in the UK. Cystic Fibrosis Trust, 2001. The Burkholderia cepacia complex: suggestions for prevention and infection control. Cystic Fibrosis Trust, 2004. Fig. 11.3.1 Typical CXR features of advanced CF lung disease and the presence of a totally implantable IV access device. H FIRTH & J HURST 248 11.4 Cystic \201 brosis genetics ZF508 as the other allele typically causes the much milder phenotype of CBAVD without respi ratory symptoms. Criteria for the diagnosis of CF (after Rosenstein and Cutting 1998) CF is the most common life-limiting autosomal recessive (AR) disorder in the white populati on. Three clinical phenotypes are associated with mutations in the CF transmembrane conduct ance regulator gene (CFTR) on 7q31 \200\22332. 1 Classical CF. Obstructive lung disease, br onchiectasis, exocrine pancreatic insuf \201 ciency, elevation of sweat chlo ride concentr ation (>60mM), and infertility in males due to congenital bilateral absence of the vas defe rens (CBAVD). Diagnosis requires at least one criterion from each group Group 1 \200 One or more characteristic phenotypic features (see below), e.g. chronic sinopulmonary dise ase, gastrointes- tinal and nutritional. Abnormalities, salt loss syndromes, and male uroge nital abnormalities, e.g. CBAVD. Sibling with CF. Positive neonatal IRT (immunoreactive try psinogen test). 2 Non-classical CF. Chronic pulmonary disease 9 pan- creatic exocrine disease elevated s weat chloride (>60 mM) CBAVD. \200 3 CBAVD. The incidence of CF in Caucasians of European extraction is 1/2000 \200\2231/4000 newborns (1/2500 in the UK). CF is rare in native Africans and Asians. The mutation spectru m and frequency are highly dependent on ethnic background. See Table 11.4.1 for the diagnos tic criteria for CF. More than 1000 mutations in CFTR have been identi \201 ed (see Table 11.4.2), of which the most common by far is delta F508 (ZF508). ZF508 encodes a three-nucle otide deletion resulting in a CFTR protein lacking phenylalanine (F) at postion 508 in the protein. This causes misfolding of the newly synthesized mutant CFTR so that it does not in tegrate into the cell membrane, but remains in the cyto- plasm where it is degraded by the ubiquitin \200\223proteosome pathway. ZF508 accounts for 70% of CF alleles, but the exact proportion varies depending on ethnic origin. The next most common mutations are G542X, G55 1D, delta1507, W1282X, and N1303K, each accounting for only 1 \200\2232.5% of known CF alle les. W1282X is common in the Ashkenazi Jewish population. Standard commercial kits for DNA diagnosis usually identify 29 mutations. In the English population this accounts for 87% of CF alleles. Thus, using a standard screen, 76% of English patients with CF will have two identi \201 able CFTR mutations, 22% will have a single identi \201 able CF mutation, an d 2% of patients with CF will have no identi \201 able mutation. Specialist labs may offer rare mutation screens. Polythymidine (Poly-T) tracts in intron 8 affect the splicing ef \201 ciency of a CFTR allele. The most ef \201 cient polymor- phism is 9T, 7T has reduced ef \201 ciency, and 5T has signi \201 - cantly reduced ef \201 ciency. R117H in cis with 5T, with ZF508 as the other allele, usually results in non-classical CF (pan- creatic suf \201 cient), whereas R117H in cis with 9T with Group 2 \200 Sweat chloride >60mM on 2 occasions ( \211 75mg of sweat is critical to reliability). Some laboratories assay sweat osmolality which is increased in CF (normal range is 62 \200\22319 6mOsm/kg) Identi \201 cation of 2 CF mutations Abnormal nasal potential difference (measur e of CFTR- mediated ion transportation) \200 Phenotypic features consistent with diagnosis of CF (after Rosenstein and Zeitlin 1998) \200 Chronic sinopulmonary disease. Persistent colonization with typical CF pathogen (Staphyloco ccus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia), chronic cough and sputum pro- duction, persistent CXR abnormalities (bronchiectasis, atelectasis, in \201 ltrates, hyperin \202 ation), airway obstruction (wheezing and air trapping), nas al polyps, X-ray or CT abnormalities of paranasal sinuses, clubbing Gastrointestinal and nu tritional abnormalities. Meconium ileus (10 \200\22320%), rectal prolapse (20%), distal int estinal obstruction, pancreatic insuf \201 ciency, recurrent pancrea- titis, focal biliary cirrhosis or multilobular cirrhosis, failure to thrive (protein \200\223calorie malnutriti on), hypopro- teinaemia and oedema, complications secondary to lack of fat-soluble vitamins Salt loss syndromes. Acute salt depletion, chronic metabolic acidosis Male urogenital abno rmalities resulting in obstructive azoospermia. CBAVD. Table 11.4.1 Functional classi \201 cation of CFTR alleles (after McKone et al. 2003) Alle le Class G542X, R553X, W1282X, R11162X, 621 \200\2231G l T, 1717 \200\2231G l A, 1078ZT, 36 59ZC ZF508, Z1507, N1303K, S549N G551D, R560T Functional effect of mutation I Defective protein production II Defective protein processing III Defective protein regulation IV* Defective protein conductance R117H, R334W, G85E, R347P 3849 +10 kbC l T,2789+5G l A, A455E 711+1G l T, 2184DA, 1898+1G l A V* Reduced amounts of functioning CFTR protein Unknown Compared with class II (including ZF508 homozygotes). classes IV and V have a signi \201 c antly lower mortality rate and milder clinical phenotype. See http://www.genet.sickkids.on. ca/cftr for the Cystic Fibrosis Analysis Consortium CF mutation database. CHAPTER 11.4 Cystic \201 brosis genetics 249 Clinical approach History: key points \200 \200 unidentified allele(s) and enable prenatal diagnosis. Pre-implantation genetic diagnosis (P GD) for ZF508 homozygotes is available in some centers. Three-generation family tree. Genotype of affected individual if known. Predictive testing This may be applicable in younger siblings of a child recently diagnosed with CF, in view of the bene \201 ts of treatment with prophylactic antibiotics and pancr eatic and vitamin supplements. Examination: key points Usually not relevant if affected individual is under the care of CF pediatrician/physician or you are seeing another family member. Other family members When an individual is diagnosed with CF, and mutation analysis is perf ormed, it is routine practice to offer carrier testing to both parents. Cascade screening o f the extended family for the mutation identi \201 ed in their relative can then be offere d. Where an individual is shown to be a CF carrier, population-based screening (see Table 1 1.4.2) can be offered to his/her partner to determine the risk to their offspring. Carrier testing of children is usually deferred until 16 years when they are of an age to be involv ed in decision-making and old enough to understand the implications of the result. Investigation DNA sample for mutation analysis of CFTR. Genetic advice Inheritance and recurrence risk \200 Autosomal recessive (AR) and so the recurrence risk to parents of an affected child=1/4. Th e following recur- rence risks are based on pedigree analysis and assuming no consanguinity , no family history of CF in a partner, and a CF carrier rate of 1/23 (see below for carrie r rates in different ethnic groups). This risk estimate can be sub- stantially modi \201 e d by CF mutation analysis in the relative and his/her partner (see below). Risk to offsprin g of healthy sib of an affected child is 2/3 \2271/23 \2271/4=1/138. Risk to offspring of a unt/uncle or half-sib of an affected child is 1/2 \2271/23 \2271/4=1/184. Risk to offspring of an affected individual is 1 \2271/23 \2271/2=1/46. Table 11.4.2 Carrier rates and mutation detection rates in different ethnic populations Population Carrier frequency Mutation detection rate with panel appropriate to ethnic group (%) Ashkenazi Jewish 1 in 23 97 Northern European 1 in 23 90 Variability and penetrance Homozygosity for ZF508 and compound heterozygosity or homozygosi ty for other non-functional alleles are associ- ated with the classical form of CF. Even in classical CF the age of onset and rate and progression of pulmonary dis- ease are very var iable (in \202 uenced by modi \201 er genes, infec- tion, nutrition, therapy, smoking, et c.). ZF508 homozygotes vary considerably in their manifestation of gastrointestinal, hepato biliary, and pulmonary disease. Monozygotic CF twins are more concordant than dizygotic CF twins. The CF phenotype may be modi \201 ed by loci in the partially imprinted region on 7 q 3 of CFTR that determine stature, food intake, and energy homeostasis. All classical cas es of CF (ZF508 homozygotes) have pancreatic insuf \201 ciency but there is considerable v ariability in pulmonary disease. Decline in lung function in CF is associated with coloni- sation by Pseudomonas aeruginosa and Burkholderia cepacia. A partially functional allele in combination with a non- functional allele (e.g. ZF508) is a typical picture in non- classi cal CF. However, since the standard screening panel comprises mainly non-functional alleles , many patients with non-classical CF will have only one identi \201 able CF allele, i.e. those patients in whom clinical diagnosis is most challenging are often those most difficul t to diagnose genetically. In comparison with ZF508 homozygotes, ZF508/R117H, ZF508/A455E, ZF508/3849+10kb C l T and ZF508/ 2789+5G l A are associated with mild clinical manifes tati ons. Hispanic 1 in 46 57 African-American 1 in 65 75 Asian 1 in 90 30 Natural history and management Potential long-term complications \200 Respiratory failure. Pulmonary disease is the main cause of morbidity and mortality in pati ents with CF. Heart \200\223 lung transplantation may be considered for end-stage disease. Diabetes. 25 \200\22350% have an abnormal glucose tolerance test (GTT) by their 20s and 5% require insulin. Liver disease. 5% of adults have cirrhosis and portal hypertension. Male i nfertility. 97% of males with CF have CBAVD with obstructive azoospermia. Pregnancy may be possible with assisted reproductive technology in which case offer mutation analysis to par tner. Surveillance Evidence is emerging that management of CF in pediatric and adult CF centers r esults in a better clinical outcome. In the US median survival has reached 31.1 years for m en and 28.3 years for women. Survival to the 30s and 40s is no longer rare. Median survival for patients with pancreatic suf \201 ciency (non-classical CF) is 56 years. Pregnancy in women with CF Fertility in women with CF is impaired, but successful preg- nan cy is possible. In a retrospective study from France, of 75 pregnancies, 64 were liveborn ( 18% premature and 30% low-birthweight), there were 5 miscarriages, 5 therapeutic abortions, and one maternal death. Three women died in the year following a pregnancy, all of whom ha d a FEV1 Prenatal diagnosis Possible by chorionic villus sampling (CVS) at 11 weeks gestation if bot h mutations are known. If a single or neither mutation is known, diagnosis of CF is secure, and paternity is certain, it is possible to offer linkage studies to capture H FIRTH & J HURST 250 Expert advisers David A. Lomas, Professor, Respiratory Medicine Unit, Department of Medicin e, University of Cambridge, Cambridge and Di Bilton, Consultant Respiratory Physician and D irector of the Adult CF Unit, Papworth Hospital, Cambridge, England. <50% before pregnancy. A retrospective audit of 33 suc- cessful pregnancies from Scandinavi a found that preterm delivery occurred in 24%. The lung function of women delivering preter m was signi \201 cantly lower than that of those delivering at term, and they were most li kely to have other CF complications including diabetes, asthma, or liver disease. Lung func tion did not deteriorate during preg- nancy, but the need for IV antibiotics was doubled. W omen with mild to moderate disease may safely go through pregnancy. \200 Further reading Dankert-Roelse JE, te Meerman GJ. Screening for cystic \201 brosis \200 \224 time to change our position? [editorial]. New Engl J Med 1997; 337: 997 \200\223998. Offer mutation analysis to partner (offer CVS if partner is a CF carrier). Refer to CF phys ician for assessment of likely impact of pregnancy on respiratory reserve. Increased risk o f gestational diabetes due to pancreatic insuf \201 ciency in women with classical CF. Con sider the drug regimen of your patient and whether any of the drugs have teratogenic potent ial. Pregnancy should be jointly managed by an obstetrician with special expertise in mater nal and fetal medicine and a CF specialist. Durie PR. Pancreatitis and mutations of the cystic \201 brosis gene [editorial]. New Engl J Med 1998; 339: 687 \200\2238. Gillet D, de Braekeleer M, Bellis G, et al. Cystic \201 brosis and preg- nancy. Report fr om French data (1980 \200\2231999). Br J Obstet Gynaecol 2002; 109: 912 \200\223918. Mahadeva R, Webb K, Westerbeek RC, et al. Clinical outcome in relation to care in centers s pecializing in cystic \201 brosis: cross sec- tional study. Br Med J 1998; 316: 1771 \200 \2231777. Massie RJ, Wilcken B, van Asperen P, et al. Pancreatic function and extended mutation analy sis in DeltaF508 heterozygous infants with an elevated immunoreactive trypsinogen but norma l sweat electrolyte levels. J Pediatr 2000; 137: 214 \200\223220. Neonatal screening Most neonatal screening programs for CF combine assay of immunoreactive trypsinogen (IRT) on a dried blood spot (Guthrie card), with analysis for common CF mutatio ns, e.g. ZF508. An IRT of 60 \200\22370mcg/l is equivocal and >70mcg/l is positive. This ap proach has been well stud- ied but misses some children with CF and detects more ZF508 carr iers than expected. The excess of ZF508 heter- ozygotes is associated with the presence of a second muta- tion or the 5T allele in some infants. In one study of 57 subjects with posi tive IRT who were ZF508 heterozy- gotes, three had clinical CF at 1 year. McKone EF, Emerson SE, Edwards KL, et al. Effect of genotype on phenotype and mortality in cystic \201 brosis: a retrospective cohort study. Lancet 2003; 361: 1671 \200\2231676. Mekus F, Laabs U, Veeze H, et al. Genes in the vicinity of CFTR modu- late the cystic \201 brosis phenotype in highly concordant or discord- ant F508del homozygous sib pairs. Hu m Genet 2003; 112: 1 \200\22311. Neill AM, Nelson-Piercy C. Hazards of assisted conception in women with severe medical disease. Hum Fertil 2001; 4: 239 \200\223245. \230degaard I, Stray-Pedersen B, Halberg K, et al. Maternal and fetal morbidity in pregnan cies of Norwegian and Swedish women with cystic \201 brosis. Acta Obstet Gynecol Scand 20 02; 81: 689 \200\223705. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998; 132: 589 \200\223595. Support group Cystic Fibrosis Trust <www.cftrust.org.uk>. Rosenstein BJ, Zeitlin PL. Cystic \201 brosis. Lancet 1998; 351: 277 \200\223282. This page intentionally left blank N JARAD 252 11.5 Extra-pulmonary manifestations of cystic \201 brosis Introduction Impairment of the structure of the CFTR is the hallmark of CF. This protein is present in the cell membrane of many organs in addition to the lung; the nose, pancreas, l iver, gas- tro-intestinal track and the reproductive system. This results in CF being a tru ly multisystem, multi-organ disorder. It is recommended that patients take their enzymes prior to food for ease of compliance. Th e recommended dose is 500 units of lipase per kg of body weight, but can vary between patie nts. Younger children are given these preparations as microspheres with a fruit puree or a taste-masking material. The maximum recommended daily dose is 2500 units of lipase per kg p er meal or a total of 10,000 units daily. Adverse effects of pancreatic supplementation inc lude oral and peri-anal irritation. It has been suggested that high doses of lipase might b e associated with \201 brosing colonopathy. If symptoms persist despite high doses of enz ymes, input from an experienced CF dietitian is needed. The pancreas Impaired secretory function of the pancreas Over 85% of all CF people suffer f rom pancreatic insuf \201 - ciency (PI). There is a strong correlation between the degree of PI and the genetic pro \201 le. Patients carrying class III and IV mutations and who ha ve a relatively preserved CFTR function tend to be pancreatic semi-suf \201 cient or suf- \201 cient. In contrast, over 99% of patients who are homozy- gotes for the Delta F508 mu tation have pancreatic insuf \201 ciency. Thickened pancreatic secretions block the pancre atic duct. This is followed by a series of processes starting with duct injury and obstruct ion and ending with auto-digestion, which start in utero. Another important function of the CFTR is to mediate the secretion of bicarbonate in the pancreatic duct epithelium. This is an essential component which eases the secretion and solubility of the digestive pancreati c enzymes. The exocrine function particularly of lipase but also of bile reaching the intes tine are adversely affected in an acid envi- ronment. The failure of suf \201 cient quanti ties of lipolytic and proteolytic enzymes reaching the intestinal tract leads to steatorhoe a and malabsorption. AUTHOR \200\231S TIP Common causes of reduced efficacy of pancreatic supplementation includ e: \200 \200 lack of adherence to treatment; neutralization of activities by increased acidity in the pr oximal intestinal tract \200\223 try H2-histamine receptor antagonists or proton pump inhi bitor; lack of ef \201 cacy of that brand for individual \200\223 try alter- nate brand. Cystic \201 brosis-related diabetes mellitus (CFRD) The role of CFRD in the natural histo ry of CF has increas- ingly as patients survive longer and hence its prevalence and adverse effects become manifest. The prevalence of CFRD has been estimated to be 5% in all CF pati ents but ranges between 15 \200\22322% in patients over the age of 16. The impact of pre-di abetic state and diabetes in CF patients: \200 \200 \200 Clinical manifestations Symptoms start when lipase and protease levels fall below 5%. The m ain features in infancy and childhood are combi- nation of hunger and malabsorption. Steato rhoea, with greasy and offensive stool is an early symptom, followed by diarrhea, abdominal pain and failure to thrive. Laboratory features re \202 ect malabsorption of fat, protein s and vitamins and include hypoalbuminaemia, anemia and reduced plasma levels of fat-solubl e vitamins. accelerated decline in lung function; increase rate of pulmonary exacerbations (Fig. 11.5.1 ); premature mortality. 100 X2 = 14.6 p <0.0022 Diagnosis Prior to the era of sweat testing, the clinical features out- lined earlier made pediatricians suspect CF. In undiag- nosed cases, the easiest investigation is measurement of elastase-1 in the stool. Another more cumbersome method is the measurement of fat globul es in the stool over a 72-hour collection. 75 50 % 25 0 No P Exs 1 \200\2232 P Exs 3 \200\2234 P Exs More than 4 P Exs AUTHOR \200\231S TIP Even in asymptomatic CF patients, malabsorption may be present. The ea siest and most reliable test is the measurement of elastase-1 in a small stool sample. Fig. 11.5.1 Prevalence of CFRD in 499 CF patients in the Southwest region of England accord ing to the frequency of annual pulmonary exacerbations (P Exs). Pathogenesis of CFRD Almost all patients with CFRD are pancreatic insuf \201 cient. CFRD i s probably caused by the insidious physical destruc- tion of Beta cells, leading to decreas ed insulin levels. The \201 rst biochemical manifestation is delayed secretion of insulin . Post-prandial delay in insulin secretion accounts for impaired oral glucose tolerance tes t (OGTT) which is one of the main methods of diagnosis of CFRD. Treatment Porcine lipase and protease have revolutionized the man- agement of PI in CF pati ents. These are now available in different strengths as microspheres in several commerciall y available preparations. Pancreatic enzyme supplementations are manufactured in enteric co ated preparations. The outer layer is dissolved at a high PH releasing the enzymes. CHAPTER 11.5 Extra-pulmonary manifestations of cystic \201 brosis 253 The manifestations of the pre-diabetic state are those of increased numbers of pulmonary ex acerbations, acceler- ated decline in lung function and more pronounced weight loss. Polydi psia and polyurea are occasionally but not often present. variable doses according to their eating habits and the results of their glucose monitoring . For patients who require overnight feeding, additional short acting prepara- tions should be prescribed prior to starting the feed. Oral hypoglycaemic agents are not currently reco m- mended unless patients have a suspected type II features (obesity) or are unable or unwi lling to take insulin. All patients with CFRD should have at least one annual measurement o f glycosylated hemoglobin (HB A1C) with the aim of keeping this under 7%. CFRD is not acont ra-indication for either liver or lung transplant. Diabetic CF patients do not have worse t rans- plant outcome, but they are prone to have impaired dia- betic control due to surgery and the use of corticosteroids in the early post transplant phase. Diagnosis and classi \201 cations There are three methods of diagnosing CFRD: 1. Raised fa sting plasma glucose, 2. OGTT results consistent with diabetes as in Table 11.5.1. 3. Raise d plasma glucose during continuous glucose moni- toring. CFRD is divided into three categories which might present as different stages: Category 1: impaired OGTT but normal plasma fasting and random glucose (biochemical diabetes) Category 2: raised random plasma glucose within the diabe- tes range but normal fasting glucose Cate gory 3: raised random and fasting plasma glucose. Abdominal pain: the gut in CF Abdominal pain is common in CF patients. In the author \200 \231s unit 72% of CF patients declared that they had abdominal pain at their an annual asse ssment questionnaire. Reasons for abdominal pain are illustrated in Table 11.5.2. Table 11.5.1 The World Health Organization protocol Table 11.5.2 Causes of abdominal pain in CF The UK CF Trust Diabetes Working Group recommends that the WHO classi \201 cation of diagn osis of diabetes is adapted for CFRD. OGTT must be performed at least 30 days away from acu te chest infection. \200 \200 \200 \200 \200 \200 Malabsorption due to under-use of pancreatic supplements Constipation (Fig. 11.5.2) Distal intestinal obstructive syndrome (DIOS) Peptic ulceration Gall stones and cholecystitis Gast ro-oesophageal re \202 ux disease (GORD) Pancreatitis 120 minutes venous blood sample Plasma venous sample < 7.8 mmol/l Normal Plasma venous sample 7.9 \200\22311.0 mmol/l Impaired Plasma venous sample \211 11.1 mmol/l Diabetic Despite many similarities with type I DM, acute and chronic complications are encountered l ess frequently and are less severe Diabetic ketoacidosis has been described but rare. Backg round diabetic retinopathy is seen in approximately 15% after 5 years and 10% after 10 year s of diagnosis of diabetes. More complex prolipherative retinopathy with its sight threaten ing complications is rare. Microvascular nephropathy has been described, but it is too mild to cause renal failure. Central nervous and car- diac ischaemic events are rare due to a c ombination of fac- tors including: reduced longevity of patients, absent of other co-morbid ity such as hypercholesterolemia and heavy cigarette smoking being unusual. Screening for diabetes in CF patients Annual OGGT is recommended as a screening method for CFRD after the age of 12 years. OGTT can be repeated in 12 months if normal or impaired. If the patient has increased symptoms of decline in lung function and weight loss OGTT can be repeated sooner. Management A low/reduced calorie diet is not appropriate in CFRD. Adequate nutrition is ess ential for all CF patients. Patients should not be discouraged from eating high calorie foo d, but they should not rely on them as the sole source of calo- ries. Rather, patients shou ld be encouraged to adapt a bal- anced diet. Education is needed to emphasize the differenc e between usual diabetes and CFRD. Close monitoring of body mass index is important in the management of CFRD. Insulin replacement is the mainstay of treatment of CFRD. Short acting and long acting preparations are available. Most patients are provided with a combination o f both at Fig. 11.5.2 MRI of the abdomen showing bowel fecal impaction (white arrows) in a 32 female CF patient with chronic refractory constipation. This patient takes 6 sachets of bulk laxat ive daily as well as a daily phosphate enema. N JARAD 254 Simple laxatives such as lactulose, sodium docusate and Kleen Prep. N acetylcysteine (NAC) used in our unit as orange- \202 a- voured sachets (200mg twice daily). NAC is thought to reduce the stool viscosity by breaking the mucoprotein content. Gatsrogra \201 n is given during acute stages. Gastrogra \201 n is a mucosal irritant and an osmotic laxative. The d ose is 100ml diluted in 400ml of water daily for three to four days. This could be given or ally or through a naso-gastric tube. The same dose could be given as an enema. Anti emetics and gastrointestinal lavage can be used in more refractory cases. Meconium ileus (MI) in infants The composition of meconium in CF infants differs from that in normal infants. Pancreatic insuf \201 ciency plays an important part in the process of formation of MI. It is thought that the mechanisms of MI are: increased level of lactose an d other undigested components coupled with dehydrated meconium. The uncomplicated MI is man ifested in the \201 rst few days of life with bowel obstruction causing a triad of: const ipation, vomiting and distended abdomen with \201 lling in the right lower quadrant of th e abdomen. In less than half of cases, complicated MI occurs with features of features of v olvulus and bowel perforation with intra-peritoneal infection. Management of the uncomplica ted form is to try to reverse the process by repeated gastrographin enemas. The suc- cess r ate varies and complications including bowel perfora- tion have been reported. Management o f complicated MI is surgical. This includes resection of the abnormal area and peritoneal t oilet. Intestinal anastomosis or temporary stoma may be formed according to the status of t he intestinal tract detected intra-operatively. Cystic \201 brosis liver disease (CFLD) The bile is more viscous in CF patients than in n on CF individuals as with other mucous secretions. Bile plugging at the level of small and medium sized bile ducts results in areas of micro-cirrhosis. This is seen at post-mortem an d tends to be asymptomatic. CFLD is a well recognized feature of cystic \201 brosis. Seve re decompensated liver disease happens in childhood and adolescent stages. Paradoxically de spite the increase in age for CF patients the incidence of liver disease is decreasing. The incidence of biochemical abnormality and impaired liver architecture is approximately 50%. Liver decompensation,on the other hand, occurs only in less than 5%. There are three stage s of CFLD: 1 biochemical: manifested by impaired liver enzymes; 2 structural: in which the images shows fatty in \201 ltration, irregular liver architecture including rough liver ed ges; and 3 de-compensated liver failure which manifests with portal hypertension, hypoalbum inaemia, ascites and impaired coagulation. Distal intestinal obstructive syndrome (DIOS) The prevalence of DIOS in adult CF patients h as been esti- mated to be 15%. The mechanisms are different from MI. It has been postulated that DIOS occur due to \200 \200 \200 sub-optimal management of pancreatic insuf \201 ciency; dehydrated intestinal content; and impaired intestinal motility. Features of DIOS vary between simple constipation to symptoms of intestinal obstruction inc luding nausea and vomiting. A painful poorly de \201 ned mass is often palpable in the rig ht lower quadrant of the abdomen. Normally there are no signs to suggest local or systemic in \202 ammation. If these are present appendicitis or extra-uterine pregnancy in women sh ould be suspected. Diagnosis is mainly done on clinical grounds. Plain abdomi- nal \201 l m may reveal signs of distal intestinal obstruction including dilatation of intestinal loop s (Fig. 11.5.3). Abdominal ultrasound, CT scan and MRI may be used to distinguish DIOS from appendicitis. Investigations All CF patients should undergo measurement of liver func- tion tests at leas t once a year during their annual assess- ment. For those with impaired liver function test s, liver ultrasound by experienced radiologist should be done. MRI has an increasing role i n identifying the anatomy and complications of liver disease including portal hyperten- sio n (Fig. 11.5.4). When clinical or radiological manifesta- tions of complicated liver diseas e are seen, non-invasive measurement of portal vein pressure and an edonscopy to elucidate and manage oesophageal varices should be implemented. LIVER SPLEEN Fig. 11.5.3 Dilatation of the proximal bowel in a 32-year-old patient with repeated episode s of DIOS. The management of DIOS is now mainly medical. Oral and intravenous \202 uids for re-hydra tion are both part of the treatment and prevention. Other measures include: Fig. 11.5.4 An MRI scan of a 22-year-old CF patient with macro nodular liver cirrhosis, spl enomegaly and variceal changes in branches of the portal vein (white arrow). CHAPTER 11.5 Extra-pulmonary manifestations of cystic \201 brosis 255 Table 11.5.3 Risk factors for reduced BMD in CF patients Management Ursodeoxycholic acid (URSO) is the only medical treatment available. This is a h ydrophilic bile salt which is though to increase the \200\230pourability \200\231 of bile salt. It has also been reported that URSO might be protective of both epi- thelial cells of the bile ducts and of the hepaticocytes. The benefits of URSO have not been established by randomized controlled trial, but it has been suggested by clinical observation and in one open label study to improve liver biochemistry. It is unlikely that URSO would reverse live r damage. Liver transplantation (figure 11.5.5) in advanced non-reversible liver disease is advocated in any or a combi- nation of the following circumstances: 1.Portal hyperten- sio n with oesophageal varices. 2. Ascitis 3. Biochemical abnormalities of severe hepatic decom pensation such as hypo-albuminaemia and impaired clotting factors and 4. Hepatic encepahalo pathy. \200 \200 \200 \200 \200 Malabsorption of vitamin D and vitamin K Persistent uncontrolled pulmonary infection Admini stration of glucocorticoids Reduced body mass index Reduced mobility Reduced level of sex h ormone Osteoporosis is de \201 ned as decreased bone mass which includes loss of bone collagen an d bone calcium in a similar proportion. In osteomalacia, the content of calcium in the bone s is reduced with a relative preservation of bone collagen. Therefore there is a reduction of the ratio of mineralised/and non-mineralised bone. Diagnosis is by bone density is measu red using dual energy x-ray absorbiometry (DEXA). The frequency of the test should be proba bly every two years. The signi \201 cance of the \201 ndings are outlined in Table 11.5. 4. Prevention and management The main aim of management is to treat bone pain and to reduce st ress fractures. As reduced BMD is now well rec- ognised early diagnosis and preventive stra tegies are employed to minimize progressive bone loss. Prevention and management of reduced BMD is multifac- eted. The three main areas are: 1 optimizing nutritional intake including vitamin D and calcium; 2 encouraging physical activities; and 3 management of pulmonary exacerbations. Randomized controlled trials have con \201 rmed that a combi- nation of oral vitamin D, oral calcium and bisphosphonate are effective in the management of reduced bone mineral density. These s tudies included organ transplant recipients. The effects are similar are for either intrave nous pamidro- nate or oral alendronate. For patients who are likely to remain on glucocorti coids for a lengthy duration, for example those with allergic broncho-pulmonary aspergillos is, bisphosphonate should start with or shortly after the introduction of glucocorti- coids . Table 11.5.4 outlines the indications for administration of bisphosphonate in CF patients with reduce BMD. Fig. 11.5.5 A 22-year-old patient who underwent a liver transplant. The patient has percuta neous enterogastric (PEG) feeding with a tube in situ. Survival rate for liver transplantation is favorable with one year survival reaching 82% an d 10 year survival of over 60%. The status of the lungs and microbiology are carefully asse ssed for liver transplant recipients. Contraindications of liver transplant include: \200 \200 Severe ventilatory failure with impaired gas exchange, Pulmonary infection with the epidemi c strains genomovar III of Burkhuldria cepacia (also known as Cenoce pacia,) and Psychosoci al status deemed to influence adherence to life-long administration of cytotoxic agents use d to prevent graft rejection and of follow-up in specialist clinic. Table 11.5.4 Indications of bisphosphonate treatment Reduced Z score on DEXA scan below \210\2222.0 despite optimal treatment Reduced Z score b elow \210\2221.5 in organ transplant candidates or recipients Patients likely to have a le ngthy course of glucocorticoids Patients sustained stress fractures Patients with failure t o increase weight, body mass index less than 17 and a Z score of less than \210\2221.5 \200 \200 Paradoxically the lungs often improve after liver transplant. Possible reasons for this are : 1 reduced intra-pulmonary shunt; 2 probable anti-in \202 ammatory properties of the cyto toxic Bisphosphonate is usually a life-long treatment. Musculoskeletal pain is a recognized occas ionally associ- ated with the use of bisphosphonate. The mechanism is not established. Howe ver, treatment with a short course of prednisolone prior to IV pamidronate suggests an in \202 am- matory mechanism for the pain. agents; and 3 improved nutritional status and increased body mass index which tends to occur following liver transplantation. Reduced bone mineral density BMD (osteomalacia and osteoporosis): Reduced BMD is now a reco gnized, preventable and treat- able CF complication. Possible reasons are outlined in Table 11.5.3: The upper airways in CF patients It is reasonable to regard the respiratory tract as a pass age starts at the nostrils and ends at the alveoli. This fact is true N JARAD 256 in CF where impaired CFTR in the upper airway is mani- fested with life long incurable dise ases. Sinusitis and nasal polyps In the author \200\231s unit, over 75% of patients admitte d to chronic nasal symptoms and 62% are aware of having chronic sinusitis with acute \202 are up. Mucosal in \202 ammation results in narrowing and blockage of the nasal outlets o f the maxillofacial and frontal sinuses. This leads to under-developed facial sinuses seen in CF patients. Nasal polyps are probably an exaggerated manifestation of in \202 amed muc osa. They are histologically different from allergic nasal polyps. Symptoms of rhino-sinusi tis start during childhood with the triad of runny nose, nasal congestion, and post-nasal d rip. Acute on chronic sinusitis often precede symptoms of pulmonary exacerbations. Most pat ients interpret this as a viral disease (cold) followed by respiratory symptoms In chronically infected patients, swabs from sinus secre- tions often grow Pseudomonas aeru ginosa and Haemophillus in \202 uenzae which are implicated in the pathogenesis. Management Acute sinusitis responds well to antibiotics provided for pulmonary exacerbation s. Oral antibiotics typically with quinolones help with isolated episodes of sinusitis. Nas al corticosteroids reduce the nasal in \202 ammatory proc- ess. Systemic corticosteroids a re useful in reducing the size of nasal polyps. Nasal decongestants are useful symptomatic management during the acute phase, but should be used only for a short period of time to av oid vasomotor disease which is a phe- nomenon in which the nasal vessels do not constrict a fter prolong use of decongestant. Surgical management consists of resection of nasal polyps . Irrigation of the sinuses has also a short symptomatic bene \201 t AUTHOR \200\231S TIP A careful history which rules out viral nasal symptoms in the patients surrounding or when nasal symptoms occur outside the cold season suggest that the patient suffers from acute CF sinusitis. The reproductive system and pregnancy Several surveys showed that CF patients of both gende rs felt that adequate information about sexual functions and reproduction have not been pro vided during repeated consultations. Male CF patients Almost 97% of male CF patients are infertile due to azoospermia. This is b ecause of bilateral absence of vas deferens and atrophy of the seminal vesicle, ejaculary d uct and body and tail of epidydymis. The testicles are normal in architecture and histology and able to produce active sperms. Sexual potency is not affected. With the increase survi val and improved quality of life, male patients are increasingly seeking fertility assistan ce. Combining sperm harvesting with intra-cytoplasmic sperm injection (ICSI) are the standa rd methods. The conception rate is variable. Female CF patients The fallopian uterine ducts are patent, but the mucous is more viscous a nd less well hydrated than in normal females. Delayed puberty and abnormal menarche are wel l recog- nised in CF female The reported rate of fertility in female CF patients varies. A conception rate after 2 years of active sexual contact ranged from 20 \200\22375%. We advis e that all female CF patients should regard them- selves to be fertile and if they do not w ish to they should take similar birth control precautions as non CF persons. AUTHOR \200\231S TIP Almost all male CF patients are azoospermic. Conversely, all female CF patients should be regarded as fertile and should be given a proper contraception advise i f they do not wish to conceive. CF and pregnancy Retrospective studies showed no adverse outcome on the mother or the child when FEV1 was over 50% of predicated values. During a consultation on pregnancy, the discu ssion should be supportive and sensitively tailored according to the general performance an d FEV1 of the patient. The following areas need to be discussed. 1 The effect of late stage s of pregnancy on lung function Fig. 11.5.6 MRI of facial sinuses. The right side shows thickened mucosa in both sides with reduced air space in the maxillofacial sinuses. On the left side, there are absent air spa ces with obvious bilateral large nasal polyps (white arrow). Facial X ray should no longer be used to make a diagnosis of sinusitis. Facial CT scan or p referably MRI scan (Fig. 11.5.6) are the investigations of choice. The radiolo- gical featu res are those of thickened mucosa and reduced or absent air spaces. especially for those with advanced lung disease. CHAPTER 11.5 Extra-pulmonary manifestations of cystic \201 brosis 257 2 The effect of CF and the CF drugs on pregnancy and the higher rate of miscarriage, extra- uterine pregnancy and pre-term delivery compared to non-CF persons.