2. HEMOCHROMATOSIS - Introduction
• It is the abnormal accumulation of iron in parenchymal organs, leading
to organ toxicity.
• This disease is caused by a mutation in a gene that controls the amount
of iron the body absorbs from food.
• The two common mutations, C282Y and H63D of the gene HFE located
on chromosome 6, is the most often cause of this condition.
• It is one of the most common autosomal recessive genetic disorder.
• Secondary hemochromatosis is caused by disorders of erythropoiesis and
treatment of the diseases with blood transfusions.
3. HEMOCHROMATOSIS - Epidemiology
• The worldwide frequency of the C282Y is about 1.9% and that of the
H63D mutation is about 8.1%.
• Hemochromatosis has the same prevalence in Europe, Australia, and
other Western countries.
• This is less common among patients of African descent.
• Men are affected with hemochromatosis nearly 2-3 times as often as
women, with an estimated ratio of 1.8:1 to 3:1.
• Hemochromatosis usually becomes apparent after age 40 years in men
and after age 50 years in women.
4. HEMOCHROMATOSIS - Pathophysiology
HFE gene
defect
(homozygous)
defective
binding
of transferrin
to its receptor
↓ hepcidin
synthesis by
the liver
unregulated
ferroportin
activity
in enterocytes
↑
intestinal iron
absorption
iron accumulati
on throughout
the body
damage to the
affected organs
5. HEMOCHROMATOSIS - Clinical Features
• Patients may be asymptomatic or may present with general and organ-
related signs and symptoms.
• Early symptoms include:
severe fatigue (74%)
impotence (45%)
arthralgia (44%)
• The most common signs at the time of presentation:
hepatomegaly (13%)
skin pigmentation (70%)
arthritis
6. HEMOCHROMATOSIS - Clinical Features
• Cirrhosis (13%)
• Diabetes mellitus (48%)
• Arthropathy
• Amenorrhea, impotence, hypogonadism
• Cardiomyopathy
• Osteopenia and osteoporosis
• Hair loss
• Koilonychia
7. HEMOCHROMATOSIS - Diagnosis
Laboratory tests
• ↑ Serum iron
• ↑ Ferritin in serum (>200 μg/L)
• ↓ Total iron-binding capacity
(TIBC)
• ↑ Transferrin saturation (>45%)
• ↑ Liver enzymes (AST, ALT)
Genetic tests
• Genetic tests for the C282Y and
H63D mutations are done
• Indications
o First-degree relative with
hemochromatosis
o Confirmed iron overload
8. Imaging
• MRI: estimate the iron
concentration in the liver
• Chest x-ray and echo-
cardiography: diagnose and
monitor cardiac hemochromatosis
Liver biopsy
• Indications
o elevated liver enzymes, increased
serum ferritin levels (>1000 μg/L)
•Histology
o Color stain: Prussian blue
o Pronounced siderosis in iron stain-
ing with iron deposits primarily
observed in hepatocytes
o Macrophages containing
hemosiderin: cytoplasmic
granules that stain golden-
yellow (caused by
chronic hemolysis)
HEMOCHROMATOSIS - Diagnosis
9. HEMOCHROMATOSIS - Treatment
• Dietary changes
o Diet low in iron
o Restriction of alcohol and vitamin C supplements
o Consumption of tea
•Therapeutic phlebotomy (first-line treatment)
o Initially 1–2 phlebotomy sessions per week; after reaching
target ferritin and hemoglobin levels, phlebotomy should be performed every 2–4
months.
o Target levels: serum ferritin 20–50 μg/L; hemoglobin >12 g/dL (or 120 g/L)
o Prognosis: initiation of therapy in the pre-cirrhotic phase → normal life expectancy
and no organ damage
•Drug-induced iron chelation
o Agents: deferoxamine, deferasirox, or deferiprone
o Indication: particularly when phlebotomy is contraindicated
10. ALPHA-1 ANTITRYPSIN DEFICIENCY (AATD) - Introduction
• It is an inherited condition that increases the risk of lung and liver
disease.
• Alpha1-antitrypsin is a protein made by the liver whose function is to
protect the lungs.
• This genetic defect alters the configuration of the alpha1-antitrypsin molecule
and prevents its release from hepatocytes.
• The impact is a predisposition for obstructive pulmonary disease and
liver disease.
• This disorder affects about 1 in 1,500 to 3,500 individuals with European
ancestry.
11. AATD - Etiology
• AATD is caused by mutations in the SERPINA1 gene located in the long
arm of chromosome 14
•M is the normal allele
•S mutation causes a moderate decrease in AAT production.
•Z mutation causes a significant decrease in AAT production.
• PiMM: 100% expression of normal protein and therefore normal serum
levels of AAT
• PiMS: 80% of normal serum levels of AAT
• PiSS, PiMZ, PiSZ: 40–60% of normal serum levels of AAT
• PiZZ: 10–15% of normal serum levels of AAT (severe AAT deficiency)
• The inheritance of this condition is autosomal codominance
12. AATD - Pathophysiology
accumulation
of AAT in
hepatocellular
endoplasmic
reticulum
hepatocyte
destruction
hepatitis and
liver cirrhosis
deficient
AAT
uninhibited
neutrophil
elastase
activity
destruction
of the
pulmonary
parenchyma
panacinar
emphysema
• Gene mutation induces a conformational change in the structure
of AAT protein → dysfunctional (or absent) AAT
Effect on liver
Effect on lungs
13. AATD - Clinical Features
• Pulmonary manifestations
o Cough
o Wheezing
o Dyspnea
o Diminished breath sounds
o Barrel chest
• Hepatic manifestations
o Prolonged neonatal jaundice
o Hepatitis
o Cirrhosis
o Increased risk of hepatocellular carcinoma (HCC)
14. AATD - Diagnosis
• Serum: decreased antitrypsin
protein levels
• Electrophoresis:
decreased alpha-1 peak
• Chest x-ray
o Low and flat diaphragm
o Widened intercostal spaces
o Hyperinflation and
increased
basilar radiolucency of
both lungs with rarification
of peripheral pulmonary
vessels
15. AATD - Diagnosis
• Chest CT
o Panacinar emphysema
o Bronchiectasis
o Bullae
• Liver biopsy
o PAS-positive, spherical inclusion bodies in
periportal hepatocytes
o Signs of cirrhosis
16. AATD - Treatment
• General measures
o Avoid active and passive exposure to cigarette smoke
o Preventive vaccination (e.g., influenza vaccine, pneumococcus vaccine)
• Symptomatic treatment
o Bronchodilators
o Pulmonary rehabilitation
o Nutritional support if necessary
• Antitrypsin replacement: in patients with severe AAT deficiency (e.g.
ATT <57 mg/dL) and evidence of decreased airflow
• Liver transplantation
o Results in correction of AAT deficiency
o Considered for end-stage liver disease
17. WILSON DISEASE – Introduction
• Also known as hepatolenticular degeneration, is an autosomal
recessive metabolic disorder in which impaired copper excretion
causes it to accumulate in the liver, brain and other vital organs.
• Age of onset: 5–35 years (mean age 12–23 years)
• Prevalence: ∼ 1/30,000 (USA)
18. WILSON DISEASE – Pathophysiology
• Autosomal recessive mutations in the ATP7B gene (Wilson gene) on chromosome 13,
which encodes for the membrane bound copper transporting ATPase → defective
ATP7B protein
accumulation in
the liver, cornea
,CNS, kidneys,
and enterocytes
↑
free serum
copper
Reduced
biliary copper
excretion
↓
serum
ceruloplasmin
Reduced
incorporation
of copper
into apoceru-
loplasmin
19. WILSON DISEASE – Clinical Features
• Liver
o Acute liver failure
o Acute or chronic hepatitis
o Cirrhosis
o Hepatosplenomegaly
o Portal hypertension
o Abdominal pain
o Jaundice
o Ascites
o Hepatic encephalopathy
• Kayser-Fleischer rings: Copper accumulation in Descemet membrane of
the cornea that results in 1–2 mm wide, green-brown rings in the
periphery of the iris
20. WILSON DISEASE – Clinical Features
• Neurological symptoms
o Dysarthria
o Dystonia
o Parkinsonism
o Drooling
o Tremor (usually asymmetric, affecting the hands): Resting tremor,
Intention tremor, Wing-beating tremor
o Behavioral changes (e.g., depression, irritability, psychosis)
o Cognitive impairment
• Renal: Fanconi syndrome
21. WILSON DISEASE – Diagnosis
• Slit lamp examination: Kayser-Fleischer rings (best initial test)
• Blood tests
o ↑ Transaminases
o CBC: Coombs-negative hemolytic anemia, thrombocytopenia
o ↓ Serum ceruloplasmin (normal value >20 mg/dL)
o ↑ Free serum copper, but ↓ total serum copper
• Urine tests: ↑ Urine copper excretion (over 24 hours)
22. WILSON DISEASE – Diagnosis
• Liver biopsy: if other tests are inconclusive
o Hepatic copper concentration (>250 μg/g dry weight)
o Histology: copper staining
• Genetic testing: can be performed for confirmation;
consider also testing family members
• Cranial MRI
o Hyperintensities in the putamen, thalamus,
and brain stem due to copper accumulation
o “face of the giant panda” sign-
midbrain copper accumulation
23. WILSON DISEASE – Treatment
• Low-copper diet: avoid foods such as organ meats, shellfish, nuts, and
chocolate
• Regular check-ups: liver biochemical tests every 6 months if disease is
stable
• Liver transplantation in cases of fulminant liver failure
• Initial therapy: chelating agents- penicillamine, trientine or zinc salts
• Maintenance therapy: zinc salts or low dose chelating agents
