1. Inherited Metabolic Liver Diseases
Lectures27
α1-ANTITRYPSIN DEFICIENCY

2. • It is characterized by the excessive accumulation of
body iron, most of which is deposited
in parenchymal organs such as the
LIVER,PANCREAS.
Types :Primary & Secondary
Bronze Diabetes
Pigment Cirrhosis, Disorder of Iron overload
Less commonly
affected organs: Heart,
endocrine glands, skin,
synovium and testis.

3. I. Idiopathic, Primary or
Heriditary Hemochromatosis
At least four genetic variants of
hereditary hemochromatosis are
recognized.
The most common form is an autosomal
recessive disease of adult onset
caused by mutations in the HFE
gene.
HFE- for High Fe (Iron)

4. II. Secondary Hemochromatosis
Secondary Iron-overload
Acquired forms of iron accumulation from known
sources of excess iron are called secondary iron
overload (Hemosiderosis). Due to
Multiple transfusions,
Ineffective erythropoiesis
Increased iron intake.
Secondary/ Acquired/ Hemosiderosis
Thalassaemia,
Sideroblastic anaemias,
Alcoholic cirrhosis or
Multiple transfusions

5. We will use the terms
• HEMOCHROMATOSIS for the
HEREDITARY disease and
• HEMOSIDEROSIS for the ACQUIRED
deposition of iron in some tissues.

6. Characteristic features of Fully developed Hemochromatosis
Fully developed cases exhibit (Triad):
(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.
Triad - CDP

7. Etiopathogenesis
Normally, the body iron content is 3-4 gm (2-6 gm)
which is maintained in such a way that intestinal
mucosal absorption of iron is equal to its loss. This
amount is approximately 1 mg/day in men and 1.5
mg/day in menstruating women.
In haemochromatosis, however, this amount goes up
to 4 mg/day or more, as evidenced by elevated
serum iron (normal about 125 μg/dl) and
increased serum transferrin saturation (normal
30%).

8. The total body iron pool ranges from 2 - 6 gm in
normal adults; about 0.5 gm is stored in the liver,
98% of which is in hepatocytes.
In hemochromatosis, total iron accumulation may
exceed 50gm, over one third of which
accumulates in the liver.
In hereditary hemochromatosis, iron accumulates over the
lifetime of the affected person from excessive intestinal
absorption.

9. Pathogenesis
• In hereditary hemochromatosis there is a defect
in the regulation of intestinal absorption of
dietary iron, leading to net iron accumulation of
0.5 to 1.0 g/year. The hereditary hemochromatosis
gene, responsible for the most common form of this
disorder, is called HFE. Expression of the mutated
(overexpressed) HFE protein on small intestinal
enterocytes leads to inappropriately upregulated
absorption of iron and its binding to transferrin,
the major iron carrying molecule in blood.

10. Pathogenesis
Hepcidin levels are reduced in all currently
known genetic forms of hemochromatosis.
When hepcidin levels are reduced there is
increased iron absorption.
Hepcidin, the iron hormone produced by the liver, normally
downregulates the efflux of iron from the intestines and
macrophages into the plasma and inhibits iron absorption.

11. Pathogenesis
• Hereditary hemochromatosis manifests typically
after 20 gm of storage iron has accumulated.
Regardless of source, excessive iron seems to be
directly toxic to tissues by the following
mechanisms:
• Lipid peroxidation by iron-catalyzed free radical
reactions
• Stimulation of collagen formation
• Direct interactions of iron with DNA

12. Morphology
The liver typically is slightly larger than normal,
dense, and chocolate brown.
Fibrous septa develop slowly, linking portal tracts to
each other and leading ultimately to cirrhosis in an
intensely pigmented liver.
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.

13. Hereditary hemochromatosis. In this Prussian blue– stained
histologic section, hepatocellular iron appears blue. The parenchymal
architecture is normal.

14. Clinical features
1. Hepatomegaly
2. Abdominal Pain
3. Skin Pigmentation
4. Diabetes Mellitus
5. Arrhythmias, cardiomyopathy
6. Arthritis.
Males predominate (5 -7 : 1) with slightly earlier
clinical presentation,
partly because physiologic iron loss
(menstruation, pregnancy) delays iron
accumulation in women.

15. • Amenorrhea
• Loss of libido
• Impotence
• Triad of Cirrhosis (Hepatomegaly, Skin
pigmentation, DM)
• Death due to: Cirrhosis, HCC, Cardiac disease

16. Diagnosis
• Serum Iron
• Serum Transferrin Saturation
• Serum ferritin
• Liver biopsy
• HFE ( Screening of relatives for mutations)
• MRI
• Estimation of chelatable iron stores using chelating
agent (e.g. desferrioxamine)

17. Treatment
Phlebotomies (bloodletting)
Iron chelators (Deferoxamine )
Treatment of iron overload does not remove the risk for development of HCC,
because of the oxidative damage of DNA produced by iron.

18. Prognosis
• A third of those untreated develop hepatocellular
carcinoma
• The risk of HCC development in patients with
hemochromatosis is 200-fold higher than in
normal populations.
200 200

19. Hepatolenticular Degeneration

20. Definition
• Wilson disease is an autosomal recessive disorder
caused by mutation of the ATP7B gene, resulting
in impaired COPPER excretion into BILE and a
failure to incorporate (add in) COPPER into
CERULOPLASMIN.
This autosomal recessive disorder is marked by the accumulation of toxic levels
of copper in many tissues and organs, principally the liver, brain, and eye.
The cause is loss-of-function mutations in the ATP7B gene,
more than 300 of which have been identified.
ATP7B gene- the normal hepatic copper- excreting
gene. “ATPase, Cu++ transporting, beta polypeptide

21. Physiology
Normal copper physiology involves the following sequence:
1. Absorption of ingested copper (2 to 5 mg/day)
2. Plasma transport in complex with albumin
3. Hepatocellular uptake, followed by binding to an α2-
globulin (apoceruloplasmin) to form ceruloplasmin
4. Secretion of ceruloplasmin-bound copper into plasma,
where it accounts for 90% to 95% of plasma copper
5. Hepatic uptake of desialylated, senescent ceruloplasmin
from the plasma, followed by lysosomal degradation and
secretion of free copper into bile

22. Pathogenesis
In Wilson disease, the initial steps of copper absorption and
transport to the liver are normal. However, without ATP7B
activity, copper cannot be passed on to apoceruloplasmin
and therefore cannot be excreted into bile, the primary
route for copper elimination from the body. Copper thus
accumulates progressively in hepatocytes, apparently
causing toxic injury by a three-step mechanism:
(1) promoting the formation of free radicals,
(2) binding to sulfhydryl groups of cellular proteins, and
(3) displacing other metals in hepatic metalloenzymes.

23. Pathogenesis
Usually by the age of 5 years, copper begins to escape
from the overloaded, damaged hepatocytes into
the circulation. Free copper generates oxidants that
can lead to red cell hemolysis. It also is deposited in
many other tissues, such as the brain, cornea,
kidneys, bones, joints, and parathyroid glands,
where it also produces damage through the same
mechanisms that injure hepatocytes.
Concomitantly, urinary excretion of copper
increases markedly.

24. Morphology
• Inflammation
• Hepatocyte necrosis
• Macrovesicular steatosis,
• vacuolated hepatocellular nuclei,
• Mallory bodies.
• Cirrhosis
Hepatic changes ranging from relatively
minor to massive damage and
mimicking many other diseases.
In the brain, toxic injury primarily affects the basal
ganglia, particularly the putamen, which
demonstrates atrophy and even cavitation. Nearly all
patients with neurologic involvement develop eye
lesions called Kayser-Fleischer rings (green
to brown deposits of copper in Descemet membrane
in the limbus of the cornea)—hence the alternative
designa- tion of this condition as hepatolenticular
degeneration (lenticular – related to lenses).

25. Morphology
Excess copper deposition can often be demonstrated
by special stains (e.g., rhodanine stain for copper,
orcein stain for copper-associated protein). Because
copper also accumulates in chronic obstructive
cholestasis, and because histologic analysis cannot
reliably distinguish Wilson disease from other
causes of liver disease, demonstration of hepatic
copper content in excess of 250 µg/g dry weight is
most helpful for making a diagnosis.

26. Clinical Features.
Age between 6 and 40.
The most common presentation is acute or chronic
liver disease.
Unlike nearly all other forms of cirrhosis,
hepatocellular carcinoma is quite uncommon in
Wilson disease.
Triad of features: 1. Cirrhosis of the liver. 2. Bilateral
degeneration of the basal ganglia of the brain. 3. Greenish-
brown pigmented rings in the periphery of the cornea
(Kayser-Fleischer rings).

27. Neuropsychiatric manifestations, including mild
behavioral changes,
frank psychosis, or a Parkinson disease–like
syndrome (such as tremor)
Ceruloplasmin is a ferroxidase enzyme that in
humans is encoded by the CP gene.
Ceruloplasmin is the major copper-carrying
protein in the blood, and in addition plays a
role in iron metabolism.

28. Biochemical abnormalities in Wilson’s disease include
the following:
1 Decreased serum ceruloplasmin (due to impaired
synthesis of apoceruloplasmin in damaged liver and
defective mobilisation of copper from
hepatocellular lysosomes).
2. Increased hepatic copper in liver biopsy (due to
excessive accumulation of copper in the liver).
3. Increased urinary excretion of copper.
4. However, serum copper levels are of no diagnostic
help and may vary from low-to-normal-to-high
depending upon the stage of disease.

29. Biochemical Diagnosis
• AN INCREASE IN HEPATIC COPPER CONTENT (THE
MOST SENSITIVE AND ACCURATE TEST), and
• INCREASED urinary excretion of copper (the most
specific screening test).
• Demonstration of Kayser-Fleischer rings
(green to brown deposits of copper in Desçemet's
membrane in the limbus of the cornea) further
favors the diagnosis.
Descemet's membrane is the basement membrane that lies between the corneal
proper substance, also called stroma, and the endothelial layer of the cornea.

30. Treatment
• Early recognition and
• long-term copper chelation therapy (as with D-
penicillamine, or Trientine) or
• zinc-based therapy.
• Liver Transplantation

31. α1-ANTITRYPSIN (Glycoprotein)
DEFICIENCY
α1-Antitrypsin deficiency is an autosomal
recessive disorder marked by
abnormally low levels of α1-
antitrypsin (Glycoprotein).
Causes LUNG (Emphysema) & LIVER (Cirrhosis) diseases
AAT - Protease inhibitor

32. • The major function of this protein is the
inhibition of proteases,
particularly
• NEUTROPHIL ELASTASE,
• CATHEPSIN G, &
• PROTEINASE 3,
• which are normally released from
neutrophils at sites of inflammation.
Protease inhibitor (Pi)

33. • AAT deficiency leads to pulmonary emphysema,
because a relative lack of this protein permits the
unrestrained activity of tissue-destructive
proteases. Hepatic disease results from retention
of mutant AAT in the liver.
Out of 24 different alleles labelled alphabetically, PiMM
is the most common normal phenotype, while the most
frequent abnormal phenotype in α-1-antitrypsin
deficiency leading to liver and/or lung disease is PiZZ
in homozygote form.

34. Pathogenesis
AAT is a small (394–amino acid) plasma glycoprotein
synthesized predominantly by hepatocytes. The AAT
gene, located on human chromosome 14, is very
polymorphic, and at least 75 forms have been
identified. Most allelic variants produce normal or
mildly reduced levels of serum AAT. However,
homozygotes for the Z allele (PiZZ genotype) have
circulating AAT levels that are only 10% of normal
levels. AAT alleles are autosomal codominant (relating to
two alleles of a gene pair in a heterozygote that are both fully expressed), and
consequently PiMZ heterozygotes have
intermediate plasma levels of AAT.

35. • The PiZ polypeptide contains a single amino acid
substitution that results in misfolding of the nascent
polypeptide in the hepatocyte endoplasmic
reticulum. Because the mutant protein cannot be
secreted by the hepatocyte, it accumulates in the
endoplasmic reticulum and triggers the so-called
unfolded protein response, which can lead to
induction of apoptosis .

36. • Curiously, all persons with the PiZZ genotype
accumulate AAT in the liver, but only 8% to 20%
develop significant liver damage. This manifestation
may be related to a genetic tendency in which
susceptible persons are less able to degrade
accumulated AAT protein within hepatocytes.

37. Morphology
• α1-Antitrypsin deficiency is characterized by the
presence of round-to-oval cytoplasmic globular
inclusions in hepatocytes, which in routine H&E
stains are acidophilic and indistinctly
demarcated from the surrounding cytoplasm.

40. Morphology
• By electron microscopy cytoplasmic globules lie
within smooth, and sometimes rough,
endoplasmic reticulum.
• Hepatic injury associated with PiZZ homozygosity
may range from marked cholestasis with hepatocyte
necrosis in newborns, to childhood cirrhosis, to a
smoldering chronic hepatitis or cirrhosis that
becomes apparent only late in life.

41. Clinical features
• Of all newborns with AAT deficiency, 10% to 20%
exhibit cholestasis.
• In older children, adolescents, and adults,
presenting symptoms may be related to chronic
hepatitis, cirrhosis, or pulmonary disease.
• The disease may remain silent until cirrhosis
appears in middle to later life.
• Hepatocellular carcinoma develops in 2% to 3% of
adults with PiZZ genotype, usually but not always in
the setting of cirrhosis

42. Treatment
• The treatment, and the cure, for severe hepatic
disease is orthotopic liver transplantation.
Orthotopic – in the normal or usual position

43. SUMMARY
• Inherited Metabolic Diseases
• Hemochromatosis is characterized by accumulation of iron
in liver, pancreas, heart, pituitary gland, joints and other
tissues. It is usually caused by mutations in the HFE gene,
which encodes a protein that influences intestinal iron
uptake.
• Wilson disease is the result of accumulation of copper in
the liver, brain, and eyes; it is caused by a mutation in the
metal ion transporter ATP7B.
• α1-Antitrypsin (AAT) deficiency in persons of PiZZ geno-
type causes pulmonary emphysema (due to increased
elastase activity) and liver injury (caused by the accumula-
tion of misfolded AAT).