space of disse).
The histological structure of the liver can be considered as either acini, with the
portal triad at the centre, or lobular with the hepatic vein at the centre and the
portal triad at the periphery.
Cells of the liver

Endothelial cells: Maintain sinusoidal circulation by initiating

contraction/dilation
Kupffer cells: Macrophages of the liver, filter portal blood
Stellate cells: Produce extracellular matrix, and are overactive in cirrhosis
NK cells: Innate immune response.

Functions of the liver

Synthetic roles: Clotting factors, albumin, carrier proteins, bile salts,

LDL/VLDL
Storage: Glycogen, fat soluble vitamins, fats
Metabolic roles: Urea cycle, drug metabolism, Vit D production, bilirubin
metabolism
Immunological: Kupffer cells

Definitions of liver disease

Acute injury/disease
This occurs in a patient with no pre-existing disease, and resolves in 6 months.
Examples include Hep A, Hep E, CMV, EBV, and drug induced liver injury.
Chronic liver disease
Chronic liver disease starts with acute liver disease, but progresses beyond 6
months to leave ongoing effects. It may progress to cirrhosis and its
complications.
Causes include alcohol, hep C, NASH and autoimmune liver disease.
Fulminant hepatic failure

This is defined as the development of encephalopathy in under 2 weeks in a

patient with a previously healthy liver

Common signs of liver disease

Spider naevi: Oestrogen causing vasodilation. These fill from the centre,
whereas telangiectasia fills from the edge
Leukonychia: Albumin deficiency
Clubbing
Dupuytrens contracture
Parotid swelling: Due to fatty infiltration
Testicular atrophy: Reduced oestrogen metabolism leads to the loss of
secondary sexual characteristics
o Gynaecomastia
o Loss of male pattern hair
Mild splenomegaly
Fetor hepaticus
Porto-systemic anastamosis

LFTs
Aminotransferases
ALT and AST are both found in the liver, but ALT is far more specific; AST is also
found in the heart, intestine and skeletal muscle. ALT is a cytosolic enzyme, and
so is indicative of cell leakage.
Raised ALT
ALT is very specific to the liver, as it has very low concentration in the kidney and
skeletal muscles. Half-life is 47 hours.
AST:ALT ratio
Normally, AST is less than ALT. In alcoholic liver disease however, the AST:ALT
ratio is 2:1 or more.
Wilsons disease can cause the AST:ALT ratio to exceed 4.
ALP
This is found in the liver and bone predominately, and to a lesser extent in the
kidneys. In the liver it is present on bile duct epithelium, and is displaced due to
bile salts. Takes a week to be induced to high levels, so is a poor acute marker.
Gamma-GT
Gamma GT is preferentially raised in biliary outflow obstruction rather than
hepatocellular damage.
However, its usefulness is limited by its lack of specificity. Gamma-GT can also be
raised in MI, pancreatic disease, COPD, renal failure and diabetes.
If MCV also elevated, it points towards alcohol abuse.
Markers of synthetic function
Bilirubin (conjugated), albumin, glucose and prothrombin time are all good
markers of synthetic function. If these are deranged, it suggests reasonably
severe liver disease.

Thrombopoeitin is produced by the liver, and is dependent on functional liver

mass. The fibrosed, cirrhotic liver will produce less, leading to
thrombocytopaenia.

Findings by disease
ALT >500
Acute hepatitis: Viral, ischaemic, toxins, autoimmune
ALT 100-200
NASH, autoimmune, chronic viral hepatitis
Isolated ALP raised
Cholestasis without hepatic involvement. Gall bladder disease most likely.

Criteria for transplant

The current UK criteria for a liver transplant are as follows:
1) It is highly likely that the lifespan will be shorted, or the QoL is so poor that
life is intolerable
2) 50% chance of liver more than 5 years after the transplant, with an
acceptable QoL
Indications
1) Fulminant hepatic failure
2) HCC within the Milan Criteria
a. Single tumour <5cm or up to three <3cm
b. Absence of vascular invasion
c. No extra-hepatic manifestations
The UKELD (UK model for end stage liver disease) is used to determine the
likelihood of death without a transplant being performed. The higher the UKELD
score, the more priority the patient has for transplant.
Contraindications to transplant
1)
2)
3)
4)
5)

Severe malnutrition and muscle wasting

Infection- if acute, it can wait until the infection is cleared
AIDS
Serious medical co-morbidities
Inability to comply with post-transplant medication

Abscess disease
Pyogenic abscesses
Pyogenic abscesses account for 80% of liver abscesses. The vast majority are
seeded form the biliary tree (60%), but the rest can come through the portal
venous system (sepsis), surgery, or be cryptogenic (20%).
Symptoms
They present almost always with a continuous or spiking fever, alongside more
variable symptoms of RUQ pain, weight loss, N/V, malaise and chills.

Signs
RUQ tenderness is noted in 50%, with hepatomegaly and jaundice also often
noted. There is a right sided pleural effusion in around 15%.

Amoebic abscesses
Amoebic liver abscesses arise as an extra-intestinal manifestation of entamoeba
histiolytica, which travels to the liver from the colon.
Like pyogenic abscesses, they present with fever and abdominal pain. A
subacute presentation involves weight loss in addition to this.
Investigations include serological tests for amoeba, which are 100% sensitive but
have false negatives if there is bowel disease.

Alcoholism
Alcoholic liver disease
Fatty change
The increased NADH production associated with alcohol metabolsim leads to
increased lipogenesis, which invariably ends up in the liver. Furthermore, the
reduced synthetic function means the liver is less able to create lipoproteins to
transport it, leading to the accumulation of fat.
This fat is irritant, creating an inflammatory response. This initially leads to
fibrosis of the area around hepatic venules (perivenular fibrosis) before
proceeding to cirrhosis. On histology, Mallory bodies are noted (cytoplasmic
inclusions).
Often there are no signs or symptoms. When present, they are vague feelings of
malaise, with nausea and vomiting due to alcohol abuse. Hepatomegaly may be
present.
Fatty liver disease can normally be reversed by encouraging the patient to stop
drinking and limiting fat intake. So long as hepatitis and cirrhosis have not set in
yet, the liver should return to normal.

Alcoholic hepatitis
Following on from the fatty change, or acutely in severe overdose, there is
infiltration by white cells and there is hepatic necrosis (zone 3).
The clinical features of alcoholic hepatitis vary. They range from a well patient
with few clinical signs, to one with jaundice, ascites, abdominal pain and fever in
response to the necrosis.
Management may be supportive, but some patients will require admission if they
are unwell. Steroids improve short term outcomes.
Treatment for encephalopathy and ascites will need initiating on admission.
Patients are advised to stop drinking for life, as even small amounts sustain the
damage and predispose to cirrhosis.
In very severe cases, with acute liver failure, transplant is an option but
unfortunately many return to drinking.

Alcoholic cirrhosis
This is the final stage of alcoholic liver disease, yet patients can still be
superficially well. Initial presentation is usually with the complications of cirrhosis
or alcohol abuse, such as polyneuropathy.
Diagnosis and management is the same as cirrhosis of other causes.

Managing addiction
Identifying addiction
Various screening tools exist such as CAGE: Cut down, annoyed, guilty, eyeopener, and AUDIT exist to identify potential problem drinkers.

Managing withdrawal
The Glasgow modified alcohol withdrawal scale is a scoring system used to
inform the dose of sedative required to treat a withdrawing alcoholic. Patients are
scored on the basis of their signs and symptoms, and given different doses of
diazepam accordingly.
General principles are to wean off gently, refer to the alcohol liason team, treat
withdrawal with sedation, and give nutritional supplements such as Pabrinex to
limit the risk of Wernickes encephalopathy.
Some patients need inpatient management for their withdrawal, particularly
those at risk of suidice, with low social support, or those with a history of
withdrawal reactions.

Complications of withdrawal
Delirium tremens is rapid onset confusion in withdrawing alcoholics, normally
three days after they stop withdrawing.
During prolonged alcohol abuse, the brain adapts by increasing levels of
excitatory neurotransmitters such as glutamate and their NMDA receptors, and
reducing the level of inhibitory such as GABA. Once the alcohol intake reduces,
these increase the risk of seizures and are the cause of delirium tremens.

Complications
Haematological
Alcoholics often have a macrocytic anaemia, with various mechanisms
underpinning this.
1) Malnourished: Low in b12/folate, leading to a megaloblastic anaemia
2) BM toxicity: Alcohol is directly toxic to bone marrow, causing structural
abnormalities and reduced haematopoiesis.
3) Primary macrocytosis: Without B12/folate deficiency
Alcohol also has a direct effect on clotting, through its inhibition of platelet
production in the bone marrow, and platelet function. Interestingly, alcohol also
has an anti-fibrinolytic effect; alcoholics are at increased risk of stroke.
Lipid levels

Alcohol increases the production of TAGs. When alcohol is metabolised to

acetaldehyde, NAD+ is converted into NADH. NADH is a signal of high energy,
inhibiting the conversion of acetyl co-A to citrate. Instead, acetyl co-A is shunted
into the lipogenesis pathway, to make more TAGs.
Hypertriglycerideaemia is a potential risk factor for arteriosclerosis, affecting the
kidneys and the microvasculature. The effect is not yet fully proven.
Alcoholic neuropathy
The metabolite of alcohol breakdown acetaldehyde has a directly neurotoxic
effect. This is turn affects the nerves in a length-dependent manner, much like in
diabetes. Patients complain of distal paraesthesia and weakness, which can in
turn affect gait.
Alcoholic ketoacidosis
The pathophysiology of alcoholic ketoacidosis is complex. Primarily, there is a
decrease in insulin secretion due to the starved state of a chronic alcoholic.
Secondly, there is an increased in the NADH/NAD+ ration, as NAD+ is consumed
in the metabolism of alcohol.
The increased NADH/NAD+ ratio impairs gluconeogenesis, and stimulates
lipolysis, which in turn leads to ketogenesis. The ketogenesis is favoured by the
starved state, which directs fats into useful ketones for a respiratory substrate.
As a result of the concurrent dehydration found in many alcoholics, and the
kidneys are unable to excrete the ketones, and so an acidosis sets in.
Cerebral implications
Alcohol causes cerebral atrophy, which in turn predisposes to subdural bleeds, in
patients who are intrinsically more likely to fall over.
The toxicity of alcohol on brain cells also increases the risk of dementia.

Wernicke encephalopathy
This arises as a result of thiamine deficiency, which is depleted in alcoholics as
consequence of malnourishment and metabolic abnormalities. Thiamine is
intrinsically important for carbohydrate metabolism, and also regulates the
osmotic gradient.
In its absence, it leads to cell swelling and disruption of the blood-brain-barrier. It
targets the cerebellum, diencephalon (hypothalamus, thalamus, mammillary
bodies) and frontal lobe, leading to a presentation of:
1) Ataxic gait: Cerebellum
2) Confusion: Frontal lobe
3) Opthalmoplegia: Cerebellar dysfunction causing nystagmus
It can also present with hypotension and amnesia. It is treated by the timely
administration of thiamine.
Unless treated properly, it progresses to Korsakoffs psychosis with anterograde
amnesia and retrograde amnesia

Chronic liver disease

Alpha-1 antitrypsin deficiency
Epidemiology
Deficiency in alpha-1 antitrypsin leads to unregulated activity of neutrophil
elastase in the liver, and also leads to dysregulation of the inflammatory cascade
in the liver.
It is an autosomal recessive disorder, carried on chromosome 14 with a carrier
frequency of 1/10. 7
Presentation

Lung: Dyspnoea as a result of COPD

Liver: Cholestatic jaundice and cirrhosis (only 10-15%)

Diagnosis

Serum A1AT will be low, but is also an acute phase protein so may appear
falsely normal.
Genotyping
Liver diopsy

Management
No effective management exists. Get a family tree, and work out who else in the
family is at risk and will need testing.
Conservative management includes stopping smoking and avoiding alcohol to
prevent disease from progressing. Only transplant prolongs life.

Autoimmune hepatitis
Epidemiology
It occurs most commonly in women with a bi-modal distribution of 10-30, and
>45.
Pathophysiology
AIH occurs in genetically susceptible individuals after an environmental trigger.
This leads to T cell autoimmunity against liver antigens, causing necrosis and
inflammation of the liver.
Presentation
Around 40% present with acute hepatitis, deranged LFTs and jaundice. Some can
present with body-wide autoimmune signs such as polyarthritis, fever, malaise,
urticaria, pleurisy and glomerulonephritis.
In those over 40, the disease is often symptomatic. However in young adults it
presents aggressively with acute hepatitis and stigmata of cirrhosis.
Investigations
Bloods

LFTs: Transferases high, ALP and GGT less so but still raised.

FBC: Normochromic normocytic anaemia with thrombocytopaenia

Clotting: Raised INR
Serology:
o Type 1: ANA, anti-smooth muscle
o Type 2: Anti-liver-kidney microsomal (anti-LKM 1)

Disease associations
Pernicious anaemia, UC, thyroiditis, DM, PSC.
Treatment
Medical
Immunosuppression with steroids, or azathioprine as a steroid-sparing agent.
Budesonide has fewer side effects and similar efficacy, so is an option.
Surgical
Liver transplant is indicated for end-stage cirrhosis, with recurrence reasonably
common. 10 year survival is 75%.

Haemochromatosis
Epidemiology
Hereditary haemochromatosis is an autosomal recessive condition, characterised
by excessive levels of iron in the blood due to increased intestinal iron
absorption.
It predominately arises before the age of 40, occurring earlier in males. The
mutation is most commonly (85%) of the HFE gene on chromosome 6, and is
most common in Caucasians. The penetrance of the gene is relatively low, so not
everyone homozygous for the causative alleles will develop haemochromatosis.
There are 4 types of haemochromatosis in total, each affecting a different gene.
Pathology
The exact mechanism remains uncertain. HFE interacts with transferrin, leading
to abnormal uptake of iron into intestinal mucosal cells. The expression of
hepcidin, a protein which normally inserts ferroportin into the membrane to allow
iron release, is also disrupted.
Together, there is increased iron uptake and decreased iron exporting, leading to
increased levels of intracellular iron. This iron is deposited in the joints, pancreas,
liver, heart, pituitary, adrenals and skin to cause body wide disease.
Presentation
Early presentation
Asymptomatic, arthralgia (MCPs and knee).
Late
Slate-grey skin, signs of chronic liver disease, cirrhosis, dilated cardiomyopathy,
osteoporosis.

Endocrine
Bronze diabetes due to iron deposition in the pancreas, hypogonadism from
pituitary dysfunction, hyporeninaemic hypoaldosteronism.
Assessment
Bloods:

Serum ferritin: Massively raised

LFTs: Deranged
Transferrin saturation: >45%
Glucose: Diabetes

Other:

Echocardiogram: Dilated cardiomyopathy

Liver MRI: Iron overload, high senisitivity

Management
Conservative
Ensure any supplements have no iron in them, and take tea with meals to limit
iron absorption.
Medical
3 weekly venesection (1 unit every 1-3 wks). Monitor complications and treat
accordingly e.g. diabetes, CCF
Prognosis
Venesection returns life expectancy to normal. In those who develop cirrhosis,
22-30% develop HCC especially if HBV positive, old or abuse alcohol.
Monitoring
Monitor ferritin levels, as transferrin saturations remain raised until iron levels
significantly decreased.

Non-alcoholic fatty liver disease

This condition can lead to cirrhosis in around 1% of patients, and potentially onto
HCC. 1-3% of patients with NAFLD have non-alcoholic steatohepatitis.
Risk factors
The typical patient is a middle aged, obese female. Risk factors include diabetes,
dyslipidaemia, jejunoileal bypass and Wilsons disease.
Pathology
Initially, the liver is infiltrated with fat due to metabolic dysfunction e.g. obesity,
DM. Oxidative stress then leads to the oxidation of these lipids, which results in
inflammation.
This inflammation then induces fibrosis, which is supported by insulin resistance.
It can then progress onto NASH with or without cirrhosis.

Presentation
Most patients are asymptomatic, but in those who present it is with the
complications of cirrhosis once the condition has progressed.
Diagnosis
LFTs are mildly deranged, but definitive diagnosis can be achieved with
ultrasound demonstrating a fatty liver.
Management
Risk factor control
Weight loss, BP and diabetes control with diet, exercise and medication where
necessary. The risk of death due to the cardiovascular risk greatly outweighs the
risk of death from liver disease.

Primary biliary cirrhosis

Epidemiology
PBC is rare, with a prevalence of 4/100,000. It mostly affects females (9:1).
Pathology
Interlobular bile ducts are destroyed by granulomatous inflammation, causing
cholestasis that then proceeds to cause fibrosis, cirrhosis and portal
hypertension.
The cause is incompletely understood, but is thought to be predisposed to by
genetics and triggered by the environment. Examples of environmental triggers
include pollutants and infection.
Presentation
Patients are often symptomatic, and only discovered on routine examination or
screening. Vague symptoms of lethargy and pruritus precede jaundice by years.
Signs
Jaundice, hepatomegaly, signs of hyperlipidaemia: Xanthoma, xanthelasma.
Hepatosplenomegaly.
Investigations
Bloods

LFTs: Massively deranged ALP with mild derangement in ALT and AST.
Serology: Smooth muscle antibody (50%), anti-mitochondrial antibody
(95%)
Immunoglobulins: IgM raised

Complications
Reduced bile release due to cholestasis leads to fat-soluble vitamin
malabsorption (ADEK), which in turn leads to osteomalacia and coagulopathy.
Management

Symptomatic

Pruritus: Colestyramine. Naloxone/naltrexone can also be useful

Diarrhoea: Codeine

Specific

Fat soluble vitamins: Bile salt replacement in high dose to aid their
absorption
Liver transplantation for end-stage disease or life-changing pruritus

Prognosis
Once jaundice present, survival is <2 years.

Primary sclerosing cholangitis

PSC involves fibrosing inflammation of both intra and extrahepatic bile ducts.
Epidemiology
In 75% of cases, PSC is associated with cases of IBD. The IBD often predates PSC.
It is associated with HLA-A1/B8/DR3, and has a predisposition towards men.
Disease associations
Alongside IBD, patients with AIH are also predisposed.
Clinical features
PSC is normally detected asymptomatically, as part of routine screening for
patients with IBD. In those who are symptomatic, pruritus with fatigue, jaundice
and cholangitis are the common presenting syndromes.
Diagnosis
Bloods:

LFTs: Increased ALP, increased bilirubin

Serology: ANCA (60%)

Imaging:

MRCP/ERCP: Demonstrate duct disease, and its extent

Complications
PSC is associated with greatly increased risk of colorectal cancer.
Management
Liver transplant is the only cure for end-stage disease, with recurrence in 30%
over 5 years. Colestyramine can be used to manage pruritus.

Wilsons disease
Epidemiology
Wilsons disease is a rare disorder of copper metabolism, found in roughly
3/100,000 people. It is inherited in an autosomal recessive pattern on
chromosome 13 which codes for ATP7B, which is a copper excreting ATPase.

Physiology
There is a failure of copper incorporation into procaeruloplasmin, which then
leads to a low serum caeruloplasmin. Also, the biliary excretion of copper is
impaired.
The copper is deposited in the liver, brain, kidneys and bone to cause
widespread dysfunction.
Presentation
Children
In children, the disease presents with liver signs of hepatitis, cirrhosis, and
fulminant hepatic failure.
Young adults
Young adults present with CNS symptoms of dysarthria, tremor, hemiballismus
and personality change. IQ is reduced.
Other signs
Kayser-fleischer rings (copper in iris), blue lunalae (nails), arthritis, hypermobility,
grey skin
Diagnosis
Bloods:

Deranged LFTs
Low serum copper
Low caeruloplasmin
o Falsely low: protein deficiency
o Falsely high: Ceruloplasmin is an acute-phase protein

Other

Urinary copper
Liver biopsy
Brain MRI: Copper in basal ganglia, cerebellum and brainstem.

Cirrhosis
Causes
Commonest

Rare

Common in M

Common in F

Alcohol

Alpha-1
antitrypsin
Methotrexate
Haemochromat
osis

PSC of IBD

Autoimmune
hepatitis
PBC

NASH
HBV
HCV

Occurs in
early
adulthood
Wilsons
disease
Anti-LKM

Pathology
The chronic inflammation of the liver leads to necrosis, and then to fibrosis. The
fibrosis arises due to the activity of stellate cells, which lay down collagen in the
Spaces of Disse. The subepithelial fibrosis affects circulation of both blood and
bile.
On histology, there are regenerating nodules, separated by fibrous septa,
associated with the loss of normal hepatic architecture.

Diagnosis
History
Risk factors for chronic disease:

Hepatitis: Tatoos, piercings, IVDU, sexual history, transfusion prior to 1990

Alcohol: History of alcohol abuse
NASH: Diabetes, metabolic syndrome, obesity
Rarer: Family history of PSC/haemochromatosis/Wilsons

Examination
Signs of chronic liver disease, and complications of cirrhosis (ascites, oedema,
encephalopathy)
Bloods
Low platelets (reduced TPO), clotting, LFTs
Imaging
Ultrasound in first instance. Fibroscan is quick, and more specific than other
imaging.

Complications
Ascites
50% of cirrhotics will develop ascites over 10 years, due to the loss of the oncotic
effect of albumin which is no longer synthesised effectively in the liver.
Once ascites sets in, the two year mortality is 50%.
Portosystemic hypertension
Portal hypertensive gastropathy
Dilation of the mucosal veins of the stomach, with friability of the mucosa and
ectatic veins present on the surface.
Hepatic encephalopathy
Pathophysiology
Bacteria in the gut convert nitrogen products into ammonia, which is then
absorbed into the liver through the portal system. Ammonia is not removed due
to dysfunction of the urea cycle, and so crosses the BBB to exert osmotic
pressure in the brain. This leads to cerebral oedema, and consequent
dysfunction.

Stages
1) Psychomotor slowing, constructional apraxia, cognitive dysfunction,
agitation, insomnia
2) Lethargy, disorientation, asterixis
3) Drowsy, low GCS
4) Coma
Management
Lactulose and rifamixin (antibiotic) clear out and reduce the production of
ammonia respectively. If encephalopathy is established, IV mannitol can offload
fluid in an attempt to shift the oedema.
Pleural effusions
These can occur, not due to deficiency in albumin but in-fact due to defects in
the diaphragm, which allows fluid of ascites to enter the thorax. As a result of
negative intra-thoracic pressure, this is reasonably easily done. Normally they
occur on the right side.
Lymphenodopathy
This can occur in late stage cirrhosis, but is not indicative of malignancy unless
other signs and symptoms are present.
Imaging findings
Ultrasound
On ultrasound, the liver will be fibrosed, which shows as brightness. There will be
nodules on the liver, and the liver will be small.
In addition, splenomegaly and ascites will be noted.

Management
Rifaximin is an antibiotic of the Rifamycin class, which has a side effect of
reducing the recurrence of hepatic encephalopathy.
Beta blockers can be used to lower portal pressures, to reverse the effects of
portal hypertension.

Prognosis
Once ascites set in, mortality is 50% in 2 years.
Poor prognostic indicators include low albumin, low Na, raised PTT, persistent
jaundice, ascites and developing neuropsychiatric complications.

Infectious hepatitis
The different strains of viral hepatitis have different characteristics, and a
knowledge of this is vital in understanding their significance and treatment.

Summary table
Type
Spread

Hep A
RNA
Faeco-oral

Hep B
DNA
Blood

Hep C
RNA
Blood

Hep D
RNA
Blood

Hep E
RNA
Faeco-oral

Saliva

Incubation
Age
Carrier
state
Chronic
disease
Liver
cancer

Short (2-3
wks)
Young
No

Vertical
Saliva
Sexual
Long (1-5
months)
Any
Yes

Saliva
Rarely
sexual
Long

No
No

Short

Any
Yes

Intermedia
te
Any
?

Yes

Yes

Yes

No

Yes

Rare

No

No

Any
No

Hepatitis A
This is the most common form of viral hepatitis, and spreads through faecal-oral
routes. It is an RNA virus.
It leads to non-specific viral symptoms of nausea, arthralgia, anorexia and fever.
After 1-2 weeks some (not all) develop jaundice, which progresses to obstructive
jaundice as intrahepatic cholestasis occurs.
ALT is massively raised (>500) and returns to normal over 20 weeks or so.
Management is supportive. Patients need to avoid alcohol, and are only given
interferon in the rare cases of fulminant hepatitis.

Hepatitis B
This DNA virus is predominately spread through vertical, haematogenous, saliva
and sexual pathways. Vertical inheritance is the commonest worldwide, but is
preventable. 7
Pathogenesis
The HBV virus is not directly pathogenic, and the cell damage is created as part
of the immune response. Cytotoxic T cells recognise the virus, but are
suppressed by regulatory T cells to allow for a chronic viral load.
There are two main phases to Hep B infection:
1) Replicative phase: Acute viral replication with hepatic inflammation. The
patient is highly infectious.
2) Integrated phase: The HBV genome becomes integrated into the host, and
transcribed as part of cell replication. Now the patient is less infective.
Presentation
The presentation of Hep B is very similar to that of Hep A, with non-specific viral
illness. Arthalgia is more common. Patients can also develop glomerulonephritis.
Diagnosis
Serology of HBV and its clinical significance
Antigens

HBsAg: Surface antigen. Present in both acute and chronic infection (>6
months)
HBeAG: Pre-core antigen. Found in acute hepatitis, so persistence implies
a continued infective state/development of chronicity
HBV DNA: Implies viral replication. Levels indicate response to treatment

Antibodies

Anti-HBs: Antibody against surface antigen, which implies immunity

through either previous exposure or vaccination
Anti-Hbe: Implies seroconversion i.e. transition to passive carrier state;
now body can attack all parts of the virus.
Anti-HBc:
o IgM: Acute hepatitis in high titre, chronic in low titre
o IgG: Past exposure to HBV. Cleared if HBsAg is negative.

Other

HIV antibody: 10% of those with HBV have concurrent HIV.

Management
General
Take a sexual history and ensure sexual contacts are vaccinated. Hepatitis B is a
notifiable disease. Refer all who are HbsAg positive to a
gastroenterologist/hepatologist.
Anti-viral
Peg-interferon is first line, given for a 48 week course. Tenovir is second line for
those who do not undergo anti-Hbe seroconversion, or who relapse (develop
HbeAg positivity).
Side effects of interferon include:

Serious: Bone marrow suppression, recurrent infection

Less serious: Myalgia, headache, reversible hair loss

Preventing vertical transmission

Offer tenovir in the third trimester to prevent vertical transmission.
Complications
Fulminant hepatic failure, cirrhosis, HCC, glomerulonephritis, cryoglobulinaemia

Hepatitis C
Hepatitis C is a blood-borne RNA virus, primarily transferred through blood but
also through sexual intercourse in some cases. 15-25% clear the virus once
infected, but the rest progress to chronic disease.
Risk factors
Transfusion before 1990, IVDU, sexual intercourse (rare, only 5% transmission),
needlestick injury.

Risk factors for rapid progression to severe disease

Alcohol abuse, male gender, co-existing HBV/HIV, diabetes, advancing age.
Presentation
Acute HCV is normally asymptomatic. 20-30% have jaundice, deranged liver
enzymes, and another 20-30% have non specific symptoms of fever, anorexia
and malaise.
Chronic HCV is again normally asymptomatic. Cirrhosis develops in 20-30% over
20 years, and of these 1-4% develop HCC.
Diagnosis
Bloods:

LFTs: Show moderately raised transferases

Serology: HCV RNA, anti-HCV antibodies
Clotting: ?liver synthetic function
HIV testing

Imaging:
LFTs are insensitive at detecting the severity of disease, which can only be
achieved through:

Ultrasound: Focal lesions, splenomegaly, cirrhosis

Associated conditions
Patients with HCV are at increased risk of:
Diabetes, Sjogrens, thyroiditis, polyarteritis nodosa, AIH, immune
thrombocytopaenia, cryoglobulinaemia.
Management
The global aims of management are to prevent cirrhosis, liver failure and
hepatocellular carcinoma. Patients should be advised to avoid alcohol, as it has
been shown to hasten the progression of disease.
Drug treatment
Peginterferon alfa-2a (SC, once weekly) alongside oral ribavirin is the NICE
guidance. New protease inhibitors such as boceprevir have been recommended
by NICE, and have the potential to stop HCV from evading the immune system.

Hepatitis D
Hepatitis D is an RNA virus, which is unable to replicate on its own but is
activated by the presence of HBV.
It is transmitted through blood, much like HBV. It can arise as a result of coinfection, whereby it enters the body at the same time as HBV. Diagnosis is
confirmed by the presence of anti-HDV IgM, in the presence of Anti-HBc IgM.
It can also present as a superinfection, on top of chronic HBV, leading to an acute
flare.

Hepatitis E
Another faecal-oral RNA virus like Hep A, which causes acute liver disease. There
is no carrier state, and management is normally supportive.

Other
CMV hepatitis
CMV can cause hepatitis, as part of a glandular fever type syndrome in normally
healthy individuals. Those with an impaired immune response will require antiviral treatment.
EBV colitis
EBV commonly causes mildly deranged LFTs with mild jaundice, but a clinical
picture of hepatitis is rare. A mono-spot test is usually positive.