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.

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.

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.