Inherited Liver Diseases

Inherited Liver Diseases


A. Pathogenesis. Wilson’s disease

is a treatable, genetic disorder. The metabolic defect leads to progressive accumulation of copper in the liver, brain (particularly in the basal ganglia), cornea, and kidneys, causing severe functional impairment leading to irreversible damage. If not treated, this disease is invariably fatal, but with early diagnosis and treatment, the clinical manifestations can be prevented and reversed.

Wilson’s disease is an autosomal recessive disorder. The abnormal gene is distributed worldwide with a prevalence of heterozygotes of 1 in 200 and homozygotes of 1 in 30,000. The genetic defect is on chromosome 13 near the red-cell esterase locus. In 95% of patients, there is also an absence or deficiency of serum ceruloplasmin, the main copper-transporting protein in blood. This deficiency is caused by a decrease in transcription of the ceruloplasmin gene located on chromosome 3.

B. Copper metabolism

1. Copper concentration in the liver.

The liver of a human newborn contains six to eight times the copper concentration of an adult liver. Within the first 6 months of life, this diminishes to a concentration of 30 mg/g of dry tissue. Thereafter, throughout life, the liver concentration of copper is maintained at this steady state by careful regulation of intestinal absorption and transport and of the liver stores through the synthesis of plasma and tissue copper proteins and excretion of copper from the body in the bile.

2. Absorption and excretion.

Approximately 50% of the average dietary intake of 2 to 5 mg of copper is absorbed from the proximal small intestine and loosely binds to albumin. It is promptly cleared by the liver, where it is incorporated into specific copper proteins such as cytochrome oxidase and ceruloplasmin or is taken up by lysosomes before being excreted in bile. There are two main routes by which copper is mobilized from the liver.

a. Synthesis of copper-containing ceruloplasmin and its release into the circulation.

b. Biliary excretion amounting to 1.5 mg of copper per day. This is the principal route of elimination of copper from the body.

3. Genetics.

The copper excess seen in Wilson’s disease has been shown to be the result of decreased biliary excretion and not an increase in the absorption of copper. The defect is caused by mutations in the Wilson’s gene (ATP7B) on chromosome 13 gene. The gene ATP7b encodes a cation-transporting P-type adenosine triphosphatase that is expressed in the liver, kidney, and placenta. Mutations in ATP7b result in disordered export of copper from the liver into bile with resultant accumulation of copper cation in hepatocytes. The ATP7b protein is present primarily in the trans-Golgi where it is critical for excretion of copper into bile, as well as providing appropriate copper for binding to ceruloplasmin. Lack of functional ATP76 limits the availability of copper for ultimate incorporation into ceruloplasmin. When copper is not available for binding, an apoprotein is secreted from the hepatocytes that is rapidly degraded in the plasma, resulting in the hallmark of Wilson’s disease, diminished circulating ceruloplasmin levels.

4. Family screening.

More than 200 mutations have been identified in the Wilson’s gene. Once a proband has been identified as having Wilson’s disease, it may be possible to screen siblings on the basis of genetic analysis. As an autosomal recessive disorder, 1 in 4 siblings may be expected to be homozygous for the gene defect. Genetic testing of siblings requires the sequencing of both alleles of the ATP7b gene in the proband and then subsequent comparison of those alleles to the ATP7b alleles in the siblings.

C. Copper toxicity

1. Acute toxicity.

Ingestion of gram quantities of copper causes serious gastrointestinal and systemic injuries and occasionally hepatic necrosis. Generally, however, the vomiting and diarrhea that follow the ingestion of copper salts protect the patient from serious toxic effects.

2. Chronic toxicity.

Hepatic copper overload may occur in disorders other than Wilson’s disease. These include primary biliary cirrhosis, extrahepatic biliary artesian, Indian childhood cirrhosis, and other chronic cholestatic disorders. The excess hepatic copper may aggravate the underlying pathologic process by direct damage to the organelles or through promotion of fibrosis.

D. Diagnosis

1. Clinical presentation.

Wilson’s disease has many modes of presentation. It may simulate several different neurologic and psychiatric disorders. It may present as asymptomatic elevation of the transaminases, chronic active hepatitis, fulminant hepatitis, cirrhosis of the liver, acquired hemolytic anemia, renal disease, or eye abnormalities such as sunflower cataracts and Kayser-Fleischer (K-F) rings.

a. Liver disease is the most common presentation of Wilson’s disease in childhood. About 40% of all patients with Wilson’s disease come to medical attention with evidence of liver disease. Because an increase of 30 to 50 times the normal hepatic concentration of copper can occur without any clinical manifestations, symptoms of liver disease do not appear before 6 years of age. However, one half of the patients have symptoms by 15 years of age. Thus, overt Wilson’s disease is encountered predominantly in older children, adolescents, young adults, and rarely in older adults.

i. Forms. The hepatic disease may take several different forms.

a) Commonly it begins insidiously and runs a chronic course characterized by weakness, malaise, anorexia, mild jaundice, splenomegaly, and abnormal liver chemistry tests. The disease may mimic acute viral hepatitis, mononucleosis, or chronic active hepatitis.

b) Fulminant hepatitis may occur suddenly, characterized by progressive jaundice, ascites, and hepatic failure. The outcome is usually fatal, particularly when the disorder is accompanied by hemolytic anemia.

c) Some patients present with the typical picture of postnecrotic cirrhosis with spider angiomata, splenomegaly, portal hypertension, ascites, bleeding esophageal varices, or thrombocytopenia mimicking idiopathic thrombocytopenic purpura (ITP). The liver enzymes may be normal. The diagnosis of Wilson’s disease should always be considered in patients younger than 30 years with negative serology for viral hepatitis; with a history of chronic active hepatitis; or with juvenile, cryptogenic, or familial cirrhosis. Although fewer than 5% of such patients have Wilson’s disease, it is one of the few forms of liver disease for which specific and effective therapy is available.

ii. Histology. There is no one specific histologic profile to identify Wilson’s disease in liver biopsy specimens. In the early stages of copper accumulation, when copper is diffusely distributed in the cytoplasm, it is undetectable by rhodanine or rubeanic acid stains. At this stage, lipid droplets are seen in the hepatocytes with ballooned, vacuolated nuclei containing glycogen. This initial steatosis progresses to fibrosis, then ultimately to
cirrhosis. With time and progression of the liver disease, the hepatocyte lysosomes seem to sequester the excess copper, which is detectable throughout some nodules by routine histochemical staining. Because of the variable stainability and the irregular distribution of copper among adjacent nodules, absence of a positive rhodanine or rubeanic acid stain on a histologic slide does not exclude the diagnosis of Wilson’s disease. The parenchyma usually is infiltrated with mononuclear cells. There may be cholestasis, focal necrosis, and Mallory’s hyalin. In other cases, the histology may resemble that of acute or chronic active hepatitis.

Once macronodular cirrhosis develops, the microscopic findings are nonspecific. Hepatocytes may contain some cytoplasmic lipid, vacuolated glycogen-containing nuclei, and cytoplasmic inclusions containing copper-rich lipofuscin granules.

b. Neurologic disease is the most common presentation of Wilson’s disease. The usual age of onset is 12 to 32 years. The most common symptoms are as follows:

i. Incoordination particularly involving fine movements such as handwriting, typing, and piano playing.

ii. Tremor is usually at rest but intensifies with voluntary movement and emotion. It ranges from a fine tremor of one hand to generalized tremor of the arms, tongue, and head. It may be slow, coarse, or choreoathetoid. Dystonia, ataxic gait, spasticity, and rigidity are late neurologic manifestations.

iii. Dysarthria begins with difficulty in enunciating words and progresses to slurring of speech, microphonia, and aphasia.

iv. Excessive salivation occurs early in the course of the disease.

v. Dysphagia is progressive and oropharyngeal; patients have difficulty initiating swallowing, leading to regurgitation and aspiration.

c. K-F rings are corneal copper deposits laid in the Descemet’s membrane in layers appearing as granular brown pigment around the periphery of the iris. They may be absent in early stages but are present in all patients in the neurologic stage of Wilson’s disease. Most K-F rings can be visualized by the naked eye, but some require slit-lamp examination.

d. Psychiatric disease. Almost all of the patients demonstrate some form of psychiatric disturbance, which may appear as teenage adjustment behavior, anxiety, hysteria, or a manic-depressive or schizoaffective disorder. Psychotropic drugs may accentuate the neurologic manifestations of Wilson’s disease and increase the patient’s problems.

e. Hematologic disease. In a few patients, Wilson’s disease presents as a Coombs-negative hemolytic anemia with transient jaundice. It may be intermittent and benign, or it may occur with fulminant hepatitis. The hemolysis occurs during phases of hepatocellular necrosis with sudden release of copper from necrotic hepatocytes into the circulation. This effect is indicated by a marked rise in the concentration of nonceruloplasmin copper in the blood and in the amount of copper excreted through the urine.

With portal hypertension and splenomegaly, hypersplenism may result in thrombocytopenia and pancytopenia. Progressive liver disease also gives rise to clotting factor deficiencies and bleeding.

f. Kidney disease. Renal abnormalities result from accumulation of copper within the renal parenchyma. These abnormalities range from renal insufficiency with decreased glomerular filtration rate to proximal tubular defects resembling Fanconi’s syndrome, renal tubular acidosis, proteinuria, and microscopic hematuria.

g. In disorders involving “inflammation” and metabolic syndrome iron overloading may occur due to reduced iron egress. Iron is essential for many bacterial and viral pathogens. Hepciden plays a key role in protecting the body’s precious iron from these pathogens. In response to inflammatory cytokins, hepcidin degrades ferroprotin, thus preventing iron from entering
the bloodstream where it could be used by the invading pathogens. This leads to iron accumulation in the macrophages. With chronic inflammation this may lead to iron restricted erythropolisis and anemia.

2. Diagnostic studies

a. Serum ceruloplasmin. Ninety-five percent of patients with Wilson’s disease have a serum ceruloplasmin concentration less than 20 mg/dL. Because approximately 20% of heterozygotes also have diminished levels, deficiency of ceruloplasmin is not sufficient for the diagnosis of Wilson’s disease. Patients with fulminant hepatitis and 15% of patients with Wilson’s disease presenting with only a hepatic disorder may have a ceruloplasmin concentration of 20 to 30 mg/dL due to a slight increase of this acute-phase reactant protein with inflammation. Hypoceruloplasminemia also may be found in patients with nephrotic syndrome, protein-losing enteropathy, or malabsorption; these conditions can be distinguished easily from Wilson’s disease.

b. Serum copper. Because ceruloplasmin is the main copper-transporting protein in the blood, total serum copper levels are often decreased in patients with Wilson’s disease, but free copper is elevated and is therefore responsible for excess copper deposition in various tissues. The determination of the serum free copper concentration represents the most reliable finding for the initial diagnosis of Wilson’s disease. This value is calculated as the difference between total serum copper concentration and the amount of copper bound to ceruloplasmin (0.047 mmol of copper per mg of ceruloplasmin).

c. Urinary copper excretion. Serum free copper is readily filtered by the kidneys and accounts for the increased urinary copper excretion seen in Wilson’s disease. Most patients have urinary copper excretion levels greater than 1.6 mmol per day. However, urinary copper levels often are elevated also in patients with cirrhosis, chronic active hepatitis, or cholestasis. This measurement does not distinguish these entities from Wilson’s disease, therefore, despite the administration of D-penicillamine, an agent that increases urinary copper excretion.

d. Liver biopsy should be obtained for histologic studies and quantitative hepatic copper concentration in excess of 250 µg/g. Edition of dry tissue is compatible with the diagnosis of Wilson’s disease. To obtain a reliable result, it is essential that contamination of the specimen with traces of copper be avoided (a disposable biopsy needle minimizes this hazard) and that an adequate sample (ideally 1 cm in length) be submitted for analysis. A trasjugular biopsy is inadequate for quantitative purposes. Other disorders such as primary and secondary biliary cirrhosis and long-standing bile duct obstruction can also lead to a very elevated hepatic copper concentration by interfering with hepatic excretion of copper into bile. These patients, however, have elevated ceruloplasmin levels.

e. In the rare patient with a normal serum ceruloplasmin concentration in whom a liver biopsy is contraindicated because of clotting abnormalities, a radio copper loading test can be performed using 64Cu, with a half-life of 12.8 hours, given to patients by mouth (p.o.) (2 mg) or intravenous (IV) (500 mg); the serum concentration of radioactive copper is plotted with time in hours.

In individuals who do not have Wilson’s disease, radioactive copper appears and disappears from the serum within 4 to 6 hours. A secondary rise of radioactivity appears in the serum after the isotope is incorporated by the liver into freshly synthesized ceruloplasmin. In patients with Wilson’s disease, this secondary rise in radioactivity is absent, since the rate of hepatic incorporation of radio copper into ceruloplasmin is diminished.

f. K-F rings are present in all patients with Wilson’s disease who have neurologic manifestations, but they may be absent in patients presenting only with hepatic disease. If they are not visible, they should be sought with slit-lamp examination.

g. In Wilson’s disease presenting as fulminant hepatitis, the combination of a disproportionately low serum alkaline phosphatase level and a comparatively
modest aminotransferase Mia with jaundice and clinical and histologic evidence of hepatic necrosis suggests Wilson’s disease. The ratio of the serum alkaline phosphatase to the total serum bilirubin also may be used.

h. All siblings of known patients should be screened for the possibility of Wilson’s disease by physical examination, slit-lamp examination of the corneas, and determinations of serum ceruloplasmin and aminotransferase concentrations.

E. Treatment.

Untreated Wilson’s disease causes progressive damage of the liver, brain, and kidneys. Until the late 1940s, patients usually died before reaching 30 years of age. The prognosis improved substantially after the introduction of the copper-chelating agent D-penicillamine in the 1950s. It is important to establish a firm diagnosis of Wilson’s disease, because the patient will be on lifelong therapy.

1. Diet.

The dietary intake of copper should be less than 1.0 mg per day. Foods rich in copper such as organ meats, shellfish, dried beans, peas, whole wheat, and chocolate should be avoided.

2. D-Penicillamine

was the first oral drug used for the treatment of any stage of Wilson’s disease. Penicillamine chelates heavy metals, especially copper, and facilitates their urinary excretion, thus shifting the equilibrium from tissues to plasma. It is also antiinflammatory and may interfere with collagen synthesis and fibrosis. Pyridoxine, 25 mg daily, is given to compensate for the weak antipyridoxine effects of penicillamine.

The usual daily dose is 0.75 to 2.0 g p.o. The effectiveness of therapy can be monitored using the calculated free serum copper concentration, which should be less than 1.6 mmol/L. The earlier the therapy is instituted, the better the results. The histologic abnormalities and many of the symptoms are reversed; however, already established cirrhosis, portal hypertension, and some neurologic abnormalities such as dystonia, rigidity, dysarthria, and dementia may not be reversible.

Up to 20% of patients have sensitivity reactions within weeks of the institution of penicillamine therapy. These reactions include fever, rash, lymphadenopathy, polyneuropathy, leukopenia, and thrombocytopenia. Dose reduction or short-term interruption of penicillamine therapy followed by restarting treatment at slowly increasing doses is usually successful in overcoming these side effects. For the 5% to 10% of patients who have serious penicillamine toxicity (lupus, nephrotic syndrome, pemphigus, and elastosis of skin, myasthenia gravis, thrombocytopenia, or severe arthralgias), another chelating agent, and trientine dihydrochloride, may be used.

3. Trientine dihydrochloride

is another chelating cupruretic agent used in the treatment of Wilson’s disease. It has less of a cupruretic effect than penicillamine, but its clinical effectiveness is comparable. Typical dosage for initial therapy in adults is 750 to 1,500 mg per day in divided doses, and 750 to 1,000 mg per day for typical maintenance therapy. Trientine dihydrochloride has a better safety profile than penicillamine. No hypersensitivity reactions have been reported. Reversible sideroblastic anemia and bone marrow toxicity have been observed in patients who were overtreated with resultant copper deficiency. Due to its better safety profile, trientine dihydrochloride is now the drug of choice in the treatment of Wilson’s disease. Both D-penicillamine and trientine dihydrochloride should be continued without interruption during pregnancy. Noncompliance with or interruption of the penicillamine or trientine dihydrochloride regimen is often followed by recurrence of symptoms or fulminant hepatitis.

4. Oral zinc.

Orally administered zinc sulfate (200-300 mg t.i.d.) has been found to be effective in the treatment of Wilson’s disease, especially in patients who cannot tolerate cupruretic treatment. Orally administered zinc induces the synthesis of intestinal metallothionein, thus increasing the capacity for copper binding by the epithelial cells and trapping the metal in the intestinal mucosa, thereby preventing its systemic absorption. In addition, zinc may exert a protective effect by inducing metallothionein in the hepatocytes, thus decreasing the toxic effects of copper. In some patients, large doses of zinc are associated with headaches, abdominal cramps, gastric irritation, and loss of appetite. Zinc
also interferes with absorption of iron, alters immune responses, and affects the serum lipoprotein profile.

Oral zinc therapy may serve as an adjunct to standard chelation therapy with D-penicillamine or trientine; however, there are reports that have raised concerns regarding the formation of zinc-penicillamine complexes that may diminish or abolish the therapeutic effectiveness of both drugs when used in combination.

Zinc is not recommended as the sole agent for initial therapy of symptomatic patients, but it is recommended as maintenance therapy at 150 mg per day in three divided doses to keep patients at negative copper balance. Zinc acetate is better tolerated than zinc chloride or sulfate.

5. Tetrathiomolybdate,

an agent that appears to block the absorption of copper by holding the metal in a tight, metabolically inert bond, has been used in some patients intolerant to penicillamine. It is not commercially available for use in North America. Although the drug is generally well tolerated, at least two cases of bone marrow suppression have been documented. Further clinical trials are needed before it may be used as a primary therapy for Wilson’s disease.

6. Monitoring.

Periodic physical examinations, slit-lamp examinations of the cornea for documentation of the disappearance of K-F rings, and measurements of 24-hour urinary copper excretion and serum free copper should be performed to assess the effectiveness of therapy.

7. Significant clinical improvement

may occur only after 6 to 12 months of uninterrupted treatment.

8. Fulminant hepatic failure

may develop in a number of patients with Wilson’s disease, either as an initial manifestation of the disease or as a consequence of noncompliance with medical therapy. A smaller subset of patients will have cirrhosis and hepatic decompression unresponsive to medical interventions outlined above.

9. Orthotopic liver transplantation (OLT)

is a lifesaving procedure for patients with fulminant hepatitis or irreversible hepatic insufficiency due to Wilson’s disease. The metabolic abnormality is reversed and the disease is cured. One-year survival following liver transplantation is now approximately 80%. The replacement of the affected liver expressing the mutant A7P7b gene protein product with a donor organ that expresses the normal gene protein product is expected to correct the defect in hepatic copper metabolism. Thus, the allograft is not susceptible to copper accumulation.

However, the resolution of the extra hepatic manifestations of Wilson’s disease after OLT has been less than universal. Thus, OLT in the absence of decompensated liver disease and solely for the management of extrahepatic disease such as neurologic defects is not routinely recommended. Liver cell transplantation is currently under study as an alternative to liver transplantation.


Hemochromatosis refers to a group of disorders in which excessive iron absorption, either alone or in combination with parenteral iron loading, leads to a progressive increase in total body iron stores. Iron is deposited in the parenchymal cells of the liver, heart, pancreas, synovium, and skin, and the pituitary, thyroid, and adrenal glands. Parenchymal deposition of iron results in cellular damage and functional insufficiency of the involved organs.

A. Classification of hemochromatosis

1. Genetic.

a. Heredity hemochromatosis (HH) associated with HFE, TPR2, HJV, and HAMP.

b. Ferroportin disease

c. Aceruloplasminemia

d. Hyporovatransferrinemia

e. Frederick’s ataxia

2. Acquired

a. Refractory anemias (e.g., thalassemia, spherocytosis, aplastic, sideroblastic anemia).

b. Chronic liver injury (e.g., alcoholic cirrhosis, chronic viral hepatitis B and C, post-portacaval shunt).

Jun 11, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Inherited Liver Diseases

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