43 057 Umschlag engl. 28.04.

2004 11:11 Uhr Seite 1

LIVER DISEASES
AND HEPATIC
ENCEPHALOPATHY
Scientific Product Monograph

Merz Pharmaceuticals GmbH

Frankfurt am Main
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 3

LIVER DISEASES
AND HEPATIC
ENCEPHALOPATHY
Scientific Product Monograph

Merz Pharmaceuticals GmbH

Frankfurt am Main
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 4

CONTENTS

Product profile 6 6 Clinical results with Hepa-Merz® 72

6.1 Clinical research with Hepa-Merz® 74
1 Liver function and hepatic encephalopathy 9 6.2 Experimental clinical studies with Hepa-Merz® 75
1.1 Ammonia metabolism and detoxification function of the liver 9 6.2.1 Effects of Hepa-Merz® on ammonia concentration 75
1.2 Liver diseases as the cause of hepatic encephalopathy 13 6.2.2 Effects of Hepa-Merz® on protein synthesis in muscle 82
6.2.3 Effects of Hepa-Merz® on neurometabolites 84
2 Hepatic encephalopathy – clinical picture and pathogenesis 23 6.3 Clinical results with intravenous Hepa-Merz® therapy 86
2.1 Definition and clinical forms of hepatic encephalopathy 23 6.3.1 Hepa-Merz® infusion in comparison with placebo 86
2.2 Precipitating factors in hepatic encephalopathy 27 6.3.2 Meta-analysis of placebo-controlled trials 93
2.3 Pathogenesis of hepatic encephalopathy 30 6.4 Clinical results with oral Hepa-Merz® therapy 96
2.3.1 Neuropathological changes 30 6.4.1 Hepa-Merz® Granules in comparison with placebo 96
2.3.2 Ammonia and the glial hypothesis 32 6.4.2 Hepa-Merz® Granules in the medical practice 100
2.3.3 Additional pathological mechanisms 35 6.4.3 Hepa-Merz® Granules in comparison with lactulose 105
6.5 Summary of results with Hepa-Merz® 106
3 Diagnosis of hepatic encephalopathy 40
3.1 Diagnostic procedures 40 7 Safety and tolerability 108
3.2 Early diagnosis 42
3.3 Criteria for assessing degree of severity 8 Chemistry, toxicology and pharmacokinetics of Hepa-Merz® 110
and monitoring the course of disease 45 8.1 Chemico-physical data 110
8.2 Toxicology 111
4 Treatment of hepatic encephalopathy 51 8.3 Pharmacokinetics 111
4.1 General therapeutic concepts 51
4.2 Dietary therapy 52 9 Basic information 112
4.3 Drug therapy 53
10 Abbreviations 117
5 Mechanism of action and pharmacodynamics of Hepa-Merz® 59 11 References 119
5.1 Mechanism of action 59
5.2 Pharmacodynamic effects in animal experiments 62
5.2.1 Effects of Hepa-Merz® on ammonia metabolism 62
5.2.2 Effects of Hepa-Merz® on metabolism in the brain 64

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PRODUCT PROFILE
Hepatic The clinical picture of hepatic encephalopathy (HE) ari-
encephalopathy ses as a complication of chronic and, more rarely, acute
liver disease. It is a potentially reversible functional
disorder of the brain with neurological and psychiatric
symptoms which may occur with different degrees of
severity (HE grades 0-4) and in varying combinations.
Deficits of psychomotor function can be demonstrated
in the early stages; even at the start, these represent a
certain risk especially at work and in traffic. At first there
are mild non-specific disturbances of sleep, drive,
mood and cognitive function. As the condition prog-
resses, symptoms of psychomotor retardation and neuro-
muscular disturbances (e.g. asterixis) occur as well as
disorientation and memory defects. With higher grades
of HE, the clinical picture is characterised by increas-
ingly altered levels of consciousness (hepatic coma).
The early diagnosis of hepatic encephalopathy is of
great importance for the future course of the condition
and is possible with e.g. psychometric tests that are
easy to perform.
Functional impairment The most common cause of hepatic encephalopathy is
of the liver cirrhosis of the liver. Hepatic encephalopathy occurs in
up to 70% of patients with cirrhosis at some time during
the course of their disease. These patients in particular
should be carefully monitored for signs of hepatic en-
cephalopathy. Increasing structural replacement with con-
nective tissue leads to the loss of functioning hepatic
parenchymal tissue and a reduction in the detoxification
capacity of the liver. In addition, developing portal
hypertension leads to the formation of a collateral circu-
lation through which non-detoxified blood can by-pass
the liver to reach the systemic circulation. Both these
6 7
mechanisms contribute to the neurotoxins present in
portal vein blood reaching the brain via the systemic cir-
culation. Once there, neurotoxic ammonia in particular
disrupts the function of neurones and astrocytes, giving
rise to the symptoms of hepatic encephalopathy. An
important aim of treatment is therefore the reduction of
the ammonia present in the body by lowering the
amount of ammonia produced and increasing its detox-
ification.
The active ingredient of Hepa-Merz® infusion concen- L-ornithine-
trate, granules and chewable tablets is L-ornithine- L-aspartate
L-aspartate, the salt of the natural amino acids ornithine lowers neurotoxic NH3
and aspartate. Through the mechanism of substrate
activation, the two substances stimulate the urea cycle
(which metabolises ammonia to urea) in the liver and
glutamine synthesis in the liver, muscle and brain. Urea
and glutamine (after further metabolism) can be excret-
ed via the kidneys. L-ornithine-L-aspartate thus activa-
tes the two important metabolic pathways in the human
body for the detoxification of ammonia.
L-ornithine-L-aspartate has been used for many years L-ornithine-
for the treatment of conditions associated with impaired L-aspartate
hepatic detoxification (e.g. in cirrhosis of the liver) and is effective
its sequelae, when there are symptoms of minimal (sub- and well-tolerated
clinical) and overt hepatic encephalopathy. Hepa-Merz®
is usually well tolerated or very well tolerated.
In the most recent clinical trials, the efficacy of Hepa- L-ornithine-
Merz® infusion concentrate and granules was tested L-aspartate
against placebo. L-ornithine-L-aspartate showed a sta- evidence-based
tistically significant effect with respect to an improve- medicine
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 8
ment in mental state (reduction in the HE grade), in-
creased detoxification (reduction of the ammonia con-
centration in the blood) and positive effects on psycho-
motor function (reduction of time required in the number
connection test). With these findings, evidence-based
medicine criteria for demonstrating efficacy have been
fulfilled.
Summary:
The efficacy of Hepa-Merz® infusion concentrate and granules in the
treatment of minimal (subclinical) and overt hepatic encephalopathy in
liver disease associated with impaired hepatic detoxification (e.g. in
cirrhosis of the liver) has been clearly demonstrated in placebo-control-
led clinical trials. Treatment with L-ornithine-L-aspartate lowers the
ammonia concentration and thus improves the mental state and psycho-
motor performance. Hepa-Merz® is well or very well tolerated in the
majority of cases.
8 9
1 LIVER FUNCTION AND
HEPATIC ENCEPHALOPATHY
Hepatic encephalopathy is a complication of both chronic
and acute liver diseases. The most common underlying
cause is the reduced detoxification capacity of the
damaged liver in combination with a collateral porto-
systemic circulation through which ammonia-containing
blood by-passes the liver to reach the systemic circula-
tion.
1.1 Ammonia metabolism and detoxifi-
cation function of the liver
An important function of the liver as a metabolic organ Ammonia production
is the detoxification of ammonia produced from nitro- in the intestine,
gen-containing compounds. In the hepatic cells ammo- muscle and kidneys
nia is converted to urea and glutamine which can be
excreted via the kidneys.
The ammonia present in the blood is released endoge-
nously during cell metabolism from nitrogen-containing
compounds such as proteins, amino acids, nucleic
acids and amines, or synthesised by the intestinal flora
and absorbed into the blood stream. A large quantity of
ammonia originates in the intestines. Mention should be
made of both bacterial ammonia production in the large
intestine and abacterial degrading of nitrogen-contain-
ing metabolites in the small intestine.
Ammonia synthesis in the muscles and kidneys contrib-
utes to the ammonia concentration in the blood to a
smaller extent. Ammonia produced in the muscle in-
creases in proportion to the work of the muscle; in
resting muscle, ammonia uptake and excretion are
approximately in equilibrium. In the kidneys, only a small
quantity of ammonia is produced under normal conditions.
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 10

An increase in ammonia synthesis is seen in special
circumstances e.g. on treatment with diuretics and in
hypokalaemia.
In the liver itself, large quantities of ammonia are also
produced during protein breakdown. This is immediate-
ly detoxified, however, so that the liver does not contrib-
ute to the blood ammonia concentration when its function
is intact.
type of (reversible) detoxification also takes place in the
brain and the liver.
Glutamine is broken down in the kidneys by the action
of glutaminase to give glutamate and ammonia; gluta-
mate is further converted to a-ketoglutarate by the
release of a second ammonia molecule. The ammonia
released in the kidneys can be excreted in the urine; a
small quantity is re-absorbed.

Ammonia Ammonia is physically dissolved in the blood and is in

metabolism equilibrium with ammonium ions (NH3/NH4+); this is pH-
Urea
in the body dependent. With a rise in the pH (alkalosis), the propor-
tion of diffusible toxic ammonia (NH3) increases.

Under physiological conditions there is a natural equi- Small intestine Large intestine

librium between ammonia production and ammonia

detoxification. The normal non-toxic serum levels in the
peripheral blood are in the region of 30 µmol/l. The
highest ammonia concentrations are found in the portal
vein blood, which carries the ammonia produced in the
intestinal tract.
Muscle Liver
Figure 1.1 summarises the pathways involved in the
Glutamine
metabolism of ammonia in the human body.
The liver is the most important organ to detoxify am-
monia produced in the large and small intestine, Urea
muscles and kidneys. Most of the urea produced there
is excreted via the kidneys, with a small proportion
Kidney
being excreted via the gastrointestinal tract.
Urea
Some of the ammonia present in the human body is
detoxified in the muscles. Glutamine is produced from Fig 1.1: Ammonia metabolism in the body

ammonia and glutamate. Apart from muscle tissue, this

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Ammonia Some 70-80% of the ammonia present in the portal These highly specialized cells, also referred to as scav-
detoxification vein blood is removed during passage through the liver. enger cells, form only 5-10% of the liver parenchymal
in the liver This is due to the synthesis of urea and glutamine. cells.

Urea synthesis and glutamine synthesis take place in Summary:

two different cell systems organized sequentially in the A large proportion of the ammonia present in the blood comes from the
hepatic acinus (Figure 1.2). gastrointestinal tract, with contributions in the internal milieu from mus-
cles and kidneys. Ammonia-containing blood is transported through the
portal vein to the liver where it is detoxified by the formation of urea and
glutamine. Functional units of periportal and perivenous hepatocytes in
Periportal hepatocytes Perivenous hepatocytes the acini of the liver control the ammonia concentration in the blood.

Cytosol Cytosol
Mitochondrion
Mitochondrion
Glutaminase 1.2 Liver diseases as the cause of
hepatic encephalopathy
Carbamyl
phosphate Glutamine synthetase
Glutamine synthetase I The most common liver disease that causes hepatic
encephalopathy is cirrhosis of the liver. This can also
Glutamine
arise as the result of other liver diseases (e.g. hepatitis,
Urea
fatty liver). Genetic enzyme deficiencies and acute liver
failure are much less common causes of hepatic en-
Glutamine Glutamine cephalopathy.
Urea
Hepatic encephalopathy is a relatively frequent complica- Hepatic encephalopa-
Figure 1.2: Detoxification of ammonia in the liver. Formation of urea and glutamine in periportal and
tion of cirrhosis of the liver, particularly if there is a collat- thy is a common com-
perivenous hepatocytes (after Häussinger, 1990) NH4+: Ammonia; Cbm-P: Carbamyl phosphate; Orn: eral portosystemic circulation. Hepatic encephalopathy plication of cirrhosis
Ornithine; Cit: Citrulline; Arg-Suc: Arginine succinate; Arg: Arginine can be demonstrated in 30-70% of these patients. The of the liver
pathology of cirrhosis of the liver consists of destruction of
In periportal hepatocytes, ammonia is converted to urea the normal parenchymal structure and replacement of the
in the urea cycle. In the subsequently activated perive- parenchyma with nodular connective tissue. This is a
nous hepatocytes, the ammonia is metabolised to glu- common chronic liver disease with a prevalence of about
tamine by the action of glutamine synthetase. 1%.

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Cirrhosis: The cause of cirrhotic changes in the liver in more than
causes and half of the patients is chronic alcohol intoxication. In a
degree of severity third, cirrhosis is the result of hepatitis. More rarely there
is a metabolic cause (e.g. Wilson’s disease, haemo-
chromatosis, alpha-1-antitrypsin deficiency etc.)
or vascular cause (e.g. chronic right ventricular failure)
or an unexplained disease process. Progression of
cirrhosis is more or less the same whatever the aetiology.
The degree of severity of cirrhosis is usually expressed
by the Child-Pugh classification, stages A, B and C,
which takes into account the laboratory parameters of
bilirubin, albumin and the prothrombin time as well as
ascites and encephalopathy (Table 1.1).
Parameter Number of Points
1 2 3 brain.
Haemodynamic consequences of cirrhosis
of the liver
The connective tissue changes with resultant loss of Portal hypertension
vital hepatic parenchyma increase the vascular resis- and toxic NH3-
tance of the liver leading to the development of portal concentration in
hypertension. Raised pressure in the portal vein induces the brain
the formation of a collateral circulation between the por-
tal system and other veins, known as a portosystemic
shunt. Portal vein blood by-passes the liver through
oesophageal and abdominal varices, rectal varices,
abdominal wall vessels and intrahepatic collaterals to
hepatic veins. This means that portal vein blood which
is particularly rich in ammonia (due to absorption of the
ammonia produced in the gastrointestinal tract) flows
directly into the systemic circulation, by-passing the
liver through these collateral vessels. Because of the
resultant hyperammonaemia, muscles and the brain
take up greater amounts of ammonia to compensate;
this gives rise to toxic ammonia concentrations in the

Encephalopathy Grade 0 Grade I/II Grade III/IV Reduced ammonia detoxification in the liver
Ascites none slight severe
Bilirubin (mg/dl) ≤2 2–3 >3 At the same time, the loss of functioning hepatic tissue
Bilirubin (µmol/l) (≤34) (34–51) (>51) has an effect on the detoxification capacity of the liver.
Albumin (g/dl) >3,5 2,8–3,5 <2,8
Ammonia can no longer be broken down in sufficient
Prothrombin time (seconds above standard) 1–3 4–6 >6
quantities. Urea synthesis and glutamine synthesis are
or INR <1,7 1,8–2,3 >2,3
reduced in patients with cirrhosis. In contrast, there is
Table 1.1: Assessment of hepatic function reserve based on Child-Turcotte criteria, modified by Pugh. increased activity of glutaminase, which converts gluta-
Addition of the points gives the Child-Pugh stage: A (5-6 points), B (7-9) and C (10-15) mine into ammonia, i.e. release of ammonia is greatly
increased in the cirrhotic liver (Figure 1.3).

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% synthesis rate/wet liver weight Percentage ± SEM Normal state Haemodynamic causes Metabolic causes
µmol/hxg

Control
500
Fatty liver **
Cirrhosis
400

300
Urea Urea Urea
Glutamine Glutamine Glutamine
200
NH +4 NH +4 NH +4
100
**
** * **
0
Urea synthesis Glutamine synthesis Glutaminase
activity
*p<0,01 **p<0.0005 vs control

Figure 1.3: Activity of urea synthesis, glutamine synthesis and glu-
taminase in biopsies of histologically-confirmed normal liver tissue,
fatty liver tissue and cirrhotic liver tissue. The data are based on the
calculation of synthesis rate per wet liver weight (µmol/h x g). The
synthesis rate of control liver tissue corresponds to 100% (after
Gerok, 1996)
Figure 1.4 gives an overview of the factors playing a role
in portosystemic encephalopathy – pathological hae-
modynamics and reduced detoxification in the liver.
Both mechanisms contribute to the increased ammonia
in the blood and the occurrence of hepatic encephalop-
athy.
The clinical course of cirrhosis of the liver is generally
chronic and progressive. The most important complica-
tions are bleeding from oesophageal or abdominal var-
ices, ascites, jaundice, clotting disorders, renal failure
and hepatic encephalopathy. On average, about 40%
of patients with cirrhosis develop overt hepatic en-
cephalopathy during the course of the disease.
Figure 1.4: Pathophysiology of hepatic encephalopathy in cirrhosis
of the liver (after Gerok, 1995)
Data on the incidence of subclinical hepatic encephalop-
athy vary, ranging from 30% to 80% (Häussinger and
Maier, 1996). Early stages in particular often remain
unrecognized.
Fatty liver (steatosis) is the most widespread liver dis- Fatty liver and
ease in the population. It may be the result of various cirrhosis
conditions (e.g. diabetes mellitus, disorders of lipid
metabolism) or toxic effects (alcohol, drugs, industrial
toxins). The most common cause is toxic damage due
to alcohol misuse.
An increased deposit of triglycerides in the hepatic cells
is characteristic of fatty liver. Firstly small deposits can
be seen (fine droplet fatty change). As the condition
progresses, the size of the fat droplets in the hepatic
cells increases (large droplet steatosis).

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The fatty deposits lead to an overall enlargement of the
liver.
Symptoms of a fatty liver include sensations of pressure
and fullness in the right side of the upper abdomen and
frequently also pain in the region of the liver, as well as
flatulence, fullness, nausea and reduced performance.
The enlarged liver is usually easily palpable through the
abdominal wall. Results of liver-specific laboratory tests
may occasionally be abnormal, depending on the extent
of liver damage and loss of function.
With fatty liver the detoxification function may already be
limited. Studies have shown that urea and glutamine
synthesis are reduced in fatty livers (see Figure 1.3).
Values lie somewhere between those in cirrhotic tissues
and those found in healthy livers. It is therefore probable
that minimal hepatic encephalopathy is also present in
patients with fatty livers, or can develop under the
influence of additional precipitating factors (see section
2.2).
At first these processes are reversible with the removal
of the cause, i.e. in most cases misuse of alcohol. With
continued presence of the toxin, the process frequently
progresses with increasing fibrosis developing into cir-
rhosis of the liver. The effects of alcohol may also give
rise to inflammation of the liver with hepatic cell necrosis
and cell infiltration – alcoholic hepatitis – which may also
develop into cirrhosis of the liver.
18
Non-alcoholic steatohepatitis (NASH) also belongs in Non-alcoholic
the group of non-alcoholic fatty changes in the liver, steatohepatitis (NASH)
with a spectrum ranging from steatosis through steato-
hepatitis and steatofibrosis up to cirrhosis.
Inflammation of the liver may have various underlying Hepatitis and cirrhosis
causes. The most important of these are hepatitis vi- of the liver
ruses, autoimmune processes and drugs. On occasion
the cause may not be identified. Chronic hepatitis may
develop into cirrhosis of the liver and hence be an indi-
rect cause of hepatic encephalopathy.
Viral hepatitis is the most common. Table 1.2 gives an
up-to-date overview of hepatotropic viruses (Caspary
2001). As a rule, acute viral hepatitis heals without caus-
ing cirrhosis. Hepatic encephalopathy may occur in
fulminant viral hepatitis even without cirrhosis. In chron-
ic hepatitis, cirrhotic changes in the liver arise as part of
the inflammatory process. Chronic viral hepatitis can
therefore be an indirect cause of hepatic encephalop-
athy. Hepatitis B, for example, becomes chronic in
some 10% of cases and a number of these patients go
on to develop cirrhosis. In contrast, hepatitis C follows
a chronic course in some 80% of cases and often
develops into cirrhosis of the liver.
19
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HAV HEV HBV HDV HCV Normal CAH IIa CAH IIb CAH  cirrhosis
Picorna- Calici- Hepadna- Delta- Flavi- n=50 n=44 n=41 n=37
Virus family viridae viridae viridae viridae viridae
160 *
Genome RNA RNA DNA RNA RNA
*
Incubation time (days) 14–45 14–60 30–180 30–180 14–180

Ammonia (µg/dl)
120 *
Transmission faecal-oral faecal-oral parenteral parenteral parenteral
Diagnositics (acute infection) anti-HAV anti-HEV HbsAg anti-HDV anti-HCV
80
IgM IgM anti-HBc-IgM IgM HCV-RNA
Becomes chronic no no <5 % <10 % 50–80 %
40
(adult) (co-infection) arterial
90 % <80 % venous
0
(perennial) (super-infection)
Cirrhosis of the liver – – 20–30 % 30–40 % 20–30 % Figure 1.5: Arterial and venous plasma ammonia concentrations in
with chronic hepatitis different stages of chronic active hepatitis (mean ± standard devia-
Oncogenicity no no yes ? yes tion). The statistical significance * (p<0.05) refers to the comparison
with normal controls (after Müting et al., 1988).
Notifiable disease* I, D I, D I, D I, D I, D CAH: chronic active hepatitis
Table 1.2: Characteristics of hepatotropic viruses (after Caspary 2001); I = illness; D = death;
*Obligation to notify disease in accordance with §3 of the Federal Infectious Diseases Protection Law
Fulminant viral hepatitis in particular but also drug-induc- Acute liver failure
ed toxic reactions may rarely lead to acute liver failure
which has a dramatic clinical picture. This is defined by
In less common autoimmune hepatitis, loss of immunologi- the combination of severe liver insufficiency and alter-
cal tolerance leads to self-destruction of the liver. The ation in the level of consciousness with hepatic en-
etiology and mechanisms are mostly unclear. The cephalopathy. The diminution in liver function is character-
inflammatory process leads to loss of functioning paren- ized by a rapid fall in clotting factors, with a sharp rise
chyma and to fibrotic changes in the liver. in transaminases and accompanying jaundice. The
appearance of hepatic encephalopathy is an unfavour-
In chronic hepatitis, the reduced detoxification capacity of able prognostic sign. Various classifications of the
the damaged liver tissue appears even before cirrhosis degree of severity of acute liver failure have been de-
develops. A study on patients with chronic hepatitis showed fined based on the interval between the appearance of
that even before the formation of a by-pass circulation – jaundice and encephalopathy. In general it can be said
associated with progressive liver damage – there is an in- that the more quickly hepatic encephalopathy follows
crease in the blood ammonia concentration (Figure 1.5). the signs of jaundice, the worse the prognosis, i.e. 1 week

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in hyperacute forms and more than 4 weeks in sub-
acute.
The symptoms of encephalopathy in acute liver failure
do not basically differ from hepatic encephalopathy due
to other causes. However, there is a risk of cerebral
oedema and fatal cerebral herniation as a result of
raised intracranial pressure. The prognosis in acute liver
failure is poor; mortality without a liver transplant is
about 80%.
Summary:
The most common liver disease which causes hepatic encephalopathy
is cirrhosis of the liver. The typical picture of disease includes liver cell
damage with reduced detoxification capacity in combination with colla-
teral portosystemic circulations. Other liver conditions may develop into
cirrhosis during the course of the disease e.g. fatty liver or hepatitis. In
acute liver failure, hepatic encephalopathy may occur without cirrhosis
or portosystemic shunts.
22
2 HEPATIC ENCEPHALOPATHY –
CLINICAL PICTURE AND PATHOGENESIS
2.1 Definition and clinical forms of
hepatic encephalopathy
Hepatic encephalopathy (HE) is a metabolically induc- Definition of hepatic
ed, potentially reversible, functional disturbance of the encephalopathy
brain which may occur during the course of chronic and
acute liver diseases (see section 1.2). The term encom-
passes a syndrome of individual neurological and
psychological components that may occur in different
combinations and with varying degrees of severity. The
symptoms and signs of hepatic encephalopathy do not
basically differ from encephalopathies of other genesis;
the definition therefore includes a concurrently demon-
strable liver disease.
Occasionally, portosystemic encephalopathy (PSE) is
classified as a subgroup of hepatic encephalopathy.
This refers to encephalopathy in cirrhosis of the liver in
combination with portosystemic collateral circulations
(see section 1.2). However, this form cannot basically
be distinguished from other forms of hepatic encepha-
lopathy.
The clinical picture of hepatic encephalopathy is very Clinical picture and
variable and can be associated with impairment of intel- degree of severity
lectual and psychomotor functions as well as changes
in personality and level of consciousness. Clinical pro-
gression varies greatly: acute, episodic, fluctuating and
chronic forms are possible.
Hepatic encephalopathy is divided into five degrees
of severity according to the West Haven criteria, on
the basis of clinical symptoms and signs as well as
the findings of psychometric tests (Table 2.1). These
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divisions are based largely on the mental state of the Minimal (subclinical) encephalopathy is present in 30-
patient; they range from HE grade 0 with no distur- 70% of people with cirrhosis. The burden of this distur-
bance of consciousness to deep coma with HE grade bance depends on the demands made on the individu-
IV. al. Diminished performance may be of particular
importance in manual work (e.g. operating conveyer
belt) and driving a car. Reduction in the quality of life
HE grade State of conciousness/ Behaviour Neuromuscular and personal safety may be associated even with HE
intellect symptoms grade 0 (see section 3.2).

Minimal clinically normal but clinically normal but disturbance of fine

Typical symptoms and signs of HE grades I-IV are pre- Overt hepatic
subclinical abnormal pathological abnormal pathological motor function
and psychometric tests and psychometric tests sented in Table 2.1. The degree of severity of hepatic encephalopathy
I reduced concentration and personality changes disturbance of fine encephalopathy can progress very quickly.
prolonged reaction time, motor function Neuropsychiatric symptoms of overt hepatic encepha-
sleep disorders, fatigue
(reduced alertness) lopathy are extremely variable. The first clinical indica-
II retardation, lethargy marked personality asterixis, slurred tions are, for example, sleep disturbances, loss of drive
changes, temporal speech and mood swings as well as loss of fine motor func-
disorientation
tions. Poor attention span, lack of concentration and
III disorientation, somnolence, bizarre behaviour, hypo- and hyperreflexia,
stupor delusions asterixis, convulsions reduced mental agility can be taken as signs of dimin-
IV coma ceased areflexia, loss of tone ished cognitive function. As these are non-specific, they
are often not recognized as signs of hepatic encepha-
Tab. 2.1: Degrees of severity of hepatic encephalopathy: Classification of the mental state according lopathy. With HE grade II, symptoms of psychomotor
to West Haven criteria (modified after Conn and Bircher 1994)
retardation with disorientation and memory defects
appear. Characteristic flapping tremor (asterixis) is a
sign of neuromuscular disorder, as are ataxia, dysarthria
Minimal hepatic In the stage of minimal (subclinical or latent) hepatic and increased reflexes. Occasionally, hallucinations and
encephalopathy encephalopathy – HE grade 0 – the patient has no delusions occur.
complaints and on direct questioning has no symptoms Changes in personality – often the intensification of a
belonging to grade I. Sleep, concentration, fine motor previously existing characteristic – may be pronounced.
functions, general performance and mood are not In the later stages of hepatic encephalopathy, alter-
affected. Even so, results of psychometric and neuro- ations in the level of consciousness determine the
psychological tests show subtle abnormalities, provid- clinical picture. HE grade IV is characterised by deep
ing evidence of cerebral disturbance in the sense of coma with response only to painful stimuli.
retardation of psychomotor functions.

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Hepatic Hepatic encephalopathy may also occur in acute liver 2.2 Precipitating factors in
encephalopathy in failure, e.g. with fulminating hepatitis (see section 1.2). hepatic encephalopathy
acute liver failure This is basically indistinguishable from the symptoms
seen with chronic liver disease; however, the distur- A great variety of factors can precipitate or exacerbate Many precipitating
bances of cerebral function appear more abruptly and hepatic encephalopathy (Figure 2.1). Often there is factors
progress more rapidly. States of delirium, restlessness interplay of several factors. The severity of the cirrhosis
and seizure tendency are more common than with and the extent of collateral circulation do not necessar-
other forms of hepatic encephalopathy. ily determine the likelihood of encephalopathy. Hepatic
encephalopathy may be induced by a certain combina-
tion of precipitating factors even in patients without
recognizable impairment of liver function and no mark-
ed portosystemic shunt volume.
Summary:
The definition of hepatic encephalopathy encompasses the liver disease
Increased ammonia in the brain Volume deficiency
and the cerebral dysfunction. Assessment of the severity of the condition
• Increased ammonia production: • Diuretics
is made clinically on the basis of the mental state (HE grade in accordance
Protein-rich diet (in forced mobilization of ascites)
with West Haven criteria). With the minimal or subclinical form (HE grade
GI bleeding • Vomiting
0) there are no obvious clinical deficiencies but the results of psychomet-
Hypokalaemia • Diarrhoea
ric tests are abnormal. Increasing deterioration of the level of conscious-
Constipation • Bleeding
ness becomes apparent with HE grades I-IV, reaching deep coma by HE
Infection
grade IV.
• Increased passage of ammonia Drugs
into the brain:
Metabolic alkalosis Transjugular intrahepatic porto-
(esp. diuretics) systemic stent shunt (TIPS)
Vomiting
Hypoxia

Figure 2.1: Precipitating factors in hepatic encephalopathy (after Caspary 2001)

The majority of precipitating factors is associated with

increased nitrogen or an increased number of nitro-
genous metabolites in the blood.

26 27
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The common precipitating factors of azotaemia, bleed-
ing from shunt varices, infections and protein-rich diet,
lead to increased nitrogenous compounds that are bro-
ken down to ammonia which cannot be sufficiently
detoxified because of impaired liver function. At the
same time there is decompensation of ammonia detox-
ification.
Hypovolaemia, aspiration of ascites, diuresis, hypoka-
laemia or hyponatraemia may lead to disturbances of
fluid balance, acid-base balance and electrolyte con-
centrations. As a result, more ammonia may be produc-
ed in the kidneys, hepatic and renal blood flow be
reduced and detoxification in the liver impaired. Di-
uretics also directly inhibit urea synthesis in the liver.
Metabolic acidosis also adversely affects urea synthe-
sis.
Other factors that commonly precipitate overt hepatic
encephalopathy are sedatives and tranquillisers, espe-
cially benzodiazepines. These substances have a neu-
rodepressant action and in this way may promote hepat-
ic encephalopathy. Since these drugs are metabolized
in the liver, impaired hepatic function prolongs their half-
lives; this means that a relative overdose may occur
even when normal dosages are taken. Sedative drugs
should therefore be prescribed for patients with cirrho-
sis only in special circumstances.
Alcohol induces hepatic encephalopathy not only by
causing cirrhosis of the liver; it may also act as a precip-
itating factor through its neurodepressant effects.
28
Hepatic encephalopathy may also be precipitated TIPS and hepatic
following the creation of a transjugular intrahepatic encephalopathy
portosystemic shunt (TIPS) as a therapeutic measure.
Encephalopathy becomes overt in about a quarter of
TIPS patients. The main indications for a TIPS are
haemodynamic problems, especially prophylaxis of
recurrent bleeding from oesophageal or abdominal
varices. If there is not already severe hepatic encephalop-
athy (grade II-IV), the risk of encephalopathy has to be
accepted, since these haemodynamic complications are
difficult to treat and potentially fatal. Elderly patients
(>60 years of age) are particularly at risk. The patho-
physiological changes responsible for the manifestation
of hepatic encephalopathy in patients with shunts are
described in section 1.2.
Summary:
All conditions that increase the ammonia concentration in the blood – by
increasing ammonia production or disrupting detoxification – are pos-
sible precipitating factors in the manifestation of hepatic encephalopa-
thy. Neurodepressant agents (e.g. benzodiazepines, alcohol) may like-
wise precipitate hepatic encephalopathy. When a TIPS is created as a
therapeutic measure, the risk of hepatic encephalopathy must also be
accepted. Elderly patients (>60 years of age) are particularly at risk.
29
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2.3 Pathogenesis of hepatic chromatin. These pathological changes indicate a key

encephalopathy role for the astrocytes in the pathogenesis of enceph-
alopathy (Figure 2.2).
Explanation of the pathogenesis of hepatic encepha-
lopathy requires investigation of the relationship be-
tween liver function and cerebral function, two highly
complex systems. Results are frequently not easy to
interpret and give rise to further questions. The many
symptoms and signs and their variability with respect
to the degree of severity and progression make it dif-
ficult to find a common pathomechanism that explains
all the forms of encephalopathy.
Despite intensive scientific research, it has not yet
been possible to completely elucidate the pathophys-
iological mechanisms of hepatic encephalopathy.
However, it is certain that increased ammonia con-
centration in the blood contributes to the pathogene-
sis. There is probably synergy with other pathome-
chanisms.
Figure 2.2: Alzheimer type II astrocytes
Alz: Alzheimer astrocyte, N: normal astrocyte
2.3.1 Neuropathological changes

Swelling of Hepatic encephalopathy is basically a reversible dis-

astrocytes turbance of cerebral function. Damage to neuronal
cells is not seen. In neuropathological studies, how-
ever, changes can be identified in the morphology of
the astrocytes. In acute liver failure, the astrocytes are
swollen. In cirrhosis of the liver, neuropathological
changes can be seen, which are described as Alzhei-
mer type II astrocytosis. These astrocytes are charac-
terized by large swollen nuclei and margination of the
The astrocytes are important components of the blood-
brain barrier. The uptake of substances from the blood
into the brain requires the transastrocyte transport
mechanism. Astrocytes are in close contact with neuro-
nal cells and are involved in the metabolic processes of
neurotransmitters and regulation of ion concentrations
in the brain.

30 31
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2.3.2 Ammonia and the glial The mechanism of neurotoxicity of ammonia in the brain Neurotoxicity
hypothesis has not yet been completely explained. There is experi- of ammonia
mental evidence of disturbances of the cerebral energy
Pathogenetic An increased ammonia concentration in the blood cer- metabolism and neurotransmission, direct modulation
significance tainly contributes to the manifestation of hepatic en- of neuronal activity and an indirect effect on the neu-
of ammonia cephalopathy. There is no pathogenetic concept in rones via the astrocytes. On the basis of recent studies,
which ammonia does not play a key role. The following functional disturbance of the astroglia with resulting
points in particular support this: dysfunction of the neuronal cells is possibly the most
important neurotoxic mechanism of action of ammonia.
• In most patients with hepatic encephalopathy, the
ammonia concentration in the blood is raised. Accumulation of glutamine (a product of ammonia Ammonia and
Only 10% of patients have normal levels. detoxification) in the cells is the main cause of the astro- glial swelling
• In cases of hyperammonaemia, lowering the cyte swelling. Only these cells contain glutamine syn-
ammonia concentration leads to improvement in thetase, an enzyme capable of detoxifying ammonia in
the symptoms. the brain (Figure 2.3).
• Hepatic encephalopathy occurs far and away
most commonly in patients with cirrhosis of the
liver and portosystemic collateral circulations, in
whom insufficiently detoxified blood – especially
with respect to ammonia – reaches the brain.
NORMAL HYPERAMMONAEMIA
• There is a certain correlation between ammonia
concentration and the severity of the hepatic SYNAPSE ASTROCYTE SYNAPSE ASTROCYTE
encephalopathy. Gln Gln
• Conditions where the ammonia is raised can pre- Gln Gln
NH3 Gln NH3 Gln
cipitate or exacerbate hepatic encephalopathy,
while a fall in ammonia concentration improves
Glu NH3 NH3 Glu NH3 NH3
Glu Glu
the clinical symptoms and signs. Glu Glu

In animal experiments hyperammonaemia induces GLU-RECEPTOR GLU-RECEPTOR

changes that are also seen in liver patients (e.g. cerebral
oedema and raised intracranial pressure) as well as
numerous neurochemical changes similar to those
found in humans.
Figure 2.3: Diagrammatic representation of glutamate-glutamine cycle in the glutamatergic synapse
and the influence of hyperammonaemia
(Gln = glutamine; Glu =glutamate; (1) = glutaminase; (2) = glutamine synthetase)

32 33
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 34
Other substances such as cytokines and benzodiaze-
pines or conditions such as hyponatraemia may be
synergistic to the ammonia effects and thus contribute
to the astrocyte swelling, or may even be the main
cause of this change.
Figure 2.4 gives an overview of the different factors
contributing to the pathogenesis of hepatic encepha-
lopathy.
Changes in post- Changes in Changes in the
synaptic receptors neurotransmitters blood-brain barrier
Swelling and functional disturbance of the astroglia
Neurotoxin ammonia/amino acid imbalance
Impaired liver function
Figure 2.4: Interplay of various pathogenetic factors in hepatic encephalopathy
In acute liver failure, glial swelling occurs with clinically
overt cerebral oedema. Findings from recent studies
have shown that there is also a disturbance of cell vol-
ume homeostasis with glial swelling in chronic liver dis-
eases and hepatic encephalopathy (Häussinger et al,
2000).
Many potential functional disturbances of the glial cells
themselves and of the glial-neuronal communications
34
may arise. There may be changes in the permeability of
the blood-brain barrier with symptoms of raised intra-
cranial pressure. In addition, effects on the activity of ion
channels, disturbances of neurotransmitter and recep-
tor functions, and damage to the neuronal energy sup-
ply are to be expected. The glutamatergic neurotrans-
mitter system that controls cognitive function is
probably involved in the process; due to the increased
consumption of glutamate needed to detoxify ammo-
nia, glutamate deficiency results in the glutamatergic
neurones. Frequently it cannot be determined how
much the functional changes in neuronal activity are
due to direct toxic effects of ammonia and how much
to indirect effects of the glial swelling.
2.3.3 Additional pathological
mechanisms
Besides the role of ammonia and the concept of glial
swelling, there are indications that additional patho-
mechanisms exist. These may be synergistic or may
even determine the manifestation of hepatic encepha-
lopathy.
There is evidence for considering the neurotoxic effects Other endogenous
of other endogenous substances – for example, mer- neurotoxins
captans which are formed during the breakdown of
sulphur-containing amino acids (e.g. methionine) by
bacteria. These substances are responsible for the
characteristic foetor hepaticus. They inhibit Na+/K+
ATPase and potentiate the neurotoxicity of ammonia.
35
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 36
Phenols are also neurotoxins; they lead to coma in ani-
mal experiments. They are derivatives of the amino
acids phenyl alanine and tyrosine, and are formed in the
gastrointestinal tract.
Short and medium chain fatty acids are produced
by the physiological intestinal flora during the break-
down of fatty acids, and can also be formed in the liver
itself. They inhibit Na+/K+ ATPase and urea synthesis in
the liver. In addition, there is some evidence that these
compounds increase the tryptophan uptake into the
brain and thus affect transmitter metabolism.
Increased The blood-brain barrier is a complex physiological
permeability of the functional unit which protects the brain from metabolic
blood-brain barrier disturbances in the rest of the body. In acute liver
failure, the permeability of the blood-brain barrier is
increased in a non-specific manner. Certain changes in
the blood-brain barrier are also seen in chronic liver fail-
ure. The transport capacity for neutral amino acids is
increased but reduced for basic amino acids, ketone
bodies and glucose. At the same time, the ammonia-
dependent rise in intracerebral glutamine formation
increases the uptake of neutral amino acids into the
brain. The selective changes in permeability that can be
observed are possibly related to the glial swelling.
Amino acid imbalance In chronic liver disease, the blood shows a typical
and “false neurotrans- amino acid distribution profile. The quantitative rela-
mitters” tionship between aromatic (tyrosine, phenyl alanine,
tryptophan) and branched-chain amino acids (valine,
leucine, isoleucine) shifts towards the aromatic amino
acids. On the basis of this observation, it is assumed
36
that the concentrations of aromatic amino acids in the Neurotoxicity
brain also increase while the branched-chain amino of ammonia
acid concentrations are reduced (Figure 2.5).
NH3
Glutamate
Glutamine Glutamate Glutamine
Glutamine Glutamine
Figure 2.5: Diagrammatic representation of ammonia and amino acids exchange. Ammonia taken up
into the brain is converted to glutamine, which is exchanged for the branched-chain amino acids
(BCAA) and aromatic amino acids (AAA) present in the plasma, which use the same transport system.
In the case of portosystemic encephalopathy, increased levels of ammonia in the blood lead to raised
concentrations of glutamine in the brain. The higher AAA to BCAA concentration ratio in the blood
promotes the entry of AAAs into the brain through exchange with glutamine (after Conn, 1994)
The aromatic amino acids are substrates for neuro-
transmitter synthesis – tyrosine and phenyl alanine for
dopamine, and tryptophan for serotonin. The excess
supply of substrates may mean that substances such
as tyramine, octopamine and phenyl ethanola-
mine are formed via secondary metabolic pathways.
These act as “false neurotransmitters” by competing
with the normal transmitters for the same receptors and
thereby disrupting neuronal activity.
37
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GABA-ergic On the basis of the therapeutic neurodepressant effects

transmission of benzodiazepines, which are notable precipitating fac-
tors for hepatic encephalopathy, the hypothesis has
been proposed that so-called endogenous benzodiaze-
pines and related substances (endozepines) which can
be found in the blood and brain as well as in plant prep-
arations and foodstuffs, contribute to the pathogenesis
of hepatic encephalopathy by their agonistic actions on
the GABA receptors. Gamma-aminobutyric acid
(GABA) is an important inhibitory neurotransmitter in the
brain and GABA receptors are to be found on neurones
and astrocytes. Activation of the GABA-ergic system
has a neurodepressant effect.
Summary:
Every last detail of the pathogenesis of hepatic encephalopathy has not
yet been fully elucidated. Ammonia certainly plays a key role. The asso-
ciated glial hypothesis, which assumes an underlying mechanism of dis-
rupted interaction between the altered astrocytes and other cellular ele-
ments of the brain, brings the various findings together in a
comprehensive manner. The concept of synergistic mechanisms be-
tween the observed influencing factors is plausible and correlates with
the variable symptoms and signs to be seen in hepatic encephalopathy.

Serotonin, The increased uptake of tryptophan into the brain leads

noradrenaline to an increased formation of serotonin. The density of
serotonin receptors decreases while their affinity
increases. Changes regarding the neurotransmitter
noradrenaline are also seen in hepatic encephalopathy,
which may possibly have pathogenetic significance.

Zinc, manganese Results of recent studies have suggested an associa-

tion between hepatic encephalopathy and the trace
elements zinc and manganese. It has been shown
that the activity of enzymes in the urea cycle is reduced
when there is zinc deficiency.

NMR studies in patients with hepatic encephalopathy

have indicated deposits of manganese in the basal
ganglia.

The question of how relevant these findings are to

pathogenesis remains open.

38 39
43 057 WiBro englisch 13.05.2004
Diagnosis of hepatic
encephalopathy on
the basis of the
clinical picture
Liver function tests
• Transaminases (GOT, GPT)
• Cholestasis parameters
(AP, γ−GT)
• Bilirubin
• Total proteins with
electrophoresis/albumin
• Prothrombin time
Blood glucose
Electrolytes
(with calcium and phosphate)
Creatinine, urea
Table 3.1: Laboratory tests in hepatic encephalopathy (after Gerber and Schomerus, 2000)
40
17:18 Uhr Seite 40
3 DIAGNOSIS OF HEPATIC
ENCEPHALOPATHY
3.1 Diagnostic procedures
The diagnosis of hepatic encephalopathy is made on
the basis of the clinical picture (see West Haven criteria)
and must be considered in every patient with neuro-
psychiatric disturbances and liver disease. The diagno-
sis is easy in known cases of cirrhosis of the liver or ful-
minating hepatitis but presents difficulties when the liver
disease has not yet been diagnosed.
Clinico-chemical blood tests may be worthwhile in re-
vealing a hitherto unsuspected liver disease or hyper-
ammonaemia syndrome, but have only limited rele-
vance in the diagnosis of hepatic encephalopathy.
The following summary proposed by Gerber and
Schomerus indicates the relevant laboratory tests that
may be useful in this context (Table 3.1).
Drug screening (urine and blood)
Alcohol levels
Blood gas analysis
Fasting ammonia concentration
Cultures
(blood, urine, sputum, faeces)
Hepatitis and HIV
Ascites (cells and culture)
Blood picture, C-reactive protein,
erythrocyte sedimentation rate
In alcoholics with cirrhosis of the liver, Wernicke-Korsakov Differential diagnosis
syndrome and delirium tremens from alcohol withdraw-
al must in particular be included in the differential diag-
nosis of hepatic encephalopathy. Subdural haematoma
and other vascular processes, space-occupying
lesions, intoxication, encephalitis, hypothyroidism and
metabolic disorders such as hypo- or hyperglycaemia,
uraemia and hyponatraemia have all to be considered
as well.
With hepatic encephalopathy, changes in the EEG are Electrophysiological
visible as abnormal slowing of the baseline activity investigations
although this is not pathognomic. Similar changes can
be seen with uraemia, CO2 poisoning, vitamin B12 defi-
ciency, hypoxia or hypoglycaemia. In addition, it is dif-
ficult to evaluate changes because a reference EEG is
not usually available for the patient. It is often the case
that no clear boundary can be drawn between normal
and pathological. Similar restrictions exist in respect to
investigations with evoked potentials (VEP, P300). And
these methods are also relatively time consuming and
expensive. Electrophysiological methods are therefore
not of prime importance in the diagnostic work-up of
overt symptoms.
The main indication for imaging procedures in the Imaging techniques
differential diagnosis of hepatic encephalopathy is the (CT, MRI etc.)
exclusion of other cerebral processes, especially
cerebral haemorrhage. If symptoms corresponding to
bleeding etc. are present, these imaging techniques
are first-line investigations.
41
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Using specific test procedures and a standardized test Reduced fitness to

Summary:
drive, a study conducted recently by a research group drive in patients with
Hepatic encephalopathy is diagnosed on the basis of the clinical picture.
at the University of Hamburg, in collaboration with the subclinical hepatic
The necessary investigations for the differential diagnosis of this condi-
Föhrenkamp clinic of the Mölln BfA rehabilitation centre, encephalopathy
tion include laboratory tests, imaging procedures and occasionally elec-
showed that patients with cirrhosis of the liver and sub-
trophysiological examinations.
clinical hepatic encephalopathy were not completely fit
to drive. Not only was their ability to drive a car severe-
ly restricted but also the ability to adapt their driving
3.2 Early diagnosis behaviour to the general rules of the road, as can be
seen in Figure 3.1 (Wein et al., 2002).
Diminished Early recognition of hepatic encephalopathy is of partic-
performance in ular clinical relevance, i.e. diagnosis in HE grade 0.
subclinical hepatic Disturbances of consciousness are not yet noticeable
Marks
encephalopathy with minimal or subclinical hepatic encephalopathy but 5 SHE Group of patients with cirrhosis of the liver BF observing pedestrians
without subclinical hepatic encephalopathy SI checking safe to proceed
impairment of intellectual function already exists. This is SHE+ Group of patients with cirrhosis of the liver GEB observing speed
with subclinical hepatic encephalopathy restrictions
important to the patient for two reasons: KK Clinical control subjects BH observing obstacles
4
RB observing rules
BL signalling
• Recognition of incipient hepatic encephalopathy is an ZF rapid merging
GEA adaptation of speed
indication of the decompensation of the underlying 3
OW orientation by signposts
VB observing right of way
cirrhosis and the necessity of treatment. ABH maintaining distance
• Even the existing limitations represent a risk to the 2
SP keeping in lane
EP parking
patient at work (especially manual occupations) or SE getting into the correct
lane
driving a car. AB hill starts
1 BEA obeying traffic lights
BF SI GEB BH RB BL ZF GEA OW VB ABH SH EP SE AB BEA

Reductions in performance such as slower reaction

times, inaccurate perception of geometric shapes and
reduced visual selection abilities, which are at first bare-
ly noticeable, are important at work or driving a car. In
addition, there are personality changes such as reduc-
ed emotional stability, loss of self-control and self-criti-
cism as well as a tendency to dissimulate (Häussinger
and Maier, 1996). The risks of a road traffic accident or
an accident during manual work are thereby increased.
Figure 3.1: Test drive: Marks gained in driving categories (after Wein et al., 2002)
Note: Marks in school reports etc. in Germany are scored with 1 being the highest
Diminished function in minimal hepatic encephalopathy Psychometric
is best identified with the aid of psychometric tests. procedures in
Moreover, these tests are relatively easy and cheap to subclinical hepatic
administer (see section 3.3). encephalopathy

42 43
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In certain cases, minimal hepatic encephalopathy in

42
patients with cirrhosis of the liver can also be recognized
HE 0
in the EEG. Evoked potential tests (especially P 300) like-
40 SHE SHE
wise show a certain diagnostic sensitivity for the early
SHE
diagnosis of hepatic encephalopathy. However, because

CFF (Hz)
38 HE I
the procedure has relatively high technical requirements, it
is not generally used for routine diagnostic investigation.
36

HE I
Critical flicker A procedure that has recently become established in the
34
frequency diagnostic investigation of hepatic encephalopathy is the 0 1 3 5 7 9
determination of the critical flicker frequency (CFF). In this Days

test, the patient is shown a light that flickers with increas- Figure 3.3: CFF in patients with cirrhosis during and after recovery
ing or decreasing frequency. With ascending frequency, from an episode of hepatic encephalopathy (Kircheis et al., 2002)
the patient sees the light become constant (= fusion fre-
quency). In the reverse procedure, the stable light starts
to flicker as the frequency descends. The CFF is clearly Summary:
altered in patients with subclinical hepatic encephalopa- The early diagnosis of hepatic encephalopathy in HE grade 0 is particu-
thy compared with healthy people. As the severity of the larly important for the patient. Hitherto unrecognized diminution of per-
condition increases, the CFF falls (Figure 3.2), and rises formance increases the risk of accidents at work or in road traffic.
again with improvement in the HE episode (Figure 3.3) Psychometric tests are simple to administer and appropriate for the
(Kircheis et al., 2002). early diagnosis of reduced intellectual function in hepatic encephalopa-
thy. The determination of CFF is also very promising.
50 ns.
ns.
p < 0,01

p < 0,001
45 p < 0,001

p < 0,001
3.3 Criteria for assessing degree
40
p < 0,01

p < 0,001
of severity and monitoring
the course of disease
CFF (Hz)

35

Estimating the degree of severity of hepatic HE grade and

30 encephalopathy depends in the first line on the mental mental state
state. This is evaluated on the basis of the patient’s
25
Controls HE 0 SHE HE I HE II
clinical symptoms, in accordance with the HE grades of
Conn and co-workers described above (see Table 2.1).
Figure 3.2: CFF in patients with cirrhosis of the liver (Kircheis et
44 al., 2002) 45
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 46
PSE index for The PSE index represents an extension developed by
monitoring progress Conn and co-workers (Conn and Bircher, 1994). In
addition to the mental state (c.f. Table 2.1), this index
includes the semiquantative assessment of the symp-
tom of asterixis (Table 3.2), the time taken to complete
the number connection test (Table 3.4), the EEG (Table
3.3) and the ammonia concentration (Table 3.5). Grad-
ing of each variable is weighted (mental state x3, each
of the others x1) and added together to give a maxi-
mum PSE score of 28 points. The ratio of the individu-
al score obtained to the maximum score gives the PSE
index. The PSE index is more complex than the HE
grading and is suitable for monitoring progress.
Asterixis Even though asterixis (flapping tremor) as a sign of neu-
romuscular disturbance is frequently present and is
considered to be characteristic of hepatic encephalop-
athy, it is not actually specific to this condition. It also
appears with other disorders (e.g. intoxication, hypo-
magnesaemia etc.). From the clinical point of view,
however, it is suitable for diagnosing, evaluating the
severity of the condition, and monitoring its progress.
Table 3.2 shows a semiquantitative classification for the
PSE index.
Grade 0 No tremor
Grade 1 Rare tremor (1–2 per 30 seconds)
Grade 2 Occasional, irregular tremor
(3–4 per 30 seconds)
Grade 3 Frequent tremor (5–30 per 30 seconds)
Grade 4 Virtually uninterrupted tremor present
Table 3.2: Semiquantitative grading of asterixis (flapping tremor)
(after Conn and Bircher, 1994)
46
As a rule, in patients with hepatic encephalopathy, EEG
abnormal slowing of baseline activity and an increase in
amplitude can be seen in parallel with the degree of
severity. Table 3.3 shows a semiquantitative classifica-
tion of frequency for the PSE index.
Grade 0 Alpha-frequency, 8.5–12 cycles per second (cps)
Grade 1 7–8 cps
Grade 2 5–7 cps
Grade 3 3–5 cps
Grade 4 maximum 3 cps
Table 3.3: Semiquantitative grading of the EEG (after Conn and
Bircher, 1994)
Many psychometric tests are used to establish Psychometric test
and quantify deterioration of intellectual function. This procedures
includes slowing down of the psychomotor perfor-
mance speed as well as restriction of both visual spatial
orientation and visual constructive ability. Validated and
quantifiable psychometric test procedures which
determine these deficits are the number connection
test (NCT) versions A and B, the digit symbol test
(DST) and the line tracing test (LTT).
From the practical point of view, a test should be sim-
ple to explain and quick to perform as well as quick and
easy to evaluate. Taking these points into consideration,
the number connection test (NCT) has proved itself to
be a valuable tool (Conn and Bircher, 1994). Table 3.4
shows the standard forms used for versions A and B of
this test.
47
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Figure 3.4: Number connection test, Versions A (NCT-A) and B (NCT-B). In NCT-A the numbers have to be Figure 3.5: (left) The line tracing test shows a complicated trace. Using a pencil, the patient has to rapidly fol-
joined consecutively in numerical order (1,2,3…) as quickly as possible. In the more complicated NCT-B, low the original 5 mm wide track from beginning to end without going over the edges – at the same time, this
the numbers and letters must be connected alternately numerically and alphabetically (1,A,2,B…). Evalu- is one way of testing “fitness to drive”. Evaluation considers both the time taken to complete the test and the
ation of both tests is based on the time required to complete the test (Conn 1977) number of errors (Schomerus et al., 1981)
Figure 3.6: (right) In the digit symbol test, the blanks should be filled in as quickly as possible with the sym-
bols corresponding to the numbers given at the beginning. Evaluation depends on the total number of cor-
Table 3.4 shows a semiquantitative grading of the time rectly inserted symbols within 90 seconds
taken to perform the number connection test A for the
PSE index. Figures 3.5 and 3.6 show the line tracing test As most forms of hepatic encephalopathy are associat- Ammonia
and digit symbol tests. These are also evaluated accord- ed with an increased nitrogen load and/or reduced concentration
ing to the time required to complete the sequences. detoxification of ammonia, the determination of the
ammonia concentration in the blood provides diagnos-
Grade 0 15–30 seconds tic evidence as well as an indication of the severity of
the condition. Although the ammonia concentration in
Grade 1 31–50 seconds
arterial blood does not rise in strict proportion to the
Grade 2 51–80 seconds
severity of the hepatic encephalopathy, there is a posi-
Grade 3 81–120 seconds tive linear correlation between these two parameters
Grade 4 >120 (test cannot be carried out) (Conn and Bircher, 1994). Poor correlation may partly
Table 3.4: Semiquantitative grading of the number connection test
be attributed to difficulties with the analytical methods
A (after Conn and Bircher, 1994) used.

48 49
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In a recent study, it has been shown that a method not
customarily used (partial pressure measurement of
gaseous or “free” ammonia, which passes more easily
into the brain) gives a closer correlation with the HE
grade than conventional measurements of the total
concentration of arterial ammonia (Kramer et al., 2000).
Table 3.5 shows a semiquantitative grading of the arte-
rial ammonia concentration for the PSE index.
Grade 0 Within normal range (<60 µmol/l)
Grade 1 1–1.33 x upper limit of normal
Grade 2 1.33–1.67 x upper limit of normal
Grade 3 1.67–2.0 x upper limit of normal
Grade 4 >2 x upper limit of normal
Table 3.5: Semiquantitative grading of the arterial ammonia
concentration (after Conn and Bircher, 1994)
Summary:
Suitable means of classifying and monitoring the degree of severity of
hepatic encephalopathy include the HE grading of the mental state and
the PSE index, which also takes into account the semiquantitative grad-
ing of other factors – asterixis, EEG, number connection test and ammo-
nia concentration.
50
4 TREATMENT OF HEPATIC
ENCEPHALOPATHY
The management of hepatic encephalopathy depends
mainly on the severity of the clinical picture. Intensive
medical care will be required as first line therapy in the
case of fulminating hepatic failure, while prophylactic
measures to prevent progression and avoidance of pre-
cipitating factors need to be considered in the treat-
ment of subclinical encephalopathy.
4.1 General therapeutic concepts
The search for precipitating factors of hepatic encepha- Eliminating
lopathy is of prime importance in both treatment of the precipitating factors
acute case and prevention. Such factors play a role in
70-80% of patients (see section 2.2). Successfully elim-
inating the most common precipitating factors –
gastrointestinal bleeding, azotaemia, sedatives, infec-
tions and excessive protein consumption – may prevent
progression and overt symptoms in many cases. The
most important measures that have to be considered
stem from the need to eliminate these factors (Häussinger
and Meier, 1996):
• Stop bleeding
• Treat anaemia (aim: haematocrit = 30%)
• Treat acidosis with bicarbonate
• Correct electrolytes to within normal range
• Discontinue diuretics
• Treat infections with antibiotics
• Discontinue sedatives
• Reduce protein intake
• Make every effort to obtain abstinence
from alcohol
51
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 52
Knowledge of the precipitating factors is also very rele-
vant to prophylaxis against recurrence. By avoiding
such factors (e.g. sedatives, alcohol, and excessive
protein consumption) and early treatment (e.g. infec-
tions) the progression of hepatic encephalopathy can
be positively influenced.
4.2 Dietary therapy
Regulation of An adequate diet is extremely important for patients
protein intake with hepatic encephalopathy and/or predisposing liver
disease. These patients often suffer from loss of appe-
tite and do not consume enough calories. This poor diet
favours protein catabolism which is associated with the
increased formation of ammonia. Reduction in muscle
mass disrupts extrahepatic ammonia detoxification
since muscle tissue contributes to detoxifying ammonia
(see section 1.1). Resistance to infection also falls with
inadequate nutrition. Active dietary therapy has a corre-
spondingly favourable effect on the prognosis.
With acute hepatic encephalopathy, the temporary
reduction of protein intake to 20-30 g/day is indicated.
The protein intake can then gradually be increased until
a daily intake of 1 g/kg body weight is reached. Long-
term protein restriction which was previously mandato-
ry is now considered obsolete. Such protein restriction
can only be justified in special cases of marked protein
intolerance. In the majority of cases an adequate balanc-
ed diet improves the patent’s prognosis.
52
4.3 Drug therapy
Although not yet elucidated in every detail, the Pharmacotherapeutic
neurotoxin ammonia plays an undisputed key role in the principles in hepatic
pathogenesis of hepatic encephalopathy. As in the encephalopathy
past, the therapeutic objective is still the reduction of
pathologically elevated levels of ammonia in the blood
(see section 2.3).
The active substances used are selected principally in
an effort to reduce ammonia production, promote
ammonia detoxification, correct the amino acid imbal-
ance and have a positive effect on neurodepression.
Reduction of intestinal ammonia production
Cleaning out the intestinal tract should eliminate nitro-
genous substances from which ammonia is produced.
Non-absorbable disaccharides (e.g. lactulose) are
mainly used for this purpose. Apart from their laxative
actions, disaccharides also affect ammonia production
in the intestinal flora. In bacterial metabolism, their
breakdown products increase the incorporation of nitro-
gen into bacterial proteins, so that less ammonia is re-
leased; this in turn reduces the ammonia concentration
in the portal vein blood. Non-absorbable antibiotics
(e.g. neomycin) are used to reduce the physiological
flora in the large intestine and thus also to reduce the
production of ammonia.
Increase in extra-intestinal ammonia detoxification
An important therapeutic means of increasing ammonia
detoxification is stimulation of the urea cycle activity in
the periportal hepatocytes and stimulation of glutamine
53
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 54
synthetase in the perivenous hepatocytes (also known
as scavenger cells). L-ornithine-L-aspartate im-
proves the detoxification of ammonia by supplying aspar-
tate for glutamine synthesis in the perivenous scaven-
ger cells. Ornithine promotes the urea cycle in the
periportal hepatocytes. Both oral (6 g three times a day)
and parenteral (20 g/day) administration of L-ornithine-
L-aspartate leads to a demonstrable reduction in hyper-
ammoniaemia as well as improvements in the impaired
mental functions of hepatic encephalopathy.
The use of benzoate is based on a different principle.
This substance increases the excretion of ammonia.
Zinc is a co-factor of all the enzymes in the urea cycle.
Administration of zinc supplements should therefore
stimulate urea synthesis.
A plant pharmaceutical, silymarin (an extract of milk
thistle seeds), is used to protect the liver. Studies on this
extract have shown that it prevents the entry of toxins
into liver cells, supports protein synthesis and stimu-
lates regeneration of damaged hepatocytes. Lowering of
the blood ammonia concentration is not to be expected
with silymarin.
Correcting the amino acid imbalance
The administration of branched-chain amino acids
(BCAA), i.e. leucine, isoleucine and valine, redresses the
amino acid imbalance which adversely affects neuro-
transmitter metabolism in the brain and peripheral pro-
tein metabolism.
54
Effects on neurodepression
Inhibition of the GABA-ergic system with the group of
substances known as benzodiazepine antagonists
(e.g. flumazenil) counteracts the neurodepressant
effects of the GABA-ergic activation.
With the exception of silymarin, the active substances Pharmacotherapeutic
mentioned above are currently used in clinical practice efficacy
for the treatment of hepatic encephalopathy. Informa-
tion on the efficacy of these substances has in the past
been widely based on empirical findings and on the
results of studies where the methods used no longer
meet current research standards.
In the meantime, criteria for the demonstration of treat-
ment efficacy have been drawn up for clinical trials.
Apart from general criteria (such as randomization,
double-blinding, testing against placebo controls or
standard drug therapy, and the inclusion of a sufficient
number of cases), the definition of efficacy criteria is of
particular relevance in studies on hepatic encephalopa-
thy. End points for demonstrating efficacy are basically
clinical outcome measures such as the mental state (HE
grade) and the PSE index which includes criteria such
as psychometric tests and ammonia concentration (see
section 3.3).
Conducting such studies is made particularly difficult by
the great variability of symptoms and the spontaneous
progression of hepatic encephalopathy. Even so, the
necessary evidence of efficacy has in the meantime
been provided for some of the active substances in use
today – forming the basis of “evidence-based medicine”.
55
43 057 WiBro englisch 13.05.2004
Evidence-based
effectiveness of
drug therapy
Therapeutic principle
Reduction of intestinal
ammonia production
Increasing extra-intestinal
ammonia detoxification
Correcting amino acid
imbalance
Benzodiazepine receptor
antagonists
Table 4.1: Drug therapy of hepatic encephalopathy. Evidence of efficacy from placebo-controlled
trials (after Ferenci and Müller, 1999)
56
17:18 Uhr Seite 56
An evidence-based medicine review of the pharmaco- Acute HE:
therapy of hepatic encephalopathy has been published • Elimination of precipitating factors:
recently. Studies with adequate methodology have GI bleeding, azotaemia, diuretics, sedatives, infections, increased
been carried out for some of the substances (Table 4.1). dietary proteins, hypokalaemia and/or metabolic acidosis, hypo-
volaemia, hypoxia, spontaneous bacterial peritonitis (SBP)
• Measures to reduce ammonia concentration:
Endoscopic control of bleeding, nasogastric lavage; oral lactulose (20-
50 ml x 3) or lactulose enema (300 ml in 1200 ml H2O)
Active substance Results of placebo-controlled • Protein restriction:
trials 0-30 g for max three days, then increase by 10 g/day to reach 1g/kg
Lactulose enema better than placebo body weight with sufficient calorie intake.
• Oral neomycin:
Oral lactulose not definitively better than 50-100 mg/kg body weight/day in 3-4 divided doses if inadequate
placebo (number of cases too response to lactulose
small) • Flumazenil:
Neomycin not better than placebo If the patient has previously been treated with benzodiazepines
L-ornithine-L-aspartate better than placebo • L-ornithine-L-aspartate (Hepa-Merz®):
60 g/day i.v. (max. 5 g/h) if the above measures have been un-
successful
Branched-chain amino better than placebo
• Branched-chain amino acids (BCAA):
acids (BCAA)
By infusion, if the above measures have been unsuccessful
Flumazenil better than placebo • Paramomycin:
4 g/day in 2-4 divided doses or vancomycin (250 mg x 4) or
metronidazole (400 mg x 2)
• If the above are unsuccessful or the HE deteriorates, liver
transplantation should be considered
Chronic persistent HE
This review shows that positive results from placebo- • Lactulose: 20-50 ml x 3
controlled trails are already available for some drugs. • Protein restriction – only if lactulose is ineffective:
1 g protein/kg body weight/day. If not tolerated, vegetable proteins or
At the present time, the following recommendations are branched-chain amino acids (BCAA) oral 0.25 g/kg body weight/day
made for the treatment of acute and chronic hepatic • L-ornithine-L-aspartate (Hepa-Merz®): 6-9 g/day x 3
encephalopathy (Table 4.2; after Caspary, 2001) • Prevention of precipitating factors (see above)
• Consider indications for liver transplantation!
Table 4.2: Treatment recommendations for acute and chronic
hepatic encephalopathy (after Caspary, 2001)
57
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5 MECHANISM OF ACTION AND

PHARMACODYNAMICS OF HEPA-MERZ ®

Further studies are in the planning stage and will be 5.1 Mechanism of action
carried out with the aim of meeting the criteria of evi-
dence-based medicine for the treatment of hepatic Detoxification of ammonia takes place predominantly in Stimulation of
encephalopathy. the liver in the periportal and perivenous hepatocytes (see the urea cycle and
section 1.1). Ammonia is converted to urea in the urea glutamine production
cycle; ammonia reacts with glutamate to form glutamine in the liver
(see Figure 1.2).
Summary:
L-ornithine-L-aspartate is able to promote the detoxifica-
Treatment of hepatic encephalopathy includes intervening in the known
tion of ammonia by stimulating disrupted urea and gluta-
pathomechanisms. This includes the exclusion of precipitating factors
mine synthesis (Figure 5.1)
and correction of the dietary deficiencies that frequently exist. Pharma-
cotherapy aims principally to reduce the ammonia production, promote
ammonia detoxification, correct amino acid imbalance and counteract Perivenous hepatocytes
Periportal hepatocytes
neurodepression. In recent years – for reasons of quality assurance and
Ornithine α-Ketoglutarate, Aspartate
cost reduction – the requirements of evidence-based medicine have
come to the forefront of medical practice. Such evidence of efficacy Cytosol Malate Cytosol
definitely exists for L-ornithine-L-aspartate.
Mitochondrion
α-Keto- Mitochondrion
Glutaminase glutarate

Carbamyl-
Glutamine phosphate Glutamine synthetase
synthetase

Glutamine

Urea

Glutamine Glutamine
Urea

Figure 5.1: Effects of L-ornithine-L-aspartate on urea and glutamine synthesis

Urea synthesis is an irreversible liver-specific process,

which takes place primarily in the periportal hepato-
cytes. Ornithine activates the enzyme carbamyl phos-
phate synthetase necessary for this process. Since orni-

58 59
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 60
thine also acts as a substrate in urea synthesis, it is
involved in the activation of the urea cycle in several
ways and thus in the irreversible (final) ammonia detoxi-
fication.
Effects of ornithine on the urea cycle:
- substrate for urea synthesis
- activator of carbamyl phosphate synthetase
Aspartate and ornithine likewise support glutamine syn-
thesis. Glutamine synthesis (addition of ammonia to
glutamate) is localized to the perivenous hepatocytes.
The prerequisite for this reaction is a sufficiently large
supply of glutamate. As has recently been shown,
aspartate (via α-ketoglutarate), glutamate and other
dicarboxylates are taken up almost exclusively by peri-
venous cells. By making aspartate available (after its
conversion into dicarboxylates) L-ornithine-L-aspartate
supplies the perivenous cells with substrates for the
synthesis of glutamine. In this way, ammonia detoxifica-
tion is increased through the formation of glutamine by
the action of glutamine synthetase (Häussinger, 1990;
Stoll and Häussinger, 1989; Häussinger et al., 1990;
Stoll et al., 1991; Stoll and Häussinger, 1991).
Stimulation of ammo- Reversible detoxification of ammonia via glutamine syn-
nia detoxification by thesis in the liver, brain and muscles (see section 1.1) is
glutamine synthesis also increased by L-ornithine-L-aspartate.
60
Effects of aspartate on glutamine synthesis:
- substrate for glutamine formation
Through increased glutamine formation, the therapeutic
administration of L-ornithine-L-aspartate (Hepa-Merz®)
also leads to an increase in ammonia detoxification in
the brain and muscles. This mechanism is of particular
importance where there is a marked collateral circula-
tion or acute liver failure, when detoxification in the liver
is reduced or temporarily ceases.
Summary:
The therapeutic administration of L-ornithine-L-aspartate (Hepa-Merz®)
increases ammonia detoxification in two ways:
• Activation of the urea cycle in the liver by making available the meta-
bolic substrates ornithine and aspartate.
• The substrates ornithine and aspartate promote the formation of
glutamate and thus stimulate ammonia detoxification via glutamine
synthesis in the liver, brain and muscles.
Ammonia detoxification via glutamine synthesis in the brain and muscle
tissue makes an additional contribution to the ammonia reducing effects
of L-ornithine-L-aspartate in cases of hyperammonaemia when detoxifi-
cation in the liver is by-passed or temporarily ceases.
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5.2 Pharmacodynamic effects in
animal experiments
5.2.1 Effects of Hepa-Merz ® on
ammonia metabolism
Experimental animal The effects of L-ornithine-L-aspartate on ammonia
studies on ammonia metabolism have been investigated in many experimen-
metabolism tal animal studies. Parameters such as the protective
effect against liver damage (induced by carbon tetra-
chloride, ammonium acetate or ammonium chloride),
reduction in ammonia levels and increase in urea syn-
thesis have been tested in various animal models
(mouse, rat, rabbit, dog) (Greenstein et al, 1956; Salva-
tore et al., 1959; Salvatore and Bocchini, 1961; Shioya
et al., 1964; Salvatore et al., 1964; Grossi et al., 1967;
Zicha and Zicha, 1968; Hermann, 1972; Zieve et al.,
1986). As well as L-ornithine-L-aspartate, the individual
components and other amino acids have sometimes
been tested to compare their effects. In these studies,
ammonia metabolism tended towards normal and there
was a reduction in the ammonia toxicity on treatment
with L-ornithine-L-aspartate.
Activation of urea In a more recent study, the effects of L-ornithine-
cycle enzymes by L-aspartate on hyperammonaemia and urea metabo-
L-ornithine- lism in cirrhotic rats were investigated (Gebhardt et al.,
L-aspartate 1997). Cirrhosis was induced by carbon tetrachloride
(CCl4). In cirrhotic animals, the activities of carbamyl
phosphate synthetase and arginase were lowered, indi-
cating reduced functioning of the urea cycle.
62
The administration of L-ornithine-L-aspartate signifi-
cantly increased the activity of these two enzymes by
30% and 40% respectively, reaching almost normal
levels. At the same time, there was a significant increase
in the urea concentration of about 34%. The fall in the
ammonia concentration was also significant (Figure 5.2).
800
8
∗∗ 600
7
Ammonia (µM)
Urea (µM)
6 400
5 ∗
200
4
3 0
C OA C OA
Urea Ammonia
Figure 5.2: Serum concentrations of urea and ammonia in cirrhotic
rats without (pink column) and with L-ornithine-L-aspartate (red
column). Mean ± SEM given for each group; differences between
test animals and untreated controls are significant at *p<0.03 and
**p<0.004 (after Gebhardt et al., 1997)
Examination of hepatocyte cultures from the two
groups showed a higher urea production in the hepato-
cytes from L-ornithine-L-aspartate-treated rats in com-
parison with the untreated cirrhotic rats. It can be con-
cluded from these results that treatment of cirrhotic rats
with L-ornithine-L-aspartate increases urea synthesis
and thus the capacity to detoxify ammonia.
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5.2.2 Effects of Hepa-Merz ® on
metabolism in the brain
Reduced NH3- con- To elucidate its mechanism of action, L-ornithine-
centration and over- L-aspartate was administered to rats with portocaval
coming amino acid shunts and hyperammonaemia induced by ammonium
imbalance in the brain acetate infusion (Vogels et al., 1995). This is a valid ani-
mal model of hepatic encephalopathy in subacute liver
failure. In comparison with controls, significantly lower
ammonia concentrations were measured in the blood
(322 ± 40 vs 500 ± 32 mM, p<0.01) and in the brain
(2.06 ± 0.2 vs 2.73 mM, p<0.05) following administra-
tion of L-ornithine-L-aspartate. Lowering of serum
ammonia levels could be attributed to the significantly
higher urea synthesis in animals treated with L-ornithine-
L-aspartate. In this group, glutamine and glutamate in
the blood (signs of increased glutamine synthesis) were
significantly higher than in the control group. In the
cerebral dialysate, glutamate was significantly increased
while glutamine showed a trend towards higher levels.
Both in the blood and brain the ratio between
branched-chain amino acids and aromatic amino acids
(BCAA/AAA) tended towards normal, mainly due to the
reduction of aromatic amino acids. With respect to the
criteria for encephalopathy (EEG, clinical grading) these
were less pronounced on treatment with L-ornithine-
L-aspartate, although the differences did not reach sta-
tistical significance.
In-vivo measurement A further study carried out by Slotboom et al. (1994) in
of ammonia in the the same animal model reported on the additional
brain
64
effects of L-ornithine-L-aspartate on cerebral metabo-
lism (in-vivo measurement of ammonia). In-vivo mea-
surements were carried out by proton magnetic reso-
nance spectroscopy (proton MRS) with special
application and analysis procedures. This method
demonstrated a reduction in the ammonia with the
administration of L-ornithine-L-aspartate, as well as a
smaller rise in lactate and a slower increase in glutamine
in comparison with controls. All changes were statisti-
cally significant. Even though the increase in glutamine
and lactate in the brain in hyperammonaemia is well-
known, it was not previously possible to investigate this
in vivo. For the first time, these results demonstrated in
vivo metabolic changes in the brain providing evidence
of the protective effects of L-ornithine-L-aspartate in
hyperammonaemia.
The uptake of radioactively-labelled ornithine and Transport of ornithine
aspartate into the brain was investigated in a different into the brain
animal model (Albrecht et al., 1994). Acute hepatic
encephalopathy was induced in rats by hepatotoxic
thioacetamide. Substance uptake was given by the brain
uptake index (BUI) calculated from the radioactivity
measured and administered. The BUI was investigated
in three stages: a coma stage (3 administrations of
thioacetamide) a milder stage (2 administrations) and a
group with induced hyperammonaemia (ammonium
acetate) without liver damage. In the coma group, the
BUI for ornithine increased after 24 hours to 275% of
control levels and milder stages, to 220% of control
levels after 7 days and 442% after 21 days (each sig-
nificant at p<0.05).
65
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 66
Induced hyperammonaemia did not lead to increased
uptake of ornithine into the brain.
Aspartate is not normally transported across the blood-
brain barrier. The BUI for L-aspartate did not increase in
any of the three stages, an indication that the blood-
brain barrier remains intact in this animal model.
It can be concluded from the results of this study that
ornithine administered therapeutically in the form of
L-ornithine-L-aspartate is taken up into the brain in cases
of hepatic encephalopathy, probably through activation
of the transport system across the blood-brain barrier.
Transport system for Using the same animal model (hepatic encephalopathy
ornithine and arginine induced by 2 doses of thioacetamide), this research
across the blood- group conducted a further study to investigate the
brain barrier transport system for ornithine across the blood-brain
barrier in more detail (Albrecht et al., 1996). Ornithine
passes across the blood-brain barrier in the same way
as the other two dibasic amino acids, arginine and ly-
sine, via a common saturatable transport system (g+
transporter). The objective of the study was to deter-
mine whether the BUIs of radioactively-labelled orni-
thine, arginine and lysine were different in this model
of hepatic encephalopathy.
The BUI for ornithine increased to 186% after 7 days
and to 345% after 21 days in comparison with the
untreated controls (p<0.05 vs controls in both cases).
The corresponding values for arginine were 30% and
42%, respectively (p<0.05 vs controls in both cases),
i.e. transport into the brain decreased. There were no
66
relevant changes for lysine. From these study results,
the authors concluded that the transport system across
the blood-brain barrier is modified by as yet unidentified
factors, possibly released by the damaged liver. The g+
transporter which normally gives preference to arginine
may change in structure or conformation to preferen-
tially transport ornithine, or a normally latent ornithine-
specific transport system is activated.
The protective effects of L-ornithine-L-aspartate and Coma-protective
the possible mechanism of action were investigated in effects through
rats with portocaval shunts and hyperammonaemia stimulation of central
induced by ammonium acetate infusion (Rose et al., and peripheral ammo-
1998). It was shown that L-ornithine-L-aspartate infu- nia detoxification
sions could prevent ammonium acetate-induced coma
in all animals. None of the rats treated with L-ornithine-
L-aspartate showed any deterioration of neurological
status under these conditions although all the non-
treated animals did.
These protective effects of L-ornithine-L-aspartate were
associated with a smaller rise in ammonia levels in the
blood and an increase in the urea concentration
(p<0.01 and p<0.05 vs controls). In both plasma and
cerebrospinal fluid (CSF), concentrations of glutamate
and glutamine were significantly higher than in the con-
trol animals. The branched-chain amino acids were
higher in the plasma than in the control group, but only
leucine was higher in the CSF.
These results show the protective effects of L-ornithine-
L-aspartate with respect to hyperammonaemia-induced
coma. The mechanism of action consists on the one hand
67
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of peripheral stimulation of urea and glutamine synthesis
and increased central glutamine synthesis on the other.
Protective effects In acute liver failure (ALF) the development of cerebral
of Hepa-Merz® in oedema with raised intracranial pressure and cerebral
cerebral oedema herniation are the most important causes of death. The
effects of L-ornithine-L-aspartate were tested in an ani-
mal model of acute liver failure, induced by hepatic
devascularisation (Rose et al., 1999). In this model,
treatment with L-ornithine-L-aspartate infusions led to
Coma appeared in the control groups after about 11
hours but not until 15 hours with L-ornithine-L-aspartate
infusions (p<0.02). The water content of brain tissue
was significantly less in the L-ornithine-L-aspartate-
treated animals than those given saline infusions and
approached levels in the control animals (Figure 5.4).
p < 0.05
83,0
p < 0.001 p < 0.001
82,5

% water in brain tissue

plasma ammonia concentrations approaching normal in 82,0
comparison with controls (Figure 5.3). The appearance 81,5
of signs of severe encephalopathy – defined as pre- 81,0
coma and coma, in accordance with the degree of 80,5
severity – were significantly delayed. 80,0
79,5

700 L-ornithine-L-aspartate infusion 79,0

Saline infusion Controls ALF ALF
Ammonia concentration

600 saline OA
in plasma (µg/dl)

500 infusion infusion

400 Figure 5.4: Effects of L-ornithine-L-aspartate (OA) infusions on the
300 water content of the brain tissue in comparison with normal controls
* and animals given saline infusions in a model of acute liver failure
200 (ALF) with encephalopathy. The individual values are shown with
**
100 **
means (horizontal lines) for each group as well as the differences
between the groups (p<0.01, p<0.05) (after Rose et al. 1999)
0
Baseline +6 hours Pre-coma Coma
Administration of OA
or saline
The observed protective effects of L-ornithine-L-aspar-
Figure 5.3: Effects of L-ornithine-L-aspartate infusions on the plas- tate were accompanied by increased plasma concen-
ma ammonia concentration in comparison with controls given sa-
line infusions in a model of acute liver failure with encephalopathy.
trations of glutamate, γ−aminobutyric acid (GABA), tau-
The first measurement after baseline was taken 6 hours after liga- rine and alanine as well as the branched-chain amino
tion of the hepatic artery. The stages of pre-coma and coma were acids leucine, isoleucine and valine. Increased gluta-
defined on the basis of the neurological status. The means ± SE are
shown for each group. Differences between the groups are statisti- mate concentrations deliver the substrate for ammonia
cally significant at *p<0.05 and **p<0.01 (after Rose et al., 1999) detoxification via glutamine synthesis. In agreement

68 69
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with this, glutamine in the plasma was significantly rais-

ed (p<0.02), indicating increased glutamine synthesis in
the muscles. Also in agreement, direct measurement of
glutamine synthetase in the muscle showed that the
activity of this enzyme was doubled in animals treated
with L-ornithine-L-aspartate. In this animal model of
acute liver failure, increased glutamate concentrations
can regularly be demonstrated in the extracellular fluid
of the brain. It is therefore assumed that this contributes
to the development of cerebral oedema in acute liver
failure. Lowering of the CSF glutamate levels by 60% as
seen in this experiment and the concurrent reduction in
water content support this hypothesis. Glutamine in the
CSF remains virtually unchanged.
Summary:
Results of animal experiments carried out in models of the various forms
of encephalopathy in hyperammonaemia and acute liver failure show the
protective effects of L-ornithine-L-aspartate with respect to hyperam-
monaemia and encephalopathy. Various methods have shown the
mechanisms of action to be the lowering of the ammonia concentrations
in the blood and brain. The reasons for this are increased urea synthesis
in the liver and stimulation of glutamine synthesis which has been
demonstrated in the muscle and sometimes also in the brain. Transport
of ornithine across the blood-brain barrier has been demonstrated. Orni-
thine contributes to the observed therapeutic effects possibly by the
promotion of glutamate formation in the brain.

Results in animal models of acute liver failure with en-

cephalopathy show the ammonia-lowering effects of
L-ornithine-L-aspartate together with a protective effect
against the development of cerebral oedema and ence-
phalopathy. Lowering of the ammonia can be attributed
to increased ammonia detoxification through stimula-
tion of glutamine synthesis in the muscles.

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6 CLINICAL RESULTS WITH

HEPA-MERZ ®

Experimental clinical studies

Authors Study design Duration- No. of Aetiology of Test drug/placebo Efficacy of L-ornithine-L-aspartate
of study patients hyperammonaemia or control

Henglein-Ottermann 1976 Rd pc 90 min 20 Cirrhosis; administration of an OA i.v. (5 g/h) vs 10% sorbitol - ammonia-lowering effect
crossover, NH4Cl infusion (placebo)
intra-individual
Leweling et al. 1991 Rd db pc 8h 10 Cirrhosis; induction of OA i.v. (5, 20, 40 g/day) vs - dose-dependent reduction of ammonia in blood, increase in
crossover hyperammonaemia by 0.9% NaCl (placebo) BCAA/AAA ratio
design protein consumption
Reynolds et al. 1999 Rd pc 7 days 16 Cirrhosis OA i.v. (40 g/8h) vs placebo - increased rate of protein synthesis in muscle after meals
- inhibition of catabolic metabolism in muscles

Rees et al. 2000 Rd pc 60 min 8 Cirrhosis, oral glutamine OA i.v. (5 g/h) vs placebo - suppression of expected rise in ammonia
load (20 g) - stabilization of psychometric functions

Delcker et al. 2002 Open 24 h 15 Cirrhosis OA i.v. (40 g/8h) - decrease in arterial NH3 concentration and in glutamate + glutamine/
HE I, II creatine ratios
- close correlation of both parameters

Clinical Trials with intravenous L-ornithine-L-aspartate

Authors Study design Duration- No. of Aetiology of Test drug/placebo Efficacy of L-ornithine-L-aspartate
of study patients hyperammonaemia or control

Kircheis et al. 1997 Rd db pc 7 days 126 Cirrhosis OA i.v. (20 g/day) - improvement of mental function
vs 5% fructose (placebo) - reduction in time required for NCT
- ammonia-lowering effect
Feher et al. 1997 Rd pc db 7 days 80 Cirrhosis OA i.v. (20 g/4h) vs placebo - reduction in ammonia levels

Clinical Trials with oral L-ornithine-L-aspartate

Authors Study design Duration- No. of Aetiology of Test drug/placebo Efficacy of L-ornithine-L-aspartate
of study patients hyperammonaemia or control

Stauch et al. 1998
Liehr et al. 1992
Rd db pc 14 days 66 Cirrhosis OA oral (3x 6 g/day) - improvement of mental function
vs placebo - reduction in time required for NCT
- ammonia-lowering effect
Rd controlled 14 days 42 Cirrhosis OA oral (3x 9 g/day) - effects of OA and lactulose with respect to improvement
vs lactulose oral (3x 30 ml) of mental function
- reduction in time required for NCT and lowering of ammonia

Table 6.1: Controlled clinical trials with Hepa-Merz®(L-ornithine-L-aspartate, OA) in patients with Rd: randomised; db: double-blind; pc: placebo-controlled
hyperammonaemia and hepatic encephalopathy

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6.1 Clinical research with
Hepa-Merz ®
Clinical research with The clinical efficacy of Hepa-Merz® (L-ornithine-
Hepa-Merz® and L-aspartate) in liver diseases has already been compre-
evidence-based hensively investigated and reported in therapeutic
medicine observations and clinical trials (Kalk, 1958; Kosozu
1966; Schäfer, 1968; Aschke,1969; Melzer et al., 1969;
Vorberg, 1969; Baumann, 1970; Schmitt and Ziegler,
1970; Wotzka and Weber, 1972; Leonhardt and Bun-
gert, 1972; Hunold, 1973; Schmidt, 1974; Müting and
Reikowski, 1980; Hendricks and Hellweg, 1984; Müller-
Kengelbach, 1986; Müting et al., 1988; Handschuh,
1990; Müting et al., 1992; Podymova and Nadinskaya,
1998). In these studies the use of Hepa-Merz®, as infu-
sion, oral administration or a combination of the two,
was documented in patients with mild to severe liver
insufficiency. The underlying cause of hepatic dysfunc-
tion was most often cirrhosis, although patients with
other liver diseases were also treated. The documented
duration of the studies ranged from a few days to sev-
eral years.
In the past few years, clinical trials on the efficacy and
tolerability of Hepa-Merz® (L-ornithine-L-aspartate)
have been conducted in accordance with general
methodological advances in clinical research and evi-
dence-based medicine (see sections 6.3 and 6.4).
These include, in particular, criteria such as placebo
controls, double blind conditions, randomized alloca-
tion to treatment arms, sufficient numbers of patients
according to estimates of the number of cases requir-
ed, conduction of the trial in accordance with good
74
clinical practice (GCP) etc. In this way the requirements
for evidence-based medicine (see section 4.3) are also
clearly met for treatment with Hepa-Merz® (L-ornithine-
L-aspartate).
6.2 Experimental clinical studies
with Hepa-Merz ®
6.2.1 Effects of Hepa-Merz ® on
ammonia concentration
From a very early stage, measurement of the ammonia Ammonia
concentration has been included in clinical studies as a concentrations
key feature of the mechanism of action. Changes in the in clinical studies
ammonia concentrations on treatment with L-ornithine- with Hepa-Merz®
L-aspartate were closely related to the clinical thera-
peutic efficacy (Schmitt and Ziegler, 1970; Leonhardt
and Bungert, 1972; Müting and Reikowski, 1980,
Müting et al., 1992). In the majority of the more recent
clinical studies, the ammonia concentration was also
determined, that is to say, was one of the main out-
come measures. In the following controlled experimen-
tal clinical studies, various aspects of the effects of
L-ornithine-L-aspartate on hyperammonaemia were
investigated.
In a controlled clinical study, ammonia concentrations in Controlled clinical
venous blood were investigated after hyperammon- studies with
aemia had been experimentally induced in patients with experimental
cirrhosis and in healthy volunteers, with and without the hyperammonaemia
administration of L-ornithine-L-aspartate (Henglein-
Ottermann, 1976). For this purpose, hyperammon-
aemia was induced in 10 patients with cirrhosis and 10
75
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 76

healthy volunteers by giving them ammonium chloride +

NH4 (µg/dl) ✱
p < 0.05 x ± SEM
infusions (40 mg/kg body weight over 60 minutes) and
800
load-response curves were plotted from the blood sam- L-ornithine-L-aspartate (5 g/h)
ples taken over a total of 2 hours. As expected, the NH4CI infusion (40 mg/kg BW) ✱

600
concentrations in cirrhotic patients were statistically sig-
nificantly higher at all times than in the healthy test sub-
jects (peak levels in each case were reached 60 mi- 400

nutes after the start of the infusion). The infusion was

repeated on another day in the study, but this time with 200

the additional administration of 5 mg L-ornithine-

L-aspartate (randomized test sequence). This showed 0
that the higher peak ammonia concentrations mea-
sured in the cirrhotic patients after 60 minutes could be 0 30 50 60 70 90 120
significantly reduced by the administration of L-ornithine- Time (min) after the NH4CI infusion

L-aspartate (p≤0.05) so that the overall load-response NH4CI NH4CI + OA

curve was flatter. As expected, administration of
L-ornithine-L-aspartate made no difference to the
ammonia concentrations in people with healthy livers
(Figure 6.1).
Figure 6.1: Effects of Hepa-Merz® on the hyperammonaemia induc-
ed by ammonium chloride infusion (40 mg NH4Cl/kg BW) in
patients with cirrhosis of the liver

Lowering of ammonia Ammonia loading demonstrated the reduced detoxifica-
in patients with tion ability of the cirrhotic liver though an – in contrast to
cirrhosis the healthy liver – overall higher concentration of am-
monia in the blood with a more prolonged duration,
which could be significantly lowered by the administra-
tion of L-ornithine-L-aspartate, especially the peak
values.
Dose-dependent The dose-effect relationships of L-ornithine-L-aspartate
effects on postprandi- to the physiological postprandial hyperammonaemia
al hyperammonaemia and the amino acid profile in the plasma were investi-
gated in a randomized double-blind, placebo-controlled
study with a four-way crossover design (Lewling et al,
1991, Staedt et al., 1993). Ten patients with cirrhosis of
the liver and hyperammonaemia (postprandial >120
µg/dl) each underwent four test procedures in varying
order. An 8-hour infusion containing 5 g, 20 g or 40 g of
L-ornithine-L-aspartate or placebo was given during
each treatment unit, so that, by the end of the study,
data were available for analysis from each patient at
each of the four doses. Two protein loads were given on
each study day, similar to normal dietary habits: 0.25
g/kg body weight in the mornings and 0.5 g/kg body
weight at lunchtime.

76 77
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 78

Analysis of the ammonia concentration from venous
blood showed that, in comparison with placebo, post-
prandial hyperammonaemia was lowered by the admin-
istration of L-ornithine-L-aspartate in a dose-dependent
manner, and with the highest dose it was almost pre-
vented (Figure 6.2). All postprandial values were lower
with L-ornithine-L-aspartate than with placebo; with a
dose of 40 g, the difference in peak levels at 11 o’ clock
was statistically significant. The analysis also showed
that, compared with placebo, L-ornithine-L-aspartate
caused a significant rise in serum urea, a sign of increas-
ed ammonia detoxification.

✱
p < at 9:00 ✱
p < at 13:00 The amino acids alanine, arginine, glutamate, glutamine Amino acid profile and
p < at 9:00 p < at 13:00
+ + ✱✱
NH4 (µg /dl) ✱✱ NH4 (µg /dl) and proline which are metabolically linked to the met- peripheral metabolism
400 400 abolism of ornithine and aspartate, increased markedly
✱ ✱✱ under the administration of L-ornithine-L-aspartate,
sometimes in a statistically significant manner when
350 350
compared with placebo. On the other hand, the amino
✱ acids methionine, phenylalanine, tyrosine, threonine,
✱
300 ✱✱ 300 serine and glycine were reduced in a dose-dependent
✱✱
manner. The reduction in these amino acids, which are
not metabolically closely associated with L-ornithine-
250 250 L-aspartate, may be interpreted as peripheral retention
(decreased release or increased uptake in the periphery).
200 200 The authors discuss the effects as an indication of the
improvement in protein equilibrium and an anticatabolic
effect of L-ornithine-L-aspartate in muscle tissue as a
150
➨

150
➨

Protein load Protein load contribution to the observed lowering of ammonia.

(0,25 g/kg BW) (0,5 g/kg BW) A supplementary evaluation of the study data (Staedt et
al., 1993) quantified the relationship of branched-chain
100 100
9 11 13 hours 13 15 17 hours amino acids (BCAA) to aromatic amino acids (AAA). In
patients with cirrhosis, there is often a shift in the equilib-
Placebo OA (5g) OA (20g) OA (40g) rium between these two groups, in favour of the aro-
matic amino acids (see section 2.2.3). After protein load-
Figure 6.2: Venous ammonia concentrations (median ± SEM) with infusions of Hepa-Merz® at doses of
5 g, 20 g and 40 g and placebo, with protein loading at 9:00 and 13:00 hours. Postprandial hyperam- ing, the mean BCAA/AAA quotient under placebo clearly
monaemia (significant increases at 11:00 and 15:00 on placebo) were prevented at 15:00 with 20 g fell from 1.6 to 1.2. With the administration of
and at 11:00 and 15:00 with 40g L-ornithine-L-aspartate. Peak values measured at 11:00 with 40 g OA
L-ornithine-L-aspartate (40 g), however, the quotient
were significantly lower than with placebo (after Staedt et al., 1993)
was increased from 1.4 to 1.5. This result is a sign that

78 79
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 80
the amino acid imbalance tends towards normal on
treatment with L-ornithine-L-aspartate.
The results of these controlled studies demonstrated
that the effects L-ornithine-L-aspartate on postprandial
hyperammonaemia are dose-dependent. In addition,
they showed that L-ornithine-L-aspartate causes chang-
es in the amino acid profile that can be interpreted as
anticatabolic actions, as well as having a positive effect
on the preexisting imbalance between branched-chain
and aromatic amino acids found in patients with cir-
rhosis.
Increase in ammonia With hepatic insufficiency, the ammonia concentration
and reaction times in the blood rises to unphysiological levels after a pro-
after protein loading, tein meal. A controlled clinical study was carried out to
compared with investigate whether, due to its specific effects, the
placebo administration of L-ornithine-L-aspartate protected
against a rise in ammonia after protein loading and, as
a result, had a positive effect on psychometrically
measurable functional deficiencies (Rees et al., 2000).
Eight patients with cirrhosis of the liver were each
subjected to two loading tests with 20 g glutamine. In
randomized sequence, either 5 g L-ornithine-L-aspartate
or placebo was infused concurrently. Ammonia
concentrations in the blood were determined before
and after the glutamine load and psychometric tests
performed at the same time.
As expected, the glutamine load caused an increase in
venous ammonia, the baseline being 27 ± 5 µmol
(mean ± SEM).
80
However the increase seen on treatment with L-ornithine-
L-aspartate was significantly less than with placebo
(Figure 6.3).
100
80 62 µmol/l
Ammonia µmol/l
60
36 µmol/l
40
20
0
L-ornithin-L-aspartate Placebo
Figure 6.3: Venous ammonia concentration after protein loading
(20 g glutamine) on treatment with Hepa-Merz® (left) and placebo
(right) in patients with cirrhosis of the liver. Figures shown are the
mean values (after Rees et al., 2000)
Parallel to the inhibition of the ammonia increase after
protein loading, the administration of L-ornithine-
L-aspartate stabilized psychometric functions. While
the reaction time to a visual stimulus (choice reaction
time, CRT) was significantly prolonged after a protein
load and placebo, there was no prolongation of reaction
time when L-ornithine-L-aspartate was administered
(Figure 6.4).
The results of these controlled clinical studies show that
the administration of L-ornithine-L-aspartate counter-
acts metabolic disturbance after a protein meal in
patients with cirrhosis and, in parallel to this, the
psychometric functions remain stable.
81
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 82

the start of treatment and 7 days afterwards, the protein

L-ornithine-L-aspartate Placebo
450 synthesis rate in muscle was tested both in a fasting
416 state and after the ingestion of food, using a special
406 404

Reactiontime in ms
procedure (leucine incorporation). The results of the
400 390
study showed a return to the normal response on
L-ornithine-L-aspartate, with a significant increase in
the protein synthesis rate in muscle after the ingestion
350
of food from 0.044 ± 0.009 to 0.071 ± 0.022% per hour
(mean ± SEM, p=0.06). In contrast, there were no
300 changes on placebo treatment. Under fasting condi-
before after before after tions, the protein synthesis rate in muscle was further
glutamine load glutamine load reduced on placebo while it stabilized on L-ornithine-
Figure 6.4: Reaction time in choice reaction test (CRT) before and
L-aspartate (Figure 6.5 and Table 6.2).
after protein loading (20 g glutamine) on Hepa-Merz® (left) or pla-
cebo (right) in patients with cirrhosis of the liver. Figures shown are OA group Placebo group
the mean values (after Rees et al., 2000) fasting after food fasting after food
Day 1 0.051 (0.015) 0.044 (0.009)* 0.047 (0.016) 0.046 (0.016)
Day 7 0.047 (0.015) 0.071 (0.022)* 0.035 (0.012) 0.049 (0.023)
6.2.2 Effects of Hepa-Merz ® on
Tab. 6.2: Protein synthesis rate (%/h) in muscle of cirrhotic patients;
protein synthesis in muscle means (SEM) *p=0,06

Protein synthesis Muscle wasting is a characteristic symptom in cirrhosis

%/h
rate in muscle in of the liver and is, as a rule, associated with an unfa- 0,03
L-ornithine-L-aspartate Placebo

comparison with vourable prognosis. In people with healthy livers, the 0,025
placebo rate of protein synthesis in muscle tissue rises after the 0,02
intake of food, whereas this increase is lacking or

Protein synthesis
0,015

reduced in cirrhotic patients. A controlled clinical study 0,1

(Reynolds et al., 1999) was carried out to investigate 0,005

whether, because of its favourable effects on the metab- 0

0,027 0,003 OA (fasting)
-0,005
olism of ammonia and amino acid equilibrium, L-orni- -0,004 OA (posprandial)
-0,01 Placebo (fasting)
thine-L-aspartate also beneficially influenced protein -0,012 Placebo (posprandial)
-0,015
metabolism. Sixteen patients with cirrhosis of the liver fasting posprandial fasting posprandial

and muscle wasting were randomized to infusions of 40 g Fig. 6.5: Representation of the values from Tab. 6.2 as the difference
L-ornithine-L-aspartate or placebo for 7 days. Prior to between day 1 and day 7

82 83
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The results can be interpreted as the inhibition of catabolic
muscle metabolism and stimulation of protein synthesis in
the muscle due to L-ornithine-L-aspartate.
6.2.3 Effects of Hepa-Merz ® on
neurometabolites
Ammonia and Neurometabolites in the brain can be demonstrated in vivo
neurometabolites using proton magnetic resonance spectroscopy (proton
in the brain MRS) (Delcker et al., 2002). The typical changes seen in
hepatic encephalopathy relate in particular to the concen-
tration of glutamine which is increased in the brain – possi-
bly as a result of the increased ammonia in the blood and
the stimulation of glutamine synthesis in the astrocytes
(Figure 6.6).
given an infusion of 40 g L-ornithine-L-aspartate. Imme-
diately before and 6 hours after the start of the infusion,
MRS investigations were carried out in the parietal
region and at the same time, the arterial ammonia con-
centration was determined.
It was shown that the ammonia concentration in arteri-
al blood and the Glut+Gln/Cr ratio in the brain correlat-
ed in a statistically significant manner (r = 0.72,
p<0.001). Both parameters decreased with the infusion
of L-ornithine-L-aspartate, and the extent of these
changes also correlated in a statistically significant
manner (r = 0.54, p<0.04). Figure 6.7 shows NMR
spectra before and after the infusion of Hepa-Merz®.

Glu Gln Glu + Gln

Glu + Gln

prior to ornithine aspartate infusion after ornithine aspartate infusion

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0
Figure 6.6: Characteristic neurometabolite concentrations in ppm ppm
patients with hepatic encephalopathy
In an open study, it was investigated whether the ratio Figure 6.7: Nuclear magnetic resonance spectra before and after Hepa-Merz® infusion. On the right a clear
lowering of the glutamate and glutamine concentrations in the brain can be seen following the infusion
of glutamine + glutamate in relation to creatine
(Glut+Gln/Cr) changed when L-ornithine-L-aspartate These results confirm that, in parallel to the reduction in
was given, and whether this ratio correlated with the ammonia concentration, L-ornithine-L-aspartate has an
lowering of the ammonia concentration seen with effect in reducing the glutamine and glutamate concen-
L-ornithine-L-aspartate. With these objectives, fifteen trations in the brain. At the same time, this investigation
patients with grade I/II hepatic encephalopathy were presents a new parameter for clinical studies on hepatic

84 85
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 86
encephalopathy which can be used in vivo to deter-
mine quantitative changes in neuro-metabolites in the
brain.
6.3 Clinical results with intra-
venous Hepa-Merz ® therapy
6.3.1 Hepa-Merz ® infusion in
comparison with placebo
Placebo-controlled A multicentre randomized double-blind placebo-con-
double-blind trial on trolled trial was carried out to demonstrate the efficacy
126 patients with and tolerability of L-ornithine-L-aspartate infusion con-
cirrhosis of the liver centrate (Kircheis et al., 1997). One hundred and twen-
and HE grade 0 ty-six patients with cirrhosis of the liver and chronic
(subclinical) to II (persistent) overt hepatic encephalopathy (grades I/II,
West Haven criteria) or subclinical hepatic encephalop-
athy (SHE and performance time for number connec-
tion test A >30 seconds) were enrolled. In addition, all
patients had to have demonstrable hyperammonaemia
(venous ammonia concentration >50 µmol/l).
The patients were given daily in-patient treatment for
seven days, receiving an infusion of 20 g L-ornithine-
L-aspartate (4 ampoules infusion concentrate) dissolv-
ed in 250 carrier solution over 4 hours (N=63), or a cor-
responding placebo infusion (N=63). At the same time
they were given a diet containing 1 g protein/kg body
weight per day divided into three meals. Investigations
were carried out before the start of treatment (time 0)
and after 2, 4 and 7 days. The main efficacy parameters
were the postprandial venous ammonia concentration
and the time required for NCT-A. Further efficacy
86
parameters were the HE grade, the PSE index and the
venous ammonia concentration under fasting condi-
tions.
The results of venous ammonia concentrations showed Fasting and
statistically significant differences in favour of L-ornithine- postprandial
L-aspartate (Figure 6.8). The mean values under fasting ammonia
conditions before the start of treatment were 81 ± 38 concentrations
µmol/l in the L-ornithine-L-aspartate group and 83 ± 43
µmol/l in the placebo group. After seven days they had
decreased on average by 17 ±37 µmol/l and 6 ± 32
µmol/l, respectively (before/after comparison). The
group differences in favour of L-ornithine-L-aspartate
therapy were statistically significant after 4 and 7 days
(p=0.0155 and p=0.0188). The mean postprandial
ammonia concentration of 83 ± 37 µmol/l initially mea-
sured in the L-ornithine-L-aspartate group was lower
than that of 91 ± 48 µmol/l in the placebo group. After
7 days’ treatment the mean postprandial ammonia con-
centrations had decreased by 16 ± 40 µmol/l and by 10
± 36 µmol/l, respectively. The group differences in
favour of L-ornithine-L-aspartate treatment were signifi-
cant on days 2 and 4 (p<0.013) and showed a tenden-
cy towards significance on day 7 (p=0.078).
Statistically significant group differences in the time Performance time
required for the NCT-A were also seen in favour of for the number
L-ornithine-L-aspartate treatment (Figure 6.9). connection test
A sub-evaluation of the degree of severity of the hepat-
ic encephalopathy showed that the group differences
with grade II were the most pronounced, but were also
significant with subacute hepatic encephalopathy (SHE) HE grading
and grade I. The mental state recorded on the basis of and PSE index
87
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 88

160 100
** ***

Fasting ammonia (µmol/l)

140 * **
* 80 *
120

NCT-A (seconds)
*** ** *** P 75
100
P 75 60 Mittelwert
80 Mittelwert Median
Median
60 P 25 40 P 25

40
20
20
*p < 0.05, **p > 0.01, ***p < 0.001 *p < 0.05, **p > 0.01, ***p < 0.001
0 0
0 2 4 7 0 2 4 7 0 2 4 7 0 2 4 7
Duration of treatment (in days)
Duration of treatment (in days)
160
Postprandial ammonia (µmol/l)

Mean ±SD OA (P25 bis P75)

140
* Median Placebo (P25 bis P75)
120 *
** P 75
100 *** Figure 6.9: Effects of L-ornithine-L-aspartate (left) versus placebo
Mittelwert
80 Median (right) on the time required to perform the number connection test.
60 P 25 Figures given are the mean (black square) and standard deviation,
median (white square), 25th and 75th percentiles and the group dif-
40
ferences between the two treatments (after Kircheis et al., 1997)
20
*p < 0.05, **p > 0.01, ***p < 0.001
0
0 2 4 7 0 2 4 7
the changes in the HE grade after 7 days’ treatment
Duration of treatment (in days)
with L-ornithine-L-aspartate. With HE grade 0, a reduc-
Mean ± SD OA (P25 to P75)
tion in the NCT performance time from the baseline
Median Placebo (P25 to P75)
value to <30 s was taken as evidence of improvement.
Figure 6.8: Reduction in ammonia levels (µmol/l) over a period of 7 L-ornithine-L-aspartate was clearly superior to placebo.
days on treatment with L-ornithine-L-aspartate (left) versus placebo
(right). Figures given are the mean (black square) and standard devia-
tion, median (white square), 25th and 75th percentiles and the group In addition, changes in the modified PSE index were
differences between the two treatments (after Kircheis et al., 1997) evaluated. HE grade, venous ammonia concentration
and NCT performance time were taken into account in
clinical criteria (HE grade) improved more clearly after 7 the calculation. The mean of the PSE index at the start
days’ treatment with L-ornithine-L-aspartate (from of treatment was 0.28 ± 0.12 in both the L-ornithine-
mean 0.97 ± 0.53 to 0.42 ± 0.33) than on placebo (0.91 L-aspartate and the placebo groups. By the end of
± 0.48 to 0.72 ± 0.52). Statistical analysis showed sig- treatment (day 7), it had fallen to 0.135 ± 0.10 in the
nificant differences between the groups (p<0.001) in L-ornithine-L-aspartate group and to 0.22 ± 0.14 on
favour of L-ornithine-L-aspartate. Figure 6.10 shows placebo. Both the comparison of treatments on day 7

88 89
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 90

• 1 patient was excluded before the start of the trial

Patients with improvement in HE grade

N
40 37 because of non-cooperation
L-ornithine-L-aspartate
35 Placebo group:
Placebo
30 • 1 patient with advancing cardiac failure
25
20 19
20
In the three patients (5%) with gastrointestinal symp-
15 12
9 9 toms or nausea/vomiting, a causal relationship with the
10
6 L-ornithine-L-aspartate infusion cannot be ruled out.
5 2
0
Overall HE HE SHE The results of the double-blind trial show the efficacy of
grade II grade I L-ornithine-L-aspartate in comparison with placebo
Figure 6.10: Number of patients with improvement in the HE grade with respect to the mental state, the ammonia concen-
after 7 days’ treatment with L-ornithine-L-aspartate or placebo in tration and the performance time for the NCT-A. The
the various subgroups (SHE = subclinical hepatic encephalopathy)
(after Kircheis et al., 1997) product was predominantly well tolerated without caus-
ing any serious adverse reactions.
and the before/after comparison between the groups
showed statistically significant differences in favour of A further multicentre, randomized double-blind trial has Placebo-controlled
L-ornithine-L-aspartate (p=0.0011 and p=0.0003, also been carried out with placebo control (Feher et al., double-blind trial on
respectively). 1997). In this study, 80 patients with alcohol-induced 80 patients with
cirrhosis of the liver and established hyperammon- cirrhosis of the liver
Safety and Infusion therapy was well tolerated by 88% of the aemia (defined as >50 µmol/l) were enrolled. Over 7 and hyperammonaemia
tolerability patients in the L-ornithine-L-aspartate groups and days, the patients received either a four-hour infusion
100% of the patients given placebo. Adverse events of 20 g L-ornithine-L-aspartate in 250 ml saline solu-
with shortened duration of treatment occurred in 7 tion (N=40) or physiological saline (N=40). Investiga-
patients: tions were carried out after 3, 5 and 7 days. The
ammonia concentration was measured in the morn-
L-ornithine-L-aspartate group: ings, in the fasting state. Clinical symptoms and signs
• 3 patients with gastrointestinal symptoms (nausea/ were also recorded.
vomiting)
• 1 patient with an acute abdomen due to a At the start of the study, mean venous ammonia con-
perforated ulcer centrations were comparable, at 77 µmol/l in the
• 1 patient who developed hepatorenal syndrome L-ornithine-L-aspartate group and 82 µmol/l in the pla-
cebo group. During the course of treatment, the mean

90 91
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values sank by 32% (to 52 µmol/l after 7 days) on
L-ornithine-L-aspartate and by 15% (to 70 µmol/l after 7
days) on placebo. On treatment with L-ornithine-L-aspar-
tate, the mean ammonia concentration fell almost to the
upper limit of normal. The difference between the test
group and placebo was statistically significant (p<0.05).
Evaluation of relevant clinical symptoms showed a
decrease for all criteria in both treatment groups. Al-
though this was more pronounced in the OA group, it
did not reach statistical significance because of the
increased number of cases. There was, however, a
trend towards a clear reduction in the patient numbers
in the L-ornithine-L-aspartate (LOLA) group in compari-
son with placebo (Table 6.3).
L-aspartate group and 28 in the placebo group. The Overall assessment of
number of patients who showed no improvement was therapeutic success
clearly higher in the placebo group (12 vs 7). The over-
all assessment of tolerability showed that L-ornithine-
L-aspartate was predominantly well or satisfactorily
tolerated, and poorly tolerated in only 3 cases. No
adverse effects were seen in either treatment group.
The results of this placebo-controlled trial once again
confirm the efficacy of Hepa-Merz® in patients with cir-
rhosis of the liver and raised ammonia concentrations,
as well as its good tolerability
6.3.2 Meta-analysis of placebo-
controlled trials

At the end of treatment, an overall assessment of ther- In the context of a meta-analysis, a quantitative system- Meta-analysis of
apeutic success was made by the physician. Clinical ic overview of randomized placebo-controlled clinical randomized placebo-
improvements were seen in 33 patients in the L-ornithine- trials with L-ornithine-L-aspartate infusion concentrate controlled clinical
was carried out to investigate treatment effects trials with L-ornithine-
LOLA LOLA Placebo Placebo
before after before after (Delcker et al., 2000). The data analysis was conduct- L-aspartate infusion
Fatigue 21 10 27 17 ed in accordance with the QUORUM statement on the concentrate
Feeling of fullness 19 14 22 16 quality of reports for meta-analyses (Moher et al.,
Gastrointestinal 16 6 17 6 1999). Blinded individual data on 246 patients from five
symptoms randomized controlled clinical trials formed the basis of
Nausea 15 4 7 5 the evaluation. Two of these trials had already been
Loss of appetite 22 11 22 13 published and biometric final reports were available for
Jaundice 21 14 25 19 the other three.
Foetor hepaticus 9 5 11 9
Ascites 21 20 21 18 In all five trials, patients with hepatic encephalopathy as
Pruritus 4 2 7 5 a complication of cirrhosis of the liver were treated with
Table 6.3: Number of patients with clinical symptoms or signs be-
either L-ornithine-L-aspartate infusion concentrate or
fore and after 7 days’ treatment with Hepa-Merz® or placebo (after placebo over a period of 7 days. The mental state (HE
Feher et al., 1997)
92 93
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 94

grade), the number connection test A (NCT-A) perfor- ence between treatments after 7 days was statistically
mance time and the venous ammonia concentrations significant with p=0.015.
were used for the analysis of efficacy.
100 L-ornithine-L-aspartate infusion
With respect to the mental state of the patients, there Placebo
90
was a significant improvement on L-ornithine-L-aspar-

Ammonia (µmol/l)
tate in comparison with placebo after 7 days’ treatment. 80
The odds ratio was 3.22 with a 95% confidence inter- 70
val of 1.38 to 7.55 (p<0.01). 60

50
The performance time for the number connection test
p < 0.015
was more clearly reduced on L-ornithine-L-aspartate 40
treatment than with placebo (Figure 6.11). The differ- Day 0 1 after 3 4 5 6 after
2 days 7 days
ence between treatments after 7 days was statistically
significant at p<0.001. Figure 6.12: Venous postprandial ammonia concentrations before
the start of treatment (Day 0) as well as after 2 and 7 days’ treat-
ment with L-ornithine-L-aspartate or placebo. Figures given are the
The venous postprandial ammonia concentration also mean ± SEM, database 246 patients (after Delcker et al., 2000)
showed a significantly greater reduction on L-ornithine-
L-aspartate than on placebo (Figure 6.12). The differ- L-ornithine-L-aspartate was predominantly well tolerat-
ed. Documented adverse effects were restricted to
80 L-ornithine-L-aspartate infusion nausea, vomiting and fatigue.
Placebo
70

60
Seconds

Summary:
50
In summary, this meta-analysis based on the individual data of 246
40
patients from randomized placebo-controlled clinical trials shows that 7
30 days’ treatment with Hepa-Merz® infusion concentrate leads to improve-
p < 0.001
20 ment of the mental state, reduction in the time needed to complete the
Day 0 1 after 3 4 5 6 after number connection test and lowering of the ammonia concentration in
2 days 7 days the blood, while generally being well tolerated. The treatment differ-
Figure 6.11: Performance time for the number connection test ences in comparison to placebo were always statistically significant in
(NCT-A) before the start of treatment (Day 0) as well as after 2 and favour of Hepa-Merz® infusion concentrate.
7 days’ treatment with L-ornithine-L-aspartate or placebo. Figures
given are the mean ± SEM, database 246 patients (after Delcker et
94 al., 2000)
95
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 96

6.4 Clinical results with oral
Hepa-Merz ® therapy
In the long-term treatment of associated conditions and
sequelae of diseases with impaired detoxification func-
tion of the liver (e.g. cirrhosis), it is important that an
effective oral form of the medicinal product is also avail-
able. L-ornithine-L-aspartate can be used long-term in
the form of Hepa-Merz® Granules 6000 (1 sachet with
10 g granules contains 6 g L-ornithine-L-aspartate) or
Hepa-Merz® Granules 3000 (1 sachet with 5 g granules
contains 3 g L-ornithine-L-aspartate). The efficacy of
this pharmaceutical form has also been studied in clini-
cal trials.
6.4.1 Hepa-Merz ® Granules in
At the same time all participants were given a diet con-
taining 1 g protein/kg body weight/day in three divided
meals. Examinations were carried out prior to the start of
treatment (day 0) and after 7 and 14 days. The main out-
come measures were postprandial venous ammonia
concentration (1 hour after the morning protein meal) and
the performance time for the NCT-A carried out at the
same time. Further parameters of efficacy included the
mental state (HE grade), the PSE index and the venous
ammonia concentrations under fasting conditions.
The results of venous postprandial ammonia concen-
tration showed statistically significant differences in
favour of L-ornithine-L-aspartate in both the before/
after comparison and in the group comparison (Figure
6.13).

Posprandial ammonia level measured (µmol/l)

comparison with placebo
180
**
160
Placebo-controlled The efficacy of L-ornithine-L-aspartate granules com- 140
double-blind trial pared with placebo was tested in a multicentre **
120
in 66 patients with randomized double-blind trial in 66 patients with cirrhosis 100
cirrhosis of the liver of the liver and stable chronic overt (HE grade I/II) or 80
and HE grade 0 subclinical hepatic encephalopathy (HE grade 0) 60
(subclinical) to II (Stauch et al., 1998). Further inclusion criteria were 40
hyperammonaemia (fasting venous ammonia concen- 20
**p < 0.01
0
tration >50 µmol/l) and a performance time >30 s in the 0 7 14 0 7 14
number connection test (NCT-A). Duration of treatment (in days)
The patients were given 2 sachets of Hepa-Merz®
Mean ± SD OA (P25 to P75)
Granules 3000 (each containing 3 g L-ornithine-
Median Placebo (P25 to P75)
L-aspartate) dissolved in water, three times a day (total
Figure 6.13: Effects of L-ornithine-L-aspartate (left) and placebo (right)
daily dose: 18 g) for 14 days (N = 34) or a correspond-
on the postprandial venous ammonia concentration. Figures given are
ing placebo (N = 32). the mean (black square) and standard deviation, median (white
square), 25th and 75th percentiles (after Stauch et al., 1998)
96 97
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 98

A similar result was seen in the venous ammonia con-
centrations measured under fasting conditions. Here
the group difference was clearly in favour of L-ornithine-
L-aspartate.
With respect to the second main outcome measure, the
performance time for the NCT-A, there was a statisti-
cally significant group difference in favour of L-ornithine-
L-aspartate after 14 days (p<0.05). While the time
required for the test stayed more or less constant in the
placebo group, it was progressively shortened on treat-
ment with L-ornithine-L-aspartate (Figure 6.14).
change was seen with placebo (1.16 ± 0.65 vs 0.93 ±
0.63, p>0.05).
With the baseline clinical assessment of HE 0, a reduc-
tion in the NCT-A performance time to <30 seconds
was taken as evidence of improvement. The clinical
relevance of the treatment difference between L-ornithine-
L-aspartate and placebo is particularly obvious when
considering the number and proportion of patients with
improvement of the HE grade. More than twice as many
patients improved on L-ornithine-L-aspartate as did on
placebo.

120 Calculation of the modified PSE index included the HE

**
100 ** grade, the postprandial venous ammonia concentration
and the NCT performance time. In accordance with the
80
NCT-A (sec)

statistically significant group differences in favour of

60
L-ornithine-L-aspartate found in these three parame-
40 ters, the difference in the PSE index was also statisti-
20 cally significant at p<0.01. The mean PSE index in the
**p < 0.01
0 L-ornithine-L-aspartate group was 0.29 ± 0.11 at the
0 7 14 0 7 14
start of treatment, improving to 0.20 ± 0.14 after 14
Duration of treatment (in days)
days (p<0.01). The corresponding values for the place-
Mean ± SD OA (P25 to P75) bo group were 0.32 ± 0.12 vs 0.28 ± 0.15 (n.s.).
Median Placebo (P25 to P75)

Figure 6.14: Effects of L-ornithine-L-aspartate (left) and placebo
(right) on performance time in the number connection test. Figures
given are the mean (black square) and standard deviation, median
(white square), 25th and 75th percentiles (after Stauch et al., 1998)
The HE grade established clinically showed a statisti-
cally significant improvement, from a mean of 1.04 ±
0.54 to 0.68 ± 0.47, after 14 days’ treatment with
L-ornithine-L-aspartate (p<0.05) while no significant
Treatment was predominantly well tolerated in both
groups (L-ornithine-L-aspartate 94% and placebo
81%). Two patients in the L-ornithine-L-aspartate group
and 6 patients in the placebo group rated the tolerabili-
ty as moderate. No patients showed any adverse reac-
tions to the medication. One patient in each group was
excluded from the trial prematurely because of poor
compliance.

98 99
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 100
One further patient on placebo had to be switched to
another therapy because of worsening encephalopathy.
Summary:
These placebo-controlled clinical trials show that the oral form of L-orni-
thine-L-aspartate is comparable to L-ornithine-L-aspartate infusion con-
centrate with respect to efficacy and tolerability.
6.4.2 Hepa-Merz ® Granules in the
medical practice
Observation of use In order to study the effectiveness and tolerability of
in 1167 patients treatment with L-ornithine-L-aspartate granules under
with liver diseases conditions of medical practice, observation of use was
carried out in 250 internal and general medical prac-
tices (Grüngreiff and Lambert-Baumann, 2001).
Records were kept on patients with chronic liver dis-
eases who had previously been unsuccessfully treated
with general non-pharmacological measures and in
whom the physician saw an indication for medication
with L-ornithine-L-aspartate granules. Besides the
usual medical history, data concerning diagnosis, dos-
age and duration of treatment, therapeutic monitoring
(clinical symptoms and routine laboratory tests) and
tolerability were documented. In total, data were collect-
ed on 1167 patients. The mean age of these patients
was 53.5 years (18 to 87 years) and the majority were
men (71%). On average, the liver disease had been
known about for some 4-5 years. The underlying cause
most frequently suspected by the physician was alco-
100
hol misuse (71%); viral infections, medicines, industrial
chemicals and other aetiological factors were also men-
tioned. The most frequent diagnosis was that of fatty
liver (55.5%), followed by cirrhosis of the liver (32.4%)
and chronic hepatitis (21.7%). Other diagnoses were of
lesser importance (multiple entries were possible).
It was planned that parameters routinely used by the Laboratory tests
physician to monitor the course of the disease – aspar- for therapeutic
tate aminotransferase (AST), alanine amino-transferase monitoring
(ALT), gamma-glutamyl transferase (γ−GT), bilirubin and
the prothrombin time – would be measured before and
after treatment. Evaluation of these parameters showed
clear reductions in the mean values of AST, ALT, γ−GT
and bilirubin with a slight increase in the prothrombin
time over the entire patient population. Figure 6.15
gives an overview of the three largest diagnostic groups
– patients with fatty liver, cirrhosis of the liver and chron-
ic hepatitis – and the most frequently measured param-
eters AST, ALT and γ−GT.
The results show very clearly that there was a reduction
in the clinically relevant parameters in all three diagnos-
tic groups, most pronounced in patients with fatty liver.
Patients were also subdivided into three groups with
respect to the daily dose (normal dose 9 g L-ornithine-
L-aspartate/day, <9 g OA/day and >9 g OA/day) and to
the duration of therapy (<30 days, 31-60 days, 61-90
days) in order to investigate the relationship of these cri-
teria to the therapeutic effects. There was a positive
relationship between the percentage reduction in the
liver enzymes and the daily dosage and duration of
treatment.
101
43 057 WiBro englisch 13.05.2004 17:18 Uhr Seite 102

% The clinical symptom of “fatigue” which was recorded

20 also showed a clear improvement during the course of
treatment. In 178 of the patients with cirrhosis of the

Percentage reduction in transaminases

10
liver, very marked fatigue was recorded initially; this
0

before and after treatment

improved in 95% of the patients. The mild to moderate
-10
fatigue experienced by 157 patients at the start of treat-
-20 ment was no longer present in 53% of these patients at
-30 the final assessment, as can be seen in Figure 6.16.
-40 At the end of the observation period, the treating physi- Overall assessment
-50 cians made an overall assessment of the effectiveness of efficacy and
and tolerability of treatment with L-ornithine-L-aspartate. tolerability
-60
AST ALT γ-GT Analysis of these data showed their positive assess-
-70
n = 963 cirrhosis
ment of treatment success (Figure 6.17).
fatty liver
chr. hep.

Improvement in HE/fatigue in patients with cirrhosis

Figure 6.15: Changes in AST, ALT and γ−GT on treatment with Hepa- 180
Merz® Granules in the three largest diagnostic groups. Data on
patient numbers (N) and percentage decrease in transaminases (after 160
Grüngreiff and Lambert-Baumann, 2001) 140

Number of patients
120

Additional factors which had positive effects on the 100

levels of the liver enzymes were good compliance and 80
a definite abstinence from alcohol during the period of 60
Improvement in observation. In 348 of the patients with cirrhosis, infor- 40
clinical symptoms mation was supplied on hepatic encephalopathy (HE).
20
on L-ornithine- In 105 (30%) of these patients mild (HE grade I) and in
0
L-aspartate 27 (8%) moderate (grade II) hepatic encephalopathy
HE I HE II severe mild
was initially diagnosed. Analysis showed that 78% of fatigue fatigue
the patients with moderate hepatic encephalopathy
n = 348 before treatment
improved to a lower grade and 49% of the patients
after treatment
with grade I hepatic encephalopathy regressed to
grade 0. Figure 6.16: Effects of treatment with Hepa-Merz® Granules on the
clinical parameter “fatigue” (after Grüngreiff and Lambert-Baumann,
2001)
102 103
43 057 WiBro englisch 13.05.2004 17:19 Uhr Seite 104

And in only 8 cases did the physician consider that 6.4.3 Hepa-Merz® Granules in
there was a possible or probable causal relationship comparison with lactulose
between L-ornithine-L-aspartate and adverse events.
These were mild and mainly gastrointestinal symptoms. The disaccharide lactulose – which is not cleaved in the Controlled clinical
There were no serious adverse drug reactions. gastrointestinal tract – has been used for a long time in studies in patients
the treatment of hepatic encephalopathy (see section with cirrhosis
Therapeutic Tolerability 4.3). However, the therapeutic use of lactulose is limited
efficacy because of its frequently occurring adverse effects
(gastrointestinal symptoms, diarrhoea). Because the
mechanisms of action of L-ornithine-L-aspartate and
lactulose are basically different, a direct comparison of
the efficacy and tolerability of the two substances
seemed to be clinically relevant.
very good very good
good good
To this end, a monocentre randomized clinical trial in
moderate/slight moderate/slight
parallel groups was carried out (Liehr et al., 1992;
none
Kircheis et al., 1993; Krüger et al., 1994) in which 48
Figure 6.17: Overall assessment of the efficacy (left) and tolerability
patients with cirrhosis of the liver, hyperammonaemia
(right) of treatment with Hepa-Merz® Granules at the end of treatment, (>50 µmol/l) and minimal or overt hepatic encephalop-
shown as percentages (after Grüngreiff and Lambert-Baumann, 2001) athy were included. The patients were treated for 14
days with either L-ornithine-L-aspartate granules (3 x
Summary: 9 g per day) or lactulose (initial dose 3 x 33 g, followed
The results of this observation of use in 1167 patients with chronic liver by individual adjustment of the daily dose). Both groups
disease substantially confirm the efficacy and the good tolerability of showed a reduction in the mean NCT performance
Hepa-Merz® Granules shown in controlled clinical trials, under conditions time: from 58 s to 47 s in the L-ornithine-L-aspartate
pertaining to the medical practice. groups and from 66 s to 53 s in the lactulose group.
The mean ammonia concentration was lowered only on
L-ornithine-L-aspartate (from 120 µmol/l to 105 µmol/l).
Mean values of γ−GT improved in both groups. HE
grading also improved in both groups, whereby 29% of
patients on L-ornithine-L-aspartate no longer had any
discernable HE at the end of treatment compared with
only 5% of lactulose patients. Treatment with L-ornithine-

104 105
43 057 WiBro englisch 13.05.2004 17:19 Uhr Seite 106
L-aspartate was much better tolerated than lactulose
therapy. 45% of the patients treated with lactulose
reported adverse reactions, mostly diarrhoea commenc-
ing within the first three days.
6.5 Summary of results with
Hepa-Merz ®
Effects of L-ornithine- Pharmacodynamic effects and dose-effect relationships
L-aspartate were investigated in experimental clinical studies with
L-ornithine-L-aspartate. It has been shown that treat-
ment with L-ornithine-L-aspartate:
• lowers the elevated ammonia concentration in the
blood and increases the formation of urea
• reduces or prevents pathological postprandial
ammonia levels in the blood
• counteracts amino acid imbalance (increase of the
BCAA/AAA ratio)
• improves protein synthesis in the muscle
(evidence of anti-catabolic action)
• stabilized psychometric functions and the mental
state under protein loading
• reduces pathological glutamine and glutamate
concentrations in the brain in parallel with the
lowering of ammonia in the arterial blood
• has dose-dependent effects.
Efficacy and The results of experimental clinical studies are in agree-
tolerability of ment with the findings of experimental animal studies. The
L-ornithine- clinical efficacy and tolerability of L-ornithine-L-aspartate
L-aspartate as an infusion, with oral administration or a combination
of the two, have been investigated in many observations
106
of therapeutic use and clinical studies in patients with mild
to severe impairment of hepatic function. The majority
were patients with cirrhosis but patients with other liver
diseases were also treated. The documented duration of
treatment ranged from a few days to several years.
Recent placebo-controlled double-blind trials with
L-ornithine-L-aspartate infusion concentrate and
L-ornithine-L-aspartate granules have been carried out
in accordance with the current requirements of evidence-
based medicine. With respect to its efficacy in cirrhosis
of the liver and hepatic encephalopathy (subclinical to
HE grade II), average and clinically relevant findings on
treatment with L-ornithine-L-aspartate in comparison
with placebo show that:
• the mental state improves (significant reduction in the
HE grade)
• the PSE index falls significantly
• performance time in the number connection test is
significantly reduced
• ammonia concentrations in the fasting and postpran-
dial states are significantly lowered.
The results of experimental clinical studies, many obser-
vations of therapeutic use and clinical trials with L-orni-
thine-L-aspartate have thus been confirmed in accor-
dance with the criteria of evidence-based medicine.
The tolerability of L-ornithine-L-aspartate was good;
serious adverse reactions did not occur. In a few cases,
patients receiving L-ornithine-L-aspartate infusion ther-
apy experienced mild gastrointestinal symptoms which
could be interpreted as evidence of adverse drug reac-
tions to L-ornithine-L-aspartate.
107
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7 SAFETY AND TOLERABILITY

Data on safety and tolerability of Hepa-Merz® from the
observations of therapeutic use, clinical studies and
especially the placebo-controlled double-blind trials
have proven that the tolerability of L-ornithine-L-aspar-
tate is very good. There were no cases of serious ad-
verse drug reactions.
In the placebo-controlled double-blind trials with large
case numbers, there were three cases (5% of the
L-ornithine-L-aspartate treated patients) of mild gastro-
intestinal disturbances i.e. nausea/vomiting with infu-
sion therapy (Kircheis et al., 1997); there were no cases
in the placebo group. In the largest placebo-controlled
trial with L-ornithine-L-aspartate granules, there were
no adverse events at all in either group (Stauch et al.,
1998).
With severely impaired hepatic function, the infusion
should be reduced to a rate that the individual can toler-
ate.
Because of its mechanism of action, L-ornithine- Attention to renal
L-aspartate leads to the increased formation of urea function (creatinine
which has to be eliminated via the kidneys. L-ornithine- not greater than
L-aspartate should therefore not be used in cases 3 mg/dl)
where there is severe impairment of renal function. As a
general rule, the creatinine level should not be greater
than 3 mg/dl.

It is known from spontaneous notification of suspected

adverse drug reactions and reports from therapeutic
practice that nausea occasionally occurs on infusion
therapy, with vomiting rarely. The symptoms are gener-
ally transient and are reversible with a reduction in the
dose or the rate of infusion.

Rate of infusion In summary it can be said that L-ornithine-L-aspartate

should not be greater therapy is generally very well tolerated and that adverse
than 5 g L-ornithine- reactions may occur rarely, in the form of mild gastroin-
L-aspartate per hour testinal disturbances. To prevent such reactions, a
maximum infusion rate of 5 g L-ornithine-L-aspartate
infusion concentrate per hour is recommended.

108 109
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8 CHEMISTRY, TOXICOLOGY AND

PHARMACOKINETICS OF HEPA-MERZ ®

8.1 Chemico-physical data 8.2 Toxicology

Toxicological tests of L-ornithine-L-aspartate on rats

Chemical name (S) - 2,5 – diaminopentanoic acid – (S) 2 amino succinate and dogs following single doses and after repeated
INN L-ornithine-L-aspartate administration of infusions over 4 weeks gave a no-
Structural formula H NH3 effect level of approx. 1500 mg/kg.
O C C CH2 CH2 CH2 NH3 O C CH2 C C O

O NH3 O H O Reproduction studies on mutagenicity found no abnor-

Molecular formula C 9 H19 N3 O6 malities. There is no need to suspect any carcinogenic
Molecular weight 265.3 potential.
Appearance white or colourless crystalline powder
Odour odourless
Taste metallic, salty 8.3 Pharmacokinetics
Solubility readily soluble in water, poorly soluble in ethyl alcohol
L-ornithine-L-aspartate is rapidly absorbed and cleav-
ed into L-ornithine and L-aspartate. The elimination
L-ornithine-L-aspartate, the stable salt of the naturally- half-life of each the amino acids is short – approx. 40
occurring amino acids, L-ornithine and L-aspartic acid, minutes. Some L-aspartate also appears unchanged in
is available in the pharmaceutical forms of granules, the urine.
chewable tablets and infusion concentrate. 1 sachet of
Hepa-Merz® Granules 3000 contains 3.0 g of L-ornithine- The bioavailability is 82.2 ± 28% after either intrave-
L-aspartate; 1 sachet of Hepa-Merz® Granules 6000 nous or oral administration.
contains 6.0 g of L-ornithine-L-aspartate. Hepa-Merz®
Chewable tablets, containing 3.0 g L-ornithine-
L-aspartate, have the great advantage that no water or
other fluid is required to take them. Their pleasant fruit
flavour aids patient compliance. 10 ml infusion con-
centrate contain 5.0 g L-ornithine-L-aspartate in water
for injection.

110 111
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9 BASIC INFORMATION

Hepa-Merz ® Granules Contraindications

Severe impairment of kidney function (renal failure)
Active substance Serum creatinine should not be greater than 3 mg/100ml.
L-ornithine-L-aspartate
Use in pregnancy and lactation:
Composition Ornithine-aspartate has no known damaging effects
1 sachet with 5 g granules contains during pregnancy and lactation.
Contains fructose.
Active ingredients When taken according to the dosage recommenda-
L-ornithine-L-aspartate 3.0 g tions, each dose of the granules supplies 1.13 g fruc-
tose per sachet. Due to the possibility of hitherto unde-
Other ingredients tected fructose intolerance, this medicinal product
Citric acid, anhydrous should only be given to babies and young children after
Saccharin sodium consultation with the treating physician. It is absolutely
Sodium cyclamate essential that adolescents and adult patients with he-
Fructose reditary fructose intolerance consult the treating physi-
Povidone cian before taking this medicinal product.
Flavourings
E 110 colouring Adverse reactions
None known
Note for people with diabetes
1 sachet with granules contains 1.13 g fructose Warnings
(corresponding to 0.11 carbohydrate exchanges) This medicine contains the colouring agent E 110 (Sun-
set yellow) which may cause allergic reactions – includ-
Indications ing asthma – in people who are particularly sensitive
Treatment of associated conditions and sequelae of to this substance. Allergy is seen more frequently in
diseases with impaired hepatic detoxification (e.g. people who are allergic to acetyl salicylic acid.
cirrhosis of the liver), when there are symptoms and
signs of minimal or overt hepatic encephalopathy.

112 113
43 057 WiBro englisch 13.05.2004 17:19 Uhr Seite 114

Mode of action Hepa-Merz ® Infusion concentrate

Hepa-Merz® contains L-ornithine-L-aspartate, which
stimulates ammonia detoxification by increasing urea Active substance
synthesis in the urea cycle. In addition it detoxifies the L-ornithine-L-aspartate
extrahepatic ammonia in the tissues.
Composition
Dosage 1 ampoule with 10 ml contains
Take the contents of 1-2 sachets Hepa-Merz® Granules
dissolved in water, up to three times a day Active ingredients
L-ornithine-L-aspartate 5.0 g
Interactions with other medicines
None known Other ingredients
Water for injection

Indications
Treatment of associated conditions and sequelae of
diseases with impaired hepatic detoxification (e.g. cir-
rhosis of the liver), when there are symptoms and signs
of minimal or overt hepatic encephalopathy; especially
for the treatment of incipient loss of consciousness
(pre-coma) and clouding of consciousness (coma)

Contraindications
Severe impairment of kidney function (renal failure).
Serum creatinine should not be greater than 3 mg/100ml.

Use in pregnancy and lactation

Ornithine-aspartate has no known damaging effects
during pregnancy and lactation.

Adverse reactions
Occasionally nausea has been reported and rarely
vomiting. However these are usually transient and do

114 115
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10 ABBREVIATIONS

not require discontinuation of the medicinal product: AAA Aromatic amino acids
they disappear with reduction in the dose or the rate of ALF Acute liver failure
infusion. ALT Alanine aminotransferase
AP Alkaline phosphatase
Warnings AST Aspartate aminotransferase
None BCAA branched-chain amino acids
BUI Brain uptake index
Mode of action CAH Chronic active hepatitis
Stimulation of ammonia detoxification by increasing CC Clinical control group
urea synthesis in the urea cycle. Extrahepatic detoxifi- CFF Critical flicker frequency
cation of ammonia in the tissues. CHE Cholinesterase
ChT Chewable tablet
Dosage cps Cycles per second
As long as not otherwise prescribed, up to 4 ampoules CRT Choice reaction time
daily. With incipient loss of consciousness (pre-coma CT Computerised tomography
and clouding of consciousness (coma) up to 8 am- Cr Creatinine
poules within 24 hours, depending on the severity of the dl Decilitre
condition. DST Digit symbol test
EEG Electroencephalogram
Interactions with other medicines Fig Figure
None known GABA Gamma aminobutyric acid
GCP Good clinical practice
GOT Glutamic-oxaloacetic transaminase
GDH Glutamate dehydrogenase
Gln Glutamine
Glu Glutamate
GPT Glutamic-pyruvic transaminase
γ-GT Gamma-glutamyl transferase
HE Hepatic encephalopathy
INR International normalised ratio (= thromboplastin time)
l Litre
LD Lethal dose
LTT Line tracing test

116 117
43 057 WiBro englisch 13.05.2004 17:19 Uhr Seite 118

11 REFERENCES

MRI Magnetic resonance imaging 11.1 General references

MRS Magnetic resonance spectroscopy
µmol Micromol Blei AT, Butterworth RF (Eds.). Hepatic Encephalopathy.
mg Milligram Seminars in Liver Disease 1996; Vol. 16, No. 3, Thieme,
N Number New York, Stuttgart.
NASH Non-alcoholic steatohepatitis
NCT Number connection test Blei AT. Diagnosis and treatment of hepatic encephalop-
NH3/NH4+ Ammonia/ammonium ion athy. Bailliere's Clinical Gastroenterology 2000; 14(6):
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Notes Notes

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43 057 WiBro englisch 13.05.2004 17:19 Uhr Seite 132

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