Nonpulmonary Manifestations of Cystic Fibrosis

53

NONPULMONARY MANIFESTATIONS OF CYSTIC FIBROSIS Najma N. Ahmed, MD, MSc, FRCP(C), and Peter R. Durie, MD, FRCP(C)

Cystic fibrosis is characterized by the abnormal secre­ tion of fluid, electrolytes, and macromolecules by exocr­ ine glands. In 1989, Tsui and colleagues isolated the CF gene on chromosome 7, and this led to the discovery of its gene product, the cystic fibrosis transmembrane con­ ductance regulator (CFTR), which functions as a cAMPdependent chloride channel.1 The pathophysiologic basis of CF centers on the defective function of this protein in various tissues. In the gastrointestinal (GI) tract, CFTR is expressed in the crypt and villous cells of the intestine, the apical membrane of cholangiocytes, and the apical mem­ brane of the pancreatic ductal epithelium. CFTR also is expressed in the reproductive tract, resulting in altered fertility in patients with CF. The absence or dysfunction of CFTR in various tissues results in a broad spectrum of disease manifestations involving the bronchopulmo­ nary tree, exocrine pancreas, hepatobiliary system, and the male reproductive system. The spectrum of clinical manifestations is summarized in Box 53-1. This c­ hapter presents a summary of the current knowledge of the extrapulmonary manifestations of cystic fibrosis.

PANCREATIC DISEASE Pathobiology Quantitative pancreatic stimulation testing shows that patients with CF have abnormal ductal chloride and bicar­ bonate secretion.2 Under normal conditions, the pancreas secretes 2.5 L/day of a bicarbonate-rich fluid. In patients with cystic fibrosis, impaired electrolyte transport results in a reduction in fluid secretion, which leads in turn to protein hyperconcentration and ductal obstruction by viscous secretions (Fig. 53-1).3 Impaired ductal secretion of Cl− by dysfunctional or absent CFTR was proposed to reduce the amount of Cl− available for transport via the ductal apical Cl−/HCO3− exchanger, resulting in low levels of pancreatic bicarbonate secretion.4 However, it is now understood, that pancreatic bicarbonate secretion can also occur in the absence of luminal chloride.5 CFTRmediated Cl− transport results in the depolarization of the ductal epithelial cell, which stimulates entry of bicarbon­ ate via basolateral electrogenic Na/HCO3− cotransporters. Bicarbonate is then secreted via a predominantly conduc­ tive pathway.6 CFTR is also permeable to bicarbonate but at a level of only 25% compared with its chloride perme­ ability, and the role of CFTR-mediated HCO3− transport under physiologic conditions is unclear. In its most severe form, pancreatic disease begins in utero. There is rapid progression of acinar damage within the first year of life in patients with pancreatic insuffi­ ciency. Morphologic evaluation of the pancreas in infants

dying with CF has shown a marked lack of development of acinar tissue. Duct obstruction by proteinaceous secre­ tions is thought to lead to duct dilatation and acinar loss. Histologically, there is extensive destruction of pancre­ atic acini, with replacement by fat and fibrous tissue. It is important to note that in order to develop pancreatic insuf­ ficiency, over 95% of pancreatic function must be lost.

Pancreatic Phenotype Cross-sectional data indicate that approximately 85% of CF patients are pancreatic insufficient (PI) and require enzyme supplementation. The remaining patients have adequate pancreatic reserve to allow for adequate nutri­ ent digestion and do not require enzymes. This group of patients is termed pancreatic sufficient (PS). Studies have shown that PS patients are diagnosed at a later age, have lower mean sweat chloride concentrations, and better pulmonary function than patients with pancreatic insuffi­ ciency. Moreover, the PS patients, as a group, have better survival. In contrast, PI patients are more likely to have meconium ileus, distal intestinal obstruction syndrome, and severe liver disease. Newborn screening programs have shown that approx­ imately 60% of patients are PI at diagnosis. Infants with PI have high serum trypsinogen levels at diagnosis that decline to undetectable levels by 7 years of age. The majo­ rity of the PS infants progress to PI within the first 2 to 3 years of life. Such patients show a progressive but delayed decline in serum trypsinogen levels. As we later describe, the remaining PS patients show prolonged retention of their pancreatic sufficient status.

Genotype-Phenotype Correlations Over 1700 different mutations or putative mutations have been identified in the CFTR gene, most of which are rare. Genotype-phenotype studies have shown that the strongest association between the CFTR genotype and the clinical phenotype is in the exocrine pancreas. The PI and PS phenotypes are associated with distinct “severe” or “mild” mutations in the CFTR gene, respec­ tively. Patients who are PI at diagnosis, or who progress to PI, carry “severe” mutations on both alleles, whereas patients who are PS, carry at least one “mild” mutation. The “mild” allele confers a dominant effect over the “severe” allele. This subject is covered in more detail in Chapter 50. The pancreatic phenotype has been shown to corre­ late with the functional consequences of CFTR muta­ tions. Over 95% of patients with severe class I, II, and

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Cystic Fibrosis

BOX 53-1  Clinical Manifestations of Cystic Fibrosis Systemic

• Failure to thrive • Malnutrition/Kwashiorkor • Micronutrient deficiencies

Esophagus

• Gastroesophageal reflux • Esophagitis/stricture • Esophageal varices

Pancreas

• Pancreatic insufficiency • Pancreatitis • CF-related diabetes

Intestine

• Meconium ileus • DIOS • Constipation • Rectal prolapse • Fibrosing colonopathy

Hepatobiliary Extrahepatic

• Microgallbladder • Distended Gallbladder • Cholelithiasis • Common bile duct stenosis • Cholangiocarcinoma • Sclerosing cholangitis

Intrahepatic

• Neonatal cholestasis • Steatosis • Focal biliary cirrhosis • Multilobular cirrhosis

Reproductive

• Infertility due to obstructive azoospermia in men • Impaired fertility in women

DIOS, Distal intestinal obstruction syndrome.

III mutations, are pancreatic insufficient or progress to pancreatic insufficiency after diagnosis. In contrast, most patients with mild class IV and V mutations are consis­ tently pancreatic sufficient.7

Clinical Presentation Pancreatic Insufficiency The vast majority of patients present in infancy or early childhood with classic manifestations of CF such as meconium ileus, malnutrition/growth failure, steator­ rhea, and rectal prolapse. Even patients diagnosed by newborn screening at 6 to 8 weeks of age may have signs and symptoms of malnutrition with or without respira­ tory symptoms. Stool testing shows microscopic evidence of undigested triglyceride, increased fecal fat losses fol­ lowing a 72-hour balance study, or low fecal enzymes (elastase-1 or chymotrypsin). There may be biochemical evidence of fat-soluble vitamin deficiencies. At presen­ tation, up to 50% of conventionally diagnosed patients may be hypoalbuminemic. Infants can present with

hypoproteinemia, edema, growth failure, and ascites.8,9 A small minority of CF patients with PI manage to elude diagnosis until later childhood, and rarely, adolescence. Pancreatic Sufficiency Patients with the “nonclassic” PS phenotype usually pres­ ent later in childhood and early adulthood. Clinical man­ ifestations are frequently quite subtle, usually involving a single organ, and unlike patients with the pancreatic insufficient form of CF, patients usually experience rela­ tively normal growth and do not have symptoms of mal­ digestion. Sweat chloride measurements are, on average, lower in PS patients than those observed in the PI CF patient population, and in many cases, individual values may be within the normal or borderline range. Cross-sectional data from Toronto indicate that appro­ ximately one fifth of nonclassic CF patients develop pan­ creatitis, and in one third of PS patients, the diagnosis of pancreatitis preceded the diagnosis of CF.10–12 Liver disease also may be an isolated presenting feature of CF ­disease, although this is extremely uncommon.

Assessment of Pancreatic Function An accurate assessment of pancreatic function is essential in the management of patients with CF. Pancreatic func­ tion should be objectively assessed at the time of diag­ nosis, and furthermore, patients who are PS should be monitored regularly for evidence of progression to pan­ creatic insufficiency. Pancreatic function may be assessed using several methods. Most commonly 72-hour fecal fat balance studies are used to identify patients with the PI phenotype. Accurate measurement of fat intake is criti­ cal in obtaining a valid result. Pancreatic insufficiency is defined by fat losses of more than 15% of intake in infants less than 6 months of age, while in older infants a cutoff of more than 7% of intake is used. Serum trypsinogen can distinguish PI from PS in patients older than 7 years of age. At birth, serum levels are usually elevated, but then decline to low or undetectable levels in PI patients by 5 to 7 years of age. In contrast, PS patients show fluctuat­ ing levels both within and above the normal range at all ages. In patients who are PS at diagnosis and progress to PI, there is a delayed decline in serum trypsinogen levels. Fecal pancreatic elastase-1 is a useful alternative test for the assessment of pancreatic function, although it does have some limitations. The test is not influenced by the concurrent ingestion of pancreatic enzymes. A negative test result (>100 μg/g stool) had a 99% predictive value for ruling out pancreatic insufficiency. In patients with CF, the sensitivity and specificity were 100%. However, in other conditions causing steatorrhea, including short gut and Shwachman-Diamond syndrome, fecal elastase-1 measurements had lower specificity.13 Quantitative pancreatic function testing, using duode­ nal intubation and a marker perfusion technique, is use­ ful to quantify pancreatic reserve, as well as fluid and anion secretion. However, this test is limited by its inva­ sive nature, cost, and complexity. Quantitative exocrine pancreatic function has been shown to correlate with the functional consequences of CFTR gene mutations. Patients with class I, II, or III mutations have severely impaired

Nonpulmonary Manifestations of Cystic Fibrosis

Duct

Chapter 53

NORMAL ACINAR AND DUCTAL SECRETION Acinus

Centro-acinar cell High protein concentration

Diluted alkaline protein secretion H2O

H 2O Acinar cell

Ductal cell Cl

Zymogen granules

CFTR

HCO3

Cl

HCO3

HCO3

Ca c-AMP

Na Secretin

HCO3 Cl

CCK ACh

Secretin/VIP

A

CYSTIC FIBROSIS Duct

Acinus

Protein precipitation and obstruction Concentrated acidic protein secretion

High protein concentration H2O Centro-acinar cell

Ductal cell Cl

CFTR

HCO3

Acinar cell Zymogen granules

Cl HCO3 HCO3

Ca c-AMP

Na Secretin

HCO3 Cl

Secretin/VIP

CCK ACh

B Under normal circumstances (A) Cl and HCO3 secretion provides a driving force for the movement of fluid into the lumen of the duct, which maintains the solubility of secreted proteins in a dilute, alkaline solution. In CF (B), impaired anion transport results in decreased secretion of more acidic fluid, which leads to precipitation of secreted proteins. Intraluminal obstruction of the ducts then causes progressive pancreatic damage and atrophy.

acinar and ductular function compared with controls. In contrast, those with class IV or V mutations have a wide range of enzyme output extending from just above the threshold for developing PI into the normal range.

Management of Pancreatic Insufficiency Only patients who have documented pancreatic insuffi­ ciency should receive pancreatic enzyme supplementation. There is a wide variety of commercial pancreatic enzymes available in tablet, powdered, or microencapsulated forms.

783

FIGURE 53-1.  Pathophysiology of pancreatic disease in CF.

Enteric-coated pH-resistant microsphere preparations are most commonly used. These preparations were devel­ oped to protect the enzymes from degradation by acid and pepsin in the stomach. They allow for release of the enzymes at a pH of 5.5 to 6, and in theory, the enteric coating of the microspheres should dissolve in the prox­ imal small intestine. Ideally, the dose of enzyme should be determined by nutrient intake of fat, protein, and car­ bohydrate. However a simplified approach based on the patient's age and weight has been established (Table 53-1). Usually, half the standard dose is used for snacks. Current

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Cystic Fibrosis TABLE 53-1 DOSING GUIDELINES FOR PANCREATIC ENZYMES AGE

DOSE OF ENZYMES

Infant

2,000-4,000 units lipase/120 mL formula or breastfeeding

< 4 years

1,000- 2,500 units lipase/kg/meal

> 4 years

500 -2,500 units lipase/kg/meal

guidelines recommend a dose of 1000 U lipase/kg/meal for children under 4 years of age or at 500 U lipase/kg/meal for children over 4 years of age. The dose should not exceed 10,000 U lipase/kg/day. The total daily dose should reflect three meals per day and two to three snacks per day. Patients should be maintained on a high-energy diet that is rich in fat, and growth should be monitored closely. The response to pancreatic enzymes is extremely vari­ able from patient to patient; consequently, dosing require­ ments may vary. If response to enzyme therapy is poor, growth is poor, or symptoms persist, the patient should be reevaluated for other contributing factors (Box 53-2). Patients should not arbitrarily increase enzyme dosing without consulting their CF team. The dose should not exceed 10,000 lipase U/kg/day because of the increased risk of fibrosing colonopathy, which is discussed later.14 Children who are unable to swallow whole capsules may open the capsule and the contents may be mixed with a small amount of apple sauce or other acidic food. The microspheres should not be crushed or allowed to sit in food. Enzymes should be stored in a cool dark place and expiration dates should be followed One factor that can interfere with the efficacy of pan­ creatic enzymes is the inability of the CF pancreas to produce the normal alkaline secretions that help neutral­ ize acidic gastric contents entering the small bowel. The lower intestinal pH results in impaired enzyme release,

BOX 53-2 Factors Affecting Response to Enzyme Supplements Enzyme Supplements

• Inappropriate storage • Expiration of product

Poor Compliance

• Refusal of medication • Incorrect administration • Desire to lose weight

Dietary Issues

• Excessive juice intake (carbohydrate malabsorption) • Inappropriate eating behavior (i.e., frequent small meals) • High fat “ fast foods”

Low Intestinal pH

• Inadequate breakdown of enteric coating • Contents released all at once

Concurrent Gastrointestinal Disorder Adapted from Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35(3):246-259.

and/or reduced enzyme activity. Acid-suppression ther­ apy may therefore be useful to raise the intestinal pH. Furthermore, severe cholestatic hepatobiliary disease can contribute to malabsorption in CF. Investigations should be pursued to identify other comorbid conditions if patients do not respond to therapy. A poor response to therapy also may result from a concomitant gastrointes­ tinal disorder, including chronic giardiasis, celiac disease, inflammatory bowel disease, and bacterial overgrowth.

Complications of Therapy Fibrosing Colonopathy The first description of colonic strictures in CF patients occurred in 1994. In fibrosing colonopathy, there is colonic narrowing with circular intramural fibrosis that may be limited to the ascending colon or may extend to involve the entire colon. Barium enema may demonstrate a localized apple core–like lesion in the ascending colon, or the entire colon may appear contracted and featureless. Bowel wall thickness is increased on two-dimensional imaging. However, evidence of bowel wall thickening should be interpreted with caution because unaffected patients with CF have colonic wall thickening on ultra­ sound.15,16 Histology may show evidence of severe fibrosis in the lamina propria, and superficial inflammation with eosinophils, cryptitis, or apoptosis (Fig. 53-2). Although the precise cause is unknown, retrospective case-control studies showed a strong risk association with high-dose pancreatic enzyme use. Patients at higher risk for this complication include children under 12 years of age who have been taking enzymes with lipase intake exceeding 6000 U/kg/meal for more than 6 months. Other risk factors may be a history of distal intestinal obstruc­ tion syndrome, meconium ileus, or prior intestinal sur­ gery.17 Clinically, patients may have obstructive symptoms, abdominal pain, bloody diarrhea, or poor weight gain. A significant subgroup of patients with fibrosing colo­ nopathy has required surgical intervention. Patients with this condition need to be monitored closely because they may develop strictures. Management of patients with fib­ rosing colonopathy also includes immediate reduction of the dose of enzyme supplements to within the recom­ mended range.14 The long-term prognosis for patients with this condition remains unclear. Allergy Immediate hypersensitivity reactions to pancreatic ­extracts have been reported in patients, caregivers, and parents of patients with CF. Clinical symptoms often mimic asthma, but severe anaphylactic reactions have been reported. This reaction is an IgE-mediated phenomenon and is a rare occurrence.18,19

CYSTIC FIBROSIS–RELATED DIABETES MELLITUS (CFRD) Pathobiology Glucose intolerance in CF was first described in 1938 by Andersen.20 However, it was not until 1962 that dia­ betes mellitus (DM) was established as a secondary

Nonpulmonary Manifestations of Cystic Fibrosis

B

Diagnosis

A

FIGURE 53-2.  Histologic findings in fibrosing colonopathy. Classifi­cation system for CFTR mutations (see text for details). Intestinal cross- section from a patient with fibrosing colonopathy illustrating (A) nonspecific acute and chronic inflammation in the mucosa (arrow), (B) hypertrophy of the muscularis mucosa, and (C) a ring of fibrous tissue.

complication of CF. Only patients with pancreatic insuf­ ficiency are at risk for this complication. Approximately one third of CF patients have CFRD, although this var­ ies based on the age and ethnicity of the population, and also depends on the rigor of screening. Children with CF who are under 10 years of age appear to have a similar risk of insulin-requiring DM compared with that of the general population. Beginning in adolescence, the over­ all incidence of CFRD is 3% to 4%. During adolescence and adulthood, the incidence of CFRD progressively increases, with the median age of onset being 20 years of age. As many as 45% to 50% of patients over the age of 30 have CFRD.21 In addition, a family history of type 2 diabetes increases the risk of CFRD threefold. The pathogenesis of CFRD is unclear but is thought to result from the accumulation of viscous secretions in the pancreatic duct leading to duct obstruction, progressive pancreatic fibrosis, fatty infiltration, and amyloid deposi­ tion. A reduction in islet cell mass also has been described. Recently, it has been suggested that an increase in oxida­ tive stress and the accumulation of misfolded CFTR in the endoplasmic reticulum (ER) of islet cells may result

Rarely, patients may present with overt symptoms such as polydipsia and polyuria. More frequently patients are asymptomatic or present with subtle symptoms such as impaired growth or delayed puberty. There also may be an unexplained decline in lung function. CFRD may be intermittent at first and may occur in association with physical stress such as infection, nocturnal enteral feed­ ings, or steroid treatment. The recommended diagnostic tool for CFRD is the oral glucose tolerance test (OGTT). The CF diabetes consen­ sus conference proposed a classification system for CFRD, which is shown in Table 53-2.23 Studies have shown that a subgroup of CF patients may have diabetic glucose toler­ ance as illustrated by an OGTT without fasting hypergly­ cemia. Moreover, there is no consensus on whether such patients should be treated with insulin. In type 1 and 2 DM, fasting glucose is the diagnostic test of choice; how­ ever, in CFRD a number of patients will be missed if this is used as the sole screening test. Thus, an OGTT may be required. Hemoglobin A1c (HbA1c) is not a reliable diagnostic screening test because it may be falsely low. Recently, continuous glucose monitoring has been sug­ gested as a potential diagnostic tool24; patients who had a blood glucose of >7.8 mmol/L at least 4.5% of the time were more likely to have a decline in FEV1 than nondia­ betic CF controls.

Management Nutritional management of CFRD is aimed at maintaining normal nutritional status. A multidisciplinary approach that includes members of the CF and endocrine teams is essential. Strong evidence-based data for the manage­ ment of CFRD is lacking; therefore, current management is based on extrapolation from standard CF and diabetes care. It is vitally important to maintain normal growth in adolescents or to maintain an acceptable body mass

Chapter 53

C

in ER stress leading to beta cell apoptosis. Basal insulin secretion appears to be maintained in CF patients with or without CFRD. However, there is a reduction in insulin secretion in response to stimulation. While insulin resis­ tance is not involved in the pathogenesis of CFRD, it may exacerbate hyperglycemia because of a reduction in peripheral and hepatic insulin sensitivity. There has been some debate regarding the impact of CFRD on morbidity and mortality. However, a recent multicenter study showed that patients with CFRD had worse lung function and nutritional status and con­ cluded that CFRD reduces survival. Treatment with insu­ lin appears to reverse the decline in pulmonary function and restore nutritional status. Long-term morbidity from microvascular complications including diabetic retinopa­ thy and nephropathy was initially thought to be low, but recent studies have shown high incidence, which appears to be similar to type-2 diabetes mellitus.22 In contrast, macrovascular complications appear to be rare, likely because of steatorrhea and loss of lipoproteins.

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Cystic Fibrosis TABLE 53-2  CLASSIFICATION OF GLUCOSE INTOLERANCE IN CYSTIC FIBROSIS GLUCOSE TOLERANCE CFRD with fasting hyperglycemia CFRD without fasting hyperglycemia Impaired glucose tolerance Normal glucose tolerance Indeterminate

FASTING BLOOD GLUCOSE (MMOL/L) ≥ 7.0 < 7.0 <7.0 <7.0 <7.0

2-HOUR BLOOD GLUCOSE (MMOL/L) AND AND AND AND

N/A ≥ 11.1 7.8-11.1 <7.8 Mid-OGTT >11.1 or postprandial hyperglycemia by continuous glucose monitoring

CFRD, Cystic fibrosis–related diabetes mellitus; OGTT, oral glucose tolerance test.

index (BMI) (20 to25 kg/m2) in adults. Therefore, instead of adjusting nutrient intake to maintain euglycemia, insu­ lin therapy should be adjusted to permit an appropriate energy intake for the CF patient. As with all patients with CF, 35% to 40% of calories should be derived from fat. Carbohydrate intake should not be excessively restricted, and patients should follow a daily diet consisting of three meals and three snacks.21 Approximately 15% of patients with CFRD have fast­ ing hyperglycemia, and this group will require insulin therapy.21 Studies have documented that the initiation of treatment results in a stabilization of lung function and nutritional status. At the present time, there is no evidence of a defined role for oral hypoglycemic agents. Insulin therapy is tailored on an individual basis because there are no data on specific insulin regimens in patients with CFRD. Most regimens combine a basal bolus schedule with intermittent doses of short-acting insulin at mealtimes. HbA1c measurements should be done to monitor long-term glycemic control. Patients also should be screened annually for the development of microvas­ cular complications with an eye exam and urinalysis for microalbuminuria. Patients with CFRD without fasting hyperglycemia are at risk of progression to fasting hyperglycemia and should be monitored carefully. Recent data suggest that these patients also may benefit from insulin therapy. A recent study compared the effect of insulin vs. oral hyper­ glycemic therapy vs. placebo. Patients treated with insu­ lin had an improvement in the rate of BMI loss at 1 year, while no change was seen in the placebo group.25 Patients treated with the oral hypoglycemic agent had an initial improvement, but this was not sustained at 1 year. Patients with impaired glucose tolerance should also be closely monitored for progression and the development of clinical symptoms but there is no evidence for the initia­ tion of treatment in this group.

INTESTINAL DISEASE Pathobiology CFTR is localized to the apical surface of intestinal crypt and villous cells. At the cellular level, mutations give rise to impaired chloride and bicarbonate secretion by epi­ thelial cells, resulting in decreased fluid content in the intestinal lumen. In the CF intestine, the consequences of impaired fluid and electrolyte transport are demonstrated clinically by meconium ileus (MI) in the infant and distal

intestinal obstruction syndrome in the older child and adult. CF meconium has a lower water content and a high protein concentration that is thought to result in more viscous, adherent meconium on the ileal surface, leading to luminal obstruction. Meconium ileus occurs in about 15% to 20% of patients and is almost exclusively seen in individuals who carry two severe mutations (class I, II, or III). Concordance studies have shown that the risk of ­developing MI in affected siblings is increased if the index case has MI; conversely, the risk is decreased if the index case does not have MI. Given that only a subset of patients d ­ evelops MI, the effect of secondary genetic factors on intestinal disease has been evaluated. Using a CF mouse model, a modifier locus for the intestinal phenotype was identi­ fied on murine chromosome 7.26 Subsequently, a ­modifier locus for meconium ileus was identified on human chro­ mosome 19q1327 (CFM1), in a region that is syntenic to the murine locus. However, further studies were unable to replicate these findings in other populations. Nonetheless, it remains possible that CFM1 is a genetic modifier in the French-Canadian population in which it was studied initially. Recently another potential modi­ fier locus has been identified on chromosome 12p13.3. Further study of this region identified that the ADIPOR2 gene plays a role in the development of MI.28 This gene encodes one of two adiponectin receptors; however, the mechanism by which this may influence the development of MI remains unclear. Although CFTR plays a major role in fluid and elec­ trolyte transport in the intestine, more recent studies have suggested that other chloride channels also play a role and may therefore have an impact on disease manifestations.29,30

Clinical Manifestations of Intestinal Disease Intestinal disease in CF can present with various mani­ festations, and it appears that both genetic factors other than CFTR and environmental factors contribute to a specific phenotype. CFTR-related Intestinal Diseases Meconium Ileus Meconium ileus (MI) may be the earliest clinical manifes­ tation of CF. In patients with this condition, one should have a high index of suspicion for CF. However, patients

Nonpulmonary Manifestations of Cystic Fibrosis

A

it is common in those with the complicated form. Patients with complicated MI have a higher incidence of surgical complications. A recent evaluation in an animal model suggests that surfactant may be considered as an alterna­ tive therapy for the treatment of MI33 Survival of patients with MI is over 90% and long-term survival is similar to CF patients without this complication.34 Distal Intestinal Obstruction Syndrome Because of the viscous nature of intestinal contents, some CF patients develop symptoms of partial or complete bowel obstruction at an older age. This is a result of ins­ pissated material in the ileum, cecum, and proximal colon. Previously, this condition was termed MI equivalent; how­ ever, it has been renamed distal intestinal obstruction syndrome (DIOS). More recently, definitions have been proposed to clearly separate DIOS from constipation, and a further distinction has been suggested between complete and incomplete DIOS.35 Complete DIOS is defined as (1) complete intestinal obstruction as evidenced by bilious vomiting or fluid levels in the small bowel on abdominal x-ray; (2) a fecal mass in the ileocecum; and (3) abdomi­ nal pain, distension, or both. Incomplete DIOS is defined as (1) a short history of abdominal pain or distension or both and (2) fecal mass in the ileocecum but without signs of complete obstruction. Approximately 4% to 5% of patients with CF will develop DIOS, most of whom are PI. DIOS appears to be more common among patients who had MI in infancy. In addition, the incidence of DIOS appears to increase with age, occurring most commonly in adolescents and adults.

B

FIGURE 53-3.  Meconium ileus. A, Abdominal x-ray showing air-fluid levels in the small bowel and granular material in the right lower quadrant with an absence of air in the colon. B, Barium enema showing the presence of inspissated material in the small bowel and a microcolon.

Chapter 53

without CF may also present with MI, especially pre­ mature infants; therefore, further diagnostic testing is required to confirm the diagnosis.31 MI can be simple, in which there is bowel obstruction, or complicated, which is characterized by both intrauterine complications and bowel obstruction. Approximately, 50% of patients with MI develop complications that include ileal atresia, ­necrosis, intestinal volvulus, or meconium peritonitis sec­ ondary to bowel perforation. Clinically, the infant presents with signs and symptoms suggestive of intestinal obstruction, including abdomi­ nal distension and bilious vomiting without the passage of meconium. X-rays may show multiple dilated bowel loops with a ground glass appearance, with or without calcification, in the right lower quadrant. Contrast stud­ ies with non-ionic contrast material, which should be avoided in patients with suspected perforation, show an unused microcolon and ileal obstruction (Fig. 53-3). In simple MI, nonsurgical intervention using a hyper­ tonic contrast medium such as Gastrografin32 will often relieve the obstruction by allowing for dissolution and subsequent passage of the inspissated meconium. Because the hypertonicity of these agents may induce dehydra­ tion or fluid and electrolyte disturbances, intravenous fluid and electrolyte therapy is recommended. Failure of enema therapy or complicated MI is an indication for surgical intervention. In some cases, the inspissated material can be manually disimpacted or irrigated and removed. A T-tube ileostomy may be placed for instilla­ tion of N-acetylcysteine or Gastrografin. Surgical resec­ tion is hardly ever required in cases with simple MI, but

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Cystic Fibrosis Clinically, patients present with abdominal pain that may be associated with a palpable fecal mass in the right lower quadrant. In most cases, there is no associated vomiting. However, on the rare occasion that there is vomiting, com­ plete bowel obstruction should be entertained. It is important to consider other entities that may present with similar fea­ tures, including appendicitis, appendiceal abscess, intussus­ ception, Crohn's disease, and fibrosing colonopathy. Plain x-rays are helpful if they demonstrate a fecal mass in the right lower quadrant, with or without evidence of obstruc­ tion. Sonography or computed tomography may be impor­ tant to rule out other causes for the patient's symptoms. A number of options for managing DIOS can be tailored to the severity of symptoms. In milder cases, mineral oil or other laxatives may be of benefit. Patients who fail treat­ ment with mineral oil should be considered for oral or naso­ gastric lavage using a balanced electrolyte and polyethylene glycol solution.36 The lavage solution is usually admin­ istered at a rate of 750 mL to 1000 mL/hr (20 mL/kg/hr for younger children with a maximum volume of 100 mL/kg) to a total volume of 4 to 6 L. Contraindications to lavage include complete obstruction or signs of peritonitis. Gastrografin enemas, or enemas with other hyperos­ molar contrast media, also may be useful, both to pro­ vide further imaging and to help relieve the obstruction, particularly if complete bowel obstruction is suspected. Adequate volumes of contrast are required to enter the ileum. Gastrografin should not be used if the patient is dehydrated or has symptoms and signs of peritonitis. N-acetylcysteine, a mucolytic agent, also may be of bene­ fit. Patients with recurrent DIOS can be considered for the placement of a button gastrostomy or gastrostomy button in the appendix to allow for regular irrigation.37 Constipation Patients with CF are much more likely to have constipa­ tion than true DIOS. The history is often helpful in dis­ tinguishing the two problems because patients with DIOS usually have normal stool frequency and consistency. In contrast, patients with constipation may have abdominal cramping, altered frequency of bowel movements, and dif­ ficulty passing stool. Unlike the findings in DIOS, x-rays show diffuse distribution of fecal material throughout the colon. Patients with constipation should be evaluated for evidence of a poor compliance or inadequate response to enzyme therapy. Treatment involves long-term laxative use, such as mineral oil. Severe cases may require colonic lavage with a balanced electrolyte solution. Rectal Prolapse Rectal prolapse occurs in approximately one fifth of patients with CF and in about 50% of cases; it may be the presenting feature of CF disease. Most cases pres­ ent at a young age between 1 month and 3 years of age. Rectal prolapse is more common in PI patients and may be related to the bulky stools. In most cases, it resolves spontaneously after 3 years of age. In patients for whom this is the presenting feature of CF, the institution of enzyme supplementation may result in improvement, but some patients will continue to prolapse for some time. In patients with constipation, treatment of the constipation is also of benefit. Surgical intervention is rarely indicated.

Appendicitis Appendicitis is often difficult to diagnose in patients with CF. Symptoms may be mild and other diagnoses such as DIOS are often considered first. It is therefore important to have a high index of suspicion for this condition to avoid a delay in diagnosis and an increased risk of com­ plications, which include abscess formation, perforation, and portal vein thrombosis. The incidence of acute appen­ dicitis is reported to be lower in patients with CF than in the general population (1% vs. 7%). Clinical symptoms may be mild or severe, and the milder presentation may be tempered by concurrent antibiotic use. The presence of peritoneal signs or fever should lead to further evaluation either by ultrasound or CT. Data from Toronto covering a 10-year period show that 9/803 patients with CF under­ went an appendectomy. In all patients, an initial diagnosis of DIOS had been made. Five out of the 9 patients had surgery within 3 days of symptom onset. In the remain­ ing patients, the diagnosis was delayed and all developed appendiceal abscesses.38 Intussusception Intussusception occurs in patients with CF with an esti­ mated prevalence of 1%. Patients may present with clas­ sical colicky abdominal pain, vomiting, and a palpable mass with rectal bleeding.39 However, the symptoms can be quite nonspecific and may resemble DIOS. Most intus­ susceptions are ileoileal or ileocolic, and the lead point for the intussusception is thought to be mucoid fecal material that is adherent to the intestinal mucosa. The diagnosis is made by ultrasound, single contrast enema, or air enema. The latter two interventions can be used to reduce the intussusception.40 Surgical intervention for manual reduc­ tion or resection is rarely required. Secondary Intestinal Complications Pseudomembranous Colitis Up to 50% of patients with CF are colonized with Clostridium difficile.41 This high colonization rate may be related to chronic antibiotic use. However, pseudomem­ branous colitis is considered to be rare, according to case report data.41–43 Despite its rare occurrence, C. difficile– related colitis has been fatal in patients with CF.43 In our experience, CF patients with C. difficile colitis may not present clinically with diarrhea or bloody diarrhea but may present dramatically with toxic megacolon. Other patients may have subtle symptoms that mimic other clin­ ical diagnoses. Stool testing for C. difficile toxin should be performed if the clinical diagnosis is unclear. In addition, patients with CF who have undergone lung transplanta­ tion, appear to be at higher risk for developing C.difficile– associated diarrhea.44 Treatment should be instituted with metronidazole or oral vancomycin if indicated. Patients with toxic megacolon may need emergency subtotal col­ ectomy as a lifesaving intervention.43 Gastroesophageal Reflux Disease Gastroesophageal reflux is common in both children and adults with CF. The etiology is likely multifactorial and may be related to respiratory disease, physiotherapy, and transient relaxation of the lower esophageal sphinc­ ter. Based on pH monitoring, there is an estimated 20%

Nonpulmonary Manifestations of Cystic Fibrosis

Associated Conditions Inflammatory Bowel Disease (IBD) Crohn's disease has been reported in patients with cys­ tic fibrosis.48–50 In one study, the prevalence of Crohn's disease was shown to be eleven times that observed in a non-CF population.51 Symptoms of inflammatory bowel disease may mimic CF-associated symptoms, such as DIOS. Investigations should be initiated, if despite appro­ priate management of CF, there is continued abdomi­ nal pain, anemia, hypoalbuminemia, and poor weight gain or growth disturbance. Furthermore, any extraint­ estinal features suggestive of IBD should prompt further investigation. Gastrointestinal Malignancies There are reports of an increased risk of gastrointesti­ nal malignancy in patients with CF. This trend is becom­ ing more evident as patient survival increases. A large population-based study has shown an approximately sevenfold increased risk of GI-related malignancy. Cholangiocarcinoma has been reported,52,53 as well as early onset colon cancer,54 pancreatic adenocarcinoma,55 and intestinal adenocarcinoma.56 Furthermore, patients undergoing transplantation may be at even higher risk because of the use of immunosuppressive medication. It is therefore important to be vigilant for these complications because the symptoms may mimic other CF-associated manifestations.

HEPATOBILIARY DISEASE Liver disease was described in the earliest reports of cystic fibrosis by Andersen.20 The presence of bile duct plugging in the livers of CF patients led to the hypothesis that bile duct obstruction by viscous secretions was the trigger for progressive liver damage. Liver disease in CF is character­ ized by abnormalities of the intrahepatic and extrahepatic biliary tract. There is a spectrum of liver abnormalities ranging from mild elevation of liver enzymes to focal bil­ iary cirrhosis; multilobular biliary cirrhosis with portal hypertension; and rarely, liver failure. Because the devel­ opment of liver disease is often not accompanied by clini­ cal symptoms, early identification of CF-associated liver disease is difficult.

Pathobiology CFTR is expressed exclusively at the apical surface of cholangiocytes and the epithelium of the gallbladder but not in hepatocytes. It plays a role in ductal secretion by creating both osmotic and electrogenic driving forces for the passive movement of sodium and water. The api­ cal chloride gradient also is thought to facilitate HCO3− secretion via CFTR and the Cl−/HCO3− exchanger. CFTR also may be involved in the regulation of other ion chan­ nels in bile duct epithelium. Histologic evaluation of the liver demonstrates ultra­ structural abnormalities of cholangiocytes, suggesting that injury to these cells may be the first step leading to portal fibrosis. Dysfunction of CFTR leads to an alter­ ation in bile composition with increased concentrations of bile acids and other biliary constituents, resulting in inspissations and obstruction of small bile ducts. This in turn may lead to the release of pro-inflammatory cyto­ kines and the activation of hepatic stellate cells. Almost all patients with CF have minor focal hepatobi­ liary manifestations of disease. However, only a subset of patients with CF (5%) develops severe liver disease with cir­ rhosis and portal hypertension (CFLD). CFLD is more com­ mon in males and usually manifests early with a median age at diagnosis of about 10 years. In a recent cross-­sectional evaluation of a large number of patients with CFLD (N = 260), more than 90% of subjects were diagnosed before 20 years of age.57 There is no correlation between specific CFTR mutations, but CFLD patients carrying severe mutations on both alleles carry a greater risk of having liver disease.58 The early age of onset of CFLD and the low preva­ lence, even in subjects with the same mutations, suggest that additional genetic factors play a role in its pathogenesis. In a recent study, a candidate gene association study of a num­ ber of genes identified was used to interrogate for potential genetic modifiers of the hepatic phenotype, including those that were associated with CFLD in previous studies that used very small numbers of patients. Following replication analysis in a replication cohort, the alpha-1-­protease inhibi­ tor (SERPINA1) Z allele was the only gene that conferred an increased (five-fold) risk of CFLD.

Clinical Presentation A wide variety of intrahepatic and extrahepatic mani­ festations of disease have been described in CF patients. (Table 53-3) Despite the relatively low prevalence of CFLD, it remains the most important nonpulmonary cause of mortality in CF. Identifying patients at risk of severe liver disease is not straightforward because hepatic biochemistry is a poor predictor of CFLD. Given the recent findings that the SERPINA1 gene is a genetic mod­ ifier in CFLD, if additional genetic modifiers of CFLD are identified, genotyping has the potential for identifying those at higher risk for severe disease. A careful physical examination should be done at each clinic visit to monitor for evidence of hepatospleno­ megaly. The presence of a firm liver that may be enlarged, or splenomegaly, strongly suggests the presence of signifi­ cant liver disease. With disease progression, the liver may shrink and no longer be palpable.

Chapter 53

incidence of gastroesophageal reflux in infants with CF; however, the proportion of patients reporting symptoms is higher.45 In some patients with CF, postural drainage may exacerbate symptoms, and alteration of the physio­ therapy technique may be beneficial. Some reports sug­ gest that gastroesophageal reflux is more frequent in patients with severe lung disease.46 There have been sev­ eral case reports of complications, including esophageal stricture and Barrett's esophagus.47 The diagnosis is usually established by symptoms such as heartburn, regurgitation, dysphagia, or anorexia. Eso­ phagogastroscopy and esophageal biopsy may be useful if the diagnosis is in doubt, or if the response to ther­ apy is poor. Treatment with H2-receptor antagonists or proton-pump inhibitors usually results in symptomatic improvement.

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790

Cystic Fibrosis TABLE 53-3 HEPATOBILIARY MANIFESTATIONS OF CYSTIC FIBROSIS INCIDENCE (%) Extrahepatic Microgallbladder Distended gallbladder Cholelithiasis Common bile duct stenosis Cholangiocarcinoma Sclerosing cholangitis

30 20 1-10 Rare Rare Rare

Intrahepatic <2

Neonatal cholestasis Steatosis Focal biliary cirrhosis Multilobular cirrhosis

20-60 11-70 5-15

TABLE 53-4  ASSESSMENT FOR LIVER DISEASE HISTORY

PHYSICAL EXAMINATION

LABORATORY INVESTIGATION

Jaundice (including neonatal history)

Liver span, texture

AST, ALT, GGT, ALP

Pruritus

Splenomegaly

Bilirubin (total and direct)

Hematemesis/ melena

Ascites

Albumin

Bruising/bleeding

Chronic liver disease

INR, PTT

Medication use

Nutritional status

CBC, differential, platelets

Alcohol intake Family history of liver disease

Screen for other causes of liver disease if indicated

ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate amino­ transferase; CBC, complete blood count; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; PTT, partial thromboplastin time.

Annual blood tests are often done in patients with CF (Table 53-4), and in our experience, approximately 40% of patients have biochemical abnormalities that gener­ ally are one-fold to two-fold higher than the upper ref­ erence limits. These values tend to fluctuate with time in each individual. In those with cirrhosis, coagulation status and albumin should be monitored to assess liver synthetic function. There is no association between elevated trans­ aminase values and the severity or progression of liver dis­ ease. However, if biochemical tests are more than four-fold above the upper reference limits, it is important to consider biliary tract obstruction with stones or sludge or another cause of liver disease. Other etiologies include viral hepati­ tis, metabolic liver disease, autoimmune liver disease, drug

toxicity, structural abnormalities, and hepatic congestion secondary to right heart failure. It should also be noted, that normal biochemical hepatic tests do not exclude severe CF-associated liver disease.2,59,60 Ultrasound is a useful monitoring tool for assessing CF patients suspected of liver disease. It can show the pres­ ence of extrahepatic abnormalities (gallbladder abnor­ malities, cholelithiasis, and bile duct dilatation) and define the size and texture of the liver and spleen. In more advanced liver disease, Doppler studies can document the direction of flow in the portal vein and sometimes detect varices. Sonography also may be useful in document­ ing hepatic abnormalities in the absence of biochemical abnormalities. Recently, hepatic elastography (Fibroscan) has been evaluated as a screening tool in patients with CFLD.61 This technique uses sonography to assess the degree of liver stiffness and has been shown to be useful in the identification of fibrosis in other chronic liver dis­ eases. However, further study is required to determine the utility of this test in CFLD. Liver biopsy is not recommended as a routine procedure for the evaluation of CF-associated liver disease. It may be helpful if a diagnosis of non-CF-related liver disease is sus­ pected, or it may be useful to assess whether there is pre­ dominantly steatosis or focal biliary c­ irrhosis. Because of its focal nature, a normal biopsy does not exclude the pres­ ence of CF-associated liver disease. From a technical per­ spective, if a biopsy is to be performed, it should be done using ultrasound guidance to ­ determine a safe location because the lungs may be hyperinflated. Ultrasound guid­ ance also can be useful to target a specific affected region of the liver. Contraindications to percutaneous liver biopsy include an uncorrectable ­coagulopathy, thrombocytopenia (<80,000/uL), dilated intrahepatic ducts or hepatic veins, significant ascites, or concerns regarding patient coopera­ tion. If a biopsy is warranted in such patients, a transjugu­ lar or laparoscopic approach should be considered.

Disease Manifestations Extrahepatic Complications Microgallbladder Microgallbladder is present in up to 30% of patients with CF of all ages. Twenty percent of patients less than 5 years of age have gallbladder anomalies, and this increases to 40% by 5 and 10 years of age, and to 60% between 15 and 20 years of age. Gallbladder dysfunction also has been reported. The underlying cause of these abnormali­ ties is unclear. Cholelithiasis The incidence of gallstones in patients with CF appears to be decreasing. Early studies indicated that between 8% and 12% of children with CF had gallstones. The inci­ dence appears to increase with age, and a separate study showed that among adults, 24% to 33% had gallstones. However, recent studies suggest that prevalence figures may be as low as 1%. The development of cholelithiasis is likely related to the presence of lithogenic bile secondary to increased losses of bile acids.62 Patients with pancreatic insufficiency have

Nonpulmonary Manifestations of Cystic Fibrosis

Abnormalities of the Biliary Tree Biliary tree abnormalities, which were first described at autopsy in CF adults, identified focal dilatation and fibrosis of the biliary tree, cholelithiasis, and solitary paraductal mucous cysts. Subsequently, it has become apparent that the intrahepatic and extrahepatic bile ducts can be obstructed with sludge or mucus. Endoscopic ret­ rograde cholangiopancreatography (ERCP) or percuta­ neous transhepatic cholangiograms (PTC) often reveal images that appear identical to sclerosing cholangitis. Distal common bile duct stenosis was first described in case reports, which identified extrinsic compression of the distal common bile duct by the fibrotic head of the pan­ creas.65,66 A prospective study using hepatobiliary scin­ tigraphy and transhepatic cholangiography showed that 96% of patients with CF-related liver disease had evi­ dence of biliary tract obstruction suggestive of bile duct stenosis, whereas this was not seen in any of the patients without CFLD.60 However, other ERCP studies67,68 sug­ gest that the prevalence of this complication is less than 10% among patients with CF-associated liver disease. Patients with common bile duct stenosis or intrin­ sic common bile duct obstruction with stones or sludge may present with right upper quadrant pain or jaun­ dice.60 These patients also appear to have more severe steatorrhea. If this condition is suspected, an abdominal ultrasound and hepatobiliary scintigraphy should be per­ formed. If these tests are suggestive of biliary obstruction more detailed imaging by ERCP or PTC should be per­ formed. Such procedures can be diagnostic and therapeu­ tic because sludge or stones can be removed, strictures can be dilated, biliary stents can be placed, or a sphincter­ otomy can be performed. If the problem is persistent or recurrent, surgical intervention may be required to relieve the obstruction. Cholangiocarcinoma Cholangiocarcinoma has been reported rarely in adult patients with cystic fibrosis.53,69 Although rare, this com­ plication should be considered in adult CF patients who present with obstructive jaundice, abdominal pain, or weight loss.69

Intrahepatic Complications Neonatal Cholestasis The exact incidence of neonatal cholestasis in CF infants is unclear. Some believe that this complication is rare, while other studies have shown that up to 68% of infants may have evidence of cholestasis70 An association between the presence of MI and the development of neonatal cholestasis has been suggested,71 although this has not been confirmed.59 Clinically, infants may present with jaundice or acholic stools. Consequently, CF should always be considered in the differential diagnosis of neonatal cholestasis. The clinical picture can sometimes be difficult to distinguish from extrahepatic biliary atresia (EHBA). Hepatobiliary scintigraphy may not distinguish between CF and extra­ hepatic biliary atresia. Similarly, the histologic findings of bile duct proliferation and plugging may be similar in both conditions. Characteristic inspissated, eosinophilic material within the bile ducts of CF liver biopsies is not a feature of extrahepatic biliary atresia. It is important to differentiate between CF and EHBA because most infants with CF have spontaneous resolution of their cholestasis, while those with biliary atresia need to undergo a Kasai portoenterostomy in a timely fashion. There have been occasional reports of patients with both CF and extrahe­ patic biliary atresia. The long-term prognosis of patients with neonatal cho­ lestasis is not well defined, but it appears that most of these patients do well.72 While the occasional infant with neonatal cholestasis has developed multilobular cirrhosis at an older age, there is no clear evidence of an associa­ tion between the two entities. Hepatic Steatosis Many patients with CF also develop hepatic steatosis; however, it is unclear as to whether this entity progresses to fibrosis. Autopsy studies have documented steatosis in 60% of liver biopsy specimens. Steatosis may be focal or involve the entire liver and may occur in isolation or in association with fibrosis and cirrhosis. While the patho­ genesis of CF-associated steatosis is not understood, malnutrition, essential fatty acid deficiency, increased cytokine release, and concomitant medication use have all been implicated as risk factors. Clinically, patients may or may not have an enlarged, soft liver. Ultrasound may be helpful to determine the pres­ ence of steatosis, but magnetic resonance imaging (MRI) may be required. Careful nutritional assessment should be performed, documenting dietary intake and enzyme use. A thorough history also should be performed, spe­ cifically regarding alcohol and medication use. Diabetes mellitus also can be associated with steatosis, and OGTT should be performed if clinically indicated.63 Focal Biliary Cirrhosis Focal biliary cirrhosis is the pathognomonic hepatic lesion of CF. It occurs with variable frequency, but the incidence appears to increase with age. One autopsy study indi­ cated that 72% of patients who died after the age of 24 had focal biliary changes.73 A subset of patients with focal biliary cirrhosis may progress to multilobular biliary cir­ rhosis. Grossly, the liver may show fibrotic changes, which may be superficial or may create a furrowed appearance.

Chapter 53

increased bile acid losses in the stool, which does not appear to occur in PS patients. There are multiple mecha­ nisms by which malabsorption leads to the development of gallstones, including interference with the binding of bile salts to ileal receptors, as well as bile acid precipi­ tation. Defective chloride transport by biliary epithelium also may play a role by altering the viscosity of bile and allowing for stone formation. Gallstones may be identified as an incidental finding on imaging. The majority of patients remain asymptomatic and no intervention is required. Laboratory investigations may show elevation of gamma glutamyl transpeptidase (GGT), alkaline phosphatase, and bilirubin in those who present with biliary colic. If symptoms are persistent or recurrent, a laparoscopic or open cholecystectomy should be considered. At the time of cholecystectomy, an intra­ operative cholangiogram and liver biopsy also should be performed.63 Ursodeoxycholic acid is not useful in the management of gallstones in CF patients.64

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792

Cystic Fibrosis Histologically, there are varying degrees of focal portal fibrosis and bile duct obstruction with bile duct prolifera­ tion, and adjacent areas may appear normal. Periodic acidSchiff positive material may be seen obstructing the ducts. Most patients with focal biliary cirrhosis are asymptomatic and do not develop any significant hepatic complications. Liver enzymes may be normal or moderately elevated. Multilobular Biliary Cirrhosis Multilobular biliary cirrhosis is the most severe form of CF-related liver disease. The time frame for develop­ ment of this complication is variable, but the median age of diagnosis is 9 years. The primary complications are related to portal hypertension and hypersplenism. Most patients show stable hepatocellular function for many years, even decades. On examination, a nodular liver may be appreciated, often on palpation of the left lobe. Splenomegaly, which can be massive, is an indication of the d ­evelopment of portal hypertension. Abdominal distension, with dilated abdominal wall veins, spider nevi, and p ­ almar erythema may become evident with progressive liver disease. Evidence of hypersplenism can be seen on lab­ oratory t­esting with thrombocytopenia and/or a­nemia or neutro­penia. With the development of cirrhosis and portal hypertension, patients may present with ­secondary ­complications, including variceal hemorrhage. Ultrasonography may suggest fibrosis and cirrhosis, but it is not very sensitive. However, it can help document the direction of portal venous flow and may reveal the pres­ ence of varices, although it is not a reliable diagnostic tool. Deterioration in nutritional status also may be noted as liver function worsens, and fat-soluble vitamin levels may be low and difficult to correct. The development of jaundice, hypoalbuminemia, and coagulopathy are usu­ ally late and ominous signs, indicative of hepatic failure.

Management of Liver Disease Pharmacologic Interventions No specific therapy has been shown to alter the course of cirrhosis in CF. Ursodeoxycholic acid (UDCA), has been shown to improve bile flow.74 It also may displace toxic bile acids75 and improve bicarbonate secretion by cholan­ giocytes.75 Treatment does result in improvement of rou­ tine biochemical tests,76,77 but there is no evidence that it alters the long-term outcome. Furthermore, there does not appear to be any beneficial effect on nutritional sta­ tus or when advanced liver disease is already present.78 In theory, if there were a method to identify which patients with CF were at risk for severe biliary cirrhosis, it would be possible to assess the long-term prophylactic poten­ tial of UDCA. Pharmacokinetic studies indicate that the therapeutic dose of UDCA is 20 mg/kg/day divided twice daily.76 Taurine therapy has been recommended for patients with CF-associated liver disease, either alone or in addi­ tion to UDCA. CF patients with liver disease may be defi­ cient in taurine secondary to bile acid malabsorption. UDCA also may increase the taurine required for bile acid conjugation.79 However, a randomized controlled trial did not show any significant effect on liver function

or fecal fat excretion.77 At present, there is no evidence to support the routine use of this agent. Nutrition Patients with CFLD are at higher risk of malnutrition, and special attention should be paid to their nutritional requirements. Energy requirements may be higher as a result of increased intestinal fat losses. Protein intake should not be restricted unless encephalopathy develops. Fat-soluble vitamin levels should be monitored closely and doses increased as necessary. Guidelines for vitamin supplementation in the setting of liver disease are shown in Table 53-5. Following a change in dose, levels should be repeated in 1 to 2 months.80 Portal Hypertension and Hypersplenism Patients with portal hypertension should be counseled regarding the risk for variceal bleeding. Appropriate precautions should be taken to prevent blunt abdom­ inal trauma, which could lead to splenic rupture. Gastrointestinal bleeding also can occur as a result of portal gastropathy or portal colopathy. Patients are also at increased risk of bleeding because of thrombocytope­ nia related to hypersplenism. At present, there is insufficient evidence for prophylactic treatment of portal hypertension in patients with CF before the first variceal bleed. Studies in adults with known varices have shown that beta-blockade is useful in the prevention of first variceal hemorrhage.81 However, there have not been any randomized controlled trials in children. Furthermore, the possibility of bronchospasm as a side effect makes these agents less appealing for patients with CF. The treatment of variceal bleeding is no different from patients with other causes of portal hypertension. Emergent treatment with packed red blood cells and platelets, as well as fresh frozen plasma to correct the coagulopathy, may be required. Adjuvant treatment with intravenous octreo­ tide and proton pump inhibitors also should be insti­ tuted.82 If the bleeding does not respond to conservative measures interventional endoscopy should be undertaken. Endoscopic intervention with sclerotherapy or variceal band ligation may be required, depending on the age of the patient and the size and nature of the varices. These procedures usually are performed serially until varices are ablated. Annual follow-up should then be done to screen TABLE 53-5 FAT-SOLUBLE VITAMIN DOSAGE IN PATIENTS WITH LIVER DISEASE DOSE

LAB MONITORING

Vitamin E

15-25 IU/kg/day

Vitamin E levels

Vitamin D

800-1,600 IU/day vitamin D2 or D3

25-hydroxyvitamin D

Vitamin K

2.5 mg/day (infants)

INR

Vitamin A

5,000-10,000 IU/day (adolescents/adults) Optimal dose not clear: 2-4× RDA

Retinol, retinolbinding protein

INR, International normalized ratio; RDA, recommended daily allowance.

Nonpulmonary Manifestations of Cystic Fibrosis

Liver Failure Patients with CFLD often remain stable with adequate hepatocellular reserve for years and even decades. How­ever, referral to a transplant centre before the onset of end-stage liver failure is important, given the long waiting times for cadaveric donors. Once hepatocellular dysfunction devel­ ops, initial treatment is supportive and includes correction of the coagulopathy; treatment of ascites; and management of hypoglycemia, fluid and electrolytes, and hepatic enceph­ alopathy. Treatment of ascites often results in symptomatic improvement, and maintenance therapy with spironolac­ tone may be useful in managing fluid retention. If hepatic encephalopathy develops, treatment with lactulose should be instituted along with dietary protein restriction. Five-year survival following liver transplant approaches 90% and is similar to that of patients undergoing liver transplantation for other reasons.83 There is no evidence that immunosuppressive therapy adversely affects pulmo­ nary disease. In our experience, patients with CFLD are more likely to die of end-stage lung disease (or require a lung transplant) before hepatocellular failure occurs. In fact, CFLD patients with stable hepatocellular function can tolerate sole lung transplantation with no worse prog­ nosis or lung function than CF patients without CFLD.84 This affects the timing of transplantation because CF patients listed for lung-liver transplant are likely to face a sig­ nificantly longer wait for multiple organs to become avail­ able. If they were listed for sole lung transplantation, their chances of surviving to transplantation potentially would be much improved. Nonetheless, there are several reports of a few patients who have undergone successful combined transplants of the lung and liver with 1- and 5-year actuar­ ial survival rates of 85% and 64.2%, respectively.

NUTRITION Pathobiology Malnutrition has been an important concern in CF since early descriptions of the disease. Both impaired weight gain and linear growth are seen in CF patients; however,

Needs • Increased intestinal losses • Pancreatic insufficiency • Bile salt metabolism • hepatobilary disease • GE reflux • Increased energy expenditure • Pulmonary disease • Increased energy losses • CF related diabetes

over the past decade, aggressive nutritional support has resulted in improved nutritional status and survival. Nutritional support is an integral part of comprehensive care of individuals with CF, with the target being to main­ tain normal growth. The impact of nutrition support on survival is most strikingly shown by a comparative study of two CF clin­ ics (Boston and Toronto). The major difference between these two clinics at the time of the study was the approach to nutrition, with the Toronto clinic having a more aggres­ sive approach to nutritional intervention. The patients attending the Toronto clinic were taller, and the Toronto male patients also were heavier. In this study, Corey and colleagues85 showed marked differences in patient sur­ vival despite no other differences in the patient popula­ tion and their pulmonary function. This study therefore suggests that improved survival is linked to better nutri­ tional status. The pathogenesis of malnutrition in CF is complex. It is likely the result of a number of factors that ultimately lead to energy imbalance (Fig. 53-4). Firstly, there are increased energy losses in CF patients with pancreatic insufficiency because of maldigestion/malabsorption. Despite adequate enzyme supplementation, persistent fat and protein maldigestion occurs as a result of multiple factors (see Box 53-2). Furthermore, increased energy losses can occur in the setting of CF-related diabetes and CF-related liver disease. Energy intake also plays a role in the development of the energy imbalance in CF. Oral intake may be limited for multiple reasons, including anorexia secondary to respiratory disease, gastroesopha­ geal reflux, DIOS, and advanced liver disease. There are variable reports regarding energy intake in CF patients, with some studies showing increased intake in those with normal growth compared with those with growth retardation. However, other studies have found nutrient intakes to be close to the normal range. Resting energy expenditure (REE) in CF patients is increased, which correlates with worsening pulmonary status. The precise basis for the increase in REE in patients with CF however is not clear; the relationship to the severity of lung dis­ ease suggests that it is due to inflammation or increased work of breathing. While it has been suggested that a component of increased REE is due to the underlying CF defect, not all studies have demonstrated evidence that the primary CF defect results in increased cellular energy expenditure.

Intake • Anorexia (due to severe lung disease) • Cytokine release (due to inflammation) • Esophagitis • Iatrogenic fat restriction • Distal intestinal obstruction syndrome • Psychosocial issues • Feeding disorders • Depression

FIGURE 53-4.  Model for the development of energy imbalance in cystic fibrosis.

Chapter 53

for recurrence. Some patients may require a transjugular intrahepatic portosystemic shunt or a surgical shunt pro­ cedure if bleeding cannot be controlled with endoscopic therapy. Unlike other patients with cirrhosis who have a high 1-year mortality rate, median survival after the first episode of variceal bleeding in CF is 8.4 years.

793

Section VIII

794

Cystic Fibrosis Ultimately, it is the imbalance between energy needs, losses, and intake that results in an energy deficit in patients with CF. Furthermore, over time, with progres­ sion of lung disease, there may be an increasing energy deficit and weight loss. Loss of muscle mass in turn impacts respiratory status, resulting in a vicious cycle with progressive nutritional and pulmonary deteriora­ tion. It is important to emphasize that this imbalance can be corrected with adequate caloric intake.

Nutritional Management A multidisciplinary approach to nutritional therapy is imperative. Patients should have anthropometrics done at diagnosis and each visit and should have their diet and enzyme intake reviewed. Patients with CF should follow a high energy diet with supplemental fat. This is done in an attempt to optimize caloric intake and pre­ vent an energy deficit. Because of impaired fat absorp­ tion, patients with PI do not appear to be at risk of hyperlipidemia. However, lipid levels should be moni­ tored if the patient has pancreatic sufficiency, if there is a family history of hyperlipidemia, or if the patient has undergone a lung or liver transplant and is on immuno­ suppressive agents that are known to affect lipid metabolism. In patients who are losing weight, it is important to review all three components that contribute to energy balance, namely, energy intake, losses, and expendi­ ture. Dietary records can be used to assess intake, and fat absorption can be assessed using 72-hour fat balance studies. If available, indirect calorimetry can be used to estimate energy expenditure. Alternatively, energy require­ ments can be estimated using the following equation: basal metabolic rate × 1.1 (for malabsorption) × activity factor (1.5 to 1.7) + 200 to 400 kcal/day. Intervention is then targeted appropriately to increase caloric intake and optimize enzyme supplementation. In some patients, nutritional therapy with nasogastric or gastrostomy feedings is needed to improve nutritional status or maintain energy balance. Several studies have examined the benefit of enteral feeding in patients with CF.85–87 Short-term supplementation is generally of no long-term benefit. Although there is an initial improve­ ment in nutritional status with supplementation, this effect is lost when supplementation is ceased. However, studies have shown that long-term nocturnal enteral supplementation results in improvements in growth and

body composition. Although there is no direct evidence that nutritional intervention results in improved longterm survival, several studies have shown a decrease in the rate of deterioration of pulmonary function following improvement in nutritional status.

Vitamin Supplementation Fat-soluble vitamin deficiency is common in patients with CF because of pancreatic insufficiency and hep­ atobiliary dysfunction A prospective study of patients identified by newborn screening indicated that 35% of patients had vitamin A, D, or E deficiency.80 Follow-up of these patients showed that while vitamin A and D deficiency resolved with supplementation, vitamin E deficiency was still common. Vitamin E deficiency can lead to hemolysis and, if prolonged, to periph­ eral neuropathy. Vitamin A deficiency can result in night blindness, keratomalacia, pigmentary retinopa­ thy, and even permanent corneal damage. Moreover, it also may result in immune dysfunction and may predis­ pose to infection. Prepubertal children with CF do not appear to have osteopenia, although this has been well documented in adolescents and adults.88 Osteopenia in patients with CF is likely caused by many factors. Vitamin D supplementation is important to maintain normal bone mineralization because it has been shown that bone demineralization occurs in these patients. Adults with CF are at a high risk of complications sec­ ondary to vitamin D deficiency, including the devel­ opment of fractures. This is of even more importance in patients living in areas with reduced sunlight exposure. Subclinical vitamin K deficiency, measured by serum PIVKA-II (prothrombin-induced in vitamin K absence) has been shown to be almost universal in PI patients with CF who do not receive supplementation.89 However, sup­ plementation does not appear to return PIVKA-II levels to normal in all patients.90 This may be related to inad­ equate dosing because there is little evidence regarding appropriate dosing of vitamin K. Subclinical vitamin K deficiency may be important in the development of meta­ bolic bone disease in patients with CF because of its role in the carboxylation of the bone matrix protein osteocal­ cin. Serial monitoring of fat-soluble vitamin levels should be performed in patients with pancreatic insufficiency, and doses of supplements should be adjusted if necessary (Table 53-6).

TABLE 53-6 RECOMMENDED DOSAGE OF FAT-SOLUBLE VITAMINS FOR CF PATIENTS WITH PANCREATIC INSUFFICIENCY 0-12 MONTHS Vitamin A (IU) Vitamin D (IU) Vitamin E (IU) Vitamin K (mg)*

1,500 400 40-50 0.3-0.5

1-3 YEARS 5,000 400-800 80-150 0.3-0.5

3-8 YEARS 5,000-10,000 400-800 100-200 0.3-0.5

>8 YEARS 10,000 400-800 200-400 0.3-0.5

*Objectively determined dosing guidelines are not available for vitamin K, and dosage should be adjusted according to coagulation parameters and PIVKA-II (­prothrombin-induced in vitamin K absence) levels Adapted from Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35(3):246-259.

Nonpulmonary Manifestations of Cystic Fibrosis

Male Infertility The vast majority of adult men with CF are infertile due to obstructive azoospermia.91,92 While earlier studies att­ ributed CF male infertility to congenital bilateral agenesis of the vas deferens (CBAVD), more detailed evaluation of the reproductive tract has revealed a variety of obstruc­ tive anatomic abnormalities.93 It is also recognized that 1% to 2% of otherwise healthy males who are infertile also have obstruc­ tive azoospermia. Phenotype evaluation of these men reveal that more than two thirds of them carry at least one CFTR gene mutation, and on extensive mutation ­analysis, up to 50% carry CFTR gene alterations on both alleles.94,95 All have at least one mild class IV or class V mutation on at least one allele. A subset of these patients may fulfill diagnostic criteria for CF. These findings suggest that the male genital tract is exqui­ sitely sensitive to even minor losses of CFTR function, because the majority of healthy men with CBAVD do not appear to have any evidence of clinically significant CF-associated disease in other organs.

CFTR and Pancreatitis As mentioned previously, patients with CF may present with pancreatitis. However, there is increasing evidence of a role for CFTR in the pathogenesis of recurrent acute

and chronic pancreatitis. A number of studies have shown that approximately 40% of patients with recurrent acute or chronic pancreatitis carry CFTR mutations on one or both alleles.12,96 However, this does not necessarily imply that they have CF. Many of the mutations found in this group of patients are rare, and the functional con­ sequences are unknown. Careful clinical evaluation at a specialized CF clinic is required to determine if such patients fulfill the diagnostic criteria for CF.97 At present, identification of CFTR mutations on one or both alleles alone is not sufficient to establish a diagnosis of CF.

CONCLUSION The discovery of the CFTR gene has provided great insight into the pathogenesis of cystic fibrosis. However, it has become clear that it is a complex disease and that there are probably a number of genetic and environmental fac­ tors that contribute to the development of disease hetero­ geneity. With continuing improvement in survival, many other complications such as gastrointestinal malignancies, CFRD, and issues concerning fertility are now becoming evident. Comprehensive care addressing all aspects of CF, in childhood and adulthood, continues to be central to optimizing the health and well-being of these patients.

References The complete reference list is available online at www. expertconsult.com

Chapter 53

SINGLE ORGAN MANIFESTATIONS OF CFTR DYSFUNCTION

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