Yves Deugnier, Liver Unit and CIC INSERM 0203, Pontchaillou University Hospital, Rennes 35033, France
Bruno Turlin, Department of Pathology and INSERM U 522, Pontchaillou University Hospital, Rennes 35033, France
Correspondence to: Yves Deugnier, Professor of Hepatology, Liver Unit and CIC INSERM 0203, Pontchaillou University Hospital, Rennes 35033, France. email@example.com
Telephone: +33-2-99284297 Fax: +33-2-99284112
Received: 2007-03-30 Accepted: 2007-05-09
Although progress in imaging and genetics allow for a noninvasive diagnosis of most cases of genetic iron overload, liver pathology remains often useful (1) to assess prognosis by grading fibrosis and seeking for associated lesions and (2) to guide the etiological diagnosis, especially when no molecular marker is available. Then, the type of liver siderosis (parenchymal, mesenchymal or mixed) and its distribution throughout the lobule and the liver are useful means for suggesting its etiology: HLA-linked hemochromatosis gene (HFE) hemochromatosis or other rare genetic hemochromatosis, nonhemochromatotic genetic iron overload (ferroportin disease, aceruloplasminemia), or iron overload secondary to excessive iron supply, inflammatory syndrome, noncirrhotic chronic liver diseases including dysmetabolic iron overload syndrome, cirrhosis, and blood disorders.
© 2007 WJG. All rights reserved.
Key words: Iron; Liver; Biopsy; Hemochromatosis; Ferroportin; HLA-linked hemochromatosis gene; Hepcidin; Metabolic syndrome
Deugnier Y, Turlin B. Pathology of hepatic iron overload. World J Gastroenterol 2007; 13(35): 4755-4760
Progress in molecular genetics and in liver imaging have allowed for the noninvasive diagnosis of most cases of inherited disorders of iron metabolism. However, liver pathology remains often useful to assess associated lesions-especially fibrosis-in patients with HLA·linked hemochromatosis gene (HFE) and, mainly, nonHFE hemochromatosis, and to guide the etiological diagnosis of iron overload in the absence of a molecular marker. Moreover, because iron is more and more considered as a putative (co) factor of morbidity in patients with chronic liver diseases of various causes, iron excess must be recognized, indicated, qualified, quantified and interpretated even when it seems to be contingent upon a well established hepatic disorder.
Assertion of iron overload
In the normal liver, iron is present
at a concentration lower than 20
of dry weight. But, it is not histologically
visible. Iron deposits are usually difficult to identify on usual
stains unless they are abundant. Therefore, every
liver biopsy should be routinely
stained using not only
Description of iron overload[2,3] Distribution
The cellular distribution of iron deposits within hepatocytes, sinusoidal and portal macrophages, sinusoidal and portal endothelial cells, and biliary cells must be precisely described according to lobular areas in order to differentiate the following types of liver siderosis.
Parenchymal iron overload: It is related to intestinal iron hyperabsorption. Then, because it comes to the liver through the portal vein, iron deposits within hepatocytes as fine granules at the biliary pole of cells, and is distributed throughout the lobule according to a decreasing gradient from periportal to centrolobular areas. Mesenchymal iron deposits may be found at a latter stage when the amount of hepatocytic iron is high and responsible for sideronecrosis.
Mesenchymal iron overload: It corresponds to iron deposition within Kupffer cells and/or portal macrophages. Iron loaded cells are either isolated or grouped together without any lobular systematization. When associated, hepatocytic iron deposits are rough, sparse and usually located within cells close to iron loaded macrophages.
Mixed iron overload: It presents with the histological characteristics of the previous two types and corresponds usually to complex conditions or to massive iron loading.
It is also important to precise whether iron distribution throughout the liver is homogeneous or not, i.e. whether lobules (or, in case of cirrhosis, nodules) are equally iron loaded or not[4,5].
Biochemical hepatic iron concentration: Irrespective of the method used (colorimetry or atomic absorption), the biochemical determination of hepatic iron concentration (HIC) is considered as the reference method for quantifying iron in the liver[1,6] In normal subjects, HIC ranges from 10 to 36 mmol/g of dry weight. Iron excess is considered as mild up to 150, moderate between 150 and 300, and important above 300. Cases with HIC greater than 1000 are exceptionnal. Results obtained from fresh tissue and from deparaffinized blocks are equivalent. Therefore, determination of HIC on deparaffinized tissue should be the rule because it allows for histological control. This is especially relevant when iron distribution is heterogeneous as in the cirrhotic liver[4,5].
Histological semiquantitative assessment:
Several scoring systems have been proposed. The Scheuer’s scoring
system, either in its original presentation or
modified according to Rowe et al or to Searle
et al is widely used
because it is simple (Table 1).
However, it was not satisfactorily validated. The system
proposed by the authors (Table 2)
Both the type of iron overload and associated hepatic lesions may guide towards the right etiology (Table 3).
Genetic iron overload
Genetic hemochromatosis: Genetic hemochromatosis corresponds to 4 disorders transmitted as autosomal recessive traits, two with late onset (adult type: HFE hemochromatosis and iron overload related to mutation on the receptor transferrin 2 gene) and two with early onset (juvenile type related to mutations on the hemojuvelin or the hepcidin gene). From a histological point of view, these disorders are very similar because of a common pathophysiology consisting in an impairment of hepcidin production whose degree modulates the severity of iron burden.
In early GH, iron remains located within hepatocytes, at the biliary pole of cells. It is distributed according to a decreasing gradient from periportal to centrolobular areas. This results in a typical parenchymal iron overload pattern.
With the passage of time, hepatocytic iron load increases, and then periportal sideronecrosis occurs. Sideronecrosis is responsible for macrophage activation, which leads to both development of fibrosis, and redistribution of iron towards nonparenchymal cells. In the absence of other cause of chronic liver disease, cirrhosis develops when hepatic iron concentration exceeds 400 mmol/g. GH related cirrhosis consists of large fibrous septa resembling biliary cirrhosis, while preserving the vascular architecture of the liver for a long time. This likely explains why portal hypertension and hepatic failure are rare features in GH patients. According to series, 25% to 50% of GH patients are still diagnosed at the cirrhotic stage.
Liver cancer is a frequent complication in GH. Most cases are hepatocellular carcinomas (HCC) developed in a cirrhotic liver. However, some cases of HCC have been reported in GH patients with no cirrhosis, and frequency of cholangiocarcinoma reports is increasing. Two types of preneoplastic lesions have been reported and should be sought for at histological examination: (1) Iron-free-foci consist of sublobular nodular clusters of hepatocytes devoid of iron or with a low iron content within an otherwise iron-overloaded liver. Most often, they exhibit a proliferative pattern with either large or small cell dysplasia in 50% of cases. More than half the patients with IFF on their initial liver biopsy will develop. (2) Von Meyenburg complexes have also been reported as abnormally numerous in the surrounding liver of patients with GH complicated with cholangiocarcinoma.
Nonhemochromatotic genetic iron overload
The ferroportin disease:
The ferroportin disease
is a dominant hereditary iron overload disorder characterized by
phenotypic variability. In most cases, iron deposits are found
within macrophages (mesenchymal type) with no
Hereditary aceruloplasminemia: Hereditary aceruloplasminemia[17,18] is an exceptionnal disease transmitted as a recessive trait. Under the lens, iron is found predominantly in parenchymal cells. No case of liver cirrhosis has been described even in the most iron overloaded cases.
African iron overload : African iron overload is a rare disorder characterized by a mixed hepatic iron overload frequently complicated with cirrhosis. It is related to excessive iron intake, and likely underlaid by nonHFE genetic factors.
Excessive iron supply
When brought parenterally: (i.e. through multiple transfusions), iron is initially localized within Kupffer cells and portal macrophages. With time, it is usually redistributed towards surrounding parenchymal cells, which results in a mixed and heterogenous pattern.
In case of excessive chronic iron intake: mixed hepatic iron overload may develop as reported in elite road cyclists.
It is a frequent cause of mesenchymal hepatic siderosis related to a defect of iron release from Kupffer cells due to increased production of hepcidin. Iron deposits are usually sparse and distributed throughout the lobule.
Noncirrhotic chronic liver diseases
Dysmetabolic iron overload
Dios is a frequent
condition corresponding to the association of an unexplained hepatic
iron overload with usually normal transferrin saturation and
features of metabolic syndrome[21,22]. The histological
pattern of DIOS is mixed, both mesenchymal (throughout the entire
lobule) and parenchymal (predominating in periportal area).
Iron excess is usually mild and averages 100 mmol/g.
However, in 30% of cases, the hepatic iron concentration to age
ratio exceeds 2, a threshold previously considered as highly
suggestive of GH before the discovery of the HFE gene. Either
steatosis or steatohepatitis is present in 50% of cases. Bridging
fibrosis or cirrhosis is found in 12% of
Alcoholic liver disease: Mixed and mild hepatic siderosis is found in 5% to 20% of chronic alcoholics, even in the absence of cirrhosis. A direct effect of alcohol on hepcidin production could be involved.
Chronic hepatitis: Hepatic iron deposition is found in 35% to 56% of patients with chronic hepatitis. This was especially demonstrated in patients with chronic hepatitis C. The histological pattern is usually mesenchymal with frequent iron deposits in endothelial cells. Iron excess has been shown to be correlated with necrotico-inflammatory changes, and to decrease after interferon therapy. Moreover, iron removal before or at the time of interferon therapy could result in histological improvement, even in nonresponders.
Wilson disease: Mixed iron overload is frequently found in the liver of patients with Wilson disease. Its mechanism is likely multifactorial, and involves low serum ceruloplasmin levels, hemolysis, necrotico-inflammatory changes and cirrhosis.
Cirrhosis: Significant liver siderosis is found in 35 to 78% of patients with end-stage cirrhosis, irrespective of the cause of cirrhosis[4,5]. Iron deposits are mainly located within hepatocytes, predominate in remaining periportal areas, and, in some cases, can mimic GH. However, liver siderosis secondary to cirrhosis is distributed very heterogeneously from a nodule to another and absent from fibrous septa, biliary cells and vascular walls. This usually allows for correct diagnosis, and points to the need, in case of cirrhosis, for interpretating hepatic iron concentration according to histological findings. It is likely that nontransferrin bound iron (NTBI) plays a key role in the development of iron overload in cirrhosis. Indeed, in severe cirrhosis, serum tranferrin levels are low due to hepatic failure which results in increased saturation of tranferrin and, then, in the appearance of NTBI, a special form of iron that is avidly taken up by hepatocytes.
Hepatocellular carcinoma: Parenchymal or mixed iron overload is frequently present in the nontumorous part of the liver of patients with hepatocellular carcinoma (HCC), whether they have cirrhosis or not. This supports the (co)carcinogenic role of iron suggested by numerous experimental and epidemiological studies.
Porphyria cutanea tarda: Mixed, heterogeneous and mild hepatic siderosis is encountered in 60% to 70% of patients with porphyria cutanea tarda (PCT). Searching for intrahepatocytic inclusions when faced with mixed iron overload is suitable, because the clinical diagnosis of PCT may be missed.
Dyserythroipioiesis: In well compensated dyserythropoietic syndromes, intestinal iron absorption is increased secondary to impairment in iron incorporation into red cell precursors. With time, severe hepatic iron overload resembling GH may develop, even in the absence of blood transfusions. Once transfusions are required, iron deposits in both parenchymal and mesenchymal cells resulting in a mixed pattern.
Place of liver biopsy in the management of iron overload disorders
Recent progress in both imaging and genetics have resulted in reducing the role of liver biopsy in the diagnosis of hepatic iron overload.
Positive diagnosis: MRI allows for a specific and sensitive detection and reliable quantification of excessive hepatic iron content when comprised between twice the upper limit of normal and 300 mmol/g dry weight. Then, liver biopsy is no longer necessary to ascertain iron overload.
Aetiological diagnosis: MRI also allows for classifying iron excess as parenchymal, mesenchymal or mixed according to organ iron deposition (liver and/or spleen and/or spine). Then it provides guidance for the aetiological diagnosis process, especially with respect to the first choice of genotyping tests. This was recently well illustrated by Pietrangelo et al in patients with ferroportin mutations. Moreover, in these patients, MRI contributed to establish phenotypic/genotypic correlations, and to understand the pathophysiology of the disease by demonstrating, beside the classical mixed pattern of iron accumulation, a nonclassical parenchymal pattern related to the N144H ferroportin mutation.
Disease severity: Once the positive and aetiological diagnosis of hepatic iron overload has been made, it is mandatory to assess the degree of hepatic damage, that is to determine whether severe fibrosis has developed or not. This will remain the major goal of liver biopsy as long as noninvasive tests for fibrosis-including biochemical markers, and elastometry-are not validated in patients with iron overload syndromes.
Currently, indication of liver biopsy can be discussed according to the phenotypic presentation of iron excess.
In case of hemochromatotic phenotype (= increased transferrin saturation with parenchymal iron deposition), performing liver biopsy depends on HFE genotyping:
In C282Y homozygotes, liver biopsy is no longer necessary for diagnosis, but remains suitable with respect to prognosis. Guyader et al demonstrated that, when the liver was not clinically enlarged AND serum ferritin level was lower than 1000 ng/mL AND serum AST level was normal, there was never significant liver fibrosis (i.e. grade 3 or 4 fibrosis according to the METAVIR scoring system). On the contrary, when one, two or all these conditions were not met, there was a significant risk of fibrosis calculated as 1/(1 + exp [-(-6.7620 + 3.2934 AST(iu/l) + 0.0013 ferritin(ng/ml) + 2.5317 hepatomegaly(0 :1)]). Accuracy of Guyader’s algorithm was further validated in Canadian patients. Since then, other equations of prediction of (non)fibrosis have been proposed[33,34] based upon age and serum ferritin level or serum ferritin level, serum AST level and platelets count. But, either they were not further correctly validated or they were not as simple for clinical use as Guyader’s algorithm. Then, currently there is a global consensus to perform liver biopsy for fibrosis evaluation in C282Y homozygotes with either increased liver size, serum ferritin level higher than 1000 ng/mL or abnormal serum AST levels except when the diagnosis of cirrhosis is clinically obvious or when the predictive equation gives a risk close to 100%. Recently, Powell et al showed that obesity-related steatosis may have a role as a cofactor in liver injury-especially fibrosis-in C282Y homozygotes. This has clinically important implications, but does not modify indications of liver biopsy in these patients.
In a C282Y-H63D compound heterozygote presenting with mild increase in transferrin saturation-usually comprised between 45% and 60% and in serum ferritin-usually < 500 ng/mL and with no biochemical abnormalities and clinical liver symptoms, it can be reasonably assumed that the HFE genotype is responsible for the abnormalities in iron metabolism, and that the patient is free of risk of fibrosis. Then, liver biopsy is not necessary.
In all other cases, the diagnostic procedure must be conducted irrespective of HFE genotype. Indeed, C282Y and H63D heterozygosity as well as H63D homozygosity not only are frequent (up to 1/3 of subjects in European general populations), but do not result, in a given subject, in clinically relevant perturbances of iron metabolism even if large genotyping studies[36-39] have shown that some of them induced slight but significant increase in serum ferritin and/or transferrin saturation. Then, liver biopsy remains suitable to search for an additional cause of either iron overload or chronic liver disease. The most frequent finding is heterogeneous parenchymal iron overload complicating alcoholic or viral liver cirrhosis[4,5,40]. Much more rarely, liver biopsy discovers marked iron overload suggesting an associated mutation on another gene involved in iron metabolism. In that case, the precise description of iron deposition, and associated lesions may participate in defining the choice of diagnostic molecular tests: mesenchymal or mixed iron deposition with no significant fibrosis is suggestive of ferroportin disease (which sometimes presents with TS > 60%) while parenchymal iron overload suggests the diagnostic of juvenile haemochromatosis in a young adult with usually severe fibrosis (mutation on the hemojuvelin or hecidin gene) and that of transferrin receptor 2-related haemochromatosis in an adult with or without fibrosis.
In the absence of hemochromatotic phenotype (= low, normal or slightly elevated transferrin saturation), the question is whether increased serum ferritin levels are related to iron overload or not. MRI can replace liver biopsy to answer this question, and histological examination of the liver can be restricted to patients with significant iron deposition at MRI (i.e. hepatic iron concentration > 100 mmol/g dry weight) and/or elevated serum transaminase levels and/on abnormal noninvasive predictive tests of fibrosis. In such a situation, the most frequent finding is mild and mixed iron overload with either metabolic or alcoholic steatohepatitis or chronic hepatitis C or porphyria cutanea tarda. Much more rarely, histological examination reveals marked iron overload with no significant fibrosis corresponding to ferroportin disease (mesenchymal type-normal or sligthly increased transferrin saturation) or to hereditary aceruloplasminemia (parenchymal type-low transferrin saturation).
Due to the widespread use of genotyping, of MRI and of noninvasive predictive markers of hepatic fibrosis, liver biopsy is less and less performed for diagnostic and prognostic purposes in C282Y homozygous patients. Conversely, it remains often necessary in other patients in order to guide the etiological diagnosis of hepatic iron overload by describing and semi-quantifying iron excess and by assessing associated lesions.
1 Imbert-Bismut F, Charlotte F, Turlin B, Khalil L, Piton A, Brissot P, Le Charpentier Y, Delattre J, Opolon P, Deugnier Y, Poynard T. Low hepatic iron concentration: evaluation of two complementary methods, colorimetric assay and iron histological scoring. J Clin Pathol 1999; 52: 430-434 PubMed
2 Turlin B, Deugnier Y. Evaluation and interpretation of iron in the liver. Semin Diagn Pathol 1998; 15: 237-245 PubMed
3 Deugnier YM, Loreal O, Turlin B, Guyader D, Jouanolle H, Moirand R, Jacquelinet C, Brissot P. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology 1992; 102: 2050-2059 PubMed
4 Deugnier Y, Turlin B, le Quilleuc D, Moirand R, Loreal O, Messner M, Meunier B, Brissot P, Launois B. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis. Am J Surg Pathol 1997; 21: 669-675 PubMed
5 Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology 1997; 112: 882-888 PubMed
6 Brissot P, Bourel M, Herry D, Verger JP, Messner M, Beaumont C, Regnouard F, Ferrand B, Simon M. Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods. Gastroenterology 1981; 80: 557-565 PubMed
7 Olynyk JK, O'Neill R, Britton RS, Bacon BR. Determination of hepatic iron concentration in fresh and paraffin-embedded tissue: diagnostic implications. Gastroenterology 1994; 106: 674-647 PubMed
8 Scheuer P, Williams R, Muir A. Hepatic pathology in relatives of patients with haemochromatosis. J Pathol Bacteriol 1962; 84: 53-64
9 Rowe JW, Wands JR, Mezey E, Waterbury LA, Wright JR, Tobin J, Andres R. Familial hemochromatosis: characteristics of the precirrhotic stage in a large kindred. Medicine (Baltimore) 1977; 56: 197-211 PubMed
10 Deugnier YM, Guyader D, Crantock L, Lopez JM, Turlin B, Yaouanq J, Jouanolle H, Campion JP, Launois B, Halliday JW. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases. Gastroenterology 1993; 104: 228-234 PubMed
11 Deugnier YM, Turlin B, Powell LW, Summers KM, Moirand R, Fletcher L, Loreal O, Brissot P, Halliday JW. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology 1993; 17: 30-34 PubMed
12 Turlin B, Deugnier Y. Histological assessment of liver siderosis. J Clin Pathol 1997; 50: 971 PubMed
13 Loreal O, Haziza-Pigeon C, Troadec MB, Detivaud L, Turlin B, Courselaud B, Ilyin G, Brissot P. Hepcidin in iron metabolism. Curr Protein Pept Sci 2005; 6: 279-291 PubMed
14 Morcos M, Dubois S, Bralet MP, Belghiti J, Degott C, Terris B. Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum. Am J Clin Pathol 2001; 116: 738-743 PubMed
15 Deugnier YM, Charalambous P, Le Quilleuc D, Turlin B, Searle J, Brissot P, Powell LW, Halliday JW. Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients. Hepatology 1993; 18: 1363-1369 PubMed
16 Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis 2004; 32: 131-138 PubMed
17 Kono S, Suzuki H, Takahashi K, Takahashi Y, Shirakawa K, Murakawa Y, Yamaguchi S, Miyajima H. Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of aceruloplasminemia. Gastro-enterology 2006; 131: 240-245 PubMed
18 Miyajima H. Genetic disorders affecting proteins of iron and copper metabolism: clinical implications. Intern Med 2002; 41: 762-769 PubMed
19 Gordeuk VR. African iron overload. Semin Hematol 2002; 39: 263-269 PubMed
20 Deugnier Y, Loreal O, Carre F, Duvallet A, Zoulim F, Vinel JP, Paris JC, Blaison D, Moirand R, Turlin B, Gandon Y, David V, Megret A, Guinot M. Increased body iron stores in elite road cyclists. Med Sci Sports Exerc 2002; 34: 876-880 PubMed
21 Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, Le Gall JY, Brissot P, David V, Deugnier Y. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117: 1155-1163 PubMed
22 Moirand R, Mortaji AM, Loreal O, Paillard F, Brissot P, Deugnier Y. A new syndrome of liver iron overload with normal transferrin saturation. Lancet 1997; 349: 95-97 PubMed
23 Turlin B, Mendler MH, Moirand R, Guyader D, Guillygomarc'h A, Deugnier Y. Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients. Am J Clin Pathol 2001; 116: 263-270 PubMed
24 Bridle K, Cheung TK, Murphy T, Walters M, Anderson G, Crawford DG, Fletcher LM. Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 2006; 30: 106-112 PubMed
25 Guyader D, Thirouard AS, Erdtmann L, Rakba N, Jacquelinet S, Danielou H, Perrin M, Jouanolle AM, Brissot P, Deugnier Y. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol 2007; 46: 587-955 PubMed
26 Brissot P, Loreal O. Role of non-transferrin-bound iron in the pathogenesis of iron overload and toxicity. Adv Exp Med Biol 2002; 509: 45-53 PubMed
27 Turlin B, Juguet F, Moirand R, Le Quilleuc D, Loreal O, Campion JP, Launois B, Ramee MP, Brissot P, Deugnier Y. Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver. Hepatology 1995; 22: 446-450 PubMed
28 Deugnier Y. Iron and liver cancer. Alcohol 2003; 30: 145-150 PubMed
29 Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V, Deugnier Y. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004; 363: 357-362 PubMed
30 Pietrangelo A. Non-invasive assessment of hepatic iron overload: are we finally there? J Hepatol 2005; 42: 153-154 PubMed
31 Pietrangelo A, Corradini E, Ferrara F, Vegetti A, De Jong G, Luca Abbati G, Paolo Arcuri P, Martinelli S, Cerofolini E. Magnetic resonance imaging to identify classic and nonclassic forms of ferroportin disease. Blood Cells Mol Dis 2006; 37: 192-196 PubMed
32 Guyader D, Jacquelinet C, Moirand R, Turlin B, Mendler MH, Chaperon J, David V, Brissot P, Adams P, Deugnier Y. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998; 115: 929-936 PubMed
33 Beaton M, Guyader D, Deugnier Y, Moirand R, Chakrabarti S, Adams P. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis. Hepatology 2002; 36: 673-678 PubMed
34 Morrison ED, Brandhagen DJ, Phatak PD, Barton JC, Krawitt EL, El-Serag HB, Gordon SC, Galan MV, Tung BY, Ioannou GN, Kowdley KV. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 2003; 138: 627-633 PubMed
35 Powell EE, Ali A, Clouston AD, Dixon JL, Lincoln DJ, Purdie DM, Fletcher LM, Powell LW, Jonsson JR. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005; 129: 1937-1943 PubMed
36 Moirand R, Jouanolle AM, Brissot P, Le Gall JY, David V, Deugnier Y. Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives. Gastroenterology 1999; 116: 372-377 PubMed
37 Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211-218 PubMed
38 Deugnier Y, Jouanolle AM, Chaperon J, Moirand R, Pithois C, Meyer JF, Pouchard M, Lafraise B, Brigand A, Caserio-Schoenemann C, Mosser J, Adams P, Le Gall JY, David V. Gender-specific phenotypic expression and screening strategies in C282Y-linked haemochromatosis: a study of 9396 French people. Br J Haematol 2002; 118: 1170-1178 PubMed
39 Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352: 1769-1778 PubMed
40 Villeneuve JP, Bilodeau M, Lepage R, Cote J, Lefebvre M. Variability in hepatic iron concentration measurement from needle-biopsy specimens. J Hepatol 1996; 25: 172-177 PubMed
41 Laine F, Bendavid C, Moirand R, Tessier S, Perrin M, Guillygomarc'h A, Guyader D, Calon E, Renault A, Brissot P, Turlin B, Deugnier Y. Prediction of liver fibrosis in patients with features of the metabolic syndrome regardless of alcohol consumption. Hepatology 2004; 39: 1639-1646 PubMed
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