Biomedical subjects
M Y Morgan
Publications and source records attributed to M Y Morgan.
Treatment of alcohol-related liver disease with thioctic acid: a six month randomised double-blind trial.
A randomised double-blind trial of thioctic acid (alpha-lipoic acid), 300 mg/day versus placebo was carried out in 40 patients with pre-cirrhotic alcohol-related liver disease over a six month period. Twenty patients received the active drug and 20 placebo. Twenty-two of the 40 patients (55%) abstained from alcohol and showed significant improvements (p less than 0.01) in mean values for serum aspartate transaminase, serum glutamyl transpeptidase, and mean corpuscular volume. Seventeen of the 22 (77%) showed overall histological improvement on liver biopsy. The remaining 18 patients (45%) continued to drink but significantly reduced their mean daily alcohol intake (p less than 0.001). No significant changes occurred in their laboratory indices, but five of the 18 (28%) showed overall histological improvement. Changes occurred irrespective of treatment with thioctic acid, which suggested that, over six months, this drug did not influence the course of alcohol-related liver disease.
Plasma amino-acid patterns in liver disease.
Plasma amino-acid concentrations were measured in 167 patients with liver disease of varying aetiology and severity, all free of encephalopathy, and the results compared with those in 57 control subjects matched for age and sex. In the four groups of patients with chronic liver disease (26 patients with chronic active hepatitis, 23 with primary biliary cirrhosis, 11 with cryptogenic cirrhosis, and 48 with alcoholic hepatitis +/- cirrhosis) plasma concentrations of methionine were significantly increased, while concentrations of the three branched chain amino-acids were significantly reduced. In the first three groups of patients plasma concentrations of aspartate, serine, and one or both of the aromatic amino-acids tyrosine and phenylalanine were also significantly increased, while in the patients with alcoholic hepatitis +/- cirrhosis plasma concentrations of glycine, alanine, and phenylalanine were significantly reduced. In the three groups of patients with minimal, potentially reversible liver disease (31 patients with alcoholic fatty liver, 10 with viral hepatitis, and 18 with biliary disease) plasma concentrations of proline and the three branched chain amino-acids were significantly reduced. Patients with alcoholic fatty liver also showed significantly reduced plasma phenylalanine values. Most changes in plasma amino-acid concentrations in patients with chronic liver disease may be explained on the basis of impaired hepatic function, portal-systemic shunting of blood, and hyperinsulinaemia and hyperglucagonaemia. The changes in patients with minimal liver disease are less easily explained.
Macrocytosis in alcohol-related liver disease: its value for screening.
The incidence of macrocytosis, defined as a mean corpuscular volume (MCV) of greater than 95 fl and large red cells on peripheral blood film, was determined in 303 alcoholics with liver disease (95 females: 208 males), 60 non-alcoholics with chronic liver disease (44 females: 16 males) and 35 control subjects (15 females: 20 males). Macrocytosis was found in 70.3% (213/303) of alcoholics with liver disease and in 23.3% (14/60) of non-alcoholics with liver disease, P less than 0.001. MCV values greater than 100 fl were seen in 49.5% (150/303) of alcoholics, but in only 3.3% (2/60) of non-alcoholics, P less than 0.001. Macrocytosis was more frequent in female, 86.3% (82/95) than in male alcoholics 63.0% (131/208), P less than 0.001. Serum folate values less than 3 microgram/l were found in 14.5% (44/303) of alcoholics and in 11.7% (7/60) of non-alcoholics. Low serum folate values were found in 18.3% (39/213) of alcoholics with macrocytosis and in 35.9% (28/78) of those with macrocytic anaemia. Twenty alcoholics with pre-cirrhotic liver disease were followed over three months. Macrocytosis was present in 85.0% (17/20) at the outset and in 40% (8/20) 3 months later. The changes in MCV were independent of alcohol intake and serum folate values. Macrocytosis is a useful diagnostic indicator of alcoholism. MCV values greater than 100 fl in patients with liver disease almost invariably indicate alcohol-related disease. In the short-term, changes in MCV are of little use in monitoring alcohol intake.
Alcoholism treatment in a medical setting.
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Erythrocyte transketolase activity in alcoholic liver disease.
Erythrocyte transketolase activity and its stimulation in vitro by the addition of thiamine pyrophosphate (TPP effect) was measured in 64 normally nourished alcoholics with well-compensated liver disease and in 20 control subjects. Biochemical evidence of thiamine deficiency as judged by low transketolase activity was found in 19 alcoholics (29.7%). In 5 of these 19 patients the TPP effect was abnormally high, indicating depleted thiamine stores. IN the other 13 patients the TPP effect was either normal or low, suggesting a deficiency or an inability to use the transketolase apoenzyme, probably as a result o long-standing thiamine deficiency or the presence of liver disease. a further eight patients (12.5%) had normal transketolase activity but a low TPP effect, perhaps reflecting failure of hte coenzyme TPP to recombine with the transketolase apoenzyme in the presence of normal thiamine stores. There was no relationship between transketolase activity and the daily alcohol consumption, the duration of alcoholism, or the histological severity of the liver disease. Thiamine should be given routinely to alcoholics even if their diet appears adequate and their liver disease is minimal or well compensated.
Enteral nutrition in chronic liver disease.
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Markers for detecting alcoholism and monitoring for continued abuse.
Several biochemical and haematological abnormalities are associated with excessive alcohol intake and some are used in the recognition and management of alcoholics. The ideal biological marker for detecting and monitoring alcoholics should be sensitive and highly specific for alcohol abuse; its value should be affected by changes in alcohol intake over relatively short periods of time and it should be quick, simple, convenient and inexpensive to estimate. At the present time no simple reliable marker is available which fulfills these criteria. Measurements of serum aspartate transaminase, serum gamma-glutamyl-transpeptidase and mean corpuscular volume are of proven value however and the majority of alcoholics can be detected and monitored by combining the measurements of these three tests. Blood/breath alcohol measurements are of limited value for detection but are useful for follow up. Measurement of the plasma alpha-amino-n-butyric acid/leucine ratio is of disputed value and not likely to be of great practical use. Measurement of serum alpha-lipoproteins, erythrocyte delta-aminolaevulinic acid dehydrase activity and qualitative estimation of serum transferrin have all been proposed as markers for alcohol abuse and are currently under evaluation.
Treatment of alcohol-related liver disease with (+)-cyanidanol-3: a randomised double-blind trial.
A randomised double-blind trial of (+)-cyanidanol-3(Catechin), 2 g/day versus placebo, was carried out in 40 patients with pre-cirrhotic alcohol-related liver disease over a three month period. Twenty received the active drug and 20 placebo; one non-compliant patient in the treatment group was withdrawn. Forty-one per cent (16/39) abstained from alcohol and showed significant improvements (P < 0.005) in mean values for serum aspartate transaminase, serum gamma glutamyl transpeptidase, and mean corpuscular volume. Ten of the 16 showed overall histological improvement on liver biopsy. Fifty-nine pr cent (23/39) continued to drink, though significantly reducing their mean daily alcohol intake (P < 0.001). No significant changes occurred in this group in mean serum enzyme values, though the mean value for mean corpuscular volume improved significantly (P < 0.01) and 16 of the 23 showed overall histological improvement. Changes occurred irrespective of treatment with Catechin which suggests that, over a three month period, this drug did not influence the course of alcohol-related liver disease.
HLA-B8, immunoglobulins, and antibody responses in alcohol-related liver disease.
Ninety-two British, caucasian, alcoholic patients with liver disese were grouped on the basis of hepatic histology into fatty change, hepatitis with or without cirrhosis, and cirrhosis alone. Men with alcoholic hepatitis with or without cirrhosis showed an increased incidence of the histocompatibility antigen HLA-B8 (P less than 0.02). Increased measles antibody titres were found in patients without cirrhosis with or without hepatitis and were associated with the B8 phenotype in both sexes. Rubella antibody titres and percentage DNA-binding were raised in patients with cirrhosis and showed no association with the B8 phenotype. Concentrations of IgM and IgA were were raised in patients with stetosis and with hepatitis, while in patients with cirrhosis IgG concentrations were also increased. Low titres of autoantibodies were found in all histological groups. It is possible that the development of hepatitis in response to alcohol abuse may be influenced, at least in men, by a gene linked to the B locus. Otherwise, immune processes associated with alcohol-related liver disease are probably secondary phenomena.
An epidemic of type B viral hepatitis: its course and outcome.
Between June and August, 1977 there was a small epidemic of type B viral hepatitis in a market town in South-East England during which 4 people developed acute hepatitis. Their close friends and contacts were all negative for hepatitis B surface antigen (HBsAg) at this time. One year later, in July 1978, 3 of the original 4 patients were available for follow-up. All were HBsAg negative but hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc) positive. Two had disturbed liver function tests and chronic persistent hepatitis on liver biopsy. Also at this time 2 of the original contacts were found to show evidence, from the serum markers, of previous infection by the type B virus. Both had abnormal liver function tests and showed chronic persistent or chronic active hepatitis on liver biopsy. A further subject was identified who had had an overt hepatitis 1 year previously and who also showed evidence of continuing liver disease. The origin of the epidemic and its spread through the group were identified. The varying modes of transmission, and the variation in clinical picture and sequelae are discussed. The importance of anti-HBc as a marker of hepatitis B virus infection is emphasised.
Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy.
Six patients with cirrhosis and severe chronic hepatic encephalopathy were treated with bromocriptine. All showed significant overall improvement clinically and in 3, the electroencephalogram became normal. The cerebral blood flow increased significantly from 32.7 +/- 2.4 (mean +/- 1 SE) to 40.5 +/- 1.5 ml/100 g brain/min (P less than 0.05). Similarly, there were significant improvements in the cerebral oxygen consumption from 2.2 +/- 0.4 to 3.3 +/- 0.4 ml/100 g brain/min (P less than 0.02) and in cerebral glucose consumption from 2.1 +/- 0.6 to 6.6 +/- 1.6 mg/100 g brain/min (P less than 0.02). Cross-over to placebo produced overall deterioration, more marked in the patients who had received the active drug for the shorter time period. No serious side effects were seen; the drug was well tolerated in doses of up to 15 mg daily and is a useful treatment for chronic hepatic encephalopathy when the response to conventional therapy has been poor.
Hepatic siderosis in alcoholics.
In a population of 157 (120 males, 37 females) predominantly British alcoholics with liver disease, the incidence of some degree of hepatic siderosis, as estimated by stainable parenchymal iron, was 57.3%. The incidence of significant siderosis (grades III and IV) was 7%, and was similar for both sexes. In the female alcoholics there was a significant correlation between age and the degree of siderosis (P less than 0.05)--four of the five females with significant siderosis being premenopausal. In the male alcoholics there was a significant inverse relationship between the grams of ethanol consumed per day and the degree of siderosis (P less than 0.05) and a significant correlation between the percentage saturation of iron-binding protein and the degree of siderosis (P less than 0.05). The mean daily iron intake from alcoholic beverages was 1.5 mg; there was no relationship between the amount of iron ingested in the alcohol and the degree of siderosis. In this population of alcoholics the incidence of significant siderosis in both sexes was low.
Factors affecting plasma amino acid concentrations in control subjects.
Plasma amino acid concentrations were determined in groups of normal control subjects under fasting and postprandial conditions. Differences were observed that were found to be, to a considerable extent, sex-related. Fasting females had lower concentrations than fasting males of several amino acids, although postprandial differences in concentrations between the sexes were not significant. Under the dietary conditions normal for a British population, no significant diurnal variation of plasma amino acid concentrations was found. Reducing the dietary protein by 30% failed to affect plasma amino acid concentrations; however, increasing the dietary protein by 50% resulted in a significant increase in the plasma concentrations of several amino acids, and induced a significant degree of variation throughout the day in six, proline, half-cystine, methionine, valine, leucine, and isoleucine. The importance of these results with regard to the interpretation of population mean values and disease diagnosis is discussed.
Alcohol and the liver.
This paper discusses briefly the definition of alcoholism, the extent of the problem in Britain, the roles of ethanol toxicity and malnutrition in causing liver damage, and the types of liver damage seen in alcoholics.
Portal fibrosis in the livers of alcoholic patients.
Liver biopsies in nine of 70 male alcoholics seen during a 12 month period showed predominantly portal fibrosis with fatty change, but little or no alcoholic hepatitis. None of the 30 female alcoholics seen during the same period showed this appearance. The nine men were younger and of lower socioeconomic class than the other male alcoholics, but had similar alcoholic history. Seven of the nine had chronic pancreatitis, diagnosed in six patients on the results of the pancreatic scan, Lundh meal and endoscopic retrograde pancreatography and in one because of pancreatic calcification and steatorrhoea. Serum tests for hepatitis B surface antigen were negative but five showed hepatitis B antibody. Four had serological evidence of previously treated or active syphilis compared with only one of the remaining 61 male alcoholics. Two had pulmonary tuberculosis and both had received isoniazid. Four of the other 61 alcoholics gave a history of tuberculosis similarly treated. At least one cause for the portal fibrosis other than primary alcoholic liver disease was found in all nine patients. Portal fibrosis in an alcoholic in the absence of severe alcoholic hepatitis should lead to a search for other causal factors. In particular, chronic pancreatitis should be excluded even if the patient is asymptomatic.
Plasma ratio of valine, leucine and isoleucine to phenylalanine and tyrosine in liver disease.
The molar ratio valine + leucine + isoleucine/phenylalanine + tyrosine was determined in the plasma of patients with liver disease of varying aetiology and severity and in an age and sex matched control group. In the control group of 58 subjects the mean ratio was 3.3 +/- 0.5 (ISD). The mean ratio was significantly lowered in groups of 25 patients with alcoholic cirrhosis (P less than 0.001), 25 patients with chronic active hepatitis (P less than 0.001), 23 patients with primary biliary cirrhosis (P less than 0.001), and 11 patients with cryptogenic cirrhosis (P less than 0.001). In a group of 50 patients with cirrhosis, the ratio was significantly lowered (P less than 0.001) irrespective of the presence of hepatic encephalopathy. A good correlation existed between the value of the ratio and the severity of the liver disease as judged histologically, with values of the ratio appearing to reflect histological change irrespective of the patient's clinical condition. There was no significant diurnal variation in the value of the ratio. Lowering of this plasma amino acid ratio appears to be secondary to liver disease and quite independent of the presence of hepatic encephalopathy.
Serum prolactin in liver disease and its relationship to gynaecomastia.
Serum immunoreactive prolactin was measured in 150 patients with liver disease of varying aetiology and severity and in 45 control subjects. The upper limit of the reference range for serum prolactin was 331 mU/l. Eighteen patients with liver disease (12%) had unexplained hyperprolactinaemia. No relationship existed between the prolactin value and the sex of the patient, the aetiology of the liver disease, the severity of the liver disease, or the presence of gynaecomastia. The cause of the hyperprolactinaemia in patients with liver disease and its clinical implications need further investigation.