1. Hereditary hemochromatosis is an inherited condition characterized by excessive absorption of dietary iron, which is then deposited in vital organs like the liver, heart and pancreas. 2. It is caused by mutations in the HFE gene, which regulates the protein hepcidin that controls iron absorption. The most common mutation is C282Y. 3. Clinical features include liver disease, diabetes, arthritis and skin pigmentation. Treatment involves regular phlebotomy to reduce iron levels until they are normal.

1. Hepatology lectures for
5th Sem;MBBS
Pratap Sagar Tiwari
MBBS,MD (Medicine),DM (Hepatology)

2. Hereditary
Hemochromatosis

3. BACKGROUND
• The normal daily diet contains about 10–20 mg of iron. Of this, 1–1.5 mg (10 %) is
absorbed.
• The average adult male has about 1,000 mg of stored iron (enough for about three
years), whereas women on average have only about 300 mg (enough for about six
months).
• About 70 percent of your body's iron is found in the red blood cells of your blood called
hemoglobin and in muscle cells called myoglobin.
• One unit of transfused blood contains about 200-250 mg of iron.

4. NORMAL IRON PHYSIOLOGY
• The normal daily diet contains about 10–20 mg of iron. Of this, 1–1.5 mg (10 %) is
absorbed.
• This amount depends on body stores and demands of the erythroid progenitors, more
being absorbed if stores are reduced and as the need increases.
• The absorption process, sited in the duodenum and upper small intestine.
Heme iron
Non Heme iron
Principally found in meat as Hb or myoglobin. Easily absorbed because it is not
influenced by the many ligands in the diet; directly taken up into enterocytes by an
absorption pathway .
Accounts for the majority of the iron in plants, is less well absorbed.
Found in antioxidant-rich plant foods that have proven to protect against
inflammation and chronic diseases.

5. IRON ABSORPTION AND TRANSPORT:
REGULATORS
(1) the HFE gene
(2) the Divalent metal transporter‐ 1 (DMT‐1)
(3) the intracellular mechanisms for controlling the expression of transport and storage
proteins, in particular iron regulatory proteins (IRPs)
(4) the Basolateral iron transporter (called IREG‐1 or ferroportin)
(5) Hepcidin, a polypeptide that plays a pivotal role in iron regulation

6. 4. Fe2+ is transported into mucosal cells by the divalent metallic transporter 1 (DMT1).
5. The Fe2+ in mucosal cells is either sequestered away as mucosal ferritin in enterocytes, which is later lost by
shedding of epithelial cells, or crosses the basolateral membrane via ferroportin (FPN).
6. Fe2+ is converted to Fe3+ by hephaestin located on the basolateral membrane of the enterocyte.
7. Fe3+ enters into the circulation and is transported bound to plasma transferrin (TF).
8. Transferrin-bound iron stimulates the synthesis of hepcidin in the liver, which in turn inhibits ferroportin
function and blocks the release of iron from enterocytes.
MECHANISM OF IRON ABSORPTION 1. Heme iron is transported into
mucosal cells via the heme
transporter.
2. Heme iron is released from its
porphyrin network and enters a
common pathway with nonheme
iron.
3. Nonheme iron is reduced from
ferric ion (Fe3+) to ferrous ion
(Fe2+) via the enzymatic action of
ferrireductase or ascorbic acid
(Duodenal cytochrome b-related
ferric reductase (dcytb)) present on
the apical surface of the
enterocyte.

7. FERRITIN
• Ferritin is the major cellular iron storage
protein.
• Plasma ferritin is also an indirect marker
of the total amount of iron stored in the
body; hence, serum ferritin is used as a
diagnostic test.
High serum ferritin levels are also seen with hypoxia and
inflammatory conditions, such as hepatitis, alcohol excess,
fatty liver, and some cancers.
➢ Ferritin that is not combined with iron is called apoferritin.
➢ Iron is stored in a protein complex as ferritin or the related complex hemosiderin
(digested ferritin and lysosomes). For eg The breakdown of heme gives rise to
biliverdin and iron. The body then traps the released iron and stores it as hemosiderin
in tissues.

8. TRANSFERRIN
• Transferrin is a blood plasma glycoprotein that
plays a central role in iron metabolism and is
responsible for ferric-ion delivery.
• They are produced in the liver and contain binding
sites for two Fe3+ ions. Human transferrin is
encoded by the TF gene.
• When not bound to iron, transferrin is known as
"apotransferrin"
• Transferrin regulates the absorption of iron into
the blood. Transferrin exists in relationship to the need for iron:
When iron stores are low, transferrin levels increase,
whereas transferrin is low when there is too much iron.
Transferrin saturation, measured as a percentage, is a medical laboratory value.
It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, this value tells how
much serum iron is bound.

9. TRANSFERRIN
↓ Transferrin
↑ Transferrin
Iron deficiency anemia
Pregnancy (↑ iron delivery to placenta)
Oral contraceptives (↑ synthesis)
Iron overload diseases
Protein malnutrition
Note: An absence of transferrin: atransferrinemia, a condition characterized by anemia and hemosiderosis in
the heart and liver that leads to heart failure and many other complications. Ferritin, gets secreted more into
the bloodstream so as to bind with the excessive free iron and hence serum ferritin levels rises.
When plasma transferrin levels rise, there is a reciprocal decrease in percent transferrin
iron saturation, and a corresponding increase in total iron binding capacity in iron
deficient states.
TRANSFERRIN ∞ TIBC
↑ TRANSFERRIN SATURATION

10. EXTRA NOTE
IDA AOCD Iron overload
Serum Iron level ↓ ↓ ↑
Ferritin ↓ ↑/N ↑
Transferrin ↑ N/↓(ample iron but
not available)
↓
TIBC ↑ N/↓ ↓
Transferrin saturation ↓ ↓ (dt low serum iron) ↑
Hepcidin ↓ ↑ ↑

11. CAUSES OF INHERITED HEPATIC IRON OVERLOAD

12. HAEMOCHROMATOSIS: definition
• A condition in which the amount of total body iron is increased; the excess
iron is deposited in, and causes damage to, several organs, including the liver.
It may be primary or secondary to other diseases.

14. PATHOPHYSIOLOGY OF HH
• The HFE protein regulates the production of a protein called hepcidin.
• Approx 90% of pts are homozygous for a single point mutation resulting in
a cysteine to tyrosine substitution at position 282 (C282Y) in the HFE
protein.
• A histidine-to-aspartic acid mutation at position 63 (H63D) in HFE causes a
less severe form of haemochromatosis.
• Fewer than 50% of C282Y homozygotes will develop clinical features of
haemochromatosis.

15. APPROACH
TS
N/↓ TS ↑ TS
Rule out
• Alcohol
• Inflammation
• Cell necrosis
• Cancer
• Metabolic
syndrome
>300 ug/l male
>200 ug/l female
Ferroportin Disease, Aceruloplasminemia, atransferrinemia, DMT-1 deficiency,etc
Hyperferritinemia-
cataract syndrome
No Iron Overload Iron Overload
MRI/Liver biopsy
↑Ferritin
> 45%
< 45%
None HFE
Hemochromatosis
C282Y/C282Y
C282Y/H63D
HFE gene testing

17. CLINICAL FEATURES
• Overt haemochromatosis is 10 times more frequent in males than females.
• Women are spared by iron loss with menstruation and pregnancy. Female
pts with haemochromatosis usually, but not always, have absent or scanty
menstruation, have had a hysterectomy, or are many years postmenopausal.
• Haemochromatosis is rarely diagnosed before the age of 20 years, and the
peak incidence period is between 40 and 60 years of age.

18. CLINICAL FEATURES
• Symptomatic disease usually presents in men over 40 years of age with
features of liver disease (often with hepatomegaly), type 2 diabetes or
heart failure.
• Fatigue and arthropathy are early symptoms but are frequently absent.
• Leaden-grey skin pigmentation due to excess melanin occurs, especially in
exposed parts, axillae, groins and genitalia: hence the term ‘bronzed
diabetes’.
• Impotence, loss of libido and testicular atrophy are recognised
complications, as are early-onset osteoarthritis targeting unusual sites such
as the metacarpophalangeal joints, chondrocalcinosis and pseudogout.
• Cardiac failure or cardiac dysrhythmia may occur due to iron deposition in
the heart.

19. CLINICAL PRESENTATION HH

20. MANAGEMENT
• Treatment consists of weekly venesection of 500 mL blood (250 mg iron)
until the serum iron is normal; this may take 2 years or more.
• The required frequency of maintenance phlebotomy depends on the rate of
iron accumulation (generally once every 2–4 months).
• The aim is to reduce ferritin to under 50 μg/L (5 μg/dL). Thereafter,
venesection is continued as required to keep the serum ferritin normal.

21. • Pts must be advised to maintain adequate intake of dietary protein, vitamin B12, and
folate, while avoiding iron-rich foods and ascorbic and citric acids, which are thought to
increase the absorption of iron.
• Alcohol should be avoided while iron depletion therapy is in progress, particularly given
that heavy alcohol intake is a/with higher serum iron markers, increased severity of
clinical disease, and increased risk of cirrhosis and HCC in C282Y homozygotes.
• Phlebotomy can result in improved cardiac function, better control of diabetes,
heightened energy levels, reduction of abdominal pain, and resolution of skin
hyperpigmentation.
• However, some complications of HH are irreversible, including arthropathy,
hypogonadism, advanced cirrhosis, and HCC .
• Hypogonadism may lessen in men aged less than 40 years at diagnosis.

22. ASYMPTOMATIC DISEASE
• First-degree family members should be investigated, preferably by genetic
screening and also by checking the plasma ferritin and transferrin
saturation.
• Liver biopsy is indicated in asymptomatic relatives only if the LFTs are
abnormal and/or the serum ferritin is greater than 1000 μg/L (100 μg/dL)
because these features are a/with significant fibrosis or cirrhosis.
• Asymptomatic disease should also be treated by venesection until the
serum ferritin is normal.

23. PROGNOSIS
• Pre-cirrhotic patients with HHC have a normal life expectancy, and even
cirrhotic patients have a good prognosis compared with other forms of
cirrhosis (three-quarters of patients are alive 5 years after diagnosis).
• Screening for hepatocellular carcinoma is mandatory because this is the
main cause of death, affecting one-third of patients with cirrhosis,
irrespective of therapy.
• Venesection reduces but does not abolish the risk of HCC in the presence of
cirrhosis.

24. OTHERS:
• IRON CHELATORS: Deferoxamine & Deferasirox
• Studies have demonstrated that PPIs reduce intestinal absorption of nonheme iron and
may thus decrease the requirement for frequent phlebotomy.
• Erythrocytapharesis is an extracorporeal blood separation method whereby whole blood
is extracted from a donor or pt, the red blood cells are separated, and the remaining
blood is returned to the circulation.
• Hepcidin administration has been shown to diminish iron accumulation in mice, implying
that increasing hepcidin levels might be able to mitigate iron overload in HH.
• Patients with end-stage liver disease due to HH should be evaluated for liver
transplantation. The survival of patients with genetic haemochromatosis after liver
transplant may be less than that of other recipients (53 versus 81% survival at 25
months).

25. END OF SLIDES

26. ETC