epatology Lectures
Hemochromatosis
Soha Nageb
Lecturer of Internal Medicine
Internal Medicine Department
Faculty of Medicine
MUE
Physiology of iron
metabolism
Iron Absorption
• Absorption of iron occurs in the duodenum and upper jejunum and depends on specific carrier
mechanisms. The transporter protein Divalent Metal Transporter 1 (DMT1), located on the
apical surface of enterocytes, facilitates the uptake of non-haem ferrous iron (Fe2+) from the
intestinal lumen. Ferric iron (Fe3+) in the intestinal lumen must be reduced to ferrous iron
(Fe2+) by duodenal cytochrome B reductase (DcytB) before uptake by DMT1.
• The iron within enterocytes can either be stored as ferritin, or transferred into the
bloodstream via the protein ferroportin. Once in the blood, iron is bound to the transport
protein transferrin, and is mostly transported to bone marrow for erythropoiesis. Some iron is
taken up by macrophages in the reticuloendothelial system as a storage pool.
Regulation
• The absorption of iron is primarily regulated by a peptide called hepcidin, which is
expressed by the liver. Hepcidin functions by directly binding to ferroportin, resulting in its
degradation and therefore preventing iron from leaving the cell. Hepcidin also functions by
inhibiting transcription of the DMT1 gene, thus reducing iron absorption.
Iron Excretion
• Firstly, it is important to note that the human body has no specific mechanism for iron
excretion, and therefore regulating iron absorption to match the natural losses, is a crucial
part of iron metabolism.
• Approximately 1-2mg of iron is lost from the body each day from the skin and
gastrointestinal mucosa. A well-balanced diet contains sufficient iron to balance this loss,
as approximately 10% of the 10-20 mg of dietary iron in a balanced diet is absorbed each
day.
• This iron can be haem iron from animal sources, or non-haem iron from whole grains, nuts,
seeds, legumes, and leafy greens.
• Haem iron is more readily absorbed than inorganic iron which consists of both ferric (Fe3+)
and ferrous (Fe2+) iron. Ferric iron must first be reduced to the ferrous form before it is
absorbed.
Iron Recycling
• On a daily basis, only a small fraction of the total iron requirement is gained
from the diet. Most of the iron requirement is met from the recycling of iron
within the reticuloendothelial system, which is released from storage and
returned to the active pool.
• Iron Storage
• Iron is stored in two forms, ferritin and its insoluble derivative hemosiderin. All
cells have the ability to sequester iron as either ferritin or hemosiderin. The
highest concentrations of stored iron are in the liver, spleen, and bone marrow.
Hemochromatosis
ESSENTIALSOFDIAGNOSIS
Usually suspected because of a family history or an elevated iron saturation or
serum ferritin.
Most patients are asymptomatic; the disease is rarely recognized clinically before
the fifth decade.
Hepatic abnormalities and cirrhosis, heart failure, hypogonadism, and arthritis.
HFE gene mutation (usually C282Y/C282Y) is found in most cases.
• Definition: an autosomal recessive disease caused by a mutation in
the HFE gene on chromosome
• Epidemiology: The frequency of the C282Y mutation averages 7% in
Northern European and North American White populations,
resulting in a 0.5% frequency of homozygotes (of whom 38–50%
will develop biochemical evidence of iron overload but only 28%
of men and 1% of women will develop clinical symptoms). The
C282Y mutation and hemochromatosis are uncommon in Blacks
and Asian
• Pathogenesis:
The HFE protein play an important role in the process by which
duodenal crypt cells sense body iron stores, and a mutation of
the gene leads to increased iron absorption from the duodenum.
A decrease in the synthesis or expression of hepcidin, the
principal iron regulatory hormone, is thought to be a key
pathogenic factor in all forms of hemochromatosis.
Clinical Findings
• A. Symptoms and Signs
• The onset of clinical disease is usually after age 50 years—earlier in men than in women;
• however, because of widespread liver biochemical testing and iron screening, the
diagnosis is usually made long before symptoms develop.
• Early symptoms are nonspecific (eg, fatigue, arthralgia).
• Later clinical manifestations include:
1- a symmetric arthropathy that is similar to osteoarthritis and calcium pyrophosphate
deposition disease (and ultimately the need for joint replacement surgery in some cases)
2- hepatomegaly and evidence of hepatic dysfunction, liver cirrhosis, 10-20% develop HCC
3- skin pigmentation (combination of slate-gray due to iron and brown due to melanin,
sometimes resulting in a bronze color)
4- cardiac enlargement with or without heart failure or conduction defects.
5- endocrinal: diabetes mellitus with its complications, and erectile dysfunction in men.
B. Laboratory Findings
1- mildly ABNORMAL LIVER TESTS: (AST, alkaline
phosphatase),
2- IRON PROFILE: an elevated plasma iron with, greater than
45% transferrin saturation, a low TIBC and an elevated serum
ferritin
3- Testing for HFE mutations is indicated in any patient with
evidence of iron overload.
• C. Imaging
MRI and CT may show changes consistent with iron overload of
the liver.
D. Liver biopsy
• the liver biopsy characteristically shows extensive iron
deposition in hepatocytes and in bile ducts, prussian blue stain
Differential diagnosis
• Secondary hemosiderosis
• Acquired disorder
• Associated with hemolytic anemia, increase iron overload
Tr e a t m e n t
1- NUTRITION: avoid foods rich in iron (such as red meat), alcohol,
vitamin C, raw shellfish, and supplemental iron
2- phlebotomy:
A. deplete iron stores: weekly phlebotomies of 1 or 2 units (250–500
mL) of blood (each containing about 250 mg of iron) in all
symptomatic patients, for up to 2–3 years
B. Maintainance phlebotomies (every 2–4 months) to maintain serum
ferritin levels between 50 -100 mcg/L
3- a proton pump inhibitor, reduces intestinal iron absorption,
decreases the maintenance phlebotomy volume requirement
4- chelating agents is indicated for patients with hemochromatosis and
anemia or in those with secondary iron overload due to thalassemia
who cannot tolerate phlebotomies.
A. deferoxamine is administered intravenously or subcutaneously in a dose
of 20–40 mg/kg/day infused over 24 hours and can mobilize 30 mg of
iron per day; however, treatment is painful and time-consuming.
B.Two oral chelators, deferasirox, 20 mg/kg once daily, and deferiprone, 25
mg/kg three times daily, have been approved for treatment of iron
overload due to blood transfusions however, these agents have a
number of side effects and drug-drug interactions.
Prognosis
Diagnosis and use of chelating therapy:
A. hepatic fibrosis may regress, and in pre-cirrhotic patients,
cirrhosis may be prevented. In patients with cirrhosis, varices
may reverse, the risk of variceal bleeding declines, and the
risk of hepatocellular carcinoma may be reduced.
B.Cardiac conduction defects may improve with treatment.
C.Joint disease, endocrinal disorders (diabetes mellitus, and
hypogonadism) may not reverse with treatment of
hemochromatosis.
D.MORTALITY: is related to serum ferritin level (greater than
1000 mcg/L) and is mainly caused by complications of liver
disease
1- Clinical manifestations of hereditary
hemochromatosis are uncommon in which of the
following?
• A. Postmenopausal women
• B. Elderly men
• C. Premenopausal women
• D. Elderly women
2- Which of the following is the most common
complication of hereditary hemochromatosis?
• A. Cardiomyopathy with heart failure
• B. Diabetes
• C. Erectile dysfunction
• D. Liver disease
• Answer: D: Liver disease is the most common complication and may progress
to cirrhosis; 20 to 30% of patients with cirrhosis develop hepatocellular
carcinoma. A: Cardiomyopathy with heart failure is the 2nd most common
fatal complication. B: Glucose intolerance or diabetes mellitus is a common
initial presentation. C: In men, the initial symptoms may be hypogonadism
and erectile dysfunction caused by gonadal iron deposition.
3- The treatment for hereditary hemochromatosis
is usually which of the following?
• A. Abstinence from alcohol
• B. Chelation therapy
• C. Phlebotomy
• D. Decreased consumption of iron-containing foods
4- Systemic regulation of iron absorption is mediated
by ?
•A. Hepcidin
•B. Ferroportin
•C. Ferritin
•D. DMT1
5-Plasma iron transport protein is ?
A. Hepcidin
B. Ferroportin
C. Transferrin
6- Hepatocytes are an important site of iron storage
in the form of ?
A. Ferritin
B. Hemosiderin
C. Transferrin
D. Ferroportin
