Download Drug- and toxin-induced hepatotoxicity PATHOLOGICAL

Acute liver failure
Drug- and toxin-induced hepatotoxicity
Risk factors for drug-induced hepatotoxicity include the
extremes of age, abnormal renal function, obesity, preexisting liver disease and concurrent use of other hepatotoxic agents. Some drug toxicities occur in an intrinsic,
dose-dependent, predictable manner (e.g. paracetamol) but
most are idiosyncratic, immunologically mediated reactions,
usually to a metabolite.
Hepatocellular damage following paracetamol overdose is
related to the production of a toxic metabolite of paracetamol
(N-acetyl-para benzoquine imide), which accumulates when
hepatic glutathione has been overwhelmed (Black, 1980),
although individuals vary considerably in their susceptibility
to liver damage induced by this agent. Paracetamol toxicity
is dose-dependent, but its effects are exaggerated by drugs
that induce cytochrome P-2ε1 such as phenytoin, and especially by alcohol (which not only induces cytochrome P-2ε1
but also depletes hepatic glutathione both directly and as a
consequence of malnutrition). Therefore, alcoholics taking
therapeutic doses of paracetamol, for example, are at risk of
developing ALF, particularly after an episode of binge drinking. Prolonged fasting is also a risk factor for paracetamol
hepatoxicity. Management of paracetamol overdose is discussed further in Chapter 19.
PATHOLOGICAL CHANGES IN ALF
ALF is the result of cytotoxic and/or cytopathic injury. Hepatotoxic viruses, drugs or their toxic metabolites and other
toxins can cause direct cytotoxic injury. Cytopathic injury,
on the other hand, is caused by an immune-mediated injury
to hepatocytes that express abnormal cell surface antigens
(e.g. idiosyncratic drug reactions).
In ALF there is massive coagulative necrosis of liver cells
throughout the hepatic lobule, often with preservation of
the reticular framework, although ultimately the normal
reticulin architecture of the lobule collapses. There may be
infiltration with polymorphonuclear cells, lymphocytes,
mononuclear cells or eosinophils, interspersed with islands
of regenerating hepatocytes. In viral ALF the initial injury
involves the periportal region, but then spreads to encompass all zones. In contrast, drug-induced injury and ischaemic damage begin around the central vein and spread
rapidly to involve the periportal region. Severe fatty
degeneration with accumulation of microventricular fat in
intact cells is seen in ALF associated with pregnancy,
Reye’s syndrome and sodium valproate or tetracycline
administration.
CLINICAL FEATURES, INVESTIGATIONS AND
DIAGNOSIS (Tables 14.2 and 14.3)
The clinical features of ALF are largely attributable to failure
of the normal functions of the liver (synthesis, storage and
detoxification). Typically patients present with jaundice,
coagulopathy, marked elevation of liver aminotransferases
and, by definition, encephalopathy. Certain patterns of presentation, which may be indicative of the aetiology, have
383
been described. For example, patients with paracetamol
overdose typically present with severe coagulopathy and
encephalopathy, but may not be jaundiced, whereas those
with non-A, non-B hepatitis are usually deeply jaundiced at
presentation and are less likely to develop cerebral oedema.
Many patients subsequently develop sepsis, cardiovascular
instability, metabolic acidosis, renal failure, cerebral oedema
and multiple-organ failure.
Hepatic encephalopathy
The syndrome of ALF is differentiated from severe acute
hepatitis by the development of encephalopathy. This presents as an acute mental disturbance which usually progresses
over several days, but deep coma may develop in just a few
hours. Occasionally the evolution of the disease is prolonged
over several months. Often, the initial changes are subtle
(e.g. a change in personality, lack of attention to personal
detail, perhaps with euphoria or depression and some
slowing of mentation). Later, the patient may become confused and begin to behave inappropriately. Drowsiness is a
prominent feature and some patients will sleep continually,
although at this stage they can be roused. Difficulty with
writing and an inability to reproduce shapes (e.g. a star)
accurately are characteristic (constructional apraxia);
these skills can be tested repeatedly in order to follow the
patient’s progress. A ‘flapping’ tremor (asterixis) can often be
demonstrated at this stage and is associated with a rigid
facies, muscle stiffness and dysarthria. Some patients may
become extremely agitated as their level of coma deepens;
they may require sedation and mechanical ventilation to
ensure their safety. Many patients will then lose consciousness and progress to deep coma with hypertonia, decerebrate
and/or decorticate posturing and disturbances of vital
reflexes.
Hepatic encephalopathy can be classified clinically into
five grades, as shown in Table 14.4. In practice, however,
such classifications are complicated by spontaneous fluctuations in coma grade and the necessity to administer sedatives
to patients who are agitated or aggressive or to enable invasive procedures to be performed.
The electroencephalographic (EEG) changes (Fig. 14.1)
correlate with the degree of cerebral dysfunction and,
although not necessary to establish the diagnosis, serial
EEGs can be performed, together with regular clinical assessment of the grade of encephalopathy, in order to follow the
patient’s progress.
Cerebral oedema may be present in over 80% of patients
with grade IV encephalopathy, although more recent studies
suggest that the incidence has fallen to around 40%. Cerebral
oedema is uncommon in patients with SFHF and chronic
liver disease.
Other clinical features
In the early stages, the liver may be palpable, although later
in the illness it becomes small. Signs of chronic liver disease
such as palmar erythema, spider naevi, splenomegaly and
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INTENSIVE CARE
Table 14.2 Clinical features of fulminant hepatic failure
Encephalopathy
Cerebral oedema
Jaundice
Hepatic foetor, nausea, vomiting, right-upper-quadrant pain
Coagulopathy and bleeding
Reduced synthesis of clotting factors
Thrombocytopenia
Upper gastrointestinal haemorrhage
Haemorrhage from nasopharynx, respiratory tract and into
retroperitoneal space
Metabolic disturbances
Hypoglycaemia
Metabolic alkalosis
Lactic acidosis
Electrolyte disturbances
Hypokalaemia
Hyponatraemia
Hypernatraemia (unusual)
Hypomagnesaemia
Hypocalcaemia
Hypophosphataemia
Cardiovascular dysfunction
Hypotension
Vasodilatation
Increased cardiac output
Microcirculatory dysfunction:
Maldistribution of flow
Increased capillary permeability
Tissue hypoxia
Respiratory dysfunction
Hyperventilation
Intrapulmonary shunts
Acute lung injury/acute respiratory distress syndrome
Pulmonary aspiration
Atelectasis
Bronchopneumonia
Impaired host defences and sepsis
Bacteraemia
Spontaneous bacterial peritonitis
Pneumonia
Urinary tract infections
Translocation of gut-derived organisms and cell wall components
Renal dysfunction
Prerenal
Acute tubular necrosis
(Hepatorenal syndrome)
Pancreatitis
Rare complications
ascites are usually absent, but when ALF follows a more
protracted course, both spider naevi and ascites may occur.
In some cases, the patient may present with nausea, vomiting
and abdominal pain (often in the right upper quadrant),
suggestive of an ‘acute abdomen’.
The signs of encephalopathy are usually accompanied by
rapidly increasing jaundice and a characteristic hepatic foetor,
Myocarditis
Pneumonia caused by atypical organisms
Aplastic anaemia
Transverse myelitis
Peripheral neuropathy
an unpleasant sweetish smell due to exhalation of mercaptans. The rise in serum bilirubin concentration is associated
with the appearance of bilirubin and its breakdown products
in the urine. The diagnosis may, however, be difficult if the
mental disturbance precedes the development of clinical
jaundice. This occurs particularly in children with ALF and
in adults who have taken a paracetamol overdose.
Acute liver failure
Table 14.3 Investigations in fulminant hepatic failure
Daily
Bilirubin, alkaline
phosphatase,
aminotransferases
Haemoglobin, white blood
count
Prothrombin time, platelet
count
Urea, creatinine, sodium,
potassium, magnesium
Total protein, albumin,
calcium, phosphate
Chest radiograph, ECG
More frequently
Blood sugar
Blood gases
Acid–base
When indicated
Cultures of blood, urine,
sputum, intravascular
cannulae
ECG, CT scan, ultrasonography
Ammonia levels
Liver biopsy
To establish aetiology
Serological investigations for
viral hepatitis
Drug screen (especially
paracetamol)
Plasma caeruloplasmin
concentration and urinary
copper excretion for
Wilson’s disease
CT, computed tomography; ECG, electrocardiogram.
385
Serum aminotransferase levels are initially nearly
always markedly elevated, often to more than 2000 u/L, but
the alkaline phosphatase level is usually only moderately
raised. Serum albumin, because of its long half-life, generally
remains normal until later in the illness. A fall in aminotransferase levels despite increasing hyperbilirubinaemia
and a worsening coagulopathy indicate total destruction of
liver cells and is associated with a very poor prognosis.
Plasma levels of α-fetoprotein, prealbumin and factor V, as
well as the prothrombin time, have been used as prognostic
indicators (see below). Blood ammonia levels are usually
increased, although routine determination of ammonia
levels is not recommended (see below).
BLEEDING
Patients with ALF invariably develop a severe coagulopathy.
The prothrombin time (or the international normalized
ratio (INR) for prothrombin) is always markedly prolonged,
reflecting reduced hepatic synthesis of clotting factors (V,
VII, IX and X). Later this may be compounded by a fall in
fibrinogen levels. The production of factors XI and XII may
also be impaired. The prothrombin time and coagulation
factor V levels (Izumi et al., 1996) can be a useful guide to
the progress and prognosis of ALF. Factor VIII, which is
synthesized in vascular endothelium, is markedly elevated in
ALF and a ratio of factor VIII to V of more than 30 has been
associated with a poor prognosis (Pereria et al., 1992). A
number of anticoagulation factors, such as protein C and
protein S, are also synthesized by the liver and the coagulation profile in ALF may become difficult to distinguish
from DIC, especially since thrombocytopenia is also common.
The latter may be due to hypersplenism, bone marrow
Table 14.4 A grading system for hepatic encephalopathy
Grade
Level of consciousness
Personality and
intellect
Neurological signs
Electroencephalographic
abnormalities
0
Normal
Normal
None
None
Subclinical
Normal
Normal
Abnormalities only on
psychometric analysis
None
1
Inverted sleep pattern,
restlessness
Forgetfulness, mild
confusion, agitation,
irritability
Tremor, apraxia,
incoordination,
impaired handwriting
Triphasic waves
(5 cycles/second)
2
Lethargy, slow responses
Disorientation as regards
time, amnesia,
decreased
inhibitions,
inappropriate
behaviour
Asterixis, dysarthria,
ataxia, hypoactive
reflexes
Triphasic waves
(5 cycles/second)
3
Somnolence but rousable,
confusion
Disorientation as regards
place, aggressive
behaviour
Asterixis, hyperactive
reflexes, Babinski
signs, muscle rigidity
Triphasic waves
(5 cycles/second)
4
Coma
None
Decerebration
Delta activity
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INTENSIVE CARE
Fig. 14.1 Electroencephalographic
changes in hepatic coma. Highvoltage slow waves with some
triphasic components best seen at
the front of the head.
5
1
2
6
3
7
8
4
50 μV
1 sec
Drowsy, restless
Alert
suppression or DIC. Functional platelet abnormalities have
also been described in association with morphological
changes; platelet adhesion is increased, but aggregation
decreased. The platelet count tends to decrease progressively
during the course of ALF and is lower in those who die.
Upper gastrointestinal haemorrhage is a potentially lethal
complication of ALF and may be related to oesophagitis,
gastric erosions or duodenal ulceration. Acute portal hypertension commonly develops after about 3 weeks and may
result in variceal haemorrhage. Bleeding may also occur
from the nasopharynx, the respiratory tract or into the retroperitoneal space. Intracerebral haemorrhage is unusual.
METABOLIC DISTURBANCES
Hypoglycaemia is common and may be due to raised plasma
insulin levels combined with depletion of glycogen stores
and a failure of hepatic gluconeogenesis. The development
of a metabolic alkalosis is probably related to hypokalaemia
and defective urea synthesis. In the later stages of ALF a lactic
acidosis is common, probably reflecting both anaerobic
metabolism and reduced clearance of lactate. The development of a metabolic acidosis is associated with a poor
prognosis.
ELECTROLYTE DISTURBANCES
In the absence of renal failure there is a marked tendency to
hypokalaemia due to inadequate potassium intake, vomiting
and secondary hyperaldosteronism. Hypomagnesaemia can
be precipitated by the excessive use of diuretics. Hyponatraemia is also common, especially later in the course of ALF,
and is due to redistribution of sodium into the cells combined with increased renal retention of water. Hypernatraemia, on the other hand, is unusual but can be precipitated
by the sodium load in transfusions of fresh frozen plasma
(FFP), human albumin solution (HAS) or colloidal solutions and is sometimes exacerbated by dehydration due to
hyperglycaemia or diuretic administration. Hypocalcaemia
may occur. Hypophosphataemia is common. Interestingly, in
patients with severe paracetamol-induced hepatotoxicity,
hyperphosphataemia (perhaps caused by renal dysfunction
in the absence of hepatic regeneration) has been associated
with a poor outcome (Schmidt and Dalhoff, 2002).
CARDIOVASCULAR DYSFUNCTION (see Chapter 5)
Hypotension is common, even in the absence of haemorrhage or obvious sepsis, and is associated with a poor prognosis. The peripheral resistance is low and cardiac output is
usually increased. Even when blood pressure is normal, severe
tissue hypoxia may be present, as evidenced by a metabolic
acidosis and raised blood lactate levels. Furthermore, there
is an inverse correlation between the mixed venous lactate
concentration and both the systemic vascular resistance and
the oxygen extraction ratio, suggesting that vasodilation is
associated with maldistribution of microcirculatory flow and
tissue hypoxia (Bihari et al., 1985). There is also a generalized
increase in capillary permeability leading to hypovolaemia
and interstitial oedema. It has been postulated that the
hyperdynamic circulation that is characteristic of liver failure
may be related to induction of nitric oxide (NO) synthase,
possibly in response to endotoxaemia (Vallance and
Moncada, 1991). Certainly impaired Kupffer cell function
and the presence of portosystemic shunts may promote bacteraemia/endotoxaemia and exaggerate the inflammatory
response.
Arrhythmias are also common and may be related
to hypoxia, acid–base disturbances or electrolyte
abnormalities.
RESPIRATORY DYSFUNCTION
A respiratory alkalosis due to hyperventilation is common
in the early stages of ALF and may be a result of stimulation
of the respiratory centre by toxins or an intracellular
acidosis. Later, hypoxic depression of the respiratory centre
may supervene and sudden unexpected respiratory arrest
may occur, in some cases related to severe intracranial
hypertension.
Acute liver failure
Many patients with ALF will be hypoxaemic and this may
be due to intrapulmonary shunts (associated with diffuse
dilatation of the pulmonary vasculature and, in some cases,
pleural spider naevi) or pulmonary oedema. The commonest abnormality is non-cardiogenic pulmonary oedema (acute
lung injury/acute respiratory distress syndrome (ALI/ARDS);
see Chapter 8), which occurred in more than a third of
patients in one series and is often associated with cerebral
oedema (Baudouin et al., 1995). It has been suggested that
precapillary arteriolar dilatation disrupts pulmonary capillaries by exposing them to an increased hydrostatic pressure,
but it seems more likely that the development of ALI/ARDS
is simply a manifestation of the generalized increase in capillary permeability.
The presence of ascites may contribute to respiratory
difficulty. Respiratory dysfunction may also be related to
pulmonary aspiration, atelectasis or bronchopneumonia.
IMPAIRED HOST DEFENCES AND SEPSIS
A number of abnormalities have been identified as contributing to the increased susceptibility of patients with ALF to
infection. These include a deficiency of complement factors
involved in both the classical and alternative pathways (Wyke
et al., 1980), impaired opsonization, a reduced chemoattractant activity of patients’ sera for normal polymorphonuclear
leukocytes (Wyke et al., 1982a) and a reduction in plasma
fibronectin levels (Gonzalez Calvin et al., 1982). It has also
been suggested that decreased hepatic production of hepatocyte growth factor-like/macrophage-stimulating protein
might cause impaired Kupffer cell phagocytosis in ALF
(Harrison et al., 1994). Consequently, bacteraemia/bacterial
infections are relatively common and are most often due to
Gram-positive organisms (mainly streptococci and Staphylococcus aureus in the early stages, with coagulase-negative
staphylococci and enterococcci being encountered later),
whereas Escherichia coli is the commonest type of Gramnegative organism isolated (Wade et al., 2003; Wyke et al.,
1982b). Common sites of infection include peritoneum,
lung, intravascular devices and urinary tract. Line sepsis,
cholangitis and endocarditis also occur. Fungal infections
are sometimes seen, usually after the first week of intensive
care. The usual signs of infection such as fever and leukocytosis are often absent.
RENAL DYSFUNCTION (Eckardt, 1999)
Renal impairment is common in patients with ALF and
occurs in up to 75% of cases secondary to paracetamol overdose and in 30% of all other cases. The aetiology is usually
multifactorial. Prerenal factors such as intravascular volume
depletion due to gastrointestinal haemorrhage, diarrhoea or
excessive diuretic administration are frequently implicated.
Acute tubular necrosis (ATN) may be precipitated by hypotension, sepsis, DIC or the administration of nephrotoxic
drugs. Patients with jaundice generally appear to be at
increased risk of developing ATN. Occasionally combined
liver and renal disease may be due to a common pathogenic
mechanism which directly or indirectly affects both organs
387
(e.g. glomorulonephritis associated with viral hepatitis).
Paracetamol may cause direct renal toxicity and renal
failure occurs in more than 75% of cases of paracetamol
poisoning.
Hepatorenal syndrome (Epstein, 1992) (see also Chapter
13). This is a diagnosis of exclusion and can be defined as
renal failure occurring in a patient with liver failure in the
absence of clinical, laboratory or anatomical evidence of
other possible causes. In clinical practice it can be difficult
to distinguish hepatorenal syndrome from other causes of
acute renal failure. Renal impairment is considered to be
functional and reversible because:
■
■
■
■
pathological lesions are minimal and inconsistent;
normal function returns if the liver recovers;
kidneys from patients with hepatorenal syndrome function normally after transplantation into recipients with
normal liver function (Koppel et al., 1969);
renal function recovers when patients with hepatorenal
syndrome undergo successful liver transplantation
(Gonwa et al., 1991).
The pathogenesis of hepatorenal syndrome remains obscure,
but renal dysfunction appears to be related to intense intrarenal vasoconstriction with preferential cortical ischaemia
and reduced glomerular filtration which is unresponsive to
expansion of the circulating volume. The factors responsible
for these changes have not yet been fully elucidated, but
possibilities include:
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■
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■
■
■
■
diminished perfusion pressure;
endotoxaemia;
hepatorenal and portorenal reflexes;
activation of the renin–angiotensin system;
increased sympathetic nervous system activity;
alterations in the balance between vasodilator prostaglandins and vasoconstrictor thromboxanes;
a relative impairment of renal kallikrein production.
There is also some evidence to suggest that endothelins are
involved in the pathogenesis of the hepatorenal syndrome
(Moore et al., 1992; Soper et al., 1996).
Since renal tubular function is preserved in the face of a
reduced GFR, the capacity for sodium reabsorption and the
concentration of urine are relatively normal. In contrast to
ATN, therefore, urine sodium is low (< 10 mmol/L), urine
osmolality is high (> 1000 mosmol/kg) and the urine-toplasma creatinine ratio is higher than 10. Blood urea may be
deceptively low because of the reduced capacity of the liver
to metabolize ammonia to urea. Nevertheless, using electron
microscopy some degree of tubular damage can be demonstrated (Mandal et al., 1982) and most believe that hepatorenal syndrome can evolve into ATN. The prognosis of
hepatorenal syndrome is poor.
PANCREATITIS
Biochemical and radiological evidence of pancreatitis may
be found in more than 30% of patients with ALF and should
388
INTENSIVE CARE
be suspected in those with cardiovascular instability or
hypocalaemia. Pancreatitis is associated with more severe
multiple-organ dysfunction, more rapid deterioration and
an increased mortality.
RARE COMPLICATIONS
Rare complications of ALF include:
■
■
■
■
■
myocarditis;
pneumonia due to atypical organisms;
aplastic anaemia;
transverse myelitis;
peripheral neuropathy.
Establishing the cause of ALF
It is important to determine the cause of ALF because:
■
■
■
in some cases specific therapy may be indicated;
there may be implications for the spontaneous recovery
of liver function;
screening of family members (e.g. Wilson’s disease) or
close contacts (e.g. viral hepatitis) may be required.
Clinical examination is usually unhelpful but the likely cause
of ALF can often be ascertained from a careful history.
Hepatitis B infection is associated with intravenous drug
abuse, blood transfusion and inoculation injuries, while
hepatitis A and E arise from ingestion of contaminated food
or water and often occur in epidemics. The hepatitis B virus
may also be spread via contaminated acupuncture needles,
by tattooing and by close personal contact (e.g. sexual intercourse, particularly in homosexuals).
Serological investigations should include hepatitis A
immunoglobulin M (IgM) antibody, hepatitis B core antigen
antibody (HBcAb), hepatitis B surface antigen (HBsAg),
hepatitis B e antigen (HBeAg) and hepatitis B DNA, as well
as hepatitis C, D and E serology.
There may be a history of drug ingestion (intentional,
with or without suicidal intent, or accidental) or exposure
to poisons or chemicals. Appropriate drug screening, especially for paracetamol, should then be performed.
Halothane hepatitis should be suspected when the signs
of hepatocellular necrosis, often accompanied by fever and
chills, develop within 2 weeks of exposure.
Acute fatty liver of pregnancy usually presents as nausea,
repeated vomiting and abdominal pain between the 30th
and 38th week of gestation, and may continue to deteriorate
even following delivery.
When Wilson’s disease is suspected, plasma caeruloplasmin levels and urinary copper excretion should be determined pre- and post-penicillinamine challenge. The eyes
should be examined for Kayser–Fleischer rings. If present
they confirm the diagnosis, but their absence does not
exclude the condition.
Liver biopsy may confirm the aetiology of ALF and can
determine the degree of hepatocyte necrosis. This may
provide some indication of prognosis, although sampling
error may misrepresent the overall degree of necrosis. More-
over the presence of coaglopathy usually precludes the
percutaneous approach and the transjugular route may
therefore be preferred. In practice liver biopsy is indicated
only very occasionally, usually to exclude underlying cirrhosis or malignancy (e.g. lymphoma).
Imaging the liver by ultrasound or computed tomography
(CT) scanning may be useful to exclude hepatic vein thrombosis, chronic liver disease, space-occupying lesions or
biliary obstruction, as well as to determine liver size and to
assess liver vasculature if transplantation is contemplated.
PATHOGENESIS OF ENCEPHALOPATHY
AND CEREBRAL OEDEMA
Altered cerebral metabolism, abnormal neurotransmitter
function, direct effects on neuronal membranes, disturbed
activity of Na+/K+ ATPase or, most likely, a combination of
these factors, are thought to be responsible for the disturbance of neurotransmission that precipitates hepatic
encephalopathy (Riordan and Williams, 1997). These abnormalities are in turn largely related to the accumulation of
toxic substances normally metabolized by the liver. Although
there are many similarities between the clinical and biochemical features of encephalopathy in ALF and chronic
liver impairment, there are also a number of respects in
which they differ; in particular, cerebral oedema is a common
and important complication of ALF, but is extremely rare in
chronic liver disease. In both cases, the disturbance of cerebral function is often exacerbated by:
■
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■
■
hypoglycaemia;
alterations in acid–base homeostasis;
fluid and electrolyte abnormalities;
hypoxia and hypercarbia;
systemic inflammation (usually sepsis).
In addition, patients with ALF are very sensitive to the effects
of analgesics and sedatives, not only because of impaired
drug metabolism, but also because of increased cerebral
sensitivity and changes in plasma protein binding.
Examples of recognized toxins that accumulate in liver
failure include:
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■
ammonia (colonic bacteria probably play a limited role
in ammonia production, whereas enterocytes are a major
source of ammonia);
fatty acids;
bile acids (unlikely to play a role in the pathogenesis of
encephalopathy);
mercaptans (derived from methionine);
phenols;
various aromatic amino acids.
The serum amino acid profile is abnormal in both chronic
liver impairment and ALF. In patients with chronic liver
disease and superimposed acute insults, there is an increase
in blood levels of the aromatic amino acids and a reduction
in the concentrations of the branched-chain amino acids.
References pages 383–388
Baudouin SV, Howdle P, O’Grady JG, et al.
(1995) Acute lung injury in fulminant hepatic
failure following paracetamol poisoning.
Thorax 50: 399–402.
Bihari D, Gimson AE, Lindridge J, et al.
(1985) Lactic acidosis in fulminant hepatic
failure. Some aspects of pathogenesis and
prognosis. Journal of Hepatology 1: 405–
416.
Eckardt K-U (1999) Renal failure in liver
disease. Intensive Care Medicine 25: 5–14.
Epstein M (1992) The hepatorenal
syndrome – newer perspectives. New
England Journal of Medicine 327: 1810–
1811.
Gonwa TA, Morris CA, Goldstein RM, et al.
(1991) Long-term survival and renal function
following liver transplantation in patients with
and without hepatorenal syndrome –
experience in 300 patients. Transplantation
51: 428–430.
Gonzalez Calvin J, Scully MF, Sanger Y, et
al. (1982) Fibronectin in fulminant hepatic
failure. British Medical Journal 285: 1231–
1232.
Harrison P, Degen SJ, Williams R, et al.
(1994) Hepatic expression of hepatocytegrowthfactor-like/macrophage-stimulating
protein mRNA in fulminant hepatic failure.
Lancet 344: 27–29.
Izumi S, Langley PG, Wendon J, et al.
(1996) Coagulation factor V as a prognostic
indicator in fulminant hepatic failure.
Hepatology 23: 1507–1511.
Koppel MH, Coburn JW, Mims MM, et al.
(1969) Transplantation of cadaveric kidneys
from patients with hepatorenal syndrome.
Evidence for the functional nature of renal
failure in advanced liver disease. New
England Journal of Medicine 280: 1367–
1371.
Mandal AK, Lansing M, Fahmy A (1982)
Acute tubular necrosis in hepatorenal
syndrome: an electron microscopy study.
American Journal of Kidney Diseases 2:
363–374.
Moore K, Wendon J, Frazer M, et al. (1992)
Plasma endothelin immunoreactivity in liver
disease and the hepatorenal syndrome.
New England Journal of Medicine 327:
1774–1778.
Pereria LM, Langley PG, Hayllar KM, et al.
(1992) Coagulation factor V and VIII/V ratio
as predictors of outcome in paracetamol
induced fulminant hepatic failure: relation to
other prognostic indictors. Gut 33: 98–102.
Schmidt LE, Dalhoff K (2002) Serum
phosphate is an early predictor of outcome
in severe acetaminophen-induced
hepatotoxicity. Hepatology 36: 659–665.
Soper CP, Latif AB, Bending MR (1996)
Amelioration of hepatorenal syndrome with
selective endothelin-A antagonist. Lancet
347: 1842–1843.
Vallance P, Moncada S (1991)
Hyperdynamic circulation in cirrhosis: a role
for nitric oxide? Lancet 337: 776–778.
Wade J, Rolando N, Philpott-Howard J, et
al. (2003) Timing and aetiology of bacterial
infections in a liver intensive care unit.
Journal of Hospital Infection 53: 144–146.
Wyke RJ, Rajkovic IA, Eddleston AL, et al.
(1980) Defective opsonisation and
complement deficiency in serum from
patients with fulminant hepatic failure. Gut
21: 643–649.
Wyke RJ, Yousif-Kadaru AG, Rajkovic IA, et
al. (1982a) Serum stimulatory activity and
polymorphonuclear leucocyte movement in
patients with fulminant hepatic failure.
Clinical and Experimental Immunology 50:
442–449.
Wyke RJ, Canalese JC, Gimson AE, et al.
(1982b) Bacteraemia in patients with
fulminant hepatic failure. Liver 2: 45–52.
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