Alpha-1 Antitrypsin Deficiency and Other Metabolic Liver Diseases

Alpha-1 antitrypsin (α-1 AT), a serine protease of the SERPIN superfamily, inhibits tissue proteases such as neutrophil elastase and proteinase 3.

α-1 AT is encoded by the SERPINA1 gene on the long arm of chromosome 14 (14q31-32.2); α-1 ATD is an autosomal codominant disorder affecting up to 1 in 1800 live births.

PiMM (Pi = protease inhibitor), the normal variant, is the phenotype present in 95% of the population and is associated with normal serum levels of α-1 AT.

>100 allelic variants of α-1 AT are recognized. Not all variants are associated with clinical disease.

The Z α-1 AT protein is caused by a single nucleotide substitution (Glu to Lys). The variant is most common in persons of northern European descent.

PiZZ and PiSZ phenotypes are associated with severe deficiency and liver disease, whereas the PiMZ phenotype leads to an intermediate deficiency and rarely causes liver disease. Low circulating levels of α-1 AT cause emphysema, whereas liver disease is caused by retention of the abnormally folded protein in the endoplasmic reticulum.

α-1 ATD predisposes children and adults to liver disease.

Liver involvement is often first identified in the newborn period as a result of persistent cholestatic jaundice. Affected infants tend to be small for gestational age. From 10% to 15% of persons with the PiZZ phenotype present with liver disease in the first years of life ( Table 20.1 ).

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  Of those presenting with neonatal liver disease, 10% to 30% develop moderate to severe liver disease with coagulopathy, poor growth, and ascites in childhood.

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  In a prospective study from Sweden of children identified by newborn screening, 85% of PiZZ children demonstrated improvement in both clinical and laboratory signs of liver disease over an 18-year period. Only 5% to 10% of all PiZZ children developed significant liver disease ( Fig. 20.1 ).

  

Serum aminotransferase, alkaline phosphatase, and gamma-glutamyltranspeptidase (GGTP) levels may all be elevated.

Emphysema develops in 60% to 70% of adults with α-1 ATD older than 25 years of age, especially in those who smoke tobacco, with a peak in the fourth and fifth decades.

Vascular abnormalities, including spontaneous carotid artery dissection and neutrophilic panniculitis, are also associated with α-1 ATD.

Liver disease is associated with retention of abnormally folded Z protein in the endoplasmic reticulum of hepatocytes. Liver disease occurs in the PiZZ and PiSZ phenotypes but rarely in persons with PiMZ. Liver disease does not occur with the other variants (e.g., PiSS).

Far fewer patients exhibit liver and lung disease associated with α-1 ATD than estimated by population human genetic estimations, a finding that suggests involvement of unidentified genetic and environmental factors and modifier genes in the development of tissue damage.

The pathogenesis of α-1 ATD–associated liver disease is not completely understood. The following theories have been proposed:

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  Accumulation of mutant protein in the endoplasmic reticulum may result in hepatotoxicity. This theory is supported by a transgenic mouse model and a study demonstrating delayed protein degradation of mutant α-1 AT Z protein in persons with liver disease compared with those without liver disease.

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  Autophagy, a cellular mechanism for disposal of accumulated proteins, has been suggested to be defective in those with liver disease.

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  Other inherited traits for protein degradation and environmental factors (e.g., viral hepatitis) may increase accumulation of the defective protein and result in increased liver injury.

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  Liver disease is unlikely to be a consequence of a “proteolytic attack” mechanism, which is the likely mechanism responsible for lung injury.

The PiMZ state may predispose to more severe liver injury in various hepatic disorders (HBV and HCV infections, alcoholic liver disease, CF-associated liver disease, NAFLD).

The diagnosis of α-1 ATD is established by a serum α-1 AT level, phenotype (Pi typing), or genotype.

Serum levels of α-1 AT are generally decreased in affected patients; however, α-1 AT is an acute phase reactant and can be falsely elevated. Serum concentrations are rarely higher than 50 to 60 mg/dL in patients with the PiZZ phenotype. The PiMZ or PiSZ phenotype correlates with an α-1 AT level that is 50% of normal.

Liver histology showing diastase-resistant globules that are periodic acid–Schiff positive in the endoplasmic reticulum of periportal hepatocytes is classic for the disease, but these features should not be used for diagnosis because some patients with PiMZ also have these findings (see Fig. 20.1 ).

The diagnosis should be considered in all adults and children with chronic hepatitis or cirrhosis of unknown origin, children presenting with portal hypertension of unknown origin, and infants with neonatal cholestasis.

No specific therapies are available for α-1 ATD–associated liver disease at this time.

Infants with cholestasis may benefit from fat-soluble vitamin supplements (vitamins A, D, E, and K) and infant formula containing medium-chain triglyceride oil. In addition, treatment with ursodeoxycholic acid may increase bile flow and reduce liver injury associated with cholestasis, although no evidence indicates a direct long-term benefit in α-1 ATD.

Avoidance of cigarette smoking, including secondhand smoke, and of environmental pollution exposure is mandatory to delay the onset or slow the progression of lung disease. Replacement therapy with purified or recombinant α-1 AT by infusion has been successful in slowing the decline in forced expiratory volume in a nonrandomized trial, and this therapy is often used.

LT is the recommended treatment for α-1 ATD–associated end-stage liver disease and liver failure.

The recipient assumes the donor Pi phenotype and is no longer at risk for emphysema. Long-term survival is excellent. LT should be pursued before lung decompensation precludes LT.

Somatic gene therapy, in which a normal α-1 ATD gene is transferred to an organ capable of synthesizing the mature protein that could be secreted into the circulation, is potentially useful for the treatment of lung disease. Gene therapy for treatment of liver disease requires delivery of peptides to the endoplasmic reticulum to prevent polymerization of mutant protein or manipulation of the degradation system in those at risk for liver disease. The technology is currently limited by poor transfer of gene products and unknown safety risks.

Small molecule pharmacologic chaperone therapy, RNA interference of PiZZ gene translation, and manipulation of autophagy are being evaluated as possible future treatment strategies.

Screening is recommended for all relatives of patients with α-1 ATD to identify PiZZ or PiSZ family members and is mandatory for siblings of affected patients. Universal newborn screening has not been instituted.

This disease is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the terminal enzyme in phenylalanine and tyrosine degradation.

This autosomal recessive defect has an incidence of 1 in 100,000. The disorder is most prevalent in French Canadians in Quebec, Canada, where it has an incidence of 1 in 1800.

Many mutations of the FAH gene have been identified; no correlations exist between the genotype and the severity of disease. A founder mutation has been found in Quebec.

The disorder is characterized by progressive cholestasis and liver failure, renal tubular dysfunction, and hypophosphatemic rickets.

It may manifest as acute hepatic failure in infancy, neonatal cholestasis, rickets, or failure to thrive, or, later in childhood, as compensated or decompensated cirrhosis. The acute form usually manifests with poor growth, irritability, and vomiting. Death from liver failure by 1 to 2 years of age is not uncommon in untreated patients.

Patients have a characteristically prolonged prothrombin time despite mild elevations in aminotransferase and bilirubin levels and may have hypoglycemia with fasting. Serum alkaline phosphatase levels may be disproportionately elevated because of rickets caused by renal tubular involvement.

Neurologic crises develop and resemble acute intermittent porphyria, presumably from competitive inhibition of δ-aminolevulinic acid (ALA) dehydratase by succinylacetone.

Cardiomyopathy, particularly interventricular septal hypertrophy, is found in 30% of newly diagnosed patients. This complication resolves during treatment in most patients.

The incidence of HCC in untreated persons is high, even in the first 2 to 3 years of life.

Tyrosine metabolites, including tyrosine and succinylacetone, proximal to the FAH blockage accumulate.

Succinylacetone and succinylacetoacetate inhibit enzymes, including porphobilinogen synthase, and this process results in increased levels of ALA, which is responsible for acute neurologic crises.

The pathogenesis of liver injury caused by the accumulation of toxins is not understood.

Liver histology is characterized by macrovesicular steatosis, pseudoacinar formation of hepatocytes, hemosiderosis, and variable hepatocyte necrosis and apoptosis. Periportal fibrosis progresses to micronodular cirrhosis with regenerative nodules.