Published: July 2014
Last Reviewed: August 2017
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|
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.
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.
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 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.
© 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.
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.
|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.
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.
|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.
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.