The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study.

BACKGROUND: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. RESULTS: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. CONCLUSIONS: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.

Molecular Analysis of 55 Spanish Patients with Acute Intermittent Porphyria.

Acute intermittent porphyria (AIP) results from a decreased activity of hepatic hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. AIP is an autosomal dominant disorder with incomplete penetrance, characterized by acute neurovisceral attacks precipitated by several factors that induce the hepatic 5-aminolevulinic acid synthase, the first enzyme in the heme biosynthesis. Thus, a deficiency in HMBS activity results in an overproduction of porphyrin precursors and the clinical manifestation of the disease. Early diagnosis and counselling are essential to prevent attacks, and mutation analysis is the most accurate method to identify asymptomatic carriers in AIP families. In the present study, we have investigated the molecular defects in 55 unrelated Spanish patients with AIP, identifying 32 HMBS gene mutations, of which six were novel and ten were found in more than one patient. The novel mutations included a missense, an insertion, two deletions, and two splice site variants. Prokaryotic expression studies demonstrated the detrimental effect for the missense mutation, whereas reverse transcription-PCR and sequencing showed aberrant splicing caused by each splice site mutation. These results will allow for an accurate diagnosis of carriers of the disease in these families. Furthermore, they increase the knowledge about the molecular heterogeneity of AIP in Spain.

Molecular analysis of 19 Spanish patients with mixed porphyrias.

Porphyrias are rare diseases caused by alterations in the heme biosynthetic pathway. Depending on the afected enzyme, porphyrin precursors or porphyrins are overproduced, causing acute neurovisceral attacks or dermal photosensitivity, respectively. Hereditary Coproporphyria (HCP) and Variegate Porphyria (VP) are mixed porphyrias since they can present acute and/or cutaneous symptoms. These diseases are caused by a deficiency of coproporphyrinogen oxidase (CPOX) in HCP, and protoporphyrinogen oxidase (PPOX) in VP. Herein, we studied nineteen unrelated Spanish patients with mixed porphyrias. The diagnosis of either, HCP or VP was made on the basis of clinical symptoms, biochemical findings and the identification of the mutation responsible in the CPOX or PPOX genes. Two patients presented both acute and cutaneous symptoms. In most patients, the biochemical data allowed the diagnosis. Among eleven patients with HCP, ten CPOX mutations were identified, including six novel ones: two frameshift (c.32delG and c.1102delC), two nonsense (p.Cys239Ter and p.Tyr365Ter), one missense (p.Trp275Arg) and one amino acid deletion (p.Gly336del). Moreover, seven previously described PPOX mutations were identified in eight patients with VP. The impacts of CPOX mutations p.Trp275Arg and p.Gly336del, were evaluated using prediction softwares and their functional consequences were studied in a prokaryotic expression system. Both alterations were predicted as deleterious by in silico analysis. Aditionally, when these alleles were expressed in E. coli, only p.Trp275Arg retained some residual activity. These results emphasize the usefulness of integrated the biochemical tests and molecular studies in the diagnosis. Furthermore, they extend knowledge on the molecular heterogeneity of mixed porphyrias in Spain.

Multiple primary malignancies in Spanish patients with hepatocellular carcinoma: analysis of a hospital-based tumor registry.

BACKGROUND AND AIM: Little is known about the etiological associations and clinical features of extrahepatic primary malignant (EHPM) neoplasms in subjects with hepatocellular carcinoma (HCC). The aim of this study was to characterize this phenomenon in a consecutive series of Spanish patients in order to define its natural history and influence on survival. METHODS: A retrospective analysis of 245 patients with HCC during the period 1999-2003 was performed. Subjects identified with a second primary malignancy elsewhere constituted the EHPM group and were compared to patients with HCC alone. RESULTS: Eighteen patients (7.3%) had one or two associated extrahepatic malignancies (mean age 67.7 +/- 9.7 years); of these, 17 had double cancer and one patient, triple. Nine of the 19 EHPM occurred before HCC diagnosis. The associated cancers included five cases of colorectal carcinoma, four cases of head and neck carcinoma, three cases of genitourinary cancer, two cases of lymphoproliferative disorder, one lung carcinoma, one skin melanoma, one breast carcinoma, and two cancers of unknown origin. Age and sex distribution, etiology of underlying hepatopathy, and liver function tests did not differ significantly between both groups. There was no difference between the overall survival rates. CONCLUSIONS: EHPM is not rare among Spanish patients with HCC, although no specific clinicopathological features were detected in this population. Our results suggest that the association of another primary tumor with HCC does not imply a worse prognosis. The possibility of development of EHPM should be kept in mind when deciding on therapy and follow-up of HCC.

Sarcoidosis presenting as an osteolytic skull lesion: a case report and review of literature on skull sarcoidosis.

Bone sarcoidosis of the skull is an infrequent presentation of sarcoidosis. We describe a 51-year-old man who consulted due to inflammatory-appearing nodulation in the right supraorbital region. Images showed a solitary osteolytic lesion extending to soft tissues with increased scintigraphic uptake. The anatomopathological study revealed the presence of non-caseating epithelioid granulomas, compatible with sarcoidosis. Steroid treatment led to a marked remission of the lesion, without evidence of relapse during a follow-up period of 1 year. The literature dealing with skull sarcoidosis is reviewed.