Description of the condition

Cystic fibrosis (CF) is a life‐limiting autosomal recessive disorder caused by mutations in the CF transmembranes conductance regulator (CFTR) gene on chromosome 7, which is expressed on epithelial cells. It is a multi‐organ disease primarily affecting the lungs, pancreas, sweat glands, reproductive tract (Wolffian ducts in males), gastro‐intestinal tract and liver (Davis 2006). The incidence of CF varies between Asia, Europe and the USA. In Asia, while the condition is severely under‐diagnosed, its prevalence is rare. The incidence of CF is 1 in 2000 to 3000 newborns in the European countries; 1 in every 3500 births in the USA (WHO 2015). Further, a mean prevalence of CF was 0.737 per 10,000 people in some of the countries in the European Union, 0.797 per 10,000 in the USA, and 2.98 per 10,000 in the Republic of Ireland (Farrell 2008). The mortality data for the white population in the USA from 1999 to 2006 was 3708 people (CDC 2010).

Cystic fibrosis‐associated liver disease (CFLD) is an early complication of CF which occurs mostly in the first decade of life, particularly in people with a history of meconium ileus or pancreatic insufficiency and severe (class I to III) mutations (Colombo 2002; Nagel 1989). Advanced liver disease presents mainly during pre‐puberty and puberty with a median age at diagnosis of 12 years (Lindblad 1999). The incidence rate (number of new cases per year) of CFLD is 1.8% (Colombo 2002).

With increased life expectancy, CFLD has emerged as a significant cause for morbidity and mortality (Simmonds 2008) and evidence of clinically significant liver disease is found in around 25% of people with CF. Between 3% and 5% develop pulmonary hypertension (PHT) due to severe cirrhosis during the first decade of life, with a median age of diagnosis of 10 to 11 years of age; 90% of those affected are diagnosed before 20 years of age (Bartlett 2009; Debray 1999; Gooding 2005). A prevalence rate for CFLD of 41% at 12 years of age has been reported (Lamireau 2004). CFLD may progress to chronic obstructive cholangiopathy, focal biliary cirrhosis and multilobular cirrhosis with associated PHT with or without variceal bleeding and end‐stage liver disease. Cirrhosis and PHT can negatively impact on respiratory function due to organomegaly (abnormal enlargement of organs), ascites and intra‐pulmonary shunting (Smith 2004). PHT is an increase in the blood pressure within a system of veins called the portal venous system. Clinically significant PHT is defined as a hepatic venous pressure gradient of 10 mm Hg or more (Bari 2012). Most people with CFLD are asymptomatic. Approximately 10% of people with CFLD and PHT progress to advanced liver disease (Rowland 2011). Liver failure may occur subsequently (Melzi 2006).

Diagnosis of CFLD should be made when at least two of the following variables are present (Debray 2011):

• abnormal physical examination: a palpable liver edge more than 2 cm below the bottom edge of the rib cage on the mid‐clavicular line and a prominent left lobe palpable in the epigastrium, confirmed by ultrasound;

• abnormal liver function tests: an increase in transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and gamma‐glutamyl transpeptidase (GGT) levels above the upper normal limits on at least three consecutive occasions over 12 months, after other causes of liver disease;

• ultrasonographic evidence of liver involvement (an increased parenchymal echogenicity, irregular margins, nodularity) or PHT (splenomegaly, increased think ness of lesser omentum, spontaneous spleno‐renal anastomosis, large collateral veins, ascites) or biliary abnormalities (bile duct dilatation);

• a liver biopsy may be indicated if there is diagnostic doubt.

There is a developing role for transient elastography (also known as Fibroscan®) for investigating CFLD, despite the absence of adequate validation against histology and other long‐term outcomes such as PHT, bleeding risk, cirrhosis, synthetic failure and transplantation (Ledder 2014). This method is widely used to stage liver fibrosis as an alternative to a liver biopsy; it measures liver stiffness, and it is also a valuable tool to detect and quantify CFLD in children and adults with CFLD (Ledder 2014; Malbrunot‐Wagner 2011; Menten 2010; Sadler 2015; Witters 2009). Liver stiffness is an accurate non‐invasive indicator in assessing the progression of liver disease in people with CF (Kitson 2013).

Description of the intervention

The principle of managing PHT in people with CFLD is not dissimilar to its management in those without CFLD.

In adults with evidence of PHT and the presence of varices, non‐selective beta‐blockers (NSBB) should be considered to prevent or reduce the number of bleeding events (Cheng 2005). The two most commonly used NSBB for preventing bleeding are propranolol and nadolol. Their dose is titrated to achieve the resting heart rate of 55 beats per minute or a reduction of heart rate by 25% from baseline, and adjusted to maximal tolerated doses. Propranolol is usually started at a dose of 20 mg twice daily and nadolol at a daily dose of 40 mg (Garcia‐Tsao 2007). However, in people with CF with a broncho‐constrictive element to their lung disease, NSBB may be contraindicated. Some studies in children suggest a possible benefit with few side effects, but there are no control data from these studies (Shashidhar 1999).

In adults and children with acute bleeding varices, the preferred initial intervention is upper gastro‐intestinal endoscopy with band ligation or sclerotherapy (Brigman 2006; Debray 1999; Efrati 2003; Price 1996; Stringer 1993). Endoscopic therapies have no effect on either portal flow or resistance (Garcia‐Tsao 2007). Endoscopic variceal band ligation is indicated as the primary variceal prophylaxis as well as the preferred therapy for variceal haemorrhage (Gluud 2012) and a single‐ or multi‐band ligator may be used (Wong 2000). Endoscopic variceal band ligation is very effective with a high success rate in both acute variceal bleeding episodes as well as for primary prophylaxis (Funakoshi 2012; Mileti 2011). Band ligation must be repeated periodically until the varices have been ablated (Gooding 2005). During sclerotherapy, a chemically irritating compound (ethanolamine or tetradecyl sulphate) is injected into (intravariceal) or adjacent to (paravariceal) a varix to control active bleeding or for variceal decompression (Gugig 2012; Kahan 1989). Sclerotherapy has been shown to be inferior to band ligation and is recommended only in specific cases, such as very young children, in whom banding is not possible (due to size of gastroscope and banding device) (Brigman 2006). Sclerotherapy is no longer used in the secondary prophylaxis of variceal haemorrhage in adults.

A balloon tamponade (Sengstaken Tube) is indicated only in cases of massive variceal bleeding in the absence, or failure, of definitive endoscopic treatment.

In a small number of individuals, for example those with severe PHT and refractory variceal haemorrhage in whom therapeutic endoscopy treatment has failed, a transjugular intrahepatic porto‐systemic stent shunt (TIPSS) should be considered either as a long‐term treatment option or as a bridge to transplant (Brigman 2006). An interventional radiologist generally inserts the TIPSS; a catheter is placed into the jugular vein and advanced into the hepatic vein, where a needle is used to form a tract between the left portal vein and the right hepatic vein. This tract is expanded with a balloon angioplasty catheter and a stent is then placed, forming a permanent porto‐systemic (PS) shunt (Efrati 2003; Gugig 2012). The diameter of the stent is generally between 8 mm and 10 mm.

Surgical PS shunting could be considered in selected individuals with preserved liver function and without severe respiratory disease or deterioration (Debray 1999; Efrati 2003). This procedure is indicated for large varices at a high risk of bleeding and failure to respond to a banding programme (Ledder 2014). For individuals with non‐cirrhotic PHT, in particular with extrahepatic portal vein thrombosis, PS shunt surgery represents the only effective therapy to prevent recurrent bleeding and repeated endoscopies for many years. Non‐selective shunts (mesocaval, portocaval), selective shunts (distal spleno‐renal) and intermediate shunts may be used (Gugig 2012).

Liver transplantation is the treatment of choice for decompensated or end‐stage CFLD or uncontrollable variceal bleeding despite an intensive therapeutic endoscopic programme (Cox 1987; Kobelska‐Dubiel 2014; Mack 1995; Noble‐Jamieson 1996). Whole‐liver, reduced‐liver or split‐liver transplant techniques are used (Melzi 2006).

How the intervention might work

Treatment with NSBB lowers cardiac output and causes vasoconstriction in the gastrointestinal tract, thereby reducing portal and collateral blood flow in the abdomen. However, this treatment is reserved for selected individuals only and should be avoided in those with CFLD who have a broncho‐constrictive element to their respiratory disease. These agents have been shown to prevent bleeding in more than 50% of people with medium or large varices (Garcia‐Tsao 2007).

Individuals undergoing variceal band ligation will have endoscopy sessions at regular intervals until the varices are ablated. In children this will generally be carried out under general anaesthesia and consequently, if frequent endoscopy sessions are required, may potentially have a negative impact on respiratory function.

A TIPSS places a stent between the intrahepatic portions of the portal vein and the hepatic vein and leads to a reduction of portal venous pressure and thus a reduction of pressure in oesophageal and gastric varices, preventing further variceal haemorrhage; it is reported to successfully control active and potentially life‐threatening variceal bleeding in more than 90% of cases. This technique is associated with low complication rates, but major risks include TIPSS dysfunction with stenosis, occlusion or thrombosis and new‐onset or worsened encephalopathy. In the long term, regular radiographic examination (ultrasound scans or TIPSS venogram, or both) are necessary to ensure that the TIPSS is functioning correctly and not suffering from blockages (Pozler 2003).

Surgical PS shunting aims to divert portal blood flow and as such decrease portal pressure leading to a reduced risk of bleeding (Ledder 2014). Surgical PS shunting improves hypersplenism without deteriorating liver function or encephalopathy (Wolff 2003). The non‐selective shunts, communicate with the entire portal system and have been associated with higher rates of hepatic encephalopathy compared with the selective shunts. The distal spleno‐renal shunt is a selective shunt which connects the distal end of the splenic vein to the left renal vein with interruption of all collateral vessels (e.g. coronary vein and gastroepiploic veins). In effect it separates the portal venous circulation into a decompressed gastrosplenic venous circuit (thus reducing the pressure on gastric and oesophageal varices) and a high‐pressure superior mesenteric venous system that continues to perfuse the liver. Liver function is preserved by a distal spleno‐renal shunt which is associated with a lower incidence of portal systemic encephalopathy (D’Amico 1995). Potential complications include onset or worsening of hepatic encephalopathy, shunt thrombosis or occlusion (Debray 1999; Efrati 2003). Hepatic encephalopathy is the most common adverse event developed after treatment with PS shunting for PHT (Flass 2013).

Liver transplantation is indicated in people with CFLD with progressive hepatic dysfunction, development of ascites and jaundice, intractable variceal bleeding, hepato‐pulmonary and porto‐pulmonary syndrome, severe malnutrition unresponsive to intensive nutritional support, deteriorating quality of life (QoL) related to liver disease or deteriorating pulmonary function or both (Debray 2011; Fridell 2003; Ikegami 2008; Melzi 2006; Nash 2008). Based on these factors, two scoring systems are currently available to evaluate the need for liver transplantation in adults with CFLD (Milkiewicz 2012; Noble‐Jamieson 1996). No such specific scoring systems exist for children. Liver transplantation in this group does not improve long‐term nutritional status, but short‐term improvement in pulmonary function after liver transplantation has been reported. Some of the initial improvement in lung function may reflect the resolution of the effects of severe PHT such as pulmonary oedema, intrapulmonary shunting ascites and organomegaly, in addition to reduced infection resulting from improved immune function, particularly neutrophil function (Dowman 2012). One further study showed there is improvement in QoL after liver transplantation (Moyer 2009).

Why it is important to do this review

Evidence‐based guidelines from the European and American Board of Gastroenterology recommend screening for and treating large varices in adults with severe PHT without a history of variceal bleeding (Shneider 2012). They suggest the use of NSBB as a first‐step therapy in adults with grade two or grade three varices, band ligation if beta‐blockers are contra‐indicated or have failed (secondary prophylaxis), and the placement of a TIPSS in cases of ligation failure (tertiary prophylaxis) (De Franchis 2005). In contrast, there is a paucity of data to recommend specific approaches for the management of PHT in children; and extrapolation of care models for adults to children may not be appropriate (Shneider 2012).

There are currently no clear recommendations for treating advanced liver disease in people with CF (Debray 2011). Furthermore, for people with CFLD, no specific recommendations exist with respect to the prevention and treatment of variceal haemorrhage. In addition, because of their lung disease, the use of beta‐blockers is usually contra‐indicated. Regular screening or therapeutic endoscopies may require general anaesthesia (particularly when carried out in children) and may lead to a reduction in lung function or predisposition to infection.