There are a number of disorders of the liver that fit within the categories of genetic, metabolic, and infiltrative disorders. Inherited disorders include hemochromatosis, Wilson's disease, α1 antitrypsin (α1AT) deficiency, and cystic fibrosis (CF). Hemochromatosis is the most common inherited disorder affecting Caucasian populations, with the genetic susceptibility for the disease being identified in 1 in 250 individuals. Over the past 15 years, it has become increasingly apparent that nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes found in the U.S. population. With the obesity epidemic in the United States, it is estimated that 20% of the population may have abnormal liver enzymes on the basis of NAFLD and 3% may have nonalcoholic steatohepatitis (NASH). Infiltrative disorders of the liver are relatively rare.
Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism (Chap. 357). Our knowledge of the disease and its phenotypic expression has changed since 1996, when the gene for HH, called HFE, was identified, allowing for genetic testing for the two major mutations (C282Y and H63D) that are responsible for HFE-related HH. Subsequently, several additional genes/proteins involved in the regulation of iron homeostasis have been identified, contributing to a better understanding of cellular iron uptake and release and the characterization of additional causes of inherited iron overload (Table 309-1).
Table 309-1 Classification of Iron Overload Syndromes |Favorite Table|Download (.pdf)
Table 309-1 Classification of Iron Overload Syndromes
Hereditary Hemochromatosis (HH)
HFE-related (type 1)
Other HFE mutations
HJV—hemojuvelin (type 2a)
HAMP—hepcidin (type 2b)
TfR2-related HH (type 3)
Ferroportin-related HH (type 4)
African iron overload
Secondary Iron Overload
Parenteral iron overload
Chronic liver disease
Most patients with HH are asymptomatic; however, when patients present with symptoms, they are frequently nonspecific and include weakness, fatigue, lethargy, and weight loss. Specific, organ-related symptoms include abdominal pain, arthralgias, and symptoms and signs of chronic liver disease. Increasingly, most patients are now identified before they have symptoms, either through family studies or from the performance of screening iron studies. Several prospective population studies have shown that C282Y homozygosity is found in about 1 in 250 individuals of Northern European descent, with the heterozygote frequency seen in approximately 1 in 10 individuals. It is important to consider HH in patients who present with the symptoms and signs known to occur in established HH. When confronted with abnormal serum iron studies, clinicians should not wait for typical symptoms or findings of HH to appear before considering the diagnosis. However, once the diagnosis of HH is considered, either by an evaluation of abnormal screening iron studies, in the context of family studies, in a patient with an abnormal genetic test, or in the evaluation of a patient with any of the typical symptoms or clinical findings, definitive diagnosis is relatively straightforward. Transferrin saturation [serum iron divided by total iron-binding capacity (TIBC) or transferrin, times 100%] and ferritin levels should be obtained. Both of these will be elevated in a symptomatic patient. It must be remembered that ferritin is an acute-phase reactant and can be elevated in a number of other inflammatory disorders, such as rheumatoid arthritis, or in various neoplastic diseases, such as lymphoma or other cancers. Also, serum ferritin is elevated in a majority of patients with NASH, in the absence of iron overload.
At present, if patients have an elevated transferrin saturation or ferritin level, genetic testing should be performed; if they are a C282Y homozygote or a compound heterozygote (C282Y/H63D), the diagnosis is confirmed. If the ferritin is >1000 μg/L, the patient should be considered for liver biopsy because there is an increased frequency of advanced fibrosis in these individuals. If liver biopsy is performed, iron deposition is found in a periportal distribution with a periportal to pericentral gradient; iron is found predominantly in parenchymal cells, and Kupffer cells are spared.
Treatment: Hereditary Hemochromatosis
Treatment of HH is relatively straightforward with weekly phlebotomy aimed to reduce iron stores, recognizing that each unit of blood contains 200 to 250 mg of iron. If patients are diagnosed and treated before the development of hepatic fibrosis, all complications of the disease can be avoided. Maintenance phlebotomy is required in most patients and usually can be achieved with 1 unit of blood removed every 2–3 months. Family studies should be performed with transferrin saturation, ferritin, and genetic testing offered to all first-degree relatives.
Wilson's disease is an inherited disorder of copper homeostasis first described in 1912 (Chap. 360). The Wilson's disease gene was discovered in 1993, with the identification of ATP7B. This P-type ATPase is involved in copper transport and is necessary for the export of copper from the hepatocyte. Thus, in patients with mutations in ATP7B, copper is retained in the liver, leading to increased copper storage and ultimately liver disease as a result.
The clinical presentation of Wilson's disease is variable and includes chronic hepatitis, hepatic steatosis, and cirrhosis in adolescents and young adults. Neurologic manifestations indicate that liver disease is present and include speech disorders and various movement disorders. Diagnosis includes the demonstration of a reduced ceruloplasmin level, increased urinary excretion of copper, the presence of Kayser-Fleischer rings in the corneas of the eyes, and an elevated hepatic copper level, in the appropriate clinical setting. The genetic diagnosis of Wilson's disease is difficult because >200 mutations in ATP7B have been described with different degrees of frequency and penetration in certain populations.
Treatment: Wilson's Disease
Treatment consists of copper-chelating medications such as d-penicillamine and trientine. A role for zinc acetate has also been established. Medical treatment is lifelong, and severe relapses leading to liver failure and death can occur with cessation of therapy. Liver transplantation is curative with respect to the underlying metabolic defect and restores the normal phenotype with respect to copper homeostasis.
α1 Antitrypsin Deficiency
Alpha-1-antitrypsin (AAT) deficiency was first described in the late 1960s in patients with severe pulmonary disease. AAT is a 52 kD glycoprotein produced in hepatocytes, phagocytes, and epithelial cells in the lungs, which inhibits serine proteases, primarily neutrophil elastase. In AAT deficiency, increased amounts of neutrophil elastase can result in progressive lung injury from degradation of elastin leading to premature emphysema. In the 1970s, AAT deficiency was discovered as a cause of neonatal liver disease, so-called “neonatal hepatitis.” It is now known to be a cause of liver disease in infancy, early childhood, adolescence, and in adults.
In AAT deficiency, variants in the proteinase inhibitor (Pi) gene located on chromosome 14, alters AAT structure interfering with hepatocellular export. Aggregated, deformed polymers of AAT accumulate in the hepatocyte endoplasmic reticulum. There are over 75 different AAT variants. Conventional nomenclature identifies normal variants as PiMM; these individuals have normal blood levels of AAT. The most common abnormal variants are called S and Z. Individuals homozygous for the Z mutation (PiZZ) have low levels of AAT (about 15% of normal) and these patients are susceptible to liver and/or lung disease, yet only a proportion (about 25%) of PiZZ patients develop disease manifestations. Null variants have undetectable levels of AAT and are susceptible to premature lung disease.
AAT deficiency has been identified in all populations; however, the disorder is most common in patients of Northern European and Iberian descent. The disorder affects about 1 in 1500 to 2000 individuals in North America. The natural history of AAT deficiency is quite variable because many individuals with the PiZZ variant never develop disease, whereas others can develop childhood cirrhosis leading to liver transplantation.
In adults, the diagnosis often comes in the course of evaluation of patients with abnormal liver test abnormalities or in a work-up for cirrhosis. A hint to diagnosis may be coexistent lung disease at a relatively young age or a family history of liver and/or lung disease. Patients may have symptoms of pulmonary disease with cough and dyspnea. Liver disease may be asymptomatic other than fatigue, or patients may present with complications of decompensated liver disease.
Diagnosis of AAT deficiency is confirmed by blood tests showing reduced levels of serum AAT, accompanied by Pi determinations. Most patients with liver disease have either PiZZ or PiSZ; occasionally, patients with PiMZ have reduced levels of AAT, but they usually do not have a low enough level to cause disease. Liver biopsy is often performed to determine stage of hepatic fibrosis and shows characteristic PAS-positive, diastase-resistant globules in the periphery of the hepatic lobule.
Treatment α1 Antitrypsin Deficiency
Treatment of AAT deficiency is usually nonspecific and supportive. For patients with liver involvement, other sources of liver injury, such as alcohol, should be avoided. Evidence for other liver diseases (e.g., viral hepatitis B and C, hemochromatosis, NAFLD, etc.) should be sought and treated if possible. Smoking can worsen lung disease progression in AAT and should be discontinued. Patients with lung disease may be eligible to receive infusions of AT, which has been shown to halt further damage to the lungs. If liver disease becomes decompensated, transplantation should be pursued and is curative. Following transplant, patients express the Pi phenotype of the donor. Finally, risk of hepatocellular carcinoma is significantly increased in patients with cirrhosis due to AAT deficiency.
CF should also be considered as an inherited form of chronic liver disease, although the principal manifestations of CF include chronic lung disease and pancreatic insufficiency (Chap. 259). A small percentage of patients with CF who survive to adulthood have a form of biliary cirrhosis characterized by cholestatic liver enzyme abnormalities and the development of chronic liver disease. Ursodeoxycholic acid is occasionally helpful in improving liver test abnormalities and in reducing symptoms. The disease is slowly progressive.
Nonalcoholic Fatty Liver Disease
NAFLD was first described in the 1950s when fatty liver was characterized in a group of obese patients. In 1980, Ludwig and colleagues at the Mayo Clinic described 20 obese, diabetic, nonalcoholic patients who had similar findings on liver biopsy to patients with alcoholic liver disease, and the term nonalcoholic steatohepatitis was introduced. The prevalence of NAFLD in the United States and Europe ranges from 14–20%. This increased prevalence relates directly to the obesity epidemic seen in these populations. In the United States, NASH is thought to occur in ∼3% of the general population, with fibrosis due to NASH being seen in >40% of obese patients. The spectrum of NAFLD includes simple hepatic steatosis, which, over time, can progress to NASH, with the subsequent development of fibrosis and cirrhosis. Causes of macrovesicular steatosis are listed in Table 309-2. It is now known that many patients with hitherto identified “cryptogenic” cirrhosis in fact have liver disease on the basis of NASH, with the resolution of the steatosis once patients become catabolic due to cirrhosis.
Table 309-2 Causes of Macrovesicular Steatosis |Favorite Table|Download (.pdf)
Table 309-2 Causes of Macrovesicular Steatosis
Insulin resistance, hyperinsulinemia
Type 2 diabetes
Protein deficiency (Kwashiorkor)
Chronic hepatitis C—genotype 3
Indian childhood cirrhosis
Most patients who come to medical attention with NAFLD are identified as a result of incidentally discovered elevated liver enzymes (ALT, AST). When patients are symptomatic, symptoms include fatigue or a vague right upper quadrant discomfort. ALT is generally higher than AST, and aminotransferases are only mildly (1.5–2 times the upper limit of normal) elevated. Recent studies have shown that many patients can have advanced fibrosis with NASH and even cirrhosis due to NASH with normal liver enzymes, indicating that the prevalence of the disease is likely to be even greater than was previously suspected. NASH is frequently seen in conjunction with other components of the metabolic syndrome (hypertension, diabetes mellitus, elevated lipids, and obesity), with NAFLD being considered the hepatic manifestation of this syndrome (Chap. 242). Insulin resistance is the underlying link between these various disorders and numerous studies have shown that virtually all patients with NASH have insulin resistance. Abnormal ferritin values are seen in ∼50% of patients with NASH, and an elevated ferritin level may be a marker of insulin resistance in NASH.
The diagnosis of NAFLD requires a careful history to determine the amount of alcohol used. Most investigators in the field of fatty liver disease require that <20 g/d of alcohol be consumed to exclude alcoholic liver disease. Laboratory testing for other liver diseases such as hepatitis B and C, iron studies, ceruloplasmin, α-1 antitrypsin levels, and autoimmune serologies should also be determined. Imaging studies can show characteristic features of a fatty liver, but the ultimate diagnosis of either hepatic steatosis or NASH requires liver biopsy. Liver biopsy shows characteristic macrovesicular steatosis with occasional microvesicular fat being identified. A mixed inflammatory infiltrate is found in a lobular distribution. The histologic features of NASH are very similar to those seen in alcoholic liver disease; Mallory's hyaline can be seen in both disorders, although the number of hepatocytes containing Mallory's hyaline and the size of the deposits are frequently greater in alcoholic liver disease than in NASH. The fibrosis that occurs in NASH has a characteristic perivenular and perisinusoidal distribution. Most cross-sectional studies show that up to 30–40% of NASH patients can develop advanced fibrosis, with cirrhosis being identified in 10–15% of individuals in series. Increasingly, patients are being identified with cryptogenic cirrhosis who have most likely had NASH for decades. These patients can develop liver failure and require liver transplantation, and some patients can progress to the development of hepatocellular cancer. Often, when cirrhotic, these patients will not have steatosis on biopsy, but following transplant, NAFLD will frequently recur.
Treatment: Nonalcoholic Fatty Liver Disease
The mainstay of treatment of fatty liver disease is weight loss and exercise, which is often difficult to achieve in this population. As an aid to weight loss, orlistat, which is a reversible inhibitor of gastric and pancreatic lipase, has been shown to result in a small decrease in body weight and is usually fairly well tolerated. This medication is now available over-the-counter. Bariatric surgery has been used and shows striking success, but is obviously a fairly drastic maneuver for induction of weight loss. Recent studies have focused on the presence of insulin resistance at the center of the pathophysiologic mechanisms of NAFLD. The thiazolidinedione medications are PPAR gamma inhibitors, which improve insulin sensitivity within the adipocyte and skeletal muscle by upregulating specific protein kinases involved in decreasing fatty acid synthesis. Two drugs—pioglitizone and rosiglitizone—are currently available and are being evaluated as potential therapeutic options in the treatment of NASH. Antioxidants have also been used, and a recent large multicenter study has shown benefit from vitamin E supplementation. Treatment of hyperlipidemia with statin-type agents has shown improvement in liver enzymes, but they have not been assessed for effects on histology. Ursodeoxycholic acid has been used and improves liver enzymes in patients with many liver diseases, but it has not been definitively helpful for fatty liver disease. At present, efforts should be directed to encouraging patients with NAFLD to lose weight and exercise.
There are a number of rare lipid storage diseases that involve the liver, including the inherited disorders of Gaucher's and Niemann-Pick disease (Chap. 362). Other rare disorders include abetalipoproteinemia, Tangier disease, Fabray's disease, and types I and V hyperlipoproteinemia. Hepatomegaly is present due to increased fat deposition and increased glycogen found in the liver.
The porphyrias are a group of metabolic disorders in which there are defects in the biosynthesis of heme necessary for incorporation into numerous hemoproteins such as hemoglobin, myoglobin, catalase, and the cytochromes (Chap. 358). Porphyrias can present as either acute or chronic diseases, with the acute disorder causing recurring bouts of abdominal pain, and the chronic disorders characterized by painful skin lesions. Porphyria cutanea tarda (PCT) is the most commonly encountered porphyria. Patients present with characteristic vesicular lesions on sun-exposed areas of the skin, principally the dorsum of the hands, the tips of the ears, or the cheeks. About 40% of patients with PCT have mutations in the gene for hemochromatosis (HFE), and ∼50% have hepatitis C; thus, iron studies and HFE mutation analysis as well as hepatitis C testing should be considered in all patients who present with PCT. PCT is also associated with excess alcohol use and some medications, most notably estrogens.
The mainstay of treatment of PCT is iron reduction by therapeutic phlebotomy, which is successful in reversing the skin lesions in the majority of patients. If hepatitis C is present, this should be treated as well. Acute intermittent porphyria presents with abdominal pain, with the diagnosis made by avoidance of certain precipitating factors such as starvation or certain diets. Intravenous heme as hematin has been used for treatment.
Amyloidosis is a metabolic storage disease that results from deposition of insoluble proteins that are aberrantly folded and assembled and then deposited in a variety of tissues (Chap. 111). Amyloidosis is divided into two types, primary and secondary, based on the broad concepts of association with myeloma (primary) or chronic inflammatory illnesses (secondary). The disease is generally considered rare, although, in certain disease states or in certain populations, it can be more common. For example, when associated with familial Mediterranean fever, it is seen in high frequency in Sephardic Jews and Armenians living in Armenia and less frequently in Ashkenazi Jews, Turks, and Arabs. Amyloidosis frequently affects patients suffering from tuberculosis and leprosy and can be seen in upwards of 10–15% of patients with ankylosing spondylitis, rheumatoid arthritis, or Crohn's disease. In one surgical pathology series, amyloid was found in <1% of cases. The liver is commonly involved in cases of systemic amyloidosis, but it is frequently inapparent clinically and only documented at autopsy. Pathologic findings in the liver include positive staining with the Congo red histochemical stain where there is an apple-green birefringence noted under polarizing light.
Granulomas are frequently found in the liver when patients are being evaluated for cholestatic liver enzyme abnormalities. Granulomas can be seen in primary biliary cirrhosis, but there are other characteristic clinical (e.g., pruritus, fatigue) and laboratory findings (cholestatic liver tests, antimitochondrial antibody) that allow for a definitive diagnosis of that disorder. Granulomatous infiltration can also be seen as the principal hepatic manifestation of sarcoidosis, and this is the most common presentation of hepatic granulomas (Chap. 329). The vast majority of these patients do not require any specific treatment other than what would normally be used for treatment of their sarcoidosis. A small subset, however, can develop a particularly bothersome desmoplastic reaction with a significant increase in fibrosis, which can progress to cirrhosis and liver failure. These patients may require treatment with immunosuppressive therapy and may require liver transplantation. In patients who have granulomas in the liver not associated with sarcoidosis, treatment is rarely needed.
Diagnosis requires liver biopsy, and it is important to establish a diagnosis so that a cause for the elevated liver enzymes is carefully identified. Some medications can cause granulomatous infiltration of the liver, the most notable of which is allopurinol.
Involvement of the liver with lymphoma can sometimes be with bulky mass lesions but can also be as a difficult-to-diagnose infiltrative disorder that does not show any characteristic findings on abdominal imaging studies (Chap. 110). Patients may present with severe liver disease, jaundice, hypoalbuminemia, mild to moderately elevated aminotransferases, and an elevated alkaline phosphatase.
A liver biopsy is required for diagnosis and should be considered when routine blood testing does not lead to a diagnosis of the liver dysfunction.