Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States

doi:10.7326/0003-4819-137-12-200212170-00007

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Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States

Journal Article•DOI•

Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States

George Ostapowicz¹, Robert J. Fontana², Frank V. Schioødt¹, Anne M. Larson³, Timothy J. Davern⁴, Steven Han⁵, Timothy M. McCashland⁶, A. Obaid Shakil⁷, J. Eileen Hay⁸, Linda S. Hynan, Jeffrey S. Crippin⁹, Andres T. Blei¹⁰, Grace Samuel, Joan S. Reisch, William M. Lee¹, Raj Santyanarayana¹¹, Cary Caldwell¹¹, Lawton Shick¹¹, Nathan M. Bass⁴, Smita Rouillard⁴, E Atillasoy¹², Steven L. Flamm¹⁰, Kent G. Benner¹³, Hugo R. Rosen¹³, Paul Martin⁵, Rise Stribling⁵, Eugene R. Schiff¹⁴, Maria Torres¹⁴, Victor J. Navarro¹⁵, Brendan M. McGuire¹⁶, Raymond T. Chung¹⁷, Diane R. Abraczinskas¹⁷, Jules L. Dienstag¹⁷ - Show less +29 more•Institutions (17)

University of Texas Southwestern Medical Center¹, University of Michigan², University of Washington³, University of California, San Francisco⁴, University of California, Los Angeles⁵, University of Nebraska Omaha⁶, University of Pittsburgh⁷, Mayo Clinic⁸, Baylor University Medical Center⁹, Northwestern University¹⁰, Washington University in St. Louis¹¹, Icahn School of Medicine at Mount Sinai¹², Oregon Health & Science University¹³, University of Miami¹⁴, Yale University¹⁵, University of Alabama at Birmingham¹⁶, Harvard University¹⁷

17 Dec 2002-Annals of Internal Medicine (American College of Physicians)-Vol. 137, Iss: 12, pp 947-954

TL;DR: The primary aim was to compare presenting clinical features and liver transplantation in patients with acute liver failure related to acetaminophen hepatotoxicity, other drugs, indeterminate factors, and other causes.

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Abstract: Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent causes of acute liver failure. The cause of liver failure and coma grade at admission were...

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Journal Article•DOI•

Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.

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Anne M. Larson¹, Julie Polson², Robert J. Fontana³, Timothy J. Davern⁴, Ezmina Lalani², Linda S. Hynan², Joan S. Reisch², Frank V. Schiødt², George Ostapowicz², A. Obaid Shakil⁵, William M. Lee² - Show less +7 more•Institutions (5)

University of Washington Medical Center¹, University of Texas Southwestern Medical Center², University of Michigan³, University of California, San Francisco⁴, University of Pittsburgh⁵

01 Dec 2005-Hepatology

TL;DR: In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States, and education of patients, physicians, and pharmacies to limit high‐risk use settings is recommended.

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1,705 citations

Additional excerpts

...0001 MELD score (n 268) 36 (11-53) 28 (7-52) <....
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...2-90) 91 Serum acetaminophen ( g/dL) 18 (0-400) 119 64 (0-644) 118 Narcotic/acetaminophen use 83 (63%) 131 22 (18%) 122 Antidepressant use 48 (37%) 131 46 (38%) 122 Serum ALT (U/L) 3,319 (126-18,079) 130 5,326 (179-19,826) 122 Platelets (thousands/ L) 126 (15-699) 131 120 (5-447) 120 Admission Hepatic Coma stage 3 (1-4) 131 2 (1-4) 118 Admission Hepatic Coma (stages 3-4) 72 (55%) 131 47 (39%) 122 Peak hepatic coma stage 3 (1-4) 131 3 (1-4) 120 Peak hepatic coma (stages 3-4) 89 (68%) 131 72 (59%) 122 Met King’s criteria 26 (20%) 131 8 (7%) 122 Creatinine 2 74 (57%) 131 53 (43%) 122 INR 3 56 (42%) 131 68 (56%) 122 ALT 3,500 63 (48%) 131 88 (72%) 122 Bilirubin 4 73 (56%) 131 74 (61%) 122 MELD 20 113 (88%) 129 102 (87%) 117 APACHE II 15 75 (66%) 113 49 (57%) 86 BMI 25 (17-51) 97 24 (16-56) 99...
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Journal Article•DOI•

Wilson's Disease

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Aftab Ala¹, Aftab Ala², Ann P. Walker², Keyoumars Ashkan, James S. Dooley², Michael L. Schilsky³ - Show less +2 more•Institutions (3)

Frimley Park Hospital NHS Foundation Trust¹, University College London², Cornell University³

03 Feb 2007-The Lancet

TL;DR: The discovery of the Wilson's disease gene has opened up a new molecular diagnostic approach, and could form the basis of future gene therapy.

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1,207 citations

Journal Article•DOI•

HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.

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Ann K. Daly¹, Peter T. Donaldson¹, Pallav Bhatnagar¹, Yufeng Shen², Itsik Pe'er², Aris Floratos², Mark J. Daly³, David Goldstein⁴, Sally John⁵, Matthew R. Nelson⁶, Julia Graham¹, B. Kevin Park⁷, John F. Dillon⁸, William Bernal⁹, Heather J. Cordell¹, Munir Pirmohamed⁷, Guruprasad P. Aithal¹⁰, Christopher P. Day¹ - Show less +14 more•Institutions (10)

Newcastle University¹, Columbia University², Harvard University³, Duke University⁴, Pfizer⁵, Research Triangle Park⁶, University of Liverpool⁷, Ninewells Hospital⁸, King's College⁹, University of Nottingham¹⁰

01 Jul 2009-Nature Genetics

TL;DR: Findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

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Abstract: Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

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949 citations

Cites background from "Results of a Prospective Study of A..."

...Idiosyncratic hepatotoxicity accounts for 13% of acute liver failure cases in the United States, and 75% of affected individuals either die or require liver transplantatio...
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Journal Article•DOI•

An official ATS statement: hepatotoxicity of antituberculosis therapy.

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Jussi J. Saukkonen, David L. Cohn, Robert M. Jasmer, Steven Schenker, John A. Jereb, Charles M. Nolan, Charles A. Peloquin, Fred M. Gordin, David Nunes, Dorothy B. Strader, John Bernardo, Raman Venkataramanan, Timothy R. Sterling - Show less +9 more

15 Oct 2006-American Journal of Respiratory and Critical Care Medicine

TL;DR: Systematic steps for prevention and management of TB DILI are recommended, including patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring.

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Abstract: Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

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944 citations

Cites background from "Results of a Prospective Study of A..."

...DILI has replaced viral hepatitis as the most apparent cause of acute liver failure (6)....
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Journal Article•DOI•

Idiosyncratic drug hepatotoxicity

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Neil Kaplowitz¹•Institutions (1)

University of Southern California¹

01 Jun 2005-Nature Reviews Drug Discovery

TL;DR: The current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.

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Abstract: The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone) In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans

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926 citations

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References

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Journal Article•DOI•

Early indicators of prognosis in fulminant hepatic failure

[...]

John O'Grady¹, Graeme J.M. Alexander¹, Karen M. Hayllar¹, Roger Williams¹•Institutions (1)

University of Cambridge¹

01 Aug 1989-Gastroenterology

TL;DR: The successful use of orthotopic liver transplants in fulminant hepatic failure has created a need for early prognostic indicators to select the patients most likely to benefit at a time when liver transplantation is still feasible.

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1,839 citations

"Results of a Prospective Study of A..." refers background or result in this paper

...Previous European studies have suggested that acute liver failure is more likely to be fatal in patients older than 40 years of age and those younger than 10 years of age (24)....
[...]
...In keeping with previous studies (24), our results suggest that coma grade at admission may be an important determinant of outcome and emphasize the importance of early transfer to an intensive care setting....
[...]

Journal Article•DOI•

Third national health and nutrition examination survey

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Kurt R. Maurer

01 Dec 1985-American Heart Journal

951 citations

Journal Article•DOI•

Acute liver failure: redefining the syndromes

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John O'Grady¹, S W Schalm, Roger Williams¹•Institutions (1)

University of Cambridge¹

31 Jul 1993-The Lancet

TL;DR: Hyperacute liver failure is the authors' suggested term for cases in which encephalopathy occurs within 7 days of the onset of jaundice; this group includes the sizeable cohort likely to survive with medical management despite the high incidence of cerebral oedema.

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835 citations

"Results of a Prospective Study of A..." refers background or methods in this paper

...Symptom duration is considered to be a major variable in determining the prognosis of patients with acute liver failure (15)....
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...Symptom Duration Since symptom duration has also been used to predict outcome, we used the methods described by O’Grady and colleagues (15) to stratify patients with non–acetaminophen-related liver failure....
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...5) and any hepatic encephalopathy within 26 weeks of the first symptoms without previous underlying liver disease (15)....
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...Paradoxically, patients with hyperacute onset of hepatic encephalopathy ( 8 days of symptoms before coma) have been considered to have a better prognosis than those with acute (8 to 28 days of symptoms) or subacute ( 28 days of symptoms) onset (15, 32)....
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Journal Article•

The management of fulminant hepatic failure

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C Trey, C S Davidson

01 Jan 1970-Progress in liver diseases

717 citations

"Results of a Prospective Study of A..." refers background or methods in this paper

...Hepatic coma was graded on a standard scale of I to IV, as described elsewhere (1, 2)....
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...Acute liver failure is characterized by severe and sudden liver cell dysfunction leading to coagulopathy and hepatic encephalopathy in previously healthy persons with no known underlying liver disease (1)....
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Journal Article•DOI•

Fulminant and subfulminant liver failure: definitions and causes.

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Jacques Bernuau, Bernard Rueff, Jean-Pierre Benhamou

01 May 1986-Seminars in Liver Disease

TL;DR: Unless hepatic transplantation proves to be applicable in FHF of many etiologic diagnosis may continue to have important therapeutic indications in at least some cases with this syndrome.

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Abstract: Fulminant or subfulminant liver failure, complicated by encephalopathy and in many cases by death is seen to be a syndrome that may result from numerous causes. Although viral hepatitis, drug-induced hepatitis, and hepatitis due to various types of poisonings, in decreasing frequency, account for 90% of all cases, a variety of miscellaneous conditions account for the remainder. Consideration of the possibility of these less common etiologies by the clinician is of considerable importance, since some, including massive malignant involvement (such as leukemia) or acute fulminant Wilson's disease, may respond to specific treatment measures. Thus, unless hepatic transplantation proves to be applicable in FHF of many etiologic diagnosis may continue to have important therapeutic indications in at least some cases with this syndrome.

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580 citations