Chapter 18 –Metabolic Liver Disease - HEMOCHROMATOSIS

Question 1

What is Hemochromatosis?

Answer 1

Hemochromatosis was first described by von Recklinghausen in 1889.

It is characterized by the
Hemochromatosis most of which is deposited in parenchymal organs such as the liver and pancreas.

Iron can also accumulate in the heart, joints, or endocrine organs.
Hemochromatosis (also known as primary or hereditary hemochromatosis) is a homozygousrecessive inherited disorder [47] that is caused by excessive iron absorption.

Question 2

What is secondary secondary
hemochromatosis, acquired hemochromatosis, or hemosiderosis?

Answer 2

Accumulation of
iron in tissues,which mayoccur as a consequence of parenteral administration of iron,usually in theform of transfusions, or other causes ( Table 18-6 ), is variably known as secondary
hemochromatosis, acquired hemochromatosis, or hemosiderosis.

We will use the terms
hemochromatosis for the hereditary disease and hemosiderosis for the acquired deposition of
iron in some tissues.

Question 3

What is the usage of the term hemochromatosis and hemosiderosis with actually the same meaning?

Answer 3

We will use the terms
hemochromatosis for the hereditary disease and hemosiderosis for the acquired deposition of iron in some tissues.

HemoSIDEeffects kaya secondary ;)

Question 4

TABLE 18-6 – Classification of Iron Overload

I. HEREDITARY HEMOCHROMATOSIS

Answer 4

• Mutations of genes encoding HFE, transferrin receptor 2 (TfR2), or hepcidin
• Mutations of genes encoding HJV (hemojuvelin: juvenile hemochromatosis)
• (Neonatal hemochromatosis) [*]

Question 5

TABLE 18-6 – Classification of Iron Overload

II. HEMOSIDEROSIS (SECONDARY HEMOCHROMATOSIS)

Answer 5

A. Parenteral iron overload

• Transfusions
• Long-term hemodialysis
• Aplastic anemia
• Sickle cell disease
• Myelodysplastic syndromes
• Leukemias
• Iron-dextran injections

B. Ineffective erythropoiesis with increased erythroid activity

• β-Thalassemia
• Sideroblastic anemia
• Pyruvate kinase deficiency

C. Increased oral intake of iron

• African iron overload (Bantu siderosis)
• *D. Congenital atransferrinemia**
• *E. Chronic liver disease**
• Chronic alcoholic liver disease
• Porphyria cutanea tarda

F. Neonatal hemochromatosis

Question 6

(Neonatal hemochromatosis) [*]

Answer 6

Neonatal hemochromatosis develops in utero and does not appear to be a hereditary condition.

Question 7

What is the total total body iron pool in normal adults?

Answer 7

2 to 6 gm ;

about 0.5 gm is stored in the liver, 98% of which is in hepatocytes.

Question 8

In hemochromatosis,
total iron accumulation may exceed 50 gm, over one third of which accumulates in the liver. The
following features characterize this disease:

Answer 8

• Fully developed cases exhibit (1) micronodular cirrhosis in all patients; (2) diabetes mellitus in 75% to 80% of patients; and (3) skin pigmentation in 75% to 80% of patients.
• • Iron accumulation is lifelong but the injury caused by excessive iron is slow and progressive; hence symptoms usually first appear in the fifth to sixth decades of life.
• • Males predominate (5 to 7 : 1) with slightly earlier clinical presentation, partly because physiologic iron loss (menstruation, pregnancy) delays iron accumulation in women

Question 9

​Fully developed cases of hemochromatosis,exhibit what?

Answer 9

• (1) micronodular cirrhosis in all patients;
• (2) diabetes mellitus in 75% to 80% of patients; and
• (3) skin pigmentation in 75% to 80% of patients

Question 10

What is the reason why symptoms of hemochromatosis first appear in the fifth to sixth decades of life?

Answer 10

Iron accumulation is lifelong but the injury caused by excessive iron is slow and progressive.

Question 11

What is the reason for male predominance in hemochromatosis?

Answer 11

Males predominate (5 to 7 : 1) with slightly earlier clinical presentation, partly because
**physiologic iron loss (menstruation, pregnancy) delays iron accumulation in women.**

Question 12

How is iron concentration regulated in the body?

Answer 12

Because there is no regulated iron excretion from the body, the total body content of iron is
tightly regulatedbyintestinal absorption as described below.

Question 13

What is the pathogenesis of hemochromatosis?

Answer 13

Because there is no regulated iron excretion from the body, the total body content of iron is
tightly regulated by intestinal absorption as described below.

In hemochromatosis, regulation of
intestinal absorption of dietary iron is abnormal,leading tonet iron accumulation of 0.5 to 1.0
gm/year, mainly in the liver.

The disease manifests itself typically after 20 gm of stored iron have accumulated.

Question 14

Excessive iron appears to be directly toxic to host tissues, by the following
mechanisms:

Answer 14

• (1) lipid peroxidation via iron-catalyzed free radical reactions,
• (2) stimulation of collagen formation by activation of hepatic stellate cells, and
• (3) interaction of reactive oxygen species and of iron itself with DNA, leading to lethal cell injury or predisposition to hepatocellular carcinoma. The actions of iron are reversible in cells that are not fatally injured, and removal of excess iron with therapy promotes recovery of tissue function

Question 15

What is the main regulator of iron absorption?

Answer 15

The main regulator of iron absorption is the protein hepcidin (also known as liver expressed antimicrobial peptide or LEAP1), encoded by the HAMP gene.

Hepcidin, which also has
antibacterial activity, is produced in hepatocytes as an 84 amino acid propeptide that is cleaved
into a mature form of 25 amino acids and smaller circulating forms of 20 and 23 amino acids.

Hepcidin binds to the cellular iron efflux channel ferroportin (FPN), causing internalization and proteolysis of the channel.

This prevents the release of iron from intestinal cells and macrophages; thus hepcidin lowers plasma iron levels.

Conversely, a deficiency in hepcidin causes iron overload .

Question 16

What is the transcription of hepcidin increased?

Answer 16

Transcription of hepcidin is increased by inflammatory cytokines and iron.

Question 17

Hepcidin is decreased by what?

Answer 17

• iron deficiency,
• hypoxia and
• ineffective erythropoiesis.

Question 18

Other proteins involved in iron metabolism, do so by regulating hepcidin levels. These include:

Answer 18

• (1) hemojuvelin (HJV), which is expressed in the liver, heart, and skeletal muscle;
• (2) transferrin receptor 2 (TfR2), which is highly expressed in hepatocytes, where it mediates the uptake of transferrin-bound iron, and
• (3) HFE, the product of the hemochromatosis gene.

Question 19

Lack of hepcidin expression caused by mutations in hepcidin, HJV, TfR2, and HFE cause hemochromatosis.

What is the most of these?

Answer 19

Of these mutations, those in HFE are the most common, as discussed below.

Question 20

Which of the mutations cause a severe form of hereditary hemochromatosis?

Answer 20

Mutations of HAMP and HJV cause a severe form of hereditary hemochromatosis, known as juvenile hemochromatosis.

Question 21

What mutation cause the classic form of hereditary adult hemochromatosis, a milder disease than the juvenile form?

Answer 21

Mutations of HFE and TfR2

Question 22

What does the mutation of ferroportin cause?

Answer 22

a distinctive iron storage disease that is different from hereditary hemochromatosis. T

Question 23

What is the precise mechanisms by which HFE, HJV, and TfR2 regulate hepcidin and ferroportin?

Answer 23

remain to be determined.

Question 24

What is serine protease (TMPRSS6)?

Answer 24

was recently identified as an iron sensor that suppresses HAMP expression.

Question 25

The adult form of hemochromatosis is almost always caused by mutations of what?

Answer 25

HFE

, a gene located on the short arm of chromosome 6 at 6p21.3, close to the HLA gene locus.

It encodes an HLA class I-like molecule that regulates intestinal absorption of dietary iron.

The most
common HFE mutation is a cysteine-to-tyrosine substitution at amino acid 282 (called C282Y),
due to a single G to A transition at nucleotide 845 (G845A).

This mutation, which causes
inactivation of the protein, is present in 70% to 100% of the patients diagnosed with hereditary
hemochromatosis.

The other common mutation is H63D (histidine at position 63 to aspartate).
The H63D homozygous state and C282Y/H63D compound heterozygous mutations often cause
only mild iron accumulatio

Question 26

What is the difference between the C282Y mutation and H63D?

Answer 26

The C282Y mutation is largely confined to white populations of European origin, while the H63D
has a worldwide distribution.

The frequency of C282Y homozygosity is 0.45% (1 of every 220 persons), and the heterozygous frequency is 11%, making hereditary hemochromatosis one of
the most common genetic disorders in humans. However, the penetrance of this disorder is low
in patients with the homozygous C282Y mutation, so the genetic condition does not lead to
clinical disease in all individuals.

Question 27

The morphologic changes in hereditary hemochromatosis are characterized
principally by:

Answer 27

• (1) deposition of hemosiderin in the following organs (in decreasing order of severity): liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid and parathyroid glands, joints, and skin (detected by the Prussian blue histologic reaction or by atomic absorption analysis of tissue);
• (2) cirrhosis; and
• (3) pancreatic fibrosis. In the liver, iron becomes evident first as golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes, which stain blue with the Prussian blue stain ( Fig. 18-26 ).

With increasing iron load, there is progressive involvement of the rest of the lobule, along with bile duct epithelium and Kupffer cell pigmentation. Iron is a direct hepatotoxin, and inflammation is characteristically absent. At this stage, the liver is typically slightly larger than normal, dense, and chocolate brown.

Fibrous septa develop slowly, leading ultimately to a micronodular pattern of cirrhosis in an intensely pigmented liver.

Question 28

What is the standard for
quantitating hepatic iron content?

Answer 28

Biochemical determination of hepatic tissue iron concentration .

Question 29

In normal individualswhat is the iron content of liver tissue?

Answer 29

less than 1000 μg per gram dry weight of liver.

Adult patients with hereditary hemochromatosis exhibit over 10,000 μg iron per gram dry weight;

Question 30

How much iron gram dry weight are associated with the developments of fibrosis and cirrhosis?

Answer 30

hepatic iron concentrations in excess of 22,000 μg per gram dry weight are associated with the
development of fibrosis and cirrhosis

Question 31

Decribe the appearance of pancreas in hereditary hemochromatosis?

Answer 31

The pancreas becomes intensely pigmented, has diffuse interstitial fibrosis, and may exhibit some parenchymal atrophy.

Hemosiderin is found in both the acinar and the islet cells, and sometimes in the interstitial fibrous stroma.

Question 32

What is the apperance of heart in hereditary hemochromatosis?

Answer 32

The heart is often enlarged and has hemosiderin
granules within the myocardial fibers, producing a striking brown coloration to the
myocardium.

A delicate interstitial fibrosis may appear.

Question 33

What is the apperance of skinin hereditary hemochromatosis?

Answer 33

Although skin pigmentation is partially attributable to hemosiderin deposition in dermal macrophages and fibroblasts, most of the
pigmentation results from increased epidermal melanin production.

The combination of these
pigments imparts a characteristic slate-gray color to the skin.

Question 34

What is the reason why in skin there is a characteristic of slate-gray color in hereditary hemochromatosis

Answer 34

Although skin pigmentation is partially attributable to hemosiderin deposition in dermal macrophages and fibroblasts, most of the
pigmentation results from increased epidermal melanin production.

The combination of these
pigments imparts a characteristic slate-gray color to the skin.

Question 35

What happens when there is hemosiderin deposition in joint synovial linings?

Answer 35

With hemosiderin deposition in
the joint synovial linings, an acute synovitis may develop.

Excessive deposition of calcium
pyrophosphate damages the articular cartilage, producing a disabling polyarthritis referred to
as pseudo-gout.

Question 36

What happens to the testis in hereditary hemochromatosis?

Answer 36

The testes may be small and atrophic but are not usually significantly pigmented.

It is thought that the atrophy is secondary to a derangement in the hypothalamicpituitary
axis resulting in reduced gonadotropin and testosterone levels.

Question 37

Answer 37

FIGURE 18-26 Histologic appearance of hereditary hemochromatosis.

Hepatocellular iron
deposition is dark-brown in H&E stain

(A) and blue in Prussian blue–stained section

(B).
This is a section from an early stage of the disease, in which parenchymal architecture is
normal.

Question 39

Classical hemochromatosis is more often a diseas of what gender and age?

Answer 39

is more often a disease of males and rarely becomes evident before age 40.

Question 40

What are the principal manifestation of hemochromatosis?

Answer 40

The principal manifestations include:

• hepatomegaly,
• abdominal pain,
• skin pigmentation (particularly in sun-exposed areas),
• deranged glucose homeostasis or frank
• diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and
• atypical arthritis.
• In some patients, the presenting complaint is hypogonadism (e.g., amenorrhea in the female, impotence and loss of libido in the male).
• The classic triad of pigment cirrhosis with hepatomegaly, skin pigmentation, and diabetes mellitus might not develop until late in the course of the disease.
• Death may result from cirrhosis or cardiac disease.

Question 41

What is the classic triad of pigment cirrhosis ?

Answer 41

• hepatomegaly,
• skin pigmentation, and
• diabetes mellitus

might not develop until late in the course of the disease

Question 42

What is the signficant cause of death in hemochromatosis?

Answer 42

A significant cause of death is hepatocellular carcinoma; the risk is 200-fold
greater than in the general population, and treatment for iron overload does not remove the
risk for this tumor.

Question 44

Fortunately, hemochromatosis can be diagnosed long before irreversible tissue damage has
occurred.

What screening test are done?

Answer 44

• Screening involves demonstration of very high levels of serum iron and ferritin, exclusion of secondary causes of iron overload, and liver biopsy if indicated.
• Screening of family members of probands is important. Heterozygotes also accumulate excessive iron, but not to a level that causes significant tissue damage.
• Currently most patients with hemochromatosis are diagnosed in the subclinical, precirrhotic stage due to routine serum iron measurements (as part of other diagnostic workup).

Question 45

How is hemochromatosis patient treated?

Answer 45

They are treated by regular phlebotomy

and have a normal life expectancy.

Question 46

What is Neonatal hemochromatosis?

Answer 46

• (also called congenital hemochromatosis) is a disease of unknown
• origin manifested by severe liver disease and extrahepatic hemosiderin deposition. [49]
• not an inherited disease;
• liver injury, leading to hemosiderin accumulation, occurs in utero, and might be related to maternal alloimmune injury to the fetal liver.

Question 47

What is the correct diagnosis for Neonatal hemochromatosis?

Answer 47

Extrahepatic hemosiderin deposition, detected by buccal biopsy, needs to be documented for the correct diagnosis.

.

Question 48

What is the TREATMENT for Neonatal hemochromatosis?

Answer 48

There is no specific treatment, except for supportive care, and liver transplantation in severe cases

Question 49

What is the most common causes of hemosiderosis( secondary or acquired hemochromatosis)?

Answer 49

are disorders associated with ineffective erythropoiesis, such as severe forms of thalassemia (
Chapter 14 ) and myelodysplastic syndromes ( Chapter 13 ).

In these disorders, the _excess iron
results not only from transfusions, but also from increased absorption._

Question 50

How can chronic hemolytic anemias acquire systemic hemosiderosis and parenchymal injury?

Answer 50

Transfusions alone,

when given repeatedly over a period of years (such as in patients with chronic hemolytic
anemias), can also lead to systemic hemosiderosis and parenchymal organ injury.

Question 51

Alcoholic cirrhosis is often associated with a modest increase in stainable iron within liver cells.

However, this represents alcohol-induced redistribution of iron, since total body iron is not significantly increased.

T or F

Answer 51

True

Question 52

What is Bantu siderosis?

Answer 52

The rather unusual form of iron overload resembling hereditary hemochromatosis occuring in sub-Saharan Africa. the result of ingesting large quantities of alcoholic beverages fermented in iron utensils (Bantu siderosis). Home brewing in steel drums continues to this day,
and genetic susceptibility to this disease, such as mutations of ferroportin has been proposed
in these populations. [50]

Question 53

Chronic HBV and HCV infection may increase iron storage within hepatocytes.

T or F

Answer 53

True

Question 54

-END-