Haemochromatosis

• Haemochromatosis is a disease of iron overload. Iron is absorbed in excess, transferrin becomes saturated, and iron is deposited in liver, pancreas, heart, joints and endocrine glands.
• Hereditary haemochromatosis is most often due to HFE C282Y homozygosity in people of northern European ancestry. H63D and non-HFE genes cause a smaller share, and juvenile forms begin in the second or third decade.
• Secondary iron overload follows repeated transfusion, ineffective erythropoiesis, chronic liver disease and other acquired causes. It behaves differently from hereditary disease, and iron tends to sit in macrophages and Kupffer cells before it becomes toxic.
• A raised transferrin saturation above 45% with an elevated ferritin is the usual first clue. HFE genotyping confirms the common form; MRI quantifies iron without a biopsy; biopsy is reserved for staging fibrosis when ferritin is above 1000 ng/mL or liver tests are abnormal.
• Weekly removal of 500 mL of blood is the main treatment. The induction target is a ferritin of 50 to 100 ng/mL; maintenance is usually 3 to 4 sessions a year. Iron chelators are reserved for people who cannot be phlebotomised or for secondary overload.
• Untreated iron overload can lead to cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, hypogonadism and infection with Vibrio vulnificus, Listeria monocytogenes and Yersinia enterocolitica.

By the end of this page you should be able to:

1. Explain normal iron absorption and the central role of hepcidin and ferroportin.
2. Distinguish hereditary haemochromatosis from secondary iron overload, and name the main HFE and non-HFE genotypes.
3. Recognise the clinical pattern of iron deposition: fatigue, MCP joint arthralgia, bronze skin, diabetes, hypogonadism, cardiomyopathy and cirrhosis.
4. Choose sensible initial tests and know when MRI and liver biopsy are needed.
5. Plan phlebotomy induction and maintenance, including when erythrocytapheresis or chelation is appropriate.
6. Explain prevention, family screening, low-resource care and the difference between the 2011/2019 and the 2022 guidance.

It is useful to think of iron overload as a spectrum rather than a single event. In HFE haemochromatosis three stages are recognised: genetic susceptibility with no iron excess; iron overload without tissue damage; and iron overload with fibrosis or organ damage. Not every C282Y homozygote reaches the third stage, and many carriers are found only because routine blood tests are abnormal. ^[2]

Hereditary and secondary iron overload are separated by cause, not by the blood tests alone.

Hereditary haemochromatosis is overwhelmingly a condition of populations of northern European origin. Genetic susceptibility (C282Y homozygosity) is seen in roughly 1 in 250 Caucasians, with the highest rates in Nordic or Celtic ancestry; fully expressed disease with end-organ damage is seen in fewer than 10% of those homozygotes. ^[2] The C282Y homozygote genotype explains about 80% to 85% of typical patients. ^[2] H63D alone is frequent but usually does not cause iron loading; H63D is most important as a compound heterozygote with C282Y. ^[2][4]

In large screening studies, roughly 30% of C282Y homozygotes have a normal ferritin level and no iron excess. ^[2] In one population study of about 30,000 Caucasian subjects aged 40 to 69 years, iron overload-related disease was present in 28% of male and 1% of female C282Y homozygotes. ^[2] The difference between the sexes reflects menstrual blood loss and pregnancy-related iron loss, which protect women until around menopause. ^[2][1] Even so, when women are diagnosed they present about a decade later than men in older series, and the sex ratio has equalised as screening improves. ^[2]

Non-HFE forms account for the remaining 10% to 15% of inherited iron overload. Juvenile haemochromatosis is rare but clinically severe, with symptoms in the 20s, hypogonadism and cardiomyopathy. ^[2][1] African iron overload is reported mainly in sub-Saharan Africa and can be worsened by dietary iron. ^[2]

There are no modifiable risk factors for hereditary haemochromatosis; the "risk" is being born with the genotype. Important acquired cofactors determine whether iron loading becomes dangerous:

• Alcohol excess greatly increases the chance of cirrhosis. In one study, more than 60% of haemochromatosis patients drinking over 60 g of alcohol per day had cirrhosis, compared with under 7% of lighter drinkers. ^[2]
• Viral hepatitis (hepatitis B or C), metabolic dysfunction-associated steatotic liver disease and porphyria cutanea tarda can all raise iron indices and may unmask a heterozygote. ^[2]
• Transfusion, parenteral iron, chronic haemodialysis and iron-loading anaemias are independent causes of overload. ^[2]
• The penetrance of C282Y homozygosity is incomplete, and modifier genes are being described. These modifiers partly explain why family members with the same mutation can have very different outcomes. ^[2][4]

The human body has no regulated way to excrete iron. Control is at the gut. Hepcidin, a 25-amino acid peptide made mainly by hepatocytes, is the principal iron-regulatory hormone. ^[2] It binds ferroportin, the iron exporter on duodenal enterocytes, splenic macrophages and hepatocytes, and internalises and degrades it. ^[2] When hepcidin is high, iron absorption and release are suppressed; when it is low, iron flows into the circulation. ^[2]

Hepcidin is induced by iron excess and inflammation and suppressed by iron deficiency, hypoxia and ineffective erythropoiesis. ^[2] Mutations in HFE, hemojuvelin (HJV), hepcidin (HAMP) or transferrin receptor 2 (TFR2) reduce hepcidin expression, so ferroportin stays on the cell surface and iron absorption continues inappropriately. ^[2] A second signalling layer uses bone morphogenetic protein 6: BMP6 binds its receptor on hepatocytes and, through SMAD, activates hepcidin; hemojuvelin acts as a BMP6 coreceptor. ^[2]

In HFE disease, transferrin saturation rises early. Once transferrin is saturated, non-transferrin-bound iron appears and is taken up avidly by hepatocytes, pancreatic beta cells, cardiomyocytes and endocrine cells. ^[1] That explains why liver, pancreas, heart and pituitary are the organs that suffer. ^[1]

Iron is not only stored; it is catalytic. Experimental iron overload produces lipid peroxidation, mitochondrial and lysosomal injury and profibrogenic signalling. ^[2] Kupffer cells activated by injured hepatocytes release cytokines that drive hepatic stellate cells to lay down collagen. ^[2] A small group of patients progress to cirrhosis and, once cirrhosis is established, to hepatocellular carcinoma. ^[2]

Iron deposition differs between hereditary and secondary disease. In hereditary haemochromatosis, iron loads hepatocytes in a periportal pattern early on. In secondary overload, iron appears first in Kupffer cells and macrophages, because the iron is delivered by transfusion or macrophage recycling rather than by diet. ^[1][3] That histological difference is one reason liver biopsy still has a role in non-HFE or mixed disease. ^[2][3]

The classic "bronze diabetes" picture is now a late presentation. Most patients are found by biochemical abnormalities or family screening before organ damage. ^[2] When symptoms do occur, they are non-specific and develop after the age of 40 in men and 50 in women. ^[1]

History:

• Fatigue and weakness, often described as apathy or brain fog. ^[1][2]
• Arthralgia, classically of the second and third metacarpophalangeal joints, sometimes with hook-like osteophytes and chondrocalcinosis. Larger joints (ankles, hips, knees) can also be involved. ^[1][2]
• Abdominal pain and right upper quadrant discomfort from hepatomegaly. ^[2]
• Loss of libido, impotence and amenorrhoea from hypogonadotropic hypogonadism. ^[1][2]
• Hypopituitarism, including growth-hormone deficiency, can occur in severe or juvenile disease. ^[1][2]
• Symptoms of diabetes (thirst, polyuria) and, later, complications. ^[1]
• Dyspnoea and palpitations from cardiomyopathy or arrhythmia. ^[1][2]
• Darker skin pigmentation, often described as bronze or slate-grey. ^[1]

Examination:

• Hepatomegaly, cutaneous stigmata of chronic liver disease, splenomegaly. ^[2]
• Arthritis, joint swelling and chondrocalcinosis. ^[2]
• Dilated or restrictive cardiomyopathy, congestive heart failure, arrhythmias. ^[1][2]
• Generalised increased pigmentation and koilonychia. ^[1][2]
• Testicular atrophy and hypogonadism. ^[2]
• Hypothyroidism in some patients. ^[2]

Organs that matter and organs that are spared:

• Liver involvement is the most common: about 75% of patients. ^[1]
• Pancreatic beta-cell injury leads to diabetes. ^[1]
• Cardiomyopathy is the second leading cause of death in haemochromatosis. ^[1]
• Hypogonadotropic hypogonadism is the most common endocrine dysfunction after diabetes; juvenile forms are especially prone to it. ^[1]
• Lung, kidney and eye are characteristically spared in hereditary disease, which helps separate iron overload from multi-organ storage disorders. Hypothyroidism and adrenal dysfunction can occur but are uncommon. ^[2]

Severity in series from the 1970s and 1980s shows how differently patients present when found late: cirrhosis on biopsy in 57% to 94%, hepatomegaly in 54% to 83%, skin pigmentation in 43% to 82% and clinical diabetes in up to 55%. ^[2] Modern series, with earlier detection, are much milder, which is exactly why sensitive biochemical screening matters. ^[2]

Iron overload should be suspected whenever aminotransferases are persistently abnormal, ferritin is high, or a patient has the joint, endocrine and cardiac pattern described above. The main task is to decide whether the overload is hereditary, secondary or only a biochemical epiphenomenon.

The initial screen is a transferrin saturation and a serum ferritin. Transferrin saturation is serum iron divided by total iron-binding capacity. In the 2011 AASLD guideline normal subjects have a saturation of about 20% to 50%, while asymptomatic and symptomatic haemochromatosis cohorts show 45% to 100% and 80% to 100% respectively. ^[2] Ferritin is not specific, but it correlates with body stores once inflammation is excluded. ^[2]

Contemporary thresholds differ slightly between guideline groups, which is worth stating plainly:

• AASLD materials use a transferrin saturation cut-off of 45%, identifying 97.9% to 100% of C282Y homozygotes. ^[3]
• The EASL 2022 review summarised in JCEH recommends genetic testing when ferritin is above 200 microg/L in females or above 300 microg/L in males AND transferrin saturation is above 45% in women or above 50% in men, or when a raised transferrin saturation persists without explanation. ^[4]
• In one large series, ferritin above 250 microg/L in men and above 200 microg/L in women was positive for 77% and 56% of C282Y homozygotes. ^[2]
• In the HEIRS screening study, ferritin was raised above 300 microg/L in men and above 200 microg/L in women in 88% of male and 57% of female C282Y homozygotes. ^[2]
• A ferritin under 200 ng/mL in premenopausal women and under 300 ng/mL in men and postmenopausal women, together with a transferrin saturation under 45%, argues against iron overload in 97% of cases. ^[1]

Serum iron in symptomatic haemochromatosis is often 180 to 300 microg/dL, rising above 100% transferrin saturation; even asymptomatic patients sit at 45% to 100% saturation with ferritin 120 to 1000 microg/L in women and 150 to 1000 microg/L in men. ^[2] Ferritin above 1000 microg/L separates patients at high risk of cirrhosis from those at low risk. ^[2]

Genetic testing is not a screening test for everyone; it is requested when iron studies are abnormal or when a first-degree relative is affected. ^[2][4] HFE C282Y is the principal mutation: homozygosity accounts for over 80% of clinically overt hereditary haemochromatosis. ^[2][4] H63D is no longer regarded as a disease-causing variant on its own; when iron overload is present with H63D homozygosity or compound C282Y/H63D, environmental and other genetic causes must be considered. ^[4] Between 14% and 30% of patients referred for phlebotomy are compound heterozygotes. ^[4]

A negative C282Y result does not end the hunt. Non-HFE genes can be tested with a panel including rare HFE variants, caeruloplasmin, BMP6, SLC40A1, HAMP, HJV, TFR2 and transferrin, especially when onset is early. ^[4] Ethnicity matters because HFE loss-of-function variants are a more significant cause of haemochromatosis in non-European populations. ^[4]

HFE testing should be offered to first-degree adult relatives, particularly of C282Y homozygotes. ^[4] For children of a proband, testing the other parent first can avoid unnecessary testing in the child. ^[2]

MRI is the best non-invasive tool for quantifying hepatic and cardiac iron. The paramagnetic properties of iron shorten T2* and T2 relaxation, producing signal loss that can be converted to hepatic iron concentration. MRI also separates hereditary from secondary patterns: hepatocyte-predominant (parenchymal) iron versus Kupffer-cell-predominant iron. ^[1][2] In suspected cardiac involvement, cardiac MRI is indicated, and it should be performed in all patients with juvenile haemochromatosis. ^[4]

Liver stiffness by transient elastography can rule out advanced fibrosis when the measurement is under 6.4 kPa, although the evidence base in haemochromatosis is limited. ^[4] Serum-based fibrosis scores such as FIB-4 have been proposed, but the thresholds appear lower than for other liver diseases. ^[4]

Biopsy is now mainly a staging tool, not a diagnostic one. ^[2][3]

• In C282Y homozygotes, biopsy is recommended if liver enzymes are raised or ferritin is above 1000 microg/L, to stage fibrosis and confirm cirrhosis. ^[2][4]
• When ferritin is under 1000 microg/L and liver enzymes are normal, fewer than 2% of C282Y homozygotes have cirrhosis in the absence of another risk factor such as alcohol or viral hepatitis. ^[2][3]
• Biopsy is also used for non-HFE phenotypes, where genetic panels are unrevealing, to assess hepatic iron concentration, iron staining pattern and fibrosis. ^[2][3]
• Biopsy can confirm advanced fibrosis, predict hepatocellular carcinoma risk and guide the need for variceal screening. ^[2]

Treatment means iron depletion. The main method is phlebotomy because it is cheap, safe, effective and removes about 200 to 250 mg of iron per 500 mL unit. ^[2][1] Early treatment, before cirrhosis and before diabetes, improves survival and can reverse fatigue, abdominal pain, skin pigmentation and insulin requirements. ^[2] Arthropathy, hypogonadism and established cirrhosis are much less responsive. ^[2]

Phlebotomy is stratified in some guidelines: start in C282Y homozygotes with ferritin above 300 microg/L in men and above 200 microg/L in women, plus a transferrin saturation of at least 45%. ^[3] Homozygotes with normal ferritin can be monitored with yearly iron studies and liver enzyme tests. ^[3]

• Remove 500 mL of whole blood weekly, or twice weekly if tolerated. ^[1][2][3]
• Check haemoglobin before each session; defer if it is 11 g/dL or lower. ^[1][2]
• Remove 1 to 2 units per session only when the routine is well established and the patient is stable. ^[2]
• Check serum ferritin after every 10 to 12 phlebotomies (about every 3 months). ^[2]
• Stop frequent phlebotomy when ferritin falls to 50 to 100 ng/mL. ^[1][2][3][4]
• Avoid overshooting into iron deficiency, because it is unnecessary and poorly tolerated. ^[2]
• Patients with advanced cardiac involvement need caution: rapid iron mobilisation can precipitate arrhythmia. ^[2]

The induction target of 50 ng/mL, and not lower, is one of the EASL 2022 changes. ^[4] Maintenance target thereafter is 50 to 100 ng/mL, with some flexibility for older or less tolerant patients. ^[4] Transferrin saturation should not be used to monitor response, because it may stay raised after ferritin reaches the target. ^[4]

About 30% of patients reaccumulate iron slowly or not at all; many need only 1 to 2 units per year, while others need monthly phlebotomy. ^[2] The AASLD practice resources quote maintenance phlebotomy every 3 to 4 sessions per year; EASL-based summaries similarly quote 3 to 4 times a year. ^[1] An alternative way of stating the same range, used in some protocols, is every 2 to 4 months depending on the ferritin trend. ^{[1] [3]} The ferritin target remains 50 to 100 ng/mL. ^[1][2]

Erythrocytapheresis removes red cells selectively, returning plasma and platelets, so it suits thrombocytopenic or hypoproteinaemic patients and those with cardiac disease, in whom haemodynamic fluctuation is a worry. ^[1][4] It is now recognised as an alternative induction therapy when equipment and expertise exist. ^[4] Some studies show fewer procedures, quicker iron removal and less fatigue, but the technique is expensive and not universally available. ^[1][4] Sessions are usually every 2 to 3 weeks, with a minimum post-procedure haemoglobin over 10 g/dL. ^[1]

Chelators are second-line for hereditary disease, when phlebotomy is impossible (inaccessible veins, severe anaemia, advanced cardiac iron overload) and first-line for transfusional overload. ^[2][4]

• Deferoxamine is given by continuous subcutaneous infusion, about 40 mg/kg per day for 8 to 12 hours overnight, 5 to 7 nights a week. Doses of 20 to 40 mg/kg per day are cited for secondary iron overload. ^[2]
• Deferasirox is an oral chelator with the most haemochromatosis evidence; ferritin fell at tolerable doses of about 10 mg/kg. ^[2][4]
• Deferiprone is an oral option, chiefly used where it is licensed for transfusional overload. ^[1]
• Chelation is toxic and is not first-line for hereditary disease. ^[1]

For severe systemic iron overload, iron chelation plus deferring further transfusion are the main tools; liver iron concentration is sometimes used to monitor response. ^[2]

Dietary iron restriction adds very little compared with phlebotomy: a low-iron diet removes 2 to 4 mg per day, whereas each phlebotomy mobilises 200 to 250 mg. ^[2] What matters is avoiding sources of harm:

• Avoid iron supplements and iron-fortified foods. ^[1][2]
• Avoid vitamin C supplements; pharmacological vitamin C accelerates iron mobilisation and can saturate transferrin. ^[1][2]
• Avoid alcohol completely if cirrhosis is present; otherwise restrict it. ^[1][4]
• Avoid raw or undercooked shellfish and seawater contact with broken skin because of Vibrio vulnificus, which can cause fulminant sepsis with roughly 50% mortality. ^[1][2][4]
• Reduce red meat. ^[1]
• Proton pump inhibitors can reduce non-haeme iron absorption and have been shown to reduce phlebotomy frequency, but they are off-label adjuvants, not first-line therapy. ^[4]

Family studies show biochemical and clinical expression in homozygous relatives, and population data show 28% of male and 1% of female C282Y homozygotes developing iron-related disease. ^[2] Screening of first-degree relatives is therefore a core task, not an afterthought. ^[2][4]

• Screen adult first-degree relatives with iron studies and HFE genotyping at a single visit. ^[2][4]
• In probands' children, test the other parent first; a normal result makes the child an obligate heterozygote. ^[2]
• C282Y heterozygotes and H63D heterozygotes can be reassured that progressive iron overload is unlikely, but remind them that these genotypes can still be cofactors in other liver diseases. ^[2]
• Relatives who carry C282Y homozygosity or compound heterozygosity with raised ferritin can start phlebotomy; if their ferritin is normal, yearly iron studies suffice. ^[2]
• Screening the general population is not recommended. ^[3]

Pregnancy removes 0.5 to 1 g of iron and is often well tolerated in mild to moderate haemochromatosis without advanced liver disease; phlebotomy can usually be paused. ^[4] If phlebotomy is continued it should be reduced to a target ferritin of 45 microg/L or more, because iron deficiency has adverse fetal effects. ^[4] Advanced fibrosis or cirrhosis increases both maternal and fetal risk and should be excluded before conception. ^[4] A higher incidence of pregnancy-induced hypertension and venous thromboembolism has been reported in pregnant haemochromatosis patients. ^[1]

HJV and HAMP mutations cause early, severe iron overload. Symptoms may appear in the 20s, and hypogonadism with cardiomyopathy dominates. ^[1][2] Cardiac MRI should be performed in all patients with juvenile haemochromatosis because cardiac involvement is highly prevalent. ^[4]

Untreated hereditary haemochromatosis shortens life. Sustained iron excess leads to:

• Cirrhosis and portal hypertension, which are not reversed by iron removal once established. ^[2]
• Hepatocellular carcinoma, responsible for about 30% to 45% of deaths in these patients. ^[1][2]
• Diabetes mellitus from pancreatic islet injury. ^[1]
• Dilated or restrictive cardiomyopathy, arrhythmia and heart failure; cardiomyopathy is the second leading cause of death. ^[1]
• Hypogonadotropic hypogonadism, impotence and amenorrhoea. ^[1]
• Arthropathy, particularly of the second and third metacarpophalangeal joints, with chondrocalcinosis. ^[1][2]
• Osteoporosis. ^[1]
• Increased susceptibility to bacterial infection: Listeria monocytogenes, Yersinia enterocolitica, Escherichia coli and Vibrio vulnificus are the most common culprits, because macrophage function is impaired and iron supports microbial growth. ^[1]
• Untreated disease carries roughly a 30% mortality within five years of clinical onset, from hepatocellular carcinoma, liver failure or heart failure. ^[1]

Prognosis has improved greatly with earlier diagnosis. Early treatment before cirrhosis and before diabetes substantially reduces morbidity and mortality. ^[2] Patients treated before cirrhosis can expect a life expectancy close to that of the general population. ^[1][2] Once cirrhosis or hepatocellular carcinoma have developed, survival falls sharply. ^[1][2] Liver transplantation is an option for end-stage disease; modern outcomes are comparable with other transplant indications when pre-operative iron depletion has been achieved. ^[2]

Both the AASLD practice materials and the EASL 2022 clinical practice guideline are referenced throughout this page (AASLD 2011 guideline, the AASLD clinical pearl summarised 2021 and linked 2022 updates; EASL 2022 CPG, reviewed in the open-access JCEH paper). ^[2][3][4][5]

Points of agreement:

• Haemochromatosis is suspected with a high transferrin saturation and an elevated ferritin. ^[2][4]
• C282Y homozygosity is the commonest genotype. ^[2][4]
• First-line treatment is phlebotomy, to a ferritin in the 50 to 100 ng/mL range. ^[2][4]
• Family screening of first-degree adult relatives is recommended. ^[2][4]
• Iron chelators are second-line or are reserved for secondary overload. ^[2][4]

Points where guidance differs or has changed:

• H63D: older practice treated H63D homozygosity or C282Y/H63D as a milder form of disease. EASL 2022 no longer regards H63D as a disease-causing variant on its own and recommends treating according to phenotype rather than genotype. ^[4]
• Biopsy: both now discourage routine diagnostic biopsy for iron; it is used for fibrosis staging when ferritin exceeds 1000 microg/L or liver enzymes are abnormal. ^[2][4]
• Treatment target: EASL 2022 set the induction target at 50 microg/L and the maintenance target at 50 to 100 microg/L, partly to avoid iron deficiency and poor tolerability. ^[4]
• Non-invasive fibrosis: EASL 2022 recommends transient elastography cut-offs (under 6.4 kPa ruling out advanced fibrosis) and FIB-4, while noting the evidence is limited. ^[4]
• HCC surveillance: EASL 2022 considers surveillance for bridging fibrosis (METAVIR F3, Ishak 4 to 5) as well as cirrhosis, though the recommendation is weak; AASLD guidance historically screens cirrhotic patients. ^[4]
• Monitoring: EASL 2022 advises against using transferrin saturation to monitor treatment, because it can remain raised after ferritin normalises. ^[4]
• Pregnancy: EASL 2022 holds that iron deficiency should be avoided and phlebotomy can usually be paused, reducing intensity only if continued. ^[4]

The 2011 AASLD guideline also remains useful for the phlebotomy algorithm (one 500 mL unit weekly or twice weekly, ferritin checked every 10 to 12 phlebotomies, stop at 50 to 100 microg/L) and for the 20 to 250 mg per unit of iron removed. ^[2]

• Transferrin saturation and ferritin are cheap and available in most settings; they are the first and often the only tests needed to raise suspicion. ^[1][2]
• HFE genotyping may be unavailable or unaffordable; where it is, a C282Y result is not necessary to treat a patient who clearly has iron overload and no other cause. ^[1][2]
• MRI for iron quantification is often unavailable. A ferritin above 1000 microg/L with abnormal liver tests is enough to justify biopsy where that is safer, or referral. ^[2][4]
• Phlebotomy is the cheapest treatment in the world and can be performed at any blood service or clinic. ^[1][2]
• Chelators are expensive and toxic; they should not be used where phlebotomy is possible. ^[1][2]
• Vibrio vulnificus sepsis is a risk wherever raw shellfish is eaten in coastal regions; advice to avoid raw seafood is free and life-saving. ^[1][2]
• Family screening can be offered without molecular testing by using iron studies and careful history. ^[2]
• Where no specialist liver service exists, patients with cirrhosis or suspected hepatocellular carcinoma should be referred on the basis of clinical suspicion, imaging and alpha-fetoprotein rather than waiting for a complete work-up.

Iron metabolism and hepcidin; chronic liver disease; cirrhosis and its complications; hepatocellular carcinoma; alcoholic liver disease; viral hepatitis; type 2 diabetes mellitus; arthropathy and osteoarthritis; sexual health and hypogonadism; thalassaemia, sickle cell disease and myelodysplastic syndromes; porphyria cutanea tarda; endocrine assessment and magnetic resonance imaging of the liver.