Pathobiology

The pancreas is composed of endocrine cells that secrete hormones, exocrine cells that make digestive enzymes, and duct cells that secrete bicarbonate and water. The exocrine pancreas consists of cells organized into acini and a duct system that leads to the small intestine. The pancreatic juice secreted from the duct cells is clear, colorless, and nearly isotonic. In both animals and humans, bicarbonate seems to drive fluid secretion by the pancreatic ducts. Bicarbonate allows the highly concentrated proteins that are secreted by the pancreatic acinar cells to remain in a soluble state. Moreover, bicarbonate is important for neutralizing gastric acid to create the optimal pH for pancreatic enzymes, bile acids, and micelles. The adult pancreas normally secretes 1–2 L of a bicarbonate-rich fluid each day. The basis of the bicarbonate secretion relies on the exchange of luminal chloride for bicarbonate, but the exact mechanism is still not fully understood. The CF transmembrane conductance regulator (CFTR) protein is located in the apical membrane of the epithelial cells of the pancreatic ducts. The apical Cl ⁻ /HCO ₃ ⁻ exchanger is dependent on the expression of CFTR, which functions as the apical Cl ⁻ channel. Most likely, the apical anion exchanger in the pancreatic duct cells is a member of the SLC26 family. A physical association between SLC26A6 and CFTR has been suggested due to the presence of a PDZ domain at the C terminus of SLC26A6, which is identical to that of CFTR. Furthermore, they both bind through the PDZ motif to scaffolding proteins. It is possible that SLC26A6 and CFTR interact through these scaffolding proteins, allowing CFTR to stimulate the apical anion exchange. However, the classic proposal of a 1 : 1 exchange of Cl ⁻ /HCO ₃ ⁻ cannot explain the large sustained secretion of bicarbonate. Two of the members of the SLC26 family, SLC26A3 and SLC26A6, have been proposed to work in conjunction to achieve normal bicarbonate secretion. SLC26A3 secretes Cl ⁻ :HCO ₃ ⁻ in a ratio of 2 : 1, whereas the ratio by SLC26A6 is 1 : 2. This information, combined with the location of SLC26A6 at the proximal ducts and SLC26A3 at the distal ducts, may explain the high bicarbonate concentration found in normal pancreatic juice. However, it does not appear that the combination of the two exchangers are able to reach the necessary concentration of luminal bicarbonate. Alternatively, the activation of the WNK1-OSR1/SPAK (protein kinase with no lysine 1-oxidative stress response kinase 1/sterile20-related, proline-alanine rich kinase) pathway causes CFTR to become permeable to HCO ₃ ⁻ , which allows for the generation of the necessary concentration of 140 mmol/L of HCO ₃ ⁻ of normal pancreatic juice.

Dysfunction of CFTR, as in CF, results in impaired electrolyte transport and thus a reduction in fluid secretion. Thus the pancreatic juice in individuals with CF is significantly more concentrated then controls. These thickened secretions then lead to obstruction of the pancreatic ducts, as well as inflammation and injury ( Fig. 52.1 ).

Pathophysiology of pancreatic disease in cystic fibrosis.

Pancreatic Insufficiency

Pancreatic insufficiency (PI) occurs when the amount of digestive enzymes delivered to the intestine is inadequate for nutrient digestion. Steatorrhea, the presence of excess fat in the stool, then occurs. Infants with PI at diagnosis often have decreased weight gain, minimal fat stores, and reduced serum albumin and blood urea nitrogen (BUN) levels. Children with PI may present with growth failure, weight loss, abdominal bloating, foul-smelling stools, edema, or diarrhea. Parents of children who are toilet-trained may report that the stools appear to be floating due to the high fat content of the stool, although stools may float due to increased air content, and this is seen in other conditions as well. It is possible that with mild PI, stools appear normal. Imaging of the pancreas will show atrophy with replacement by fatty tissue in individuals with PI.

CF is the most common cause of PI in childhood. Approximately two-thirds of children with CF are pancreatic insufficient at birth, and approximately 90% will develop PI by 1 year of age. Individuals with two mutations from class I, II, or III CFTR mutations typically have severe pancreatic disease resulting in PI. In patients with severe disease, the obstruction and destruction of exocrine function begins in utero. The damage to the pancreas that occurs in utero forms the basis for newborn screening for CF disease. Serum immunoreactive trypsinogen (IRT) is a precursor to trypsin that is elevated in the blood of infants with CF. When pancreatic dysfunction is present, release of pancreatic enzymes is impaired, and IRT accumulates in the blood stream. Therefore most infants with CF have elevated blood levels of IRT. It has been shown that children who develop PI and those diagnosed with PI in early infancy have similar patterns of IRT levels. One study found that IRT determinations alone were not sufficient to demonstrate differences between mild and severe disease in the first year of life, suggesting ongoing pancreatic damage, and thus elevated IRTs, in both groups.

Pancreatic Sufficiency

Approximately 10%–15% of individuals with CF produce sufficient amounts of pancreatic enzymes to prevent malabsorption of nutrients and are considered to be pancreatic sufficient (PS). These individuals tend to have at least one of the CFTR mutations that are associated with mild pancreatic disease (class IV or V). However, if only one mild CFTR mutation is present, then this does not exclude the possibility of developing PI in the future. On average, sweat chloride levels are lower in individuals with PS as compared with those with PI. Individuals with PS also tend to have less severe lung disease and better nutritional status than those who have PI. With milder disease, the diagnosis of CF tends to occur later in childhood or early adulthood. Twenty percent of individuals with CF who are PS will develop pancreatitis. The diagnosis of pancreatitis may, in some cases, precede the diagnosis of CF.

Assessment of Pancreatic Function

Every individual with CF should be screened for PI at diagnosis. In addition, individuals with at least one severe CFTR mutation (class I, II, or III) should be screened at least annually for PI. Evaluation of pancreatic function can be made by direct or indirect testing. Direct testing requires stimulation of the pancreas (with secretin, cholecystokinin, or both) and collection of pancreatic fluid for analysis. To obtain pancreatic fluid for direct testing, a tube or an endoscope must be placed in the small intestine, which is invasive and often requires sedation. In children who require long-term follow-up for their PI, repeated invasive testing is not feasible. Indirect tests are noninvasive and less costly, so they are typically preferred. However, with mild pancreatic exocrine dysfunction, indirect testing can be less sensitive and specific. In contrast, direct stimulation of the pancreas with secretin has high sensitivity and specificity in identifying PI.

The 72-hour quantitative fecal fat balance method has been used as an indirect test to diagnose PI. If fecal fat excretion is more than 15% of total fat intake in infants less than 6 months of age, and 7% in older infants, then malabsorption is present. Compliance remains an issue with this test because it requires a 3- to 5-day stool collection and a complete dietary history. In addition, most patients with fat malabsorption have diarrhea, which makes complete collection difficult, especially in infants with absorbable diapers. Due to these limitations, alternatives to the fecal fat balance test have been sought. The most commonly used of the indirect tests is fecal pancreatic elastase-1. Children do not have to stop pancreatic enzyme supplementation to complete this test. However, the presence of intestinal villous atrophy, as in celiac disease, or acute episodes of diarrhea can lead to falsely low values. The specificity and sensitivity of fecal pancreatic elastase-1 in a pediatric CF cohort is 100% when a value of less than 100 µg/g is used. The specificity of this test was lower in individuals with non-CF pancreatic disease (e.g., Shwachman-Diamond syndrome). Overall, the negative predictive value was 99%. An empiric trial of pancreatic enzyme replacement therapy (PERT) in an individual with a strong clinical history of PI could also be considered.

Management of Pancreatic Insufficiency

In CF, treatment for PI focuses on optimizing PERT to promote absorption of nutrients and fat-soluble vitamins. In 1991 the US Food and Drug Administration (FDA) mandated that all pancreatic enzymes be approved; prior to the enactment of FDA standards in 2010, PERT was not regulated. Currently, six approved products are available. Each product includes a combination of lipase, protease, and amylase. These enzymes are in the form of granules or microspheres with a pH-sensitive coating to allow release in the alkaline environment of the small intestine. Dosing for PERT is based on the lipase component. Because of this, it is not advisable to use an unregulated generic or nonproprietary preparation because the amount of lipase can potentially vary even in the same product. More importantly, enzyme dosage should not exceed 2500 lipase units/kg per meal or 4000 lipase units/g fat per day (10,000 lipase units/kg/day total) to avoid fibrosing colonopathy. Fat-based dosing of PERT relies more on the number of fat grams per meal or snack than the person’s weight. This method may be more applicable for infants ingesting around the same amount every day and individuals with tube feedings or reliance on packaged foods. The dose should be no more than 2500 lipase units/kg per feeding, with a maximum daily dose of 10,000 lipase units/kg. Caution should be used to avoid prolonged contact of the enzymes with the oral mucosa because this may cause ulceration. If the capsule needs to be opened, the microspheres should be administered with a food that can be swallowed whole (like applesauce, gelatins, or pureed bananas that do not require chewing) and the mouth should be inspected after to ensure no retention of any beads. PERT should be taken just prior to the start of a meal or snack. If the individual continues to have abnormal stools, bloating, or belly pain, despite PERT, dosing may be adjusted until the maximum daily dose is reached. If symptoms continue despite maximum dosing, then acid suppression therapy may be tried to help the enteric coating of the PERT dissolve by providing a more alkaline environment. The provider should keep in mind the significant potential side effects of these medications (tachyphylaxis with H2 receptor antagonists; increased susceptibility to pneumonia, increased susceptibility to Clostridium difficile, and possible impact on bone health with the proton pump inhibitors). If clinical symptoms persist, then the provider should investigate further for other etiologies such as small bowel bacterial overgrowth, constipation, celiac disease, or chronic giardiasis.

Treatment of Fibrosing Colonopathy

Antiinflammatory treatments including prednisone pulses and antibiotics have been used with varying success. In extreme cases the use of balloon dilation or surgical resection of the fibrosed portion of the colon may be necessary. There is consensus on limiting doses of PERT to 2500 lipase units per meal or 10,000 lipase units per kg per day.

Clinical Presentation of Liver Disease

Liver disease in CF is often subclinical and the majority of individuals are asymptomatic until the development of advanced disease. Advanced CFLD typically develops around 10 years of age and is often slowly progressive. CFLD accounts for 2.8% of overall mortality in the CF population. Physicians should remain vigilant for signs of advanced liver disease such as splenomegaly or thrombocytopenia.

A thorough physical examination should be completed with every visit because the most common clinical finding in CFLD is hepatomegaly on routine physical examination. The liver may be felt 2–3 cm below the right costal margin or the xyphoid, with enlargement potentially limited to the right or left lobe. The examiner may note that the liver is firm and nodular. If the liver feels smooth, the hepatomegaly may be the result of fatty infiltration of the liver, which is felt to be a benign condition. However, given the recent studies of the progression of nonalcoholic steatohepatitis to cirrhosis, the implications of hepatic steatosis in CFLD may change. It also should be noted that a cirrhotic liver tends to be small and therefore no hepatomegaly may be found on abdominal examination. Even without hepatomegaly, the physician could still be guided towards the diagnosis of significant liver disease by the presence of splenomegaly, resulting from portal hypertension, a late complication of cirrhosis.

Besides hepatosplenomegaly, other signs of liver disease are less common on physical examination. Spider nevi, palmar erythema, jaundice, edema, distension of abdominal wall veins, and ascites can be seen with chronic liver disease. These manifestations are found in more advanced disease with the exception of jaundice in early infancy. Cholestasis, or elevation in the conjugated bilirubin, tends to be the earliest manifestation of liver involvement in CF occurring in 2% of infants with CF. Cholestasis generally resolves within 3 months but occasionally can mimic biliary atresia.

Diagnosis of Liver Disease

Early diagnosis of CFLD remains problematic even with published guidelines for the management of liver and biliary tract disease in CF. Unfortunately, there are no tests currently available to identify individuals with CF who are at high risk of developing liver cirrhosis. In general, the combination of physical examination findings, biochemical results, and imaging are used to make the diagnosis of CFLD.

Routine annual blood work may reveal an elevation in AST, ALT, or GGT. As mentioned earlier, intermittent elevations in these values are common and do not necessarily indicate significant liver disease. Normal values may even be found in the setting of multilobular biliary cirrhosis. However, persistent elevation of AST, ALT, or GGT greater than three times the upper limit of normal is rare. Elevation of AST and ALT, with normal GGT, may indicate hepatic steatosis. The possibility of hepatic steatosis should prompt further testing for deficiencies in essential fatty acid, carnitine, and choline, as well as assessment for malnutrition. However, hepatic steatosis can also be present in individuals with adequate nutritional status. Elevation of alkaline phosphatase without an elevation in GGT can be found in growing children and does not indicate liver disease.

The AST to platelet ratio index (APRI) has been studied in the setting of non-CF–related liver disease as a noninvasive marker of liver fibrosis and cirrhosis. More recently, investigators looked at APRI as a predictor of liver fibrosis in individuals with CF. They found that APRI correlated well with severe fibrosis but tended to overestimate earlier stages of fibrosis.

In general, further evaluation should be considered if an individual’s ALT or GGT remain elevated for 6 months or more. At that time, it would be prudent to evaluate for other causes of liver disease such as alpha-1 antitrypsin deficiency, celiac disease, autoimmune disease, Wilson disease, chronic viral hepatitis, primary sclerosing cholangitis, drug toxicity, and toxins. Evaluation of liver synthetic function should also be checked with albumin, prothrombin time (PT), international normalized ratio (INR), and glucose. However, only approximately 10% of individuals with CF and cirrhosis will develop synthetic failure.

Doppler ultrasound of the liver should be ordered when CFLD is suspected. This noninvasive modality provides information about the appearance of the liver without any radiation exposure, which is preferred in this CF population, which is often exposed to chest x-rays and computed tomography (CT) scans of the chest. A homogeneous pattern is typically associated with hepatic steatosis. However, it is important to keep in mind that periportal steatosis and focal fibrosis have a similar appearance on ultrasound. Individuals with heterogeneous parenchyma of the liver found on ultrasound are thought to be at increased risk for development of cirrhosis. A pattern indicative of cirrhosis of the liver, including heterogeneous echogenicity and coarse echo texture of the liver parenchyma accompanied by nodularity of the liver contour, can also be found. Surprisingly, 3.3% of individuals with CF, not known to have cirrhosis, were found to have a cirrhotic pattern on ultrasound in a prospective, multicenter study of using ultrasound to predict hepatic fibrosis. The investigators found that an abnormal ultrasound liver pattern was associated with CF-related diabetes, whereas a normal ultrasound was associated with early Pseudomonas aeruginosa infection. However, a normal liver ultrasound does not preclude significant liver fibrosis.

The liver Doppler ultrasound also provides information about CFLD by documenting the flow patterns of the vasculature, as well as the presence of dilatation. Hepatofugal flow (away from the liver) in the portal vein, as well as recanalization of the umbilical vein, suggests advanced portal hypertension. Ultrasound can also detect thrombosis of the portal or splenic veins which leads to splenomegaly. Finally, increased right heart pressure leading to hepatomegaly may be suggested by dilated hepatic veins.

Magnetic resonance imaging (MRI) and abdominal CT both provide useful information regarding hepatic steatosis versus fibrosis. Because MRI does not require radiation, it is generally preferred over CT. Even though CT is not the test of choice, the liver is often seen on unenhanced CT of the chest ( Fig. 52.3 ). Transient elastography (FibroScan) is another noninvasive technique that uses ultrasound, rather than radiation, to quantify liver stiffness which correlates with liver fibrosis. Furthermore, magnetic resonance cholangiography (MRCP) allows evaluation of the intrahepatic and extrahepatic bile ducts. Thus a beaded appearance to the intrahepatic ducts, suggestive of sclerosing cholangitis, or choledocholithiasis can be seen with MRCP.

Computed tomography scan of an individual with cystic fibrosis demonstrating cirrhosis of the liver.

Liver biopsy is viewed as the gold standard for the diagnosis of a variety of non-CF–related liver diseases. However, in CFLD, the disease tends to be patchy and sampling error is possible. Obtaining two cores, or dual pass, has been advised for evaluation because it improves detection of fibrosis by 22% compared with a single core. Liver biopsy tends to be helpful when there is a question of an additional or alternative disease process, for determining the extent of fibrosis, or for identifying the predominant liver lesion (steatosis or focal biliary cirrhosis [FBC]). The liver biopsy can demonstrate focal portal fibrosis and inflammation, cholestasis, and bile duct proliferation in FBC, which is primarily a histologic diagnosis that is often clinically silent. FBC is the pathognomonic histopathologic liver lesion in CF and may rarely progress to multilobular cirrhosis.

Management of Liver Disease

Unfortunately, a therapy to slow down or reverse fibrosis in CFLD has not been identified. Current management focuses on supportive care and addressing complications of advanced liver disease. Prevention of concomitant liver disease by ensuring complete vaccination against hepatitis A and hepatitis B is also essential to the treatment of individuals with CFLD.

The use of ursodeoxycholic acid (UDCA) in CFLD remains controversial. The proposed benefits include improved bile flow, displacement of toxic hydrophobic bile acids, cytoprotection, and stimulation of biliary bicarbonate secretion. UDCA is typically well tolerated, although the side effect of diarrhea has been reported. Typical dosing of UDCA is 20 mg/kg per day divided into two doses.

However, a 2014 Cochrane review did not find sufficient evidence to recommend routine use in individuals with CF. Specifically, this review underlined the paucity of randomized controlled trials evaluating the effectiveness of UDCA in CF. The available studies did not assess prevention of liver disease in individuals with CF, portal hypertension, liver transplantation, or survival. Furthermore, a study evaluating high-dose UDCA (28–30 mg/kg per day) in primary sclerosing cholangitis was terminated due to an increase risk of death or liver transplantation in the group receiving UDCA. Thus the role of UDCA in CF remains unclear.

In the CF population, for which nutrition already remains an important focus of care, the development of liver disease exacerbates this issue. It has been recommended that individuals with CF receive 150% of the recommended daily allowance (RDA) for calories by increasing dietary fat as opposed to carbohydrate supplements due to the risk of developing CF-related diabetes mellitus. The requirements of fat-soluble vitamins (A, D, E, and K) are also increased in CFLD and higher doses are often needed. Fat-soluble vitamin levels should be monitored closely and the doses adjusted accordingly. Pancreatic enzymes should be optimized to allow maximal absorption of long-chain triglycerides and essential fatty acids.

Recognizing the development of portal hypertension is essential to the care of individuals with CFLD. Signs of this CFLD complication include splenomegaly, leucopenia, and thrombocytopenia. Reversal of, or abnormal, portal vein flow can be identified on liver Doppler ultrasound. Other complications associated with portal hypertension include variceal bleeding, low oxygen saturations due to hepatopulmonary syndrome, or abdominal distension due to ascites.

The greatest concern with portal hypertension is the life-threatening complication of variceal bleeding from either esophageal or gastric varices. An individual with an acute variceal bleed may present with hematemesis or passage of maroon-colored or melanotic stools. In children with portal hypertension, unlike in adults with portal hypertension, screening for the presence of varices is not recommended because there is no evidence-based therapy that is safe and effective to prevent the first variceal bleed (also known as primary variceal prophylaxis). However, recent expert opinion has suggested that adult guidelines can be followed after puberty for variceal screening at the discretion of the treating physician. Unfortunately, there is a paucity of literature in dealing with primary prophylaxis for varices in pediatrics; there are several case studies but only one randomized clinical trial. In one retrospective study of 38 children with CF and liver cirrhosis, variceal bleeding occurred in 50%; two of the children had exposure to salicylates prior to the bleed. Thus salicylic acid and nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided to minimize the risk of bleeding from esophageal or gastric varices.

Once a variceal bleed has occurred, the child is at high risk of recurrence of bleeding. The prevention of a second bleeding episode is called secondary prophylaxis. In adults the preferred method for secondary prophylaxis is the use of a long-term nonselective β blocker with serial endoscopic variceal ligation (EVL) until the obliteration of the varices is complete. The use of a nonselective β blocker has not been adequately studied in children for secondary prophylaxis. Furthermore, the pulmonary side effects of nonselective β blockers would most likely preclude their use in children with CF. Thus EVL is the preferred method of secondary prophylaxis in pediatrics. EVL is not possible in infants weighing less than 12 kg due to the size of the equipment needed for EVL, so endoscopic sclerotherapy is used as secondary prophylaxis in these patients.

Gastric varices tend to be technically more difficult to address in pediatrics than in adults. In the adult literature, EVL can be performed with gastric varices that extend onto the cardia on the lesser curvature of the stomach. Injection of cyanoacrylate glue is another option for treatment of gastric varices. In children with difficult to control gastric varices or recurrent variceal bleeding, caregivers may consider the options of surgical portosystemic shunt or bypass procedure, transjugular intrahepatic portosystemic shunt (TIPS), or liver transplantation. Hepatic encephalopathy has occurred after portosystemic shunting; treatment includes lactulose and nonabsorbable antibiotics.

The decision on when to proceed with liver transplantation in the CF population has been controversial. Proposed indications include progressive hepatic dysfunction (decreasing albumin level and coagulopathy not correctable with vitamin K), development of ascites or jaundice, variceal bleeding not amenable to standard therapy, hepatopulmonary syndrome, unresponsive severe malnutrition, deteriorating quality of life, and deteriorating pulmonary function (Tiffeneau-Pinelli index FEV ₁ /FVC <50%). Relative contraindications to liver transplant include colonization with multidrug resistant P. aeruginosa or Burkholderia cepacia due to the high risk of postoperative infection, which may be lethal. The database for the United Network for Organ Sharing (UNOS) showed that 148 children with CF underwent liver transplantation alone, with a 5-year unadjusted survival of 86%. In an adjusted analysis the CF liver transplant recipients had inferior survival rates in long-term follow-up as compared with recipients with other indications for liver transplantation. A higher incidence of anastomotic biliary strictures requiring creation of a Roux-en-Y portoenterostomy has been reported in CF liver transplant recipients, possibly due to their underlying CF-related bile duct disease. Most of the CF liver transplant recipients will develop diabetes, but 60% of untransplanted individuals with CF-related portal hypertension will develop diabetes as well. Other than the development of diabetes, CF liver transplant recipients do not have increased mortality from other complications from CF (pulmonary failure, infections). Some advocate for isolated liver transplantation prior to deterioration of lung function because combined liver-lung transplantation carries a worse prognosis. However, it has been reported that outcomes for isolated liver transplantation and combined liver-lung transplantation in CF recipients are comparable.