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Antibiotics
Rifampicin is an antibiotic, and an enzyme inducer reported to increase 2hr. post
prandial serum levels of bile acids in patients with cirrhosis of the liver [20]. A study
that assessed the enzyme-inducing effect of rifampicin in patients with liver disease
reported an improvement in their pruritus [21]. Rifampicin has been studied to treat
pruritus in patients with PBC in several clinical studies, none of which had compa-
rable designs [22–24]. One double-blind, randomized placebo-controlled crossover
study of 4weeks duration studied the effect of rifampicin at doses of 150mg by
mouth twice a day for patients with serum bilirubin greater than 3 mg/dl, and
150mg three times a day for patients with serum bilirubin lower than 3mg /dl in
nine patients with PBC.Rifampicin was reported to be associated with a signicant
decrease in the 7-day aggregated visual analog score for pruritus [22]. In one study,
rifampicin was reported to be more effective than phenobarbital in inducing amelio-
ration of pruritus [23]. Two published meta-analyses have reported that rifampicin
administration is associated with relief of pruritus in cholestasis [6, 25] and that in
short term, the side effects were not major and disappeared after discontinuation of
the drug. Side effects of rifampicin, however, remain a serious concern [23, 26] as
cases of hepatitis and hepatic failure have been associated with rifampicin adminis-
tration over periods longer than reported in some publications [22–24]; therefore, if
rifampicin is prescribed, close and regular follow-up of blood tests, including liver
panel, is necessary.
The mechanism of the reported antipruritic effect of rifampicin is unknown.
Rifampicin is an agonist ligand of the pregnane X receptor, the stimulation of which
induces drug-metabolizing enzymes and transporters [27]; thus, rifampicin admin-
istration may result in the relief of pruritus by stimulating the intrahepatic metabo-
lizing pathways, leading to the metabolism and excretion of substances, including
the pruritogen(s). In addition, it may have opiate antagonist activity [28].
Changes inNeurotransmission
Opiate Antagonists
The pharmacological increase in opioidergic tone, e.g., after the intrathecal admin-
istration of morphine in clinical medicine, is associated with pruritus [29, 30]. This
type of pruritus is prevented and ameliorated by opiate antagonists, suggesting an
opioid-receptor mediated effect [31, 32]. There is also evidence to suggest that in
cholestasis, there is an increased opioidergic tone [33]; thus, this altered neurotrans-
mission may mediate the pruritus. If increased opioidergic tone mediates the pruri-
tus of cholestasis, opiate antagonist drugs such as naloxone should decrease the
pruritus and its behavioral manifestation, scratching activity. The effect of
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intravenous naloxone infusions on hourly scratching activity was studied in a dou-
ble-blind, randomized placebo-controlled, crossover study of four consecutive days
duration in 29 patients with cholestasis and pruritus, 19 of whom had PBC [34].
Naloxone infusions at a dose of 0.2 micrograms per kg per min preceded by 0.4mg
intravenous bolus were associated with a signicant 34% decrease in the geometric
mean of hourly scratching activity compared to placebo infusions [34]. The results
of other controlled clinical trials [35–42], some of which included behavioral meth-
odology (i.e., recording of scratching activity) [34, 36, 39, 40] have also revealed
that the administration of naloxone [36], and the opiate antagonists nalmefene [35,
39, 40], and naltrexone [37, 38, 41, 42], is associated with an amelioration of the
pruritus in patients with cholestasis. These results support the hypothesis that
endogenous opioids mediate, at least in part, the pruritus of cholestasis. A publica-
tion of a meta-analysis reported that opiate antagonists signicantly reduced the
pruritus of cholestasis [6]. Although there are concerns on the use of meta-analyses
to derive strong conclusions on therapeutic interventions because of the heterogene-
ity of clinical studies, the rationale to use this type of drug and the results from
several clinical studies from different parts of the world support the use of this type
of medication to treat pruritus in patients with PBC [38, 39, 40–42].
The limiting factor on the use of opiate antagonists for the treatment of the pru-
ritus of cholestasis is the opioid withdrawal-like reaction that can be experienced by
patients with cholestasis after the intake of opiate antagonists [35, 36, 34, 40].
Naltrexone at a dose of 50mg orally per day [38] was associated with an improve-
ment in the visual analog score for pruritus; however, 50mg may be a high dose to
start treatment because of the potential risk of an opioid withdrawal-like reaction;
thus, a lower dose can be given by cutting the tablet in four and taking a quarter
(12.5mg) every day to be increased by a quarter every 3–7days, until the pruritus
is ameliorated. Doses of 250mg of naltrexone per day have been required to control
pruritus in some patients [43]. Alternatively, the protocol implemented in a random-
ized double-blind placebo-controlled study that included 29 patients with cholesta-
sis and pruritus can be followed [34]. Patients can be admitted to the hospital for
intravenous infusions of naloxone, at a dose of 0.2 micrograms/kg/min, a dose asso-
ciated with opiate antagonist effect, in 250 or 500cc of a suitable intravenous solu-
tion, preceded by an intravenous bolus administration of 0.4mg [34] for 48hours
followed by the introduction of oral naltrexone and discontinuation of the infusion.
The opiate withdrawal-like reaction can be characterized by abdominal pain, high
blood pressure, tachycardia, goose bumps, nightmares, depersonalization, or by a
feeling of not being right. It is not possible to predict who will develop an opiate-
withdrawal like reaction. Clinical experience has suggested that patients who have
severe pruritus may have a higher opioidergic tone and may be at risk for a more
severe reaction; these patients may benet from the initiation of ultralow naloxone
infusions in the hospital, even at lower doses than those stated above (e.g., 0.002
micrograms/kg/min) [44] to be gradually increased as described above. The dose
should not be increased if signs of an opiate-withdrawal like syndrome develop; in
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general, the drug can be held or maintained at the same dose, as the reaction tends
to subside spontaneously [39, 40]. Hepatotoxicity is not common [45], but it has
been reported [46]; thus, follow-up of the comprehensive metabolic panel is recom-
mended. In patients with decompensated liver disease, naltrexone metabolites can
accumulate in the body [47]; therefore, reducing the dose is necessary. As liver
disease progresses, pruritus tends to cease; thus, the need to use naltrexone in
decompensated liver disease is not common [48].
Naloxone nasal spray is now available as an emergency treatment of opiate over-
dose in the community [49]. NARCAN Nasal Spray is supplied as a single-dose
intranasal spray containing 2 or 4mg of naloxone hydrochloride in 0.1mL [49].
This preparation could be used as an alternative to treat the pruritus of cholestasis in
a properly designed protocol (Sunny Patel, MD, 2019, unpublished personal com-
munication, with permission).
The use of nalfurane, a kappa-agonist drug, was reported to ameliorate the pru-
ritus of cholestasis [50]; this result provides support for the role of the endogenous
opioid system in the pruritus of cholestasis, as follows: (i) the stimulation of the mu
receptor is associated with scratching behavior in laboratory animals [51, 52] and
pruritus in human beings [29, 30], (ii) the stimulation of the kappa receptor prevents
the pruritogenic and the scratching producing effect from the stimulation of the mu
receptor [51, 52]. In this context, butorphanol is an antagonist at the mu opioid
receptor and an agonist at the kappa receptor [53]. In a patient with intractable pru-
ritus from liver disease secondary to chronic hepatitis C, butorphanol in nasal spray
form (1mg per application) was associated with prolonged relief of pruritus [54]. It
was subsequently reported that butorphanol was associated with pruritus relief in a
series of patients with PBC [55]. The potential addiction to butorphanol, initially
considered low [56], is important [57]; thus, the use of this drug to treat the pruritus
of cholestasis has to be considered carefully, e.g., short courses. Anecdotal reports
on the use of codeine, an agonist at the mu opioid receptor [58], and buprenorphine,
an agonist at the mu receptor, and an antagonist at the kappa receptor [59] in asso-
ciation with amelioration of the pruritus of cholestasis have been published. These
reports have to be reconciled with the effects of butorphanol in regards to its recep-
tor preference.
Serotonin Antagonists
The serotonin system participates in the neurotransmission of nociceptive stimuli
[60], the rationale provided to study ondansetron, a serotonin antagonist at the type
3 receptor, to treat pruritus in cholestasis. In addition, ondansetron has been reported
to ameliorate pruritus associated with the administration of opiates [61]. Ondansetron
was reported to decrease the pruritus associated with cholestasis in studies that used
subjective methodology only [62–65]; however, studies that incorporated behav-
ioral methodology have not conrmed an antipruritic effect of ondansetron in cho-
lestasis [66, 67].
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Antidepressants
Antidepressants, including selective serotonin reuptake inhibitors [68–70] and mir-
tazapine, a noradrenergic and serotonergic related antidepressant, have been
reported to have antipruritic effects [71–73].
Sertraline, a selective serotonin reuptake inhibitor, was reported to be associated
with pruritus relief in patients with PBC [74, 75]. Sertraline was evaluated in a con-
trolled study which consisted of a dose-nding open-label rst phase of 21 patients,
followed by the second phase, in which 12 patients with liver disease, including
PBC, participated in a randomized placebo-controlled cross over design. At doses
associated with relief of pruritus (75–100mg) in the rst phase of the study, this
drug was reported to decrease the pruritus and its cutaneous consequences, i.e.,
scratch marks as measured by a visual analog scale and by a physical examination
in the second phase [75]. Eight of twenty-one subjects associated the use of sertra-
line with mood stability, and those who met the criteria for depression at baseline
improved on sertraline; however, it was reported that the decrease in the visual
analog score for pruritus was independent of the improvement in depression [75].
Potential Regulation ofa24-Hour Rhythm
ofScratching Behavior
The expression of a 24-hour rhythm in scratching behavior displayed by some
patients with cholestasis and pruritus suggested that this behavior may be under
circadian control. It provided the rationale to study the effect of bright-light photo-
therapy indirectly reected toward eyes in patients with chronic liver disease and
pruritus in a pilot study [76]. Bright-light phototherapy was associated with marked
suppression of outbursts of scratching over the day. However, after 8weeks of treat-
ment, the hourly scratching activity was not signicantly different from the baseline
value [76]. It was suggested that this type of light therapy could be used in combina-
tion with other antipruritic interventions, but controlled studies to test this idea have
not been conducted.
Drugs toTreat theLiver Disease
Ursodeoxycholic acid, a treatment approved for PBC, has not been consistently
found to decrease the pruritus of cholestasis [2].
Fibrates are being studied to treat cholestatic liver disease including PBC and
PSC. Bezabrate is a peroxisome proliferator-activated receptor (PPAR) agonist
reported in association with relief of pruritus. The effect may be from the salutary
effects of this type of drug on the disease itself, as interpreted by the investiga-
tors [77].
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Bezabrate at doses of 400mg per day in combination with ursodeoxycholic
acid in patients with PBC was reported to be associated with decrease or disappear-
ance of pruritus as measured by the visual analog and the 5-D scale after a period of
treatment of 38months [78]. Alone, also at a dose of 400mg per day, bezabrate
was associated with relief of pruritus measured by a visual analog and the 5-D
scales, in patients with cholestasis, in a double-blind randomized, placebo- controlled
trial of 21days duration. The improvement was interpreted to have resulted from a
decrease in liver injury [77].
Other interventions have been reported to decrease the sensation of pruritus as
assessed by various subjective methods in controlled studies, uncontrolled observa-
tions, and case series and reports in patients with liver disease, including hepatic
enzyme inducers umecinol [79] and phenobarbital [23], the antibiotic metronida-
zole [80], antioxidants [81], androgens [82], phototherapy to the skin [83], the anes-
thetic propofol [84, 85], dronabinol, an agonist at the cannabinoid receptor B1 [86],
lidocaine [87], S-adenosylmethionine [88], methotrexate [89], and tacrolimus [90].
In the context of the exclusive use of the subjective methodology in studies of
pruritus, in a randomized, double-blind placebo-controlled trial of the drug gaba-
pentin, the placebo intervention was associated with almost complete suppression
of scratching behavior and a decrease in the visual analog score for pruritus, in
contrast to the active drug, which seemed to worsen pruritus and its behavioral con-
sequence, scratching [91]. These results emphasize the uncertainty in interpreting
the outcomes of any intervention to treat pruritus in studies that use subjective meth-
odology only and the importance of including behavioral methodology to record
scratching in clinical trials of pruritus [91].
Erythema and edema, the classic ndings of histamine-mediated pruritus, are
absent from the skin of patients with liver disease and pruritus. Antihistamine drugs
do not appear to have any specic antipruritic effect in patients with cholestasis.
Still, some patients report relief on this type of medication [92], which may result
from its sedative properties. Sedation mediated by antihistamines may help patients
sleep, which is often interrupted in patients with pruritus; however, the dryness of
mucous membranes associated with this type of drug may limit its use in patients
with PBC and sicca symptoms.
Patients with severe pruritus are at risk for depression and suicidal ideations and
actions. The patients may require hospital admission for parenteral administration
of medications, including opiate antagonists. Intractable pruritus can be an indica-
tion for liver transplantation. As pruritus can be intermittent, the decision to perform
a liver transplant has to be weighed against the complications of that procedure.
However, patients with pruritus of cholestasis suffer tremendously; accordingly,
liver transplantation should be considered as an alternative.
The management of patients with pruritus includes skincare to identify any pri-
mary pruritic skin lesions; the use of soaps for sensitive skin may help.
A guidance to treat patients with pruritus from cholestasis is provided in
Table15.1.
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Fatigue
In a study of patients with cholestasis, most of whom had PBC, a decrease in fatigue,
as assessed by a visual analog scale, was reported after administering the opiate
antagonist nalmefene [35]. This result may suggest that increased opioidergic tone
may contribute to the fatigue of PBC [33]; however, the effect of opiate antagonists
on fatigue has not been studied in controlled clinical trials.
The use of antioxidants was not conrmed to be associated with an improvement
in fatigue as assessed by the Fisk Fatigue Severity Score in a double-blind, random-
ized placebo-controlled study [81].
The mechanism that supports the stimulant effect of modanil used to treat nar-
colepsy is unknown; however, it was reported to decrease fatigue in a case series of
patients with PBC [93]. Patients with PBC were reported to sleep during the day
signicantly more than a control group, as assessed with sleep monitors [94]. These
ndings were provided as a rationale to the study of modanil at doses from 100 to
200 mg in an open-label trial of 8 weeks duration in 21 patients with PBC and
excessive daytime sleepiness [95]. The degree of daytime sleep correlated with
fatigue severity, assessed by the PBC-40, a disease-specic health-related quality of
life measure [95]. Modanil was associated with a signicant improvement in the
Skin care
Cholestyramine 4 g before and after breakfast;
add 4 g at lunch and dinner, if necessary, not to exceed 16 g per day
Relief
Yes
No relief
Continue therapy;
Check coagulation profile periodically
*Opiate antagonists
*Rifampicin
*Sertraline
• Naloxone, 0.4 mg by intravenous bolus immediately followed by intravenous
infusions of naloxone (0.2 micrograms per kg/minute) (33).Dose can be increased
gradually (e.g. every 4 hours) to 0.8 micrograms per kg/minute
• After 12 to 24 hours of infusion therapy start oral naltrexone, 12.5 mg (a
quarter of a tablet), once a day for 3 days.
• Increase dose of naltrexone by 12.5 mg per day , if the patient has not
experienced relief of the pruritus, to 50 mg per day
• Higher doses than 50 mg in divided doses have been used (42).
• 150 mg orally, twice a day, if
serumbilirubin >3 mg/dl or
150 mg orally three time a day
if serum bilirubin <3 mg/dl
(21).
• Check liver profile two and
four weeks after starting the
medication, and at least
monthly thereafter. If changes
in liver profile suggest
hepatotoxicity, stop rifampicin
•
Naltrexone can be started without a leading phase of naloxone infusions, 12.5 mg
(a quarter of a tablet), once a day for 3 days
•
Increase dose of naltrexone by 12.5 mg per day , if the patient has not
experienced relief of the pruritus, to 50 mg per day
• If the patient experiences any signs of opiate withdrawal like reaction, the dose ca n
be maintained at the prior dose for a day or two with subsequentincrease, until
relief of pruritus is attained
• Check blood work after the initiation of naltrexone
• 75 mg
orally daily,
to be
increased
to 100 mg
daily (74).
* The combination of these
drugs in the treatment of
pruritus has not been
studied.
Medication reconciliation is
required prior to the
initiation of any form of
therapy
Patients not responsive to treatments above
• Refer to other options to treat pruritus in text.
• Refer patient for liver transplant evaluation
• Consider MARS
TM
therapy
Explore clinical trial options
Table 15.1 Treatment of patients with the pruritus of cholestasis
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fatigue domain score compared to baseline, as assessed by the PBC-40; in addition,
modanil was associated with a signicant decrease in daytime somnolence [95].
Aerobic training increases maximal work capacity, which leads to a reduction in
the percentage of total capacity required for activities of daily living. This reduction
is associated with decreased fatigue. During an 8-week structured exercise program,
aerobic training was associated with decreased fatigue as assessed with validated
fatigue questionnaires in three patients with chronic hepatitis C [96]. These prelimi-
nary results support the conduct of studies of aerobic training for the treatment of
fatigue secondary to PBC.
There are no specic therapies for the treatment of fatigue in liver disease.
Portal Hypertension
Cirrhosis is dened as a change in liver architecture to a nodular structure [97]. It is
a diagnosis of histology [97]. Efforts to obtain information on the status of the liver
by noninvasive techniques are vigorous, including scores such as FIB-4, brosure,
APRI, magnetic resonance imaging (MRI) elastography, the interpretation of the
liver shape via computed tomography (CT) scan and sonogram, and transient elas-
tography because liver biopsy is an invasive procedure not devoid of complications
[98, 99].
Portal hypertension is dened as an increase in portal venous pressure. It is a
complication of cirrhosis from any etiology and relatively severe liver injury in the
absence of cirrhosis, e.g., alcoholic hepatitis. Portal hypertension is classied as
prehepatic, intrahepatic, and post hepatic [100]. The liver diseases included in this
book are associated with intrahepatic portal hypertension. Noncirrhotic portal
hypertension is an entity characterized by portal hypertension in the absence of liver
disease; however, cirrhosis is the most common cause of portal hypertension
[100, 101].
The normal pressure gradient between the portal vein and the vena cava is
1–5mmHg; complications from portal hypertension tend to arise when the gradient
increases to at least 10. The portal pressure gradient results from the relationship
between portal blood ow and the vascular resistance against which the blood must
ow; accordingly, portal pressure increases due to an increase in the blood ow, an
increase in resistance, or a combination of both [101]. The causes of the increased
resistance include the existence of obstacles to blood ow, e.g., brosis and nodule
formation, and a functional resistance resulting from the contraction of resident
cells, including hepatic stellate cells and vascular smooth muscle. In portal hyper-
tension, there is an intrahepatic deciency of nitric oxide, mostly due to a decrease
in the release of eNOs and increased oxidative stress, which leads to enhanced scav-
enging due to increased oxidative stress [102, 103]. The marked arteriolar vasodila-
tation that characterizes the vasculature of the organs that drain into the portal vein,
i.e., the splanchnic circulation, results from excess in nitric oxide, as well as altered
production of prostacyclin, carbon monoxide, endocannabinoids, glucagon, and by
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angiogenesis, mediated by vascular endothelial growth factor (VEGF) and platelet-
derived growth factor (PDGF) [101, 104, 105]. The paradox of decreased nitric
oxide inside the liver and increased nitric oxide in the splanchnic vasculature medi-
ates the pathogenesis of portal hypertension [106].
Diversion of blood ow from the liver to the systemic circulation is sustained via
collaterals that form from the vascular connections that close after embryological
development, and include gastroesophageal varices; in addition, angiogenesis medi-
ated by VEGF and PDGF contribute to a collateral circulation through which a
substantial proportion of the blood volume circulates in cirrhosis and advanced por-
tal hypertension [101, 104, 105].
Guidelines for the screening and management of portal hypertension and its
complications are available from several medical societies and are updated regu-
larly, consistent with the evolution of information and changes in practice; the
reader is referred to them for guidance [107].
Upper gastrointestinal endoscopy (EGD) has been recommended to screen for
gastroesophageal varices at the time a diagnosis of cirrhosis is made [108]; how-
ever, with the advent of transient elastography, it is considered that patients with
liver stiffness less than 20 kilopascals and a platelet count greater than 150,000/mm
3
do not require a screening EGD at diagnosis because the probability of having high-
risk varices is less than 5% [107]. For all other patients, EGD is recommended at the
time of diagnosis of cirrhosis [107].
If varices are not found, a repeat endoscopy is recommended in 2 years. In
patients in whom the driving cause of the liver disease has been removed, i.e., cure
of hepatitis C virus infection, abstinence from alcohol in liver disease from alcohol,
the procedure can be repeated in 3years [107].
Nonselective beta-blockers, carvedilol, or variceal ligation are recommended to
prevent the index bleed in patients with large varices dened as an estimated diam-
eter greater than 5mm; the experience of the endoscopist and patient’s preference
should be considered in deciding how to proceed [107]. Pharmacological therapy
may be preferred over endoscopic variceal ligation in patients with large varices not
associated with high bleeding [109]. The dose of nonselective beta-blocker, e.g.,
propranolol, nadolol, with the dose adjusted to what is maximally tolerated, is rec-
ommended, with a target of a heart rate of 60 [109]; carvedilol can be prescribed to
patients who cannot tolerate nonselective beta-blockers. Patients intolerable to
pharmacological therapy should be managed with variceal ligation to eradica-
tion [107].
Patients identied as having high-risk (for bleeding) varices, e.g., red wale sign
[110], should be started on beta-blockers in tandem with banding, as the eradication
of varices does not decrease portal pressure, and thus, the risk remains. The use of
endoscopic variceal ligation is also recommended to prevent the index bleed in
patients with cirrhosis, Child’s class B and C; however, the guidelines suggest that
the decision regarding what intervention to use be considered in the context of local
expertise [109, 107]. If this option is taken, variceal ligation should be repeated
every 2weeks, depending on the tolerance of the endoscopist and stability of the
patients, e.g., post banding ulcers, until eradication is documented, followed by
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surveillance upper endoscopy 1–3months after eradication, and every 6–12months
subsequently.
Gastroesophageal varices develop from connections between short gastric and
coronary veins and the esophageal, azygos, and intercostal veins (Fig.15.1); rectal
and ectopic varices may also develop. Bleeding from gastroesophageal varices is
one of the complications from cirrhosis and portal hypertension that changes the
course of a patient’s life, i.e., it is one of the events that dene decompensation of
liver disease and is associated with a mortality that ranges between 15–20%. Patients
who survive an index bleed have a high probability of rebleeding and death. At
1–2years, the probability of rebleeding is 63%, and that of dying in association with
such is 33% [
111]. Thus, prevention of subsequent bleeding is pivotal in the man-
agement of patients with gastroesophageal varices and should be implemented [112].
The recommendations on the management of suspected variceal bleeding include
uid resuscitation and blood transfusions, as necessary, a 7-day course of antibiotic
therapy with ceftriaxone, the drug recommended at present, 1g intravenously every
24hours, and pharmacological therapy to decrease portal pressure with intravenous
infusions of octreotide, an analog of somatostatin [107, 112, 113]. Upper endoscopy
within 12hours of presentation to determine the source of bleeding is recommended
in cases where there is room for resuscitation. If not, endoscopy should be per-
formed as soon as possible [107, 112, 113] after appropriate protection of the air-
way via endotracheal intubation. If the bleed is considered variceal in origin,
endoscopic therapy with variceal ligation or sclerotherapy should be provided [109].
The use of proton pump inhibitors during acute variceal bleeding seems controver-
sial. Persistent or recurrent variceal bleeding in spite of combined pharmacological
and endoscopic therapy should be managed with the placement of a transjugular
intrahepatic portosystemic shunt (TIPS). Balloon tamponade is recommended as a
Fig. 15.1 Contrast enhanced
computed tomography on a
45 year old man with
cirrhosis and portal hyperten-
sion showing a nodular liver
(thin black arrow), ascites
(white large arrow),
gastroesophageal varices
(small white arrow), and
splenomegaly (small
black arrow)
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temporary measure prior to endoscopic management or TIPS placement [109]. The
recommendations to manage bleeding from gastric varices include sealing the vari-
ces with adhesive substances, where available, variceal ligation, and balloon-
occluded retrograde transvenous obliteration (BRTO) [114]. TIPS placement is
recommended for patients in whom the bleeding does not cease despite pharmaco-
logical and endoscopic therapy [109].
Ascites
Ascites is the accumulation of uid in the abdominal cavity. The pathophysiology
of ascites concerns the splanchnic vasodilatation that characterizes portal hyperten-
sion, i.e., hyperdynamic circulation, and that leads to a decrease in effective arterial
blood volume [115], which leads to activation of vasoconstrictor systems, the renin–
aldosterone system, and of antidiuretic hormone, which results in sodium and uid
retention [115]. Splanchnic vasodilatation is due to an excess of nitric oxide (NO)
[106]. As disease progresses, impaired excretion of free water ensues, and cardiac
output, which initially increases, decreases likely secondary to a form of cirrhotic
cardiomyopathy, further decreasing organ perfusion, all of which results in further
uid and sodium retention.
Ascites results from portal hypertension in 80% of the cases. In patients with
liver disease, portal hypertension is a sine qua non for the formation of ascites.
Ascites tends to develop at a rate of 5–10% per year, with 60% of patients with cir-
rhosis having ascites after 10years of diagnosis [116]. The survival of patients after
the development of ascites was reported to be from 45% to 82% at 1year, and 22%
to 52% at 5years [117]; thus, ascites is recognized as a dening complication in the
natural history of cirrhosis, i.e., from compensated to decompensated state [117,
118], and an indication for referral to liver transplantation when clinically
detected [119].
In portal hypertension secondary to cirrhosis, there is an increase in blood vol-
ume and lymph formation, which overwhelms the intrahepatic lymphatic ducts,
resulting in the pouring of lymph from the liver’s surface into the abdominal cavity,
i.e., ascites [120]. Ascites is a complication of conditions that lead to sinusoidal
portal hypertension, including thrombosis of hepatic veins, sinusoidal obstruction
syndrome or venoocclusive disease, severe alcoholic hepatitis, and cirrhosis; it is
unusual to have ascites formation in cases in which the obstruction to blood ow is
presinusoidal, e.g., schistosomiasis, congenital hepatic brosis, idiopathic portal
hypertension (i.e., noncirrhotic). In cases in which the block to blood ow is outside
the liver, ascites occurs when there is repercussion on the sinusoids to cause
increased pressure, such as in right-sided congestive heart failure, constrictive peri-
carditis, and obstruction of the inferior vena cava, e.g., by congenital webs but, it
does not occur when the obstruction is in the splenic or portal veins.
The hepatic sinusoids ow from their origin in their portal tract to the central
veins; they are lined by endothelial cells, Kupffer cells, and hepatic stellate cells,
15 Complications ofLiver Disease
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