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Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy.

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Cerebrospinal Fluid Content of Diazepam
Bindng Ihbitor in Chronic Hepatic
Encephalopathy
Jeffrey D. Rothstein, MD, PhD,” Guy McKhann, MD,” Patrizia Guameri, PhD,? Maria Luisa Barbaccia, MD,?
Alessandro Guidotti, MD,t and Erminio Costa, M D t
The neuropeptide diazepam binding inhibitor (DBI) is an endogeneom allosteric modulator of gamma-aminobutyric
acid (GABA)receptors at the benzodiazepine recognition site. Recent theories on the neurochemical cause for hepatic
encephalopathy have implicated activation of inhibitory neurotransmitter GABA systems. In 20 patients with hepatic
disease, bIood and cerebrospinal fluid (CSE) levels of ammonia and amino acids were measured. As in previous studies
there was a selective elevation of CSF amino acids as well as a correlation between CSF glutamine levels and encephalopathy. CSF DBI levels were maximally elevated 5-fold in patients with hepatic encephalopathy, but they were
normal in those patients with liver disease not associated with changes in mental status and in patients with nonhepatic
encephalopathy. Levels of DBI correlated with the clinical staging of hepatic encephalopathy. These data suggest that
DBI may participate in the modulation of cerebral function in hepatic encephalopathy.
Rothstein JD, McKhann G, Guarneri P, Barbaccia ML, Guidotti A, Costa E. Cerebrospinal fluid content of
diazepam binding inhibitor in chronic hepatic encephalopathy. Ann Neurol 1989;26:57-62
Hepatic encephalopathy is a potentially lethal complication of liver disease. Multiple hypotheses have been
generated as to its etiology and considerable evidence
points to ammonia as an important toxin in the cause
of this disorder El]. Despite intense study, the neurochemical basis for this encephalopathy remains
unknown. Although ammonia clearly interferes with
cerebral function, its mechanism is probably multifactorial. Since the early 1980s a new theory has
emerged, implicating the inhibitory amino acid neurotransmitter, gamma-aminobutyric acid (GABA), and
its postsynaptic receptor, the GABAAreceptor [1-31.
The GABAA receptor is a large supramolecular
complex that includes the chloride ionophore, a beta
subunit with binding sites for GABA, and an alpha
subunit that is an allosteric modulatory center with
binding sites for several compounds, including the
anxiolytic benzodiazepines and the anxiogenic betacarbolines 141. GABA acts at this complex by increasing chloride conductance, thereby causing neuronal
hyperpolarization. It is known that benzodiazepines act
as “positive” allosteric modulators of GABAergic
transmission, thereby increasing GABAergic activity
and general central nervous system (CNS) inhibition.
In contrast, beta-carbolines act as “negative” allosteric
modulators of GABAergic transmission, decreasing
GABAergic activity and thus increasing general CNS
arousal 151.
The possibility that GABA is involved in hepatic
encephalopathy was suggested by studies demonstrating that this receptorial domain is altered in some 13,
6, 71, but not all f8-10], animal models of hepatic
encephalopathy. Of particular interest, the application of GABA receptor agonists has been shown to
produce encephalopathies with electrophysiological
changes similar to those in hepatic encephalopathy
[ l l , 121. Moreover, administration of the benzodiazepine antagonist flumazenil (Ro 15-1788, Hoffman-La Roche, Nutley, NJ) to patients with hepatic
encephalopathy increased their level of consciousness
113, 141 as well as converted the typical electroencephalograph (EEG) of hepatic encephalopathy (triphasic
slow waves) to essentially a normal pattern 1133. In
addition, preliminary data with positron emission tomography and C1‘-labeled flumazenil demonstrated
that receptor sites for benzodiazepines, or flumazenil
uptake into the CNS, may be increased in patients
with a history of hepatic encephalopathy 1151. These
data suggest that increased GABA inhibitory tone
plays a role in hepatic encephalopathy.
From the *Department of Neurology, Johns Hopkins University
School of Medicine, Baltimore, MD, and tFidia-Georgetown Instimte for the Neurosciences?GeorgetownUniversitY,
Washington,
Received Nov 18, 1988, and in revised form Dec 19. Accepted for
publication Dec 20, 1988.
DC.
Address correspondence to Dr Rothstein, Depanmentof Neurology, Johns Hopkins Hospital, Meyer 1-130, 600 North Wolfe St,
Baltimore, MD 21205.
Copyright 0 1989 by the American Neurological Association 57
Recently, Costa and Guidotti and their colleagues
IS, 16- 191 identified, sequenced, and biologically
characterized a novel neuropeptide, diazepam binding inhibitor (DBI), that selectively inhibits diazepam
and beta-carboline-3-carboxylatebinding to neuronal
membranes. These data indicate that DBI may be an
endogenous, negative allosteric modulator of GABAergic transmission, decreasing GABAergic activity.
Diazepam binding inhibitor and peptide fragments
of DBI have been shown to exist in human brain
and spinal fluid Cl8, 20).
We have investigated the changes in DBI content of
cerebrospinal fluid (CSF) in patients with clearly
defined hepatic encephalopathy. We report that CSF
DBI levels are significantly elevated in patients with
hepatic encephalopathy and are correlated with the severity of encephalopathy.
Material and Methods
Subjects
Four study groups were instituted. These included patients
with hepatic encephalopathy, patients with encephalopathy
from other nonhepatic disorders, patients with liver disease
but no encephalopathy, and patients without encephalopathy
or liver disease but with other neurological diseases.
A total of 20 patients with hepatic disease were studied (8
women, 12 men; age range, 40-65; mean age
SD, 46 ?
16 years). Ten had biopsy-proven chronic active hepatitis, 7
had Laennec’s cirrhosis, 2 had primary biliary cirrhosis, and 1
had Wilson’s disease. Thirteen patients had chronic recurrent
encephalopathy (Group HE) and 7 had liver disease without
encephalopathy (Group LD). Evidence for chronic hepatocellular disease was based on the following: presence of ascites, history of esophageal varices, decreased serum albumin
(< 3.0 mg/lOO ml), prothrombin ratio greater than 1.2, and
serum bilirubin greater than 2.5 mgil00 ml. All patients had
biopsy-proven cirrhosis. None had any recent exposure to
benzodiazepine drugs. Hepatic encephalopathy was precipitated in most patients by either gastrointestinal bleeding
or increased intake of dietary protein.
Five patients without hepatic disease (1 woman, 4 men;
age range, 22-65; mean age ? SD, 41 ? 19 years) with
encephalopathy due to uremia, sepsis, or encephalitis were
also studied.
Patients without encephalopathy consisted of 9 male and
11 female patients with an age range of 30 to 64 and a mean
age
SD of 47 ? 12 years. These patients had other
neurological diseases that included migraine headache, multiple sclerosis, chronic meningitis, dementia, and chronic demyelinating polyneuropathy.
*
*
Patient Evaluation
Each patient underwent a complete neurological examination, an EEG, lumbar puncture with CSF analysis, and
routine serum biochemical tests. Lumbar punctures were
performed with the patient in the lateral decubitus position
at the L3-4 or LA-5 interspace. Patients were excluded if
lumbar puncture was deemed unsafe, that is, for those patients with prothrombin time ratios greater than 1.3 or
58
Annals of Neurology
Vol 26
N o 1 July 1989
platelet counts less than 40,000, or both 121-231. Based on
these criteria about 50% of all patients initially seen were
excluded from the study. Patients with mild encephalopathy
were able to understand the risks of the study. For patients
with more advanced encephalopathy, consent was obtained
from informed nearest relatives. A Johns Hopkins clinical
investigation protocol for these studies had been previously
approved (RPN-87- 10-19-0 1).
The degree of hepatic encephalopathy was monitored by
several clinical and electrophysiological measures. Serial
neurological examinations with specific attention to the
motor examination, which classified adventitious movements, and the cognitive examination were performed in all
patients. Electrophysiological evidence of encephalopathy
was monitored with EEG. In addition, each patient was
grouped according to a clinical severity scale often used
in hepatic encephalopathy: stage 1, irritability, agitation,
tremulousness, diminished attention span; stage 2, slowed
mentation, lethargy, disorientation, asterixis, paratonia; stage
3, confusion, delirium, Babinski’s sign, stupor; and stage 4,
coma (241. Of these subjects 5 had no clinically overt signs
of encephalopathy , and 15 had hepatic encephalopathy ranging from stage 1 to stage 4. In some instances, CSF was
obtained from the same patient during periods of hepatic
encephalopathy and normal mental status.
Cerebrospinal fluid findings in patients with hepatic encephalopathy were compared with CSF findings in patients
who had lumbar punctures for other medical indications. A
true control population of healthy volunteers is not included
because it was deemed unethical to perform lumbar punctures in a normal subject. Consequently, we obtained CSF
from patients on the inpatient or outpatient neurology and
medical services at Johns Hopkins Hospital.
Laboratory Analysis 4 CSP and Serarn
Approximately 10 ml CSF was collected for the following
studies: glucose, protein, cell count, amino acid analysis, and
ammonia levels. Small aliquots (-2 ml) of CSF and serum
were frozen (-70°C) for DBI analysis. Plasma and CSF
amino acid analysis was performed by automated ionexchange chromatography on a Beckman 6300.
Neuropeptide Analysis
Samples of serum and CSF for DBI analysis were quantified
under a blinded protocol and were all assayed by the same
investigator. DBI was quantified by a radioimmunoassay that
specifically detects this peptide f l 8 , 201. A number of polypeptides known to be present in brain or CSF, or both, did
not cross-react significantly with the antiserum. These included histone, small myelin basic protein, lysozyme, leuenkephalin, substance P, vasointestinal peptide, cholecystokinin, and GABA-modulin. Cerebrospinal fluid did not
interfere with the radioimmunoassay because 100 (*l CSF
from control subjects or encephalopathic patients added
to several concentrations of standard DBI had no effect on
the kinetic characteristics of the radioimmunoassay. The
radioimmunoassay was not influenced by the addition
of diazepam, oxazepam, desmethyldiazepam, imipramine,
haloperidol, or morphine in concentrations up to
M in
the incubation medium. Standard DBI, serum, and CSF sam-
.
CSF DBI
(pmdem
#
/
/
/
/
/
/
/
:I
4 1
0
1
#
#
/
/
#
/
/
Fig 1 . High-pressure liquid chromatographic separation of
diazepam binding inhibitor (DBI) immunoreactivity (DBI-IR)
in a control patient (C) and in a patient with hepatic encephalopathy (HE). Acid$ed cerebrospinalfluid (CSF, 2.0 ml), containing trace amounts o f ' 2 5 ~ - to
~ ~monitor
I
recovery, was applied to a 300 x 7.8 mm revwse-phase micro-Bondapak CIR
column. The column was h e l p e d with a linear gradient of
0.1% triJEuoroaceticacid-acetonitrile (ACN).
ples analyzed in triplicate had an intra-assay variability of less
than 5%. Previous studies had demonstrated no significant
gradient in human DBI immunoreactivity concentration in 4
successive 5-ml fractions of lumbar CSF {20, 251. Furthermore, DBI concentrations in ventricular and spinal CSF have
been shown to be similar {ZS].
Statistical Analysis
Statistical analysis of data was performed by one-way analysis
of variance (ANOVA) using the SAS General Linear Models Procedure (SAS Institute, Cary, NC) and by correlation
coefficient determination. When appropriate, Spearman's
rank correlation coefficient was calculated. Values are expressed as mean * SD.
RSultS
SpeczjZcity of DBI Assay
DBI was reliably measured in human CSF. The data
shown in Figure 1 indicate that when CSF from normal individuals or encephalopathic patients was chromatographed by reverse-phase hlgh-pressure liquid
chromatography, only one major peak of irnmunoreactivity was detected with a DBI antiserum. This
immunoreactive peak had an elution volume identical
to that of standard human DBI extracted from human
brain.
Cerebrospinal Fluid and Plasmu Amino Acids
N o significant differences were noted in CSF or
plasma amino acid levels in the control subjects in this
Fig 2. Cerebrospinalfluid (CSF) leueh o f diazepam binding inhibitor (DBI) in control patients (C). in patients with nonhepatic encephalopathy (NHE), in patients with liver disease
without mentalstatus changes (LD),und in patients with hepatic encephalopathj (HE).Dotted line represents the mean for
each group.
experiment and in those previously published for normal subjects. Results of CSF amino acid analysis were
similar to those found in previously published reports
for chronic liver disease [26]: Multiple amino acids,
including methionine, glutamine, tyrosine, phenylalanine, threonine, and histidine, were significantly elevated in patients with hepatic encephalopathy (data not
shown). In accord with other studies, tyrosine was increased in the plasma of patients with hepatic encephalopathy [26]. No significant differences were seen in
either CSF glucose or protein levels between any of
the groups examined. As in previously published reports, clinical staging of encephalopathy was found to
have a positive association with CSF glutamine levels
(r, = 0.922,p < 0.01) [27, 281.
DBI Levels i n Encephalopathic and
Nonencephaloputhic Groups
Cerebrospinal fluid DBI levels were found to be significantly altered among the groups examined (Fd,42 =
42.5, p < 0.01). The neuropeptide was elevated approximately 3-fold ( p < 0.01) in patients with hepatic
encephalopathy (Group HE, Fig 2), with an average
level of 3.6 pmol/ml. In patients with severe (stage 4 )
hepatic encephalopathy, the average level of CSF DBI
was increased 5-fold. Notably, patients with hepatic
disease without neurological abnormalities did not
demonstrate elevations of this neuropeptide in their
CSF (Group LD, Fig 2). The level of DBI quantified in
the CSF of normal subjects (Group C, Fig 2) in this
study (1.3 i 0.4 pmol/ml) was similar to those previously published [20]. In 5 additional patients with
nonhepatic encephalopathy (clinical stages 3-4; Group
NHE, Fig 2), average CSF DBI levels were found to
Rothstein et al: DBI in Chronic Hepatic Encephalopathy 59
_i
4
0
3
2lX
1
0-
I
0
t
D
I
1
2
3
4
clinical Score
Fig 3. Correlation of cerebrospinaljuid diazepam binding inhibitor (CSF DBI) Levels and ilinical rating of hepatic encephalopathy in patients with liver &ease without mental stutus
changes (LD) and in patients with stage.r 1-4 hepatic encephaloputhy.
be normal (1.7 f 0.8 pmol/ml). Neither age nor sex
had a significant effect on the concentration of DBI in
CSF. Serum DBI (1 pmol/ml) levels did not reliably
correlate with CSF DBI (Y = 0.531,p < 0.11) levels in
control subjects or encephalopathic patients.
Rekationsbip Between DBI and Degree
of Encepbalopathy
Clinical rating of encephalopathy correlated with CSF
DBI quantification (1; = 0.924, p < 0.01) by nonparametric statistical analysis (Fig 3). We evaluated 2
patients before and after orthotopic liver transplant.
Preoperatively 1 patient was not encephalopathic and
had a normal CSF DBI level (1.6 pmol/ml). Postoperatively acute graft rejection developed and the patient
became encephalopathic (stage 4 ) with an attendant
rise in CSF DBI to 3.54 pmol/ml. Conversely, preoperatively 1 encephalopathic patient was found to have a
CSF DBI level of 8.5 pmol/ml and, with the subsequent improvement of mental status after orthotopic
liver transplant, CSF DBI was restored to normal.
Changes in CSF or serum ammonia did not correlate
reliably with the changes in CSF DBI. Furthermore,
no correlation was seen between serum or CSF ammonia and the degree of encephalopathy.
Discussion
The present study was designed to examine the levels
of DBI in patients with hepatic encephalopathy. We
found that the endogenous neuropeptide DBI is elevated in the CSF of patients with hepatic encephalopathy. This neuropeptide in its intact form is a negative (beta-carboline-like) allosteric modulator of the
GABAA receptor. In addition, it has been hypothesized to be a precursor of a family of brain peptides,
some of which may act as negative (beta-carboline-
60 Annals of Neurology Vol 26 No 1 July 1080
like) and others as positive (diazepam-like) allosteric
modulators of GABAergic transmission 151. Multiple
DBI peptide fragments have been identified and are
localized in neuronal synaptic vesicles 1231. DBI is
unevenly distributed in brain tissue and is present in
concentrations compatible with proposed physiological
functions [291. Human brain also contains DBI fragments, which are now being investigated [30}. Moreover, a synthetic fragment of human DBI (DBI 5170), made up of 20 amino acid residues, and usually
referred to as eicosaneampeptide, has been characterized
biologically for its ability to cause proconflict actions in
rats 1311. This peptide acts on the GABAA receptor,
with biological properties similar to those observed for
DBI.
DBI has been shown to reduce GABA-induced
chloride channel opening in the CNS 1191 and, as
such, lessens general CNS inhibition. One might
speculate that to maintain homeostasis in a state of
increased GABA activity, other regulators, such as
DBI, would act to diminish the exaggerated GABA
activity. Therefore, based on the current theory of increased GABAergic tone in hepatic encephalopathy, it
could be postulated that the production and release of
DBI would be increased, leading to an increase of DBI
content in spinal fluid. Such an increase was demonstrated in the present study. An increase in DBI,
which might compensate for an altered GABAergic
transmission, has been previously demonstrated in a
rat model of bentodiazepine tolerance 132).
The presence of endogenous benzodiazepines in hepatic encephalopathy has been suggested [33, 341, and
several recent trials with the bentodiazepine antagonist
flumazenil in European studies have pointed to its
usefulness in the treatment of hepatic encephalopathy.
Larger European clinical trials are currently under way.
Studies on animals have provided similar results f35,
361. In patient studies, administration of flumazenil led
to an alleviation of hepatic coma in most instances as
well as concomitant improvement in the EEG [13, 14,
37-39]. In fact, chronic administration of this drug has
allowed resumption of normal dietary protein loads in
a patient who was previously intolerant 1381. These
observations may implicate a role for a positive
(diazepam-like) endogenous ligand for the allosteric
modulatory center of GABAA receptor in the pathogenesis of hepatic encephalopathy.
The hypothesis that a positive diazepam-like, endogenous allosteric modulator of GABAA receptor is
present in the CNS and can be released in the synaptic
cleft together with GABA is supported by recent electrophysiological experiments conducted in primary
cultures of rat cortical neurons [40). These studies
demonstrated that positive (diazepam-like) allosteric
modulators of GABAA receptors, sensitive to the application of flumazenil, are co-released with GABA
after nerve depolarization. Whether this positive, endogenous allosteric modulator is a peptide fragment of
DBI is under investigation.
Although the role of DBI in the pathogenesis of
hepatic encephalopathy remains to be elucidated, our
studies clearly demonstrate that this precursor for an
endogenous ligand of a GABAA receptor allosteric
center is increased in encephalopathic patients and returns to normal in patients with normal mental status
after hepatic transplantation. In fact, CSF levels of DBI
correlate with clinical stages of hepatic encephalopathy
as well as other biochemical indexes such as CSF
glutamine levels. Moreover, CSF DBI levels were not
elevated in patients with severe encephalopathy secondary to uremia, sepsis, or encephalitis, suggesting
that the DBI response in hepatic encephalopathy is
specific. Plasma DBI levels were not associated with
CSF DBI levels, which suggests a primary CNS origin
for the increase in DBI content detected in spinal
fluid.
Measurement of compounds found in the CSF is
often used to assess physiological function. The major
advantage to this approach is the ability to assess indirectly CNS metabolism in vivo rather than relying on
postmortem tissue. A disadvantage of this technique is
the limited availability of samples. In the present study,
for ethical and medical reasons, single samples were
obtained, except in patients in whom repeat analysis
was medically indicated.
We recently measured DBI in postmortem brains
from 2 patients with hepatic encephalopathy who died
several months after our initial examination. No significant difference was seen in these tissue levels when
they were compared to postmortem brain tissue of
neurologically normal control patients (unpublished
data). Importantly, it is known that alterations in neuropeptide turnover may not result in changes in neuropeptide tissue levels 14 11. DBI turnover, however, can
be estimated by measuring DBI-specific mRNA as
well as biologically active fragments of this neuropeptide. In future studies we will determine if changes in
CSF DBI parallel changes in brain tissue levels of DBI
processing products and DBI mRNA expression in
animal models of hepatic encephalopathy.
There are several possible explanations for how an
endogenous allosteric modulator of GABAA receptor
may be involved in heparic encephalopathy. Hepatic
encephalopathy is associated with increased GABA activity and an increased turnover of DBI, which may be
viewed as an attempt by an endogenous mechanism to
reduce an overactive inhibitory GABAergic system.
Alternatively, as some DBI processing products may
have a positive rather than negative modulatory action,
their increase may be responsible for an increased
GABAergic tone in hepatic encephalopathy. It is important to point out that no single agent is likely to be
completely responsible for hepatic encephalopathy, as
several compounds capable of depressing cerebral
function are circulating in patients with liver failure.
Investigations on the specificity of the endogenous
benzodiazepine response as well as the use of benzodiazepine antagonists in extensive clinical trials
should provide further insight into the pathogenesis of
hepatic encephalopathy and better therapeutic options.
Addendum
Since submission of this article, Grimm and associates
(Lancet 1988;2:1392-1394) reported that intravenous
flumazenil rapidly improved 12 of 20 episodes (609%)
of hepatic encephalopathy in 17 patients with acute or
chronic hepatic failure. The majority of the nonresponders had concomitant cerebral edema.
This research was supported by grants from the Johns Hopkins
Hospital. We are indebted to Drs J. Burdick and F. Herlong for
their clinical support.
This paper was presented in part at the 113th Annual Meeting of the
American Neurological Association, Philadelphia, PA, October
1988.
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contents, encephalopathy, inhibitors, hepatica, diazepam, binding, chronic, fluid, cerebrospinal
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