Paracetamol hepatotoxicity.
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Acetaminophen↗
Biomedical subjects
J E Hegarty
Publications and source records attributed to J E Hegarty.
Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression.
We report two cases of recurrence of primary biliary cirrhosis (PBC) in the transplanted liver whilst maintained on a FK506-based immunosuppressive regime, the first to be described. One patient experienced symptoms in association with the development of cholestasis. In both there was a persistence of serological markers of PBC and liver histology revealed florid bile duct destruction and a granulomatous reaction.
Adult↗
Intestinal bile acid malabsorption in cystic fibrosis.
This study aimed at examining the mechanisms participating in excessive faecal bile acid loss in cystic fibrosis. The study was designed to define the relation between faecal fat and faecal bile acid loss in patients with and without cystic fibrosis related liver disease; to assess terminal ileal bile acid absorption by a seven day whole body retention of selenium labelled homotaurocholic acid (SeHCAT); and to determine if small intestinal bacterial overgrowth contributes to faecal bile acid loss. The study population comprised 40 patients (27 men; median age 18 years) with cystic fibrosis (n = 8) and without (n = 32) liver disease and eight control subjects. Faecal bile acid excretion was significantly higher in cystic fibrosis patients without liver disease compared with control subjects (mean (SEM) 21.5 (2.4) and 7.3 (1.2) micromoles/kg/24 hours respectively; p < 0.01) and patients with liver disease (7.9 (1.3) micromoles/kg/24 hours; p < 0.01). No correlation was found between faecal fat (g fat/24 hours) and faecal bile acid (micromoles 24 hours) excretion. Eight (33%) of cystic fibrosis patients had seven day SeHCAT retention < 10% (normal retention > 20%). SeHCAT retention in cystic fibrosis patients with liver disease was comparable with control subjects (30.0 (SEM) 8.3% v 36.8 (5.9)%; p = NS) while SeHCAT retention in cystic fibrosis patients who did not have liver disease was significantly reduced (19.9 (3.8); p < 0.05). Although evidence of small bowel bacterial overgrowth was present in 40% of patients no relation was found between breath hydrogen excretion, faecal fat, and faecal bile acid loss. The results are consistent with the presence of an abnormality in terminal ideal function in patients with cystic fibrosis who do not have liver disease and that a defect in the ileal absorption of bile acids may be a contributory factor to excessive faecal bile acid loss. Faecal bile acid loss in cystic fibrosis is unrelated to the presence of intraluminal fat or intestinal bacterial overgrowth.
Adolescent↗
Parathyroid crisis and acute viral hepatitis B infection.
The simultaneous development of acute hyperparathyroidism and viral hepatitis B infection in a 72 year old male is described. Resolution of the hepatitis was accompanied by improvement in the parathyroid hormone mediated hypercalcaemia. It is postulated that antibodies to the hepatitis B virus may have altered the calcium 'set point' allowing uncontrolled synthesis and release of parathyroid hormone during the acute illness.
Acute Disease↗
Postprandial changes in portal haemodynamics in patients with cirrhosis.
Previous studies have shown that portal venous pressure increases in patients with cirrhosis after a protein meal. Since this increase may be mediated by an increase in hepatic blood flow or postsinusoidal hepatic vascular resistance, the present study was designed to examine the precise relation between the postprandial changes in these three variables in patients with cirrhosis and portal hypertension. Estimated hepatic blood flow (EHBF; indocyanine green clearance), portosystemic gradient (PSG; wedged free hepatic venous pressure), and postsinusoidal hepatic vascular resistance (PSR = PSG/EHBF) were measured simultaneously before and at 10 minute intervals after a high protein meal, containing 80 g protein, 40 g carbohydrate and 12 g fat (600 kcal) in nine patients (seven alcoholic, two non-alcoholic) with cirrhosis and portal hypertension. After the meal, the portosystemic gradient increased by 33% from mean (SEM) 15.6 (0.9) mm Hg to 20.7 (1.3) mm Hg, (p less than 0.01; Wilcoxon signed ranks test) within 30 minutes. Coincident with this increase in portosystemic gradient, estimated hepatic blood flow increased by 69.2% from 20.1 (1.7) ml/min/kg to 33.9 (2.5) ml/min/kg (p = 0.01), peak values occurring at 25 minutes, at which time the postsinusoidal hepatic vascular resistance had decreased by 31% from 1.10 (0.1) 10(-2) mm Hg/ml/min to 0.8 (0.5) 10(-2) mm Hg/ml/min (p = 0.01). These results suggest that the postprandial increase in portal venous pressure in patients with cirrhosis is mediated by an increase in hepatic blood flow and modified by a simultaneous decrease in postsinusoidal resistance.
Adult↗
Biliary complications of cystic fibrosis.
One hundred and four adult patients with cystic fibrosis were evaluated for the presence of liver disease as defined by abnormal liver function tests of six months' duration, histological evidence of fibrosis or cirrhosis, or the presence of portal hypertension, or both. Twenty patients fulfilled these criteria and were evaluated further for the presence of biliary tract abnormalities with biliary scintigraphy using 99Tc diisopropylphenyl-carboxymethyl iminodiacetic acid (DISIDA) and endoscopic retrograde cholangiography. Clearance of 99Tc DISIDA from the liver and biliary tree was diminished at 45 (E45) and 60 (E60) minutes in the patients with liver disease compared with those without liver disease; E45 = 37.8% and 65.8%, p less than 0.01; E60 = 48.2% and 77.5%, p less than 0.01 respectively. Serial analogue images of the extrahepatic biliary tree were consistent with common bile duct obstruction with retention of DISIDA and tapering of the common bile duct in seven of 18 patients with and two of 10 patients without liver disease. Endoscopic retrograde cholangiography showed changes consistent with sclerosing cholangitis, with beading and stricturing of the intrahepatic ducts in 12 of the 14 patients. In all 14 patients, including those in whom biliary scintigraphy had suggested obstruction, no abnormality of the common bile duct was identified. These results indicate that abnormalities of the bile ducts in patients with cystic fibrosis related liver disease are confined to the intrahepatic biliary tree and that common bile duct strictures do not contribute to either the progression or development of liver disease in these patients.
Adolescent↗
Immunological aspects of liver disease.
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Autoimmune Diseases↗
In vitro effect of TP-1 (a calf thymic extract) on suppressor T-cell function of patients with autoimmune chronic active hepatitis.
Concanavalin A-activated T-lymphocyte suppression of IgG production was found to be significantly impaired in patients with untreated active autoimmune chronic hepatitis when compared to normals or patients with inactive disease. When the dose-response effect of TP-1, a calf thymic extract, on in vitro suppressor cell activity was assessed, lymphocytes from six out of eight patients with previously reduced suppressor cell function showed a significant improvement, while over a similar range the suppressor cell activity of most normal controls declined. These results support the possibility that defective immunoregulation in patients with autoimmune chronic active hepatitis may be related to a deficiency in thymic hormone levels.
Adjuvants, Immunologic↗
Controlled clinical trial of acyclovir in chronic hepatitis B virus infection.
A randomised, controlled trial comparing acyclovir, 45 mg/kg/day as a continuous IV infusion for 28 days, with no other therapy, was carried out in 30 stable HBsAg carriers seropositive for HBeAg for more than 6 months. Twenty-eight had hepatitis B virus DNA-polymerase activity and/or hepatitis B virus DNA in serum at entry into the study. There were no significant adverse effects of therapy. At 12 months, seroconversion from HBeAg to anti-HBe had occurred in four of 15 treated patients, one of whom had also developed anti-HBs, compared with only one of 15 in the untreated group (95% confidence limits 12% and 51%). Seroconversion from HBeAg to anti-HBe was accompanied by return of serum liver function tests to normal and improved liver histology. The results of this study indicate that acyclovir is of no significant benefit in chronic HBeAg carriers with stable disease.
Acyclovir↗
T and B cell function in alcoholic liver disease.
Increased in vivo synthesis of immunoglobulin in patients with alcoholic liver damage has been attributed to direct activation of B cells, although other defects of lymphocyte function have been identified suggesting a more generalised defect. In the present study we have investigated the role of T cell regulation of immunoglobulin production in alcoholic liver disease analysed according to the presence or absence of alcoholic hepatitis. Spontaneous production of IgG and IgA was elevated and co-culture experiments confirmed hyper-reactivity of B cells, but also suggested impaired T cell function. Suppressor cell activity for IgG and IgA was impaired. Similarly, the response to pokeweed mitogen for IgG and IgA was defective, although this was more marked for secretion than for proliferation suggesting an associated T helper defect. No differences in the immunological abnormalities were identified between those with alcoholic hepatitis and those with other alcoholic liver diseases. This study demonstrates a broad defect of T cells and a hyper-reactivity of B cells in patients with alcoholic liver disease, irrespective of the severity of hepatic inflammation.
Adult↗
A controlled trial of acyclovir in stable chronic HBsAg, HBeAg-positive carriers.
Histological remission is recognised to follow loss of viral replication in chronic hepatitis B virus infection. The aim of antiviral therapies has been to accelerate seroconversion from HBeAg to anti-HBe, but so far none has been shown to be of significant advantage in adequate, controlled trials and toxicity has been common. A randomised controlled trial of acyclovir, 45 mg/kg/day by continuous intravenous infusion for 28 days versus no therapy has been completed in 30 patients positive for HBsAg and HBeAg for a minimum of 6 months. Patients were stratified for sex, histology and homosexual activity. Twenty-eight days therapy was associated with only a modest reduction in serum markers of viral replication. At 12-months DNAp was lost in 5/15 treated and 2/11 of the untreated group, while of the latter, 2 patients initially negative became positive. Seroconversion from HBeAg to anti-HBe had occurred in 4 of 15 treated and 1 of 15 untreated patients (95% confidence limits 12% and 51%) and was associated with histological improvement. Acyclovir had only a weak effect on viral replication and did not significantly accelerate the rate of seroconversion to anti-HBe.
Acyclovir↗
Randomised controlled trial of azathioprine withdrawal in autoimmune chronic active hepatitis.
To assess the value of azathioprine in the maintenance therapy of autoimmune chronic active hepatitis a controlled trial of azathioprine withdrawal was carried out in 50 patients who had been maintained in remission on a combination of azathioprine and prednisolone. The patients were randomly allocated to remain on combination therapy (23) or to discontinue azathioprine (27). These 2 groups were comparable at the start of the study. Over a follow-up period of up to 3 years, biochemical and histological relapse occurred in 8 patients in the azathioprine-withdrawal group but in only 1 patient in the combination-therapy group. Cumulative probability of relapse was 32% among the patients in the withdrawal group, compared with 6.0% for those in the combination group.
Adult↗
Ranitidine and hepatotoxicity.
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Hepatitis C↗
HLA A1-B8-DR3 and suppressor cell function in first-degree relatives of patients with autoimmune chronic active hepatitis.
The relationship between suppressor T cell function and the inheritance of the A1, B8, DR3 haplotype was studied in 17 healthy, first-degree relatives of patients with autoimmune chronic active hepatitis. A marked defect in suppressor cell function was found significantly more often in A1, B8, DR3-positive relatives (5 of 7) compared with those who were A1, B8, DR3-negative (1 of 10; P = 0.017). Less marked abnormalities were also found in the A1, B8, DR3-negative relatives compared with A1, B8, DR3-negative control subjects. The results indicate that the defects in suppressor cell function in patients with untreated chronic active hepatitis result from the inheritance of genetic factors linked to the major histocompatibility complex and other gene loci and are not secondary to hepatic inflammation.
Autoimmune Diseases↗
B1 selective adrenoreceptor blockade for the long term management of variceal bleeding. A prospective randomised trial to compare oral metoprolol with injection sclerotherapy in cirrhosis.
Oral metoprolol, in a dose sufficient to reduce resting pulse rate by 25%, was compared with repeated injection sclerotherapy for the long term management of variceal bleeding. The prospective, randomised study was undertaken in 32 patients with biopsy proven cirrhosis and variceal bleeding who were Grade A or B on a modified Child's classification. In the 15 patients receiving metoprolol, portal pressure showed a mean fall of 3.7 mmHg (17.3 +/- 1.2 to 13.6 +/- 1.2 mmHg, p less than 0.01) after four weeks of continuous therapy, as compared with pretreatment levels. Nine of the 15 patients taking metoprolol had further bleeding (total of 21 episodes) compared with six of 17 in the sclerotherapy group (nine episodes). The risk of bleeding per patient/month of follow up was three times higher in the metoprolol group compared with those treated by sclerotherapy (0.14 and 0.04 respectively, p less than 0.025). Rebleeding in the metoprolol group occurred in six of the patients who had a fall in portal pressure of 10% or more.
Clinical Trials as Topic↗
Relative nutritional value of whole protein, hydrolysed protein and free amino acids in man.
To compare their effects on nitrogen balance, diets containing either lactalbumin whole protein, its peptide-rich enzymic hydrolysate or an equivalent mixture of free amino acids as the sole source of dietary nitrogen were fed to two healthy subjects, each studied for 38 days on two separate occasions. The nitrogen intake (47 mg/kg body wt/day) induced a state of negative nitrogen balance, stimulating nitrogen conservation. Net daily nitrogen balance (mean +/- SD) in subject 1 was -0.23 +/- 0.72 g (amino acids) vs + 0.05 +/- 0.52 g (protein) and -0.21 +/- 0.58 g (amino acids) vs -0.05 +/- 0.57 g (hydrolysate), and in subject 2, -0.19 +/- 0.60 g (amino acids) vs -0.16 +/- 0.51 g (protein) and -0.42 +/- 0.35 g (amino acids) vs -0.62 +/- 0.34 g (hydrolysate). Analysis of these results by the cumulative sum technique showed no significant differences in the effect of the three nitrogen sources on nitrogen balance. This study indicates that there is no nutritional evidence to support the current practice of prescribing expensive enteral diets containing peptides or amino acids rather than the much cheaper whole protein to patients with normal gastrointestinal function.
Amino Acids↗
In vitro studies on the mechanism of increased serum IgM levels in primary biliary cirrhosis.
To evaluate the mechanisms underlying the increase in serum IgM in primary biliary cirrhosis (PBC) studies were designed to examine IgM production in vitro and to assess the relative contribution of intrinsic B cell activity and immunoregulatory T cell balance to IgM synthesis. The number of peripheral blood lymphocytes (PBL) producing IgM (spontaneous and pokeweed mitogen (PWM) stimulated) at the end of a seven day culture period was similar in PBC patients and control subjects while the amount of IgM synthesized (spontaneous and PWM stimulated) during this period was significantly greater in the patient group, implying that the amount of IgM produced per B cell was increased in PBC. Co-culture of autologous and allogeneic T and B lymphocytes and irradiation of T lymphocytes from patients and normal subjects clearly implicated abnormal suppressor T cell function, rather than autonomous B cell hyperactivity, as the cause of the increased IgM synthesis. Direct studies of T cell function indicated that although concanavalin A (Con A) activated suppressor cells inhibited proliferation of IgM producing B cells in the majority of PBC patients, they were unable to inhibit IgM synthesis. The demonstration of a disparity between IgM synthesis and the proliferation of IgM-producing B cells, together with the observation that the abnormality of T cell function is largely confined to the control of IgM secretion, is consistent with the presence of at least two different suppressor subpopulations regulating IgM production. In PBC the main suppressor cell abnormality seems to affect regulation of IgM secretion rather than B cell proliferation.
B-Lymphocytes↗
IgG production in 'autoimmune' chronic active hepatitis. Effect of prednisolone on T and B lymphocyte function.
In vitro IgG production was measured using peripheral blood mononuclear cells from patients with autoimmune chronic active hepatitis (CAH) to determine whether the increased serum IgG levels were related to abnormalities of T or B lymphocyte function. A marked increase in spontaneous and pokeweed mitogen-induced proliferation of IgG producing cells was observed in 30 patients with untreated autoimmune CAH when compared with 25 normal subjects and 21 patients with autoimmune disease in whom a remission had been induced and maintained by prednisolone (P less than 0.01). Co-culture experiments clearly demonstrated that abnormalities of T lymphocyte function in untreated autoimmune CAH were responsible for the heightened IgG production in vitro. Pre-incubation of T lymphocytes from untreated patients with 5 X 10(-8)M prednisolone significantly reduced the number of cells producing IgG (P less than 0.05), suggesting that the modulation of the immune response following corticosteroid therapy is likely to be due to an alteration in T lymphocyte function.
Adult↗