Cystic Fibrosis Related Hepatobiliary Involvement

Description

Cystic fibrosis (CF) is the most common disorder with a genetic cause in the Western world. In Europe, it affects about 1 in 5000 births.

Liver disease and issues of the biliary tract are common in people with cystic fibrosis and can impact their daily life. These issues are generally termed CF-related hepatobiliary involvement (CFHBI), and range from abnormal blood tests (elevated liver enzymes) to advanced liver disease: cirrhosis and/or portal hypertension. Cirrhosis is a condition of advanced liver damage that involves extensive scarring of the liver. About 5-10% of people with cystic fibrosis with CFHBI develop cirrhosis, and many of these cases involve portal hypertension. Portal hypertension is a condition where the pressure in the main blood vessel to the liver is elevated, which can cause enlargement of the spleen and enlarged blood vessels in the stomach. 
Some people with cystic fibrosis and liver or biliary tract involvement also have a slightly elevated risk of liver cancers. 

CFHBI is usually without symptoms and is not detectable by physical examination, unless advanced liver disease is present. If advanced liver disease is present, clinical signs like liver or spleen enlargement, a distinctive rash, and bleeding symptoms can occur. Advanced liver disease in people with cystic fibrosis typically develops during childhood and is thus mainly diagnosed in childhood age. In most cases, CFHBI is detected or suspected during routine blood tests, or via imaging (mostly ultrasound, sometimes MRI).

It is currently not well known why CFHBI, with or without advanced liver disease, develops in one person with cystic fibrosis and not in another. In general, people with cystic fibrosis due to certain types of gene mutations seem to develop CFHBI more than others, although the link between the two is not very strong. Gene mutations are changes in the genetic code that can cause disease, such as the mutations in the CFTR-gene that cause cystic fibrosis.
Other factors that could contribute to developing liver disease involve general lifestyle measures that apply to everyone. Maintaining a healthy diet, avoiding alcohol exposure, and physical exercise can contribute to avoiding damage to the liver. Conversely, an unhealthy life style can accelerate CFHBI development or worsen it.

Diagnosis

Involvement of the liver and biliary tract in cystic fibrosis varies greatly, which is why confirming or ruling out the disease cannot be done with one single test. It is also important to know that liver and bile duct issues can change over time.

Doctors sometimes use a classification system (see additional information at the end of this document) that incorporates the diverse aspects of the diagnosis and to monitor changes over time. When CFHBI is initially diagnosed, a thorough workup is often done to rule out other causes of chronic liver disease besides cystic fibrosis.

Blood tests

CFHBI frequently involves abnormal blood tests. The blood tests associated with the liver (more specifically called enzymes, which are a certain type of protein) are part of routine follow-up in all people with cystic fibrosis. The 3 liver enzymes also used for CFHBI classification are:

• Aspartate aminotransferase (AST, sometimes also abbreviated as GOT);
• Alanine aminotransferase (ALT, sometimes also abbreviated as GPT);
• Gamma-glutamyl aminotransferase (GGT).

When one or more of these enzymes are elevated in your blood test, this does not necessarily imply that you have CFHBI, because they can be elevated due to many other causes (many involving self-resolving causes). When your liver enzymes are elevated, doctors will usually follow-up these tests over time, and order additional investigations if this is appropriate for your situation. Some other routine blood tests that can aid in evaluating the liver and biliary tract, are: bilirubin, coagulation tests, albumin, and blood platelets.

Imaging

Another important way to investigate involvement of the liver and/or biliary tract, is by imaging of the liver. This is usually done by ultrasound, where the person who performs this investigation uses an ultrasound probe to visualize the liver, biliary tract, gallbladder and other parts of the abdomen.
Sometimes, an MRI scan is performed to provide more details about the biliary tract or the liver. Performing an MRI is not routinely performed in all people with cystic fibrosis and requires the patient to lay still for around 30 minutes. Both ultrasound and MRI are imaging techniques that do not use radiation.

Liver stiffness measurement

Liver stiffness measurement is performed to measure how hard (stiff) your liver is. This is usually done by a similar ultrasound device, sometimes it is measured during an MRI scan. It is mostly useful for long-term follow-up and should best be performed before the patient has eaten. 

Liver biopsy

A liver biopsy involves taking a small piece of liver using a hollow needle for microscopy and is performed using local anesthesia in adults. In children, sedation or general anesthesia is used to perform this procedure. A liver biopsy is not usually needed to diagnose CFHBI and is only done if there are specific reasons, like ruling out other liver diseases that cannot be diagnosed with other tests.

Treatment

Treatment of CFHBI involves addressing its various symptoms, as there is no specific treatment for liver and bile duct issues in cystic fibrosis.

Non-medicine related treatment

Specialized nutritional care is crucial for all people with cystic fibrosis, whether or not they have CFHBI. This includes receiving enough calories every day to support growth in children or maintaining the right body mass in adults. Besides ensuring sufficient calories, providing supplemental vitamins (vitamins A, D, E, and K) tailored to the individual needs, and regular follow-up of blood sugar levels by the cystic fibrosis care team are all very important. Nutritional care is performed by a specialist team, together with you as a patient. 

Medications

Ursodeoxycholic acid (UDCA) is a medication that is often prescribed for liver abnormalities with different causes. It can also be prescribed for CFHBI, although it is not equally useful for all people with CFHBI.

In case of advanced liver disease, additional medications can be required to better control the consequences and prevent complications, as in all cases of advanced liver disease, regardless of the cause. 

CFTR-modulator therapy is more recent medication and is used in many people with cystic fibrosis. These medications target the underlying disease mechanism of cystic fibrosis and can significantly improve lung function and reduce infections. Experience in the effect of CFTR-modulator therapy on the liver and biliary tract is still limited. As a consequence, it is currently unknown whether CFTR-modulator therapy has an effect on the course of liver and biliary tract involvement (CFHBI).

Liver transplantation

Transplantation of the liver involves removal of the damaged liver by surgery, and replacing it with a liver from a donor. This can be an entire liver, or a part of a donor liver. It is important to note that people with cystic fibrosis only rarely need a liver transplantation. Even when there is advanced liver disease, this can usually be managed for long without the need for liver transplantation. 
On the other hand, if liver transplantation is ever needed, it will be well prepared and can be a very successful treatment for CFHBI. 

Management

Because CFHBI usually does not cause any symptoms, you will most likely not experience any related symptoms during daily life. Regular monitoring is essential to detect CFHBI and its complications early, and it will be checked by your doctors. This should be done in specialized centers with expertise in cystic fibrosis care. 

The techniques detailed in section 2 ‘Diagnosis’ will be performed by your doctors whenever necessary. Usually, whether or not you have CFHBI will not change which doctor will be most involved in your regular follow-up.  
However, it is possible that a liver doctor (hepatologist) follows up on your condition, together with your usual physicians. This can involve separate checkups, or joint consultations, where the liver doctor and your usual doctor will counsel and examine you together in the same room. Normally, regular follow-up of blood tests and imaging (ultrasound or MRI) are enough for monitoring. 
If advanced liver disease is present, more frequent follow-up can be necessary to prevent or timely detect complications and can additionally involve endoscopy of the stomach and esophagus (see figure 3). 
Endoscopy of the stomach and esophagus is performed when the risk of enlargement of blood vessels in the stomach is elevated and can involve treatment of these enlarged blood vessels by ligature (putting an elastic band around the vessel), or injection of a compound in the vessel to shrink it. It is almost always performed under general anesthesia.

Nutritional follow-up by a specialized nutritionist and cystic fibrosis care team is very important in all people with cystic fibrosis, independent of CFHBI. At present, there are no specific nutritional recommendations for CFHBI besides what is generally advised to all people with cystic fibrosis.