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Therapeutics 133
Side effects
Constipation, abdominal cramps, dizziness.
Cautions/contraindications
Active ulcerative colitis or infective diarrhoea associated with bloody stools.
Nausea and vomiting
Antiemetics should be prescribed only when the cause of vomiting is known
(e.g. drugs, particularly cytotoxic chemotherapy, post-operative, motion sickness, pregnancy and migraine) because otherwise they may delay diagnosis.
If antiemetic drug treatment is indicated, the drug is chosen according to the
aetiology of vomiting. Dexamethasone has antiemetic effects and is used in
vomiting associated with cancer chemotherapy. It has additive effects when
given with high-dose metoclopramide or with a 5-HT3-receptor antagonist
such as ondansetron. The mechanism of action of dexamethasone as an
antiemetic is unknown but may involve reduction of prostaglandin synthesis.
Antihistamines
Indications
Motion sickness, drug-induced vomiting, vestibular disorders, such as vertigo
and tinnitus.
Mechanism of action
Competitive antagonist at the histamine H1 receptor (e.g. cyclizine, promethazine).
Side effects
Drowsiness, antimuscarinic effects (urinary retention, dry mouth, blurred
vision), palpitations, arrhythmias and rashes.
Cautions/contraindications
Caution in prostatic hypertrophy, urinary retention, glaucoma and pyloroduodenal obstruction (due to antimuscarinic effects).
Phenothiazines
Mechanism of action
Phenothiazines (e.g. prochlorperazine) act centrally by blocking the chemoreceptor trigger zone (CTZ) in the fourth ventricle. Many drugs produce vomiting
by an action on the CTZ.
Indications
Phenothiazines are used for the prophylaxis and treatment of nausea and
vomiting associated with diffuse neoplastic disease, radiation sickness
and vomiting caused by drugs such as general anaesthetics, opioids and
134 Gastroenterology and nutrition
cytotoxics. Chlorpromazine is associated with more sedation and is usually
reserved for nausea and vomiting of terminal illness.
Side effects
As for other antipsychotic agents.
Domperidone and metoclopramide
Mechanism of action
Block dopamine receptors and inhibit dopaminergic stimulation of the CTZ.
Indications
Domperidone is used particularly in post-operative nausea and vomiting and
also gastro-oesophageal reflux disease and dyspepsia. Metoclopramide is particularly used in nausea and vomiting associated with cytotoxics or radiotherapy.
Side effects
Central nervous system effects are produced by metoclopramide and
to a lesser extent by domperidone (due to limited passage across the
blood–brain barrier). Extrapyramidal effects include acute dystonias,
akathisia and a parkinsonism-like syndrome. Drowsiness with high doses
of metoclopramide. Galactorrhoea is caused by hyperprolactinaemia as a
result of dopamine receptor blockade.
Cautions/contraindications
Contraindicated in gastrointestinal obstruction, 3–4 days after gastrointestinal
surgery where increased motility may be harmful, and phaeochromocytoma.
5-HT3-receptor antagonists
Mechanism of action
5-HT3-receptor antagonists (e.g. ondansetron) block the 5-HT3-receptors in
the CTZ and in the gut.
Indications
Particularly effective against vomiting induced by highly emetogenic chemotherapeutic agents and radiotherapy used for treating malignancy and
post-operative vomiting that is resistant to other agents.
Side effects
Headache, constipation, hypersensitivity reactions. Following i.v. administration: seizures, chest pain, arrhythmias, hypotension and bradycardia.
Cautions/contraindications
Caution with prolonged QT interval and cardiac conduction disorders.
Liver, biliary tract
4
Liver disease is common throughout the world. In the developed world, it
is most often due to non-alcoholic fatty liver disease (NAFLD) and alcohol
excess, while in the developing world, chronic viral hepatitis B or hepatitis C
are the leading causes of liver mortality. Cirrhosis represents the final common pathway for liver disease and is characterized by progressive fibrosis of
the liver parenchyma leading to portal hypertension and deterioration of liver
function. In decompensated cirrhosis, the median overall survival is 2 years,
which is a far worse prognosis than for many cancers.
The liver is the main site for metabolism of most drugs and alcohol. Other
major functions include:
• Control of synthesis and metabolism of protein. All circulating proteins
except γ-globulins (made by lymphocytes) are synthesized in the liver.
These include albumin (maintains intravascular oncotic pressure and
transports water-insoluble substances, e.g. bilirubin and some drugs
in plasma), transport and carrier proteins (e.g. transferrin), components
of the complement system and all factors involved in coagulation. The
liver eliminates nitrogenous waste by degradation of amino acids and
conversion to urea for renal excretion.
• Maintenance of blood sugar. The liver releases glucose into the blood
in the fasting state, either by breakdown of stored glycogen or by
synthesizing glucose from amino acids (from muscle) or glycerol (from
adipose tissue).
• Lipid metabolism. Most of the body’s cholesterol is manufactured in
the liver but the remainder comes from food. Cholesterol is used to
make bile salts and certain hormones, including oestrogen, testosterone
and the adrenal hormones. The liver also synthesizes lipoproteins and
triglycerides (most are of dietary origin).
• Metabolism and excretion of bilirubin and bile acids. Bile acids are
formed from cholesterol, excreted into bile and pass into the duodenum
via the common bile duct (CBD), where they solubilize lipid for digestion
and absorption. Bilirubin is formed from the breakdown of mature red
cells and eventually excreted in urine and faeces.
andpancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
A routine blood sample for liver biochemistry will be processed by an
automated multichannel analyser to produce serum levels of bilirubin, aminotransferases, alkaline phosphatase, γ-glutamyl transpeptidase (γ-GT) and
136 Liver, biliary tract andpancreatic disease
total proteins. These tests are often referred to as ‘liver function tests’ (LFTs)
which is misleading as they do not accurately reflect the liver’s function.
They are best referred to as ‘liver blood tests’ or ‘liver biochemistry’. Liver
synthetic function is determined by measuring the prothrombin time (clotting
factors are synthesized in the liver) and serum albumin, which are increased
and reduced, respectively, with impaired function. Hypoalbuminaemia is
also found in hypercatabolic states (e.g. chronic inflammatory disease and
sepsis) and where there is excessive renal (nephrotic syndrome) or intestinal
(protein-losing enteropathy) albumin loss. A prolonged prothrombin time
may also occur as a result of vitamin K deficiency in biliary obstruction (low
concentration of intestinal bile salts results in poor absorption of vitamin K);
however, unlike in liver disease, clotting will be corrected by administering
10 mg vitamin K intravenously (i.v.) for 2–3 days.
• Bilirubin (normal range <17 μmol/L, 1.00 mg/dL) is the breakdown
product of haemoglobin (see p. 141). Serum bilirubin is normally almost
all unconjugated. In liver disease, an increase is usually accompanied
by other liver biochemistry abnormalities. Differentiation between
conjugated and unconjugated bilirubin is only necessary in congenital
disorders of bilirubin metabolism (e.g. Gilbert’s disease) or to exclude
haemolysis.
• Aminotransferases. These enzymes (referred to as transaminases) are
contained in hepatocytes and leak into the blood following liver cell
damage. Two are assayed:
• Aspartate aminotransferase (AST) is primarily a mitochondrial enzyme
and is also present in the 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 cytosolic enzyme, more specific to
the liver so that a rise only occurs with liver disease.
The ALT/AST ratio is a useful clinical indicator. In viral hepatitis,
ALT > AST unless cirrhosis is present, when AST > ALT. In alcoholic
liver disease and steatohepatitis the AST is often greater than the ALT.
Thus in patients with viral hepatitis, an AST/ALT ratio >1 indicates
cirrhosis, and in patients without cirrhosis in whom AST > ALT, alcohol
or obesity should be considered the most likely cause.
• Alkaline phosphatase (ALP). This is present in hepatic canalicular and
sinusoidal membranes, bone, intestine and placenta. The origin can be
determined by electrophoretic separation of isoenzymes or bone-specific
monoclonal antibodies. However, if the γ-GT is also abnormal, the ALP is
presumed to come from 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 level.
Raised levels also occur, usually without jaundice, with hepatic infiltrations
(e.g. metastasis) and cirrhosis. The highest serum levels (>1000 IU/L)
occur with hepatic metastasis and primary biliary cirrhosis.
Liver Biochemistry and Liver Function Tests 137
• γ-Glutamyl transpeptidase. This is a microsomal enzyme present in liver
and many other tissues. Activity can be induced by alcohol and drugs
such as phenytoin and warfarin. Mild elevation of γ-GT is common, even
with minimal alcohol consumption, but it is raised in fatty liver disease.
In the absence of other liver function test abnormalities, a slightly raised
γ-GT can safely be ignored.
• Total proteins and globulin fraction. The globulin fraction is often raised in
autoimmune hepatitis and a fall indicates successful therapy.
Additional blood investigations
• Haematological:
• Thrombocytopenia is a common finding in cirrhosis, often aggravated
by alcohol. A low platelet count should be regarded as indicative of
cirrhosis unless another cause can be found.
• Excessive use of alcohol causes red blood cell macrocytosis.
• Biochemical:
• α1-Antitrypsin enzyme deficiency can produce cirrhosis.
• α-Fetoprotein is normally produced by the fetal liver. Its reappearance
in increasing and high concentrations in adults indicates
hepatocellular carcinoma.
• Urinary copper is raised, and serum copper and caeruloplasmin are
low in Wilson’s disease
• Viral markers:
• Viruses are a major cause of liver disease. Virological studies have a
key role in diagnosis.
• Serum autoantibodies:
• Antimitochondrial antibody (AMA) in serum is found in over 95% of
patients with primary biliary cholangitis (PBC). Several different AMA
subtypes are described, depending on their antigen specificity, and are
also found in autoimmune hepatitis and other autoimmune diseases.
• Nucleic, smooth muscle (actin) and liver/kidney microsomal antibodies
can be found in serum, often in high titre, in patients with autoimmune
hepatitis. These serum antibodies are also present in other
autoimmune conditions and other liver diseases.
• Antinuclear cytoplasmic antibodies (ANCA) can be found in the serum
of patients with primary sclerosing cholangitis.
• Genetic analysis:
• Genetic 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.
Approach to interpretation of abnormal
liverbiochemistry
A predominant elevation of serum aminotransferases indicates hepatocellular injury. Elevation of serum bilirubin and alkaline phosphatase in
138 Liver, biliary tract andpancreatic disease
excess of aminotransferases indicates a cholestatic disorder such as
primary biliary cirrhosis, primary sclerosing cholangitis or extrahepatic
bile duct obstruction. An isolated rise in bilirubin is most likely due to
Gilbert’s disease. The approach to investigating elevated serum bilirubin
is discussed under ‘Jaundice’. A careful history (alcohol consumption,
exposure to hepatotoxic drugs, risk factors for chronic liver disease),
physical examination (particularly features of chronic liver disease), simple
laboratory tests (viral hepatitis, metabolic and autoimmune liver disease,
Table4.1) and an ultrasound (US) examination of the liver are the first steps
for patients with a persistent elevation of serum aminotransferases. A liver
biopsy may subsequently be necessary.
OTHER INVESTIGATIONS IN LIVER AND BILIARY DISEASE
Imaging with abdominal US and computed tomography (CT) is widely used
in the investigation of liver and biliary disease. US is usually performed first
and is a more useful test for lesions in the gall bladder and bile duct. Colour
Doppler ultrasound will demonstrate vascularity within a lesion and the direction of portal and hepatic vein blood flow.
Hepatic stiffness (transient elastography). Using a US transducer, a
vibration of low frequency and amplitude is passed through the liver, the
velocity of which correlates with hepatic stiffness. Stiffness (kPa) increases
with worsening liver fibrosis (sensitivity and specificity 80%–95% compared
to liver biopsy). It cannot be used in the presence of ascites and morbid
obesity, and it is affected by inflammatory tissue and congestion.
Endoscopic ultrasound (EUS). A small high-frequency ultrasound probe
is incorporated into the tip of an endoscope and placed by direct vision into
the gut lumen. The close proximity of the probe to the pancreas and biliary
tree permits high-resolution ultrasound imaging, which enables pancreatic
tumour staging. Needle aspiration provides cytological/histological tissue
and may also be used to drain pancreatic and peripancreatic fluid collections.
Computed tomography (CT) examination. During or immediately
following i.v. contrast injection, both arterial and portal venous phases are
enhanced, enabling precise characterization of a lesion and its vascular supply.
Magnetic resonance imaging (MRI). This imaging modality produces
cross-sectional images without radiation. It is the most sensitive investigation
of focal liver disease.
Magnetic resonance cholangiopancreatography (MRCP). MRCP
involves manipulation of data acquired by MRI to visualize the ‘water-filled’
bile and pancreatic ducts. This non-invasive technique has replaced diagnostic
(but not therapeutic) endoscopic retrograde cholangiopancreatography (ERCP).
Upper gastrointestinal (GI) endoscopy. This is used for diagnosis
and treatment of varices, detection of portal hypertensive gastropathy and
associated lesions such as peptic ulcers.
Other Investigations in Liver and Biliary Disease 139
Table 4.1 Causes of chronic liver disease and cirrhosis
Cause Non-invasive markers of aetiology
Common
Alcohol History of excess alcohol, ↑ serum γ-GT, ↑
Hepatitis B ± D HBsAg ± HBeAg/DNA in serum
Hepatitis C HCV antibodies and HCV RNA in serum
Others
Primary biliary cholangitis Serum antimitochondrial antibodies, ↑ serum
Secondary biliary cirrhosis Dilated extrahepatic ducts on imaging
Autoimmune hepatitis Serum autoantibodies, ↑ serum IgG
Haemochromatosis Family history, ↑ serum ferritin, ↑ transferrin
Budd–Chiari syndrome Presence of known risk factors, caudate lobe
Wilson’s disease <40 years old, ↓ serum caeruloplasmin, ↓
Drugs Drug history, e.g. methotrexate
α1-Antitrypsin (AAT)
deficiency
Cystic fibrosis (CF) Presence of extrahepatic manifestations of CF
NAFLD Features of the metabolic syndrome,
Sclerosing cholangitis:
primary (PSC) and
secondary
Metabolic storage diseases Presence of extrahepatic features
Idiopathic (cryptogenic) Absence of any identifiable cause including on
AA T, α1-antitrypsin; CF, cystic fibrosis; ERCP, endoscopic retrograde
cholangiopancreatography; γ-GT, γ-glutamyl transpeptidase; HBeAg, hepatitis B e
antigen;HBsAg, hepatitis B surface antigen; IBD, inflammatory bowel disease; IgG,
immunoglobulin G; IgM, immunoglobulin M; HCV, hepatitis C virus; MCV, mean
corpuscularvolume; MRCP, magnetic resonance cholangiopancreatography; NAFLD,
non-alcoholic fatty liver disease; pANCA, peripheral antineutrophilic cytoplasmic antibody;
PSC, primary sclerosing cholangitis; US, ultrasound.
MCV
IgM
saturation, HFE gene
hypertrophy, abnormal flow in major hepatic
veins on US
serum total copper, ↑ 24-h urinary copper
excretion, Kayser–Fleischer rings
Young age, associated emphysema, ↓ serum
AAT
hyperechoic liver on US
Most PSC patients have IBD and serum
p-ANCA multifocal stricturing and dilatation
ofbile ducts on cholangiography (either MRCP
or ERCP)
liver biopsy
140 Liver, biliary tract andpancreatic disease
Endoscopic retrograde cholangiopancreatography (ERCP). This
procedure 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. Therapeutic ERCP is used to remove common bile duct stones
or drain the biliary system by passing a tube (stent) through an obstruction.
Pancreatitis is the most common complication following ERCP but cholangitis
is also seen. Broad-spectrum antibiotics should be given prophylactically to
patients with suspected biliary obstruction or history of cholangitis.
Percutaneous transhepatic cholangiography (PTC). Under local
anaesthesia, a fine flexible needle is passed into the liver and contrast
injected slowly to outline the whole of the biliary tree. PTC is performed
if ERCP fails or is likely to be technically difficult. In difficult cases, ERCP
and PTC may be combined, PTC showing the biliary anatomy above the
obstruction and ERCP the more distal anatomy. The main complications are
bleeding and cholangitis with septicaemia. Prophylactic antibiotics should
be administered.
Liver biopsy. Liver biopsy is almost always performed as a day case under
US guidance. Histological examination of the liver is valuable in the differential
diagnosis of diffuse or localized parenchymal disease. Contraindications
include a prolonged prothrombin time (by 3–5 seconds), platelet count
<50 × 109/L, extrahepatic cholestasis and suspected haemangioma or an
uncooperative patient. The mortality rate is less than 0.02% when performed
by experienced operators. A transjugular approach is used when liver histology
is essential for management but coagulation abnormalities or ascites prevent
a percutaneous approach. Assessment of liver fibrosis and cirrhosis is made
by histopathological examination of a liver biopsy specimen. Disadvantages of
liver biopsy are sampling error and its invasive nature. Most complications of
liver biopsy occur within 24 hours (usually in the first 2 hours). Complications
include biliary peritonitis and bleeding into the peritoneum or into the bile duct
(haemobilia).
Markers of liver fibrosis. An accurate assessment of fibrosis is critical
for appropriate management of many liver disorders. A variety of different
systems have been developed to assess the extent of liver fibrosis. These range
from simple algorithms using standard haematological and biochemical tests
(e.g. AST to platelet ratio index score) to measurements of liver function
analysed with commercial algorithms (FibroTest) or measurements of matrix
metalloproteins (enhanced liver fibrosis test). In general, these markers have
been developed for chronic hepatitis C but may be applied to other liver disorders.
The current assays have a high sensitivity/specificity for the detection of cirrhosis
but are less effective at detecting intermediate levels of fibrosis. Combining
mechanical, non-invasive tests for fibrosis, such as transient elastography and
fibrosis markers, enables assessment of fibrosis without liver biopsy. Imaging
(US, CT and MRI) will detect advanced liver disease such as nodularity and portal
hypertension but will not assess the earlier stages of fibrosis.
Jaundice 141
SYMPTOMS AND SIGNS OF LIVER DISEASE
Acute liver disease, such as viral hepatitis, may be asymptomatic or present
with generalized symptoms of lethargy, anorexia and malaise in the early
stages with jaundice developing later. Chronic liver disease may also be
asymptomatic, only discovered by an incidental finding of abnormal liver
biochemistry. Some patients with chronic liver disease may present at a late
stage with complications of cirrhosis such as:
• Ascites with abdominal swelling and discomfort
• Haematemesis and melaena due to bleeding oesophageal varices
• Confusion and drowsiness due to hepatic encephalopathy.
Patients presenting this way are often extremely unwell and a detailed
history may not be possible. However, physical examination will often reveal
the signs of chronic liver disease (Fig. 4.1). Pruritus (itching) occurs in
cholestatic jaundice from any cause but is particularly common in primary
biliary cirrhosis when it may be the only symptom at presentation. Pruritus
may occur in association with other systemic and skin diseases.
JAUNDICE
Jaundice (icterus) describes the yellow discoloration of the sclerae and skin
that occurs as a result of a raised serum bilirubin. It is usually detectable
clinically when the bilirubin exceeds 50 μmol/L (3 mg/dL).
Bilirubin is derived predominantly from the breakdown of haemoglobin
in the spleen and is carried in the blood bound to albumin. Unconjugated
bilirubin is conjugated in the liver by glucuronyl transferase to bilirubin
glucuronide, which is then excreted in bile via the bile duct into the
small intestine. In the terminal ileum, conjugated bilirubin is converted
to urobilinogen and excreted in the faeces (as stercobilinogen, which is
responsible for the brown pigmentation of faeces) or reabsorbed and
excreted by the kidneys (Fig. 4.2).
For clinical and diagnostic purposes, three major categories of jaundice
can be considered:
• Haemolytic jaundice
• Congenital hyperbilirubinaemias: impaired conjugation of bilirubin
or bilirubin handling by the liver. Other than raised bilirubin, liver
biochemistry is normal.
• Cholestatic jaundice: failure of bile secretion by the liver or bile duct
obstruction. Liver biochemistry is abnormal.
Haemolytic jaundice
Increased breakdown of red blood cells leads to increased production of bilirubin, which usually results in mild jaundice (68–102 μmol/L or 4–6 mg/dL),
as the liver can usually handle the levels of increased bilirubin derived
142 Liver, biliary tract andpancreatic disease
Compensated
Decompensated
Spider naevi,
small vessels found in the distribution of superior vena cava;
erythema), reddening of palms at the thenar and hypothenar eminences is a
non-specific change indicative of a hyperdynamic circulation;
a distinctive must
General
Jaundice
Fever
Loss of body hair
Xanthelasmas
Parotid enlargement
Spider naevi
Gynaecomastia
Neurological, i.e.
Disorientation
Drowsy → coma
Hepatic flap
Fetor hepaticus
Liver (small or large)
Splenomegaly
Ascites
Liver palms
Clubbing
Dilated veins on
abdomen
Dupuytren’s
contracture
Xanthomas
Scratch marks
Testicular atrophy
Purpura
Oedema
Pigmented ulcers
telangiectases that consist of a central arteriole with radiating
y, sweet breath odour in severe liver disease.
Fig. 4.1 Physical signs in chronic liver disease.
liver palms (palmar
fetor hepaticus,
from haemolysis. Unlike the conjugated hyperbilirubinaemia of cholestatic
jaundice, unconjugated bilirubin is not water soluble and therefore does not
pass into the urine. Urinary urobilinogen is increased. Causes include haemolytic anaemia, e.g. sickle cell disease. Investigations demonstrate features
of haemolysis, with raised serum unconjugated bilirubin and an otherwise
normal liver biochemistry.