Biomedical subjects
Publications and source records attributed to M P Salaspuro.
A new method for measuring "free" acetaldehyde in plasma, the author's procedure avoids the precipitation of protein and almost completely eliminates the spontaneous formation of acetaldehyde from ethanol.
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In baboons blood ethanol disappearance was 11.6% faster at high ethanol (HE) concentrations (45-20 mM) than at low ethanol concentrations (LE) (15-5 mM). The feeding of alcohol in a liquid diet for three months or up to five years augmented the difference between HE and LE to 14 and 28.6% respectively. These results were confirmed in a preliminary experiment with a human volunteer given ethanol for four weeks under metabolic ward conditions. The findings are in favour of the existence and induction of a non-ADH high Km pathway for ethanol oxidation. The common medicolegal practice of calculation previous blood-ethanol levels by linear extrapolation should be re-considered.
Infusion of ethanol (0.6 g/kg body wt) caused marked hypoglycaemia in subjects fasted for 36 h. Previous administration of the alcohol dehydrogenase (ADH) inhibitor 4-methylpyrazole (4-MP, 7 mg/kg body wt i.v.) strongly suppressed the ethanol-induced hypoglycaemia. The rate of ethanol elimination was 84.6 mg/kg per hour. 4-MP at the dose used caused a 21% reduction of ethanol elimination, but had no significant effect on blood acetaldehyde levels. 4-MP also significantly suppressed the ethanol-induced elevation of blood lactate and almost completely prevented the increase in the 3-hydroxybutyrate/acetoacetate ratio, but had only a slight effect on the lactate/pyruvate ratio of venous blood. The results demonstrate that the hypoglycaemia and lactacidaemia produced by the oxidation of alcohol can be prevented by a dose of 4-MP that diminishes or prevents the ethanol-induced shift in the NAD-coupled redox state of the liver.
The effect of alcohol on cardiac rhythm was examined in ten male volunteers with a history of acute myocardial infarction. ECG monitoring with a portable ECG recorder was carried out for a period of 48 hours. After a control period of 15-18 hours an exercise test was performed and repeated after a standard dose (0.5 g/kg b.wt.) of alcohol. Then the patients were allowed to drink alcohol freely for two and half hours. The third exercise test was performed on the second morning. Heart rate at rest and sitting on a bicycle was highest in the third test, during the "hangover" period (p less than 0.05). With a submaximal work load heart rate, and also the heart rate-blood pressure pressure product, were highest after a standard dose of alcohol in the second test (p less than 0.05 and less than 0.01 respectively). The number of ectopic beats showed no significant difference in repeated exercise tests. On tape recordings, however, five of the ten patients experienced changes in cardiac rhythm after alcohol. In two patients the number of ectopic beats increased, the third patient had three successive ventricular ectopic beats after alcohol ingestion and in the fourth patient multiple sinus arrests occurred. In one patient a higher heart rate after alcohol ingestion abolished the ventricular ectopic focus seen during the control period.
The familial occurrence of immunological, virological, biochemical and histopathological abnormalities has been studied in 39 first degree relatives of patients with primary biliary cirrhosis (PBC) and in 58 first degree relatives of patients with chronic active hepatitis (CAH). Tissue antibodies were more frequent in relatives than in age- and sex-matched controls. Abnormal immunoglobulin levels were demonstrated in about half of the relatives. Very high antibody titres to measles and rubella occurred only in the relatives of the patients with CAH. Moreover the raised titres tended to be clustered in a few families in which also the propositi had very high viral antibody titres. Liver biopsy was performed only on the relatives with biochemical abnormalities. Unspecific inflammatory changes were observed in 5 relatives of the patients with CAH and in 4 relatives of the patients with PBC. An active liver disease was detected in two relatives of the PBC-group and in one of the CAH-group. A marked accumulation of various immunological and histopathological abnormalities in four families was observed.
Liver specimens from 103 patients with various hepatic diseases and from 297 consecutive liver biopsies examined routinely were stained with orcein after oxidation of the tissue sections with potassium permanganate. Orcein-positive dark brown cytoplasmic material could be demonstrated in 27 cases with long-standing cholestasis. These patients had either primary biliary cirrhosis, the cholestatic liver disease of ulcerative colitis or chronic active hepatitis, advanced alcoholic cirrhosis or secondary biliary cirrhosis due to extrahepatic biliary obstruction. Orcein-positive material could not be demonstrated in congenital disorders of bilirubin metabolism or in hemochromatosis. Similarly, it could not be found in acute, toxic, alcoholic or chronic persistent hepatitis.
The histological criteria of chronic hepatides (chronic persistent and aggressive hepatitis) and primary biliary cirrhosis are well characterized and documented in the literature. Histology forms the diagnostic basis for chronic hepatides. Diagnostic changes are seen, however, only in some cases of primary biliary cirrhosis (PBC) and only in the early stages of the disease. Difficulties are met especially in differentiating PBC from chronic aggressive hepatitis (CAH). There is a considerable histological overlap and mixed forms occur. Orcein-positive material, which is a copper-binding protein with high content of sulphydryl groups, accumulates in liver cells in long standing cholestatic liver diseases and can be demonstrated histochemically in routine biopsy specimens. It is seen in PBC in at least 70% of biopsy specimens which confirms the biliary nature of the disease. In CAH orcein positive material can be demonstrated in 20% of specimens but only from patients who also have features of PBC. This group of patients may therefore have both biliary disease are hepatocellular damage, and can be separated from CAH by the orcein method.
Clinical, biochemical and immunological variables were analyzed in 30 patients with orcein-negative (ON) chronic active hepatitis (CAH), 4 patients with ON primary biliary cirrhosis (PBC), 8 patients with orcein-positive (OP; intracellular copper-binding protein seen histologically in liver biopsy specimens) CAH and 15 patients with OP-PBC. A marked elevation of serum bile acids, alkaline phosphatase, leusine aminopeptidase, gammaglutamyl transpeptidase and cholesterol concentrations, and highly pathological BSP Tm values were characteristic for OP-cases. In addition the faecal fat level was increased and bile acids decreased in OP-cases. Serum levels of IgG or IgM and the occurrence of smooth muscle, mitochondrial or glomerular antibodies were identical in ON- and OP-CAH as well as also in ON- and OP-PBC. 49 patients were treated with a combination of prednisone and azathioprine from 4 to 72 months (mean 22). 26 patients with ON-CAH responded biochemically and morphologically to the treatment. No treatment failures were found in ON-CAH. In contrast treatment failure was confirmed in every treated OP-PBC or OP-CAH. The results suggest that orcein-positivity indicates a poor response to prednisone-azathioprine treatment of CAH.
4-Methyl pyrazole (4-MP, a specific inhibitor of alcohol dehydrogenase) reduced ethanol elimination by 30-50% and completely removed the ethanol-induced inhibition of galactose elimination in 2 control subjects. Ethanol elimination was accelerated in 2 alcoholics with adequate nutrition, but the effect of 4-MP was comparable to that in controls. In 2 other alcoholic subjects, who reported poor nutritional intake, intermediate rates of ethanol elimination were observed and 4-MP had almost no effect on ethanol or galactose elimination. These results suggest that alcohol abuse may result in an increased contribution to ethanol elimination by pathways other than that involving alcohol dehydrogenase (ADH) and that the decreased contribution from ADH, possibly potentiated by inadequate nutrition, may diminish the ethanol-induced shift in the NAD-coupled redox state. Since liver damage produced by alcohol abuse is believed to be related to changes from the normal redox state caused by ethanol, these results may explain why alcoholic liver damage is uncommon in alcoholics living on a marginal diet. Since 4-MP effectively eliminates the ethanol-induced shift in the redox state, a therapeutic trial with 4-MP in alcoholics with a high risk for liver disease is indicated.
Liver biopsies from 18 patients with primary biliary cirrhosis (PBC) and from 25 patients with chronic active hepatitis (CAH) were stained by orcein after oxidation of the tissue sections with potassium permanganate. In 15 out of the 18 cases which could be classified on clinical, biochemical and immunological basis as PBC, the hepatocytes, usually periportally, contained cytoplasmic stainable material. 5 out of the 25 CAH patients contained the same material, but four of these patients were clinically atypical and showed features of cholestatic form of CAH and features crosslinking with PBC. All patients in both groups were serologically hepatitis-B antigen negative. The orcein staining method seems to be a reliable addition to differentiating histologically between PBC and CAH.