0
ONLINE EXCLUSIVES
Pulmonary, Critical Care, and Sleep Pearls |

A Teenager Presents With Fulminant Hepatic Failure and Acute Hemolytic AnemiaFulminant Hepatic Failure and Hemolytic Anemia FREE TO VIEW

Somnath Bose, MD; Abraham Sonny, MD; Nadeem Rahman, MD
Author and Funding Information

From Critical Care Anesthesiology (Dr Bose), Outcomes Research (Dr Sonny), and Cleveland Clinic Lerner College of Medicine (Dr Rahman), Anesthesiology Institute, Cleveland Clinic Foundation, Cleveland, OH.

CORRESPONDENCE TO: Somnath Bose, MD, Critical Care Anesthesiology, Anesthesiology Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, G-58, Cleveland, OH 44195; e-mail: somnathbose@gmail.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):e100-e104. doi:10.1378/chest.14-1391
Text Size: A A A
Published online

A teenager was admitted to an outside hospital ED following an episode of melena. He had been complaining of intermittent abdominal pain, nausea, malaise, and easy fatigability for 2 months, with significant worsening of symptoms 2 weeks prior to this episode. He had no significant medical, surgical, or family history. On presentation at the outside ED, he was found to be profoundly icteric and encephalopathic. Initial laboratories suggested anemia, acute kidney injury, and acute liver failure, leading to a presumptive diagnosis of acute fulminant liver failure necessitating transfer to our institution.

Figures in this Article

Upon transfer to our ICU, the patient was encephalopathic (grade 3-4) and had asterixis. Ophthalmic examination was unremarkable except for icterus. He was tachycardic (heart rate of about 110 beats/min), and bilateral lung fields were clear, although air entry was slightly diminished at bases. His abdomen was soft, distended, and diffusely tender to palpation. Flanks were dull to percussion, and a fluid thrill was palpable.

The initial laboratory values at the outside ED were as follows: hemoglobin, 10.5 g/dL; platelets, 89,000/μL; WBC, 21,400/μL; bilirubin (BILI), 39.6 mg/dL; alanine aminotransferase (ALT), 37 U/L; aspartate aminotransferase (AST), 140 U/L; creatinine, 3.63 mg/dL; and electrolytes, Na/K:133:6.2 mEq/L. Admission ICU laboratory values were as follows: hemoglobin, 8.8 g/dL; platelets, 68,000/μL; WBC, 25,000/μL; BILI, 51 mg/dL (primarily conjugated); ALT, 37 U/L; AST, 140 U/L; creatinine, 2.77 mg/dL; and electrolytes, Na/K:140:5 mEq/L. Alkaline phosphatase (AP) level was normal throughout. Serum lactate dehydrogenase was elevated, haptoglobulin level was low, and reticulocyte count was also elevated (10%). Peripheral blood smear showed spur cells but no schistocytes. Findings from acute and remote hepatitis panel and workup for autoimmune hepatitis were unrevealing, as were screening for HIV and a drug toxicology screen. Serum acetaminophen level was normal. CT scan of the abdomen performed at the outside ED showed cirrhotic morphology of the liver with multiple regenerating nodules and ascites (Fig 1).

Figure Jump LinkFigure 1 –  Coronal section of the CT scan showing a shrunken liver with small nodules and irregularities on surface (white arrows).Grahic Jump Location
What is the probable cause of the patient’s acute fulminant hepatic failure, and what tests should be performed?
Answer: Measure serum copper and ceruloplasmin levels for probable acute hepatic failure caused by Wilson disease

Serum copper level was found to be high (> 50 μg/dL [normal, 0-10 μg/dL]) and serum ceruloplasmin (Cp) was low (9 mg/dL [normal, 21-45 mg/dL]). Other differentials for the presentation were acute autoimmune hepatitis, acute on chronic viral hepatitis, hemolytic uremic syndrome, and drug-induced hepatitis.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism and is thought to be caused by a defect in the ATP7B gene, located on chromosome 13, which codes for a transmembrane copper-transporting adenosine-triphosphatase enzyme. This enzyme is responsible for the transport of copper to Golgi bodies, its incorporation into Cp, and its subsequent excretion into bile. Manifestation of WD can be protean: neurologic, hepatic, or even psychiatric. Patients who present with neurologic manifestations tend to be older than those with a predominantly hepatic manifestation. Approximately 5% of WD presents as acute fulminant liver failure, and this is almost inevitably fatal without liver transplant; hence, the establishment of a quick, reliable diagnosis is of paramount importance.

Several mechanisms have been suggested to explain the pathogenesis of fulminant WD, most of which are based on the accumulation of large amounts of copper in the liver parenchyma, the tipping point being either copper-mediated cellular apoptosis or a viral infection (eg, human parvovirus B 19). The diagnosis of WD is often a challenge given the nonspecific symptoms; however, the presence of a hemolytic picture with low AP and modestly elevated AST to ALT ratios in the setting of fulminant hepatic failure in children or young adults should trigger suspicion for WD. Classically, elevated serum copper and low serum Cp values have been associated with a diagnosis of WD; however, their usefulness in the acute setting is uncertain. Measurement of liver copper content is the most important test when other tests are inconclusive but it is invasive and unsafe in a patient with coagulopathy. Kayser Fleischer (KF) rings in the cornea, initially thought to be pathognomonic of WD, have now been described in primary biliary cirrhosis and other diseases with biliary retention. Ideally, the presence of KF rings should be evaluated under a slit lamp by an experienced ophthalmologist. Although KF rings are almost inevitably seen in patients presenting with neurologic manifestations of WD, they may or may not be visible in patients presenting with hepatic manifestation of the disease.

An AP to BILI ratio of < 4 yields a sensitivity of 94% and a specificity of 96% and a likelihood ratio of 23 for diagnosing fulminant WD. Additionally, an AST to ALT ratio > 2.2 has been shown to have a sensitivity of 94% and a specificity of 86% with a likelihood ratio of 7 for fulminant WD. The combination of these two has a specificity and sensitivity approaching about 100% for diagnosis of fulminant WD. Thus, it is possible to establish a presumptive diagnosis with the help of simple, readily available laboratory tests in the acute setting without actually needing to wait for biochemical tests of copper metabolism, which often may not be readily available.

Treatment with zinc and chelators (penicillamine/trientine) has been described as a first-line therapy for WD. Liver transplant remains the only therapeutic option in patients with acute liver failure caused by WD or in those with failed medical management. Liver transplant affords excellent long-term survival and leads to normalization of liver function and copper metabolism within 6 months of transplant. Transplant has also been shown to improve neurologic manifestations, leading to the suggestion that patients with neurologic manifestations of WD should probably be evaluated for liver transplant if they are resistant to standard therapy and supportive measures. There are reports of survival following acute liver failure caused by WD in pediatric patients and young adults with the help of chelating agents in conjunction with therapeutic plasma exchange, a molecular adsorbent recirculating system, and albumin dialysis. However, these reports are mostly anecdotal, and the efficacy of these modalities is unclear at this time. Liver transplant remains the definitive cure for acute WD, and management is primarily supportive until an organ becomes available.

Clinical Course

A presumptive diagnosis of acute hepatic failure caused by WD was established, and the patient was listed for emergent liver transplant. Figure 2 shows the trend of ALP and BILI in this patient, with the ALP to BILI ratio persistently below 4, whereas Figure 3 shows the temporal profile of AST and ALT, with AST to ALT values consistently above the cutoff of 2.2. His initial Model for End-stage Liver Disease (MELD) score was 47. He was intubated orotracheally for airway protection, and mechanical ventilation was initiated. He had severe lactic acidosis upon admission, which progressively worsened (pH, 7.25-7.08; lactate, 10-18 mmol/L). He received aggressive hemodynamic support, continuous veno-venous hemofiltration, and transfusion of blood products in view of rapidly deteriorating hemodynamic status, worsening metabolic acidosis, and coagulopathy. Broad-spectrum antibiotics were started for treatment of positive blood and peritoneal cultures. Although a CT scan of the brain did not reveal any intracranial bleeding or significant cerebral edema, an intracranial bolt revealed significant intracranial pressure spikes, which persisted despite maximal intracranial pressure-lowering therapy. His condition deteriorated rapidly despite maximal support; a transplant was deemed futile at that point, and he was de-listed. Realizing the futility of the situation, the family withdrew support, and the patient expired on day 4 of the ICU stay.

Figure Jump LinkFigure 2 –  Temporal trend of ALP and bilirubin.Grahic Jump Location
Figure Jump LinkFigure 3 –  Temporal trend of AST and ALT.Grahic Jump Location

  • 1. Acute WD should be considered in the differential diagnosis of children and young adults presenting with fulminant hepatic failure and hemolytic anemia.

  • 2. Prompt diagnosis is the key because this condition is uniformly fatal without liver transplant.

  • 3. AP remains within normal limits in WD. A combination of an AP to BILI ratio < 4 and an AST to ALT ratio > 2.2 provides strong support for the diagnosis of acute WD in the correct clinical context.

  • 4. Low serum Cp and high serum copper levels are considered pathognomonic of WD; however, these indexes may be unreliable in the acute setting.

  • 5. Correct identification of index cases is important for genetic screening of family members and early initiation of chelation therapy.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors acknowledge Soumi Ray, PhD, for providing the illustrations accompanying this manuscript. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Schilsky ML, Sternlieb I. Overcoming obstacles to the diagnosis of Wilson’s disease. Gastroenterology. 1997;113(1):350-353. [PubMed]
 
Strand S, Hofmann WJ, Grambihler A, et al. Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95 (APO-1/Fas) mediated apoptosis. Nat Med. 1998;4(5):588-593. [CrossRef] [PubMed]
 
Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. Lancet. 2007;369(9559):397-408. [CrossRef] [PubMed]
 
Korman JD, Volenberg I, Balko J, et al; Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48(4):1167-1174. [CrossRef] [PubMed]
 
O’Brien A, Williams R. Rapid diagnosis of Wilson disease in acute liver failure: no more waiting for the ceruloplasmin level? Hepatology. 2008;48(4):1030-1032. [CrossRef] [PubMed]
 
Shiraishi A, Hoshina T, Ihara K, Doi T, Ohga S, Hara T. Acute liver failure as the initial manifestation of Wilson disease triggered by human parvovirus b19 infection. Pediatr Infect Dis J. 2012;31(1):103-104. [CrossRef] [PubMed]
 
Weiss KH, Schäfer M, Gotthardt DN, et al. Outcome and development of symptoms after orthotopic liver transplantation for Wilson disease. Clin Transplant. 2013;27(6):914-922. [CrossRef] [PubMed]
 
Guillaud O, Dumortier J, Sobesky R, et al. Long term results of liver transplantation for Wilson’s disease: experience in France. J Hepatol. 2014;60(3):579-589. [CrossRef] [PubMed]
 
Reynolds HV, Talekar CR, Bellapart J, Leggett BA, Boots RJ. Copper removal strategies for Wilson’s disease crisis in the ICU. Anaesth Intensive Care. 2014;42(2):253-257. [PubMed]
 
Walshe JM. The Kayser-Fleischer ring. Br J Hosp Med (Lond). 2014;75(3):C38-C39. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Coronal section of the CT scan showing a shrunken liver with small nodules and irregularities on surface (white arrows).Grahic Jump Location
Figure Jump LinkFigure 2 –  Temporal trend of ALP and bilirubin.Grahic Jump Location
Figure Jump LinkFigure 3 –  Temporal trend of AST and ALT.Grahic Jump Location

Tables

Suggested Readings

Schilsky ML, Sternlieb I. Overcoming obstacles to the diagnosis of Wilson’s disease. Gastroenterology. 1997;113(1):350-353. [PubMed]
 
Strand S, Hofmann WJ, Grambihler A, et al. Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95 (APO-1/Fas) mediated apoptosis. Nat Med. 1998;4(5):588-593. [CrossRef] [PubMed]
 
Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. Lancet. 2007;369(9559):397-408. [CrossRef] [PubMed]
 
Korman JD, Volenberg I, Balko J, et al; Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48(4):1167-1174. [CrossRef] [PubMed]
 
O’Brien A, Williams R. Rapid diagnosis of Wilson disease in acute liver failure: no more waiting for the ceruloplasmin level? Hepatology. 2008;48(4):1030-1032. [CrossRef] [PubMed]
 
Shiraishi A, Hoshina T, Ihara K, Doi T, Ohga S, Hara T. Acute liver failure as the initial manifestation of Wilson disease triggered by human parvovirus b19 infection. Pediatr Infect Dis J. 2012;31(1):103-104. [CrossRef] [PubMed]
 
Weiss KH, Schäfer M, Gotthardt DN, et al. Outcome and development of symptoms after orthotopic liver transplantation for Wilson disease. Clin Transplant. 2013;27(6):914-922. [CrossRef] [PubMed]
 
Guillaud O, Dumortier J, Sobesky R, et al. Long term results of liver transplantation for Wilson’s disease: experience in France. J Hepatol. 2014;60(3):579-589. [CrossRef] [PubMed]
 
Reynolds HV, Talekar CR, Bellapart J, Leggett BA, Boots RJ. Copper removal strategies for Wilson’s disease crisis in the ICU. Anaesth Intensive Care. 2014;42(2):253-257. [PubMed]
 
Walshe JM. The Kayser-Fleischer ring. Br J Hosp Med (Lond). 2014;75(3):C38-C39. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543