Metabolic disorders can be the consequence of external factors and individual susceptibility. Sporadic porphyria cutanea tarda (sPCT) is an idiopathic disorder of liver heme synthesis exhibiting inhibition of uroporphyrinogen decarboxylase, characterised by dermal and hepatic deposition of uroporphyrins from oxidation of sensitive uroporphyrinogens (uroporphyria). sPCT is associated with alcohol, estrogenic drugs, HIV and hepatitis C, as well as a poorly understood influence of iron. Hexachlorobenzene (HCB) and reputably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause a similar disorder. The hepatic aspects modelled in susceptible rodents in response to HCB and TCDD are potentiated by iron. Importantly, iron overload alone eventually causes hepatic uroporphyria in genetically susceptible mice. To determine whether this genetic susceptibility to iron toxicity is the consequence of a single genetic variant or is multigenic, a low power F2 intercross cross from sensitive SWR and resistant DBA/2 strains was used to detect chromosomal quantitative trait loci (QTL) associated with uroporphyria development enhanced by the heme precursor 5-aminolevulinic acid (5-ALA). Multiple QTL contributed to the development of uroporphyria. Differential gene expressions comparing mice of parent strains and the F2 extremes of resistance and susceptibility suggested possible contributions associated with QTL. Positions of QTL and the confidence regions were compared with those observed previously for uroporphyria induced more rapidly by TCDD in iron-loaded mice and showed overlapping but not identical loci. A difference in uroporphyric response to iron loading occurred with another sensitive strain, C57BL/10ScSn, whether maintained on one of two well-defined, but similar, same source commercial diets. Uroporphyria developed with a nutritionally enhanced diet rather than a lean maintenance diet. One common observation with uroporphyria was decreased expression of Glul for glutamine synthetase. The findings illustrate the interaction of polygenic factors, external factors and diet in models of idiopathic human disorders such as sPCT.

Porphyria cutanea tarda (PCT) is caused by inherited or acquired defects of uroporphyrinogen decarboxylase (UROD) in the heme biosynthetic pathway. Altered iron homeostasis via hemochromatosis gene (HFE) mutations is one of many susceptibility factors associated with the sporadic form of PCT. Though sarcoidosis is not commonly associated with PCT, prior reports of hepatic sarcoidosis postulated that hepatic granulomas affect UROD activity by direct interference or immunological mechanisms. Here we describe a case of acquired PCT in the setting of (HFE):c.845G>A (p.Cys282Tyr) and (HFE):c.187C>G (p.His63Asp) compound heterozygosity, hepatic steatosis, and cutaneous sarcoidosis.

Porphyria cutanea tarda (PCT) is a skin disorder characterized by abnormal heme synthesis. We present a 45-year-old man with intermittent skin lesions recurring annually for years. Skin biopsy and measurement of serum heme precursors confirmed a diagnosis of PCT. He had persistently elevated alanine and aspartate transferase. He was referred to hematology and had genetic testing with iron studies which also revealed hereditary hemochromatosis (HH). Therapeutic phlebotomy was initiated, which led to resolution of iron overload and skin lesions. We highlight the associated conditions of PCT and HH, their common therapy of phlebotomy, and initial manifestations of HH.

Porphyria cutanea tarda has a complex etiology with genetic factors not completely elucidated. The miscegenation of the Brazilian population has important implications in the predisposition to diseases. There are no studies concerning the genetic ancestry of patients with porphyria cutanea tarda from a mixed population. Thirty patients living in Rio de Janeiro with sporadic porphyria cutanea tarda were studied for the genetic ancestry through informative markers - INDELS. There was a significant predominance of European ancestry across the sample of patients with porphyria cutanea tarda (70.2%), and a small contribution of African and Amerindian ancestry, 20.1% and 10.9%, respectively.

Metabolomic profiling combines Nuclear Magnetic Resonance spectroscopy with supervised statistical analysis that might allow to better understanding the mechanisms of a disease. In this study, the urinary metabolic profiling of individuals with porphyrias was performed to predict different types of disease, and to propose new pathophysiological hypotheses. Urine 1H-NMR spectra of 73 patients with asymptomatic acute intermittent porphyria (aAIP) and familial or sporadic porphyria cutanea tarda (f/sPCT) were compared using a supervised rule-mining algorithm. NMR spectrum buckets bins, corresponding to rules, were extracted and a logistic regression was trained. Our rule-mining algorithm generated results were consistent with those obtained using partial least square discriminant analysis (PLS-DA) and the predictive performance of the model was significant. Buckets that were identified by the algorithm corresponded to metabolites involved in glycolysis and energy-conversion pathways, notably acetate, citrate, and pyruvate, which were found in higher concentrations in the urines of aAIP compared with PCT patients. Metabolic profiling did not discriminate sPCT from fPCT patients. These results suggest that metabolic reprogramming occurs in aAIP individuals, even in the absence of overt symptoms, and supports the relationship that occur between heme synthesis and mitochondrial energetic metabolism.