J. Douglas Maxwell

Kinetics of hepatic bile acid handling in cholestatic liver disease: Effect of ursodeoxycholic acid

BACKGROUND/AIMS Ursodeoxycholic acid (UDCA) is clinically beneficial in chronic cholestatic liver disease, but the underlying mechanisms are unclear. It has been suggested that intrahepatic retention of endogenous hydrophobic bile acids contributes to cholestasis and that the hydrophilic bile acid UDCA reduces this retention; the aim of our study was to test these hypotheses. METHODS Twelve patients with primary biliary cirrhosis (PBC) and 5 with primary sclerosing cholangitis (PSC) were studied before and during UDCA (10 mg.kg-1.day-1) and compared with 11 healthy controls. Following intravenous 75Se labeled homocholic acid taurine (75SeHCAT) in the fasting state, abdominal gamma camera imaging was performed for 90 minutes. Initial hepatic uptake, transit time, net, and absolute excretory rates for 75SeHCAT were measured. RESULTS Mean initial hepatic uptake was not different between patients and controls (17.2% and 19.9% dose/minute, not significant). However, net and absolute excretory rates were significantly reduced in patients (1.4% vs. 3.7% dose/minute, P < 0.0001; and 2.35% vs. 3.96% dose/minute, P < 0.02, respectively), and hepatic transit time was prolonged (18.7 minutes vs. 11.6 minutes, P < 0.002). UDCA improved net and absolute hepatic excretory rates and transit time (1.43% to 1.96% dose/minute, P < 0.001; 2.35% to 3.15% dose/minute, P < 0.005 and 18.7 to 14.7 minutes, P < 0.001, respectively). However, UDCA did not alter initial hepatic uptake. CONCLUSIONS In PBC and PSC, there is a defect in hepatic bile acid excretion but not in uptake, implying bile acid retention. This retention is reduced by UDCA.

Epidemiology and Management of Diverticular Disease of the Colon

Colonic diverticula are protrusions of the mucosa through the outer muscular layers, which are usually abnormally thickened, to form narrow necked pouches. Diverticular disease of the colon covers a wide clinical spectrum: from an incidental finding to symptomatic uncomplicated disease to diverticulitis. A quarter of patients with diverticulitis will develop potentially life-threatening complications including perforation, fistulae, obstruction or stricture. In Western countries diverticular disease predominantly affects the left colon, its prevalence increases with age and its causation has been linked to a low dietary fibre intake. Right-sided diverticular disease is more commonly seen in Asian populations and affects younger patients. Its pathogenesis and relationship to left-sided diverticular disease remains unclear. Diverticular disease of the colon is a significant cause of morbidity and mortality in the Western world and its frequency has increased throughout the whole of the 20th century. Since it is a disease of the elderly, and with an aging population, it can be expected to occupy an increasing portion of the surgical and gastroenterological workload. It is uncertain what symptoms uncomplicated diverticular disease gives rise to: there is an overlap with irritable bowel syndrome. Diagnosis is primarily by barium enema and colonoscopy, but more sophisticated imaging procedures such as computed tomography (CT) are increasingly being used to assess and treat complications such as abscess or fistula, or to provide alternative diagnoses if diverticulosis is not confirmed.Initial therapy for uncomplicated diverticulitis is supportive, including monitoring, bowel rest and antibacterials. CT is used to guide percutaneous drainage of abscesses to avoid surgery or allow it to be performed as an elective procedure. Surgery is indicated for complications of acute diverticulitis, including failure of medical treatment, gross perforation, and abscess formation that cannot be resolved by percutaneous drainage. Complications of chronic diverticulitis (fistula formation, stricture and obstruction) are also usually treated surgically. However, the indications for, and the timing and staging of operations for diverticular disease are often difficult decisions requiring sound clinical judgement. Factors such as the number of episodes of inflammation, the age of the patient, and his/her overall medical condition play a role in determining whether or not a patient should undergo surgical resection. Laparoscopic surgery may be associated with less pain, less morbidity and shorter hospital stays, but its exact role is yet to be defined. Diverticular disease of the colon is the most common cause of acute lower gastrointestinal haemorrhage, which can be massive. Although the majority of patients stop bleeding spontaneously, angiographic and surgical treatment may be required, while the place of endoscopic haemostasis remains to be established.

Is there an irritable bladder in the irritable bowel syndrome

In this prospective case controlled study 16 premenopausal women with documented irritable bowel syndrome were recruited from the gastroenterology clinic and 16 premenopausal controls without symptoms of irritable bowel syndrome were recruited from the gynaecology clinic. All women answered a standardised bowel and urinary symptom questionnaire and underwent twin channel subtracted cystometry. Women with irritable bowel syndrome also underwent oesophageal balloon distension studies for perception and pain. Oesophageal and bladder sensory thresholds were compared. Urinary frequency and urgency and the urodynamic finding of detrusor instability were significantly more common in women with irritable bowel syndrome (P < 0.05). We were unable to demonstrate a relationship between first sensation of bladder fullness and oesophageal perception or between maximum bladder capacity and oesophageal pain thresholds. These findings suggest that there is an irritable bladder in the irritable bowel syndrome and support the concept that irritable bowel syndrome is part of a generalised disorder of smooth muscle.

Chronic Liver Disease—An Increasing Problem: A Study of Hospital Admission and Mortality Rates in England, 1979–2005, with Particular Reference to Alcoholic Liver Disease

AIMS To determine time trends in hospital admissions for chronic liver disease in England between 1989/1990 and 2002/2003, mortality rates in England and Wales between 1979 and 2005, and the influence of alcohol-related disease on these trends. METHODS Hospital episode statistics for admissions in England were obtained from the Information Center for Health and Social Care and mortality data for England and Wales from the Office for National Statistics. RESULTS Hospital admission rates for chronic liver disease increased by 71% in males and 43% in females over the study period. This increase was largely due to alcoholic liver disease, admission rates for which more than doubled between 1989/1990 and 2002/2003. While there was a smaller rise for chronic viral hepatitis B and C, admission rates declined for hepatitis A, autoimmune hepatitis, and primary biliary cirrhosis. Mortality rates for chronic liver disease more than doubled between 1979 and 2005. Two thirds of these deaths were attributable to alcohol-related liver disease in 2005. The highest rate of alcoholic liver disease mortality was in the 45-64 age group, and the largest percentage increase between 1979 and 2005 occurred in the 25-34 age group. CONCLUSIONS Hospital admissions and mortality in England from chronic liver disease are increasing. The underlying reasons are complex, but alcohol-induced liver disease makes a major contribution. There are clear social and health implications if the trend continues and addressing alcohol-related liver disease should be a public health priority.

Serum intercellular adhesion molecule-1 in alcoholic liver disease and its relationship with histological disease severity

BACKGROUND Infiltration of the liver by leukocytes is a histological feature of alcoholic liver disease. Intercellular adhesion molecule-1 (ICAM-1) mediates the migration of lymphocytes from the circulation to target sites of inflammation. It has been demonstrated in the liver of alcoholic liver disease subjects and as a circulating soluble form (sICAM-1). The origin of sICAM-1 and its relationship to disease severity is unknown, although it has been postulated that it may arise from activated T lymphocytes and is an inflammatory marker. AIMS The aim of the study was to determine the relationship of sICAM-1 to clinical and histological severity of alcoholic liver disease and to serum T-cell (soluble interleukin-2 receptor (sIL-2R), beta 2-microglobulin) and monocyte (neopterin) immune activation markers. METHODS Serum from 48 outpatients with biopsy proven alcoholic liver disease (steatosis = 9, cirrhosis = 28, hepatitis +/- cirrhosis = 11), 31 with primary biliary cirrhosis and 27 normals was assayed for sICAM-1, sIL-2R, beta 2-microglobulin, and neopterin. RESULTS sICAM-1 was significantly elevated, p = 0.0001, in alcoholic liver disease and primary biliary cirrhosis patients compared to normals. Circulating sIL-2R (p = 0.0001) and beta 2-microgloblin (p = 0.0034) were significantly elevated in alcoholic liver disease compared to controls. There was a highly significant correlation between levels of sICAM-1 and histological grade of disease, Rs = 0.80 (p = 0.0001), but no significant correlation with clinical correlates of disease severity or circulating immune activation markers. CONCLUSIONS sICAM-1 is elevated in alcoholic liver disease, is a marker of histological severity of disease and does not appear to originate from activated T lymphocytes. Measurements of sICAM-1 may be useful in assessing histological severity of alcoholic liver disease.

Soluble E-selectin and vascular cell adhesion molecule-1 (VCAM-1) in primary biliary cirrhosis

BACKGROUND/AIMS E-selectin and vascular cell adhesion molecule-1, important in leucocyte adhesion, have recently been detected in soluble form in the circulation. However, their clinical significance remains unclear. Our aims were to determine whether the levels of these molecules are increased in primary biliary cirrhosis, and to relate these to histological disease stage, biochemical measures of liver damage and to lymphocyte activation. METHODS We studied 42 patients with primary biliary cirrhosis, nine with primary sclerosing cholangitis, 14 with alcoholic liver disease and 17 healthy subjects. Circulating E-selectin and vascular cell adhesion molecule-1 levels were measured by enzyme-linked immunosorbent assay. In subgroups of patients with primary biliary cirrhosis, hepatic bile acid uptake and excretory rates and T-cell activation were also determined. RESULTS Soluble E-selectin and vascular cell adhesion molecule-1 levels were significantly elevated in primary biliary cirrhosis compared to healthy controls. However, there was no difference between primary biliary cirrhosis and other liver disease groups. In primary biliary cirrhosis, both adhesion molecules correlated with disease stage, but differed in their relationships with specific liver function tests. They did not correlate with either hepatic bile acid uptake or excretion, or lymphocyte activation. CONCLUSIONS We conclude that soluble E-selectin and vascular cell adhesion molecule-1 are elevated in chronic liver diseases. In primary biliary cirrhosis, they reflect the stage of disease and may reflect the degree of leucocyte adhesion and migration.

Testing for haemochromatosis in a liver clinic population: relationship between ethnic origin, HFE gene mutations, liver histology and serum iron markers

Objective To identify the most appropriate testing strategy for genetic haemochromatosis in a liver clinic population by determining the ethnic distribution of the HFE mutations and the relationship between serum iron markers, hepatic siderosis and HFE genotype. Design and setting Observational study of 427 patients being investigated for abnormal liver function tests between 1997 and 2000 attending a liver clinic at a teaching district general hospital in south London, UK. Methods All patients were tested for H63D and C282Y gene mutations, and the ethnic origin was determined. Data were available for most patients for non-fasting serum iron, ferritin and transferrin saturation on presentation and fibrosis and siderosis scores from liver biopsy. Results The C282Y mutation was not detected in any patients of Asian or Afro-Caribbean origin but was found almost exclusively in northern Europeans, especially those classified as Celtic, one in seven of whom were heterozygous for this mutation. Three per cent of all the patients tested were C282Y homozygotes. The H63D mutation was distributed more widely. An elevated serum transferrin saturation was both a more sensitive and a more specific test for genetic haemochromatosis than either serum ferritin or iron. Significantly raised mean siderosis scores were found on liver biopsy in C282Y homozygote and C282Y/H63D compound heterozygote groups but not in wild-type, simple heterozygote, or H63D homozygote groups. Forty-five per cent of the C282Y homozygotes detected already had cirrhosis. Conclusions In a multiracial liver clinic population, previously undiagnosed C282Y homozygosity was found to be common (3% in our study) but restricted to those of northern European heritage, particularly those with Celtic ancestry. A serum transferrin saturation proved a better initial test to select patients for genotyping than serum iron or ferritin. Laboratory costs can be minimized with no loss of diagnostic sensitivity by selecting patients for genotyping based on northern European ethnic origin and raised serum transferrin saturation.