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.

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.

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.

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.

[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.

[Spontaneous bacterial peritonitis, a severe complication in patients with liver cirrhosis]. / Spontane bacteriële peritonitis, een ernstige complicatie van levercirrose.

Three patients with hepatic cirrhosis and ascites, a 65-year-old man, a 17-year-old woman and a 49-year-old man, were admitted to hospital for progressive drowsiness, increased ascites, and melaena, respectively. An elevated number of polymorphonuclear leukocytes was found in the ascites. The three patients became more and more seriously ill. On the basis of the laboratory findings, a diagnosis of 'spontaneous bacterial peritonitis' was made. The patients recovered after administration of antibiotics. The signs and symptoms of spontaneous bacterial peritonitis can range from subtle, renal dysfunction or an altered mental state to the signs ofan acute abdomen. The common signs of infection such as fever and an elevated leukocyte count are present in only 50% of the patients. Gram-negative bacteria are most frequently isolated from cultures of the ascites fluid. The 1-year mortality is still 50-70% and is partly a result of the underlying liver disease. Prophylactic oral administration of a quinolone decreases the risk of spontaneous bacterial peritonitis in patients with gastrointestinal haemorrhage and in patients with a prior episode of spontaneous bacterial peritonitis. Long-term prophylaxis has been associated with the development of infections with quinolone-resistant microorganisms.

[Hepatic hydrothorax]. / Hepatische hydrothorax.

Hepatic hydrothorax was diagnosed in four patients with liver cirrhosis, three men aged 65, 41, and 48 and a woman aged 48. They presented with either right-sided or bilateral pleural-fluid accumulations in the absence of cardiopulmonary disease. In the first man with no concurrent ascites, the disorder was missed, resulting in prolonged chest tube drainage, multiple severe complications and death. In the 41-year-old man chest tube drainage was also associated with complications including renal failure and encephalopathy. Pleurodesis was effective in the woman while in the remaining man hepatic hydrothorax was only a temporary, asymptomatic finding. Pleural effusions in cirrhotic patients should be considered and managed as hepatic hydrothorax unless diagnostic studies reveal a different aetiology. Absence of ascites is not uncommon and should not delay the correct diagnosis. The gradient between pleural and serum albumin concentration is typically more than 11 g/l. Prolonged chest tube drainage is dangerous and should be avoided. In cases refractory to salt restriction and diuretic therapy, transjugular introduction of an intrahepatic portosystemic shunt is the treatment of choice. Recently, pleurodesis combined with thoracoscopic repair ofdiaphragmatic defects has been reported as a potentially effective form of therapy.

[A retrospective study on the role of antibodies against soluble liver antigen (anti-SLA antibodies) and other autoantibodies in the diagnostics of autoimmune hepatitis]. / Een retrospectieve studie naar de rol van antistoffen tegen oplosbaar ('soluble') leverantigeen (anti-sLA-antistoffen) en van andere autoantistoffen bij de diagnostiek van auto-immune hepatitis.

OBJECTIVE: To determine the diagnostic value of antibodies against soluble liver antigen (anti-SLA antibodies) and a number of other antibodies for the diagnosis ofautoimmune hepatitis (AIH). DESIGN: Retrospective. METHOD: Anti-SLA, antinuclear antibodies (ANA), antibodies against smooth muscle (anti-SMA), anti-neutrophil cytoplasm antibodies (peri-nuclear pattern; pANCA) and antibodies against liver-kidney microsomal antigen type 1 (anti-LKM-1) were determined in the sera of 97 patients with AIH and 121 patients with other liver disorders including viral, drug-related and alcoholic liver disease. The sensitivity and specificity of each of the antibodies, or a combination ofantibodies, were calculated for the diagnosis 'AIH'. RESULTS: Anti-SLA antibodies were found only in AIH patients (specificity: 100%); 1 in 7 AIH patients (14%) had these antibodies and in 2% they were the only detectable antibodies. Anti-LKM-1 antibodies also showed a 100% specificity for AIH although the sensitivity was much lower (2%). Whilst the sensitivity of ANA (53%), pANCA (39%) and SMA (39%) was higher, the specificity of these antibodies for AIH was lower. 20% of AIH patients tested negative for all autoantibodies. The simultaneous presence of more than one antibody increased the probability of AIH diagnosis. CONCLUSION: When AIH is suspected, the presence of one or a combination ofanti-SLA, ANA, anti-SMA, anti-LKM-1 and pANCA antibodies is helpful for the often difficult differential diagnosis between AIH and other liver disorders. Anti-SLA antibodies are specific for AIH and appear to be a useful diagnostic parameter.

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.

[Fever as a sign of inflammatory syndrome in a female patient with hepatic haemangioma]. / Koorts als uiting van inflammatoir syndroom bij een patiënte met een leverhemangioom.

A 41-year-old patient presented with fever, night sweats, general malaise, abdominal pain, and substantial weight loss. Laboratory analysis suggested an inflammatory process. Diagnostic imaging revealed a hepatic haemangioma with a diameter of 20 cm. Because such giant haemangiomas of the liver can lead to inflammatory syndrome, the tumour was surgically removed. Pathological analysis confirmed the clinical diagnosis and evidence of extensive thrombosis and other vascular defects was found. Following treatment, the symptoms resolved without further complications. In patients with a giant haemangioma in the liver who present with an inflammatory syndrome, the haemangioma should be considered as the causal factor. For these patients, resection is the treatment of choice.

A randomized trial in primary biliary cirrhosis comparing ursodeoxycholic acid in daily doses of either 10 mg/kg or 20 mg/kg. Dutch Multicentre PBC Study Group.

BACKGROUND: Ursodeoxycholic acid (UDCA) prolongs transplantation-free survival in primary biliary cirrhosis (PBC). However, the optimal therapeutic dose has not been established. AIM: To compare the effects of UDCA administered in daily doses of 10 vs. 20 mg/kg on symptoms, liver biochemistry and biliary UDCA enrichment. METHODS: A 6-month multicentre randomized open controlled trial was conducted to assess the effects of an increase in the dose of UDCA to 20 mg/kg/day vs. continuation of 10 mg/kg/day for patients who had not achieved biochemical normalization during treatment for at least 6 months with the 10 mg/kg dose. Clinical and laboratory evaluations were performed at entry and at 3-month intervals. The percentage UDCA in duodenal bile was assessed at entry and at 6 months. RESULTS: Sixty-one patients were enrolled. No side-effects of UDCA were observed. Within the 20 mg/kg/day group significant decreases were found for alkaline phosphatase (- 8%; P = 0.003), aspartate aminotransferase (- 11%; P = 0.01), alanine aminotransferase (- 17%; P < 0.001), gamma-glutamyl transferase (- 34%; P < 0.001), immunoglobulin M (- 11%; P = 0.002) and cholesterol (- 8.1%; P < 0.001). In the 10 mg/kg group none of these parameters differed significantly from baseline. No significant differences between dose groups for symptom scores or serum bilirubin were found. Biliary enrichment with UDCA increased from 37% to 46% in the 20 mg/kg group (P = 0.02) while remaining stable in the 10 mg/kg group. CONCLUSIONS: Liver biochemistry improved in PBC patients receiving UDCA 20 mg/kg/day compared to a dose of 10 mg/kg/day. Both doses were equally well tolerated. These results indicate that UDCA 10 mg/kg/ day is a suboptimal dose for treating PBC.

Measuring plasma fibrinogen levels in patients with liver cirrhosis. The occurrence of proteolytic fibrin(ogen) degradation products and their influence on several fibrinogen assays.

In patients with liver cirrhosis the fibrinogen molecule is under constant attack of various proteolytic enzymes, which might affect results of the different assay systems for fibrinogen. We therefore studied the measurement of fibrinogen in the plasma of patients with mild, moderate and severe cirrhosis of the liver. Fibrinogen levels were measured with the Clauss method (functional fibrinogen); an enzyme immuno assay (EIA) for HMW + L MW fibrinogen; and an assay that measures the total clottable fibrinogen. With all three methods we found normal or slightly increased fibrinogen levels in patients with mild or moderate cirrhosis, whereas patients with severe cirrhosis had decreased levels. No evidence was found for increased partial fibrinogen proteolysis, resulting in increases of LMW'-fibrinogen in cirrhotic patients. We further observed that fibrinogen degradation products levels increased slightly with the severity of the disease, but were still in the normal range in patients with severe cirrhosis. This indicates a very low level of primary fibrinolysis. Fibrin degradation products levels increased much stronger, which points to intravascular coagulation. The levels of the fibrin degradation products remained below the level where they are expected to influence the Clauss assay. In patients with liver cirrhosis the measurement of plasma fibrinogen levels with the three studied methods give comparable results. We suggest to apply the Clauss assay in cirrhotic patients because of this and because it has good reproducibility and because the test is cheap, quick and easy to perform.