Hemocromatosis hereditaria

¿Qué es la hemocromatosis hereditaria?

Sinónimos: hemocromatosis genética, hemocromatosis vinculada a HLA, diabetes de bronce

Hereditary haemochromatosis (HHC) is an autosomal recessive genetic disease in which increased intestinal absorption of iron causes accumulation in tissues which may lead to organ damage. Organs that may be affected by the amount of iron deposits include the liver, pancreas, joints, heart and skin

Liver fibrosis, cirrhosis and hepatocellular carcinoma are the most serious complications of iron overload. Early diagnosis and treatment are therefore essential.

Epidemiología¹²

• Hereditary haemochromatosis is the most common autosomal recessive disorder in White populations, with a prevalence of 1 in 300 to 1 in 500.

• HHC type 1 is primarily seen in people of Northern European descent but types 2-4 are seen throughout the world.

• HHC is 6 times more common in White people than Black.

• Men are affected 2-3 times more commonly than women.

causas de la hemocromatosis hereditaria (etiología)¹

Defects of the HFE gene (located on the short arm of chromosome 6) cause the majority of cases of inherited haemochromatosis, which is often referred to as HFE haemochromatosis (HFE-HC). HFE was the only known gene associated with haemochromatosis but it is now known that there are other genetic associations.³

Type 1 hereditary hemochromatosis occurs in patients who are typically homozygous for loss-of-function mutations in HFE. While more than 100 HFE mutations can cause Type 1 hereditary hemochromatosis, the most common mutation is the p.Cys282Tyr or C282Y variant; the second most common mutation is the p.His63Asp or H63D mutation.

Type 2 hereditary hemochromatosis is also inherited in an autosomal recessive pattern and the typical age of onset is in adolescence or early adulthood (15 to 20 years). Historically, this disease was referred to as "juvenile" hemochromatosis. Type 2a is due to a mutation in the gene HFE2. Type 2b is due to mutations in the hepcidin antimicrobial peptide (HAMP) gene on chromosome 19.

Type 3 hereditary hemochromatosis, also inherited in an autosomal recessive fashion, is due to mutations in the transferrin-receptor gene (TFR2) on chromosome 7.

Type 4 hereditary hemochromatosis is the only known type to be inherited in an autosomal dominant fashion. The mutations occur in the ferroportin transport protein known as ferroportin/solute carrier family 40 member 1, encoded by SCL40A1 on chromosome 2.

Hereditary haemochromatosis symptoms and signs¹⁴

• Early diagnosis can be difficult because HHC is often asymptomatic until the late stages of disease. Diagnosis of type 1 HHC is usually made between the ages of 40 and 50 in males and after the menopause in females (due to blood - and therefore iron - loss in menstruation.

• Initial symptoms are usually vague and nonspecific. Almost all patients complain of fatigue and lethargy; arthralgia is also common.

• It is common for people to have symptoms for up to 10 years before the diagnosis is made.

• HHC may be diagnosed incidentally - eg, following abnormal serum ferritin or pruebas de función hepática (LFTs).

• Type 2 HHC is usually diagnosed before the age of 20, type 3 between the ages of 30 and 40, and type 4 at any age between 10 and 80.¹

• Symptoms of advanced disease include:

  • Diabetes.

  • Koilonychia - koilonychia affecting the thumb and forefinger is seen in 50% of people with HHC.

  • Diffuse hyperpigmentation - this is seen in 90% of people with HHC. It was historically described as "bronzing of the skin",

  • Hepatic involvement. Liver dysfunction is seen in 75% of patients; jaundice may or may not be present. Liver involvement can cause abdominal pain, hepatomegaly, cirrhosis, portal hypertension, ascites, and splenomegaly.

  • Arthropathy, especially of the second and third metacarpophalangeal joints but also the knees, wrists, hip, back, neck, and feet.

  • Cardiac involvement. This can lead to arrhythmias, restrictive or dilated cardiomyopathy, and cardiac failure.

  • Pituitary hypogonadism. This can be seen in decreased libido or erectile dysfunction. Amenorrhoea may occur in women.

  • Hypopituitarism, thyroid dysfunction, adrenal dysfunction and parathyroid defects.

  • Osteoporosis.

  • Parkinsonism, chorea, and tremors. This is thought to be due to iron deposition in the basal ganglia, dentate, red nuclei, and the substantia nigra.

  • Infections. There is an increased risk of infection with Yersinia enterocolitica, Listeria monocytogenes, y V vulnificus.

  • Cancer. The risk of hepatocellular carcinoma is 20 times higher in people with HCC than the general population.

Detección⁵

Recommendations for genetic testing:

• Población general: no se recomienda la detección genética de HFE-HC, ya que la penetrancia de la enfermedad es baja y solo en algunos homocigotos C282Y progresará la sobrecarga de hierro.

• No se recomienda realizar pruebas de HFE en pacientes con artritis o artalgia inexplicadas o con diabetes tipo 2.

Investigaciones y diagnóstico de la hemocromatosis hereditaria

Esto implica la evaluación de la sobrecarga de hierro, la genética y el daño en los órganos. Estas pruebas requieren una interpretación cuidadosa.

Investigaciones iniciales⁵

• The first step in testing for haemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin.

  • La ferritina sérica es la prueba bioquímica más utilizada para detectar la sobrecarga de hierro. La ferritina sérica es una prueba muy sensible para la sobrecarga de hierro en la hemocromatosis y concentraciones séricas normales prácticamente descartan la sobrecarga de hierro.

  • Sin embargo, la ferritina tiene poca especificidad, ya que los valores elevados pueden ser el resultado de una variedad de condiciones inflamatorias, metabólicas y neoplásicas, como la diabetes mellitus, el consumo de alcohol y la necrosis hepatocelular u otras células.

  • La concentración de hierro sérico y la saturación de transferrina no reflejan cuantitativamente las reservas de hierro en el cuerpo y, por lo tanto, no deben usarse únicamente como marcadores de sobrecarga de hierro en los tejidos.

• Tests to exclude other common causes of hyperferritinaemia: inflammation (check CRP), chronic alcohol consumption, liver cell necrosis (alanine aminotransferase), metabolic syndrome (blood pressure, BMI, triglycerides, glucose), anaemia (haemoglobin, mean cellular volume and further tests depending on ethnic background - eg, testing for sickle cell disease).

• pruebas de función hepática (LFTs).

• Otros análisis, incluyendo investigaciones endocrinas, pueden ser indicados, dependiendo de la situación clínica.

• Las investigaciones para otras causas de función hepática anormal (por ejemplo, serología de hepatitis) pueden ser relevantes.

Investigaciones adicionales⁵

• Genetic testing:

  • Individuals with clinical and biochemical signs of haemochromatosis, elevated transferrin saturation and high serum ferritin concentrations, or otherwise unexplained persistently elevated transferrin saturation should be genetically tested for haemochromatosis after informed consent for genetic testing has been obtained.

  • Patients with increased liver iron evident on liver biopsy or MRI should be clinically assessed and biochemically tested for haemochromatosis (serum ferritin and transferrin saturation).

  • Adult individuals with a positive family history of first-degree relatives with haemochromatosis should be genetically tested for haemochromatosis after informed consent for genetic testing has been obtained.

• Biopsia hepática:

  • In C282Y homozygote patients with increased iron stores, liver biopsy is no longer necessary to diagnose haemochromatosis.

  • Liver biopsy may still be indicated - eg, to show whether iron stores are increased or not and in assessing liver fibrosis. It may also be indicated where liver enzymes are elevated in a diagnosed case of haemochromatosis or where serum ferritin levels are more than 1000 µg/L.⁶
    One large American study found that hepatic fibrosis and cirrhosis can exist without symptoms.⁷

• MRI may be useful to detect and quantify hepatic iron excess and may also help to identify heterogeneous distribution of iron within the liver, differentiate parenchymal from mesenchymal iron overload and to detect small iron-free neoplastic lesions.

Diagnóstico diferencial

Differential diagnosis of HHC:

• Otras formas hereditarias de hemocromatosis: síndrome hereditario de catarata por ferritina H, deficiencia de hem oxigenasa, sobrecarga de hierro neonatal, aceruloplasminemia, atransferrinemia congénita o hipotransferrinemia, defecto en el gen del transportador de metales divalentes 1.

• Sobrecarga de hierro secundaria:

  • Anemias por acumulación de hierro.

  • Eritropoyesis ineficaz.

  • Síndromes talassémicos.

  • Anemia sideroblástica.

  • Síndrome mielodisplásico.

  • Anemia diseritropoyética congénita.

  • Sobrecarga de hierro parenteral (incluyendo múltiples transfusiones de sangre).

• Other diagnoses: síndrome metabólico, la obesidad, hipertensión, resistencia a la insulina.

• Toxicidad por medicamentos.

• Diálisis crónica.

• Chronic liver disease, hepatitis, consumo excesivo de alcohol, esteatohepatitis no alcohólica, cirrosis hepática.

• Porfiria cutánea tarda.

• Other types of skin pigmentation - eg, Enfermedad de Addison.

• Other forms of liver disease - which may co-exist or contribute.

Tratamiento y manejo de la hemocromatosis hereditaria¹⁸

• Patients with HFE-HC and evidence of excess iron should be treated with phlebotomy. Phlebotomy is usually carried out by removing 500 ml of blood (250 mg iron) once or twice a week. Adequate hydration before and after treatment and avoidance of vigorous physical activity for 24 hours after phlebotomy are recommended.

• Once iron levels are stabilised, lifelong, but less frequent, phlebotomy (typically 3-4 times a year) is required. The aim to obtain a ferritin level of less than 50 µg/L. Some people with hereditary haemochromatosis may achieve this by donating blood.

• La flebotomía puede mejorar la eliminación de hierro y la sensibilidad a la insulina, la pigmentación de la piel y la fatiga, pero no tendrá efecto en la cirrosis, el hipogonadismo o la artropatía.

• Alcohol should be avoided in HHC.

• Para minimizar el riesgo de complicaciones adicionales, los pacientes con HFE-HC podrían vacunarse contra la hepatitis A y B mientras tengan exceso de hierro.

• Trasplante de hígado:

  • La enfermedad hepática en etapa terminal puede ser una indicación para el trasplante de hígado.

  • Los pacientes con condiciones de sobrecarga de hierro tienen una tasa de supervivencia más baja después del trasplante que aquellos que no la tienen.

Monitoreo

• La ferritina sérica es la principal prueba utilizada porque se correlaciona con los síntomas y el riesgo de complicaciones.

• Cuando la ferritina sérica es inferior a 1000 μg/L, el riesgo de daño hepático grave es inferior al 1%. Los niveles de ferritina sérica por encima de 1000 μg/L son una indicación para una biopsia hepática debido al riesgo de cirrosis.

• Cuando una biopsia hepática muestra cirrosis, la detección periódica de carcinoma hepatocelular, mediante ecografía o resonancia magnética, es fundamental.

Pronóstico

• Los pacientes homocigotos C282Y con HC clínicamente confirmado tienen un mayor riesgo de desarrollar enfermedad hepática y carcinoma hepatocelular.

• Los estudios observacionales de pacientes que recibieron un tratamiento adecuado y oportuno muestran que la mortalidad general no es mayor que en la población general.