Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants.

BACKGROUND/AIMS: Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis. METHODS: Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68). RESULTS: Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers. CONCLUSION: Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking.

In-111 transferrin scintigraphy in cirrhosis with hypoalbuminemia: evidence for protein-losing enteropathy in a small group of selected cases.

BACKGROUND: Hypoalbuminemia commonly observed in cirrhosis is considered to be mainly related to hepatocellular dysfunction. However, the correlation between the decrease in serum albumin and liver function is far from linear and arguments in favor of an additive role of protein-losing enteropathy have been brought by a few studies. AIM: To assess the potential role of protein-losing enteropathy in a group of patients with cirrhosis, portal hypertension, and hypoalbuminemia. DESIGN AND METHODS: Eleven patients with documented cirrhosis, portal hypertension, and a low serum albumin level compared to liver function underwent an (111)In-transferrin scintigraphy. RESULTS: Using this sensitive method of investigation, nine exhibited features suggestive of exudative enteropathy. Serum albumin level and digestive protein loss were even correlated (Pearson's coefficient = -0.529, one-sided p = 0.047). Protein loss were however not correlated with the degree of portal hypertension or with the extent of liver dysfunction evaluated by the aminopyrine breath test. CONCLUSIONS: Our preliminary data obtained in a small group of selected patients with cirrhosis, portal hypertension, and hypoalbuminemia indicate that protein-losing enteropathy may represent an appreciable and underestimated cause of hypoproteinemia.

Ulcerative colitis associated with IgG4 cholangitis: similar features in two HLA identical siblings.

BACKGROUND: IgG4-associated cholangitis (IAC) can mimic primary sclerosing cholangitis although, in contrast to the latter, it is highly responsive to steroid therapy. IAC is known to be associated with autoimmune pancreatitis and has also been shown to be part of a more complex autoimmune IgG4 syndrome. However, an association with inflammatory bowel disease (IBD), a condition in which its identification may have therapeutic and prognostic importance, has not yet been described. CASE REPORTS: We report the cases of two HLA identical siblings both DRB *1501 positive exhibiting features of IAC together with ulcerative colitis. Subsequent high resolution HLA typing performed by sequence-based-typing showed similar alleles in both siblings: A *0301 A *3201 B *07 (0702/62) B *1401 C *0702 C *0802 DRB1 *1501. There is indirect evidence that this hitherto undescribed association, likely to be strongly linked to a genetic background, might account for a proportion of the cases of cholangitis associated with IBD. CONCLUSION: Appropriate investigation for IBD-associated cholangitis is mandatory to identify IAC, the recognition of which has particular therapeutic and prognostic implications.

Liver transplantation for nonsteroidal anti-inflammatory drug-induced liver failure: nimesulide as the first implicated compound.

Among industrialized countries, the rate of drug-induced liver failure varies widely accounting for about 1-12% of the indications for liver transplantation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are with antibiotics the most frequently involved compounds. In this single-center series of 57 consecutive cases of acute liver failure treated by orthotopic liver transplantation, five were related to NSAIDs-induced liver damage, three being due to nimesulide use. This has to be taken as a further warning about the potential for this compound to induce liver failure.

Prognostic risk factors of survival after resection of hepatocellular carcinoma.

BACKGROUND/AIMS: Surgical resection is a standard treatment of hepatocellular carcinoma, but liver cirrhosis is known to be associated to a high tumor recurrence rate. METHODOLOGY: A retrospective study of 55 consecutive patients (37 males, 18 females) suffering from hepatocellular carcinoma having undergone surgical resection. Hepatocellular carcinoma developed in 29 patients with normal liver (group A) and in 26 patients with chronic liver disease (CLD) (group B). Patients were significantly older and at high-risk in Group B. RESULTS: Radical liver resection was achieved in 98% (100% in group A; 96% in group B). Overall 2-month mortality was 2% (0% in group A; 4% in group B). The 5-year overall and disease-free survival was respectively 55% and 35%. However, the 5-year overall and disease-free survival was significantly better in Group A (71% and 59%) compared to Group B (37% and 6%) (p < 0.001), respectively. Multivariate statistical analysis demonstrated that age > 50 years, poor tumor differentiation and presence of satellite nodules were significant independent adverse predictive factors of overall and disease-free survival. CONCLUSIONS: Resection of HCC is safe and effective with satisfactory overall and disease-free survival rates, except when underlying chronic liver disease and poor tumor differentiation are present.

The oxyhemoglobin dissociation curve in liver cirrhosis.

STUDY OBJECTIVES: To trace the entire oxyhemoglobin dissociation curve (ODC) in a cohort of cirrhotic patients in stable condition who were candidates for orthotopic liver transplantation (OLT). DESIGN: Prospective cohort study. SETTING: A large academic hospital. PATIENTS AND METHODS: We traced the entire ODC in whole blood in standard conditions (pH 7.4; PCO2, 40 mm Hg; temperature, 37 degrees C) for 50 cirrhotic candidates for OLT (27 men and 23 women) and 50 age- and height-matched healthy subjects (27 men and 23 women). All subjects were nonsmokers or ex-smokers for at least 5 years. We also measured 2,3 diphosphoglycerate (2,3 DPG) in RBCs, plasma ions, and arterial blood gases in all subjects according to standard methods. Mixed venous blood was also obtained from the 50 cirrhotic patients. RESULTS: Mean ODC was the same in the two groups. However, for the cirrhotic patients, the dispersion of the PO2 values of oxygen saturation percentage (SO2%) from 20 to 80% was significantly larger (p < 0.01 to p < 0.0001). In the cirrhotic patients, the mean PO2 for half-saturation of hemoglobin (P50) was 7.11 + 0.14 mEq/L chloride (p < 0.001) plus 0.36 mEq/L inorganic phosphate (p < 0.05) plus 0.25 micromol/gram of hemoglobin (gHb) 2,3 DPG (p < 0.00002) in absolute numerical values. Sodium, potassium, and calcium, three plasma ions disturbed in cirrhotic patients, did not contribute to determine the mean P50. DISCUSSION: In patients with cirrhosis, increased dispersion of PO2 values for a given level of SO2% may be related to four factors: (1) an observed alteration of the enzymes controlling the phosphoglycerate shunt; (2) hypothyroidism, which may affect 7 to 20% of patients with primary biliary cirrhosis; (3) the type of ongoing treatment, eg, diuretics and/or propranolol; and (4) plasma ion disturbances. CONCLUSIONS: We describe the ODC by three indexes: shape, position, and an index of dispersion of the PO2 values for a given level of SO2%. In addition, when the latter is increased, we suggest that other factors than pH, temperature, carbon dioxide, and inorganic phosphates are acting on the position of the ODC.

Chronic stomal variceal bleeding after colonic surgery in patients with portal hypertension: efficacy of beta-blocking agents?

In patients with portal hypertension, ileostomy or colostomy carries the risk of the development of stomal varices at the site of the mucocutaneous junction of a stoma. Such varices are often the source of difficult-to-treat recurrent or chronic bleeding. In this setting, transjugular intrahepatic portosystemic shunt insertion and embolisation is considered the best therapeutic approach in spite of relatively high mortality and morbidity rates. We report the cases of three consecutive patients with portal hypertension of various causes and chronic stomal variceal bleeding in whom beta-blocking therapy resulted in the drying up of bleeding and the prevention of its recurrence for periods of time ranging between 2 and 42 months.

Hereditary hyperferritinaemia-cataract syndrome: a challenging diagnosis for the hepatogastroenterologist.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a relatively rare disorder with an autosomal dominant trait. It can be caused by various mutations within the iron responsive element (IRE) of the L-ferritin gene. These mutations result in an increased translation of L-ferritin mRNA and consequently the accumulation of L-ferritin in different fluids and tissues. HHCS patients present with an isolated hyperferritinaemia in the absence of any sign of iron overload. Early onset bilateral cataract, probably due to accumulation of ferritin crystals in the lens, is the only presenting clinical manifestation. Internists, especially gastrohepatologists, should be aware of this syndrome and differentiate it from haemochromatosis which is much more frequent, in order to avoid unnecessary imaging procedures, liver biopsies and an eventual venesection therapy, which will only lead to microcytic anaemia. In the present paper we report the first cases with HHCS diagnosed in Belgium. At diagnosis, the seven known affected members of three different families had ferritin levels between 603 and 3432 microg/l (normal < 150 microg/l), and this in combination with normal iron and transferrin values. All of them were known with early-onset bilateral cataract and our postulated diagnosis of HHCS was confirmed after genetic sequencing of the L-ferritin gene, which showed a C39U point mutation in the first family, and an A40G point mutation in the IRE loop segment in the two other families. The other investigated members of the three families had normal ferritin values, no history of early-onset cataract and genetic analyses could not reveal a mutation in the IRE of their L-ferritin gene. In current clinical practice, gastroenterologists should remember that elevated ferritin levels in the absence of documented iron overload is not haemochromatosis.

Bile duct disorders.

Drug-induced bile duct injury related prolonged or chronic cholestasis is recognized as a common side effect of treatment with several drugs. The severity and duration of the clinical symptoms suggest that this increase in number of reports is not only related to clinician and pathologists being increasingly aware of the condition, but also may represent a true increase in incidence likely related to a time-related growing experience with newer drugs. This clinical presentation encompasses a wide variety of features that may be the source of diagnostic difficulties, especially in the cases where cholestasis occurs days or weeks after the completion of therapy. Even more puzzling is the initial picture of hepatocholangitis, which may be silent and ensuing bile duct paucity with chronic anicteric cholestasis may be another source of diagnostic difficulties in the long-term. These diagnostic difficulties suggest that some of the cases of the so-called "idiopathic adulthood ductopenia" may originate from overlooked drug induced vanishing bile duct syndrome. The pathogenesis of the syndrome remains largely unknown and the determinants of prognosis and outcome. From reproducible data obtained in different studies investigating HLA-dependent predisposition, one may assume that genetics plays a major role even if other unknown additive factors are also likely involved. Severity of initial hepatocholangitis is likely to represent another important determinant of severity and prognosis, however to be assessed in larger longitudinal studies. Therapy of large bile duct injury mimics that of primary sclerosing cholangitis. Treatment of small bile duct injury remains disappointing. Corticosteroids are invariably ineffective. Ursodeoxycholic acid as been shown to induce improvement of clinical and biochemical cholestasis in some selected cases, its efficacy being however unpredictable. Preliminary data about the natural history of the vanishing bile duct syndrome suggest that therapy might be more effective when initiated early.

Persistent decreased plasma cholecystokinin levels in celiac patients under gluten-free diet: respective roles of histological changes and nutrient hydrolysis.

Celiac disease is associated with impaired cholecystokinin (CCK) release. The mechanism by which CCK release is impaired is poorly understood and seems to be related to the mucosal atrophy or to decreased stimulation due to reduced intraduodenal nutrient hydrolysis. The aims of our study were to evaluate basal and postprandial CCK in celiac patients presenting with distinctive types of mucosal lesions (normal, infiltrative and atrophic), and to study the role of protein hydrolysis on CCK release. Plasma CCK was measured in 20 celiac patients (normal mucosa: n=6; infiltrative type: n=6; atrophic type=8) and 9 controls, before and after ingestion of a polymeric or a semi-elemental meal. Significant decreases in basal CCK plasma (B 0.6 [95% CI, 0.3-1.3] pmol/l; p<0.003) and postprandial CCK area under curve (AUC 34 [19-61] pmol/l x 120 min, p<0.0001) were observed in patients with an atrophic mucosa compared with treated patients (B 1.6 [1.0-2.4] pmol/l, AUC 267 [172-414] pmol/l x 120 min) or healthy volunteers (B 1.0 [0.7-1.4] pmol/l, AUC 186 [131-264] pmol/l x 120 min). A significant defective CCK release was also observed in patients with an infiltrative type: B 0.4 [0.2-0.7] pmol/l and AUC 56 [31-101] pmol/l x 120 min; p<0.0001. Administration of a semi-elemental diet did not correct the defective CCK release. In conclusion, the decreased CCK levels observed in celiac patients are not strictly related to the mucosal atrophy but rather to the lymphocytic infiltrate. Administration of a predigested meal did not correct the impaired CCK release. Some inhibitory mechanism could be involved in the CCK cell dysfunction observed in celiac patients presenting with lesser degrees of disease activity.

Severe hepatitis associated with the use of black cohosh: a report of two cases and an advice for caution.

In spite of the fact that severe side effects have been reported, black cohosh [Actaea racemosa (syn. Cimifuga racemosa)] is likely to be one of the most popular herbs used in the treatment of postmenopausal symptoms and menstrual dysfunction. We report the cases of two patients, one with submassive liver necrosis and the other with chronic hepatitis most likely related to the use of two different preparations containing black cohosh. This represents another advice for caution concerning this popular preparation of inconsistent therapeutic value.

Jaundice as a misadventure of a green tea (camellia sinensis) lover : a case report.

The case of a 76-year-old retired surgeon and lover of green tea (camellia sinensis) infusions who developed a clinical, sero-biochemical and histological picture of severe subacute hepatitis is reported. The clinical presentation was that of jaundice with asthenia and weight loss. Abnormal liver function tests were associated with hyper-gammaglobulinemia, and the transient presence of anti-smooth-muscle antibodies and ANCA. Liver histology showed mixed features of lobular hepatitis with central collapses, portal inflammatory cells infiltration and interface hepatitis. All other potential causes of hepatitis were excluded on the basis of clinical, biochemical and serological data. Herbal preparation withdrawal resulted in a slow and continuous improvement with a complete clinical and sero-biochemical resolution after 7 months.

Nifuroxazide-induced acute pancreatitis: a new side-effect for an old drug?

We report the case of a middle-aged woman who developed a typical picture of acute pancreatitis together with systemic features of immunoallergy after the intake of two capsules (200 mg) of nifuroxazide. Even if acute pancreatitis is a rare adverse event of nitrofuran derivative therapy, nifuroxazide-induced pancreatitis as not been previously described. As suggested by associated systemic features, the disease is likely of immunoallergic origin.

The outcome after transjugular intrahepatic portosystemic shunt (TIPS) for hepatic hydrothorax is closely related to liver dysfunction: a long-term study in 28 patients.

OBJECTIVES: Hepatic hydrothorax is a rare but challenging complication of cirrhosis. The Transjugular Intrahepatic Portosystemic Shunt (TIPS) appears as one of the most successful approach of therapy. METHODS: To assess long-term efficacy and safety, we reviewed 28 patients (Child B/C: 43/57%) who underwent TIPS placement for refractory hepatic hydrothorax in our institution between 1992 and 2001. RESULTS: The 30-days mortality was 14%, reaching 25% at 90 days. The one-year survival without liver transplantation was 41.2%. Reduction in the volume of pleural effusion and improvement in clinical symptoms was observed in 68% while a complete radiological and echographic disappearance of hydrothorax was documented in 57%. Statistical analysis showed that poor liver function was predictive of mortality and non-response. Of the different liver function parameters and in this small series, the Child-Pugh score was more discriminating than the recently described Mayo risk score. CONCLUSION: This study shows that TIPS is effective in the treatment of hepatic hydrothorax for selected patients. Poor liver function is a strong predictive of bad outcome.

Cytomegalovirus-associated protein losing gastropathy in an immunocompetent adult: a case report.

Cytomegalovirus infection of the gastro-intestinal tract is frequent and may be serious in the immunocompromised patient. We report a case of cytomegalovirus infection in an immunocompetent young man who presented total food intolerance, pleural effusion and oedema as the result of severe protein losing hypertrophic gastropathy. Hypertrophic gastropathy with severe mucosal protein loss has been described in Menetrier's disease, a condition of unknown cause which involves foveolar hyperplasia of the gastric mucosa. Related hypoalbuminemia is responsible for a clinical picture of diffuse edema. In adults, the natural course of the disease is marked by a chronic course and carries a bad prognosis. In our case, the disease ran a protracted disabling course, likely shortened by ganciclovir therapy, followed by slow clinical, endoscopic and biochemical resolution after several' months course.

The place of liver transplantation in Caroli's disease and syndrome.

Caroli's disease (CD) or syndrome (CS) are rare inherited disorders which may cause severe, life-threatening, cholangitis or which may lead to hepatobiliary degeneration. The typical cystic biliary anomalies are often associated to congenital hepatic fibrosis (CHF) and, less frequently, to cystic renal disease especially autosomic recessive polycystic kidney disease (ARPKD). The place of liver transplantation (LT) in the treatment of CD or CS is evaluated based on our own experience of three successfully transplanted patients, the literature review of 19 patients and the European experience with 110 patients collected in the European Liver Transplant Registry. LT should be proposed as a definitive therapeutic option once severe cholangitis or (suspicion of) malignant transformation is present. The frequently used radiological, endoscopical or surgical biliary drainage procedures carry a high morbidity and mortality rate. In case of concomitant symptomatic CHF and renal failure, combined or sequential hepatorenal transplantation should be carried out, dependent on the evolution of the hepatic and renal disease. In case of associated ARPKD, renal transplantation is often indicated early on because of the more rapid progression of the renal component of the disease.

Vaginal bleeding complicating portal hypertension: a particular entity - report of two cases and review of the literature.

Vaginal haemorrhage arising from varices is an exceptional complication of portal hypertension. Two cases successfully treated by transjugular intrahepatic portosystemic stent shunt are presented here. Both these patients previously had a total hysterectomy as did three out of four cases reported in the literature. Clinicians should be aware of 'vaginal bleeding' in the context of both hysterectomy and chronic liver disease in order to adopt the correct diagnostic and therapeutic approach. Definitive treatment can be obtained only if the underlying portal hypertension is adequately taken into consideration.

Preoperative assessment of pancreatic tumors using magnetic resonance imaging, endoscopic ultrasonography, positron emission tomography and laparoscopy.

BACKGROUND: The appropriate preoperative evaluation of a pancreatic tumor remains a matter of debate. METHODS: We retrospectively evaluated an institutional strategy including magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), positron emission tomography (PET) and laparoscopy (LAP) for detection and staging of pancreatic tumors suspected to be malignant. RESULTS: In a consecutive series of 59 patients screened by MRI, PET, EUS and LAP between July 1998 and November 2002, 48 patients were found to bear pancreatic adenocarcinoma and surgery was performed in 27 of them. For tumor detection, the sensitivity of EUS was superior to MRI and PET (98 vs. 87.5 and 87.5%, respectively, p = 0.13). MRI best assessed loco-regional staging, i.e. arterial involvement. For the detection of distant metastases, the sensitivity of all preoperative examinations taken separately was low. When laparotomy was performed with a curative intent according to all four examinations, occult metastasis or carcinomatosis was discovered in 7/27 patients and the overall predictive value of resectability was thus 74%. Five-year and median survival were significantly better in resected vs. non-resected patients (39% and 26 months vs. 0% and 8 months, p = 0.0006). CONCLUSIONS: MRI can be recommended has the first examination in patients bearing pancreatic tumors, complemented by EUS if the findings of MRI are non-conclusive. For detection of distant metastasis, only the combination of all preoperative examination was proved to be more accurate than a single technique.

Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn's disease.

Ciprofloxacin, a fluorinated quinolone, is a powerful antibiotic widely used for its broad spectrum of activity in ambulatory and long-term care setting. Until now, ciprofloxacin administration has been associated with a few cases of acute, sometimes cholestatic jaundice or fulminant hepatic failure believed mainly related to idiosyncratic hypersensitivity. We report a case of delayed and prolonged cholestatic hepatitis with ductopenia occurring after 6 months of treatment in a patient with Crohn's disease. This observation suggests the potential for the drug to induce long-term likely dose-related severe hepatotoxicity.