What’s new?

C Non-invasive quantitative US and MRI techniques are playing an

increasing role in the assessment of fibrosis, fat and iron in

parenchymal liver disease

C The combination of liver-specific contrast agents, diffusion-

ASSESSMENT OF LIVER DISEASE

Imaging the liver and biliarytractTom L Kaye

J Ashley Guthrie

weighted imaging, and improved MRI technology has

increased the accuracy of focal liver lesion detection and

Abstract characterization, in many cases avoiding the need for biopsy

C CT dose-reduction techniques such as iterative reconstruction

have been introduced, which can substantially reduce patient

dose in multi-phase hepatobiliary examinations

C Image-guided ablative and endovascular treatments such as

RFA now have an established role in the treatment of hepato-

cellular carcinoma and unresectable hepatic malignancy

A variety of modalities is available to image the liver and biliary tract,

many offering complementary information, with a combination of tech-

niques often being required to make the diagnosis or determine optimal

patient management. Ultrasound is commonly used as the primary inves-

tigation as it is safe, cheap and widely available. Computed tomography

has a central role for emergency imaging, cancer diagnosis and staging,

and assessment of treatment response. Magnetic resonance imaging is

excellent for interrogating the liver parenchyma, and is the modality of

choice for characterizing a focal liver lesion and non-invasive investiga-

tion of the biliary tree. The addition of hepatobiliary contrast agents

and diffusion-weighted imaging has further improved accuracy. This

article describes the role of each of these modalities, highlighting several

common, benign and malignant hepatobiliary disease processes. Other

less commonly used modalities such as PET/CT and cholescintigraphy

are described and various hepatobiliary interventional techniques are

summarized.

Keywords Bile ducts; biliary tract diseases; cholangiography; computed

tomography; liver; liver diseases; magnetic resonance imaging; positron-

emission tomography; ultrasonography

Ultrasonography

Ultrasonography (US) remains the most widely performed pri-

mary investigation for suspected hepatobiliary disease, owing to

its wide availability and avoidance of ionizing radiation.

Biliary disease

In the fasted state, the gallbladder appears on US as an oval

hypo-echoic structure with a smooth thin wall. Gallstones

usually appear as mobile echogenic foci with posterior

acoustic shadowing, and are identified with >95% accuracy in

the gallbladder, but less so in the common bile duct due

to adjacent bowel gas.1 The US findings in acute cholecystitis

include mural thickening (>3 mm), pericholecystic fluid and

a positive sonographic Murphy’s sign (Figure 1).2 Gallbladder

polyps appear as fixed luminal defects without acoustic

Tom L Kaye BMBS BMedSci MSc(Edin) FRCR is a Radiology Registrar at St

James’s University Hospital, Leeds, UK. Competing interests: none

declared.

J Ashley Guthrie MB BChir FRCR is a Consultant Radiologist at St James’s

University Hospital, Leeds, UK. Competing interests: Dr Guthrie has

received honoraria for lecturing and chairing sessions for Bayer

HealthCare.

MEDICINE 43:10 562

shadowing. Adenomyomatosis and chronic cholecystitis are

other common benign causes of mural thickening demon-

strated on US. Carcinoma of the gallbladder can present as a

polypoid luminal tumour or as diffuse wall thickening and is

often difficult to differentiate from benign conditions. Gall-

bladders containing polyps >1 cm are generally resected due

to such difficulties.

US has a major role in identifying biliary dilatation in the

context of jaundice or right upper quadrant pain, which may be

caused by obstructive pathology (duct stones, benign or malig-

nant strictures), but dilatation is also found after cholecystec-

tomy, prolonged fasting or with sphincter of Oddi dysfunction.

The common hepatic duct (CHD) normally measures up to 6 mm

until age 60, with a further allowance of 1 mm per decade

thereafter.3 The double duct sign refers to dilatation of the

pancreatic (>4 mm) and common duct, which is suggestive of a

pancreatic head or ampullary tumour and is usually further

investigated by multiphasic computed tomography (CT).

Liver disease

The normal liver has a uniform and homogenous echotexture.

Fatty infiltration gives a diffusely echogenic liver, with attenua-

tion of the US beam as it passes deep into the organ. With the

recognition of non-alcoholic fatty liver disease as a cause of

chronic liver disease there is interest in using US attenuation

parameters to quantify steatosis, although this is not established

as a clinical tool at present.

In cirrhosis the liver usually appears coarse and echogenic.

Common features include surface nodularity, atrophy of the right

lobe, hypertrophy of the caudate lobe and enlargement of the

gallbladder fossa and umbilical fissure. Associated findings

related to portal hypertension include reduced, reversed or ab-

sent portal vein flow, varices, splenomegaly and ascites.4

Changes in stiffness correlate with fibrosis, currently assessed

by invasive liver biopsy, and can now be quantified using US (or

magnetic resonance imaging; MRI) via techniques such as tran-

sient elastography (FibroScan�), performed without generating

images, or shear-wave elastography, where stiffness is measured

in a region of interest while imaging the liver.5

� 2015 Elsevier Ltd. All rights reserved.

Figure 1 (a) US image showing normal thin walled gallbladder. (b) acute calculous cholecystitis. The gallbladder wall is diffusely thickened (dashed white

arrows) and contains echogenic bile, with a gallstone impacted in the neck (solid white arrows).

ASSESSMENT OF LIVER DISEASE

Doppler ultrasound

The frequency shift of an ultrasonic wave (Doppler effect) that

occurs when it is reflected from a moving target (such as blood)

can be used to create a colour map of blood flow and direction

(colour Doppler) or a targeted waveform of blood flow (spectral

Doppler). This is commonly used to interrogate the major hepatic

vessels in chronic liver disease and after liver transplantation.

Contrast-enhanced ultrasound (CEUS)

Grey-scale US has modest sensitivity (50e65%) for metastatic

disease and hepatocellular carcinoma (HCC).6,7 It can differen-

tiate simple cysts reliably but is limited in the characterization of

solid focal lesions. CEUS improves both lesion detection and

characterization.8 It involves the intravenous injection of

microbubble contrast media. Benign lesions are usually iso- or

hyper-echoic to background liver in the late phase of enhance-

ment (Figure 2). Although comparable to CT and MRI for lesion

detection and characterization in ideal circumstances,9 multiple

lesions and lesions near the diaphragm or obscured by bowel gas

are difficult to evaluate.

Computed tomography

Modern multi-detector CT is widely used and versatile, allowing

rapid imaging of a large volume with high spatial resolution,

facilitating accurate multi-phase imaging of the liver and biliary

tree. Iodinated contrast is used for most examinations; it is

contra-indicated in those with severe renal impairment or a

history of anaphylactic reaction. The high-radiation dose of CT

should be considered (especially with multiphase imaging), but

can be reduced by decreasing scanning dose parameters, peak

kVp and mA. Increased computing power has enabled iterative

reconstruction techniques to further reduce dose.10

Imaging the acute abdomen

CT retains an important role for imaging in the emergency

situation. In major trauma, dual phase imaging or a military

protocol with a single biphasic contrast injection has a high ac-

curacy for traumatic liver injuries and active arterial

MEDICINE 43:10 563

bleeding.11,12 High-quality 3D reformats of hepatobiliary

vascular anatomy are useful for planning endovascular inter-

vention in cases of vascular injury.

CT demonstrates complications of cholecystitis such as ne-

crosis, perforation, or pericholecystic abscess (Figure 3). Intra-

hepatic or perihepatic fluid collections and abscesses are

accurately depicted and CT can facilitate drainage. In severe

acute pancreatitis CT is widely used for identifying complications

such as necrosis, collections or bleeding.

Hepatobiliary oncology imaging

Metastases are by far the most common malignant liver lesions,

exceeding primary liver tumours by a factor of at least twenty. CT

is used for staging and to assess response to treatment for the

majority of malignancies that metastasize to the liver and pri-

mary tumours arising from the liver, pancreas and biliary tree.

The blood supply to the liver is via the hepatic artery (25%) and

portal vein (75%), with most tumours taking their blood supply

from the hepatic artery and displaying a varying degree of

vascularity. Hypervascular tumours such as hepatocellular car-

cinoma (HCC) or neuroendocrine malignancy should be imaged

in the arterial phase to maximize contrast enhancement between

tumour and background liver.

The majority of metastases from other sources (such as

colorectal cancer) are hypovascular and best depicted on the

portal venous phase scan. Triple-phase CT (unenhanced, arterial

and portal venous phase) is used to clarify the cause of biliary

obstruction identified on US (when stones are not suspected) and

to stage pancreatic malignancy.13

Characterization of liver lesions

In cases where MRI is contraindicated or unsuitable, multi-phase

CT may be used to characterize liver lesions. European and

American Liver Associations allow multiphasic CT to be used as

a non-invasive means of diagnosing HCC in patients with

cirrhosis. Key diagnostic criteria include arterial hypervascularity

with ‘washout’ demonstrated on a portal venous or 3-

minute delayed acquisition.14,15 Benign lesions, such as

� 2015 Elsevier Ltd. All rights reserved.

Figure 2 (a) Grey scale US image in a 24-year-old female shows a well-defined isoechoic mass adjacent to the gallbladder fossa. (b) CEUS images shows

avid homogenous arterial enhancement within the lesion, (c) which is near isointense in the delayed phase with a faint central scar visible. (d) Sub-

sequent coronal hepatobiliary phase MRI image shows persisting uptake of contrast with a central scar, confirming focal nodular hyperplasia (FNH).

ASSESSMENT OF LIVER DISEASE

haemangiomas, focal nodular hyperplasia (FNH) and adenomas,

can be identified although contrast resolution is inferior to MRI

and characterization of lesions smaller than 1 cm is poor.16

Magnetic resonance imaging

MRI is a versatile imaging technique, allowing manipulation of

sequence parameters to vary soft tissue contrast or obtain

structural data. It is the examination of choice for imaging

complex biliary disease and characterizing liver lesions in both

the normal and cirrhotic liver. MRI has excellent liver-to-lesion

contrast resolution and incurs no ionizing radiation. The addi-

tion of hepatocyte-specific contrast agents and diffusion-

weighted images (DWI) has further improved sensitivity and

specificity.17 Limitations include cost, length of examination

(particularly for unwell patients who cannot lie still), and con-

traindications such as pacemakers and implants.

Biliary disease

Magnetic resonance cholangiopancreatography (MRCP) uses

heavily weighted T2 sequences to display static or slow-moving

fluid within the biliary tree and pancreatic duct. MRCP can

identify ductal stones as small as 2 mm with comparable accu-

racy to endoscopic retrograde cholangiopancreatography

(ERCP)18 (Figure 4a). Flow artefacts, intra-ductal gas and adja-

cent pulsatile vascular compression can lead to false-positive

MEDICINE 43:10 564

interpretation. Both benign (iatrogenic, post-inflammatory or

secondary to primary sclerosing cholangitis (PSC)) and malig-

nant strictures can be identified (Figure 4b). Malignant biliary

strictures tend to be longer, with wall thickening and an irregular

margin.19

Variant biliary anatomy is well demonstrated and MRCP can

identify the relationship between the pancreatic duct and cystic

pancreatic tumours. More recently, functional assessment of

biliary excretion and pancreatic exocrine function has become

possible using hepatobiliary contrast media and secretin-

stimulated MRCP, respectively. Direct cholangiography (ERCP)

has now been largely replaced as a diagnostic test, being reserved

for tissue biopsy, stone extraction or stent insertion.

Diffuse and focal liver disease

MRI can characterize both diffuse liver disease and focal liver

lesions, in certain cases obviating the need for biopsy. A standard

liver protocol usually includes T2-weighted sequences that pro-

vide an overview of anatomy and can help identify simple cysts

or haemangiomas. In- and out-of-phase T1 imaging is used to

identify cellular fat within a lesion (such as in adenomas, HCC or

areas of focal fatty infiltration), or to detect iron deposition in

haemochromatosis or haemosiderosis. Various contrast agents

can be used to achieve imaging in the arterial, portal venous and

delayed phases. MRI can be used accurately to quantify fat and

� 2015 Elsevier Ltd. All rights reserved.

Figure 3 Perforated cholecystitis with hepatic abscess. Coronal (a) and axial (b) contrast enhanced CT images show irregular thick walled gallbladder

containing a large stone (solid white arrows), with extensive multi-loculated hepatic abscess (dashed white arrows).

ASSESSMENT OF LIVER DISEASE

iron, and MR elastography is under evaluation as a means of

measuring fibrosis.

Gadolinium chelates are commonly used and are confined to

the extracellular space, behaving in a similar way to iodinated

contrast used in CT. Hepatocyte-specific contrast agents (such as

gadobenate dimeglamine and gadoxetic acid) show a degree of

active uptake by lesions with hepatocyte function and are

excreted into the bile, providing additional information about the

cellular constituents of a focal lesion.

The use of DWI gives unique information about the move-

ment of water molecules at the cellular level. Malignant lesions

have a significantly lower apparent diffusion co-efficient (ADC)

and display greater diffusion restriction than benign lesions

(Figure 5).20 DWI is particularly useful in the detection of ma-

lignant lesions in the non-cirrhotic liver.

MRI allows accurate characterization of benign liver lesions,

such as haemangiomas, adenomas and FNH, differentiating them

Figure 4 (a) Reconstructed MRCP maximum intensity projection (MIP) showing

(solid white arrow). (b) Reconstructed MRCP MIP showing the classic findings

diverticula affecting the intrahepatic ducts. A dominant CBD stricture (dashed w

inflammatory.

MEDICINE 43:10 565

from primary and secondary malignant lesions. In both the

cirrhotic and non-cirrhotic liver, MRI is the investigation choice

for demonstrating the anatomical distribution of disease with

high accuracy before liver resection and transplantation.

Positron emission tomography e CT

FDG (2-[fluorine-18]fluoro-2-deoxy-D-glucose) positron emission

tomography with CT (PET/CT) is a functional imaging technique

using a glucose analogue that is taken up by metabolically active

tissues and tumour cells. PET/CT is frequently used for demon-

strating disseminated malignant disease and may identify occult

primary tumours in patients with metastatic liver disease from an

unknown primary. It is unreliable for the identification of HCC

(although a high standardized uptake value (SUV) correlates

with poor differentiation21) and is inferior to MRI for identifica-

tion of liver metastases. It may improve the detection rate of

proximal biliary dilatation with a 9 mm calculus in the common bile duct

of primary sclerosing cholangitis (PSC) with beading, stricturing and

hite arrow) was investigated for cholangiocarcinoma but was found to be

� 2015 Elsevier Ltd. All rights reserved.

Figure 5 Typical MRI appearances of a HCC. (a) T2 axial image shows mildly hyperintense lesion in the left lobe. (b)e(d) Arterial, hepatobiliary phase and

DWI axial images after gadoxetate disodium show arterial enhancement, reduced uptake of hepatobiliary contrast and diffusion restriction.

ASSESSMENT OF LIVER DISEASE

occult metastatic disease in HCC (as these tend to be less well

differentiated tumours), cholangiocarcinoma and gallbladder

cancer but is not in widespread use for detecting these tumours.

It can differentiate benign from malignant liver lesions, the latter

usually having an SUV of greater than 3.5.21 PET/CT is

commonly used to identify occult metastatic disease in patients

with colorectal liver metastases being assessed for liver resec-

tion. Limitations include cost, low spatial resolution, large radi-

ation burden and lack of specificity.

Cholescintigraphy

This technique involves an intravenous injection of a

technetium-99 labelled hepatobiliary iminodiacetic acid (99m Tc-

HIDA), which is taken up by the liver and excreted in the bile.

The technique retains an important role in the paediatric setting,

differentiating between biliary atresia and neonatal hepatitis. In

biliary atresia there is good hepatic uptake but no excretion into

the bowel 24 hours after injection. It is rarely used as a first-line

investigation in the diagnosis of acute cholecystitis, although it is

highly accurate. Absence of activity in the gallbladder after

4 hours is diagnostic as HIDA cannot enter through an inflamed

and oedematous cystic duct. False positives can occur due to

underlying liver disease or after a prolonged fast.

Endoscopic US (EUS)

EUS is an invasive technique in which a high-frequency trans-

ducer is attached to the tip of an endoscope. The left lobe of the

liver, pancreas, biliary tree, and associated nodal chains can be

MEDICINE 43:10 566

evaluated. EUS is more sensitive than US or CT for detecting

early chronic pancreatitis, biliary microlithiasis and small

pancreatic or ampullary masses. Fine-needle aspiration of lymph

nodes and solid and cystic pancreatic lesions can be performed.22

Hepatic interventional oncology

Percutaneous radio-frequency ablation (RFA) is an accepted

treatment modality for unresectable HCC and liver metastases.

A needle is introduced into the tumour under US or CT guid-

ance and rapidly alternating current produces frictional heat

leading to liquefactive necrosis. Local disease control is ach-

ieved in up to 98% of patients with colorectal liver metastases

<3e4 cm and for HCC <5 cm 4-year survival is comparable to

surgery.23 Alternative ablative therapies include cryotherapy,

microwave and laser therapy and high-intensity focused US.

These may be combined with endovascular treatments such as

trans-arterial chemoembolization (TACE) or Yttrium-90 radio-

embolization in which microspheres are delivered to the

tumour and emit beta radiation. Successfully ablated lesions

followed up with CT show no residual internal enhancement,

sometimes with intra-lesional air bubbles and a surrounding

hypervascular rim.24 A

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