Wilson’s disease (hepatolenticular degeneration). Wilson’s disease is a familial disorder of copper metabolism transmitted as an autosomal recessive trait. It most often becomes manifest between ages 8 and 30 years; symptoms usually do not develop before age 6 years. About 30%-50% of patients initially develop hepatic symptoms, about 30%-40% begin with neurologic symptoms, and about 20%-30% initially are said to have psychiatric abnormalities such as schizophrenia. A few patients develop a Coombs’-negative hemolytic anemia. Children are more likely to be first seen with hepatic symptoms, although symptoms may occur at any age. In children, these most commonly take the form of chronic hepatitis, although in some patients the test results may resemble acute hepatitis virus hepatitis. A macronodular type of cirrhosis develops later and is usually present in patients with late-stage Wilson’s disease, whether or not there were symptoms of active liver disease. Some patients present with minimally active or with nonactive cirrhosis. Neurologic symptoms typically originate in the basal ganglia area (lentiform nucleus) of the brain and consist of varying degrees of incoordination, tremor, spasticity, rigidity, and dysarthria. There may also be a peculiar flapping tremor. Some young or middle-aged adults develop premature osteoarthritis, especially in the knees.

Wilson’s disease is characterized by inability of the liver to manufacture normal quantities of ceruloplasmin, an alpha-2 globulin that transports copper. For reasons not entirely understood, excessive copper is deposited in various tissues, eventually producing damage to the basal ganglia of the brain and to the liver. The kidney is also affected, leading to aminoaciduria, and copper is deposited in the cornea, producing a zone of discoloration called the Kayser-Fleischer ring.

Clinical diagnosis. The triad of typical basal ganglia symptoms, Kayser-Fleischer ring, and hepatic cirrhosis is virtually diagnostic. However, many patients do not have the textbook picture, especially in the early stages. The Kayser-Fleischer ring is often grossly visible but in many cases can be seen only by slit lamp examination. All patients with neurologic symptoms are said to have the Kayser-Fleischer ring as well as about 50% (range, 27%-93%) of those with hepatic symptoms. The Kayser-Fleischer ring is present in only about 20% (range, 0%-37%) of asymptomatic patients detected during family study investigation or at the beginning of symptoms from hepatic disease without neurologic findings. Overall, about 25% of patients (range, 22%-33%) do not have a demonstrable Kayser-Fleischer ring at the time of diagnosis. Patients with primary biliary cirrhosis or, occasionally, other types of chronic cholestatic liver disease may develop a corneal abnormality identical to the Kayser-Fleischer ring.

Plasma ceruloplasmin assay. Laboratory studies may be of value in diagnosis, especially in the preclinical or early stages. Normally, about 90%-95% of serum copper is bound to ceruloplasmin, one of the alpha-2 globulins. The primary excretion pathway for serum copper is through bile. The serum ceruloplasmin level is low from birth in 95% (range, 90%-96%) of homozygous patients, and is considered the best screening test for Wilson’s disease. About 10% (range, 6%-20%) of Wilson’s disease heterozygotes have decreased serum ceruloplasmin. However, normal newborn infants usually have decreased ceruloplasmin levels, and the test is not considered reliable until 3-6 months of age. Although a normal ceruloplasmin level (over 20 mg/100 ml; 200 mg/L) is usually interpreted as excluding Wilson’s disease, about 5% (range, 4%-10%) of homozygous Wilson’s disease patients have values greater than 20 mg/100 ml. This is more likely to be found in younger children and in those with hepatic disease. Estrogen therapy, pregnancy, active liver disease of various etiologies, malignant lymphoma, and occasionally various acute inflammatory conditions (since ceruloplasmin is one of the “acute reaction” proteins) can raise ceruloplasmin levels in variable numbers of cases. Smoking is reported to raise ceruloplasmin levels about 15%-30%. Although a decreased ceruloplasmin level is usually considered suggestive of Wilson’s disease, about 5% of normal persons may have values less than 20 mg/100 ml (200 mg/L), and values may be decreased in hereditary tyrosinemia, Menke’s kinky hair syndrome, the nephrotic syndrome, malabsorption syndromes such as sprue, and in various liver diseases (about 20% of cases in one study. However, it is possible that some patients with liver disease and decreased ceruloplasmin levels actually have Wilson’s disease).

Liver biopsy has also been used for diagnosis. The microscopic findings are not specific, and most often consist of either macronodular cirrhosis (often with some fatty change and occasionally with Mallory bodies) or chronic active hepatitis (10%-15% of patients with Wilson’s disease). The most typical finding is increased hepatic copper content by special stains (or tissue analysis, if available). For histologic staining of copper, fixation of the biopsy specimen in alcohol rather than the routine fixatives is recommended. Here again, it is advisable to wait 6-12 weeks after birth. Increased hepatic copper content is not specific for Wilson’s disease, since some degree of copper increase has been reported to occur in some patients with postnecrotic cirrhosis due to hepatitis virus hepatitis, in patients with primary biliary cirrhosis, and occasionally in patients with other chronic cholestatic syndromes. Also, increased hepatic copper content is not present in all patients with Wilson’s disease, especially in small-needle biopsy specimens.

Serum and urine copper. Total serum copper levels are decreased in 85%-90% of Wilson’s disease patients. However, serum copper not bound to serum ceruloplasmin is usually normal or increased. Twenty-four-hour urine copper excretion in symptomatic Wilson’s disease is increased in 90% of patients. However, 24-hour copper excretion is often normal in presymptomatic patients. Increased urine copper excretion is not specific for Wilson’s disease and may be found in various types of cirrhosis, especially those with some degree of cholestasis and in 10%-30% of chronic active hepatitis patients. However, these conditions usually have normal or elevated serum ceruloplasmin levels.

DNA probes. The gene affected in Wilson’s disease has been found on the long arm of chromosome 13, close to the gene responsible for retinoblastoma. DNA linkage probes for Wilson’s disease have been reported. In some cases, the retinoblastoma probe has been used.

Other laboratory abnormalities. Besides abnormalities in copper metabolism, over 50% of patients (78% in one study) have a low serum uric acid level, a finding that could arouse suspicion of Wilson’s disease if supporting evidence is present. Other laboratory findings that may be encountered in some patients are low serum phosphorus levels, thrombocytopenia (about 50%; range, 22%-82%, due to cirrhosis with secondary hypersplenism), aminoaciduria, glucosuria, and uricosuria. A Coombs’-negative hemolytic anemia occurs in a few patients.

Hemochromatosis. Hemochromatosis is an uncommon disease produced by idiopathic excess iron absorption from the GI tract, which leads to excess deposition of iron in various tissues, especially the liver. There still is dispute as to which iron storage diseases should be included within the term hemochromatosis. In this discussion, hemochromatosis refers to the hereditary iron storage disorder and hemosiderosis to nonhereditary (secondary) forms. Hemochromatosis is transmitted as an autosomal recessive trait with the gene being located on the short arm of chromosome 6 close to the class I histocompatibility antigen (HLA) locus. Males are affected more often than females (3:2 in one series), and males seem overall to have more severe disease than females. HLA-A3 antigen is present in 70%-80% of patients (vs. 20%-30% in the normal population).

Clinical onset of the disease is usually between ages 40 and 60 years. Signs, symptoms, and laboratory abnormalities depend on the stage of disease and (probably) whether there is also a significant degree of alcohol intake. Cirrhosis, diabetes mellitus, and bronze skin pigmentation form a classic triad diagnostic of hemochromatosis. However, this triad is a late manifestation, and in one study including more early cases it was present in less than 10% of the patients. The most frequent symptom is joint pain (47%-57% of patients; 50%-75% in patients with severe disease), which can be confused with rheumatoid arthritis. Hepatomegaly is present in 54%-93% of patients, cirrhosis on liver biopsy in 57%-94%, heart failure in 0%-35%, hypogonadism (in males) in 18%-61%, skin pigmentation in 51%-85% (not really noticeable in many patients), and clinically evident diabetes in 6%-72%. Alcoholism (15%-50%) or poor nutrition was frequent in some series. Hepatoma has been reported to develop in 15%-30% of patients.

Laboratory findings include the expected blood glucose abnormalities of diabetes (chapter 28) in those patients with overt diabetes, and decreased glucose tolerance in some of those without clinical diabetes. AST levels are elevated in 46%-54% of cases, reflecting active liver cell involvement. In one series, AST, alkaline phosphatase (ALP), and gamma-glutamyltransferase were normal or only mildly elevated unless the patient was alcoholic.

Laboratory iron studies. The body iron abnormality is manifested by actual or relative increase in serum iron levels and decrease in total iron-binding capacity (TIBC), producing increased saturation (% saturation) of the TIBC. In addition, hemosiderin very often can be demonstrated in the urine sediment by iron stains. The most sensitive laboratory test for hemochromatosis is percent saturation of TIBC (or of transferrin), which is greater than 60% (reference range, 16%-50%) in over 90% of male homozygotes and the 60% of females who have iron loading but which misses the 40% of females who do not have iron loading. Transferrin saturation of 50% detects most males or females with or without iron loading. Therefore, it has been proposed that the screening cutoff point should be 60% for males and 50% for females. Serum iron level is increased in more than 80% of patients and serum ferritin level is increased in more than 72% of patients; both of these tests are usually abnormal in affected males but much more variable in females. However, in one report about one third of patients with chronic hepatitis B or C also had elevated serum iron, ferritin, and percent saturation, and serum ferritin is often increased by various acute inflammatory conditions. Liver biopsy demonstrates marked deposition of iron in parenchymal cells and frequently reveals cirrhosis.

The most widely used screening test is serum iron. Elevated values raise the question of hemochromatosis. About 2.4% of normal persons are reported to have elevated serum iron values that spontaneously return to the reference range within 1-2 days. The effect of serum diurnal variation and day-to-day variation must be considered. Serum iron levels can also be increased in chronic hepatitis B or C infection (46% of cases in one study) and in hemosiderosis (nonhereditary iron overload) due to blood transfusion, chronic severe hemolytic anemias, sideroblastic anemias, alcoholic cirrhosis, parenteral iron therapy, and considerably increased iron intake. Several other conditions that may be associated with increased serum iron levels are listed in Table 37-2. Various conditions can lower the serum iron level (especially chronic iron deficiency and moderate or severe chronic disease without iron deficiency), and if one of these conditions is superimposed on hemochromatosis, the serum iron level might be decreased sufficiently to reach the reference range area.

As noted earlier, the best screening procedure is percent saturation of transferrin. This is calculated by dividing the serum iron value by the TIBC value. However, like serum iron, increase in percent transferrin saturation is not specific for hemochromatosis, since there are other conditions that decrease percent saturation, especially alcohol-related active cirrhosis. One study found that drawing specimens after an overnight fast considerably decreased false elevation of percent saturation. In addition, there is considerable variation in the literature as to the percent saturation cutoff point that should be used (50%-80%, with the majority using either 50% or 62%). The lower levels increase sensitivity in detecting hemochromatosis; the higher levels eliminate many patients who do not have hemochromatosis.

Definitive diagnosis is made by liver biopsy and measurement of hepatic iron content. Even liver biopsy iron may not differentiate hemochomatosis from hemosiderosis in some cases, and the liver cells of patients with cirrhosis but without demonstrable abnormality of iron metabolism may display some degree of increased iron deposition.

Family member screening. Hemochromatosis rarely becomes clinically evident before age 30, so that screening family members of patients has been advocated to detect unrecognized homozygotes to begin therapy before clinical symptoms develop. One study found that percent transferrin saturation detected about 90% of occult homozygotes, whereas assay of serum iron levels detected about 85% and assay of serum ferritin levels detected about 50%.