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Types of Chronic Liver Disease and Cirrhosis 173
Management
Treatment is with lifelong ursodeoxycholic acid (10–15 mg/kg daily by
mouth), a naturally occurring dihydroxy bile acid. It slows disease progression and reduces the need for liver transplantation. The mechanism of action
is incompletely understood. It should be given early in the asymptomatic
phase. Pruritus may be helped by colestyramine and malabsorption of fatsoluble vitamins (A, D and K) is treated by supplementation. Bisphosphonates
should be administered for osteoporosis. Liver transplantation is indicated in
patients with advanced disease (serum bilirubin persistently >100 μmol/L).
Prognosis
Asymptomatic patients may show a near-normal life expectancy. In symptomatic patients with jaundice, there is a steady downhill course with death
in approximately 5 years without transplantation.
Secondary biliary cirrhosis
Cirrhosis can result from months of prolonged large duct biliary obstruction.
Causes include bile duct strictures, CBD stones and sclerosing cholangitis. US
examination followed by MRCP is performed to outline the ducts. ERCP may
then be necessary to treat the cause, e.g. stone removal.
Hereditary haemochromatosis
Hereditary haemochromatosis (HH) is an autosomal recessive disorder which
is prevalent among Caucasians. It affects 1 in 400 in the population, of which
approximately 10% are gene carriers. There is excessive iron deposition in
various organs eventually leading to fibrosis and functional organ failure.
Aetiology
HH is characterized by an abnormal increase in iron absorption from the upper
small intestine. In most cases, HH is due to a mutation in the gene HFE on the
short arm of chromosome 6. The normal HFE protein is expressed in the small
intestine and plays a role in the regulation of iron absorption. Two missense
mutations of the HFE gene account for most cases of HH. This involves a
change of cysteine at position 282 for tyrosine (C282Y mutation) or a change
of histidine at position 63 to aspartate (H63D mutation). Human leucocyte
antigen (HLA)-A3, -B7 and -B14 occur with increased frequency in patients
with HH compared with the general population. In a minority of patients, iron
overload is due to defects in other proteins involved in iron metabolism.
Clinical features
Most patients are diagnosed when elevated serum iron or ferritin levels are
noted on routine biochemistry or screening is performed because a relative
174 Liver, biliary tract andpancreatic disease
Table 4.11 Clinical presentation of haemochromatosis
Health screening (often symptomatic)
Abnormal liver biochemistry
Abnormal iron studies
Familial and/or population screening
Symptomatic disease due to iron deposition in:
Liver: hepatomegaly, lethargy
Pancreas: diabetes mellitus
Myocardium: cardiomegaly, heart failure, conduction disturbances
Pituitary and gonads: loss of libido, impotence
Joints: arthralgia
Skin: hyperpigmentation
is diagnosed with HH. Presentation may also be with symptoms and signs of
iron loading in parenchymal organs (Table 4.11). There is a reduced incidence
of overt disease in women because of extra iron losses associated with menstruation and a smaller dietary intake of iron.
Investigations
• Serum liver biochemistry is often normal, even with cirrhosis.
• Serum iron is elevated and total iron-binding capacity (TIBC) reduced.
Transferrin saturation (serum iron/TIBC) is >45% (normal <33%).
• Serum ferritin reflects iron stores and is usually greatly elevated (often
>500 μg/L).
• Genotyping (by PCR reaction using whole blood samples) for mutation
analysis of the HFE gene is performed in patients with elevated ferritin
and transferrin saturation.
• Patients with abnormal iron studies and mutations of the HFE gene are
treated by phlebotomy without the need for liver biopsy. Assessment of
the degree of fibrosis is performed by non-invasive tests or liver biopsy in
patients who are predicted to have significant hepatic injury (abnormal liver
biochemistry or serum ferritin > 1000 μg/L). Liver biopsy and measurement
of hepatic iron content are performed if the diagnosis is in doubt.
Causes of secondary iron overload, such as multiple transfusions, must
be excluded. In addition, in alcoholic liver disease, hepatic iron stores may
increase. The precise reason is unknown but the hepatic iron concentration
does not reach the very high levels seen in haemochromatosis.
Management
The mainstay of treatment is venesection to remove excess iron. Up to
500 mL of blood (containing 250 mg of iron) is removed twice-weekly until
Types of Chronic Liver Disease and Cirrhosis 175
iron stores are normalized (as assessed by serum ferritin and transferrin
saturation). This may need to be continued for up to 2 years, and then three
or four venesections per year are required lifelong to prevent reaccumulation
of iron. Surveillance for HCC is performed in patients with cirrhosis.
Genotyping to detect HFE mutations and iron studies should be performed
on first-degree relatives of affected individuals.
Prognosis
The major complication is the development of HCC in patients with cirrhosis.
This can be prevented by venesection before cirrhosis develops. Life expectancy will then be the same as for the normal population.
Wilson’s disease (hepatolenticular degeneration)
This is a rare, recessively inherited disorder. Mutations in the ATP7B gene
on chromosome 13 result in decreased secretion of copper into the biliary
system and reduced incorporation of copper into procaeruloplasmin, the
precursor of caeruloplasmin. Copper accumulates in the liver (leading to fulminant hepatic failure and cirrhosis), basal ganglia of the brain (parkinsonism
and eventually dementia), cornea (greenish-brown rings called Kayser–
Fleischer rings) and renal tubules. Diagnosis is made by demonstrating low
total serum copper and caeruloplasmin, increased 24-hour urinary copper
excretion and increased copper in a liver biopsy specimen. Treatment is
with penicillamine or trientene (to chelate copper) or zinc (reduces copper
absorption). Liver transplantation is offered to those with end-stage liver
disease or fulminant hepatic failure. First-degree relatives are screened and
homozygotes should be treated.
α1-Antitrypsin deficiency
This is a rare cause of cirrhosis. Mutations in the α1-antitrypsin (α1-AT)
gene on chromosome 14 lead to reduced hepatic production of α1-AT,
which normally inhibits the proteolytic enzyme neutrophil elastase. The
genetic variants of α1-AT are characterized by their electrophoretic
mobilities as medium (M), slow (S) or very slow (Z). The normal genotype is
PiMM. Most patients with clinical disease are homozygote for Z (PiZZ) and
develop chronic liver disease (due to accumulation of the abnormal protein within the liver) and early-onset emphysema due to proteolytic lung
damage. Diagnosis is made by demonstrating low serum levels of serum
α1-AT and confirmed by genotype assessment. On liver histology, α1-AT-
containing globules are seen in hepatocytes. Treatment is for chronic lung
and liver disease. Intravenous augmentation therapy with plasma-derived
α1-AT is used but this not widely available. Patients should be advised to
stop smoking.
176 Liver, biliary tract andpancreatic disease
Alcohol and the liver
Alcohol is the most common cause of chronic liver disease in the Western
world. Alcoholic liver disease occurs more commonly in men, usually in the
fourth and fifth decades, although patients can present in their 20 s with
advanced disease. Although alcohol acts as a hepatotoxin, the exact mechanism leading to hepatitis and cirrhosis is unknown. As only 10%–20% of
persons who drink excessively develop cirrhosis, genetic predisposition and
immunological mechanisms have been suggested.
There are three major pathological lesions and clinical illnesses associated
with excessive alcohol intake.
Fatty change
This is the most common biopsy finding in alcoholic individuals. Regular alcohol use, even for a few weeks, can result in fatty liver (steatosis), a disorder in
which hepatocytes contain macrovesicular droplets of triglycerides. Symptoms
are usually absent, and, on examination, there may be hepatomegaly.
Laboratory tests are often normal, although an elevated MCV and γ-GT may
suggest increased alcohol intake. The fat disappears on cessation of alcohol
intake but with continued drinking it may progress to fibrosis and cirrhosis.
Alcoholic hepatitis
Alcoholic hepatitis generally occurs after years of heavy drinking and may
coexist with cirrhosis. Histologically, in addition to steatosis (see above),
there are ballooned (swollen) hepatocytes that often contain amorphous
eosinophilic material called Mallory bodies, surrounded by neutrophils. There
may be fibrosis and foamy degeneration of hepatocytes.
Clinical features
The cardinal sign of alcoholic hepatitis is a rapid onset of jaundice. Other
symptoms and signs are nausea, anorexia, right upper quadrant pain,
encephalopathy, fever, ascites and tender hepatomegaly.
Investigations
• Liver biochemistry shows elevated AST and ALT with a disproportionate
rise in AST (usually AST: ALT ratio >2) and the absolute values for AST
and ALT usually <500 IU/L; higher values suggest acute hepatitis due
to another cause. The bilirubin may be markedly elevated, 300–500
μmol/L, reflecting the severity of the illness. Serum albumin is low and
prothrombin time prolonged.
• Serum electrolytes are frequently abnormal with hyponatraemia. An
elevated serum creatinine may predict the development of hepatorenal
syndrome.
Primary Sclerosing Cholangitis 177
• Full blood count shows leucocytosis, elevated MCV and often
thrombocytopenia (results from bone marrow hypoplasia and/or
hypersplenism associated with portal hypertension).
• Microscopy and culture of blood, urine and ascites are performed to
search for an underlying infection.
• US (liver and biliary) is useful to identify biliary obstruction and HCC,
which may also be present.
• Liver biopsy (often via the transjugular approach because of abnormal
clotting) is not always required. Diagnosis is usually made on the basis
of clinical presentation, neutrophilia, elevated INR and liver biochemistry
profile.
Management
Patients are advised to stop drinking for life, as this is undoubtedly a precirrhotic condition. The prognosis is variable: despite abstinence, liver disease is progressive in many patients but abstinence significantly improves
survival.
Patients with severe alcoholic hepatitis require supportive treatment
and adequate nutritional intake must be maintained, if necessary, via a
nasogastric tube. Steroid therapy is sometimes used although it does not
confer any survival benefit. Steroids are contraindicated if renal failure,
infection or bleeding is present. Pentoxifylline, a phosphodiesterase inhibitor
with many effects including modulation of tumour necrosis factor (TNF)-α
transcription, also reduces mortality, which it is thought to do mainly by the
prevention of hepatorenal syndrome.
Alcoholic cirrhosis
This represents the final stage of liver disease from alcohol abuse. There is
destruction of liver architecture and fibrosis with regenerating nodules giving rise
to micronodular cirrhosis. Although patients may be asymptomatic, they often
present with one of the complications of cirrhosis and there are usually signs
of chronic liver disease. Investigation is as for cirrhosis in general. Management
is directed at the complications of cirrhosis and patients are advised to stop
drinking for life. Abstinence from alcohol improves the 5-year survival rate.
PRIMARY SCLEROSING CHOLANGITIS
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease
characterized by a progressive obliterating fibrosis of intra- and extrahepatic
ducts, leading to cirrhosis. The cause is unknown. More than 75% of cases
have ulcerative colitis, which may be asymptomatic. Patients are often
diagnosed during an asymptomatic phase. Routine blood tests in a patient
with inflammatory bowel disease reveal abnormal liver biochemistry, often a
178 Liver, biliary tract andpancreatic disease
raised alkaline phosphatase. Patients present with symptoms such as pruritus, jaundice or cholangitis. Sixty per cent of patients have myeloperoxidase
antineutrophilic cytoplasmic antibodies (ANCA). Diagnosis is usually by MRCP
or liver biopsy. Treatment is usually limited to management of complications arising from chronic liver disease and eventually liver transplantation.
Extrahepatic strictures may be amenable to dilatation at ERCP. High-dose
ursodeoxycholic acid (30 mg/kg) may slow down disease progression.
Cholangiocarcinoma (bile duct cancer) occurs in up to 15% of patients.
Sclerosing cholangitis, secondary to Cryptosporidium infection, is seen in
patients with acquired immunodeficiency syndrome (AIDS).
BUDD–CHIARI SYNDROME
In this condition, occlusion of the hepatic vein obstructs venous outflow from
the liver and the resulting congestion within the liver leads to hypoxic damage and necrosis of hepatocytes.
Aetiology
Common causes include a hypercoagulable state associated with myeloproliferative disorders, malignancy, oral contraceptives and inherited
thrombophilias. The cause is unknown in 20% of cases.
Clinical features
Clinical manifestations depend on the extent and rapidity of the hepatic vein
occlusion and whether a venous collateral circulation has developed. Right
upper quadrant pain, hepatomegaly, jaundice and ascites are typical features.
Acute disease may also present with fulminant hepatic failure. Cirrhosis may
develop in the chronically congested liver, resulting in portal hypertension and
the development of varices and other features of portal hypertension. A clinical picture similar to Budd–Chiari may develop in right-sided cardiac failure,
inferior vena cava obstruction or constrictive pericarditis.
Investigations
Doppler US is the initial investigation of choice. This will show abnormal flow
in the major hepatic veins or inferior vena cava as well as thickening, tortuosity, and dilatation of the walls of the hepatic veins. Non-specific findings
include hepatomegaly, splenomegaly, ascites and caudate lobe hypertrophy.
If the US is normal but clinical suspicion is high, CT or MRI may demonstrate
abnormalities. Liver biopsy is often unnecessary in making a diagnosis but it
will show centrizonal congestion, necrosis and haemorrhage.
Treatment
The goals of therapy are three-fold:
• To restore hepatic venous drainage. This is usually only feasible in the acute
state and it entails thrombolysis, angioplasty and stent insertion or TIPS.
Liver Abscess 179
• Treatment of complications related to ascites and portal hypertension.
• Detection of the underlying hypercoagulable disorder and prevention of
further clot formation.
LIVER ABSCESS
Liver abscesses are pyogenic, amoebic or hydatid.
Aetiology
The cause of pyogenic liver abscess is often unknown although biliary sepsis
or portal pyaemia from intra-abdominal sepsis may be responsible. Other
causes include trauma, bacteraemia or direct extension from, for example,
a perinephric abscess. The organisms most commonly found include E. coli
and Streptococcus milleri but anaerobes such as Bacteroides are also seen.
An amoebic abscess results from the spread of Entamoeba histolytica from
the bowel to the liver via the portal venous system.
Clinical features
Symptoms are often non-specific and may include fever, lethargy, weight loss
and abdominal pain. The liver may be enlarged and tender and there may be
consolidation or effusion in the right side of the chest. Patients with amoebic
liver abscess often do not give a history of dysentery.
Investigations
• Laboratory abnormalities reflect the non-specific findings of infection,
including anaemia, raised ESR and low albumin. Serum alkaline
phosphatase is usually raised and bilirubin often normal.
• A US will show single or multiple rounded lesions that are
hypoechoicinrelation to the surrounding liver. CT is diagnostic
andshows the abscesses as non-enhancing cavities with a
surroundingrim of inflammation that are enhanced in relation to
therestof the liver.
• Serological tests for amoebae, e.g. complement-fixation test or enzymelinked immunosorbent assay (ELISA), are almost always positive in
amoebic liver abscess.
Management
Amoebic liver abscess. These abscesses are diagnosed on the basis
of clinical and radiological features (migrants from and travellers to endemic
countries who have a single abscess in the right lobe of the liver) and are
treated with metronidazole without the need for aspiration of the abscess.
Pyogenic abscess. Pyogenic abscesses should have percutaneous
aspiration under radiological control and usually a pigtail catheter is inserted
for continuous drainage. The initial antibiotic regime is subsequently
adjusted, depending on the organisms obtained from the aspirate.
180 Liver, biliary tract andpancreatic disease
LIVER DISEASE IN PREGNANCY
Viral hepatitis is the most common cause of jaundice in pregnancy. Three
types of liver disease are specific to pregnancy: intrahepatic cholestasis (presenting with pruritus, elevated liver enzymes and increased serum bile acids),
acute fatty liver of pregnancy (a severe fulminating illness with jaundice,
vomiting and hepatic coma) and haemolysis (occasionally producing jaundice) which occurs in pre-eclamptic toxaemia. The three conditions present
most commonly in the third trimester and resolve with delivery of the baby.
LIVER TUMOURS
The most common malignant liver tumours are metastatic, particularly those
from the gastrointestinal tract, breast or bronchus. Primary liver tumours are
either benign or malignant. Liver cysts and haemangiomas are common and
may be confused with tumours on initial imaging. They do not usually require
any further treatment.
Hepatocellular carcinoma (hepatoma)
HCC is the fifth most common cancer worldwide. The wide geographical distribution of HCC is probably due to regional variations in exposure to hepatitis
B and C viruses and environmental pathogens.
Aetiology
The majority of HCCs occur in patients with chronic liver disease or cirrhosis, especially viral hepatitis. Primary liver cancer is also associated
with other forms of cirrhosis, such as alcoholic cirrhosis, NAFLD-associated
cirrhosis and haemochromatosis. Males are affected more than females.
Other aetiological factors are aflatoxin (a metabolite of a fungus found in
groundnuts) and androgenic steroids, and there is a weak association with
the contraceptive pill.
Clinical features
Weight loss, anorexia, fever, ascites and abdominal pain occur. The rapid
development of these features in a patient with cirrhosis is highly suggestive of HCC. Because of surveillance by serum AFP estimation and
liver US, HCC is increasingly found in asymptomatic patients with known
cirrhosis. A focal lesion in the liver in a patient with cirrhosis is highly
likely to be HCC.
Investigations
• Serum AFP may be raised but is normal in at least a third of patients.
• US or CT scan shows large filling defects in 90% of cases.
Gallstones 181
• MRI or angiography is useful in cases where there is doubt in diagnosis.
• Biopsy is only performed when there is a doubt in diagnosis as there is a
risk of tumour seeding in the percutaneous needle biopsy tract.
Management
Surgical resection or liver transplantation is occasionally possible.
Percutaneous ablation therapy using ethanol injection or high-frequency US
probes will produce necrosis of the tumour. Transarterial chemoembolization
involves the injection of a chemotherapeutic agent and Lipiodol into the
hepatic artery. It is used in the treatment of large unresectable tumours.
Chemotherapy given intravenously has a very limited role.
Prognosis
Overall, the median survival is only 6–20 months.
Benign liver tumours
The most common forms are haemangiomas, usually found incidentally
on liver US or CT scan. They require no treatment. Hepatic adenomas are
less common, and they are associated with the use of oral contraceptives.
Resection may be required if there are symptoms (e.g. pain, intraperitoneal
bleeding).
GALLSTONES
Gallstones are present in 10%–20% of the population. They are most
common in women, and the prevalence increases with age.
Pathophysiology
Gallstones are of two types:
• Cholesterol gallstones account for 80% of all gallstones in the Western
world. Cholesterol is held in solution by the detergent action of bile
salts and phospholipids with which it forms micelles and vesicles.
Cholesterol gallstones only form in bile which has an excess of
cholesterol, either because there is a relative deficiency of bile salts
and phospholipids or a relative excess of cholesterol (supersaturated
or lithogenic bile). The formation of cholesterol crystals and gallstones
in lithogenic bile is promoted by factors that favour nucleation such as
mucus and calcium. Gallstone formation is further promoted by reduced
gall bladder motility and stasis. The mechanism of cholesterol gallstone
formation in patients with risk factors (Table 4.12) is frequently
multifactorial (cholesterol supersaturation, nucleation factors and
reduced gall bladder motility).
• Pigment stones consist of bilirubin polymers and calcium bilirubinate.
They are seen in patients with chronic haemolysis (e.g. hereditary
182 Liver, biliary tract andpancreatic disease
s
Sphincter of Oddi
Table 4.12 Risk factors for cholesterol gallstones
Increasing age
Sex (F > M)
Family history
Multiparity
Obesity ± metabolic syndrome
Rapid weight loss
Diet (e.g. high in animal fat/low fibre)
Ileal disease or resection (leading to bile salt loss)
Diabetes mellitus
Acromegaly treated with octreotide
Liver cirrhosis
Common hepatic duct
Hartmann’s pouch
Hepatic duct
Impacted in
cystic duct
(acute cholecystitis )
Gall bladder
Asymptomatic
gallstones
Duodenum
Ampulla of Vater
Fig. 4.8 The complications of gallstones.
spherocytosis and sickle cell disease) in which bilirubin production is
increased and cirrhosis. Pigment stones may also form in the bile ducts
after cholecystectomy and with duct strictures.
Causing biliary
obstruction
Common bile duct
Pancreatic duct
Stone causing
gallstone
pancreatitis
Clinical presentation
Most gallstones never cause symptoms and cholecystectomy is not indicated
in asymptomatic cases. The complications are summarized in Fig. 4.8.