Diagnosis and management of hereditary hemochromatosis: lifestyle modification, phlebotomy, and blood donation Free

A 56-year-old Caucasian man presented to the general practitioner for fatigue experienced over the last few months. His family and past medical history were unremarkable. The physical examination showed mild hepatomegaly but no skin discoloration, scleral jaundice, edema, splenomegaly, or ascites. He did not take any medication or illicit drugs; his alcohol intake was moderate (1 to 2 drinks daily). No other risk factor for liver disease was apparent. His lifestyle was sedentary, and his body mass index was 25.3  kg/m². Initial blood tests showed a normal complete blood count (hemoglobin [Hb] level, 15.9  g/dL; mean corpuscular volume, 98 fL), C-reactive protein, AST, albumin level, glucose level, and prothrombin time. Hyperferritinemia (890  µg/L; normal value <300) and mildly increased ALT (46  U/L; normal value <40) were noted. The patient was referred to our center for a suspected iron overload (IO) disorder.

The discovery of hepcidin at the beginning of this century was a turning point in understanding iron homeostasis disorders.^1,2 Nowadays, the term hemochromatosis is reserved for a group of genetically determined IO disorders sharing the common pathophysiology of insufficient hepcidin production or activity in the absence of a primary red blood cell disorder.³ This specification is important to distinguish hemochromatosis from other disorders due to hepcidin suppression by factors released during ineffective erythropoiesis, like non–transfusion-dependent thalassemias or myelodysplastic syndromes.^3-5 The liver hormone hepcidin physiologically maintains body iron content in the optimal range of 3 to 4 g by negatively modulating ferroportin, the main cellular iron exporter.² Insufficient ferroportin inhibition in duodenal enterocytes leads to lifelong hyperabsorption of dietary iron that accumulates as humans lack mechanisms for excreting excess iron. Central to the pathogenesis of hemochromatosis is the expansion of the plasma iron pool, also due to the uncontrolled release by macrophages (Figure 1), resulting in increased transferrin saturation (TSAT). Values above 45% to 50% represent a diagnostic hallmark, far more than hyperferritinemia. Exceeding the transferrin-binding capacity promotes the formation of non–transferrin-bound iron, which is avidly taken up by hepatocytes, cardiomyocytes, and endocrine cells,⁶ where it causes damage likely through oxidant stress and/or ferroptosis.⁷ 

Table 1 shows the classification of hemochromatosis proposed by the International BIOIRON Society in 2022, now universally adopted.⁸ Apart from the genes encoding the key players of the hepcidin/ferroportin axis (HAMP and SLC40A1), HFE and TFR2 encode membrane proteins involved in sensing iron levels for homeostatic hepcidin regulation. HJV encodes a bone morphogenetic protein (BMP) coreceptor (Figure 1). The exact molecular mechanisms underlying hepcidin regulation are still incompletely understood (reviewed elsewhere).⁹ All hemochromatosis forms are autosomal recessive, except for dominant ultrarare gain-of-function SLC40A1 mutations leading to hepcidin resistance, which functionally recapitulates hepcidin deficiency. SLC40A1 loss-of-function mutations cause ferroportin disease, a distinct disorder characterized by normal TSAT, predominant macrophage iron accumulation, and low to normal Hb levels, possibly resulting in poor phlebotomy tolerance.^3,10 In hemochromatosis, conversely, macrophages are generally iron-poor due to uncontrolled ferroportin release.¹⁰ The most common hemochromatosis form is, by far, HFE related due to homozygosity for the p.Cys282Tyr (C282Y) variant of Celtic origin,⁷ present in more than 80% of patients of Northern European descent. The other forms are rare and collectively designed as “non-HFE.” The clinical manifestations are common to all hemochromatosis types but vary from asymptomatic mild elevation of iron tests to multiorgan failure (Figure 2). This is mainly related to the penetrance of the genetic defect, minimal in HFE and maximal in HJV and HAMP (also called “juvenile” forms). The C282Y disrupts a cysteine bond on the HFE protein, preventing its membrane localization. This blunts hepcidin response to increased serum iron, but hepcidin baseline levels are only slightly reduced or inappropriately normal.¹¹ This mild defect explains the long-delayed onset of HFE-H so that only a minority of C282Y homozygotes, prevalently males after the fourth through sixth decade, develop a clinical disease. The testosterone inhibition of hepcidin also likely contributes to the different gender penetrance.¹² Iron losses with menses generally protect females until menopause. HFE-H resembles a multifactorial rather than a monogenic disorder. Acquired cofactors like alcohol and hepatitis C virus, which both inhibit hepcidin synthesis, as well as other causes of liver morbidity, especially metabolic-associated fatty liver disease (MAFLD), amplify the genetic defects.¹² As MAFLD is estimated to affect approximately 25% of the world's adult population,¹³ the coexistence with HFE-H is anything but rare, underscoring the relevance of lifestyle modification. Genetic modifiers also play a role. A recent analysis from the UK Biobank (including 2890 C282Y homozygotes) has shown a significant contribution of a polygenic risk score built up with common polymorphisms in many iron-regulating genes.¹⁴ The risk of developing clinically relevant IO in subjects with the relatively common C282Y/H63D HFE genotype is exceedingly low unless cofactors clearly predominate.^3,7,8 

At the opposite end of the spectrum, HJV (and HAMP) mutations impair the major regulatory axis, resulting in very low to undetectable hepcidin levels (Table 1). In general, non-HFE hemochromatosis is characterized by high penetrance in both genders with minimal or no influence by cofactors, early onset (second through third decade for HJV and HAMP, third through fourth for TFR2), and predominant hypogonadism and heart failure.^15,16 Consanguinity is not infrequent, and mutations are distributed worldwide. Due to genetic heterogeneity, digenic inheritance is possible, and some cases remain molecularly undefined after extensive next-generation sequencing (NGS) analyses.³ 

This middle-aged man presented with mild nonspecific symptoms and hyperferritinemia, a common cause of hematological consultation with a wide differential diagnosis.¹⁷ Ferritin can increase because of inflammation, cytolysis, and several inherited or acquired metabolic alterations.^18,19 Only a minority of patients have a true IO disorder. The differential diagnosis is based on clinical history and the measurement of TSAT.^3,4,17 Metabolic hyperferritinemia (MHF, according to a recent consensus statement) is by far the most common cause in daily practice.²⁰ TSAT is typically normal, and the patient shows 1 or multiple dysmetabolic features, including MAFLD (Figure 3).²¹ The pathogenesis of MHF is complex and incompletely understood, likely reflecting subtle alterations of iron trafficking and/or inflammation,²⁰ with poor correlation with histologically proven liver iron deposits.²² No clear benefit for iron depletion has been demonstrated. Rather, as MHF is consistently associated with the risk of cardiovascular complications (particularly if ferritin is >500  mg/L), lifestyle amelioration is mandatory and often reduces ferritin.²² Patients with the triad high ferritin/normal TSAT/absence of dysmetabolic features fall in the category of “unexplained hyperferritinemia” related to rare disorders and should be referred to specialized centers.^3,23 

In the index case, elevated TSAT (88%) indicated HFE-H as the likely diagnosis. The first-level genetic test confirmed C282Y homozygosity.

Appropriate staging is crucial after the diagnosis of hemochromatosis. Nowadays, most patients are diagnosed in an early or preclinical phase due to increased awareness and iron studies prescribed during “routine” analyses (Figure 2).²⁴ Except for the rare “juvenile” forms, hemochromatosis is generally a mild disease with an excellent prognosis. Advanced liver fibrosis (ALF) or cirrhosis implies a less favorable prognosis and the need for surveillance for hepatocellular carcinoma (HCC) even after iron depletion.^4,23 Tools for staging are summarized in Figure 4. Arthropathy and/or ferritin levels higher than 1000  mg/L can be informative, being associated with ALF.^4,23,25 Noninvasive tools recently proposed include FibroScan and simple scores like FIB-4/APRI but require validation in large cohorts.^4,23 

Magnetic resonance is widely used to estimate liver iron content and iron in the heart and pancreas.^3,4 Different algorithms based on signal alteration induced by ferromagnetic iron are used according to local equipment and expertise.²⁶ A liver biopsy is now reserved for cases with equivocal results after noninvasive evaluations. Extrahepatic complications should be searched in patients with advanced disease or symptoms suggesting organ damage.

We did not perform further evaluations in our patient with a ferritin level lower than 1000  mg/L, no symptoms, and reassuring tests for ALF (FIB-4 score and FibroScan).

Notwithstanding the advance in hemochromatosis' pathophysiology, phlebotomy that mobilizes iron for erythropoiesis remains the mainstay of treatment.^4,23,27 It is relatively easy, cheap, and highly effective in most patients. The classical induction, maintenance, and monitoring schedules are summarized in Table 2. In the index case, the ferritin target (50  mg/L) was reached after 29 phlebotomies (corresponding to ~4.8  g removed iron). Tolerance was excellent and the fatigue resolved. Note that the patient's high-normal Hb level and mean corpuscular volume values are frequent in HFE-C282Y individuals,^3,8,28 reflecting a tendency to sustained erythropoiesis, likely contributing to their unique tolerance of phlebotomies. Maintenance phlebotomy to avoid reaccumulation was 3 per year, with on-target ferritin levels (50-100  mg/L) and normal transaminases. The patient was eventually enrolled as a blood donor according to local protocol.⁴ The benefits of phlebotomy in hemochromatosis have been systematically reviewed.²⁹ Improved survival was reported in patients adequately phlebotomized.²⁹ Reversal of liver fibrosis and sometimes even cirrhosis is documented,^4,23 significantly reducing the long-term risk of HCC.³⁰ Current guidelines suggest that all patients with high ferritin (>200 or >300  mg/L in females and males, respectively), even if asymptomatic, should be treated to prevent progressive iron accumulation.^4,23,31 Management during pregnancy should be individualized, but most patients can suspend phlebotomy.⁴ 

The only clinical manifestation that may not respond to phlebotomy is arthropathy,⁴ nowadays a major determinant of impaired quality of life.³² Occasionally, it can appear after successful iron depletion and has been associated with prolonged TSAT greater than 50%.²³ However, lowering TSAT below 50% is difficult in most patients, even if ferritin is kept near the iron- deficiency range. From a pathophysiology standpoint, it must be remembered that phlebotomy-induced iron deficiency can further aggravate hepcidin deficiency.¹² Whether innovative therapeutic approaches with hepcidin agonists (see below) will be useful remains to be determined.

Accepting hemochromatosis individuals as blood donors has long been debated for possible safety and ethical concerns regarding nonaltruistic donation. No real risk in both aspects has ever been demonstrated.³³ Current US Food and Drug Administration policies (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=630.15) and most European countries allow blood donation from uncomplicated patients, although statements and applications vary, leaving some discretion at single centers. Some guidelines explicitly support the adoption of “hemochromatosis donor programs.”⁴ This might counterbalance the lack of motivation to pursue lifelong health care attendance in asymptomatic patients. Moreover, a reverse ethical argument is the possible underutilization of a precious resource in the context of progressively shrinking donations.³³ 

Erythrocytapheresis is an isovolemic procedure that can remove nearly 4-fold more red blood cells than 1-unit phlebotomy, preserving patients' plasma proteins, clotting factors, and platelets and reducing the time frame of the induction phase.^4,23 Disadvantages include cost and the need for specialized equipment and staff. A blinded study comparing erythrocytapheresis vs sham treatment (plasmapheresis) in C282Y homozygotes with moderate hyperferritinemia (300-1000  mg/L) showed a significant reduction of fatigue score,³¹ supporting treatment in paucisymptomatic cases. We use erythrocytapheresis only in selected patients with advanced liver or heart complications with poor tolerance to phlebotomy-induced hypovolemia. Similarly, iron chelators are generally restricted to severe cases, especially with advanced heart failure.^{4,15,16,23,34} Continuous intravenous deferoxamine has been reported to reverse end-stage heart failure in patients initially listed for transplantation.¹⁵ In less severe settings, oral iron chelators can be considered when phlebotomy is problematic (Table 2).^4,23 

Rusfertide, a hepcidin mimetic peptide successfully used in polycythemia vera,²⁸ has been recently employed in a proof-of- concept trial enrolling HFE-H patients in the maintenance phase.³⁵ Compared to phlebotomy alone, adding rusfertide reduced the rates of phlebotomy. It also decreased TSAT, which could be advantageous in the long term. A reduced need for attending health care facilities may improve the quality of life, especially in patients living in remote areas. Further studies are needed to corroborate these results and demonstrate cost-effectiveness.³⁶ Rusfertide slows iron absorption and facilitates redistribution but does not induce iron loss. Thus, it is likely useless for the depletion phase.

Lifestyle measures are integral to the appropriate management of hemochromatosis (Table 2). Being both common in the general population, C282Y homozygosity and MAFLD may coexist. The same may be true for alcohol liver injury. Body weight should be kept normal through regular physical activity and a healthy diet. There is no reason to prescribe drastic diets (eg, devoid of red meat), as iron is ubiquitous in foods. We generally advise a Mediterranean diet with low consumption of meats and processed foods. Alcohol should be avoided in patients with signs of liver disease and during the induction phase, while moderate consumption can be allowed in uncomplicated cases after iron depletion. Attention should be paid to dietary supplements, often containing iron. Patients should avoid raw or undercooked shellfish and contact of wounds with seawater, both possibly contaminated by Vibrio vulnificus, an iron-avid pathogen that may cause life-threatening infections.³⁷ Proton pump inhibitors decrease iron absorption and can reduce the need for phlebotomy when prescribed for other reasons. However, their specific use in hemochromatosis is not recommended.⁴ 

Since our patient was overweight, regular physical activity was recommended.

Cascade first-degree family screening is indicated whenever hemochromatosis is diagnosed. Due to the low/delayed clinical penetrance, in HFE-H analyses of children can be deferred until late adolescence.^4,23 For the same reason, population screening is usually not recommended.⁴ However, the recent UK Biobank follow-up study has shown increased morbidity (especially osteoarthritis and the need for joint replacement) and a slightly increased mortality in unrecognized older C282Y homozygous males.³⁸ Future guidelines may reconsider this point, at least in Caucasian males after the fifth and sixth decades.²³ 

The index patient had a 62-year-old brother living in a rural area whose test results indicated C282Y homozygosity. His biochemical profile showed ferritin level, 1020  mg/L; TSAT, 78%; and a mild elevation of transaminases. Two years before, he had received a diagnosis of seronegative undifferentiated arthritis with poor response to hydroxychloroquine. A physical examination and plain radiogram showed typical hemochromatosis arthropathy of the hands (Figure 5). The Fib-4 score and FibroScan confirmed the high probability of ALF,²⁵ making a liver biopsy unnecessary. There were no clinical or biochemical signs of other relevant complications. Phlebotomy, surveillance for HCC, and physiotherapy of involved joints were started.

A 27-year-old woman of Greek origin was referred to our center because of marked hyperferritinemia (1340  µg/L) and a moderate elevation of transaminases, performed because of fatigue and the recent onset of shortness of breath during exercise. She also reported oligomenorrhea in the last year. The parents, both in good health, were first cousins. The physical examination showed nuanced skin hyperpigmentation and mild hepatomegaly. Her lungs were clear, and no peripheral edema was evident, ruling out overt heart decompensation. TSAT was 93% and the HFE C282Y negative. An MR T2* scan revealed severe liver and heart IO. A liver biopsy showed grade 4-plus siderosis, especially in periportal hepatocytes and bile duct cells, and mild fibrosis. Iron depletion was immediately started by erythrocytapheresis, which was well tolerated and followed by standard phlebotomy. A total of approximately 5.5 g of iron were removed in the following 6 months. The patient recovered a good exercise tolerance and menses gradually normalized. An in-house NGS iron panel revealed homozygosity for the HJV missense variant p.Gly320Val.³⁹ 

The diagnosis of non–HFE-H is based on clinical and laboratory elements, and treatment must be prioritized over molecular characterization.³ A comprehensive approach is needed to properly manage non–HFE-H cases, which can be severe or life-threatening. Nevertheless, the prognosis can still be reverted in advanced cases.

We are indebted to Prof. Clara Camaschella for lifelong invaluable mentoring and for critical review of the manuscript.

Domenico Girelli: no competing financial interests to declare.

Giacomo Marchi: no competing financial interests to declare.

Fabiana Busti: no competing financial interests to declare.

Domenico Girelli: nothing to disclose.

Giacomo Marchi: nothing to disclose.

Fabiana Busti: nothing to disclose.