Hepatology

Inherited Metabolic Liver Diseases

Anthony S. Tavill

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There are many inherited metabolic diseases that may have a pathologic impact on the liver. In many cases, the liver component of these diseases is only an epiphenomenon of a more generalized systemic disorder. Examples of such epiphenomena are glycogen and lipid storage diseases, in which hepatomegaly is a manifestation of the underlying metabolic defect, although the liver is not necessarily the major target organ. However, there are three genetically determined diseases in which the liver may be the principal target organ, with manifestations of acute, subacute, or chronic disease that may become evident in early or later life. These are hereditary hemochromatosis (HH), a major disorder of iron overload, Wilson’s disease, a genetic disorder of copper overload, and alpha1-antitrypsin (α1-AT) deficiency, a disorder in which the normal processing of a liver-produced protein is disturbed within the liver cell.

In some cases, the awareness of these conditions is brought about by suspicion based on a specific clinical syndrome. In other cases, these conditions have to be excluded when faced with nonspecific liver disease abnormalities, such as elevated liver enzyme levels, hepatomegaly, or previously undiagnosed portal hypertension. In the case of hemochromatosis, the approach to early diagnosis has moved one step further, with an awareness that markers of iron overload may be present in the serum long before liver disease has developed. These chapters will focus on discussions of these three conditions.

Certain key concepts (Box 1) are common to all three conditions and need to be emphasized at the outset. First, although the recognition of inherited liver disease is often the process of exclusion of more common causes (e.g., viruses, alcohol, autoimmunity), it is important to emphasize that awareness of the clinical features of these metabolic liver diseases should promote a proactive diagnostic evaluation. Second, inherited metabolic liver disease may manifest in childhood or may be delayed until adult life and, in some cases, may regress after the childhood or adolescent years, only to reappear later in life. Third, with the advent of molecular diagnostic testing, phenotypic assessment of these conditions may be now complemented in certain cases by genotypic evaluation. Fourth, with the availability of effective treatments, there has been a dramatic impact on the prognosis of metabolic liver diseases in both childhood and adult life, further emphasizing the importance of early diagnosis. Finally, in several conditions (e.g., α1-AT deficiency, Wilson’s disease), liver transplantation corrects the primary biochemical abnormality in the liver and effectively cures the disease.

Box 1: Key Concepts
  1. Awareness of the clinical features of inherited metabolic liver diseases should promote proactive diagnostic evaluation.
  2. The clinical features of certain inherited metabolic liver diseases may manifest in childhood, disappear during growth and development, and reappear in adult life.
  3. Molecular diagnostic testing has made genotypic evaluation available for some diseases to complement phenotypic diagnosis.
  4. Preemptive treatment may prevent the development of phenotypic complications in some diseases (e.g., hereditary hemochromatosis and Wilson’s disease), and orthotopic liver transplantation may be curative in others (e.g., alpha1-antitrypsin deficiency and Wilson’s disease).

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Alpha1-Antitrypsin Deficiency

Anthony S. Tavill

Loutfi S. Aboussouan

Definition

Alpha1-antitrypsin (α1-AT) deficiency is a common inherited disorder associated with retention of the liver-produced protein α1-AT in the liver and low levels of α1-AT in the serum. In the most severe form of α1-AT deficiency, the clinical features consist of early-onset emphysema, neonatal hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. However, phenotypic expression throughout life is extremely variable. The gene for α1-AT is located on chromosome 14, and mutations at the protease inhibitor (PI) locus lead to a single amino acid substitution (glutamic acid for lysine 342) that impairs secretion of the mutant gene product, leading to retention of α1-AT in the hepatocyte and low levels of α1-AT in the serum. Because the phenotype is expressed by autosomal codominant inheritance, each allele is responsible for 50% of the circulating α1-AT level. Approximately 100 allelic variants have been described, only some of which are associated with liver disease. The Z allele is the mutation associated with maximum deficiency in α1-AT.

Epidemiology

The frequency of this pathogenic PI Z allele in the U.S. population of European descent is between 0.01 and 0.02, with the homozygous deficiency state affecting 1 in 2000 to 7000 of the population. The major deficiency occurs in the PI ZZ phenotypes, with indirect epidemiologic approaches and more direct population-based screening methods estimating that about 60,000 people in the United States are homozygous for this phenotype. In Scandinavia, the frequency of the Z allele is considerably higher, resulting in one PI ZZ in 1600 live births. The PI Z allele is confined predominantly to whites and is found rarely in African Americans or Asians. There are many other allelic combinations that may have clinical relevance, including the MZ heterozygous state and other combinations, such as PI SZ, which are also associated with α1-AT deficiency in the serum.

Pathophysiology

α1-AT is the predominant serine PI in the blood, accounting for the alpha1 peak on serum protein electrophoresis. α1-AT functions by inhibition of tissue proteinases that include enzymes such as neutrophil elastase, cathepsin G, and various other proteinases. This is a relatively low-molecular-weight protein, composed of 394 amino acids and several carbohydrate side chains. α1-AT is also an acute-phase protein, and its synthesis may increase significantly in response to injury or inflammation.

Despite its name, α1-AT reacts much more readily with neutrophil elastase than with trypsin, in a mutually suicidal interaction that normally maintains an adequate protective screen against the elastolytic burden of neutrophil elastase. α1-AT deficiency shifts this balance in favor of elastolytic breakdown, most commonly manifesting as emphysema.

The synthesis of α1-AT occurs within the endoplasmic reticulum of the hepatocyte and undergoes multiple complex foldings and insertions of carbohydrate side chains. Genetic mutations responsible for α1-AT deficiency may interfere with synthesis, export from the cell, and the ability to function as a proteinase inhibitor.

The Z variant results from a single point mutation leading to the substitution of glutamic acid for lysine at position 342. The resultant variant polypeptide is relatively unstable and becomes polymerized within the endoplasmic reticulum, resulting in the periodic acid–Schiff (PAS)-positive globules that can be seen on light microscopy. Only the α1-AT variants that lead to this type of polymerization are associated with a gain of function defect leading to liver cell damage. The rare "null" variant is not characterized by accumulation of α1-AT within the hepatocyte and is not associated with liver damage.

In contrast, polymerization of mutated antitrypsin prevents its secretion from the hepatocyte, so that only about 15% of the PI ZZ antitrypsin is secreted into the plasma. Polymerization and the rare null variant both result in a loss of function defect, which increases the risk of developing emphysema.

Approximately 100 allelic variants have been described in the α1-AT gene locus, resulting in a complex genetic classification based on the phenotypic features of the circulating α1-AT protein. The most common variant, PI M, is present in approximately 95% of the U.S. white population and is regarded as the normal variant associated with normal serum levels of functional α1-AT. Only about 15 alleles (encompassing deficiency, dysfunctional, and null alleles) are associated with liver disease, lung disease, or bleeding diathesis. Deficiency alleles, such as PI Z and PI S, may result in decreased levels of circulating α1-AT but with completely normal functioning proteins. The MM phenotype is therefore designated as manifesting a 100% concentration of circulating α1-AT. The heterozygous combination MZ yields 50%, SZ 37.5%, and ZZ 15% of this normal MM value. Approximately 95% of all α1-AT deficiency states leading to clinical manifestations are made up of PI ZZ homozygotes. Certain alleles, such as the S allele, either in the homozygous state or associated with the M allele, do not appear to be associated with the abnormally polymerized molecules within the endoplasmic reticulum and have not been incriminated in the development of liver or lung disease unless combined with the Z allele. The products of these various alleles have distinctive characteristics on isoelectric focusing, which provides a means for the specific identification of the PI types (see later, "Diagnosis").

Signs and Symptoms

The association of α1-AT deficiency and liver disease in children was first described in 1969 by Harvey Sharp at the University of Minnesota. Many subsequent clinical studies have observed that liver disease occurrence in α1-AT deficiency is bimodal, affecting children in neonatal life or early infancy and, less commonly, adults in late middle life. In both these groups, the homozygous form of α1-AT deficiency is the underlying genetic predeterminant (Table 1).

Table 1: Clinical Manifestations of Alpha1-Antitrypsin Deficiency*
Children Adults
Neonatal or infant hepatitis Chronic obstructive pulmonary disease
Prolonged cholestasis in infancy Chronic hepatitis
Hepatosplenomegaly Cirrhosis with or without portal hypertension
Hepatocellular carcinoma

*Alpha1-antitrypsin deficiency may also be asymptomatic.
© 2002 The Cleveland Clinic Foundation.

Children with PI ZZ Deficiency of Alpha1-Antitrypsin

Much of the information on the clinical presentation of α1-AT deficiency in this population has come from experience in Scandinavia. Two thirds of newborns deficient in α1-AT have abnormal liver enzyme levels, and approximately 10% develop persistent cholestasis during the first year of life. Many of these infants appear to undergo a spontaneous remission, and only about 3% of the originally diagnosed neonates progress to fibrosis or cirrhosis during the childhood and teenage years. Nevertheless, careful surveillance has revealed that many of these have persistently abnormal liver enzyme levels.

Newborns with the most fully expressed form of the disease show evidence of acute neonatal hepatitis, with a predominantly conjugated hyperbilirubinemia. This jaundice may persist for as long as 1 year, with associated evidence of defective growth and the consequence of malabsorption of fat-soluble vitamins. Physical signs include hepatomegaly, splenomegaly, and possible signs of coagulopathy.

Adults with PI ZZ Deficiency of Alpha1-Antitrypsin

Most adults with PI ZZ α1-AT deficiency are identified by their pulmonary symptoms and show signs and symptoms of chronic obstructive pulmonary disease, with emphysema developing in about 80% to 100% of individuals with that phenotype. This condition is frequently aggravated by cigarette smoking. The emphysema associated with α1-AT deficiency has distinctive features, including early onset (in the fourth or fifth decade of life), predominant involvement of the lung bases, and panacinar pathology. In contrast, individuals with α1-AT–replete emphysema are older, with predominantly apical and centrilobular emphysema.

The prevalence of associated liver disease has probably been underestimated, but 10% to 40% of these adults may have evidence of cirrhosis. The risk of cirrhosis becomes higher with advancing years, particularly in men. In these cases, a man older than 50 years with evidence of cirrhosis, portal hypertension, or hepatocellular carcinoma with no underlying predisposing cause should evoke suspicion of an underlying metabolic defect such as hemochromatosis or α1-AT deficiency. The features of the liver disease appear to be rapidly progressive when diagnosed at this stage, with a high likelihood of death within 4 years of the identification of liver disease.

Heterozygous Alpha1-Antitrypsin Deficiency

A number of studies have asserted a role for a single mutant allele in the development of so-called cryptogenic liver disease in adults. Because many of these heterozygous states are associated with intermediate α1-AT deficiency, it will be necessary to carry out prospective studies to evaluate the pathophysiologic consequences of the heterozygous state. In the pediatric arena, there is no indication of any significant long-term consequences of heterozygous α1-AT. In adults, however, it has been suggested that the presence of a single Z allele may increase susceptibility or act synergistically with other risk factors for liver disease. These associated conditions include chronic viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. Many of these synergistic conditions may be associated with an inflammatory response, leading to further defects in α1-AT poly¬merization and degradation within the hepatocyte.

Diagnosis

α1-AT deficiency is an example of an inherited metabolic disorder in which the definition of the phenotype also defines the genotype (Box 2). Determination of the α1-AT serum level by quantitative immunoprecipitation is insufficient evidence for the diagnosis of α1-AT deficiency. This is because serum levels may be falsely elevated as a result of the particularly robust acute-phase response of this protein. Therefore, determination of the quantitative level of α1-AT must be combined with phenotypic analysis. This defines the phenotype of the variant PI proteins in the serum and is performed by isoelectric focusing. Patients with the most severe form of deficiency have an allelic variant that migrates to a higher isoelectric point and can be defined as PI ZZ phenotypes, and therefore by inference as PI ZZ genotypes. Interpretation of the electrophoretic patterns on isoelectric focusing will determine the homozygous or heterozygous states, and will define the specific mutant alleles based on their relative position between anode and cathode. Finally, the molecular genetic tools for defining the defect in the nucleotide coding sequence for each of the defective alleles have been developed for population studies but are not currently routinely available in diagnostic laboratories.

Epidemiologic considerations have established a threshold amount of α1-AT necessary to protect the lung from emphysema. This protective threshold level is 80 mg/dL by radial diffusion, and 11 μM when referenced to functional elastase activity (normal values, 150 to 350 mg/dL or 20-53 μM, respectively). In PI ZZ individuals, serum α1-AT levels cluster around a mean value of approximately 6 μM.

The American Thoracic Society and European Respiratory Society have provided guidelines that recommend testing for α1-AT deficiency in the following cases: (1) early-onset emphysema (younger than 45 years); (2) emphysema in the absence of a recognized risk factor; (3) emphysema with prominent basilar hyperlucency; (4) unexplained liver disease; (5) necrotizing panniculitis; (6) antiproteinase 3–positive vasculitis (C-ANCA positive vasculitis); (7) family history of any of the following: emphysema, bronchiectasis, liver disease, or panniculitis; or (7) bronchiectasis without evident cause.

In patients with manifestations of liver disease, liver biopsy for light microscopy and histochemistry and possible electron microscopy is valuable for staging liver disease and for identification of the PAS-positive–diastase-resistant globules within the hepatocytes. In neonates, the globules may be indistinct and ill developed, but they increase with age. In adult patients, in particular, they may be associated with portal and periportal inflammation. Confirmation of the nature of the globules may be provided by immunohistochemical techniques, using immunoperoxidase coupled to α1-AT antibody. Finally, the location of these globules within the endoplasmic reticulum may be confirmed by electron microscopy.

Box 2: Diagnostic Tests for Alpha1-Antitrypsin Deficiency
  • Determination of quantitative level of serum alpha1-antitrypsin and phenotypic analysis of alpha1-antitrypsin by isoelectric focusing
  • Gene analysis
  • Liver biopsy for:
    • Light microscopy with evaluation of diastase-resistant, periodic acid–Schiff-positive globules
    • Immunochemistry for alpha1-antitrypsin
    • Electron microscopy

© 2002 The Cleveland Clinic Foundation.

Treatment

In advanced and decompensating liver disease, the only available approach is orthotopic liver transplantation (OLT). This is the most common inherited disorder leading to liver transplantation in children. As in Wilson’s disease, the outcome of OLT is extremely good, and replacement of the liver provides the recipient with the donor’s α1-AT phenotype.

Newer approaches that may have an impact on the secretion of α1-AT from the hepatocyte may prove helpful, but these are in the experimental stage of development. Finally, although consideration of gene therapy may ultimately provide the most hopeful approach for α1-AT deficiency, this will have to be achieved with the removal of the aberrant mutant gene, which will pose a considerable challenge.

Because α1-AT deficiency is associated with variable phenotypic expression, it is reasonable to counsel patients with regard to all other possible sources of liver injury, such as alcohol abuse. A similar approach has been adopted for those with lung injury—counseling patients regarding the deleterious effects of smoking.

Augmentation therapy refers to the exogenous infusion of purified pooled human plasma α1-AT. It can be given on a weekly, biweekly, or monthly basis. Although this has become the mainstay of specific therapy in α1-AT deficiency with emphysema, the technique offers no significant help in improving the liver injury. Studies have suggested that augmentation can reduce the number of lung infections, slow the rate of decline of lung function, reduce mortality, and reduce the rate of loss of lung tissue as determined by computed tomography (CT) scanning.

Outcomes

The outcomes of treatment, short of liver transplantation, present conflicts of purpose when they are aimed at preventing both liver and lung diseases. This is because the benefits of any approach that increases the serum levels of α1-AT to protect the lungs may not always offer similar protection to the liver. Only liver transplantation offers an effective cure for the condition by correcting the recipient phenotype and normalizing the circulating levels of α1-AT.

Summary
  • Alpha1-antitrypsin (α1-AT) deficiency is an inherited liver disorder caused by disordered α1-AT secretion by the hepatocyte, with varying phenotypic features.
  • The most severe forms are characterized by neonatal hepatitis, chronic hepatitis, cirrhosis, hepatocellular cancer, and early-onset emphysema.
  • Approximately 100 allelic variants of the α1-AT gene have been described. The Z variant is the one associated with the most severe phenotypic features.
  • Diagnosis is confirmed by phenotypic analysis of the variant forms of α1-AT in the serum and, when there are manifestations of liver disease, by a liver biopsy, with immunohistochemical and ultrastructural evaluations.
  • Treatment is by liver transplantation for decompensated liver disease, and by augmentation therapy for the relief and prevention of symptomatic emphysema.
  • Liver transplantation cures the metabolic defect in α1-AT deficiency.

Suggested Readings

  1. American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818-900.
  2. Berg NO, Eriksson S: Liver disease in adults with alpha-1-antitrypsin deficiency. N Engl J Med 1972;287:1264-1267.
  3. Carrell RW, Lomas DA: Alpha 1-antitrypsin deficiency—a model for conformational diseases. N Engl J Med 2002;346:45-53.
  4. Fischer HP, Ortiz-Pallardo ME, Ko Y, et al: Chronic liver disease in heterozygous alpha 1-antitrypsin deficiency PiZ. J Hepatol 2000;33:883-892.
  5. Perlmutter DH: The cellular basis for liver injury in alpha 1-antitrypsin deficiency. Hepatology 1991;13:172-185.
  6. Perlmutter DH: Clinical manifestations of alpha 1-antitrypsin deficiency. Gastroenterol Clin North Am 1995;24:27-43.
  7. Rosen HR: Liver disease associated with alpha 1-antitrypsin deficiency. In Rosen HR, Martin P (eds): Metabolic Liver Disease: Clinics in Liver Disease, vol 2. Philadelphia, WB Saunders, 1998, pp 175-185.
  8. Sharp HL, Bridges RA, Krivit W, Freier EF: Cirrhosis associated with alpha-1-antitrypsin deficiency: A previously unrecognized inherited disorder. J Lab Clin Med 1969;73:934-939.
  9. Stoller JK, Aboussouan LS: Alpha1-antitrypsin deficiency. Lancet. 2005;365:2225-2236.

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Hemochromatosis

Anthony S. Tavill

Definition

Hereditary hemochromatosis (HH) is defined as an inherited disorder of iron metabolism that leads to progressive, parenchymal, cellular iron overload in many tissues of the body—in particular in the liver, pancreas, and heart (Box 3). When the degree of iron overloading reaches a critical level, structural and functional damage to these organs may become apparent, and these constitute the phenotypic evidence for HH. The genotypic definition is based on a single missense mutation, the so-called C282Y mutation, of the HFE gene on the short arm of chromosome 6, which has a major role in the regulation of iron metabolism. When this mutation is present in both copies of the gene, homozygous HH is said to be present. Not every individual who is homozygous for this mutation develops phenotypic evidence of iron overload. Furthermore, there are other hereditary forms of iron overload based on alternative mutations of the HFE gene or mutations of other genes that may also play a role in the regulation of iron metabolism.

Prevalence

The HFE gene and its mutation were first described in 1996.The HFE gene has considerable homology with other major histocompatibility complex class 1 antigens. The principal mutation at amino acid position 282 in the protein product of this gene leads to the substitution of tyrosine for cysteine, which has a profound effect on the function of this protein. Retrospective analyses of individuals in the United States with phenotypic or familial evidence for homozygous HH have revealed that 83% to 100% were homozygous for the C282Y mutation. Another mutation, H63D, located at the 63 position of the HFE protein, was present in association with the C282Y mutation in approximately 4% of similar populations. These persons are termed compound heterozygotes. Subsequent studies from other countries have confirmed an average prevalence of C282Y homozygosity of approximately 90% in previously diagnosed HH patients. Approximately 10% of individuals with a clinical condition that is phenotypically similar to HH lack the C282Y mutation. Mutations of other genes not located on chromosome 6 also may play a role in iron metabolism and are currently being investigated.

Box 3: Causes of Iron Overload

Hereditary Hemochromatosis

  • Type 1—HFE-related
    • C282Y homozygotes
    • C282Y : H63D compound heterozygotes
    • Rare alternative HFE mutations
  • Types 2, 3, and 4—Non-HFE mutations

Secondary Iron Overload

  • Iron-loading anemias with or without blood transfusion
  • Chronic liver diseases
  • Hepatitis B and C
  • Alcoholic liver disease
  • Nonalcoholic fatty liver disease
  • Porphyria cutanea tarda
  • Dietary iron overload
  • Miscellaneous causes
  • African iron overload with or without genetic predisposition
  • Neonatal iron overload
  • Aceruloplasminemia
  • Atransferrinemia

It is now evident that HH is the most common identified mendelian genetic disorder in the white population. Although its geographic distribution is worldwide, it is particularly common in individuals of Northern European descent, particularly of Nordic or Celtic ancestry. Overall, its prevalence in the white population is approximately 1 in 300, with a higher prevalence of 1 in 150 to 200 in the Anglo-Celtic-Nordic population.

Pathophysiology

Before mutational analysis was available, it was believed that the homozygous genetic abnormality inevitably led to progressive iron overload. With the availability of genotypic analysis, it is now apparent that the homozygous state for the mutation does not invariably lead to iron overload. There are those who have the genetic mutation on both alleles but who do not express it phenotypically. However, in those who do, there appears to be a pathophysiologic predisposition to increased inappropriate absorption of dietary iron, which leads to the progressive development of life-threatening complications of cirrhosis, hepatocellular cancer, diabetes, and heart disease. The normal HFE protein is expressed predominantly in the crypt cells of the upper intestine where, in association with the transferrin receptor, it may play a role in sensing the iron status of the body. Evidence has suggested that the mutant HFE protein is unable to provide this sensing, therefore “misinforming” the villous cell of the small intestine that iron deficiency might be present. This may lead to upregulation of the iron transport protein normally expressed on the villous cell, thereby explaining the inappropriate intestinal absorption of dietary iron. Although the genetic predisposition to increase iron absorption is present at birth, the disease may take 40 to 50 years or longer to progress to significant organ damage. Therefore, it is useful to think of the evolution of this clinical condition as a series of stages that begins with clinically insignificant iron accumulation based on the genetic abnormality (from 0 to 20 years of age, 0 to 5 g parenchymal iron storage). Subsequently, this evolves to a stage of iron overload without evident disease (at approximately 20 to 40 years of age, 5 to 20 g parenchymal iron storage). If left untreated, the condition may progress to the stage of iron overload with organ damage (usually at 40 years of age or older, and with more than 20 g of parenchymal iron storage).

Signs and Symptoms

With the increased awareness of hereditary hemochromatosis as a common clinical condition in whites, the disease is being diagnosed as a condition of predisposition to iron overload before the classic clinical symptoms and signs develop. In the past 40 years, the percentage of individuals with this condition who were symptomatic, with evidence of target organ damage, has been overtaken by a predominance of individuals who are asymptomatic, with only laboratory evidence for iron overload but with no abnormal physical signs. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation—so-called bronzed diabetes—is now a rare finding.

Even in the absence of early diagnoses based on abnormal serum iron markers, or on abnormal liver function found incidentally or by appropriate family screening, many early symptoms of HH are nonspecific. These consist of weakness, malaise, fatigue, lethargy, and weight loss that may not evoke an awareness, even in the astute clinician, unless appropriate laboratory tests are performed. At this stage, there may be no abnormal physical signs or only a minimal degree of hepatomegaly. Development of arthralgias, loss of libido, or impotence may also not arouse the suspicion of HH unless appropriate laboratory tests are performed. These features may antedate the more classic and specific clinical findings associated with involvement of the liver, pancreas, heart, and skin. At this later point in the development of the condition, usually when there is significant heavy iron overload, patients may reveal marked hepatomegaly, abnormal liver enzyme levels, skin pigmentation resulting both from iron deposition and increased melanin, glucose intolerance, and cardiac signs indicative of a dilated cardiomyopathy, with associated cardiac dysrhythmias and congestive heart failure.

As the liver disease progresses, portal hypertension with ascites, splenomegaly, and additional cutaneous features of chronic liver disease become apparent. These features of progressive liver disease are greatly accelerated in the face of coexisting risk factors such as alcohol abuse, hepatitis C, or nonalcoholic steatohepatitis. Features of hypogonadism may be difficult to interpret as specific for iron overload because they are common complications of end-stage liver disease.

Diagnosis

The diagnostic approach to HH may be targeted at distinct populations (Box 4). These may be symptomatic individuals with unexplained features of liver disease, type 2 diabetes mellitus associated with hepatomegaly and elevated liver enzyme levels, and early-onset atypical arthropathy, cardiac disease, and male sexual dysfunction. In the asymptomatic group, one has to consider the diagnosis in the first-degree relatives of confirmed cases of HH in those with abnormal serum iron markers during routine testing, or other patients referred to the liver clinic with unexplained elevation of liver enzyme levels, asymptomatic hepatomegaly, or radiologic features on CT scanning or magnetic resonance imaging (MRI) suggestive of hepatic iron overload.

Because it is agreed that clinical HH is the result of iron overload, the diagnosis is based on the documentation of increased iron stores—namely, increased hepatic iron concentrations associated with elevated serum ferritin levels. As serologic iron markers have become more widely available in recent years, most patients with HH are now identified while still asymptomatic and without evidence of target organ damage. Now, with the availability of mutational analysis, HH may be further defined genotypically in a first-degree relative by the finding of C282Y homozygosity or C282Y-H63D compound heterozygosity. There is evidence to support the cost effectiveness of sequential testing of these target populations by a combination of indirect phenotypic markers of iron overload in the serum followed by mutational analysis to confirm the presence of classic HFE-related HH (Fig. 1). In this type of analysis, the cost effectiveness of such an approach remains valid, even assuming that as few as 20% of individuals with C282Y homozygosity will ever develop life-threatening complications of the disease.

Box 4: Target Populations for the Diagnosis of Hereditary Hemochromatosis (HH)
  1. Patients with clinical manifestations compatible with HH
    1. Unexplained liver disease, hepatomegaly, or elevated liver enzyme levels
    2. Type 2 diabetes mellitus with associated liver disease, cardiomyopathy, or early-onset sexual dysfunction
    3. Early-onset arthropathy, cardiomyopathy, cardiac dysrhythmias. or sexual dysfunction
  2. Patients without clinical manifestations of HH
    1. First-degree relatives of a patient with identified HH
    2. Incidental finding of elevated serum iron markers (e.g., iron saturation or serum ferritin)
    3. Incidental finding of elevated liver enzyme levels or hepatomegaly, or a compatible computed tomography or magnetic resonance imaging scan of the liver

Data on the sensitivity, specificity, and positive and negative predictive value of phenotypic screening tests have been provided by studies of healthy blood donors, large-scale screening of a healthy population, and first-degree relatives of detected homozygotes. The diagnostic algorithm (see Fig. 1) from the guidelines adopted by the liver and gastroenterology subspecialty societies proceeds in three steps, beginning with phenotypic evaluation and followed by mutational analysis of those individuals with confirmed elevated serum iron markers.

The initial step in the diagnostic approach to HH is the fasting transferrin iron saturation (TS). This is the ratio of serum iron to total iron binding capacity, expressed in μg/dL multiplied by 100. An elevated TS value is the earliest phenotypic manifestation of HH. This is the relatively small circulating iron compartment that appears to be very sensitive to increased dietary iron absorption. The presence of an associated elevated serum ferritin level is usually indicative of accumulating iron stores. Both TS and serum ferritin are susceptible to nonspecific elevation, particularly in the presence of inflammatory diseases and other causes of liver disease. Earlier studies, based largely on evaluation of first-degree relatives of HH patients, have suggested that the combination of these tests has a high degree of sensitivity, specificity, and positive predictive value. Subsequent studies in unselected populations have suggested much lower degrees of sensitivity for both these markers in asymptomatic C282Y homozygotes. However, these tests may now be automated and are relatively inexpensive, providing the most effective means for the early detection of iron overload. Furthermore, a normal serum ferritin level in combination with a TS value lower than 45% has a negative predictive value of 97% and exceeds the accuracy of any of the indirect tests used in isolation. The decision to use a value of 45% for TS is based on studies that suggest values in excess of this correctly identify at least 98% of C282Y homozygotes. However, it is recognized that values in excess of 45% may often include C282Y heterozygotes and others with relatively minor degrees of secondary iron overload (e.g., those with alcoholic liver disease, nonalcoholic steatohepatitis, and chronic hepatitis C, and those who have had surgical portacaval shunts). Finally, the serum ferritin level may have an additional prognostic value; individuals with a ferritin level higher than 1000 ng/mL have a greatly increased likelihood of developing hepatic fibrosis or cirrhosis.

The second stage in the algorithm is genetic mutation analysis for the C282Y and H63D mutations of the HFE gene. This step is reserved for individuals with a fasting TS value higher than 45% and an elevated serum ferritin level. The presence of HFE mutations can now be detected by polymerase chain reaction testing on samples of whole blood, which is available commercially. Individuals with serum indicators of iron overload who are found to be homozygotes for the C282Y mutation are candidates for phlebotomy therapy; in those with no risk factors for significant liver injury, therapeutic phlebotomy may be undertaken without need for a liver biopsy. These usually include those younger than 40 years, with no clinical evidence of liver disease (e.g., increased liver enzyme levels, hepatomegaly) whose serum ferritin level is lower than 1000 ng/mL. Finally, the current recommendation is to offer mutation analysis to first-degree relatives of known HH patients, regardless of the phenotypic markers of iron overload. In such individuals, the presence of homozygosity for the major mutation provides an indication for subsequent regular evaluation of transferrin saturation and serum ferritin levels. Adults who are determined to be homozygous for the major mutation may be offered guidance about the likelihood of the presence of the mutation in their children by appropriate mutation analysis in the spouse. The failure to detect either mutation in the spouse offers reassurance that the children can be only obligate heterozygotes.

The third step of the algorithm advances evaluation through therapeutic phlebotomy. However, the option remains to perform a liver biopsy when there is a strong suggestion of liver disease. Furthermore, liver biopsy is also recommended for compound heterozygotes with elevated TS and abnormal liver enzyme levels or clinical evidence of liver disease. Liver biopsy has a value in the documentation of the presence of cirrhosis or other possible causes of liver disease responsible for elevated liver enzyme levels or hepatomegaly, thereby contributing to evaluation of prognosis in a patient with HH. Finally, the liver is the most easily accessible tissue for accurately assessing the level of iron stores. The degree and cellular distribution of iron stores are assessed using Perls’ Prussian blue test, which provides a qualitative assessment of iron stores based on stainable iron. Grade IV staining is defined as deposition of iron in all zones of the acinus. In addition, quantitative iron determination may be made on fresh-frozen or formalin-fixed tissue. A hepatic iron concentration (HIC) of more than 1800 μg/g dry weight (equal to approximately 32 μmol/g) is indicative of excess iron in the tissue. Because excessive iron deposition in homozygotes who develop iron overload is usually a lifelong progressive accumulation, the rate of iron accumulation itself may provide powerful evidence of homozygous HH. A rate in excess of 1.9 μmol/g/yr is found in most HH homozygotes. This rate is defined as the hepatic iron index, which used to be regarded as the gold standard for homozygous HH. It is now recognized that up to 15% of genotypic homozygotes may have a rate of iron accumulation lower than 1.9 μmol/g/yr; such a definition, based on the hepatic iron index, is no longer regarded as essential for diagnosis. In individuals with HH who are older than 20 years, the HIC is usually at least three times the upper limit of normal (approximately 5400 μg/g), although it is recognized that spuriously low levels of hepatic iron may occur for various reasons, including voluntary blood donation. The HIC is usually elevated to levels exceeding 14,000 μg/g dry weight in those who have already developed hepatic fibrosis or cirrhosis; they are usually older than 40 years. In certain cases, these manifestations of liver damage may occur at a younger age and at lower levels of hepatic iron. In the absence of cofactors such as alcohol or hepatitis, it is rare to see fibrosis or cirrhosis in those younger than 40 years.

It is therefore important to emphasize that the value of liver biopsy is not limited to determination of the HIC. Rather, the documentation of cirrhosis on liver biopsy also has a significant impact on the prognosis in terms of morbidity and mortality in HH patients. Individuals who are treated before the development of cirrhosis usually have a normal life expectancy.

Treatment

The treatment of HH is simple and relatively safe. Therapeutic phlebotomy will effectively mobilize and remove iron stores and, when adhered to on a regular basis, will maintain them at normal levels (Table 2). Patients should be encouraged to adhere to a regimen of phlebotomy of one unit of blood once or twice weekly as tolerated initially. This will remove approximately 250 mg of iron for each unit of phlebotomy, depending on the starting hematocrit value. In situations in which total body iron stores exceed 20 to 30 g, this regimen of phlebotomy may take up to 2 to 3 years to complete. The aim is to reduce iron stores to a level just short of iron deficiency. The hematocrit value should be monitored before each phlebotomy and should be postponed if it falls by more than 20% of its starting value. It is reasonable to check the serum ferritin level after every 10 to 12 phlebotomies. The serum ferritin level may be expected to fall progressively with iron mobilization, and it can be confidently assumed that effective mobilization of the iron stores will be completed when the serum ferritin level falls below 50 ng/mL.

Table 2: Treatment of Hereditary Hemochromatosis
Initial Treatment Maintenance Treatment
  • Phlebotomy of one unit of blood (500 mL) weekly or twice weekly, as tolerated.
  • Check hematocrit and hemoglobin values before each phlebotomy to ensure that they decrease no more than 20% below starting value.
  • Check serum ferritin level at intervals; stop frequent phlebotomy when it falls below 50 ng/mL.
  • Avoid vitamin C supplements.
  • One phlebotomy every 2-3 mo (approximately) to maintain serum ferritin level between 25 and 50 ng/mL.
  • Avoid vitamin C supplements.

Subsequently, a maintenance schedule may be initiated, and it can be expected that a one-unit phlebotomy may be necessary every 2 to 3 months. The aim of maintenance therapy is to keep the serum ferritin level between 25 and 50 ng/mL, thereby avoiding overt iron deficiency. Currently, phlebotomy is a therapeutic procedure, with a coding recognized by the Centers for Medicare and Medicaid Services (formerly the Health Care Finance Administration) and third-party insurers. Although there is continued elevation of the TS level until late in the course of therapy, it is important to avoid pharmacologic doses of vitamin C, which may result in accelerated mobilization of iron. This might saturate the circulating transferrin and lead to potentially toxic complications, such as cardiac dysrhythmias and cardiomyopathy. Deferoxamine (Desferal) is an iron-chelating agent reserved for those with secondary iron overload caused by dyserythropoietic anemia. Finally, there are many specialists who prescribe erythropoietin, which is given systemically to promote red cell production in those who are unable to mount a bone marrow response to phlebotomy.

Outcomes

There have been several longitudinal studies that have provided powerful evidence that initiation of phlebotomy therapy before cirrhosis and/or diabetes develop will significantly reduce the morbidity and mortality of HH. These data have provided the impetus for the treatment of asymptomatic individuals with homozygous HH and markers of iron overload and of others with evidence of potentially toxic levels of storage iron. In symptomatic patients, treatment is also indicated to attenuate progressive organ damage. There are certain clinical symptoms and signs that may be improved by phlebotomy (e.g., fatigue, malaise, skin pigmentation, abdominal pain, level of insulin requirements in diabetics). Other clinical features may be less responsive to iron mobilization (e.g., arthropathy, hypogonadism, established cirrhosis). Primary liver cell cancer accounts for about 30% of all iron-related deaths in HH, with another 20% ascribed to complications of cirrhosis.

Therefore, the preemptive treatment of asymptomatic patients before these complications develop may play a major role in the reduction of mortality from HH. What is more debatable in light of the available methods for mutation analysis is whether everyone who is a C282Y homozygote will inevitably develop iron overload, with its potential complications. Because the definition of HH is still based initially on phenotypic manifestations, there are no convincing arguments to treat genetically predisposed individuals who have no indirect markers of iron overload. This has been used as one of the proposed arguments against any recommendation at present for widespread genetic screening for hereditary hemochromatosis. Nevertheless, evidence points to a majority of genetically predisposed individuals—that is, C282Y homozygotes—particularly males exhibiting elevated iron markers. We do not have accurate predictors of how many of these will go on to develop tissue iron overload, and most specialists currently favor prophylactic phlebotomy in these cases.

Because cirrhosis in its fully developed form is not reversible by iron removal, the potential remains for decompensated liver disease in these individuals and may provide an indication for considering OLT. Mortality rates in HH patients who have had transplants are less satisfactory than in those who have had transplants for other causes of liver disease. Because most post-transplantation deaths in these patients occur in the perioperative period as a result of cardiac or infection-related complications, it has been suggested that every endeavor should be made to diagnose HH at an early enough time point to permit adequate removal of excess iron stores before OLT. Again, it should be emphasized that iron removal treatment in HH before the development of cirrhosis or diabetes can help maintain normal life expectancy, providing a persuasive argument for preventive therapy.

Summary
  • Hemochromatosis is defined as iron overload affecting the parenchymal cells of the liver and other organs caused either by inherited or acquired (secondary) disorders.
  • Hereditary hemochromatosis (HH) is most commonly caused by homozygous C282Y mutations of the HFE gene on the short arm of chromosome 6, leading to excessive absorption of dietary iron by the enterocyte.
  • Although the phenotypic features of elevated iron markers in the serum are seen in the majority of individuals with the homozygous mutations C282Y, particularly males, the classic findings of cirrhosis and bronzed diabetes occur in a variable minority (5% to 10%).
  • Diagnosis of hemochromatosis is by phenotypic evaluation of iron overload using indirect serum markers and, ultimately, in select individuals, by liver biopsy, and by genotypic evaluation using mutation analysis of the HFE gene in blood samples.
  • Treatment of HH is indicated by iron removal using phlebotomy in those with confirmed iron overload. Early treatment before evidence of tissue damage will prevent cirrhosis, with complicating liver cancer, and diabetes. Removal of iron in secondary forms of iron overload has not been evaluated to date in controlled trials. In iron-loading anemia, early treatment with iron chelators is indicated.

Suggested Readings

  1. Adams P, Brissot P, Powell LW: EASL International Consensus Conference on Haemochromatosis. J Hepatol 2000;33:485-504.
  2. Adams PC, Chakrabarti S: Genotypic/phenotypic correlations in genetic hemochromatosis: Evolution of diagnostic criteria. Gastroenterology 1998;114:319-323.
  3. Bacon BR, Powell LW, Adams PC, et al: Molecular medicine and hemochromatosis: At the crossroads. Gastroenterology 1999;116:193-207.
  4. Bacon BR, Olynyk JK, Brunt EM, et al: HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999;130:953-962.
  5. Beutler E, Felitti VJ, Gelbart T, Ho N: The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000;133:329-337.
  6. Beutler E, Felitti VJ, Koziol JA, et al: Penetrance of 845 G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359:211-218.
  7. Feder JN, Gnirke A, Thomas W, et al: A novel MHC class 1-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408.
  8. Niederau C, Fischer R, Purschel A, et al: Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-1119.
  9. Olynyk JK, Cullen DJ, Aquilia S, et al: A population study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724.
  10. Tavill AS. Clinical implications of the hemochromatosis gene [editorial]. N Engl J Med 1999;341:755-757.
  11. Tavill AS; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association: Diagnosis and management of hemochromatosis. Hepatology 2001;33:1321-1328.
  12. Tavill AS, Adams PA: A diagnostic approach to hemochromatosis. Can Gastroenterology 2006;20:535-540.
  13. U.S. Preventive Services Task Force: Screening for hemochromatosis: Recommendation statement. Ann. Intern Med 2006;145;204-208.
  14. Whitlock EP, Garlitz BA, Harris EL, et al: Screening for hereditary hemochromatosis: Asystematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145:209-223.

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Wilson's Disease

Anthony S. Tavill

Definition

Wilson’s disease (WD) is a genetic disorder in which there is excessive accumulation of copper in the liver and brain because of an inherited defect in the biliary excretion of copper. A comprehensive practice guideline has been published by the American Association for the Study of Liver Diseases and represents the state of the art management of Wilson’s disease. Recommendations in this review are consistent with that guideline.

Prevalence

WD is transmitted from generation to generation by autosomal recessive inheritance. Only homozygotes for this disorder who inherit disease-specific mutations of both alleles of the Wilson’s disease gene may go on to manifest clinical evidence of the condition. Such individuals have been described in many different ethnic groups and number about 1 in 30,000 of the worldwide population. As described later, particular mutations are found more frequently in specific populations or ethnic groups with varying phenotypic expression in some of these mutations. However, it is known that heterozygotes with a mutation of a single allele do not develop disease, although they may show varying degrees of abnormality in serum copper markers.

Pathophysiology

Copper is an essential cofactor for many enzymes and proteins and plays a role in the mobilization of tissue iron stores. Copper in the diet is absorbed relatively efficiently by the small intestine, is bound relatively loosely by circulating plasma proteins, and is delivered to the liver from the portal circulation. The transport of copper from the hepatocytes to bile is critical in overall copper homeostasis, because biliary excretion undergoes minimal enterohepatic recirculation. The protein ATP7B is important in the vesicular pathway of hepatic copper transport into bile. The WD gene mutation occurs on chromosome 13, and in homozygous form leads to the absence or diminished function of the hepatic protein ATP7B, resulting in a decrease in biliary copper excretion and ultimately in the hepatic accumulation of copper. Along with this failure of biliary excretion, there is also reduced incorporation of copper into ceruloplasmin, a serum glycoprotein that contains six copper atoms per molecule and is synthesized predominantly in the liver. The process of copper incorporation into apoceruloplasmin is also dependent on ATP7B. This process is absent or diminished in most patients with WD, leading to a reduced circulating level of serum ceruloplasmin in most patients.

When copper accumulates beyond the normal safe storage capacity of the liver, hepatocellular injury results. Furthermore, when the storage capacity of the liver for copper is exceeded or when additional cellular copper is released because of hepatocellular damage, levels of non–ceruloplasmin-bound copper in the circulation are elevated and copper accumulates in a number of extrahepatic sites, in particular the brain. As copper "spills" over to other organs from the liver, pathologic manifestations become evident in the brain, kidneys, eyes, and joints.

The pathologic evidence for copper accumulation in the liver evolves from early infancy to adult life. The earliest pathologic changes may consist of steatosis and distinctive mitochondrial changes. With progression and without treatment, the liver may show signs indistinguishable from chronic hepatitis and ultimately develops cirrhosis. In some cases, there is fulminant hepatic failure with parenchymal necrosis and collapse of lobular architecture. In the brain, the predominant neuropathologic changes of advanced untreated WD are concentrated in the lenticular nuclei, which have the highest copper levels and with increasing copper accumulation undergo various forms of degeneration. Similarly, abnormalities in the renal tubules and glomeruli, periarticular and articular tissues, and the eyes may all become sites that manifest copper damage.

Signs and Symptoms

Signs and symptoms of liver, neurologic, and psychiatric disease are the most common clinical manifestations of symptomatic WD (Table 3). In contrast, those found by family screening are frequently asymptomatic. Failure to diagnose and treat WD results in the development of hepatic insufficiency, ultimately hepatic failure and, in some patients, neuropsychiatric disease.

Table 3: Signs and Symptoms of Wilson’s Disease
Asymptomatic Symptomatic
  • Biochemical abnormalities alone
  • Biochemical abnormalities and Kayser-Fleischer rings
  • Hepatic disease—chronic active hepatitis, cirrhosis, fulminant hepatitis
  • Neurologic disease—dystonia, dysarthria, tremors, involuntary choreiform movements (e.g., features of cerebellar or extrapyramidal disease)
  • Psychiatric disease, particularly with associated organic neurologic disease
  • Renal disease—aminoaciduria, nephrocalcinosis
  • Arthropathy with osteochondritis dissecans
  • Opthalmologic manifestations—Kayser-Fleischer rings, sunflower cataracts
  • Hematologic manifestations—hemolysis

© 2002 The Cleveland Clinic Foundation.

The clinical spectrum of liver disease in WD patients varies widely. Younger patients may be found by family screening or by the presence of isolated abnormalities of liver function. Overt disease may be delayed in some patients, and they may present with features of chronic liver disease indistinguishable from other forms of chronic active hepatitis or end-stage liver disease. In the latter case, with established cirrhosis, features of portal hypertension such as ascites, edema, or hypersplenism and hepatic encephalopathy may be observed. If untreated, these individuals will progress ultimately to hepatic insufficiency, liver failure, and death. Unfortunately, there are some whose disease may be obscured until adolescence, when they may present with fulminant hepatitis and associated hemolytic anemia. These are circumstances that are frequently fatal without timely, life-saving OLT.

There are other patients with WD whose first presenting symptoms are neurologic or psychiatric; often they are patients in the third decade of life or even older. Most of these patients with central nervous system disease have occult significant liver disease at the time of presentation. The neurologic disease manifests predominantly as motor abnormalities, with disabling parkinsonian features of dystonia, hypertonia, and rigidity, with tremors and dysarthria. In rarer cases, WD may manifest with abnormalities of other organ systems—namely, renal tubular abnormalities, arthropathy, and cardiomyopathy with dysrhythmias.

Ophthalmologic findings include Kayser-Fleischer rings and sunflower cataracts. Kayser-Fleischer rings are most marked at the upper and lower poles of the limbus, the junction between the cornea and sclera, and are caused by the granular deposition of elemental copper on the inner surface of the cornea in Descemet’s membrane. The rings have a golden brown or greenish appearance on slit-lamp examination. By the time the neurologic changes occur, usually in the third decade of life, Kayser-Fleischer rings are almost invariably present, although there are exceptions to this rule.

Diagnosis

WD should be considered and excluded in any individual between childhood and age 40 years who has unexplained hepatic, neurologic, or psychiatric disease (see Table 3). In particular, it should be considered in children or young adults with atypical extrapyramidal or cerebellar motor dysfunction, neuropsychiatric disease, elevated aminotransferase levels, or other features of acute or subacute liver disease and with unexplained non–immune-mediated hemolysis. In these cases, WD must be considered whether or not there is a family history of liver or neurologic disease. Usually, the diagnosis can be confirmed on the basis of clinical and biochemical evaluations without the need for liver biopsy.

Table 4: Diagnostic Tests for Wilson’s Disease
Level 1 Tests Level 2 Tests Level 3 Tests
Low serum ceruloplasmin level (<20 mg/dL) Liver histopathology and stainable copper Ultrastructural study of hepatocytes
Kayser-Fleischer rings Liver copper concentration (>250 μg/g dry weight) Mutational gene analysis for Wilson’s disease
Raised serum free copper level (non–ceruloplasmin-bound) (>25 μg/dL) Incorporation of radiocopper into ceruloplasmin
24-hr urinary copper (>100 μg/24 hr)

Data from Roberts EA, Schilsky ML: A practice guideline on Wilson disease. Hepatology 2003;37:1475-1492.

As a practical algorithm, there are three levels of tests used to confirm the diagnosis of Wilson’s disease (Table 4). Level 1 tests consist of determination of the serum ceruloplasmin concentration, total serum copper concentration and, by derivation, the circulating non–ceruloplasmin-bound copper concentration and 24-hour urine copper excretion, together with slit-lamp examination of the eyes for Kayser-Fleischer rings. Testing for the serum ceruloplasmin concentration is routinely available in all clinical laboratories; the normal range is 20 to 50 mg/dL. Approximately 95% of homozygous WD patients have values lower than 20 mg/dL. It should be noted, however, that approximately 5% of all homozygotes, whether symptomatic or not, and 15% to 50% of WD patients with liver disease, may maintain normal levels of ceruloplasmin. Spuriously normal levels of ceruloplasmin may occur as a result of acute-phase responses based on active inflammation. Conversely, low serum ceruloplasmin concentrations may occur in various hypoproteinemic states and in up to 20% of asymptomatic WD heterozygotes. A rare cause of extremely low ceruloplasmin levels may be hereditary aceruloplasminemia.

The total serum copper concentration is made up of ceruloplasmin-bound copper and free copper, bound more loosely to albumin or smaller circulating peptides. The ceruloplasmin and therefore the ceruloplasmin copper levels are typically low in WD and may explain an overall reduction in total serum copper concentration. However, when the free (i.e., non–ceruloplasmin-bound) copper is calculated by subtracting the ceruloplasmin copper from the total serum copper level, this is usually found to be elevated, typically to more than 25 μg/dL in WD. To calculate the free copper level, the ceruloplasmin (in mg/dL) is multiplied by 3; this value is then subtracted from the total serum copper level (in μg/dL).

Slit-lamp evaluation of the cornea for Kayser-Fleischer rings should be performed by an experienced ophthalmologist. Kayser-Fleischer rings are present in almost every patient with neurologic disease, but may be absent in younger patients with hepatic manifestations only.

The measurement of 24-hour urinary copper excretion usually exceeds 100 μg/24 hr in WD and reflects the increased plasma non–ceruloplasmin-bound copper. Spuriously elevated increases in urinary copper levels may occur in the face of fulminant liver failure and in patients with nephrotic levels of proteinuria. It should be emphasized that the 24-hour urine samples must be collected in metal-free containers.

In the absence of Kayser-Fleischer rings, level 2 tests are important for the diagnostic confirmation of WD. Liver biopsy for hepatic copper concentrations is an invaluable diagnostic tool. Most homozygotes for WD have levels higher than 250 μg/g dry weight, with normal values rarely exceeding 50 μg/g. Intermediate values may be seen in heterozygotes. A number of hepatic conditions manifesting extreme cholestasis may have elevated hepatic copper concentrations but can usually be diagnosed by other clinical, serologic, or histologic criteria. Liver biopsies may be evaluated for copper concentration after being dried overnight at 56° C in a vacuum oven, with part of the biopsy specimen separated and fixed in formalin before histopathologic evaluation. The evaluation should include immunohistochemical staining for copper.

Level 3 tests include incorporation of radiocopper into ceruloplasmin and molecular genetic studies to provide evidence for mutations in the ATP7B gene. In practice, the incorporation of isotopes of copper into ceruloplasmin is impractical in most centers. Such tests have been used to validate the diagnosis of WD in the minority of patients with normal ceruloplasmin levels, or when there was previously a contraindication to liver biopsy. The availability of the transjugular route of liver biopsy has made such tests unnecessary in most cases.

Currently, molecular genetic studies are confined to haplotype analysis of family members of an affected individual. Such tests involve evaluation of DNA polymorphisms in the nucleotide regions surrounding the ATP7B gene. There have been multiple disease-specific mutations of the WD gene described in probands with the disorder. Even the most common of these mutations account for only 15% to 30% of most WD populations. Newer technologies that use molecular genetic testing in newly discovered patients with clinical manifestations of the disease might pinpoint disease-specific mutations in contradistinction to polymorphisms of the gene.

Treatment

Depending on the mode of manifestion of WD, treatment options consist of orally administered pharmacologic agents (Table 5) or OLT. Liver transplantation should not be regarded as a treatment of last resort, but it may be the only means of timely intervention in patients presenting with acute or subacute liver failure or decompensating end-stage liver disease. Ideally, patients should be diagnosed early enough for medical therapy to attenuate or abolish symptoms and prevent progression of the disease.

Table 5: Treatment of Wilson’s Disease*
Drug Dose and Route of Administration
Penicillamine (Cuprimine, Depen) 250 mg tid or qid PO
Trientine (Syprine) 250 mg tid or qid PO
Zinc salts—sulfate, gluconate, or acetate† 50 mg tid PO (as elemental zinc)

*In all therapies, the goal is to reduce the serum free copper level (non–ceruloplasmin bound) to less than 10 μg/dL.
†Zinc salts may be substituted as a maintenance therapy after adequate decoppering has been achieved, but may be the treatment of choice in select asymptomatic Wilson’s disease patients.
© 2002 The Cleveland Clinic Foundation.

It is generally agreed that patients with symptoms or signs of hepatic insufficiency or chronic active hepatitis with or without neurologic manifestations should be offered chelation therapy with penicillamine or trientine. These drugs are administered orally and remove copper from potentially toxic sites. In contrast, zinc salts serve to block the intestinal absorption of dietary copper by stimulating the synthesis of various endogenous copper chelators, such as metallothioneins. Penicillamine was the first copper chelator to be developed; unfortunately, it has been incriminated as causing some toxic side effects, which leads to discontinuation of the drug in 10% to 15% of patients. Trientine was developed more recently and is considered preferable by many experts as first-line therapy in patients with hepatic or neurologic disease, or both. Zinc salts may be considered as initial therapy for asymptomatic patients or for those intolerant of penicillamine or trientine. With any of these treatments, patients should be evaluated for clinical and biochemical improvements and normalization of markers of copper metabolism, in particular the level of free serum copper and urinary copper output. With stabilization of these clinical and biochemical parameters, patients can be switched to maintenance therapy. This may consist of reduction in the dose of penicillamine or trientine or, in some cases, switching from these chelating agents to zinc salts (see Table 5).

Dietary intake of foods rich in copper should be avoided, particularly during the initial phase of treatment. Organ meats, nuts, chocolate, and shellfish should be avoided. These restrictions may be partially lifted during the maintenance phase of treatment.

For WD patients who become pregnant, the doses of penicillamine or trientine should be reduced during the second trimester and the first 2 months of the third trimester, to 500 mg/day maximum, and to 250 mg/day for the month before delivery and for up to 1 month postpartum. A similar approach to reduction in therapy with chelating agents is applied to patients undergoing surgery to allow for complete wound healing.

The key to long-term success of pharmacologic treatment for WD is the patient’s adherence to treatment. Evaluation of response is based on improvement in the signs of liver or neurologic disease and improvement in biochemical markers of liver function. Further assessment is based on periodic monitoring of urinary copper output, slit-lamp examinations and, most importantly, by reduction in the level of non–ceruloplasmin-bound copper in the serum. With adequacy of treatment, this should decrease to 10 μg/dL or lower. Inadequate treatment or lack of compliance is usually associated with a level above 25 μg/dL. In the context of chelation therapy, urinary copper excretion initially exceeds 1000 μg/day and, subsequently, on maintenance treatment, should be between 250 and 500 μg/day. Values lower than this usually suggest nonadherence to treatment. In contrast, on zinc therapy, urinary copper excretion usually falls to lower than 150 μg/day.

OLT is indicated in the extreme circumstances mentioned when there is evidence of impending liver failure. Transplant recipients develop the normal donor phenotype with regard to markers of copper metabolism and do not require additional pharmacologic therapy for WD, except possibly in the case of residual neurologic symptoms and signs.

Outcomes

Even with established cirrhosis or chronic active hepatitis, the prognosis is excellent for patients who adhere fully to pharmacologic therapy. Neurologic or psychiatric symptoms may be slow to recover and may not be completely reversible. However, features of both neurologic disease and hepatic insufficiency usually stabilize on treatment, and only a watch and wait approach can be recommended. In cases of liver decompensation, following OLT, the 1-year survival rate is comparable with that for other causes of liver failure. Although neurologic symptoms may improve post-OLT, the extent of neurologic involvement itself in the absence of liver failure is not an indication for OLT.

Summary
  • Wilson’s disease (WD) is a genetic disease of the liver that leads to excessive copper storage in the liver, brain and, to a lesser degree, in other organs, occurring in about 1 in 30,000 individuals worldwide.
  • The gene mutation(s) lead(s) to defective hepatic secretion of copper into bile and copper incorporation into ceruloplasmin.
  • Clinical features relate to the toxic effects of excessive copper in the liver, brain, corneas, blood, kidneys, and joints and may manifest from childhood to adulthood.
  • A diagnostic algorithm has been published using ascending levels of clinical, laboratory, and tissue biochemical testing. Molecular genetic testing is not yet routinely available in the clinic.
  • Early treatment using zinc to diminish intestinal copper absorption and oral chelators to remove excessive tissue copper have been shown to prevent progression, reverse clinical complications of tissue copper damage, and improve survival in patients with WD.
  • Liver transplantation is life-saving in those with complications of irreversible end-stage liver disease and acute liver failure.

Suggested Readings

  1. Brewer GJ, Johnson VD, Dick RD, et al: Treatment of Wilson’s disease with zinc. XVII: Treatment during pregnancy. Hepatology 2000;31:364-370.
  2. Petrukhin K, Fischer SG, Pirastu M, et al: Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet 1993;5:338-343.
  3. Roberts EA, Schilsky ML; Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada: A practice guideline on Wilson disease. Hepatology 2003;37:1475-1492.
  4. Scheinberg IH, Gitlin D: Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson’s disease). Science 1952;116:484-485.
  5. Schilsky ML, Scheinberg IH, Sternlieb I: Liver transplantation for Wilson’s disease: Indications and outcome. Hepatology 1994;19:583-587.
  6. Schilsky ML, Tavill AS: Wilson’s disease. In Schiff ER, Sorrell M, Maddrey W (eds): Schiff’s Diseases of the Liver, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2007, pp 1023-1040.
  7. Sternlieb I, Scheinberg IH: Prevention of Wilson’s disease in asymptomatic patients. N Engl J Med 1968;278:352-359.
  8. Sternlieb I: Wilson’s disease and pregnancy [editorial]. Hepatology 2000;31:531-532.
  9. Tanzi RE, Petrukhin K, Chernov I, et al: The Wilson disease gene is a copper-transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344-350.
  10. Walshe JM: Copper chelation in patients with Wilson’s disease: A comparison of penicillamine and triethylene tetramine dihydrochloride. Q J Med 1973;42:441-452.

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