What is Cystic Fibrosis and Liver Disease?
Cystic fibrosis, or CF, is a genetic disorder that mainly affects white individuals. The condition happens in about 1 out of every 3,500 births. This disorder affects various systems in the body. It’s caused by changes in a specific gene called the cystic fibrosis transmembrane conductance regulator (CFTR). This gene is found on chromosome 7. It creates a protein that helps regulate how chloride, a component of salt, is absorbed through the walls of cells.
This chloride channel protein created by the CFTR gene is found in the cells of the lungs, digestive system, reproductive system, and skin. When this gene has mutations, it disrupts chloride’s movement and water flow in and out of cells. This disruption thickens secretions and can result in the malfunction of organs.
Even though CF mainly affects the lungs, it can also lead to liver disease in about 10 to 15% of CF patients. The improvement in diagnosing and managing CF has increased patients’ lifespan. However, it has led to an increase in occurrences of liver complications. When CFTR isn’t working properly; it disrupts how bile is made, causing long-term damage to liver cells. This damage can cause a wide range of liver complications, from bile buildup to scarring around the portal veins, blockage of bile ducts, and abnormal liver structure. These conditions can progress to severe scarring of the liver, high blood pressure in the liver, and liver failure.
What Causes Cystic Fibrosis and Liver Disease?
Cystic fibrosis-related liver disease is believed to be caused by changes in the moisture and pH levels of the bile (a fluid produced by the liver to help digest food). This change is due to a mutation, or change, in the CFTR gene, which is found in cells that manage the balance of chloride (a kind of salt) within the body.
There are about 2000 known mutations of the CFTR gene, and they’re grouped into five categories depending on what issue they cause. These can range from the gene not making enough protein, not processing the protein properly, issues with the opening of the cell channel, reduced chloride movement through the cell, to decreased protein synthesis. The most common mutation involves the deletion of a specific component called phenylalanine at location 508 (F508del) on chromosome 7. This mutation is found in 80% to 90% of cystic fibrosis patients.
However, no specific CFTR mutations have been directly linked to cystic fibrosis-related liver disease. Research has shown certain risk factors including being male, having mutations in classes I-III, related pancreatic issues, and a condition called meconium ileus present at birth. In a small study, it was found that 51% to 55% of liver disease patients with cystic fibrosis had the F508 mutation.
It should be noted that cystic fibrosis patients with the same CFTR mutation can have different liver conditions, suggesting that environmental factors or other potential causes like medication used in cystic fibrosis treatment, chronic infections, and malnutrition may play a role in the development of liver disease related to cystic fibrosis.
Risk Factors and Frequency for Cystic Fibrosis and Liver Disease
Cystic fibrosis (CF) is a disease that affects people differently based on their geographical background and ethnicity. It’s more commonly seen in white people, with about 1 in every 2,000 to 3,000 newborns being affected. The numbers are lower in Latin American and African American populations, with 1 in every 4,000 to 10,000 and 1 in every 15,000 to 20,000 newborns affected respectively. While we don’t know much about the disease’s prevalence in other racial groups, we do know that CF can lead to liver disease in about 10% to 15% of patients.
Based on a research study, the rate of CF was found to be 2.5 for every 100 patients each year during the first 10 years of their life. However, this rate significantly drops in the second decade. About 5% to 10% of people with CF develop a specific type of liver disease, called multilobular cirrhosis, during the first 10 years of life. The disease can be deadly and is the third most common cause of death among CF patients, with an overall mortality rate of 2.5%.
Signs and Symptoms of Cystic Fibrosis and Liver Disease
Cystic fibrosis, or CF, can negatively affect the liver in about 15% to 17% of patients, usually starting before or during their teenage years. The ways this can show up vary widely, from causing unnoticed changes to liver function tests to causing serious liver disease. In babies with CF, an unusual cause of liver disease could be a condition called cholestasis. Although this is rare, it tends to occur in about 50% of newborns with CF, especially if they also have a blockage in their intestines from hard stool.
The most common sign of liver disease related to cystic fibrosis is an enlarged liver, which can be found during a regular check-up. This enlargement might be because the liver is filled with fat or because of scar tissue in the liver’s bile ducts. The liver function tests might also show abnormal results.
- Enlarged liver
- Changes in liver function tests
In 1% to 10% of patients, there may be a blockage in the common bile duct, inflammation in the gallbladder or both, which could cause belly pain and turning yellow. Severe liver disease in cystic fibrosis affects about 7% of patients, and is marked by scarring in many parts of the liver, which can cause high blood pressure in the portal vein. This can make lung disease worse, and also increase the chance of getting sicker or dying.
Testing for Cystic Fibrosis and Liver Disease
Diagnosing liver disease related to cystic fibrosis can be quite tricky because there isn’t a test that’s both highly sensitive and specific. Many times, signs of the disease aren’t seen until the liver is severely damaged and blood pressure in the liver increases. However, the detection of this condition in the early stages is based on thorough health checks, chemical tests, and various imaging techniques.
It is observed that around 40% to 50% of patients with cystic fibrosis show occasional increases in certain liver enzymes in their blood even when they do not display any symptoms. Unfortunately, these fluctuations cannot accurately predict the presence of liver damage. If these liver enzymes remain persistently elevated, it’s essential to investigate further to rule out other conditions such as viral hepatitis, autoimmune liver disease, celiac disease, Wilson disease, and iron overload disorder. As cystic fibrosis-associated liver disease usually affects the bile ducts in the liver, it is also important to rule out other diseases that similarly affect these ducts.
Emerging blood tests using various markers, such as the ratio of certain liver enzymes to platelets and a score known as the Fibrosis-4 index, can be useful in detecting liver damage early on.
Ultrasound scanning is a vital tool in diagnosing this condition as it is good at detecting fatty liver, scar formation in specific regions of the bile ducts, complex liver damage, and abnormalities in the bile ducts. However, a normal ultrasound result does not necessarily mean that the patient has a low risk for developing scars in the liver. Even patients with cystic fibrosis who present with normal ultrasound results may still progress to severe liver damage. Other imaging methods like CT and MRI scans are useful to distinguish between liver scarring and fat deposition and are highly helpful to detect bile duct irregularities. A technique that involves the controlled creation of mechanical waves (vibration controlled transient elastography) is gaining recognition as an affordable and non-invasive test to determine the stage of liver scarring. Employing this technique alongside the newer blood tests can help establish the extent of liver fibrosis.
While liver biopsy (sampling of liver tissue) is considered the most definitive test for diagnosing and determining the severity of this condition, it is not routinely recommended because of its invasive nature and the disease’s patchy distribution in the liver. More in-depth biopsy techniques have been shown to have a 22% improved detection rate compared to simpler methods when testing patients with suspected cystic fibrosis-associated liver disease.
Recently, two diagnostic criteria for this condition were suggested. These criteria consider multiple factors, including physical examination, lab tests, imaging techniques, vibration controlled transient elastography, non-invasive biomarkers, and liver biopsies.
Treatment Options for Cystic Fibrosis and Liver Disease
There is currently no proven treatment that can effectively slow the progression of liver disease associated with cystic fibrosis. The primary focus of management, once the disease has been diagnosed, is to handle the complications of portal hypertension and cirrhosis.
Portal hypertension, or high blood pressure in the blood vessels of the liver, is a common issue for those with advanced liver disease. This condition should be assessed using a variety of methods, including physical examinations, ultrasound scans, and blood tests. When portal hypertension occurs, it can lead to esophageal and gastric varices, which are enlarged veins that can cause bleeding. To prevent this, anyone who has cystic fibrosis-associated liver disease should be checked for these varices using a special kind of endoscopy. If large varices are found, treatment to prevent bleeding will be required, which could involve medication, endoscopic treatment, surgery or radiological intervention.
Cysts in the liver associated with cystic fibrosis may sometimes lead to liver cirrhosis. The treatment for this is not fully understood and can lead to a tightening of the airways. A procedure known as endoscopic variceal band ligation is considered the best way to prevent and treat varices. However, if bleeding continues, other treatments such as a liver transplant might be necessary. Surgical intervention is also an option but is generally reserved for extreme cases to decrease the risk of further liver damage.
Fluid buildup in the abdomen, known as ascites, is seen as a negative indicator for prognosis. This condition is usually managed through a restricted diet and medication. In these instances, a referral for a liver transplant should be considered. Meanwhile, brain dysfunction due to liver failure, known as hepatic encephalopathy, is rare but can occur after treating portal hypertension.
Patients with cystic fibrosis-associated liver disease often need regular imaging studies to screen for liver cancer. It is also common for these patients to have malnutrition due to reduced absorption of fat and protein in the body. Therefore, a balanced diet that is high in protein and fat along with supplemental nutrients is recommended.
The drug ursodeoxycholic acid’s role in managing this disease is controversial with studies showing mixed results. New medications that target the proteins affected by cystic fibrosis seem promising, but further research is needed.
Liver transplantation can greatly increase the life expectancy of people with the disease; however, the best time and criteria for this procedure are still not well-defined. Recommendations suggest considering transplantation when certain symptoms of liver failure increase, like low albumin levels in the blood, worsening jaundice and fluid buildup, uncontrollable bleeding of varices, lung-related complications, severe malnutrition, or reduced life quality due to advanced liver disease.
Reports show that worsening liver function negatively impacts nutrition and long-term prognosis. Therefore, liver transplantation is beneficial. If advanced lung disease is present along with liver disease, combined lung and liver transplantation might be considered. Generally, the results of liver transplantation for cystic fibrosis-associated liver disease are promising, with a good survival rate after one and five years. However, this procedure doesn’t necessarily improve long-term lung outcomes.
What else can Cystic Fibrosis and Liver Disease be?
Primary Sclerosing Cholangitis (PSC) is a long-term liver disorder where the small tubes carrying bile both inside and outside of the liver, become inflamed and eventually damaged. This can lead to serious liver disease. This condition is often found in people with Inflammatory Bowel Disease (IBD). PSC shares many similarities with liver disease associated with cystic fibrosis which is often linked to the interaction of certain bile acid receptors.
In contrast to cystic fibrosis liver disease which only affects tubes inside the liver, PSC can affect both inside and outside liver tubes, potentially leading to end-stage liver disease.
Secondary Sclerosing Cholangitis (SSC) is another chronic liver disorder that closely resembles PSC. However, SSC has an identifiable cause and can even be considered as a type of cystic fibrosis liver disease. Also, repeated pancreatitis which is common in cystic fibrosis patients, is a known cause of SSC. Before diagnosing any form of cystic fibrosis liver disease, doctors should rule out other liver illnesses such as bile duct stones, ischemic cholangitis, and recurring infectious cholangitis.
Drug-induced liver damage is another potential problem among these patients, especially since they commonly use antibiotics to treat recurring sinus infections. Certain medications related to the CFTR gene – which is defective in cystic fibrosis – might cause a mild increase in important liver enzymes.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a typical liver disorder affecting about 10-20% of kids. This condition includes diverse liver issues ranging from a buildup of fat in the liver to non-alcoholic steatohepatitis (NASH) leading to serious liver disease. It’s the number one cause of liver fibrosis and cirrhosis in Western children.
NAFLD is frequently seen in cystic fibrosis patients too, with 20-60% having a condition called hepatic steatosis, which is a buildup of fat in the liver. We don’t yet understand why hepatic steatosis is common among cystic fibrosis patients, stressing the need for more long-term research.
What to expect with Cystic Fibrosis and Liver Disease
As people with Cystic Fibrosis (CF) are living longer, liver complications associated with the disease have become a significant health concern. Indeed, liver disease should be seen as an early sign of cystic fibrosis, affecting more than one-fourth of CF patients.
Although the risk factors for CF-related liver disease aren’t entirely clear, monitoring for signs of liver complications should begin early in life, especially for patients with certain types of CF mutations, males, and those with specific birth conditions and pancreatic issues.
A study that looked at the prognosis of CF patients with liver disease found worsening weight percentiles, but not a significant increase in incidents of breathing failure, the need for oxygen therapy, or more frequent hospitalizations. Mortality rates did not differ significantly between CF patients with and without liver disease, but liver disease did increase the overall sickness level.
The impact of lung transplantation on the progression of CF-related liver disease isn’t fully understood. Some studies suggest that liver disease doesn’t seem to be affected by lung transplantation. For patients with worsening conditions, liver transplantation alone or along with a lung transplant may improve outcomes.
Given its influence on overall sickness and mortality rates, it’s crucial to identify Cystic Fibrosis-related liver disease early.
Possible Complications When Diagnosed with Cystic Fibrosis and Liver Disease
Cystic fibrosis-associated liver disease is a complication that happens due to Cystic fibrosis (CF). It impacts around 5% to 10% of CF patients, causing complex liver disease (multilobar cirrhosis) during their early life. This condition turns out to be the primary cause of non-lung-related deaths, accounting for 2.5% of overall CF mortality.
Most patients start showing signs of increased blood pressure in the portal vein system (portal hypertension) in their second decade of life. This condition often leads to upper GI bleeding originating from swollen veins in the esophagus (esophageal varices).
Further complications of severe cirrhosis include the development of excess fluid in the abdomen (ascites), which is generally a foreboding sign, as well as mental confusion due to liver disease (hepatic encephalopathy), abnormal blood movement to the lungs (hepatopulmonary syndrome), high blood pressure between the liver and lungs (portopulmonary syndrome), low platelet counts (thrombocytopenia), reduced white blood cell counts (leukopenia), and liver cancer (hepatocellular carcinoma).
Complications of Severe Cirrhosis:
- Development of excess fluid in the abdomen (ascites)
- Mental confusion due to liver disease (hepatic encephalopathy)
- Abnormal blood movement to the lungs (hepatopulmonary syndrome)
- High blood pressure between the liver and lungs (portopulmonary syndrome)
- Low platelet counts (thrombocytopenia)
- Reduced white blood cell counts (leukopenia)
- Liver cancer (hepatocellular carcinoma)
Preventing Cystic Fibrosis and Liver Disease
Cystic fibrosis is a disease that gradually worsens over time, passed down from parents to their children. To get cystic fibrosis, a child needs to receive a specific mutated gene from each parent. This condition affects many parts of the body. People of Caucasian descent are more likely to carry this gene mutation.
With advancements in treatment, the life expectancy of those who have cystic fibrosis has greatly improved in the past ten years. Nowadays, a condition called cystic fibrosis-associated liver disease (CFLD) is the third most common cause of death for cystic fibrosis patients, following lung-related issues and complications from organ transplants. CFLD contributes to 5% of all cystic fibrosis deaths. Factors that increase the risk of developing this condition include being male, having a certain type of stomach blockage at birth, and having more severe forms of cystic fibrosis.
Up until recently, most people diagnosed with CFLD were children. However, recent research shows that a second wave of the liver disease can be seen in adults, and doctors are not yet clear on why this happens. Currently, there is no universally agreed way to diagnose CFLD because symptoms can vary and the disease affects the liver unequally.
It is recommended to check for CFLD on a yearly basis. Catching it early can help to prevent or delay serious associated health problems and reduce the chances of death. Once progressive CFLD is identified, making a regular check for a particular kind of high blood pressure and managing the associated complications can take place. Doctors should consider a liver transplant for patients with worsening liver failure, noticeable by complications related to high blood pressure in the liver, progressively low levels of a protein called albumin, problems with blood clotting, severe malnutrition, declining lung function and a decrease in quality of life.
