Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2826_Библиотеки_им_академика_М_И_Перельмана.pdf
Unconjugated bilirubin
Gall bladder
Liver
bound to albumin
Bilirubin glucuronide
Common bile duct
Jaundice 143
Red cells
Spleen
Urobilinogen
Gut
Urobilinogen excreted (as
stercobilinogen) in faeces
Fig. 4.2 Pathways in bilirubin metabolism.
Congenital hyperbilirubinaemia
Kidney
Urobilinogen excreted by
the kidneys
The most common congenital hyperbilirubinaemia is Gilbert’s syndrome,
which affects 2%–7% of the population. It is asymptomatic and is usually
picked up by an incidental finding of a slightly raised serum bilirubin (17–102
μmol/L, 1–6 mg/dL). Mutations in the gene coding for UDP-glucuronyl transferase lead to reduced enzyme activity and reduced conjugation of bilirubin
with glucuronic acid. Genetic testing is possible in these cases. Diagnosis is
based on the findings of unconjugated hyperbilirubinaemia with otherwise
normal liver biochemistry, full blood count, smear and reticulocyte count (thus
excluding haemolysis) and the absence of signs of liver disease. The patient
should be reassured that no further investigation or treatment is necessary.
Other congenital abnormalities of bilirubin metabolism (Crigler–Najjar,
Dubin–Johnson and Rotor’s syndromes, benign recurrent intrahepatic
cholestasis) are rare.
Cholestatic jaundice
This can be divided into the following (Fig. 4.3):
144 Liver, biliary tract andpancreatic disease
Types
Prehepatic
Cholestatic
Intrahepatic
Extrahepatic
HAEMOGLOBIN
BILIRUBIN
CONJUGATION
GALL BLADDER
PANCREAS
Causes
Haemolysis
Viral hepatitis
Drugs
Alcoholic hepatitis
Cirrhosis – any type
Autoimmune cholangitis
Pregnancy
Recurrent idiopathic cholestasis
Some congenital disorders
Infiltrations
Common duct stones
Carcinoma
– bile duct
– head of pancreas
– ampulla
Biliary stricture
Sclerosing cholangitis
Pancreatitis pseudocyst
Fig. 4.3 Causes of jaundice.
• Intrahepatic cholestasis caused by hepatocellular swelling in parenchymal
liver disease or abnormalities at a cellular level of bile excretion
• Extrahepatic cholestasis resulting from obstruction of bile flow at any
point distal to the bile canaliculi.
In both types, there is jaundice with pale stools and dark urine and the
bilirubin is conjugated. However, intrahepatic and extrahepatic cholestatic
jaundice must be differentiated as their management is quite different.
Investigations
An outline of the approach to the investigation of jaundice is shown in
Fig.4.4.
• Serum liver biochemistry will confirm jaundice. The AST tends to be
high early in the course of hepatitis with a smaller rise in alkaline
phosphatase. Conversely, in extrahepatic obstruction, the alkaline
phosphatase is elevated, with a smaller rise in the AST.
• US examination shows dilated bile ducts in extrahepatic cholestasis and
may identify the level of obstruction and its cause (e.g. gallstones, tumours).
• Serum viral markers for hepatitis A or hepatitis B are present in acute viral
hepatitis. Antibodies to hepatitis C virus (HCV) develop late in the course of
acute infection but HCV RNA is usually detectable by 1–2 weeks.
• Other tests: prothrombin time may be prolonged as a result of vitamin
K malabsorption and is corrected by administration of vitamin K. Serum
autoantibodies are present in autoimmune liver disease.
Hepatitis 145
Country of origin, duration of illness, drugs,
History
blood transfusions, travel, alcohol, weight loss,
sexual orientation, i.v. drug use, recent anaesthetic,
recent consumption of shellfish
Examination
Signs of chronic liver disease, hepatomegaly,
splenomegaly, palpable gall bladder
Ultrasound
Are the bile ducts dilated?
Dilatation of the CBD suggests
extrahepatic cholestasis
ERCP/MRCP/PTC
ERCP = endoscopic retrograde cholangiopancreatography
MRCP = magnetic resonance cholangiopancreatography
PTC = percutaneous transhepatic cholangiogram
Fig. 4.4 Approach to the investigation of cholestatic jaundice. The order of
investigation is influenced by the age of the patient and hence the likely cause
of jaundice. A young person is most likely to have intrinsic liver disease, e.g.
viral hepatitis, and it may be more appropriate to organize tests to exclude these
conditions before proceeding to ultrasound. CBD, common bile duct; ERCP, endoscopic
retrograde cholangiopancreatography; i.v., intravenous; MRCP, magnetic resonance
cholangiopancreatography; PTC, percutaneous transhepatic cholangiography.
No dilatation of the ducts
Viral markers, autoantibodies
? liver biopsy
HEPATITIS
The pathological features of hepatitis are liver cell necrosis and inflammatory
cell infiltration. Hepatitis is divided into acute and chronic types on the basis
of clinical and pathological criteria.
Acute hepatitis is most commonly caused by one of the hepatitis viruses
(Fig. 4.5). This is usually self-limiting, with a return to normal structure and
function. Occasionally, there is progression to massive liver cell necrosis.
146 Liver, biliary tract andpancreatic disease
Wilson’s disease
Carbon tetrachloride
Non-viral infections
Toxoplasma gondii
Leptospira icterohaemorrhagiae
Coxiella burnetii (Q fever)
Other
e.g. Pregnancy
Circulatory insufficiency
Fig. 4.5 Causes of acute parenchymal damage.
Clinically, the patient may be jaundiced, with an enlarged and tender liver,
and there is laboratory evidence of hepatocellular damage with raised serum
aminotransferase levels. Disease severity is assessed by the prothrombin
time and serum bilirubin. Alcoholic hepatitis is distinguished from other
causes of acute hepatitis by characteristic laboratory abnormalities.
Chronic hepatitis is defined as sustained inflammatory disease of
the liver lasting more than 6 months (Table 4.2). Chronic viral hepatitis is
the principal cause of chronic liver disease, cirrhosis and hepatocellular
carcinoma (HCC) worldwide.
e.g. Amanita phalloides (mushrooms)
Aflatoxin
Viral infections
Virus A, B, (D), C, E
Epstein–Barr virus
Cytomegalovirus
Yellow fever virus
Others – rare
Drugs
e.g. Paracetamol
Alcohol
Poisons
Viral hepatitis
The different features of common forms of viral hepatitis are summarized in
Table 4.3. Hepatitis A always and hepatitis E usually cause acute infections,
while hepatitis B, C and D may cause acute or chronic disease. All cases must
be notified to the appropriate public health authority. This allows contacts to
be traced and data provided on disease incidence.
Hepatitis A
Epidemiology
Hepatitis A (HAV) is the most common type of acute viral hepatitis. It occurs
worldwide and particularly affects children and young adults. Spread is
Hepatitis 147
Table 4.2 Causes of chronic hepatitis
Viral
Hepatitis B ± D
Hepatitis C
Autoimmune
Drugs
Methyldopa
Nitrofurantoin
Isoniazid
Ketoconazole
Hereditary
Wilson’s disease
Others
Inflammatory bowel disease
Alcohol
faecal–oral and arises from the ingestion of contaminated food (e.g. shellfish,
clams) or water. The virus is excreted in the faeces of infected individuals for
about 2 weeks before the onset of illness and for up to 7 days afterwards.
It is most infectious just before the onset of jaundice.
Clinical features
After an average incubation period of 28 days, the viraemia causes non-specific
prodromal symptoms such as nausea and anorexia. Many recover at this stage
and remain anicteric. An anicteric infection is common in children and confers
lifetime immunity. After 1 or 2 weeks, some patients become jaundiced, with dark
urine and pale stools, and the prodromal symptoms improve. There is moderate
hepatomegaly and the spleen is palpable in 10% of cases. Occasionally, lymphadenopathy and skin rash are present. The illness is self-limiting and usually
resolves in 3–6 weeks. Rarely, there is fulminant hepatitis, coma and death.
Investigations
• Liver biochemistry shows raised ALT and a raised bilirubin when jaundice
develops.
• Blood count may show a leucopenia with relative lymphocytosis and
a high erythrocyte sedimentation rate (ESR). The prothrombin time is
prolonged in severe cases.
• Acute HAV infection is diagnosed through the detection of anti-HAV
immunoglobulin (Ig)M in the serum; the presence of anti-HAV IgG
indicates previous infection.
Table 4.3 Some features of viral hepatitis
A B D C E
Virus RNA DNA RNA RNA RNA
Transmission
(main sources)
Faecal–oral
Saliva
*Blood/blood products
Sexual
*Blood/blood products
Saliva
*Blood/blood products
Vertical
Saliva
Incubation
Chronic liver
2–6 weeks 1–5 months 1–3 months 2–6 months
No Yes Yes Yes
disease
Liver cancer
Mortality (acute)
*Blood/blood products includes transfusion of infected blood or blood products or by contaminated needles used by drug addicts, tattooists or acupuncturists.
**Chronic hepatitis in immunosuppressed patients.
No Yes Rare Ye s
<0.5% <1% <1%
Faecal–oral
3–8 weeks
No**
No
1%–2% (pregnant women 10%–20%)
148 Liver, biliary tract andpancreatic disease
Hepatitis 149
Differential diagnosis
The differential diagnosis includes other causes of jaundice and in particular
other types of viral and drug-induced hepatitis.
Management
There is no specific treatment. The prognosis is excellent, with most patients
making a complete recovery. Hospital admission is not usually necessary.
Avoidance of alcohol is only recommended for the few weeks when the
patient is ill. Patients may complain of feeling unwell for several months following resolution of symptoms and biochemical parameters. This is known as
the post-hepatitis syndrome and treatment is by reassurance. HAV hepatitis
never progresses to chronic liver disease.
Prophylaxis
Active immunization: A formaldehyde-inactivated HAV vaccine is given to
travellers to areas of high prevalence (Africa, Asia, South America, Eastern
Europe and the Middle East), patients with chronic liver disease (in whom the
disease is more severe) and persons at risk of occupational exposure (staff
and residents of homes with severe learning difficulties and workers at risk
of exposure to untreated sewage). A single dose produces antibodies that
persist for at least 1 year, with immunity lasting beyond 10 years.
Control of hepatitis also depends on good hygiene. Travellers to high-risk
areas should drink only boiled or bottled water and avoid suspicious food.
Passive immunization: Human immunoglobulin is given to close
contacts of confirmed cases of hepatitis A to prevent infection. HAV
vaccine should also be given.
Hepatitis B
Epidemiology
Hepatitis B virus (HBV) is present worldwide. The UK and the USA have a low
carrier rate (0.5%–2%) but this rises to 10%–20% in parts of Africa and the
Middle and Far East. Vertical transmission from mother to child during parturition is the most common method of transmission worldwide. HBV is not
transmitted through breast feeding. HBV is also spread through blood (e.g. by
transfusion of infected blood or blood products, or by contaminated needles
employed by drug users, tattooists or acupuncturists) or sexual intercourse
(particularly men who have sex with men) and by horizontal transmission in
children through minor abrasions or close contact with other children.
Viral structure
The infective virion or Dane particle is a 42-nm particle comprising an inner core
or nucleocapsid surrounded by an outer envelope of surface protein (hepatitis B
surface antigen, HBsAg). This surface coat is excessively produced by the infected
hepatocytes and can exist separately from the whole virion in serum and body fluid.
150 Liver, biliary tract andpancreatic disease
Jaundice
The HBV genome is variable, and genetic sequencing can be used to
define different HBV genotypes, i.e. A–H. These genotypes may influence
the chance of responding to interferon treatment (A > B; C > D) but all
genotypes respond equally well to nucleoside analogues.
Mutations occur in the various reading frames of the HBV genome. These
mutants can emerge in patients with chronic HBV infection (escape mutants)
or can be acquired by infection. HBsAg mutants are produced by alterations
in the ‘a’ determinants of the HBsAg proteins with usually a substitution of
glycine for arginine at position 145. This results in changes in the antibody
binding domain and may confer resistance to the vaccine.
In patients with some HBV genotypes (particularly D), a mutation in the
pre-core region occurs when a guanosine (G) to adenosine (A) change creates
a stop codon that prevents the production of hepatitis B e antigen (HBeAg).
The synthesis of hepatitis B core antigen (HBcAg) is unaffected. This mutation
may be associated with HBeAg-negative disease but other mutations in the
core promoter region can also lead to HBeAg-negative disease. To detect
infectivity, HBV DNA must always be measured as no eAg should be present.
Acute HBV infection
HBV penetrates the hepatocyte and in immunocompetent adults there is
a strong cellular immune response to the foreign HBV proteins expressed
(A) Acute infection
HBsAg
ALT Anti-HBc (IgM)
Anti-HBs
HBV DNA
HBeAg
Anti-HBe
012345
Infection
Months
Incubation Symptoms
Fig. 4.6 Time course of the events and serological changes seen following
infection with hepatitis B virus. ALT, alanine aminotransferase; anti-HBc, antihepatitis B core antibody; anti-HBe, anti-hepatitis e antibody; anti-HBs, antihepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B
surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M.
Hepatitis 151
61
anti-HBc may be the only serological indicator of recent HBV infection in a period
(B) Development of chronic hepatitis followed by seroconversion
Replicative phase
HBV
DNA
06
Months Years
HBeAg
Anti-HBe
Seroconversion
Symptoms
(A) Acute infection.
Antigens
HBsAg appears in the blood from about 6 weeks to 3 months after an acute
infection and then disappears.
HBeAg rises early and usually declines rapidly.
Antibodies
Anti-HBs appears late and indicates immunity.
Anti-HBc is the first antibody to appear and high titres of IgM anti-HBc suggest
an acute and continuing viral replication. It persists for many months. IgM
when HBsAg has disappeared and anti-HBs is not detectable in the serum.
Anti-HBe appears after the anti-HBc and its appearance relates to a decreased
infectivity, i.e. a low risk.
(B) Development of chronic hepatitis followed by seroconversion.
HBsAg persists and indicates a chronic infection (or carrier state).
HBeAg persists and correlates with increased severity and infectivity and the
development of chronic liver disease. When anti-HBe develops (seroconversion)
the Ag disappears and there is a rise in ALT.
HBV DNA suggests continual viral replication. For mutants, see text.
Fig. 4.6, cont’d
HBsAg
ALT
042
by hepatocytes. This response leads to clearance of the infection in 99%
of infected adults and is marked by the disappearance of HBsAg from the
serum, the development of antibodies to surface antigen (anti-HBs) and
immunity to subsequent infection (Fig. 4.6A and Table 4.4). Acute infection
may be asymptomatic or produce symptoms and signs similar to those seen
152 Liver, biliary tract andpancreatic disease
in hepatitis A. Occasionally it is associated with a rash or polyarthritis affecting the small joints. One per cent of patients develop fulminant liver failure.
Investigation is generally the same as for hepatitis A. There is no specific
therapy for acute HBV infection and management is supportive.
Chronic HBV infection
The persistence of HBsAg in the serum for more than 6 months after acute
infection defines chronic infection. Progression from acute to chronic
infection depends on several factors including the virulence of the virus
and the immunocompetence and age of the patient. When HBV infection is
acquired at birth (vertical transmission) or early childhood, there is a high
level of immunological tolerance. Cellular immune response to hepatocytemembrane HBV proteins does not occur and chronic infection is the norm.
This immune tolerant phase is characterized by minimal hepatic inflamma-
tory activity and normal or near-normal serum ALT despite positive HBeAg
and high levels of HBV replication. This phase may persist for two to three
decades before an immune clearance phase that lasts for a variable period
of time occurs. This is characterized by high HBV DNA levels as before
but it is an active hepatitis that might lead to fibrosis and cirrhosis with
elevated serum ALT. This phase ends with clearance of HBeAg and the
development of anti-HBe (HBeAg seroconversion). There is also a marked
decrease in serum HBV DNA and normalization of serum ALT (the inactive
HBsAg carrier state).
In the immune clearance phase, some patients will develop viral
mutations (see above) that do not produce HBeAg but continue to replicate
at a high level, with progressive liver damage and fluctuating serum levels
of aminotransferases (reactivation phase). Acquisition of infection later in life
is associated with a very short immune tolerance phase or none at all. Most
patients clear the virus (see acute HBV infection, p. 150) and only a small
percentage will progress to chronic infection (see Fig. 4.6B).
Table 4.4 summarizes the serological markers of HBV infection at various
stages.
Treatment of chronic infection: who to treat
Patients who present with detectable HBsAg and clinical and/or epidemiological factors suggestive of chronic infection can be considered for treatment
without waiting for the 6-month period that defines chronicity. In HBsAgpositive individuals, there is a strong relationship between ongoing HBV
replication and the risk of progression of chronic liver disease to cirrhosis,
hepatocellular carcinoma (HCC) or both. Treatment is given to patients most
likely to develop progressive liver disease. Thus patients with chronic HBV
infection (HBsAg-positive), high serum levels of HBV DNA (≥20 000 IU per mL)
and elevated serum ALT should be given antiviral treatment (see below). If
cirrhosis is present, treatment should be given irrespective of ALT or HBV
DNA levels. Antiviral therapy is not used for inactive HBV carriers (normal