Inherited Metabolic Liver Diseases

Lectures27

α1-ANTITRYPSIN DEFICIENCY

• 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.

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)

II. Secondary HemochromatosisSecondary Iron-overload

Acquired forms of iron accumulation from known sources of excess iron are called secondary iron overload (Hemosiderosis). Due to

Multiple transfusions, Ineffective erythropoiesisIncreased iron intake.Secondary/ Acquired/ Hemosiderosis

Thalassaemia, Sideroblastic anaemias, Alcoholic cirrhosis or Multiple transfusions

We will use the terms

• HEMOCHROMATOSIS for the HEREDITARY disease and

• HEMOSIDEROSIS for the ACQUIRED deposition of iron in some tissues.

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

EtiopathogenesisNormally, 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%).

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 50 gm, 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.

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.

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.

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

MorphologyThe 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.

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

architecture is normal.

Clinical features

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

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

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

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

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)

TreatmentPhlebotomies (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.

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

Hepatolenticular Degeneration

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

PhysiologyNormal 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

PathogenesisIn 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.

PathogenesisUsually 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.

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).

MorphologyExcess 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.

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).

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.

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.

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.

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

penicillamine, or Trientine) or

• zinc-based therapy.

• Liver Transplantation

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

• 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)

• 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.

PathogenesisAAT 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.

• 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 .

• 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.

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.

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.

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

Treatment• The treatment, and the cure, for severe hepatic

disease is orthotopic liver transplantation.

Orthotopic – in the normal or usual position

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).