Cystic fibrosis diagnosed at age 45 based on symptoms of acute pancreatitis.
A 45-year-old Caucasian woman was hospitalized because of progressively worsening midepigastric abdominal pain for 5 days. The pain, which was insidious in onset, was described as constant, nonradiating, nonpositional, and exacerbated by eating and drinking. She also had fever, chills, night sweats, nausea, and nonbilious vomiting for 1 day. She denied biliary colic, jaundice, scleral icterus, abdominal distention, hematemesis, melena, hematochezia, diarrhea, menorrhagia, or metromenorrhagia. She had had recurrent streptococcal and Pseudomonas sp. pneumonias since childhood. She was a nonsmoker, was diagnosed with bronchiectasis several years earlier, and had a chronic cough productive of yellow sputum. She had Mycobacterium avium pulmonary infection at age 40 and nasal polyps at age 42. She took minocycline for approximately 1 year for acne and levofloxacin orally for recent worsening of her chronic productive cough.
Both her mother and father had type II diabetes mellitus. She did not drink alcohol, smoke, or use illicit drugs. She had no tattoos and no history of sexually transmitted diseases or blood transfusions.
On admission, her temperature was 98.7[degrees]F; heart rate, 93 beats per minute; blood pressure, 129/77 mm Hg; respiratory rate, 18 breaths per minute; and arterial oxygen saturation, 98% on room air. Her body mass index was 29.4 kg/[m.sup.2]. She was mildly distressed due to abdominal pain. She was not jaundiced. Her mucus membranes were dry and pink. The neck was supple, with no jugular venous distention, thyromegaly, or lymphadenopathy. Her abdomen was soft and nondistended, and bowel sounds were diminished. There was exquisite tenderness to palpation in the midepigastrium approximately 4 cm above the umbilicus, with no rebound or guarding. Murphy's, Cullen's, and Grey Turner's signs were not present. She had no hepatosplenomegaly, suprapubic tenderness, or palpable masses.
The patient's white blood cell count was 13,600 cells/[mm.sup.3]. Serum amylase and lipase levels were 477 and 512 units/L, respectively. Serum triglyceride and calcium levels were 46 and 8.9 mg/dL, respectively. Computed tomography of the abdomen/pelvis was significant for acute pancreatitis (Figure 1) without necrosis or abscess. No gallstones, strictures, or bile duct dilatation were visualized; bronchiectasis (Figure 2) was present in the lingula and right middle lobe. Endoscopic ultrasound disclosed no abnormalities. The common bile duct was 5.8 mm in diameter. Sputum cultures were positive for Pseudomonas aeruginosa.
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The patient was placed on bowel rest and given 0.9% normal saline at 200 cc/h and intravenous morphine as needed for pain. Her 10-day regimen of oral levofloxacin was continued. The patient's abdominal pain lessened within the first 48 hours of admission, and an oral diet was initiated on hospital day 3. Her amylase and lipase levels decreased to normal by hospital day 4. Her serum immunoglobulin-G level was normal at 1110. A cystic fibrosis transmembrane receptor (CFTR) genetic panel was ordered. The patient was eventually advanced to a regular oral diet without complications or recurrence of abdominal pain, and she was discharged home after 8 days.
This patient's diagnosis of acute pancreatitis was straightforward, but determining the etiology of the disease was somewhat elusive. The Table lists some possible etiologies (1-13). The history of recurrent Pseudomonas sp. and streptococcal pneumonias since childhood, bronchiectasis, Mycobacterium avium pulmonary infection, and nasal polyps suggested that the acute pancreatitis was secondary to previously undiagnosed cystic fibrosis. This hypothesis was confirmed by genetic tests, which revealed a compound heterozygous mutation: a [DELTA]F508 mutation (phenylalanine deletion) in exon 10 of the CFTR gene and a D1152H (aspartic acid to histidine) mutation in exon 18 of the CFTR gene. The combination of these mutations is consistent with cystic fibrosis when mutations are present on opposite chromosomes.
Cystic fibrosis is classically a pediatric disease. It is an autosomal recessive disease of the long arm of chromosome 7 on the CFTR gene. One in 22 to 25 Caucasians are heterozygotes; this mutation is the most common monogenic mutation among Caucasians. The average age at diagnosis is 2.9 years. The median survival is 32 years for males and 29 for females. Complications consist of recurrent Pseudomonas sp. pulmonary infections, which are the most common cause of morbidity and mortality, as well as bronchiectasis, pancreatic exocrine and endocrine insufficiency, biliary cirrhosis, intestinal obstruction, nasal polyps, and, in men, congenital absence of bilateral vas deferens, causing infertility.
There are approximately 1250 known CFTR mutations, with homozygous [DELTA]F508 being the most common. Heterozygous [DELTA]F508 mutation in combination with a second heterozygous mutation, however, results in varying phenotypic expressions of the disease. These milder forms are typically compound heterozygotes, as seen here, with one other reported case being the same [DELTA]F508/D1152H mutation--a 46-year-old nonsmoker presenting with bronchiectasis and recurrent acute respiratory tract infections (14). There are other case reports of adult-onset clinical disease presenting with chronic cough, recurrent childhood "bronchitis," idiopathic acute pancreatitis, and pancreatic exocrine insufficiency. Sweat chloride levels are normal in most of these cases (9). Furthermore, a strong association has been revealed between idiopathic pancreatitis and CFTR mutations. In a study by Cohn et al, patients with chronic idiopathic pancreatitis had single CFTR mutations 11 times the expected frequency and two abnormal CFTR alleles at a rate 80 times the expected frequency (8).
Clinical disease in cystic fibrosis results from defective or absent cyclic adenosine monophosphate (AMP)-dependent chloride secretion and sodium absorption. In the lungs, reduced chloride secretion reduces the salt and water content of bronchiolar mucus and periciliary liquid. As a result, mucus adheres to airway surfaces, leading to recurrent infection and bronchiectasis. Approximately 70% of adults have persistent Pseudomonas aeruginosa in their airways.
Pancreatitis in cystic fibrosis is thought to occur via a CFTR-mediated secretory abnormality as well. CFTR is present at higher levels in intralobular and proximal ductular epithelial cells and at lower levels in pancreatic acinar cells (12). CFTR at these sites regulates a chloride channel in the chloride/bicarbonate exchanger located in the apical membrane and mediates the secretion of a bicarbonate-rich alkaline fluid that, in turn, maintains the solubility of secreted enzymes. Loss of CFTR function, or its dysfunction, results in reduced intraluminal fluid and bicarbonate secretion. Scheele et al (10) have suggested that reduced luminal pH inhibits endocytosis of secretory granule proteins and reduces the solubility of secreted luminal proteins. Presumably, complete loss of CFTR function induces rapid pancreatic atrophy through obstruction by secreted protein. In patients with pancreatic sufficiency, the presence of functional acinar cells is a prerequisite for pancreatitis; a change in ductal and acinar function must in some way be the precipitating event. Pancreatitis occurs in approximately 2% of patients with known cystic fibrosis.
Our patient had acute pancreatitis, most likely secondary to undiagnosed cystic fibrosis. Both drug-induced pancreatitis secondary to minocycline and idiopathic pancreatitis are less likely possibilities. Because cystic fibrosis is usually diagnosed in the pediatric population, milder forms manifesting during adulthood are probably underdiagnosed. When evaluating an adult patient with idiopathic pancreatitis--especially in the presence of common cystic fibrosis disease sequelae such as recurrent sinopulmonary infections, bronchiectasis, nasal polyps, intestinal obstruction, biliary cirrhosis, or male infertility--a diagnosis of cystic fibrosis should be considered. Sweat chloride tests may be normal in these patients. Genetic testing may be required to solidify the diagnosis (15).
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(4.) Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am 1990;19(4):783-791.
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(7.) Runzi M, Layer P. Drug-associated pancreatitis: facts and fiction. Pancreas 1996;13(1):100-109.
(8.) Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339(10):653-658.
J. Matt Brunson, MD, Debbie Bridges, MD, Robert Anderson, MD, Nichole Graves, MD, and Christopher Schwann, BS
From the Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas.
Corresponding author: J. Matt Brunson, MD, Resident, Department of Internal Medicine, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246 (e-mail: JonathBr@BaylorHealth.edu).
Table. Etiology of acute pancreatitis Category Specific causes Statistical data Cholelithiasis, pancreas Most common cause: Mechanical divisum, ductal tumors, cholelithiasis causes 35% ampullary stenosis of AP; 3%-7% of patients with cholelithiasis develop AP (1) Ethanol, methanol, Alcohol is second most Toxic organophosphate poisoning, common cause of AP; 10% of scorpion chronic alcoholics develop AP Hypertriglyceridemia, Incidence in Metabolic hypercalcemia hyperlipidemia: type I, 35%: type II, 15%: type V, 30%-40% (3, 4) Drugs: tetracycline, minocycline, thiazides, furosemide, azathioprine, Other valproic acid, salicylates, Drugs: 1.4% (6, 7) didanosine, metronidazole, tamoxifen Trauma, post-ERCP, alpha-1- antitrypsin deficiency, infection Cystic fibrosis transmembrane conductance Typically only patients Genetic regulator (CFTR); cationic <25 years are tested for trypsinogen gene; serine a genetic etiology (8-12) protease inhibitor, Kunitz type 1 (SPINT1) Category Details Proposed mechanisms Mechanical obstruction of ampulla of Vater and reflux of pancreatic enzymes Proposed mechanism: Toxic ethanol increases synthesis of lysosome and enzyme (2) Triglyceride levels >1000 mg/dL (4, 5); hypercalce- Metabolic mia proposed mechanism: induction of trypsinogen (3) Infectious agents: mumps, coxsackievirus, hepatitis B, Mycoplasma sp., Other Legionella sp., Aspergillus sp., Toxoplasma sp., Cryptosporidium sp., Ascaris sp. CFTR details: defective HC03/chloride exchanger Genetic in pancreatic ductal apical membrane AP indicates acute pancreatitis; FRCP, endoscopic retrograde cholangiopancreatography.