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In evaluating patients with HE, it is essential to review medications and eliminate
sedatives, especially benzodiazepines, which lead to increased gabaergic neuro-
transmission. The physical examination of a patient with HE is characterized by
minimal attention span and constructional apraxia. Completion of the number con-
nection test is delayed [205]; this test can be given in the clinic and provides an
objective evaluation against which to assess the effect of treatment. Asterixis is a
typical nding of HE (see above). Electroencephalogram shows the typical triphasic
sharp and slow waves of HE [206], with a predominance of theta activity (slowing)
as the degree of HE progresses [207]. The interpretation of EEG requires expertise,
and it is a desirable tool to incorporate as a measure in clinical trials of HE.
The treatment of HE includes the identication of precipitating factors and their
reversal. The precipitating factors tend to be dehydration, gastrointestinal bleeding,
infections, sedative use, and electrolyte imbalance. In this context, hypokalemia is
notorious for causing HE because it is associated with an increase in ammonia gen-
esis and decreased urinary ammonia excretion; hypokalemia (an acidosis) stimu-
lates glutamine uptake and the expression of ammoniagenic enzymes in the proximal
tubule, thus increasing ammonia concentration in blood [208], changes that appear
to contribute to HE in patients with impaired liver function.
The pharmacological therapy of HE includes lactulose, a nonabsorbable disac-
charide, considered the rst line of treatment, although debate remains regarding
the robustness of the data derived from clinical studies [186, 209]. The rationale for
the use of lactulose [210] includes: (i) absence of specic disaccharidase on the
microvillus membrane of enterocytes in the human small bowel, allowing lactulose
to enter the colon. In the colon, lactulose (and lactitol, also used in HE’s manage-
ment outside the United States) is catabolized by the colonic bacteria to short-chain
fatty acids, including lactic and acetic acids, which results in a decrease in pH of the
stool to approximately 5. The acidic milieu propitiates the formation of NH4+,
which is nonabsorbable, from NH3+, which gets trapped in the colon, thus decreas-
ing the concentration of ammonia in the blood; the importance of an acidic colonic
environment in the management of HE has been documented in clinical studies
[211], (ii) increased incorporation of ammonia by bacteria for synthesis of nitrogen
compounds, (iii) change in colonic ora from urease producing bacteria, which con-
tribute to ammonia production, to non-urease producing Lactobacillus species
[212], and (iv) cathartic properties that result in a decrease in time available for
ammonia to be absorbed from the colon [213]; the value of catharsis in the manage-
ment of HE has been reported in clinical studies that included other agents [214].
In acute HE, in patients who can swallow, a dose of 30ml of lactulose is admin-
istered every hour until diarrhea occurs and then tapered to 2–3 times a day to cause
2–3 soft bowel movements, targeted to the improvement of symptoms, i.e., avoid-
ance of an excessive number of bowel movements stands to reason. Lactulose can
be administered by enemas if necessary [210].
The rationale to use antibiotics to treat patients with HE is to decrease the num-
ber of bacteria that contribute to ammonia production; neomycin, metronidazole,
and vancomycin have been studied [210]. Rifaximin is a nonabsorbable antibiotic
that changes the gut microbiota toward a less encephalopathogenic mix than the
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endogenous ora; it is approved for the treatment of HE at a dose of 550mg orally
twice a day, at which dose the drug was documented to decrease the risk of overt HE
recurrence in adult subjects. It is used in combination with lactulose, the dose of
which can be changed to suit the patient’s convenience while still offering clinical
improvement [215, 216].
Other treatments that have been used in HE include sodium benzoate, zinc,
branched chain amino acids, and probiotics [186].
HE has a profound negative impact on the lives of patients with liver disease.
Liver transplantation (LT) is a therapeutic alternative for patients with decompen-
sated liver disease as per established criteria [186]. In cases of HE from portosys-
temic shunts, their closure is indicated prior to referral for LT or at the time of
surgery [186].
Cardiomyopathy
Cardiac dysfunction may be present in as many as 50% of patients who undergo
liver transplantation for end-stage liver disease [217].
Cirrhotic cardiomyopathy was dened as: (i) systolic dysfunction with a resting
ejection fraction of less than 55% associated with a blunted increase in cardiac out-
put in response to exercise or pharmacological stimulation; (ii) diastolic dysfunc-
tion with an early diastolic atrial lling ratio less than 1.0 (corrected to age),
deceleration time greater than 200 milliseconds, and prolonged isovolumetric relax-
ation time greater than 80 milliseconds; (iii) with supporting criteria that include
electrophysiological abnormalities, e.g., prolonged QT, abnormal chronotropic
response, electromechanical uncoupling, enlarged left atrium, increased myocardial
mass, increased brain natriuretic peptide, and pro-peptide, and increased troponin I
[218]. Right ventricular dysfunction is also involved [219].
The heart function is best evaluated by echocardiogram in patients with cirrhosis.
The treatment of cirrhotic cardiomyopathy concerns the improvement of left
ventricular function done with sodium restriction, diuretics, and afterload reduction,
except in advanced disease because of profound peripheral vasodilation intrinsic to
the hemodynamic milieu of portal hypertension [220].
Cardiac alterations in cirrhosis are reported to be reversed after liver transplanta-
tion [220].
Hepatopulmonary Syndrome
The hepatopulmonary syndrome (HPS) is a complication of cirrhosis and portal
hypertension characterized by abnormal arterial oxygenation through ventilation-
perfusion mismatch that results from intrapulmonary vascular dilatation [221]. The
clinical manifestations of HPS include dyspnea, and platypnea, dened as shortness
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of breath on sitting up and improved on lying down. The characteristic physical
ndings are orthodeoxia, dened as hypoxemia exacerbated in the upright position,
digital clubbing, and cyanosis.
The mechanism that leads to pulmonary vasodilation is considered to be multi-
factorial from data derived mostly from animal studies, and include: (i) endothelin-
1, which is increased in cirrhosis and portal hypertension stimulates pulmonary
endothelial nitric oxide synthase (eNOS), which results in increased production of
nitric oxide (NO), the most potent endogenous vasodilator [222–224]; (ii) bacterial
translocation, which is a feature of portal hypertension and which is associated with
accumulation of macrophages, triggers production of inammatory cytokines,
including tumor necrosis factor (TNF) alpha, which leads to an increase in the pro-
duction of inducible nitric oxide synthase (iNOS) [225, 226]; (iii) an increase in
macrophage-induced heme oxygenase-1 (HO-1) increases the production of carbon
monoxide, a pulmonary vasodilator [227]; and (iv) pulmonary angiogenesis medi-
ated by macrophages and increased in TNF-alpha stimulates production of vascular
endothelial growth factor (VEGF) [104, 228]. As portal hypertension is character-
ized by a hyperdynamic circulation, the rapidity with which mixed venous blood
circulates through the capillaries, which normally measure 8–15μm and can be as
dilated as 100μm in diameter, does not allow for appropriate gas exchange because
oxygen has to travel a longer distance from the alveolus to the center of the dilated
vessels, as interpreted from animal studies [224], thus causing a ventilation-
perfusion mismatch, resulting in arterial hypooxygenation and high alveolar-arterial
gradient [229], worsened by the right to left shunts (venous to arterial) from arterio-
venous shunts [230]. The diagnosis of HPS is made by excluding primary cardio-
pulmonary disease and by identifying gas exchange alterations. Oxygen saturation
of less than 96% by pulse oximeter should trigger the exclusion of HPS.This test is
reported to have a sensitivity of 100% and a specicity of 88% in patients with a
partial pressure of oxygen (PaO2) of less than 70% [231, 232]. A contrast bubble
echocardiogram is the initial recommended diagnostic test; it is done by administer-
ing agitated normal saline while doing a transthoracic echocardiogram. The bubbles
opacify the right ventricle from where they are transported to the lungs via the pul-
monary circulation where they are absorbed; in the presence of a right to left shunt,
bubbles immediately appear in the left ventricle, i.e., early shunting; however, in the
presence of intrapulmonary shunt, as in hepatopulmonary syndrome, bubbles appear
in the left atrium three cardiac cycles after the administration of agitated saline, i.e.,
delayed shunting thus supporting the diagnosis of HPS.
Another diagnostic modality is the use of radionuclide lung perfusion scanning.
Intravenously injected technetium-labeled macroaggregated 20-micron albumin
(Tc-99m MAA) normally gets trapped almost completely within the pulmonary
capillary bed. In HPS, the Tc-99m MAA particles pass through the dilated pulmo-
nary capillaries and enter the systemic circulation, being trapped in the capillaries
of the brain, kidneys, and other organs. Normally less than 6% of Tc-99m MAA
particles bypass the lung to lodge themselves into the capillaries of other organs
[233, 234].
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Two ndings have been reported from pulmonary angiography in HPS, type 1,
characterized by the diffuse spongiform appearance of pulmonary vessels in the
arterial phase, and type 2, small arteriovenous communications; however, it is not
recommended as a screening test as it is invasive and not sensitive for the diagno-
sis of HPS.
The treatment of HPS depends on its severity. For patients with mild or moderate
HPS, dened as A-a gradient ≥ to 15mmHg, with a PaO2±80mmHg, or A-a gra-
dient ≥ to 15 mmHg, PaO2 ≥ 60mmHg and< 80 mmHg, respectively, clinical
follow up, including pulse oximetry every six months, is recommended. Oxygen
supplementation is not recommended unless hypoxemia occurs during exercise
(e.g., 6-minute walk test) or sleep. Patients with severe HPS, dened as A-a gradient
≥ to 15mmHg with a PaO2≥50mmHg and<60mmHg, and for patients with very
severe HPS, dened as <50mmHg or patients with a PaO2< 300 mmHg while
breathing 100% oxygen [221] should be evaluated for liver transplantation, which
is reported to be associated with improvement in symptoms of HPS and oxygen-
ation over the rst year post surgery [235, 236].
Investigational therapies have included TIPS [237] and embolization in
patients with large shunts [238, 239]. A study that explored the use of garlic,
which contains allium sativum, which decreases the production of nitric oxide,
documented an increase in baseline arterial oxygen concentration by 25%, as
compared to an increase by 7% as compared to placebo, prescribed in a random-
ized fashion [240].
Portopulmonary Hypertension
Portopulmonary hypertension (PoPH) is dened as the coexistence of portal hyper-
tension and pulmonary arterial hypertension regardless of cirrhosis [241], in the
absence of volume overload or intrinsic cardiopulmonary disease. It was reported to
be present in 6% of liver transplant candidates [242]. From a registry that included
637 patients with PoPH, 57% had compensated cirrhosis [243]. A genetic predispo-
sition to develop PoPH has been explored with reported multiple single nucleotide
polymorphisms in the genes that code for estrogen receptor 1, aromatase, phospho-
diesterase 5, angiopoietin 1, and calcium-binding protein A4 [242].
The clinical manifestations of PoPH include dyspnea, fatigue, syncope, orthop-
nea, and peripheral edema [244]. Many patients are asymptomatic. On physical
exam, jugular vein distension, a loud P
2
, or a murmur suggestive of tricuspid insuf-
ciency may be appreciated, with leg edema out of proportion to ascites in advanced
cases. Hypoxemia is not common.
Histologically, the pulmonary vasculature displays proliferation of the intima,
with media hypertrophy, brosis, and thrombosis leading to thickened arterial walls
and impaired blood ow, which result in increased pulmonary vascular resistance
[245, 246]. The mediators of such changes are unknown. It is considered that a
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disequilibrium between vasoconstrictor and vasodilator substances contributes to
the pathogenesis of PoPH, and they include thromboxane A2, interleukin-1, inter-
leukin- 6, angiotensin-1, glucagon, serotonin, and ET-1A [247–250].
A Doppler transthoracic echocardiogram can be used to screen for PoPH; if a
systolic pulmonary arterial pressure greater than 40mmHg is identied [244], direct
measurement of pulmonary pressures is done by right heart catheterization [251]. A
mean pulmonary artery pressure greater than 25mmHg in association with a pul-
monary capillary wedge pressure less than 15 mmHg is diagnostic of PoPH. In
addition, a transpulmonary gradient greater than 10mmHg and a high pulmonary
vascular resistance are used to differentiate pulmonary arterial hypertension from
pulmonary venous hypertension from the hyperdynamic circulation and hypervol-
emia of portal hypertension [244].
Patients with PoPH should be referred to centers with expertise in this condition.
Drugs that have been used to treat PoPH have been taken from the experience with
primary pulmonary hypertension [252]; however, calcium channel blockers and
anticoagulation are not recommended for PoPH.The therapies that have been tried
in PoPH include endothelin receptor antagonists, e.g., bosentan, which can be asso-
ciated with hepatitis, thus, follow-up for possible liver injury is necessary, and maci-
tentan, which, in a multicenter, randomized, double-blind, placebo-controlled,
phase 4 trial was documented to decrease pulmonary vascular resistance, signi-
cantly, without hepatotoxicity [253], phosphodiesterase inhibitors, e.g., sildenal,
prostacyclin analogs, e.g., epoprostenol, vasopressin analogs, e.g., terlipressin, and
tyrosine kinase inhibitors, e.g., imatinib have been considered.
The use of beta-blockers to prevent variceal bleed in patients with PoPH is not
recommended because of the effect on cardiovascular hemodynamics [254].
Liver transplantation is not an option in patients with severe pulmonary hyper-
tension because of high operative and perioperative mortality from cardiovascular
complications [253]. Patients with pulmonary arterial pressure are less than
35mmHg are considered for liver transplantation.
Fat Malabsorption
Fat malabsorption may be a complication of cholestasis, but the degree of steator-
rhea is modest, with over 70% of the ingested fat being absorbed [255]; important
fat malabsorption in patients with cholestasis, including that from PBC, can be
treated with the administration of medium-chain triglycerides [255]. There is litera-
ture on an association between PBC and celiac disease [256, 257]; thus, in patients
with PBC and ndings suggestive of malabsorption of fat or deciencies in ele-
ments such as magnesium and iron, celiac disease should be excluded and specic
treatment, i.e., gluten-free diet, recommended.
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Vitamin Deciencies
Retinol provides vitamin A from animal sources and beta carotene from plant
sources. Retinol-binding protein regulates the uptake of retinol by intestinal cells.
The absorption of beta-carotene depends on the availability of bile acids in the small
intestine. In addition to poor absorption secondary to bile acid deciency, decreased
availability of retinol-binding protein, which results from chronic hepatobiliary dis-
ease, contributes to vitamin A deciency because of the impaired release of the
vitamin from liver stores [258]. Enhanced urinary clearance of retinol due to de-
ciency in transthyretin, a thyroxine-binding globulin to which retinol-binding glob-
ulin is bound in the circulation, may also occur. Zinc is necessary for the activation
of retinol to a photochemical compound; in addition, the hepatic secretion of reti-
nol-binding protein depends on zinc; thus, it is necessary to check zinc levels and
correct a deciency if present [259]. Oral doses of 25,000 international units (IU)
per day [260] to 30,000IU three times a week [261] have been recommended for
vitamin A supplementation. Vitamin A can be toxic to the liver and other organs;
accordingly, it must be supplemented not to exceed what is considered normal lev-
els, administered under supervision, and intermittently [259].
Endogenous production is the most important source of vitamin D.The metabo-
lism of vitamin D has been reported to be normal, at least in patients with PBC
[262]. These facts have suggested that poor exposure to sunlight in a debilitated
chronically ill patient may be the main cause of vitamin D deciency in cholestasis.
Vitamin D, parathyroid hormone, and calcitonin regulate plasma calcium and phos-
phorus homeostasis; thus, these elements may be abnormal in cases of vitamin D
deciency. Doses that have been recommended for vitamin D supplementation
include 400–4000IU orally per day [263], or 50,000IU orally three times a week
[261]. Prolonged supplementation of vitamin D can lead to hypercalcemia and soft
tissue calcications, although these are not common complications [264, 265].
The main vitamin E sources are the naturally occurring tocopherols, which
require micellar solubilization for absorption; thus, deciency is a complication of
conditions associated with cholestasis. Vitamin E inhibits the oxidation of unsatu-
rated fatty acids, prevents lipid peroxidation, and is a scavenger of free radicals.
Vitamin E deciency manifests itself with a neurological syndrome characterized
by peripheral neuropathy, cerebellar degeneration, and abnormal eye movements,
i.e., reverse internuclear ophthalmoplegia. Retinal degeneration has been ascribed
to vitamin E and A deciencies alone or combined. In children, the complications
of vitamin E deciency are more severe than in adults with cholestasis [266].
Recommendations to treat deciency of vitamin E include 100mg twice a day [261]
or 10 to 25IU/kg/day [267].
Vitamins K1 and K2 require micellar solubilization for absorption in the small
intestine. The forms that contribute to vitamin K activity are K1 or phytonadione,
found in most vegetables, and K2, a series of menaquinones, formed by
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Gram- positive bacteria in the intestine. Other compounds that have vitamin K activ-
ity are structurally related to menadione (K3) [268]. Vitamin K deciency may pres-
ent with coagulopathy, as measured by prolonged prothrombin time secondary to
deciency of vitamin K-dependent clotting factors, or it may be subclinical [269].
Coagulopathy from vitamin K deciency resolves upon administration of the vita-
min, which can be given subcutaneously at doses of 1–10mg of vitamin K1 daily
for three consecutive days. In patients with chronic cholestasis, vitamin K de-
ciency may be prevented by monthly administration of 10mg of vitamin K subcu-
taneously [268]. The intramuscular administration of vitamin K, or any other
medication, is contraindicated in patients with coagulopathy because of the risk of
intramuscular hemorrhage. If the coagulopathy results from hepatocellular failure,
it will not resolve in association with vitamin K administration.
It is important to supplement vitamin deciencies as documented by blood levels
and replace them, as required [270]. Periodic checkups of serum vitamin levels to
provide sufcient but not excessive amounts can guide vitamin supplementation, in
general. Selected recommended regimes to supplement vitamins when there is de-
ciency are listed in Table15.2.
Gynecomastia
Gynecomastia is a physical nding in men with cirrhosis. In control subjects, gyne-
comastia was reported in 55% of the group versus 44% of men with cirrhosis. The
total estrogen-free testosterone ratio and the estradiol-free testosterone ratio was
similar between the patients with cirrhosis and those without, results interpreted to
suggest factors other than estrogen contribute to the pathogenesis of gynecomastia
in cirrhosis, or that there may be an increase in the sensitivity to estrogens in breast
tissue in cirrhosis [271].
Table 15.2 Selected regimens for vitamin supplementation in patients with cholestasis and
vitamin deciencies
Decient vitamin Preparation Dose/mode of administration/frequency
A Vitamin A 30,000IU/orally / three times per week
[261].
D Cholecalciferol 50,000IU/ orally/ three times a week
[261].
E tocopherol 100mg twice a day
[261]
K K
1
1–10mg/ SC/ daily for three consecutive days or monthly
a
[268].
a
for patients who have chronic cholestasis
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Cholelithiasis
The prevalence of cholelithiasis in patients with cirrhosis is higher than that of the
general population [272] and reported as 25–30% [273]. There are specic recom-
mendations for the management of gallstones associated with symptoms, which
will not be reviewed in this section; however, it is important to know that in patients
with cirrhosis from any cause, gallbladder surgery carries important risks for com-
plications that must be considered in collaboration with hepatobiliary surgeons, if
surgery is being considered [274–276].
Malnutrition
The prevalence of malnutrition and sarcopenia was reported as 23 to 60% from a
recent review [277]. Malnutrition can be profound in patients with end stage liver
disease and is associated with a negative impact on the quality of life, and decreased
survival including over the post liver transplant period [278]. It is recommended that
patients with cirrhosis ingest 35 to 40 kcal/kg of body weight, with 1 to 1.5 g/kg of
protein, preferably plant and dairy based. Six to eight meal “events” have been rec-
ommended, with snacks between breakfast, and lunch, and lunch and dinner [279,
280]. We emphasize on a night snack, e.g., hard-boiled egg, especially in hospital-
ized patients to avoid a prolonged overnight fasting. In patients with decompensated
liver disease, branched chained amino acid and leucine enriched amino acid supple-
ments are suggested. Patients who cannot have adequate oral intake, episodic enteral
nutrition is recommended [280]. Early referral to the nutritionist is part of the care
of patients with liver disease.
Acknowledgments The author acknowledges Dr. Anatole Sladen for having contributed
the Figure.
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