1. Metabolic & Inherited Liver Diseases
Lectures 25, 26
α1-ANTITRYPSIN
DEFICIENCY

2. Metabolic Liver Disease
1.Type2 diabetes
2.Obesity
3.Dyslipidemia

3. • Hemochromatosis
• Wilson disease
• α1-ANTITRYPSIN DEFICIENCY

5. • Hemochromatosis was first described by von
Recklinghausen in 1889. It is characterized by
the excessive accumulation of body iron,
most of which is deposited in parenchymal
organs such as the liver and pancreas.

6. Primary or Heriditary
Hemochromatosis
Hemochromatosis is a
homozygous-recessive
inherited disorder that is
caused by excessive iron
absorption.

7. Secondary Hemochromatosis
• Accumulation of iron in tissues, which may
occur as a consequence of parenteral
administration of iron, usually in the form of
transfusions, or other causes, is variably
known as secondary hemochromatosis,
acquired hemochromatosis, or
hemosiderosis.

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

9. The total body iron pool ranges from 2 to 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 50 gm, over one third of which
accumulates in the liver.

10. Characteristic features of Hemochromatosis
• 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.

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

12. • There are at least four genetic variants of
hereditary hemochromatosis. The most
common form is an autosomal recessive
disease of adult onset caused by mutations in
the HFE gene.

13. 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 gm/year. HFEgene is
resposible for this disorder.

14. • HFE regulates the levels of hepcidin,
the iron hormone produced by the
liver. Hepcidin normally down-regulates the
efflux of iron from the intestines and
macrophages into the plasma and
inhibits iron absorption.
• When hepcidin levels are reduced there is
increased iron absorption.

15. • Hereditary hemochromatosis manifests
typically after 20gmof
storage iron has accumulated.

16. Regardless of source, excessive iron
seems to be directly toxic to tissues by
the following mechanism:
(1) Lipid peroxidation by iron-catalyzed free radical
reaction,
(2) Stimulation of Collagen formation
(3) Direct interaction of iron with DNA.
Whatever the actions of iron, they may be reversible,
with the exception of nonlethal DNA damage.

17. Morphology
• 1. The deposition of hemosiderin
• 2. Cirrhosis
• 3. Pancreatic fibrosis
The pancreas, heart, skin, joints and testes may
also be affected.

18. Clinical features
1. Hepatomegaly
2. Abdominal Pain
3. Skin Pigmentation
4. Diabetes Mellitus
5. Arrhythmias, cardiomyopathy
6. Arthritis.

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

20. • Treatment of iron overload does not remove
the risk for development of HCC, because of
the oxidative damage of DNA produced by
iron.

21. Diagnosis
• Serum ferritin
• Liver biopsy
• HFE
• MRI

22. Treatment
Phlebotomies (bloodletting)
Deferoxamine

23. 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.

25. 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 copper into ceruloplasmin.

26. • Deficiency in the ATP7B protein causes a
decrease in copper transport into bile,
impairs its incorporation into ceruloplasmin,
and inhibits ceruloplasmin secretion into the
blood.
• These changes cause copper accumulation in
the liver and a decrease in circulating
ceruloplasmin.
• The copper causes toxic liver injury, through
the production of ROS.

27. Morphology
• Inflammation
• Hepatocyte necrosis
• Macrovesicular steatosis,
• vacuolated hepatocellular nuclei,
• Mallory bodies.
• Cirrhosis

28. Clinical Features.
Age between 6 and 40.
The most common presentation is acute or
chronic liver disease.

29. • Neuropsychiatric manifestations,
including mild behavioral changes,
• frank psychosis, or a Parkinson disease–like
syndrome (such as tremor

30. Biochemical Diagnosis
• a decrease in serum ceruloplasmin,
• an increase in hepatic copper content (the most
sensitive and accurate test), and
• increased urinary excretion of copper (the most
specific screening test).

31. • 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.

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

33. Mamoon Manzoor
Mashwani

34. Metabolic &
Inherited Liver
Diseases
Part II

35. α1-ANTITRYPSIN
DEFICIENCY
α1-Antitrypsin deficiency is an
autosomal recessive disorder
marked by very low levels of α1-
antitrypsin.

37. α1-
Antitrypsin• α1-Antitrypsin is a small 394–amino acid
plasma glycoprotein synthesized
predominantly by hepatocytes.

39. • The major function of this protein is the
inhibition of proteases,
particularly neutrophil elastase, cathepsin G,
and proteinase 3, which are normally
released from neutrophils at
sites of inflammation.

42. α1- Antitrypsin deficiency leads to the
development of:
• pulmonary emphysema,
• liver disease,
• cutaneous panniculitis (inflammation of subcutaneous adipose tissue) ,
• arterial aneurysm,
• bronchiectasis,
• Wegener's granulomatosis (vasculitis)

43. 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.

46. Cirrhosis

50. Treatment
• The treatment, and the cure, for severe
hepatic disease is liver transplantation.

51. Cholestasis is a condition where bile
cannot flow from the liver to the
duodenum.

52. Neonatal Hepatitis
• Neonatal hepatitis is an
inflammation of the liver
that occurs in early
infancy, usually one to two
months after birth.

53. Causes of Neonatal Hepatitis
• Neonatal hepatitis mainly caused by a
virus, such as hepatitis B virus,
cytomegalovirus, rubella virus, herpes simplex
virus and gastro-intestinal virus. Toxoplasma
gondii parasite, Li Division Thac bacteria,
syphilis, etc., is also one of the causes of
neonatal hepatitis.

54. NEONATAL CHOLESTASIS
• Prolonged conjugated hyperbilirubinemia in the
neonate, termed neonatal cholestasis, affects
approximately 1 in 2500 live births.
Cholestasis is a condition
where bile cannot flow
from the liver to the
duodenum.