Advertisement
Mayo Clinic Proceedings Home

Arthritis Prediction of Advanced Hepatic Fibrosis in HFE Hemochromatosis

      Abstract

      Objective

      To evaluate whether arthritis predicts the likelihood of advanced hepatic fibrosis in HFE hemochromatosis.

      Patients and Methods

      We conducted a retrospective, cross-sectional analysis of 112 well-characterized patients with HFE hemochromatosis and liver biopsy–validated fibrosis staging recruited between January 1, 1983, and December 31, 2013. Complete clinical, biochemical, hematologic, and noninvasive serum biochemical indices (aspartate aminotransferase to platelet ratio index [APRI] and fibrosis 4 index [FIB4]) were available. Scheuer fibrosis stages 3 and 4, APRI greater than 0.44, or FIB4 greater than 1.1 were used to define advanced hepatic fibrosis. Comparisons between groups were performed using categorical analysis, unpaired or paired t test.

      Results

      Male (n=76) and female (n=36) patients were similar in age. Nineteen patients had advanced hepatic fibrosis, and 47 had hemochromatosis arthritis. Arthritis was significantly associated with the presence of advanced hepatic fibrosis as determined by liver biopsy (sensitivity, 84%, [95% CI, 62% to 95%]; negative predictive value, 95% [95% CI, 87% to 99%]; relative risk, 7.4 [95% CI, 2.5 to 23]; P<.001), APRI (sensitivity, 75% [95% CI, 55% to 88%]; negative predictive value, 91% [95% CI, 81% to 96%]; relative risk, 4.5 [95% CI, 2.0 to 10.2]; P<.001), or FIB4 (sensitivity, 61% [95% CI, 41% to 78%]; negative predictive value, 67% [95% CI, 68% to 90%]; relative risk, 2.2 [95% CI, 1.1 to 4.6]; P=.03). Mean cell volume values were significantly higher pretreatment in patients with F3-4 fibrosis (96.7±1.1 fL) compared with F0-2 fibrosis (93.4±0.5 fL; P=.004) and declined following treatment (F3-4, 93.2±0.9 fL, P=.01; F0-2, 91.7±0.6 fL, P=.01).

      Conclusion

      Advanced hepatic fibrosis is strongly associated with arthritis in HFE hemochromatosis. The absence of arthritis predicts a low likelihood of advanced hepatic fibrosis, supporting its use as a clinical marker for advanced hepatic fibrosis in HFE hemochromatosis.

      Abbreviations and Acronyms:

      APRI (aspartate aminotransferase to platelet ratio index), FIB4 (fibrosis 4 index), HH (HFE hemochromatosis), HIC (hepatic iron concentration), MCV (mean cell volume), NPV (negative predictive value), PPV (positive predictive value), SENS (sensitivity), SPEC (specificity)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Olynyk J.K.
        • Cullen D.J.
        • Aquilia S.
        • Rossi E.
        • Summerville L.
        • Powell L.W.
        A population-based study of the clinical expression of the hemochromatosis gene.
        N Engl J Med. 1999; 341: 718-724
        • Beutler E.
        • Felitti V.J.
        The clinical penetrance of hereditary hemochromatosis.
        Hepatology. 2003; 37: 711
        • Adams P.C.
        • Reboussin D.M.
        • Leiendecker-Foster C.
        • et al.
        Comparison of the unsaturated iron-binding capacity with transferrin saturation as a screening test to detect C282Y homozygotes for hemochromatosis in 101,168 participants in the Hemochromatosis and Iron overload Screening (HEIRS) Study.
        Clin Chem. 2005; 51: 1048-1052
        • Olynyk J.K.
        • Trinder D.
        • Ramm G.A.
        • Britton R.S.
        • Bacon B.R.
        Hereditary hemochromatosis in the post-HFE era.
        Hepatology. 2008; 48: 991-1001
        • Allen K.J.
        • Gurrin L.C.
        • Constantine C.C.
        • et al.
        Iron-overload–related disease in HFE hereditary hemochromatosis.
        N Engl J Med. 2008; 358: 221-230
        • Bridle K.R.
        • Frazer D.M.
        • Wilkins S.J.
        • et al.
        Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.
        Lancet. 2003; 361: 669-673
        • Asberg A.
        • Hveem K.
        • Thorstensen K.
        • et al.
        Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons.
        Scand J Gastroenterol. 2001; 36: 1108-1115
        • Olynyk J.K.
        • Hagan S.E.
        • Cullen D.J.
        • Beilby J.
        • Whittall D.E.
        Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study.
        Mayo Clin Proc. 2004; 79: 309-313
        • Olynyk J.K.
        Hereditary haemochromatosis: diagnosis and management in the gene era.
        Liver. 1999; 19: 73-80
        • European Association for the Study of the Liver
        EASL clinical practice guidelines for HFE hemochromatosis.
        J Hepatol. 2010; 53: 3-22
        • Bacon B.R.
        • Adams P.C.
        • Kowdley K.V.
        • Powell L.W.
        • Tavill A.S.
        Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.
        Hepatology. 2011; 54: 328-343
        • Niederau C.
        • Fischer R.
        • Sonnenberg A.
        • Stremmel W.
        • Trampisch H.J.
        • Strohmeyer G.
        Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.
        N Engl J Med. 1985; 313: 1256-1262
        • Niederau C.
        • Fischer R.
        • Pürschel A.
        • Stremmel W.
        • Häussinger D.
        • Strohmeyer G.
        Long-term survival in patients with hereditary hemochromatosis.
        Gastroenterology. 1996; 110: 1107-1119
        • Ong S.Y.
        • Gurrin L.C.
        • Dolling L.
        • et al.
        Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial.
        Lancet Haematol. 2017; 4: e607-e614
        • Barton J.C.
        • Bertoli L.F.
        • Rothenberg B.E.
        Screening for hemochromatosis in routine medical care: an evaluation of mean corpuscular volume and mean corpuscular hemoglobin.
        Genet Test. 2000; 4: 103-110
        • Adris N.
        • Hazeldine S.
        • Bentley P.
        • et al.
        Detection of HFE Haemochromatosis in the clinic and community using standard erythrocyte tests.
        Blood Cells Mol Dis. 2019; 74: 18-24
        • Powell L.W.
        • Dixon J.L.
        • Ramm G.A.
        • et al.
        Screening for hemochromatosis in asymptomatic subjects with or without a family history.
        Arch Intern Med. 2006; 166: 294-301
        • Adams P.C.
        • Speechley M.
        The effect of arthritis on the quality of life in hereditary hemochromatosis.
        J Rheumatol. 1996; 23: 707-710
        • Chin J.
        • Powell L.W.
        • Ramm L.E.
        • Ayonrinde O.T.
        • Ramm G.A.
        • Olynyk J.K.
        Utility of hepatic or total body iron burden in the assessment of advanced hepatic fibrosis in HFE hemochromatosis.
        Sci Rep. 2019; 9: 20234
        • Olynyk J.K.
        • St Pierre T.G.
        • Britton R.S.
        • Brunt E.M.
        • Bacon B.R.
        Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging.
        Am J Gastroenterol. 2005; 100: 837-841
        • St Pierre T.G.
        • Clark P.R.
        • Chua-anusorn W.
        • et al.
        Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance.
        Blood. 2005; 105: 855-861
        • Chin J.
        • Powell L.W.
        • Ramm L.E.
        • Hartel G.F.
        • Olynyk J.K.
        • Ramm G.A.
        Utility of serum biomarker indices for staging of hepatic fibrosis before and after venesection in patients with hemochromatosis caused by variants in HFE.
        Clin Gastroenterol Hepatol. 2021; 19: 1459-1468.e5
        • Falize L.
        • Guillygomarc'h A.
        • Perrin M.
        • et al.
        Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases.
        Hepatology. 2006; 44: 472-477
        • Bardou-Jacquet E.
        • Morandeau E.
        • Anderson G.J.
        • et al.
        Regression of fibrosis stage with treatment reduces long-term risk of liver cancer in patients with hemochromatosis caused by mutation in HFE.
        Clin Gastroenterol Hepatol. 2020; 18: 1851-1857
        • Schumacher Jr., H.R.
        Hemochromatosis and arthritis.
        Arthritis Rheum. 1964; 7: 41-50
        • Carroll G.J.
        • Breidahl W.H.
        • Bulsara M.K.
        • Olynyk J.K.
        Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load.
        Arthritis Rheum. 2011; 63: 286-294
        • Deugnier Y.
        • Morcet J.
        • Lainé F.
        • et al.
        Reduced phenotypic expression in genetic hemochromatosis with time: role of exposure to non-genetic modifiers.
        J Hepatol. 2019; 70: 118-125
        • Carroll G.J.
        • Breidahl W.H.
        • Olynyk J.K.
        Characteristics of the arthropathy described in hereditary hemochromatosis.
        Arthritis Care Res (Hoboken). 2012; 64: 9-14
        • Hamilton E.
        • Williams R.
        • Barlow K.A.
        • Smith P.M.
        The arthropathy of idiopathic haemochromatosis.
        Q J Med. 1968; 37: 171-182
        • Bardou-Jacquet E.
        • Lainé F.
        • Guggenbuhl P.
        • et al.
        Worse outcomes of patients with HFE hemochromatosis with persistent increases in transferrin saturation during maintenance therapy.
        Clin Gastroenterol Hepatol. 2017; 15: 1620-1627
        • Dallos T.
        • Sahinbegovic E.
        • Stamm T.
        • et al.
        Idiopathic hand osteoarthritis vs haemochromatosis arthropathy—a clinical, functional and radiographic study.
        Rheumatology (Oxford). 2013; 52: 910-915
        • Heiland G.R.
        • Aigner E.
        • Dallos T.
        • et al.
        Synovial immunopathology in haemochromatosis arthropathy.
        Ann Rheum Dis. 2010; 69: 1214-1219
        • Kiely P.D.
        Haemochromatosis arthropathy - a conundrum of the Celtic curse.
        J R Coll Physicians Edinb. 2018; 48: 233-238
        • Rehman A.
        • Carroll G.J.
        • Powell L.W.
        • Ramm L.E.
        • Ramm G.A.
        • Olynyk J.K.
        Arthropathy in hereditary haemochromatosis segregates with elevated erythrocyte mean corpuscular volume.
        Scand J Rheumatol. 2021; 50: 139-142
        • Scheuer P.J.
        Classification of chronic viral hepatitis: a need for reassessment.
        J Hepatol. 1991; 13: 372-374
        • Valenti L.
        • Fracanzani A.L.
        • Rossi V.
        • et al.
        The hand arthropathy of hereditary hemochromatosis is strongly associated with iron overload.
        J Rheumatol. 2008; 35: 153-158
        • Altes A.
        • Ruiz A.
        • Martinez C.
        • et al.
        The relationship between iron overload and clinical characteristics in a Spanish cohort of 100 C282Y homozygous hemochromatosis patients.
        Ann Hematol. 2007; 86: 831-835