Cimetidine for prevention of acute gastrointestinal bleeding.
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Acute Disease↗
Biomedical subjects
H L Bonkowsky
Publications and source records attributed to H L Bonkowsky.
Metabolism of hepatic haem and 'green pigments' in rats given 2-allyl-2-isopropylacetamide and ferric citrate. A new model for hepatic haem turnover.
We have studied effects of single doses of 2-allyl-2-isopropylacetamide and ferric citrate on hepatic haem turnover in rats. Haem was pre-labelled by intraperitoneal administration of 5-amino-[4-(14)C]laevulinate 4h before other treatments. Computer-assisted analysis of the haem decay curve showed that at least two exponential components were involved implying two haem pools. In control rats the size of the rapidly-turning-over pool was 38% of the total. Treatment with 2-allyl-2-isopropylacetamide alone resulted in a 2.3-fold increase in the fractional size of this pool. Treatment with ferric citrate alone increased the size of this pool 1.8-fold; treatment with both agents together had no measurable effect beyond that produced by 2-allyl-2-isopropylacetamide. The apparent rate constant for disappearance of labelled haem from the first pool was not affected by treatment with 2-allyl-2-isopropylacetamide or ferric citrate, indicating that these treatments affect hepatic haem turnover primarily by altering the distribution of haem synthesized in the liver. The increased haem degradation after treatment with 2-allyl-2-isopropylacetamide alone was associated with the accumulation of ;green pigments' in the liver. These pigments were detectable 1.5h after drug treatment; their total amount increased steadily for 28h and then declined. Despite this increase in amount, radioactivity of the ;green pigment' fraction fell rapidly in a biphasic fashion. Some of the radioactivity that initially was found in the ;green pigment' fraction was later found in an aqueous fraction, not extractable by acidic ethyl acetate. Rats given ferric citrate together with 2-allyl-2-isopropylacetamide accumulated less ;green pigments'.
Acetamides↗
Pulmonary hypertension as a presentation of hepatocarcinoma. Report of a case and brief review of the literature.
A case, unique in the literature, is reported in which a primary carcinoma of the liver presented a right-sided heart failure and pulmonary hypertension. The diagnosis of hepatocarcinoma was established by needle biopsy of the liver. Later, postmortem examination demonstrated that the pulmonary arterial tree was severely compromised by multiple tumor microemboli, despite the persistent lack of characteristic roentgenographic abnormality in our patient. In reviewing the literature, we found rare cases of occult renal cell carcinoma, choriocarcinoma and one of occult hepatocarcinoma, which presented as pulmonary embolism. These were diagnosed by pulmonary embolectomy, human chorionic gonadotrophin levels or autopsy, respectively. In another small group of reported cases of known carcinoma (gastric, breast, colonic) the patients had a clinical picture of "idiopathic" pulmonary hypertension or of pulmonary hypertension with pulmonary metastases. Pulmonary hypertension in these cases resulted from carcinomatous lymphangitis and/or tumor microembolization, as in our case. We report this case to emphasize the necessity of including occult carcinoma in the differential diagnosis of pulmonary hypertension and right ventricular failure.
Carcinoma, Hepatocellular↗
Experience with the red cell uroporphyrinogen synthase (URO-S) assay in kindreds with acute intermittent porphyria (AIP).
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Acute Disease↗
Seizure management in acute hepatic porphyria: risks of valproate and clonazepam.
Seizures may occur in acute intermittent porphyria or other hepatic porphyrias. Management is difficult, because barbiturates and hydantoins exacerbate the porphyric state. We studied one patient with major motor seizures and acute intermittent porphyria. The seizure disorder was exacerbated by phenytoin and did not respond to a high-carbohydrate diet or to intravenous hematin. Clonazepam was ineffective in treating the seizures and, in high doses, seemed to exacerbate the porphyria. Both clonazepam and valproate were porphyrinogenic in experimental test systems. Because both drugs may exacerbate the acute hepatic porphyrias, bromide remains the drug of choice to treat these seizures.
5-Aminolevulinate Synthetase↗
Hormonal requirements for the induction of cytochrome P-450 in hepatocytes cultured in a serum-free medium.
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Animals↗
Evidence for multiple sites of regulation of heme synthesis in murine erythroleukemia cells.
Friend murine erythroleukemia (MEL) cells can be induced to differentiate along the erythroid pathway by such dissimilar agents as dimethyl sulfoxide (DMSO), butyrate, inhibitors of DNA synthesis, and certain highly polar agents. This study showed differential biochemical effects of the potent inducers DMSO and butyrate on the heme biosynthetic pathway in three clones of Friend MEL cells. When the cells were incubated with combinations of DMSO and butyrate, hemoglobin production was less than that amount produced when each inducer was incubated singly with the cells. Procaine, a local anesthetic that competes with Ca2+ and thus affects membrane permeability, slightly inhibited DMSO-mediated hemoglobin production but almost tripled the level stimulated by butyrate alone. Similarly, EDTA, which also can bind Ca2+ and which can modify the activity of heme biosynthetic enzymes, also inhibited hemoglobin production mediated by DMSO, whereas it stimulated hemoglobin production in cells exposed to butyrate. Total porphyrin accumulation was greater in DMSO-treated cells than in butyrate-treated cells, which suggests that butyrate induces the enzymes of the heme pathway more efficiently than does DMSO. DMSO and butyrate may affect the heme biosynthetic pathway by multiple mechanisms or, alternatively, they may affect the multistep pathway at various points, producing partial blocks or incomplete enzyme induction.
Animals↗
Iron and the liver: subcellular distribution of iron and decreased microsomal cytochrome P-450 in livers of iron-loaded rats.
To understand better the intracellular iron distribution and metabolic consequences of chronic hepatic iron overload, rats were given large doses of iron dextran or ferric citrate intraperitoneally. They accumulated large quantities of iron within Kupffer cells and hepatocytes. The relative subcellular iron distributions were similar in controls and iron-loaded rats, despite a ten- to 20-fold difference in hepatic iron concentration. Electron microscopy of whole liver and subcellular particulate fractions suggested that iron was present in highest concentration in lysosomes, which were rendered more labile by its presence. Nevertheless, quantitative iron determinations on all subcellular fractions, obtained by two preparative methods, showed that most of the iron was present in the "soluble" fraction. The amount of iron in the "microsomal" fraction varied, depending on the techniques used for preparation of this fraction. Cytochrome P-450 and total heme concentrations were decreased 40% to 50% in microsomes isolated from iron-loaded livers.
Animals↗
Chronic hepatic inflammation and fibrosis due to low doses of paracetamol.
Chronic hepatic necrosis developed in a man who had been taking 4 g of paracetamol daily for about a year (cumulative dose 1700 g). Liver biopsy done 23 days after the drug was stopped showed prominent diffuse central necrosis and portal changes. Repeat biopsy 5 months later showed chronic active hepatitis. This prompted anti-inflammatory treatment, with subsequent improvement in liver histology. Liver concentrations of reduced glutathione and paracetamol metabolism, assessed 1-1 1/2 years after drug was stopped, were normal; the basis for this patient's drug sensitivity is thus unclear. In some patients, chronic ingestion of therapeutic doses of paracetamol may produce hepatic necrosis and hepatitis which persist long after the drug has been discontinued.
Acetaminophen↗
Assay of delta-aminolevulinic acid synthetase in homogenates of mouse, rat, and human liver: species differences in requirement for an exogenous succinyl-CoA-generating system.
Conditions required for optimal assay of low levels of activity of hepatic delta-aminolevulinic acid synthetase have been studied, comparing dilute homogenates of mouse, rat, and human livers. The assay method used was a modification of that described by Ebert et al. (Biochim, Biophys, Acta (1970) 208, 236-250), and livers were studied from both untreated animal and human subjects and subjects pretreated with porphyrinogenic compounds. In homogenates of mouse and human but not rat liver, maximal rates of delta-aminolevulinic acid formation required addition to the incubation mixture of an exogenous system for succinyl-CoA generation. The requirement for this generating system was increased if livers from pretreated subjects were frozen and stored prior to assay, suggesting that the endogenous capacity for succinyl-CoA generation was more labile than delta-aminolevulinic acid synthetase under these conditions. Of the metabolic inhibitors tested (F-, malonate, and arsenite), only F- (100 mM final concentration) enhanced activity. Increasing the permeability of mitochondria by quick freeze-thawing of fresh homogenates just before assay did not increase the rate of delta-aminolevulinic acid formation.
5-Aminolevulinate Synthetase↗
Human hepatic delta-aminolaevulinate synthase: requirement of an exogenous system for succinyl-coenzyme A generation to demonstrate increased activity in cirrhotic and anticonvulsant-treated subjects.
1. We have studied activity of delta-aminolaevulinate synthase in needle liver biopsy specimens obtained from 12 human cirrhotic subjects, five subjects who had ingested anticonvulsants and from control subjects. Liver iron concentrations and quantitative urinary excretions of porphyrins plus their precursors were also determined. 2. In liver homogenates from subjects of each group, addition of an exogenous system for generation of succinyl-coenzyme A (CoA), including succinic thiokinase, resulted in appreciable enhancement of activity beyond that obtained without this system. 3. Mean activities for delta-aminolaevulinate synthease were not significantly different among patient groups when assayed without the exogenous succinyl-CoA-generating system, but liver homogenates from cirrhotic patients and subjects ingesting anticonvulsants had significantly higher activities than control subjects in the presence of the succinyl-CoA-generating system. 4. Although mean liver iron concentration in the cirrhotic group was slightly higher than in control subjects, and in control subjects there was some correlation between liver iron concentration and activity of delta-aminolaevulinate synthase, variations in this activity could not be accounted for solely on the basis of chronic hepatic deposition. Nor were these variations ascribable to differences among subjects in ingestion of ethanol before biopsy or severity of hepatic inflammation as judged biochemically and histologically. 5. Cirrhotic subjects excreted more uro- and copro-porphyrin than control subjects, whereas subjects ingesting anticonvulsants excreted more delta-aminolaevulinic acid and porphobilinogen than control subjects. However, these increases were small and not sufficient to account for all the increased delta-aminolaevulinic acid which potentially could have been formed by these subjects. 6. These considerations raise the possibilities that in vivo: (a) rate of human hepatic synthesis of delta-aminolaevulinic acid is modulated by the supply of succinyl-CoA; (b) the rate of hepatic synthesis of haem is increased in cirrhotic patients and subjects ingesting anticonvulsants; (c) other important routes exist for disposition of haem precursors in these subjects, besides utilization for haem synthesis.
5-Aminolevulinate Synthetase↗
Colitis and hepatitis caused by methyldopa.
Acute, severe colitis and hepatitis developed in a 55-year-old man on two occasions in relation to administration of methyldopa. He also had fever, skin rash, and eosinophilia, suggesting drug allergy. All symptoms and signs remitted after he stopped taking the drug. It appears that this agent is capable of producing acute colitis as well as the previously recognized hepatitis.
Acute Disease↗
Inheritance in protoporphyria. Comparison of haem synthetase activity in skin fibroblasts with clinical features.
The activity of haem synthetase, the enzyme which chelates iron to protoporphyrin to form haem, was measured in cultured skin fibroblasts of children with protoporphyria and their parents from three families. In each family, one parent had deficient haem synthetase activity (3-0-11-1 pmol protohaem formed/mg protein/h) when compared to values in eight non-porphyric controls (means 24-9, range 13-7-51-5). The level of activity in the three parents was similar to that in their affected children. In two families the parent with deficient activity was also thought to be the carrier of the abnormal gene, as judged from a history of photosensitivity and analysis of erythrocyte protoporphyrin concentrations, but in the third family the pattern of inheritance could not be determined from these criteria. The activity of delta-aminolaevulinic acid synthetase was normal in cultured fibroblasts from the protoporphyric children and their parents, excluding a generalised defect in haem-pathway enzymes. These results support the premise that deficient haem synthetase activity, inherited in an autosomal dominant patter, is the primary defect in protoporphyria.
Adolescent↗
Comparative effects of glycerol and dextrose on porphyrin precursor excretion in acute intermittent porphyria.
The effects of dietary manipulations on excretion of the porphyrin precursors, delta-aminolevulinic acid (ALA), and porphobilinogen (PBG) were studied in eight patients with acute intermittent porphyria. Three diet periods of 9-17 days comprised each study. In each patient, a "baseline" protein, fat, and carbohydrate intake was kept constant throughout. In addition, during the first diet period each patient received 150 g dextrose; during the second, this was replaced by an isocaloric amount of neutral fat; and during the third, the fat was replaced by 150 g glycerol. In each of the patients, three comparisons of the effect of diet on both ALA and PBG excretion were made: (1) 300 g carbohydrate versus 150 g carbohydrate (dextrose versus fat), (2) 150 g carbohydrate + 150 g glycerol versus 150 g carbohydrate (glycerol versus fat), and (3) 300 g carbohydrate versus 150 g carbohydrate + 150 g glycerol (dextrose versus glycerol). For each of these three diet comparisons, there are sixteen individual comparisons possible for the effect of diet on porphyrin precursor excretion, eight for ALA and eight for PBG. Thus, the mean values for ALA and PBG excretions during each of the diet periods are statistically compared internally within each individual patient. Increasing carbohydrate intake from 150 g to 300 g by isocaloric substitution of dextrose for fat produced a significant (p less than 0.05) decline in eight of the sixteen comparisons of ALA and PBG excretion. Addition of 150 g glycerol by isocaloric substitution for fat caused a significant (p less than 0.05) decline in nine of the sixteen possible comparisons. In the sixteen comparisons of isocaloric dextrose and isocaloric glycerol-substituted diets, dextrose produced significantly (p less than 0.05) lower porphyrin precursor excretion in four cases and glycerol produced significantly (p less than 0.05) lower values in five. One patient showed no significant change on any of the diets. Of the four patients having symptoms believed referrable to porphyria during the study, three reported an improvement in symptoms during the high glycerol intake. The effects of dietary perturbations on porphyrin precursor excretion in acute intermittent porphyria are variable, but glycerol appears to be capable of decreasing the excretions and may prove useful in treating some of these patients.
Acute Disease↗
Acute granulomatous hepatitis. Occurrence in cytomegalovirus mononucleosis.
Two previously healthy adults with acute granulomatous hepatitis attributable to cytomegalovirus (CMV) monucleosis had prolonged fever, heterophil-negative lymphocytosis with numerous atypical forms, minor alterations in hepatic function, and evidence on biopsy, of a nonspecific acute hepatitis with granulomata. Infection with CMV was corroborated by a rising titer of complement-fixing antibody in case 1 and by a high titer of antibody that later fell in case 2. It is important to exclude CMV ivfection as an etiologic factor in cases of acute granulomatous hepatitis and fever of unknown origin.
Acute Disease↗
Heme synthetase deficiency in human protoporphyria. Demonstration of the defect in liver and cultured skin fibroblasts.
The final step in heme biosynthesis is chelation of porphyrin with Fe++ catalyzed by the mitochondrial enzyme heme synthetase. We have employed a sensitive radiochemical assay for this enzyme, using 59Fe and deuteroporphyrin or protoporphyrin as substrates. In this method iron is maintained in the ferrous state, oxygen is excluded from the incubation system, and labeled heme product is extracted into ethyl acetate. This assay has been used to measure the activity of heme synthetase in homogenates of liver, obtained by needle biopsy, and in sonicates of human skin fibroblasts, cultured in vitro. In addition, activity of the first enzyme of the heme synthetic pathway, delta-aminolevulinic acid synthetase, has been measured in fibroblast lysates. Lysates of fibroblasts from eight patients with protoporphyria had activities of delta-aminolevulinic acid synthetase which did not differ significantly from those of eight normal fibroblast lines, whereas activity of heme synthetase, with either deuteroporphyrin or protoporphyrin as substrate, was markedly decreased in sonicates of skin fibroblasts from these patients, the mean being 8% of control with deuteroporphyrin and 14% with protoporphyrin as substrate. In homogenates of liver from five patients with protoporphyria, activity of heme synthetase was also significantly less than that found in six patients without prophyria, the mean being 13% of control with protoporphyrin as substrate. These results provide evidence that decreased activity of heme synthetase is the basic defect in the heme synthetic pathway in protoporphyria. This deficiency is probably responsible for protoporphyrin accumulation and hence the biochemical and clinical features observed in protoporphyria.
5-Aminolevulinate Synthetase↗
Porphyrin synthesis and mitochondrial respiration in acute intermittent porphyria: studies using cultured human fibroblasts.
The formation of variation of delta-aminolevulinic acid (ALA) and of porphyrins, as well as respiratory metabolism, have been studied in skin fibroblasts from six normal control subjects and seven patients with acute intermittent porphyria. The mean activity of ALA synthetase was the same in both groups, whereas the mean activity of uroporphyrinogen I synthetase (as measured by the conversion of porphobilinogen [PBG] to porphyrins) was significantly decreased in fibroblasts from porphyric subjects, the mean value being 52 per cent that of control subjects (p less than or equal to 0.001). The findings of decreased uroporphyrinogen synthesis without an increase in ALA synthetase in mitochondria-containing cells from subjects with acute intermittent porphyria are compatible with the concept that defective PBG ultilization is the fundamental defect in heme biosynthesis in this disease and the possibility that ALA synthetase is "irreversibly" repressed in nonhepatic tissues. Respiration of the cells was studied polarographically. The two types of cells showed similar overall rates of respiration and in general responded to substrates and inhibitors as expected. Of the inhibitors tested (rotenone, amytal, antimycin, and cyanide), only rotenone showed a differential effect: respiration of fibroblasts from porphyric patients was not as sensitive to the inhibitor as was that of the control subjects. These results are interpreted as suggesting a possible defect in mitochondrial NADH oxidation in acute intermittent porphyria.
5-Aminolevulinate Synthetase↗
Letter: Hazard of propranolol in treatment of acute prophyria.
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Adult↗