Transcript Hereditary haemochromatosis, siderophilia, bronze diabetes, history

This lecture was conducted during the Nephrology Unit
Grand Ground by Medical Student rotated under
Nephrology Division under the supervision and
administration of Prof. Jamal Al Wakeel, Head of Nephrology
Unit, Department of Medicine and Dr. Abdulkareem Al
Suwaida, Chairman of the Department of Medicine.
Nephrology Division is not responsible for the content of the
presentation for it is intended for learning and /or education
purpose only.
Hemochromatosis
Presented by:
Ohoud Al Ahmed
Medical Student
December 12, 2008
• also called
hereditary haemochromatosis,
siderophilia and bronze diabetes.
• History:
– First described in 1865 by Armand
Trousseau (bronze diabetes).
– The recognition of iron infiltration of the
pancreas was made by Friedrich Daniel
von Recklinghausen in 1890.
Pathophysiology
• Is a hereditary disease characterized by
excessive absorption of dietary iron
resulting in a pathological increase in
total body iron stores (up to 10-fold of
the normal).
• leads to deposition of iron as
haemosiderin, which is toxic to tissues,
in multiple organs:
liver, pancreas, heart, joints, pituitary,
adrenals and skin.
• Middle-aged males (after their forties
and fifties), are more frequently and
severely affected than women in whom
the disease tends to present ~10years
later (menstrual blood loss is
protective).
• There are also juvenile forms of
hereditary haemochromatosis that
present in childhood with the same
consequences of iron overload.
Genetics
• HH is one of the commonest inherited diseases in
those of Northern European in particular those of
British or Irish descent (carrier rate ~1:10,
homozygosity ~1:200).
• The gene responsible for most HH is called HFE
found on the short arm of chromosome 6
• The 2 major allele mutations in the HFE are
termed C282Y and H63D. C282Y accounts for 6090% of HH, and H63D accounts for 3-7%, with
compound heterozygotes accounting for 1-4%.
Pathophysiology:-
Liver
HFE gene
Lumen
iron
iron
Enterocyte
hepcidin
Vessel
DMT-1 (divalent metal transporter), Ferroportin,
Recently, a classification has been
developed (with chromosome locations):
Description
OMIM
Mutation
Locus
Haemochromatosis type 1:
"classical"-haemochromatosis
235200
HFE
6p21.3
Haemochromatosis type 2A:
juvenile haemochromatosis
602390
hemojuvelin ("HJV", also
known as HFE2)
1q211
Haemochromatosis type 2B:
juvenile haemochromatosis
606464
hepcidin antimicrobial
peptide (HAMP) or HFE2B
9q137
Haemochromatosis type 3
604720
transferrin receptor-2 (TFR2
or HFE3)
Q222q
ferroportin (SLC11A3)
32
Haemochromatosis type 4
604653
autosomal dominant
haemochromatosis (all others are
recessive), gene mutation
Clinical Features
• Asymptomatic (incidentaly discovered).
• Protean in its manifestations.
The more common clinical
manifestations include
• Malaise.
• Liver cirrhosis (with >10% chance of HCC).
• Insulin resistance (often patients have
already been diagnosed with DM type 2).
• Erectile dysfunction, hypogonadism and
decreased libido.
• Congestive heart failure, arrhythmias or
pericarditis.
• Arthritis of the hands (esp. 2nd, 3rd MCP
joints), but also the knee and shoulder joints.
• Adrenal insufficiency.
Liver cirrhosis
Less common findings include:
• Deafness
• Dyskinesias, including Parkinsonian symptoms
• Dysfunction of certain endocrine organs:
– Parathyroid gland (leading to hypocalcaemia)
• A darkish colour of skin (see pigmentation)
• An increased susceptibility to certain infectious
diseases caused by siderophilic microorganisms:
– Vibrio vulnificus infections from eating seafood
– Listeria monocytogenes
– Yersinia enterocolica
– Salmonella enterica (serotype Typhymurium)
– Klebsiella pneumoniae
– Escherichia coli
– Rhizopus arrhizus
– Mucor species
Investigations
• Standard diagnostic tests.
• Routine tests.
• Functional tests.
Investigations
• Standard diagnostic tests:
– serum transferrin saturation test (>80%).
– serum ferritin test (>1000 ng/ml).
– Serum iron
– TIBC
– HFE genotyping
• Routine tests.
• Functional tests.
Test
Sensitivity
Specificity
positive
predictive
value
negative
predictive
value
serum iron
68%
> 180 mcg/dL (32
mcmol/L)
83%
61%
87%
transferrin
saturation
> 50%
82%
88%
74%
93%
serum ferritin
> 400 ng/mL
88%
95%
88%
94%
elevation of
transferrin
saturation or
serum ferritin
94%
86%
73%
97%
Investigations
• Standard diagnostic tests.
• Routine tests:
– CBC
– Renal function
– U&E
– Liver enzymes (elevated but normal in 18%)
– Glucose and/or OGTT
• Functional tests.
Investigations
• Standard diagnostic tests.
• Routine tests.
• Functional tests (based on the history):
–
–
–
–
ECG and ECHO (CMP, HF)
Blood glucose monitoring.
Joint X-rays (chondrocalcinosis, degenerative OA)
Liver biopsy (quantifies iron loading, assess
disease severity esp. cirrhosis). Risks: BBI.
– MRI (quantifies iron loading)
Liver biopsy
Normal liver
Slight overload
Moderate
overload
Major overload
Differential Diagnosis
• African iron overload (Bantu siderosis).
• Secondary haemochromatosis (transfusional
iron overload / hemosiderosis): ~40L in total.
In those with hereditary anemias such as (Bthalassemia M, SCA, and Diamond-Blackfan
anemia).
• Dyserythropoeisis (myelodysplastic
syndrome).
Management
•
•
•
•
Phebotomy (venesection / bloodletting).
Initiated when ferritin levels reach 300 mg/L.
1unit/week
Every bag of blood (450-500 ml) contains 200250 mg of iron.
• until ferritin levels are less than 20 mg/L.
• maintenance venesection 1-4 donations/yr for
life.
• Aim: Hct <0.5,
ferritin <100 micg/L,
•
transferrin sat <40%.
TIBC >50 micmol/L,
Other aspects of management:
• Diabetes HbA1C levels (may be falsely low)
• OTC self-medications: make sure that they contain
no iron.
• Dietary intake: maintaining a well-balanced low iron
diet. Limiting intake of fruit, fruit juice and red
meat.
• Drinking tea or coffee, Taking calcium and foods
containing oxalic and phytic acids with meals
reduces iron absorption.
• Treatment of organ damage (HF with diuretics and
ACEI).
Screening
• Using?
– serum ferritin
– genotype
• Whom?
– 1st-degree relatives
– Have any of the following signs & symptoms:
•
•
•
•
•
•
Joint disease
Severe fatigue
Heart disease
Elevated liver enzymes
Impotence
Diabetes.
Prognosis
• Venesection returns life expectancy to
normal if non-cirrhotic and nondiabetic.
• Arthropathy may improve or worsen.
• Gonadal failure is irreversible.
References:• Haemochromatosis – wikipedia, the free encyclopedia.
last modified on 28 November 2008.
• Oxford handbook of clinical medicine, 7th edition. 2007.
• Assessment of Silent Liver Fibrosis in
Hemochromatosis C282Y, Homozygotes With Normal
Transaminase Levels. CLINICAL
GASTROENTEROLOGY AND HEPATOLOGY 2008;6:713–
714
Studies of Phlebotomy Therapy in
Hereditary Hemochromatosis
Verified by National Institutes of Health Clinical Center
• First Received:
December 9, 2000
• Last Updated:
November 20, 2008
• Health Authority: United States: Federal
Government.
1) Compare the usefulness of the ferritin test with that
of MCV in guiding phlebotomy therapy.
2) Examine whether keeping iron levels low during
maintenance therapy can help heal severe liver
disease and improve arthritis in affected patients.
3) Design a system for making blood collected from
hemochromatosis donors available for transfusion
into other patients.
Thank you
Ohoud M. Al-Ahmed