Chapter 6 – Portal Hypertension in Children




Abstract




A portal system is one, which by definition, begins and ends with capillaries. The major portal system in humans is one in which the capillaries originate in the mesentery of the intestines and spleen and end in the hepatic sinusoids. Capillaries of the superior mesenteric and splenic veins supply the portal vein with a nutrient- and hormone-rich blood supply. The partially oxygenated portal venous blood supplements the oxygenated hepatic arterial flow to give the liver unique protection against hypoxia. Blood flow from the hepatic artery and portal vein is well coordinated to maintain consistent flow and explains the ability of the liver to withstand thrombosis of either of these major vascular structures. This well-regulated blood flow in conjunction with the very low resistance found in the portal system results in a low baseline portal pressure in healthy individuals.





Chapter 6 Portal Hypertension in Children



Benjamin L. Shneider



Introduction


A portal system is one, which by definition, begins and ends with capillaries. The major portal system in humans is one in which the capillaries originate in the mesentery of the intestines and spleen and end in the hepatic sinusoids. Capillaries of the superior mesenteric and splenic veins supply the portal vein with a nutrient- and hormone-rich blood supply. The partially oxygenated portal venous blood supplements the oxygenated hepatic arterial flow to give the liver unique protection against hypoxia. Blood flow from the hepatic artery and portal vein is well coordinated to maintain consistent flow and explains the ability of the liver to withstand thrombosis of either of these major vascular structures. This well-regulated blood flow in conjunction with the very low resistance found in the portal system results in a low baseline portal pressure in healthy individuals.


Portal hypertension, defined as an elevation of portal blood pressure above 5 mm Hg, is one of the major causes of morbidity and mortality in children with liver disease. The high prevalence of cholangiopathies and cholestatic disease in pediatric liver disorders (e.g., biliary atresia), as compared with adult liver disorders, predisposes to the expression of portal hypertension earlier in the clinical course of liver disease relative to the manifestation of the sequelae of hepatic insufficiency. Portal hypertension is a complication in a wide variety of pediatric liver disorders (Table 6.1). Its complications are some of the leading indications for liver transplantation. Systematic investigations of the pathophysiology and treatment of portal hypertension have been performed primarily in adults. Since the previous edition of this chapter, there has been a continued growth in the investigation of portal hypertension in children. A PubMed search of pediatric portal hypertension reveals a dramatic increase in publications between 2012 and 2019, recent examples of which represent a spectrum of areas of investigation [15]. As before, caution needs to be exercised in the extrapolation of the results of randomized trials in adults to the care of children. Current approaches to the care of children with portal hypertension appear to be variable and are in large part adapted from experience in adults to meet the needs of children [6].




Table 6.1 Pediatric Diseases Associated with Portal Hypertension






















Anatomic level Disorder
Extrahepatic disorders

Venous obstruction


Splenic vein thrombosis


Portal vein thrombosis/cavernous transformation


Budd–Chiari syndrome


Inferior vena cava obstruction

Intrahepatic disorders

Biliary tract disease


Extrahepatic biliary atresia


Cystic fibrosis


Choledochal cyst


Sclerosing cholangitis


Intrahepatic cholestasis syndromes


Alagille syndrome


Byler disease


Bile duct hypoplasia


Congenital hepatic fibrosis


Caroli disease

Hepatocellular disease

Autoimmune hepatitis


Hepatitis B and C


Wilson disease


α1-antitrypsin deficiency


Glycogen storage type IV


Toxins


Ethanol


Methtrexate


6-mercaptopurine

Miscellaneous

Chronic congestive heart failure


Arteriovenous fistula


Splenomegaly


Vitamin A


Arsenic


Vinyl chloride


Miscellaneous


Histiocytosis X


Venoocclusive disease


Schistosomiasis


Gaucher disease


Hepatoportal sclerosis


Peliosis


Idiopathic portal hypertension


Portal hypertension in general is the result of a combination of increased portal resistance and/or increased portal blood flow mediated by a complex interaction of anatomic and vasoactive factors [7, 8]. The signs and symptoms of portal hypertension are primarily a result of decompression of this supraphysiologic venous pressure via portosystemic collaterals and can be best understood by examination of the portal venous anatomy (Figure 6.1). Splenomegaly and its associated hypersplenism result from splenic congestion, whereas esophageal and rectal varices form from decompression through portosystemic collaterals. Hemorrhage from esophageal varices is the major cause of morbidity and mortality associated with portal hypertension. Decompression of portal hypertension via portosystemic collaterals by definition leads to portosystemic shunting and results in related complications, including hepatic encephalopathy, hepatopulmonary syndrome and portopulmonary hypertension. Portal hypertension plays a key role in the pathogenesis of the development of ascites and complications related to ascites, including bacterial peritonitis and hepatorenal syndrome. This chapter will review experimental models of portal hypertension, the pathophysiology of portal hypertension, its clinical presentation, and strategies for evaluation and treatment of its sequelae. Where appropriate, important differences between adult and pediatric disease will be highlighted.





Figure 6.1 Sites of portosystemic communication.


(Reprinted from Pillai AK, Andring B, Patel C, et al. Portal hypertension: a review of portosystemic collateral pathways and endovascular interventions. Clin Radiol 2015;70:1047–59, with permission.)


Experimental Models of Portal Hypertension


Animal models of portal hypertension have been critical in the study of the pathophysiology of portal hypertension [9]. The clinical applicability of the results of these studies may be directly dependent on the experimental method used to induce the portal hypertension. Two commonly used techniques, which may be most relevant to pediatrics, are bile duct ligation and partial stenosis of the portal vein. Bile duct ligation involves ligation and transsection of the common bile duct. Transsection is essential because of the finding of recanalization of the common bile duct when simple ligation is performed. Bile duct ligation would appear to be most applicable to diseases characterized by high-grade cholestasis, especially biliary atresia. An important proviso is the fact that bile duct ligation models are relatively short term secondary to the degree of illness of the animal. The mdr2 knock-out mouse has features of biliary cirrhosis and may be a better long-term model for portal hypertension related to cholangiopathies. The partial portal vein ligation model involves ligature constriction of the portal vein to a set diameter (usually based on a catheter size) and is akin to portal vein obstruction. Varying the size of the catheter permits generation of graded degrees of portal hypertension. Other techniques of generating animal models of portal hypertension include hepatotoxin (e.g., CCl4 or thioacetamide) exposure, metabolic simulation of fatty liver disease (e.g., methionine choline deficient diet) and infection with Schistosomiasis mansoni. In all of these approaches, in vivo monitoring is performed with pressure gauges and thermodilution catheters, and by radioactive microsphere distribution. This allows for accurate direct measurement of important parameters of portal hypertension, including heart rate, arterial and portal blood pressures, portal venous and hepatic artery blood flow, and portosystemic shunting. Cardiac output and systemic and portal resistances can be calculated from these direct measurements. The role of endogenous physiologic mediators and the effect of a variety of pharmacologic agents on these parameters can thus be carefully assessed. Application of these models to genetically modified mice has permitted assessment of individual gene products in the pathophysiology of portal hypertension.



Pathophysiology of Portal Hypertension


A great deal of the biological and molecular biological understanding of the pathophysiology of portal hypertension stems from analysis and models of sinusoidal disease and as such the direct applicability to pediatric etiologies may be limited (Figure 6.2) [7, 8]. Fluid mechanics are useful in understanding the pathophysiology of portal hypertension. Pressure is directly proportional to both blood flow through the portal system and resistance to that flow. In most circumstances it appears that the initial abnormality in the development of portal hypertension is an increase in the vascular resistance to flow of blood between the splanchnic bed and the right atrium. The etiology of this increased resistance is variable but usually involves compromise of the vascular lumen. Because resistance is inversely related to the radius of the lumen raised to the fourth power, small changes in the vasculature can result in large changes in pressure. The anatomic level of the vascular change can be prehepatic, intrahepatic (e.g., sinusoidal), or posthepatic. Compromise of the vascular lumen may be exacerbated by sinusoidal microthrombi that are observed in many chronic liver diseases. Increases in resistance are the result of more than architectural changes, and include alterations in intrahepatic vascular tone mediated by a variety of compounds including nitric oxide, endothelin and eicosanoids. It is clear that changes in resistance cannot completely explain the picture of portal hypertension. Portosystemic shunting should decompress the system and return portal pressures toward normal, yet this is not the case. A hyperdynamic state is clinically apparent in most patients with portal hypertension and has been well documented in a variety of animal models of portal hypertension. This is manifested by tachycardia and decreased systemic vascular resistance and was first identified in adults in the 1950s [10]. The reduction in systemic vascular resistance lies primarily in the mesenteric bed and is mediated by a distinct group of compounds including glucagon, nitric oxide, carbon monoxide, prostacyclin and bile acids to name a few. Overall, these hemodynamic changes lead to a substantial increase in portal venous inflow and thus maintenance of portal hypertension. Enhanced angiogenesis is another critical process involved in the pathogenesis of portal hypertension. Compounds like vascular endothelial growth factor, placental growth factor and platelet-derived growth factor mediate angiogenesis that is critical in the formation of portosystemic collaterals and may exacerbate both increased hepatic resistance to blood flow and mesenteric blood flow. Detailed understanding of the molecular biology of these factors that underlie portal hypertension is quite complex and critical to the development of novel pharmacologic therapies for portal hypertension.





Figure 6.2 Pathophysiology of portal hypertension.


(Reprinted from Fernandez M. Molecular pathophysiology of portal hypertension. Hepatology 2015;61:1406–15, with permission.)


Increased Vascular Resistance


The portal and hepatic venous systems are low-resistance systems in healthy individuals. It is useful to divide the increased vascular resistance seen in portal hypertension into intra- and extrahepatic sources and architectural versus vasogenic alterations. In addition, intrahepatic pathologies are referred to as sinusoidal, while extrahepatic are divided into presinusoidal and postsinusoidal lesions. Vasogenic alterations may be more responsive to pharmacologic therapies, although antifibrogenic and thrombolytic approaches have the potential to impact on architectural changes. Long-standing passive congestion of blood in the liver has been associated with the development of cirrhosis, which leads to increased resistance by other mechanisms and is becoming a major issue in the long-term follow-up of children who have undergone Fontan procedures. The suprahepatic vena cava and/or hepatic veins can be partially or totally obstructed by membranes or thrombosis leading to an entity often referred to as Budd–Chiari syndrome, a classical postsinusoidal lesion. This can be an acute or chronic process. The pathophysiology of the obstruction is typically related to compression by a mass, often a tumor, or thrombosis related to myeloproliferative disease or a hypercoagulable state [11]. Vasculopathies like Behcet’s syndrome can also predispose to thrombosis of the hepatic veins. The pediatric manifestations of Budd–Chiari syndrome have been reviewed [12]. Portal pressure was elevated in 19 of 20 children studied, and esophageal varices were present in 11. A clear etiology for the obstruction could be demonstrated in only five of the children, although more recent case-series have had higher yields on etiology [13].


One of the more common pediatric causes of increased extrahepatic resistance is extrahepatic portal vein obstruction (EHPVO). In a very large pediatric series, the second most common specific diagnosis leading to endoscopic management of varices in children was EHPVO [4]. Although the etiology is obscure in most instances, neonatal umbilical vein catheterization, omphalitis, or trauma has been associated with EHPVO. A variety of congenital malformations also have been associated with portal vein obstruction, including cardiac and urinary tract anomalies. As in Budd–Chiari syndrome, hypercoagulable states may predispose to the development of portal vein thrombosis. These conditions include deficiencies in protein S, protein C, and antithrombin III, and specific mutations in Factor V, Factor II, and methyltetrahydrofolate reductase. Systemic conditions such as paroxysmal nocturnal hemoglobinuria also can contribute. Cavernous transformation is the appearance of the recanalization of or collaterals around a thrombosed portal vein. These lesions lead to portal hypertension directly because portal resistance is markedly elevated. Compression of the biliary system by the cavernoma may lead to biliary disease [14]. In general, hepatic function is intact, especially early in the course of the disease, and the major morbidity and mortality are a direct result of complications stemming from the associated portal hypertension, particularly esophageal varix hemorrhage. Effective management of these complications can be especially rewarding, because of very limited ongoing liver disease. Results of the study of the portal vein stenosis model of portal hypertension may be particularly applicable to this subgroup of pediatric patients. Splenic vein obstruction can result in portal hypertension, although this is uncommon in children. Identification of splenic vein thrombosis as the cause of portal hypertension is very important, because splenectomy can be curative [15].


Intrahepatic causes of increased portal resistance constitute the remainder of the diseases associated with pediatric portal hypertension. The mechanisms of increased resistance are more varied than the extrahepatic etiologies. In many pediatric forms of chronic liver disease, resistance is increased secondary to impingement on the intrahepatic portal venule lumen as opposed to sinusoidal effects seen in adults. Hepatocyte swelling and hyperplasia in combination with portal tract inflammation and fibrosis are the major factors involved. Collagen deposition in the space of Disse also may contribute to increased intrahepatic resistance, although this has not been well studied in pediatric diseases. One of the major clinical differences from the extrahepatic etiologies of portal hypertension, especially in EHPVO, is the presence of ongoing hepatocellular injury. Biliary tract disease is a common cause of significant liver disease in children. Biliary atresia and its sequelae after hepatoportoenterostomy make up a large percentage of clinical series of advanced pediatric liver disease [4]. Other relatively common pediatric disorders that primarily involve the biliary tract include cystic fibrosis, choledochal cysts, sclerosing cholangitis, total parenteral hyperalimentation-related cholestasis, Alagille syndrome, chronic rejection, congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease, and the progressive intrahepatic cholestasis syndromes (especially bile salt export pump (BSEP) and multidrug resistance 3 disease (MDR3) disease). These diseases, which primarily involve the biliary system, lead to bile duct proliferation, portal inflammation, and fibrosis. These processes all result in compromise of the portal venules and with more advanced disease compromise of the sinusoidal lumen (akin to adult primarily hepatocellular disease), leading to increased resistance to portal flow. Early in the course of disease, hepatocyte function is preserved, resulting in the expression of manifestations of portal hypertension to a greater extent and at an earlier time than issues related to hepatocellular dysfunction. Thus, therapeutic interventions directed at preventing complications of portal hypertension in children with biliary disease may be relatively more meaningful, given the potential long-term function of the liver. In fact, successful management of variceal hemorrhage in children with biliary atresia may postpone the need for liver transplantation for extended periods of time [16]. This is in contrast to adults, where variceal hemorrhage is often a harbinger of poor short-term prognosis [17]. The greater prevalence of biliary tract disease in children (e.g., biliary atresia) relative to adults (e.g., alcoholic liver disease, hepatitis C and fatty liver disease) makes the complications of portal hypertension relatively more significant in pediatric vs. adult liver disease. Adult therapeutic approaches should not necessarily be directly applied to children because of the difference in underlying liver function and the different pathophysiologies of the underlying diseases relative to the development of portal hypertension. Bile duct obstruction models of portal hypertension may be more applicable to the majority of pediatric diseases, although the utility of this model is significantly compromised by the clinical instability and shortened life span of animals with complete bile duct obstruction. Genetic models of biliary disease (e.g., Alagille, cystic fibrosis, ARPKD, MDR3) may be interesting new systems for the study of portal hypertension.


In most types of liver disease, vasoactive substances may play an important role in regulating intrahepatic resistance to blood flow (Figure 6.2) [7, 8]. In contrast to the peripheral vasodilatation seen in cirrhosis, intrahepatic resistance is increased. The ability of the hepatic sinusoidal endothelial cells to secrete and respond to vasodilators is impaired. Local levels of nitric oxide may be reduced in the liver and novel means of increasing these levels locally may yield new avenues for the treatment of portal hypertension. Levels of endothelin-1, a potent vasoconstrictor, have been found to be elevated in chronic liver disease associated with cirrhosis. Liver injury appears to induce increased release of endothelin-1 from either endothelial or stellate cells in the liver. This endothelin acts locally to cause vasoconstriction of the preterminal portal venules and thus cause significant elevations in portal pressure. Eicosanoids, like prostaglandins and thromboxane A2, are increased in liver injury as a result of increased cyclooxygenase activities and also mediate enhanced vasoconstriction within the liver.


Primarily hepatocellular disorders are also seen in children and can lead to portal hypertension. Included in this group of diseases are chronic hepatitis (particularly autoimmune and hepatitis B and C), Wilson disease, α1-antitrypsin deficiency, and a variety of metabolic and toxin-related disorders. In these disorders, changes in hepatic architecture and cirrhotic nodule formation lead to increases in portal resistance. In addition, in those disorders that are characterized by significant portal inflammation (e.g., autoimmune hepatitis and Wilson disease), the portal tract inflammation can lead to a pathophysiology similar to that seen in primary biliary tract disease. The ultimate effect is a compromise of the sinusoidal lumen. In addition, postsinusoidal resistance is most likely increased due to fibrosis and architectural changes. The end result is more similar to chronic liver diseases in adults as there is a greater degree of liver dysfunction present at the time of the manifestation of portal hypertension. Therefore for these diseases extrapolations of the results of adult clinical series are more realistic.


A variety of rare disorders exist that lead to portal hypertension, but do not fit into the schema of intrahepatic (primary biliary tract or hepatocellular) or extrahepatic etiologies of portal hypertension. These diseases are not common in children and are included as examples of other pathophysiologies involved in the development of portal hypertension. The theory that increased portal inflow alone can lead to portal hypertension is supported by the finding of portal hypertension in patients with splanchnic arteriovenous fistulas or splenomegaly. Venoocclusive disease of the hepatic venule and hepatoportal sclerosis may increase portal resistance by sclerosis of the venous vessels as opposed to extrinsic compression. Venoocclusive disease is most commonly associated with chemotherapy but has been reported to be reversible when it is related to pyrrolizidine-containing tea. Defibrotide prophylaxis may prevent chemotherapy-related venoocclusive disease and has reduced the prevalence of this problem in bone marrow transplant recipients. The entity of noncirrhotic portal hypertension is being increasingly recognized and is an enigmatic disorder that is manifest by portal hypertension in the face of normal to near-normal liver function test results, patent hepatic and portal veins, and portal fibrosis without evidence of either cirrhosis or nodule formation [18, 19]. Inherited forms of noncirrhotic portal hypertension/venopathy have been recently described [3, 20]. These entities are autosomal dominant and as such careful family history is warranted in these disorders. Nodular regenerative hyperplasia of the liver is another poorly understood disorder that is associated with noncirrhotic portal hypertension. It is seen in the setting of the use of medications such as 6-thioguanine, but can be an isolated idiopathic phenomenon. Schistosomiasis, one of the leading causes of portal hypertension in the world, is uncommon in the pediatric age range. Portal tract inflammation results from the host response to the parasitic egg in the hepatic venule, leading to compromise of the intrahepatic portal vein lumen. The degree of fibrosis seen in schistosomiasis may have a genetic basis. Pharmacologic treatment of the schistosomiasis may ameliorate the related portal hypertension.



Systemic Vasodilatation


Increased resistance to portal blood flow may be the primary event in the development of portal hypertension, but it is clear that a variety of hemodynamic changes contributes to and amplifies the increased portal blood pressure that is observed. Both clinical studies and animal models have demonstrated the hemodynamic events that occur. Most of these investigations have not been performed in children or pediatric models, so the findings should be interpreted with caution. The hyperdynamic circulatory state is characterized by increased cardiac output, decreased splanchnic arteriolar tone, and decreased splanchnic vascular vasoconstrictor responsiveness. The net result is increased portal inflow, which directly contributes to portal hypertension. A variety of factors may be involved in the development of this hyperdynamic state, and dissection of their relative contributions to the resulting hyperdynamic circulation is important, but difficult at best.


Increased cardiac output in advanced liver disease is the result of increased venous return to the heart and diminished cardiac afterload. Arteriolar vasodilatation is one of the key elements of this process. Parabiotic models indicate that humoral mediators are involved. When the output of the carotid artery of a portal hypertensive rat is infused into the superior mesenteric vein of a normal rat, total vascular resistance of the mesentery is reduced in the recipient rat. Similar studies in which the donated blood is subjected to hepatic metabolism do not show this effect. Thus, portosystemic shunting may be important for the development of this vasodilatation.


A variety of mediators have been proposed to contribute to this vasodilatation, although the recent focus has been primarily on the role of nitric oxide [7, 8]. The role of NO is complex and may be organ-specific, with reduced levels in the liver leading to increased vascular resistance, while increased levels in the splachnic bed lead to vasodilatation. Statins may impact intrahepatic NO levels. An expanded intravascular volume is an important part of the pathophysiology of the hyperdynamic circulation, via an increase in venous return and preload. Vasodilatation alone or associated with advanced liver disease is primarily responsible for increased sodium retention and increased vascular volume. This is the result of the renal response to vasodilatation and effective diminished perfusion. Sodium restriction and/or diuretic therapy might be useful in the management of all patients with significant portal hypertension. Glucagon causes vasodilatation and is increased in advanced liver disease. This is partly the result of portosystemic shunting and bypassing of normal hepatic metabolism, but in addition pancreatic output of glucagon is elevated. Prostaglandins, adenosine, calcitonin gene–related peptide, carbon monoxide and endocannabanoids also have been thought to mediate the vasodilation in cirrhosis.


Advances in our understanding of systemic signaling by bile acids through receptors like FXR and TGR5 have added new complexities in assessing the impact of bile acids in advanced liver disease [21]. It is clear that very high levels of bile acids will result in vasodilatation, but these levels may only be seen in severe cholestasis. Bile acids have the potential to modulate NO production and can inhibit Endothelin-1 release. Obeticholic acid, an FXR agonist, can increase intrahepatic endothelial nitric oxide synthetase (eNOS) activity. The effects of bile acids on the heart are equally complicated. Both positive and negative effects on cardiac function have been described and levels and species of bile acids may be relevant [22, 23]. Cardiomyopathy, described in severe cholestasis associated with biliary atresia, may have significant negative impact after liver transplantation [24].


Alterations in serotonergic and sympathetic tone play a part in the pathogenesis of portal hypertension. Decreased responsiveness of the mesenteric vasculature to endogenous vasconstrictors plays an additional important role in the pathogenesis of portal hypertension. This is underscored by the importance of the use of nonspecific ß-blockers for the treatment of portal hypertension, as the ß2 blockade permits enhanced adrenergic tone in the splanchnic bed. Carvedilol, which combines nonspecific beta- and alpha-1 blockade, has been shown to have enhanced activity in the treatment of portal hypertension [25].


Enhanced angiogenesis has recently been described as part of the pathophysiology of portal hypertension. Vascular endothelial, placental and platelet-derived growth factors are increased in cirrhosis and may mediate enhanced angiogenesis. In the splanchnic bed angiogenesis increases blood return to the liver, while in the periphery it may open up portosystemic collaterals.


Overall a complex cycle of events leads to the hyperdynamic circulation, which is responsible for the forward flow portion of the pathophysiology of portal hypertension. A baseline state of liver disease and increased portal resistance initiates the process. Hepatocellular dysfunction and portosystemic shunting result in the generation of a variety of humoral factors, which lead to vasodilatation, enhanced cardiac output and increased plasma volume. Splanchnic arteriolar vasodilatation, mesenteric venodilatation and mesenteric angiogenesis leads to increased portal inflow and elevated portal pressure. This leads to further portosystemic shunting and increased levels of circulating vasodilators, and may lead to worsened hepatocellular injury. The self-perpetuating cycle of portal hypertension and portosystemic shunting continues until a state of equilibrium is reached, which consists of increased portal pressure and a hyperdynamic circulation. Ultimately, this results in decreased portal perfusion of the injured liver which enhances the progression of the underlying chronic liver disease.



Clinical Manifestations


The clinical presentation of portal hypertension can be dramatic, because it can be the first symptom of long-standing silent liver disease. In large series of children with portal hypertension, approximately two thirds of the children present with hematemesis or melena, usually from rupture of an esophageal varix [26, 27]. Gastrointestinal hemorrhage also can be associated with bleeding from portal hypertensive gastropathy, gastric antral vascular ectasia, or from gastric, duodenal, peristomal, or rectal varices. Variceal hemorrhage is the result of increased pressure within the varix, which leads to changes in the diameter of the varix and increased wall tension. When wall tension exceeds variceal wall strength, physical rupture of the varix occurs. Given the high blood flow and pressure in the portosystemic collateral system coupled with the lack of a natural mechanism to tamponade variceal bleeding, the rate of hemorrhage can be striking and life threatening. Almost all of the patients reported in the above series had splenomegaly at the time of hemorrhage; thus, the combination of gastrointestinal hemorrhage and splenomegaly should be suggestive of portal hypertension until proven otherwise. The sentinel bleeding episode in these children occurred at a wide range of ages, starting as early as two months of age. No particular peak age of presentation has been demonstrated. Many of the episodes of hemorrhage that have been reported have been associated with upper respiratory tract infections, fever, or aspirin ingestion. It is possible that increases in abdominal pressure from coughing associated with respiratory infections and increases in cardiac output from the tachycardia associated with fever may result in increases in portal pressure and increased tendency to hemorrhage. Aspirin ingestion is associated with platelet dysfunction and gastrointestinal mucosal damage, both of which would predispose to hemorrhage. Other physiologic factors have been associated with increased portal pressures, which might increase the risk of variceal hemorrhage. These factors include physical exercise, blood or food in the stomach, and normal circadian rhythms.


The most common presentation of portal hypertension is splenomegaly. In many instances this is first discovered on routine physical examination. Many patients will have been aware of a vague fullness in the left upper quadrant for many years. Occasionally manifestations of hypersplenism, including thrombocytopenia, leukopenia, petechiae, or ecchymoses, will prompt evaluation, leading to the discovery of portal hypertension. Extensive hematologic evaluations, including bone marrow biopsies, are sometimes undertaken before portal hypertension is considered. Thus, the hematologist should include a liver profile and potentially Doppler ultrasonography in the evaluation of any child with thrombocytopenia, especially if there is the simultaneous finding of leukopenia. Rarely will the associated cytopenias lead to clinically relevant disease. Although splenomegaly is a common finding in patients with portal hypertension, splenic size does not seem to correlate well with portal pressure [28]. Splenic rupture is a persistent concern in children with portal hypertension, although it has rarely been reported [29].


Certain cutaneous vascular patterns are specific to portal hypertension. Prominent vascular markings on the abdomen are the result of portocollateral shunting through subcutaneous vessels. The direction of flow through these veins can be indicative of the site of obstruction. When the inferior vena cava is occluded, drainage is usually cephalad, although it is caudad below the umbilicus if the inferior vena cava is patent. Decompression of portal hypertension through the umbilical vein results in prominent periumbilical collaterals, which have been referred to as a caput medusa. An audible venous hum, the Cruveilher–Baumgarten murmur, can occasionally be appreciated through these vessels. Caput medusae are rarely seen in children, partly because of the high prevalence of EHPVO associated with umbilical vein obliteration. Portal hypertensive rectopathy or rectal varices may be more common than generally appreciated. In children with short gut, stomal varices, which are a site of low resistance, are often easily observed and a common site of hemorrhage.


Hepatopulmonary syndrome (pulmonary arteriovenous shunting) is an important clinical manifestation of portal hypertension [30]. In this condition, there is intrapulmonic right to left shunting of blood, which results in systemic desaturation. Diagnostic criteria exist but are difficult to apply in many cases in children, particularly because of the requirement of the demonstration of an increased age-corrected alveolar-arterial oxygen gradient. Hepatopulmonary syndrome is associated with orthodeoxia; reduced oxygenation in an upright compared to recumbent position. Arterial sampling of blood is technically difficult if not impossible in a child in an upright position and the impact of tachypnea associated with the pain of the procedure is unknown. The mechanisms involved in the development of hepatopulmonary syndrome are unknown, but they are likely to include many of the vasoactive substances involved in the genesis of the hyperdynamic circulation, including nitric oxide and endothelin-1. One of the best-described animal models of hepatopulmonary syndrome is bile duct ligation, which is especially relevant given the high prevalence of this problem in biliary atresia. Interestingly, hepatopulmonary syndrome can occur in the absence of intrinsic liver disease and has been described as a sequelae of congenital portosystemic shunting. Thus portosystemic shunting may be the key pathologic event leading to hepatopulmonary syndrome. The prevalence of hepatopulmonary syndrome in chronic pediatric liver disease is not well characterized and depends on the method of diagnosis. Symptomatic hepatopulmonary syndrome (e.g., shortness of breath, exercise intolerance, and digital clubbing) is typically a late manifestation, and thus series that depend on symptomatic presentation likely underestimate the true prevalence of this complication. Agitated saline echocardiography is a very sensitive measure of intrapulmonic shunting and can easily detect asymptomatic disease [31]. Positive echocardiographic studies were reported in 64% of children with biliary atresia who were prospectively studied [32]. The clinical relevance of this finding is not known, as the natural history of mild shunting is not well described. Macro-aggregated albumin scanning can be used to quantify the degree of shunting, which can be useful in clinical decision-making and in follow-up of hepatopulmonary syndrome. In a large pediatric series, 26 of 1,116 children with chronic liver disease had clinically significant pulmonary arteriovenous shunting [33]. A variety of medical treatments have been tried and not found to be effective in treating this unusual complication of portal hypertension. Liver transplantation is very effective in reversing hepatopulmonary syndrome, but theoretically may have limited efficacy in children with very severe disease. Full reversal of the shunting may take many months. Efficacy of transplantation is primarily limited by the ability of a particular patient to tolerate the perioperative cardiopulmonary stress of surgery. Screening for hepatopulmonary syndrome should be included in the evaluation and treatment of any child with portosystemic shunting, cirrhosis and/or portal hypertension. In light of the orthodeoxia associated with this condition, measurement of peripheral oxygen saturation in children who are upright at the time of testing should be an effective screen. Any children with oxygen saturations persistently below 97% should undergo further testing, including agitated saline echocardiography and/or macroaggregated albumin scanning, to assess the presence or absence of hepatopulmonary syndrome and its severity. Transcutaneous oxygen saturation measurements are not always easy to perform and a normal value may not always exclude significant hepatopulmonary syndrome [34].


Pulmonary hypertension is pathophysiologically related to but distinct from hepatopulmonary syndrome [35]. It results from remodeling of the pulmonary arteries as opposed to development of intrapulmonic shunting. It is an unusual but worrisome manifestation of pediatric liver disease and can be preceded by hepatopulmonary syndrome [30, 36]. Routine screening for this rare complication is recommended in adults but is not typically done in children as the screening may require invasive right-sided cardiac catheterization. Non-invasive screening utilizes echocardiography; when a tricuspid jet is present right-sided pressures can be estimated and disease documented at an early stage. Without that jet, echocardiography will only detect severe disease manifest by intraventricular septal bowing. Endothelin-1 receptor antagonists, prostacyclin analogues and sildenafil may be effective in some cases of portopulmonary hypertension, although clear documentation of efficacy of medical therapies is limited [37]. Severe portopulmonary hypertension, defined by a pulmonary artery pressure greater than 50 mmHg, is a relative contra-indication to liver transplantation due to high perioperative mortality. Unlike hepatopulmonary syndrome, portopulmonary hypertension does not typically completely reverse after isolated liver transplantation, although some improvements in children have been reported. Optimal timing of liver transplantation in portopulmonary hypertension is uncertain in light of limited granular knowledge of the natural history of this complication. Avoidance of early transplantation is desirable but the high risk associated with severe disease balances against that goal.


Other major manifestations of portal hypertension impact the kidney and brain. Renal-related complications include ascites and hepatorenal syndrome. Sodium retention, which is probably initiated by the already discussed systemic vasodilatation, may lead to ascites as an initial presentation of portal hypertension. The elevated portal blood pressure increases the Starling forces, which drive fluids out of the intravascular space into the peritoneum. In addition, impaired lymphatic drainage contributes to the development of ascites. Portal hypertension predisposes to bacterial translocation in the intestine and bacterial peritonitis. Very late stage cirrhosis is associated with enhanced free-water retention and hyponatremia. Hepatorenal syndrome is a particularly ominous complication of the renal disease associated with portal hypertension. Type 1 hepatorenal syndrome is an acute form of renal failure, which cannot be ascribed to other causes of renal failure (e.g., infection, nephrotoxic medications, shock or other forms of nephropathy). Short-term mortality is very high in patients with acute hepatorenal syndrome, although recently described treatment strategies have improved this outlook somewhat. There is little published experience with the diagnostic criteria and management of hepatorenal syndrome in children [38, 39]. Hepatic encephalopathy is a complication associated with portosystemic shunting typically in the setting of advanced liver disease and relatively significant hepatocellular dysfunction. Minimal hepatic encephalopathy may be more common than clinically appreciated in children with portal hypertension, as specific neuropsychiatric testing needs to be employed to identify the issue [40, 41]. Minimal hepatic encephalopathy may manifest as behavioral (e.g., attention deficit hyperactivity disorder) in children. The true prevalence of this issue and potential therapeutic approaches to it are unclear. Overt hepatic encephalopathy is relatively uncommon in pediatrics and typically a feature of quite advanced disease.



Natural History


An accurate description of the natural history of portal hypertension in children is essential for a rigorous assessment of the efficacy of traditional and novel forms of therapy. A variety of complex and relatively accurate modeling systems of portal hypertension in adults have been developed [42]. Unfortunately, the natural history of pediatric portal hypertension is difficult to accurately assess, in part due to the wide range of disorders that result in portal hypertension in children. Many of these disorders have unique pathophysiologies and clinical courses. Some are associated with extrahepatic issues like pulmonary disease in cystic fibrosis that can have major effects on overall outcome. The most confounding problem in attempting to retrospectively describe the natural history of portal hypertension in children is the wide variety of therapeutic interventions that have been applied in a noncontrolled manner. In addition there are only a few distinct diagnostic entities in which the prevalence of portal hypertension is high enough to generate clinically significant series. Extrahepatic portal vein obstruction and biliary atresia represent two entities where clinically meaningful series of “untreated” patients exist and can be used as a guide to the natural history of pediatric portal hypertension.



Extrahepatic Portal Vein Obstruction


Extrahepatic portal vein obstruction is a useful example of the natural history of portal hypertension in the setting of slowly progressive liver disease. The presentation in children is usually one of gastrointestinal hemorrhage or the incidental discovery of splenomegaly. In two retrospective series, 167 patients presented from the ages of 10 days to 75 years [27, 28]. In most cases it was not possible to date the event leading to EHPVO. As a result, it is unclear if the wide age range can be used as evidence for long-standing clinically benign disease. In 21 cases of presumed neonatal portal venous obstruction, presentation by hemorrhage was gradual over a period of as long as 12 years. Although the vast majority of the patients at some time in their life experienced gastrointestinal hemorrhage, a significant number of patients never bled. Four patients had fatal first hemorrhage episodes, although three of these instances were blamed on insufficient blood supplies. Sixty-one patients received medical management alone. Four described above died during their initial bleeding episode. Of the remainder, eight (13%) subsequently died of gastrointestinal hemorrhage. A minority of patients had no further episodes of hemorrhage. Most had several more episodes of bleeding, with a general observation of decreased frequency and severity after puberty. This phenomenon of apparently “out-growing” portal hypertension may be the result of recanalization of the portal vein or the development of collaterals and spontaneous portosystemic shunts through sites other than the gastroesophageal varices. Ascites and end-stage liver disease is unusual in EHPVO. Subtle hepatic encephalopathy may be more prevalent than previously thought [40]. Hepatopulmonary syndrome and portopulmonary hypertension are potential long-term sequelae. Failure to thrive, pubertal delay and a form of biliary disease that has cystic features and manifestations akin to sclerosing cholangitis has been reported in long-term follow-up [43]. It has been hypothesized that the biliary disease is the result of partial obstruction from the cavernoma associated with the portal vein obstruction. In summary, portal vein obstruction is associated with potentially, but rarely life-threatening gastrointestinal hemorrhage. The time from portal vein obstruction to hemorrhage appears to be quite variable, as is the clinical course. Minimal ongoing hepatic injury makes portal vein obstruction a more benign form of portal hypertension. Treatment recommendations must be tailored to the individual on a case-by-case basis with an understanding of the expertise of the treating center and physicians. Accumulating reports of the success of mesentericoportal (meso-Rex) bypass surgery needs to be incorporated into the clinical decision-making in the management of individuals with EHPVO [44]. The physiologic restoration of normal portal flow after this procedure has profound implications in its role in the management of EHPVO and will likely change the natural history of this disease.



Biliary Atresia


Biliary atresia is the leading cause of significant pediatric liver disease and the single most common indication for liver transplantation in children [45]. Unlike EHPVO, this is an example of a disease where portal hypertension is associated with ongoing and progressive liver disease. Biliary atresia is universally fatal in early childhood unless operative intervention is undertaken. At the time of portoenterostomy, portal hypertension has been documented, and its subsequent natural history is complicated by the variable results of portoenterostomy [46]. With regard to natural history, it is reasonable to consider biliary atresia as two distinct disorders dichotomized based upon the establishment of bile flow after hepatoportoenterostomy. In those infants with no bile flow (i.e., failed hepatoportoenterostomy) relentless progression of biliary cirrhosis leads to complications of portal hypertension and end-stage liver disease beginning in the first year of life. Survival with native liver beyond three years of age is rare in these children. In contrast, the clinical course of infants with a successful hepatoportoenterostomy is much more variable, although complications of portal hypertension are common in childhood [47]. Variceal hemorrhage is a common problem in children with biliary atresia and can occur as early as the first year of life [48, 49]. In the setting of reasonable access to medical care first variceal hemorrhage is unlikely to be fatal in biliary atresia. Variceal hemorrhage in biliary atresia is expected to be recurrent and potentially fatal and as such secondary prophylaxis is clearly indicated, although prospects of liver transplantation need to be considered in this context. Given the progressive nature of portal hypertension associated with biliary atresia, the effects of interventions, both medical and surgical, are more easily discerned. Stratification of the natural history on the basis of response to hepatoportoenterostomy is critical.



Diagnostic Evaluations


Portal hypertension should be suspected in any child with significant gastrointestinal hemorrhage or unexplained splenomegaly. Physical examination should be directed at assessing for evidence of chronic liver disease. Care should be taken to look for growth failure or cutaneous lesions consistent with chronic liver disease (e.g., telangiectasia, palmar erythema). The combination of gastrointestinal hemorrhage and splenomegaly is highly suggestive of portal hypertension until proven otherwise. Ascites is an important physical finding associated with portal hypertension. Abdominal ascites can be difficult to assess on physical examination in some children due to poor cooperation with the exam and potential confounding features of abdominal distension due to hepatosplenomegaly or viscus distention with gas. Acute and unexpected weight gain in the setting of chronic liver disease may be a valuable indicator of the presence of ascites. Laboratory studies should be aimed at evaluation of liver function. In addition, white blood cell and platelet counts may give evidence of hypersplenism. Thrombocytopenia in the setting of clinically suspected portal hypertension are reasonable predictors of the potential for the presence of esophageal varices [50]. In children with portal vein thrombosis or Budd–Chiari syndrome investigation of thrombophilia or myeloproliferative disease is potentially indicated.


A wide variety of diagnostic tests is available to document and quantify features of portal hypertension. It is important to remember that portal pressure is rarely assessed directly as a quantitative measurement, although indirect quantitative measurements (hepatic venous pressure gradient, HVPG) are available and have been primarily assessed in adults. Many of the quantitative studies are invasive and most useful in a research setting to study response to treatment and in some cases to predict risk of gastrointestinal hemorrhage. Because of the complexity in application of these studies in pediatrics a research operational definition of clinically evident portal hypertension has been proposed and is based upon clinical features of hypersplenism (splenomegaly and thrombocytopenia) or the presence of endoscopically confirmed varices or ascites that requires chronic diuretic therapy [51]. In the pediatric age range a combination of ultrasonography, flexible fiberoptic and/or capsule endoscopy can usually determine if portal hypertension or esophageal varices are present or absent. In light of limitations (see “Other Investigations” below), it is unlikely that HVPG measurements will become part of routine assessment of portal hypertension in children.



Ultrasonography


Ultrasonography coupled with Doppler flow examination provides a wealth of non-invasive and relatively inexpensive data, making this an investigation of choice in children. As with many other procedures, the information obtained is directly dependent on the skill and experience of the operator together with the cooperativeness of the patient. An abdominal survey can yield important information, including hepatic size and echogenicity along with features of nodularity suggestive of cirrhosis. A small liver in the setting of portal hypertension is a potentially worrisome finding. Increased echogenicity is commonly seen in cirrhosis. Intrahepatic bile ducts can be assessed for evidence of dilatation consistent with extrahepatic obstruction or Caroli disease. Spleen size can be easily measured and will give indirect evidence about the presence or absence of portal hypertension. Unfortunately, spleen size does not appear to correlate directly with portal pressure and by itself is not a highly accurate predictor of the presence or absence of varices. Renal abnormalities, associated with portal vein thrombosis and congenital hepatic fibrosis/Caroli disease, can easily be detected. Finally, clarity about the presence or absence of ascites may be provided. Rigorous semi-quantitative documentation of the volume of ascites is not well validated in children and trace or scant ascites is of uncertain significance in children with chronic liver disease.


Doppler insonation of the hepatic and mesenteric vasculature affords potentially very valuable additional information. The presence or absence of patent vessels can be determined in addition to vessel diameter, direction of blood flow in the vessel, and the presence or absence of echogenic material within the blood vessel. Vascular anomalies are usually readily detected. In children, normal nonfasting portal blood flow as assessed by Doppler examination is hepatopedal at 10–30 cm/s, although considerable variability exists in this measurement. Portal vein velocity decreases in severe portal hypertension as intrahepatic resistance increases. Hepatofugal flow in the left gastric, paraduodenal, or paraumbilical veins is consistent with portal hypertension, although this may be a relatively late finding. Reversal of flow in the superior mesenteric vein or splenic vein may be indicative of spontaneous mesentericocaval or splenorenal shunts, respectively. Hepatic arterial flow is often increased in portal hypertension as part of the normal compensation for diminished portal venous inflow. In selected studies in adults, careful analysis of either portal venous blood flow or superior mesenteric artery flow velocity has revealed a correlation with portal pressure. Unfortunately, these quantitative ultrasound studies have not been universally useful and have not been characterized in children.



Liver and Spleen Stiffness


In progressive liver disease there is a correlation between fibrosis and portal hypertension. Sequential liver biopsy is not routine in children and as such non-invasive markers of fibrosis have the potential for particular value in assessing portal hypertension in pediatrics. Liver stiffness has been incorporated into the Baveno criteria for assessment of chronic liver disease and for the identification of adults who might benefit from screening endoscopy [52]. In adults, stiffness has been typically assessed in hepatocellular diseases like alcohol-related liver disease, viral hepatitis and fatty liver disease. Pediatric investigations have been undertaken in very different diseases, most of which are biliary in nature. Therefore direct use of cut-offs developed in adults for pediatrics may not be appropriate. Despite this important difference, liver-based assessment of liver stiffness may be useful in identifying children with clinical features of portal hypertension, along with those who may have high risk varices [53]. Spleen stiffness is not as well characterized but may also be useful in assessing portal hypertension in children [54].



Endoscopy


Flexible fiberoptic endoscopy can be used for the definitive determination of the presence of esophageal varices, which can be a defining feature of portal hypertension (Figure 6.3). This examination is especially useful in determining if gastrointestinal hemorrhage in a child with chronic liver disease is secondary to variceal rupture. The differential diagnosis includes gastric or duodenal ulcers, gastritis, Mallory-Weiss tears and portal hypertensive gastropathy. Eight of 22 children with cirrhosis and upper gastrointestinal hemorrhage had gastric or duodenal ulcers, and as such one cannot assume that bleeding is necessarily from varices in children with portal hypertension [55]. In adults, the endoscopic appearance of varices can be predictive of the risk of future hemorrhage. The red wale sign, cherry-red spot and variceal size are particularly associated with increased risk of hemorrhage. These findings have been systematically evaluated in children at a single center, with the characterization of similar features of varices that are at high risk for hemorrhage [4]. It remains to be seen whether there is sufficient interobserver agreement on this endoscopic classification to permit widespread use of these endoscopic predictors [2]. Capsule endoscopy can be used to look for esophageal varices in children, although size issues and the ability of a young child to swallow the capsule may limit its use [5].





Figure 6.3 Endoscopic view of varices. Three columns of varices are seen.



Other Investigations


A variety of other diagnostic investigations exist for the assessment of portal hypertension. Most of these studies have not been extensively characterized in children secondary to their invasive nature. Selective angiography of the celiac axis, superior mesenteric artery, and splenic vein can be especially useful in assessing the extrahepatic vascular anatomy. In particular these studies are helpful in cases of suspected EHPVO and are essential for surgical decompression of this lesion. These studies may be essential for the diagnosis and appropriate therapy of splenic vein thrombosis. A combination of ultrasonography, inferior cavography, computed tomographic scanning with intravenous contrast, or magnetic resonance venography can be used to document the vascular lesions associated with Budd–Chiari syndrome [12]. Portal pressure can be directly measured by examination of splenic pulp pressure during splenoportography, although this is primarily an historical technique. The hepatic venous pressure gradient (HVPG) is one of the classic measurements used in assessing portal hypertension in adult patients [56]. A balloon-tipped catheter is inserted into the antecubital vein and advanced to the hepatic vein, where free and wedged hepatic vein pressures can be measured. The wedged hepatic vein pressure is usually a good index of portal vein pressure when the main lesion in the hepatic vasculature is limited to the sinusoidal area. The difference between the free and wedged hepatic vein pressures is the HVPG. An HVPG of greater than 12 mmHg appears to be needed for variceal hemorrhage to occur. In addition, the HVPG is a reproducible measurement for studying the effects of a variety of medical and surgical interventions. Growing evidence in adults indicates the potential importance of HVPG measurements. Responses of HVPG to pharmacotherapy may be predictive of future chances of recurrent variceal hemorrhage. Given the relatively invasive nature of this measurement, there is limited well documented pediatric experience with HVPG outside of that associated with the placement of transjugular intrahepatic portosystemic shunts. HVPG measurements are feasible in children and yield results similar to adults, although an important caveat is the unexpected finding of intrahepatic venovenous collaterals in biliary atresia, which can influence the accuracy of this measurement [57]. In addition, HVPG measurements are not as accurate in presinusoidal liver disease, which is the case for many of the prevalent pediatric forms of chronic liver disease (e.g., biliary atresia, portal vein thrombosis, etc.). It is hoped that assessment of liver or spleen stiffness might eventually supplant the need for HVPG.

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Feb 26, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 6 – Portal Hypertension in Children
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