Hepatitis E: a largely underestimated, emerging threat.

Hepatitis E virus has two distinct clinical and epidemiological patterns based on the varying genotypes. Genotypes 3 and 4 cause widespread, sporadic infection in high-income countries and are emerging as the most common type of viral hepatitis in much of Europe. These infections carry significant morbidity and mortality in the growing numbers of immunosuppressed patients or in patients with established liver disease. Furthermore the growing extra-hepatic associations of the virus, including neurological and kidney injury, suggest that it may have been misnamed as a 'hepatitis' virus. This review explores current understanding of the epidemiology, virology and clinical presentations of hepatitis E infection and identifies vulnerable patient groups, who are at serious risk from infection. Guidance is offered regarding the diagnosis, treatment and prevention of this growing public health hazard.

The role of hepatitis E virus testing in drug-induced liver injury.

BACKGROUND: Locally acquired hepatitis E is an emerging infection in developed countries and can be misdiagnosed as drug-induced liver injury. AIM: To study the role of hepatitis E virus (HEV) testing in drug-induced liver injury. METHODS: Retrospective review of a cohort of patients with suspected drug-induced liver injury (n = 69) and hepatitis E (n = 45). The standard criteria for drug-induced liver injury were applied. Patients with suspected drug-induced liver injury who met these criteria were retrospectively tested for HEV on stored sera taken at the time of presentation. The two cohorts were compared to determine variables that predicted either of the diagnoses. RESULTS: Forty-seven out of 69 patients had criterion-referenced drug-induced liver injury. 22/47 were HEV negative and thus had confirmed drug-induced liver injury. 19/47 were not tested for HEV, as there was no sera available from the time of presentation. 6/47 were HEV positive and thus did not have drug-induced liver injury, but had hepatitis E infection. Compared to patients with confirmed drug-induced liver injury, patients with hepatitis E were significantly more likely to be male (OR 3.09, CI 1.05-9.08); less likely to present in November and December (0.03, CI 0.01-0.52); have lower serum bilirubin (P = 0.015); and higher serum alanine aminotransferase (P < 0.001) and alanine aminotransferase/alkaline phosphatase ratio (P < 0.001). CONCLUSION: The diagnosis of drug-induced liver injury is not secure without testing for HEV.

Jaundice as a presentation of heart failure.

On rare occasions the first manifestation of heart disease is jaundice, caused by passive congestion of the liver or acute ischaemic hepatitis. We looked for this presentation retrospectively in 661 patients referred over fifty-six months to a 'jaundice hotline' (rapid access) service. The protocol included a full clinical history, examination and abdominal ultrasound. Those with no evidence of biliary obstruction had a non-invasive liver screen for parenchymal liver disease and those with suspected heart disease had an electrocardiogram, chest X-ray and echocardiogram. 8 patients (1.2%), bilirubin 31-79 micromol/L, mean 46 micromol/L, had a primary cardiac cause for their jaundice. All had dyspnoea, an increased cardiothoracic ratio on chest X-ray and an abnormal electrocardiogram. The jugular venous pressure was raised in the 3 in whom it was recorded. In 6 patients the jaundice was attributed to hepatic congestion and in 2 to ischaemic hepatitis. All patients had severe cardiac dysfunction. Jaundice due to heart disease tends to be mild, and a key feature is breathlessness. The most common mechanism is hepatic venous congestion; ischaemic hepatitis is suggested by a high aminotransferase.

Clinical economics review: the management of gallstone disease.

Surgical techniques have an inherent advantage over oral bile therapy and extracorporeal shock-wave lithotripsy because they remove both gallstones and the gallbladder, thus preventing stone recurrence. Moreover, surgical techniques are more effective for patients with symptomatic gallstones compared with non-surgical techniques. Laparoscopic surgery is the best therapy from the clinical economic viewpoint being cost-minimal, effective and beneficial compared with other surgical and medical techniques. However, non-surgical techniques may be preferable in selected patients at high risk from general anaesthesia such as the elderly and those with significant cardiopulmonary disease.

Octreotide increases the proportions of arachidonic acid-rich phospholipids in gall-bladder bile.

BACKGROUND AND AIMS: Octreotide treatment of acromegalic patients induces cholesterol gallstone formation, in part by impairing cholecystokinin release and gall-bladder contraction. However, there are few data on the effect of octreotide on biliary arachidonic acid-rich phospholipids or mucin glycoprotein, factors which also influence cholesterol gallstone formation. METHODS: In acromegalic patients studied before and during 3 months of octreotide treatment, we measured mucin glycoprotein concentrations and the molecular species of phosphatidylcholine, and related the results to the cholesterol saturation and percentage of deoxycholic acid in gall-bladder bile. RESULTS: The relative proportions of the major arachidonic acid-rich phosphatidylcholine species, PC 16:0-20:4 and PC 18:0-20:4, increased significantly during octreotide treatment. These changes were associated with a rise in the cholesterol saturation index and a non-significant twofold increase in mucin glycoprotein concentration. There were significant correlations between PC 16:0-20:4 and the cholesterol saturation index, percentage of vesicular cholesterol and percentage of deoxycholic acid in gall-bladder bile. CONCLUSIONS: In acromegalic patients, octreotide increases the proportions of arachidonic acid-rich phospholipids, with associated rises in: (a) the cholesterol saturation index and percentage of vesicular cholesterol, and (b) the percentage of deoxycholic acid in gall-bladder bile-changes similar to those found in patients with cholesterol-rich gall-bladder stones.

Gallstones during octreotide therapy.

Gallbladder stones (GBS) are found in up to 50% of patients receiving octreotide, but the reported prevalence of cholecystolithiasis in patients treated with octreotide is variable and little is known about gallstone incidence, composition, pathogenetic mechanisms, dissolvability, and primary prevention. Octreotide treatment apart, in industrialised societies most GBS are mixed in composition, cholesterol-rich (arbitrarily greater than 70% cholesterol by weight), radiolucent (70%), and, given a patent cystic duct (70%), dissolvable in bile rendered unsaturated in cholesterol by oral ursodeoxycholic (UDCA) +/- chenodeoxycholic (CDCA) acid treatment. They form when (1) GB bile becomes supersaturated with cholesterol (as the molar ratio of cholesterol to phospholipids in biliary vesicles approaches 1:1, the vesicles become unstable); (2) there is an imbalance between pro- and anti-nucleating factors, which favors cholesterol crystal precipitation; and (3) there is stasis within the GB as a result of altered motor function and/or excess mucus that traps the crystals. These changes may be associated with altered (4) biliary bile acid composition (more DCA and less CDCA than normal), and/or (5) phospholipid fatty acid composition (arachidonyl-rich lecithin acting as a substrate for mucosal prostaglandin synthesis which, in turn, may influence both gallbladder motility, and mucus glycoprotein synthesis and secretion). During octreotide treatment, meal-stimulated cholecystokinin (CCK) release is impaired leading to GB hypomotility, but little is known about the effects of octreotide on biliary cholesterol saturation, crystal nucleation time, mucus glycoprotein concentration, bile acid or phospholipid fatty acid composition. Most, but not all, reports suggest that the prevalence of GBS in octreotide-treated patients is considerably greater than that in age-, sex-, and weight-matched controls, but proof (by pre-treatment and on-treatment ultrasound) that the GBS were absent before, but developed during, therapy is not always available. Furthermore, there are few data on analysis of GBS composition in patients developing stones during treatment, although initial reports suggest that octreotide-associated GBS are also radiolucent, cholesterol-rich, and dissolve with oral bile acid treatment. Maximum GBS attenuation values, measured in Hounsfield Units (HU) by localized computerized tomography scanning of the GB, predict stone composition and dissolvability: GBS with scores of less than 100 HU are cholesterol-rich and dissolve well with oral bile acid treatment. However, preliminary results in 11 acromegalic patients treated with 200 to 600 micrograms octreotide/d for 29 to 68 months show that the HU scores range from 23 to 490 (mean +/- SEM, 116 +/- 41), suggesting that at least four of these 11 patients have non-cholesterol stones.(ABSTRACT TRUNCATED AT 400 WORDS)

Regional bone mineral density after orthotopic liver transplantation.

OBJECTIVES: Although there is a fall in lumbar spine bone mineral density (BMD) after liver transplantation, little is known about femoral neck or total body BMD. Therefore we determined: (a) the proportion of patients with preexisting hepatic osteopenia before transplantation and (b) the effects of transplantation on global and regional BMD. DESIGN: Retrospective analysis of BMD measurements of patients before and up to 2 years after liver transplantation. METHODS: BMD was assessed by dual energy X-ray absorptiometry in 56 patients, before and at regular intervals after liver transplantation, for up to 24 months, to measure total body, lumbar spine (L2-L4) and femoral neck BMDs. RESULTS: Pre-transplant, 23% of patients had osteoporosis (a negative Z score > 2). Paired data before and after transplantation revealed no change in total body BMD. However, there was a fall in lumbar spine BMD (1.04+/-0.03 to 1.02+/-0.03 g/cm2; P < 0.04) at 1 month after transplantation. The reduction in lumbar spine BMD was seen up to 12 months, BMD at 18-24 months being similar to pre-transplant values. Femoral neck BMD also fell (0.96+/-0.06 to 0.83+/-0.04 g/cm2; P < 0.03), but only after 6-9 months, thereafter remaining below pre-transplant values until the end of the follow-up period. CONCLUSIONS: Although osteopenia is common in patients with liver disease, total bone density does not fall after transplantation. Nonetheless regional lumbar spine and femoral neck bone density does fall after transplantation with a risk period for femoral neck fracture which may extend for up to 2 years.

The usefulness of faecal haemoglobin, albumin and alpha-1-antitrypsin in the detection of gastrointestinal bleeding.

A pilot study was undertaken to find out whether faecal haemoglobin, albumin and alpha-1-antitrypsin from patients with gastrointestinal disorders could distinguish active bleeders from non-active bleeders and healthy volunteers. Alpha-1-antitrypsin is not as readily degraded by endogenous and bacterial breakdown as haemoglobin and albumin and consequently could be a better marker for occult bleeding.

Ultrasound-guided percutaneous fine needle puncture of the gallbladder for studies of bile composition.

Ultrasound-guided percutaneous fine needle puncture of the gallbladder (PFNP-GB) is invaluable for diagnostic and research purposes, but there are few reports about its safety. We therefore describe the efficacy and side-effects of 43 consecutive gallbladder punctures in 39 patients. PFNP-GB was successful in 40/43 (93%), but failed in three. Bile was completely aspirated in 28 of the 40 (70%) successful procedures. After 36 of the 43 punctures (84%), the patients remained asymptomatic, although on seven occasions (16%) the patients complained of right upper quadrant pain 0.5-12 h after the procedure. In six of these, the pain resolved in 2-24 h, although one developed a leucocytosis (22 x 10(9) 1(-1)). The seventh patient developed pyrexia and signs of generalized peritonism, which settled with conservative therapy. Ultrasonographic abnormalities of the gallbladder wall were seen in five of the seven symptomatic patients, consisting of: (i) an increase in the thickness of the gallbladder wall (n = 5) from less than 2 mm to 4-14 mm; (ii) peri-cholecystic collections (n = 2) measuring 5 and 11 mm in diameter; (iii) an intraluminal mucosal flap (n = 1); (iv) an intraluminal echogenic layer (n = 1); and (v) a 12 cm intraabdominal haematoma in the patient with generalized peritonism. Predictors of pain were: (i) the number of needle "passes" (3.7 +/- 0.8, range 2-8, in patients with pain vs 2.0 +/- 0.2, range 1-6, in pain-free patients, p < 0.02); (ii) the absence of gallbladder stones (p < 0.03); and (iii) incomplete aspiration of bile from the gallbladder (p < 0.02). PFNP-GB is an effective way of sampling fresh gallbladder bile, although there is a 16% risk of inducing pain and/or ultrasonographic changes in the gallbladder.

Role of intestinal transit in the pathogenesis of gallbladder stones.

Increasing evidence implicates prolonged intestinal transit (slow transit constipation) in the pathogenesis of conventional gallbladder stones (GBS), and that of gallstones induced by long term octreotide (OT) treatment. Both groups of GBS patients have multiple abnormalities in the lipid composition and physical chemistry of their gallbladder bile-associated with, and possibly due to, an increased proportion of deoxycholic acid (DCA) (percentage of total bile acids). In turn, this increase in the percentage of DCA seems to be a consequence of prolonged colonic transit. Thus, in acromegalic patients OT treatment significantly prolongs large bowel transit time (LBTT) and leads to an associated increase of the percentage of DCA in fasting serum (and, by implication, in gallbladder bile). LBTT is linearly related to the percentage of DCA in fasting serum and correlates significantly with DCA input (into the enterohepatic circulation) and DCA pool size. However, these adverse effects of OT can be overcome by the concomitant use of the prokinetic drug cisapride, which normalizes LBTT and prevents the rise in the percentage of serum DCA. Therefore, in OT-treated patients and other groups at high risk of developing stones, it may be possible to prevent GBS formation with the use of intestinal prokinetic drugs.

Risk factors for loss of lean body mass after liver transplantation.

BACKGROUND: After liver transplantation there is a fall in lean body mass. AIMS: To determine the risk factors for this fall in lean body mass using univariate and subgroup analyses. PATIENTS AND METHODS: Dual energy X-ray absorptiometry was performed in 36 patients (12 with Child-Pugh Class A, 20 with Class B and 4 with Class C disease) before and up to 24 months after liver transplantation. Univariate and sub-group comparative analyses were performed to assess possible risk factors for the fall in lean body mass post-transplantation. RESULTS: The pre-transplantation serum albumin inversely correlated with the fall lean body mass at 1 month (r = 0.55; p < 0.009) and at 6-9 months (r = 0.51; p < 0.05) post-transplantation. A positive correlation between the fall in lean body mass and: (i) cumulative dose of steroids administered at 2-5 months (r = 0.57; p < 0.05) and (ii) length of hospital stay after transplantation (r = 0.52; p < 0.05) were also observed. Neither the severity or presence of cholestatic liver disease pre-transplant, nor acute cellular rejection post-transplant were risk factors for a fall in lean mass. DISCUSSION: A hypercatabolic state post-transplant (represented by low albumin pre-transplantation), immobility, lack of exercise and steroid induced catabolism of muscle may cause the observed fall in lean mass after liver transplantation. Earlier transplantation of patients with better nutritional status and the use of low dose steroid immunosuppressive regimens may prevent the observed fall in lean body mass after transplantation.

Case report: Thromboembolic and septic complications of migrated cyanoacrylate injected for bleeding gastric varices.

Endoscopic injection of N-butyl-2-cyanoacrylate combined with radio-opaque lipiodol is widely used to achieve haemostasis in bleeding gastric varices. We present a case of migration of injected cyanoacrylate, thrombus formation and subsequent septic embolisation.

Informed consent for upper gastrointestinal endoscopy.

Informed consent for upper gastrointestinal endoscopy requires that the patient understands the nature of, and reason for, the proposed procedure, and that he or she is given adequate time to deliberate and ask questions. In a prospective study, 200 outpatients completed questionnaires immediately before, and one day after, endoscopy, which assessed satisfaction with information provided by: (a) the referring doctor, (b) a standard information sheet sent out two to four weeks before endoscopy, and (c) the endoscopist. The first 100 patients were asked to read and sign a standard consent form immediately before the endoscopy. In the second 100 patients, a new endoscopy consent form that was simpler and easier to read than the standard form was sent out with the information sheet. Patients were directed to sign the new consent form before arriving at the unit only if they had no further questions. Overall, the indication for the endoscopy, and how it would be done, were explained clearly by the referring doctor in 79% and 68% of cases, respectively. Of the first 100 patients, only 54% had read the standard consent form in the endoscopy unit before signing it. In contrast, of the second 100 patients, the new form sent with the information sheet was read by 95%, and signed by 88% before coming to the unit. Furthermore, 84% found the new form easier to read and understand than the standard form. In our unit, roughly one quarter of patients referred for endoscopy are not adequately informed about the procedure. In contrast with the standard consent form, a simple endoscopy consent form sent out with the information sheet is preferred by most patients, and safeguards against patients undergoing endoscopy without informed consent.

The predictive value of transabdominal ultrasonography in the diagnosis of biliary tract complications after orthotopic liver transplantation.

BACKGROUND: In transplant recipients with choledococholedocostomy (CDCD), endoscopic retrograde cholangiopancreatography (ERCP) remains the gold standard for the diagnosis of biliary leak or strictures. Transabdominal ultrasonography (TAUS) has been used to screen patients with suspected biliary tract complications, prior to ERCP, although the clinical effectiveness remains unclear. AIMS: To assess the predictive value of TAUS in the diagnosis of biliary tract complications after liver transplantation. METHODS: 144 consecutive ERCP and corresponding ultrasonogram reports performed over a 67 month period in 79 patients after liver transplantation were analysed retrospectively. RESULTS: 77 ERCP patients had both a TAUS and a successful ERCP. Biliary tract abnormalities were found at TAUS in 49 (64%) of the 77 patients. TAUS had an overall sensitivity of 77%, and specificity of 67%, with positive and negative predictive values of 26% and 95% respectively, when adjusted for the prevalence rate of biliary complications after liver transplantation of 12.8% in our population. The use of bile duct calibre as sole criterion for an abnormal scan improved the specificity (76%) and with a corresponding reduction in sensitivity (66%). The risk of false negative TAUS was similar in both the early and late post-transplant periods. CONCLUSIONS: A normal TAUS after liver transplantation with CDCD makes the presence of biliary complications unlikely.

Endoscopy: throat spray or sedation?

Anxious patients tolerate endoscopy poorly. It was proposed that such patients might derive most benefit from sedation, while most non-anxious patients would prefer endoscopy with lignocaine throat spray alone. In a prospective study, 200 outpatients underwent diagnostic endoscopy after receiving one of two detailed information sheets which offered them either the choice between spray or sedation (n = 100) or the same choice but encouraged those who were anxious about endoscopy to choose sedation (n = 100). When given an informed choice, most non-anxious patients prefer not to be sedated most non-anxious patients prefer not to be sedated during diagnostic endoscopy. If patients who are anxious about the procedure are advised to choose sedation, those who nevertheless opt for topical throat spray alone find the endoscopy just as comfortable. If the endoscopy were to be repeated, 73% of the spray group and 77% of the sedation group would make the same choice again. Of 33 patients who chose spray but had been given only sedation for a previous endoscopy, 26 (79%) would choose spray again for a future endoscopy. The choice of spray or sedation should reflect the patient's view as well as that of the endoscopist.

Gallbladder stone recurrence after medical treatment. Do gallstones recur true to type?

Medical treatments that dissolve or remove gallbladder stones but leave the gallbladder in situ have the disadvantage of gallstone recurrence. Little is known about the composition of recurrent stones or whether they recur true to type. In 21 patients with recurrent stones detected 5-74 months (mean +/- SEM, 26 +/- 4 months) after being rendered stone-free with dissolution therapy (N = 15) or percutaneous cholecystolithotomy (N = 6), we compared pretreatment and postrecurrence gallstone number, maximum gallstone attenuation scores measured by computed tomography (CT) and, in 13, the dissolvability of the recurrent stones with oral bile acids +/- extracorporeal shock-wave lithotripsy. Before treatment, five patients had solitary and 16 had multiple stones but on recurrence, the gallstones differed in number from the primary stones in 10 of the 21 patients. As a result of patient selection, before dissolution, the primary stones were all radiolucent with maximum CT scores of < 100 Hounsfield units (HU) (mean 45, range 10-84 HU). On recurrence, the stones were again CT-lucent in 13 of the 15 patients but were CT-dense in the remaining two (118 and 176 HU). Initially, all six patients treated by percutaneous cholecystolithotomy had radio-opaque stones, with a mean CT score of 459 (range 100-969) HU. However, on recurrence, only one had calcified stones (HU 140); the remaining five had CT-lucent stones (16-98 HU, P < 0.05). Of the 13 patients whose recurrent, plain x-ray-lucent and CT-lucent stones were treated with oral bile acids +/- lithotripsy, 12 (92%) showed evidence of gallstone dissolution. We conclude that gallbladder stones do not recur true to type in up to two thirds of patients. However, irrespective of original gallstone composition, recurrent stones are usually radio- and CT-lucent, presumed cholesterol-rich, and therefore potentially dissolvable with oral bile acids.

Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile.

Little is known about the effects of biliary deoxycholic acid on the partitioning of biliary cholesterol between vesicles and micelles and on the rate of nucleation of cholesterol microcrystals, key steps in gallstone formation. Therefore, 43 samples of fresh gallbladder bile were obtained from a heterogeneous group of patients with and without stones. Univariate and multivariate analyses were then applied to determine the inter-relationships between biliary cholesterol saturation, total lipid concentration, and bile acid species and (1) the distribution of biliary cholesterol between vesicles and micelles and (2) the cholesterol microcrystal nucleation time. The percentage of deoxycholic acid in bile was shown to be linearly related to the cholesterol saturation index (r = .54; P < .001), the vesicular cholesterol:phospholipid molar ratio (r = .53; P < .001), and the molar concentration of cholesterol in the vesicles (r = .59; P < .001). The mean proportion of biliary deoxycholic acid conjugates was also greater in patients with rapid nucleation times (23.4 +/- SEM 1.1%) than in those with slow nucleation times (17.3 +/- 1.9%; P < .05). As total bile lipid concentration increased, the proportion of total biliary cholesterol in vesicles decreased (r = .53; P < .001), whereas the molar concentration of vesicular cholesterol increased (r = .42, P < .01). The cholesterol saturation indices, total bile lipid concentration, and proportion of biliary deoxycholate were independent determinants of the molar concentration of cholesterol in vesicles. We conclude that relative increases in the percentage of deoxycholic acid and in bile lipid concentration, favor the partitioning of cholesterol into vesicles. In turn, this leads to an increase in the vesicular cholesterol:phospholipid molar ratio and thus to a decrease in the cholesterol microcrystal nucleation time.