Clinical review

Investigation of liver and biliary disease

I J Beckingham, S D Ryder. 

Jaundice is the commonest presentation of patients with liver and biliary disease. The cause can be established in most cases by simple non-invasive tests, but many patients will require referral to a specialist for management. Patients with high concentrations of bilirubin (>100 µmol/l) or with evidence of sepsis or cholangitis are at high risk of developing complications and should be referred as an emergency because delays in treatment adversely affect prognosis.

View larger version (39K): [in this window] [in a new window]   Bilirubin pathway

	Jaundice

Top Jaundice Liver function tests Plasma proteins and coagulation... Imaging in liver and... Liver biopsy

Hyperbilirubinaemia is defined as a bilirubin concentration above the normal laboratory upper limit of 19 µmol/l. Jaundice occurs when bilirubin becomes visible within the sclera, skin, and mucous membranes, at a blood concentration of around 40 µmol/l. Jaundice can be categorised as prehepatic, hepatic, or posthepatic, and this provides a useful framework for identifying the underlying cause.

Around 3% of the UK population have hyperbilirubinaemia (up to 100 µmol/l) caused by excess unconjugated bilirubin, a condition known as Gilbert's syndrome. These patients have mild impairment of conjugation within the hepatocytes. The condition usually becomes apparent only during a transient rise in bilirubin concentration (precipitated by fasting or illness) that results in frank jaundice. Investigations show an isolated unconjugated hyperbilirubinaemia with normal liver enzyme activities and reticulocyte concentrations. The syndrome is often familial and does not require treatment.

Prehepatic jaundice
In prehepatic jaundice, excess unconjugated bilirubin is produced faster than the liver is able to conjugate it for excretion. The liver can excrete six times the normal daily load before bilirubin concentrations in the plasma rise. Unconjugated bilirubin is insoluble and is not excreted in the urine. It is most commonly due to increased haemolysisfor example, in spherocytosis, homozygous sickle cell disease, or thalassaemia majorand patients are often anaemic with splenomegaly. The cause can usually be determined by further haematological tests (red cell film for reticulocytes and abnormal red cell shapes, haemoglobin electrophoresis, red cell antibodies, and osmotic fragility).

Hepatic and posthepatic jaundice
Most patients with jaundice have hepatic (parenchymal) or posthepatic (obstructive) jaundice. Several clinical features may help distinguish these two important groups but cannot be relied on, and patients should have ultrasonography to look for evidence of biliary obstruction.

View larger version (24K): [in this window] [in a new window]   Guide to investigation and referral of patients with jaundice in primary care

	Liver function tests

Top Jaundice Liver function tests Plasma proteins and coagulation... Imaging in liver and... Liver biopsy

Liver function tests routinely combine markers of function (albumin and bilirubin) with markers of liver damage (alanine transaminase, alkaline phosphatase, and -glutamyl transferase). Abnormalities in liver enzyme activities give useful information about the nature of the liver insult: a predominant rise in alanine transaminase activity (normally contained within the hepatocytes) suggests a hepatic process. Serum transaminase activity is not usually raised in patients with obstructive jaundice, although in patients with common duct stones and cholangitis a mixed picture of raised biliary and hepatic enzyme activity is often seen.

Epithelial cells lining the bile canaliculi produce alkaline phosphatase, and its serum activity is raised in patients with intrahepatic cholestasis, cholangitis, or extrahepatic obstruction; increased activity may also occur in patients with focal hepatic lesions in the absence of jaundice. In cholangitis with incomplete extrahepatic obstruction, patients may have normal or slightly raised serum bilirubin concentrations and high serum alkaline phosphatase activity. Serum alkaline phosphatase is also produced in bone, and bone disease may complicate the interpretation of abnormal alkaline phosphatase activity. If increased activity is suspected to be from bone, serum concentrations of calcium and phosphorus should be measured together with 5'-nucleotidase or -glutamyl transferase activity; these two enzymes are also produced by bile ducts, and their activity is raised in cholestasis but remains unchanged in bone disease.

Occasionally, the enzyme abnormalities may not give a clear answer, showing both a biliary and hepatic component. This is usually because of cholangitis associated with stones in the common bile duct, where obstruction is accompanied by hepatocyte damage as a result of infection within the biliary tree.

	Plasma proteins and coagulation factors

Top Jaundice Liver function tests Plasma proteins and coagulation... Imaging in liver and... Liver biopsy

A low serum albumin concentration suggests chronic liver disease. Most patients with biliary obstruction or acute hepatitis will have normal serum albumin concentrations as the half life of albumin in plasma is around 20 days and it takes at least 10 days for the concentration to fall below the normal range despite impaired liver function.

Coagulation factors II, V, VII, and IX are synthesised in the liver. Abnormal clotting (measured as prolongation of the international normalised ratio) occurs in both biliary obstruction and parenchymal liver disease because of a combination of poor absorption of fat soluble vitamin K (due to absence of bile in the gut) and a reduced ability of damaged hepatocytes to produce clotting factors.

Serum globulin titres rise in chronic hepatitis and cirrhosis, mainly due to a rise in the IgA and IgG fractions. High titres of IgM are characteristic of primary biliary cirrhosis, and IgG is a hallmark of chronic active hepatitis. Ceruloplasmin activity (ferroxidase, a copper transporting globulin) is reduced in Wilson's disease. Deficiency of ₁ antitrypsin (an enzyme inhibitor) is a cause of cirrhosis as well as emphysema. High concentrations of the iron carrying protein ferritin are a marker of haemochromatosis.

Autoantibodies are a series of antibodies directed against subcellular fractions of various organs that are released into the circulation when cells are damaged. High titres of antimitochondrial antibodies are specific for primary biliary cirrhosis, and antismooth muscle and antinuclear antibodies are often seen in autoimmune chronic active hepatitis. Antibodies against hepatitis are discussed in detail in a future article on hepatitis.

	Imaging in liver and biliary disease

Top Jaundice Liver function tests Plasma proteins and coagulation... Imaging in liver and... Liver biopsy

Plain radiography has a limited role in the investigation of hepatobiliary disease. Chest radiography may show small amounts of subphrenic gas, abnormalities of diaphragmatic contour, and related pulmonary disease, including metastases. Abdominal radiographs can be useful if a patient has calcified or gas containing lesions as these may be overlooked or misinterpreted on ultrasonography. Such lesions include calcified gall stones (10-15% of gall stones), chronic calcific pancreatitis, gas containing liver abscesses, portal venous gas, and emphysematous cholecystitis.

View larger version (252K): [in this window] [in a new window]   Computed tomogram of ampullary carcinoma (white arrow) causing obstruction of the bile duct (black arrow, bottom) and pancreatic ducts (white arrowhead)

Ultrasonography is the first line imaging investigation in patients with jaundice, right upper quadrant pain, or hepatomegaly. It is non-invasive, inexpensive, and quick but requires experience in technique and interpretation. Ultrasonography is the best method for identifying gallbladder stones and for confirming extrahepatic biliary obstruction as dilated bile ducts are visible. It is good at identifying liver abnormalities such as cysts and tumours and pancreatic masses and fluid collections, but visualisation of the lower common bile duct and pancreas is often hindered by overlying bowel gas. Computed tomography is complementary to ultrasonography and provides information on liver texture, gallbladder disease, bile duct dilatation, and pancreatic disease. Computed tomography is particularly valuable for detecting small lesions in the liver and pancreas.

Cholangiography identifies the level of biliary obstruction and often the cause. Intravenous cholangiography is rarely used now as opacification of the bile ducts is poor, particularly in jaundiced patients, and anaphylaxis remains a problem. Endoscopic retrograde cholangiopancreatography is advisable when the lower end of the duct is obstructed (by gall stones or carcinoma of the pancreas). The cause of the obstruction (for example, stones or parasites) can sometimes be removed by endoscopic retrograde cholangiopancreatography to allow cytological or histological diagnosis.

Percutaneous transhepatic cholangiography is preferred for hilar obstructions (biliary stricture, cholangiocarcinoma of the hepatic duct bifurcation) because better opacification of the ducts near the obstruction provides more information for planning subsequent management. Obstruction can be relieved by insertion of a plastic or metal tube (a stent) at either endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography.

Magnetic resonance cholangiopancreatography allows non-invasive visualisation of the bile and pancreatic ducts. It is superseding most diagnostic endoscopic cholangiopancreatography as faster magnetic resonance imaging scanners become more widely available.

	Liver biopsy

Top Jaundice Liver function tests Plasma proteins and coagulation... Imaging in liver and... Liver biopsy

Percutaneous liver biopsy is a day case procedure performed under local anaesthetic. Patients must have a normal clotting time and platelet count and ultrasonography to ensure that the bile ducts are not dilated. Complications include bile leaks and haemorrhage, and overall mortality is around 0.1%. A transjugular liver biopsy can be performed by passing a special needle, under radiological guidance, through the internal jugular vein, the right atrium, and inferior vena cava and into the liver though the hepatic veins. This has the advantage that clotting time does not need to be normal as bleeding from the liver is not a problem. Liver biopsy is essential to diagnose chronic hepatitis and establish the cause of cirrhosis.

View larger version (75K): [in this window] [in a new window]   Subcapsular haematoma: a complication of liver biopsy

Ultrasound guided liver biopsy can be used to diagnose liver masses. However, it may cause bleeding (especially with liver cell adenomas), anaphylactic shock (hydatid cysts), or tumour seeding (hepatocellular carcinoma or metastases). Many lesions can be confidently diagnosed by using a combination of imaging methods (ultrasonography, spiral computed tomography, magnetic resonance imaging, nuclear medicine, laparoscopy, and laparoscopic ultrasonography). When malignancy is suspected in solitary lesions or those confined to one half of the liver, resection is the best way to avoid compromising a potentially curative procedure.

	Footnotes

S D Ryder is consultant hepatologist, Queen's Medical Centre, Nottingham NG7 2UH.

The ABC of diseases of liver, pancreas, and biliary system is edited by I J Beckingham, consultant hepatobiliary and laparoscopic surgeon, department of surgery, Queen's Medical Centre, Nottingham (Ian.Beckingham{at}nottingham.ac.uk). The series will be published as a book later this year.