Impaired heme synthesis in a family with Pelger-Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro.

Heme synthesis was studied by measuring the activity of delta-aminolevulinic acid synthase (AmLev synthase) in granulocytes, the activity of delta-aminolevulinic acid dehydratase (AmLev dehydratase) and of uroporphyrinogen I synthase in erythrocytes as well as the concentrations of coproporphyrin and protoporphyrin in erythrocytes of 6 patients with Pelger-Huët anomaly. 3 of these patients from the same kindred had a syndrome of recurrent attacks of fever and abdominal pains, a tendency to skin infections, delayed wound healing and impaired neutrophil motility. The other 3 patients were asymptomatic. The activity of AmLev synthase was depressed in all 3 symptomatic patients and normal in the asymptomatic patients. 1 symptomatic patient had a decreased erythrocyte protoporphyrin concentration. These findings indicate a derangement of heme synthesis in the symptomatic patients. Their abdominal pain attacks could be due to heme depletion. The findings suggest that the abdominal pains of patients with porphyria could be due to decreased heme synthesis rather than due to accumulation of porphyrin precursors in tissues. The cause of the impaired neutrophil motility may be a defect in energy metabolism due to decreased supply of heme for oxidative metabolism.

Coproporphyrinogen oxidase activity and porphyrin concentrations in peripheral red blood cells in hereditary sideroblastic anaemia.

The activity of coproporphyrinogen oxidase and the concentrations of coproporphyrin and protoporphyrin (measured by HPLC) in peripheral red blood cells were established in 2 families with different types of hereditary sideroblastic anaemia. 2 males and 4 females were members of a family with an X-chromosome-linked and pyridoxine-responsive HSA, and 3 females were members of another family where the mode of inheritance is not clear and where pyridoxine did not produce a haematological response. Coproporphyrinogen oxidase activity was normal in 8 of 9 patients and slightly decreased only in 1 patient. All patients had normal red cell coproporphyrin concentrations, but red cell protoporphyrin concentration was decreased in 4 patients. These findings indicate that in vivo haem synthesis was not impaired at the step of coproporphyrinogen oxidase, hence enzymatic defects in earlier steps of haem synthesis are more evident. Earlier suggestions of impaired haem synthesis at this level, based on observed increased concentrations of coproporphyrin in peripheral red blood cells might be explained by the use of unspecific methods.

Haema synthesis during pyridoxine therapy in two families with different types of hereditary sideroblastic anaemia.

The activity of delta-aminolaevulinic acid synthase (ALA-S) as well as the concentrations of coproporphyrin and protoporphyrin in peripheral red blood cells were examined in 2 sisters and in 2 brothers with hereditary sideroblastic anaemias (HSA) of different types. The measurements were done before and during treatment by pyridoxal-5-phosphate (PLP) and/or pyridoxine chloride. Previous family studies indicated an X chromosome linked HSA in the 2 brothers, whereas the precise mode of inheritance in the 2 sisters has not been established. Previous and present studies have revealed no characteristic defect in haema synthesis in the 2 sisters and their treatment by PLP or pyridoxine produced no haematologic response although a slight stimulation of haema synthesis was observed. In contrast, the 2 brothers showed decreased activity of ALA-S and decreased protoporphyrin concentration in peripheral red blood cells. After treatment by PLP and/or pyridoxine the ALA-S activity was restored to normal. Corresponding to the stimulation of haema synthesis a partial haematological response was observed in both brothers. Stopping and restarting of pyridoxine therapy in one brother confirmed the above results. These observations indicate the presence of two genetically and biochemically different types of HSA and help us to understand the varying response to pyridoxine therapy in this rare disorder.

Haem biosynthesis in refractory sideroblastic anaemia associated with the preleukaemic syndrome.

The activities of 5 enzymes of the haem biosynthetic pathway and the protoporphyrin concentrations have been measured in peripheral red blood cells of 23 patients having a preleukaemic syndrome with refractory sideroblastic anaemia. A decreased delta-aminolaevulinic acid synthase (ALA-S) activity, an increased uroporphyrinogen I synthase activity and an increased red cell protoporphyrin concentration were consistent findings. Patients with abnormal leucocyte and/or platelet counts in the peripheral blood as well as patients with an excess of blast cells in the bone marrow had the lowest ALA-S activities. A further decrease in ALA-S activity was observed in 3 patients after leukaemic change in the disease. Patients having cytogenetic abnormalities showed no unique enzyme abnormalities. These results indicate that enzymatic disturbances of haem synthesis cannot be used as prognostic indicator of leukaemic transformation in refractory sideroblastic anaemia, but a very low ALA-S activity appears to accompany the development of a leukaemia in such patients.

The activities of delta-aminolaevulinic acid synthase and haem synthase in experimental sideroblastic anaemia. Effect of mitochondrial iron excess on the enzyme activity in peripheral red blood cells.

Experimental sideroblastic anaemia was produced in normal and in iron loaded guinea pigs by intraperitoneal (i.p.) administration of isoniazid and cycloserine. Subsequently, the activities of delta-aminolaevulinic acid synthase (ALA-S) and of haem synthase in peripheral red blood cells were measured and in particular the relationships of enzyme activities to the iron status were examined. The ALA-S activity showed a similar decrease in all animals with sideroblastic anaemia. The haem synthase activity was increased probably due to secondary induction, but it was significantly less increased in animals with the highest values for iron status. This finding indicates that mitochondrial iron accumulation may have limited the compensatory increase of haem synthase activity. It is likely that also in human sideroblastic anaemia mitochondrial iron overload may have a secondary limiting effect on the haem synthase activity in erythroid cells.

Relationships between serum lipids and malabsorption of bile acids, neutral sterols, and fats in exocrine pancreatic insufficiency.

The relationship between serum lipids, fecal steroids, and fecal fat was studied in nine men with exocrine pancreatic insufficiency due to chronic pancreatitis. The mean fecal bile acid and fat outputs were significantly increased, the neutral sterol excretion was within normal limits, and total elimination and synthesis of cholesterol were slightly increased. A positive correlation between fecal fat and neutral sterols suggests that the patients actually had cholesterol malabsorption and that the normal neutral sterol excretion was apparently the result of a low biliary cholesterol secretion. In view of the fairly small increase in cholesterol elimination, the serum cholesterol level was surprisingly low, indicating that malnutrition may have limited compensatory increase in cholesterol synthesis. Serum triglycerides were negatively correlated with fecal fat. Thus, severe malabsorption apparently also limited the triglyceride production.