Liver transplantation, cancer risk and comorbidity in acute porphyria

Sammanfattning: The porphyrias are a group of rare, mostly genetic, metabolic diseases caused by alterations in the eight enzymatic steps of the heme biosynthesis pathway. This thesis focuses on three of these diseases, acute intermittent porphyria (AIP), hereditary coproporhyria (HCP) and variegate porphyria (VP), collectively labeled acute porphyrias (AP) based on similarities in clinical and biochemical presentation. The APs are inherited in an autosomal dominant manner with low clinical penetrance. A majority of individuals with AP-associated gene variants never experience any symptoms. The common clinical feature in AP is the acute neurovisceral attacks, caused by a marked accumulation of porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG) in the liver and subsequent dissemination to the circulation. Acute porphyria attacks can involve symptoms from both the peripheral, autonomous and central nervous system including severe abdominal and muscular pain, neuropathy, gastrointestinal dysfunction, hypertension and psychiatric symptoms. Most symptomatic patients have few attacks, but a minority has a severe phenotype with recurrent attacks, leading to multiorgan involvement, high mortality risk and poor quality of life. This thesis aimed to study liver transplantation (LT) as a treatment option in patients with severe recurrent attacks, and the epidemiology of long-term AP comorbidities including cardiovascular, renal and psychiatric diseases and also the risk of malignancies, particularly primary liver cancer (PLC). In study I we collected data on pretransplant characteristics, complications, and outcomes for all patients who had a LT for AP in Europe. We used the European liver transplant register (ELTR) and clinical information from a questionnaire sent to all identified porphyria and transplant centers. In study II and III we used the Swedish porphyria register to create a cohort including all patients with AP in Sweden and a randomly selected, 10:1, age, sex and municipality matched reference cohort from the general population. Data on outcomes including PLC, non-hepatic cancers, mortality and other relevant comorbidities associated with AP was collected from national health registers. Patients with AIP and PLC identified from the national cohort in study II were included in study IV with up to three age and sex matched patients with AIP who did not develop PLC using case-control study design. We compared how life-time ALA and PBG levels collected from the porphyria register correlated to the risk of developing PLC. We identified 38 patients who had a LT for AP between 2002 and 2019. All the patients had AIP, 34 (89%) were women and the median age at LT was 37 years (range, 18-58). The overall 1-year and 5-year survival rates were 92% and 82%, similar to patients with other metabolic diseases transplanted during the same period. No patient had acute attacks after LT. Pre-transplant neuropathy improved in most patients and no worsening was observed while renal impairment in most patients did not improve. In study II we included 1 244 patients with AP (of which 1 063 (85%) had AIP) and 12 333 comparators. During follow-up from 1987 to 2015 we identified 83 (6.7%) patients with AP and PLC of whom 81 (7.6%) had AIP, compared to 25 (0.2%) among the comparators. The adjusted hazard ratio (aHR) for AIP-PLC was 44.5 (95% confidence interval (CI): 28.3–70.0), while no significant difference in PLC rate was observed for patients with HCP or VP. Elevated urinary PBG (U-PBG) was associated with an increased PLC rate and in the sub-group aged >50 years with U-PBG > ULN the annual PLC incidence was 1.8%. In study III we found that the rate of non-hepatic cancers in the same cohort was not increased among patients with AP, with the exception of kidney cancer which was identified in 10 (0.8%) patients with AP, aHR 3.92, (95% CI: 1.90–8.11). Hypertension and chronic kidney disease were more common among patients with AP but not cardiovascular or severe psychiatric diseases. In study IV we found that both ALA and PBG levels were higher among patients with AIP who developed PLC compared to controls. Patients with normal or only slightly elevated porphyrin precursor levels had low risk while patients with high or increasing levels after age 65 were identified as having high risk. In conclusion, we described the outcomes in patients who received a liver transplantation for AIP and a detailed assessment of the epidemiology of long-term comorbidities in AP. Liver transplantation is a curative treatment option with good survival rates that should be considered when other treatment options fail. Patients with clinically or biochemically active AP should be recommended biannual ultrasound surveillance from age 50 and porphyrin precursors might be used to further individualize the risk assessment.