SIGNS AND SYMPTOMS
Clinical assessment of liver
disease
Stephen D Ryder
Abstract
Chronic liver disease is increasingly common in the UK, and now causes in
excess of 5000 deaths per year. The natural history of liver injury is of
increasing fibrosis in response to hepatocellular injury, which is usually
asymptomatic until decompensation occurs. Up until this point, elevated
liver enzyme concentrations are the only indicators of disease. Thorough
investigation of abnormal liver function tests is therefore essential to
produce a diagnosis at a stage where the underlying disease is likely to
be treatable. Clinical stigmata of chronic liver disease are not present
in the absence of severe fibrotic liver disease and, if present, should
cause concern. Non-alcoholic fatty liver disease is now the commonest
cause of elevated liver enzymes, whereas alcohol remains the commonest
cause of death from cirrhosis and its complications.
Keywords alcohol; ascites; cirrhosis; hepatitis; liver enzymes
Liver disease is increasingly common in the UK, probably
reflecting an increase in the per capita intake of alcohol that has
occurred over the last decade, and the impact of hepatitis C virus
(HCV) infection. There are more than 5000 deaths from cirrhosis
each year in the UK. Most patients present with cirrhosis or
decompensated cirrhosis, and there is a clear need to identify
disease at as early a stage as possible to allow interventions that
will prevent progression of hepatic fibrosis and the development
of end-stage liver disease.
Acute liver injury has a variety of causes, the commonest of
which are viral infection, drug reactions or alcohol. Acute and
chronic liver injury can coexist; for example, acute alcoholic
hepatitis in the setting of alcoholic cirrhosis.
Chronic liver disease can be caused by a number of aetio-
logical agents. Any injury to hepatocytes will result in cell death
and proliferation of the remaining hepatocytes to maintain
hepatic cell mass. This process is highly effective, but the cyto-
kines produced cause activation of hepatic stellate cells and the
development of hepatic fibrosis. Once present, fibrosis proceeds
at a variable rate until distortion of the sinusoidal architecture
signals the presence of cirrhosis. It is important to appreciate the
chronic liver disorder is asymptomatic during most of its natural
history until cirrhosis is present, which is usually many years
from the onset of the process that caused liver injury (Figure 1).
Assessment of liver disease therefore encompasses history,
clinical findings, biochemical tests and, often, liver histology.
The aim of assessment is two-fold e to define the cause of the
liver injury, and to define its severity and the requirement
Stephen D Ryder DM FRCP is a Consultant Hepatologist at Queen’s
Medical Centre, Nottingham, UK. Competing interests: none declared.
MEDICINE 39:9
for therapy. There are two common settings in which this
assessment must be made:
 patients who present with an obvious sign of significant liver
disease, usually jaundice
 patients who present with abnormal liver biochemistry and
no significant symptoms.
These two groups differ in the route and rapidity of the investi-
gations required.
History
In all patients with possible liver disease, there are several
important factors in the history.
Risk factors for hepatitis B virus or hepatitis C virus (HCV)
infection include injecting drug use, transfusion of blood products
(usually before the introduction of screening for HCV in 1991),
amateur tattooing or body piercing, medical procedures and resi-
dence in an area of high endemicity (e.g. Sub-Saharan Africa,
South East Asia). Travel overseas is still highlighted in textbooks,
but hepatitis A is as common in the UK as in many developing
countries; hepatitis E virus is the only hepatitis virus likely to be
encountered on a brief trip abroad that is relatively uncommon in
the UK. This virus is orofaecally transmitted and is endemic in the
Indian subcontinent.
Alcohol history e it is widely believed that all liver abnor-
malities are alcohol related and that all patients lie about their
alcohol consumption. Neither is true.
 In the UK, 50e70% of cases of cirrhosis are alcohol related,
and a higher proportion of cases of abnormal liver biochem-
istry are unrelated to ethanol intake.
 Most individuals provide a reasonable estimate of their
alcohol intake that identifies whether they are at risk of
alcohol-induced liver injury. An attempt should be made to
quantify total intake in terms of units per week, and the type
and pattern of intake should be determined. Drinking above
safe limits (14 units per week for women and 21 units per
week for men) implies that alcohol could be implicated.
Drug history e adverse drug reactions account for up to 10%
of all jaundiced patients admitted to hospital. Prescribed drugs
are the usual cause; many common agents such as statins and
Natural history of hepatitis fibrosis in chronic
HCV infection
Infection Cirrhosis Symptoms Death
20–30 years 10 years 5 years
Intervention with interferon and ribavirin therapy, if undertaken
before development of cirrhosis, returns life expectancy to normal
and avoids the risk of symptomatic liver disease. Most liver
diseases have a similarly long asymptomatic natural history.
Figure 1
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 SIGNS AND SYMPTOMS

co-amoxiclav have been implicated. Most drug reactions are

idiosyncratic and can occur even after long-term exposure, as is
commonly the case with phenothiazines and minocycline. It is
important also to take a careful history of non-prescribed drugs.
Abnormal liver enzymes and acute liver failure are well-
described reactions to Chinese herbal remedies.
Family history of liver disease suggests a genetic component
to the illness. Haemochromatosis is present in 1/200 population
in the UK, and the family pedigree may include heart failure and
diabetes. a1-antitrypsin deficiency and Wilson’s disease are rare
conditions in which there may be a positive family history. Some
autoimmune diseases cluster in families, though predisposition
to these diseases is only partly genetic. First-degree relatives of
patients with primary biliary cirrhosis or autoimmune hepatitis
are at increased risk of these diseases. Figure 2 Spider naevus on the chest of a man with hepatitis C cirrhosis.
Symptoms suggesting specific liver diseases e in patients
with abnormal liver enzymes, additional symptoms may suggest
a diagnosis. Pruritus, dry eyes and mouth, and lethargy are Spider naevi (Figure 2) e a few (three or four) spider naevi
common in primary biliary cirrhosis and unrelated to the degree may be normal; a greater number, in a patient with abnormal
of hepatic fibrosis. Patients with hepatitis C often suffer lethargy, liver tests, suggests significant liver disease. They occur in the
arthralgia and right upper quadrant abdominal pain. drainage of the superior vena cava.
Palmar erythema is usually a significant sign.
History in patients presenting with jaundice Clubbing (Figure 3) is rare, but sometimes present in patients
Acute presentation with jaundice can result from parenchymal with alcoholic cirrhosis.
liver disease or obstruction of biliary tract. Certain features in the Dupuytren’s contracture e there is much debate about this
history can suggest the likely cause. sign. It may be more common in alcohol-related liver disease.
Age e acute presentation with malignant disease in the liver Leuconychia is a late sign of liver disease caused by low
or biliary tract is more likely in people who are aged 60 years or serum albumin.
older. Acute hepatitis is usually seen in younger individuals. Jaundice e when assessing a jaundiced patient, the key
Weight loss is almost universal in patients presenting with feature to look for is the presence of stigmata of chronic liver
metastatic cancer in the liver, although only 10% have symptoms disease, which suggest cirrhosis.
suggesting the site of the underlying primary tumour. Weight Ascites (Figure 4) and peripheral oedema are usually signs of
loss can also occur in those with jaundice of non-malignant severe liver disease. Generally, oedema occurs only when the
cause. Diagnostic confusion may occur in low-grade cholangitis serum albumin is less than 30 g/litre. Ascites may be demon-
caused by common bile duct stones, which can present insidi- strated by shifting dullness (Figure 5), or by a fluid thrill if the
ously with general debility, suppression of appetite and weight ascites is relatively tense and the abdominal wall thin. Ascites is
loss without any classical symptoms of cholangitis. an important sign because its presence indicates a poor prognosis
‘Obstructive’ symptoms e classically, patients with pancreatic in chronic liver disease (50% 2-year survival).
cancer have a history of a few weeks’ general ill health without Ascites may be the presenting feature of malignant disease,
pain, and pale stools and dark urine. However, this history is an particularly ovarian cancer. The distinction between malignant
unreliable means of distinguishing biliary obstruction from acute ascites and the ascites of chronic liver disease can be made
hepatic illness. Even in those with acute hepatitis A, some chole-
stasis is almost universal, and most patients have pale stools and
dark urine in the acute phase of their illness. This is also reflected
by the pattern of liver enzyme elevation; raised alanine amino-
transferase is common in biliary obstruction from stones and can
be of a magnitude similar to that seen in acute hepatitis. Imaging
and serology are always required for diagnosis.
Abdominal pain is not a useful distinguishing feature. Many
patients with common bile duct stones have no pain, and acute
hepatitis often causes pain, presumably as a result of liver capsular
swelling.

Physical examination
Physical examination is aimed at detecting signs of chronic liver
disease, most of which occur only in cirrhosis. In the context of
abnormal liver biochemistry, examination may also suggest non-
hepatic causes. The important physical signs are as follows. Figure 3 Finger clubbing in cirrhosis caused by alcohol.

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 SIGNS AND SYMPTOMS

clinically in patients with stigmata of chronic liver disease, but

often requires imaging and examination of ascitic fluid.
Hepatic encephalopathy e although most patients with hepatic
encephalopathy are also jaundiced, the two conditions do not
inevitably occur together. Encephalopathy can be the presenting
feature of chronic liver disease, in which shunting of portal venous
blood is extensive as a result of cirrhosis. It should be strongly
suspected when confusion is a predominant and variable symptom,
particularly in the presence of abnormal liver biochemistry, or a low
platelet count suggesting portal hypertension.
The classical clinical sign of hepatic encephalopathy is
a flapping tremor. However, this is not present in earlier stages of
encephalopathy, in which the only signs are mental slowness
and reversal of the normal sleep pattern. As encephalopathy
progresses, frank confusion and coma ensue. Encephalopathy
can manifest with almost any neurological sign, including hem-
iparesis, and should be considered in patients with any neuro-
logical symptom (particularly if fluctuating in severity) in whom
stigmata of chronic liver disease are present or liver function
tests abnormal. Encephalopathy can be graded and quantified by
simple bedside tests such as number connection. These provide
a more objective assessment of response to treatment than clin-
ical assessment alone.
Hepatosplenomegaly is not common even in severe liver
disease. In decompensated cirrhosis, the liver is often small
rather than large. The liver may be characteristically enlarged in
alcoholic hepatitis and primary biliary cirrhosis. The hyper-
splenism of cirrhosis and portal hypertension often results in
a low platelet count. This can occur when the spleen is neither
palpably enlarged nor even significantly bulky on radiology.
Caput medusae are dilated collateral veins on the abdominal
wall resulting from portal hypertension in patients with a patent
umbilical vein. They are rare.
Abdominal masses e an hepatic mass in a jaundiced patient
with stigmata of chronic liver disease suggests hepatocellular
cancer. This is common in cirrhosis caused by viruses. Pancreatic
cancer can present with an epigastric mass and jaundice, or
a palpable gallbladder.

Non-hepatic disease
The history and examination should also aim to exclude non-
hepatic causes of liver enzyme elevation. The most common
Figure 5 Demonstrating ascites clinically. Start from the midline and
percuss down until dull. Move the patients to 45 without moving the
hand from the point of dullness. If the dullness disappears, ascites is
present.

causes that may be difficult to diagnose clinically are right-sided

Figure 4 Abdominal distension caused by ascites.
heart failure and constrictive pericarditis (which can produce
significant hepatomegaly and abnormal liver tests with relatively
modest cardiac symptoms), endocrine disorders, diabetes and
thyroid dysfunction.
Gilbert’s disease is a relatively common cause of mild jaun-
dice. It is found in otherwise healthy individuals with jaundice
and no other symptoms. It often presents at the time of an
intercurrent infection and can cause the patient great concern. It
results from the presence of an increased number of TA repeats

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 SIGNS AND SYMPTOMS

in the promoter sequence of the uridine diphosphoglucuronatee FURTHER READING

glucuronosyltransferase 1 gene, leading to reduced enzyme Friedman LS, Martin P, Munoz SJ. Liver function tests and the objective
activity and high serum bilirubin concentration. evaluation of the patient with liver disease. In: Zakim D, Boyer TD,
Obesity should be documented by body mass index (weight eds. Hepatology. A textbook of liver disease. Philadelphia: Saunders,
(kg)/height (m)2) and, ideally, waist:hip ratio. Fatty liver 1996; 791e833.
variants now account for a significant proportion of patients Royal College of Physicians. Alcohol e can the NHS afford it? London:
presenting with elevated liver enzymes. A Royal College of Physicians, 2001.

MEDICINE 39:9 510 Ó 2011 Elsevier Ltd. All rights reserved.