The diagnostic work-up in patients with ascites: current guidelines and future prospects.

Accumulation of fluid in the peritoneal cavity - ascites - is commonly encountered in clinical practice. Ascites can originate from hepatic, malignant, cardiac, renal, and infectious diseases. This review discusses the current recommended diagnostic approach towards the patient with ascites and summarises future diagnostic targets.

Reagent strips are efficient to rule out spontaneous bacterial peritonitis in cirrhotics.

BACKGROUND: The gold standard to diagnose spontaneous bacterial peritonitis (SBP) is a polymorphonuclear neutrophil count ≥ 250 cells/µl in ascitic fluid. This test is laborious and expensive. Urine reagent strips measuring leukocyte esterase activity have been proposed as a rapid and inexpensive alternative. The aim of this study was to assess the diagnostic accuracy of the Combur reagent strip for diagnosing SBP. Furthermore the possible advantage of a photospectrometer reading over visual reading of the strip was investigated. METHODS: This prospective study includes all ascitic fluid samples of cirrhotic patients undergoing diagnostic or therapeutic paracentesis over a 12-month period. The samples were collected for the standard diagnostic work-up and in addition tested with a bedside Combur reagent strip. The strip was read visually and with an automated spectrometer. RESULTS: A total of 157 samples were obtained from 53 patients, and spontaneous bacterial peritonitis was diagnosed in 12 patients based on the ascitic polymorphonuclear neutrophil count. The sensitivity, specificity, positive predictive value and negative predictive value of the reagent strip according to the photospectrometer were 100%, 93%, 55% and 100% respectively, and 75%, 99%, 82% and 98%, respectively, for visual interpretation. The diagnostic accuracy of the photospectrometer was found to be higher than visual interpretation (p = 0.007). CONCLUSION: The diagnostic accuracy of leucocyte esterase reagent strips read out by a photospectrometer was comparable with the gold standard test and was excellent for excluding SBP. Our results support implementation of reagent strips in the diagnostic work-up of ascitic fluid.

The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.

BACKGROUND: Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus. AIM: To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus. METHODS: This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post-NBD). We analysed the duration of treatment response and associated complications. RESULTS: In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post-endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication. CONCLUSIONS: Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Serum level of Ca 19-9 increases ability of IgG4 test to distinguish patients with autoimmune pancreatitis from those with pancreatic carcinoma.

BACKGROUND: Autoimmune pancreatitis (AIP) is often difficult to distinguish from pancreatic carcinoma or other pancreatobiliary diseases. High serum levels of carbohydrate antigen 19-9 (Ca 19-9) are indicative of malignancies, whereas high levels of immunoglobulin (Ig)G4 (>1.4 g/l) are characteristic of AIP. We investigated whether serum levels of these proteins can differentiate between these diseases. METHODS: We measured levels of Ca 19-9 and IgG4 in serum samples from 33 patients with AIP, 53 with pancreatic carcinoma, and 145 with other pancreatobiliary disorders. We determined cut-off levels for each assay. Logistic regression analysis was used to evaluate combined data on Ca 19-9, IgG4, and bilirubin levels. RESULTS: Low levels of Ca 19-9 were independently associated with AIP, compared with pancreatic adenocarcinoma [odds ratio (OR) 0.28; 95% confidence interval (CI) 0.13-0.59; p = 0.0001]. Using an upper level of 74 U/ml, the assay for Ca 19-9 identified patients with AIP with 73% sensitivity and 74% specificity. Using a lower level of 2.6 g/l, the assay for IgG4 identified these patients with 70% sensitivity and 100% specificity. Combining data, levels of Ca 19-9 < 74 U/ml and IgG4 > 1.0 g/l identified patients with AIP with 94% sensitivity and 100 % specificity. CONCLUSIONS: Patients with AIP have lower levels of Ca 19-9 than those patients with pancreatic carcinoma. Measurement of either the Ca 19-9 or the IgG4 level alone are not accurate enough for diagnosis. However, the combination of Ca 19-9 < 74 U/ml and IgG4 > 1.0 g/l distinguishes patients with AIP from those patients with pancreatic carcinoma with 94% sensitivity and 100% specificity.

Self-expandable metal stents as definitive treatment for esophageal variceal bleeding.

The use of self-expandable metal stents (SEMS) has occasionally been described for the treatment of uncontrollable esophageal variceal bleeding (EVB) as a bridge to an alternative treatment option (i. e. transjugular intrahepatic portosystemic shunt [TIPS]). It is currently not known whether SEMS placement is appropriate for more than temporary hemostasis. This case series report describes five patients in whom EVB could not be controlled with variceal band ligation and who were not suitable to undergo a TIPS procedure at the time of bleeding. SEMS were placed in these patients with the intent of definitive treatment. Successful initial hemostasis was achieved in all five patients, and sustained hemostasis occurred in four. Stents were removed from two patients after > 14 days and remained in situ until death in three other patients (range 6 - 214 days). No complications related to this longer duration were observed. In one case, TIPS could be performed at a later stage. SEMS could be a definitive treatment for uncontrollable esophageal bleeding in patients with a limited life expectancy or those unsuitable for TIPS at the time of bleeding.

Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.

BACKGROUND AND AIMS: It remains unclear when anticoagulant therapy should be given in patients with non-cirrhotic portal vein thrombosis (PVT). The aim of this study was to assess the effect of anticoagulation on recurrent thrombotic events and gastrointestinal bleeding in non-cirrhotic PVT patients. METHODS: Retrospective study of all patients with non-cirrhotic PVT (n = 120), seen at our hospital from 1985 to 2009. Data were collected by systematic chart review. RESULTS: Sixty-six of the 120 patients were treated with anticoagulants. Twenty-two recurrent thrombotic events occurred in 19 patients. The overall thrombotic risk at 1, 5 and 10 years was 4%, 8% and 27%, respectively. Seventy-four percent of all recurrent thrombotic events occurred in patients with a prothrombotic disorder. Anticoagulant therapy tended to lower the risk of recurrent thrombosis (hazard ratio [HR] 0.2, P = 0.1), yet the only significant predictor of recurrent thrombotic events was the presence of a prothrombotic disorder (HR 3.1, P = 0.03). In 37 patients, 83 gastrointestinal bleeding events occurred. The re-bleeding risk at 1, 5 and 10 years was 19%, 46% and 49%, respectively. Anticoagulation therapy (HR 2.0, P ≤ 0.01) was a significant predictor of (re)bleeding. Anticoagulation therapy had no effect on the severity of gastrointestinal bleeding. Poor survival was associated with recurrent thrombotic events (HR 3.1 P = 0.02), whereas bleeding (HR 1.6 P = 0.2) and anticoagulant treatment (HR 0.5 P = 0.2) had no significant effect on survival. CONCLUSIONS: In non-cirrhotic PVT patients recurrent thrombotic events are mainly observed in patients with underlying prothrombotic disorders. Anticoagulation therapy tends to prevent recurrent thrombosis but also significantly increases the risk of gastrointestinal bleeding.

Prevalence of autoimmune pancreatitis and other benign disorders in pancreatoduodenectomy for presumed malignancy of the pancreatic head.

BACKGROUND: Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided. METHODS: All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked. RESULTS: A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients. CONCLUSIONS: The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes.

BACKGROUND: Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. AIM: To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. METHODS: Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. RESULTS: Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). CONCLUSIONS: Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.

The long-term effect of ursodeoxycholic acid on laboratory liver parameters in biochemically non-advanced primary biliary cirrhosis.

BACKGROUND AND AIMS: Ursodeoxycholic acid (UDCA) has an established effect on liver bio-chemistries in primary biliary cirrhosis (PBC). Few studies have evaluated long-term laboratory treatment effects and data beyond 6 years are not available. The aim of this study was to assess the long-term evolution of liver bio-chemistries during prolonged treatment with UDCA in biochemically non-advanced PBC. PATIENTS AND METHODS: Prospective multicenter cohort study of patients with PBC with pretreatment normal bilirubin and albumin, treated with UDCA 13-15 mg/kg/day. At yearly intervals, follow-up data including serum bilirubin, alkaline phosphatase (ALP), transaminases, albumin and IgM were collected. Data were analyzed with a repeated measurement model. RESULTS: Two hundred and twenty-five patients were included and followed during a median period of 10.3 years. Following 1-year treatment with UDCA 36-100% of the total biochemical improvement was achieved, the maximum response was observed after 3 years. After initial improvements, bilirubin and AST levels increased and albumin levels significantly decreased after 6-10 years. However, these changes were of limited magnitude. The beneficial effects on ALT and ALP were maintained while IgM continued to decrease. CONCLUSION: In non-advanced PBC the biochemical response to UDCA is maintained up to 15 years. The long-term evolution of bilirubin, albumin and ALT differs from that of ALP and AST. The mean IgM level normalised and levels continued to decrease during the period of follow-up.

Potential value of serum total IgE for differentiation between autoimmune pancreatitis and pancreatic cancer.

Autoimmune pancreatitis (AIP) is associated with a marked elevation of serum total IgG4 . Although there is evidence of autoimmunity in AIP, there are also signs of an allergic nature of its pathogenesis. Therefore, we determined both IgE and IgG4 in 13 patients with AIP, in 12 patients with pancreatic carcinoma and in 14 patients with atopic allergy and investigated the relationship between IgE and IgG4 . Total IgG4 was determined by automated nephelometry and total IgE by automated enzyme fluoroimmunoassay. Both total IgE and total IgG4 levels in patients with AIP were significantly higher than those in patients with pancreatic carcinoma (P = 0.0004 and P = 0.015, respectively). There was a significant correlation between the total IgE and total IgG4 levels in patients with AIP and patients with atopic allergy (r(s) =0.82, P=0.0006 and r(s) =0.88, P < 0.0001, respectively). The IgE/ IgG4 ratio in sera from patients with atopic allergy was significantly different (P = 0.0012) from this ratio in sera from patients with AIP. These results suggest that analysis of total IgE in serum might be useful in the differentiation between autoimmune pancreatitis and pancreatic carcinoma.

Ascites in patients with noncirrhotic nonmalignant extrahepatic portal vein thrombosis.

AIMS: To assess the frequency, natural history and prognostic implication of ascites in patients with EPVT and to identify risk factors for this complication. METHODS: A single-centre retrospective study of consecutive patients diagnosed with noncirrhotic nonmalignant EPVT between 1985 and 2009. RESULTS: One hundred and three patients [35% males; median age 43 (range 16-83) years] were included and followed up for a median time of 5.2 (range 0.9-32.5) years. Twenty-nine (28%) had ascites at the time of diagnosis. Overall survival was 91% at 5 years vs. 80% at 10 years. Survival in patients presenting with and without ascites was 83% vs. 95% at 5 years and 42% vs. 87% at 10 years (P = or < 0.01). There was no correlation between the presence of ascites and extension of the thrombus into the large splanchnic veins, duration of thrombosis or presence of gastrointestinal bleeding. CONCLUSIONS: Ascites is present in a quarter of patients presenting with noncirrhotic nonmalignant extrahepatic portal vein thrombosis. Ascites is a significant and independent prognostic factor and it is associated with a decreased long-term survival.

Double-balloon enteroscopy in Crohn's disease patients suspected of small bowel activity: findings and clinical impact.

INTRODUCTION: It is estimated that 10-30% of patients with Crohn's disease (CD) have small bowel (SB) involvement, but the exact frequency and clinical relevance of these findings is unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the SB. In this study we evaluated whether DBE is a feasible technique for detection of CD localized in the SB in CD patients with clinical suspicion of SB lesions and whether these findings have clinical impact. METHODS: Retrospectively we analyzed 52 DBE procedures in 40 CD patients (16 males, mean age 40 years, mean duration of CD 15 years). Included patients had clinical suspicion of small bowel CD activity, including persistent abdominal discomfort (n = 27), iron deficiency anemia (n = 9) and/or hypomagnesemia (n = 4). RESULTS: Active small bowel CD was found in 24 (60%) patients, leading to a change in therapy in 18 patients (75%). After a mean follow-up of 13 months, 15 (83%) had persistent clinical improvement with a significant drop of mean CDAI from 178 to 90, after a mean follow-up of 13 months. CONCLUSIONS: DBE is a useful diagnostic tool for the evaluation of SB lesions in CD patients. The significance of these findings is emphasized by the fact that adjustment of therapy in the majority of these patients leads to significant and sustained clinical improvement.

More right-sided IBD-associated colorectal cancer in patients with primary sclerosing cholangitis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and concurrent primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC) than IBD patients without PSC. The aim of this study was to investigate potential clinical differences between patients with CRC in IBD and those with CRC in IBD and PSC, as this may lead to improved knowledge of underlying pathophysiological mechanisms of CRC development. METHODS: The retrospective study from 1980-2006 involved 7 Dutch university medical centers. Clinical data were retrieved from cases identified using the national pathology database (PALGA). RESULTS: In total, 27 IBD-CRC patients with PSC (70% male) and 127 IBD-CRC patients without PSC (59% male) were included. CRC-related mortality was not different between groups (30% versus 19%, P = 0.32); however, survival for cases with PSC after diagnosing CRC was lower (5-year survival: 40% versus 75% P = 0.001). Right-sided tumors were more prevalent in the PSC group (67% versus 36%, P = 0.006); adjusted for age, sex, and extent of IBD, this difference remained significant (odds ratio: 4.8, 95% confidence interval [CI] 2.0-11.8). In addition, tumors in individuals with PSC were significantly more advanced. CONCLUSIONS: The right colon is the predilection site for development of colonic malignancies in patients with PSC and IBD. When such patients are diagnosed with cancer they tend to have more advanced tumors than patients with IBD without concurrent PSC, and the overall prognosis is worse. Furthermore, the higher frequency of right-sided tumors in patients with PSC suggests a different pathogenesis between patients with PSC and IBD and those with IBD alone.

[Dutch study on the optimal treatment strategy for patients with a first or second occurrence of gastro-oesophageal variceal bleeding: the TIPS-TRUE trial]. / Nederlandse studie naar de beste behandelstrategie bij patiënten met een eerste of tweede oesofagus- of maagvaricesbloeding: de TIPS-TRUE-trial.

The main options for secondary prevention of gastrooesophageal variceal bleeding are endoscopic therapy and treatment with propranolol. Creation ofa transjugular intrahepatic portosystemic shunt (TIPS) is currently considered a valuable secondary 'rescue' treatment when other therapies fail. Recent data suggest that the use of covered stents markedly increases the efficacy of TIPS, compared with conventional uncovered stents. Therefore, a multicentre randomised trial was designed to compare the effects of TIPS using covered stents with those of endoscopic therapy plus propranolol in patients with a first or second episode ofgastro-oesophageal variceal bleeding. TIPS will be performed in 4 university centres with relevant expertise. The trial will hopefully gain nationwide support, and all centres in The Netherlands are cordially invited to participate.

Ascites in cirrhosis: a review of management and complications.

Ascites is the most common manifestation in cirrhotic patients, and is associated with a reduced survival rate. Management of ascites is primarily focused on sodium restriction and diuretic treatment to which most patients respond appropriately. For the small group of patients who do not respond sufficiently, interventions such as large volume paracentesis and transjugular intrahepatic portosystemic shunt placement should be considered. Most important in the management of cirrhotic patients with ascites is prevention of complications. Spontaneous bacterial peritonitis and hepatorenal syndrome are severe complications with a poor prognosis when not detected and treated in an early stage. In all hospitalised patients with ascites, an infection of the ascitic fluid should be ruled out. For those patients at risk of developing spontaneous bacterial peritonitis, in particular patients after a first episode and patients with gastrointestinal bleeding, antibiotic prophylaxis should be given. To prevent the hepatorenal syndrome, substitution with albumin is essential, both in patients who experience an episode of spontaneous bacterial peritonitis and in patients treated with large volume paracentesis. For those patients unresponsive to standard treatment regimens, liver transplantation may be the only suitable treatment option.