Neonatal hepatitis with cholestatic jaundice appears in 10% to 20% of newborns with α1AT deficiency. In adolescence, presenting symptoms may be related to hepatitis or cirrhosis. Attacks of hepatitis may subside with apparent complete recovery, or they may become chronic and lead progressively to cirrhosis. Alternatively, the disease may remain silent until cirrhosis appears in middle to later adult life. HCC develops in 2% to 3% of PiZZ adults, usually in the setting of cirrhosis. The definitive treatment, for severe hepatic disease is liver transplantation. In patients with pulmonary disease, avoidance of cigarette smoking is crucial, because smoking results in accumulation of neutrophils and release of elastase in the lung that is not inactivated because of lack of α1AT. The unopposed action of neutrophil derived proteases destroys elastic fibers in alveolar walls, leading to emphysema (Chapter 13).
Fig. 16.21 α1-Anti-trypsindeficiency.Periodicacid–Schiff(PAS)stainafterdiastasedigestionoftheliver,highlightsthecharacteristicmagentacytoplas-micgranules.
HemochromatosisismostcommonlycausedbymutationsintheHFE geneandlesscommonlybymutationsinothergenes,allofwhichresultindecreasedhepcidinlevelsorfunctionandincreasedintestinalironuptake.Itischaracterizedbyaccumulationofironintheliver,pancreas,andothertissues.
Wilsondiseaseiscausedbyloss-of-functionmutationsinthemetaliontransporterATP7B,whichresultsinaccumulationofcopperintheliver,brain(particularlybasalganglia),andeyes(Kayser-Fleischerrings).
Wilsondiseaseeffectsontheliverareprotean,showingchangesrangingfromacutemassivehepaticnecrosis,tofattyliverdisease,tochronichepatitisandcirrhosis.
α1ATdeficiencyisadiseaseinwhichmutationsinα1ATleadtoitsmisfolding,causinglivertoxicityandafunctionaldeficitofα1ATintheplasma.Thisdeficiencyplacesaffectedindividualsathighriskforemphysema,particularlysmokers,duetotheunopposedeffectsofproteasesreleasedfromneutrophils.
Hepatic bile serves two major functions: (1) the emulsification of dietary fat in the lumen of the gut through the detergent action of bile salts, and (2) the elimination of bilirubin, excess cholesterol, xenobiotics, and other waste products that are insufficiently water-soluble to be excreted into urine. Processes that interfere with excretion of bile lead to jaundice and icterus due to retention of bilirubin, and to cholestasis (discussed later).
Jaundice may occur in settings of increase bilirubin production (e.g., extravascular red cell hemolysis), hepatocyte dysfunction (e.g., hepatitis), or obstruction of the flow of bile (e.g., an impacted gallstone), any of which can disturb the equilibrium between bilirubin production and clearance (summarized in
Table 16.4 ). The metabolism of bilirubin by the liver occurs in four steps: uptake from the circulation; intracellular storage; conjugation with glucuronic acid; and biliary excretion. These are discussed next.
Bilirubin is the end product of heme degradation (
Fig.