HEREDITARY HEMOCHROMATOSIS: worth the Workup
Emily Williams
Marietta College
DUE NOVEMBER 1ST. UPLOAD TO TURNITIN.COM CLASS ID: 19221801 ENROLLMENT KEY: PASP690 FINAL DRAFT DUE FEBRURARY 1ST
Abstract
There is a genetic disorder found in one million Americans and approximately 1 in every 240 caucasians of primarily Northern European descent (Bacon BR, et al. 2011). The resultant HFE gene mutation has been found to cause unrestrained iron accumulation within the body and an array of long-term complications within the liver, heart, endocrine glands and joints. This is a primary iron-overload disorder known as hereditary hemochromatosis(HH). The purpose of this article is to review the challenges regarding current diagnostic and management of HH in the clinical setting. Populations of interest are primary care providers, internists, hematologists, hepatologists, as well as patients and family members of this disease.
Keywords: Hereditary Hemochromatosis, iron-overload, gene analysis, liver disease
Introduction
It can be theorized how an intent for “prevention” of a disease can instead turn into treating its “complications”. In a disease of progressive iron absorption of an estimated 1 gram per year, complications may present before the diagnosis itself(citation). While present at birth, it is known to remain undiagnosed until the 4th and 5th decade which endorses that absence of symptoms does not dismiss the importance of early diagnosis. Furthermore, symptoms related to iron-overload are non-specific, its penetrance and mechanism of injury incompletely understood, and clinical relevance yet to be determined.
The 2011, the American Association for the Study of Liver Diseases(AASLD) developed widely used practice guidelines on diagnosis and management of HH. Included in Figure 1, these will be discussed for a better understanding of the stepwise approach used in clinical setting.
PATHOPHYSIOLOGY
To understand the process of any disease of iron-overload, the basic functions of iron must also be understood. Of those include the synthesis of heme to form hemoglobin found in red blood cells, energy metabolism, and immune response.Dietary iron is utilized within the body to make red blood cells to transport to organs, with an average intake of 1-2mg/day and the same passively excreted from the body through the intestinal system, epithelial cells, and perspiration(citation).
The International Journal of Hematology describes iron metabolism as a “semi-closed system” where there is no active means of iron excretion (Yutaka K, et al. 2008). The body self-regulates its input and output of iron so closely that only small amounts of iron are appropriate to be stored in the liver. To prevent excess iron absorption from enterocytes in the gastrointestinal lumen, iron binds to ferritin, stored within the enterocyte to keep from building up in the blood, then with ferroportin into the bloodstream. Once in the blood, transferrin shuttles the iron to be utilized for heme production with only the iron that remains stored in the liver.
Mechanism of injury In a tightly regulated system of iron metabolism and storage, when organs are burdened by a critical level of iron it has no way of getting out or appropriate means of utilizing it. The exact mechanisms for iron loading in hereditary hemochromatosis is still a topic of ongoing research but a general understanding of the pathogenesis has been identified. One mechanism is a decreased expression of hepcidin which is identified as the main hormone in iron regulation in enterocytes. This causes ferroportin to become internalized and degraded leading to inhibition of iron export in enterocytes and macrophages. An additional mechanism is of increased absorption by duodenal crypt cells where iron storage is regulated.
Long-standing iron overload results in tissue injury and fibrinogenesis in the liver. In the most severe cases, and the most common cause of death in long-standing iron overload is hepatocellular carcinoma. This is achieved from lipid peroxdation in hepatocytes causing injury and death and subsequent byproduct of kupffer cell activation. Fibrogenic cytokines are then produced, stimulating stellate cells and increasing collagen production in the liver. Pathologic liver fibrosis ensues, a troubling and preventable outcome for both patient and clinician.
CLINICAL PRESENTATION
A “classic triad” of primary iron-overload found late in the disease course is diabetes mellitus, liver cirrhosis, and skin discoloration. These skin findings are seen at iron aggregations more than five times normal at as much as 20 grams and may only present late in the course.
Of those phenotypically expressive of the disease, the most common complaints were fatigue, arthralgia, and loss of sexual drive. A survey of 2,851 participants revealed that symptom onset occurred an average of 10 years before the diagnosis of HH but since the application of genetic testing, more are presenting with abnormal iron studies in the presence of genetic predisposition.(Whitlock EP, et al. 2006)
Genetics The role of genetic testing in diagnosing hereditary hemochromatosis has evolved within the last five decades. The earliest known mutation was related to the human leukocyte antigen (HLA) on chromosome 6 but the addition of “positional cloning” in 1996 identified the HFE gene used today in genetic analysis for diagnosis of HH (Niederau C, et al. 1996). The C282Y missense mutation of the HFE protein was found to be the most common cause of primary iron overload. C282Y homozygotes are of the most concern clinically because they carry 2 C282Y mutations much more likely to develop into iron-overload. (Jacquet,E, et al. 2014)
Non-HFE causes Mutations of histidine, H63D and serine, S65C have been identified but of less concern with iron loading. Many non-HFE proteins involved in iron regulation are being studied and may play a role in iron loading which include hepcidin, hemojuvelin, transferrin receptor 2, as well as ferroportin. (Bacon BR, et all. 2011) This is something to look out for in the case of compound heterozygotes which have an C282Y allele with a mutation listed above. Though it is much less common to result in clinical disease, lifestyle modifications may be necessary such as alcohol and excess fat accumulation.
Secondary causes There are secondary causes for iron overload which should be considered in the differential diagnosis for iron-overload. According to European Association for the Study of the Liver in 2010, these causes include liver diseases such as hepatitis A, B and C, Beta thalassemia, multiple blood transfusions, hemophagocytic syndrome, malignancies, chronic inflammatory diseases and more. (EASL,2010)
Gender differences Radford-Smith and colleagues of the Internal Medicine Journal indicated that C282Y homozygosity accounts for 10 to 15% of the Northern European population but complications of iron toxicity occur in men and women at 30% and 1%, respectively. (Radford-Smith D, et al. 2018) The mechanisms behind this are the combined loss of iron in women during menstration, pregnancy, and childbirth. It is estimated that 0.5 to 1.0 mg/L of iron each day is lost during menstration. This accounts for the delayed clinical diagnosis in women to an estimated 10 to 20 years following the onset of menopause. Because of this delay, the above factors of childbearing appear to be a protective factor and reasons for a greater impact on the male gender.
Cofactors Heterozygous + factors that encourage disease manifestations are lifestyle habits which severely stress the liver such as heavy alcoholic consumption, and fatty liver disease. The effects of high levels of dietary iron consumption are not of significance unless actively treated with phlebotomy.
DIAGNOSIS
Now that genetic testing has been made available, the clinical relevance is being challenged. There are no tests to determine who will develop physical manifestations once found to contain both alleles. This presents the discussion of who should be screened and how to appropriately interpret the results. Experts expressed insight on the benefit versus risk of genotyping as part of the workup for HH and the stepwise clinical guidelines currently used in practice.
Genetic Testing. As one could expect with famililal screening and a better understanding of laboratory interpretation, more patients are presenting initially with laboratory abnormalities rather than symptoms. Ttwo investigations of patients with HH, 75 percent were asymptomatic at presentation, leaving only 25 percent with evidence of cirrhosis, diabetes, and skin hyperpigmentation at initial diagnosis (Radford-Smith D, et al. 2018).
Publications found in Genetics in Medicine indicate an estimated 1 in 10 males who are C282Y homozygotes will likely incur significant liver disease if treatment is not initiated early. (Grosse SD, et al. 2018). The potential for irreversible complications most prominently involving the liver, endocrine glands, heart, skin, and joints continuously endorses preventive measures such as early screening.
The United States Preventive Services Task Force (USTF) states that the basis of genotyping is for proof of the C282Y HFE mutation and it is the most relevant for clinical signs of the disease but not as a predictor for future disease. Furthermore, the significance of identifying this mutation is indeterminate.(Whitlock EP, et al. 2006) The Center of Disease Control does not recommend general population screening for HH in favor of iron loading evaluation only in those who are symptomatic or otherwise have a positive family history.
The American Association of the Study of Liver Disease(AASLD), American Academy of Family Physicians, and the American College of Gastroenterology recommend those with abnormal iron studies and first-degree relatives that are homozygotes should undergo genetic analysis. (Whitlock EP, et al. 2006)
SCREENING
AASLD SCREENING GUIDELINES
First degree relatives of HH It is widely endorsed that all first degree family members receive genetic screening.
A study of 735 first-degree family members of 224 individuals with homozygous clinical HH, diagnosed 80 percent of males and 53 percent under 40 years old with laboratory findings and genotype. (Bacon BR, et al,2011)
Iron study results A serum ferritin level greater than 200 to 300ng/mL in men or greater than 150 to 200ng/mL in women with transferrin saturation above 45 percent is diagnostic.
One might think that a disease of excess iron accumulation would present with an elevated serum iron, but according to the AASLD guidelines, transferrin saturation(TS) has been found to be the most sensitive and earliest indicator of the disease. Research has indicated that if TS is greater than 50 percent in women and 60 percent in men, it was 95 percent accurate in identifying an iron storage disease. (Bacon BR, et al. 2011)The reason for this is because it is an indicator of occupied iron binding sites rather than just the iron circulating the the blood.
Ferritin is a value of total body iron storage but because it is affected by numerous factors, it can cause a false positive when used in the workup of hereditary hemochromatosis. Liver diseases which cause elevated ferritin without excess iron stores are alcoholic liver disease, chronic hepatitis B and C, and Nonalcoholic fatty liver disease.Other disease processes include collagen disease, infection, lymphoma, and certain malignancies (Powell, LW, et al. 2006)
Liver Biopsy For homozygous patients greater than 40 years old with ferritin greater than 1,000 or elevated liver transaminases are appropriate for a liver biopsy to determine the extent of liver disease with iron accumulation in parenchymal cells.
Phlebotomy HH patients with liver biopsy indicates presence of liver disease from iron accumulation should receive a phlebotomy. *********
CONCLUSION
Since the recognition of hereditary hemochromatosis, the approach to diagnosis has continued to improve. Research has indicated that the appropriate questions are being asked, the seriousness of long-term complications realized. and clinical studies are currently underway for continued clinical guidance. It still remains a disease of controversy and requires further research, a knowledge base is growing to necessitate informed clinical decisions made by providers when approaching diseases of iron overload.
+put ALL complications—-heart especially!!!!
*HEIRS protocol***
Drawbacks of research
-loose meaning of the what constitutes a “clinical diagnosis”. A misuse of the meaning could cause
Survey of updated clinical guidelines for hereditary hemochromatosis patients
1. First-degree relatives of HH must be screened.
Treatment
2. If elevated serum ferritin receive phlebotomy twice a week to evacuate 400-500ml of blood **bacon BR, et al. 2011 states this to be >90 in women and >220 in men??**
3. Maintain ferritin between 50-100 mg/L during treatment
4. Even in absence of liver disease evidenced by both AST and ALT elevated, an elevated ferritin still warrants phlebotomy
5. Presence of liver cirrhosis and/or fibrosis must be evaluated and can be done through transient elastography or biopsy. If present, it is safe to phlebotomise.
6. Patients are to maintain adequate hydration before and after phlebotomy sessions and refrain from heavy physical activity for 24 hours following treatment.
General issues
7. In absence of iron overload, HH patients must be monitored yearly and treated if ferritin elevated above given range (Females 10-85mg/L normal, Males 10-220mg/L)
8. HH patients recommended to vaccinate against hepatitis A and B.
9. Those with cirrhosis:
a. receive influenza vaccination yearly and pneumococcus every 5 years.
b. Bi-annual screening for hepatocellular carcinoma with ultrasound and serum alpha fetoprotein
10. Yearly evaluation for complications (disease of heart, liver, pancreas, joints, thyroid, skin, bone)
a. Fasting glucose and hemoglobin A1C
b. If evidence of osteoarthritis, both physical and radiological assessment is recommended
Diet/Way of life
11. If currently undergoing treatment, strict avoidance of alcohol is encouraged
Recommendations HFE screening in other patient populations
1.If chondrocalcinosis with unexplained elevation in bother ferritin and transferrin saturation
2. Diabeted mellitus (type 1 and 2) with abnormal iron studies
3. NOT screened for unexplained osteoarthritis.
4. Unexplained chronic liver disease in increased transferrin saturation
References
Last Name, F. M. (Year). Article Title. Journal Title, Pages From – To.
Last Name, F. M. (Year). Book Title. City Name: Publisher Name.
Bacon br, Adams pc, Kowdley kv, et al. Diagnosis and management of hemochromatosis: 2011
practice guideline by the American Association for the Study of Liver Diseases.
Hepatology 2011; 54:328.
De Graaff B, Neil A, Sanderson K, Yee KC, Palmer AJ. Quality of life utility values for
hereditary haemochromatosis in Australia. Health and Quality of Life Outcomes.
2016;14:31. (De Graaff, B,et all. 2016)
Jacquet- bourdou E.,Philip J, Lorho R, Ropert M., Latournerie M., et al. Liver transplantation
normalizes serum hepcidin level and cures iron metabolism alterations in HFE
hemochromatosis. Hepatology, Wiley-Blackwell, 2014, 59 (3), pp.839-847. (Jacquet,E,
et al. 2014)
European Association For The Study of The Liver. EASL clinical practice guidelines for HFE
hemochromatosis. J Hepatol 2010; 53: 3–22.
Grosse S, Lyle G, Bertalli N, Allen K.Clinical penetrance in hereditary hemochromatosis:
estimates of the cumulative incidence of severe liver disease among HFE C282Y
homozygotes.( 2018) Genetics in Medicine 20, 383-389. (Grosse SD, et al.2018)
Niederau C, Fischer R, Sonnenberg A, et al. Long-term survival in patients with hereditary
hemochromatosis. N Engl J Med. 1996; 110:1107
**Radford-Smith DE, Powel EE, Powell LW, et al. Haemochromatosis: a clinical update for the
practicing physician. Internal Medicine Journal 2018. (Radford-Smith D, et al. 2018)
Powell LW, Dixon JL, Ramm GA, Purdue DM, Lincoln DJ, Anderson GJ, et al. Screening for
hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern
Med 2006;166:294-301 (Powell, LW, et al. 2006)
Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hemochromatosis in
asymptomatic subjects with or without a family history. Arch Intern Med. 2006; 166(3): 294-301. (Whitlock EP, et al. 2006)
**Vanclooster A,Wollersheim H,Vanhaecht K,et al. BMC Health Services Research. 2016 :573
https://doi.org/10.1186/s12913-016-1835-2 (Vanclooster A, et al 2016)
Yutaka K, Katsuya I, Takaaki O, et al. Body iron metabolism and pathophysiology of iron overload. International Journal of Hematology. 2008; 88(1):7-15 (Yutaka k, et al. 2008)
Tables
Table 1
Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328.