D i a g n o s i s an d M a n a g e m e n t o f H e red i t a r y H e m o c h ro m a t o s i s Reena J. Salgia,
MD*,
Kimberly Brown,
MD
KEYWORDS Hemochromatosis Iron saturation Ferritin Cirrhosis Liver transplant KEY POINTS Hereditary hemochromatosis (HH) is a diagnosis most commonly made in patients with elevated iron indices (transferrin saturation and ferritin), and HFE genetic mutation testing showing C282Y homozygosity. The HFE mutation is believed to result in clinical iron overload through altering hepcidin levels resulting in increased iron absorption. The most common clinical complications of HH include cirrhosis, diabetes, nonischemic cardiomyopathy, and hepatocellular carcinoma. Liver biopsy should be performed in patients with HH if the liver enzymes are elevated or serum ferritin is greater than 1000 mg/L. This is useful to determine the degree of iron overload and stage the fibrosis. Treatment of HH with clinical iron overload involves a combination of phlebotomy and/or chelation therapy. Liver transplantation should be considered for patients with HH-related decompensated cirrhosis.
INTRODUCTION
Although hereditary hemochromatosis (HH) is a less common cause of cirrhosis than chronic viral hepatitis, it remains the most commonly identified genetic disorder in the white population. The prevalence of HH varies worldwide, with the highest frequency of disease occurring among those of northern European ancestry.1 Since this disease was first described by Trousseau in 1865, many studies have led to a greater understanding of the underlying pathophysiology. HH was initially noted to be associated with increased iron deposition in organ tissue, leading to cirrhosis, heart failure, diabetes, arthritis, and a high risk for hepatocellular carcinoma (HCC).2 Then a seminal
Disclosures: The authors have no relevant affiliations or financial involvement. Division of Gastroenterology and Hepatology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA * Corresponding author. E-mail address: [email protected] Clin Liver Dis 19 (2015) 187–198 http://dx.doi.org/10.1016/j.cld.2014.09.011 1089-3261/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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paper in 1996 revealed the HFE gene mutation, which causes a substitution of tyrosine for cysteine at the amino acid 282 position (C282Y).3 Subsequently two additional mutations were noted, aspartate for histidine (H63D), and cysteine for serine (S65C). The most common form of HFE-related HH is associated with the C282Y homozygous mutation, and less commonly compound heterozygotes with either C282Y/H63D or C282Y/S65C.4 Non-HFE associated hemochromatosis is rare, accounting for less than 15% of inherited iron overload.5 This article provides a brief overview of the pathophysiology of hemochromatosis, and an up-to-date summary of the diagnosis and management of HH. PATHOPHYSIOLOGY
HH is a genetic disorder broadly characterized by excessive total body iron storage.1,6 Several mechanisms explain this imbalance of iron homeostasis in HH. The initial theory was noted as the “crypt cell hypothesis,” reflecting the interplay between the HFE protein and b2-microglobulin.7,8 Together these two proteins form a complex with transferrin receptor-1, which is located predominantly in the duodenal crypt enterocytes. There the complex would sense and regulate dietary iron absorption. It is also hypothesized that this complex acts at the level of the hepatocyte membrane to sense iron stores.9 However, the more recent discovery of hepcidin, a small peptide hormone that is encoded by a gene expressed in the liver, has altered the predominant theory of iron overload associated with HH. Hepcidin controls iron absorption in the duodenum. The levels of circulating hepcidin vary based on systemic iron stores.10 The interaction between HFE and the transferrin receptors is paramount to the sensing of iron at the hepatocyte membrane.11 When iron stores are elevated, hepcidin is released and binds to ferroportin in macrophages and enterocytes. There it blocks the export of iron from macrophages and decreases intestinal iron absorption (Fig. 1).12,13 When the HFE protein is mutated, the expression of hepcidin decreases and intestinal iron absorption increases. Although it remains unclear how the mutated HFE gene controls hepcidin in HH, a decrease in hepcidin results in a rise of iron efflux from macrophages and enterocytes, and increased intestinal iron absorption into organ tissue.14 Hence the liver is the major regulator of iron metabolism, and in patients with HH this mechanism is altered by abnormally low hepcidin levels.15 The presence of elevated iron stores in the liver over time can lead to hepatic fibrosis and cirrhosis. Iron has been shown to cause increased oxidative stress and damage to hepatocytes and mitochondrial function.16–18 These hepatocytes are injured and release Kupffer cells, which stimulate hepatic stellate cells to increase production of collagen.19 Over time this process leads to the development of cirrhosis. DIAGNOSIS Clinical Presentation
Because of variable penetrance of clinical HH, end-organ damage is noted in less than 10% of patients who are homozygous for the C282Y mutation.20 The clinical phenotype is expressed in 24% to 43% of males and 1% to 14% of females.21 Clinical disease is noted even less frequently in patients who are compound heterozygotes (C282Y/H63D positive), who account for approximately 5% of cases of HH.4,22 Women also present with clinical features later in life, largely related to monthly menstruation resulting in iron loss and having a protective effect. However, the disease prevalence is similar between men and women, resulting from earlier recognition and screening for this disease.23,24
Diagnosis and Management of Hemochromatosis
Fig. 1. Iron homeostasis as regulated by hepcidin. BMPR, bone morphogenetic protein receptor; FPN, ferroportin; HJV, hemojuvelin; SMAD, Sma and Mad related protein. (From Camaschella C. BMP 6 orchestrates iron metabolism. Nat Genet 2009;41(4):386–8; with permission.)
The clinical features of HH are highly variable, with signs and symptoms that can involve multiple organ systems. Aside from liver involvement leading to cirrhosis, iron overload from HH can involve the heart, pancreas, skin, pituitary gland, gonads, and joints (Table 1).1,4 Multiple studies have found that the predominant clinical features in patients with HH include (from most common to least common) cirrhosis, lethargy, hyperpigmentation of the skin, loss of libido, testicular atrophy, diabetes, abdominal pain, and arthralgias.25–27 Laboratory Testing
The initial suspicion for HH is largely made based on clinical features, biochemical abnormalities, and genetic testing, with liver biopsy less commonly needed to make an initial diagnosis. Elevated serum ferritin (SF) levels and transferrin-iron saturation (TS) are readily available serum markers that help to identify patients with HH. These tests should be performed on patients with chronically elevated liver enzymes.1 Ferritin levels greater than 200 mg/L for females and greater than 300 mg/L for males are considered abnormal.23,28 Ferritin is known to be elevated in the absence of elevated iron stores. For example, the presence of viral hepatitis, nonalcoholic fatty liver disease, or alcoholic liver disease and other chronic inflammatory conditions can all cause elevations in SF levels.1 The TS is calculated based on total body iron divided
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Table 1 Signs, symptoms, and clinical presentation of HH Organ System
Sign/Symptom
General
Weakness, fatigue, lethargy Weight loss Apathy
Liver
Abdominal pain
Hepatomegaly Splenomegaly Cutaneous stigmata (spider angiomata, palmar erythema) Gynecomastia
Cardiac
Heart failure Arrhythmia
Cardiomegaly Elevated JVP
Pancreas
Hyperglycemia from diabetes
Skin
Physical Examination
Hyperpigmentation, “bronze skin” Porphyria cutanea tarda
Endocrine
Loss of libido Hypothyroidism
Testicular atrophy
Joints
Arthralgias
Arthritis (second and third MCP) Joint swelling
Abbreviations: JVP, jugular venous pressure; MCP, metacarpophalangeal joint.
by total iron-binding capacity. A saturation level higher than 45% again raises suspicion for HH.23,28 If either the SF or TS is abnormal, then the HFE genetic mutation analysis should be performed.1 A result of C282Y homozygous genotype is consistent with a diagnosis of HH in the setting of iron overload.29 It is less common for C282Y/H63D compound heterozygous genotype or H63D homozygous genotype to develop clinically significant iron overload; however, it has been described.22,30 The Hemochromatosis and Iron Overload Screening study screened 99,711 North American patients and found that SF was elevated (>200 mg/L in women and >300 mg/L in men) in 57% of female and 88% of male C282Y homozygotes.23 Multiple studies have shown that marked elevations in SF to values greater than 1000 mg/L are a stronger predictor of advanced hepatic fibrosis and cirrhosis in patients with documented HH.29,31–33 When an elevated ferritin greater than 1000 mg/L is combined with elevated transaminases and platelet count less than 200 10(9)/L, the positive predictive value for cirrhosis is 80% in patients with C282Y homozygosity.34 These findings have also been shown to increase the mortality risk associated with HH.35 Patients with C282Y homozygosity who have normal iron studies should have an annual measurement of their ferritin level.4 Screening for Hereditary Hemochromatosis
Screening for HH should also be performed in patients with a family history of HH or a suspicion based on suspected organ involvement of elevated iron stores.1,23 Fig. 2 is a diagnostic algorithm for screening patients at-risk for HH. It is recommended that all first-degree relatives of a patient with HH should undergo family screening. Screening can be performed with SF, TS, and HFE mutation testing. The inheritance pattern is autosomal-recessive with mutations in the HFE gene on chromosome 6.3,36 Children of an affected parent can be tested or alternatively the other parent can be tested.37 It is generally recommended that if children are going to be screened, testing should be
Diagnosis and Management of Hemochromatosis
Fig. 2. Diagnostic algorithm for HH. Elevated SF is greater than 200 mg/L in females and greater than 300 mg/L in males.
done once they reach adulthood.38 There is a negligible risk of developing clinical HH before the age of 18. Histology
The main purpose of liver biopsy in the diagnosis of HH is to stage the degree of fibrosis. It is important to determine if patients have cirrhosis for prognosis and to initiate surveillance for HCC and esophageal varices.39 SF is valuable to discriminate which patients should proceed with a biopsy. Specifically, ferritin greater than 1000 mg/L in C282Y homozygotes has been shown in several studies to be predictive of cirrhosis, with a prevalence of 20% to 45%.32,34 Ferritin levels less than 1000 mg/L in the same population is associated with a low prevalence of 2% for determining cirrhosis. However, this does not apply in patients with a coexisting cause for liver disease, such as chronic viral hepatitis, alcoholic liver disease, or nonalcoholic fatty liver disease.29,31,32,34 Additionally, liver biopsy should be performed in patients with elevated iron studies, elevated liver enzymes, and non-C282Y genotypes of HH. This can exclude the presence of a coexisting cause of liver injury.1 Liver biopsy specimens should be processed using standard hematoxylin-eosin stain, Masson trichrome stain, and an additional Perl Prussian blue stain. The Prussian blue stain helps to capture the distribution of hepatic iron (Fig. 3).40 A quantitative assessment of hepatic iron stores can also be performed. This measurement, the hepatic iron concentration or similarly the hepatic iron index, is abnormal at levels higher than 36 mmol/g and 1.9, respectively.41–44 In the clinical setting, hepatic iron concentration is more commonly used, with hepatic iron index reserved more for the research
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Fig. 3. Perl Prussian blue stain on a liver biopsy in hemochromatosis. (Reproduced from University of Utah WebPath slide set; with permission.)
setting. Hepatic iron concentration has been shown to correlate well with a noninvasive method of estimating hepatic iron stores using T2-weighted MRI.45,46 Additionally, another noninvasive method of determining cirrhosis that is gaining popularity is use of transient elastography. These methods reduce the need for performing liver biopsy as frequently. Non-HFE Hereditary Hemochromatosis
There are other inherited forms of HH that are less common, and non–HFE-related. These account for less than 5% of cases of inherited HH. Examples include juvenile hemochromatosis, mutation in the transferrin receptor 2 gene, and a mutation in the ferroportin (SLC40A1) gene.5 The most common of these is juvenile hemochromatosis, which has two potential genetic mutations.47 Most common is type 2a HH, which is caused by a mutation in the hemojuvelin gene on chromosome 1q.48 Less common is type 2b HH, caused by a mutation in the hepcidin gene. The presence of this mutation results in upregulation of iron absorption.47 A mutation in the transferrin receptor 2 gene results in abnormal sensing of iron stores by hepatocytes. In turn this leads to an autosomal-recessive form of HH, also known as type 3 HH.49 The excess iron is deposited in the hepatocytes, as is similar to HFE-related HH. A rare cause of HH results from mutations in the SLC40A1 gene, responsible for the iron transporter protein, ferroportin. Mutations in this gene result in impaired iron export, with deposition of iron noted in the hepatocytes and in reticuloendothelial cells.50 The inheritance pattern is autosomal-dominant, and also known as type 4 HH.51 Genetic testing for all of these mutations is often unavailable in the clinical setting, particularly for the SLC40A1 gene mutation. Liver biopsy can be a useful diagnostic tool in patients with non-HFE HH to determine the extent of iron overload and the distribution.5,52 Presently, there are no recommendations to screen patients for non–HFE-related HH.1 MANAGEMENT AND TREATMENT Goals of Management
Early identification and treatment of patients with HH with clinical iron overload can improve their morbidity and mortality. The mainstay of treatment has been through phlebotomy. Although no randomized controlled trial has been performed comparing phlebotomy with no phlebotomy for these patients, there is evidence of improvement in certain clinical features with treatment.53,54 Phlebotomy in patients with liver disease
Diagnosis and Management of Hemochromatosis
can slow the progression to cirrhosis, and also reduces the risk of developing HCC. HCC is rare in patients with HH in the absence of cirrhosis.55 However, patients with HH-related cirrhosis are at an elevated risk of developing HCC, with 30% of disease-related deaths noted to be from the development of liver cancer.54,56 Tissue iron overload has in fact been shown to increase the likelihood of a variety of cancers, not just HCC.57 In early stages of hepatic fibrosis, reversal of fibrosis can be noted in some patients with reduction of tissue iron stores, and can also normalize liver enzymes. Once cirrhosis is established, improvement in fibrosis is not expected with phlebotomy.58 Phlebotomy can also improve diabetes management and control, decrease fatigue, improve cardiac function, reduce skin hyperpigmentation, and improve abdominal pain. Patients with arthropathy or hypogonadism rarely see improvement in symptoms with phlebotomy.58–61 Phlebotomy
The initial goal of therapeutic phlebotomy is to decrease the SF level to between 50 and 100 mg/L to assume that the excess iron stores have been depleted.1 Each unit of blood removed is 400 to 500 mL of whole blood and contains approximately 200 to 250 mg of iron. Phlebotomy should be initiated once weekly, depending on the baseline hemoglobin. The hemoglobin needs to be monitored closely, ensuring that this does not decrease to less than 80% of the baseline value.1 During the first year of phlebotomy, it is recommended that a hemoglobin is checked before each phlebotomy, and that ferritin levels are monitored with every 10 to 12 phlebotomies. TS usually does not decrease until iron stores are depleted, so it is more accurate to initially monitor the ferritin.1 Once the ferritin is reduced to 50 to 100 mg/L, testing should be done more frequently so as to avoid iron deficiency, and maintenance phlebotomy can be scheduled. The frequency of maintenance is variable, ranging for some patients every 4 weeks to yearly or even less often for others.1 During the maintenance phase, a ferritin level up to 100 mg/L is tolerated, because prior recommendations to aggressively keep the ferritin levels very low ( A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359(9302):211–8. 21. Rossi E, Olynyk JK, Jeffrey GP. Clinical penetrance of C282Y homozygous HFE hemochromatosis. Expert Rev Hematol 2008;1(2):205–16.
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22. Cheng R, Barton JC, Morrison ED, et al. Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes. J Clin Gastroenterol 2009;43(6):569–73. 23. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352(17):1769–78. 24. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358(3):221–30. 25. Edwards CQ, Cartwright GE, Skolnick MH, et al. Homozygosity for hemochromatosis: clinical manifestations. Ann Intern Med 1980;93(4):519–25. 26. Milder MS, Cook JD, Stray S, et al. Idiopathic hemochromatosis, an interim report. Medicine 1980;59(1):34–49. 27. Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313(20):1256–62. 28. Bassett ML, Halliday JW, Ferris RA, et al. Diagnosis of hemochromatosis in young subjects: predictive accuracy of biochemical screening tests. Gastroenterology 1984;87(3):628–33. 29. Bacon BR, Olynyk JK, Brunt EM, et al. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999;130(12):953–62. 30. Gochee PA, Powell LW, Cullen DJ, et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002;122(3):646–51. 31. Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998;115(4): 929–36. 32. Morrison ED, Brandhagen DJ, Phatak PD, et al. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 2003;138(8):627–33. 33. Allen KJ, Bertalli NA, Osborne NJ, et al. HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis. Hepatology 2010;52(3):925–33. 34. Beaton M, Guyader D, Deugnier Y, et al. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis. Hepatology 2002;36(3):673–8. 35. Barton JC, Barton JC, Acton RT, et al. Increased risk of death from iron overload among 422 treated probands with HFE hemochromatosis and serum levels of ferritin greater than 1000 mug/L at diagnosis. Clin Gastroenterol Hepatol 2012; 10(4):412–6. 36. Edwards CQ, Cartwright GE, Skolnick MH, et al. Genetic mapping of the hemochromatosis locus on chromosome six. Hum Immunol 1980;1(1):19–22. 37. Adams PC. Implications of genotyping of spouses to limit investigation of children in genetic hemochromatosis. Clin Genet 1998;53(3):176–8. 38. Kanwar P, Kowdley KV. Diagnosis and treatment of hereditary hemochromatosis: an update. Expert Rev Gastroenterol Hepatol 2013;7(6):517–30. 39. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46(3):922–38. 40. Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin Liver Dis 2011; 31(3):260–71. 41. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 1986;6(1):24–9.
Diagnosis and Management of Hemochromatosis
42. Kowdley KV, Trainer TD, Saltzman JR, et al. Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study. Gastroenterology 1997;113(4):1270–7. 43. Summers KM, Halliday JW, Powell LW. Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index. Hepatology 1990; 12(1):20–5. 44. Sallie RW, Reed WD, Shilkin KB. Confirmation of the efficacy of hepatic tissue iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis. Gut 1991;32(2):207–10. 45. St Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105(2):855–61. 46. Emond MJ, Bronner MP, Carlson TH, et al. Quantitative study of the variability of hepatic iron concentrations. Clin Chem 1999;45(3):340–6. 47. Pietrangelo A. Juvenile hemochromatosis. J Hepatol 2006;45(6):892–4. 48. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004; 36(1):77–82. 49. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000;25(1):14–5. 50. Olynyk JK, Trinder D, Ramm GA, et al. Hereditary hemochromatosis in the postHFE era. Hepatology 2008;48(3):991–1001. 51. Pietrangelo A, Caleffi A, Corradini E. Non-HFE hepatic iron overload. Semin Liver Dis 2011;31(3):302–18. 52. Brunt EM. Pathology of hepatic iron overload. Semin Liver Dis 2005;25(4): 392–401. 53. Adams PC, Speechley M, Kertesz AE. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 1991;101(2):368–72. 54. Niederau C, Fischer R, Purschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110(4):1107–19. 55. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S79–86. 56. Adams PC, Deugnier Y, Moirand R, et al. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 1997;25(1):162–6. 57. Ko C, Siddaiah N, Berger J, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007;27(10):1394–401. 58. 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(2): 472–7. 59. Bomford A, Williams R. Long term results of venesection therapy in idiopathic haemochromatosis. Q J Med 1976;45(180):611–23. 60. Kelly TM, Edwards CQ, Meikle AW, et al. Hypogonadism in hemochromatosis: reversal with iron depletion. Ann Intern Med 1984;101(5):629–32. 61. Cundy T, Butler J, Bomford A, et al. Reversibility of hypogonadotrophic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol 1993;38(6): 617–20. 62. Phatak P, Brissot P, Wurster M, et al. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology 2010;52(5):1671–779.
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63. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331(9):567–73. 64. Lynch SR, Cook JD. Interaction of vitamin C and iron. Ann N Y Acad Sci 1980;355: 32–44. 65. Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007;133(2):489–95. 66. Bardou-Jacquet E, Philip J, Lorho R, et al. Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis. Hepatology 2014;59(3):839–47. 67. Farrell FJ, Nguyen M, Woodley S, et al. Outcome of liver transplantation in patients with hemochromatosis. Hepatology 1994;20(2):404–10. 68. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42(5):1208–36.
MD*,
Kimberly Brown,
MD
KEYWORDS Hemochromatosis Iron saturation Ferritin Cirrhosis Liver transplant KEY POINTS Hereditary hemochromatosis (HH) is a diagnosis most commonly made in patients with elevated iron indices (transferrin saturation and ferritin), and HFE genetic mutation testing showing C282Y homozygosity. The HFE mutation is believed to result in clinical iron overload through altering hepcidin levels resulting in increased iron absorption. The most common clinical complications of HH include cirrhosis, diabetes, nonischemic cardiomyopathy, and hepatocellular carcinoma. Liver biopsy should be performed in patients with HH if the liver enzymes are elevated or serum ferritin is greater than 1000 mg/L. This is useful to determine the degree of iron overload and stage the fibrosis. Treatment of HH with clinical iron overload involves a combination of phlebotomy and/or chelation therapy. Liver transplantation should be considered for patients with HH-related decompensated cirrhosis.
INTRODUCTION
Although hereditary hemochromatosis (HH) is a less common cause of cirrhosis than chronic viral hepatitis, it remains the most commonly identified genetic disorder in the white population. The prevalence of HH varies worldwide, with the highest frequency of disease occurring among those of northern European ancestry.1 Since this disease was first described by Trousseau in 1865, many studies have led to a greater understanding of the underlying pathophysiology. HH was initially noted to be associated with increased iron deposition in organ tissue, leading to cirrhosis, heart failure, diabetes, arthritis, and a high risk for hepatocellular carcinoma (HCC).2 Then a seminal
Disclosures: The authors have no relevant affiliations or financial involvement. Division of Gastroenterology and Hepatology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA * Corresponding author. E-mail address: [email protected] Clin Liver Dis 19 (2015) 187–198 http://dx.doi.org/10.1016/j.cld.2014.09.011 1089-3261/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Salgia & Brown
paper in 1996 revealed the HFE gene mutation, which causes a substitution of tyrosine for cysteine at the amino acid 282 position (C282Y).3 Subsequently two additional mutations were noted, aspartate for histidine (H63D), and cysteine for serine (S65C). The most common form of HFE-related HH is associated with the C282Y homozygous mutation, and less commonly compound heterozygotes with either C282Y/H63D or C282Y/S65C.4 Non-HFE associated hemochromatosis is rare, accounting for less than 15% of inherited iron overload.5 This article provides a brief overview of the pathophysiology of hemochromatosis, and an up-to-date summary of the diagnosis and management of HH. PATHOPHYSIOLOGY
HH is a genetic disorder broadly characterized by excessive total body iron storage.1,6 Several mechanisms explain this imbalance of iron homeostasis in HH. The initial theory was noted as the “crypt cell hypothesis,” reflecting the interplay between the HFE protein and b2-microglobulin.7,8 Together these two proteins form a complex with transferrin receptor-1, which is located predominantly in the duodenal crypt enterocytes. There the complex would sense and regulate dietary iron absorption. It is also hypothesized that this complex acts at the level of the hepatocyte membrane to sense iron stores.9 However, the more recent discovery of hepcidin, a small peptide hormone that is encoded by a gene expressed in the liver, has altered the predominant theory of iron overload associated with HH. Hepcidin controls iron absorption in the duodenum. The levels of circulating hepcidin vary based on systemic iron stores.10 The interaction between HFE and the transferrin receptors is paramount to the sensing of iron at the hepatocyte membrane.11 When iron stores are elevated, hepcidin is released and binds to ferroportin in macrophages and enterocytes. There it blocks the export of iron from macrophages and decreases intestinal iron absorption (Fig. 1).12,13 When the HFE protein is mutated, the expression of hepcidin decreases and intestinal iron absorption increases. Although it remains unclear how the mutated HFE gene controls hepcidin in HH, a decrease in hepcidin results in a rise of iron efflux from macrophages and enterocytes, and increased intestinal iron absorption into organ tissue.14 Hence the liver is the major regulator of iron metabolism, and in patients with HH this mechanism is altered by abnormally low hepcidin levels.15 The presence of elevated iron stores in the liver over time can lead to hepatic fibrosis and cirrhosis. Iron has been shown to cause increased oxidative stress and damage to hepatocytes and mitochondrial function.16–18 These hepatocytes are injured and release Kupffer cells, which stimulate hepatic stellate cells to increase production of collagen.19 Over time this process leads to the development of cirrhosis. DIAGNOSIS Clinical Presentation
Because of variable penetrance of clinical HH, end-organ damage is noted in less than 10% of patients who are homozygous for the C282Y mutation.20 The clinical phenotype is expressed in 24% to 43% of males and 1% to 14% of females.21 Clinical disease is noted even less frequently in patients who are compound heterozygotes (C282Y/H63D positive), who account for approximately 5% of cases of HH.4,22 Women also present with clinical features later in life, largely related to monthly menstruation resulting in iron loss and having a protective effect. However, the disease prevalence is similar between men and women, resulting from earlier recognition and screening for this disease.23,24
Diagnosis and Management of Hemochromatosis
Fig. 1. Iron homeostasis as regulated by hepcidin. BMPR, bone morphogenetic protein receptor; FPN, ferroportin; HJV, hemojuvelin; SMAD, Sma and Mad related protein. (From Camaschella C. BMP 6 orchestrates iron metabolism. Nat Genet 2009;41(4):386–8; with permission.)
The clinical features of HH are highly variable, with signs and symptoms that can involve multiple organ systems. Aside from liver involvement leading to cirrhosis, iron overload from HH can involve the heart, pancreas, skin, pituitary gland, gonads, and joints (Table 1).1,4 Multiple studies have found that the predominant clinical features in patients with HH include (from most common to least common) cirrhosis, lethargy, hyperpigmentation of the skin, loss of libido, testicular atrophy, diabetes, abdominal pain, and arthralgias.25–27 Laboratory Testing
The initial suspicion for HH is largely made based on clinical features, biochemical abnormalities, and genetic testing, with liver biopsy less commonly needed to make an initial diagnosis. Elevated serum ferritin (SF) levels and transferrin-iron saturation (TS) are readily available serum markers that help to identify patients with HH. These tests should be performed on patients with chronically elevated liver enzymes.1 Ferritin levels greater than 200 mg/L for females and greater than 300 mg/L for males are considered abnormal.23,28 Ferritin is known to be elevated in the absence of elevated iron stores. For example, the presence of viral hepatitis, nonalcoholic fatty liver disease, or alcoholic liver disease and other chronic inflammatory conditions can all cause elevations in SF levels.1 The TS is calculated based on total body iron divided
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Table 1 Signs, symptoms, and clinical presentation of HH Organ System
Sign/Symptom
General
Weakness, fatigue, lethargy Weight loss Apathy
Liver
Abdominal pain
Hepatomegaly Splenomegaly Cutaneous stigmata (spider angiomata, palmar erythema) Gynecomastia
Cardiac
Heart failure Arrhythmia
Cardiomegaly Elevated JVP
Pancreas
Hyperglycemia from diabetes
Skin
Physical Examination
Hyperpigmentation, “bronze skin” Porphyria cutanea tarda
Endocrine
Loss of libido Hypothyroidism
Testicular atrophy
Joints
Arthralgias
Arthritis (second and third MCP) Joint swelling
Abbreviations: JVP, jugular venous pressure; MCP, metacarpophalangeal joint.
by total iron-binding capacity. A saturation level higher than 45% again raises suspicion for HH.23,28 If either the SF or TS is abnormal, then the HFE genetic mutation analysis should be performed.1 A result of C282Y homozygous genotype is consistent with a diagnosis of HH in the setting of iron overload.29 It is less common for C282Y/H63D compound heterozygous genotype or H63D homozygous genotype to develop clinically significant iron overload; however, it has been described.22,30 The Hemochromatosis and Iron Overload Screening study screened 99,711 North American patients and found that SF was elevated (>200 mg/L in women and >300 mg/L in men) in 57% of female and 88% of male C282Y homozygotes.23 Multiple studies have shown that marked elevations in SF to values greater than 1000 mg/L are a stronger predictor of advanced hepatic fibrosis and cirrhosis in patients with documented HH.29,31–33 When an elevated ferritin greater than 1000 mg/L is combined with elevated transaminases and platelet count less than 200 10(9)/L, the positive predictive value for cirrhosis is 80% in patients with C282Y homozygosity.34 These findings have also been shown to increase the mortality risk associated with HH.35 Patients with C282Y homozygosity who have normal iron studies should have an annual measurement of their ferritin level.4 Screening for Hereditary Hemochromatosis
Screening for HH should also be performed in patients with a family history of HH or a suspicion based on suspected organ involvement of elevated iron stores.1,23 Fig. 2 is a diagnostic algorithm for screening patients at-risk for HH. It is recommended that all first-degree relatives of a patient with HH should undergo family screening. Screening can be performed with SF, TS, and HFE mutation testing. The inheritance pattern is autosomal-recessive with mutations in the HFE gene on chromosome 6.3,36 Children of an affected parent can be tested or alternatively the other parent can be tested.37 It is generally recommended that if children are going to be screened, testing should be
Diagnosis and Management of Hemochromatosis
Fig. 2. Diagnostic algorithm for HH. Elevated SF is greater than 200 mg/L in females and greater than 300 mg/L in males.
done once they reach adulthood.38 There is a negligible risk of developing clinical HH before the age of 18. Histology
The main purpose of liver biopsy in the diagnosis of HH is to stage the degree of fibrosis. It is important to determine if patients have cirrhosis for prognosis and to initiate surveillance for HCC and esophageal varices.39 SF is valuable to discriminate which patients should proceed with a biopsy. Specifically, ferritin greater than 1000 mg/L in C282Y homozygotes has been shown in several studies to be predictive of cirrhosis, with a prevalence of 20% to 45%.32,34 Ferritin levels less than 1000 mg/L in the same population is associated with a low prevalence of 2% for determining cirrhosis. However, this does not apply in patients with a coexisting cause for liver disease, such as chronic viral hepatitis, alcoholic liver disease, or nonalcoholic fatty liver disease.29,31,32,34 Additionally, liver biopsy should be performed in patients with elevated iron studies, elevated liver enzymes, and non-C282Y genotypes of HH. This can exclude the presence of a coexisting cause of liver injury.1 Liver biopsy specimens should be processed using standard hematoxylin-eosin stain, Masson trichrome stain, and an additional Perl Prussian blue stain. The Prussian blue stain helps to capture the distribution of hepatic iron (Fig. 3).40 A quantitative assessment of hepatic iron stores can also be performed. This measurement, the hepatic iron concentration or similarly the hepatic iron index, is abnormal at levels higher than 36 mmol/g and 1.9, respectively.41–44 In the clinical setting, hepatic iron concentration is more commonly used, with hepatic iron index reserved more for the research
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Fig. 3. Perl Prussian blue stain on a liver biopsy in hemochromatosis. (Reproduced from University of Utah WebPath slide set; with permission.)
setting. Hepatic iron concentration has been shown to correlate well with a noninvasive method of estimating hepatic iron stores using T2-weighted MRI.45,46 Additionally, another noninvasive method of determining cirrhosis that is gaining popularity is use of transient elastography. These methods reduce the need for performing liver biopsy as frequently. Non-HFE Hereditary Hemochromatosis
There are other inherited forms of HH that are less common, and non–HFE-related. These account for less than 5% of cases of inherited HH. Examples include juvenile hemochromatosis, mutation in the transferrin receptor 2 gene, and a mutation in the ferroportin (SLC40A1) gene.5 The most common of these is juvenile hemochromatosis, which has two potential genetic mutations.47 Most common is type 2a HH, which is caused by a mutation in the hemojuvelin gene on chromosome 1q.48 Less common is type 2b HH, caused by a mutation in the hepcidin gene. The presence of this mutation results in upregulation of iron absorption.47 A mutation in the transferrin receptor 2 gene results in abnormal sensing of iron stores by hepatocytes. In turn this leads to an autosomal-recessive form of HH, also known as type 3 HH.49 The excess iron is deposited in the hepatocytes, as is similar to HFE-related HH. A rare cause of HH results from mutations in the SLC40A1 gene, responsible for the iron transporter protein, ferroportin. Mutations in this gene result in impaired iron export, with deposition of iron noted in the hepatocytes and in reticuloendothelial cells.50 The inheritance pattern is autosomal-dominant, and also known as type 4 HH.51 Genetic testing for all of these mutations is often unavailable in the clinical setting, particularly for the SLC40A1 gene mutation. Liver biopsy can be a useful diagnostic tool in patients with non-HFE HH to determine the extent of iron overload and the distribution.5,52 Presently, there are no recommendations to screen patients for non–HFE-related HH.1 MANAGEMENT AND TREATMENT Goals of Management
Early identification and treatment of patients with HH with clinical iron overload can improve their morbidity and mortality. The mainstay of treatment has been through phlebotomy. Although no randomized controlled trial has been performed comparing phlebotomy with no phlebotomy for these patients, there is evidence of improvement in certain clinical features with treatment.53,54 Phlebotomy in patients with liver disease
Diagnosis and Management of Hemochromatosis
can slow the progression to cirrhosis, and also reduces the risk of developing HCC. HCC is rare in patients with HH in the absence of cirrhosis.55 However, patients with HH-related cirrhosis are at an elevated risk of developing HCC, with 30% of disease-related deaths noted to be from the development of liver cancer.54,56 Tissue iron overload has in fact been shown to increase the likelihood of a variety of cancers, not just HCC.57 In early stages of hepatic fibrosis, reversal of fibrosis can be noted in some patients with reduction of tissue iron stores, and can also normalize liver enzymes. Once cirrhosis is established, improvement in fibrosis is not expected with phlebotomy.58 Phlebotomy can also improve diabetes management and control, decrease fatigue, improve cardiac function, reduce skin hyperpigmentation, and improve abdominal pain. Patients with arthropathy or hypogonadism rarely see improvement in symptoms with phlebotomy.58–61 Phlebotomy
The initial goal of therapeutic phlebotomy is to decrease the SF level to between 50 and 100 mg/L to assume that the excess iron stores have been depleted.1 Each unit of blood removed is 400 to 500 mL of whole blood and contains approximately 200 to 250 mg of iron. Phlebotomy should be initiated once weekly, depending on the baseline hemoglobin. The hemoglobin needs to be monitored closely, ensuring that this does not decrease to less than 80% of the baseline value.1 During the first year of phlebotomy, it is recommended that a hemoglobin is checked before each phlebotomy, and that ferritin levels are monitored with every 10 to 12 phlebotomies. TS usually does not decrease until iron stores are depleted, so it is more accurate to initially monitor the ferritin.1 Once the ferritin is reduced to 50 to 100 mg/L, testing should be done more frequently so as to avoid iron deficiency, and maintenance phlebotomy can be scheduled. The frequency of maintenance is variable, ranging for some patients every 4 weeks to yearly or even less often for others.1 During the maintenance phase, a ferritin level up to 100 mg/L is tolerated, because prior recommendations to aggressively keep the ferritin levels very low ( A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359(9302):211–8. 21. Rossi E, Olynyk JK, Jeffrey GP. Clinical penetrance of C282Y homozygous HFE hemochromatosis. Expert Rev Hematol 2008;1(2):205–16.
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22. Cheng R, Barton JC, Morrison ED, et al. Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes. J Clin Gastroenterol 2009;43(6):569–73. 23. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352(17):1769–78. 24. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358(3):221–30. 25. Edwards CQ, Cartwright GE, Skolnick MH, et al. Homozygosity for hemochromatosis: clinical manifestations. Ann Intern Med 1980;93(4):519–25. 26. Milder MS, Cook JD, Stray S, et al. Idiopathic hemochromatosis, an interim report. Medicine 1980;59(1):34–49. 27. Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313(20):1256–62. 28. Bassett ML, Halliday JW, Ferris RA, et al. Diagnosis of hemochromatosis in young subjects: predictive accuracy of biochemical screening tests. Gastroenterology 1984;87(3):628–33. 29. Bacon BR, Olynyk JK, Brunt EM, et al. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999;130(12):953–62. 30. Gochee PA, Powell LW, Cullen DJ, et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002;122(3):646–51. 31. Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998;115(4): 929–36. 32. Morrison ED, Brandhagen DJ, Phatak PD, et al. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 2003;138(8):627–33. 33. Allen KJ, Bertalli NA, Osborne NJ, et al. HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis. Hepatology 2010;52(3):925–33. 34. Beaton M, Guyader D, Deugnier Y, et al. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis. Hepatology 2002;36(3):673–8. 35. Barton JC, Barton JC, Acton RT, et al. Increased risk of death from iron overload among 422 treated probands with HFE hemochromatosis and serum levels of ferritin greater than 1000 mug/L at diagnosis. Clin Gastroenterol Hepatol 2012; 10(4):412–6. 36. Edwards CQ, Cartwright GE, Skolnick MH, et al. Genetic mapping of the hemochromatosis locus on chromosome six. Hum Immunol 1980;1(1):19–22. 37. Adams PC. Implications of genotyping of spouses to limit investigation of children in genetic hemochromatosis. Clin Genet 1998;53(3):176–8. 38. Kanwar P, Kowdley KV. Diagnosis and treatment of hereditary hemochromatosis: an update. Expert Rev Gastroenterol Hepatol 2013;7(6):517–30. 39. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46(3):922–38. 40. Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin Liver Dis 2011; 31(3):260–71. 41. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 1986;6(1):24–9.
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42. Kowdley KV, Trainer TD, Saltzman JR, et al. Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study. Gastroenterology 1997;113(4):1270–7. 43. Summers KM, Halliday JW, Powell LW. Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index. Hepatology 1990; 12(1):20–5. 44. Sallie RW, Reed WD, Shilkin KB. Confirmation of the efficacy of hepatic tissue iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis. Gut 1991;32(2):207–10. 45. St Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105(2):855–61. 46. Emond MJ, Bronner MP, Carlson TH, et al. Quantitative study of the variability of hepatic iron concentrations. Clin Chem 1999;45(3):340–6. 47. Pietrangelo A. Juvenile hemochromatosis. J Hepatol 2006;45(6):892–4. 48. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004; 36(1):77–82. 49. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000;25(1):14–5. 50. Olynyk JK, Trinder D, Ramm GA, et al. Hereditary hemochromatosis in the postHFE era. Hepatology 2008;48(3):991–1001. 51. Pietrangelo A, Caleffi A, Corradini E. Non-HFE hepatic iron overload. Semin Liver Dis 2011;31(3):302–18. 52. Brunt EM. Pathology of hepatic iron overload. Semin Liver Dis 2005;25(4): 392–401. 53. Adams PC, Speechley M, Kertesz AE. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 1991;101(2):368–72. 54. Niederau C, Fischer R, Purschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110(4):1107–19. 55. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S79–86. 56. Adams PC, Deugnier Y, Moirand R, et al. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 1997;25(1):162–6. 57. Ko C, Siddaiah N, Berger J, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007;27(10):1394–401. 58. 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(2): 472–7. 59. Bomford A, Williams R. Long term results of venesection therapy in idiopathic haemochromatosis. Q J Med 1976;45(180):611–23. 60. Kelly TM, Edwards CQ, Meikle AW, et al. Hypogonadism in hemochromatosis: reversal with iron depletion. Ann Intern Med 1984;101(5):629–32. 61. Cundy T, Butler J, Bomford A, et al. Reversibility of hypogonadotrophic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol 1993;38(6): 617–20. 62. Phatak P, Brissot P, Wurster M, et al. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology 2010;52(5):1671–779.
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63. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331(9):567–73. 64. Lynch SR, Cook JD. Interaction of vitamin C and iron. Ann N Y Acad Sci 1980;355: 32–44. 65. Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007;133(2):489–95. 66. Bardou-Jacquet E, Philip J, Lorho R, et al. Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis. Hepatology 2014;59(3):839–47. 67. Farrell FJ, Nguyen M, Woodley S, et al. Outcome of liver transplantation in patients with hemochromatosis. Hepatology 1994;20(2):404–10. 68. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42(5):1208–36.
