Disease Manifestations

Major complications of the CF disease occur in the respiratory tract, causing sinusitis and respiratory failure. Severe bacterial infestation of the respiratory passage is also a major problem in CF patients. The second most common complications arise in the gastrointestinal tract. Other organ systems that are involved and show complications are the sweat glands (salt loss syndrome) and reproductive system (male infertility and reduced female fertility) (Table 26.3). The disease presentation varies from patient to patient depending upon the functional status of the CFTR protein or by the type of mutation present in the CFTR gene. In addition, new evidences suggest roles for some modifier genes and environmental factors in the development of CF.33,34 The pancreas is an important gland of the digestive and endocrine system of the body carrying out both the exocrine and endocrine function. The exocrine function is carried out by the acinar cells that produce the enzymes needed to digest food, and the islets perform the endocrine function and secrete three important hormones — insulin, glucagon, and somatostatin. These hormones are necessary for glucose homeostasis in the body. The damage caused to the pancreas by the diseased condition in a CF patient results in its impaired functioning and inflammation. Three main types of pathological manifestations associated with the pancreas — PI, diabetes, and pancreatitis — have been reported in CF patients.

26.6.1 Pancreatic Insufficiency

The pancreas makes more than 25 different digestive enzymes that are secreted into the intestine. It also secretes a large amount of sodium biocarbonate, which protects the duodenum by neutralizing the acid that comes from the stomach. The digestive enzymes are released from the cells of the acini and flow down through various channels into the pancreatic duct. The pancreatic duct joins the common bile duct at the sphincter of Oddi, where both flow into the duodenum. The enzymes secreted by the pancreas digest dietary proteins, fats, and carbohydrates into simpler molecules, so that they can be absorbed by the intestinal epithelial cell from the intestinal lumen. The pancreas has a tremendous

Table 26.3 Organ Systems Involved in CF and Their Complications

Organ System

Complications

Upper: Nose Sinus Lower:

Bronchial tree Lungs

Esophagus and stomach

Pancreas

Intestinal tract

Liver

Respiratory

Nasal/sinus Polyposis Sinusitis

Cystic bronchiectasis Hemoptysis Pneumothorax Respiratory failure

Gastrointestinal

Barrett's esophagus Esopageal varices

Gastro-esophageal reflux disease (GERD)

Pancreatic insufficiency (PI)

Cystic fibrosis related diabetes (CFRD)

Pancreatitis

Meconium ileus

Distal intestinal obstruction syndrome (DIOS)

Rectal prolapse

Liver cirrhosis and liver failure

Sweat gland Reproductive system

Blood and Circulatory system

Others

Salt loss syndrome

Male infertility

Female reduced fertility

Delayed sexual development

Absence of/irregular menstruation

Hypoelectrolemia

Metabolic alkalosis

Hypersplenism

Portal Hypertension

Macrolytic anemia reserve capacity and, in fact, more than 95% of the function of the pancreas must be lost before the pancreas fails and symptoms of bloating and maldigestion develop.35,36 The large pancreatic reserve, however, also means that children can have a severe pancreatic problem without experiencing any problem with digestion. At the time of childbirth, the exocrine pancreas is not fully developed and, therefore, does not have the same ability as the mature pancreas to produce enough enzymes, in particular, those needed to digest carbohydrates and fats.37 Because of this, all healthy infants show some degree of maldigestion. The pancreas matures completely within 2 years after birth and starts functioning in the same way as an adult pancreas. The immature pancreas usually does not have any adverse effect on healthy children, but a major impact can be seen when children become malnourished or ill. Under the CF diseased condition, in some cases, the pancreas begins to be damaged even when the affected child is still in the mother's womb. The small ducts inside the pancreas, which allow digestive enzymes to reach the intestine, get blocked with mucus and proteins, and the pancreas becomes badly scarred and shrunken.37

Many children with CF have evidence of severe pancreatic failure immediately following birth, and by 2 years of age, 90% of CF cases are diagnosed, usually those with severe malnutrition. Approximately 85% of all people with CF have PI and need to take pancreatic enzymes with meals as well as additional fat-soluble vitamins. Incidences of PI in children with CF have been correlated with the type of CFTR gene mutations they carry. Of children having two classes of mutations (I and II/III), 85% suffer from PI. Later, these patients develop severe pulmonary complications, the males are infertile, and the average life expectancy is 30 years. On the other hand, the patients with Class IV and Class V mutations are pancreatic sufficient (PS), do not have steatorrhea, and, therefore, do not require pancreatic enzyme supplementation. Due to this fact, PS patients are diagnosed at a later stage, experience normal growth during childhood, and have a better prognosis than their PI counterparts. A severely affected CF phenotype is strongly associated with the presence of AF508, and 99% of those patients homozygous for this most common mutation have PI.38,39 In a study by Kristidis et al., it was determined that most genotypes carrying CFTR mutations are associated either with PI or PS, but not both.40 This might suggest the genetic association of the phenotype. Also, the mutations that confer the PS phenotype do so in a dominant fashion. In patients with the PS phenotype, progression of disease either does not occur or seems to be retarded. Based on this, CFTR mutations have been classified as severe or mild with respect to pancreatic function status, although a few indeterminate mutations seem to confer PS or PI pheno-types on a less consistent basis.40 Although the course and prognosis of CF are mainly determined by the progression of pulmonary obstruction and infection, the assessment of pancreatic damage may be of clinical relevance in the screening of patients at high risk for early development of pulmonary infection. It has been reported that patients with PI may have earlier colonization of the airway by Pseudomonas aeruginosa, the major event in the clinical development of CF.39

26.6.2 CF-Related Diabetes

The pancreas produces three important hormones of the body's endocrine system, which are required for glucose homeostasis in the blood. These are insulin, which lowers the level of sugar (glucose) in the blood; glucagon, which raises the blood sugar level; and somatostatin, which prevents the other two hormones from being released. In general, diabetes mellitus is a metabolic condition that is either caused by the hyposecretion or hyposynthesis of insulin or by acquiring the insulin resistance (i.e., the insulin that is made does not work well enough). The insulin actually helps blood glucose get absorbed by the cells of the body for energy and convert the rest to glycogen reserves and triglycerides, particularly in muscles and adipose tissues, respectively. In the absence of insulin, the cells of the body starve due to the inability to absorb sugar, while the blood sugar reaches high levels. There are two common forms of diabetes reported in literature — Type 1 diabetes (previously referred to as insulin-dependent or juvenile onset) and Type 2 diabetes (previously referred to as non-insulin dependent or adult type).41

In CF patients, the pancreas may be blocked due to the excessive secretion and accumulation of mucus. Although this does not directly stop insulin from entering the bloodstream as it is internally secreted, it may have an indirect impact due to the pancreatic damage.42 In CF patients, the damage is caused to the pancreas by its own enzymes, which are not getting out properly due to ductal blockade. These enzymes start digesting the pancreas itself, resulting in damage to the insulin-secreting cells and, thus, leads to decreased insulin production or secretion. Insulin resistance may also play a role in the development of CFRD, especially during acute infection.43 Although, the majority of non-diabetic CF patients, in their usual state of health, appear to be insulin sensitive, they may also become insulin resistant during infection. CFRD presents common features of both Type 1 and Type 2 diabetes.44 Most individuals with CFRD have the same primary problem of insulin deficiency as in Type 1 diabetes; however, the clinical presentation is more similar to Type 2 diabetes. The onset of CFRD is often asymptomatic, and in most cases it is undiagnosed for years.45 The average age of CFRD onset is 18 to 21 years. About 20 to 30% of CF patients show impaired glucose tolerance (IGT) and only one-quarter of patients over 35 years has diabetes.2 Furthermore, the percentage of those who develop diabetes mellitus increases with their extending life expectancy. According to the data registry of 22,732 CF patients maintained by the North American Cystic Fibrosis Foundation, the prevalence of diabetes was about 11.4% in 2001. The actual prevalence of diabetes, however, may be more in CF for the reason that CFRD is often asymptomatic.

The CFRD may cause a decline in the clinical status of CF patients and hyperglycemia often occurs in the patients being treated with immu-

nosuppressive therapies after lung transplantation. Thus, diabetes is a growing concern in the follow-up of CF patients. The presentation of CFRD is different from diabetes in people not having CF and, therefore, it requires unique monitoring and management. There is a continuum of glucose tolerance in CF ranging from normal glucose tolerance to increasingly severe glucose intolerance to diabetes. In their baseline state of health, CF patients are generally insulin-sensitive, but during the stress of acute infection, pregnancy, or glucocorticoid therapy, patients develop insulin resistance. When the stress resolves, the insulin resistance usually goes away and the patient moves back to their baseline. Thus, it is common for CF patients to have a temporarily higher blood glucose level during physical stress. Malnutrition may be present in CF, which can impair the ability of the pancreas to make insulin. Malnutrition due to pancreatic exocrine insufficiency is common despite enzyme supplementation. Anorexia and nausea due to impaired digestion may also cause malnutrition. Abnormal intestinal movement may affect food absorption and thus influence blood sugar levels. The occurrence of liver disease, which is often present in CF patients, also influences how the body uses nutrients. The patients with CFRD are more underweight and have worse pulmonary function than those without diabetes. It is now recommended that anyone with CF, 14 years of age or older, be routinely screened for CFRD.

26.6.3 Pancreatitis

Pancreatitis is presented by the inflammation of the pancreas and may also lead to tissue damage, when active digestive enzymes begin attacking the pancreas. In some cases, there may be bleeding into the gland, infection, and cyst formation. Enzymes and toxins may enter the bloodstream and may cause injury to other organs. Pancreatitis occurs in two forms: the acute, which is sudden and may be severe or recurrent, and the chronic, which is long, severe, and often associated with weight loss and pain in the upper abdomen. In most cases, the cause of the disease is identifiable by the patient's history and other standard laboratory tests, but in certain cases where there is no apparent underlying cause for the disease, it is referred as idiopathic pancreatitis.

Usually, the clinical manifestations of CF in the pancreas do not resemble pancreatitis; however, many studies have indicated that mutations are present in the CFTR gene in patients with idiopathic pancreatitis.46-48 In most cases, gene mutations on only one allele have been recorded with no significant pulmonary and other CF complications in patients. The molecular mechanisms that can associate the CF with pancreatitis are not yet defined. Nevertheless, it is believed that underlying mutations in CFTR predispose some CF patients to pancreatitis, when combined with other gene defects or when exposed to certain other environmental factors, such as the use of alcohol.49-51 Recent studies have given the indications that the frequency of CFTR gene mutations is underestimated and that the analysis of such mutations may be of importance toward the etiology of idiopathic pancreatitis.46,47 Investigators at veteran affairs and Duke University explored the relationship between CFTR mutations and idiopathic pancreatitis in 22 women and 5 men and referred to them for evaluation of idiopathic pancreatitis.46 The patients were tested for 17 CFTR gene mutations and also for the 5T CFTR allele, which when present markedly reduces the level of functional gene product. Ten patients (37%) had at least one such abnormality, for a mutation frequency 11-fold greater than expected. In 3 patients, both CFTR alleles were affected, exceeding the expected frequency 80-fold. In a similar study, researchers at the Manchester Royal Infirmary in the U.K. studied 134 consecutive patients with chronic pancreatitis, including 71 cases (53%) with alcohol-related pancreatitis and 60 with idiopathic disease (45%).47 They examined the 22 mutations (accounting for 95% of all mutations) and the 5T allele in Intron 8. They identified a mutation frequency nearly 2.5 times the expected figure. The frequency of the 5T allele was twice as high as expected. The CFTR mutations were found to be associated with idiopathic rather than alcohol-related disease.

Now, when the association of pancreatitis with CF has been well documented, the question arises what makes CFTR mutations susceptible to pancreatitis or is there any correlation among the various clinical manifestations? Analysis of 1075 patients with a diagnosis of CF and acute recurrent or chronic pancreatitis over a 30-year period (1966 to 1996) from the CF database have demonstrated that no patient with PI developed pancreatitis.52 Of the 110 («10% of total) patients that were diagnosed as PS, 19 (17.3 or 1.7% of total) experienced one or more attacks of pancreatitis. The mean age at diagnosis of pancreatitis was 22.7 years with a wide range (10 to 35 years). The observation that PI patients do not have pancreatitis incidence can be attributed to the loss of functional acinar tissue at an early period of life or even in utero53 The presence of functional acinar cells is a prerequisite for pancreatitis and, therefore, the PS patients with impaired CFTR function are predisposed to pancreatitis. Although it remains a subject of concern and discussion whether or not the patients with pancreatitis should be routinely screened for CFTR mutations or if such pancreatitis incidences should be considered for the diagnosis of CF,46-48 there is definitely a need to understand the relationship of CFTR mutations and pancreatitis.

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