[Epigastric symptoms and alcohol drinking in a mechanic].
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Abdominal Pain↗
Biomedical subjects
M Doss
Publications and source records attributed to M Doss.
Porphyrin studies in TCDD-exposed workers.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to inhibit uroporphyrinogen decarboxylase activity resulting in chronic hepatic porphyria. From a cross-sectional study of 170 workers in chemical industry 68 showed elevated coproporphyrin levels, interpreted as secondary coproporphyrinuria. Three persons suffered from chronic hepatic porphyria in subclinical stages. None of the workers showed an overt porphyria cutanea tarda. A low-grade zinc protoporphyrinemia was observed in three persons. Forty-three of the 170 workers were evaluable for investigating the effect of TCDD on porphyrin levels. No significant correlation was found between TCDD concentration in adipose tissue and the level of uroporphyrin and coproporphyrin. The influence of a chloracne history is described.
Adipose Tissue↗
Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria.
Cloning and expression of the defective genes for delta-aminolevulinate dehydratase (ALAD) from a patient with inherited ALAD deficiency porphyria (ADP) were carried out. Cloning of cDNAs for the defective ALAD were performed from EBV-transformed lymphoblastoid cells of the proband, and nucleotide sequences were determined. Two separate point mutations resulting in a single amino acid change in each ALAD allele were identified. One, C718----T, termed 'G1', occurred in the allele within the substrate-binding site, producing an Arg240----Trp substitution; the other, G820----A, termed 'G2', occurred downstream of this site in the other allele, resulting in an Ala274----Thr substitution. Using the reverse transcription-polymerase chain reaction, the mother, the brother, and the sister were shown to have the G1 defect. Expression of the G1 cDNA in Chinese hamster ovary cells produced ALAD protein with little activity; the G2 cDNA produced the enzyme with approximately 50% normal activity. Pulse-labeling studies demonstrated that the G1 enzyme had a normal half life, while the G2 enzyme had a markedly decreased half life. These data thus define the separate point mutations in each ALAD allele, as well as the altered properties of the two enzymic proteins encoded by the mutant genes in a patient with ADP.
Alleles↗
Cloning and expression of the defective genes in delta-aminolevulinate dehydratase porphyria: compound heterozygosity in this hereditary liver disease.
Cloning and expression of the defective genes for ALAD from a patient with inherited ADP were carried out. Two separate point mutations, termed G1 and G2, resulting in a single amino acid change in each ALAD allele, were identified. The G1 mutation (C718-->T) occurred in the allele within the substrate-binding site, producing an Arg240-->Trp substitution; the G2 mutation (G820-->A) occurred downstream of this site in the other allele, resulting in an Ala274-->Thr substitution. Using RT-PCR, the mother, the brother, and the sister were shown to have the G1 defect. Expression of the G1 cDNA in CHO cells produced ALAD protein with little activity; the G2 cDNA produced the enzyme with approximately 50% normal activity. Pulse-labeling studies demonstrated that the G1 enzyme had a normal half-life, while the G2 enzyme had a markedly decreased half-life. These data thus define two separate point mutations, one in each ALAD allele, as well as the altered properties of the two enzymic proteins encoded by the mutant genes in this patient.
Adolescent↗
Hereditary hepatic porphyria due to homozygous delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes and erythrocytes.
Activities of delta-aminolevulinic acid (ALA) dehydratase and porphobilinogen (PBG) deaminase, and haem content were determined in EB-virus transformed lymphocytes from two patients with homozygous ALA dehydratase deficiency, and their family members to determine the expression of the specific gene defect in this cell type. ALA dehydratase activity, but not PBG deaminase activity or haem content, was markedly decreased in lymphocyte preparations from both patients with homozygous enzyme deficiency, and moderately decreased in subjects heterozygous for enzyme deficiency. Immunochemical quantitation of erythrocyte ALA dehydratase suggested the presence of a cross-reactive material in a patient with a late-onset of acute hepatic porphyria due to the homozygous enzyme deficiency.
Adult↗
Message amplification phenotyping of an inherited delta-aminolevulinate dehydratase deficiency in a family with acute hepatic porphyria.
The molecular basis of the enzymatic defect responsible for acute hepatic porphyria due to delta-aminolevulinate dehydratase (ALAD) deficiency was investigated in a family including a proband with the acute disease. In order to delineate the mutation in the proband, cDNA for deficient ALAD was synthesized from the proband's cells. The ALAD phenotype was studied by message amplification phenotyping with total RNA extracted from lymphoblastoid cells of the proband and his family members. Two independent mutant alleles of ALAD were identified in the proband's cells. One mutant allele was shown to result in an amino acid substitution at residue 274 (Ala274----Thr). Message amplification phenotyping studies have also permitted us to define the ALAD phenotype of each subject in the family. This is the first mutation to be recognized in the human ALAD gene.
Cell Line↗
[The coincidence of acute intermittent porphyria and Crohn's disease].
In the course of four weeks, tetraparesis developed in a 28-year-old man with Crohn's disease for the last six years, treated with glucocorticoids and sulphasalazine. The cause was acute intermittent porphyria which had been previously overlooked because of the similar abdominal symptoms of Crohn's disease. Treatment with glucose, propranolol and haemarginate failed to bring about any improvement, but there was a remission of the porphyria. This case demonstrates that diagnosis of acute intermittent porphyria in the presence of Crohn's disease is difficult, and if delayed therapeutic measures in the face of persisting neurological complications are of little benefit.
Acute Disease↗
Diagnostic and pathogenetic implications of urinary coproporphyrin excretion in the Dubin-Johnson syndrome.
The Dubin-Johnson syndrome (DJS), a hereditary conjugated hyperbilirubinemia, is associated with an impairment of porphyrin metabolism. Total urinary coproporphyrin (CP) excretion and the urinary CP isomer I and III constellation were examined in 15 patients with DJS and 12 unaffected family members, and then compared with 50 unrelated control persons (55 +/- 15 nmol/24 h of total CP: 27 +/- 3% of isomer I; +/- SD). The patients with DJS excreted 80 +/- 7% (+/- SD) of CP isomer I (p less than 0.001). The isomer relation in two young children, 3 and 5 years old, shows an isomer reversal, with isomer I of about 95%. Studies done on four families from our patients with DJS indicate and confirm the autosomal recessive mode of inheritance. Total urinary CP was found to be elevated in subjects with DJS, reaching a mean value of 164 +/- 123 nmol/24 h (upper limit 120 nmol/24 h). Fecal CP isomers I and III were found to be in the usual physiological proportion to each other, but total fecal CP excretion had declined to the lower normal level (10 +/- nmol/g, n = 8). The pathogenetic mechanisms in DJS have not yet been fully worked out. Four possible explanations are currently under discussion: 1. an impaired hepatic excretory function: 2. a uroporphyrinogen III synthase defect; 3. an increase in porphobilinogen deaminase (uroporphyrinogen synthase) activity, or 4. a membrane-associated transport disorder with secondary metabolic changes of the isomer pool and enzyme activities.
Adolescent↗
Multiple nodular foci in the liver associated with chronic hepatic porphyria after previous treatment of breast cancer.
More than 7 years after the diagnosis and treatment of breast cancer (T1N1aM0), multiple nodular foci were observed in the liver of a 40-year-old woman at ultrasonographic examination. The lesions were confirmed by CT scan, but CT-guided liver biopsy revealed only non-specific alterations. At subsequent peritoneoscopic examination, bluish-brown foci were indeed visible on the liver surface, but guided liver biopsies again failed to corroborate the suspected metastases. Instead, histology showed mild portal fibrosis, moderate steatosis and siderosis of hepatocytes, as before. Only the intense red fluorescence of part of the biopsy material under Wood's light suggested the diagnosis of chronic hepatic porphyria or porphyria cutanea tarda, here presumably as a consequence of prolonged alcohol consumption. Subsequent porphyrin studies in urine, faeces and plasma yielded the typical constellation of latent porphyria cutanea tarda (chronic hepatic porphyria type C). The activity of erythrocyte uroporphyrinogen decarboxylase was normal, which argued against a genetic predisposition. After 1 year of strict alcohol abstinence and low-dose chloroquine treatment the "nodular foci" in the liver were no longer visible on ultrasonogram and CT scan; only proton-weighted NMR imaging (SE 1500/30) still showed ill-defined areas of higher signal intensity. The renal excretion of porphyrins had decreased considerably. The levels are now consistent with the diagnosis of subclinical chronic hepatic porphyria type A. Modern non-invasive imaging techniques are tremendously useful, but they have their pitfalls. Focal liver lesions may present serious diagnostic problems, especially when they are found in a patient with a history of carcinoma at an extrahepatic primary site. A rare example is described.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
STRETCH: a rehabilitative program for patients with breast cancer.
Participants in an exercise-based rehabilitative program for women with breast cancer were evaluated for physical disability. Of 114 women who were evaluated initially, there was almost universal evidence of restriction of range of motion or abnormal posture. Of the 47 women who were available for evaluation after completion of the eight-week program, 42 showed increases in one or more movements with no concomitant decreases. Five patients had a decrease in a single measurement. Of 96 participants evaluated for psychosocial benefits, two thirds reported positive psychologic effects.
Adult↗
[Rotor syndrome: relevance of the determination of coproporphyrin isomers in the urine in comparison with intrahepatic (alcohol-induced) cholestasis].
Porphyrin isomer examinations have been performed in two patients with Rotor syndrome (RS), one patient with Gilbert-Meulengracht syndrome and 12 patients with alcohol toxic cholestasis. Under both conditions, cholestasis and RS, total urinary coproporphyrin excretion as well as coproporphyrin isomer I was relatively and absolutely increased. Despite the different degree of the increase of coproporphyrin isomer I excretion between RS (69 vs. 72%) and cholestasis (47% on average), there are single cases with a coproporphyrin isomer I portion around 60%. In such cases, the differential diagnosis is quite difficult, so that the diagnosis "Rotor syndrome" should never be gained by one distinct examination; it is a diagnosis performed by exclusion of other diseases.
Adult↗
delta-Aminolevulinic acid dehydrase (porphobilinogen synthase) in two families with inherited enzyme deficiency.
The inheritance of a deficient delta-aminolevulinic acid dehydrase (ALA-D; synonym: porphobilinogen synthase; EC 4.2.1.24) was studied in blood samples of two families over three generations. The propositus in each family was a young male acute hepatic porphyria patient with an almost complete ALA-D deficiency in the homozygous state (ALA-D activity less than 2% of controls). Heterozygotes are clinically non-affected (mean ALA-D 36% of controls). The mode of transmission could be traced by enzyme activity and electrophoretic polymorphism studies. Heterozygotes are detected by the demonstration of enzyme activity in the gel. The notation D was used for the gene expressing the defective enzyme. The "phenotype" D-1 was observed in six, the "phenotype" D-2 in three of all heterozygotes studied. These results are compatible with a single normal allele in heterozygotes responsible for enzyme activity. Quantitative assays and the segregation pattern in both families suggest a 3-allele-system for the inheritance of ALA-D deficiency.
Alleles↗
[Hereditary coproporphyria with grand mal epilepsy, glucose-6-phosphate dehydrogenase deficiency and phenobarbital tolerance].
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Adult↗
Appearance of an inherited porphyria cutanea tarda in a child after allogeneic bone marrow transplantation for chronic myelogenous leukaemia.
We report details of a 6 1/2-year-old girl who developed porphyria cutanea tarda after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. The results of studying porphyrin metabolism in the family members are described. Expression of the disease may have been induced by the cyclophosphamide and total-body irradiation in the conditioning regimen and/or by the administration of methotrexate for the prevention of graft-versus-host disease and meningeal leukaemia.
Bone Marrow Transplantation↗
Hereditary hepatic porphyria with delta aminolevulinate dehydrase deficiency: immunologic characterization of the non-catalytic enzyme.
Immunoreactive delta-aminolevulinate dehydrase (ALA-D) was measured in lysates from two porphyric patients with ALA-D deficiency (enzyme activities were below 2% of the normal level). By using two different immunologic methods, we found a cross-reactive immunologic material (CRIM+) which corresponded to 20% and 33% of the control level. Therefore the molecular basis that accounts for the deficiency of ALA-D in these patients is a structurally modified enzyme. The methods used to determine the molecular weight (by Western blotting) and the isoelectric point (by chromatofocusing) of the mutants did not show any difference by comparison with the normal enzyme.
Electrophoresis, Polyacrylamide Gel↗
Hereditary uroporphyrinogen-decarboxylase deficiency predisposing porphyria cutanea tarda (chronic hepatic porphyria) in females after oral contraceptive medication.
Porphyria cutanea tarda (PCT) was diagnosed in 27 women aged 23-48 years (mean, 35 years) who had been under oral-hormonal-contraceptive medication for 1-18 years, in 3 women under substitutional estrogen treatment in the menopause, and in 2 men aged 65 and 76 years after estrogen treatment of prostatic carcinoma. In all patients, total urinary porphyrin excretion was elevated, with an average uro- and heptacarboxyporphyrin predominance of 88%, thus proving PCT. Of the patients, 84% showed a significant decrease of erythrocyte uroporphyrinogen-decarboxylase (UD; EC 4.1.1.37) activity to approximately 50% of control levels suggesting a hereditary predisposition for the development of a chronic hepatic porphyria. Estrogens and alcohol are capable of reducing hepatic UD activity. Women with hereditary red cell UD deficiency may be regarded as predisposed to PCT when under estrogen intake, especially in combination with the potentiating influence of alcohol and chronic liver disease. Normal erythrocyte UD values in patients with additive alcohol consumption may implicate a stronger inhibitory effect for alcohol on UD, suggesting a merely toxic form of chronic hepatic porphyria.
Adult↗
Clinical and experimental investigations of vasopressin secretion in acute porphyrias.
In 41 patients suffering from acute hepatic porphyrias the arginin-vasopressin (AVP) levels in their urine were measured by RIA. In 6 patients, AVP secretion was normal; in 8 cases AVP levels were significantly elevated, while 27 cases showed decreased levels of AVP (p less than 0.001). A linear correlation between AVP secretion and urine volume was not found. In animal experiments, 20 rats were treated with delta-aminolevulinic acid (ALA), (1.5 mmol/kg/24 h and 1.5 mmol/kg/48 h) for 4 weeks. Afterwards vasopressin production in the hypothalamo-hypophyseal system was analysed by the immunoperoxidase technique and a microdensitometric method. In ALA-treated animals, AVP positive neurones showed coarse-grained granules of different intensity and a distinct increase of peroxidase positive granules in the zona interna of the eminentia mediana. Furthermore, in comparison with the control group in ALA-treated animals the mean diameter of nuclei in AVP positive neurons was greater. While animals treated daily showed an increase of transmission in the pituitary, microdensitometric findings in animals treated at 48 hourly intervals showed an equal transmission in AVP producing nuclei compared to the control group. Our results seem to point to a toxic effect of porphyrin precursors on the CNS, which may also induce via hypothalamus lesion either diabetes insipidus or a SIADH-syndrome.
Acute Disease↗