++
End-stage liver disease is a term
that is applied to chronic liver disease that is associated with
minimal liver function or severe complications that may lead to
death. Cirrhosis represents a final common histologic pathway for
a wide variety of liver diseases, being characterized by diffuse
fibrosis and conversion of the normal liver architecture in to structurally
abnormal nodules (Fig. 425-1). Often there
is a poor correlation between histology and the clinical status
of the patient. Some patients with cirrhosis are essentially asymptomatic whereas
others have all of the sequelae of chronic liver disease discussed
below. In the era of liver transplantation various attempts to measure
the severity of chronic liver disease have been applied in order
to determine to prioritize organ distribution for liver transplantation
such that the sickest patients received organs. The measure now
applied in North America is the Model of End-Stage Liver Disease,
or MELD score. The MELD score is calculated using laboratory values
including the bilirubin, INR and
serum creatinine. The scoring system has been modified for children
less than age 12 years (PELD score) such that it uses other measures
of chronic disease relevant in children including serum albumin, bilirubin,
INR, growth failure (based on gender, height and weight) and age
at listing. Calculators to determine the MELD and PELD scores are
available at: http://www.unos.org/resources/meldpeldcalculator.asp (accessed
March 2, 2010).
++
The major complications of end-stage liver disease include malnutrition,
portal hypertension, and its ensuing risk for variceal hemorrhage
and ascites, infection, hepatic encephalopathy, and hepatorenal
and hepatopulmonary syndrome.1 Early detection
with appropriate management may prevent or ameliorate some of these
chronic complications.
+++
Malnutrition
and Specific Nutrient Deficits
++
A variety of mechanisms may contribute to malnutrition in end-stage liver
disease. These include poor dietary intake, malabsorption, increased
intestinal protein losses, low protein synthesis, disturbances in
substrate utilization, and hypermetabolism. Many of these are not
fully understood. Diminished oral intake may be the result of anorexia
of chronic disease; gastroesophageal reflux; nausea and early satiety
secondary to abdominal distention exacerbated by tense ascites,
organomegaly, delayed gastric emptying, small bowel dysmotility
and bacterial overgrowth, and altered taste sensation (dysgeusia).
Decreased concentrations of intraluminal bile acids and some medications (cholestryamine
and antibiotics) predispose the patient to malabsorption of fat
and fat-soluble vitamins. Altered protein metabolism and substrate
utilization are manifested by hyperammonemia, hypoalbuminemia, reduced
clotting factors, and hypoglycemia. Metabolic disturbances consequent
to liver disease, such as increased energy expenditure, insulin
resistance, and low respiratory quotient (indicating reduced glucose
and increased lipid oxygenation), may contribute to malnutrition
even in the early stages. Recurrent sepsis is common in patients
with end-stage liver disease, and is likely to increase energy expenditure
further. Early recognition and timely intervention are essential,
given that malnutrition is predictive of complications of end-stage
liver disease and mortality.2
++
Improving nutritional status in children with chronic liver disease
is challenging. Tracking linear growth for long-term monitoring
is mandatory. Total reliance on body weight may be misleading in
children with fluctuating ascites, organomegaly and peripheral edema,
with anthropometric assessment (triceps skinfold and midarm circumference)
challenged by small patient size and lack of age-appropriate norms.
All infants and children will require increased caloric intake,
which is usually met in part by increasing their intake to 120% to
180% of their estimated daily caloric requirement. Formulas containing
medium-chain triglyceride (MCT) are used to maximize fat absorption
in the setting of severe cholestasis, because MCTs do not require
bile acid micelles for solubilization and are directly absorbed
into the portal circulation. Increased caloric density formula may
also increase calorie intake. The goal is to deliver approximately
8 g/kg/day of fat to the child. The usefulness
of supplementing enteral feeds with branched chain amino acids remains
controversial. Whenever possible, oral feeding is preferred. For
those still encountering inadequate growth, supplementation may
be necessary, usually via initiation of nasogastric enteral tube feedings,
either as a replacement of or supplement to oral feeds. Nocturnal
drip feedings appear to be the best tolerated and can allow high caloric
intakes without the rise in serum ammonia that might be anticipated
with the increased protein intake. However, supplemental enteral feeds
do fail in many infants because of volume intolerance resulting from
ascites or organomegaly, with emesis, regurgitation, and increased
stool output often negating the expected benefits. Parenteral nutrition
should be instituted at the first signs of failure of enteral support,
and concurrently viewed as an opportunity to more easily address
free water, sodium, trace element, and vitamin deficiency requirements.
Although central venous catheter sepsis is always a concern, careful
training of caregivers can greatly decrease this risk. Early intervention
with occupational therapy and speech therapy will help address the
development of oral aversion and behavioral feeding problems that
occur in infants who receive limited oral intake.
++
Deficiencies of fat-soluble vitamins and minerals occur in patients
with chronic liver disease. Serum levels should be monitored periodically to
assess the need for supplementation. Vitamin E deficiency causes
mild hemolysis and neuroaxonal dystrophy. Less common manifestations include
myopathy, cardiomyopathy, and a pigmented retinopathy. Treatment
of vitamin E deficiency is best accomplished with use of D-alpha
tocopheryl polyethylene glycol-1000 succinate (TPGS), which enhances
absorption by the formation of mixed micelles (infants are treated
with 15–25 IU/kg/day). This form of vitamin
E may be mixed with other fat-soluble vitamins to enhance their
absorption as well. Vitamin E levels are monitored every 2 to 3
months to maintain serum vitamin E:lipid ratio (mg/g) at
a level of greater than 0.6 mg/g in infants and 0.8 mg/g
in older children.
++
Vitamin A deficiency is associated with night blindness, xerophthalmia,
and increased mortality when patients contract measles. Oral vitamin
K supplementation is indicated for those patients with a coagulopathy.
If inadequate, then intramuscular or intravenous vitamin K may be
required. Measurement of 25-OH vitamin D is best to assess vitamin
D sufficiency as levels of 1, 25 OH vitamin D may be normal despite
vitamin D deficiency. Vitamin D deficiency is treated with oral
vitamin D3 at a dosage of 3 to 10 times the Recommended
Daily Allowance (RDA) for age. Water-soluble vitamins and minerals
given as a multivitamin preparation are useful.3
++
The cause of pruritus in the setting of liver injury is unknown.
Current treatment strategies are based on the assumption that one
or more unspecified and unknown pruritogens induce itching and that
binding or eliminating these agents will alleviate symptoms. Cholestyramine,
an ion-exchange resin, is thought to bind agents in the gastrointestinal
tract that induce itching. Rifampicin inhibits bile acid uptake
by the hepatocyte, reduces intracellular bile acid concentrations,
and thus may inhibit release of an unidentified pruritogen. Opioid
antagonists such as naloxone have been noted to reduce the urge
to scratch, suggesting that an increase in opioid tone may be associated
with cholestasis and linked to pruritus. Biliary diversion is considered
only after these pharmaceutical measures have been found ineffective
or not tolerated. Intractable pruritus may be an indication for
liver transplantation.
++
Portal hypertension is defined as a portal pressure gradient
(portal vein to hepatic vein gradient) of above 10 to 12 mm Hg.
In healthy children, the portal pressure gradient rarely exceeds
7 mm Hg. Each of the causes of elevated portal pressure shares the
common mechanism of increased resistance to blood flow from the
visceral or splanchnic portal circulation to the right atrium. In
children, the location of this increased resistance and hence obstruction
of portal flow can be at the prehepatic/presinusoidal,
intrahepatic/sinusoidal, or postsinusoidal level (Table 425-1).
++
++
Clinical history should include search for possible exposure
to viral or toxic pathogens (including herbal remedies), historical
events preceding portal vein thrombosis (neonatal dehydration, systemic
infection, umbilical catheters, and phlebitis), and family history
of inherited metabolic disease or hypercoagulability (factor V mutation; protein
C, protein S, and antithrombin III deficiencies; as well as hyperviscosity
or polycythemia in infancy).
++
Physical examination findings suggesting underlying liver disease
(ascites, liver size and contour, nutritional status), hypersplenism
(spleen size, bruising), or hepatopulmonary syndrome (spider angiomas,
clubbing, cyanosis) contribute to diagnostic evaluation and therapeutic
planning. Imaging tests to confirm the presence of portal hypertension and
define the portal venous anatomy include both noninvasive and invasive
considerations, such as ultrasonography with Doppler exam, magnetic
resonance angiography or contrast-enhanced computed topography,
and ultimately mesenteric angiography. The role of upper gastrointestinal endoscopy
and liver biopsy requires consultation with a pediatric
hepatologist for assessment of risks versus benefits.4
++
The increased splanchnic venous pressures found in patients with cirrhosis
results in the engorgement of alternative venous drainage pathways
to return blood to the systemic venous system. This occurs at watershed
areas where the splanchic and systemic venous systems interdigitate
including the esophagus, anus, umbilicus and at various intra-abdominal
sites. These engorged veins are at risk for bleeding. Esophageal
variceal bleeding is one of the most life-threatening complications
seen in pediatric liver disease.5 Once varices
develop, the diameter of the varices, or the variceal wall tension,
is the main risk factor determining variceal rupture, which is directly
related to the portal pressure gradient. Signs and symptoms of variceal
bleeding include melena, hematemesis, hematochezia, dizziness, pallor,
and weakness. Patients and families must be educated to seek immediate
medical attention at the closest emergency room if any of these symptoms
or signs is observed.
++
Emergency therapy for acute variceal bleeding in children is
similar to that of adults, with aggressive management beginning with
cardiovascular resuscitation and knowledge of the range of pharmacologic,
endoscopic, and surgical therapies available.6 Initial
management includes cardiovascular stabilization of the child via
immediate placement of a large-bore intravenous cannula to allow
the rapid delivery of crystalloid or red blood cells. Many children
will also have thrombocytopenia secondary to hypersplenism, and
platelet transfusions are indicated. Clotting factor supplementation
can be considered, with recombinant factor VII, a potential option
when large fluid volumes are contraindicated.
++
Gastric lavage with saline via a nasogastric tube may be helpful
in determining the extent and duration of bleeding and to help clear the
stomach of blood to allow better visualization of the mucosa at the
time of endoscopy. Contraindications to gastric lavage include children
in whom the procedure may increase bleeding (intractable coagulopathy)
or induce esophageal perforation (recent sclerotherapy with possible
esophageal ulcerations). Coincident with resuscitation efforts,
the start of a bolus dose of a long-acting analog of somatostatin
called octreotide (1–5 ug/kg IV bolus up to 100
ug, followed by the use of continuous intravenous 1–2 ug/kg/hour
up to 25 ug/kg/hour infusion) aims to reduce splanchnic
blood flow by selective mesenteric vascular smooth muscle constriction,
without precipitating systemic vasoconstriction, thereby leading
to a decrease in portal venous inflow and a decrease in portal pressure.
++
Once hemodynamic stability is achieved, proceeding to endoscopic
evaluation is helpful to delineate a source of bleeding. Endoscopic variceal
band ligation is generally the preferred approach in the scenario
of persistent hemorrhage, with greater ease and safety in the setting
of a potentially obscured field at time of endoscopy. Sclerotherapy
remains the therapy available for those children (generally <
10 kg) who are too small in size to allow for insertion of the band ligation
device. In the child who continues to have uncontrollable bleeding,
balloon tamponade may be the only method that can stabilize the
patient until a more definitive surgical procedure can be undertaken,
such as an emergent portosystemic shunt surgery or the transjugular
intrahepatic portosystemic shunt (TIPS) procedure. Placement of
a Sengstaken-Blakemore tube, designed to balloon tamponade gastroesophageal variceal
bleeding, may be helpful, but can be safely left inflated only for
12 to 24 hours, and as such, can be viewed only as a temporizing measure.
While practice guidelines exist for acute, recurrent, and prevention
of variceal hemorrhages in adults,6 similar evidence-based
approaches for children with portal hypertension do not yet exist.4
++
Ascites is the pathologic accumulation of fluid in the peritoneal cavity.
In the child with chronic liver disease, the onset of ascites signifies
worsening of portal hypertension and hepatic insufficiency.
++
Ascitic fluid may be noninflammatory, chylous, or inflammatory (Table 425-2). In liver disease, the ascitic fluid is
a transudate that develops as a result of an increased portal venous
pressure, which results in increased intraluminal pressures in the mesenteric
capillaries and a resultant net fluid loss into the peritoneal cavity.
When hypoalbuminemia ensues, the decreased colloid osmotic pressure in
the capillary potentiates the net fluid losses into the peritoneal
cavity. Indeed, the formation of ascites is a continuous process because
of the constant replenishment of the intravascular volume as a result
of the body’s homeostatic mechanisms with sodium and water
retention that occurs in response to the systemic vasodilatation
present in end-stage liver disease. This vasodilatation leads to
a decrease in “effective” blood volume and to
activation of endogenous antinatriuretic and vasoconstrictive systems,
specifically the renin-angiotensin-aldosterone system and the sympathetic nervous
system, and circulating levels of vasopressin that lead to sodium
and water retention.
++
++
Significant volumes of ascites are easily detected on physical
examination. The abdominal flanks bulge with fluid, a fluid level
can be percussed, the umbilicus protrudes, and a fluid wave may
be detected. In addition, the liver and spleen may become ballotable
and, particularly in young children, inguinal hernias and hydroceles
may develop. Common findings on a plain film of the abdomen are
diffuse abdominal haziness, separation of bowel loops by fluid,
and medial displacement of the bowel. More subtle ascites are best
assessed by ultrasonography, which can detect small volumes of fluid,
as well as differentiating free from loculated ascitic fluid.
++
Development of ascites is a poor prognostic sign in children
with chronic liver disease, and predisposes to spontaneous bacterial
peritonitis. For this reason, a diagnostic peritoneal tap is indicated
in any child with end-stage liver disease and a non-specific clinical
deterioration. A diagnostic paracentesis in which 10 to 20 mL of
ascitic fluid is withdrawn can be safely performed even in patients
with coagulopathy. Ascitic fluid should be inspected visually, and
then sent for cell count, Gram stain and direct inoculation in blood
culture media at the bedside, glucose, LDH, triglycerides, albumin,
total protein, and amylase. Initiation of treatment with a non-nephrotoxic
broad-spectrum antibiotic is warranted following results of a cell
count with predominance of neutrophils, pending culture and sensitivity
results. An elevated ascitic fluid amylase indicates pancreatic
ascites or gut perforation. Ascites fluid in heart failure tends
to a high protein concentration. Urine leakage into the peritoneal
cavity can be differentiated from ascitic fluid by the high urea
concentration.
++
Given that sodium retention is one of the main mechanisms in
the development of ascites, a central goal of therapy is the attainment
of a negative sodium balance. Hence, sodium restriction and the
promotion of sodium excretion are the cornerstones of ascites management.7 This
is achieved by limiting sodium intake to 0.5 g/day or 1
to 2 mEq/kg/day and enhancing urinary sodium excretion
with diuretics. Severe water restriction is unnecessary unless there
is profound hyponatremia (< 125 mEq/L). The diet required
for severe sodium restriction is unpalatable for many patients and
may contribute to decrease in intake of more important nutrients.
Pharmacologic treatment, if needed, usually is begun with spironolactone
at a dose of 3 to 6 mg/kg/day divided two or three
times daily. Combination diuretic therapy may be utilized, with
the response monitored by measuring urinary sodium.
++
If refractory ascites develops leading to impaired enteral feedings
and diminished respiratory distress, the option of proceeding to
large-volume paracentesis should be approached with caution, given
complications including cardiovascular decompensation caused by
rapid fluid shifts, intraperitoneal infection, and hemorrhage. Surgical
reduction of portal pressure by portosystemic shunting poses challenges
with both maintenance of long-term patency as well as operative
morbidity and mortality in fragile pediatric patients who typically
have poor liver function. There is a very little reported experience
of the use of transjugular intrahepatic portosystemic shunt (TIPS),
a nonsurgical shunt that acts physiologically as a side-to-side
portocaval shunt, in children for the control of ascites. Such children
generally benefit more from timely liver transplantation.
+++
Spontaneous Bacterial Peritonitis
++
Spontaneous bacterial peritonitis (SBP) is defined as bacterial
infection of the ascitic fluid that occurs in the absence of a contiguous
source of infection such as an intestinal perforation or intra-abdominal
abscess. Early diagnosis is a key issue in the management of SBP.
An ascites polymorphonuclear (PMN) cell count of greater than 250/mm3 has
a sensitivity of 85% and a specificity of 93% for
a positive culture. Ascitic fluid must be inoculated directly into
blood culture vials to optimize the diagnostic yield. The most frequent
organisms isolated in children include gram-negative enteric flora
including Escherichia coli and Klebsiella,
as well as gram-positive cocci such as Streptococcus pneumoniae and
enterococci. Anaerobic infections are very rare. Initial antibiotic
therapy should be broad-spectrum until specific culture and sensitivity
results are available. Ampicillin and Cefotaxime are good first
considerations. Avoiding aminoglycosides is important because many
of these children may already have some renal compromise. Given
the high rate of recurrence of spontaneous bacterial peritonitis,
immunization with the pneumococcal antigen vaccine and initiation
of prophylactic trimethoprim-sulfamethoxazole are potentially useful.
+++
Hepatic Encephalopathy
++
Clinically evident encephalopathy in children with end-stage
liver disease appears to be less common compared with adults. However,
it is also possible that encephalopathy is underdiagnosed in children
because its more subtle manifestations are difficult to appreciate.
Further, there is no specific laboratory test that correlates well
with encephalopathy. Irritability and lethargy, two of the most
common signs, may be evident in any chronically ill child. Acute
changes in mental status in the child with end-stage liver disease
should prompt an investigation for occult gastrointestinal bleeding
(which increases ammonia production from blood in the intestinal lumen)
or an intracranial hemorrhage secondary to coagulopathy. Aggressive
diuretic therapy, concurrent infection (including SBP), and placement
of a portosystemic shunt may all precipitate the development of
encephalopathy. The main principle of management is to decrease gut-derived
nitrogen production by restricting dietary protein intake (to 1
g/kg/day during the early phase of encephalopathy),
evacuating blood from the gastrointestinal tract, and administering
oral lactulose (Older Children and Adolescents. Oral 40 to 90 mL/day
in divided doses to produce 2 to 3 soft stools/day. Infants. Oral.
2.5 to 10 mL/day in divided doses to achieve loose stools
and a stool pH < 5) or neomycin (50 to 100 mg/kg/day
divided into 3–4 doses) to reduce bacterial flora in the
bowel. Although oral lactulose is preferred, care must be taken
not to induce hypovolemia and electrolyte disturbances from increased
stool losses. Oral neomycin has some systemic absorption, which
has been associated with ototoxicity; therefore, extended use should
be avoided. Hypoglycemia should be corrected, and sufficient nonprotein
calories should be administered to prevent catabolism. Correction
of fluid and electrolyte imbalance and treatment of infection, hemorrhage,
seizures, and respiratory depression should be addressed proactively.
++
The hepatorenal syndrome (HRS) is defined as functional renal
failure in patients with severe liver disease, with clinical evidence
of oliguria (< 1 mg/kg/hour of urine output)
typically present.8 The diagnosis is supported
by a characteristic pattern of urine electrolyte abnormalities:
urine sodium of less than 10 mEQ/L, a fractional excretion
of sodium of less than 1%, and a urine-to-plasma creatinine
ratio of less than 10. Although these findings are not pathognomonic
for HRS and, in particular, do not differentiate hypovolemia from
HRS, they help to exclude unsuspected acute tubular necrosis (characterized
by an increased urine sodium and increased fractional excretion
of sodium), as well as other causes of intrinsic renal disease.
It is important not to rely solely on serum creatinine as an estimate
of the degree of renal impairment, given that children with poor
muscle mass may have a normal or even decreased serum creatinine
level in the setting of clinically overt renal failure. Other important
contributing factors to poor renal function, which must be excluded are
the effects of nephrotoxic drugs (particularly aminoglycosides and nonsteroidal
anti-inflammatory drugs). Of the childhood diseases that cause chronic
liver disease and have associated renal pathology, the most common
are hereditary tyrosinemia, Alagille syndrome, and polycystic liver-kidney
disease. HRS is best treated by timely liver transplantation, with
dialysis potentially being the mainstay of treatment while awaiting
organ availability. Complete recovery can be expected.
+++
Hepatopulmonary
Syndrome (Hps)
++
Hepatopulmonary syndrome (HPS) is associated with the triad of
hepatic dysfunction, hypoxemia, and intrapulmonary vascular dilatations,
characteristically occurring in children with long-standing liver
disease and portal hypertension. Progressive hypoxemia, which is
exacerbated by the supine position, is commonly seen on evaluation,
and does not correct with 100% oxygen, confirming the presence
of intrapulmonary shunts contributing to the alveolar perfusion
abnormalities. Abnormal extrapulmonary uptake of technetium-99m
macroaggregated albumin (MAA) after lung perfusion scanning or the
presence of early microbubble perfusion on echocardiography are
diagnostic and predictive of morbidity with general anesthesia or
liver transplantation.9 Present experience suggests
that these abnormalities are reversible following successful liver
transplantation.