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Liver· Chapter 22

Inherited Liver Diseases

Hereditary hemochromatosis (HFE C282Y, phlebotomy targets), Wilson disease (ATP7B, chelators plus zinc), alpha-1 antitrypsin PiZZ versus PiMZ, cystic-fibrosis liver disease, polycystic liver disease, and LAL deficiency. Plus the cascade-testing decisions for first-degree relatives that fellows always get asked on rounds.

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What this chapter covers

  • Section 22.1: Hereditary hemochromatosis iron metabolism, genetics, and penetrance

    Hereditary hemochromatosis iron overload is driven by inappropriately low hepcidin signaling, which removes the brake on enterocyte ferroportin and accelerates dietary iron absorption.

  • Section 22.2: HH diagnosis, phlebotomy, and HCC surveillance

    The diagnostic gate (ACG 2019, with EASL 2022 endorsing the same two-tier framework) requires fasting transferrin saturation at least 45 percent in men or 40 percent in women plus elevated ferritin (over 300 ng per mL in men or 200 ng per mL in women); HFE genotyping confirms C282Y homozygosity.

  • Section 22.3: Wilson disease diagnosis and Leipzig score

    Wilson disease (ATP7B on chromosome 13q14.3, with over 500 mutations described and approximately 380 disease-associated; H1069Q is the most common variant in European descent at 15 to 25 percent prevalence) impairs biliary copper excretion and ceruloplasmin loading.

  • Section 22.4: Wilson treatment, pregnancy, and monitoring

    First-line chelation in symptomatic Wilson is trientine, paired with zinc for maintenance and counseling on a low-copper diet (avoid shellfish, organ meats, nuts, chocolate, mushrooms).

  • Section 22.5: Alpha-1 antitrypsin deficiency

    PiZZ alpha-1 antitrypsin deficiency causes both pulmonary disease (early-onset panacinar emphysema, lower-lobe predominant in non-smokers) and hepatic disease (chronic hepatitis to cirrhosis).

  • Section 22.6: Cystic fibrosis-associated liver disease

    Cystic fibrosis affects approximately 1 in 3,000 live births in the United States and Northern Europe, and CF-associated liver disease (CFLD) develops in 5 to 10 percent of CF patients over time.

  • Section 22.7: Polycystic liver disease

    Polycystic liver disease in the autosomal dominant polycystic kidney disease (ADPKD) context accompanies kidney cysts; ADPKD is autosomal dominant with PKD1 mutations in about 85 percent and PKD2 mutations in the remainder, producing renal and hepatic cyst growth driven by abnormal cholangiocyte proliferation and fluid secretion through dysregulated planar cell polarity signaling.

  • Section 22.8: PFIC, BRIC, and Alagille syndrome

    The familial cholestatic syndromes split by GGT pattern and by progression.

Podcast episodes

  1. 01

    Hereditary Hemochromatosis

    Hereditary hemochromatosis: its gene, its low biochemical penetrance, the transferrin-saturation-then-ferritin screen that anchors the workup, and phlebotomy to a ferritin target.

  2. 02

    Wilson Disease

    Low ceruloplasmin and high urinary copper, the Leipzig score where no single test stands alone, and chelator-plus-zinc therapy. Where hemochromatosis is a failed iron brake, Wilson is a failed copper exit.

  3. 03

    A1AT, CF Liver Disease, PCLD, and Cholestatic Syndromes

    The other inherited liver diseases: alpha-one antitrypsin deficiency, cystic-fibrosis-associated liver disease, polycystic liver disease, and the familial cholestatic syndromes, each with its own recognition cue and the unifying rule that mechanism predicts therapy.