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Porphyrias are inherited diseases with low penetrance affecting the heme biosynthesis pathway. Acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP) together constitute the acute hepatic porphyrias (AHP). These diseases have been identified as risk factors for primary liver cancers (PLC), mainly hepatocellular carcinoma (HCC: range 87-100%) but also cholangiocarcinoma, alone or combination with HCC. In AHP, HCC annual incidence rates range from 0.16 to 0.35% according to the populations studied. Annual incidence rates are higher in Swedish and Norwegian patients, due to a founder effect. It increases above age 50. The pathophysiology could include both direct toxic effects of heme precursors, particularly δ-aminolevulinic acid (ALA), compound heterozygosity for genes implied in heme biosynthesis pathway or the loss of oxidative stress homeostasis due to a relative lack of heme. The high HCC incidence justifies radiological surveillance in AHP patients above age 50. Efforts are made to find new biological non-invasive markers. In this respect, we describe here the first report of PIVKA-II clinical utility in the follow-up of an AIP patient that develop an HCC. In this manuscript we reviewed the epidemiology, the physiopathology, and the screening strategy of HCC in AHP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP., Design: A retrospective population-based study., Subjects: All women aged > or =18 years (n = 190) with DNA-diagnosed AIP in northern Sweden., Results: A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty-two women (25%) aged > or =45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged > or =45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014)., Conclusions: About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.

Objective: Can renal insufficiency in subjects with acute intermittent porphyria (AIP) be due solely to, Design: A population-based study., Subjects: Subjects with AIP > or = 18 years of age (n = 386) in the four most northerly counties of Sweden., Interventions: Screening with creatinine clearance at 24 h. Patients below the lower reference level underwent a repeat clearance test and, if still low, also chromEDTA clearance., Results: 286 (74%) subjects performed the creatinine clearance test and in 57 clearance was low; the second clearance proved normal in 23 who were then excluded. Eighteen subjects with other possible medical reasons for renal insufficiency, ethical reasons or refusing further examinations were also excluded. The 16 remaining subjects with no explanation for their renal insufficiency other than AIP were then studied in detail. All 14 women, mean age 52 years, and two uraemic men, 58 and 67 years, had manifest AIP. Twelve patients had hypertension (HT) and four were normotensive in spite of renal insufficiency. Histological findings of renal biopsies revealed diffuse glomerulosclerotic and interstitial changes with additional ischaemic lesions., Conclusion: Protracted vasospasm in attacks of AIP may be a cause of renal lesions. This is discussed.

Cancer incidence and mortality risks were evaluated in a combined cohort of patients who were hospitalized for porphyria in Denmark (1977-1989) and Sweden (1965-1983). Patients were identified by using population-based hospitalization registries. The unique individual identification numbers of 530 patients with porphyria cutanea tarda (PCT) and 296 with acute intermittent porphyria (AIP) were linked to the nationwide cancer and death registries. Among patients with both types of porphyria, the authors found small but significantly elevated risks of all cancers combined (PCT: standardized incidence ratio (SIR) = 1.7, 95% confidence interval (CI) 1.3-2.2; AIP: SIR = 1.8, 95% CI 1.1-2.8) due to pronounced excesses of primary liver cancer (PCT: SIR = 21.2, 95% CI 8.5-43.7; AIP: SIR = 70.4, 95% CI 22.7-164.3) and moderate increases in lung cancer (PCT: SIR = 2.9, 95% CI 1.5-5.2; AIP: SIR = 2.8, 95% CI 0.3-10.2). PCT patients had a significantly increased risk of mortality from liver cirrhosis (standardized mortality ratio (SMR) = 8.4, 95% CI 3.1-18.4) or chronic obstructive pulmonary disease (SMR = 3.1, 95% CI 1.1-6.7). The increased risk of primary liver cancer and the increased risk of mortality from cirrhosis of the liver are consistent with findings from previous clinical surveys, but the new observations of excess lung cancer and chronic obstructive pulmonary disease require confirmation.

Objectives: To study the effects of diabetes mellitus in patients with acute intermittent porphyria (AIP). Haeme deficiency in the liver of AIP patients stimulates an increase in ALA-synthase which triggers an escalating metabolic chain reaction, leading to an increase in the porphyrin content. This reaction can be reduced by treating AIP patients with haeme arginate or with glucose., Design: A population-based study of all patients > 18 years of age having DNA-verified AIP (n = 328) living in the two most northerly counties of Sweden (Norrbotten and Västerbotten, with 550,000 inhabitants) of whom 16 had type 2 diabetes. Prevalence of diabetes was studied retrospectively in 26 AIP patients with hepatocellular carcinoma (HCC)., Results: None of the patients showed symptoms of AIP after the onset of their diabetes. Three patients had had recurrent, severe attacks for many years but when their diabetes became manifest, their urinary ALA and PBG levels decreased and the AIP symptoms resolved, to the relief of the patients. Amongst the 26 AIP patients with HCC, only one with signs of diabetes was identified (impaired glucose tolerance test)., Conclusions: This study raises the possibility that diabetes mellitus may be beneficial for patients with severe AIP.

Objective: To describe the epidemiology, pathogenesis and clinical features of hepatocellular carcinoma (HCC) in patients with acute intermittent porphyria (AIP)., Design: A retrospective population-based mortality study., Subjects: All inhabitants who died between 1978-1990 (2122) including 33 with AIP, in two municipalities in northern Sweden with a high prevalence of AIP., Interventions: Death certificates and hospital records were examined. Histological re-examination of paraffin-embedded specimens from patients with HCC was performed and hepatitis B virus content analysed., Results: HCC was found in 27% of patients with AIP versus 0.2% of the deceased non-AIP subjects, P < 0.0001. HCC was more common in women (men:women 1:2) and in manifest AIP (manifest: latent 2:1). Liver cirrhosis was more common in AIP patients (12%), especially in women, compared with controls (0.5%), P < 0.0001., Conclusions: AIP patients seem to have an increased risk of developing HCC. This tumour is more common in patients with manifest AIP and in women, a reversal of the usually reported gender ratio for HCC. No cause for developing HCC other than AIP was found. The pathogenesis may be explained by abnormalities in porphyrin metabolism and by intrinsic production of mutagenic substances, resulting in a condition of systemic overload of oxidative stress, enhancing mutation rate and liver cell injury. Liver cirrhosis appears to be more common in AIP patients and may be a preliminary stage to HCC. All AIP gene carriers aged > or = 55 should be screened for HCC.