Common metabolic liver disorders
by Vincent Biank, MD, and Grzegorz Telega, MD
Grzegorz Telega, MD, is one of the specialists at Children's Hospital of Wisconsin who sees patients with acute and chronic liver problems. The latest treatment options and surgical interventions, including liver transplantation, are available to our patients.
Grzegorz Telega, MD, is a pediatric gastroenterologist and program director of Liver Transplant and Hepatology at Children's Hospital of Wisconsin. He also is an associate professor of Pediatrics (Gastroenterology) at The Medical College of Wisconsin and a member of Children's Specialty Group.
Metabolic liver disease can range from the very obscure to the fairly common. This article focuses on two common pediatric metabolic liver disorders – Wilson's disease and alpha-1 antitrypsin deficiency. Specifically, we will discuss the epidemiology, pathophysiology, diagnosis and treatment of each of these disorders. We also will focus on some of the genetic markers currently available for each.
Wilson's disease results from the progressive accumulation of copper in the liver due to impaired biliary copper excretion. Wilson's disease originally was described in the early nineteenth century as a degenerative disorder of the central nervous system associated with cirrhosis. However, it wasn't until almost a half a century later that copper toxicity was identify as the offending etiology. Following this discovery, there has been significant progress in preventing disease progression as well as further delineation of the specific genetic defect resulting in the impaired biliary copper excretion.
Wilson's disease is an autosomal recessive disorder that can be found in all ethnicities worldwide. It has a documented prevalence of 1 in 30,000 individuals. The heterozygote carrier state has been reported to be 1 in 90 people. The majority of individuals present in their teens with primarily hepatic manifestations, while the remainder present in their 20s or 30s with neurologic or psychiatric abnormalities. Rarely are clinical symptoms present before age 5 due to the lack of copper accumulation. Furthermore, although clinical symptoms of Wilson's disease may start in childhood, the diagnosis often is not made for years or even decades due to lack of clinical suspicion. This frequently results in significant hepatic and/or neurological injury, which can be prevented if the disease is identified and treated early.
In 1993, mutations in the ATP7B gene on chromosome 13 were identified to result in Wilson's disease. Additional studies have found that mutations in ATP7B gene result in defective incorporation of copper into ceruloplasmin. Ceruloplasmin is the primary carrier protein by which copper is secreted from the liver into the systemic circulation. Consequently, the unbound copper cannot be transported from the hepatocyte to the biliary canaliculus, which ultimately results in progressive accumulation of copper in the hepatocytes, leading to cellular injury and hepatocyte death. Serum levels of ceruloplasmin frequently are decreased in individuals with Wilson's disease, however, this is thought to be the result of decreased synthesis rather that a direct consequence of the ATP7B mutation.
The liver is the major site for both the biochemical defect as well as the initial target of injury. Accordingly, individuals may present with a wide variety of liver dysfunction ranging from asymptomatic elevation of liver transaminases to fulminant liver failure. Common symptoms may include fatigue, dark or Òcola-coloredÓ urine, easy bleeding or bruising, anorexia, change in mental status or decreased school performance. Exam findings may include jaundice, ascites, hepatomegaly, splenomegaly, hematemesis or cutaneous findings including digital clubbing, palmar erythema or spider hemangiomas. Kayser-Fleischer (K-F) rings (a greenish brown ring at the periphery of the cornea) frequently are associated with Wilson's disease but also may be seen in patients with other causes of prolonged cholestasis. K-F rings are virtually always present at the time neurologic or psychiatric symptoms develop, but they frequently are absent in children who present with mainly only hepatic symptoms.
Unfortunately, establishing the diagnosis of Wilson's disease remains problematic in that there is no single laboratory test that can confirm the diagnosis. Frequently, laboratory evaluation demonstrates hyperbilirubinemia in association with elevated liver transaminases but with normal serum albumin and prothrombin time. Additional findings may include a mild hemolytic anemia and decreased serum phosphate and/or uric acid secondary to renal tubular losses. Once suspected, additional laboratory investigations would include serum ceruloplasmin, copper and 24-hour urine copper. Ultimately the diagnosis of Wilson's disease is established in patients with low serum ceruloplasmin and one of the following – an elevated 24 hour urine copper excretion, the presence of K-F rings or elevated hepatic copper concentration on liver biopsy. More recently, genetic testing has become available for diagnosis under certain circumstances, specifically, the evaluation of those with relatives known to have Wilson's disease.
Treatment of Wilson's disease is characterized by chelation of the accumulated copper and prevention of further reaccumulation. This is accomplished by initiating a diet low in copper as well as one of several copper chelating agents such as D-Penicillamine, trientine or zinc acetate. Unfortunately, without treatment, Wilson's disease remains uniformly fatal. Subsequently, for those individuals presenting with fulminant hepatic failure, liver transplant remains the only viable option for survival.
Alpha-1 antitrypsin deficiency
Alpha-1 antitrypsin is a glycol-protein synthesized by the liver. It acts as a protease inhibitor toward neutrophil proteases such as elastase, Catepsin G or Proteinase 3. Alpha-1 antitrypsin is part of the Òacute phaseÓ inflammatory response and can be elevate in inflammation. The role of alpha-1 antitrypsin is to limit the extent of tissue injury during an inflammatory response.
Alpha-1 antitrypsin deficiency is the most common genetic disorder affecting the liver and is inherited in an autosomal recessive fashion. The most common phenotype leading to liver disease is ZZ phenotype. The prevalence of ZZ phenotype is 1 in 2,000, and there is increased prevalence among individuals of northern European ancestry. Several other phenotypes have been described, specifically SZ heterozygote phenotype, which also results in liver disease, but overall is a milder form of disease. SS phenotype usually is asymptomatic. MZ heterozygotes rarely develop clinically significant liver disease, however, there is increasing evidence that patients with MZ phenotype are more susceptible to liver damage induced by drug toxicity, viral infections or fatty liver.
Z mutant 1-AT protein is abnormally folded, thus it is prone to polymerization inside the endoplasmic reticulum. Z mutant retained in endoplasmic reticulum of the liver leads to hepatotoxic effect. Liver disease is clinically significant in 10-20 percent of ZZ patients and can present as:
- Abnormal transaminases.
- Cirrhosis portal hypertension.
- Cholestatic liver disease.
- Liver cancer.
- Liver failure.
The majority (75-90 percent) of patients affected by alpha-1 antitrypsin deficiency have mild hepatic dysfunction characterized by elevated aminotransferases and mild cholestasis. The remaining 10-25 percent of patients progress to chronic liver disease with fibrosis and portal hypertension. In this group, 25-50 percent will progress to liver failure and will require liver transplant. Another 5-10 percent of patients with chronic liver disease with fibrosis or cirrhosis will develop hepatocellular carcinoma.
Due to high prevalence, clinicians should suspect alpha-1 antitrypsin deficiency in all children with cholestasis, cirrhosis/portal hypertension or persistently elevated aminotransferases. The diagnosis is established by protein immunoelectrophoresis phenotype (PI typing) genetic testing. However, the alpha-1 antitrypsin level is an acceptable test as long as the clinician remembers the level can be falsely in the normal range during any acute inflammatory phase.
Management of alpha-1 antitrypsin deficiency should focus on nutrition. Patients may need supplementation with fat-soluble vitamins and medium chain fatty acids. Clinicians should screen for evidence of portal hypertension (splenomegaly, thrombocytopenia) or hepatocellular carcinoma (alpha fetoprotein, liver ultrasound). Chaperone therapy (4 phenylbutyrate) remains experimental. Patients should avoid cigarette smoke and heavy air pollution since individuals with alpha-1 deficiency also are prone to premature development of lung emphysema.
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