What are the guideline sources, guidelines and references for Hereditary hemochromatosis ?
Guideline sources The following summarized guidelines for the evaluation and management of hereditary hemochromatosis (HH) are prepared by our editorial team based on guidelines from the Asian Pacific Association for the Study of the Liver (APASL 2023), the European Association for the Study of the Liver (EASL 2022; 2010), the American College of Gastroenterology (ACG 2019), the British Society for Haematology (BSH 2018), the European Thyroid Association (ETA 2018), and the American Association for the Study of Liver Diseases (AASLD 2011). 1 2 3 4 5 6 7 Guidelines 1. Screening and diagnosis Indications for screening, general population: As per APASL 2023 guidelines, do not obtain screening for HH in the general population. D https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 1/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway s pe S 0 3 gu de es, do ot obta sc ee g o t e ge e a popu at o As per BSH 2018 guidelines, do not obtain unselected population screening for HFE gene mutation. D As per AASLD 2011 guidelines, do not obtain screening for HH in the average-risk population. D As per EASL 2010 guidelines, do not obtain genetic screening for HFE hemochromatosis because disease penetrance is low and iron overload progresses only in a minority of C282Y homozygotes. D Indications for screening, family relatives: As per APASL 2023 guidelines, obtain screening (including genetic testing) in first-degree relatives (without phenotypic expression) of patients with HFE p.Cys282Tyr/p.His63Asp variants. B As per EASL 2022 guidelines: Obtain screening in adult first-degree relatives (focusing on siblings as they are at the highest risk of hemochromatosis) of patients with rare variants in hemochromatosis genes. B Obtain screening in adult first-degree relatives of patients with p.C282Y homozygous hemochromatosis. B As per ACG 2019 guidelines, obtain screening for HH in family members (particularly first- degree relatives) of patients diagnosed with HH. B As per BSH 2018 guidelines, obtain laboratory screening (CBC, LFTs, serum ferritin, transferrin saturation, and HFE genotyping) in first-degree relatives of patients diagnosed with HFE hemochromatosis. B As per AASLD 2011 guidelines, obtain screening for HH in first-degree relatives of patients with HFE-related HH to detect early disease and prevent complications. B As per EASL 2010 guidelines, obtain genetic screening in siblings of patients with HFE hemochromatosis. Consider screening other first-degree relatives. B Indications for testing: As per APASL 2023 guidelines, obtain testing (serum transferrin saturation, serum ferritin levels, and genetic testing) in patients of European descent with any clinical symptoms or signs compatible with the diagnosis or a family history of iron overload. Measure serum ferritin concentration and transferrin saturation in patients with symptoms, signs, or biochemical abnormalities consistent with hemochromatosis. A As per EASL 2022 guidelines, obtain clinical assessment and biochemical testing for hemochromatosis (serum ferritin and transferrin saturation) in patients with increased liver iron evident on liver biopsy or MRI. B As per AASLD 2011 guidelines: Evaluate patients with abnormal iron studies as patients with hemochromatosis, even without symptoms. B Evaluate all patients with evidence of liver disease for hemochromatosis. B https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 2/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway As per EASL 2010 guidelines: Consider obtaining HFE genotyping in patients with unexplained chronic liver disease and increased transferrin saturation, B porphyria cutanea tarda B , well-defined chondrocalcinosis, HCC, or T1DM. C Do not obtain routine HFE genotyping in patients with unexplained arthritis or arthralgia D or T2DM. D 2. Diagnostic investigations Clinical assessment: assess patients with HFE hemochromatosis for end-organ complications, including diabetes mellitus, joint disease, endocrine deficiencies, cardiac disease, porphyria cutanea tarda, and osteoporosis, before initiating treatment with phlebotomy. B Iron panel: As per APASL 2023 guidelines: Obtain serum ferritin and transferrin saturation as initial tests for hemochromatosis. A Measure hepatic iron concentration using available validated methods, including chemical estimation, in all patients with hemochromatosis and serum ferritin levels > 1,000 g/L. A As per EASL 2022 guidelines, assess serum iron parameters, including transferrin saturation and serum ferritin, as the first step in testing for hemochromatosis. B Show 2 more As per BSH 2018 guidelines, obtain a CBC, LFTs, serum ferritin and transferrin saturation in patients of North European ancestry with clinical features suggestive of genetic hemochromatosis. B As per AASLD 2011 guidelines, obtain a combination of transferrin saturation and ferritin rather than relying on a single test in patients with suggestive symptoms, physical findings, or family history of hemochromatosis. B As per EASL 2010 guidelines, measure fasting transferrin saturation and serum ferritin in patients with suspected iron overload. B As per EASL 2010 guidelines, obtain a CBC, LFTs, serum ferritin, and transferrin saturation in all confirmed C282Y homozygotes. Show 2 more Magnetic resonance imaging: As per APASL 2023 guidelines: Consider obtaining MRI after initial laboratory testing to assess the level of hepatic iron loading. B Measure hepatic iron concentration using available validated methods, including MRI, in all patients with hemochromatosis and serum ferritin levels > 1,000 g/L. A As per EASL 2022 guidelines: https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 3/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway Obtain MRI to quantify hepatic iron concentrations and to assess extrahepatic organ involvement in patients with an unclear cause of hyperferritinemia, biochemical iron overload (increased transferrin saturation and ferritin), or positive liver iron staining. B Consider obtaining MRI for detection and noninvasive quantification of iron, and to evaluate the distribution of iron in the liver in patients with suspected or confirmed iron overload disorder. E As per ACG 2019 guidelines, consider obtaining a non-contrast-enhanced MRI (in conjunction with software used for the estimation of hepatic iron concentration) in order to noninvasively measure hepatic iron concentration in the non-C282Y homozygote with suspected HH. C Assessment of liver fibrosis: As per APASL 2023 guidelines, consider obtaining a noninvasive assessment of liver fibrosis after initial laboratory testing. B Show 2 more As per EASL 2022 guidelines, assess all patients with hemochromatosis noninvasively for the presence of liver fibrosis at diagnosis to guide appropriate treatment and follow-up. B Show 3 more Evaluation for extrahepatic manifestations: As per EASL 2022 guidelines, evaluate clinically patients with hemochromatosis for extrahepatic manifestations, including: skeletal (joint pain, arthritis, osteoporosis, fractures) endocrine (diabetes) reproductive or sexual dysfunction (erectile dysfunction, loss of libido, or amenorrhea). B Show 4 more As per ETA 2018 guidelines, evaluate for central hypothyroidism in all patients with hemochromatosis or iron overload, particularly in the presence of hypothyroid manifestations. B Genetic testing: As per APASL 2023 guidelines, obtain genetic testing for hemochromatosis if both serum ferritin and transferrin saturation are elevated. A Show 3 more As per EASL 2022 guidelines, obtain genetic testing for hemochromatosis, after informed consent for genetic testing has been obtained, in patients with clinical and biochemical signs of hemochromatosis, elevated transferrin saturation and high serum ferritin concentrations, or otherwise unexplained persistently elevated transferrin saturation. B Show 4 more As per ACG 2019 guidelines: Counsel individuals with H63D or S65C mutation in the absence of C282Y mutation that they are not at increased risk of iron overload. B Avoid obtaining further genetic testing in patients with iron overload tested negative for the C282Y and H63D alleles. D https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 4/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway As per BSH 2018 guidelines: Test for HFE hemochromatosis in all adult patients of North European ancestry with raised serum ferritin of unclear etiology (> 300 g/L in males or > 200 g/L in females) and elevated random transferrin saturation (> 50% in males or > 40% in females), and normal CBC. B Test for rare iron loading genotypes or digenic inheritance in non-C282Y homozygotes with significant iron loading as confirmed by MRI and/or liver biopsy. B As per AASLD 2011 guidelines, obtain HFE mutation analysis if either of iron studies is abnormal (transferrin saturation 45% or ferritin above the ULN). B As per EASL 2010 guidelines, obtain HFE testing for the C282Y and H63D polymorphism in all patients with otherwise unexplained increased serum ferritin and increased transferrin saturation. B Obtain HFE testing only in patients with increased transferrin saturation. A Show 2 more 3. Diagnostic procedures Liver biopsy: As per APASL 2023 guidelines: Consider performing a liver biopsy after initial laboratory testing to assess the level of hepatic iron loading and liver fibrosis. B Consider performing a liver biopsy to assess for advanced hepatic fibrosis in patients with verified HFE-hemochromatosis with any of the following noninvasive markers: serum ferritin > 1,000 g/L B hepatic iron concentration > 200 mcmol/g by magnetic resonance methods B AST-to-platelet ratio index > 0.44 FIB-4 index > 1.1 mobilizable iron stores > 9.6 g B transient elastography liver stiffness measurement > 13.9 kPa. B As per EASL 2022 guidelines, consider performing a liver biopsy to assess liver fibrosis if serum ferritin is > 1,000 g/L or liver enzymes are increased. B Show 2 more As per ACG 2019 guidelines, perform a liver biopsy to determine hepatic iron concentration if there is a concomitant need to stage hepatic fibrosis or evaluate for alternate liver diseases. B As per BSH 2018 guidelines: Do not perform a liver biopsy for the diagnosis of HFE hemochromatosis. D Consider performing a liver biopsy in patients with HFE hemochromatosis, serum ferritin > 1,000 g/L and/or elevated transaminases to assess the severity of fibrosis. Consider using transient elastography to select which patients from this group require a liver biopsy. C As per AASLD 2011 guidelines, perform a liver biopsy to stage the degree of liver disease in C282Y homozygotes or compound heterozygotes if liver enzymes (ALT, AST) are elevated or if https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 5/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway ferritin is > 1,000 g/L. B Show 2 more 4. Medical management General principles: As per APASL 2023 guidelines, evaluate the phenotype of p.Cys282Tyr/p.His63Asp compound heterozygous patients and identify factors that may alter serum iron indices and/or increase hepatic iron stores or cofactors for liver disease expressivity. A As per EASL 2022 guidelines, guide the management of patients with p.C282Y/p.H63D compound heterozygosity or p.H63D homozygosity by their phenotypic presentation and the presence of additional risk factors, not the genotype alone. B Show 2 more Treatment targets: As per APASL 2023 guidelines: Target ferritin level of 50 g/L in the de-ironing phase and 50-100 g/L in the maintenance phase. A Measure Hgb at every venesection and serum ferritin at every fourth venesection during the induction phase until the serum ferritin concentration reaches 200 g/L. Measure serum ferritin at each venesection after that. Measure serum ferritin 2-3 times per year and adjust the venesection schedule accordingly during the maintenance phase. A As per EASL 2022 guidelines: Set a target of serum ferritin of 50 g/L, but not lower to avoid iron deficiency, for iron depletion during the induction phase of phlebotomy. B Consider maintaining serum ferritin with some flexibility in the range of 50-100 g/L in the maintenance phase. C As per BSH 2018 guidelines, target serum ferritin levels of approximately 20-30 g/L and transferrin saturation < 50% with phlebotomy. Monitor CBC weekly and serum ferritin and/or transferrin saturation monthly during phlebotomy. B As per AASLD 2011 guidelines, target a ferritin level of 50-100 g/L with phlebotomy. B Iron chelation therapy: As per APASL 2023 guidelines, initiate iron chelation as an alternative to phlebotomy/erythrocytapheresis in patients unable to tolerate the procedure for medical or personal reasons. B As per EASL 2022 guidelines, initiate iron depletion therapy as first-line therapy in patients with hemochromatosis and evidence of iron overload. B Show 2 more As per ACG 2019 guidelines: https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 6/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway Do not use chelation as first-line therapy in patients with HH, given the effectiveness of phlebotomy, the associated side effects of chelation including hepatic and renal toxicity, and the relatively small sample size of clinical trials supporting chelation. D Initiate iron chelation therapy for the treatment of HH in patients intolerant or refractory to phlebotomy or when phlebotomy has the potential for harm, such as in patients with severe anemia or congestive HF. B As per AASLD 2011 guidelines, initiate iron chelation with either deferoxamine mesylate or deferasirox in iron overloaded patients with dyserythropoietic syndromes or chronic hemolytic anemia. B Hepcidin agonists: insufficient evidence to support the use of hepcidin-based therapy. I Proton-pump inhibitors: do not use of PPIs routinely as the primary treatment of HH. D Management of complications: manage complications of hemochromatosis, such as liver cirrhosis, diabetes, arthropathy, hypogonadism, or porphyria cutanea tarda, regardless of whether or not hemochromatosis is the underlying cause and whether there is symptomatic relief or improvement during phlebotomy. B 5. Nonpharmacologic interventions Dietary modifications: As per APASL 2023 guidelines, advise adopting a healthy lifestyle, including maintaining normal body weight and limiting alcohol consumption, in patients with hemochromatosis. Do not restrict dietary iron intake but advise avoiding iron supplements. B As per EASL 2022 guidelines, do not off dietary modifications as a substitute for iron removal therapy. D Show 5 more As per AASLD 2011 guidelines, avoid advising any dietary adjustments during HH treatment. Avoid using vitamin C and iron supplements. D 6. Therapeutic procedures Therapeutic phlebotomy: As per APASL 2023 guidelines: Perform phlebotomy in patients with p.Cys282Tyr/p.His63Asp compound heterozygosity or p.His63Asp homozygosity with significant iron loading. Consider performing phlebotomy in patients with mild iron overload if symptomatic. A Initiate a venesection program in patients with elevated serum ferritin concentration. A As per EASL 2022 guidelines, perform therapeutic phlebotomy as first-line therapy for iron depletion. https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 7/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway As per ACG 2019 guidelines, perform phlebotomy as first-line treatment in patients diagnosed with HH, as determined by C282Y homozygosity or C282Y/H63D compound heterozygosity. B As per BSH 2018 guidelines, perform weekly phlebotomy in all fit patients with genetic hemochromatosis with biochemical evidence of iron loading, until serum ferritin is approximately 20-30 g/L and transferrin saturation < 50%. Monitor CBC weekly and serum ferritin and/or transferrin saturation monthly during this phase of phlebotomy. B As per AASLD 2011 guidelines, perform therapeutic phlebotomy weekly (as tolerated) in patients with hemochromatosis and iron overload. B Show 3 more As per EASL 2010 guidelines, perform phlebotomy in patients with HFE hemochromatosis and evidence of iron overload. B Show 3 more Erythrocytapheresis: As per APASL 2023 guidelines, consider performing erythrocytapheresis in patients having problems with symptoms from hypovolemia from phlebotomy, with cardiac morbidity, hypoproteinemia, and/or thrombocytopenia. B As per EASL 2022 guidelines, consider performing erythrocytapheresis as an alternative to therapeutic phlebotomy if available, recognizing that it is cost-effective in the induction phase because fewer interventions are required. Consider performing personalized erythrocytapheresis as the preferred treatment in selected patients. 7. Surgical interventions Liver transplantation: As per APASL 2023 guidelines, offer liver transplantation in patients with decompensated liver disease and/or HCC. Recognize that the risk of recurrence of hepatic iron loading is very low after liver transplantation and take into consideration the alternative causes should it occur. A As per ACG 2019 guidelines, consider offering liver transplantation in patients with HH with decompensated cirrhosis or HCC. B 8. Specific circumstances Young patients: Obtain genetic testing for HFE- and non-HFE-hemochromatosis in < 30 years old patients presenting with iron overload. Obtain an accurate assessment of the degree of iron overload affecting the liver and heart. B Perform early phlebotomy for the best prognosis. B Pregnant patients: As per APASL 2023 guidelines: https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 8/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway Monitor iron studies in patients with hemochromatosis contemplating pregnancy and ensure avoidance of iron deficiency. B Consider stopping phlebotomy during pregnancy with continuing monitoring iron studies. B As per EASL 2022 guidelines, ensure that patients with hemochromatosis planning to get pregnant do not have iron deficiency. B Show 2 more 9. Preventative measures Hepatitis A and B vaccination: consider providing hepatitis A and B immunization in patients with HFE hemochromatosis despite ongoing evidence of iron overload, to minimize the risk of additional complications. C 10. Follow-up and surveillance Indications for specialist referral: As per EASL 2022 guidelines, refer patients with evidence of significant, unexplained iron overload for assessment by a specialist in iron disorders. B As per BSH 2018 guidelines, refer patients with genetic hemochromatosis and serum ferritin > 1,000 g/L or raised transaminases to a hepatologist for fibrosis assessment and exclusion of cirrhosis. B As per EASL 2010 guidelines, refer all patients with serum ferritin > 1,000 g/L and/or abnormal LFTs to a hepatologist for fibrosis assessment (with elastography) to exclude the presence of cirrhosis. B Serial ferritin monitoring: As per APASL 2023 guidelines, measure serum ferritin and transferrin saturation no more frequently than once a year and up to once every 5 years, especially if previously stable and not rising in patients found to be homozygous for the HFE p.Cys282Tyr pathogenic variant or compound heterozygous for p.Cys282Tyr/p.His63Asp with normal serum ferritin. Avoid obtaining testing beyond annually as it presents a higher risk of patients forgetting to undertake this test, recognizing that it is unlikely that serum ferritin would increase from the normal range to a dangerously high level in 12 months. B Show 2 more As per AASLD 2011 guidelines, monitor patients with hemochromatosis and iron overload for reaccumulation of iron and perform maintenance phlebotomy. B As per EASL 2010 guidelines, consider monitoring ferritin annually in C282Y homozygotes without evidence for iron overload, and instituting treatment when ferritin rises above normal. C Surveillance for hepatocellular carcinoma: As per APASL 2023 guidelines, obtain surveillance for HCC with 6-monthly ultrasound, with or without AFP testing, in patients with cirrhosis due to hemochromatosis. Obtain surveillance only https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 9/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway if a diagnosis of HCC will alter management. A As per EASL 2022 guidelines, obtain screening for HCC every 6 months in patients with hemochromatosis and cirrhosis (on biopsy METAVIR F4, Ishak scoring system stage 6, or on elastography), regardless of iron depletion. B Show 6 more As per ACG 2019 guidelines, avoid obtaining routine surveillance for HCC in patients with HH with stage 3 fibrosis. D As per BSH 2018 guidelines, obtain monitoring for HCC with hepatic ultrasound and measurement of serum AFP every 6 months in patients with hemochromatosis and cirrhosis. B As per EASL 2010 guidelines, obtain monitoring with AFP and hepatic ultrasound every 6 months in patients with confirmed cirrhosis. B Likelihood Ratios Pertinent positives The following findings increase the probability of hereditary hemochromatosis in adults. 1 1 1 Finding LR+ Value Presence of C282Y homozygosity 68.3 Decreased serum unbound iron binding capacity (< 28 g/dL) 18.3 Increased serum transferrin saturation (> 46%) 12.8 Increased serum total transferrin 11.3 Show 1 more Pertinent negatives The following findings decrease the probability of hereditary hemochromatosis in adults. 1 1 1 1 Finding LR- Value T2 relaxation rate not increased 0.1 serum total transferrin not increased 0.1 Absence of C282Y homozygosity 0.2 serum unbound iron binding capacity not decreased ( 28 g/dL) 0.3 Show 2 more References 1. European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010 Jul;53 1 3 22. Open https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 10/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. Hepatol. 2022 Aug;77 2 479 502. Open 3. Bruce R Bacon, Paul C Adams, Kris V Kowdley et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Jul;54 1 328 43. Open 4. Darrell H G Crawford, Grant A Ramm, Kim R Bridle et al. Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver. Hepatol Int. 2023 Apr 17. Open 5. Fitzsimons EJ, Cullis JO, Thomas DW et al. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). Br J Haematol. 2018 May;181 3 293 303. Open 6. Kris V Kowdley, Kyle E Brown, Joseph Ahn et al. ACG Clinical Guideline: Hereditary Hemochromatosis. Am J Gastroenterol. 2019 Aug;114 8 1202 1218. Open 7. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open 8. American College of Medical Genetics. Choosing Wisely ACMG recommendations. Choosing Wisely. 2016. Open 9. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 10. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 11. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 11/11