Portal Hypertension

Introduction

Portal hypertension due to cirrhosis or pre- or posthepatic vascular events is a major cause of morbidity and mortality at all ages. Signs and symptoms of portal hypertension are primarily the result of decompression of elevated portal blood pressure through portosystemic collaterals. The major problems in children are bleeding varices, ascites and its complications (spontaneous bacterial peritonitis and hepatorenal syndrome), and malnutrition. Encephalopathy and portopulmonary hypertension, while important when they do occur, are seen less frequently in children. Splenomegaly with or without hypersplenism are common presenting features but rarely require specific intervention. Children with these conditions provide special challenges in understanding and management because of a predominance of congenital etiologies, combined with growth and developmental considerations.

Pathophysiology

In general, portal hypertension occurs when portal pressure rises above 10 mmHg, most often resulting from increased portal resistance, combined in some circumstances with increased portal blood flow. The physiological basis for maintenance of portal pressure is in accordance with Poiseuille’s law (or its analogue, Ohm’s law), where changes in portal pressure are proportional to alteration in blood flow and resistance. For example, in cirrhosis, there is initially an increase in intrahepatic resistance and then an increase in splanchnic blood flow which maintains or further increases portal pressure, giving rise to a hyperdynamic circulatory state, with increased cardiac and decreased splanchnic arteriolar tone, both of which further increase portal inflow. These dynamic vascular alterations are effected by humoral mediators, such as glucagon, prostaglandins, nitric oxide, and endothelium-derived relaxing factor, changes in intravascular volume, and alterations in adrenergic tone in the splanchnic system.

A full understanding of the effects of portal hypertension requires knowledge of the anatomy and physiology of the portal system in infants and children (Fig. 25.1). In fetal life the ductus venosus connects the umbilical vein and the inferior vena cava, and the umbilical vein joins the left branch of the portal vein, providing nutrient-/hormone-rich blood to the developing liver. Importantly, these may remain patent in some situations postnatally. In post-fetal life, portal capillaries originating in the mesentery of the intestine and spleen supply the portal vein with its nutrient-rich and hormone-rich blood supply. At the liver hilum, the portal vein divides to supply the right and left lobes of the liver, which then undergo a series of divisions supplying segments of the liver, terminating in small branches which pierce the limiting plate of the portal tract and enter the sinusoids through short channels. The partly oxygenated portal venous blood supplements the oxygenated hepatic arterial blood flow to give the liver unique protection against hypoxia.

Fig. 25.1
figure 1

The portal system and sites of portosystemic shunts in portal hypertension. A major consequence of portal hypertension is the development of collaterals between the portal venous system to the systemic circulation resulting in gastric and esophageal varices and other naturally occurring shunts from the splenic system, around the rectum, from the left renal vein, through the falciform ligament, and via the umbilical vein remnant into the inferior vena cava

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A major pathological effect of portal hypertension is the development of collaterals carrying blood from the portal venous system to the systemic circulation in the upper part of the stomach and esophagus, the rectum, and the falciform ligament and may drain into the inferior vena cava via the umbilical vein remnant or the left renal vein (Fig. 25.1). Absence or disconnection of the inferior vena cava and/or interruption to the azygos system, such as occurs in some cases of biliary atresia, may cause special concern. Similarly, in extrahepatic portal venous malformations, the splenic vein can be small or thrombosed. Only the submucosal collaterals, such as in the esophagus and stomach, and sometimes in other parts of the intestine, particularly from stoma and anastomotic sites, are associated with gastrointestinal bleeding. Portal hypertensive gastropathy, which is suggested by dilated mucosal veins and capillaries and mucosal congestion in the stomach, develops particularly in patients with cavernous transformation of the portal vein and may occur after esophageal variceal obliteration.

Causes of Portal Hypertension in Children (Table 25.1)

Portal hypertension may be derived from increased portal vascular resistance due to either extrahepatic (portal vein), posthepatic (hepatic vein), or intrahepatic block, where the block may be presinusoidal, sinusoidal, or postsinusoidal.

Extrahepatic portal venous obstruction, caused by a congenital thrombotic or atretic process or an acquired stenosis or thrombosis (most often in the context of portal vein anastomoses in liver transplantation), is an important cause of portal hypertension in children. Septic or traumatic umbilical vein injury from omphalitis and/or catheterization accounts for some cases, but most are idiopathic or perhaps a congenital malformation, where the portal vein is transformed into a cavernoma. The liver, while often small and underperfused, is histologically normal. Splenic vein or more diffuse portal system obstruction results in somewhat different hemodynamics, with an extensive collateral circulation involving a preponderance of gastric varices and sometimes ectopic varices involving paracholecystic, paracholedochal, and pancreaticoduodenal veins. Esophageal and/or gastric variceal bleeding is the most important clinical consequence, although, importantly, the occurrence of naturally occurring shunts may over time reduce the risk, usually by the second decade of life. Other features include hypersplenism with mild hemolytic anemia; easy bruising from thrombocytopenia; growth retardation, due to malabsorption, in turn due to failure of the enteropancreatic and enterohepatic circulation; and encephalopathy, due to shunting. Overt encephalopathy appears uncommon, except in the acquired forms, but subclinical signs including learning failure may occur. Although the liver may appear normal, reversible decompensation may be seen after an acute variceal hemorrhage, and functional compromise may develop in the long term.

Intrahepatic portal hypertension results from a range of presinusoidal, sinusoidal, and postsinusoidal causes of increased portal bed resistance within the liver:

  • Presinusoidal conditions, such as congenital hepatic fibrosis and nodular regenerative hyperplasia, do not result in impaired liver function. Congenital hepatic fibrosis is a developmental disorder that belongs to the family of hepatic ductal plate malformations and is characterized histologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts. Virtually all manifestations of the disease are related to portal hypertension—especially splenomegaly and varices—often with spontaneous gastrointestinal bleeding, presenting from early childhood into adult life. Liver biopsy is highly specific for the diagnosis.

  • Increased sinusoidal resistance and portal hypertension occur almost invariably in cases of cirrhosis in children. Cirrhosis is a chronic diffuse disease characterized by irreversible widespread hepatic fibrosis with regenerative nodule formation. The prominent fibrous tissue contains vascular anastomoses, which cause hemodynamic alterations and portosystemic shunting. This diffuse pathology superimposes on the primary liver disease often obscuring the nature of the original insult. The major clinical consequences are the result of both impaired hepatic function and portal hypertension. Progression to cirrhosis and portal hypertension in pediatric liver diseases is highly variable and an important consideration in management. In some conditions, such as neonatal extrahepatic biliary atresia, the development of portal hypertension can be extraordinarily rapid, occurring by 12–16 weeks of age. Other conditions, such as cystic fibrosis-associated focal biliary cirrhosis, can be compatible with normal liver function for many years, presenting with signs of portal hypertension in the second decade of life.

  • Postsinusoidal intrahepatic conditions, such as sinusoidal-obstruction syndrome (veno-occlusive disease), are rare, most often occurring in the context of chemotherapy for childhood cancers or occasionally related to toxin ingestion, e.g., bush teas.

Posthepatic portal hypertension (Table 25.1) due to obstruction to hepatic venous outflow can occur after liver transplantation (hepatic vein stenosis), as an acute hepatic vein thrombosis (Budd–Chiari syndrome), or due to cardiac lesions resulting in increased right atrial pressure and/or chronic systemic venous hypertension. Budd–Chiari syndrome is rare and may occur with some thrombophilic disorders but is usually idiopathic. Of note are the effects of a Fontan procedure, a cavo- or atrio-pulmonary shunt which allows lifesaving systemic to pulmonary blood flow for single-ventricle syndromes in neonates but results in chronic systemic venous hypertension (pressures may be >20 mmHg) and eventually portal hypertension, commonly with protein-losing enteropathy.

Table 25.1 Causes of portal hypertension in children
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Clinical Features (Table 25.2)

Table 25.2 Clinical features of portal hypertension in children
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The main clinical features of portal hypertension are splenomegaly; the occurrence of esophageal, gastric, and rectal varices; ascites and hepatorenal syndrome; nutritional growth failure; and encephalopathy. Note that splenomegaly is not present in splenic malformation syndromes and temporarily absent during acute variceal bleeding.

In extrahepatic portal hypertension, or when there is compensated liver disease, there may be no symptoms. The first indication of portal hypertension may be a gastrointestinal bleed, an incidental finding of splenomegaly, or anemia and thrombocytopenia due to hypersplenism. Commonly the liver is small and impalpable, but if due to an intrahepatic cause, it can be enlarged, hard, or nodular with palpable splenomegaly. Cutaneous features such as spider angiomata, prominent periumbilical veins (caput medusae), and palmar erythema may provide a clue. Spider angiomata may occur in healthy children under the age of 5 years and are thus not pathognomonic, but the appearance of new spiders or more than five or six may be indicative of portal hypertension. They are frequently observed in the distribution of vascular drainage of the superior vena cava and feature a central arteriole from which radiates numerous fine vessels, ranging from 2 to 5 mm in diameter. Other cutaneous features include easy bruising; fine telangiectasia on the face and upper back, white spots, most often on buttocks and arms, which when examined with a lens show the beginnings of spider angiomata; and clubbing of the fingers. On intranasal examination, prominent telangiectasia of Little’s area (in the anteroinferior part of the nasal septum where four arteries come together to form a vascular plexus) is common, associated with recurrent epistaxis. Decompensated liver disease is characterized by clinical and laboratory findings of liver synthetic failure including coagulopathy, commonly with other features including ascites and peripheral edema. Signs of hepatic encephalopathy may be subtle in children with portal hypertension. Malnutrition with reduced lean tissue and fat stores as well as poor linear growth is a well-recognized and important feature due to malabsorption and impaired protein synthesis. Portal hypertension may also be associated with changes in the systemic and pulmonary circulations, with arteriolar vasodilatation, increased blood volume, a hyperdynamic circulatory state, clubbing, and cyanosis due to intrapulmonary shunting. Renal failure is a late but serious event.

Diagnosis

While measurement of the hepatic venous pressure gradient (HVPG) is currently the best available method to evaluate the presence and severity of portal hypertension, defined as an HVPG to ≥10 mmHg, the clinical utility of HVPG measurements in managing children with portal hypertension is yet to be determined. In adults, HVPG measurements are increasingly being used for diagnosis, risk stratification, and monitoring of the efficacy of medical treatment. In the meantime, in children, confirmation of the diagnosis of portal hypertension is based on the suggestive clinical findings detailed above with or without signs of chronic liver disease and on four investigations: ultrasonography, endoscopy, liver biopsy, and angiography.

Ultrasonography with Doppler allows visualization and measurement of the size, patency, and flow of the portal vein, the occurrence of splenomegaly or a cavernoma, and information about liver size, hepatic homogeneity, and blood flow. Echocardiography is useful to exclude primary cardiac causes of hepatic venous outflow obstruction, when suspected.

Endoscopy can be performed to evaluate the presence and size of varices and the occurrence of cherry red spots (which correlate with risk of rupture) and visualize and perhaps treat the source of bleeding varices when occurring. Other features such as portal gastropathy and exclusion of other sources of GI bleeding can be visualized.

Liver biopsy either excludes liver disease, in the case of extrahepatic obstruction, or aids in the diagnosis of intrahepatic or prehepatic causes of portal hypertension. Notably, a full range of laboratory and imaging investigations should be performed prior to performing a liver biopsy to inform handling of the liver biopsy specimen with respect to specific histological and biochemical analyses. Differentiation between cirrhosis, presinusoidal, and extrahepatic causes of portal hypertension can sometimes be difficult. In presinusoidal and extrahepatic conditions, there are no signs of chronic liver disease, and transaminases and synthetic function are typically normal. In congenital hepatic fibrosis, for instance, the liver is enlarged and hard, but histologically hepatocytes are normal with prominent abnormal bile ducts in wide bands of fibrous tissue, but no nodules. In extrahepatic portal hypertension, the liver may be small but is histologically normal, although some steatosis may be evident. In contrast, obstruction to hepatic venous outflow causes centrilobular hemorrhagic necrosis with fibrosis extending from central veins to portal tracts.

Angiography, either with direct venography, MR angiography, or CT angiography, can provide important information about the site of block, the size of the liver and spleen, direction of blood flow and patency of major veins in the portal system, and relationship to the coronary, esophageal, or other varices. Suspected obstruction to hepatic venous outflow requires venography and/or cardiac catheterization which are the diagnostic procedures of choice in such cases. Pressure gradient measurements may be useful across venous blocks and to determine the magnitude of the portal pressure.

Management of Portal Hypertension

There are pharmacological, endoscopic, and/or surgical means of controlling portal pressure, which might be indicated in certain circumstances, as a bridge to transplant or as an adjunct to therapies directed at the major complications, but predominantly, therapy of portal hypertension is directed at the major complications, i.e., the prevention and/or management of variceal hemorrhage, ascites, hepatorenal syndrome, and encephalopathy (see individual sections). In cases of end-stage liver disease, liver transplantation is the primary therapy. In cases of hepatic venous outflow block, directly treatable causes, such as vena caval webs, tumors causing obstruction, or constrictive pericarditis, need to be considered. Hypersplenism, while common, rarely results in morbidity or mortality.

Pharmacological therapy is directed towards reduction of splanchnic blood flow, with the added benefit of increasing renal blood flow (Table 25.3). In acute situations, e.g., GI bleeding, somatostatin and its longer-acting analogue octreotide (maximum dose 1 mg/kg/h i.v. or 2–4 mg/kg/dose subcutaneously 8-hourly) have fewer side effects and are the drugs of choice over other splanchnic vasoconstrictors, e.g., vasopressin, (0.3 U/kg bolus over 20 min, then continuous infusion of 0.3 U/kg/h, usually for 24 h or until the bleeding has ceased, or its inactive precursor terlipressin, 0.01 mg/kg bolus 4- to 6-hourly or 0.05 mg/kg infusion over 6 h for 24–48 h). Side effects include skin pallor, abdominal colic, and chest pain. Adjunctive vasodilators, such as nitroglycerine in the form of a 10-mg patch, may reduce these effects, although are rarely required in children. Long-acting vasoactive drugs, e.g., beta-blockers (propranolol and the more selective atenolol), at high enough doses may reduce hepatic arterial and portal vein blood flow and portal pressures to <12 mmHg, suggesting a benefit for both primary and secondary prophylaxis against GI bleeding. In adults, a combination of a nonselective beta-blocker and certain nitrates (e.g., isosorbide 5-mononitrate) or combined alpha- and beta-blockade is the drug of choice, aiming at a 25 % reduction in resting heart rate. Their use in children with portal hypertension remains unstudied, however, and concern exists with their use for young children whose main mechanism of compensation to acute hemorrhage is to increase cardiac output by increasing the heart rate. When used, major adverse effects include reactive airway disease and heart block, where they are contraindicated.

Table 25.3 Pharmacotherapy in portal hypertension
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Endoscopic management of portal hypertension is directed at the treatment of variceal hemorrhage which clinically presents either as a need for emergency therapy or as a need for prophylaxis of initial or subsequent rebleeding. Episodes of minor variceal hemorrhage may spontaneously terminate, but endoscopic treatment of acute variceal bleeding by sclerotherapy or band ligation is indicated for continued bleeding after initial resuscitation and coagulation is achieved. In recognized cases of portal hypertension with varices which have not yet bled, controversy exists as to whether any therapy reduces the risk or prevents the occurrence of gastrointestinal bleeding. However, in all cases, it is reasonable to be prepared for the possibility by ensuring that the child’s caregivers understand the importance of seeking early medical advice by attending the nearest hospital for blood crossmatching and appropriate referral to a tertiary unit. There may be a case under certain circumstances (e.g., distance from tertiary center) for prophylactic endoscopic therapy, but the potential for bleeding of known varices which have never bled in children is conjectural. One controlled clinical trial in children found a reduced risk of bleeding, but an increase in portal gastropathy. Where bleeding has occurred, rebleeding risk is reduced by direct obliteration of the varices usually over 2–3 sessions, although consideration of the underlying liver disease is the major determinant of long-term management. Randomized controlled trials in adults have shown a reduction in the frequency of bleeding and improved survival. Although no randomized controlled trials have been performed in children, several large studies of sclerotherapy or banding in children with portal hypertension indicate that these procedures are safe and they reduce the chance of rebleeding.

Banding involves isolation and entrapment of a varix by suction and then applying a band ligature, using a special device attached to the endoscope. Sclerotherapy involves injection of sclerosant (ethanolamine, or tetradecyl sulfate) either para- or intravariceally, in volumes of 0.5–1.0 ml. Injecting or banding too high above the cardia can increase bleeding from a distal varix. Neither technique immediately reduces portal pressure, but they do reduce risk. With obliteration of varices, hypersplenism and portal gastropathy temporarily get worse, but ultimately with time, spontaneous portosystemic shunts can arise reducing portal pressures. Adult comparative trials of sclerotherapy vs ligation indicate equal efficacy in controlling bleeding, reducing rebleeding, and ablating varices but fewer adverse effects with banding. Both techniques are well described in children, and in general, they are complimentary; thus access to both is warranted. Band ligation may be technically difficult for small bleeding varices, particularly in infants, where band entrapment of part of the esophageal wall with perforation or bleeding can occur. In these circumstances, sclerotherapy is more appropriate. Broad-spectrum antibiotics should be prescribed (amoxicillin, cefuroxime, and metronidazole). Complications of both banding and sclerotherapy include bleeding, esophageal ulceration, perforation (mainly with banding in small children), stricture, and pain.

Surgical management of portal hypertension is a major consideration for those in whom medical therapies have failed or as acute lifesaving maneuvers. As there are various options (Table 25.4), those with primary liver disease should be evaluated and treated in a transplant center, where the range of surgical options, including liver transplantation, can be assessed. In critically ill patients with intrahepatic causes of portal hypertension, the use of a TIPS (transjugular intrahepatic portosystemic shunt) as a bridging procedure to liver transplant is the procedure of choice. A TIPS decompresses the high pressures in the portal circulation by placing a small stent between a portal and hepatic vein. As for all portosystemic shunts, one of the main complications of TIPS is hyperammonemia, with the potential for encephalopathy. Surgical portosystemic shunts may reduce the risk of gastrointestinal bleeding but decrease portal blood flow, decrease hepatic perfusion, and carry the risk of hepatic decompensation and hepatic encephalopathy, precluding or enhancing difficulty with liver transplantation. For those with preserved hepatic function who do not need transplant, e.g., patients with congenital hepatic fibrosis or extrahepatic portal hypertension, and some with CF liver disease, the choice of the type of shunt is determined by the vascular anatomy, the size of the veins, the risk of thrombosis and failure, and the risk of encephalopathy. Mesocaval shunts and the more selective distal splenorenal shunt have been the procedures of choice in the past, though a central splenorenal shunt with splenectomy is sometimes advocated if there is massive hypersplenism and pain from splenic infarcts. These shunts may not be technically possible; however, because of thrombotic involvement of splenic or mesenteric veins and particularly where varices are derived from a cavernoma, these shunts may not alter variceal pressures in the coronary esophageal veins. The Rex shunt, usually an internal jugular vein graft mesenterico-left portal vein bypass, has the advantage of restoring portal flow to the liver, reducing risk of encephalopathy, and it obviates technical problems associated with splenic vein thrombosis. First introduced for portal vein thrombosis after liver transplant, this procedure may become the surgical procedure of choice for all causes of extrahepatic portal vein obstruction. In the rare cases of an obstructed hepatic venous outflow, vena caval webs, etc. can be anatomically repaired. In unusual circumstances, a Sugiura procedure (esophageal disconnection/devascularization procedure) may be lifesaving, with the added advantage of a low risk of encephalopathy. Finally, although splenectomy is sometimes considered for treatment of hypersplenism, it is usually not indicated, as it rarely results in any morbidity or mortality.

Table 25.4 Surgical options for portal hypertension
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Ascites

Extravascular fluid accumulation, manifest predominantly in the peritoneal cavity as ascites and sometimes accompanied by peripheral edema or pleural effusions, is a common complication of portal hypertension and a sign of advanced liver disease. Ascites poses an increased risk for infections, particularly spontaneous bacterial peritonitis (SBP), as well as hepatorenal syndrome, and is typically a predictor of the need for liver transplantation in those with chronic liver disease.

Clinical Features

Clinical signs include pitting-dependent and facial edema, abdominal distension, and/or the development of hernias. Patients with gross or refractory ascites may have breathing difficulties, abdominal pain, or limitation of movement. There is shifting dullness on abdominal percussion. Abdominal ultrasonography may confirm clinical suspicion. Renal and circulatory dysfunction manifest as dilutional hyponatremia, low arterial blood pressure, low serum albumin, serum creatinine >1.2 mg/dl, and sodium retention (urine sodium less than 10 mEq/day or a urine sodium > urine potassium) may occur.

Pathophysiology

The two important factors in extravascular fluid accumulation are high portal venous pressure and low plasma oncotic pressure, both of which interact to result in fluid redistribution between intra- and extravascular spaces. Ascites represents a breakdown of intravascular volume homeostasis, which is controlled by capillary hydrostatic pressure and plasma colloid osmotic pressure, with sodium retention and decreased effective plasma volume. It may develop insidiously, e.g., in cirrhosis, particularly if malnourished, occur acutely after vascular events such as Budd–Chiari syndrome or portal vein thrombosis, or be precipitated by events such as gastrointestinal bleeding or infection.

Three related models explain the formation of ascites:

  • The underfilling model suggests that there is increased sinusoidal pressure leading to a cascade of events resulting in fluid retention from elevated portal venous pressure, increased splanchnic volume, decreased systemic vascular resistance, and decreased effective plasma volume. Resultant activation of the plasma renin–angiotensin–aldosterone system causes avid renal retention of sodium and water, leading to the accumulation of fluid. Low intravascular oncotic pressure and increased resistance to splanchnic venous outflow result in the accumulation of ascites This is supported by the fact that expansion of the plasma volume by albumin infusion commonly reverses ascites, decreases levels of renin and aldosterone, and results in a diuresis.

  • The peripheral arterial vasodilation model suggests that, in cirrhosis, peripheral arterial vasodilation is the initiating event in ascites formation. Sodium retention is the consequence of a homeostatic response similar to the underfilling model, with underfilling of the arterial circulation secondary to arterial vasodilatation in the splanchnic vascular bed. This underfilling is sensed by arterial and cardiopulmonary receptors and activates antinatriuretic factors, resulting in hypervolemia. The retained fluid initially compensates for the disturbance in the arterial circulation and suppresses the activation of sodium-retaining mechanisms. However, as the vasodilatation in the splanchnic circulation causes more marked arterial underfilling, the retained fluid does not fill the intravascular compartment adequately. Because fluid is leaking continuously into the peritoneal cavity, the sodium-retaining mechanisms become permanently activated. This theory is supported by the fact that patients with chronic liver disease are prone to the development of arteriovenous connections, implying the presence of vasoactive hormones known to be associated with peripheral vasodilatation and renal sodium retention.

  • The overflow model suggests that inappropriate renal sodium and water retention is the primary abnormality triggered by a possible hepatorenal reflex. This is supported by animal models but is mitigated by the observation that the renin–angiotensin–aldosterone system is activated in decompensated cirrhosis. These systems should be suppressed and not activated with sodium retention and volume expansion.

    These models are not necessarily mutually exclusive. Early overflow secondary to renal sodium retention may be the initiating factor, but later, diminished effective plasma volume with its accompanying hormonal changes may predominate, leading to peripheral arterial vasodilatation and further increase in sodium and water retention.

Management of Ascites (Box 25.1)

In the majority of patients, limitation of sodium ingestion, judicious use of diuretics (to increase sodium and water excretion by reducing the tubular reabsorption of sodium), and maintenance of plasma oncotic pressure (by albumin infusions) will control ascites. Reduction of fluid intake and salt restriction to reduce ascites is commonly prescribed in adults, but in children, this may have deleterious effects on growth and should be balanced by an increase in calorie content of feeds. Preferred diuretics include an aldosterone antagonist, and, if necessary, an adjunctive thiazide. The response to diuretic therapy should be evaluated by measuring body weight, urine volume, serum electrolytes, and blood urea nitrogen and sodium excretion. The initial goal of treatment is a negative fluid balance of ~10 ml/kg/day. Higher negative balances risk plasma volume depletion and decline in renal function, which may be preempted by albumin infusion. The response to spironolactone is so reliable that the plasma volume status of the patient should be investigated if no significant diuresis is achieved within 2–4 days. Loop diuretics, e.g., furosemide 1 mg/kg, are effective in conjunction with albumin infusions, but are not recommended for chronic use alone, as electrolyte and plasma volume depletion can result in prerenal failure, encephalopathy, and arrhythmias. Rarely, patients either do not respond to diuretic therapy or have diuretic-induced complications that prevent the use of high doses of these drugs.

Those with symptomatic gross ascites may require paracentesis, but this is rarely required in the treatment of children, except where there is respiratory compromise and/or abdominal compartment syndrome. Diagnostic paracentesis is indicated for unexplained fevers and suspected SBP (protein concentration <20 g/l, leukocytosis) and in the diagnosis of Budd–Chiari syndrome where an acute onset of ascites is associated with protein concentrations >20 g/l.

Box 25.1. Management of Ascites

  • Mild ascites with no discomfort or difficulties with mobility or breathing requires no specific investigation or treatment in most cases

  • Lab tests include liver panel, albumin electrolytes, creatinine, BUN, and urine Na/K

  • Monitor weight, fluid balance, and BP if low albumin

  • Nutritional support, with maintenance of adequate protein homeostasis, is important. Note: fluid/salt restriction not usually necessary in children (–>deleterious effects on nutrition). Avoid Xs dietary sodium >2–3 mmol/kg

  • Diuretics: start an aldosterone antagonist +/− a thiazide diuretic, e.g., spironolactone 3 mg/kg bid up to 6 mg/kg <10 years and 100–200 mg bid up to 600 mg >10 years, aldactizide 12.5 mg qid <3 years, 50 mgqid >3 years, or furosemide (dose ratio spironolactone to furosemide 10:2, i.e., 0.6–1.2 mg/kg/day). Side effects: hyponatremia, hyperkalemia. Note: furosemide alone is not recommended for chronic use, as electrolyte and plasma volume depletion can –> prerenal failure, encephalopathy, and arrhythmias

  • The goal of diuretic treatment is a negative fluid balance of ~10 ml/kg/day initially. Spironolactone takes 2–4 days to take effect. A urine Na> K or urine Na >15 mmol/day indicates a response. If diuresis occurs at a faster rate, there is risk of plasma volume depletion –> prerenal failure

  • Maintenance of effective plasma volume by albumin infusions 2 g/kg + furosemide 2 mg/kg repeated as necessary for albumin <2.0

  • Paracentesis: indicated for gross tense ascites –> breathing/renal difficulties (see below) or for diagnosis of unexplained fevers, e.g., spontaneous bacterial peritonitis (protein >20 g/l, leukocytosis) and in Budd–Chiari syndrome (protein <20 g/l)

  • Large volume paracentesis, combined with albumin infusions (1 g/100 ml tapped), is the preferred intervention for refractory symptomatic ascites, based on controlled trials demonstrating relative safety and efficacy. Continuous drainage is not encouraged due to risk of bacterial peritonitis

  • In severe refractory or recurrent cases, where portal hypertension is also an issue, a transjugular intrahepatic portosystemic shunt (TIPS) temporarily decreases portal pressure, decompresses the liver and reduces sinusoidal and splanchnic pressure, and can act as a bridge to transplant

  • In chronic liver disease, the only treatment of proven value for improved long-term survival is liver transplantation

  • Refractory ascites in adults has been treated with peritoneal venous shunts (Leveen or Denver), which permit flow of ascitic fluid into the venous system causing resolution of ascites and improved urinary output, but coagulopathy, infection, and cardiac failure may develop due to the shunt. Their use has not been reported in children

Spontaneous Bacterial Peritonitis

SBP is a relatively common and a potentially fatal complication of ascites in children. The condition should always be suspected in a patient with ascites and concurrent fever, abdominal pain, or neutrophilia.

Pathophysiology and Microbiology

Bacterial infections are common in chronic liver disease and may precipitate other complications, such as encephalopathy, ascites, and hepatorenal syndrome. Immune deficits associated with chronic liver disease include abnormalities of complement fixation and opsonization, impaired function of Kupffer cells, neutropenia, and alterations in mucosal barriers, particularly the gastrointestinal tract. Portal hypertension makes patients susceptible to bacteremia and SBP, perhaps by inducing bacterial translocation of the gut in the setting of impaired immunity.

Specific risk factors for SBP are ascites, low serum albumin, gastrointestinal bleeding, intensive care unit admission for any cause, and recent therapeutic endoscopy.

Characteristically, spontaneous bacterial peritonitis in children is caused by a single species, often enteric bacteria such as Klebsiella spp., E. coli, and Enterococcus, although Streptococcus pneumoniae predominate. The presence of multiple species suggests the possibility of bowel perforation and secondary peritonitis. Culture-negative neutrocytic ascites (probable SBP) is not uncommon (the ascitic fluid culture results are negative, but the PMN count is 250 cells/μl or higher).

Prevention

In those patients with ascites, efforts to prevent and/or make a timely diagnosis of SBP are an important consideration, given the gravity of this complication. Appropriate management of ascites may minimize the risk. There is no evidence to suggest benefit from prophylactic antimicrobials, but preventative measures such as pneumococcal and Haemophilus influenzae vaccination, prophylactic antibiotics for invasive procedures, and nutritional support may reduce the risk of specific infection.

Clinical Features and Diagnosis

A high index of suspicion must be maintained when caring for patients with ascites. Common signs include rapid abdominal distension, fever, vomiting, and diarrhea. Examination may reveal abdominal tenderness with rebound and decreased or absent bowel sounds. Occasionally, SBP may be relatively asymptomatic except for fever.

The diagnosis is established by abdominal paracentesis, which reveals cloudy fluid with a neutrophil leukocyte count of >250/mm. A lactate level of >25 mg/dl in combination with an ascites fluid pH <7.35 is adjunctive evidence. There may be a low protein concentration <20 g/l (as distinct from secondary peritonitis due to intestinal perforation, where protein concentrations are higher). The use of reagent strips that detect leukocyte esterase, which correlates well with laboratory polymorphonuclear leukocyte counts, leads to more rapid diagnosis.

Management: While the final choice of antibiotics is dictated best by the bacteriology, early institution of therapy with a third-generation cephalosporin, such as intravenous cefotaxime, is recommended for 14 days. A randomized controlled trial found that supplemental intravenous albumin infusions, to support intravascular volume, can reduce renal impairment. Antimicrobial prophylaxis against this disorder has not been subjected to definitive trials, but clinical experience suggests that prevention may be achieved by the use of antibiotics during invasive procedures (as above) and, in cases of recurrent SBP, a prophylactic oral antibiotic such as cotrimoxazole, ciprofloxacin, or norfloxacin.

Hepatorenal Syndrome

This syndrome is a functional progressive renal failure of unknown cause occurring in patients with severe liver disease. It is a serious complication of cirrhosis and carries a poor prognosis, unless reversed or transplantation intervenes. It may be either rapidly or slowly progressive (type I and II, respectively). Clinically, there is often a progression from ascites, through diuretic-resistant ascites, to hepatorenal syndrome.

Pathophysiology

While the pathogenesis is not fully understood, reduced renal cortical blood flow is central to the pathogenesis. There is also increased splanchnic blood pooling from portal hypertension, further decreasing renal blood flow, possibly related to upregulated endothelial nitric oxide (NO) synthase. Renal vasoconstriction may also contribute due to increased production of thromboxane, a potent vasoconstrictor, and a decrease in prostaglandin E2, a dilatory metabolite. A high incidence of glomerulosclerosis and membranoproliferative glomerulonephritis has been documented in children with end-stage liver disease at the time of liver transplant probably secondary to the chronic reduction in renal cortical blood flow. In addition to this, it has been observed that the administration of medications to counteract splanchnic vasodilation (e.g., octreotide) leads to improvement in glomerular filtration rate in patients with hepatorenal syndrome, providing further evidence that splanchnic vasodilation is important in pathogenesis. Reduced renal cortical blood flow also involves activation of the renin–angiotensin–aldosterone system, which leads to an increase in absorption of sodium from the renal tubule and is relevant to the pathogenesis of ascites. This suggests that there is a spectrum of progression from ascites to hepatorenal syndrome where splanchnic vasodilation defines both resistance to diuretic medications and the ascites (which is commonly seen in type 2 HRS) and the onset of reduced cortical blood flow leading to hepatorenal syndrome. Thus, efforts to increase glomerular filtration and renal blood flow and decrease splanchnic pooling form the basis of current approaches to supportive medical therapy.

Clinical Features and Diagnosis

Acute renal failure in children with liver disease may be due to primary renal disease, prerenal failure, acute tubular necrosis, or hepatorenal syndrome. The combination of liver failure and its associated circulatory abnormalities, refractory ascites, oliguria, and rising serum creatinine are suggestive of the diagnosis, although some patients with hepatorenal syndrome have a normal urine output. In some, there may be an added component of compartment syndrome related to tense refractory ascites.

Diagnosis of hepatorenal syndrome is typically based on altered laboratory tests and exclusion of primary renal disease and prerenal failure (Table 25.5). In addition, the rate of onset, clinical picture, and urinary indices, such as urinary sodium and creatinine concentrations, and serum creatinine level may help to distinguish prerenal and types I and II hepatorenal syndrome. In type I, the onset is acute, precipitated by gastrointestinal hemorrhage, aggressive diuresis, or an associated deterioration of liver function. It is associated with oliguria, uremia, hyperkalemia, hyponatremia, and a low urinary sodium concentration (<10 mmol/l). Initial serum creatinine levels double in less than a week. These features are similar to prerenal failure, which responds to an acute volume expansion or acute tubular necrosis, where tubular casts and high urinary sodium (>30 mmol/l) are found. Plasma volume expansion alone does not improve renal function in hepatorenal syndrome. Type II is characterized by a slower development of oliguric renal failure with a marked reduction in glomerular filtration rate and hyponatremia, again with a low urinary sodium concentration. Specifically, the production of ascites that is resistant to the use of diuretic medications is characteristic of type II HRS. Serial measurement of urinary sodium concentration and urinary osmolarity helps distinguish the condition of acute tubular necrosis, where the urinary sodium concentration may rise and the urine osmolarity is usually equal to plasma osmolarity. These measurements are unreliable if the patient is on diuretics, particularly furosemide.

Table 25.5 Features of hepatorenal syndrome
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Prevention

Specific precautions should be undertaken to prevent or identify and treat those at risk for HRS. Some of the triggers for HRS are induced by inappropriate treatment of ascites. The aggressive use of diuretic medications without colloid volume expansion should be avoided. Reduced renal blood flow associated with hypoalbuminemia should be minimized with colloid volume expansion. In those with refractory tense ascites, HRS can be induced by a compartment syndrome due to the pressure on the renal veins, and paracentesis (with appropriate volume expansion) may improve renal function. However, paracentesis without volume expansion can cause circulatory changes and precipitate HRS. In addition, nephrotoxic medications that are used either to treat complications (such as some antibiotics and antifungals) or other conditions may cause sufficient impairment in renal function in the cirrhotic patient to lead to HRS. Surveillance for and aggressive management of other triggers including hypovolemia, SBP, and gastrointestinal hemorrhage are advised.

Management

Renal failure is a serious problem in the setting of severe liver disease, but HRS is effectively reversed by liver transplantation. However, a liver is often not available in a timely manner in those who are candidates for transplantation. Acute oliguric renal failure should initially be managed with volume expansion as a diagnostic therapy as mentioned above. Once the diagnosis of HRS is realized, temporary improvement in renal function is possible with the use volume expansion in conjunction with splanchnic vasocontrictors. Thus, colloid volume expansion with regular albumin infusions (1–2 g/kg/day) in combinations with a splanchnic vasocontrictor by continuous infusion (octreotide, 3–5 mg/kg/day) or vasopressin analogues (terlipressin (0.04 mg/kg/day)) is recommended. There is evidence to suggest that a combination of midodrine and octreotide, respectively, a systemic vasoconstrictor and an inhibitor of splanchnic vasodilation, has advantages over the use of octreotide alone. Tense ascites should be relieved by paracentesis with colloid volume expansion. In refractory cases, particularly those with extreme fluid overload, renal replacement therapy may bridge individuals with hepatorenal syndrome to liver transplantation, although the condition of the patient may dictate the modality used. In selected refractory cases of HPS, in particular those with gastrointestinal bleeding, a TIPS may help reverse the hemodynamic component of the hepatorenal syndrome and improve renal function. Liver transplantation is tolerated reasonably well in patients with hepatorenal syndrome, and the HRS improves posttransplantation. The preexisting glomerular abnormalities and the posttransplant nephrotoxic effects of calcineurin inhibitors, however, may partly explain the high rates of renal dysfunction posttransplant (Table 25.6).

Table 25.6 Summary of management of hepatorenal syndrome
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