Case 33-2006 — A 43-Year-Old Man with Diabetes, Hypogonadism, Cirrhosis, Arthralgias, and Fatigue
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《新英格兰医药杂志》
Presentation of Case
A 43-year-old white man was seen at this hospital because of hypogonadism.
The patient had felt well until 6 months earlier, when he noted the gradual onset of fatigue, decreased libido, and erectile dysfunction. Ten weeks before the evaluation at this hospital, he saw his primary care physician. The levels of serum lipids, electrolytes, calcium, phosphorus, and magnesium and the results of tests of renal function were normal. The results of other laboratory tests are shown in Table 1. Seven weeks after the visit to his primary care physician, the patient saw an endocrinologist at this hospital. At that time, he reported new symptoms of dry mouth and polyuria. He thought he had lost some muscle mass because of lack of exercise. He did not have shortness of breath, a cough, a fever, night sweats, or visual changes.
Table 1. Results of Laboratory Tests.
A diagnosis of pulmonary sarcoidosis had been made 3 years earlier; abnormal findings on chest radiographs, shortness of breath, and the abnormal results of pulmonary-function tests resolved after 6 months of corticosteroid therapy and did not recur. The patient drank 5 to 10 alcoholic beverages per week and had never smoked. He worked as an engineer on a public works project and had noted no change in his exercise tolerance. He had lived in Scotland until the age of 23 years and had traveled extensively in South America, Cuba, Asia, and Egypt. He was married and had one adopted child. His father had died of heart disease at 49 years of age, and his mother was alive and well at 72 years of age. He had one brother, who was healthy.
On physical examination, the patient was a thin but well-developed man who was not in distress. His height was 1.83 m, and his weight was 81.7 kg. The blood pressure was 100/60 mm Hg, and the heart rate 88 beats per minute. The skin was tanned, with no spider angiomas or palmar erythema. The abdominal examination did not reveal organomegaly or ascites. The testicles were each estimated to be 18 ml without masses, and the prostate examination was normal. The pulse rates were normal, and there was no peripheral edema. Neurologic examination showed no asterixis and no deficits. Cranial magnetic resonance imaging (MRI) showed a partially empty sella turcica with no mass lesion of the pituitary. Results of laboratory tests are shown in Table 1.
The patient was referred to the gastroenterology clinic of this hospital. At that visit, he reported arthralgias in the ankles and a 4.5-kg weight loss during the preceding 6 months; the physical examination was unchanged. Results of additional laboratory tests are shown in Table 1.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Raymond T. Chung: When I first saw this 43-year-old man in the gastroenterology clinic, he had hypogonadotropic hypogonadism, diabetes of recent onset, arthralgias, fatigue, elevated aminotransferase levels, and iron indexes that were consistent with the presence of hemochromatosis.
Hemochromatosis is a multiorgan disorder resulting from progressive iron overload. It can be primary (hereditary hemochromatosis) or secondary (Table 2). Secondary hemochromatosis occurs predominantly in persons with ineffective erythropoiesis, including that due to thalassemias, sideroblastic anemia, and hemolysis. Chronic liver diseases such as porphyria cutanea tarda, chronic hepatitis B and C, and alcoholic and nonalcoholic fatty liver disease can all result in mild secondary iron overload. The relative preservation of the hemoglobin level and the severity of iron loading in this patient appear to rule out a secondary cause of hemochromatosis.
Table 2. Differential Diagnosis of Hemochromatosis.
Hereditary Hemochromatosis
The most common form of hereditary hemochromatosis is an autosomal recessive disorder associated with a mutation in the HFE gene on chromosome 6.1 Although 5 of every 1000 persons of northern European descent are homozygous for this mutation, the phenotypic expression of this mutation is highly variable.2,3 Less common hereditary disorders that develop in adulthood include transferrin receptor 2–related hereditary hemochromatosis and ferroportin-related iron overload. These two forms of hereditary hemochromatosis result from mutations in the iron regulatory molecules that mediate parenchymal-cell iron transport (in the case of the transferrin receptor 2–related disorder) and the release of iron by enterocytes and macrophages (in the case of the ferroportin-related disorder). African iron overload is a disorder of increased iron absorption among persons in sub-Saharan Africa and some African Americans. This patient's race and age and the pattern of his illness are most consistent with HFE-related hereditary hemochromatosis.
Clinical Manifestations of HFE-Related Hereditary Hemochromatosis
The classic presentation of HFE-related hereditary hemochromatosis is a combination of hepatomegaly, diabetes, and hyperpigmentation, reflecting parenchymal iron loading of the liver, pancreas, and skin, respectively (Table 3). This patient had diabetes and hyperpigmentation, and although he was not found to have hepatomegaly on examination, the results of his liver-function tests were abnormal and he had hypogonadotropic hypogonadism, another common finding in HFE-related hereditary hemochromatosis. Heightened awareness of hemochromatosis in recent years has resulted in the identification of nearly half of affected patients before the onset of symptoms.4,5 Both environmental and genetic modifiers can affect the phenotypic expression of hereditary hemochromatosis (Table 4). However, this patient appears to have had severe iron loading, despite the absence of known environmental factors other than regular alcohol use; this suggests the involvement of other genes that modify the phenotypic expression of hereditary hemochromatosis.
Table 3. Clinical Manifestations of Hereditary Hemochromatosis.
Table 4. Modifiers of Clinical Expression of Hereditary Hemochromatosis.
Pathophysiology of HFE-Related Hereditary Hemochromatosis
The most common mutation in HFE-related hereditary hemochromatosis is a single amino acid substitution of tyrosine for cysteine at position 282 (C282Y)1; a second mutation results in the substitution of aspartate for histidine at amino acid 63 (H63D), but persons who are homozygous for this mutation have less severe iron loading than do persons who are homozygous for the C282Y mutation. However, 4% of persons with phenotypic hereditary hemochromatosis are compound heterozygotes (C282Y/H63D). The C282Y substitution results in the disruption of a disulfide bond within the HFE protein, which impairs its cell-surface expression and results in decreased cellular iron uptake.
Two models have been proposed to explain the pathophysiology of iron overload in HFE-related hereditary hemochromatosis, neither of which has been proved. The crypt programming model suggests that defective iron absorption by the crypt cell results in the perception of iron deficiency, even in an iron-replete or iron-overloaded state.2 This iron-deficiency signal results in increased production of divalent metal transporter 1 (DMT-1), an iron transporter, causing increased uptake of iron from the intestinal lumen. Support for this model has come from studies that demonstrate up-regulation of DMT-1 in duodenal enterocytes, even with iron loading, in homozygous HFE-knockout mice. The hepcidin model proposes that the mutant HFE protein is unable to up-regulate the expression of hepcidin, a peptide secreted by hepatocytes that inhibits intestinal iron transport. This lack of up-regulation in turn leads to unchecked intestinal iron absorption. Support for the hepcidin model is provided by the observations that expression of hepcidin in the liver is suppressed in HFE-knockout mice6 and that iron deposition can be reversed by overexpression of hepcidin.7
This patient had evidence of liver and other end-organ damage. Iron accumulation in parenchymal tissues can promote the formation of reactive oxygen species and lead to cytotoxicity. In the liver, this process produces fibrosis and may ultimately lead to cirrhosis. The accumulation of high levels of iron and attendant genotoxic oxidative stress also appears to dramatically increase the risk of hepatocellular carcinoma (by a factor of more than 100) in persons with advanced hepatic fibrosis. In the pancreas, iron accumulation has a disproportionate effect on islet cells. Hypogonadism is the result of iron loading in the pituitary rather than in the testes. Within the pituitary, iron appears to be preferentially localized to gonadotropic cells; this could explain the selective involvement of the gonadal axis. The skin becomes pigmented as a consequence not only of direct iron deposition but also of the stimulatory effect of iron loading on melanocytes.
Diagnosis of Hereditary Hemochromatosis
Before the discovery of the HFE gene, the diagnosis of hereditary hemochromatosis required documentation of iron overload and family linkage studies with the use of HLA testing. During the past several decades, with earlier diagnosis, the profile of the typical patient with hereditary hemochromatosis has changed. Patients are more likely to be asymptomatic, iron overload is less severe, and fewer patients present with cirrhosis.4,5 Since the identification of the HFE gene, the diagnosis of hereditary hemochromatosis may now be made on the basis of a combination of biochemical and genotypic testing and does not necessarily require a liver biopsy to document iron overload. Evaluation of a patient such as this man with unexplained fatigue, arthralgia, hepatomegaly, elevated liver enzyme levels, early-onset male sexual dysfunction, and diabetes should include testing for hereditary hemochromatosis, with biochemical testing performed initially.
More than 98% of adults with hereditary hemochromatosis have transferrin saturation values in excess of 45%. If the initial transferrin saturation value exceeds 45%, then the patient should provide a second sample after an overnight fast, and the serum ferritin level should also be measured. If repeated testing confirms a transferrin saturation value of more than 55% or a transferrin saturation value of more than 45% with an elevated serum ferritin level (more than 300 ng per milliliter in men and more than 200 ng per milliliter in women), then HFE genotyping and evaluation for possible secondary causes of iron overload should be performed. In this patient, the transferrin saturation value (iron and iron-binding capacity in Table 1) was 97% on two occasions, so genotyping was indicated.
Genotypic testing for HFE should include analysis for mutations at C282Y and H63D. On a statistical basis, this patient would probably be homozygous for C282Y. However, 10 to 20% of persons of northern European descent are heterozygous for C282Y, and 15 to 30% are heterozygous for H63D, so heterozygosity will be common in any white population studied. Heterozygosity for C282Y alone should not be considered the sole cause of clinically significant iron overload. Persons who are homozygous for C282Y or who have heterozygosity of C282Y/H63D should undergo empirical iron reduction unless they meet the criteria for liver biopsy.
Although a liver biopsy is not required to establish the diagnosis of hemochromatosis in all patients, biopsy remains important to establish the extent of hepatic fibrosis and to identify hepatocellular carcinoma in persons with advanced fibrosis or cirrhosis. According to current recommendations, persons who are homozygous for C282Y who are younger than 40 years of age and who have normal liver function, with no hepatomegaly, and a serum ferritin level that is less than 1000 ng per milliliter can receive treatment without initially undergoing a liver biopsy. If these criteria are not met, a liver biopsy should be performed to look for the presence of fibrosis. Liver biopsy should also be considered to confirm the diagnosis of phenotypic hereditary hemochromatosis or to rule out other conditions contributing to iron loading in patients who are heterozygous for HFE mutations or do not have mutations but have persistently elevated ferritin levels. This patient met the criteria for liver biopsy on the basis of abnormal results of liver-function tests, elevated serum ferritin levels, and a clinical presentation that was consistent with hereditary hemochromatosis. The diagnostic tests included a liver biopsy in conjunction with HFE gene testing.
Dr. Raymond T. Chung's Diagnosis
Hereditary hemochromatosis due to a mutation in the HFE gene, with diabetes, hypogonadotropic hypogonadism, and probable hepatic cirrhosis.
Pathological Discussion
Dr. Joseph Misdraji: Pathological examination of the liver in iron-overload conditions includes assessment of the distribution of hepatic iron, the amount of iron, the degree of fibrosis, and the presence of iron-free foci or hepatocellular carcinoma. The liver-biopsy specimen in this case (Figure 1) shows established cirrhosis with nodular transformation of the hepatic parenchyma and fibrous septa. An iron stain demonstrates the presence of marked iron deposition in hepatocytes (grade 4 on a scale of 1 to 4) with increased iron also noted in Kupffer cells, stromal cells in the septa, and biliary epithelial cells. Areas of hepatocyte necrosis with iron-laden macrophages (sideronecrosis) are present, reflecting the severity of the iron deposition. The degree of iron deposition as assessed histologically correlates well with the tissue iron concentration assessed chemically.8,9,10 The hepatic iron concentration was 688 mmol per gram of liver tissue, dry weight (normal value, less than 80), with a hepatic iron index of 15.8 (normal value, 1.1). (The hepatic iron index is calculated by dividing the hepatic iron concentration by the patient's age.) These findings confirm the profound nature of the patient's iron overload.
Figure 1. Liver-Biopsy Specimen Showing Micronodular Cirrhosis.
The liver has been transformed into regenerative nodules composed of hepatocytes that are separated by wide bands of fibrous tissue (stained blue) (Panel A, trichrome stain). There is marked iron deposition, shown as blue granules, within hepatocytes, stromal cells, and bile duct epithelium (Panel B, Prussian blue stain).
Iron can be deposited in hepatocytes (in a parenchymal pattern), in Kupffer cells (in a mesenchymal pattern), or in both. The parenchymal pattern of iron deposition is characteristic of conditions in which iron absorption from the gut is increased. These conditions include hereditary hemochromatosis, anemias with ineffective erythropoiesis, chronic viral hepatitis, alcoholic liver disease, porphyria cutanea tarda, and cirrhosis.11 A parenchymal pattern of iron deposition has a low positive predictive value for hereditary hemochromatosis (58%), although it increases to 73% in cases such as this with marked iron deposition (grade 3 to 4 of 4). With severe iron overload, iron may also accumulate in Kupffer cells, portal mesenchymal cells, and bile-duct epithelium, but to a lesser degree than in hepatocytes, as was seen in this patient.12 The mesenchymal pattern of iron deposition is characteristic of parenteral iron overload, such as that caused by a blood transfusion,12 and this pattern has a high negative predictive value (100%) for homozygosity for C282Y.11 The picture may be mixed in complex situations such as in patients with -thalassemia who receive multiple blood transfusions.12 In this patient, the distribution and amount of iron were characteristic of HFE-related hereditary hemochromatosis.
Collections of hepatocytes that are devoid of iron, or iron-free foci, were not seen in this specimen. The hepatocytes within such foci are frequently dysplastic, with widened trabeculae, a high nuclear-to-cytoplasmic ratio, and expression of proliferative-cell nuclear antigen.13,14 Iron-free foci are seen with increased frequency in liver specimens from patients with hepatocellular carcinoma complicating hereditary hemochromatosis and are thought to be precursors of hepatocellular carcinoma.
The findings in this case are consistent with HFE-related hereditary hemochromatosis with severe iron overload. Genetic testing for HFE mutations showed homozygosity for the C282Y mutation.
Dr. Dushyant V. Sahani: After the liver biopsy, computed tomography of the abdomen and pelvis was performed; it showed enlargement of both the liver and the spleen. Magnetic resonance imaging (MRI) of the abdomen was later performed with and without the intravenous administration of contrast material. Both T1-weighted gradient–echo and T2-weighted images through the liver were obtained. The T2-weighted images showed decreased signal intensity in the myocardium (Figure 2A). There was a loss of signal intensity from the liver and pancreas, as compared with the spleen (Figure 2B) and the paraspinal muscles in the abdomen. In addition, the pancreas was atrophied. This constellation of findings is pathognomonic of hemochromatosis. The changes associated with cirrhosis, including enlargement of the caudate lobe and abnormalities in the contour of the liver surface, were also seen. The signal intensity on T2-weighted MRI images is thought to be inversely correlated with the degree of iron overload in the liver. On the basis of that hypothesis, this case would be categorized as severe hepatic iron overload.
Figure 2. MRI of the Abdomen.
T2-weighted images through the base of the heart (Panel A) and upper abdomen (Panel B) are shown. The myocardium (thin arrows in Panel A), liver (thick arrow in Panel A), and pancreas (arrows in Panel B) are appreciably darker than the spleen (asterisk in Panels A and B), indicating the presence of increased iron in these organs. A corresponding T1-weighted gradient–echo image (Panel C) shows similar findings; both the liver (white arrow) and pancreas (black arrow) appear darker than the spleen (asterisk).
T1-weighted gradient–echo images are more sensitive than T2-weighted images, and early changes associated with iron overload can be detected on T1-weighted images before clinical manifestations appear. The T1-weighted gradient–echo images in this case showed changes similar to those on T2-weighted images (Figure 2C). On imaging performed after the administration of contrast material, no focal enhancing lesions were evident.
Discussion of Management
Dr. Chung: Long-term follow-up studies have demonstrated excellent survival rates among patients with hereditary hemochromatosis who did not have cirrhosis, diabetes, cardiomyopathy, or extensive iron accumulation at the time of the diagnosis.15 Once the diagnosis has been made, a course of iron depletion and monitoring is indicated. Iron depletion reduces the symptoms and signs of virtually all the end-organ complications of hereditary hemochromatosis, with the exception of joint disease, hypogonadism, and cirrhosis.
Initially, patients with iron overload should undergo weekly therapeutic phlebotomy (each unit of blood removed contains 200 to 250 mg of iron) with regular monitoring of hemoglobin and testing of serum ferritin after each 1 to 2 g of iron has been removed. Phlebotomy should be continued until the serum ferritin level falls below 50 μg per liter or until anemia develops. Typical hereditary hemochromatosis may require the removal of 8 to 25 units of blood to achieve an adequate reduction of ferritin. This patient underwent phlebotomy approximately twice weekly for more than a year; 100 units of blood was removed before ferritin reached a target level below 50 μg per liter, which is consistent with an excess of 20 to 25 g of iron. He is currently undergoing phlebotomy every 3 months.
A number of dietary recommendations were made for this patient. He was counseled to consume red meat or organ meat in moderation and to avoid iron supplements and alcohol consumption. He was also advised to avoid vitamin C supplements, because they increase intestinal iron absorption, and not to consume raw shellfish, because it could be contaminated with Vibrio vulnificus, an iron-avid organism that often causes a fatal infection in persons with iron overload and cirrhosis.
For patients such as this one with advanced hepatic fibrosis or cirrhosis, routine ultrasound studies and serum alpha-fetoprotein measurements are recommended to screen for hepatocellular carcinoma, given the risk of this largely untreatable complication of hereditary hemochromatosis. This patient, who had signs of advanced disease, has undergone regular screening during the 6 years since his diagnosis, with no evidence of hepatocellular carcinoma. His liver function is currently adequate; however, he may eventually need a liver transplant. He was referred to an endocrinologist for the management of his diabetes, which is now well controlled with regular insulin therapy. His impotence has improved with testosterone supplementation, and his skin pigmentation has lightened. He continues to have mild arthralgias.
Once a proband has been identified with C282Y hereditary hemochromatosis, genotypic screening of all first-degree relatives should be performed.16 Some consensus statements17,18 discourage routine screening of the general population for the C282Y mutation, and it should be reserved for persons with abnormal results of iron screening tests or first-degree relatives of persons who are homozygous for the C282Y mutation.19 This patient's brother and mother are both C282Y heterozygotes. He does not have biologic children.
Dr. Stephen E. Goldfinger (Gastrointestinal Unit): Patients with hemochromatosis often present with fatigue, impotence, and arthralgia, and this condition is easily misdiagnosed by many of us as depression. One study showed that several psychiatric disorders are associated with iron overload.20 Could all of us who are looking for bronze diabetes be missing hemochromatosis in some patients?
Dr. Chung: That is an important point because early symptoms of hemochromatosis are nonspecific, and a diagnosis is often not made until more definitive symptoms develop. For this reason, when one considers population screening, there are two possible approaches. One is genotypic screening, and the second is phenotypic (biochemical) screening. Current clinical guidelines do not recommend screening the general population for the C282Y mutation because of highly variable phenotypic expression. Biochemical screening is more cost-effective and may be the more reasonable screening approach. However, one problem with biochemical screening at a threshold transferrin saturation of 45% is its high false positive rate.
Anatomical Diagnosis
Hereditary hemochromatosis due to a homozygous C282Y mutation in the HFE gene, with hepatic cirrhosis, diabetes, and hypogonadism.
Dr. Sahani reports having received grant support from Bracco Diagnostics. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Gastrointestinal Unit (R.T.C.) and the Departments of Pathology (J.M.) and Radiology (D.V.S.), Massachusetts General Hospital; and the Departments of Medicine (R.T.C.), Pathology (J.M.), and Radiology (D.V.S.), Harvard Medical School.
References
Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408.
Pietrangelo A. Hereditary hemochromatosis -- a new look at an old disease. N Engl J Med 2004;350:2383-2397.
Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724.
Adams PC, Deugnier Y, Moirand R, Brissot P. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 1997;25:162-166.
Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-1119.
Muckenthaler M, Roy CN, Custodio AO, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 2003;34:102-107.
Nicolas G, Viatte L, Lou DQ, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 2003;34:97-101.
Searle J, Leggett BA, Crawford DHG, Powell LW. Iron storage disease. In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, eds. Pathology of the liver. 4th ed. London: Churchill Livingstone, 2002:257-72.
Deugnier YM, Loreal O, Turlin B, et al. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology 1992;102:2050-2059.
Brissot P, Bourel M, Herry D, et al. Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods. Gastroenterology 1981;80:557-565.
Brunt EM, Olynyk JK, Britton RS, Janney CG, Di Bisceglie AM, Bacon BR. Histological evaluation of iron in liver biopsies: relationship to HFE mutations. Am J Gastroenterol 2000;95:1788-1793.
Turlin B, Deugnier Y. Evaluation and interpretation of iron in the liver. Semin Diagn Pathol 1998;15:237-245.
Deugnier YM, Charalambous P, Le Quilleuc D, et al. Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients. Hepatology 1993;18:1363-1369.
Blanc JF, De Ledinghen V, Trimoulet P, et al. Premalignant lesions and hepatocellular carcinoma in a non-cirrhotic alcoholic patient with iron overload and normal transferrin saturation. J Hepatol 1999;30:325-329.
Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. Ann Intern Med 1998;129:932-939.
Bulaj ZJ, Ajioka RS, Phillips JD, et al. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med 2000;343:1529-1535.
Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med 2006;145:204-208.
Iron overload and hemochromatosis: home. Atlanta: Centers for Disease Control and Prevention, 2006. (Accessed September 29, 2006, at http://www.cdc.gov/hemochromatosis.)
Tavill AS. Diagnosis and management of hemochromatosis. Hepatology 2001;33:1321-1328.
Cutler P. Iron overload and psychiatric illness. Can J Psychiatry 1994;39:8-11.(Raymond T. Chung, M.D., J)
A 43-year-old white man was seen at this hospital because of hypogonadism.
The patient had felt well until 6 months earlier, when he noted the gradual onset of fatigue, decreased libido, and erectile dysfunction. Ten weeks before the evaluation at this hospital, he saw his primary care physician. The levels of serum lipids, electrolytes, calcium, phosphorus, and magnesium and the results of tests of renal function were normal. The results of other laboratory tests are shown in Table 1. Seven weeks after the visit to his primary care physician, the patient saw an endocrinologist at this hospital. At that time, he reported new symptoms of dry mouth and polyuria. He thought he had lost some muscle mass because of lack of exercise. He did not have shortness of breath, a cough, a fever, night sweats, or visual changes.
Table 1. Results of Laboratory Tests.
A diagnosis of pulmonary sarcoidosis had been made 3 years earlier; abnormal findings on chest radiographs, shortness of breath, and the abnormal results of pulmonary-function tests resolved after 6 months of corticosteroid therapy and did not recur. The patient drank 5 to 10 alcoholic beverages per week and had never smoked. He worked as an engineer on a public works project and had noted no change in his exercise tolerance. He had lived in Scotland until the age of 23 years and had traveled extensively in South America, Cuba, Asia, and Egypt. He was married and had one adopted child. His father had died of heart disease at 49 years of age, and his mother was alive and well at 72 years of age. He had one brother, who was healthy.
On physical examination, the patient was a thin but well-developed man who was not in distress. His height was 1.83 m, and his weight was 81.7 kg. The blood pressure was 100/60 mm Hg, and the heart rate 88 beats per minute. The skin was tanned, with no spider angiomas or palmar erythema. The abdominal examination did not reveal organomegaly or ascites. The testicles were each estimated to be 18 ml without masses, and the prostate examination was normal. The pulse rates were normal, and there was no peripheral edema. Neurologic examination showed no asterixis and no deficits. Cranial magnetic resonance imaging (MRI) showed a partially empty sella turcica with no mass lesion of the pituitary. Results of laboratory tests are shown in Table 1.
The patient was referred to the gastroenterology clinic of this hospital. At that visit, he reported arthralgias in the ankles and a 4.5-kg weight loss during the preceding 6 months; the physical examination was unchanged. Results of additional laboratory tests are shown in Table 1.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Raymond T. Chung: When I first saw this 43-year-old man in the gastroenterology clinic, he had hypogonadotropic hypogonadism, diabetes of recent onset, arthralgias, fatigue, elevated aminotransferase levels, and iron indexes that were consistent with the presence of hemochromatosis.
Hemochromatosis is a multiorgan disorder resulting from progressive iron overload. It can be primary (hereditary hemochromatosis) or secondary (Table 2). Secondary hemochromatosis occurs predominantly in persons with ineffective erythropoiesis, including that due to thalassemias, sideroblastic anemia, and hemolysis. Chronic liver diseases such as porphyria cutanea tarda, chronic hepatitis B and C, and alcoholic and nonalcoholic fatty liver disease can all result in mild secondary iron overload. The relative preservation of the hemoglobin level and the severity of iron loading in this patient appear to rule out a secondary cause of hemochromatosis.
Table 2. Differential Diagnosis of Hemochromatosis.
Hereditary Hemochromatosis
The most common form of hereditary hemochromatosis is an autosomal recessive disorder associated with a mutation in the HFE gene on chromosome 6.1 Although 5 of every 1000 persons of northern European descent are homozygous for this mutation, the phenotypic expression of this mutation is highly variable.2,3 Less common hereditary disorders that develop in adulthood include transferrin receptor 2–related hereditary hemochromatosis and ferroportin-related iron overload. These two forms of hereditary hemochromatosis result from mutations in the iron regulatory molecules that mediate parenchymal-cell iron transport (in the case of the transferrin receptor 2–related disorder) and the release of iron by enterocytes and macrophages (in the case of the ferroportin-related disorder). African iron overload is a disorder of increased iron absorption among persons in sub-Saharan Africa and some African Americans. This patient's race and age and the pattern of his illness are most consistent with HFE-related hereditary hemochromatosis.
Clinical Manifestations of HFE-Related Hereditary Hemochromatosis
The classic presentation of HFE-related hereditary hemochromatosis is a combination of hepatomegaly, diabetes, and hyperpigmentation, reflecting parenchymal iron loading of the liver, pancreas, and skin, respectively (Table 3). This patient had diabetes and hyperpigmentation, and although he was not found to have hepatomegaly on examination, the results of his liver-function tests were abnormal and he had hypogonadotropic hypogonadism, another common finding in HFE-related hereditary hemochromatosis. Heightened awareness of hemochromatosis in recent years has resulted in the identification of nearly half of affected patients before the onset of symptoms.4,5 Both environmental and genetic modifiers can affect the phenotypic expression of hereditary hemochromatosis (Table 4). However, this patient appears to have had severe iron loading, despite the absence of known environmental factors other than regular alcohol use; this suggests the involvement of other genes that modify the phenotypic expression of hereditary hemochromatosis.
Table 3. Clinical Manifestations of Hereditary Hemochromatosis.
Table 4. Modifiers of Clinical Expression of Hereditary Hemochromatosis.
Pathophysiology of HFE-Related Hereditary Hemochromatosis
The most common mutation in HFE-related hereditary hemochromatosis is a single amino acid substitution of tyrosine for cysteine at position 282 (C282Y)1; a second mutation results in the substitution of aspartate for histidine at amino acid 63 (H63D), but persons who are homozygous for this mutation have less severe iron loading than do persons who are homozygous for the C282Y mutation. However, 4% of persons with phenotypic hereditary hemochromatosis are compound heterozygotes (C282Y/H63D). The C282Y substitution results in the disruption of a disulfide bond within the HFE protein, which impairs its cell-surface expression and results in decreased cellular iron uptake.
Two models have been proposed to explain the pathophysiology of iron overload in HFE-related hereditary hemochromatosis, neither of which has been proved. The crypt programming model suggests that defective iron absorption by the crypt cell results in the perception of iron deficiency, even in an iron-replete or iron-overloaded state.2 This iron-deficiency signal results in increased production of divalent metal transporter 1 (DMT-1), an iron transporter, causing increased uptake of iron from the intestinal lumen. Support for this model has come from studies that demonstrate up-regulation of DMT-1 in duodenal enterocytes, even with iron loading, in homozygous HFE-knockout mice. The hepcidin model proposes that the mutant HFE protein is unable to up-regulate the expression of hepcidin, a peptide secreted by hepatocytes that inhibits intestinal iron transport. This lack of up-regulation in turn leads to unchecked intestinal iron absorption. Support for the hepcidin model is provided by the observations that expression of hepcidin in the liver is suppressed in HFE-knockout mice6 and that iron deposition can be reversed by overexpression of hepcidin.7
This patient had evidence of liver and other end-organ damage. Iron accumulation in parenchymal tissues can promote the formation of reactive oxygen species and lead to cytotoxicity. In the liver, this process produces fibrosis and may ultimately lead to cirrhosis. The accumulation of high levels of iron and attendant genotoxic oxidative stress also appears to dramatically increase the risk of hepatocellular carcinoma (by a factor of more than 100) in persons with advanced hepatic fibrosis. In the pancreas, iron accumulation has a disproportionate effect on islet cells. Hypogonadism is the result of iron loading in the pituitary rather than in the testes. Within the pituitary, iron appears to be preferentially localized to gonadotropic cells; this could explain the selective involvement of the gonadal axis. The skin becomes pigmented as a consequence not only of direct iron deposition but also of the stimulatory effect of iron loading on melanocytes.
Diagnosis of Hereditary Hemochromatosis
Before the discovery of the HFE gene, the diagnosis of hereditary hemochromatosis required documentation of iron overload and family linkage studies with the use of HLA testing. During the past several decades, with earlier diagnosis, the profile of the typical patient with hereditary hemochromatosis has changed. Patients are more likely to be asymptomatic, iron overload is less severe, and fewer patients present with cirrhosis.4,5 Since the identification of the HFE gene, the diagnosis of hereditary hemochromatosis may now be made on the basis of a combination of biochemical and genotypic testing and does not necessarily require a liver biopsy to document iron overload. Evaluation of a patient such as this man with unexplained fatigue, arthralgia, hepatomegaly, elevated liver enzyme levels, early-onset male sexual dysfunction, and diabetes should include testing for hereditary hemochromatosis, with biochemical testing performed initially.
More than 98% of adults with hereditary hemochromatosis have transferrin saturation values in excess of 45%. If the initial transferrin saturation value exceeds 45%, then the patient should provide a second sample after an overnight fast, and the serum ferritin level should also be measured. If repeated testing confirms a transferrin saturation value of more than 55% or a transferrin saturation value of more than 45% with an elevated serum ferritin level (more than 300 ng per milliliter in men and more than 200 ng per milliliter in women), then HFE genotyping and evaluation for possible secondary causes of iron overload should be performed. In this patient, the transferrin saturation value (iron and iron-binding capacity in Table 1) was 97% on two occasions, so genotyping was indicated.
Genotypic testing for HFE should include analysis for mutations at C282Y and H63D. On a statistical basis, this patient would probably be homozygous for C282Y. However, 10 to 20% of persons of northern European descent are heterozygous for C282Y, and 15 to 30% are heterozygous for H63D, so heterozygosity will be common in any white population studied. Heterozygosity for C282Y alone should not be considered the sole cause of clinically significant iron overload. Persons who are homozygous for C282Y or who have heterozygosity of C282Y/H63D should undergo empirical iron reduction unless they meet the criteria for liver biopsy.
Although a liver biopsy is not required to establish the diagnosis of hemochromatosis in all patients, biopsy remains important to establish the extent of hepatic fibrosis and to identify hepatocellular carcinoma in persons with advanced fibrosis or cirrhosis. According to current recommendations, persons who are homozygous for C282Y who are younger than 40 years of age and who have normal liver function, with no hepatomegaly, and a serum ferritin level that is less than 1000 ng per milliliter can receive treatment without initially undergoing a liver biopsy. If these criteria are not met, a liver biopsy should be performed to look for the presence of fibrosis. Liver biopsy should also be considered to confirm the diagnosis of phenotypic hereditary hemochromatosis or to rule out other conditions contributing to iron loading in patients who are heterozygous for HFE mutations or do not have mutations but have persistently elevated ferritin levels. This patient met the criteria for liver biopsy on the basis of abnormal results of liver-function tests, elevated serum ferritin levels, and a clinical presentation that was consistent with hereditary hemochromatosis. The diagnostic tests included a liver biopsy in conjunction with HFE gene testing.
Dr. Raymond T. Chung's Diagnosis
Hereditary hemochromatosis due to a mutation in the HFE gene, with diabetes, hypogonadotropic hypogonadism, and probable hepatic cirrhosis.
Pathological Discussion
Dr. Joseph Misdraji: Pathological examination of the liver in iron-overload conditions includes assessment of the distribution of hepatic iron, the amount of iron, the degree of fibrosis, and the presence of iron-free foci or hepatocellular carcinoma. The liver-biopsy specimen in this case (Figure 1) shows established cirrhosis with nodular transformation of the hepatic parenchyma and fibrous septa. An iron stain demonstrates the presence of marked iron deposition in hepatocytes (grade 4 on a scale of 1 to 4) with increased iron also noted in Kupffer cells, stromal cells in the septa, and biliary epithelial cells. Areas of hepatocyte necrosis with iron-laden macrophages (sideronecrosis) are present, reflecting the severity of the iron deposition. The degree of iron deposition as assessed histologically correlates well with the tissue iron concentration assessed chemically.8,9,10 The hepatic iron concentration was 688 mmol per gram of liver tissue, dry weight (normal value, less than 80), with a hepatic iron index of 15.8 (normal value, 1.1). (The hepatic iron index is calculated by dividing the hepatic iron concentration by the patient's age.) These findings confirm the profound nature of the patient's iron overload.
Figure 1. Liver-Biopsy Specimen Showing Micronodular Cirrhosis.
The liver has been transformed into regenerative nodules composed of hepatocytes that are separated by wide bands of fibrous tissue (stained blue) (Panel A, trichrome stain). There is marked iron deposition, shown as blue granules, within hepatocytes, stromal cells, and bile duct epithelium (Panel B, Prussian blue stain).
Iron can be deposited in hepatocytes (in a parenchymal pattern), in Kupffer cells (in a mesenchymal pattern), or in both. The parenchymal pattern of iron deposition is characteristic of conditions in which iron absorption from the gut is increased. These conditions include hereditary hemochromatosis, anemias with ineffective erythropoiesis, chronic viral hepatitis, alcoholic liver disease, porphyria cutanea tarda, and cirrhosis.11 A parenchymal pattern of iron deposition has a low positive predictive value for hereditary hemochromatosis (58%), although it increases to 73% in cases such as this with marked iron deposition (grade 3 to 4 of 4). With severe iron overload, iron may also accumulate in Kupffer cells, portal mesenchymal cells, and bile-duct epithelium, but to a lesser degree than in hepatocytes, as was seen in this patient.12 The mesenchymal pattern of iron deposition is characteristic of parenteral iron overload, such as that caused by a blood transfusion,12 and this pattern has a high negative predictive value (100%) for homozygosity for C282Y.11 The picture may be mixed in complex situations such as in patients with -thalassemia who receive multiple blood transfusions.12 In this patient, the distribution and amount of iron were characteristic of HFE-related hereditary hemochromatosis.
Collections of hepatocytes that are devoid of iron, or iron-free foci, were not seen in this specimen. The hepatocytes within such foci are frequently dysplastic, with widened trabeculae, a high nuclear-to-cytoplasmic ratio, and expression of proliferative-cell nuclear antigen.13,14 Iron-free foci are seen with increased frequency in liver specimens from patients with hepatocellular carcinoma complicating hereditary hemochromatosis and are thought to be precursors of hepatocellular carcinoma.
The findings in this case are consistent with HFE-related hereditary hemochromatosis with severe iron overload. Genetic testing for HFE mutations showed homozygosity for the C282Y mutation.
Dr. Dushyant V. Sahani: After the liver biopsy, computed tomography of the abdomen and pelvis was performed; it showed enlargement of both the liver and the spleen. Magnetic resonance imaging (MRI) of the abdomen was later performed with and without the intravenous administration of contrast material. Both T1-weighted gradient–echo and T2-weighted images through the liver were obtained. The T2-weighted images showed decreased signal intensity in the myocardium (Figure 2A). There was a loss of signal intensity from the liver and pancreas, as compared with the spleen (Figure 2B) and the paraspinal muscles in the abdomen. In addition, the pancreas was atrophied. This constellation of findings is pathognomonic of hemochromatosis. The changes associated with cirrhosis, including enlargement of the caudate lobe and abnormalities in the contour of the liver surface, were also seen. The signal intensity on T2-weighted MRI images is thought to be inversely correlated with the degree of iron overload in the liver. On the basis of that hypothesis, this case would be categorized as severe hepatic iron overload.
Figure 2. MRI of the Abdomen.
T2-weighted images through the base of the heart (Panel A) and upper abdomen (Panel B) are shown. The myocardium (thin arrows in Panel A), liver (thick arrow in Panel A), and pancreas (arrows in Panel B) are appreciably darker than the spleen (asterisk in Panels A and B), indicating the presence of increased iron in these organs. A corresponding T1-weighted gradient–echo image (Panel C) shows similar findings; both the liver (white arrow) and pancreas (black arrow) appear darker than the spleen (asterisk).
T1-weighted gradient–echo images are more sensitive than T2-weighted images, and early changes associated with iron overload can be detected on T1-weighted images before clinical manifestations appear. The T1-weighted gradient–echo images in this case showed changes similar to those on T2-weighted images (Figure 2C). On imaging performed after the administration of contrast material, no focal enhancing lesions were evident.
Discussion of Management
Dr. Chung: Long-term follow-up studies have demonstrated excellent survival rates among patients with hereditary hemochromatosis who did not have cirrhosis, diabetes, cardiomyopathy, or extensive iron accumulation at the time of the diagnosis.15 Once the diagnosis has been made, a course of iron depletion and monitoring is indicated. Iron depletion reduces the symptoms and signs of virtually all the end-organ complications of hereditary hemochromatosis, with the exception of joint disease, hypogonadism, and cirrhosis.
Initially, patients with iron overload should undergo weekly therapeutic phlebotomy (each unit of blood removed contains 200 to 250 mg of iron) with regular monitoring of hemoglobin and testing of serum ferritin after each 1 to 2 g of iron has been removed. Phlebotomy should be continued until the serum ferritin level falls below 50 μg per liter or until anemia develops. Typical hereditary hemochromatosis may require the removal of 8 to 25 units of blood to achieve an adequate reduction of ferritin. This patient underwent phlebotomy approximately twice weekly for more than a year; 100 units of blood was removed before ferritin reached a target level below 50 μg per liter, which is consistent with an excess of 20 to 25 g of iron. He is currently undergoing phlebotomy every 3 months.
A number of dietary recommendations were made for this patient. He was counseled to consume red meat or organ meat in moderation and to avoid iron supplements and alcohol consumption. He was also advised to avoid vitamin C supplements, because they increase intestinal iron absorption, and not to consume raw shellfish, because it could be contaminated with Vibrio vulnificus, an iron-avid organism that often causes a fatal infection in persons with iron overload and cirrhosis.
For patients such as this one with advanced hepatic fibrosis or cirrhosis, routine ultrasound studies and serum alpha-fetoprotein measurements are recommended to screen for hepatocellular carcinoma, given the risk of this largely untreatable complication of hereditary hemochromatosis. This patient, who had signs of advanced disease, has undergone regular screening during the 6 years since his diagnosis, with no evidence of hepatocellular carcinoma. His liver function is currently adequate; however, he may eventually need a liver transplant. He was referred to an endocrinologist for the management of his diabetes, which is now well controlled with regular insulin therapy. His impotence has improved with testosterone supplementation, and his skin pigmentation has lightened. He continues to have mild arthralgias.
Once a proband has been identified with C282Y hereditary hemochromatosis, genotypic screening of all first-degree relatives should be performed.16 Some consensus statements17,18 discourage routine screening of the general population for the C282Y mutation, and it should be reserved for persons with abnormal results of iron screening tests or first-degree relatives of persons who are homozygous for the C282Y mutation.19 This patient's brother and mother are both C282Y heterozygotes. He does not have biologic children.
Dr. Stephen E. Goldfinger (Gastrointestinal Unit): Patients with hemochromatosis often present with fatigue, impotence, and arthralgia, and this condition is easily misdiagnosed by many of us as depression. One study showed that several psychiatric disorders are associated with iron overload.20 Could all of us who are looking for bronze diabetes be missing hemochromatosis in some patients?
Dr. Chung: That is an important point because early symptoms of hemochromatosis are nonspecific, and a diagnosis is often not made until more definitive symptoms develop. For this reason, when one considers population screening, there are two possible approaches. One is genotypic screening, and the second is phenotypic (biochemical) screening. Current clinical guidelines do not recommend screening the general population for the C282Y mutation because of highly variable phenotypic expression. Biochemical screening is more cost-effective and may be the more reasonable screening approach. However, one problem with biochemical screening at a threshold transferrin saturation of 45% is its high false positive rate.
Anatomical Diagnosis
Hereditary hemochromatosis due to a homozygous C282Y mutation in the HFE gene, with hepatic cirrhosis, diabetes, and hypogonadism.
Dr. Sahani reports having received grant support from Bracco Diagnostics. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Gastrointestinal Unit (R.T.C.) and the Departments of Pathology (J.M.) and Radiology (D.V.S.), Massachusetts General Hospital; and the Departments of Medicine (R.T.C.), Pathology (J.M.), and Radiology (D.V.S.), Harvard Medical School.
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