Background Heme deficiency in the liver of patients with Acute Hepatic Porphyrias (AHP) stimulates an increase in ALA-synthase which triggers an escalating metabolic chain reaction, leading to an increase in toxic metabolites such as ALA and PBG. Therapy with heme infusions or glucose infusions are usually first line therapies for AHP patients presenting with an acute attack. Furthermore, several experimental models have been confirming that alterations of glucose metabolism and mitochondrial bioenergetics are part of the many metabolic dysfunctions seen in this disease. Nevertheless, their actual role in precipitating the AHP symptomatology is not completely understood.

Methods Retrospective data from AHP patients records and their general biochemical laboratory results compared with ALA and PBG levels from a reference center in Brazil were analyzed

Results 13 patients (10 females and three males) were enrolled. All patients reported recurrent porphyria attacks in combination with hypoglycemia. All patient had chronic increased levels of delta-aminolaevulinic acid and porphobilinogen with normal insulin levels. None of the patients had diabetes mellitus or decreased glucose tolerance previous to the onset of the first crisis. Nevertheless, after several glucose infusions without concomitant insulin administration and before heme therapy, all patients but one developed abnormal glucose metabolism, oscillating hypo and hyperglycemia usually with normal insulin levels. Recurrent hypoglycemia was a constant finding in patients before - and even after - a new acute attack and correlated with its recurrence. Paradoxically, treatment strategies using high carbohydrate diet combined with glucose infusions did not bring any apparent benefit and seemed to worsen hypoglycemia in most of the patients.

Conclusions The characterization of carbohydrate metabolic profiles in experimental acute porphyria models has highlighted alterations in glucose metabolism, hyperinsulinemia, and abnormal hepatic glycogenolysis, gluconeogenesis and mitochondrial bioenergetics that could be associated with AHP pathophysiology Our cohort of patients showed a striking relationship involving chronic hypoglycemia and frequent recurrent attacks of acute porphyria (with most of the patients displaying chronic symptoms between attacks). In particular, glucose loading therapy seemed to worsen clinical symptomology in some patients which can be consequence of increased gut permeability (followed by increased translocation of bacterial products and insulin resistance) caused by a high-glucose diet, pointing out to the gut-liver axis as a likely contributing factor to the physiopathology of acute attacks recurrence.