Effect of liver disorders on ethanol elimination and alcohol and aldehyde dehydrogenase activities in liver and erythrocytes

1. Liver biopsies were performed in healthy control subjects and in subjects with alcoholic and non-alcoholic liver disease in order to examine alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase [ALDH; aldehyde dehydrogenase (NAD+); EC 1.2.1.3] activities. Erythrocyte ALDH and ethanol metabolism were also investigated in the same subjects. 2. Fifteen per cent of the subjects studied (seven of 48 subjects tested) presented atypical ADH activity, characterized by elevated activity at pH 7.4 or 8.8 compared with that found in subjects with the usual ADH form. However, the ethanol elimination curves obtained in two subjects with atypical ADH were indistinguishable from the kinetics of the group with normal ADH. Subjects displaying atypical ADH activity showed normal liver and erythrocyte ALDH activities. 3. Considering only the subjects with the normal ADH form, hepatic ADH activity was unaltered in subjects with non-alcoholic liver disease (chronic hepatitis or cirrhosis) and in those with alcoholic steatosis. Subjects with alcoholic hepatitis or alcoholic cirrhosis showed a lower ADH activity compared with the healthy control group. 4. In spite of the changes detected in subjects with alcoholic liver disease, curves of blood ethanol concentration after oral administration of 0.4 g of ethanol/kg were indistinguishable between the alcoholic hepatitis group and the control group. 5. Hepatic ALDH activity, assayed at 300 mumol/l acetaldehyde, was found to be diminished in all liver pathologies investigated, regardless of their aetiology. Nevertheless, erythrocyte ALDH activity was not modified in subjects with non-alcoholic or alcoholic liver disease. As a result of these findings, no relationship was found between hepatic and erythrocyte ALDH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between hepatic alcohol dehydrogenase activity and the ascorbic acid in leucocytes of patients with liver disease.

1. Hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content was measured in thirty-five patients with liver disease and in ten control subjects with duodenal ulcer. The patients with liver disease were divided into three groups consisting of non-drinkers, moderate drinkers and alcoholic/heavy drinkers. 2. There was no significant difference in hepatic alcohol dehydrogenase activity between the groups with liver disease, but all patients had less than half the hepatic alcohol dehydrogenase activity of the control subjects (P less than 0-001). 3. The ascorbic acid in leucocytes was significantly lower in the alcoholic/heavy drinker group than that in the control subjects (P less than 0-02) when the Student's t-test was applied, but no significant difference was found when the Mann-Whitney U-test was used. 4. A correlation coefficient of r = 0-77 (P less than 0-001) was observed among the thirty-five patients with liver disease when hepatic alcohol dehydrogenase activity was compared with leucocyte ascorbic acid content. An insignificant correlation (r = 0-332) was found in the control subjects with no liver disease. 5. This comparison was also significant among non-drinkers with liver disease (r = 0-873; P less than 0-001), moderate drinkers (r = 0-739; P less than 0-02) and alcoholic/heavy drinkers (r = 0-702; P less than 0-005). 6. The addition of ascorbic acid in vitro (0-5-10 mmol/1) had no effect on the activity of alcohol dehydrogenase. 7. The relation between hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content is probably a consequence of liver disease, as opposed to any specific effect of ascorbic acid deficiency of alcohol consumption on alcohol dehydrogenase activity.     

The aldehyde dehydrogenase activity in the erythrocytes of alcoholic patients]

Red cell aldehyde dehydrogenase (ALDH, EC 1.2.1.3) activity was measured by spectrophotometry in normal subjects and alcoholics after various periods of alcohol abstinence. ALDH was measured in all red cell hemolysate fractions; red cells were purified from hemoglobin by Sephadex CM-50 chromatography. The enzyme activity was found reduced in alcoholics' red cells as against that in controls. ALDH activities were somewhat increasing and approaching the normal values in the patients not using ethanol for 4 weeks or longer. These results recommend ALDH measurements in human red cells as a test for the detection of subjects abusing alcohol.     

1-14C]Ethanol breath test in alcoholic liver disease

The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.     

Inducing efficacy of ethanol on hepatic drug metabolizing enzymes in patients

In liver biopsy material of eighty-nine patients with suspected liver disease the drug-metabolizing function was investigated. The capacity of the liver to oxidatively metabolize drugs was assessed by determination of cytochrome P-450 dependent monooxygenase activity in vitro. The biotransformational function of these microsomal enzymes was tested with compounds representing the activity of oxidative drug metabolism (7-ethoxycoumarin, p-nitroanisol and cytochrome c). From the eight-nine patients sixty-one had various liver diseases not related to ethanol and twenty-eight abused ethanol. When both groups were matched for age, sex, smoking, treatment with sedatives, drugs and degree of liver damage the alcoholic group had significantly higher activities of 7-ethoxycoumarin O-deethylase (EOD: 76.9 +/- 31.1 pmol min-1 mg-1 protein, mean +/- SD) than the non-alcoholic liver disease group (42.7 +/- 14.1). The inducing effect of ethanol was most striking on the EOD activity, less for the O-demethylation of p-nitroanisol (PNA) and not present for the NADPH-cytochrome c reductase. The induced patients were analysed in detail to find out which factors were responsible for the observed scatter of enzyme activities within the alcoholic group. Alcoholics with fatty liver (n = 7) had the highest EOD activities (108.9 +/- 25.0), patients with alcoholic hepatitis (n = 10) had significantly less activity (66.0 +/- 1.9) than the former group. However, alcoholics without liver damage (n = 6) had activities not significantly different (46.0 +/- 15.8) from controls (39.4 +/- 9.1). These subgroups among the alcoholics were comparable in terms of sex, age, smoking and drinking habits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chlorpropamide-alcohol flush reaction and isoenzyme profiles of alcohol dehydrogenase and aldehyde dehydrogenase

To investigate the enzymatic basis of the chlorpropamide-alcohol flush reaction (CPAF) we compared the isoenzyme profiles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) from liver biopsies, and of ALDH alone from erythrocytes and leucocytes, in CPAF-positive and CPAF-negative subjects. No differences were seen in ADH or ALDH phenotypes, or in the relative activities of the isoenzymes, between the two groups before chlorpropamide was given; in particular, no subjects showed the 'null' ALDH phenotype that is associated with the alcohol flush reaction in oriental subjects. There was a significant decrease in erythrocyte ALDH activity after 7 days' treatment with chlorpropamide in CPAF-positive individuals but no such difference was seen in CPAF-negative subjects. These results indicate that CPAF has a different enzymatic basis from the alcohol flush reaction of oriental subjects and suggest that in CPAF-positive subjects erythrocyte ALDH may be particularly susceptible to inhibition by chlorpropamide.     

Cell-mediated immunity to acetaldehyde in alcoholic liver disease demonstrated by leukocyte migration test.

To determine whether a sensitization to ethanol metabolites occurs in alcoholic liver disease, reactivity of lymphocytes to nontoxic amounts of acetaldehyde was studied by direct elaboration of migration inhibitory factor (MIF) production. Eighteen alcoholics with various degrees of biopsy-proven liver damage showed increased MIF production in response to acetaldehyde; the mean value of the group differed significantly from 15 healthy controls, 15 subjects with nonalcoholic liver disease, and 15 alcoholics without liver involvement (P less than 0.001, P less than 0.001, P less than 0.02, respectively). Among the alcoholics with liver disease, none individuals (50%) with histological signs of advanced alcoholic hepatitis showed the highest percentage of inhibition of migration; the value differed significantly from the remaining patients with lesser degrees of hyaline necrosis in liver biopsies (P less than 0.005). These results indicate that acetaldehyde is involved in the pathogenesis of alcoholic hepatitis. Clinically, this test might facilitate the selection of patients with alcoholic hyaline necrosis.     

Optimized spectrophotometric determination of aldehyde dehydrogenase activity in erythrocytes.

We describe a reliable and sensitive semiautomated spectrophotometric assay of aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activity in erythrocytes. The hemolysate can be stabilized with sucrose, and the technique involves only microliters of hemolysate on a centrifugal analyzer. The use of microcolumns to remove interfering hemoglobin is avoided, and reproducibility of the assay has been improved by manipulating the inherent lactate dehydrogenase activity of erythrocytes by adding lactate and oxalate to the reaction mixture. These modifications have decreased the analytical imprecision of the assay, allowing a better appraisal of aldehyde dehydrogenase activity in erythrocytes as a biological marker of excess alcohol consumption. Erythrocytic ALDH activity was significantly less in 40 alcoholics than in 145 teetotallers (median activity 128 vs 219 mU/g of hemoglobin, respectively; P = 0.0001), indicating the potential of this assay as a useful marker of excess alcohol consumption.     

Assessment of erythrocyte delta-aminolaevulinate dehydratase for outpatient detection of alcoholic liver disease: comparison with gamma-glutamyltransferase and casual blood ethanol.

An enzyme temporarily depressed by alcohol ingestion, erythrocyte delta-aminolaevulinate dehydratase (delta-ALAD), was compared with afternoon casual blood ethanol and plasma gamma-glutamyltransferase (gamma-glutamyltransferase (gamma-GT) simultaneously measured in outpatients. These comprised 37 individuals with chronic alcoholism, of whom 14 had severe liver disease, 22 patients with non-alcoholic liver disease and 24 healthy control subjects. All tests distinguished poorly between those alcoholics with, and those without histological liver damage. The highest specificity for alcoholism was achieved by gamma-ALAD; the best overall performance, with highest sensitivity and specificity was, however, gamma-GT. Although there was no correlation between the results of tests in individuals, 32/37 (87%) of alcoholics had at least one of the three tests abnormal compared with 8% of controls and 64% of non-alcoholic liver disease patients. The tests are therefore complementary and may form a battery of tests for problem drinking and its physical consequences.     

Erythrocyte and leukocyte lipids in alcoholic macrocytosis

Erythrocytes and leukocytes were obtained from patients with alcoholic macrocytosis and their lipid composition compared with those from normal subjects. The patients had normal plasma cholesterol and fasting triglyceride levels with mild and fully compensated liver disease. There was no difference in the lipid composition of leukocytes from alcoholics compared with controls. Erythrocytes from patients with alcoholic macrocytosis had increased cholesterol content. The increased cholesterol content correlated with the MCV but there was no correlation between plasma and erythrocyte cholesterol. There was a decrease in erythrocyte phosphatidylethanolamine in alcoholic macrocytosis. There was no change in the fatty acid composition of the phospholipid fraction but there was an increase in the amount of linoleic acid in phosphatidylethanolamine. The double bond index, non-essential-to-essential fatty acid ratio and double bond index to saturated fatty acid ratio for the erythrocyte phospholipids were unchanged in alcoholic macrocytosis. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of erythrocyte membrane proteins from patients with alcoholic macrocytosis and control subjects showed no significant differences.     

Psychiatric outcome in alcoholic liver transplant patients

We investigated drinking behaviour and psychiatric outcome ofpatients with alcoholic liver disease after liver transplantation,to help assess the advisability of the procedure in these patients.English-speaking patients (n = 20) transplanted for alcoholicliver disease and informants, and patients transplanted fornon-alcoholic liver disease (n = 54), were assessed by semi-structuredinterviews and standardized questionnaires 1–6 years followingtransplantation. All alcoholics were abstinent for several monthsafter transplantation, but only one patient remained totallyabstinent. Sixteen of the 20 alcoholics later returned to regulardrinking; the mean daily alcohol consumption was 3.5 units.Forty percent of the group were drinking above the recommendedsafe levels for the general population and over 50% were ‘binge’drinking intermittently. The alcoholic liver transplant patientsdid not have higher levels of psychiatric or physical morbiditythan controls. Patients with alcoholic liver disease returnto drinking after a period of abstinence following liver transplantation,although at lower levels than before. Their vulnerability toalcohol abuse is not explained by higher levels of physicalor psychiatric morbidity.     

Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are most abundant in the liver, are the main enzymes involved in ethanol metabolism in humans. Gender-related differences in total liver ADH and ALDH activity among different animal species have been observed in many studies. We measured total ADH and ALDH activity, and the activity of class I-IV ADH in the livers of male and female patients. Total ADH and class I and II ADH activities were significantly higher in males than in females (P=0.0052, P=0.0074, P=0.020, respectively). Class III and IV ADH and total ALDH activities were not significantly different between the genders (P=0.2917, P=0.0590, P=0.2940, respectively). The results of our study clearly show that there is a difference in enzymatic activity between male and female patients for those isoenzymes that actively participate in ethanol oxidation in the liver (class I and II ADH), although the main form of ADH in this organ is class III ADH.     

Effect of age and sex on allyl alcohol hepatotoxicity in rats: role of liver alcohol and aldehyde dehydrogenase activities

Allyl alcohol-induced hepatotoxicity was more severe in old male rats than in young-adult male rats, as measured by release of hepatic enzymes from injured cells and loss of hepatic microsomal cytochrome P-450. The extent of toxicity in female rats was greater than in males and was unaffected by aging. The purpose of this study was to examine possible causes for these differences. The activity of alcohol dehydrogenase (ADH) with allyl alcohol as substrate was measured in liver cytosolic fractions of rats at ages representing young adulthood, middle age and old age. ADH activities were 1.7 +/- 0.1, 2.3 +/- 0.1 and 2.6 +/- 0.1 mumol/min/g of liver in male rats aged 4, 14 and 25 months, respectively. ADH activities in young-adult and old female rats were 3.8 +/- 0.1 and 3.7 +/- 0.1 mumol/min/g of liver. There was a good correlation (r = 0.99, P less than .001) between liver ADH activity and allyl alcohol-induced hepatotoxicity, measured as the release of sorbitol dehydrogenase into the bloodstream. Cytosolic free NAD+/NADH ratios in male rats were not significantly different among the three age groups; the ratios were lowest in young-adult female rats. Low Km aldehyde dehydrogenase activities in liver mitochondrial and cytosolic fractions were similar among the three age groups of male rats, and the activities in female rats were not substantially different. The results indicated that increased ADH activity is the principal cause of the age-associated enhancement of allyl alcohol hepatotoxicity in male rats.     

Serum paraoxonase-1 in chronic alcoholics: relationship with liver disease

OBJECTIVES: To investigate the relationship between serum paraoxonase-1 and liver damage in chronic alcoholic patients. To assess the diagnostic accuracy of paraoxonase-1 plus standard biochemical tests in the assessment of liver damage in alcoholics. DESIGN AND METHODS: We studied 328 chronic alcoholics and 368 healthy individuals. RESULTS: Paraoxonase-1 activity was decreased and the concentration was increased in alcoholics (P<0.001). The enzyme activity was correlated with albumin (r=0.45; P<0.001) and prothrombin time (r=0.49; P<0.001). Addition of paraoxonase-1 activity measurement to a battery of biochemical tests increased the sensitivity in differentiating between patients and controls up to 96.6% but did not improve the sensitivity in differentiating between subgroups of alcoholics. CONCLUSIONS: Paraoxonase-1 was related to the severity of alcoholic liver disease. Its measurement was useful in discriminating between patients and healthy subjects, but did not add any valuable information in subgroups of alcoholics.     

Free and total carnitine and acylcarnitine content of plasma, urine, liver and muscle of alcoholics

1. Plasma and urine free and total carnitine and acylcarnitine levels were assayed in 12 control subjects and 20 chronic alcoholics with fatty liver. Although the alcoholics had a wider range of values than the controls, there was no significant difference between the two groups. 2. Hepatic free and total carnitine and long- and short-chain acylcarnitines were assayed by a radioenzymatic method in samples from seven control subjects and seven alcoholics. No significant differences in any of the indices were noted between the patient and control groups and it was concluded that carnitine deficiency did not contribute to alcoholic fatty liver in patients without cirrhosis. 3. Skeletal muscle free and total carnitine and long- and short-chain acylcarnitines were assayed in eight alcoholics and seven control subjects. The alcoholics had significantly higher total and free carnitine levels. It is suggested that this reflects a selective enrichment of the biopsy sample with type I carnitine-rich fibres due to the type II fibre atrophy found in approximately half the patients.     

Serum carnosinase activities in patients with alcoholic chronic skeletal muscle myopathy

1. Serum carnosinase activity was assayed in a group of alcoholic patients with and without histologically proven atrophy of type II skeletal muscle fibres, and in control subjects. No significant activity was detected in muscle biopsy samples or washed erythrocytes. 2. Serum carnosinase activity was significantly lower in chronic alcoholic patients compared with a group of age-matched controls. Alcoholics with abnormal muscle biopsies had significantly lower enzyme activities than either those patients with normal muscle biopsies or the controls. Serum enzyme activities in patients with normal muscle biopsies were not significantly different from controls. 3. Serum carnosinase activity was inversely correlated with the degree of muscle atrophy as measured by the type II fibre atrophy factor. There was a positive correlation between the enzyme activity and skeletal muscle mass as reflected by the creatinine-height index. Furthermore, the enzyme activity significantly increased, with resolution or improvement in the myopathy, in patients who abstained from alcohol. 4. Kinetic studies showed that the reduced carnosinase activity was due mainly to a decrease in the apparent Vmax. The apparent Km was significantly higher in the myopathic compared with non-myopathic alcoholics. Mixing serum from controls and patients with myopathy gave the expected values, indicating the absence of a serum enzyme inhibitory factor. Acute alcohol loading had no effect on the serum carnosinase activity. 5. The decrease in serum carnosinase activity in alcoholics was not related to the severity of their liver disease. Assays of serum carnosinase in chronic alcoholics, can thus be used as a marker of their associated myopathy.     

Duodenal gamma-glutamyltransferase activity in human biopsies: effect of chronic ethanol consumption and duodenal morphology

Gamma-glutamyltransferase activity was determined in duodenal biopsies, and in the sera of forty-six non-alcoholic and eighteen alcoholic patients with a daily alcohol consumption of more than 80 g. Additionally, duodenal morphology was examined in biopsy material obtained at the same time. In both alcoholics (P less than 0.05) and in non-alcoholics (P less than 0.001) the duodenal gamma-glutamyltransferase activity revealed a significant positive correlation with duodenal villus length. In addition, alcoholics exhibited a significant decrease in duodenal villus length (338 +/- 13 vs. 363 +/- 13 microns, P less than 0.01), and a significant increase in duodenal gamma-glutamyltransferase activity (13.0 +/- 1.4 vs. 8.4 +/- 0.6 mU mg-1 protein, P less than 0.01) when compared to controls. No significant correlation was found between duodenal and serum gamma-glutamyltransferase activity in alcoholics and non-alcoholics. During follow up of two patients, duodenal gamma-glutamyltransferase activity decreased and duodenal villus length increased after withdrawing alcohol. These data underline the damaging effect of alcohol on the duodenal mucosa and demonstrate that chronic alcohol intake reversibly effects duodenal gamma-glutamyltransferase. In addition, the small intestine appears of minor importance as an origin for the elevated serum gamma-glutamyltransferase activities seen in the alcoholic.     

Autonomic neuropathy and chronic liver disease

Autonomic neuropathy has been reported in association with alcoholic cirrhosis but there is no information on its occurrence in non-alcoholic liver disease. We have examined autonomic function in 64 patients with biopsy-proven liver disease (22 with alcoholic liver disease and 42 with non-alcoholic liver disease) together with 29 age-matched controls. Forty-five per cent of patients with alcoholic liver disease and 43 per cent with non-alcoholic liver disease showed evidence of parasympathetic damage; 11 per cent of patients with alcoholic liver disease and 12 per cent with non-alcoholic liver disease had sympathetic damage. Forty-five per cent of patients with alcoholic liver disease and 22 per cent with non-alcoholic liver disease had peripheral neuropathy on clinical examination. Sixty-eight per cent of those with peripheral neuropathy also had autonomic neuropathy. This study confirms that autonomic neuropathy is common in alcoholic patients but the fact that it is found with comparable frequency in non-alcoholic liver disease suggests that the neurological defect may be secondary to the disturbed liver function. The implications of these observations with regard to prognosis of chronic liver disease are discussed.     

Ethanol and galactose metabolism as influenced by 4-methylpyrazole in alcoholics with and without nutritional deficiencies. Preliminary report of a new approach to pathogenesis and treatment in alcoholic liver disease.

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.     

Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer

The principal enzymes catalyzing the conversion of ethanol to acetate are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The activities of these enzymes are elevated in the serum during the course of alcoholism or cirrhosis. In previous investigations we have found elevated levels of ADH, ALDH, and class I ADH activity in liver cancer cells. It can suggest that these changes may be reflected by enzyme activity in the serum. In this work, the activity of ADH isoenzymes, and ALDH in the sera of patients with liver cancer was measured. Serum samples were taken from 64 patients (28 drinkers, 36 nondrinkers), with liver cancer. 25 patients had primary and 39 metastatic liver tumors. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorimetric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorimetric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. A statistically significant increase of class I ADH isoenzymes was found in the sera of cancer patients. The median activity of this class isoenzyme in the total cancer group increased about 51% (2.94 mU/L) in the comparison to the control level (1.43 mU/L). The activity of the class I ADH isoenzyme was significantly higher in the sera of patients with metastatic tumors than with primary cancers. The activity of this class in the sera of drinkers and group of moderate drinkers was significantly higher in comparison to the control group and higher in the sera of heavy drinkers when compared with moderate drinking patients. The total ADH activity was significantly higher (44%) among patients with cancer than healthy ones. The activity of class I ADH isoenzymes was elevated only in the serum of patients with metastatic liver cancer. This increase of activity seems to be caused by the enzyme released from liver cancer cells and primary tumors originating in other organs.