2. Dr.moosavi Abadan-Khordad-1397
Hemochromatosis
Dr.moosavi
Abadan-Khordad-1397

3. OBJECTIVES Review iron absorption and transport
Describe types of hemochromatosis
Hemochromatosis and the laboratory
Suspicion
Investigation
Diagnosis

4. Iron Absorption and Transport

5. Background Iron is an important nutrient, but too much can be bad
Absorb about 10% from our diet
Individual with this disease absorbs about 30%
No mechanism to eliminate iron
Excess damages liver, heart, and pancreas

6. Villus enterocyte Ferritin Macrophage Ceruloplasmin Transferrin
Bone Marrow
Liver

7. Normal Iron metabolism
Male
Female
Total body iron
Daily iron absorption
Daily iron loss
OTHER
Menstrual (monthly)
pregnancy (total)
3 - 4 g
1 – 2 mg
1- 2 mg
2 - 3 g
1 – 2 mg
1- 2 mg
OTHER mg mg

8. 20 mg / d Menstruation 20 – 40 mg /m Ferritin Macrophage Villus
enterocyte
Fe2+
1 – 2 mg /d
20 mg / d
Liver
Menstruation
20 – 40 mg /m
Bone Marrow

9. 20 mg / d Menstruation 20 – 40 mg /m Ferritin Macrophage Villus
enterocyte
Fe2+
20 mg / d
7 – 8 mg /d
1 – 2 mg /d
Liver
Menstruation
20 – 40 mg /m
Bone Marrow

10. Iron transport and absorption proteins
Transferrin
Ferritin
Transferrin receptor
Ceruloplasmin

11. Non-heme iron absorption process
Reduction of ferric to ferrous iron
Transport across brush border
Sequestration in enterocyte
Basal transport from cell
Oxidation to ferric form
Transport by transferrin
Uptake by transferrin receptors
Utilisation or storage

12. Types of Hemochromatosis

13. Different Forms
Primary or hereditary
Secondary
Juvenile
Neonatal

14. Classical or adult-onset Hemochromatosis

15. Classical Hemochromatosis
First description 1865
inherited disorder 1935
autosomal recessive disorder of excess iron deposits in parenchymal tissues causing organ damage and dysfunction
Affects liver, pancreas, heart, joints, pituitary, skin – “bronze diabetes”
Considered rare disease of elderly men

16. Hemochromatosis by 1996
Syndrome preventable if iron overload diagnosed and treated early.
Treatment simple: - phlebotomy
Recognition – high transferrin saturation and ferritin
Studies of blood donors suggested that 1:200 to 1:400 people have biochemical iron overload
Much more common than originally thought
1 in 200 in NW European populations

17. Hereditary HFE is gene for protein that regulates iron absorption
2 mutations: C282Y and H63D

18. North West European origin
C282Y mutation in HFE gene
In late 1996 an HLA linked gene on chromosome 6 p 21.3 was found to be associated with hemochromatosis patients of
North West European origin
HFE
B C E A HLA genes

19. Early Stage Symptoms Arthritis Fatigue Abdominal pain High blood sugar
Hypothyroidism
Weight loss

20. Advanced Stage Symptoms
Liver disease
Liver cancer
Diabetes
Cardiac arrhythmia
Congestive heart failure
Discolored skin

21. Clinical Manifestations
Influenced by
Age
Sex
Dietary iron
Alcohol
Blood loss in menstruation and pregnancy
Unknown factors
Alcohol abuse and Hepatitis C accelerate
Classic description: cutaneous hyperpigmentation and diabetes in a patient with cirrhosis

22. Traditional triad means diagnosed too late!
Classic Triad:
Cirrhosis (hepatic damage)
Diabetes (type II) (pancreatic damage)
Bronzing of skin (hyperpigmentation)
Traditional triad means diagnosed too late!
Damage may be only partially reversible
Goal is to detect the disease BEFORE organ damage occurs
Slide 5:
Symptoms: Traditional Concept
There is a misconception that most hemochromatosis patients present with this classic triad when in fact fewer than 15% of patients do.3
Diagnosis at this point means it is too late to prevent organ damage.
Goal is to identify and treat patients before they reach this stage.
Organ damage may only be partially reversible at this point.

23. Hepatocellular carcinoma
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 > 55 yrs, those with HBS Ag and alcohol abuse
Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis. Hepatology Dec;20(6):

24. Diagnostic testing for HH
Transferrin saturation:
> 45% indicates significant Fe accumulation
Serum ferritin - levels indicating significant iron accumulation:
>150 mcg/L pre-menopausal women
>200 mcg/L post-menopausal women
>200 mcg/L for men
Liver biopsy if ferritin >1000 to assess damage
Consider genetic testing – DNA testing for common mutations (C282Y, H63D)
Slide 15:
Diagnostic Testing for HH
Fasting transferrin saturation (TS): 2
> 45% indicates significant Fe accumulation (sensitivity and specificity 94%)3
TS = Serum iron x 100%
Total Iron Binding Capacity (TIBC)
The easiest way to get TS levels is to order serum iron and TIBC then do the TS calculation if the lab does not do the calculation for you
Patient must be fasting as TS can be increased after a meal in which there is large iron content.
Serum ferritin: at these levels indicates significant iron accumulation3
Liver biopsy if ferritin >1000 in HH to assess damage2
Genetic testing – DNA testing for common mutations (C282Y, H63D)2

25. Iron overload in liver Pearls’ Prussian blue stain of a liver biopsy from a patient with hereditary hemochromatosis. Left panel: low-power view shows intense iron stainingof hepatocytes. The blue-stained iron deposits typically 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.

26. Hepatic Iron Index (HII) in hemochromatosis - the
hepatic Iron index in four groups of patients: normal controls, alcoholic liver disease, pre-fibrotic hemochromatosis, and fibrosis and cirrhosis caused by
hemochromatosis. Among the
patients with hemochromatosis, the opens circles represent heterozygotes, andthe close circles represent homozygotes. The HII iscalculated by dividing the hepatic iron concentration by the patients age in years. All patients with homozygous hereditary hemochromatosis had an hepatic I index > 2, alevel not seen in the otherpatients. Hepatology 1986; 6:24

27. MRI Liver Slow (approx 20 mins) Relatively simple
Good correlation with iron levels and cirrhosis

29. Genetic Testing for HH Should be offered to those patients with:
Appropriate clinical presentation
Elevated transferrin saturation and ferritin
Liver biopsy suggestive of iron overload
First degree relative of a known case
* Must be offered to an affected family member or index case FIRST
Slide 16:
Genetic Testing for HH should be offered to those patients with:
Must be offered to an affected family member FIRST
A known mutation should be identified before offering DNA testing to other family members.
If the affected family member is unavailable, then refer relatives to genetics clinic for counseling and evaluation.
First-degree relatives or spouse (if there are adult children at risk since if spouse is negative, no need to test children) of a diagnosed case of HH. Some genetics centres offers testing to first-degree relatives of a carrier because HH is so common.

30. What is the value of genetic testing?
To confirm diagnosis
Sequential screening of family members
Slide 17:
What is the value of Genetic Testing?
Think of the whole family as your patient. Genetic testing allows you to identify family members at risk of developing hemochromatosis.
Predictive value: Once at-risk family members are identified, a screening or treatment plan can be developed to prevent organ damage and reduce morbidity and morality.
Screening plan to monitor for iron overload:
Serum Ferritin
Fasting Transferrin Saturation
Treatment plan to reduce further organ damage.
Phlebotomy (500mL) weekly or biweekly until serum ferritin falls below 50ng/mL2
Diet: Avoid iron supplements, vitamin C and raw fish.

31. “So if I have the gene…I’ll get the disease”
Not necessarily!
This statement refers to an important concept in genetics
Penetrance
The proportion of individuals with a mutation causing a particular disorder who exhibit clinical symptoms of that disorder
Slide 23:
“So if I have the gene…I’ll get the disease”
Penetrance is defined as the proportion of individuals with a mutation (or genotype) known to cause a specific disease who exhibit clinical symptoms of that disorder.
So, for hemochromatosis, that would be the proportion of individuals with a C282Y/C282Y or C282Y/H63D or H63D/H63D genotype who exhibit clinical symptoms of hemochromatosis.
Note that the penetrance depends on the specific genotype involved: C282Y/C282Y (majority of cases) > C282Y/H63D > H63D/H63D (very few people have symptoms).

32. Mutated HFE Genes = Hemochromatosis?
No, because of
Incomplete penetrance:
Even though some individuals have the susceptible genotype they may never manifest symptoms of the disease due to:
Environmental factors: blood donation
Genetic factors: other modifying genes
Low penetrance for C282Y homozygotes
Slide 24:
Mutated HFE Genes = Hemochromatosis?
Incomplete penetrance:
Incomplete penetrance refers to the phenomenon that not every person with a mutant genotype will exhibit clinical symptoms of the disorder.
Some factors contributing to incomplete penetrance (in HH) are environment, diet, alcohol, lifestyle (donating blood) and age at menarche & menopause, heaviness of periods, number of pregnancies, use of iron supplements and other genetic factors (modifier genes).
From the European Consensus Conference on Haemochromatosis in 2000, the proportion of C282Y homozygotes that will have iron overload assessed by serum ferritin is 19-58%.5
The exact penetrance of hemochromatosis is still under study but ranges from 1% to 55% to 100% in the literature.17 More recent data suggests the penetrance is lower than previous reports. One of the reasons for the range in penetrance is that the various studies have different definitions of hemochromatosis and different methods of ascertainment (study of blood donors’ verses a study of patients followed in a hemochromatosis clinic).
This brings us to a philosophical question: What constitutes disease?
Genotype: People with two HFE mutations (C282Y/C282Y or H63D/H63D homozygotes, C282Y/H63D compound heterozygotes)? – But they may never develop clinical symptoms of iron overload.
Biochemistry: People with the abnormal biochemistry, elevated TS (‘biochemical penetrance’) but no symptoms of iron overload? One study in Wales found that 85% of men and 44% of women with the C282Y/C282Y genotype had elevated TS – again these people may not develop clinical symptoms. 1
Clinical presentation: People with symptoms of iron overload – cirrhosis, cardiomyopathy, type 2 diabetes etc?
Thus the definition of disease can vary depending on what is being referred to; genotype or serum iron measures or symptoms of iron overload.
One of the problems in determining the penetrance of HH is that the various studies have different definitions of the clinical signs leading to the wide range of the reported percentage of penetrance.

33. Guidelines

34. Indications to consider hemochromatosis
Guidelines: Iron Overload 2001
Apply to classical Type 1 Hemochromatosis
General guidelines – indications for genetic testing
Based on fasting transferrin saturation as the primary biochemical screen

35. When to consider the diagnosis?
Adult onset diabetes
Arthritis
Unexplained cirrhosis or persistently raised liver enzymes
Congestive heart failure or cardiomyopathy
Secondary hypogonadism
Increased skin pigmentation
Not in guideline
Severe fatigue
Arthralgias

37. Genetic Testing and Treatment
First degree relatives of confirmed hemochromatosis patients can have the genetic test done directly
If iron overloaded and not C282Y homozygous consider other causes
Management (phlebotomy) is dependent on the ferritin level not the transferrin saturation
Phlebotomy - till ferritin around 50 µg/L

38. No Yes No Yes Yes No Yes No Yes No Yes No Fasting morning TS >50%
Stop
Yes No
Repeat TS and serum ferritin > normal
Check in 12 mo
Yes
Yes
Secondary Iron Overload?
Rx & Recheck No
HFE gene testing; C282Y homozygote?
Yes
1. Normal AST 2. Ferritin <1000 ug/L 3. No hepatomegaly No
Yes No
Phlebotomy
Liver Biopsy - positive for HHC
Yes No
Phlebotomy
Follow

39. Medical Management
The goal - detect patients before symptoms of iron overload.
Phlebotomy weekly or biweekly
Check ferritin every ~10 phlebotomies
Stop frequent phlebotomy when ferritin 25-50mcg/L
Maintenance phlebotomy every 3-4 months
Dietary recommendations
Consider hematology or GI consult for confirmed cases to guide treatment and monitoring
Slide 25:
Medical Management 3, 6, 2
The goal of treatment is to detect patients before they manifest symptoms of iron overload.
Early treatment can prevent organ damage and improve survival
Some symptoms may be reversible with phlebotomy
Phlebotomy:
Removal of mL of blood weekly or biweekly
Check hematocrit prior to each phlebotomy; allow hematocrit to fall by no more than 20% of normal
Check ferritin every ~10 phlebotomies
Stop frequent phlebotomy when ferritin 20-50mcg/L or transferring saturation is <30%
Continue phlebotomy at intervals (every 3-4 months) to keep serum ferritin between 20-50mcg/L
Dietary recommendations: Patients should avoid:
Vitamin C (increases the absorption of iron) and iron supplements
Excessive consumption of alcohol
Eating raw shellfish – A marine bacteria, Vibrio vulnificus causes septicemia and high mortality especially in people with chronic liver disease or other dysfunction that increases serum iron levels i.e. HH.18
Consider hematology or GI consult for confirmed cases to guide treatment and monitoring.
Management of C282Y heterozygotes (carriers)6
In C282Y heterozygotes who have indirect markers of iron overload, especially if they have abnormal liver enzymes or clinical evidence of liver disease - a liver biopsy is recommended to diagnose HH.
C282Y heterozygotes that have iron overload may carry a second undetected, RARE mutation in the HFE gene.
Generally C282Y and H63D heterozygous carriers are not at risk for iron overload.

44. Chelation therapy for HHC with deferoxamine can also lead to clinical improvement, however, it is almost never necessary

45. Diet Realistically little role Avoid large quantities Vitamin C
Increased Fe absorption
Increases Fe release from storage sites
Rare reports of inducing lethal cardiac failure