Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

OBJECTIVE: miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. METHODS: Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. RESULTS: A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. CONCLUSION: miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Dissociation of clinical, laboratory, and bone biopsy findings in adult X-linked hypophosphatemia: a case report.

X­linked hypophosphatemia (XLH) is a phosphate wasting disorder. Typical serum constellations include low serum phosphate as well as high alkaline phosphatase (ALP) and fibroblast growth factor 23 (FGF-23 ) levels. Adult XLH patients usually suffer from (pseudo)fractures, enthesopathies, impaired mobility, and osteoarthritis. We report the case of a middle-aged woman with clinically mild disease, relatively balanced laboratory values, but bone non-healing of the femur post-surgery. Transiliac bone biopsy revealed pronounced osteomalacia and severe deterioration of bone microstructure. Due to the lack of XLH-typical symptoms, the patient was not substituted with calcitriol and phosphate in adulthood. Thus, laboratory findings and radiological examinations do not necessarily reflect bone metabolism in XLH. Bone biopsies should be considered in unclear cases or prior to surgery in adults with XLH.

No evidence of mineralization abnormalities in iliac bone of premenopausal women with type 2 diabetes mellitus.

OBJECTIVES: Patients with type-2 diabetes mellitus (T2DM) have increased risk for bone fractures which points towards impaired bone quality. METHODS: We measured bone mineralization density distribution (BMDD) and osteocyte lacunae section (OLS) characteristics based on quantitative backscattered electron images of transiliac biopsy samples from n=26 premenopausal women with T2DM. Outcomes were compared to those from reference cohorts as well as between T2DM subgroups defined by clinical characteristics. RESULTS: Comparison to references did not reveal any differences in BMDD (all p>0.05) but a lowered OLS-density in cancellous bone in T2DM (-14.9%, p<0.001). Neither BMDD nor OLS-characteristics differed in T2DM subgroups defined by HbA1c (<7% versus >7%). The average degree of bone mineralization (CaMean) was higher (0.44 wt%Ca in T2DM, 0.30 wt%Ca in reference) and consistently the calcium concentration between the tetracycline double labels (CaYoung) was higher (0.76 wt%Ca, all p<0.001) in cancellous versus cortical bone. CONCLUSIONS: Our findings suggest that bone matrix mineralization was neither affected by the presence nor by the glycemic control of T2DM in our study cohort. The intra-individual differences between cancellous and cortical bone mineralization gave evidence for differences in the time course of the early mineralization process in these compartments in general.

Confluent abscesses in autochthonous back muscles after spinal injections : A case report and narrative review of the literature on low back pain and spinal injections.

Injection therapy is a frequently used method for the treatment of subacute and chronic low back pain (LBP) despite scant evidence for its effectiveness. To date there are relatively few studies comparing this method with other treatments. Moreover, there are many possible side effects associated with injection therapies, some of which are potentially life threatening. We present the case of a 59-year-old woman admitted to the emergency department with confluent abscess formations of autochthonous back muscles and staphylococcal sepsis caused by injection therapy performed by a general practitioner for LBP. The findings of this case report emphasize a careful selection of patients for this type of treatment and a multidisciplinary approach to treatment of LBP.

Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source.

Quantitative backscattered electron imaging is an established method to map mineral content distributions in bone and to determine the bone mineralization density distribution (BMDD). The method we applied was initially validated for a scanning electron microscope (SEM) equipped with a tungsten hairpin cathode (thermionic electron emission) under strongly defined settings of SEM parameters. For several reasons, it would be interesting to migrate the technique to a SEM with a field emission electron source (FE-SEM), which, however, would require to work with different SEM parameter settings as have been validated for DSM 962. The FE-SEM has a much better spatial resolution based on an electron source size in the order of several 100 nanometers, corresponding to an about [Formula: see text] to [Formula: see text] times smaller source area compared to thermionic sources. In the present work, we compare BMDD between these two types of instruments in order to further validate the methodology. We show that a transition to higher pixel resolution (1.76, 0.88, and 0.57 µm) results in shifts of the BMDD peak and BMDD width to higher values. Further the inter-device reproducibility of the mean calcium content shows a difference of up to 1 wt% Ca, while the technical variance of each device can be reduced to [Formula: see text] wt% Ca. Bearing in mind that shifts in calcium levels due to diseases, e.g., high turnover osteoporosis, are often in the range of 1 wt% Ca, both the bone samples of the patients as well as the control samples have to be measured on the same SEM device. Therefore, we also constructed new reference BMDD curves for adults to be used for FE-SEM data comparison.

Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I.

Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (-10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue.

New therapeutic options for bone diseases.

In recent years, new treatment options for both common and rare bone diseases have become available. The sclerostin antibody romosozumab is the most recently approved drug for the therapy of postmenopausal osteoporosis. Its anabolic capacity makes it a promising treatment option for severe osteoporosis. Other sclerostin antibodies for the treatment of rare bone diseases such as osteogenesis imperfecta are currently being investigated. For rare bone diseases such as X­linked hypophosphatemia (XLH) and hypophosphatasia (HPP), specific therapies are now also available, showing promising data in children and adults with a severe disease course. However, long-term data are needed to assess a sustained benefit for patients.

Bone properties in osteogenesis imperfecta: what can we learn from a bone biopsy beyond histology?

Transiliac bone biopsy samples are used to evaluate histology and bone cell activity in unclear pathological conditions. However, much additional information can be obtained from such bone samples. Using the example of osteogenesis imperfecta (OI), the current article describes how biopsy samples can be further used to study bone material characteristics including the degree of matrix mineralization, organic matrix properties, mineral particle size and bone nanoporosity. OI is a heritable collagen-related disorder that is phenotypically and genetically extremely heterogeneous. One essential finding was that OI bone is hypermineralized independently of clinical severity. Moreover, mineral particles in OI bone are of normal size or even smaller, but more densely packed than normally. Another recent finding was that in some forms of OI, collagen orientation is highly disorganized, indicating that the collagen-mineral particle network is profoundly altered in OI. These findings have contributed to the understanding of impaired bone strength in OI.

Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice.

Osteocytic osteolysis/perilacunar remodeling is thought to contribute to the maintenance of mineral homeostasis. Here, we utilized a reversible, adult-onset model of secondary hyperparathyroidism to study femoral bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging. Male mice with a non-functioning vitamin D receptor (VDRΔ/Δ) or wild-type mice were exposed to a rescue diet (RD) (baseline) and subsequently to a low calcium challenge diet (CD). Thereafter, VDRΔ/Δ mice received either the CD, a normal diet (ND), or the RD. At baseline, BMDD and OLS characteristics were similar in VDRΔ/Δ and wild-type mice. The CD induced large cortical pores, osteomalacia, and a reduced epiphyseal average degree of mineralization in the VDRΔ/Δ mice relative to the baseline (-9.5%, p < 0.05 after two months and -10.3%, p < 0.01 after five months of the CD). Switching VDRΔ/Δ mice on the CD back to the RD fully restored BMDD to baseline values. However, OLS remained unchanged in all groups of mice, independent of diet. We conclude that adult VDRΔ/Δ animals on an RD lack any skeletal abnormalities, suggesting that VDR signaling is dispensable for normal bone mineralization as long as mineral homeostasis is normal. Our findings also indicate that VDRΔ/Δ mice attempt to correct a calcium challenge by enhanced osteoclastic resorption rather than by osteocytic osteolysis.

Multidisciplinary patient care in X-linked hypophosphatemic rickets: one challenge, many perspectives.

X­linked hypophosphatemic rickets (XLH, OMIM #307800) is a rare genetic metabolic disorder caused by dysregulation of fibroblast-like growth factor 23 (FGF23) leading to profound reduction in renal phosphate reabsorption. Impaired growth, severe rickets and complex skeletal deformities are direct consequences of hypophosphatemia representing major symptoms of XLH during childhood. In adults, secondary complications including early development of osteoarthritis substantially impair quality of life and cause significant clinical burden. With the global approval of the monoclonal FGF23 antibody burosumab, a targeted treatment with promising results in phase III studies is available for children with XLH. Nevertheless, complete phenotypic rescue is rarely achieved and remaining multisystemic symptoms demand multidisciplinary specialist care. Coordination of patient management within the major medical disciplines is a mainstay to optimize treatment and reduce disease burden. This review aims to depict different perspectives in XLH patient care in the setting of a multidisciplinary centre of expertise for rare bone diseases.

Treatment Effects of Bisphosphonates and Denosumab on Survival and Refracture from Real-World Data of Hip-Fractured Patients.

We examined differences in patients' survival after hip fracture (HF) and risk for subsequent HF among patients treated with oral and intravenous bisphosphonates (oBPs, iBPs), denosumab (DMAB), and patients without therapy. We used data from all patients in Austria aged ≥ 50 who sustained a HF between 2012 and 2017 and were followed for a subsequent HF and all-cause mortality until 2017. Antiosteoporotic treatment-naïve patients, who were incident users of BPs and DMAB, were eligible for propensity score matching 1:1 to obtain comparable user groups. We applied competing risk approach and calculated cumulative incidence functions and subdistribution-hazards for refracture. Cox regression models were applied for mortality risk. A total of 54,145 hip-fractured patients were observed (1919 oBPs; 1870 iBPs; 555 DMAB users; and 42,795 untreated patients were included in the matched sets) and followed up for a median (interquartile range) of 22.6 months (26.2). Patients treated with antiresorptive medications had significantly longer survival time than patients without treatment. Receiving treatment significantly decreased a hazard of dying only for women by 17% for iBPs (HR 0.83, 95% CI 0.71-0.98, p = 0.023). For DMAB and oBPs, the results were not statistically significant. Higher risk of a subsequent HF was observed in women on DMAB (SHR 1.77, 95% CI 1.08-2.91) and on iBP (SHR 1.81, 95% CI 1.35-2.41), and in men on oBPs (SHR 2.89, 95% CI 1.58-5.30). Patients who were treated with antiresorptive medications after HF had longer survival than patients without treatment, highlighting the importance of initiation of antiresorptive treatment after HF.

Novel Developments in Primary Immunodeficiencies (PID)-a Rheumatological Perspective.

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of the most relevant new disorders, disease entities, or disease phenotypes of primary immune deficiency disorders (PID) for the interested rheumatologist, using the new phenotypic classification by the IUIS (International Union of Immunological Societies) as practical guide. RECENT FINDINGS: Newly recognized disorders of immune dysregulation with underlying mutations in genes pertaining to the function of regulatory T cells (e.g., CTLA-4, LRBA, or BACH2) are characterized by multiple autoimmune diseases-mostly autoimmune cytopenia-combined with an increased susceptibility to infections due to hypogammaglobulinemia. On the other hand, new mutations (e.g., in NF-kB1, PI3Kδ, PI3KR1, PKCδ) leading to the clinical picture of CVID (common variable immmune deficiency) have been shown to increasingly associate with autoimmune diseases. The mutual association of autoimmune diseases with PID warrants increased awareness of immunodeficiencies when diagnosing autoimmune diseases with a possible need to initiate appropriate genetic tests.

Hypophosphatasia: From Diagnosis to Treatment.

PURPOSE OF REVIEW: Hypophosphatasia (HPP) is a rare genetic disorder caused by mutations of the ALPL gene. ALPL encodes the tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Consequently, bone mineralization is decreased leading to fractures, arthralgia, and extra-skeletal manifestations including tissue calcification, respiratory failure, and neurological complications. This review summarizes the most important clinical findings, diagnosis, and treatment options for HPP. RECENT FINDINGS: Asfotase alfa is a recombinant human alkaline phosphatase, used as treatment for the underlying cause of HPP. Asfotase alfa enhances the survival in life-threatening HPP and improves bone mineralization, muscle strength, and pulmonary function. However, discontinuation of asfotase alfa leads to reappearance of bone hypomineralization. Due to its varied manifestations, HPP often mimics rheumatological and other bone diseases, thereby delaying its diagnosis. Asfotase alfa, a recombinant alkaline phosphatase, is available for the long-term enzyme replacement therapy in patients with pediatric-onset HPP to treat the bone manifestations of the disease.

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate.

Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation viaTet1andTet2and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2,Col1a1,Bglap2,Sp7,Atf4, andAlpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-κB ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of theTet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (∼20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorptionin vivo Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis.

OBJECTIVE: Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms. METHODS: Osteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus. RESULTS: WNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos. CONCLUSIONS: In osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.

Bone Involvement in Rosai-Dorfman Disease (RDD): a Case Report and Systematic Literature Review.

PURPOSE OF REVIEW: Rosai-Dorfman disease (RDD) is a rare histiocytic disorder typically presenting as painless cervical lymphadenopathy. Extranodal involvement is common and may also affect bones. Here, we present a patient with typical nodal disease and multifocal bone manifestations. Further, a systematic literature review was performed to better understand the phenotype, clinical course and treatment options of such patients. RECENT FINDINGS: RDD is a nonmalignant, classically sporadic histiocytosis. Nevertheless, increasing evidence also suggests familial forms of the disease. According to our literature review, bone involvement is exceedingly rare and heterogeneous. Clinical outcome in terms of mortality seems to be favorable in most cases. Currently, therapy strategies include surgical and immunosuppressive treatments, but the optimal treatment of osseous RDD remains to be defined. Patients with osseous RDD may present to rheumatologists with arthralgia or arthritis. Due to the rarity of the disease, diagnosis and treatment remain challenging.

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.