Archive \ Volume.11 2020 Issue 3

Evaluation of Hemochromatosis, Diagnosis and Management: Simple Literature Review

Abdulmalek Adel Aboulkhair¹, Abdulrahman Ibn Almuataz Ezzi¹, Tariek Abdullah Alharbi¹, Ali Sultan Alzughbi², Khalid Melih Marick Alshammari³, Sultan Musallam Alshammari⁴, Mansour Thallab Albagami⁴, Kawther Abdulla Alsadady⁵, Thamer Hamad M Alshahrani⁶, Fatheya Ahmed Hussain⁷, Anwar Mohammed  Al Hadhari⁸

¹ Faculty of Medicine, Ibn Sina College, Jeddah, KSA. ² Faculty of Medicine, Prince Sattam bin Abdulaziz University, Alkharj, KSA. ³ Faculty of Medicine, University of Hail, Hail, KSA. ⁴ Faculty of Medicine, Almaarefa University, Riyadh, KSA. ⁵ Faculty of Medicine, Dar Aluloom University, Riyadh, KSA. ⁶ Department of Internal Medicine, Jubail General Hospital, Jubail, KSA. ⁷ Faculty of Medicine, King Abdulaziz University, Jeddah, KSA. ⁸Faculty of Medicine, Northern Border University, Arar, KSA

Abstract

Background: Hemochromatosis is an autosomal recessive genetic disorder characterized by abnormal iron regulation in the body leading to excessive iron deposition in multiple organs. Most of the patients of hemochromatosis are presymptomatic or asymptomatic. Nevertheless, a minority of patients presents with severe complications. Objective: In this study, we aimed to discuss the published literature focused on diagnosing and managing hemochromatosis. Method: PubMed database was used for articles selection, and the following keys were used in the mesh ((“hemochromatosis”[Mesh]) and (“hemochromatosis management”[Mesh])). The articles' selection was based on the relevance to the topic as their primary endpoint. Conclusion: The stage of the disease and particularly the extent of iron overloading should be the parameters that are dependent on assessment and treatment. Phlebotomy is the mainstay of treatment in hemochromatosis cases. It improves insulin sensitivity, fatigue, and skin pigmentation. Initiating the phlebotomy before the development of liver cirrhosis has shown a significant decrease in morbidity and mortality rates. Iron chelation therapy can be an option when the hemoglobin of the patients cannot tolerate therapeutic phlebotomy.

Keywords: Hemochromatosis, Diagnosis, Management Approach  

INTRODUCTION

Hemochromatosis is an autosomal recessive genetic disorder ^{[1, 2]} characterized by abnormal iron regulation in the body ^{[3, 4]}. It is associated with excessive iron deposition in multiple organs, which may lead subsequently to multiple organ dysfunction. Different life-threatening complications can develop, such as diabetes, cirrhosis, and heart failure. It has been called “bronze diabetes” because it affects the pancreas and causes discoloration of the skin. Hereditary hemochromatosis is still considered as the most common genetic disorder in Caucasians. It most commonly arises from a mutation in the human hemochromatosis protein (HFE) gene and this gene was first described in 1996 ^[5-7]. It is common in people with northern European descent, Nordic or Celtic origin in particular with a prevalence of 1 per 220-250 individuals ^{[8, 9]}. In this article, we aimed to review the published literature that tackled this disease and discussed its complications and management.

METHOD:

PubMed database was used for articles selection, and the following keys were used in the mesh ((“hemochromatosis”[Mesh]) and (“hemochromatosis management”[Mesh])). The articles' selection was based on the relevance to the topic as their primary endpoint. Regarding the inclusion criteria, the articles were selected based on including one of the following topics: hemochromatosis, clinical manifestations, diagnosis, and management. Exclusion criteria were all other articles which do not have one of these topics as their primary endpoint.

DISCUSSION:

Traditionally, it has been thought that all individuals, who are genetically susceptible to develop iron overload syndromes, will develop phenotypic expression. Later, HFE-related hereditary hemochromatosis, with the advancement of genetic testing, got more identified in asymptomatic individuals. It also appeared in presymptomatic relatives of the previously diagnosed patients ^[7]. Therefore, HFE-related hereditary hemochromatosis patients might be diagnosed by genetic testing without or before developing any manifestations ^{[10, 11]}. Recent studies have clarified that around 70% of C282Y homozygotes develop phenotypic expression and the severe complications of hemochromatosis will appear in less than 10% of C282Y homozygotes ^{[7, 10]}. Therefore, the European Association for the Study of Liver Diseases in 2000 staged hemochromatosis into 3 different stages based on the genetic susceptibility and the disease course ^[11].

These stages are defined as follows:

1. Patients with a genetic disorder with no increase in iron stores who have ‘‘genetic susceptibility’’.
2. Patients with the genetic disorder who have phenotypic evidence of iron overload but are without tissue or organ damage.
3. Individuals who have the genetic disorder with iron overload and have an iron deposition to the degree that tissue and organ damage occurs.

Clinical Presentation:

As we implied earlier, most of the patients of hemochromatosis are diagnosed presymptomatic due to the advancement in diagnostics. This changed our look at the disease and made it an easy and early detected disease after it was only considered as severe and life-threatening ^[12]. Nevertheless, a minority of patients presents with severe complications, such as heart failure, liver function impairment, or diabetes ^{[13, 14]}. Hemochromatosis in children is associated with more cases of symptomatic heart failure and other endocrinopathies than adults. Hypo-gonadotrophic hypogonadism is one of the common endocrinopathies in juvenile hemochromatosis ^{[12, 15]}. It will lead eventually to impotence and decreased libido in men ^[16]. The reason behind it is the deposition of iron in the anterior pituitary causing a significant decrease in trophic hormones secretion. In females, amenorrhea may develop but it is much rarer than hypogonadism in men ^{[17, 18]}.

Hepatomegaly, progressive liver fibrosis and potential cirrhosis may arise in the liver but in the early stages, they can be reversible. Other associated liver diseases can worsen the complications but the most harmful co-factor is excessive alcohol consumption. Liver involvement may not appear in liver function laboratory tests in the beginning because the iron deposition in hepatocytes may not be inflammatory at the start and may not lead to fibrosis ^{[19, 20]}. Hepatic liver enzymes elevations are mostly seen when there is another liver disease. The most dangerous complication of the hepatic iron overload is hepatocellular carcinoma ^[21].

Other than liver involvement, there are several common symptoms, such as weakness and easy fatigability, and skin hyperpigmentation ^[22]. Half of the symptomatic patients develop diabetes mellitus because the iron deposition in the pancreas occurs in beta cells ^[16]. In addition, there is also a possibility for deposition of iron within the joints that may lead to arthritis involving most commonly metacarpophalangeal joints. The involvement of joints may develop chronic inflammation of the joints leading eventually to Pseudogout or Chondrocalcinosis ^{[16, 23]}.

Diagnosis:

In cases of suspected hemochromatosis, the next step is testing serum ferritin and transferrin saturation levels ^[5]. In hemochromatosis, it is expected to have high ferritin and transferrin saturation of more than 45% ^{[7, 24]}. Nevertheless, they cannot be used to confirm the diagnosis because they can be raised in cases of excessive alcohol intake or severe inflammation. Next, HFE genotype has to be tested in the suspected patients who have compatible clinical features with hemochromatosis, and patients’ first degree relatives even if there were no symptoms ^[5].

In general, the minimum criteria for the diagnosis of hereditary hemochromatosis are increased storage of iron and C282Y HFE gene mutation ^[25]. As we mentioned earlier, the presence of a gene mutation does not mandate considering the case as an active disease and it does not require unnecessary aggressive intervention. The extent of iron overloading should be the parameter that is dependent on assessment and treatment ^{[26, 27]}.

Treatment:

Phlebotomy is the mainstay of treatment in hemochromatosis cases. It might be required even twice weekly to lower the ferritin level to <50 ug/l. After that, maintaining the ferritin levels between 50-100 ug/l is cardinal in the treatment process ^{[7, 28]}. Initiating the phlebotomy before the development of liver cirrhosis has shown a significant decrease in morbidity and mortality rates. Normal life expectancy is expected in patients who did not develop liver cirrhosis. The risk of cirrhosis significantly increases with a prevalence of 20-45% in patients who present with a ferritin level of >1000 ug/l. Moreover, the risk of hepatocellular carcinoma is increased in patients with cirrhosis with an annual incidence of 3-4%. Therefore, liver biopsy should be considered in such patients. Early detection of potential malignancy can lead to early detection and probable prevention of some serious complications, such as esophageal varices ^{[5, 7]}. Phlebotomy improves insulin sensitivity, fatigue, and skin pigmentation. Unfortunately, it can rarely reverse preexisting end-organ damage. Treating the associated end-organ dysfunction is indicated as insulin for pancreatic dysfunction. Cessation of bad habits like alcohol intake is mandatory because alcohol can significantly worsen hepatic and pancreatic complications.

Iron chelation therapy can be an option when the hemoglobin of the patients cannot tolerate therapeutic phlebotomy. Iron-chelating agents help in mobilization and excretion of iron. They are available as intravenous agents, such as Deferoxamine and there are oral iron chelators, such as Deferiprone and Deferasirox ^[28].

CONCLUSION:

The stage of the disease and particularly the extent of iron overloading should be the parameters that are dependent on assessment and treatment. Phlebotomy is the mainstay of treatment in hemochromatosis cases. It improves insulin sensitivity, fatigue, and skin pigmentation. Initiating the phlebotomy before the development of liver cirrhosis has shown a significant decrease in morbidity and mortality rates. Iron chelation therapy can be an option when the hemoglobin of the patients cannot tolerate therapeutic phlebotomy.

REFERENCES

1. Wahab N R, Al-dujaili M N, AL-Khirsani H A H, Mohammed A A. The impact of increased body weight on left ventricular diastolic function. J. Adv. Pharm. Edu. Res. 2020; 10(1): 150-157.
2. Keyhanazar K. Evaluation of oocyte changes around dankhoras and drinkers at different weeks in poultry farms of Mahabad. J. Adv. Pharm. Edu. Res. 2020; 10(1): 90-95.
3. Waggiallah H A. Hepcidin As an Iron Regulator and Inflammatory Mediator in Several Clinical Conditions: Narrative. Int. J. Pharm. Phytopharm. Res. 2020; 11(3): 164-170.
4. Nourmohammadi E, Nedaeinia R, Goli M, Hosseini Teshnizi S, Sarkarizi H, Sarkarizi K, Nedaeinia M, Faraji H. Novel application of Nanotechnology in drug and Gene delivery: emphasis on Liposomes. Int. J. Pharm. Phytopharm. Res. 2018; 8(6): 81-91.
5. Sood R, Bakashi R, Hegade VS, Kelly SM. Diagnosis and management of hereditary haemochromatosis. Br J Gen Pract. 2013 Jun 1;63(611):331-2. https://doi.org/10.3399/bjgp13x668410.
6. Bacon BR. Hemochromatosis: discovery of the HFE gene. Missouri medicine, 2012; 109(2): 133-
7. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.). 2011 Jul;54(1):328. https://doi.org/10.1002/hep.24330.
8. Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary Hemochromatosis: Time for Targeted Screening. Annals of Internal Medicine, 2008; 149(4): 270. https://doi.org/10.7326/0003-4819-149-4-200808190-00009.
9. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C. Hemochromatosis and iron-overload screening in a racially diverse population. New England Journal of Medicine. 2005 Apr 28;352(17):1769-78. https://doi.org/10.1056/nejmoa041534.
10. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, McLaren CE, Bahlo M, Nisselle AE, Vulpe CD, Anderson GJ. Iron-overload–related disease in HFE hereditary hemochromatosis. New England Journal of Medicine. 2008 Jan 17;358(3):221-30. https://doi.org/1056/nejmoa073286.
11. Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis: Part II. Expert Document. Journal of hepatology. 2000 Sep 1;33(3):487-96. https://doi.org/10.1016/s0168-8278(01)80874-6.
12. Zoller H, Henninger B. Pathogenesis, diagnosis and treatment of hemochromatosis. Digestive Diseases. 2016;34(4):364-73. https://doi.org/10.1159/000444549.
13. Bardou-Jacquet E, Morcet J, Manet G, Lainé F, Perrin M, Jouanolle AM, Guyader D, Moirand R, Viel JF, Deugnier Y. Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis. Journal of hepatology. 2015 Mar 1;62(3):682-9. https://doi.org/10.1016/j.jhep.2014.10.025.
14. Wood MJ, Powell LW, Ramm GA. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood, The Journal of the American Society of Hematology. 2008 May 1;111(9):4456-62. https://doi.org/10.1182/blood-2007-11-122374.
15. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM. Natural history of juvenile haemochromatosis. British journal of haematology. 2002 Jun;117(4):973-9.https://doi.org/10.1046/j.1365-2141.2002.03509.x.
16. Geller SA, de Campos FP. Hereditary hemochromatosis. Autopsy & case reports. 2015 Jan;5(1):7. https://doi.org/10.4322/acr.2014.043.
17. Walton C, Kelly WF, Laing I, Bu'Lock DE. Endocrine abnormalities in idiopathic haemochromatosis. QJM: An International Journal of Medicine. 1983 Jan 1;52(1):99-110. https://doi.org/10.1093/oxfordjournals.qjmed.a067746.
18. Kelly TM, EDWARDS CQ, MEIKLE AW, KUSHNER JP. Hypogonadism in hemochromatosis: reversal with iron depletion. Annals of internal medicine. 1984 Nov 1;101(5):629-32. https://doi.org/10.7326/0003-4819-101-5-629.
19. Adams PC, Barton JC. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. Journal of hepatology. 2011 Aug 1;55(2):453-8. https://doi.org/10.1016/j.jhep.2011.02.010.
20. Adams PC, Speechley M, Barton JC, McLaren CE, McLaren GD, Eckfeldt JH. Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the hemochromatosis and iron overload screening study. Hepatology. 2012 Jun;55(6):1722-6. https://doi.org/10.1002/hep.25538.
21. Yang Q, McDonnell SM, Khoury MJ, Cono J, Parrish RG. Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of multiple-cause mortality data. Annals of Internal Medicine. 1998 Dec 1;129(11_Part_2):946-53. https://doi.org/10.7326/0003-4819-129-11_part_2-199812011-00005.
22. Niederau C, Strohmeyer G, Stremmel W. Epidemiology, clinical spectrum and prognosis of hemochromatosis. InProgress in Iron Research 1994 (pp. 293-302). Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2554-7_31.
23. Schumacher HR. Articular cartilage in the degenerative arthropathy of hemochromatosis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1982 Dec;25(12):1460-8. https://doi.org/10.1002/art.1780251212.
24. Emery J, Rose P. Hereditary haemochromatosis: never seen a case?. The British Journal of General Practice. 2001 May;51(466):347.
25. Tavill AS. Diagnosis and management of hemochromatosis. Hepatology. 2001 May 1;33(5):1321-8. https://doi.org/10.1053/jhep.2001.24783.
26. Adams PC, Reboussin DM, Leiendecker-Foster C, Moses GC, McLaren GD, McLaren CE, Dawkins FW, Kasvosve I, Acton RT, Barton JC, Zaccaro D. 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. Clinical chemistry. 2005 Jun 1;51(6):1048-52. https://doi.org/10.1373/clinchem.2005.048371.
27. Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians. Annals of internal medicine. 2005 Oct 4;143(7):522-36. https://doi.org/10.7326/0003-4819-143-7-200510040-00011.
28. Pietrangelo A, Deugnier Y, Dooley J, Erhardt A, Zoller H, Safadi R. EASL clinical practice guidelines for HFE hemochromatosis. Journal of hepatology. 2010 Jul 1;53(1):3-22. https://doi.org/10.1016/j.jhep.2010.03.001.