The “glucose effect” in acute hepatic porphyrias and in experimental porphyria

Abstract

The "glucose effect" was investigated in human acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria and porphobilinogen synthase defect porphyria) and in avian liver cells. 8 patients (7 women) with acute abdominal-neurological porphyria syndrome and 3 patients (2 women) in the remission phase were treated with high carbohydrate intake (approximately 500 g/24 h), mainly in form of intravenous glucose infusions. The biochemical response with a decrease of metabolites of porphyrin biosynthesis was highly significant, accompanied by clinical improvement in 10 courses of 9 patients. Two patients with delayed detection of the disease under the condition of Landry paralysis died after temporary clinical improvement due to ventricular arrythmias in one case and septicemia in the other. The importance of early diagnosis and therapy, and omission of drugs and alcohol cannot be overemphasized. Complementary studies show the "glucose effect" in drug -mediated induction of porphyrin synthesis in liver cells grown in culture: delta-Aminolevulinic acid synthase and protoporphyrin synthesis are repressed.

"Glucose Effect" and Rate Limiting Function of Uroporphyrinogen Synthase on Porphyrin Metabolism in Hepatocyte Culture: Relationship with Human Acute Hepatic Porphyrias

“…The extreme increase of porphyrin precursor excretion in acute intermittent porphyria, variegate and coproporphyria (13) can only be explained on the basis of the secondarily limiting f riction of uroporphyrinogen synthase (15 -18). Meanwhile the rate limiting function of uroporphyrinogen synthase for the conversion of ALA into protoporphyrin was proven in homogenates (19) and the "glucose effect" was demonstrated in liver cell cultures (11,(20)(21)(22). In the present study 1. the "glucose effect" on porphyrin synthesis is compared in vitro and in vivo and 2. the intriguing role of uroporphyrinogen synthase s a secondary limiting factor is considered in view of the glucose-mediated repression of counterregulation in acute hepatic porphyrias.…”

“…Porphyria precipitated by fasting (8), porphyrinuria induced by fasting in nonporphyric subjects (9) and "caloripenic porphyria" (10) were next reported and i t was suggested that a low-caloric diet or abrupt reduction in carbohydrate and protein intake may provoke Symptoms in addition'to elevating urinary ALA, pyrrol and porphyrin excretion (11,12).…”

Effects of diabetes mellitus on patients with acute intermittent porphyria

“…Carbohydrate intake blocks ALA‐synthase, which has been demonstrated in numerous clinical and experimental studies [ 4–8]. However, the mechanisms by which carbohydrates modulate the components of porphyrins and haeme synthesis are highly complex and only partially elucidated to date [ 5].…”

“…Carbohydrate intake blocks ALA‐synthase, which has been demonstrated in numerous clinical and experimental studies [ 4–8]. However, the mechanisms by which carbohydrates modulate the components of porphyrins and haeme synthesis are highly complex and only partially elucidated to date [ 5]. Treatment of AIP patients entails treating both the symptoms and the complications, but also requires an endeavour to reverse the fundamental disease process by a carbohydrate‐rich diet and by treating the attacks with intravenous infusions of glucose or haeme.…”

Variegate Porphyria

“…Though 50% of acute attacks in patients with VP may settle spontaneously, withholding the drug is always potentially risky as the onset of neuropathy is impossible to predict and is usually rapid in onset. 155 Carbohydrate loading has been shown to inhibit porphyrin synthesis 221,235,236 and glucose infusion was previously recommended as part of the management of the acute attack. The anti-porphyrogenic effect of glucose is, however, insignificant in comparison with the effect of heme replacement; where the latter is available, there is no need for glucose infusion, particularly since infusion of hypotonic fluids may aggravate hyponatraemia.…”