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28-Year-Old Man With Renal Insufficiency and Jaundice

1997; Elsevier BV; Volume: 72; Issue: 11 Linguagem: Inglês

10.1016/s0025-6196(11)63548-9

1942-5546

Konstantinos N. Lazaridis, Patrick S. Kamath,

Porphyrin Metabolism and Disorders

A 28-year-old previously healthy man sought medical assistance because of a 4-day history of right-upper-quadrant discomfort, nausea, arthralgia, and myalgia. A viral syndrome was diagnosed and treated empirically with acetaminophen. Two days later, he had jaundice and ascites and was transferred to our medical center for further evaluation. The patient's past medical and family history was unremarkable for liver disease. He denied receiving blood transfusions, participating in foreign travel, or abusing alcohol or intravenously administered drugs. Physical examination revealed a temperature of 37.0°C, blood pressure of 130/80 mm Hg, regular pulse of 75 beats/min, and respiratory rate of 18/min. The skin and sclerae were icteric. Edema of the lower extremities extended up to the knees bilaterally. Cardiovascular and chest findings were unremarkable. Ascites was demonstrated by detection of shifting dullness in the abdomen. The liver and spleen were not palpable. On percussion, the liver span was estimated at 8 cm. Neurologic findings were within normal limits. Laboratory studies showed the following: hemoglobin 9.2 g/dL, hematocrit 25.6%, total leukocyte count 8.3 × 109/L, platelet count 81 × 109/L, international normalized ratio 3.0, activated partial thromboplastin time 45.9 seconds, total bilirubin 31.8 mg/dL, direct bilirubin 20.6 mg/dL, alkaline phosphatase 115 U/L, aspartate aminotransferase (AST) 118 U/L, alanine aminotransferase (ALT) 22 U/L, lactate dehydrogenase (LDH) 365 U/L, albumin 3.1 g/dL, glucose 119 mg/dL, sodium 141 mEq/L, potassium 3.8 mEq/L, chloride 108 mEq/L, bicarbonate 19 mEq/L, creatinine 2.9 mg/dL, urea 90 mg/dL, and uric acid 1.7 mg/dL. 1.Which one of the following is least likely to have caused this patient's hepatic and kidney dysfunctions? a.Hepatitis Bb.Budd-Chiari syndrome (BCS)c.Autoimmune hepatitis (AIH)d.Wilson's disease (WD)e.Acetaminophen toxicity Our patient's initial manifestations suggested an acute deterioration of hepatic function. All the foregoing conditions could cause acute liver injury, which may lead to fulminant hepatic failure (FHF). Most hepatic diseases can be associated with renal involvement. Because the renal changes may not be specific, the diagnostic approach must be focused on the liver. Both acute and chronic hepatitis due to either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection can result in renal disease. Patients with HBV or HCV can have kidney abnormalities, including (1) glomerulonephritis, usually membranous (HBV) or membranopro-liferative (HCV), and (2) "microscopic" polyarteritis nodosa affecting the small renal arteries—an association that has been established for HBV and suggested for HCV. BCS is the consequence of obstruction of the hepatic venous outflow tract.1Shill M Henderson JM Tavill AS The Budd-Chiari syndrome revisited.Gastroenterologist. 1994; 2: 27-38PubMed Google Scholar BCS may be idiopathic (in 20 to 50% of cases), or it can be caused by myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, and other hypercoagulable states. The usual manifestations of BCS are right-upper-quadrant pain, liver dysfunction, and ascites; rarely, BCS may manifest as acute hepatic failure associated with renal dysfunction.1Shill M Henderson JM Tavill AS The Budd-Chiari syndrome revisited.Gastroenterologist. 1994; 2: 27-38PubMed Google Scholar Six to 15% of cases of AIH can manifest as acute liver failure associated with functional renal involvement.2Czaja AJ Nishioka M Toda G Zeniya M Clinical aspects of autoimmune hepatitis in North America. Autoimmune Hepatitis. Elsevier, Amsterdam1994: 27-43Google Scholar AIH affects primarily women (70%), and immunologic diseases are present in 37% of patients. Hypergammaglobulinemia and smooth muscle antibodies are the hallmarks of the disease.2Czaja AJ Nishioka M Toda G Zeniya M Clinical aspects of autoimmune hepatitis in North America. Autoimmune Hepatitis. Elsevier, Amsterdam1994: 27-43Google Scholar Wilson's disease, an inherited liver disorder, is characterized by a defect in copper metabolism.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Cirrhosis of the liver, chronic hepatitis, and FHF are the liver manifestations of WD, and reduced glomerular filtration rate and diminished renal plasma flow are renal complications.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Acetaminophen, a commonly used analgesic, can cause extensive acute liver necrosis. An acetaminophen overdose (15 g or more) can be fatal for an adult. Extended fasting and use of alcohol can worsen the hepatic injury by depleting glutathione. Within 12 to 24 hours after ingestion of toxic doses of acetaminophen, the serum ALT and AST levels begin to increase; a plateau (10,000 U/L or more) is reached at 72 hours. Acetaminophen is also nephrotoxic. Oliguric renal failure has been reported in approximately 10% of severe cases of acetaminophen overdose, even in the absence of hepatic failure. All these conditions can cause transaminase increases but not as high as with acetaminophen toxicity. The only mildly increased transaminase levels despite a substantially elevated serum bilirubin make acetaminophen toxicity the least likely cause of this patient's acute hepatic injury. His drug screen was negative. On urinalysis, only the bilirubin was abnormal, and findings on renal ultrasonography were unremarkable. 2.On the basis of the available clinical information, which one of the following diagnostic studies is leastappropriate? a.Ultrasonography of the liverb.HBV and HCV serologyc.Smooth muscle antibodiesd.Serum a1-antitrypsin (a1-AT) andphenotypee.Serum ceruloplasmin Ultrasonography of the liver is the preferred initial imaging study in patients suspected of having acute or chronic liver disease. Our patient's manifestations indicate the presence of acute hepatic failure, and ultrasonography of the liver is an appropriate diagnostic test for assessment of possible hepatic masses, parenchymal liver disease, gallbladder abnormalities, biliary obstruction, and ascites. Liver ultrasonography can detect mass lesions 10 mm or more in diameter and can distinguish cystic from solid structures. Moreover, Doppler ultrasonography allows study of the direction of blood flow or obstruction in the portal, splenic, and hepatic veins. In every patient with acute liver disease, such as our case, viral hepatitis must be excluded. Acute viral hepatitis accounts for about 70% of all cases of FHF. Only 3 to 4% of patients diagnosed with acute viral hepatitis, however, have progression to FHF. All the known hepatotropic viruses can cause FHF, but it is rare in HCV. Smooth muscle antibodies have high specificity in AIH type I, the most common type in the Western Hemisphere.2Czaja AJ Nishioka M Toda G Zeniya M Clinical aspects of autoimmune hepatitis in North America. Autoimmune Hepatitis. Elsevier, Amsterdam1994: 27-43Google Scholar Thus, the work-up of our patient for acute deterioration of liver function must include testing for smooth muscle antibodies to rule out AIH. a,-AT is synthesized by hepatocytes. Adults with a1-AT deficiency generally have nonspecific signs and symptoms of chronic liver disease.4Perlmutter DH Alpha-1-antitrypsin deficiency: biochemistry and clinical manifestations.Ann Med. 1996; 28: 385-394Crossref PubMed Scopus (37) Google Scholar Multiple normal (Ml, M2, M3) and abnormal (Z, S, P, null) variants of a1-AT have been described.4Perlmutter DH Alpha-1-antitrypsin deficiency: biochemistry and clinical manifestations.Ann Med. 1996; 28: 385-394Crossref PubMed Scopus (37) Google Scholar The ZZ phenotype is most often associated with liver disease and leads to development of cirrhosis in about 15% of patients.4Perlmutter DH Alpha-1-antitrypsin deficiency: biochemistry and clinical manifestations.Ann Med. 1996; 28: 385-394Crossref PubMed Scopus (37) Google Scholar Overall in adults, a1-AT deficiency is a silent, chronic, and slowly progressive disorder that clearly differs from the acute condition in our patient. Rarely, WD can manifest as acute liver failure.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Evaluation for suspected WD should include measurement of serum ceruloplasmin. In our patient, abdominal ultrasonography demonstrated a small liver with irregular surface, ascites, and mild splenomegaly, findings suggestive of cirrhosis of the liver. The portal, splenic, and hepatic veins, as well as the inferior vena cava, showed no obstruction; thus, the diagnosis of BCS was excluded. Serologic tests for HBV, HCV, and smooth muscle antibodies were negative. The serum ceruloplasmin was 29.1 mg/dL (normal, 22.9 to 43.1), but 10 to 15% of patients with liver manifestations of WD have normal ceruloplasmin levels.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar (Ceruloplasmin is a nonspecific phase reactant that can be increased in acute liver disease.) 3.At this stage, which one of the following tests will be the least helpful in establishing the diagnosis of this patient's liver disease? a.Total serum copperb.Serum ceruloplasmin-bound copperc.Serum free copperd.Urine coppere.Hepatic copper Total serum copper is the sum of the serum ceruloplasmin-bound copper plus the serum free or non-ceruloplasmin-bound copper.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Serum free copper is the fraction that is most likely associated with pathogenicity and can be calculated by subtracting the serum ceruloplasmin-bound copper (0.047 umol copper/mg ceruloplasmin) from the total serum copper.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar In patients with presymptomatic WD, total serum copper is usually normal, and serum free copper is higher than 0.12 Hg/dL (normal, less than 0.12).3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar The explanation for the normal total serum copper in those patients is that the increased serum free copper is insufficient to counterbalance the low levels of serum ceruloplasmin-bound copper. In contrast, patients with WD who have FHF, such as our patient, have increased levels of total serum copper because of massive release of copper from hepatocytes. In most patients with symptomatic WD, the urine copper exceeds 100 μg/24 h;3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar however, patients with FHF have urine copper in excess of 1,000 μg/24 h because of excessive release of copper from injured hepatocytes into the systemic circulation.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar In our patient, the total serum copper and the urine copper were 3.17 μg/mL (normal, 0.75 to 1.45) and 10,805 μg/24 h (normal, 15 to 60), respectively. Increased levels of serum free copper and urine copper are not pathognomonic for WD because they can be found in other chronic cholestatic liver diseases.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Finally, hepatic copper has been shown to be an unreliable and misleading test for the diagnosis of WD in patients who have FHF.5McDonald JA Snitch P Painter D Hensley W Gallagher ND McCaughan GW Striking variability of hepatic copper levels in fulminant hepatic failure.J Gastroenterol Hepatol. 1992; 7: 396-398Crossref PubMed Scopus (34) Google Scholar Thus, on the basis of our patient's clinical and laboratory findings and the exclusion of other chronic cholestatic liver diseases, all the itemized tests except the hepatic copper would be helpful in establishing the diagnosis of WD. At this stage, the patient's laboratory findings were as follows: hemoglobin 7.5 g/dL despite transfusion of packed erythrocytes, creatinine 3.3 mg/dL, total bilirubin 55.5 mg/ dL, direct bilirubin 40.5 mg/dL, serum haptoglobin less than 10.5 mg/dL, and LDH 420 U/L. The Coombs test was negative, and the peripheral blood smear showed a regenerative picture without schistocytes. 4.Which one of the following conditions is the least likelymanifestation of this patient's disease? a.Kayser-Fleischer (KF) ring and sunflower cataractb.Renal stonesc.Hepatocellular carcinomad.Grand mal seizurese.Intravascular hemolysis WD is a systemic disorder. Overall, patients have signs of liver involvement earlier than neurologic complications. Ophthalmologic examination of our patient revealed bilateral KF rings. The KF ring is a golden-brown discoloration in the limbic domain of the cornea due to copper deposition in Descemet's membrane.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Although present in about 90% of symptomatic patients with WD, KF ring is not pathognomonic of the condition inasmuch as it can also be found in patients with other chronic liver disorders, including biliary atresia, primary biliary cirrhosis, chronic AIH with cirrhosis, and cryptogenic cirrhosis. A less common ocular finding of WD is the sunflower cataract, which is also not pathognomonic of the disease. Interestingly, both KF ring and sunflower cataract disappear in most patients with WD after medical treatment (D-penicillamine). The renal manifestations of WD, which may occur in the absence of hepatic failure, include impaired glomerular filtration rate and decreased renal plasma flow, which can explain our patient's renal insufficiency. Proximal tubular defects may also develop because of the toxic effects of copper on the renal tubules. Distal renal tubular acidosis may be present and result in the development of renal stones in about 15% of cases,6Wiebers DO Wilson DM McLeod RA Goldstein NP Renal stones in Wilson's disease.Am J Med. 1979; 67: 249-254Abstract Full Text PDF PubMed Scopus (39) Google Scholar and microscopic hematuria, attributable to nephrolithiasis, is commonly found in WD. In contrast with other chronic liver diseases, hepatocellular carcinoma is extremely rare in patients with WD. Nevertheless, the incidence of hepatocellular carcinoma in these patients may increase in the future because their survival has been extended in recent years. The initial neurologic manifestations of WD are insidious, ranging from clumsiness to dysarthria and tremor, and they manifest during the second or third decade of life. Subsequently, dystonia, grand mal seizures, and rigidity develop. The incidence of seizure activity in a patient with WD is 10-fold greater than in normal persons. Cognitive function and sensation remain intact except in cases of FHF. Our patient had no neurologic findings on admission; however, during hospitalization, development of encephalopathy suggested FHF. The psychiatric manifestations of WD include behavioral, affective, and schizophrenia-like disorders. Acute intravascular hemolysis is the initial manifestation in 10 to 15% of patients with WD. Our patient's investigations disclosed no other explanations for his intravascular hemolysis except WD. Erythrocytes are thought to absorb excessive amounts of copper, a process that leads to their oxidative damage. In patients with WD, hemolysis may be temporary and self-limited and can precede the manifestations of liver involvement by years. Thus, children and young adults with Coombs'-negative hemolytic anemia should be screened for WD even if a KF ring is not present. 5.Which one of the following statements, as it relates to our patient's disorder, is not correct? a.All of this patient's first-degree relatives must be screened for the disorderb.If a relative is diagnosed with presymptomatic disease, chelation therapy should be started immediately and continued for lifec.D-Penicillamine could have prevented progression of the liver diseased.Chelation therapy with trientine and zinc is indicatede.Orthotopic liver transplantation corrects the fundamental defect in the abnormal mineral metabolism The clinical manifestations of WD are preventable if the diagnosis is made during the presymptomatic stage and appropriate treatment (chelation) begins before damage to the involved organs (liver, brain). Therefore, all first-degree relatives of patients with WD must undergo screening, including a thorough history and physical examination, liver function tests, slit-lamp ophthalmologic examination, and assessment of serum ceruloplasmin. Liver biopsy and quantitative determination of hepatic copper concentration should be done only in cases with diagnostic difficulty, D-Penicillamine, an amino acid derivative, is the standard pharmacologic therapy for patients with WD.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Indeed, it prevents progression and relieves or may even resolve the hepatic, neurologic, psychiatric, and renal manifestations of the disorder. Nonetheless, temporary neurologic deterioration can persist for months. The treatment should be lifelong, and coadministration of pyridoxine (25 mg/day) is essential to prevent the antipyridoxine effects of D-penicillamine. Trientine, another chelating agent, is primarily used in patients with WD in whom side effects to D-penicillamine have developed. Zinc acts by preventing enteric absorption and increasing fecal copper excretion. Neither of these two agents could be used in this acute case of WD because a prolonged period of administration is necessary to generate a negative copper balance. These agents, however, can serve as maintenance therapy in presymptomatic or pregnant patients with WD. Patients with WD who have FHF and multiorgan failure should be considered for urgent liver transplantation because their overall prognosis is dismal. Most patients who undergo transplantation show remarkably diminished symptoms and signs of WD because the metabolic defect of the disease is corrected by the transplanted normal liver. Advanced neurologic deficits may not be alleviated, however. Our patient continued to deteriorate despite aggressive management. He underwent orthotopic liver transplantation 6 days after admission. The explanted liver revealed well-developed micronodular cirrhosis, severe cholestasis, fatty changes, scattered small foci of hepatocyte necrosis, and intact bile ducts. Quantitative copper analysis revealed 1,856 ug of copper per gram dry weight of liver (normal, 15 to 55). The findings supported the diagnosis of WD associated with liver cirrhosis. WD is an autosomal recessive disorder with a prevalence of approximately 1 in 30,000 persons and a calculated gene frequency of 1 in 180. Although the biochemical defect of WD exists at birth, the initial signs of disease are rarely noticed before the age of 5 years. Indeed, in 50% of patients with WD, clinical symptoms become evident by the age of 15 years, but extraordinary cases initially affecting adults in their 50s and 60s have been reported. Copper was implicated in the pathogenesis of WD approximately 50 years ago. Only during the past decade, however, have the pathophysiologic mechanisms responsible for the accumulation and toxicity of copper in the affected tissues (liver, brain) been elucidated.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar The WD gene was identified after isolation and characterization of the gene responsible for Menkes' syndrome, an X-linked disorder of copper metabolism characterized by deficiency of serum copper and copper-dependent enzymes.7Davies K Cloning the Menkes disease gene.Nature. 1993; 361: 98Crossref PubMed Scopus (16) Google Scholar Recently, the abnormal gene for WD was localized to the long arm of chromosome 13 and found to be expressed primarily in liver, kidney, and placenta.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar This gene codes for a P-type adenosine triphosphatase, a transmembrane copper-transport protein that has an active role in the transfer of hepatocellular lysosomal copper into the canaliculus. Cells deficient in this protein (hepatocytes) accumulate copper gradually, and toxicity by disruption of intracellular organelles results.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Of interest, most patients with WD have a decreased level of ceruloplasmin. Ceruloplasmin, the main copper-binding glycoprotein in plasma, is produced exclusively by the liver, and its synthesis is decreased in about 90% of homozygotes and 20% of heterozygous patients with the WD gene. Approximately 10 to 15% of patients with unequivocal WD, however, have normal ceruloplasmin levels.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Although an association between WD and ceruloplasmin deficiency exists, the fundamental defect in copper metabolism in these patients is independent of this glycoprotein. Indeed, the serum ceruloplasmin concentration does not correlate with the clinical severity of the disease and, during prolonged treatment with D-penicillamine, ceruloplasmin levels usually decrease despite a favorable clinical outcome. In addition, persons heterozygous for the WD gene may have reduced levels of ceruloplasmin but never have copper toxicity in their tissues. Moreover, patients with WD given intravenous ceruloplasmin therapy do not have improved copper metabolism. Thus, serum ceruloplasmin alone cannot be used for diagnosing WD. Overall, the correlation between reduced ceruloplasmin levels and WD reflects a possible interaction between these two proteins rather than an etiologic effect of ceruloplasmin gene expression on the development of WD. Of the three described clinical manifestations of hepatic injury—cirrhosis of the liver, chronic hepatitis, and FHF— cirrhosis is the most common and may be associated with variceal bleeding or hepatic encephalopathy. Five to 35% of patients with WD have a clinical and biochemical profile of chronic hepatitis.3Zucker SD Gollan JL Zakim D Boyer TD Wilson's disease and hepatic copper toxicosis. Hepatology: A Textbook of Liver Disease. Vol 2. 3rd ed. Saunders, Philadelphia1996: 1405-1439Google Scholar Studies have shown that WD is responsible for 5 % of liver disease in patients younger than 35 years of age who were previously diagnosed with idiopathic "chronic active hepatitis." A characteristic laboratory finding in patients with WD is the only moderate increase of ALT and AST despite extensive hepatocellular inflammation and necrosis. Rarely, patients with WD (such as our patient) have FHF at initial assessment, and the clinical profile includes splenomegaly, intravascular hemolysis, and KF ring. The biochemical picture demonstrates modestly increased serum aminotransferases despite severe hepatic necrosis and hyperbilirubinemia with a normal or low alkaline phosphatase level. Typically, as in our patient, the concentration of AST is greater than that of ALT because of the associated hemolysis. Medical management of FHF due to WD is usually ineffective. Because survival longer than days to weeks is unlikely without liver transplantation, early referral to a transplantation center is imperative. In summary, this case illustrates the difficulty in diagnosing an inherited liver disease that can progress silently. The diagnostic approach should rely on both clinical and biochemical findings and the exclusion of other chronic cholestatic liver diseases.