Eine Gruppe von Antibiotika antibiotika-wiki.de , zu denen das Natürliche Antibiotikum Lincomycin und sein halbsynthetisches Analogon Clindamycin gehören. Sie haben bakteriostatische oder bakterizide Eigenschaften, abhängig von der Konzentration im Körper und der Empfindlichkeit von Mikroorganismen. Die Wirkung ist auf die Unterdrückung der Proteinsynthese in Bakterienzellen durch Bindung DER 30s-Subeinheit der ribosomalen Membran zurückzuführen. Lincosamide sind resistent gegen die Wirkung von Salzsäure Magensaft. Nach oraler Verabreichung wird schnell absorbiert. Es wird für Infektionen verwendet, die durch Gram-positive Kokken (hauptsächlich als Medikamente der zweiten Reihe) und unvorhersehbare anaerobe Flora verursacht werden.
Cuando se vincula un sitio web que vende productos farmacéuticos desde otro sitio - comprar-farmacia.es, como Search Engine Marketing a través del programa AdSense de Google, la degradación resultante puede disminuir drásticamente la cantidad de ingresos publicitarios obtenidos por el sitio web. Lo mismo se aplica a cualquier inclusión pagada. Esencialmente, el servidor de anuncios sirve una página desde su propio dominio. Si la página contiene un banner (es decir, una imagen) del dominio de una marca, la marca recibirá una parte de los ingresos publicitarios.
Versuchen Sie, bei uns zu bestellen und Sie werden nicht enttäuscht sein, beste Auswahl in der ganzen Schweiz, ausgezeichnete Produktqualität, sehr schnelle Lieferung und echte Privatsphäre!
Essential elements necessary for meaningful publication and interpretation of reports of drug induced liver injury
Minimal Elements for Diagnosis and Publication of Cases of Drug-Induced Liver Injury
Vijay K. Agarwal, MD,1 John G. McHutchison, MD,1 and Jay H. Hoofnagle, MD2
for the Drug-Induced Liver Injury Network (DILIN)
1Duke Clinical Research Institute and Duke University Medical Center, Durham, North Carolina,
and 2 Liver Disease Research Branch, Division of Digestive Diseases and Nutrition,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland
Keywords: acute liver failure, adverse drug reaction reporting systems, case reports,
Address for correspondence: Dr. John McHutchison, Duke Clinical Research Institute, Duke
University Medical Center, PO Box 17969, Durham, NC 27715. Phone: 919-668-7177. Fax:
Coauthor e-mail addresses: Minimal Elements for Reporting Drug-Induced Liver Injury Abbreviations: ALT, alanine aminotransferase; ANA, antinuclear antibody; AP, alkaline
phosphatase; CT, computerized tomography; DILI, drug-induced liver injury; ERCP, endoscopic
retrograde cholangiopancreatography; HAV, hepatitis A virus; HBc, hepatitis B core antibody;
HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; INR, international normalized ratio;
MR, magnetic resonance; MRCP, magnetic resonance cholangiopancreatography; PT,
Financial support: Funding for the DILIN network is provided by the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) under cooperative agreements:
1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238 and
Potential Conflicts of Interest. Drs. Hoofnagle and Agarwal report no potential conflicts of
interest; Dr. McHutchison has received research support and acted as a scientific adviser for
GlaxoSmithKline and Merck & Co., Inc.
Acknowledgements: The authors thank Dr. James Rochon for conducting the statistical Minimal Elements for Reporting Drug-Induced Liver Injury Abstract
Drug-induced liver disease is the single leading cause of acute liver failure in the United
States. Accurate reporting of drug-induced liver injury is essential for early detection of
hepatotoxicity and for developing a body of reliable, interpretable literature. We assessed the
extent to which published case reports of drug-induced liver disease include sufficient clinical
data for interpreting the cause of toxicity. We developed a list of 42 predetermined, specific
minimal elements considered necessary in diagnosing and evaluating causality of drug-induced
liver injury. A total of 97 published case reports or case series on hepatoxicity of 6 drugs (from 3
classes) were examined: amoxicillin/clavulanic acid (n=35), troglitazone (n=32), rosiglitazone
(n=10), pioglitazone (n=8), zafirlukast (n=8), and montelukast (n=4). Some elements, such as
patient age, sex, primary disease, and drug name, were reported in most if not all published case
reports. However, many elements were under-reported. Some publications did not mention initial
bilirubin levels (12%), many did not provide initial alkaline phosphatase levels (58%), and others
gave vague descriptions of how other diagnoses were excluded ("tests for hepatitis A, B, and C
were negative"). Data regarding serial liver test abnormalities were frequently absent. In the
aggregate of cases, exclusion of other competing viral etiology was recorded less than half the
time. Conclusion: Reports of drug-induced liver disease are often lacking in data needed for
determining the cause of adverse effects. Efforts to promote and include a listing of essential
elements in journal articles could significantly enhance the quality and clinical utility of
published case reports of drug toxicity.
Minimal Elements for Reporting Drug-Induced Liver Injury
Drug-induced hepatotoxicity represents a significant proportion of acute liver disease
cases (1) and is the single leading cause of acute liver failure in the United States (2). Drug-
induced liver injury can be caused by an array of prescription medications, as well as herbal and
dietary supplements (3). Accurate reporting of drug-induced liver disease is important for the
early detection and awareness of drug-induced hepatotoxicity as well as for developing a
prospective body of reliable, interpretable literature for agents that cause idiosyncratic hepatic
injury. Published case reports that describe adverse events can provide significant clinical insight,
especially for rare events that might not be detected in clinical trials. These reports can also
increase awareness of issues possibly associated with a drug early in its development and use,
which can thereby prompt further investigation. However, many publications or reports of drug-
induced liver disease lack important or essential details for interpreting whether such episodes
can be causally assigned to a specific drug or combination of drugs.
In 1984, professionals interested in adverse drug events and editors of major medical
journals met under the auspices of the Council for International Organizations of Medical
Sciences and proposed guidelines for editors to adopt when reviewing adverse event reports
submitted for publication (4). However, a descriptive analysis published in 2003 suggested that
many major medical journals still have only minimal requirements for publishing adverse event
reports, and some have none at all (5). To explore the extent to which published case reports
include clinically relevant data, we created a list of predetermined, specific minimal elements
that should be detailed in case reports of drug-induced liver injury. Then we examined individual
case reports involving 6 specific drugs from 3 different classes to determine the frequency for
Minimal Elements for Reporting Drug-Induced Liver Injury Experimental Procedures Minimal Elements
As a part of the ongoing development and design of the Drug Induced Liver Injury
Network (DILIN) (6), a list was developed of 18 elements that were considered necessary for
diagnosis and adequate assessment of causality (Table 1). Many of these elements are required
to complete the RUCAM causality assessment form (6-8). The elements included details of
patient's age and sex, time of starting and stopping the implicated medication, the time of onset
of symptoms and jaundice and results of laboratory tests at the onset of injury through the time to
recovery. Other important elements related to exclusion of other causes of acute liver injury
including viral hepatitis, other medications, autoimmune liver disease, biliary obstruction,
Review of Case Reports
From the list of 18 elements, a check list of 42 components of the "minimal" elements
was developed to be used to assess published case reports or case series of drug-induced liver
disease. A total of 97 publications were reviewed, related to one of 6 specific drugs:
amoxicillin/clavulanic acid (n = 35, 1992-2007) (9-17), troglitazone (n= 32, 1998-2008) (18-
35), rosiglitazone (n = 10, 2000-2008) (36-45), pioglitazone (n = 8, 2001-2007) (46-53),
zafirlukast (n = 8, 2000-2002) (54-59), or montelukast (n = 4, 2003-2007) (60-63). Two of
these drugs (amoxicillin/clavulanic acid and troglitazone) were chosen as examples of well-
known causes of clinically apparent drug-induced liver disease. The other four were chosen as
examples of agents that rarely cause liver injury but for which case reports have been important
in documenting their potential for hepatotoxicity. Articles published before 1992 were not
included because they predated availability of hepatitis C tests and advanced imaging techniques.
Minimal Elements for Reporting Drug-Induced Liver Injury
Each publication was assessed by two of the authors (VKA and JGM) independently for whether
the 42 components were accurately recorded and included for each case in each publication (if
there were multiple cases described). Elements were only recorded if they were described in the
actual case report. Vague terminology such as "viral screen negative" was not considered
Type of publication:
Each publication was also categorized by whether it was a single case report (n=23), a
brief communication (n =7), a small case series (n= 46) or a letter to the editor (n=21). Finally
each publication was categorized by type of journal in which it was published: major internal
medicine journal (n =20), gastroenterology and liver subspeciality journal (n=49) and other (n =
28). The rates of including the minimal elements were assessed by these categories of type of
Statistics:
Individual and aggregate drug data were summarized using simple descriptive statistics
including medians and percents. Two-group comparisons were performed using the Wilcoxon-
Mann-Whitney test; the Kruskal-Wallis test was applied for multi-group comparisons. All
statistical analyses were performed using SAS version 9.1.
Minimal Elements for Reporting Drug-Induced Liver Injury
While some elements, such as patient age, sex, primary disease, and drug name, were
reported in most if not all published reports, many elements were under-reported. The rates of
reporting each of the 42 elements by implicated drug are shown in Table 2 and the ten most- and
ten least-reported elements are shown in Table 3. No case report included all 42 elements. The
percent missing elements in individual publications ranged from 9% to 81% with a median of
48%. Twelve percent of publications did not mention initial bilirubin levels; many did not
provide initial alkaline phosphatase levels (58%), and others gave vague descriptions of how
other diagnoses were excluded ("tests for hepatitis A, B, and C were negative"). Data regarding
serial liver test abnormalities were often absent. In the aggregate of cases, exclusion of other
competing viral etiology was recorded less than half the time (Figure 1).
Overall, the trend of reporting was different for different classes of drugs (Figures 2-4).
Serial labs were reported more frequently for events associated with the thiazolidinediones (ALT,
44%; alkaline phosphatase, 32%; bilirubin, 52%) than with leukotriene receptor antagonists
(ALT, 25%; alkaline phosphatase, 17%; bilirubin, 25%), or with amoxicillin/clavulanic acid
(ALT, 9%; alkaline phosphatase, 17%; bilirubin, 17%). Testing for viral hepatitis and liver
imaging was done more often in toxicity cases reported with thiazolidinediones than leukotriene
receptor antagonists. For cases involving amoxicillin/clavulanic acid, the frequency of
performing individual hepatitis tests varied greatly, with IgM anti-HAV reported in 71% of cases
and HBsAg reported in 26% of cases. Concomitant diseases were infrequently reported with
amoxicillin/clavulanic acid (11%) and leukotriene receptor antagonists (33%) but more
Minimal Elements for Reporting Drug-Induced Liver Injury
The median percent of missing elements varied from 44% for the thiazolidinediones to
48% for amoxicillin/clavulanic acid and 49% for the leukotriene receptor antagonists (p = 0.34).
No significant difference was observed by journal types, with median percent missing elements
of 50% for major internal medicine journals, 48% for gastroenterology and liver subspeciality
journals and 45% in other types (p = 0.23). However, there were significant differences by
publication type (p < 0.001), with significantly fewer missing elements in single case reports
(median = 33%) than in letters to the editor (median = 50%, p < 0.001) and small case series
(median = 48%, p < 0.001); the comparison against brief communications reports (median =
43%) just failing to reach statistical significance (p = 0.07). No other pairwise comparisons by
type of publication were statistically significant.
Minimal Elements for Reporting Drug-Induced Liver Injury Discussion
In this analysis of 97 published case reports that attributed liver injury to a specific drug,
all were lacking in at least some information important in determining the cause of the injury.
Several publications did not contain information regarding important laboratory data, such as
bilirubin or alkaline phosphatase levels. Even more common was a lack of specific information
on testing for excluding viral hepatitis.
The list of elements assessed in this study was considered the minimal required for an
accurate assessment of causality in drug-induced liver disease. Thus, knowledge of the latency
between the starting of the medication and onset of injury is essential in assessing the likelihood
that the liver injury is due to the specific drug (8). Furthermore, the onset of injury needs to be
defined as either date of onset of first symptoms, appearance of jaundice (or dark urine), or first
abnormal laboratory tests found (which may occur days or weeks after actual onset).
Identification of the pattern of liver injury (whether hepatocellular, cholestatic, or mixed)
requires knowledge of serum ALT and alkaline phosphatase levels (and the upper limits of their
normal range) at the onset of injury. Assessment of the severity of the injury requires knowledge
of the peak serum bilirubin and prothrombin time or INR (6). Finally, assessment of causality in
drug-induced liver injury requires information about "dechallenge" and the time to resolution
after the medication is stopped, usually based upon serial laboratory tests for ALT, alkaline
phosphatase, or bilirubin (4-8). Yet, these results were provided in less than half of published
Drug-induced liver injury is a diagnosis of exclusion, and important conditions to exclude
are hepatitis A, B, and C, alcoholic liver disease, biliary obstruction, and liver injury due to
ischemia or other medications. Thus, minimal elements in presenting cases of drug-induced liver
Minimal Elements for Reporting Drug-Induced Liver Injury
injury should carefully define tests or elements in the clinical history for excluding these
diagnoses. Indeed, in some situations other laboratory tests beyond what was considered minimal
would be helpful, such as results of assays for anti-HEV to exclude hepatitis E, tests for lactate
dehydrogenase and creatine kinase to exclude ischemic hepatitis, or ERCP (endoscopic
retrograde cholangiopancreatography) or MRCP (magnetic resonance cholangio-
pancreatography) to fully exclude biliary obstruction. Of course, an important other cause of
liver injury is another medication or herbal being taken, which may have not been considered or
mentioned. In this regard, testing for acetaminophen levels or adducts may be important to
document the absence of a contribution by unintentional overdose of acetaminophen, particularly
in patients with severe hepatocellular injury of sudden onset.
The percentage of missing elements did not appear to vary by drug class or journal type
but was less for single case studies as compared to letters to the editor and small case series.
These differences are not unexpected, as single case reports are more focused and likely to report
more relevant elements than case series or letters to the editor which may have strict limitations
In some instances the lack of reporting of critical elements in publications may have been
because the results were normal or negative and therefore just not mentioned. Yet negative
results can be important. Features that are sometimes absent but are important in diagnosis
include absence of fever, rash, or eosinophilia. More commonly, a lack of elements may be due
to the fact that they were not done or not available. This lack should also be mentioned in
reporting instances of drug-induced liver injury, as the information can be important in assessing
the likelihood that the injury was due to the medication. Thus, the lack of pre-treatment levels of
laboratory tests, the fact that some diagnostic tests were not done (such as HCV RNA, imaging
Minimal Elements for Reporting Drug-Induced Liver Injury
of the biliary tree or liver biopsy), or the absence of follow-up laboratory tests are important in
These results support the need for a more standardized approach to the reporting of drug-
induced liver injury. Perhaps most helpful would be a checklist of minimal elements that are
considered essential for diagnosis and causality assessment of any cases of drug-induced liver
injury. Also useful would be a secondary list of elements that are helpful in many situations, but
are not always essential. Although similar standards were suggested by medical professionals
and journal editors in 1985 (4), the suggestions were not adopted for widespread use (5). Yet, in
the more than 20 years since then, the proliferation of the World Wide Web has made sharing of
such guidelines potentially much easier. Publishing guidelines that have been adopted for
widespread use include those developed by the CONSORT Group (http://www.consort-
statement.org/) for reporting results of randomized clinical trials. The CONSORT Statement
comprises a 22-item checklist, which is used for detailing design and conduct of a trial, and a
flow diagram, which is used to display the progress of participants through a trial. The
CONSORT Statement is easily accessible online, and adherence to it is currently required by
many peer-reviewed journals. The minimal elements for case reports of hepatotoxicity could be
posted on a publicly funded Web site, such as the National Library of Medicine
(http://www.nlm.nih.gov/), with the goal that they would ultimately be adopted by journal editors
Similar lists of minimal elements might be developed for other types of adverse drug
reactions, such as cardiovascular events or renal toxicity. Many of the items on our list, such as
dates of starting and stopping therapy and whether a re-challenge was performed, would be
relevant for other suspected drug-associated reactions.
Minimal Elements for Reporting Drug-Induced Liver Injury
In conclusion, reports of drug-induced liver injury are generally lacking in data needed
for determining the cause of adverse effects. Efforts to promote and include a listing of essential
elements in journal articles could significantly enhance the quality and clinical utility of
published case reports of drug toxicity.
Minimal Elements for Reporting Drug-Induced Liver Injury REFERENCES
Galan MV, Potts JA, Silverman AL, Gordon SC. The burden of acute nonfulminant drug-
induced hepatitis in a United States tertiary referral center. J Clin Gastroenterol 2005;
Lee WM. Acute liver failure in the United States. Semin Liver Dis 2003; 23:217-226.
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Causes,
clinical features, and outcomes from a prospective study of drug-induced liver injury in
the United States. Gastroenterology 2008; 135:1924-1934.
Venulet J. Informativity of adverse reactions data in medical publications. Drug Inf J
Kelly WN. The quality of published adverse drug event reports. Ann Pharmacother 2003;
Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J
for the DILIN Study Group. Drug-induced liver injury network (DILIN) prospective
study: rationale, design and conduct. Drug Saf 2009; 32: 55-68.
Benichou C. Criteria of drug-induced liver disorders. Report of an international
consensus meeting. J Hepatol 1990; 11:272-276.
Amoxicillin-clavulanic acid-induced hepatitis. Am J Otolaryngol 2007;
Minimal Elements for Reporting Drug-Induced Liver Injury
Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to
amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50:1785-1790.
Andrade RJ, Lucena MI, Fernández MC, Vega JL, Camargo R. Hepatotoxicity in patients
with cirrhosis, an often unrecognized problem: lessons from a fatal case related to
amoxicillin/clavulanic acid. Dig Dis Sci 2001; 46:1416-1419.
Rapidly progressive cholestasis: An unusual
reaction to amoxicillin/clavulanic acid therapy in a child. J Pediatr 2000; 136:121-123.
amoxicillin/clavulanic acid-related hepatotoxicity. Am J Gastroenterol 1998; 93:1363-
amoxycillin/clavulanic acid (Augmentin). J Hepatol 1995; 23:278-282.
Hautekeete ML, Brenard R, Horsmans Y, Henrion J, Verbist L, Derue G, et al. Liver
injury related to amoxycillin-clavulanic acid: interlobular bile-duct lesions and
extrahepatic manifestations. J Hepatol 1995; 22:71-77.
amoxycillin-clavulanic acid combination. Clin Investig 1994; 72:616-618.
Hepatitis associated with amoxycillin-clavulanic acid combination report of 15 cases. Gut
Julie NL, Julie IM, Kende AI, Wilson GL. Mitochondrial dysfunction and delayed
hepatotoxicity: another lesson from troglitazone. Diabetologia 2008; 51:2108-2016.
Minimal Elements for Reporting Drug-Induced Liver Injury
Caldwell SH, Hespenheide EE, von Borstel RW. Myositis, microvesicular hepatitis, and
progression to cirrhosis from troglitazone added to simvastatin. Dig Dis Sci 2001;
Menon KVN, Angulo P, Lindor KD.Severe cholestatic hepatitis from troglitazone in a
patient with nonalcoholic steatohepatitis and diabetes mellitus. Am J Gastroenterology
Chaudhary MU, Simmons DL. Case of the month. Hepatic and renal failure in a patient
taking troglitazone and metformin. J Ark Med Soc 2001; 98:16-19.
Prendergast KA, Berg CL, Wisniewski R. Troglitazone-associated hepatotoxicity treated
successfully with steroids. Ann Intern Med 2000; 133:751.
Schiano T, Dolehide K, Hart J, Baker AL. Severe but reversible hepatitis induced by
troglitazone. Dig Dis Sci 2000; 45:1039-1042.
Li H, Heller DS, Leevy CB, Zierer KG, Klein KM. Troglitazone-induced fulminant
hepatitis: report of a case with autopsy findings. J Diabetes Complications 2000; 14:175-
Jagannath S, Rai R. Rapid-onset subfulminant liver failure associated with troglitazone.
Kohlroser J, Mathai J, Reichheld J, Banner BF, Bonkovsky HL. Hepatotoxicity due to
troglitazone: report of two cases and review of adverse events reported to the United
States Food and Drug Administration. Am J Gastroenterol 2000; 95:272-276.
Murphy EJ, Davern TJ, Shakil AO, Shick L, Masharani U, Chow H, et al. Troglitazone-
induced fulminant hepatic failure. Acute Liver Failure Study Group. Dig Dis Sci 2000;
Minimal Elements for Reporting Drug-Induced Liver Injury
Fukano M, Amano S, Sato J, Yamamoto K, Adachi H, Okabe H, et al. Subacute hepatic
failure associated with a new antidiabetic agent, troglitazone: a case report with autopsy
examination. Hum Pathol 2000; 31:250-253.
Malik AH, Prasad P, Saboorian MH, Thiele DL, Malet PF. Hepatic injury due to
troglitazone. Dig Dis Sci 2000; 45:210-214.
Bell DS, Ovalle F. Late-onset troglitazone-induced hepatic dysfunction. Diabetes Care
Herrine SK, Choudhary C. Severe hepatotoxicity associated with troglitazone. Ann Intern
Vella A, de Groen PC, Dinneen SF. Fatal hepatotoxicity associated with troglitazone.
Shibuya A, Watanabe M, Fujita Y, Saigenji K, Kuwao S, Takahashi H, et al. An autopsy
case of troglitazone-induced fulminant hepatitis. Diabetes Care 1998; 21:2140-2143.
Neuschwander-Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ, et
al. Troglitazone-induced hepatic failure leading to liver transplantation. A case report.
Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM. Two cases of severe clinical and
histologic hepatotoxicity associated with troglitazone. Ann Intern Med 1998; 129:36-38.
El-Naggar MHM, Helmy A, Moawad M, Al-Omary M, Al-Kadhi Y, Habib B. Late-onset
rosiglitazone-associated acute liver failure in a patient with Hodgkin's lymphoma. Ann
Su DH, Lai MY, Wu HP. Liver failure in a patient receiving rosiglitazone therapy. Diabet
Minimal Elements for Reporting Drug-Induced Liver Injury
Menees SB, Anderson MA, Chensue SW, Moseley RH. Hepatic injury in a patient taking
rosiglitazone. J Clin Gastroenterol 2005; 39:638-640.
Dhawan M, Agrawal R, Ravi J, Gulati S, Silverman J, Nathan G, et al. Rosiglitane-
induced granulomatous hepatitis. J Clin Gastroenterol 2002; 34:582-584.
Bonkovsky HL, Azar R, Bird S, Szabo G, Banner B. Severe cholestatic hepatitis caused
by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone.
Gouda HE, Khan A, Schwartz J, Cohen RI. Liver failure in a patient treated with long-
term rosiglitazone therapy. Am J Med 2001; 111:584-585.
Ravinuthala RS, Nori U. Rosiglitazone toxicity. Ann Intern Med 2000; 133:658.
Hachey DM, O'Neil MP, Force RW. Isolated elevation of alkaline phosphatase level
associated with rosiglitazone. Ann Intern Med 2000; 133:752
Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking
rosiglitazone. Ann Intern Med 2000; 132:118-121.
Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a patient
receiving rosiglitazone. A case report. Ann Intern Med 2000; 132:121-124.
Martínez Odriozola P, Ibarmia Lahuerta J, Gutiérrez Macías A, de la Villa FM. [A new
case: pioglitazone hepatotoxicity] Med Clin (Barc) 2007; 129:158-159.
Arotçarena R, Bigué JP, Etcharry F, Pariente A. [Pioglitazone-induced acute severe
hepatitis] Gastroenterol Clin Biol 2004; 28(6-7 Pt 1): 610-611. French.
Marcy TR, Britton ML, Blevins SM. Second-generation thiazolidinediones and
hepatotoxicity. Ann Pharmacother 2004; 38:1419-1423.
Minimal Elements for Reporting Drug-Induced Liver Injury
Pinto AG, Cummings OW, Chalasani N. Severe but reversible cholestatic liver injury
after pioglitazone therapy. Ann Inter Med 2002; 137:857.
Nagasaka S, Abe T, Kawakami A, Kusaka I, Nakamura T, Ishikawa S, et al.
Pioglitazone-induced hepatic injury in a patient previously receiving troglitazone with
success. Diabetes Medicine 2002; 19:344-348.
May LD, Lefkowitch JH, Kram MT, Rubin DE. Mixed hepatocellular-cholestatic liver
injury after pioglitazone therapy. Ann Intern Med 2002; 136:449-452.
Chase MP, Yarze JC. Pioglitazone-associated fulminant hepatic failure. Am J
Maeda K. Hepatocellular injury in a patient receiving pioglitazone. Ann Intern Med
Soy M, Ozer H, Canataroglue A, Gumurdulu D, Erken E. Vasculities induced by
zafirlukast therapy. Clin Rheumatol 2002; 21:328-329.
Torres M, Reddy KR. Severe liver injury. Ann Intern Med 2001; 135:550.
Moles JR, Primo J, Fernandez JM, Hinojosa JE. Acute hepatocellular injury associated
with zafirlukast [Letter]. J Hepatol 2001; 35:541-542.
Danese S, De Vitis I, Gasbarrini A. Severe liver injury associated with zafirlukast [Letter].
Actis GC, Morgando A, Lagget M, David E, Rizzetto M. Zafirlukast-related hepatitis:
report of a further case [Letter]. J Hepatol 2001; 35:539-541.
Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ. Severe liver injury
after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 2000;
Minimal Elements for Reporting Drug-Induced Liver Injury
supplements during chronic treatment with m
Goldstein MF, Anoia J, Black M. Montelukast-induced hepatitis. Ann Int Med 2004;
Sass DA, Chopra KB, Wu T. A case of montelukast-induced hepatotoxicity. Am J
Russmann S, Iselin HU, Meier D, Zimmermann A, Simon HU, Caduff P, et al. Acute
hepatitis associated with montelukast. J Hepatol 2003; 38:694-695.
Minimal Elements for Reporting Drug-Induced Liver Injury Table 1. Minimal Elements for Reporting Drug-Induced Liver Injury. Minimal Elements
Primary disease (for which drug was prescribed)
Concomitant diseases (with special mention of heart failure or episodes of hypotension, sepsis,
Pertinent past medical history (including previous exposure to drug, previous reaction to drug or
other drugs, history of liver disease, and risk factors for liver disease, such as alcohol use)
Dates of start and discontinuation of therapy (or time from onset of event)
List of pertinent symptoms (fatigue, weakness, nausea, anorexia, abdominal pain, dark urine,
Pertinent physical findings at the time of presentation (with special mention of whether or not
there is fever, rash, jaundice, hepatic tenderness, or signs of chronic liver disease)
Medication history (other meds taken in the 3 months before onset of liver injury with dose,
Date or time of first abnormal laboratory test
Laboratory test results from before drug exposure (specifically liver tests)
Initial laboratory results at presentation (bilirubin, ALT, AP, INR or PT, and eosinophil
Minimal Elements for Reporting Drug-Induced Liver Injury
Laboratory results needed to exclude other causes (IgM anti-HAV, IgM anti-HBc, HBsAg,
Course of serum bilirubin, ALT, AP, and INR levels (preferably in a table with entries dated
from time of starting and stopping the drug and until resolution)
Imaging studies (abdominal ultrasound, CT, or MR)
Liver biopsy results (if obtained and date of procedure in relation to episode of DILI)
Whether re-challenge with the same medication was done and, if so, results of the challenge.
ALT, alanine aminotransferase; ANA, antinuclear antibody; AP, alkaline phosphatase; DILI,
drug-induced liver injury; HAV, hepatitis A virus; HBc, hepatitis B core antibody; HBsAg,
hepatitis B surface antigen; HCV, hepatitis C virus; INR, international normalized ratio; PT,
prothrombin time; CT, computerized tomography; MR, magnetic resonance.
Minimal Elements for Reporting Drug-Induced Liver Injury Table 2. Elements Included in Case Reports of Drug-Induced Liver Disease.
Amoxicillin/ Clavulanic Troglitazone Rosiglitazone Pioglitazone Zafirlukast Montelukast Minimal Elements for Reporting Drug-Induced Liver Injury
Values are percentages. aWhether re-challenge with the same medication was reported as being done or not. ALT, alanine aminotransferase; ANA, antinuclear antibody; AP, alkaline phosphatase; HAV, hepatitis A virus; HBc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; INR, international normalized ratio; PT, prothrombin time.
Minimal Elements for Reporting Drug-Induced Liver Injury Table 3. Most- and Least-Commonly Reported Elements Included in Case Reports of Drug-Induced Liver Disease Among 3 Classes of Drugs.
Percent Cases
aWhether re-challenge with the same medication was reported as being done or not. ALT, alanine aminotransferase; AP, alkaline phosphatase; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus. Minimal Elements for Reporting Drug-Induced Liver Injury Figure Legends Figure 1. Exclusion of a Competing Viral Etiology. Among 97 published case reports of drug-
induced liver disease related to specific drugs, fewer than half specified whether competing viral
etiologies were excluded. "Viral Screen Negative" represents percent of cases for which results
of tests for competing etiology were vaguely reported (for example, "tests for hepatitis A, B, and
C were negative"). ALT, alanine aminotransferase; ANA, antinuclear antibody; AP, alkaline
phosphatase; HAV, hepatitis A virus; HBc, hepatitis B core antibody; HBsAg, hepatitis B
surface antigen; HCV, hepatitis C virus.
Figure 2. Minimal Elements Reported in Published Case Reports of Hepatotoxicity With Thiazolidinediones. Reports were regarding either troglitazone (n= 32), rosiglitazone (n= 10),
and pioglitazone (n= 8). "Re-challenge" refers to whether a re-challenge with the same
medication was reported as being done or not. ALT, alanine aminotransferase; ANA, antinuclear
antibody; AP, alkaline phosphatase; HAV, hepatitis A virus; HBc, hepatitis B core antibody;
HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.
Figure 3. Minimal Elements Reported in Published Case Reports of Hepatotoxicity With Leukotriene Receptor Antagonists. Reports were regarding either zafirlukast (n=8) or
montelukast (n= 4). "Re-challenge" refers to whether a re-challenge with the same medication
Minimal Elements for Reporting Drug-Induced Liver Injury Figure 4. Minimal Elements Reported in Published Case Reports of Hepatotoxicity With Amoxicillin/Clavulanic Acid (n = 35). "Re-challenge" refers to whether a re-challenge with the
same medication was reported as being done or not.
Percent Cases Reporting Viral Screen Percent Cases Serial AP Anti-HCV Serial ALT Initial AP Final ALT Eosinophils Initial ALT Other Meds Symptoms Drug Name Re-challenge Liver Biopsy IgM anti-HAV Date Jaundice IgM anti-HBc Final Bilirubin Liver Imaging Date Stop Drug Initial Protime Date Start Drug Serial Bilirubin Date Symptoms Time Final Labs Initial Bilirubin Primary Disease Duration Therapy Date Abnormal Labs History Risk Factors History Alcohol Use History Drug Reaction History Liver Disease Labs Before Exposure Concomitant Diseases Previous Drug Exposure Relevant Physical Exam Percent Cases 20 Serial AP Anti-HCV Serial ALT Initial AP Final ALT Eosinophils Initial ALT Symptoms Liver Biopsy Drug Name Other Meds IgM anti-HAV Re-challenge Previous Drug Date Jaundice IgM anti-HBc Liver Imaging Initial Protime Final Bilirubin Date Start Drug Date Stop Drug Serial Bilirubin Date Symptoms Time Final Fabs Initial Bilirubin Primary Disease Duration Therapy Date Abnormal Labs History Risk Factors History Alcohol Use History Drug Reaction Concomitant Diseases History Liver Disease Labs Before Exposure Relevant Physical Exam Percent Cases Date Stop Serial ALT Final ALT Serial AP Anti-HCV Initial ALT Initial AP Symptoms Liver Biopsy Eosinophils Other Meds Drug Name Final Bilirubin IgM anti-HBc IgM anti-HAV Re-challenge Initial Protime Previous Drug Liver Imaging Date Start Drug Time Final Labs Serial Bilirubin Date Jaundice Date Symptoms Initial Bilirubin Primary Disease Duration Therapy Date Abnormal Labs History Alcohol Use History Risk Factors Labs Before Exposure Concomitant Diseases History Drug Reaction History Liver Disease Relevant Physical Exam
Basic, uncomplicated infection with Borrelia burgdorferi-not too ill, respond readily to antibioticsDisseminated, symptomatic disease- usually present longer, and may Need higher doses, longer duration, and also may need IV treatmentsNeed complex antibiotic regimens of long durationChronic Lyme- Patients ill for > I year, with many complications possible:Immune deficiencies (the beginnings
Operation vid Dupuytren’s kontraktur Dupuytren’s kontraktur Dupuytren’s kontraktur är en sjukdom som drabbar den bindvävsplatta som finns i handflatan. Av okänd anledning börjar cellerna bilda ny bindväv som gör att vävnaden förkortas så att fingret/fingrarna böjs och man får därför svårt att sträcka på fingrarna. Sjukdomen drabbar mest medelålders och äldre