hemochromatosis

Introduction

An autosomal recessive disorder characterized by an excess accumulation of iron in the liver & other organs.

Etiology

• genetic defect in HFE protein
• basic defect may be inappropriately high absorption of iron from the GI tract

Epidemiology

• heterozygote frequency is 10%
• 0.5% of white population is homozygous
• peak incidence between age 40-60
• iron overload is more common & occurs earlier in men

Pathology

• increased intestinal absorption
• decreased excretion of iron
• preferential deposition of iron in hepatocytes, rather than macrophages
• progressive iron overload with organ accumulation
• symptoms generally begin when iron stores exceed 20 g (normal 3-4 g)
• peroxidative damage enhanced by iron in parenchymal cells leading to fibrosis & organ failure
• hypogonadotropic hypogonadism
• cirrhosis is a poor prognostic indicator

Genetics

• gene linked to HLA-A3 & B15
• autosomal dominant & autosomal-recessive forms
  • autosomal recessive
• defect maps to chromsome 6p (gene for HFE protein)
  • C282Y mutation is most common
    • 0.64% of whites, 0.056% of hispanics, 0.015% of blacks & no Asians homozygous for C282Y mutation
    • most clinical cases are homozygous for C282Y mutation
    • C282Y homozygosity associated with hepatic malignancy & death ' among men, but not women
  • H63D mutation is second most common
  • S65C mutation is third most common
  • Asians more likely to have elevated levels of ferritin & transferrin saturation than whites, hispanics or blacks
  • low penetrance of disease
    • heterozygotes: rare
    • homozygotes: 28% of men, 1% of women with clinical disease 45% of men & 8% of women with serum ferritin > 1000 ng/mL
• defects in SLC40A1 associated with hemochromatosis type 4
• defects in HFE2 are the cause of hemochromatosis type 2A (juvenile hemochromatosis), autosomal recessive
• defects in CYBRD1 may be a cause of primary hereditary hemochromatosis
• associated with defects in TFR2 (transferrin receptor 2); defect maps to 7q22
• upregulation of UBE2D1 in livers of iron-overloaded patients

Clinical manifestations

• patients generally present with end-stage disease
  • case report would suggest otherwise
• pentads of:
  • diabetes
  • liver disease, cirrhosis
  • heart disease
  • hypogonadism, erectile dysfunction
  • arthropathy, chondrocalcinosis
• cardiovascular manifestations
  • cardiomegaly
  • congestive heart failure
  • cardiac arrhythmias
  • cardiomyopathy
    • dilated cardiomyopathy more common than restrictive cardiomyopathy
  • systolic or diastolic dysfunction
  • fatigue
• other manifestations
  • arthropathy (25-50%)
    • chondrocalcinosis
    • calcium pyrophosphate dihydrate (CPPD) crystals
    • osteoarthritis
    • 2nd & 3rd MCP joints are generally 1st to be involved followed by wrist, hip, knee, shoulder, ankle, elbow
    • case report of sacroiliac joint involvement
  • hepatomegaly & hepatic failure
  • hypogonadism, hypopituitarism, erectile dysfunction
  • darkening pigmentation of the skin (brown skin pigmentation)
• juvenile hemochromatosis onset prior to age 30

Laboratory

• serum ferritin
  • > 800 ng/mL suggests hemochromatosis
  • value of 650 ng/mL used as example in ref
  • ref suggests > 1000 mg/mL
• transferrin saturation > 60% in men (> 50% in women)
• serum iron
• total iron binding capacity (TIBC)
• serum transaminases are generally moderately elevated
  • HFE C282Y homozygotes generally have lower serum transaminases than non-homozygotes
• liver biopsy
  • MRI obviates need for liver biopsy
  • indications
    • evaluation of fibrosis & cirrhosis place patient at risk for hepatoma & hepatocellular carcinoma
  • former indications
    • > 40 years of age*
    • serum ferritin > 1000 ug/L*
    • elevated transferrin saturation, HFE genotype negative
    • formerly standard for diagnosis
    • iron > 10,000 ug/g dry weight
    • hepatic iron index > 2.0
• HLA typing within a family may help identify susceptible family members
• screen 1st degree relatives for evidence of iron overload
  • universal screening not recommended
• HFE gene mutation:
  • HFE gene p.C282Y (most common mutation)
    • test of choice
    • HFE gene p.H63D (2nd most common mutation)
    • HFE gene p.S65C (3rd most common mutation)
  • indicated when transferrin saturation > 45%
  • a non-diagnostic genotype does not rule out hemochromatosis (obtain liver biopsy)
• urinary iron following desferrioxamine
• serum LH & serum FSH may be low
• cytochrome B reductase in amniotic fluid to evaluate fetus for primary hereditary hemachromatosis
• see ARUP consult

Radiology

• plain radiographs
  • hook-like osteophytes of 2nd & 3rd metacarpophalangeal joints
  • asymmetric joint space narrowing
  • subchondral sclerosis & osteophyte formation in the hips
  • chondrocalcinosis
• magnetic resonance imaging (MRI) of liver
  • can assess extend of cardiac & hepatic iron overload

Complications

• cirrhosis
• increased risk of hepatocellular carcinoma (30% if cirrhosis has developed)
• increased risk of systemic infections*, including unusual pathogens:
  • bacterial infections
    • Yersinia enterocolitica
    • Capnocytophaga
    • Vibrio vulnificus, Vibrio cholerae
    • Escherichia coli
    • Listeria monocytogenes
  • viral infections
    • cytomegalovirus
    • hepatitis B infection
    • hepatitis C infection
    • HIV1 infection
  • fungal infections
    • Aspergillys fumigatus
    • Mucor

* iron overload syndromes associated with increased risk of infections with virulence increased by excess iron

Differential diagnosis

• secondary iron overload
• acute alcohol abuse
• advanced liver disease may be associated with elevated serum ferritin but iron saturation is usually normal
• acromegaly:
  • absence of liver inflammation
  • hypertension
  • change in hand &/or foot size, facial features

Management

• hereditary hemochromocytosis heterozygous for HFE mutation (C282Y) without symptoms or elevated serum iron & serum ferritin do not need treatment
• phlebotomy for removal of iron
  • indications:
    • symptomatic patients with evidence of end organ damage
    • asymptomatic patients with serum ferritin > 1000 ng/mL (MKSAP)
    • asymptomatic patients with serum ferritin > 800 ng/mL (NEJM)
  • removal of 500 mL of blood/week to the point of mild anemia
  • maintenance of 4-8 phlebotomies/year required
  • if initiated in the pre-cirrhotic stage, phlebotomy can:
    • render the liver normal
    • improve cardiac function
    • improve diabetes
  • one unit of blood contains ~ 0.25 g of iron
  • target serum ferritin is < 50 ng/mL; (50-100 ng/mL)
  • reduce frequency of phlebotomy if anemia develops
    • effectiveness & cost cited as reasons vs chelation therapy
• chelation therapy
  • deferoxamine (Desferal) IV
  • deferasorix (Exjade) PO
  • ascorbic acid
• treatment does NOT:
  • reverse arthropathy
  • reverse hypogonadism
  • reverse the risk of hepatocellular carcinoma if cirrhosis has developed
• treatment of arthropathy
  • NSAIDS
  • intra-articular corticosteroids
• diet:
  • avoid iron & vitamin C supplements
  • avoid raw or undercooked seafood, especially oysters (Vibrio vulnificus)
• early detection & treatment prevents complications
• screening for hepatocellular carcinoma
  • patients with fibrosis or cirrhosis
  • has not been shown to improve survival
• USPSTF recommends against routine screening
• 1st degree relatives of patients with hemochromatosis should be screened with iron studies or genetic studies
• prognosis:
  • life expectancy is normal with therapeutic phelbotomy in patients without heart disease or cirrhosis

More general terms

• cirrhosis
• genetic disease of the liver
• disorder of iron metabolism

More specific terms

• juvenile hemochromatosis (hemochromatosis type 2B)
• neonatal hemochromatosis; neonatal giant cell hepatitis

Additional terms

• hepatic iron index
• hepatocellular carcinoma
• Hereditary hemochromatosis protein; HLA-H (HFE HLAH)
• iron overload (iron poisoning)

Patient information

hemochromatosis patient information

Database

• OMIM: https://mirror.omim.org/entry/235200
• OMIM: https://mirror.omim.org/entry/606069