Dubin-Johnson syndrome

Infectious hepatitis is often the initial suspect when abnormal serum liver function test results are discovered in primary care settings. However, noninfectious liver disorders may also present with altered liver function tests. Noninfectious liver disorders require careful assessment of patient history, physical findings, and serum laboratory tests to distinguish among entities that have varying clinical implications and treatments.

Clinicians often assume that infectious hepatitis is the cause of abnormal liver function tests (LFTs), but when virologie markers are absent, other etiologies must be considered. Some of the more common noninfectious liver disorders are fatty liver, primary sclerosing cholangitis, primary biliary cirrhosis, hyperbilirubinemias (Gilbert's syndrome, Crigler-Najjar syndromes types I and II, Dubin-Johnson syndrome), hereditary hemochromatosis, Wilson's disease and alpha-1 antitrypsin deficiency. Primary care providers (PCPs) must distinguish among these noninfectious liver disorders to expedite appropriate treatment. The additional article on page 28 provides a brief discussion on autoimmune hepatitis.

* Serum Liver Function Tests

PCPs must assess four areas of liver health to determine the etiology of liver disorders: (1) hepatocellular injury, (2) cholestasis, (3) liver excretory capacity, and (4) synthesis. Tests for hepatocellular injury are aspartate aminotransferase (AST; formerly serum glutamic-oxaloacetic transaminase [SGOT],) and alanine aminotransferase (ALT; formerly serum glutamic-pyruvic transaminase [SGPT]). Serum concentrations of AST (normal:

Liver excretory capacity is measured by the concentration of serum bilirubin (normal total bilirubin: adults, 0.2-1.0 mg/dL; newborns, 1.5-12.0 mg/dL). Normally, bilirubin is broken down (conjugated) by the liver and excreted as bile into the small intestine. In conjugated (direct) hyperbilirubinemia (normal: 0.0-0.2 mg/dL), intrahepatic bilirubin is conjugated normally by the liver but, due to obstructed hepatic biliary ducts, cannot exit the liver and is absorbed into the circulatory system. Bilirubin in urine is always conjugated. Unconjugated (indirect) hyperbilirubinemia (normal: 0.0-0.8 mg/dL) is caused by excessive extrahepatic heme production, as seen in hemolysis. The liver functions normally, but is not able to conjugate the excessive extrahepatic bilirubin into bile, and the unconjugated bilirubin is absorbed into the circulatory system. Bilirubin mg/dL can be converted to µmols/L by multiplying the mg/dL by 17.10. Serum albumin (normal: 3.5-4.5 g/L) and prothrombin time (PT) (normal: 10-14 seconds) and/or international normalized ratio (INR) (normal: 0.9-1.2) are indicators of the liver's capacity for synthesis of albumin and the clotting factors II, V, VII, IX and X. As the liver loses the vital ability to synthesize these substances, serum albumin decreases and clotting times are prolonged. Low serum albumin levels and increased PT/INR are likely to occur only when 80% or more of liver function is lost.2

* Fatty Liver

Fatty liver refers to liver conditions in which hepatocytes are infiltrated with vacuoles of fat, specifically triglycerides. Steatosis refers to benign hepatic lipid infiltration in the absence of inflammation. Steatohepatitis is a more serious form of steatosis, in which there is liver inflammation (hepatitis) with potential for scarring (cirrhosis) and necrosis. The two classifications of Steatohepatitis are alcoholic Steatohepatitis and nonalcoholic Steatohepatitis.

Oxidative stress has been implicated in the etiology of fatty liver.3 The condition appears most frequently in persons with chronic excessive alcohol ingestion, obesity, and type 2 diabetes mellitus. The condition is also common in persons with protein malnutrition, third-trimester pregnancy, intestinal bypass surgery, hypertension, long-term total parenteral nutrition, and Reye's syndrome. Steatohepatitis may be caused by hepatotoxic drugs and herbs (see Table: "Hepatotoxic Drugs and Herbs").4,5 In 40%-50% of cases, no cause is ever identified.1 Acute Steatohepatitis may occur in response to acute alcohol or hepatotoxic drug overdose or severe hepatotoxic chemical exposure. The natural history of fatty liver is similar for both alcoholic and nonalcoholic etiology. The clinical course varies from mild to advanced fatty liver infiltration, according to individual progression of disease and response to treatment, with a 5 year survival rate of 25% to 60% with advanced disease.1

Patients with noninflammatory alcoholic or nonalcoholic steatosis and mild inflammatory Steatohepatitis are typically asymptomatic with incidental finding of mild, nontender hepatomegaly. Moderate alcoholic or nonalcoholic Steatohepatitis presents with jaundice, right upper quadrant (RUQ) abdominal pain, fatigue, anorexia, diminished libido, unexplained weight loss, and low-grade fever (see Table: "Major Clinical Features of Noninfectious Liver Disorders"). The liver is markedly enlarged, with smooth, rounded borders and a firm consistency. As steatohepatitis advances, hepatomegaly may actually diminish as hepatocytes wither.6 Liver borders become lumpy and irregular due to nodular cirrhosis. Signs of portal hypertension and of cirrhosis may appear (see Table: "Clinical Signs of Moderate to End-Stage Cirrhosis").1 Death is secondary to hepatic encephalopathy, hepatocellular carcinoma, or variceal hemorrhage.

Mild elevations of AST and ALT are present in asymptomatic patients with steatosis or early steatohepatitis. In nonalcoholic steatohepatitis, mild to moderate elevations of serum aminotransferases, with ALT greater than AST, are present. However, these are significantly lower than levels (>5000 U/L)6 seen in acute autoimmune hepatitis, liver ischemia, and acute acetaminophen overdose. Differential diagnoses for moderate to very high transferase increases (2 to 10 times the upper limit of normal)1 include chronic viral or autoimmune hepatitis, hepatocellular carcinoma, and ingestion of hepatotoxic medications.

In alcoholic steatohepatitis, AST concentration is greater than ALT concentration, usually with a ratio greater than two, although AST rarely exceeds 250 U/L.6 Even in acute alcohol steatohepatitis, the AST level almost never exceeds 500 U/L, and the level of ALT is usually less than 300 IU/L.2 Higher concentration of AST than ALT is also seen in acute myocardial infarction. Patients with alcoholic steatohepatitis who have minimally elevated AST, jaundice, RUQ pain and fever are often misdiagnosed with cholecystitis, a potentially fatal mistake.2

Serum AP is usually normal in steatohepatitis; however, persistent low levels of AP are occasionally seen. Serum GGT elevates, in absence of biliary obstruction, with recent intake of even moderate amounts of alcohol. Despite the fact that triglycerides are the lipid component of fatty liver, serum triglycride levels may be normal. Hypoalbuminemia and prolonged coagulation time are characteristic of advanced disease (see Table: "Major Serum Abnormalities of Noninfectious Liver Disorders").

Steatosis requires no treatment other than correction of underlying conditions, i.e., weight loss, diabetes control, and complete abstinence from alcohol intake. Steatohepatitis can also improve with the same treatment approach; however, disease that has progressed to fibrosis before treatment begins is generally irreversible. Transplantation maybe required.

* Cholestatic Diseases

Cholestasis can be caused by a number of conditions other than primary sclerosing cholangitis and primary biliary cirrhosis, selected for discussion. Differential diagnoses should include cholelithiasis, cholangitis, cholangiocarcinoma, biliary cysts, pancreatitis, pancreatic carcinoma, hepatocellular carcinoma, strictures secondary to trauma or surgery, congenital anomalies of the biliary tract, acquired immune deficiency syndrome (AIDS), helminth infestation, acute alcohol ingestion, drug reactions, or granulomatous infiltration of the liver ductal system (sarcoidosis, amyloidosis, tuberculosis, brucellosis, schistomiosis, histoplasmosis, berylliosis).3 Differential diagnosis is accomplished through serum laboratory tests, diagnostic imagery, and, in some cases, liver biopsy.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive inflammatory disease of intrahepatic and/or extrahepatic ducts. Subsequent fibrosis leads to ductal stricture formation and obstruction. The disease is predominantly seen in young adult males. The etiology of PSC is believed to be autoimmune.7,8 Approximately 50% to 75% of patients with PSC have concomitant ulcerative colitis (UC); however, only 2.5% to 7.5% of patients with UC develop PSC.9 Secondary sclerosing cholangitis results from chronic choledolithiasis, ductal carcinoma, AIDS, or surgical, traumatic, or inflammatory biliary injury.

Patients with PSC may be completely asymptomatic and without laboratory abnormalities, symptomatic with laboratory evidence of cholestasis, or have signs and symptoms of end-stage cirrhosis. Symptoms of chronic or intermittent biliary obstruction are moderate to marked hepatomegaly, RUQ pain, jaundice, pruritus and fatigue. Late-stage disease presents with signs of complete biliary obstruction, portal hypertension, and cirrhosis (see Table: "Clinical Signs of Moderate to End-Stage Cirrhosis").10 Loss of bone mass density is common in patients with PSC, leading to osteomalacia and osteoporosis.

Elevated serum AP is a classic sign of PSC. Although the AP level may rise to 10 times normal, it may be minimally elevated in advanced disease. An AP electrophoresis, GGT, or 5'-nucleotidase can confirm cholestasis as the source of AP elevation. Serum AST and ALT range from moderate to high levels, but are below the very high levels noted in acute infectious hepatitis, autoimmune hepatitis, acute drug hepatotoxicity, or liver necrosis. Because obstructed hepatic ducts prevent the excretion of conjugated intrahepatic bile, serum conjugated (direct) bilirubin is elevated in PSC. The finding of urine bilirubin is a sensitive marker for conjugated hyperbilirubinemia. Serum unconjugated (indirect) bilirubin levels may eventually rise with advanced PSC, as the liver loses the capacity to process extrahepatic bilirubin. Deficiencies of serum vitamins A and K may also present as the result of intestinal bile salt deprivation.

Ultrasonography is the appropriate first-line diagnostic test to obtain in the primary care setting because it allows the clinician to distinguish biliary obstruction versus nonobstruction. Ortega and colleagues found tissue harmonic imaging to be superior to conventional sonography.11 Endoscopic retrograde cholangiopancreatography (ERCP) is the test of choice for definitive diagnosis of PSC.12 Characteristic imaging findings in PSC are normal or dilated ductal segments between areas of strictures ("beads on a string" appearance).

Liver biopsy can confirm or exclude a preliminary diagnosis in patients with chronic liver enzyme abnormalities. However, Sorbi et al found that the liver biopsy changed the prebiopsy diagnosis of PSC in only 14% of cases in their study.8 Serum carbohydrate antigen 19-9 (CA 19-9) is elevated in patients with PSC. A serum CA 19-9 level>100 U/mL suggests the presence of cholangiocarcinoma and should be confirmed with imaging studies.13

In Western countries, 10% to 20% of patients with PSC develop cholangiocarcinoma, with a life expectancy of less than 1 year.8 Excessive alcohol consumption14,15 and chronic inflammation caused by common bile duct stent placement16 are thought to increase the risk of carcinoma. Diagnostic imaging improvements such as spiral CT scan, MRI, duplex ultrasonography and PET scan show promise as reliable tools for screening patients at risk for cholangiocarcinoma.17 Because of the high prevalence of UC in patients with PSC, researchers have studied the possibility of colon cancer as a complication of PSC. Heushen et al found that PSC was not associated with colorectal cancer.18 Shetty et al found that patients with PSC but without UC were more likely to have proximal colon malignancy, to be diagnosed at a later stage, and to succumb to the malignancy than patients with UC.19

At present, there is no cure for PSC. Bile salts, for example, ursodeoxycholic acid (UDCA) (Actigall, Ursodiol) or cholestyramine (Questran), may have benefit in alleviating symptoms of PSC. UDCA has been shown to decrease aminotransferases,20,21 lower frequency of colonic dysplasia22 and control pruritus.10 Tung et al found that results with UDCA at doses of 25-30 mg/kg/day significantly differed from results with placebo, whereas doses of 13-15 mg/kg/day did not.22 Despite the immune-mediated characteristics of PSC, corticosteroid therapy has not proven successful in suppressing the disease.23,24 Bone densitometry should be obtained every several years. Oral vitamin A 5000 U (the usual dose in a multi-vitamin) should be given to prevent loss of night vision. A hepatologist should be consulted prior to instituting parenteral vitamin K to prevent hypoprothrombinemia; the altered INR might impact negatively on the patient's priority list for transplantation.

Surgical modalities to relieve biliary obstruction include ductal stent placement, balloon dilation, and, more rarely, lysis of strictures. Self-expandable metallic stents placed in constricted biliary ducts frequently become obstructed, with a mean patency duration of 30.6 months.16 A stent may be placed temporarily and removed when the duct walls become fibrosed and rigid enough to resist compression by strictures.

Liver transplantation is the only treatment choice for end-stage PSC. The risk of malignancy and recurrence of PSC after transplantation is unknown.23-27

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic disease of uncertain etiology, although autoimmune mediation is suspected. Onset is predominantly in females between 35 and 60 years of age. Associated disorders of an autoimmune nature are frequently encountered in patients with PBC (type 1 diabetes mellitus, dry eyes and mouth [sicca syndrome], autoimmune thyroiditis and Raynaud's syndrome). Unlike PSC, PBC is not associated with complications of UC and cholangiocardnoma.

PBC progresses through four stages of liver morphology, ranging from destruction of intrahepatic bile ducts and portal inflammation to hepatic fibrosis and cirrhosis.10,28 Secondary biliary cirrhosis may develop as sequela to biliary obstruction from postoperative adhesions, chronic cholelithiasis, chronic pancreatitis, PSC, tumors of the common bile duct, cystic fibrosis and congenital biliary atresia. Clinical features and laboratory findings associated with secondary biliary cirrhosis do not differ appreciably from those associated with PBC.

Patients with PBC may be asymptomatic for a decade or longer, although most patients do eventually become symptomatic. The first complaint of symptomatic patients is often pruritus, generalized or confined to the palms of hands and the soles of feet. Jaundice develops early. Other clinical signs include steatorrhea, subcutaneous lipid deposition around the eyes (xanthelasma) and in joints (xanthoma), moderate to marked hepatosplenomegaly, clubbing, osteomalacia and osteoporosis, hyperpigmentation of skin, ecchymosis from vitamin K malabsorption, and glossitis from vitamin A deficiency.10 With disease progression, portal hypertension and cirrhosis occur.

As with PSC, the diagnosis of PBC is often made through follow-up for an unexplained, moderately elevated AP. Even in advanced PBC, the AP rarely exceeds 150-200 U/L, lower than in PSC. Because PBC is an intrahepatic disease, both conjugated and unconjugated bilirubin levels increase, with moderate to advanced hepatocellular injury. A distinctive feature of PBC, but not PSC, is a positive titer, greater than 1:4, of IgG antimitochondrial autoantibodies (AMA) in at least 90% of patients.29 Blood concentrations of immunoglobulin IgM and cryoproteins are present in 80% to 90% of PBC patients, but are absent or minimally elevated in patients with PSC.29 Serum deficiencies of vitamins A and K are due to malabsorption of fat as a result of intestinal deprivation of bile salts.

PBC should be suspected in middle-aged women with unexplained elevated AP and pruritus. A negative AMA titer in the presence of clinical symptoms of PBC warrants additional cholangiographic tests such as ERCP or percutaneous transhepatic cholangiogram for definitive diagnosis of PBC.30 Liver biopsy may determine the presence and degree of cirrhosis, but it is usually not necessary or productive in establishing a diagnosis of PBC.8

UDCA appears to be more effective for PBC than for PSC27 at doses of 10-15 mg/kg/day.10 Although UDCA (Actigall, Ursodiol) delays clinical progression of pruritus and elevation of bilirubin, amino-transferases and cholesterol, it does not halt histologic progression of PBC.30 Immunosuppressants (azathioprine [Imuran] and methotrexate) show promise as supplemental treatments to UDCA. Although Newton et al found that osteoporosis did not occur more frequently in patients with PBC than in the general population when matched for gender and age, most authorities recommend that bone densitometry be performed every several years.31 Deficiencies of vitamins K and A should be corrected as described for PSC.

Liver transplantation is required for end-stage PBC. There is a lack of consensus in the literature as to the rate of PBC recurrence posttransplantation.25,27 AMAs may persist in serum after transplantation; however, they are not implicated as the cause for recurrence of PBC.26

* Hereditary Hyperbilirubinemia

Unconjugated Hyperbilirubinemias

Hereditary unconjugated hyperbilirubinemias are caused by inherited deficiencies of the enzyme required for liver conjugation of bilirubin, UDP-glucuronosyl transferase (UGT)32 (see Table: "Hereditary Unconjugated Hyperbilirubinemias"). Deficiencies of UGT range from partial to total, and correlate with the seriousness of a specific inherited unconjugated hyperbilirubinemia disorder. Common features among hereditary unconjugated hyperbilirubinemias are normal AST, ALT, and AP levels, and normal liver histology. Hereditary unconjugated hyperbilirubinemia must be differentiated from faulty liver uptake and conjugation of bilirubin, and hemolytic disorders that cause excessive heme production, such as sickle cell anemia, spherocytosis, and RBC enzyme deficiencies.12

Gilbert's Syndrome

Gilbert's (zhel-bearz') syndrome is a common, benign genetic condition characterized by unconjugated hyperbilirubinemia. The condition, not evident at birth, is caused by a partial deficiency of UGT. The prevalence of Gilbert's syndrome is 5% to 12%, with males affected more frequently than females.33 In healthy persons who carry the genetic trait, baseline serum unconjugated bilirubin is always mildly elevated (2-3 mg/dL),2 but levels tend to escalate during physiologic illness.1 Jaundice may be mild or absent. The disorder does not require treatment, although oral phenobarbital, a stimulant to UGT enzyme activity, can completely normalize unconjugated bilirubin levels and improve liver secretion of bile.31

Crigler-Najjar Syndrome, Type I (CN-I)

CN-I is a rare (0.6-1.0 per million),31 serious unconjugated hyperbilirubinemia with markedly high serum levels of unconjugated bilirubin, i.e., 20-45 mg/dL, and complete absence of UGT. Striking serum concentration of unconjugated bilirubin is responsible for the kernicterus (bilirubin encephalopathy) that once caused certain death in infancy or early childhood. Mortaility has been reduced by phototherapy, usually 12 hours per day from birth throughout childhood, exchange transfusions, and liver transplantation. CN-I should be suspected in any newborn with jaundice lasting longer than 2 weeks.

Crigler-Najjar Syndrome, Type II (CN-II)

CN-II is somewhat more common and less serious than CN-I, but less common and more serious than Gilbert's syndrome. Diagnosis is usually made in infancy. Childhood or early adult diagnosis is possible, but rare. Serum unconjugated bilirubin levels are typically 6-25 mg/dL, and not likely to cause the kernicterus responsible for mortality of CN-I. Liver enzyme UGT is present in small amounts, i.e., 10% or less of normal. Phenobarbital therapy, required throughout lifetime, reduces unconjugated bilirubin levels by at least 25% to 3-5 mg/dL.31 Serum phenobarbital levels should be monitored every several months and maintained at approximately 20 mg/dL or higher for best effect. Phototherapy is usually not required.

* Conjugated Hyperbilirubinemia

Dubin-Johnson Syndrome (DJ)

DJ syndrome is a rare, benign genetic disorder characterized by a life-long mild elevation of serum conjugated bilirubin, and, histologically, dark staining of hepatocytes that turns the liver black. Asymptomatic jaundice may appear, but typically not until early childhood.12 Signs of intrahepatic and extrahepatic cholestasis are absent, and differentiated from cholestatic disorders by a normal AST, ALT, and AP. Rotor's syndrome is clinically identical to DJ syndrome, but without black staining of liver cells.

* Genetic Diseases

Hereditary hemochromatosis (HHC), Wilson's disease (WD), and alpha-1 antitrypsin deficiency (AATD) are the three most clinically important genetic diseases causing liver dysfunction in adults.34 AATD is the most common genetic cause of liver disease in children.35

* HHC

HHC is characterized by deleterious iron deposits in body organs. Once considered rare, HHC is now believed to be the most common genetic disease in Caucasian persons of European descent, with a prevalence of 1:250 persons.1 HHC appears to be the result of a C282Y, or less commonly, a Cys282Tyr mutation in the hemochromatosis HFE gene, resulting in excessive iron absorption in the presence of normal dietary intake and normal levels of red blood cell formation.33 Secondary hemochromatosis may occur in iron-loading anemias (thalassemia major, sideroblastic and chronic hemolytic anemias), dietary or parenteral iron administration, or chronic liver diseases, such as fatty liver. Regardless of origin, hemochromatosis has a high mortality rate if allowed to progress to the advanced stage.

Iron deposition in the liver, pancreas, and skin account for the classic HHC signs of hepatomegaly, diabetes mellitus, and blue-gray or bronze skin pigmentation typically not present in early-stage disease.36 Hepatomegaly usually precedes abnormal liver function tests. Iron deposits also occur in the heart, causing cardiomyopathy and congestive heart failure. Deposits in joints cause arthralgias, and in the pituitary gland cause testicular atrophy, infertility, loss of libido and body hair.

Onset of symptomatic HHC is usually between 40 and 60 years of age because it takes many years for surplus iron to become pathologic. Men become symptomatic at an earlier age, probably reflecting the higher dietary iron intake of men and the physiologic blood loss in reproductive-aged women.33 The most common prediagnosis complaints of fatigue, joint pain, and loss of libido are too nonspecific to provide clues to diagnosis. Type 2 diabetes occurs in up to 50% of patients with HHC, as iron deposition in the pancreas suppresses beta cell function.36

Classic serum markers of fully developed HHC are (1) serum iron > 150 mg/dL, (2) transferrin saturation percent > 45%, and (3) ferritin > 300 mcg/L in males and > 200 mcg/L in females.33,36 An elevated 12-hour fasting transferrin saturation percent is the earliest marker of HHC and the most reliable screening test for the disease.33

Transferrin saturation percent is available with an anemia panel lab test. In some laboratories, it is less costly to order a serum iron (SI) and total iron binding capacity (TIBC) combination test and manually calculate the transferrin saturation percent by dividing the SI by the TIBC (SI/TIBC = transferrin saturation %). Elevated serum ferritin level, while classic in HHC, is not a reliable screening test because ferritin also rises in many noniron-loading conditions (cancer, infection, inflammation).36 Liver aminotransferases are often normal or only slightly elevated in HHC and provide neither screening nor diagnostic value.

Occasionally, one or more serum markers of HHC are normal despite clinical signs of the disease. In these cases, a liver biopsy allows definitive diagnosis. An echocardiogram is valuable to assess heart wall thickness due to iron deposition, and cardiac dysfunction.

Phlebotomy is the only treatment for HHC. The patient should be referred to a blood bank as rapidly as possible after diagnosis. Initially, 500 mL of blood (approximately 250 mg of iron) is removed once or twice weekly. Progress in reduction of iron stores should be monitored weekly. Although transferrin saturation percents or ferritin levels are more accurate, it is more cost effective to monitor weekly with hemoglobin levels. When hemoglobin concentrations diminish to the goal of low normal level (11 g/dL), phlebotomy may be reduced to once weekly and eventually to once every 3 months or so. The time it takes to reach ideal hemoglobin levels ranges from 2 to 3 years of phlebotomy for persons with high iron loads to a matter of months for persons with low iron loads. Once ideal iron load reduction is achieved, serum transferrin saturation percent and ferritin levels should be maintained at less than 30% and less than 50 mcg/L, respectively.33 Phlebotomy should continue on a regular, not intermittent, basis. The patient on phlebotomy therapy can be managed in the primary care setting. Chelation therapy is available for patients who decline phlebotomy but has the risk of serious side effects and is expensive.36 Chelation therapy should be managed by a hepatologist.

Comorbid diabetes, arthritis, heart failure, and liver failure are treated with standard therapies. Injections of testosterone or gonadotropin may improve libido and changes in secondary sex characteristics. Patients with HHC should be cautioned against ingesting iron, vitamin C or multivitamin supplements, iron-rich foods, and raw or undercooked shellfish.36

The prognosis for patients with HHC is inversely related to the extent of liver injury. Phlebotomy can reverse skin pigmentation changes and fatigue, and, in some cases, reduce the severity of cardiac myopathy and diabetes, but does not reverse hypogonadism, arthropathy, or cirrhosis. Hepatic carcinoma is a common cause of death in patients with cirrhosis prior to phlebotomy treatment.

Testing of HHC patients' first-degree relatives age 20 and older for the C282Y mutation of the HFE gene is recommended for early diagnosis and treatment. Although this test is expensive (approximately $200), it is more cost effective than repeated iron studies.35 Screening the general population with genetic testing or iron studies is controversial because of high cost and poor sensitivity, but it is prudent to test patients with comorbid conditions or symptoms of iron overload.37

* WD

WD is an uncommon autosomal recessive disorder of aberrant copper metabolism, with prevalence among the United States Caucasian population estimated to be 1 in 55,000.38 A mutation of the gene ATP7B prevents normal liver excretion of copper, resulting in toxic accumulation of copper initially in the liver and, eventually, the cornea and lens of the eye, the brain, and the kidney.39

Symptoms usually appear between 3 to 12 years of age, with wide variance in the severity of liver disease on presentation, including asymptomatic hepatomegaly, chronic hepatitis, hemolytic anemia with jaundice and severe unconjugated hyperbilirubinemia (>47 mg/dL), acute liver failure, end-stage cirrhosis, and rarely, fulminant hepatic failure.40 In adolescent or adult onset of symptoms, the presence of Kayser-Fleischer rings and neuropsychiatric changes may be more striking than hepatic impairment. Kayser-Fleischer rings, often visible only with a slit lamp, are gold-brown or brown-green copper pigment deposits located just medial to the cornea-sclera junction (the lateral border of the iris).41 Copper deposition in the ocular lens produces an opacity with central density and peripheral "petal" pattern called "sunflower cataract".40 Neuropsychiatrie disorders include dystonia, parkinsonism, tremors, chorea, depression, mania, altered mentation, obsessive-compulsive behavior, and personality changes.42 Patients diagnosed in adolescence or young adulthood usually have cirrhosis at the time of diagnosis.

Diagnosis is confirmed by laboratory findings of low serum ceroplasmin, and elevated copper levels in serum, and 24-hour collection of urine. Elevated hepatic copper concentration is evident with liver biopsy. Life-long copper chelation therapy is required to prevent end-stage liver disease. For many years, D-penicillamine was the only copper-binding drug available. Recently, zinc and trientine have shown to be effective, with fewer side effects than D-penicillamine.43-46 Liver transplantation is required for patients with fulminant liver disease.

Genetic screening of family members is less reliable for WD than for other hereditary liver diseases because of multiple mutations of the ATP7B gene. Denaturing high-performance liquid chromatography appears to have higher sensitivity and specificity than traditional haplotyping.47

* AATD

AATD is a protein synthesized and secreted mainly by the liver that curbs protease activity. Proteases are powerful enzymes in tissues and in neutrophils that attack foreign substances in the body, e.g., inflammation, infection, and tobacco smoke. AATD allows unrestrained proteases to attack normal tissue in the lungs, causing emphysema. The exact mechanism of liver damage from AATD is unknown, but it is widely believed that liver cell injury is caused by over-accumulation of mutated alpha-1 antitrypsin protein in the hepatocytes.48

AATD is an autosomal recessive metabolic disorder caused by mutation of the gene 12.2 kb long, chromosome 14. The gene has more than 90 alleles (variants), most of which are associated with mild lung and liver disease. Alleles M and Z are associated with more serious lung and liver disease.49,48 AATD affects between 70,000 and 100,000 persons in the United States, the majority of whom are Caucasians of Northern European descent.50 There is no gender predominance.

The clinical course of both children and adults with AATD is widely variable. The spectrum of liver disease severity ranges from asymptomatic nonprogressive cirrhosis to slowly progressing cirrhosis to rapidly progressing cirrhosis and end-stage cirrhosis. Onset in the neonatal period presents with jaundice and laboratory features of cholestasis, hepatocellular injury, and, usually, hepatomegaly. Up to 70% of these children will have persistently elevated ALT and AST after cholestasis has resolved,48 although 85% to 90% of them will show no evidence of liver disease by age 18.51 Liver disease first recognized in late childhood, early adolescence, or adulthood may present with advanced liver disease, with ascites, portal hypertension, and variceal hemorrhage.48 It is estimated that 10% of patients with AATD who develop liver disease in adulthood will develop end-stage cirrhosis, and 5% to 10% will develop advanced pulmonary emphysema.48 Hepatocellular carcinoma is a common complication of AATD.52

Diagnosis of AATD should be suspected in patients with asthma, adults with early onset of emphysema (at 35 to 55 years of age, and especially if seen in nonsmokers), chronic liver disease, or unexplained liver-related clinical or laboratory findings.49 Laboratory tests to detect presence of AATD are quite simple and inexpensive. A serum alpha-1 antitrypsin level 25% less than the lower limit of normal suggests AATD. For example, if the normal serum alpha-1 antitrypsin range is 124-226 mg/dL, 25% less than the lowest normal value will be 93 mg/dL. A serum protein electrophoresis with absence of the alpha-1 globulin peak is also suggestive of AATD. Confirmation should be made with AATD protein phenotyping, the gold standard for establishing the diagnosis of AATD.48,49,52 Genetic screening of relatives for AATD is possible, but not as reliable as that for HHC because of the high number of possible mutations of the 12.2 kb long gene.34

There is currently no curative treatment for AATD. Measures to discourage disease progression include maintaining optimal nutrition, avoidance of alcohol consumption and hepatotoxic drugs and chemicals, annual influenza vaccination, and pneumovax revaccination every 6 years.49

Clinicians must carefully analyze history, physical findings and all four areas of serum liver function tests to distinguish among noninfectious liver disorders. Patterns of hepatocellular injury, cholestasis, liver excretory function, and liver synthesis direct the diagnosis, help to gauge the extent of liver damage, and determine optimal treatment or referral.

REFERENCES

1. Goroll AH, Mulley AG: Management of cirrhosis and chronic liver failure. In: Goroll AH, Mulley AG, eds. Primary care medicine, 4th edition. Philadelphia: Lippincott Williams & Wilkins, 2000;463-70.

2. Johnston DE: Special considerations in interpreting liver function tests. Am Fam Physician 1999;59(8):2223-30.

3. Podolsky DK: Infiltrative genetic and metabolic diseases affecting the liver. In: Braunwald E, Fauci AS, Kasper DL, et al., eds. Harrison's principles of internal medicine, 15th edition. New York: McGraw-Hill, 2001;1767-70.

4. Riley TR, Bhatti AM: Preventive strategies in chronic liver disease: Part I: Alcohol, vaccines, toxic medications and supplements, diet and exercise. Am Fam Physician 2001;64(9):1555-60.

5. Palacioz K: Scheduling of liver function tests. Prescriber's Letter, 2001;8(8): 170825.

6. Yoshida EM: Abnormal liver functions tests: What to do for the patient. Consultant 2003:43(4):505-13.

7. Saarinen,S, Olerup O, Broome U: Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis. Am J Gastroenterol 2000:95(11):3195-99

8. Sorbi D, McGill DB, Thistle JL, et al: Assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities. Am J Gastroenterol 2000;95(11):3206-10.

9. Raj V, Lichenstein DR: Hepatobiliary manifestations of inflammatory bowel disease. Gastroenterol Clin North Am 1999;28(2):419-513.

10. Chung RT, Podolsky DK: Cirrhosis and its complications. In: Braunwald E, Fauci AS, Kasper DL, et al., eds. Harrison's principles of internal medicine, 15th edition. New York: McGraw-Hill, 2001;1754-67.

11. Ortega D, Burns PN, Hope-Simpson D, et al.: Tissue harmonic imaging; Is it a benefit for bile duct sonography? AJR Am J Roentgenol 2001;176(3): 653-59.

12. Pratt DS: Approach to the patient with abnormal liver function tests, www.uptodate.com, 2003;1-23.

13. Rumalla A, Peterson BT: The diagnosis and therapy of biliary tract malignancy. Semin Gastrointest Dis 2000;11(13):168-73.

14. Chalasani N, Baluyut A, Ismail A, et al: Cholangiocarcinoma in patients with primary sclerosing cholangitis: A rnulticenter case-control study. Hepatology2000;31(1):7-11.

15. Lopez RR, Casenza CA, Lois J, et al.: Long-term results of metallic stents for benign biliary strictures. Arch Surg 2001;136(6):664-69.

16. Ahrendt SA, Nakeeb A, Pitt HA: Cholangiocarcinoma. Clinics in Liver Disease 2001;5(1):191-218.

17. Heushen UA, Hinz U, Allemeyer EH, et al: Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001;120(4):841-47.

18. Shetty K, Rybicki L, Brzezinski A, et al: The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1999;94(6):1643-49.

19. Harnois DM, Angulo P, Jorgensen RA, et al: High dose ursodeoxycholic acid as a therapy for patients with sclerosing cholangitis. Am J Gastroenterol 2001;96(5):1558-62.

20. Stiehl A, Benz C, Sauer P: Mechanism of hepatoprotective action of bile salts in liver disease. Gastroenterol Clin North Am 1999;28(1):195-209, viii.

21. Tung BY, Emond MJ, Haggitt RC, et al: Ursodiol is associated with lower prevalence of colonic dysplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001;134(2):89-95.

22. Angulo P, Batts LP, Jorgensen RA, et al: Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2000;95(9):2333-37.

23. van Hoogstraten HJ, Vleggaar FP, Boland GJ, et al: Budesonide or prednisone in combination with ursodeoxycholic acid in primary scleosing cholangitis: A randomized double-blind pilot study. Am J Gastroenterol 2000;95(8):2015-22.

24. Balan V, Abu-Elmagd K, Demetris AJ: Autoimmune liver disease: Recurrence after liver transplantation. Surg Clin North Am 1999;79(1):147-52.

25. Faust TW: Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation. Semin Liver Dis 2000;20(4):481-95.

26. Franco J, Saeian K: Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis. Current Gastroenterology Reports 1999;1(2):95-101.

27. Erickson JM, Mawson AR: Possible role of endogenous retinoid (vitamin A) in the pathophysiology of primary biliary cirrhosis. J Theor Biol 2000;206(1):47-54.

28. Czaja AJ, Carpenter HA, Santrach PJ, et al: Autoimmune cholangitis within the spectrum of autoimmune liver disease. Hepatology 2000;31(6):1231-38.

29. Mezey E: Diseases of the liver. In: Barker LR, Burton JR, Zleve PD, eds. Principles of ambulatory medicine, 5th edition. Baltimore, MD: Williams & Wilkins, 1999;529-40.

30. Newton J, Francis R, Prince M, et al.: Osteoporosis in primary biliary cirrhosis revisited. Gut 2001;49(2):282-87.

31. Berk P, Wolkoff A: Bilirubin metabolism and the hyperbilirubinemias. In: Braunwald E, Fand AS, Kasper DL, et al, eds. Harrison's principles of internal medicine, 15th edition. New York: McGraw-Hill, 2001; 1719.

32. Francoual J, Trioch P, Mokrani C et al: Prenatal diagnosis of Crigler-Najjar syndrome type I by single-strand conformation polymorphism (SSCP). Prenat Diagn 2002; 22(10):914-6.

33. Powell LW, Yapp TR: Hemochromatosis. Clinics in Liver Disease 2000; 4(1):211-28.

34. Morrison ED, Kowdley KV: Genetic liver disease in adults. Early recognition of the three most common causes. Postgrad Med. 2000; 107(2): 147-52, 155, 158-9.

35. Perlmutter DH: Liver injury in alpha 1-antitrypsin deficiency. CHn Liver Dis 2000;4(2):387-408

36. Pearlmen BL: Hereditary hemochromatosis: Early detection of a common yet elusive disease. Consultant 2002;42(2):237-50.

37. El-Serag HB, Inadomi JM, Kowdley KV: Screening for hereditary hemochromatosis in siblings and children of affected patients: A cost effectiveness analysis. Ann Intern Med 2000; 132(4):261-69.

38. Olivarez L, Caggana M, Pass KA, Ferguson P, Brewer GJ: Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach. Ann Hum Genet 2001; 65(Pt 5):459-63.

39. Sarkar B: Copper transport and its defect in Wilson disease: characterization of the copper-binding domain of Wilson disease ATPase. J Inorg Biochem 2000;79(1-4):187-91.

40. Tanner S: Wilson's disease. In: O'Grady JG, Lake JR, Howdle PD, eds. Comprehensive Clinical Hepatology; St. Louis:Mosby, 2000;3.21: 22.1-22.20.

41. Liu M, Cohcn EJ, Brewer GJ, et al: Kayser-Fleischer ring as the presenting sign of Wilson disease. Am J Ophthalmol 2002; 133(6):832-4.

42. Rosenblatt A, Leroi I: Neuropsychiatry of Huntington's disease and other basal ganglion disorders. Psychosomatics 2002; 41(1):24-30.

43. Loudianos G, Gitlin ID: Wilson's disease. Semin Liver Dis 2000;20(3):353-64.

44. Brewer GJ, Johnson VD, Dick RD, Hedera P, Fink JK, Kluin KJ: Treatment of Wilson's disease with zinc. XVII: treatment during pregnancy. Hepatology 2000;31(2):364-70.

45. Brewer GJ: Copper control as an antiangiogenic anticancer therapy; Lessons from treating Wilson's disease; Exp Biol Med 2001; 226(7):665-73.

46. Brewer GJ: Zinc acetate for the treatment of Wilson's disease. Expert Opin Pharmacother 2001; 2(9):1473-7.

47. Weirich G, Cabras AD, Serra S, et al: Rapid identification of Wilson's disease carriers by denaturing high-performance liquid chromatography. Prev Med 2002; 35(3):278-84.

48. Quist RG, Baker AJ, Dhawan A, et al: Metabolic diseases of the liver. In: O'-Grady JG, Lake JR, Howdle PD, eds. Comprehensive Clinical Hepatology. St. Louis: Mosby, 2000; 3.21, 22.5-22.7.

49. Alpha One Foundation: A healthcare provider guide to alpha 1 antitrypsin deficiency: www.alphaone.org, 2000;1-20.

50. Banasik J: Diagnosing alpha 1-antitrypsin deficiency. Nurse Practitioner 2001;26(1):58-62, 64, 67.

51. Volpert D, Molleston JP, Perlmutter DH: Alpha1-antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastroenterol Nutr2000;31(3):258-63.

52. Costa X, Jardi R, Rodriguez F, Miravitlles M, Cotrina M, Gonzalez D, Pascual C, Vidal R: Simple method for alpha1-antitrypsin deficiency screening by use of dried blood spot specimens. Eur Respir J 2000; 15(6):111-5.

Doris Alexander, MN, ARNP, BC

Susan Schaffer, PhD, ARNP, BC

Charles Zeilman, MSN, ARNP, BC

ABOUT THE AUTHORS

At the College of Nursing, University of Florida, Gainesville, Doris Alexander is an Assistant Professor and Dr. Schaffer is an Assistant Professor. Charles Zeilman is an Advanced Nurse Practitioner with the Gastroenterology Department at the Veteran's Administration Medical Center, Gainesville, Fla.

Copyright Springhouse Corporation Dec 2003
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