Test	Disease
Anti-mitochondrial antibody	Primary biliary cirrhosis
Anti-nuclear, smooth muscle (actin), liver/kidney microsomal antibody	Autoimmune hepatitis
Raised serum immunoglobulins:
IgG	Autoimmune hepatitis
IgM	Primary biliary cirrhosis
Viral markers	Hepatitis A, B, C, D, E and others
α-Fetoprotein	Hepatocellular carcinoma
Serum iron, transferrin saturation, serum ferritin	Hereditary haemochromatosis
Serum and urinary copper, serum caeruloplasmin	Wilson’s disease
α₁-Antitrypsin	Cirrhosis (± emphysema)
Anti-nuclear cytoplasmic antibodies	Primary sclerosing cholangitis
Markers of liver fibrosis	Non-alcoholic fatty liver disease
	Hepatitis C
Genetic analyses	e.g. HFE gene (hereditary haemochromatosis)

Liver function tests

Serum albumin

This is a marker of synthetic function and is useful to gauge the severity of chronic liver disease: a falling serum albumin is a bad prognostic sign. In acute liver disease initial albumin levels may be normal.

Prothrombin time (PT)

This is also a marker of synthetic function. Because of its short half-life, it is a sensitive indicator of both acute and chronic liver disease. Vitamin K deficiency should be excluded as the cause of a prolonged PT by giving an intravenous bolus (10 mg) of vitamin K. Vitamin K deficiency commonly occurs in biliary obstruction, as the low intestinal concentration of bile salts results in poor absorption of vitamin K.

Prothrombin times vary in different laboratories depending upon the thromboplastin used in the assay. The International normalized ratio (INR) was developed to standardize anticoagulation with coumarin derivatives, but is very variable in liver disease, and causes large differences when included in prognostic scores for cirrhosis across different centres.

Liver biochemistry

Bilirubin

Serum bilirubin is normally almost all unconjugated. In liver disease, increased serum bilirubin is usually accompanied by other abnormalities in liver biochemistry. Differentiation between conjugated or unconjugated bilirubin is only necessary in congenital disorders of bilirubin metabolism (see below) or to exclude haemolysis.

FURTHER READING

Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365:147−156.

Aminotransferases

These enzymes (often referred to as transaminases) are contained in hepatocytes and leak into the blood with liver cell damage. Two enzymes are measured:

Aspartate aminotransferase (AST) is primarily a mitochondrial enzyme (80%; 20% in cytoplasm) and is also present in heart, muscle, kidney and brain. High levels are seen in hepatic necrosis, myocardial infarction, muscle injury and congestive cardiac failure.

Alanine aminotransferase (ALT) is a cytosol enzyme, more specific to the liver so that a rise only occurs with liver disease.

Alkaline phosphatase (ALP)

This is present in hepatic canalicular and sinusoidal membranes, but also in bone, intestine and placenta. If necessary, its origin can be determined by electrophoretic separation of isoenzymes or bone-specific monoclonal antibodies. In clinical practice, if the γ-GT is also abnormal the ALP is presumed to come from the liver.

Serum ALP is raised in both intrahepatic and extrahepatic cholestatic disease of any cause, due to increased synthesis. In cholestatic jaundice, levels may be four to six times the normal limit. Raised levels also occur with hepatic infiltrations (e.g. metastases), and in cirrhosis, frequently in the absence of jaundice. The highest serum levels due to liver disease (>1000 IU/L) are seen with hepatic metastases and primary biliary cirrhosis.

γ-Glutamyl transpeptidase

This is a microsomal enzyme present in liver, but also in many tissues. Its activity can be induced by drugs such as phenytoin and by alcohol. If the ALP is normal, a raised serum γ-GT can be a useful guide to alcohol intake (see p. 1182). However, mild elevations of γ-GT are common, even with a small alcohol consumption and is also raised with fatty liver disease. It does not necessarily indicate liver disease if the other liver biochemical tests are normal. In cholestasis the γ-GT rises in parallel with the ALP as it has a similar pathway of excretion. This is also true of 5-nucleotidase, another microsomal enzyme that can be measured in blood.

Total proteins and globulin fraction

This measurement, is of little value. Serum albumin is discussed above. The proteins in the globulin fraction, raised in liver disease, can be separated by electrophoresis and is usually due to increased circulating immunoglobulins; it is polyclonal (see below).

Viral markers

Viruses are a major cause of liver disease. Virological studies have a key role in diagnosis; markers are available for most common viruses that cause hepatitis.

Additional blood investigations

Anti-mitochondrial antibody (AMA) in serum is found in over 95% of patients with primary biliary cirrhosis (PBC) (p. 338). Several different AMA subtypes are described, depending on their antigen specificity, and are also found in autoimmune hepatitis and other autoimmune diseases. AMA is demonstrated by an immunofluorescent technique and is neither organ- nor species-specific. M2 subtype is specific for PBC.

Nucleic, smooth muscle (actin), liver/kidney microsomal antibodies can be found in serum, often in high titre, in patients with autoimmune hepatitis. These serum antibodies can also be found in other autoimmune conditions and other liver diseases.

Anti-nuclear cytoplasmic antibodies (ANCA) can be found in serum of patients with primary sclerosing cholangitis.

Markers of liver fibrosis

Fibrosis plays a key role in the outcome of many chronic liver diseases. Blood tests are being used to detect and quantify fibrosis and thereby decrease the need of liver biopsy. To date, these have been developed mainly for chronic hepatitis C, and less so for non-alcoholic fatty liver disease.

Commercial tests are available which measure α₂-macroglobulin, α₂-haptoglobulin, γ-globulin, apoprotein A₁, γ-GT and total bilirubin. Some are based on age, blood ferritin, glucose, AST, ALT, platelet count and bodyweight. These results are formulated to determine a fibrosis index. The indices are sensitive and specific (>90%) for the absence of fibrosis, and have 80% sensitivity and specificity for severe fibrosis, but cannot reliably assess the severity of fibrosis.

Markers of matrix deposition include procollagen I and III peptide and type IV collagen. Markers of matrix degradation, e.g. matrix metalloproteinase (MMP) 2 and 9, and tissue inhibitors of metalloproteinases (TIMPS), e.g. TIMP1 and 2, all are being used as markers of fibrosis.

AST to platelet ratio index (APRI) is less accurate than the tests mentioned above.

Genetic analysis

These tests are performed routinely for haemochromatosis (HFE gene) and for α₁-antitrypsin deficiency. Markers are also available for the most frequent abnormal genes in Wilson’s disease (see p. 341).

Urine tests

Dipstick tests are available for bilirubin and urobilinogen. Bilirubinuria is due to the presence of conjugated (soluble) bilirubin, is found in patients with jaundice due to hepatobiliary disease, but is absent if unconjugated bilirubin is the major cause of jaundice. The presence of urobilinogen in urine in practice is of little value but suggests haemolysis or hepatic dysfunction.

Imaging techniques

Ultrasound examination

This is a non-invasive, safe and relatively cheap technique. It involves the analysis of the reflected ultrasound beam detected by a probe moved across the abdomen. The normal liver appears as a relatively homogeneous structure. The gall bladder, common bile duct, pancreas, portal vein and other structures in the abdomen can be visualized. Abdominal ultrasound is useful in:

a jaundiced patient (p. 312)

hepatomegaly/splenomegaly

the detection of gallstones (Fig. 7.6)

focal liver disease – lesions >1 cm

general parenchymal liver disease

assessing portal and hepatic vein patency

lymph node enlargement.

Figure 7.6 Gall bladder ultrasound with multiple echogenic gallstones causing well-defined acoustic shadowing. (1) gall bladder; (2) gallstones; (3) echogenic shadow.

Other abdominal masses can be delineated and biopsies obtained under ultrasonic guidance.

Colour Doppler ultrasound will demonstrate vascularity within a lesion and the direction of portal and hepatic vein blood flow (Fig. 7.7).

Figure 7.7 Doppler signal of the portal vein is shown as a trace and the visual counterpart in red showing patency and forward flow into the liver.

Ultrasound contrast agents, mostly based on production of microbubbles within flowing blood, enhance the detection of vascularity, allowing the detection of abnormal circulation within liver nodules, giving a more specific diagnosis of hepatocellular carcinoma.

Hepatic stiffness (transient elastography). Using an ultrasound transducer, a vibration of low frequency and amplitude is passed through the liver, the velocity of which correlates with hepatic stiffness. Stiffness (measured in kPa) increases with worsening liver fibrosis (sensitivity and specificity 80–95% compared to liver biopsy). It is not accurate enough to diagnose cirrhosis, and less accurate for less severe fibrosis. It cannot be used in the presence of ascites and morbid obesity, and it is affected by inflammatory tissue and congestion. Acoustic radiation force impulse is incorporated into standard B mode ultrasonography and has similar physical principles to transient elastography.

Endoscopic ultrasound (EUS)

A small high-frequency ultrasound probe is incorporated into the tip of an endoscope and placed by direct vision into the lumen of the gut. The close proximity of the probe to the pancreas and biliary tree permits high-resolution ultrasound imaging. It allows accurate staging of small, potentially operable, pancreatic tumours and offers a less invasive method for bile duct imaging. It has a high accuracy in detection of small neuroendocrine tumours of the pancreas. EUS-guided fine-needle aspiration of tumours provides cytological/histological tissue for confirmation of malignancy. EUS is also used to place transmural tubes to drain pancreatic and peripancreatic fluid collections.

Computed tomography (CT) examination

CT during or immediately after i.v. contrast shows both arterial and portal venous phases of enhancement, enabling more precise characterization of a lesion and its vascular supply (Fig. 7.8). Retrospective analysis of data allows multiple overlapping slices to be obtained with no increase in the radiation dose, providing excellent visualization of the size, shape and density of the liver, pancreas, spleen, lymph nodes and lesions in the porta hepatis. Multi-planar and three-dimensional reconstruction in the arterial phase can create a CT angiogram, often making formal invasive angiography unnecessary. CT also provides guidance for biopsy. It has advantages over US in detecting calcification and is useful in obese subjects, although US is usually the imaging modality used first to investigate liver disease.

Figure 7.8 Use of contrast-enhanced spiral CT. There is an irregular mass (arrow) in the posterior aspect of the right lobe of the liver which is only well seen on the early arterial phase enhanced scan.

Magnetic resonance imaging (MRI)

MRI produces cross-sectional images in any plane within the body and does not involve radiation. MRI is the most sensitive investigation of focal liver disease. Diffuse liver disease alters the T1 and T2 characteristics. Other fat-suppression modes such as STIR allow good differentiation between haemangiomas and other lesions. Contrast agents such as intravenous gadolinium, which allow further characterization of lesions, are suitable for those with iodine allergy, and provide angiography and venography of the splanchnic circulation. This has superseded direct arteriography.

Magnetic resonance cholangiopancreatography (MRCP)

This technique involves the manipulation of data acquired by MRI. A heavily T2-weighted sequence enhances visualization of the ‘water-filled’ bile ducts and pancreatic ducts to produce high-quality images of ductal anatomy. This non-invasive technique is replacing diagnostic (but not therapeutic) ERCP (see below), and is usually the next test if a biliary abnormality is present on US examination.

Plain X-rays of the abdomen

These are rarely requested but may show:

gallstones – 10% contain enough calcium to be seen

air in the biliary tree owing to its recent instrumentation, surgery or to a fistula between the intestine and the gall bladder

pancreatic calcification

rarely, calcification of the gall bladder (porcelain gall bladder).

Radionuclide imaging – scintiscanning

In a ^99mTc-IODIDA scan, technetium-labelled iododiethyl IDA is taken up by the hepatocytes and excreted rapidly into the biliary system. Its main uses are in the diagnosis of:

acute cholecystitis

jaundice due to either biliary atresia or hepatitis in the neonatal period.

Endoscopy

Upper GI endoscopy is used for diagnosis and treatment of varices, detection of portal hypertensive gastropathy, and for associated lesions such as peptic ulcers. Colonoscopy may show portal hypertensive colopathy. Capsule endoscopy can identify small intestinal varices.

Endoscopic retrograde cholangiopancreatography (ERCP)

This technique outlines the biliary and pancreatic ducts. It involves the passage of an endoscope into the second part of the duodenum and cannulation of the ampulla. Contrast is injected into both systems and the patient is screened radiologically. Contrast medium with a low iodine content of 1.5 mg/mL is used for the common bile duct so that gallstones are not obscured; a higher iodine content of 2.8 mg/mL is used for the pancreatic duct. Diagnostic ERCP has been replaced by MRCP in nearly all clinical settings. Therapeutic ERCP involves the following:

Common bile duct stones can be removed after performing a diathermy cut of the sphincter to facilitate their withdrawal. Sphincterotomy has a morbidity rate of 3–5%: acute pancreatitis is the commonest, severe haemorrhage is rare. There is an overall mortality of 0.4%.

The biliary system can be drained by passing a tube (stent) through an obstruction, or placement of a nasobiliary drain.

Brachytherapy can be administered after placement at ERCP for therapy of cholangiocarcinoma.

A raised serum amylase is often seen following ERCP and pancreatitis is the most common complication. Cholangitis with or without septicaemia is also seen, and broad-spectrum antibiotics (e.g. 500 mg ciprofloxacin × 2) should be given prophylactically to all patients with suspected biliary obstruction, or a history of cholangitis.

Percutaneous transhepatic cholangiography (PTC)

Under a local anaesthetic, a fine flexible needle is passed into the liver. Contrast is injected slowly until a biliary radicle is identified and then further contrast is injected to outline the whole of the biliary tree. In patients with dilated ducts, the success rate is near 100%. PTC is performed if ERCP fails or is likely to be technically difficult.

In difficult cases ERCP and PTC are sometimes combined, PTC showing the biliary anatomy above the obstruction, with ERCP showing the more distal anatomy. If an obstruction in the bile ducts is seen, a bypass stent can usually be inserted with or without temporary external biliary drainage. Contraindications of PTC are as for liver biopsy (see below). The main complications are bleeding and cholangitis with septicaemia, and prophylactic antibiotics should be given as for ERCP.

Angiography

This is performed by selective catheterization of the coeliac axis and hepatic artery. It outlines the hepatic vasculature and the abnormal vasculature of hepatic tumours, but spiral CT and magnetic resonance scanning have replaced diagnostic angiography. The portal vein can be demonstrated with increased definition using subtraction techniques replacing splenoportography (by direct splenic puncture).

In digital vascular imaging (DVI), contrast given intravenously or intra-arterially can be detected in the portal system using computerized subtraction analysis.

Hepatic venous cannulation allows abnormal hepatic veins to be diagnosed in patients with Budd–Chiari syndrome and is also used to measure portal pressure indirectly. There is a 1:1 relationship of occluded (by balloon) hepatic venous pressure, with portal pressure in patients with alcoholic or viral-related cirrhosis. The height of portal pressure has prognostic value for survival in cirrhosis, and a difference of the occluded minus the free hepatic venous pressure (hepatic venous pressure gradient HVPG) of 20% or more from baseline values or <12 mmHg, has been associated with protection from rebleeding, and prevention of other complications of cirrhosis.

Retrograde CO₂ portography is used when there is doubt about portal vein patency and can be combined with transjugular biopsy and hepatic venous pressure measurement.

Liver biopsy (Practical Box 7.1)

Histological examination of the liver is valuable in the differential diagnosis of diffuse or localized parenchymal disease. Liver biopsy can be performed on a day-case basis. The indications and contraindications are shown in Table 7.2. The mortality rate is less than 0.02% when performed by experienced operators.

Practical Box 7.1

Needle biopsy of the liver

This should be performed only by experienced doctors and with sterile precautions. Patient consent must be obtained following explanation of the procedure.

The patient’s coagulation status (prothrombin time, platelets) is checked.

The patient’s blood group is checked and serum saved for crossmatching.

The patient lies on their back at the edge of the couch.

Ultrasound examination can be used to confirm liver margins and position of the gall bladder. Alternatively, the liver margins are delineated using percussion.

Local anaesthetic is injected at the point of maximum dullness in the mid-axillary line through the intercostal space during expiration. Anaesthetic (1% lidocaine, approximately 5 mL) should be injected down to the liver capsule.

A tiny cut is made in the skin with a scalpel blade.

A special needle (Menghini, Trucut or Surecut) is used to obtain the liver biopsy while the patient holds his breath in expiration.

The biopsy is laid on filter paper and placed in 10% formalin. If a culture of the biopsy is required it should be placed in a sterile pot.

The patient should be observed, with pulse and blood pressure measurements taken regularly for at least 6 h.

Table 7.2 Indications and contraindications for liver biopsy

Liver biopsy guided by ultrasound or CT is performed when specific lesions need to be biopsied. Laparoscopy with guided liver biopsy is performed through a small incision in the abdominal wall under local anaesthesia (general anaesthesia is preferred in some centres). A transjugular approach is used when liver histology is essential for management but coagulation abnormalities or ascites prevent the percutaneous approach.

Most complications of liver biopsy occur within 24 h (usually in the first 2 h). They are often minor and include abdominal or shoulder pain which settles with analgesics. Minor intraperitoneal bleeding can occur, but this settles spontaneously. Rare complications include major intraperitoneal bleeding, haemothorax and pleurisy, biliary peritonitis, haemobilia and transient septicaemia. Haemobilia produces biliary colic, jaundice and melaena within 3 days of the biopsy.

Symptoms of liver disease

Signs of liver disease

Acute liver disease

There may be few signs apart from jaundice and an enlarged liver. Jaundice is a yellow coloration of the skin and mucous membranes and is best seen in the conjunctivae and sclerae. In the cholestatic phase of the illness, pale stools and dark urine are present. Spider naevi and palmar erythema usually indicate chronic disease but they can occur in severe acute disease.

Chronic liver disease

The physical signs are shown in Figure 7.9. However, the physical examination is sometimes normal in patients with advanced chronic liver disease.

Figure 7.9 Physical signs in chronic liver disease.

The skin

The chest and upper body may show spider naevi. These are telangiectases that consist of a central arteriole with radiating small vessels. They are found in the distribution of the superior vena cava (i.e. above the nipple line) – commonly more than five is taken as diagnostic. They are also found in pregnancy. In haemochromatosis the skin may have a slate-grey appearance.

The hands may show palmar erythema, which is a nonspecific change indicative of a hyperdynamic circulation; it is also seen in pregnancy, thyrotoxicosis or rheumatoid arthritis. Clubbing occasionally occurs, and a Dupuytren’s contracture is often seen in alcoholic cirrhosis.

Xanthomas (cholesterol deposits) are seen in the palmar creases or above the eyes in primary biliary cirrhosis.

The abdomen

Initial hepatomegaly will be followed by a small liver in well-established cirrhosis. Splenomegaly is seen with portal hypertension.

The endocrine system

Gynaecomastia (occasionally unilateral) and testicular atrophy may be found in males. The cause of gynaecomastia is complex, but it is probably related to altered oestrogen metabolism or to treatment with spironolactone.

In decompensated cirrhosis, additional signs that can be seen are shown in Figure 7.9.

Jaundice

Jaundice (icterus) is detectable clinically when the serum bilirubin is >50 µmol/L (3 mg/dL). It is useful to divide jaundice into:

Haemolytic jaundice – increased bilirubin load for the liver cells

Congenital hyperbilirubinaemias – defects in conjugation

Cholestatic jaundice, including hepatocellular (parenchymal) liver disease and large duct obstruction.

Haemolytic jaundice

The increased breakdown of red cells (see p. 375) leads to an increase in production of bilirubin. The resulting jaundice is usually mild (serum bilirubin of 68–102 µmol/L or 4–6 mg/dL) as normal liver function can easily handle the increased bilirubin derived from excess haemolysis. Unconjugated bilirubin is not water-soluble and therefore does not pass into urine; hence the term ‘acholuric jaundice’. Urinary urobilinogen is increased.

The causes of haemolytic jaundice are those of haemolytic anaemia (p. 375). The clinical features depend on the cause; anaemia, jaundice, splenomegaly, gallstones and leg ulcers may be seen.

Investigations show features of haemolysis (p. 375). The level of unconjugated bilirubin is raised but the serum ALP, transferases and albumin are normal. Serum haptoglobulins are low. The differential diagnosis is from other forms of jaundice.

Congenital hyperbilirubinaemias (non-haemolytic)

Unconjugated

Gilbert’s syndrome

This is the most common familial hyperbilirubinaemia and affects 2–7% of the population. It is asymptomatic and is usually detected as an incidental finding of a slightly raised bilirubin (17–102 µmol/L or 1–6 mg/dL) on a routine check. All the other liver biochemistry is normal and there are no signs of liver disease. There is a family history of jaundice in 5–15% of patients. Hepatic glucuronidation is approximately 30% of normal, resulting in an increased proportion of bilirubin monoglucuronide in bile. Most patients have reduced levels of UDP-glucuronosyl transferase (UGT-1) activity, the enzyme that conjugates bilirubin with glucuronic acid. Mutations occur in the gene (HUG-Br1) encoding this enzyme, with an expanded nucleotide repeat consisting of two extra bases in the upstream 5′ promoter element. This abnormality appears to be necessary for the syndrome, but is not in itself sufficient for the clinical manifestation (phenotypic expression).

Establishing this diagnosis is necessary to inform the patient that this is not a serious disease and to prevent unnecessary investigations. The raised unconjugated bilirubin is diagnostic and rises on fasting and during a mild illness. The reticulocyte count is normal, excluding haemolysis, and no treatment is necessary.

Crigler–Najjar syndrome

This is very rare. Only patients with type II (autosomal dominant) with a decrease rather than absence (type I – autosomal recessive) of UDP-glucuronosyl transferase can survive into adult life. Mutation of the HUG-Br1 gene for UDP-glucuronosyl transferase has been demonstrated in the coding region. Liver histology is normal. Transplantation is the only effective treatment.

Conjugated

Dubin–Johnson (autosomal recessive) and Rotor syndromes are due to defects in hepatic bilirubin handling. The prognosis is good in both. In the Dubin–Johnson syndrome there are mutations in both MRP2 (p. 305) transporter genes; the liver is black owing to melanin deposition.

Benign recurrent intrahepatic cholestasis

This is rare and presents in early adulthood. Recurrent attacks of acute cholestasis occur without progression to chronic liver disease. Jaundice, severe pruritus, steatorrhoea and weight loss develop. Serum γ-GT is normal. The gene has been mapped to the FIC1 locus, but the precise relation to cholestasis is unclear. It may be associated with intrahepatic cholestasis of pregnancy (p. 346).

Progressive familial intrahepatic cholestasis (PFIC) syndromes

This is a heterogeneous group of conditions defined by defective secretion of bile acids (see Figs 7.4 and 7.29). They are autosomal recessive. In type 1 (PFIC1), with cholestasis in the first weeks of life, the γ-GT is normal. The gene is on the familial intrahepatic cholestasis-1 gene (FIC1) locus, and has been mapped to a region encoding P type ATPases (ATP8BI) on chromosome 18q21. Type 2 (PFIC2) has been mapped to the bile salt export pump gene (BSEP, also called ABCB1). The protein is located in the canalicular domain of the hepatocyte plasma membrane. The phenotypic expression frequently is a nonspecific giant cell hepatitis progressing to cholestasis – in both types, the γ-GT is normal. Type 3 is due to a multidrug resistance protein 3-P-glycoprotein PGY3 (MDR-3) gene mutation (also called ABCB4 gene) leading to deficient canalicular phosphatidylcholine transport and thus toxic bile acids causing liver damage, which can lead to cirrhosis. Liver transplantation is the only cure for these syndromes.

FURTHER READING

Davit-Spraul A, Gonzales E, Baussan C et al. Progressive familial intrahepatic cholestatis. Orphanet J Rare Dis 2009; 4:1.

Cholestatic jaundice (acquired)

This can be divided into extrahepatic and intrahepatic cholestasis. The causes are shown in Figure 7.10.

Extrahepatic cholestasis is due to large duct obstruction of bile flow at any point in the biliary tract distal to the bile canaliculi.

Intrahepatic cholestasis occurs owing to failure of bile secretion. A number of cellular mechanisms in cholestasis have been described in animal models, including inhibition of the Na⁺/K⁺-ATPase in the basolateral membranes, decreased fluidity of the sinusoidal plasma membrane, disruption of the microfilaments responsible for canalicular tone, and damage to the tight junctions. In addition, inflammatory change in ductular cells interferes with bile flow.

Figure 7.10 Causes of jaundice.

Clinically in both types, there is jaundice with pale stools and dark urine, and the serum bilirubin is conjugated. However, intrahepatic and extrahepatic cholestatic jaundice must be differentiated as their clinical management is entirely different.

Differential diagnosis of jaundice

The history often gives a clue to the diagnosis. Certain causes of jaundice are more likely in particular categories of people. For example, a young person is more likely to have hepatitis, so questions should be asked about drug and alcohol use, and sexual behaviour. An elderly person with gross weight loss is more likely to have a carcinoma. All patients may complain of malaise. Abdominal pain occurs in patients with biliary obstruction by gallstones, and sometimes with an enlarged liver there is pain resulting from distension of the capsule.

Questions should be appropriate to the particular situation, and the following aspects of the history should be covered.

Country of origin. The incidence of hepatitis B virus (HBV) infection is increased in many parts of the world (p. 318).

Duration of illness. A history of jaundice with prolonged weight loss in an older patient suggests malignancy. A short history, particularly with a prodromal illness of malaise, suggests a hepatitis.

Recent outbreak of jaundice. An outbreak in the community suggests hepatitis A virus (HAV).

Recent consumption of shellfish. This suggests HAV infection.

Intravenous drug use, or recent injections or tattoos. These all increase the chance of HBV and hepatitis C virus (HCV) infection.

Men having sex with men. This increases the chance of HBV infection.

Female sex workers. This increases the chance of HBV infection.

Blood transfusion or infusion of pooled blood products. Increased risk of HBV and HCV. In developed countries all donors are screened for HBV and HCV.

Alcohol consumption. A history of drinking habits should be taken, although many patients often understate their consumption.

Drugs taken (particularly in the previous 2–3 months). Many drugs cause jaundice (see p. 348).

Travel. Certain areas have a high risk of HAV infection as well as hepatitis E (HEV) infection (this has a high mortality in pregnancy), but HAV is common in the UK.

A recent anaesthetic. Halothane (named patient basis only in UK) and occasionally isoflurane, and sevoflurane may cause jaundice, particularly in those already sensitive to halogenated anaesthetics. The risk with desflurane appears remote.

Family history. Patients with, for example, Gilbert’s disease may have family members who get recurrent jaundice.

Recent surgery on the biliary tract or for carcinoma.

Environment. People engaged in recreational activities in rural areas, as well as farm and sewage workers, are at risk for leptospirosis, hepatitis E and exposure to chemicals.

Fevers or rigors. These are suggestive of cholangitis or possibly a liver abscess.

Clinical features

The signs of acute and chronic liver disease should be looked for (p. 312). Certain additional signs may be helpful:

Hepatomegaly. A smooth tender liver is seen in hepatitis and with extrahepatic obstruction, but a knobbly irregular liver suggests metastases. Causes of hepatomegaly are shown in Table 7.3.

Splenomegaly. This indicates portal hypertension in patients when signs of chronic liver disease are present. The spleen can also be ‘tipped’ occasionally in viral hepatitis.

Ascites. This is found in cirrhosis but can also be due to carcinoma (particularly ovarian) and many other causes (see Table 7.14).

Table 7.3 Causes of hepatomegaly

A palpable gall bladder occurs with a carcinoma of the pancreas obstructing the bile duct. Generalized lymphadenopathy suggests a lymphoma.

Cold sores are seen with a herpes simplex virus hepatitis.

Investigations

Jaundice is not itself a diagnosis and the cause should always be sought. The two most useful tests are the viral markers for HAV, HBV and HCV (in high-risk groups), with an ultrasound examination. Liver biochemistry confirms the jaundice and may help in the diagnosis.

An ultrasound examination should always be performed to exclude an extrahepatic obstruction, and to diagnose any features compatible with chronic liver disease except when hepatitis A is strongly suspected in a young patient. Ultrasound will demonstrate:

the size of the bile ducts, which are dilated in extrahepatic obstruction (Fig. 7.11)

the level of the obstruction

the cause of the obstruction in virtually all patients with tumours and in 75% of patients with gallstones.

Figure 7.11 Liver ultrasound showing (a) dilated intrahepatic bile ducts (arrow), (b) common bile duct (arrow). The normal bile duct measures 6 mm at the porta hepatis.

The pathological diagnosis of any mass lesion can be made by fine-needle aspiration cytology (sensitivity approximately 60%) or by needle biopsy using a spring-loaded device (sensitivity approximately 90%).

A flow diagram for the general investigation of the jaundiced patient is shown in Figure 7.12.

Figure 7.12 Approach to patient with jaundice. CBD, common bile duct; US, ultrasound; MRCP, magnetic resonance cholangiopancreatography. *Proceed as in bottom left box (Re-check drug history …)

Liver biochemistry

In hepatitis, serum AST and ALT tend to be high early in the disease with only a small rise in serum ALP. Conversely, in extrahepatic obstruction the ALP is high with a smaller rise in aminotransferases. However, these findings cannot be relied upon alone to make a diagnosis in an individual case. The prothrombin time (PT) is often prolonged in longstanding liver disease, and the serum albumin is also low.

Haematological tests

In haemolytic jaundice the bilirubin is raised and the other liver biochemistry is normal. A raised white cell count may indicate infection (e.g. cholangitis). A leucopenia often occurs in viral hepatitis, while abnormal mononuclear cells suggest infectious mononucleosis and a Monospot test should be performed.

Other blood tests

These include tests to confirm the presence of specific causes of acute or chronic liver disease, e.g. antimitochondrial antibody (AMA) for PBC. HIV status should be established.

Hepatitis

Acute parenchymal liver damage can be caused by many agents (Fig. 7.13).

Figure 7.13 Some causes of acute parenchymal damage.

Chronic hepatitis is defined as any hepatitis lasting for 6 months or longer and is classified according to the aetiology (Table 7.4). Chronic viral hepatitis is the principal cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide.

Table 7.4 Causes of chronic hepatitis

Acute hepatitis

Pathology

Although some histological features are suggestive of the aetiological factor, most changes are similar whatever the cause. Hepatocytes show degenerative changes (swelling, cytoplasmic granularity, vacuolation), undergo necrosis (becoming shrunken, containing eosinophilic Councilman bodies) and are rapidly removed. The distribution of these changes may vary with aetiology, but necrosis is usually maximal in zone 3. The extent of the damage is very variable between individuals even when affected by the same agent: at one end of the spectrum, single and small groups of hepatocytes die (spotty or focal necrosis), while at the other end there is multiacinar necrosis involving a substantial part of the liver (massive hepatic necrosis) resulting in fulminant hepatic failure. Between these extremes there is limited confluent necrosis with collapse of the reticulin framework resulting in linking (bridging) between the central veins, the central veins and portal tracts, and between the portal tracts. The extent of the inflammatory infiltrate is also variable, but portal tracts and lobules are infiltrated mainly by lymphocytes. Other variable features include cholestasis in zone 3 and fatty change, the latter being prominent in hepatitis that is due to alcohol or certain drugs.

Chronic hepatitis

Pathology

Chronic inflammatory cell infiltrates comprising lymphocytes, plasma cells and sometimes lymphoid follicles are usually present in the portal tracts. The amount of inflammation varies from mild to severe. In addition, there may be:

loss of definition of the portal/periportal limiting plate – interface hepatitis (damage is due to apoptosis rather than necrosis)

lobular change, focal lytic necrosis, apoptosis and focal inflammation

confluent necrosis

fibrosis which may be mild, bridging (across portal tracts) or severe cirrhosis.

The overall severity of the hepatitis is judged by the degree of the hepatitis and inflammation (grading) and the severity of the fibrosis or cirrhosis (staging). In chronic viral hepatitis there are various scoring systems. For example, the Knodell Scoring System (histological activity index) uses the sum of four factors (periportal or bridging necrosis, intralobular degeneration and focal necrosis, portal inflammation and fibrosis). The Ishak score stages fibrosis from 0 (none) to 6 (cirrhosis). The METAVIR system has four stages. Scoring systems are used for drug trials and for assessing progression of disease, but are descriptions of architectural changes and not quantitative measures of fibrosis.

Viral hepatitis

The differing features of the common forms of viral hepatitis are summarized in Table 7.5.

Table 7.5 Some features of viral hepatitis

Hepatitis A

Epidemiology

Hepatitis A is the most common viral hepatitis occurring worldwide, often in epidemics. The disease is commonly seen in the autumn and affects children and young adults. Spread of infection is mainly by the faeco-oral route and arises from the ingestion of contaminated food or water (e.g. shellfish). Overcrowding and poor sanitation facilitate spread. There is no carrier state. In the UK it is a notifiable disease.

Hepatitis A virus (HAV)

HAV is a picornavirus, having the structure shown in Figure 7.14. It has a single serotype as only one epitope is immuno-dominant. It replicates in the liver, is excreted in bile and then excreted in the faeces for about 2 weeks before the onset of clinical illness and for up to 7 days after. The disease is maximally infectious just before the onset of jaundice. HAV particles can be demonstrated in the faeces by electron microscopy.

Figure 7.14 (a) The hepatitis A (HAV) virion consists of four polypeptides (VP1–VP4) which form a tight protein shell, or capsid, containing the RNA. The major antigenic component is associated with VP1. (b) Arrangement of HAV genome.