Mild Cystic fibrosis-related liver disease (CFLD) is common in CF with severe CFLD affecting 10% of patients. Pancreatitis rarely affects patients who are pancreatic insufficient, however, nearly one in five patients with CF can be affected.
Cystic fibrosis-related liver disease
CFLD is a broad term which refers to a spectrum of abnormalities ranging from mild liver enzyme derangement on routine blood tests to biliary cirrhosis with portal hypertension and liver failure. Severe CFLD is the third leading cause of death in CF, after respiratory failure and transplant-related complications.
What causes CFLD?
The underlying genetic defect in CF is due to mutations in the CF transmembrane regulator (CFTR) gene which encodes the CFTR chloride channel. The CFTR protein is located on the epithelial lining of the bile duct and gall bladder. Its key function is to hydrate bile and facilitate bile flow. Abnormal CFTR function leads to thickened and sluggish secretion which blocks the bile ducts (1, 2). This leads to excessive accumulation of toxic bile salts which causes inflammation, fibrosis and cirrhosis of the portal tract inside the liver. Furthermore, the CF gut is thought to have increased permeability. This leads to the leakage of bacterial factors from the gut into the portal circulation which incites further liver inflammation and fibrosis (1).
Clinical presentations of CFLD
Mild CFLD is common in CF. Transient liver enzyme abnormality is common in children and adults with CF and generally does not cause major issues. However, severe CFLD affects 10% of patients with CF. Severe CFLD refers to biliary cirrhosis with portal hypertension and liver failure. Portal hypertension causes enlargement of the spleen, low platelets and oesophageal and gastric varices (enlarged blood vessels). Patients with portal hypertension are at risk of significant variceal bleed. Progression of CFLD can lead to liver failure. Severe CFLD mainly affects those with severe CFTR mutations (Class I- III). Patients with the same CFTR mutations can have different disease trajectories (3). This is likely to be due to the complex interaction between the CFTR gene with other modifier genes and environmental factors in the development of CFLD. Males tend to be affected by CFLD more than females.
Other types of CFLD include neonatal cholestasis, hepatic steatosis, micro gallbladder, gallstones and biliary sludge (4). Cancer of the bile duct and gall bladder are uncommon but had also been reported in CF.
Investigations
The diagnosis CFLD diagnosis is based on clinical examination, blood test and radiological imaging including abdominal ultrasonography (US), MRI or CT scans and newer techniques such as Elastography. Liver biopsy is sometimes required to confirm the diagnosis.
Management of CFLD
To date, there is no effective treatment for preventing or slowing the progression of CFLD. Supportive management are important in CFLD. This includes optimising the nutritional status, avoiding alcohol and hepatotoxic medications and vaccination against hepatitis A and hepatitis B and varicella zoster virus. Patients with enlarged spleen should consider avoiding contact sports to prevent splenic injuries. In patients with portal hypertension, regular surveillance gastroscopies are required for the early detection and banding of varices. In patients with liver failure, liver transplant is a potential option.
Ursodeoxycholic acid (URSO) improves liver enzyme abnormalities but its efficacy in CFLD is controversial. To date, there is insufficient evidence to show URSO improves long-term clinical outcomes in CFLD.
Exciting developments in CFTR modulation therapies (e.g. ivacaftor) have demonstrated substantial clinical benefits in patients with specific CFTR mutations. These benefits include improvement in respiratory symptoms, lung function and nutritional status. However, it remains unclear if CFTR modulation therapies can also prevent or halt the progression of CFLD and further studies are required.
CF-related Pancreatitis
Pancreatitis almost exclusively affects patients with CF who are pancreatic sufficient and rarely affects patients who are pancreatic insufficient (5). Nearly one in five patient with CF who is pancreatic sufficient is affected by pancreatitis (5, 6). Pancreatitis is also an independent risk factor for developing pancreatic insufficiency later in life (1, 5, 6).
What causes CF-related pancreatitis?
CFTR is expressed on the epithelial lining of pancreatic duct. It regulates the acidity, fluidity and the enzyme content of the pancreatic fluid. Patients who are pancreatic sufficient have preserved pancreatic tissue which produces digestive enzymes. However, abnormal CFTR function causes abnormal thickened pancreatic fluid which blocks the pancreatic duct. This leads to the leakage of digestive enzymes into other parts of the pancreas, causing injury, inflammation, swelling, pain and subsequently scarring.
Clinical presentations of CF-related pancreatitis
Acute pancreatitis commonly present in late adolescence or early adulthood. Classical symptom is severe abdominal pain which might be associated with nausea and vomiting. Pancreatitis can be the first presenting symptom in patients with non-classical CF.
Diagnosis
Diagnosis is confirmed on blood test which shows raised levels of pancreatic enzymes (e.g. amylase and lipase). Radiological imaging, such as US or CT of the abdomen is sometimes required for further assessment.
Management of pancreatitis
Recognition of pancreatitis symptoms and early presentation to medical assessment is the key to facilitating the effective management of acute pancreatitis. Management is supportive which generally include gut rest, intravenous fluid and pain relief. Potential precipitating factors such as alcohol, medications and dietary factors will need to be carefully addressed. Further studies are required to assess if CFTR modulation therapies are effective in preventing CF-related pancreatitis.
Long-term outcome
Recurrent pancreatitis causes progressive inflammation and destruction of the remaining pancreatic tissue. Therefore, recurrent pancreatitis is a risk factor for the development exocrine and endocrine pancreatic function in patients who are previously pancreatic sufficient. Close clinical monitoring is required to detect pancreatic insufficiency in patients with recurrent pancreatitis.
Written by Dr Anna Tai (Consultant Physician, Respiratory Medicine, Sir Charles Gairdner Hospital) for RED Magazine, Edition 3, 2016.