Video capsule retention in inflammatory bowel disease: an unusual presentation and discussion of retrieval methods.

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal (GI) tract. Video capsule endoscopy (VCE) is widely used to investigate the small bowel, and capsule retention is the most serious potential complication. Endoscopic and surgical management has been reported, but in the absence of bowel obstruction, there is little consensus as to which should be employed. In this case report, we describe a patient who was investigated with VCE for weight loss and anaemia. He had previously undergone colectomy with ileoanal pouch formation for ulcerative colitis (UC). Capsule retention occurred at an ileal stricture and he was subsequently diagnosed with Crohn's disease (CD). We describe his medical management and successful capsule retrieval using endoscopic methods. This case also highlights the importance of screening for intestinal strictures in an atypical presentation of UC following colectomy.

Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease.

BACKGROUND: The thiopurine drugs, azathioprine and mercaptopurine (MP), are established treatments for IBD. However, therapeutic failure caused by adverse drug reactions occurs frequently. AIM: To study combination of allopurinol with reduced-dose thiopurine in an attempt to avoid adverse drug reactions in the treatment of IBD. METHODS: Patients with drug reactions to full-dose thiopurines were recruited for combination therapy in two IBD centres in this retrospective study. Dosing was guided by measuring thiopurine methyltransferase (for UK patients) or thioguanine nucleotides and methyl-6MP (Australian patients). Response was monitored by clinical activity indices. RESULTS: Of 41 patients, 25 had non-hepatic and 16 had hepatitic reactions. Clinical remission was achieved in 32 patients (78%) with a median follow-up of 41 weeks (range 0.5-400). Patients who did not respond to combination therapy tended to fail early with the same adverse reaction. The relative risk of having an adverse reaction with methyl-6MP in the top interquartile range was 2.7 (1.3-28) times that with methyl-6MP in the lower three quartiles (95% confidence interval). CONCLUSION: The combined experience from our centres is the largest reported experience of this combination therapy strategy in IBD, and the first to provide evidence for benefit in thiopurine and allopurinol co-therapy to avoid non-hepatitic adverse drug reactions.

Prescribing statins to patients with nonalcoholic fatty liver disease: real cardiovascular benefits outweigh theoretical hepatotoxic risk.

Statins are among the most widely prescribed drugs in the western world and play a significant role in reducing cardiovascular risk. However, concern regarding their hepatic safety profile has meant that patients with concurrent liver pathology are often denied such benefits. In this review we consider the evidence for and against the prescription of statins to patients with nonalcoholic fatty liver disease, a group typically associated with high cardiovascular risk. Contrary to current opinion, we find that there is considerable evidence for and little evidence against the prescription of statins to this population and suggest that the guidelines advising against their use in these patients should be reviewed.

Weight loss, dietary advice and statin therapy in non-alcoholic fatty liver disease: a retrospective study.

BACKGROUND: Studies have shown that weight loss can have a favourable effect upon non-alcoholic fatty liver disease (NAFLD). However, the most effective means of achieving weight loss and safety profile of lipid-lowering drugs in the presence of NAFLD is unknown. AIM: To investigate the effect of dietary advice and lipid-lowering drugs, particularly statins, on patients with NAFLD and dyslipidaemia. DESIGN: Observational records based study. METHODS: We studied 71 patients with NAFLD and dyslipidaemia diagnosed and treated between 1996 and 2002 at University Hospital Lewisham. Some were referred to a dietician for weight loss advice as part of their management. After treatment all patients were assessed for changes in weight, serum alanine transaminase (ALT) and serum lipids including serum cholesterol, serum high density lipoprotein (HDL) and serum triglycerides. RESULTS: Thirty-seven male and 34 female patients with NAFLD and dyslipidaemia were followed up for a mean period of 440 +/- 374 days (median 335). Regression analysis revealed a significant association between changes in weight and changes in serum ALT (p < 0.039). Dietary advice failed to reduce body weight but significantly lowered the serum cholesterol to HDL ratio (p = 0.05). Only 15.4% of patients taking statins experienced a rise in serum ALT > or = 40 U/l, and in each case the rise was transient, returning near baseline or below without discontinuation of statin treatment. CONCLUSIONS: Weight loss appears to improve NAFLD, and dietary advice and lipid-lowering drugs may be beneficial for patients with NAFLD and dyslipidaemia even if weight loss is not achieved. Statins appear to be safe and efficacious in this group.

Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease.

BACKGROUND: Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid 'triple therapy' improved renal graft survival. AIM: To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study. METHODS: Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co-therapy with low-dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co-therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests. RESULTS: Of 11 patients (three Crohn's disease, eight ulcerative colitis) treated, nine (82%) remain in long-term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu-like symptoms. Two stopped: one nausea, one abnormal liver function (stealosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions. CONCLUSIONS: Allopurinol co-therapy with low-dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long-term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses.

A growing burden: the pathogenesis, investigation and management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in western countries, and its incidence is increasing. This review outlines the significant health burden posed by NAFLD and discusses what is presently known about its pathogenesis, including the roles of the metabolic syndrome, obesity, insulin resistance, hepatic steatosis, reactive oxygen species, inflammatory cytokines and adipocytokines. The way in which NAFLD is clinically diagnosed is described, and areas of uncertainty surrounding its investigation are identified, before discussing the relative merits of the limited treatment options available and looking ahead to potential therapeutic strategies for the future.

Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.

Biochemical markers of acute pancreatitis.

Serum amylase remains the most commonly used biochemical marker for the diagnosis of acute pancreatitis, but its sensitivity can be reduced by late presentation, hypertriglyceridaemia, and chronic alcoholism. Urinary trypsinogen-2 is convenient, of comparable diagnostic accuracy, and provides greater (99%) negative predictive value. Early prediction of the severity of acute pancreatitis can be made by well validated scoring systems at 48 hours, but the novel serum markers procalcitonin and interleukin 6 allow earlier prediction (12 to 24 hours after admission). Serum alanine transaminase >150 IU/l and jaundice suggest a gallstone aetiology, requiring endoscopic retrograde cholangiopancreatography. For obscure aetiologies, serum calcium and triglycerides should be measured. Genetic polymorphisms may play an important role in "idiopathic" acute recurrent pancreatitis.

A controlled trial of ondansetron in the pruritus of cholestasis.

BACKGROUND: In patients with pruritus of cholestasis, response to conventional drug treatment may be unsatisfactory. Activation of 5-hydroxytryptamine receptors on dermal sensory nerve-endings plays a role in the perception of pruritus. The 5-hydroxytryptamine(3) receptor antagonist, ondansetron, has been used in the treatment of pruritus of cholestasis, but there are few controlled data. AIM: To determine whether ondansetron is effective in treating the pruritus of cholestasis. METHODS: A total of 19 patients with resistant pruritus were randomized, double blind, to receive either ondansetron 8 mg or placebo as a single intravenous bolus, followed by oral ondansetron 8 mg or placebo twice daily for 5 days. Patients' perception of pruritus was recorded hourly using a visual analogue scale, and scratching activity measured by means of a piezo-electric crystal attached to the fingernail. RESULTS: Mean pruritus score using visual analogue scale and scratching activity were reduced on the first treatment day compared with baseline in both the ondansetron and placebo groups (P < 0.05), but there were no significant differences in mean pruritus perception or scratching activity between the two groups. CONCLUSION: Ondansetron was of no benefit in this group of pruritic patients during short-term treatment.

Transdermal hormone replacement therapy improves vertebral bone density in primary biliary cirrhosis: results of a 1-year controlled trial.

BACKGROUND: Retrospective studies have suggested that hormone replacement therapy may reduce the rate of bone loss in primary biliary cirrhosis, but no controlled data are available. METHODS: Forty-two post-menopausal women with primary biliary cirrhosis were treated with calcium and vitamin D, either alone (n = 21) or together with transdermal hormone replacement therapy (n = 21). Bone densitometry was performed at baseline and at 1 year, and serum and urinary markers of bone turnover were measured at three-monthly intervals. RESULTS: At entry, 17 patients (40%) had spinal or femoral osteopenia (T score - 1 to - 2.5) and nine (21%) had osteoporosis (T < - 2.5). In those given hormone replacement therapy, there was a significant decrease in the mean urinary deoxypyridinoline :creatinine ratios at 3 months (7.8 vs. 6.1 nm/mm creatinine for no hormone replacement therapy vs. hormone replacement therapy; P = 0.04) and a 48% reduction in urinary calcium excretion at 1 year (0.66 vs. 0.32 mm/mm creatinine; P = 0.01). Repeat bone densitometry at 1 year revealed a 2.25% increase in the hormone replacement therapy group (P = 0.02), compared with a non-significant 0.87% decrease in L2-L4 bone mineral density in those not given hormone replacement therapy. Both treatment regimens were well tolerated, with no increase in cholestasis. CONCLUSIONS: Compared with calcium and vitamin D alone, supplemental treatment with transdermal hormone replacement therapy for 1 year improved the vertebral bone density and urinary markers of bone turnover in post-menopausal women with primary biliary cirrhosis.

Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome.

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

Brush cytology in the assessment of pancreatico-biliary strictures: a review of 406 cases.

AIMS: To assess the accuracy of brush cytology in patients investigated for pancreatico-biliary strictures. METHODS: All pancreatico-biliary brush cytology specimens submitted from two major teaching hospitals over a 6.5 year period were reviewed. Four hundred and forty eight satisfactory specimens from 406 patients with adequate clinical and/or pathological follow up data were examined in the study period. RESULTS: Two hundred and forty six patients (60.6%) were shown to have neoplastic strictures. One hundred and forty seven tumours were identified cytologically, including 87 of 146 pancreatic carcinomas, 29 of 47 cholangiocarcinomas, one of one bile duct adenoma, four of seven carcinomas of the gallbladder, eight of 13 ampullary carcinomas, two of three ampullary adenomas, 10 of 16 malignancies of undetermined origin, none of two islet cell tumours, one of three hepatocellular carcinomas, and five of eight metastatic tumours. The three adenomas identified on brush cytology could not be distinguished from adenocarcinoma morphologically. One hundred and sixty patients (39.4%) had benign strictures, most often as a result of chronic pancreatitis and bile duct stones. There were three false positive cytological diagnoses mainly as a result of the misinterpretation of cases with relatively scant and/or degenerative atypical epithelial cells. Forty one cases were reported as atypical or suspicious of malignancy on brush cytology, of which 29 were ultimately shown to have carcinoma. The overall diagnostic sensitivity and specificity were 59.8% and 98.1%, respectively. The sensitivity increased from 44.3% in the initial third of cases to 70.7% in the final third of cases examined in the series. CONCLUSIONS: Brush cytology, in conjunction with other clinical and radiological investigations, is a useful technique in the assessment of patients with suspected pancreatico-biliary neoplasia.

Co-amoxiclav jaundice: clinical and histological features and HLA class II association.

BACKGROUND AND AIMS: Jaundice associated with co-amoxiclav has been increasingly recognised. We aimed to characterise its clinical and histological features and to investigate linkage with human leucocyte antigen class II haplotypes. METHODS: We identified cases in the west of Scotland in the period 1991-1997 and performed polymerase chain reaction amplification and oligonucleotide probing on whole blood. RESULTS: Twenty two cases were identified (10 male, mean age 59.1 years). Jaundice occurred a median of 17 days after drug commencement, with a median peak bilirubin level of 225 micromol/l (range 84-598) and median duration of jaundice 69 days (range 29-150). Two patients had primary biliary cirrhosis and two other patients had persistently abnormal liver biochemistry on follow up. One death occurred in a frail elderly woman despite resolving jaundice. The frequency of jaundice was 1 in 78 209 co-amoxiclav prescriptions. Liver biopsy, available in 12 patients, showed perivenular bilirubinostasis, accompanying reactive ceroid laden macrophages, and portal inflammation with focal injury to interlobular bile ducts. Fourteen of 20 patients had DRB1*1501 compared with 27 of 134 controls (p<2.5 x 10(-6); odds ratio (OR) 9.25; relative risk (RR) 6.43). Of these, seven patients were homozygous for DRB1*1501(p< 10(-8); OR 35.54; RR=8.68) compared with two of 134 controls. All patients with DRB1*1501 had the extended haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602. There were no clinical or histological differences between genotypes. CONCLUSIONS: Co-amoxiclav associated hepatotoxicity may have a genetic basis and be delayed, severe, and prolonged, although complete recovery is usual.

Sialochemical markers of salivary gland involvement with Sjögren's syndrome secondary to rheumatoid arthritis and primary biliary cirrhosis.

Sjögren's syndrome is an autoimmune condition affecting the lacrimal and salivary glands and can be associated with rheumatoid arthritis and primary biliary cirrhosis. Parotid salivas collected from patients and normal controls were analysed for lactoferrin, IgA and beta2-microglobulin (measured by ELISA), and cystatin (measured by a enzyme inhibition assay). Output data provided less variable means, whilst expressing results as a proportion of the total protein provided greater specificity as markers for Sjögren's syndrome. Levels of specificity for IgA, lactoferrin and beta2-microglobulin were all high (100, 95 and 100%, respectively). Sensitivity levels of these markers (but not cystatin) tended to be similar for Sjögren's syndrome secondary to primary biliary cirrhosis (IgA, 25%; lactoferrin, 63%; and beta2-microglobulin, 50%), compared to Sjögren's syndrome secondary to connective tissue diseases such as rheumatoid arthritis (IgA, 50%; lactoferrin, 86%; and beta2-microglobulin; 38%).

A case of adult chronic copper self-intoxication resulting in cirrhosis.

Copper "supplements" taken in a dose of 30-60 mg/day during 3 years caused severe liver cirrhosis necessitating orthotopic liver transplantation.

Mycobacterial DNA not detected in liver sections from patients with primary biliary cirrhosis.

BACKGROUND/AIMS: Recent studies in primary biliary cirrhosis have reported the detection of serum antibodies against Mycobacterium gordonae and of mycobacterial DNA in liver sections. The aim of this study was to investigate whether mycobacterial DNA is present in liver biopsy material in primary biliary cirrhosis. METHODS: Archival liver biopsy specimens from 11 patients with primary biliary cirrhosis (10 female, mean age 52 years) and 11 patients with autoimmune hepatitis (10 female, mean age 53 years) were identified. Positive control tissue comprised five archival lymph node specimens from patients with tuberculous lymphadenopathy, three of which had stained positive on ZN staining, and also a liver biopsy specimen from a patient with tuberculous hepatitis (ZN positive). Fixed sections were deparaffinised and DNA was extracted by mechanical disruption with glass beads. DNA was purified by use of diatoms and lysis in guanidinium thiocyanate in a technique previously validated for archival DNA. Primers were directed to amplify a partial 16S ribosomal RNA gene yielding the species-specific character for mycobacteria, and also to amplify the constitutively-expressed human gene GAPDH. RESULTS: The polymerase chain reaction was shown to be capable of detecting 1 fg of M. gordonae DNA in 'spiked' samples, equivalent to 1-5 bacterial cells. No mycobacterial DNA was detected in liver biopsy samples from either the primary biliary cirrhosis or autoimmune hepatitis groups. Of the tuberculous control sections, mycobacterial DNA was detected in four of five lymph nodes and the liver biopsy specimen. GAPDH amplification was detected in all tested samples from liver disease and tuberculous control samples. CONCLUSION: These data do not support a role for mycobacteria in the aetiology of primary biliary cirrhosis.

Spirituality and leadership. Genuine leaders recognize the sacredness of the human presence.

Functionalism, which is the dominant philosophy of our time, views the world externally and mechanically and describes things in terms of how they work. But it cannot answer the "why" or (especially) the "who" questions. Leadership, however, requires an ability to recognize the sacredness of individuality. Each of us lives simultaneously in four different words: system, society, behavior, and experience. True leaders know that effecting change is possible only in the realm of experience. Change often begins in the human imagination, from which true leaders draw five necessary qualities: integrity, a gift for awakening others, compassion, spontaneity, and an ability to make use of failure--which is of course at the heart of crucifixion, resurrection, and incarnation. Healthcare today is caught up in a conversation between mission and market. Catholic healthcare leaders, who believe healthcare is a human right, will have to use all their powers of memory and imagination to invoke the vision of the ministry's founders. In that way, they may reawaken our numbed hearts.