European Association for Study of the Liver (EASL) clinical practice guidelines on haemochromatosis

Abstract

The European Association for the Study of the Liver has recently updated guidance on haemochromatosis with a more extensive discussion on investigation and management.[ The new guidance focuses on non-invasive methods for fibrosis assessment and early diagnosis to include more extensive genetic testing if needed. Early diagnosis and treatment is vital as it reduces morbidity and mortality. We review this guideline and offer key updated messages with a focus on new developments since the last guidance and key aspects of current practice.

Key messages.

• Liver fibrosis should be chiefly assessed with non-invasive markers.

• A cut-off at 6.4 kPa on transient elastography to rule out advanced fibrosis is suggested but with limited evidence.

• A ferritin under 1000 µg/L is associated with a minimal risk of liver fibrosis.

• Advances in genetic testing have led to improved diagnosis of rarer genetic types although management can be complex.

• MRI can be used to differentiate primary from secondary cases of iron overload.

Commentary

Haemochromatosis is caused by genetic mutations leading to increased body iron accumulation, which mainly affects the liver. If untreated, liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) can result.¹ Mutations in the HFE gene, principally C282Y, are associated with the majority of cases. Rarely, haemochromatosis is caused by mutations in other genes, often called non-HFE haemochromatosis as listed in table 1. In the UK, prevalence of haemochromatosis varies, in Scotland and Northern Ireland, 1 in 113 people are affected and in England and Wales, 1 in 150 are affected.² Homozygosity for the C282Y variant of the HFE gene is present in approximately 80% of patients of European descent with the disease.

Table 1.

Types of hereditary haemochromatosis

Classification and protein	Gene	Inheritance	Frequency
Type 1 HFE	HFE	Autosomal recessive	Common
Non-HFE haemochromatosis
Type 2A haemojuvelin	HJV	Autosomal recessive	Rare
Type 2B hepcidin	HAMP	Autosomal recessive	Rare
Type 3 transferrin receptor 2	TFR2	Autosomal recessive	Rare
Type 4 ferroportin (type 4A loss of function and type 4B gain of function)	SLC40A	Autosomal dominant	Rare
Type 5	FTH1	Autosomal dominant	Rare. Identified in one family in Japan

Disease penetrance estimates among people with C282Y homozygosity in studies varies due to different definitions of disease. Disease penetrance is higher in males and with increasing age as iron accumulates over time.¹ In a recent UK Biobank cohort study of 2890 participants with C282Y homozygosity, haemochromatosis was eventually diagnosed in 21.7% of male and 9.8% of female patients by end of follow-up (mean of 7 years).³ A previous longer study (12 years) found similar rates of iron overload reported in men (28%) and lower in women (1.2%) with C282Y homozygosity.⁴ A systematic review found that up to 38%–50% of people with C282Y homozygosity may develop iron overload, with 10%–33% eventually developing haemochromatosis-associated morbidity.⁵ The latter statistic illustrates that not everyone with HFE-haemochromatosis will develop morbidity demonstrating a variable spectrum of disease among people who have been diagnosed.

Disease penetrance based on symptoms is difficult to calculate due to the non-specific nature of several symptoms. The non-specific nature of symptoms contributes to delays in diagnosis, which can be misdiagnosed for years. Of 1689 patients in a recent survey extrahepatic manifestations were common, 86.5% described arthritis or joint pain, 73.1% described fatigue, 38% depression, 60.4% brain fog, 70.4% skin problems and 57.3% sexual health problems.⁶ Clinical symptoms depend on the disease stage. In patients with severe or early-onset disease, extrahepatic manifestations include hypogonadotropic hypogonadism, impotence, hypothyroidism, skin pigmentation, diabetes, heart failure and cardiac arrhythmias. Results of a global patient survey revealed unmet needs in care and diagnosis. One-third of respondents were not offered liver function tests at diagnosis and almost a quarter of respondents said that immediate family members were not offered or were refused genetic testing, despite recommendations.⁷

Diagnosis

Figure 1 shows a suggested algorithm for diagnosis and testing. Patients with symptoms consistent with haemochromatosis, those with iron overload on liver biopsy or MRI and patients with abnormal liver transaminases should be tested. The first step is serum iron parameters. The clinical practice guideline (CPG) states that haemochromatosis is suspected with elevated transferrin saturation (TSAT) >45% and ferritin >200 in females and TSAT >50% and ferritin >300 in males and postmenopausal women.¹ Premenopausal women are considered to have a lower ferritin at diagnosis due to menstruation. The new CPG states that fasting does not improve diagnostic utility. Caution should be taken in interpretation as ferritin is an acute phase reactant and can be elevated in alcohol excess, metabolic syndrome, advanced cirrhosis and acute liver failure.

Figure 1.

Algorithm for diagnosis of suspected haemochromatosis. *Rare genetic testing to include at minimum HFE, HAMP, HJV, TFR2, SCL40A1, BMP6, CP and TF.

In those patients with high TSAT and high serum ferritin or persistent unexplained elevated TSAT; HFE genotype testing is the secondary step. Homozygosity for C282Y would confirm the diagnosis. In patients who are not C282Y homozygotes, diagnosis requires confirmation of hepatic iron overload on MRI and thereafter consideration of testing for rare genetic variants as well as excluding secondary causes of iron overload.¹ Differentiation of secondary causes of iron overload from haemochromatosis is a common clinical problem encountered as ferritin is often elevated in patients with non-alcoholic fatty liver disease. However, normally these patients do not have a transferrin saturation >45%. Table 2 lists secondary causes of iron overload.

Table 2.

Secondary cause of iron overload

Group	Disease
Liver diseases	Hepatitis B and C, alcohol-related liver disease, NAFLD
Haematological	Haemolytic anaemias, for example, beta-thalassaemia, porphyria cutanea tarda
Iatrogenic	Excessive iron supplementation Chronic transfusion
Others	Metabolic syndrome

NAFLD, non-alcoholic fatty liver disease.

The CPG states that phlebotomy has not been conclusively proven in studies to be beneficial in patients with iron overload related to metabolic liver disease.¹ Therefore, correct diagnosis is needed. As well as genetic testing, MRI helps differentiate between the two groups as shown in table 3. The accumulation of iron leads to signal loss in the affected tissues on MRI, particularly with the T2*-weighted sequences.⁸

Table 3.

Differences between primary and secondary causes of iron overload on MRI

Condition	MRI findings
Primary iron overload	Reduction in signal intensity in the liver but not spleen or bone marrow. Secondary imaging features include hepatomegaly, cirrhosis and signs of heart failure. Additionally, MRI can give non-invasive estimates of hepatic iron concentration.
Secondary iron overload disorders	Reduction in signal intensity in liver and spleen. Additionally haemosiderosis disorders, for example, thalassaemia presents with iron deposition mainly in spleen/bone marrow.

Understanding of genes that cause hereditary haemochromatosis has improved. The CPG outlines the minimum gene set for the assessment of haemochromatosis to include the classical five genes that cause types 1–4 haemochromatosis; HFE, HAMP, HJV, TFR2 and SCL40A1 (table 1). Additionally, they include three other genes: bone morphogenetic protein 6 (BMP6), which ultimately leads to the upregulation of hepcidin gene transcription and leads to a haemochromatosis like phenotype; Caeruloplasmin (CP) gene where homozygous mutations result in Hereditary Acaeruloplasminaemia, and TF mutations (encoding transferrin), causing an absence of transferrin-bound iron available for erythroid cells and decrease in hepcidin expression. The latter two mutations cause low plasma transferrin levels, anaemia but excess systemic iron.⁹ Of note, anaemia is not a feature of haemochromatosis, which is a differentiating feature from these conditions.

Clinical exome sequencing and panel gene sequencing can be used to cover even more genes, but results may be difficult to interpret as the phenotypes of these diseases are variable. Decisions on treatment should consider the phenotype, family history, coexisting diseases and lifestyle. Testing for the H63D variant of the HFE gene is controversial. H63D homozygosity or combination H63D/C282Y is associated with mild iron overload. However, in the presence of additional risk factors for liver disease, this can occasionally result in clinically significant iron overload but not to the extent of C282Y homozygotic patients.¹ First degree adult relatives should be tested for these variants and a particular focus should be given to siblings of haemochromatosis patients as they are at the highest risk.

Management

Staging of liver fibrosis

All patients should be assessed for the degree of fibrosis. FIB-4 is a well-evaluated serum-based marker for liver fibrosis assessment that is simple to use. A limited number of studies have evaluated its use but with lower thresholds than in other disease. The CPG recommends using transient elastrography with a cut-off at 6.4 kPa to rule out advanced fibrosis but with weak evidence.¹ A small single-centre study using transient elastography reported a high negative predictive value for excluding advanced liver fibrosis, but larger studies are needed.¹⁰ Evidence from large scale studies shows that when ferritin is under 1000 ug/L, the risk of severe fibrosis is minimal.¹ However, this is difficult to interpret in the presence of other chronic diseases. It is suggested that if serum ferritin is over 1000 µg/L or liver enzymes are increased, a liver biopsy can be considered to clarify the stage of disease where this is unclear from non-invasive tests. In this context, liver biopsy is rarely done to stage fibrosis.

Specific therapy

Iron depletion therapy with therapeutic phlebotomy is the first-line treatment for haemochromatosis. In the early stages, phlebotomy will improve fatigue, prevent or halt liver fibrosis, reverse cardiac disease and normalise life expectancy. There is evidence that phlebotomy leads to regression of liver fibrosis and cirrhosis in a subset of patients.¹ In a retrospective study, there was regression in 70% of F3 patients and 20% of F4 patients after a median 9.5 years.¹¹ Suggested targets are ferritin of <50 µg/L during induction and 50–100 µg/L ferritin during the maintenance phase. In the CPG, the panel commented that a more relaxed maintenance target of ferritin of <200 µg/L for women and <300 µg/L for men could be allowed, recognising that ferritin of under 50 µg/L is poorly tolerated by elderly patients. This is usually achieved by phlebotomy of 500 mL of blood every 1–2 weeks initially followed by 2–4 monthly sessions. If haemoglobin (Hb) falls below 120 g/L then phlebotomy intervals are increased and if Hb falls below 110 g/L then phlebotomy is discontinued temporarily. Iron deficiency needs to be avoided.

Erythrocytaphereis is an alternative therapy whereby whole blood is extracted from the patient, the red blood cells are separated and the remaining blood is returned to the patient. Studies have shown that fewer procedures are required than phlebotomy with a reduction in cost at induction. It reduces fatigue and serum iron parameters more effectively than a sham procedure.¹² This therapy depends on availability and the patient’s needs

Iron chelating agents are available in selected cases as a second-line treatment after careful risk assessment by specialist centre. In juvenile cases, these agents may be necessary in cardiac disease and case reports exist. Inaccessible veins, needle phobia and life-threatening cardiac iron overload are indications. Treatment with deferoxamine, off label deferasirox (DFX) and deferiprone have been described but evidence is very limited. DFX is the most studied and tolerated at low doses in a phase II trial of 10 patients with haemochromatosis.¹³ Proton pump inhibitors can be a useful addition as they reduce non-heme iron absorption but not as monotherapy.

Hepatoma screening

In their CPG, European Association for the Study of the Liver (EASL) suggests that patients with cirrhosis and advanced fibrosis should be enrolled in a hepatoma screening service. Patients with F3 fibrosis may be considered for screening based on evidence that patients with chronic hepatitis C and bridging fibrosis are at risk of HCC. In a recent UK biobank study, C282Y homogeneous male patients were shown to have a significantly increased risk of incidental primary hepatic malignancy (7.2%) and all-cause mortality (19.5%) compared with males without the variant (0.6% and 15.1%, respectively). Females with the C282Y alleles did not have a significant statistical association with HCC.³ A further study showed increased rate of HCC among patients who were homozygous for C282Y and the H63D/C282Y compound heterozygotes, with an increased all-cause mortality.¹⁴ The overall prevalence of HCC is contentious depending on the type of study reviewed, the EASL guidance states that in patients diagnosed with haemochromatosis prevalence is approximately 10%–30% almost exclusively in cirrhosis and this is independent of iron depletion.¹ HCC screening is cost-effective and should be offered to all haemochromatosis patients with advanced fibrosis and cirrhosis

Extrahepatic diseases

Extrahepatic diseases should be assessed and investigated. Joint disease is a common problem and does not respond well to phlebotomy. Common joints affected are ankles and the second and third metacarpal joints. Pathologically, it is similar to osteoarthritis except with a faster cartilage destruction. Treatment is with analgesia, physiotherapy and joint replacement. Incidence of joint replacement is higher in patients who have haemochromatosis. Management of other extrahepatic disease is discussed in the CPG but are out of scope of this review.

General approach

The management of haemochromatosis should include dietary and lifestyle advice. Control of cofactors of liver disease and dietary advice are specified in table 4.

Table 4.

Cofactors to be avoided in haemochromatosis

Factor	Advice
Alcohol	Patients with cirrhosis should avoid alcohol. Otherwise, alcohol should be limited especially during iron depletion phase.
Fruit juices and citrate foods	Should be consumed in moderation
Iron supplementation	Avoided as well as fortified foods
Vitamin C supplementation	Avoided
Red meat consumption	Limited
Raw or undercooked shellfish	Avoided consumption and handling due to the risk of Vibrio vulnificus infection that can be life-threatening
Obesity	Weight control advised to prevent the coexistence of NAFLD and which has been shown to increase morbidity

NAFLD, non-alcoholic fatty liver disease.

Further research

Studies are currently limited in haemochromatosis. Research in this area is to be encouraged to produce more evidence-based recommendations. Specifically, studies reviewing the thresholds for non-invasive detection of advanced fibrosis in haemochromatosis is needed. In addition, the frequency of assessment needs to be determined. Finally, further research is needed on alternative therapies such iron chelating agents in patients who cannot tolerate phlebotomy.

Conclusion

Treatment for haemochromatosis with phlebotomy has been proven to reverse cases of liver fibrosis and impacts mortality and morbidity in this cohort of patients. Therefore, early diagnosis and management is of utmost importance. Non-invasive tests to stage fibrosis are simple to use but more evidence is needed in haemochromatosis. Symptoms such as fatigue and joint disease are common and continue to significantly affect quality of life and should be actively managed. Phlebotomy remains the mainstay of treatment. Here, we provide a summary of the new guidelines, but we ask you to refer to the full guidance for a more detailed overview on the management of this condition. Adoption of the CPG would foster early diagnosis of haemochromatosis and appropriate treatment of this complex group of patients, which would reduce their progression to cirrhosis and morbidity, with its attendant complications and costs to healthcare providers.

Ethics statements

Patient consent for publication

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