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the latter found in the space of Disse, between the sinusoids and the hepatocytes.
Hepatic sinusoids are histologically unique because of the absence of a basement
membrane and the presence of fenestrae, i.e., pores of approximately 100–500nm
in diameter through which microvilli of hepatocytes can be appreciated by elec-
tron microscopy, and which make them permeable to proteins that circulate in the
blood through the sinusoids. It is suggested that the uid within the space of
Disse in communication with the liver interstitial space enters the lymphatics
channels present in the portal tracts and the central veins as hepatic lymph. As
there is permeability via the sinusoids, the protein concentration in plasma and
uid within the space of Disse is almost identical, e.g., 95% homogeneity [121].
The hepatic lymph drains out of the liver via vessels from the hepatic hilum to the
thoracic duct.
The direct consequence of increased sinusoidal pressure and ascites can be
appreciated by the marked increase in lymph production from portal hypertension,
i.e., lymph production increases by 60% for every millimeter increase in portal pres-
sure [122]. It has been demonstrated in experimental models of sinusoidal hyperten-
sion from venous obstruction that there is a marked increase in lymph ow via the
hepatic and thoracic ducts (e.g., 8–9 liters per day), regardless of the presence or
absence of ascites [123]. As the lymph cannot be contained within the channels,
there is pouring of it from the liver’s surface into the abdominal cavity; thus, ascites
from sinusoidal portal hypertension is lymph [122, 124–126]. Intestinal permeabil-
ity increases in advanced liver disease, thus providing a second source of uid
toward ascites accumulation [127, 128]. It is considered that hepatic and splanchnic
lymph contributes to ascites.
In portal hypertension from cirrhosis, the permeability of the sinusoids dramati-
cally decreases because of capillarization [129], with the marginal areas of regener-
ating nodules being irrigated by capillaries, although sinusoids remain in the center
of the nodules; as a result of capillarization, the protein concentration of the drain-
ing lymph decreases to about 65% of that of plasma [130]. The hepatic sinusoids are
completely impermeable to albumin in some patients [131].
Cirrhosis is a sodium avid state, which plays a fundamental role in the pathogen-
esis of ascites. Prior to ascites formation, sodium retention happens in the collecting
tubules, and, in the late stages, in the proximal tubules [132]. Sodium is reabsorbed,
followed by water, leading to the expansion of extracellular uid volume and inter-
stitial uid. Patients with compensated cirrhosis do not retain sodium, but they
exhibit abnormal sodium handling as evidenced by the inability to excrete an acute
sodium loading [133, 134]. However, patients with cirrhosis and substantially high
portal pressure retain sodium when exposed to mineralocorticoids, in contrast to
noncirrhotic normal controls who develop transient sodium and water retention that
subsides within a few days [135, 136].
Contributing to uid overload and hyponatremia in cirrhotic patients with ascites
is the impaired excretion of free water, which varies in degree among patients with
cirrhosis, portal hypertension, and ascites [137, 138].
Characterization of ascites, which can be made with a few milliliters of uid,
e.g., 20 ml, is fundamental in managing patients with this complication. Serum
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protein concentration and portal pressure determine the ascitic uid protein concen-
tration in patients with chronic liver disease.
A seminal study in patients with chronic liver disease provided information now
established as the gold standard to conrm ascites as a complication of portal hyper-
tension [139]. In 56 patients with chronic liver disease, the ascites and serum con-
centrations of albumin and globulin and transhepatic portal pressure were
simultaneously measured to reveal that the mean concentration of albumin in ascites
was 1.04±0.73 gm/dl and that of globulin 1.31±0.80 gm/dl, with a total ascites
protein concentration of 2.35±1.49 gm/dl. In serum, the mean albumin concentra-
tion was 2.58±0.57 gm/dl, and that of globulin 3.91± 0.86 gm/dl, with the total
serum protein concentration of 6.49± 1.30 gm/dl. The serum to ascites albumin
concentration gradient was 1.54±0.45 gm/dl. The mean transhepatic portal pres-
sure above the inferior vena cava was 14.5 ±4.3 mm Hg. The serum to ascites
albumin concentration gradient correlated strongly with the mean transhepatic por-
tal pressure above the inferior vena cava (r=0.73, p<0.0001). The protein concen-
tration in ascites correlated signicantly with the serum albumin, serum globulin,
and the mean transhepatic portal pressure above the inferior vena cava, although
these variables did not correlate with each other. The additional analysis docu-
mented a high correlation of the protein in ascites with the serum albumin concen-
tration after correction for serum globulin and serum to ascites albumin concentration
gradient (r= 0.97, p< 00001), or transhepatic portal pressure above the inferior
vena cava (r=0.90; p<0.0001). These data indicated that most of the variation in
protein concentration in ascites in the study group was associated with serum pro-
tein and transhepatic portal pressure above the inferior vena cava, or serum ascites
albumin concentration gradient. It was further documented that the difference
between the groups of patients in whom the concentration of protein in ascites was
≤2.5 vs. ≥ 2.5 gm/dl was due to differences in serum albumin and serum globulin
in combination with the serum to ascites albumin concentration gradient (r=0.808),
or transhepatic portal pressure above inferior vena cava (r=0.806). The variables
described could identify the low and high ascitic uid protein groups in 96% and
93% of patients, respectively. These data were interpreted to indicate that the serum
to ascites albumin concentration gradient is associated with the degree of portal
hypertension and that the difference in the concentration of protein in ascites among
patients with chronic liver disease is related to variations in portal pressure and
serum protein concentration [139].
The use of the serum albumin ascites gradient (SAAG), i.e., the subtraction of
the albumin concentration in the uid from that of the serum, has been established
as the method to identify ascites from portal hypertension when the difference is
≥1.1g/dl, as documented in a study that included 901 paired samples of ascites and
serum in which portal hypertension was accurately identied in 96.7% of cases [140].
The difference between the serum albumin and the ascites albumin originates
from the fact that, as a result of the capillarization of the hepatic sinusoids in cir-
rhosis, the intimate connection between the blood that circulates through the sinu-
soids and that of the space of Disse is lost; thus, there is a difference in concentration
of albumin (vide supra).
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To perform a paracenthesis, the author prefers the linea alba, approximately 2cm
below the umbilicus, as the site to enter the peritoneal cavity to obtain ascites uid.
The bladder should be empty. We avoid the left quadrant of the abdomen because of
splenomegaly; the spleen can be punctured inadvertently. With the advent of point
of care sonogram and the collaboration with interventional radiology, the best areas
to puncture can be identied. The techniques for the procedure are established [141].
Ascites from portal hypertension tends to be clear and straw colored. The neces-
sary tests in the characterization of ascites from portal hypertension include ascites
concentration of protein and albumin obtained simultaneously from ascites and
serum, and protein to calculate the SAAG; it is possible to use serum data from the
immediate periprocedure days. Total white blood cell count and differential, and
ascites culture is included as the exclusion of infection is fundamental in the man-
agement of patients with ascites. In this regard, in patients with cirrhosis and ascites,
if the uid protein concentration is <1.5g/dL in association with a serum creatinine
≥1.2 mg/dL, a blood urea nitrogen level ≥ 25 mg/dL, or a serum sodium
≤130mEq/L, or liver failure, as per a Child–Pugh score≥9 and a bilirubin ≥3mg/
dL prophylaxis with antibiotics to prevent SBP (e.g., quinolones) is indicated
whether patients are hospitalized or not.
Ascites has been graded as grade 1 when it is only detectable by sonogram, grade
2, characterized by abdominal distension, and grade 3, associated with marked
abdominal distension [142].
The management of ascites concerns treating the cause of liver disease, e.g.,
alcohol abstinence in liver disease from alcohol use, viral hepatitis, and sodium
restriction in combination with diuretics. Sodium consumption is limited to
80–120mmol/day. In our clinic, we recommend no salt added and no food con-
sumed from a bag or can, i.e., freshly prepared food ideally. This recommendation
is a challenge faced by patients with difcult social circumstances, e.g., homeless-
ness, and shelter dwellers; thus, an effort to provide education in consultation with
a dietitian is fundamental. The treatment of grade 1 ascites has not been studied in
clinical trials; however, it seems reasonable to limit sodium intake and avoid drugs
that can enhance sodium retention, e.g., nonsteroidal anti- inammatory drugs
(NSAIDs). Although salt restriction and spironolactone, an aldosterone antagonist,
can be used in the initial management of ascites, limited response to this single
diuretic therapy and hyperkalemia limit this therapy. Thus, the addition of a loop
diuretic, e.g., furosemide, is favored [143–145]. Spironolactone is a once-a-day
drug that can be started at a dose of 50mg, in combination with furosemide, at
20mg per day. The aim is to induce a weight loss not to exceed 1lb. per day in
patients without peripheral edema and two pounds per day in patients with edema
[146]. The dose can be increased not sooner than 72hours after the initiation of
therapy. We favor a slow increase in the dose of diuretics not sooner than every
seven days, during weekly evaluations in the clinic with results of serum electro-
lytes, blood urea nitrogen, and creatinine. The published guidelines recommend
doses of spironolactone and furosemide to be 100mg and 40mg, respectively, to be
increased to 200mg and 80mg, respectively, and 400mg and 160mg, respectively,
the maximum doses recommended [144]. The clinician should be able to titrate the
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doses according to tolerability and response to therapy. It is pivotal that sodium
intake is limited; thus, the measurement of urine excretion of sodium helps to con-
rm adherence to sodium restriction and response to diuretics, which should help to
adjust doses. In this regard, a 24-hour urine collection is useful but cumbersome to
complete; thus, a random spot urine sodium concentration greater than the potas-
sium concentration is reported to correlate with the 24-hour sodium excretion.
When the ratio is greater than one, there should be a uid loss, with an increase in
the ratio indicating an increase in urine sodium excretion and thus water, which fol-
lows sodium [147]. Diuretics’ side effects include intravascular volume depletion
and electrolyte imbalance, leading to renal insufciency and hepatic encephalopa-
thy [146]. In cases of hyponatremia within a range of 120–125mmol/L, it is recom-
mended that diuretics be discontinued [145]. After ascites is satisfactorily mobilized,
i.e., conversion to grade 1 [148], diuretic doses should be decreased to the lowest
possible to keep maximum diuresis.
The initial treatment of grade 3 ascites is large volume paracentesis, dened as
the removal of at least 5 liters of ascites per session [144], in association with intra-
venous infusions of albumin, 8g/L removed, to prevent post paracentesis circula-
tory dysfunction [149–151]; diuretic therapy is prescribed according to tolerability
and renal function [152].
Refractory ascites is dened as that which cannot be mobilized in association
with sodium restriction and maximal doses of diuretics or that recur within 4weeks
of removal [142, 148]. Two categories have been further dened: (1) diuretic resis-
tant ascites: “… that cannot be mobilized or the early recurrence of which cannot be
prevented because of lack of response to dietary sodium restriction and intensive
diuretic therapy,” and (2) “… that cannot be mobilized or the early recurrence of
which cannot be prevented because of the development of diuretic-induced compli-
cations that preclude the use of effective diuretic dosage” [148]. Diagnostic criteria
for refractory ascites include lack of response to sodium restriction and diuretic
therapy alone after at least 1week of therapy with maximum doses (see above), i.e.,
weight loss of fewer than 2 lbs. per day, recurrence of ascites to grades 2 or 3 within
4weeks of mobilization, and complications from diuretics, i.e., hepatic encepha-
lopathy in the absence of a precipitating factor, renal insufciency with doubling of
serum creatinine to more than 2mg/dl in patients who are responding to diuretics,
hyponatremia to serum sodium to <125, and hypokalemia of <3meq/L or hyperka-
lemia to >6 meq/L. Patients with refractory ascites can be managed with large-
volume paracentesis. Diuretic treatment should be discontinued in patients with
refractory ascites unless natriuresis exceeds 30mmol per day [144, 145].
A transjugular intrahepatic peritoneal shunt (TIPS) shunts blood from an intra-
hepatic portal branch to a hepatic vein; it decreases portal pressure, and improves
effective arterial volume after the rst 4–6 weeks of insertion, with subsequent
diuresis [153]. Recurrence of ascites is lower in association with TIPS than with
diuretic therapy [153]. Complications from TIPS include hepatic encephalopathy,
occlusion of the graft itself, hemolysis, and liver failure; thus, their use must be
individualized [145] and in collaboration with a liver transplant center, in our view.
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The absolute contraindications for TIPS are elevated right or left heart pressures,
heart failure or severe cardiac valvular insufciency, rapidly progressive liver fail-
ure, severe or uncontrolled hepatic encephalopathy, uncontrolled systemic infection
or sepsis, unrelieved biliary obstruction, polycystic liver disease, extensive primary
or metastatic hepatic malignancy, and severe, uncorrectable coagulopathy [154].
Patients who cannot have TIPS can be managed with midodrine, an alpha 1
adrenergic agonist associated with improved systemic perfusion and renal function.
At a dose of 7.5mg orally three times a day in combination with diuretics, mido-
drine was associated with a signicant increase in natriuresis, urine volume, mean
arterial pressure, and decrease in plasma renin activity after one month of treatment,
and a signicant increase in cardiac output and peripheral vascular resistance at
3months of therapy, with reported mortality signicantly higher in the group that
received diuretics alone, in a randomized controlled trial that included 20 patients in
each arm [155].
Nonsteroidal anti-inammatory drugs (NSAIDs) block prostaglandins, which
are endogenous vasodilators; thus, NSAIDs in patients with cirrhosis should not be
used as they induce sodium retention and ascites formation. The use of angiotensin-
converting enzyme (ACE) inhibitors should be avoided in patients with ascites as
they will block the endogenous vasoconstriction that develops to maintain renal
blood ow. Nephrotoxic drugs should be avoided.
The Alfapump® transfers ascites to the urinary bladder for elimination. It has
been documented to remove ascites effectively and be associated with improved
quality of life; bacterial infections and electrolyte imbalance were documented as
the most serious side effects. The use of this device may become an alternative to
the management of patients who require large volume paracentesis (LVP) [156].
Hepatic Hydrothorax
Hepatic hydrothorax is uid in the thoracic cavity in patients with decompensated
liver disease from the escape of ascites into the chest, most commonly in the right
side, via rents in the diaphragm and facilitated by the negative pressure in associa-
tion with inspiration in patients without pulmonary or cardiac disease [157]. The
uid is transudate with a serum to pleural uid albumin gradient >1.1g/dl. Peritoneal
scintigraphy can be performed to conrm the uid trajectory. It can be complicated
by empyema [157]. The prognosis of patients who develop hepatic hydrothorax is
poor, with survival reduced to 8–12months; thus, patients should be evaluated for
liver transplantation [157].
Treatment of hepatic hydrothorax is diuretics and sodium restriction. The use of
chest tubes is contraindicated. TIPS can be used as temporalizing therapy. In patients
who cannot have liver transplantation, pleurodesis is an option; however, the com-
plication rate is high. Repair of well-dened diaphragmatic defects via thoracos-
copy has been reported [158].
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Hyponatremia
Patients who develop hypovolemic hyponatremia, usually secondary to diuretics,
require volume repletion with normal saline. Patients with hypervolemic hyponatre-
mia require the restriction of uids to 1–2 liters, as tolerated. The threshold at which
treatment is necessary varies, usually being between 120 and 125 meq/L [144],
although 130meq/L has also been cited [145].
Bacterial Infections
Patients with cirrhosis are vulnerable to infections from an impaired immune sys-
tem, dysbiosis, and bacterial translocation [159–161]. Subtle signs of infection must
be sought in the evaluation of patients with liver disease.
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis (SBP) is infected ascites without an identied
intraabdominal focus of infection [162]. The pathogenesis of this condition includes
bacterial translocation, a phenomenon that concerns the migration of bacteria from
the intestinal lumen to the mesenteric lymph nodes from where they infect ascites
hematogenously [160, 163], increased intestinal permeability, and bacterial over-
growth. It is usually monomicrobial, with Escherichia coli being the most common
bacteria; the presence of more than one organism or fungi or anaerobes tends to
suggest a secondary source.
The clinical presentation of SBP includes fever and abdominal pain, but a subtle
deterioration of hepatic, renal, and mental status is a clue to the diagnosis. Patients
who undergo paracentesis, whether diagnostic or therapeutic, should have SBP
excluded (see above).
A total neutrophil count in ascites of at least 250 cells is diagnostic of SBP.Ascites
uid should be inoculated directly into culture bottles at the bedside. Complete
blood count and blood cultures should also be done simultaneously, prior to antibi-
otic administration, which should be started liberally based on clinical suspicion;
cefotaxime, 2g every 8hours intravenously, is the treatment of choice for 5–7days,
in association with albumin 1.5mg/kg by infusion on day one and 1mg/kg on day
three of treatment. A repeat ascites analysis 48hours post initiation of therapy is
recommended to conrm the efcacy of therapy; if the results do not suggest a suc-
cessful response to treatment, i.e., a decrease in the total polymorphonuclear cell
count, secondary bacterial peritonitis should be suspected, and studies to exclude it
should be done [145]. Prompt administration of antibiotics has been documented as
the most important predictor of survival [164]. The probability of SBP in
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hospitalized patients with liver disease is 20% [165]; thus, careful follow up of
patients with liver disease and ascites who did not have SBP at hospitalization is
critical, i.e., paracentesis should be repeated, and antibiotics administered, accord-
ing to the clinical situation. Patients who are on beta-blockers should have these
discontinued if they develop SBP [166].
After the rst episode of SBP, prophylaxis with ciprooxacin, 500mg orally per
day is recommended; an alternative to this medication is daily, double strength
trimethoprim- sulfamethoxazole [144].
Renal Insufciency
The impairment of renal function is detrimental to the survival of patients with cir-
rhosis. Decompensated liver disease complicated by renal insufciency portends
poor survival, characterizing the last stages of liver dysfunction.
Patients with cirrhosis may have chronic kidney disease in association with
comorbidities including diabetes and hypertension, or from intrinsic disease includ-
ing IgA nephropathy and glomerulonephritis secondary to chronic viral hepatitis.
Chronic kidney disease is dened as a glomerular ltration rate (GFR) of <60ml/
min per 1.73 m2 for more than 3 months. Acute kidney disease is dened as a
decrease in GFR of <60ml/min per 1.73m2, or a reduction in GFR by at least 35%,
or an increase in serum creatinine by at least 50%, all three for less than 3months.
Acute kidney injury (AKI) is dened by renal impairment of short duration; speci-
cally, the increase in serum creatinine by more than 0.3mg/dl within 48hours, or an
increase in serum creatinine by 50%, documented or presumed to have occurred in
the 7days prior to the measure [167]. The stages of AKI are: (1) an increase in
serum creatinine to ≥0.3 mg/dl, or by ≥1.5- to two-fold from baseline, with 1a
including patients in whom serum creatinine did not exceed 1.5mg/dL, and whose
mortality is similar to that of patients without AKI, and 1b, including patients whose
serum creatinine increased beyond 1.5mg /dl, whose short term mortality may be
comparable that of patients who have not developed AKI [168], (2) an increase in
serum creatinine to two- to threefold from baseline, and (3) an increase in serum
creatinine by more than threefold from baseline, or a serum creatinine ≥4mg/dl
with an acute rise of ≥0.3mg/dl or dialysis initiation [167].
Precipitating factors of AKI must be identied rapidly to address them quickly.
In this regard, dehydration from the use of diuretics, infection, gastrointestinal
bleeding, and NSAIDs use are common precipitating factors of AKI in patients with
cirrhosis. AKI in patients with cirrhosis is associated with poor prognosis with a
reported survival of 2–30% in hospitalized patients with this complication [169].
The management of AKI includes discontinuation of diuretics and any drugs
contributing to renal impairment. Beta-blockers should be discontinued, although
there are differences of opinion regarding this matter [144, 145]. Volume repletion
with crystalloids, as appropriate, and, in cases of gastrointestinal bleeding, blood
transfusions to keep the hemoglobin between 7 and 9g/dl [170]. In patients with
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tense ascites, paracentesis should be performed in association with albumin infu-
sions at doses of 8g/liter removed [149–151, 171], which has been reported to be
associated with improvement in renal function. Patients with ascites should receive
albumin infusions in the same manner done during LVP in the absence of AKI.Based
on the consensus published in 2007 [172] and on the recommendations from the
European Association for the Study of Liver Disease [145], when AKI does not
have an identiable cause(s), its stage is greater than 1a, or it is associated with
infection, patients should receive 20% albumin infusions at a dose of 1g/kg of body
weight for two consecutive days up to 100g total.
Traditionally the terminology of acute renal insufciency, now acute kidney
injury, has been pre renal, associated with decreased renal perfusion due to dehydra-
tion, renal, due to intrinsic renal disease including acute tubular necrosis, glomeru-
lonephritis, and interstitial nephritis, and post-renal, secondary to obstruction,
which may be of sufcient magnitude to lead to hydronephrosis. All types of AKI
can develop in patients with cirrhosis; the use of biomarkers to identify the type of
AKI is being proposed, with urinary neutrophil gelatinase-associated lipocalin
(NGAL) and interleukin 18 being reported to differentiate patients with acute
tubular necrosis from other types of renal impairment [173].
Hepatorenal Syndrome
Hepatorenal syndrome (HRS) is a complication unique to patients with decompen-
sated liver disease and is associated with a poor prognosis. HRS happens in the
context of altered hemodynamics secondary to portal hypertension characterized by
profound systemic vasodilatation accentuated in the splanchnic circulation medi-
ated, at least in part, by excessive production of nitric oxide (NO), and which results
in ineffective arterial volume, i.e., relative hypovolemia, and the activation of the
neurohumoral systems of rescue including the renin–angiotensin–aldosterone sys-
tem, the sympathetic nervous system, and non-osmotic release of antidiuretic hor-
mone. In cirrhosis, at rst, there is an increase in sodium and water retention in
response to the relative hypovolemia, which results in increased intravascular vol-
ume and increased cardiac output. However, as cirrhosis progresses, there is
increased vasodilatation, with further activation of vasoconstrictive systems, lead-
ing to vasoconstriction and decreases in renal blood ow [174, 175] and deteriora-
tion of cardiac function, i.e., high output heart failure, as the heart cannot keep up
with perfusion demands, further contributing to renal hypoperfusion and dysfunc-
tion [148, 176, 177]. HRS has traditionally been considered to be caused by extra-
renal factors that cause functional renal failure. This interpretation has been
supported by the improved or normalized renal function in patients with HRS after
liver transplantation, suggesting that it was the liver and the hemodynamic compli-
cations of portal hypertension that perpetuated the renal dysfunction [178], and by
the suggested normality of renal histology in patients with HRS. However, there is
a paucity of data in this regard; thus, the idea of HRS as being only functional is
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being reconsidered [145]. In this context, it is being suggested that the pathogenesis
of HRS be considered under the light of recent data documenting the role of inam-
mation and microvascular dysfunction on mitochondrial function and the effect of
profound cholestasis on renal function [179, 180].
Muscle Cramps
Sixty-seven percent of subjects in a study comprised of 101 patients with cirrhosis
experienced muscle cramps [181]. An electromyogram of a muscle during a cramp
was reported to reveal involuntary repetitive ring of motor unit action potentials at
high rates up to 150 per second, producing a sustained muscle contraction [181].
Patients with cramps were reported to have had signicantly lower serum albumin
concentrations than those without cramps. Cramps were associated with impaired
quality of life. The etiology of muscle cramps, including those in patients with cir-
rhosis, is unknown.
Treatments used to treat muscle cramps in patients with cirrhosis include albu-
min infusions [182], based on the hypothesis that decreased effective arterial vol-
ume is increased by albumin, thus improving perfusion, and baclofen, which, in a
randomized, placebo-controlled study was associated with the disappearance of
muscle cramps at 3months of treatment, at a dose of 30 mg per day (e.g., 10mg
three times a day) [183].
Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a reversible neuropsychiatric behavioral complica-
tion of cirrhosis, acute liver failure, and chronic portosystemic shunting, character-
ized by inhibitory neurotransmission. Pathological brain ndings similar to those
found in patients with congenital hyperammonemia resulting from inherited defects
of urea cycle enzymes, i.e., Alzheimer’s type II astrocytosis, have been described in
HE [184–187].
HE is detrimental to patients with survival signicantly decreased in those con-
tinuing to have this complication at one year after its rst episode [188, 189].
The pathogenesis of HE is unknown. Hyperammonemia in association with
increased GABAergic neurotransmission, which is inhibitory, in relationship to
neurosteroids is considered to contribute to the pathogenesis of this complication of
liver disease [190–196].
Nitrogen, which is ingested in food, is converted to ammonia. NH4+ is the form
in which ammonia exists in human beings in physiological conditions and is pro-
duced by transamination followed by deamination of biogenic amines and amino
groups of nitrogenous bases such as purine and pyrimidine, and from the effect of
intestinal bacterial through the action of urease on urea [197–199]. The
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concentration of ammonia in the portal system is signicantly higher than that of the
systemic circulation. Through the urea cycle, the liver converts ammonia to urea by
combining it with ornithine, bicarbonate, and aspartate, and is excreted as urea
through the kidneys, which are instrumental in ammonia metabolism [199].
In liver disease or portosystemic shunting, the uptake of ammonia by the liver is
decreased; thus, it circulates at high concentrations systemically. The brain lacks the
urea cycle. In the brain, ammonia’s clearance concerns its combination with gluta-
mate to form glutamine in the cortical Alzheimer’s type II astrocyte. The excess of
glutamine results in astrocytes’ swelling, associated with impaired intercellular
communication and neurotransmission [184, 196].
There is a proposed relationship between ammonia and GABA-ergic neurotrans-
mission in the pathogenesis of HE.Ammonia in the brain is associated with the
upregulation of the peripheral type of benzodiazepine receptors on the astrocyte
mitochondrial membrane, which results in the formation of neurosteroids, which
increase GABAergic neurotransmission via GABA A receptors [193–196].
Improvement of patients with HE, albeit of short duration, in association with u-
mazenil, a GABA A receptor antagonist, supports the hypothesis of increased
GABA ergic tone contributing to HE [200].
Other theories proposed to explain HE include altered serotonin neurotransmis-
sion, false neurotransmitters, inammation, manganese neurotoxicity, and gut dys-
biosis [201, 202]. In addition, genetic susceptibility has been reported in patients
with cirrhosis and HE; specically, glutaminase TACC and CACC haplotypes were
reported as risks for the development of overt HE [203].
HE has been classied as type A in acute liver failure cases, type B when associ-
ated with portosystemic shunts in the absence of liver disease, and C when associ-
ated with cirrhosis, portal hypertension, and portosystemic shunting. Type C HE has
been further classied as episodic, persistent, and minimal [186, 204]. HE can be
episodic, usually triggered by commonly identied precipitating factors (see below),
recurrent, when bouts occur in intervals of at least 6months, and persistent when
behavioral manifestations are always present, with superimposed relapses of overt
HE. HE has also been classied according to the existence of precipitating factors,
i.e., nonprecipitated and precipitated.
Clinically, patients may have covert HE or may be in a coma. The exclusion of
causes of encephalopathy and altered mental status beyond liver disease is part of
the assessment of patients with liver disease and includes acute head injury, remote
subdural hematoma, and space-occupying lesions, which require radiological tests
[186]. The West Haven classication of HE grades it from 0 to 4 with 0 exhibiting
no clinical ndings; (1) including decreased attention span, sleep alterations, and
the presence or absence of asterixis; (2) including lethargy, disorientation to time,
amnesia related to recent events, and asterixis; (3) including somnolence, confu-
sion, disorientation to place with asterixis tending to be absent; and (4) character-
ized by coma. Family members can help to identify ndings of HE in patients with
covert HE, which include subtle personality changes. Changes in sleep patterns are
typical of HE, with patients being awake at night and sleepy during the day [186].
15 Complications ofLiver Disease
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