Metabolic & Inherited Liver Diseases

Lectures 25, 26

α1-ANTITRYPSIN DEFICIENCY

Metabolic Liver Disease

1.Type2 diabetes

2.Obesity3.Dyslipidemia

• Hemochromatosis• Wilson disease

• α1-ANTITRYPSIN DEFICIENCY

• 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.

Primary or Heriditary Hemochromatosis

Hemochromatosis is a homozygous-recessive inherited disorder that is caused by excessive iron absorption.

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.

• We will use the terms hemochromatosis for the hereditary disease and

• hemosiderosis for the acquired deposition of iron in some tissues.

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.

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.

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

• 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.

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.

HFE gene is resposible for this disorder.

• 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.

• Hereditary hemochromatosis manifests

typically after 20gm of

storage iron has accumulated.

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.

Morphology• 1. The deposition of hemosiderin• 2. Cirrhosis• 3. Pancreatic fibrosisThe pancreas, heart, skin, joints and testes may

also be affected.

Clinical features

1. Hepatomegaly2. Abdominal Pain3. Skin Pigmentation4. Diabetes Mellitus5. Arrhythmias, cardiomyopathy6. Arthritis.

• Amenorrhea• Loss of libido• Impotence• Triad of Cirrhosis (Hepatomegaly, Skin

pigmentation, DM) • Death due to: Cirrhosis, HCC, Cardiac disease

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

Diagnosis

• Serum ferritin• Liver biopsy• HFE• MRI

TreatmentPhlebotomies (bloodletting)Deferoxamine

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.

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.

• 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.

Morphology

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

Clinical Features.

Age between 6 and 40. The most common presentation is acute or

chronic liver disease.

• Neuropsychiatric manifestations, including mild behavioral changes,

• frank psychosis, or a Parkinson disease–like syndrome (such as tremor

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).

• 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.

Treatment• Early recognition and• long-term copper chelation therapy (as with

D-penicillamine, or Trientine) or• zinc-based therapy. • Liver Transplantation

Mamoon Manzoor Mashwani

Metabolic & Inherited Liver Diseases

Part II

α1-ANTITRYPSIN DEFICIENCY

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

α1-Antitrypsin• α1-Antitrypsin is a small 394–amino acid

plasma glycoprotein synthesized predominantly by hepatocytes.

• 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.

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)

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.

Cirrhosis

Treatment• The treatment, and the cure, for severe

hepatic disease is liver transplantation.

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

duodenum.

Neonatal Hepatitis• Neonatal hepatitis is an

inflammation of the liver that occurs in early infancy, usually one to two months after birth.

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.

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.