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Background: Lactose intolerance is defined as the presence of gastrointestinal symptoms, such as bloating, abdominal pain or diarrhoea, after consumption of lactose in individuals with lactose malabsorption. Most cases involve primary lactose intolerance, caused by a loss of activity of the enzyme lactase, needed for digestion of lactose. A traditional method of establishing lactose intolerance is the hydrogen breath test (HBT), accompanied by a questionnaire to document complaints experienced by the patient during the test. Due to knowledge on lactase-persistent alleles, DNA genotyping has become available for the diagnostic work-up for lactose intolerance. Both methods are currently in use. The aim of this study is to provide a definite diagnostic approach for patients suspected of lactose intolerance in a Dutch population., Methods: In this retrospective, observational study, patients aged 15 years or older were included after presenting to their treating physician with symptoms suggestive of lactose intolerance. HBT, including a questionnaire to document complaints and DNA genotyping of LCT-13,910 C/T was performed for each patient as part of a routine diagnostic work-up., Results: 1101 patients were included (29% men). Positive and negative predictive value, sensitivity and specificity of HBT versus DNA genotyping were 80% (CI 75-84), 97% (CI 96-98), 89% (CI 84-92) and 94% (92-96) respectively. The use of the questionnaire added little diagnostic value., Conclusions: In a population with a high prevalence of lactase-persistent alleles, we advise to exclude HBT from the diagnostic route for suspected lactose intolerance, and replace it with genotyping of lactase-persistent alleles.

Objectives: To describe all iron deficiency anaemia (IDA)-related causes during follow-up of patients newly diagnosed with IDA and to assess whether a delayed colorectal cancer (CRC) diagnosis influences survival., Design and Setting: Retrospective cohort study of patients from general practices in the Dordrecht area, the Netherlands., Participants: Men and women aged ≥50 years with a new diagnosis of IDA (ie, no anaemia 2 years previously)., Method: From February 2007 to February 2018, all relevant data were collected from the files of the referral hospital. Early IDA-related cause was defined as established within 18 weeks after IDA diagnosis. Cox proportional-hazards regression was used to analyse survival of patients with CRC diagnosis., Results: 587 patients with IDA were included with a median follow-up of 4.6 years. Early and late IDA-related causes could be established in 32% and 8% of patients, respectively. Early and late CRC was found in 8% and 2% of patients, respectively, and were located mainly right sided. After adjustment for age, gender and TNM classification, mortality risk was lower in patients with IDA with early CRC diagnosis, but not significantly (HR 0.30, 95% CI 0.09 to 1.02)., Conclusion: Even with extended follow-up, the cause of IDA remains elusive in the majority of patients with IDA in general practice. However, patients with IDA are at increased risk for in particular right-sided CRC and a late diagnosis of CRC appears to have a detrimental effect on survival in patients with IDA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Paroxysmal nocturnal hemoglobinuria (PNH), a rare benign hematological disorder, presents with a wide variety of clinical symptoms. A direct Coombs-negative hemolytic anemia combined with an increased LDH = Lactate dehydrogenase level are signs to test for PNH. Follow-up does not need any microscopic review's only flow cytometric PNH clone size.

Background: Criteria assessing biochemical response to ursodeoxycholic acid (UDCA) are established risk stratification tools in primary biliary cholangitis (PBC). We aimed to evaluate to what extent liver tests influenced patient management during a three decade period, and whether this changed over time., Methods: 851 Dutch PBC patients diagnosed between 1988 and 2012 were reviewed to assess patient management in relation to liver test results during UDCA treatment. To do so, biochemical response at one year was analysed retrospectively according to Paris-1 criteria., Results: Response was assessable for 687/851 (81%) patients; 157/687 non-responders. During a follow-up of 8.8 years (IQR 4.8-13.9), 141 died and 30 underwent liver transplantation. Transplant-free survival of non-responders (60%) was significantly worse compared with responders (87%) (p < 0.0001). Management was modified in 46/157 (29%) non-responders. The most frequent change observed, noted in 26/46 patients, was an increase in UDCA dosage. Subsequently, 9/26 (35%) non-responders became responders within the next two years. Steroid treatment was started in one patient; 19 patients were referred to a tertiary centre. No trend towards more frequent changes in management over time was observed (p = 0.10)., Conclusion: Changes in medical management occurred in a minority of non-responders. This can largely be explained by the lack of accepted response criteria and of established second-line treatments for PBC. Nevertheless, the observation that response-guided management did not increase over time suggests that awareness of the concept of biochemical response requires further attention,particularly since new treatment options for PBC will soon become available.

In two female patients of 62 and 81 years old, a metabolic encephalopathy was diagnosed which was ascribed to the use of valproic acid. Both had elevated ammonia levels in arterial blood, without hepatic failure. The first patient eventually became comatose and required artificial ventilation. After discontinuation of the valproic acid and with the aid of supportive measures, both women recovered. In patients with an impaired level of consciousness who are using valproic acid, a metabolic encephalopathy caused by this drug should be considered. Elevated levels of ammonia can be found but are not mandatory. Discontinuation of valproic acid will lead to recovery of consciousness.

A 26-year-old man was treated with piperacillin-tazobactam because of suspected cholangitis and a 77-year-old man was given ciprofloxacin because of an infected knee-prosthesis. They both developed symptoms of an interstitial nephritis: malaise and laboratory deviations. The symptoms disappeared after the antibiotics were withdrawn. No other explanation for the renal function disorders could be found in either patient. Piperacillin-tazobactam and ciprofloxacin are considered to be relatively safe and serious adverse effects are rare. Acute interstitial nephritis may, however, occur and its clinical presentation may not be very informative. Withdrawal of the culprit usually leads to recovery.

Osteoporosis is not a significant problem in the majority of patients with primary biliary cirrhosis (PBC). However, substantial bone-related morbidity may occur in patients with advanced disease, in particular after liver transplantation. The cause of osteoporosis in PBC is multifactorial, and pathophysiological mechanisms specifically related to PBC have not been defined. In general, the principles of management followed in post-menopausal osteoporosis also apply in chronic liver disease. Dual energy X-ray absorptiometry is currently the method of choice for monitoring bone mineral density. Avoidance of conditions with potential negative effects on bone mass, and maintaining adequate serum vitamin D levels and calcium intake form the cornerstone in preventing osteoporosis. Bisphosphonates are the most logical choice when specific medical treatment of PBC-associated osteoporosis is indicated, as well as for preventing bone loss during glucocorticoid treatment and after liver transplantation. Recent studies suggest that active vitamin D analogues are effective alternatives in the post-transplant setting., (Copyright 2000 Harcourt Publishers Ltd.)

Background/aims: Ursodeoxycholic acid has been reported to be of potential benefit for primary sclerosing cholangitis but little is known about the long-term biochemical, histological and radiological efficacy or the optimum frequency of ursodeoxycholic acid administration., Methods: A 2-year multicentre randomised controlled trial was initiated to assess the effects of ursodeoxycholic acid (10 mg kg(-1).d(-1), given in either single or multiple daily doses, on symptoms, serum liver tests, cholangiographic and histological findings and the occurrence of treatment failure. Liver biopsies were taken and endoscopic retrograde cholangiography was performed at entry and after 2 years; follow-up examinations were at 3-month intervals. Treatment failure was defined as death, liver transplantation, 4-fold increase in serum bilirubin, variceal bleeding, de novo ascites or cholangitis. Actuarial survival was compared with predicted survival using the revised Mayo natural history model for primary sclerosing cholangitis., Results: Forty-eight patients were enrolled. In one case, ursodeoxycholic acid had to be discontinued because of gastro-intestinal complaints. No other side-effects were observed. After 2 years of follow-up, treatment was not associated with a beneficial effect on either symptoms or liver histology. Serum liver tests (alkaline phosphatase, y-glutamyl transferase, aspartate aminotransferase) improved significantly in both groups, while serum bilirubin (which was near normal at entry) and IgG remained stable. No major changes in radiographic bile duct appearance seemed to be present. After 2 years, actuarial survival was 91% (95 CI 83%-99%), which is comparable to the predicted 97% survival rate. Treatment failure occurred in 15% of cases. No significant differences in any of the study endpoints (symptoms, serum liver tests, cholangiographic findings, histology, disease progression) were found between the two groups., Conclusions: Ursodeoxycholic acid is well tolerated in primary sclerosing cholangitis. Significant effects on biochemical parameters were found and symptoms, bilirubin and histology did not deteriorate. No advantage of a multiple daily dose over a single dose was observed.

Pruritus is a frequent, distressing and sometimes disabling symptom of liver and biliary tract disorders. Results of treatment are sometimes disappointing and the pathophysiology is still largely unknown. It was recently discovered that endogenous opioids contribute to the perception of itching and that opiate receptor antagonists can reduce the overstimulation of these receptors and thereby attenuate the itching. A stepwise treatment strategy focusing successively on ion exchange resins, rifampicin and opiate receptor antagonists leads to effective alleviation of itching in most patients.

Background & Aims: The efficacy of currently available therapeutic agents for cholestatic pruritus is often disappointing. The aim of this study was to assess the antipruritic effect of naltrexone, an oral opiate receptor antagonist., Methods: Sixteen patients with pruritus of chronic cholestasis were randomized to receive naltrexone (4-week course of 50 mg naltrexone daily) or placebo. Pruritus, quality of sleep, fatigue (using visual analogue scales), side effects, and liver function were assessed every 2 weeks. Serum naltrexone and 6 beta-naltrexol concentrations in all patients and 5 healthy controls were measured during the first day of naltrexone treatment., Results: Mean changes with respect to baseline were significantly different, in favor of the naltrexone group, for daytime itching (-54% vs. 8%; P < 0.001) and nighttime itching (-44% vs. 7%, P = 0.003). In 4 naltrexone-treated patients, side effects (transient in 3 cases) consistent with an opiate withdrawal syndrome were noted. No deterioration of the underlying disease was observed. Naltrexone and 6 beta-naltrexol levels did not differ between patients and controls, and there was no significant association with treatment response., Conclusions: For patients with cholestatic liver disease and itching, refractory to regular antipruritic therapy, oral naltrexone may be an effective and well-tolerated alternative.

Background: Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance., Aim: The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated., Methods: Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg-1 day-1) in a single dose at bed time (n = 13) or in three divided gifts with meals (n = 14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between., Results: Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean +/- SEM) was 40.1 +/- 2.4 in the single dose group vs 40.8 +/- 2.8 in the multiple dose group (p = NS) and was positively correlated with biochemical improvement (AP: r = 0.47, p = 0.02; GGT: r = 0.58, p = 0.002; ASAT: r = 0.67, p = 0.002; ALAT: r = 0.52, p = 0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens., Conclusion: Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.

Background & Aims: Seventy percent of patients with primary sclerosing cholangitis (PSC) have concomitant ulcerative colitis. Smoking and previous appendectomy may protect against ulcerative colitis. The aim of this study was to examine these factors in patients with PSC., Methods: Fifty-nine patients with PSC, 130 patients with ulcerative colitis and normal liver biochemistry, and 197 control subjects were interviewed about smoking behavior and history of appendectomy., Results: There were less current smokers in the PSC and ulcerative colitis groups than in the control group (19%, 12%, and 38%, respectively). The resulting odds ratio for current smoking was 0.37 (95% confidence interval, (0.18-0.76) in the PSC group and 0.23 (95% confidence interval, 0.13-0.41) in the ulcerative colitis group. Percentage of persons who ever smoked was also significantly less in the PSC group (41% vs. 56% in the control group). Frequency of previous appendectomy in the PSC and ulcerative colitis groups was not significantly different from that of controls (19%, 9%, and 14%, respectively)., Conclusions: Smoking but not previous appendectomy is associated with decreased risk of PSC.