Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.

BACKGROUND: Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. PURPOSE: The aim of this study was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. METHODS: To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (< or = 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. RESULTS: The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23-105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. CONCLUSIONS: Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.

Natural history of HIV infection in Filipino female commercial sex workers.

A prospective follow-up study of the progression of HIV infection, from seroconversion to onset of opportunistic infections (OI) indicative of immune deficiency and to death, was performed in a cohort of 54 HIV-1 antibody positive Filipino female commercial sex workers (FCSW). The cumulative probability of having a CD4+ T cell count of < 200/mm3 and/or an OI indicative of severe immune deficiency was 52.9% within 5 years and 73.8% within 6 years after seroconversion. The cumulative probability of death was 52.1% within 6.5 years following seroconversion and 52.7% within 1.5 years after a depressed (< 200/mm3) CD4+ T cell or onset of an OI. Although several OI associated with immune impairment were observed, a CD4+ cell count of < 200/mm3 was the initial indicator of a failing immune system in more than 50% of the patients. Mycobacterium tuberculosis or unidentified acid fast bacilli (presumed to be M. tuberculosis) and Pneumocystis carinii pneumonia were the initial indicators of immune deficiency in the remaining patients.

Pouchitis in young patients after the ileal pouch-anal anastomosis.

SUMMARY: : The purpose of this study was to determine the incidence of pouchitis after the ileal pouch-anal anastomosis in young patients, and to identify possible predisposing factors. The study design included long-term follow-up of young patients after closure of their temporary diverting ileostomy, through regular visits, a detailed questionnaire, or phone call. The Kaplan-Meier method was used to summarize survival free of pouchitis in several subgroups. A logistic regression analysis of just the patients with pouchitis was used to determine whether any clinical variables could discriminate between those with acute and those with chronic pouchitis. We are closely following 97 patients with an ileal pouch-anal anastomosis-83 patients for chronic ulcerative colitis and 14 patients for familial polyposis. They have been followed for a median of 7.5 years (range 1-14.5 years). Forty-six patients (47%) developed pouchitis-44 (53%) patients after ulcerative colitis and 2 (14%) patients after polyposis. Most (92%) had loose and/or frequent stools, many had incontinence (62%) and bloody stools (62%), and less (37%) had cramping. Endoscopy was done in 82% of the patients; erythema and/or friability was seen in all patients, often with ulcers or erosions (35%); no polyposis patients had ulcers. We could not identify any predisposing factor. Metronidazole was the treatment of choice, but some patients required long-term treatment with sulfasalazine and/or steroid enemas. Pouchitis is a common long-term complication of the ileal pouch-anal anastomosis after ulcerative colitis. No predisposing factor has yet been identified in these young patients.

Use of subcutaneous deferoxamine in a child with hemochromatosis associated with congenital dyserythropoietic anemia, type I.

A 12-year-old girl with congenital dyserythropoietic anemia, type I, was diagnosed as having hemochromatosis. Deferoxamine was given subcutaneously for 14 months. Iron overload, as measured by liver iron and serum ferritin levels, was reduced substantially, liver function tests improved, and hepatomegaly decreased. Toxicity was negligible.

Total colectomy with rectal mucosectomy and ileoanal anastomosis for chronic ulcerative colitis in children and young adults.

Total colectomy with rectal mucosectomy and ileoanal anastomosis has been utilized as a sphincter-saving operation in young people with chronic ulcerative colitis. From 1977 to 1979, our section of pediatric surgery performed this procedure on 12 children and young adults with chronic ulcerative colitis, with encouraging results. All patients are alive and well, and all have had excellent rectal continence. Follow-up ranges from 7 to 27 months. Eight patients describe an excellent result, two have had a fair result, and two have required a temporary ileostomy. Numerous loose stools have been observed early, but stools become formed by diet and medical management, and early return to school and work has been possible. The number of stools continues to decrease for at least 1 year.

6-mercaptopurine therapy in selected cases of corticosteroid-dependent Crohn's disease.

Nineteen patients (12 children and 7 adults) with severe Crohn's disease, all of whom were dependent on corticosteroids, were treated with 6-mercaptopurine. All patients received a daily dose of 6-mercaptopurine of 50 mg; in two pediatric patients with a poor response after 2 months, the dosage was increased to 75 mg/day. A complete or partial response to 6-mercaptopurine therapy was noted in 47% of patients, and therapy failed in 53%. The age of the patients, prior resection, or initial symptoms did not influence the response. The clinical response was better in male than in female patients and in patients with involvement of both the small intestine and the colon than in those with only enteritis. 6-Mercaptopurine is a possible alternative to long-term corticosteroid therapy or surgical treatment in selected patients with severe Crohn's disease.

Surreptitious use of salicylates: a cause of chronic recurrent gastroduodenal ulcers.

We describe five patients who had chronic recurrent gastroduodenal ulcers and pain, intestinal obstruction, bleeding, or a combination of these symptoms. Four patients required surgical intervention because of a poor response to medical therapy. The ulcers recurred in all patients, despite evidence of achlorhydria in two of them. Although the patients denied the use of salicylates, all of them had therapeutic blood levels of salicylates. A salicylate level should be determined in patients with severe ulcer disease that is resistant to medical therapy or that is recurrent after appropriate surgical therapy when the presence of hypergastrinemia or hyperchlorhydria has been definitely excluded. A low serum level of uric acid can also be a clue to the abuse of salicylates.

Autosomal dominant familial Mediterranean fever-like syndrome with amyloidosis.

We report a pedigree in which a syndrome that resembled familial Mediterranean fever occurred in four family members over three successive generations. All four patients had systemic amyloidosis. Typically, patients with familial Mediterranean fever show an autosomal recessive inheritance pattern. The disorder commonly afflicts Sephardic Jews, Arabs, and persons of Turkish descent. Colchicine therapy dramatically reduces the attack rate of serositis. The family described herein is unique because of their European ethnicity and the autosomal dominant inheritance pattern. Unlike typical familial Mediterranean fever, colchicine had no influence on the attacks and did not prevent amyloidosis in the three patients who received this treatment.

D-Lactic acidosis and encephalopathy after jejunoileostomy: response to overfeeding and to fasting in humans.

Two patients with recurring attacks of encephalopathy after jejunoileostomy for morbid obesity had elevated D-lactate concentrations in blood and urine. The syndrome and the biochemical abnormalities were reproduced by ingestion of a high carbohydrate diet. In the second case, fasting and intravenous supplementation with amino acids and glucose resulted in the disappearance of D-lactate from the urine and blood and amelioration of the symptoms. Stool cultures from the second patient were shown to be capable of producing D-lactate, and concentrations of D-lactate in saline and peptone yeast broth filtrates of the stool paralleled the changes in urinary excretion of the D-lactate during fasting and overfeeding. Thus, we have demonstrated a temporal relationship between the neurologic symptoms and the elevated concentrations of D-lactate in blood, urine, and stool. Whether D-lactate accounts for part or all of the encephalopathic changes remains to be determined.

Long-term follow-up of young patients with chronic hereditary or idiopathic pancreatitis.

We conducted a retrospective study of patients younger than 20 years of age who had a diagnosis of chronic pancreatitis and underwent assessment at the Mayo Clinic between 1960 and 1990. Those with a known etiologic factor for the pancreatitis (such as a virus, trauma, alcohol, or hyperlipidemia) were excluded from the study. We compared the clinical course of the 42 patients who had hereditary pancreatitis (HP)--defined as at least two family members affected by the condition--with that of the 28 patients who had idiopathic pancreatitis (IP). The mean age at initial assessment was 7 years for those with HP and 12 years for those with IP. All patients in both groups had abdominal pain. Vomiting was more frequent in patients with HP than in those with IP; otherwise the initial symptoms were similar in both groups. Patients with HP, however, had more complications, including pseudocysts (seven patients), steatorrhea (four), ascites (three), portal hypertension (two), and diabetes (one), than did patients with IP (one each had diabetes, steatorrhea, and a pseudocyst). Complications or pain necessitated surgical intervention in 23 of 42 patients with HP versus 4 of 28 patients with IP. Overall in comparison with IP, HP seems to be a more severe variant of chronic pancreatitis, inasmuch as it is associated with more frequent complications and need for surgical intervention.

Collagenous colitis: a clinicopathologic correlation.

Collagenous colitis is an unusual cause of chronic, watery diarrhea. To characterize this disease, we reviewed biopsy specimens and the clinical records of 17 patients (9 women and 8 men) with this diagnosis. Intermittent diarrhea with symptom-free intervals lasting years was found in 7 of the 17 patients. Two patients had incapacitating arthralgias, and nine had a mild weight loss. Collagen deposition beneath the surface epithelium formed a continuous layer in 11 but was discontinuous in 5 of the 16 patients who had undergone rectal or colonic biopsies at our institution. The thickness of the collagen band was variable (maximum, 93 microns). The symptoms of the patients did not correlate with the thickness of the collagen layer. Variability in collagen thickness may be related to disease phase and increases the need to obtain multiple biopsy specimens from the sigmoid colon and rectum. The optimal treatment for collagenous colitis is difficult to determine because three of six patients treated only symptomatically in our study had resolution of their diarrhea.

Toxic shock syndrome, a newly recognized disease entity. Report of 11 cases.

The toxic shock syndrome has only recently been described. Eleven female patients aged 13 to 43 years (median 17) with toxic shock syndrome have been seen at the Mayo Clinic since August 1975. One patient died. Seven patients had one or more recurrences. As previously described, the syndrome was often life-threatening, afflicted mostly menstruating females, and was characterized by a very brief prodromal illness consisting of high fever, vomiting, diarrhea, conjunctivitis, headache, irritability, sore throat, myalgias, abdominal tenderness, and erythematous rash. The disorder can progress to hypotension or prolonged refractory shock, adult respiratory distress syndrome, diffuse intravascular coagulation with severe thrombocytopenia, and renal failure. Pancreatitis was observed in two cases. During convalescence, pronounced desquamation and peeling of the skin occurred. Numerous laboratory abnormalities are observed. In 5 of the 11 patients, Staphylococcus aureus was isolated from conjunctiva, oral cavity or nares, vagina, or stool. A recently described pyrogenic exotoxin was identified in the isolates of three patients; its etiologic role remains speculative. Therapy is mainly supportive. Antistaphylococcal therapy for the acute illness and for prevention of recurrences has not yet proved to be of any benefit. The role of vaginal tampons, if any, in the pathogenesis of this disorder remains unclear.

Postdilution hemofiltration in the management of acute hepatic failure: a pilot study.

We conducted a pilot study to assess the feasibility and efficacy of postdilution hemofiltration (PDHF) in the management of acute hepatic failure. From January 1984 through May 1986, we encountered seven patients with acute hepatic failure and entered these consecutive patients in the study; three had non-A, non-B hepatitis and one each had type B hepatitis, fulminant Wilson's disease (hepatolenticular degeneration), acute allograft (liver) failure, and acute fatty liver of pregnancy. Two of these seven patients were unable to undergo PDHF because of a precarious hemodynamic status. Of the five patients treated with PDHF, four had amelioration of hepatic encephalopathy; in two of these patients, a close temporal relationship was noted between the improvement and the procedure. Four patients had appreciable thrombocytopenia related to PDHF and bleeding complications. Our preliminary results support a possible role for PDHF as a temporary artificial liver support system for patients with acute hepatic failure.

Enteric protein loss after the Fontan operation.

OBJECTIVE: The current study was undertaken to assess the frequency of excessive enteric protein loss and protein-losing enteropathy in the relatively early period after the Fontan operation. DESIGN: Protein excretion was determined in 26 of 27 consecutive patients who underwent the Fontan procedure between January and June 1990 at the Mayo Clinic. MATERIAL AND METHODS: At two testing intervals during the first 4 months after the Fontan operation, alpha 1-antitrypsin clearance and fecal alpha 1-antitrypsin concentration studies were done. RESULTS: All results were normal for the first postoperative test period (2 to 8 weeks). For the second study period, all 17 patients tested had normal alpha 1-antitrypsin clearances. One of the 17 patients had an appreciably increased fecal alpha 1-antitrypsin concentration and transient protein-losing enteropathy. CONCLUSION: Excessive enteric protein loss and protein-losing enteropathy are relatively uncommon during the first 4 months after the Fontan operation.

Measurement of heparin concentration in whole blood with the Hepcon/HMS device does not agree with laboratory determination of plasma heparin concentration using a chromogenic substrate for activated factor X.

UNLABELLED: Measurement of circulating heparin concentration has been suggested to optimize anticoagulation during cardiopulmonary bypass. The Hepcon/HMS device (Medtronic HemoTec, Inc., Parker, Colo.) uses heparin/protamine titration to quantitatively determine heparin concentration. Extensive validation of this instrument is still lacking. METHODS: Agreement between heparin concentrations measured by the Hepcon/HMS system and by laboratory determination was evaluated in 16 patients undergoing cardiac operations. For laboratory determinations, plasma heparin concentration was derived from the measure of anti-Xa activity by means of chromogenic substrate technique. The Hepcon/HMS instrument and cartridges measured whole blood heparin concentration. Samples were analyzed 5 minutes after administration of heparin, 15 and 30 minutes after the start of cardiopulmonary bypass, 5 minutes after aortic unclamping, at the end of cardiopulmonary bypass, and after administration of protamine. Data were plotted and interpreted according to the method of Bland and Altman: First, a difference less than 1.4 U/ml (i.e., +/- 0.7 U/ml) was chosen as acceptable, because it would not cause major difficulties in clinical interpretation; second, the difference between the two measurement techniques was plotted against the mean of the two measures. RESULTS: The mean difference (bias) between heparin concentrations derived by the Hepcon/HMS device and those obtained by laboratory determination was as expected for measures performed on whole blood versus plasma (1.45 U/ml). Nevertheless, heparin concentrations derived by the Hepcon/HMS device may be as much as 2.76 U/ml above or 6.17 U/ml below the concentrations measured in the laboratory, differences well outside the predetermined limits of agreement and clearly unacceptable for clinical purposes. CONCLUSION: We conclude that heparin concentrations determined with the Hepcon/HMS instrument do not agree with laboratory determination of heparin concentration. Monitoring of heparin concentrations during bypass with the Hepcon/HMS device cannot be recommended.

Protein-losing enteropathy after the Fontan operation.

Patients were observed after the Fontan operation to determine the frequency and severity of protein-losing enteropathy. A total of 427 patients who survived for 30 days after the Fontan operation, performed between 1973 and January 1987, were analyzed and, thus far, protein-losing enteropathy has developed in 47 of 427. The cumulative risk for the development of protein-losing enteropathy by 10 years was 13.4% among 30-day survivors, and 5-year survival after the diagnosis was 46%. Hemodynamic studies done coincident with the diagnosis of protein-losing enteropathy have shown increased systemic venous pressure, decreased cardiac index, increased pulmonary vascular resistance, and increased ventricular end-diastolic pressure. Medical management of protein-losing enteropathy was only partially successful. Statistical analysis has shown that factors related to protein-losing enteropathy were ventricular anatomy, increased preoperative ventricular end-diastolic pressure, longer operative bypass time, increased length of hospital stay, and postoperative renal failure. This study suggests that scrupulous selection of cases for the Fontan operation is mandatory and that certain perioperative factors may predispose to this serious complication of the Fontan procedure.

Heterotopic gastric mucosa in the common bile duct.

Gastric heterotopia within the biliary system is rare and is generally an incidental finding. Only a few patients have biliary symptoms specifically attributable to heterotopia. A unique case of symptomatic gastric heterotopia of the common bile duct is presented and the literature reviewed.

Long-term follow-up of the ileoanal anastomosis in children and young adults.

The purpose of this study was to carry out a long-term study of the ileoanal anastomosis (IAA) in children and young adults, comparing the straight IAA to the J pouch. One hundred twenty-one young people who had undergone IAA were studied, with 114 available for long-term follow-up. One hundred one were 18 years and under. Forty-nine patients had a straight IAA and 72 had a J-pouch reservoir. There were no deaths. After surgery, three children had intraabdominal sepsis and one had pelvic sepsis, but it did not lead to excision of the IAA. The mean stool frequency in all 114 patients was 5.0 +/- 2.5 per day and 1.2 +/- 1.1 at night. The mean number of stools for the straight IAA was 6 per day and 2.1 at night. The mean number of stools for the straight IAA with balloon dilations was 5.8 per day and 1.2 at night, and for the J pouch it was 4 per day and 1 at night. Patients with both the J pouch and straight IAA had good to excellent sensation, with patients with the J pouch always able to distinguish flatus from stool in 87% of patients and almost always in 13%. Daytime continence was very good in both groups. Moderate nighttime loss of stool occurred in 10 patients, 6 with a straight IAA and 4 with a J pouch. Ninety-five percent of the 114 patients were satisfied or very satisfied, with most children with a J pouch very satisfied. The J pouch remains the procedure of choice in young people.

Surgical treatment of ulcerative colitis in children.

Our finding in 100 patients indicate that elective surgical treatment of ulcerative colitis in children has a low mortality rate in contrast to emergency surgery (2.3% versus 23%). Morbidity associated with these procedures is moderate and appears to be decreasing (13%), as shown by the comparison between the experience in the 1960s and that in the 1970s. Results with the newer surgical procedures have been encouraging; 60% of patients with Brooke ileostomy have been very satisfied as compared with 90% of patients with Kock pouch and of those with rectal mucosectomy with ileoanal anastomosis. Ileorectostomy was not a satisfactory procedure in this series. Additionally, after surgical treatment, the median height percentile increased from the thirty-ninth to fifty-seventh percentile. Finally, and important, 96% of the patients in this series reported that their general health at follow-up was good to excellent and that they had minimal limitation in their activities.

Colectomy with rectal mucosectomy and ileoanal anastomosis in young patients. Its use for ulcerative colitis and familial polyposis.

Twenty-five children and young adults underwent colectomy with rectal mucosectomy and ileoanal anastomosis for chronic ulcerative colitis or familial polyposis. Follow-up ranged from three to 35 months. A simpler and shorter modification of the operation was used in 12 patients. Balloon catheter dilations were performed in nine patients before closure of the ileostomy to begin enlargement of the neorectum; 24 patients underwent closure of their temporary ileostomy. All patients are alive and well and participate full time in school or work. Two patients had mechanical bowel obstruction; on critical retrospective review, one patient was found to have Crohn's disease that necessitated removal of the rectal cuff. The clinical result was considered excellent in 11 patients, good in seven, fair in three, and poor in three. A gradual decrease in frequency of stooling was observed as the neorectum enlarged during the first year postoperatively. All patients had very good anal sphincter tone with voluntary rectal continence. Although some soiling and leakage occurred, especially during sleeping, these complications decreased with time.