Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation.

We report here a young female who underwent a successful deceased donor liver transplant for hepatic vein thrombosis. Five years after transplantation she developed postpartum atypical hemolytic uremic syndrome (aHUS). She did not recover renal function. Mutation screening of complement genes in her DNA did not show any abnormality. Mutation screening of DNA available from the donor showed a nonsense CFH mutation leading to factor H deficiency. Genotyping of the patient showed that she was homozygous for an aHUS CD46 at-risk haplotype. In this individual, the development of aHUS has been facilitated by the combination of a trigger (pregnancy), an acquired rare genetic variant (CFH mutation) and a common susceptibility factor (CD46 haplotype).

Current concepts in the assessment and treatment of hepatic encephalopathy.

Hepatic encephalopathy (HE) is defined as a metabolically induced, potentially reversible, functional disturbance of the brain that may occur in acute or chronic liver disease. Standardized nomenclature has been proposed but a standardized approach to the treatment, particularly of persistent, episodic and recurrent encephalopathy associated with liver cirrhosis has not been proposed. This review focuses on the pathogenesis and treatment of HE in patients with cirrhosis. The pathogenesis and treatment of hepatic encephalopathy in fulminant hepatic failure is quite different and is reviewed elsewhere.

Adjuvant therapy used in conjunction with combination therapy for chronic hepatitis C improves sustained virus response rates in genotype 1 patients.

Combination treatment with pegylated interferon (Peg-IFN) and ribavirin remains the gold standard in the treatment of chronic hepatitis C. This therapy is limited by many side-effects including anaemia, neutropenia and reduced quality of life. The use of adjuvant agents to reduce the frequency of dose reductions because of haematological side-effects has been proven to be effective but there are few reports of what effect the use of these adjuvant therapies is having on sustained virological response (SVR). The aim of the study was to assess the clinical impact on sustained virological response of adjuvant therapies during combination therapy with Peg-IFN and ribavirin for chronic hepatitis C. A total of 132 patients, 96 males, were included in the study. The overall SVR was 66.7%, with 50% of genotype 1/4/6 (n = 27/54) patients achieving SVR and 78.2% of genotypes 2/3. The overall SVR of the treatment naïve patients (83/121) was 68.6%. Fifty-one of these patients were genotype 1 with 49.0% (25/51) of this group achieving SVR. The genotype 2/3 group of treatment naïve patients reached an SVR of 82.9% (58/70). Adjuvant therapy was used in 57 patients (43.8%). With the use of supportive adjuvant therapy, we achieved an overall SVR of 66.7% and in treatment naïve patients 68.6%. In genotype 1 patients, SVR rates of up to 46% have been reported in previous studies without the use of erythropoietin and granulocyte colony stimulating factor. We have demonstrated the SVR for genotype 1 can be improved to 50% overall.

Early experience with chronic hepatitis C in Northern Ireland: epidemiology and response to monotherapy.

UNLABELLED: Chronic hepatitis C virus (HCV) infection has become a major health problem affecting an estimated 170 million people worldwide. The epidemiology of HCV and its response to treatment in Northern Ireland has not been described before. Our aims were to determine the epidemiology, histological stage, suitability for treatment and response to treatment in patients with hepatitis C presenting to one clinic in Northern Ireland. All patients were prospectively recruited with hepatitis C attending the Liver Clinic, Royal Victoria Hospital during the period December 1992 to June 1997. Sixty patients (33 male, mean age 44 years, range 19-84 years) who tested anti-HCV antibody positive were identified. The predominant genotypes were 1b (33%), 3a (28%) and 1a (26%). Most patients (78%) were asymptomatic at the time of detection and only four (7%) gave a history of jaundice. The most common modes of transmission were i.v. drug use in 30 (50%) and blood products in 20 (33%) patients. Forty-eight (86%) of the 56 patients tested were PCR positive for HCV RNA. Fifty-one patients (85%) underwent liver biopsy of whom 13 had cirrhosis (22% of original group). Twenty-nine patients were suitable for treatment, but three declined treatment and only 26 (43%) started interferon-alpha. During treatment 17 (65%) patients became PCR negative and eight (31%) remained PCR negative 12 months after completion of therapy. Liver histology was assessed before and after interferon treatment in 17 patients and showed no change in total necroinflammatory scores (p = 0.1) or staging of architectural change (p = 0.55). CONCLUSIONS: The epidemiology and response to therapy of HCV in Northern Ireland appear comparable to elsewhere in the UK. Only a minority of anti-HCV positive non-haemophiliac patients progress to have interferon therapy suggesting that the cost of treating chronic HCV may not be as great as initially thought.

An audit of metal stent palliation for malignant biliary obstruction.

BACKGROUND AND AIMS: Endoscopic stent insertion is the optimum method of palliation for malignant biliary obstruction. Metal stents have several advantages over the polyethylene alternatives, but are significantly more expensive. It has been reported that patients need to survive beyond 6 months to make metal stents more cost-effective. The aim of this study was to audit the performance of expanding metal biliary stents in our endoscopy unit, and to identify factors that might help with patient selection. METHODS: The records of all patients who were selected for endoscopic metal stent insertion at the Royal Perth Hospital for malignant biliary obstruction between September 1994 and November 1998 were reviewed. RESULTS: Thirty-two patients (16 males, mean age 71 years (range 34-88 years) were identified and followed up for a mean 201 days (range 3-810 days). Fifteen (47%) had cholangiocarcinoma, 13 (41%) had pancreatic cancer, and four had metastatic disease as the cause of obstruction. Mortality rates after metal stent insertion were 16, 41 and 55% at 30, 90 and 180 days, respectively. In total, 24 (75%) patients died during the follow-up period. Eleven (34%) stents became obstructed during follow up with a median time to occlusion of 125 days (range 44-729 days). Patients with cholangiocarcinoma had significantly longer survival than pancreatic cancer cases (median 286 vs 58 days, P = 0.04). No other factors were found to correlate with the survival or stent complications. CONCLUSIONS: Less than half of this mixed cohort survived beyond 6 months. Metal stent palliation of malignant biliary obstruction should probably be targeted at those with cholangiocarcinoma, as these patients tend to survive longer.

Microsatellite analysis provides evidence of neoplastic transformation in long-segment, but not in short-segment, Barrett's oesophagus.

It has been suggested that the high prevalence of short segments of specialised intestinal metaplasia (SIM) at the gastro-oesophageal junction is associated with the rising incidence of oesophageal adenocarcinoma. Our aims were to document the prevalence of short segments of SIM at the gastro-oesophageal junction in patients attending for routine endoscopy and to determine if there was molecular evidence of neoplastic transformation in those with SIM. Patients (n = 101) were recruited from randomly selected upper gastro-intestinal endoscopy lists. Biopsy specimens were taken at the squamo-columnar junction to assess the prevalence of SIM. Frozen sections were assessed for molecular evidence of neoplastic transformation using microsatellite analysis. Squamo-columnar biopsies were suitable for analysis in 95 patients, of whom 20 (21%) had oesophagitis and 2 (2%) had Barrett's oesophagus (>3 cm of endoscopically apparent columnar-lined oesophagus). Twenty patients had SIM at the gastro-oesophageal junction, including 2 with Barrett's oesophagus and 18 with short segments of SIM, one of whom had an associated intramucosal adenocarcinoma detected incidentally by histology. Three of the 20 cases with SIM exhibited novel microsatellite alleles, 2 with Barrett's oesophagus and 1 with short segment SIM and an associated adenocarcinoma. The 18 patients with short segments of SIM at the gastro-oesophageal junction were significantly older than those without SIM.

The effect of treating reflux oesophagitis with omeprazole on quality of life.

BACKGROUND/AIMS: Despite the commonplace nature of heartburn and reflux oesophagitis, little is known of their impact on patients' quality of life. The aim of this study was to assess quality of life in oesophagitis patients before and after medical therapy and compare the results with a sample of the general population. METHODS: Consecutive attenders with frequent heartburn and grade II-III oesophagitis on endoscopy were recruited from one of two centres and treated with omeprazole 20 mg BD for 8-14 weeks. A symptomatic questionnaire, including the Short Form-36 (SF-36) quality of life questionnaire, was completed before and at the end of treatment. Actual quality of life scores were compared with 'expected' scores derived from a sample (n = 3015) of the Northern Ireland population. RESULTS: Seventy two (83%) of the 87 patients recruited were healed after 14 weeks therapy and 77 completed the SF-36 before and after therapy. Three quality of life parameters (bodily pain, vitality and social function) were significantly lower before treatment than the 'expected' scores. Seven of the quality of life parameters measured by the SF-36 showed a significant improvement after treatment and the eighth (mental health) just failed to achieve a significant improvement (P = 0.06). Comparison of the improvements in SF-36 scores for those who were healed with scores for those who were not healed showed no significant difference. CONCLUSIONS: Patients with grade II-III oesophagitis and frequent heartburn have lower quality of life scores for some parameters than would be expected in the general population. Treatment of the oesophagitis with omeprazole 20 mg BD causes a significant improvement not just in reflux symptoms but in several physical and mental aspects of quality of life regardless of whether or not the oesophagitis is healed.

Three- to 4.5-year prospective study of prognostic indicators in gastro-oesophageal reflux disease.

BACKGROUND: Data on the long-term natural history of gastro-oesophageal reflux disease (GORD) are sparse. This prospective study was designed to determine the clinical outcome on the basis of therapeutic requirements 3 to 4.5 years after initial diagnosis of GORD and to identify specific prognostic indicators of a poor outcome. METHODS: One hundred and one GORD patients were followed up by symptomatic questionnaire 3 to 4.5 years after diagnosis and offered repeat investigation with endoscopy and oesophageal pH monitoring if symptoms persisted. RESULTS: Seventy-seven (76%) patients responded (mean follow-up period, 39 months; range, 32-54 months); of these, 28 had grade-II or -III oesophagitis at initial endoscopy, 17 had normal endoscopy but abnormal pH monitoring, and 32 had normal investigations but frequent heartburn. At follow-up 32 (42%) were taking acid suppression therapy, and a further 15 patients started acid suppression therapy after repeat investigation indicated a need to do so, giving a total of 47 (61%) patients receiving acid suppression. The following factors predicted a need for acid suppression at follow-up: oesophagitis on initial endoscopy (P = 0.009), abnormal pH monitoring (P = 0.0005), increased age (P < 0.0005), and increased body mass index (BMI) (P = 0.001). Gender, smoking status, alcohol intake, and lower oesophageal sphincter pressure had no prognostic value. Regression analysis confirmed that age (P = 0.0007), BMI (P = 0.04), and endoscopy result (P = 0.04) all independently affected outcome. CONCLUSIONS: Most GORD patients still require acid suppression therapy 3 to 4.5 years after initial diagnosis. Age, BMI, and presence of oesophagitis at initial endoscopy all independently predict those who will require long-term acid suppression therapy.

The effect of healing oesophagitis on oesophageal motor function as determined by oesophageal scintigraphy and ambulatory oesophageal motility/pH monitoring.

BACKGROUND: Oesophagitis has been shown by standard manometry to be associated with impaired oesophageal motility, but it remains unclear if this abnormality improves with healing of oesophagitis. AIM: To determine if healing of oesophagitis improves oesophageal motility using solid bolus oesophageal transit scintigraphy and combined ambulatory oesophageal motility/pH monitoring. METHODS: Patients with grade II-III oesophagitis underwent ambulatory motility/pH monitoring (using a Konigsberg catheter with four pressure transducers at 5 cm intervals) and solid bolus scintigraphy before and after treatment with omeprazole 20 mg b.d. for 8-14 weeks. RESULTS: Three (11%) of the 28 patients failed to heal. Initial scintigraphy was abnormal in 18 (67%) of 27 patients (one refused scintigraphy). Twenty-three of the 25 healed patients had repeat studies showing no significant change in the number which were abnormal (16 (64%), P = 1.0) or the overall oesophageal transit time (P = 0.65). Due to intolerance of the technique, only 11 patients had ambulatory motility/pH performed both before and after healing, giving the study 90% power to detect a 5 mmHg increase in peristaltic amplitude. No significant improvement was seen in any motility or pH parameter after healing of oesophagitis. CONCLUSION: Analysis of oesophageal motility showed no improvement in peristaltic activity after healing of oesophagitis, suggesting that the abnormal motility is either a primary disorder or an irreversible consequence of mucosal damage.

Maintenance therapy with cisapride after healing of erosive oesophagitis: a double-blind placebo-controlled trial.

BACKGROUND: There are few data on the role of prokinetic agents as maintenance therapy in moderately severe reflux oesophagitis despite the high relapse rate of this condition after healing. AIMS: To determine whether cisapride is more effective than placebo as maintenance therapy after healing of moderate erosive oesophagitis in two respects: first, in preventing symptomatic relapse and preserving quality of life; and, second, in improving oesophageal motor function. PATIENTS: Forty-two patients whose grade II-III oesophagitis had been healed with omeprazole were randomized to receive either cisapride 20 mg nocte or placebo for 6 months. Oesophageal pH monitoring and manometry were performed before starting maintenance therapy and after 4 weeks, and symptomatic status and quality of life were assessed at weeks 0, 4, 13 and 26. RESULTS: After 4 weeks of maintenance therapy, lower oesophageal sphincter pressure improved in the cisapride group (16.4-21.9 mmHg, P = 0.01) but not in the placebo group (25.5-22.7 mmHg, P = 0.2). Oesophageal pH monitoring showed no significant changes in either group. Sixteen (76%) cisapride patients and 12 (57%) placebo patients withdrew within 4 weeks owing to symptomatic relapse (P = 0.2). After 26 weeks, 21 (100%) cisapride and 17 (81%) placebo patients had relapsed (log-rank analysis of survival time P = 0.07). Quality of life parameters deteriorated in both treatment groups to a similar degree. CONCLUSION: Maintenance therapy with cisapride 20 mg nocte improves the lower oesophageal sphincter pressure in patients whose oesophagitis has been healed with omeprazole. However, cisapride is no better than placebo in preventing symptomatic relapse or deterioration in quality of life.

Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux--the "sensitive oesophagus".

BACKGROUND: At least 10-15% of patients with reflux symptoms have a normal endoscopy and physiological levels of acid reflux on pH monitoring. Such patients with 50% or more of symptoms associated with acid reflux episodes have "a positive symptom index" (SI), and it has been proposed that this defines the "sensitive oesophagus". AIM: To test the response to omeprazole 20 mg twice daily for four weeks of patients with normal levels of acid reflux using a randomised, placebo controlled, double blind, cross-over design. PATIENTS: Eighteen patients with normal levels of reflux, 12 of whom had a positive SI. METHODS: Response was measured by symptomatic assessment and the SF-36 quality of life (QOL) questionnaire. RESULTS: Patients with a positive SI showed the following improvements on omeprazole compared with placebo: decrease in symptom frequency (p < 0.01), severity (p < 0.01) and consumption of antacids (p < 0.01). In the group with a negative SI only one patient clearly improved. The QOL parameters for bodily pain (65.6 v 53.4, p = 0.03) and vitality (60.6 v 48.8, p = 0.049) were significantly better on omeprazole than placebo for the group overall. CONCLUSION: Omeprazole improves symptoms in 11 of 18 patients with normal endoscopy and pH monitoring, particularly those with a positive SI. This supports the theory that such patients have an oesophagus which is "sensitive" to acid reflux and are part of the GORD spectrum.

Disease progression in gastro-oesophageal reflux disease as determined by repeat oesophageal pH monitoring and endoscopy 3 to 4.5 years after diagnosis.

OBJECTIVES: Reflux oesophagitis may progress to complications such as Barrett's mucosa and stricture formation. However, few studies have assessed long-term disease progression in oesophagitis patients and fewer still have considered disease progression in the significant proportion of gastro-oesophageal reflux disease (GORD) patients who do not have oesophagitis at diagnosis. The aim of this study was to reassess GORD patients 3 to 4 years after initial diagnosis and determine whether or not disease progression had occurred. METHODS: Prospective follow-up of 101 GORD patients at least 32 months after initial assessment with oesophageal pH monitoring and upper gastrointestinal endoscopy. Patients were invited to complete a symptomatic questionnaire and undergo repeat investigation with the same techniques. RESULTS: Seventy-seven (76%) patients responded (mean follow-up period 39 months, range 32-54 months) of whom 28 initially had oesophagitis (group A), 17 had normal endoscopy but abnormal pH monitoring (group B) and 32 had normal investigations but typical reflux symptoms (group C). At the time of follow-up, 57 (74%) patients either had frequent heartburn or were taking daily acid suppression therapy. Fifty-two (68%) responders had at least one repeat investigation: 44 (57%) had repeat pH monitoring; 43 (56%) had repeat endoscopy. Three (11% of the 28 responders) group A patients had developed Barrett's mucosa, 4 (24% of responders) group B patients had developed oesophagitis and 10 (31% of responders) group C patients had developed abnormal pH monitoring (4), oesophagitis (4) or both (2). CONCLUSION: Three-quarters of GORD patients still have troublesome symptoms at least 3 years after diagnosis and a significant proportion show endoscopic progression of the condition's severity.

Natural history of reflux oesophagitis: a 10 year follow up of its effect on patient symptomatology and quality of life.

BACKGROUND: Although oesophagitis is the most common diagnosis made at upper gastrointestinal endoscopy, data on the longterm outcome of affected patients are sparse. AIMS: This study assessed the level of reflux symptoms, quality of life, drug consumption, and complications in patients at least 10 years after diagnosis of oesophagitis at one centre. PATIENTS: One hundred and fifty two patients with typical reflux symptoms and a first time diagnosis by endoscopy of grade I-III oesophagitis between 1981 and 1984, were followed up using a postal questionnaire and telephone interview. RESULTS: Eighteen of 152 patients had died, 33 failed to respond, and 101 replied (mean follow up 11 years, range 121-160 months). Over 70% of patients still had heartburn at least daily (32%) or weekly (19%) or required daily acid suppression treatment (20%). Two patients (2%) had developed oesophageal strictures and one had Barrett's oesophagus. Two of eight quality of life scores (physical function and social function) measured by the Short Form-36 were significantly lower than Northern Ireland population scores. CONCLUSION: Nearly three quarters of patients previously diagnosed as having oesophagitis still had significant morbidity related to gastro-oesophageal reflux disease more than 10 years after diagnosis. Some quality of life scores were significantly lower than those of the general population.

Asystolic arrest as a presentation of sarcoidosis.

A 41-year-old man who presented with a history of sudden loss of consciousness suffered two further episodes during which asystole was documented. Subsequent investigations included exercise stress testing, thallium scintigraphy, electrophysiological studies, CT-scan of chest, Kveim test and a gallium-67 scan, which led to a presumptive diagnosis of averted sudden death as a first presentation of sarcoidosis with primary cardiac involvement.