HEREDITARY HEMOCHROMATOSIS

1
HEREDITARY HEMOCHROMATOSIS

• Suhail Allaqaband
• Sinai Samaritan Medical Center
• Milwaukee, WI

2
HEREDITARY HEMOCHROMATOSIS

• Autosomal recessive disorder in which mutations
  in the HFE gene cause increased intestinal iron
  absorption and the deposition of excessive amount
  of iron into the liver, pancreas, and other
  organs
• The most common genetic disorder in the US white
  population
• heterozygot carriers is about 10
• homozygous state is approx 1 in 250 to 300

3
PATHOPHYSIOLOGY

• HHC is characterized by increased absorption of
  iron
• In contrast to normal subjects, the absorption of
  iron in HHC is not regulated by iron stores
• This leads to progressive iron accumulation
• Patients with HHC absorb 2 to 4 mg of iron/day
  (normal 1 mg/day in males)
• The retention of 3 mg of iron/day will lead to
  net iron accumulation of approximately 1 g/yr
• Women become symptomatic later in life, because
  of the extra iron loss associated with menses,
  pregnancy, and lactation

4
DIFFERENTIAL DIAGNOSIS

• HHC should be distinguished from secondary iron
  overload
• anemia with inefficient erythropoiesis
• iron overload due to chronic liver disease
• multiple blood transfusions
• parenteral or oral iron supplements

5
CLINICAL MANIFESTATIONS

• Classic bronze diabetes hyperpigmentation,
  diabetes mellitus, liver cirrhosis
• Other Clinical features
• fatigue
• hepatomegaly (elevated serum aminotransferase)
• arthropathy
• hypogonadism (impotence in males)
• hypothyroidism
• cardiomyopathy

6
CLINICAL MANIFESTATIONS

• Classic triad of cirrhosis, DM, and skin
  pigmentation occurs late in the disease, when the
  total body iron content has reached as high as 20
  g (gt that five times normal)
• However, most patients are currently diagnosed
  when elevated serum iron levels are noted on a
  routine screening panel or screening is performed
  because of a relative diagnosed with HHC
• Approximately 75 of such patients are
  asymptomatic at presentation

7
Liver disease

• Progressive iron deposition is associated with
  hepatomegaly, elevated liver enzymes, and the
  eventual development of cirrhosis
• Reversibility with iron removal is more likely
  early in the course of the disease but can occur
  in patients with cirrhosis and varices
• Iron overload in HHC also potentiates the
  development of alcoholic liver disease

8
Hepatocellular carcinoma

• 152 homozygotes were studied prospectively for 1
  to 229 months
• At diagnosis, cirrhosis was present in 97
  patients and absent in 55
• During follow-up, hepatocellular carcinoma
  developed in 28 of the 97 (28.8) patients with
  cirrhosis but in none of those without
• The risk was increased significantly in patients
  gt 55 yrs, those with HBS Ag and alcohol abuse
• Prognostic factors for hepatocellular carcinoma
  in genetic hemochromatosis. Hepatology 1994
  Dec20(6)1426-31

9
Diabetes Mellitus

• DM is present in approximately 50 of patients
  with HH who present with symptoms
• This complication is due to progressive iron
  accumulation in the pancreas
• A separate issue is whether all patients with
  diabetes should be screened for hemochromatosis

10

• Prevalence of genetic haemochromatosis among
  diabetic patients. Lancet 1989 Jul292(8657)233
• Prevalence of the DM was investigated in 418
  patients attending a diabetic clinic
• 21 (5) patients had a persistently high serum
  ferritin and 5 of these had transferrin
  saturations consistently over 55
• HH was confirmed by liver biopsy in 4
• The estimated prevalence was 0.96, twice that in
  the general population
• Screening of diabetic patients for HH may be more
  cost-effective than screening in the general
  population

11
Arthropathy

• HHC may be associated with an arthropathy that
  displays the full spectrum of crystal deposition
  disease (ie, pseudogout, chondrocalcinosis, and
  chronic arthropathy)
• Characteristic radiologic findings squared-off
  bone ends and hook-like osteophytes in the MCP
  joints, particularly in the 2nd 3rd MCP joints
• In contrast to many other manifestations of HHC,
  symptoms of arthropathy do not generally respond
  to iron removal

12
Dilated Cardiomyopathy

• HHC can produce DCM characterized by the
  development of heart failure and conduction
  disturbances
• Cardiac disease may be the presenting
  manifestation in up to 15 of patients
• Treatment with phlebotomy has been associated
  with reversal of the left ventricular dysfunction
  
• However, irreversible myocardial dysfunction can
  occur with advanced disease

13
Secondary Hypogonadism

• Hemochromatosis results in iron deposition in
  pituitary cells
• Hypogonadism is the most common endocrine
  abnormality causing decreased libido and
  impotence in men
• Other pituitary deficiencies may occur, but are
  much less frequent
• Amenorrhea can occur in women

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DIAGNOSIS OF IRON OVERLOAD

• A diagnosis of HHC is suggested by
• Elevated fasting transferrin saturation (NL 20
  -50)
• Elevatd ferritin

Serum iron concentrationTransferrin
saturation ----------------------------------
Total iron binding capacity
15

• Fasting Transferrin saturation of ? 60 in men
  and ? 50 in women will detect about 90 of
  patients with HHC
• High transferrin saturation is the earliest
  phenotypic evidence of HHC
• A plasma ferritin level gt 300 µg/L in men and
  200 µg/L in women provides further support for
  the diagnosis of iron overload
• However, as many as 30 of women with HHC under
  age 30 do not have an elevated transferrin
  saturation
• Also, since ferritin is an acute phase reactant,
  both inflammatory diseases, hepatitis, and
  malignancy can raise the plasma ferritin
  concentration

16

• The definitive test for the diagnosis of iron
  overload is liver biopsy
• Hepatic iron content is reported as µmol/g dry
  weight of liver
• Normal values are less than 36 µmol/g, while
  values above 71 µmol/g are highly suggestive of
  HHC
• This value can be divided by the subject's age in
  yrs to give the hepatic iron index a value gt or
  1.9 is virtually diagnostic of homozygous HHC
• Noninvasive tests, such as magnetic resonance
  imaging, are not sufficiently accurate,
  particularly in patients who have hepatic
  fibrosis or mild degrees of iron overload

17
Iron overload in liver Pearls Prussian blue
stain of a liver biopsy from a patient with
hereditary hemochromatosis. Left panel
low-power viewshows intense iron stainingof
hepatocytes. The blue-stained iron
depositstypically start at the periphery of the
liver lobule and extends centrally. Right
panel high-power view shows intense on staining
(in blue) of hepatocytes. Courtesy of Stanley
L. Schrier, M.D.
18
Hepatic Iron Index (HII) in hemochromatosis -
the hepatic Iron index in four groupsof
patients normal controls, alcoholic liver
disease, pre-fibrotichemochromatosis, and
fibrosis and cirrhosis caused by hemochromatosis.
Among the patients with hemochromatosis, the
opens circlesrepresent heterozygotes, andthe
close circles represent homozygotes. The HII
iscalculated by dividing thehepatic iron
concentration bythe patients age in years.
Allpatients with homozygoushereditary
hemochromatosis had an hepatic I index gt 2,
alevel not seen in the otherpatients.
Hepatology 1986 624
19
Genetics of hereditary hemochromatosis

• In 1996, a candidate gene for HHC was identified
  now termed HFE
• HFE gene contains two missense mutations
• One of these mutations results in a
  cysteine-to-tyrosine substitution at amino acid
  282 (C282Y)
• Of 178 patients from 32 different medical centers
  around the US, C282Y was found to be homozygous
  in 83 of patients

20
Genetics of hereditary hemochromatosis

• However, other studies have shown that other
  defects can also lead to HHC
• Approximately 4 to 5 of patients with HHC have
  been shown to be compound heterozygotes, ie, one
  allele with the C282Y mutation and one allele
  with an H63D mutation
• A few patients are homozygotes for H63D

21
Genetics of hereditary hemochromatosis

• Genetic testing for HFE mutations is commercially
  available
• It may play an important role in the diagnosis of
  HH, particularly in siblings of a patient with HH
• However, genotyping cannot provide information
  about the degree of increased body iron stores or
  organ damage and thus cannot replace liver biopsy

22
MASS BIOCHEMICAL OR GENETIC SCREENING

• The value of mass screening for HHC remains a
  topic of debate
• Screening is attractive because of the relatively
  high prevalence in the population (particularly
  Caucasian), and the fact that early detection and
  treatment can have a significant impact on
  morbidity and mortality
• A number of studies, in several different
  populations, have provided evidence that
  screening with measurements of transferrin
  saturation are effective in identifying patients
  with HHC, particularly in white males

23
MASS BIOCHEMICAL ORGENETIC SCREENING

• Many authors concluded that the cost per life per
  year saved was less than that considered
  acceptable for many common medical interventions
• They recommend that practitioners consider
  including a serum transferrin saturation in
  routine screening of asymptomatic white men

24
MASS BIOCHEMICAL OR GENETIC SCREENING

• A consensus statement from the CDC and the
  National Human Genome Research Unit does not
  recommend population-based genetic screening for
  HHC at this time
• This recommendation was based upon uncertainty
  regarding the prevalence and penetrance of HFE
  mutations and the optimal care of asymptomatic
  individuals who have this mutation

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TREATMENT

• The simplest, cheapest and most effective way to
  remove iron is by phlebotomy
• Each 500 mL of whole blood discarded contains 200
  to 250 mg of iron
• The optimal regimen for phlebotomy in HHC has not
  been established
• Many hematologists maintain weekly phlebotomies
  until iron deficiency hematopoiesis is induced as
  evidence by a hemoglobin concentration of about
  11 g/dL, MCV in the low 80s, and transferrin
  saturation of 10 to 20 percent

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TREATMENT

• Many gastroenterologists recommend weekly
  phlebotomy until iron stores are normalized
  (defined as a serum ferritin concentration below
  50 ng/mL and transferrin saturation below 50 )
• The induction of iron deficiency is not viewed as
  necessary

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TREATMENT

• After the initial course of phlebotomy, the
  patient should initially be monitored every two
  to three months
• Maintenance therapy is required to prevent
  reaccumulation of iron
• Most patients require a 500 mL phlebotomy every
  two to four months (4 to 8 x per year)
• Chelation therapy for HHC with deferoxamine can
  also lead to clinical improvement, however, it is
  almost never necessary

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No
Fasting morning TS gt50
Stop
Yes
No
Repeat TS and serum ferritin gt normal
Check in 12 mo
Yes
Yes
Secondary Iron Overload?
Rx Recheck
No
HFE gene testing C282Y homozygote?
Yes
1. Normal AST2. Ferritin lt1000 ug/L3. No
hepatomegaly
No
No
Yes
Phlebotomy
Liver Biopsy - positive for HHC
No
Yes
Phlebotomy
Follow
29
References

• Update on Hereditary Hemochromatosis and the HFE
  GeneBrandhagen D, Fairbanks V, Batts K,
  Thibodeau SMayo Clin Proc. 199974917-921