Figure 25.1 BA. Biliary cirrhosis in an infant with BA who underwent a Kasai procedure. One can notice the characteristic green discolouration of the liver and the obvious cirrhotic nodular formation.
25.3.1.3 PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS
Progressive familial intrahepatic cholestasis (PFIC) is a group of diseases characterised by mutations in the hepatocellular transport system genes involved in bile synthesis [17]. Three types have been reported. Type 1 PFIC (formerly known as Byler’s disease†) (ATP8B1) presents with jaundice in the first few months of childhood. Patients also present with extrahepatic manifestations (pancreatitis and diarrhoea) and pruritus. Type 2 PFIC (ABCB11) also presents with cholestasis in infancy and is characterised by pruritus. Because ABCB11 is found in the liver only, patients do not have extrahepatic manifestations. Type 2 is associated with an increased risk of developing hepatocellular carcinoma (HCC). Only 30% of type 3 PFIC (ABCB4) will suffer from cholestasis. It can occur in infancy, but also throughout adulthood. Pruritus is less frequent. Management is oriented towards improving cholestasis (using ursodeoxycholic acid), pruritus (using nasobiliary drains or surgical derivation procedures) and nutritional status. Procedures have been developed to cause either a partial diversion of bile or a bile malabsorption in order to palliate the symptoms of PFIC or even improve on the overall health of the liver [18,19]. Those who fail to improve with these lesser procedures will have to undergo liver transplantation, which is curative for types 2 and 3 PFIC [20].
25.3.1.4 CYSTIC FIBROSIS
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR transmembrane regulator gene. This leads to an alteration in the transport of sodium and chloride ions across the epithelial border, ultimately resulting in increased density of various exocrine tissue secretions. About 30% of CF patients will develop liver disease (CFLD), and 2%–5% will ultimately develop PHT. Patients with CF requiring a liver transplant tend to suffer from more complications than patients undergoing transplant for other diseases [21,23]. Therefore, the use of portosystemic shunt surgical procedures is an option to be considered in the treatment of PHT in this population who have well-compensated cirrhosis and who may be reasonably expected to not require transplantation for at least 5 years [23].
25.3.1.5 α-1-ANTITRYPSIN DEFICIENCY
α-1-Antitrypsin deficiency (A1AT) is the most frequent genetic disease leading to liver transplant in the paediatric population. It occurs in 1:2000–5000 live births in North America and presents as neonatal cholestasis or hepatitis. The liver dysfunction can progress to liver failure and cirrhosis. These patients have an increased risk of HCC. There is no medical treatment for this condition, but liver transplant might be required when end-stage liver disease (ESLD) occurs [15].
25.3.1.6 AUTOIMMUNE DISEASES
Autoimmune diseases and viral hepatitis constitute the most common cause of cirrhosis in older children and adolescents. They include autoimmune hepatitis (AIH), primary biliary cirrhosis and primary sclerosing cholangitis (PSC).
AIH is characterised by chronic nonresolving liver inflammation of unknown aetiology. Two subtypes have been identified: type 1 AIH is associated with anti-nuclear (ANA) and anti-smooth muscle (ASMA) antibodies and occurs in older children and teenagers, while type 2 AIH is associated with anti-liver/kidney micro-somal (LKM-1) antibodies and affects children earlier in life. Medical treatment should be initiated in paediatric patients suffering from AIH, as they tend to have a more severe disease than the adult population. In the case of refractory disease evolving in cirrhosis, liver transplant might be indicated.
PSC is characterised by inflammation and fibrosis of both intra- and extrahepatic bile ducts, ultimately evolving in the development of multifocal strictures. It is associated with inflammatory bowel disease, with 90% of patients with PSC also suffering from ulcerative colitis. Treatment is aimed at treating strictures, and liver transplant might be needed in cases of advanced disease.
25.3.2 Noncirrhotic portal hypertension
Noncirrhotic causes of PHT are subdivided as prehepatic, hepatic or posthepatic. Prehepatic causes include EHPVO, and as mentioned earlier, this subject will not be discussed in this chapter.
25.3.2.1 HEPATIC
Noncirrhotic PHT arising from abnormalities in the liver is further divided as being presinusoidal, sinusoidal or postsinusoidal.
25.3.2.1.1 Presinusoidal
Congenital hepatic fibrosis (CHF) is an autosomal recessive disease affecting primarily the kidneys and the liver. The median age at diagnosis is 0–20 years. A ductal plate malformation will lead to the development of PHT. Only 10% of CHF cases will be isolated. Sixty-five percent of patients will also suffer from autosomal recessive polycystic kidney disease (ARPKD), while 26% will also present with Caroli’s disease* or other forms of choledochal cyst. PHT occurs in 50%–85% of patients, but they can also present with cholangitis, variceal bleed and splenomegaly. They are at increased risk for developing cholangiocarcinoma [24].
Idiopathic PHT is also known as noncirrhotic portal fibrosis, idiopathic PHT, obliterative venopathy and idiopathic noncirrhotic PHT. It is characterised by clinical features of PHT (massive and disproportional splenomegaly with or without hypersplenism), with preserved liver function and patent portal and hepatic veins. Various aetiologies are suspected: infection, prothrombotic conditions, medication and toxins, possible immunological contribution (as it affects mainly females) and genetics. Pathologically, periportal and perisinusoidal fibrosis is found, with dilated portal venous trunks and thrombosis found in smaller and medium-sized portal venous branches, giving the name obliterative portal venopathy [24]. Diagnosis is made through clinical findings associated with pancytopenia, but preserved liver function tests.
25.3.2.1.2 Postsinusoidal
Veno-occlusive disease (VOD) is also known as the sinusoidal obstruction syndrome. It is a complication of chemotherapy toxicity, mostly described for the treatment of haematologic malignancies and following bone marrow transplant. In the paediatric population, it has also been reported following treatment with dactinomycin for Wilms’ tumour,† rhabdomyosarcoma, neuroblastoma and other solid tumours. It typically occurs 10 days following chemotherapy administration, and presents with jaundice, painful hepatomegaly and fluid retention (including ascites). Diagnosis is made through hepatic venous pressure measurements. Treatment is through supportive care. There is also growing evidence for the use of defibrotide in the treatment of VOD [25].
25.3.2.2 POSTHEPATIC
25.3.2.2.1 Budd–chiari syndrome
Budd–Chiari syndrome (BCS) is characterised by an obstruction of the hepatic venous outflow and is associated with ascites, hepatomegaly and development of PHT, but in the absence of right heart failure. It can be caused by endoluminal causes (web and membranes) or by external compression (e.g. tumours). Myeloproliferative disorders, prothrombotic states and neoplasia are other possible causes. BCS will remain idiopathic in 10% of cases. Treatment is multimodal, using medication (anticoagulation and diuretics), and through the use of interventional radiology (angioplasty, stenting or TIPS). Liver transplant can ultimately be required if other modalities fail [26,27].
25.3.2.2.2 CARDIAC CONDITIONS
Various cardiac conditions are associated with the occurrence of PHT. of mention, constrictive pericarditis, right-sided heart failure and restrictive cardiomyopathy have all been reported. Patients with a history of congenital heart disease (including those who have undergone a Fontan procedure) are at risk of developing complications of PHT [28].
25.4.1 Gastrointestinal bleeding
Various series from the paediatric literature have reported that two-thirds of paediatric patients with PHT will initially present with an episode of upper gastrointestinal bleeding (UGIB). Most often, the bleeding will originate from a ruptured oesophageal varix [6].
Gastrointestinal varices develop because of the combination of increased portal vein pressure, coupled with an increase in intrahepatic resistance and splanchnic flow. Collaterals then develop and formerly obliterated vessels will regain patency [6]. Bleeding is most often triggered by conditions associated with increased intra-abdominal pressure (respiratory tract infection associated with coughing), increased cardiac output (fever) or medication (aspirin or nonsteroidal anti-inflammatory drugs). There is an associated increase in pressure in the varix, causing an increase in variceal wall tension that eventually is greater than the variceal wall strength itself, resulting in variceal rupture. Bleeding can also occur from other variceal sites; in the adult literature, gastric varices occur with a prevalence of 17%–25% (compared with 50%–60% for oesophageal varices) and have a 16% bleeding risk at 1 year. Duodenal varices would be responsible for 2%–5% of all variceal bleeding, while colorectal varices, despite being highly prevalent (77%), rarely are a cause of bleeding [29]. Variceal bleed can occur as early as 2 months of age, but age at first bleed varies according to the underlying liver disease. Following a first bleeding episode, patients carry a 70% risk of a subsequent bleeding episode. Variceal bleeding also carries the risk of developing various complications, including the need for blood transfusions and intensive care unit admission, septicaemia, ascites and overall prolonged hospital length of stay [1]. The mortality of variceal bleed has been reported to be up to 8% in the paediatric population [30].
25.4.2 Splenomegaly and hypersplenism
Splenomegaly is often incidentally diagnosed on physical examination, while when questioned, patients may mention having left upper quadrant fullness. It is the second most frequent clinical presentation for PHT after gastrointestinal bleed. Pancytopenia is also often encountered, which may prompt a referral to a haematologist. If splenomegaly is identified in the setting of pancytopenia, liver functions tests and an abdominal US should be ordered to identify underlying undiagnosed liver disease and to avoid referral for possible splenectomy. Splenectomy should not be performed in those patients first because it will not treat the underlying disease and therefore will not improve symptoms, but also because it will prevent those patients from benefiting from a distal splenorenal shunt (DSRS) [31].
25.4.3 Ascites
Increased sodium retention and portal vein pressure associated with impaired lymphatic drainage will place PHT patients at risk for developing intra-abdominal ascites. Treatment is therefore a combination of fluid and sodium restriction, diuretics, albumin infusions and paracentesis if respiratory compromise develops. Antibiotics should be used if there is suspicion for superinfection after performing a diagnostic paracentesis [6].
25.4.4 Hepatopulmonary syndrome and portopulmonary hypertension
Both hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are rare complications of PHT associated with ESLD in the paediatric population. Both conditions are by-products of portosystemic shunting.
HPS diagnostic criteria are
1. Hypoxaemia
2. ESLD (associated with PHT)
3. Evidence of intrapulmonary shunting by echocardiography imaging [32]
PPH is usually diagnosed by evidence of pulmonary hypertension (mean pulmonary artery pressure [PAP] > 25 mmHg and increased pulmonary vasculature resistance) in the setting of ESLD.
The development of HPS in cirrhotic patients appears to be mediated through an increase in NO and ET-1 leading to pulmonary vasodilatation. PPH is characterised by obstructive and remodelling changes in the pulmonary arterial vasculature [33,34]. PHT patients with ESLD presenting with dyspnoea and recurrent respiratory infections should raise the suspicion for HPS. PPH is often incidentally diagnosed following observation of cardiomegaly on chest X-ray, and will be further confirmed using an echocardiogram, followed by right heart catheterisation.
Liver transplantation is curative for both HPS and PPH. In the adult population, they are associated with an increased perioperative risk, as PPH increases the risk of sudden cardiac death and right ventricle failure. However, these findings have not been observed as frequently in the paediatric population [35].
PHT workup should start with laboratory testing, including complete blood count, liver enzymes, cholestatic evaluation, albumin, ammonia level, coagulation panel and a comprehensive metabolic panel. The first imaging to be performed should be an abdominal US. It will evaluate the liver itself, the patency of the liver vasculature (portal vein and hepatic veins) and the spleen and its vessels. Computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP), or both, can be performed to characterise US findings and define anatomy.
Confirmation of PHT is done through indirect portal pressure evaluation through HVPG measurements by interventional radiology. HPVG is obtained by calculating the difference between the ‘free’ hepatic vein pressure and the ‘wedged’ hepatic vein pressure. By occluding a hepatic vein with a balloon, the catheter is wedged and thus reflects the pressure transmitted from the upstream vessels, which is the portal vein. As mentioned earlier, findings of either PVP > 10 mmHg or HPVG > 4 mmHg are diagnostic of PHT. Although the safety of HPVG measurement has mostly been established in the adult population (with a risk of 0%–1% minor complications) [3], studies performed in children now show that HPVG measurement in them is feasible and safe, in both the acute and the chronic setting. It has been reported in children as young as 1 month of age and weighing as little as 3.7 kg [36,37]. However, in such delicate situations, close discussion with interventional radiology is obviously required to ensure the safety of patients.
At the same time as pressure measurements, a transjugular liver biopsy can be performed to contribute to the underlying liver disease diagnosis and will aid in evaluating for liver cirrhosis.
In patients with bleeding, upper gastrointestinal endoscopy is the gold standard to evaluate the presence of varices, their size and location (oesophagus, stomach or duodenum) and for findings compatible with recent bleeding (red marks on the varices). Endoscopy remains an imperfect diagnostic tool for the diagnosis of oesophageal varices in patients with PHT but without a history of bleeding. It is invasive and requires general anaesthesia, and there is a subjective interobserver variation when evaluating varices. Lastly, there is no validated variceal size grading system in the paediatric population [1]. Therefore, noninvasive methods are currently being evaluated to help in the diagnosis of both PHT and oesophageal varices.
Thrombocytopenia is a common complication of PHT. A low platelet count (<115,000) has been described as a predictor of oesophageal varices in the paediatric population. Splenomegaly is also a finding in patients with PHT, and some studies have shown that such patients are up to 15-fold more likely to have varices. One study in children with PHT has shown splenomegaly to have a sensitivity of 98%, but only a specificity of 27%, when compared with endoscopy in diagnosing varices. The ratio of the platelet count to spleen size (centimetre) is also under evaluation to help identify PHT patients with oesophageal varices. The cut-off for diagnosis would be a ratio of <1.0, although it has not reached statistical significance in the paediatric population. Gana et al. have described the clinical prediction rule (CPR) calculated from platelet count, spleen size z-score and albumin concentration to help in identifying patients at risk for developing oesophageal varices [38]. A cut-off of 115 appears to be diagnostic. Although it is still under evaluation, other groups [39] have shown that this tool appears to be reproducible in the paediatric population. Last, the use of transient elastography to evaluate for either liver or spleen stiffness has been evaluated to help in the diagnosis of PHT. It evaluates for either liver fibrosis or spleen congestion, both of which are associated with PHT [40].
25.6.1 Medication
The effects of nonselective β-blockers (NSBBs) in the adult population have been widely studied in randomised and controlled studies. NSBBs will have various effects leading to a decrease in portal pressure by decreasing the splanchnic flow to the portal vein and its collaterals. Cardiac β-1 blockade will result in a decrease in cardiac output, while splanchnic vascular β2 blockade will allow α1 splanchnic vasoconstriction [41]. In the adult population, it has been shown to decrease the risk of variceal bleed by up to 50% in cirrhotic patients. The medication is titrated up to the point of reaching a decrease of 25% in heart rate, and the optimal dose is determined when achieving a reduction of HPVG of <12 mmHg.
Reports of the use of β-blockers in children are uncontrolled case studies, by comparison. Dosage varies from 1–8 mg/kg/day. Various concerns about the use of β-blockers in children have been verbalised, mainly in regard to the risk of being unable to generate a tachycardic response in the setting of hypovolaemic shock due to variceal bleed. Also, there is the risk of side effects from the use of β-blockers, including airway disease, decreased exercise tolerance, hypoglycaemia and behavioural changes [1,42]. Because there is currently no data on safety and efficacy of β-blockers in the paediatric population, their use in primary or secondary prophylaxis of variceal bleed in children is not recommended [5].
25.6.2 Endoscopy
Endoscopic prophylaxis of variceal bleed can be obtained through endoscopic sclerotherapy (EST) or EVL. In the adult population, literature has shown that EVL is superior to EST in both primary and secondary prophylaxis for variceal bleed. A higher number of procedural complications have been associated with EST (oesophageal ulceration, perforation and stricture), and therefore it is no longer recommended.
In the paediatric population, EVL has been shown to be technically feasible in children as small as 12–15 kg. It is well tolerated, associated with a low major complication rate and effective in reducing variceal bleeding occurrence. However, experts currently do not recommend the use of EVL as primary prophylaxis, as it has only been reported in a small number of nonrandomised studies in children. On the other hand, one randomised trial has evaluated the use of EVL for secondary prophylaxis in the paediatric population and has shown the technique to be safe and more effective than sclerotherapy in preventing recurrence of bleeding [42]. Currently, EST is used in the paedatric population for small patients in whom the EVL device would be too large to be used. Otherwise, EVL has supplanted EST in the management of variceal bleed in children.
25.6.3 Transjugular intrahepatic portosystemic shunt
A TIPS is a stent placed through the jugular vein to establish an artificial communication (shunt) between the portal vein and the systemic circulation (via a hepatic vein), therefore reducing the pressure in the portal vein and treating the complications associated with PHT. In the adult population, it is not used for primary prophylaxis of variceal bleed, as NSSBs and EVL have been demonstrated to be effective and less invasive. However, it is used as a rescue measure in the setting of acute variceal bleed, or for prevention of rebleeding from oesophageal and gastric varices [43]. The experience with TIPS in the paediatric population is limited. First, there can be a size limitation from the patients themselves, and second, there is limited expertise in that field. Therefore, currently, TIPS is reserved in the setting of intractable variceal bleeding, when the surgical risk to perform a portosystemic shunt procedure would be too high, and as a bridge to liver transplant [6]. An exception to this situation would be in children too small for the use of polytetrafluoroethylene (PTFE)-coated stents, as the risk of occlusion for a noncoated stent is so high that a surgical shunt creation would be favoured [1].
25.6.4 Portosystemic shunts
Surgical portosystemic procedures are now most often used in the setting of recurrent variceal bleed because of the improvement in endoscopic management of varices in acute bleeding. Children with well compensated liver disease who do not require a liver transplant but have continued bleeding from recurrent oesophageal varices or gastric varices and/or portal hypertensive gastropathy can often be helped with portosystemic shunts [29,44,45]. Portosystemic shunt surgeries may be divided into ‘selective’ and ‘nonselective’ shunts. Nonselective shunts include mesocaval and portocaval shunts. Despite being effective at decompressing varices and decreasing variceal bleed, they also decrease blood flow to the liver, therefore preventing hepatic metabolism of gut toxins, and are thus associated with an increased risk of hepatic encephalopathy. Underlying liver disease can also worsen with decreased hepatic vascular inflow [6]. The shunts are created using an interposition graft. Synthetic (PTFE) graft is preferred over biological (internal jugular vein) graft, because the latter is more easily compressible. If a patient has already undergone a splenectomy, those shunts will constitute the only surgical shunting options from which the patient can benefit.
Figure 25.2 DSRS shunt. This is a venogram of a DSRS in a patient who was suspected of having an anastomotic stricture. In fact, free flow is visible in the splenic vein (arrow), into the renal vein (double arrow).
The DSRS (Figure 25.2) is described in Box 25.1. This is a selective portosystemic shunt effective in decompressing varices and decreasing variceal bleeding, and it is associated with a low postoperative complication rate. Postoperative complications are rare, with a lower risk of hepatic encephalopathy when compared with nonselective shunts. Ascites sometimes occurs and can be medically treated. Postoperative follow-up is performed by following platelet count and by assessing spleen size on physical exam. A US can also be used to assess patency of the shunt, especially when thrombocytopenia recurs or when spleen size increases, and therefore anastomotic stricture of the shunt is suspected. This complication can most often be treated by angioplasty.
25.6.5 Other surgical procedures
In patients with PHT and underlying liver disease ultimately requiring liver transplant, or in patients with decompensated liver disease, results of portosystemic shunts are poor with an increased incidence of recurrent bleed, hepatic encephalopathy and overall mortality. Therefore, liver transplant is the treatment of choice, as it relieves the PHT and also treats the underlying liver disease.
The modified Sugiura * procedure comprises a devascularisation of the oesophageal and gastric beds and an oesophageal transection, without performing a splenectomy. It is an effective measure in the treatment of refractory variceal bleed despite EVL, or massive uncontrollable bleeding [46].
Despite being reported in the literature as an effective intervention for the treatment of hypersplenism or splenomegaly, splenectomy should be avoided in paediatric PHT patients. Indeed, the splenectomy will prevent the creation of a DSRS, and the only surgical options at variceal decompression will be through nonselective shunts.
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