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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

The American Association for the Study of Liver Diseases (AASLD) practice guidelines provide recommendations in diagnosing and managing patients with liver disease from available scientific evidence in combination with expert consensus opinions. The aim was to systematically review the evolution of recommendations from AASLD guidelines and identify gaps limiting the evidence-based foundations of these guidelines. Initial and current AASLD guidelines published from January 1998 to August 2012 were reviewed. The AGREE II instrument was used to evaluate rigor and transparency of guideline development. The number of recommendations, distribution of grades (strength or certainty), classes (benefit versus risk), and types of recommendations were evaluated. Whenever possible, multiple versions were evaluated for evolving scientific evidence. A total of 991 recommendations from 28 guidelines on 17 topics were evaluated. From initial to current guidelines, the total number of recommendations increased by 36% (512 to 699). The largest increases were from chronic hepatitis B virus (HBV) (+71), liver transplantation (+53), and autoimmune hepatitis (AIH) (+27). Most current recommendations are grade II (44%) and less than 20% are grade I. The AGREE II evaluation showed global improvement in guideline quality. Both HBV and chronic hepatitis C guidelines had greatest increases in grade I recommendations (+383% and +67%, respectively). The greatest increases in treatment recommendations were from HBV (grade I, +1,150%), liver transplantation (grade II, +112%), and AIH (grade III, +105%). Conclusion: Despite significant increases in the numbers of recommendations within AASLD practice guidelines over time, only a minority are supported by grade I evidence, highlighting the need for developing well-designed investigations to provide evidence for areas of uncertainty and improving the quality of future guidelines in hepatobiliary diseases. (Hepatology 2013; 58:2142–2152)

Abbreviations
AASLD

American Association for the Study of Liver Diseases

ACC

American College of Cardiology

AHA

American Heart Association

AHRQ

Agency for Healthcare Research and Quality

AIH

autoimmune hepatitis

ALF

acute liver failure

GRADE

Grading of Recommendation Assessment, Development, and Evaluation

HBV

hepatitis B virus

HCV

hepatitis C virus

HCC

hepatocellular carcinoma

IOM

Institute of Medicine

NAFLD

nonalcoholic fatty liver disease

PBC

primary biliary cirrhosis

PSC

primary sclerosing cholangitis

TIPS

transjugular intrahepatic portosystemic shunt

Clinical practice guidelines are systematically developed statements that attempt to synthesize large amounts of available scientific information for providing best practices to healthcare providers.[1] These statements often represent the official opinion of single or multiple professional societies and are developed by individuals recognized for their expertise and contributions to the field. Topics often covered include conditions (diseases, signs, and symptoms) and technologies (diagnostic tests and therapeutic procedures) where recommendations about preferred approaches for patient management are provided. The creation of recommendations is often based on a formal review and analysis of the published literature along with weighing the strength of the available scientific evidence. In situations where the data are inconclusive or absent, recommendations are often based on consensus expert opinion.

Internationally, more than 3,700 clinical practice guidelines from 39 countries are identified within the Guidelines International Network database.[2] In the U.S., there are over 2,300 guidelines registered within the National Guidelines Clearinghouse which is supported by the Agency for Healthcare Research and Quality (AHRQ).[3] Given the variability in terms of breadth and depth from available clinical practice guidelines, the U.S. Congress has identified the importance of establishing rigorous processes for developing trustworthy, consistent, and scientifically valid documents. In turn, the Institute of Medicine (IOM) released eight standards for the development of clinical practice guidelines in March 2011.4 Within the framework of the IOM's recommendations, there has been little systematic review of the body of clinical practice guidelines put forth by various medical societies. Recently, clinical practice guideline catalogs from the American College of Cardiology (ACC)/American Heart Association (AHA) and all endocrinology guidelines published in North America from 2007-2010 have been examined.[5, 6]

The field of hepatology has experienced significant growth in the production of relevant scientific literature over the past few decades. However, the question of whether clinical practice guidelines have truly evolved with more evidence-based recommendations has not been systematically investigated. Thus, we performed a systematic review of the American Association for the Study of Liver Diseases (AASLD) clinical practice guidelines issued from January 1998 to August 2012 with the aim of evaluating the evolution of recommendations that have been issued over time. The ultimate goal was to evaluate methodological rigor and quality of reporting of AASLD guidelines, elucidate possible gaps that limit the use of evidence-based medicine to support certain recommendations within the AASLD guidelines, and to highlight potential opportunities for improvement.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
Guideline Selection

All initial published versions of the AASLD practice guidelines for a given topic issued from January 1998 to August 1, 2012 were abstracted for data.[7-23] If available, the current updated versions for each topic was also evaluated.[18, 24-34] Current AASLD guidelines are defined as the most recently published document on a specific topic which is posted on the AASLD website as of August 1, 2012 (http://www.aasld.org). For this investigation, only complete clinical practice guidelines and position papers were evaluated, thus focused updates were not included.

Evaluation of Methodological Rigor and Transparency

To evaluate the evolutionary process of guideline development and quality of reporting, the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used on all comparable guidelines and position papers.[35] The AGREE II has been widely used in the assessment of methodological rigor and transparency of guideline development and has been cited for its validity and reliability. Briefly, this tool that evaluates 23 items organized into six domains (scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence) followed by two global rating items (overall assessment) and includes a user manual that provides guidance on rating of each item. The scope and purpose domain evaluates the specific health questions covered by the guideline, target population, and the overall objective of the guideline. The stakeholder involvement domain evaluates the appropriateness of the guideline development group and its representation of the views of its intended users. The rigor of development domain evaluates the systemic methodology used to gather and synthesize evidence, methods of recommendation formulation, and the mechanisms to update them. The clarity of presentation domain evaluates the overall structure, format, and language of the guideline. The applicability domain evaluates barriers, facilitators, and ease of implementation and resource implications of guideline application. Finally, the editorial independence domain evaluates the extent to which external influences or competing interests may have affected the specific guideline.

For this study, three appraisers conducted the assessment (C.K., S.S., N.S.) after using the online training tools recommended by the AGREE collaboration. After guideline evaluation, domain scores were calculated (as per the AGREE II manual) by summing all individual scores in each domain and then scaling the total as a percentage of the maximum possible score for a given domain according to the formula:

  • display math
Evaluation of Strength of Recommendations

All guideline recommendations published by the AASLD are classified by a “grade” or “level” of recommendation. The “grade” or “level” designations are synonyms and provide an assessment of strength or certainty for a given recommendation. For the purposes of this study, the grade/level designation will be designated as “grade” hereafter.

Since 1998, the AASLD practice guideline development program has used three evidence classification systems to grade recommendations. These include (1) the Infectious Diseases Society of America's Quality Standards; (2) the American College of Cardiology / American Heart Association system; and (3) the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup system (Table 1).[36-39] Despite the use of three systems, these schemes are based on the same criteria and comparable structure. Therefore, for the purposes of this study, a composite grade system was created to represent all of the issued recommendations:

  1. Data derived from multiple randomized controlled trials, or meta-analysis, involving a number of participants to be of statistical power and where further research is unlikely to change the confidence in the estimate of clinical effect.
  2. Data derived from a single randomized trial or nonrandomized studies, cohort or case-control analytic studies, and multiple time series where further research may change confidence in the estimate of the clinical effect.
  3. Evidence based on clinical experience, descriptive studies, opinion of respected authorities where further research is very likely to impact confidence on the estimate of clinical effect.
Table 1. Historical Summary of Grades of Evidence and Classes of Recommendations Used by the AASLD
Grade of Evidence
1998-2003
I = Evidence from multiple well-designed randomized controlled trials, each involving a number of participants to be of sufficient statistical power
II = Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case-control analytic studies, or well-designed meta-analysis
III = Evidence based on clinical experience, descriptive studies or reports of expert committees
IV = Not rated
2004-2010
I = Randomized controlled trials
II-1 = Controlled trials without randomization
II-2 = Cohort or case-control analytic studies
II-3 = Multiple time series, dramatic uncontrolled experiments
III = Opinion of respected authorities, descriptive epidemiology
2007-2010
A = Data derived from multiple randomized clinical trials or meta-analysis
B = Data derived from a single randomized trial, or nonrandomized studies
C = Only consensus opinion of experts, case studies or standard-of-care
2010-Present
High (A) = Further research is unlikely to change confidence in the estimate of the clinical effect
Moderate (B) = Further research may change confidence in the estimate of the clinical effect.
Low (C) = Further research is very likely to impact confidence on the estimate of clinical effect.
Class of Recommendations
1998-2000
A = Survival benefit
B = Improved diagnosis
C = Improvement in quality of life
D = Relevant pathophysiologic parameters improved
E = Impacts cost of health care
2007-2010
I = Conditions for where there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful and effective
II = Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment
Ila = Weight of evidence/opinion is in favor of usefulness/efficacy
Ilb = Usefulness/efficacy is less well established by evidence/opinion
III = Conditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not useful/effective and in some cases may be harmful
2011-Present
Strong (1) = Factors influencing the strength of the recommendation included the quality of evidence, presumed patient-important outcomes, and cost
Weak (2) = Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, or higher cost or resource consumption
Evaluation of Types of Recommendations

Another aim of this study was to evaluate the evolution of the type of recommendations issued by the AASLD. Recommendations provided in AASLD practice guidelines can be classified into three types:

  • (1) Recommendations based on known features of a given liver disease which should prompt further evaluation (i.e.: “Wilson Disease must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder.”[33]).
  • (2) Recommendations on specific testing for a given liver disease (i.e.: “Liver biopsy is recommended to stage the degree of liver disease in C282Y homozygotes or compound heterozygotes if liver enzymes (ALT, AST) are elevated or if ferritin is >1000 μg/L.”[30]).
  • (3) Recommendations on specific treatment for a given liver disease (i.e.: “UDCA in a dose of 13-15 mg/kg/day orally is recommended for patients with PBC who have abnormal liver enzyme values regardless of histological stage.”[31]).

Thus, all recommendations for this analysis were classified into one of three categories: (1) Feature of Disease Recommendation; (2) Diagnostic Recommendation; or (3) Treatment Recommendation.

Evaluation of Benefit Versus Risk of Recommendations

As previously discussed, three different guideline classification systems have been used during the evolution of AASLD practice guidelines. Depending on the system used, certain guidelines provided information regarding benefit versus risk for a given recommendation. This information is different from the “grade” of recommendation and was designated as the “class” of recommendation. In the final part of this analysis, we evaluated the evolution of “class” recommendations provided in multiple versions of guidelines for a specific liver disease topic. However, unlike the grade systems assessing strength and certainty, the “class” systems used over time differed greatly and the development of a composite scoring system could not be created for comparative analysis. Therefore, the “class” analysis was only performed on guidelines that used the same scoring system.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
Historical Guideline Summary

From January 1998 to August 1, 2012, the AASLD issued 28 clinical practice guidelines on 17 topics, yielding a total of 991 recommendations. When examining the initial publication for each AASLD guideline topic, a total of 512 recommendations were issued. The three guidelines with the greatest number of recommendations include Vascular Disorders of the Liver (64), Hepatitis C (HCV) (49), and the Diagnosis and Management of Nonalcoholic Fatty Liver Disease (NAFLD) (45). Of these 512 recommendations, 14% were grade I recommendations, 40% were grade II, and 46% were grade III (Table 2). Regarding the types of recommendations, 14% were Feature of Disease recommendations, 28% were Diagnostic Recommendations, and 58% were Treatment Recommendations (Supporting Table 1).

Table 2. Data Summary of the First Issued Guidelines Evaluated by Grade and the Current Guidelines Evaluated by Grade
First Issued Guideline Evaluation By Grade
   Grade IGrade IIGrade III
GuidelineYearNumber of RecommendationsNumberNumberNumber
AIH2002234 (17%)6 (26%)13 (56%)
ALF2005447(16%)7(16%)30 (68%)
Ascites1998228 (36%)6 (27%)8 (36%)
HBV2001276 (22%)13 (48%)8 (30%)
HCC2005214 (19%)12 (57%)5 (24%)
HCV2004499 (18%)15(31%)25(51%)
Hemochromatosis2001120 (0%)12 (100%)0 (0%)
PBC2000222 (9%)1 (4%)19 (86%)
TIPS2005262 (7%)18 (69%)6 (23%)
Transplantation2000250 (0%)1 (4%)24 (96%)
Wilson Disease2003210 (0%)8 (38%)13 (62%)
Vascular2009642 (3%)30 (47%)32 (50%)
Varices20072510 (40%)6 (24%)9 (36%)
PSC2010366 (17%)22 (61%)8 (22%)
Biopsy2009340 (0%)7 (20%)27 (80%)
Alcoholic Liver2010166 (37%)6 (37%)4 (25%)
NAFLD2012456 (13%)34 (76%)5 (11%)
Summary 51272 (14%)204 (40%)236 (46%)
% median  15.9%37.5%36.4%
% quartile 1  3.13%24.00%23.81%
% quartile 3  19.05%57.14%61.90%
Current Guideline Evaluation By Grade
   Grade IGrade IIGrade III
GuidelineYearNumber of RecommedationsNumberNumberNumber
   NumberNumberNumber
AI H2010505 (10%)6 (12%)39 (78%)
Alcoholic Liver2010166 (37%)6 (37%)4 (25%)
ALF2011487 (15%)7 (15%)34 (71%)
Ascites2009306 (20%)13 (43%)11 (37%)
Biopsy2009340 (0%)7 (21%)27 (79%)
HBV20099829 (30%)38(39%)31(32%)
HCC2010225 (23%)11 (50%)6 (27%)
HCV20097015 (21%)31 (44%)24 (34%)
Hemochromatosis2011174 (23%)10 (59%)3 (18%)
PBC2009155 (33%)5 (33%)5 (33%)
PSC2010366 (17%)22 (61%)8 (22%)
TIPS2009285 (18%)17 (61%)6 (21%)
Transplantation2005780 (0%)46 (59%)32 (41%)
Varices20072510 (40%)6 (24%)9 (36%)
Vascular2009642 (3%)30 (47%)32 (50%)
Wilson Disease2008231 (4%)16 (70%)6 (26%)
NAFLD2012456(13%)34(76%)6(13%)
Summary 699112 (16%)305 (44%)283 (40%)
% median  17.9%44.3%33.3%
% quartile 1  8.59%33.33%25.00%
% quartile 3  23.53%58.97%41.03%
Current Guideline Summary

As of August 1, 2012, 17 AASLD guidelines were published or updated between 2005-2012, with a total of 699 recommendations identified. The greatest number of recommendations came from the Chronic Hepatitis B (HBV) (98), Liver Transplantation (78), and HCV (70) guidelines (Table 2).

In evaluating the grade of recommendations for current guidelines, 16% were grade I, 44% were grade II, and 40% were grade III recommendations (Table 2). Individually, grade II recommendations represented the majority of recommendations in 13 of 17 guidelines. The only guideline with a majority of grade I recommendations was the Prevention and Management of Gastrointestinal Varices and Variceal Hemorrhage in Cirrhosis guideline (40%). In contrast, the Autoimmune Hepatitis (AIH), acute liver failure (ALF), and Liver Biopsy guidelines had a majority of grade III recommendations (Table 2).

Methodological Rigor and Transparency Evaluation

Of the 17 guideline topics published by the AASLD, 11 had initial published versions along with complete updates that were available for comparison using the AGREE II assessment tool. In this comparison, most guideline topics experienced increases in the six domains evaluated by the AGREE II (range 0%-53%) along with improvements in the overall assessment (range 0%-33%) (Table 3). As a whole, the editorial independence domain had the greatest percentage increases in all guideline topics (10 of 11 topics); however, it was the worst scoring domain of current guidelines (range 39%-64%). The HBV guidelines had the most improvement in terms of percentage change (5 of 6 domains). In evaluating the overall quality of current guidelines based on domains, the Role of Transjugular Intrahepatic Portosystemic Shunt in the Management of Portal Hypertension (TIPS) guideline had the highest domain score for stakeholder involvement, whereas the HBV guideline had the highest domain scores for: scope and purpose, rigor of development, clarity of presentation, applicability, and editorial independence (shared with primary biliary cirrhosis [PBC]) (Table 3).

Table 3. Evolutionary Rigour and Transparency Evaluation by AGREE II
 Domain 1. Scope and PurposeDomain 2. Stakeholder InvolvementDomain 3. Rigour of DevelopmentDomain 4. Clarity of PresentationDomain 5. ApplicabilityDomain 6. Editorial IndependenceOverall Guideline Assessment
 %% %%%%
AIH (2002)7454588158656
AIH (2010)76596085653967
Percentage Change263473311
ALF (2005)83565681502572
ALF (2011)83565685585072
Percentage Change00148250
Ascites (1998)76566380671172
Ascites (2008)80576585694283
Percentage Change422633111
HBV (2001)87595980671172
HBV (2009)10059721007964100
Percentage Change1301320135328
HCC (2005)83566385755072
HCC (2010)85596385785089
Percentage Change24003017
HCV (2004)85576485714289
HCV (2009)85576985765389
Percentage Change00506110
Hemochromatosis (2001)70565974722272
Hemochromatosis (2011)80576785724783
Percentage Change9281102511
PBC (2000)70505667611156
PBC (2009)81566385676489
Percentage Change11671965333
TIPS (2005)81635981764472
TIPS (2009)83636985765683
Percentage Change2010401111
Transplant (2000)83445470561750
Transplant (2005)89596081675683
Percentage Change615611113933
Wilson (2003)81466074612272
Wilson (2008)85486381646183
Percentage Change422733911
Comparison of Recommendation Grades Between Current Guidelines

Current AASLD guidelines were evaluated by grade of recommendation (strength) with the type of recommendation (Feature of Disease Recommendation, Diagnostic Recommendation, and Treatment Recommendation). In this evaluation, the most frequent types of recommendation were Treatment Recommendations (61%) followed by Diagnostic Recommendations (25%) and Features of Disease Recommendations (15%) (Supporting Table 2).

The Treatment Recommendation category had a predominance of grade II recommendations (39%), followed by grade III (37%) and grade I (24%) recommendations. The guidelines that contributed the most to the overall number of Treatment Recommendations were HBV (18%) and HCV (12%) practice guidelines.

In the Diagnostic Recommendation category, grade II recommendations were most commonly observed (54%) followed by grade III (40%) and grade I (6%) (Supporting Table 2). The greatest proportion of diagnostic recommendations came from the HBV, NAFLD, and vascular disorders of the liver (12% for all) guidelines.

In the Feature of Disease Recommendation category, the majority of recommendations were grade II (52%), followed by grade III (42%) and grade I (6%) (Supporting Table 2). The greatest proportion of Feature of Disease recommendations were found in the Liver Transplantation (27%) and vascular disorders of the liver (19%) guidelines.

Comparison of Recommendation Grades Between Initial and Current Guidelines

Among 17 guideline topics, 11 documents have complete updates that were eligible for comparison. The average time elapsing from initial publication to the current version of the guidelines was 7.2 years (range, 5-11 years). In these 11 topics, the overall number of recommendations increased by 124% (from 292 to 654 recommendations). All of the guideline topics had an increase in the number of recommendations over time except for PBC, which had a 47% decrease (Table 4). The three guidelines with the greatest increase in the number of recommendations were HBV (+71, 263%), Liver Transplantation (+53, 212%), and AIH (+27, 117%).

Table 4. Grade Comparison Between First and Current Guidelines
Grade Comparison Between First and Current Guidelines
GuidelineYearNumber of RecommendationsGrade I # (Change)Grade I %Grade I % change %Grade II # (Change)Grade II %Grade II % change%Grade III # (Change)Grade III %Grade III % change %
AIH200223417% 626% 1357% 
 2010505 (+25%)10%−43%6 (0%)12%−54%39 (+200%)78%38%
ALF200544716% 716% 3068% 
 2011487 (0%)15%−8%7 (0%)15%−8%34 (+13%)71%4%
Ascites199822836% 627% 836% 
 2009306 (−25%)20%−45%13 (+117%)43%59%11 (+37%)37%1%
HBV200127622% 1348% 830% 
 20099829 (+383%)30%33%38 (+192%)39%−19%31 (+287%)32%7%
HCC200521419% 1257% 524% 
 2010225 (25%)23%19%11 (−8%)50%−13%6 (+20%)27%15%
HCV200449918% 1531% 2551% 
 20097015 (67%)21%17%31 (+107%)44%45%24 (−4%)34%−33%
Hemochromatosis20011200% 12100% 00% 
 201117424% 10 (−17%)59%−41%318% 
PBC20002229% 15% 1986% 
 2009155 (+150%)33%267%5 (+400%)33%633%5 (−74%)33%−61%
TIPS20052628% 1869% 623% 
 2009285 (+150%)18%132%17 (−6%)61%−12%6 (0%)21%−7%
Transplantation20002500% 14% 2496% 
 2005780 (0%)0% 46 (+4500%)59%1374%32 (+33%)41%−57%
Wilson Disease20032100% 838% 1362% 
 2008231 (+100%)4% 16 (+100%)70%83%6 (−54%)26%−58%
change in #  40  101  46  
change in % median  46% 18%53% −8%17% −3%
change in % quartile 1  19% −17%−1% −16%−3% −51%
change in % Quatile 3  150% 58%136% 71%36% 6%

In evaluating individual guideline topics for the greatest change in number of grade I recommendations, the HBV guideline had the greatest increase (+23, 383%) followed by HCV (+6, 67%) increase (Table 4). In contrast, the Management of Adult Patients with Ascites due to Cirrhosis guideline had a 25% decrease in the number of grade I recommendations.

For grade II recommendations, the greatest increase was observed with the Liver Transplantation guideline (+44, 4500%) followed by HBV (+25, 192%) and finally HCV (+16, 107%) (Table 4). By contrast, the guidelines covering topics such as hepatocellular carcinoma (HCC), hemochromatosis, and TIPS guidelines had a reduced number of grade II recommendations. The greatest increase in grade III recommendations was observed with the AIH guideline (+26, 200%), followed by HBV (+23, 287.5%) and Liver Transplantation (+8, 33.3%) (Table 4). The guidelines focused on PBC, Wilson's disease, and HCV had a decrease in the number of grade III recommendations between the initial and revised versions.

Comparison of Recommendation Grades Between Initial and Current Guidelines According to Type of Recommendation

In this comparison, the grade of recommendations (strength) between initial and current guidelines were evaluated based on the type of recommendation (Features of Disease Recommendation, Diagnostic Recommendation, and Treatment Recommendation). In the Feature of Disease Recommendation category, the Liver Transplantation guideline had the greatest overall increase in the number of recommendations (+19, 271%), most of which consisted of grade II recommendations (Supporting Table 3). This was followed by AIH and HCV, which also saw the greatest increases in grade II recommendations.

In the Diagnostic Recommendation category, the greatest numerical increase was again seen in the Liver Transplantation guideline (+16, 800%), followed by HBV (+11, 122%) and AIH (+4, 133%) (Supporting Table 3). Notably, all three guidelines had the greatest increases in grade II recommendations. In contrast, the PBC and HCC guidelines had a decrease in the number of diagnostic recommendations from initial to current versions.

In the Treatment Recommendation category, the HBV guideline had the greatest increase in recommendations (+58, 387%), most notably with grade I recommendations (Supporting Table 3). This was followed by AIH (+21, 105%) with a predominant increase in grade III recommendations, and the Liver Transplantation (+18, 112%), which had a notable increase in grade II recommendations.

Evaluation of Classes of Evidence

Since the introduction of evidence classes to quantify benefit (class I) versus risk (class III), a total of 12 out of 17 AASLD guideline topics have used the “classes of evidence” system in at least one version of the publication. In the initial publication for a given guideline topic, 10 out of 17 topics used this system. The initial guidelines developed between 2001-2005 did not use the “classes of evidence” system. Only 3 of 17 guideline topics (Management of Ascites, Hemochromatosis, and PBC) with initial and recent versions continued to use the class system. However, since different class systems were used on subsequent guideline revisions, a direct comparison was not possible.

Of the current guidelines that used the classes of evidence system in their recommendations, 9 of the 12 guideline topics used the ACC/AHA system while the other three (Hemochromatosis, Primary Sclerosing Cholangitis [PSC], and NAFLD) used the GRADE system (Table 5). In the ACC/AHA system, 327 recommendations were issued, with 214 (65.4%) designated as class I recommendations suggesting evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective (Table 5). In evaluating the classes of evidence system based on types of recommendations, 64% were treatment recommendations, 23% were diagnostic recommendations, and 13% were features of disease recommendations (Supporting Table 4). In the GRADE classes of evidence system, a total of 98 recommendations were provided and 89% of the recommendations were designated class I recommendations (Supporting Table 4).

Table 5. Class Comparison of Current Guidelines
Class Comparison of Current Guidelines
Class I, II, IIA, IIB, Ill Comparison
GuidelineYearNumber of RecommendationsClass I NumberClass II NumberClass IIA NumberClass IIB NumberClass III Number
AIH20105014 (28%)0 (0%)31 (62%)1 (2%)4 (8%)
Alcoholic Liver20101613 (81%)0 (0%)0 (0%)0 (0%)3 (20%)
Ascites20093015 (50%)0 (0%)10 (33%)2 (7%)3 (10%)
Biopsy20093430 (88%)0 (0%)2 (6%)2 (6%)0 (0%)
HCV20097034 (49%)1 (1%)25 (36%)5 (7%)5 (7%)
PBC20091514 (93%)0 (0%)1 (7%)0 (0%)0 (0%)
Varices20072519 (76%)0 (0%)3 (12%)0 (0%)3 (12%)
Vascular20096453 (83%)0 (0%)3 (5%)2 (3%)6 (10%)
Wilson Disease20082322 (96%)0 (0%)0 (0%)1 (4%)0 (0%)
summary 327214 (65%)1 (0.3%)75 (23%)13 (4%)24 (7%)
% median  81%0%7%3%8%
% quartile 1  50%0%5%0%0%
% quartile 3  88%0%33%6%10%
Class 1-2 Comparison
GuidelineYearNumber of RecommendationsClass 1 NumberClass 2 Number
Hemochromatosis20111715 (88%)2 (12%)
PSC20103631 (86%)5 (14%)
NAFLD20124539 (87%)6 (13%)

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

The AASLD clinical practice guidelines provide a set of recommendations for guidance in managing patients with acute and chronic liver disease. Since 1998, these guidelines have provided an additional 36% increase in the overall number of recommendations from the initial development of specific guidelines. However, despite this substantial increase, less than 15% of all recommendations are categorized as grade I, suggesting that the evidence used to develop most recommendations does not come from randomized controlled trials, for a variety of reasons. Therefore, areas with insufficient evidence where randomized trials can be conducted to improve the evidence base should be identified for development.

In using the AGREE II guideline assessment tool for assessing methodological rigor and transparency, we identified both global and domain-specific improvements in guideline quality from documents created from 1998 to 2012. The current AASLD guidelines appear either comparable or superior by AGREE II evaluation with other medical specialties both nationally and globally that have undergone similar evaluation.[40-42] This assessment demonstrates the AASLD's commitment on continued review of its recommendations along with improving the overall quality of its published guidelines for clinical use.

On AGREE II evaluation, the greatest percentage of improvement in the six different domains was found in editorial independence, although its performance was the least impressive among domains assessed by this evaluation. This domain relates to the formulation of recommendations not being unduly biased with competing interests. This measure exemplifies how conflict of interest has become a major issue in the development of practice guidelines, especially when 40% of recommendations within the current AASLD guidelines require input from expert clinicians (as shown by the number of grade III recommendations). Thus, in accordance with the findings of the IOM's recommendations,[4] the AASLD has developed and revised a detailed policy for assessing conflict of interest in identifying writing group members for current guidelines being developed and revised, which has reduced the potential effects of bias in these documents. However, there will continue to be room for improvement with future guidelines.

In this analysis, the greatest increases in the overall number of recommendations were from practice guidelines related to HBV, liver transplantation, and AIH. Given that there are an estimated 350 million persons worldwide infected with HBV where the risk for cirrhosis and hepatocellular carcinoma is measurable, it is reasonable to expect that a large volume of research is performed in this area.[27] Extensive research of HBV has resulted in a wide array of tools at the clinician's disposal: diagnostic tests for evaluation and monitoring of disease, vaccination to decrease future prevalence of disease, and multiple treatment modalities including interferon and nucleos(t)ide analogs. These observations coincide temporally with current HBV practice guidelines containing the greatest increases in grade I recommendations overall and the greatest increase in the number of treatment recommendations. Similarly, the second largest increase in grade I recommendations was observed within the HCV guideline in association with the approval of direct-acting antiviral agents (DAA) and genetic host factors such as interleukin (IL)−28B. The next complete revision of the HCV guidelines is expected to have even greater increases in both the overall number and grade I recommendations based on continued advances in HCV research.

It is also not surprising that the AASLD guidelines on liver transplantation had a large increase in the number of recommendations from initial to updated publication. Prior to the era of liver transplantation, patients with advanced liver disease usually died within months to years.[34] Now, many patients have the opportunity for extended survival with excellent quality of life after liver transplantation. Interestingly, the increased number of recommendations were dominated by grade II statements and no increases in grade I recommendations.

The third greatest increase in the number of recommendations between guidelines occurred within the topic of AIH. Since the initial 2002 guidelines, additional work in this field such as a modification of the original scoring system of the International Autoimmune Hepatitis Group, enhanced diagnostic serologic testing, and new data leading to multiple recommendations on therapy including the management of refractory disease. Despite the large increase in the number of recommendations on this topic, the majority are still grade III in nature. A number of these recommendations will not likely undergo evaluation by randomized clinical trials (i.e., those related to diagnosis), but additional randomized trials for therapies including those used for refractory disease would be most welcome.

Although most guidelines have evolved with increased numbers of recommendations, the PBC and Management of Adult Patients with Ascites in Cirrhosis guidelines had a decrease in grade I recommendations. In the PBC guideline, the overall decrease of recommendations can be attributed to a >70% decrease in grade III recommendations, with only minor increases in grade I and II recommendations. In the Management of Adult Patients with Ascites in Cirrhosis guideline, there was a 25% decrease in grade I recommendations because of the withdrawal of a recommendation in the management of tense ascites and a separate recommendation on serial therapeutic paracentesis where the strength of available evidence was demoted in the current version of the guideline. Both of these changes are examples of where recommendations are eliminated over time when evidence and/or practices do not support prior recommendations.

In evaluating the classes of evidence (risk versus benefit), a direct comparison between initial topic guidelines and current guidelines was not possible. To improve their utility for clinicians and facilitate future comparisons, subsequent guideline revisions should consider moving to a simplified class system that could be applied to all liver disease topics. Such a standardized method of assessing risk and benefit for each individual recommendation would aid clinicians in the delivery of optimal patient care. The current GRADE system may satisfy many of these attributes.

Implications for Guideline Writing

The current AASLD format is to develop comprehensive practice guidelines focusing on assisting practitioners with the diagnosis and management of acute and chronic liver disease. It is expected to have varying degrees of strong or weak recommendations based on varying levels of evidence, as few interventions have been subjected to randomized controlled trials. While the goal in theory is to optimize medical management and improve patient care, it is common in practice to follow recommendations based on lower strengths of evidence as shown by similar guidelines developed in other areas of medicine.[5, 6]

The overall increase in number of recommendations is also likely due to the growing complexity in the diagnosis and treatment of liver disease. Atypical or variable presentations of disease, differential responses to therapy, and unique aspects within special populations including children and the elderly would require more definitive guidelines to aid the clinicians. Thus, with increasing evidence will come greater numbers of recommendations and perhaps stronger recommendations. However, regardless of the type of evidence, the quality of future clinical practice guidelines can be further improved, as identified by domains evaluated in the AGREE II instrument.

Study Limitations

The current analysis does not account for changes over time regarding the aims and practices of AASLD practice guideline development program, whereby the numbers of recommendations and distribution across classes may have been influenced. Given the lengthy time span, turnover of writing groups, and the use of several grading systems in these guidelines, there may have been unanticipated changes in definitions, standards, and thresholds in the determination of grades of recommendations that were not easily measurable. Additionally, the sporadic use of class systems and significant changes between systems prohibited a comprehensive class comparison. With the adoption of the current GRADE system for recent and future guideline updates by the AASLD, the deficiencies in assessing quality of evidence and strength of recommendations will hopefully be alleviated.

In conclusion, the evolution of the AASLD practice guidelines is featured by a substantial increase in the overall number of recommendations to assist healthcare providers in the management of patients with liver disease. With the exception of practice guidelines focused on chronic viral hepatitis (HBV and HCV), the bulk of evidence for these recommendations still derive from observational studies or expert consensus opinions. Ideally, the basis of medical practice should be as evidence-based as possible and we should aim to perform the highest quality research to answer clinical dilemmas whenever feasible. Nonetheless, guideline development should continually strive to generate recommendations with the highest quality of evidence possible while minimizing the effect of bias from extrinsic sources. Additionally, guideline developers should continue to strive to produce highest-quality documents with compelling methodological rigor and transparency. Whenever possible, clinical practice guidelines should highlight the need for additional research agenda to fill gaps within clinical care that have the greatest impact on patient outcomes.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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