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• W4366756031 abstract "Many clinicians are concerned that volunteers with nonalcoholic fatty liver disease (NAFLD) are included as healthy control subjects in laboratory reference interval testing and surreptitiously increase alanine aminotransferase (ALT) values. This view is supported by epidemiology studies reporting ALT elevations among patients at risk for NAFLD.1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1160) Google Scholar,2Ruhl C.E. Everhart J.E. Upper limits of normal for alanine aminotransferase activity in the United States population.Hepatology. 2012; 55: 447-454Crossref PubMed Scopus (109) Google Scholar In these studies, use of fixed ALT cutoffs that disregard the laboratory’s reference intervals were suggested to more sensitively detect liver disease. These fixed ALT cutoffs were then incorporated into 4 US liver and gastrointestinal guidelines affecting clinical care and research. However, clinicians may be unaware that while fixed ALT cutoffs can be used in Europe and wherever global ALT assay standards are employed,3Schumann G. Bonora R. Ceriotti F. et al.IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. International Federation of Clinical Chemistry and Laboratory Medicine. Part 4. Reference procedure for the measurement of catalytic concentration of alanine aminotransferase.Clin Chem Lab Med. 2002; 40: 718-724Crossref PubMed Google Scholar these do not apply in North America where the same blood sample yields widely varying results when measured using different ALT assays.4Adeli K. Higgins V. Seccombe D. et al.National survey of adult and pediatric reference intervals in clinical laboratories across Canada: a report of the CSCC Working Group on Reference Interval Harmonization.Clin Biochem. 2017; 50: 925-935Crossref PubMed Scopus (25) Google Scholar,5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar In the United States, analyzers and assays vary between laboratories and yield clinically important ALT measurement differences, especially within the normal range.5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar These differences arise as ALT assays use diverse modalities (eg, colorimetric, spectrophotometric, electrochemical, and other)6Huang X.-J. Choi Y.-K. Im H.-S. et al.Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques.Sensors. 2006; 6: 756-782Crossref Scopus (295) Google Scholar and conditions (eg, pH, temperature, and use of pyridoxal 5′-phosphate) that alter enzymatic activity and ALT results.4Adeli K. Higgins V. Seccombe D. et al.National survey of adult and pediatric reference intervals in clinical laboratories across Canada: a report of the CSCC Working Group on Reference Interval Harmonization.Clin Biochem. 2017; 50: 925-935Crossref PubMed Scopus (25) Google Scholar,6Huang X.-J. Choi Y.-K. Im H.-S. et al.Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques.Sensors. 2006; 6: 756-782Crossref Scopus (295) Google Scholar Among these differences, pyridoxal 5′-phosphate (or vitamin B6) is a critical coenzyme for aminotransferase activity and may be deficient in alcoholic and malnourished patients.7Diehl A.M. Potter J. Boitnott J. et al.Relationship between pyridoxal 5′-phosphate deficiency and aminotransferase levels in alcoholic hepatitis.Gastroenterology. 1984; 86: 632-636Abstract Full Text PDF PubMed Scopus (101) Google Scholar Without its addition to ALT assays, spuriously low ALT values can be observed in some patients. The addition of pyridoxal 5′-phosphate to ALT assays enhances the consistency of ALT measurements. Pyridoxal 5′-phosphate is frequently missing in ALT assays performed in the United States, and clinicians may be unaware of whether it is used or how it may affect results in their laboratory. To increase the sensitivity of ALT to identify asymptomatic liver disease (eg, NAFLD and chronic hepatitis C), the use of a fixed “normal” ALT cutoff was promoted in an influential Italian analysis of blood donors.1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1160) Google Scholar After excluding hepatitis B and C and HIV, ALT was assessed in nearly 4000 donors at low risk for NAFLD (with normal glucose, triglycerides, and cholesterol; body mass index < 25 kg/m2; and no medication use). In this low-risk group, Prati et al1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1160) Google Scholar defined the upper limit of normal (ULN) for ALT as 30 U/L for men and 19 U/L for women within a single laboratory using a single method and without prospectively assessing these cutoffs. Use of these suggested ALT ULN is inappropriate in the United States where ALT results vary significantly by laboratory analyzer and assay method.8Medicare, Medicaid and CLIA programs; regulations implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA)—HCFA. Final rule with comment period.Fed Regist. 1992; 57: 7002-7186PubMed Google Scholar,9College of American Pathologists. Laboratory Accreditation Program.https://www.cap.org/laboratory-improvement/accreditation/laboratory-accreditation-programGoogle Scholar Because of these sources of variation, Valenti et al10Valenti L. Pelusi S. Bianco C. et al.Definition of healthy ranges for alanine aminotransferase levels: a 2021 update.Hepatol Commun. 2021; 5: 1824-1832Crossref PubMed Scopus (21) Google Scholar advised the following: “While waiting for a harmonization of laboratory techniques, clinicians should be aware of which method has been used in each patient and apply the appropriate threshold.” Despite the evidence supporting the use of ALT reference intervals, fixed ALT cutoffs have been applied inappropriately in 4 US liver and gastrointestinal guidelines11Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1462) Google Scholar, 12Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (2130) Google Scholar, 13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (542) Google Scholar, 14Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (51) Google Scholar and in the American Association of Clinical Endocrinology clinical practice guideline for NAFLD,15Cusi K. Isaacs S. Barb D. et al.American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD).Endocr Pract. 2022; 28: 528-562Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar which affects clinical care and research.16Takyar V. Nath A. Beri A. et al.How healthy are the “healthy volunteers”? Penetrance of NAFLD in the biomedical research volunteer pool.Hepatology. 2017; 66: 825-833Crossref PubMed Scopus (25) Google Scholar,17Green D.M. Wang M. Krasin M.J. et al.Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.Hepatology. 2019; 69: 94-106Crossref PubMed Scopus (10) Google Scholar The 2016 American Association for the Study of Liver Diseases (AASLD) guidelines for treatment of chronic hepatitis B reported the following: “It is recognized that the normal ALT levels of healthy adults are 30 U/L for males and 19 U/L for females”11Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1462) Google Scholar and advised “Thus, using these ALT cutoffs for normal, the recommendation to consider treatment of adults with ALT values of 2 times the ULN (>60 U/L for males and >38 U/L for females…”11Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1462) Google Scholar The American College of Gastroenterology (ACG) clinical guideline on the evaluation of abnormal liver chemistries codified its ALT thresholds as “A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed by physicians.”13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (542) Google Scholar Incorporating this ACG guideline, the AASLD 2018 hepatitis B guidance updated their 2016 guideline as follows: “The ULN for ALT in healthy adults is reported to be 29-33 U/L for males and 19-25 U/L for females. An ULN for ALT of 35 U/L for males and 25 U/L for females is recommended to guide management decisions.”12Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (2130) Google Scholar The American Association of Clinical Endocrinology NAFLD guideline endorsed both Prati et al’s1Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1160) Google Scholar and the ACG guideline’s cutoffs13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (542) Google Scholar and recommended further risk stratification in patients with ALT exceeding 30 U/L, regardless of sex.15Cusi K. Isaacs S. Barb D. et al.American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD).Endocr Pract. 2022; 28: 528-562Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Similarly, the AASLD 2023 NAFLD practice guidance cautioned that “normative values for ALT reported by most laboratories exceed what is considered a true normal” and advised “As a general rule, ALT >30 U/L should be considered abnormal.”14Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (51) Google Scholar With an increasing number of guidelines recommending fixed normal ALT cutoffs (including the ACG clinical guideline on the evaluation of abnormal liver chemistries13Kwo P.Y. Cohen S.M. Lim J.K. ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35Crossref PubMed Scopus (542) Google Scholar), multiple researchers have followed these guidelines and analyzed ALT data using fixed ALT cutoffs.16Takyar V. Nath A. Beri A. et al.How healthy are the “healthy volunteers”? Penetrance of NAFLD in the biomedical research volunteer pool.Hepatology. 2017; 66: 825-833Crossref PubMed Scopus (25) Google Scholar,17Green D.M. Wang M. Krasin M.J. et al.Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.Hepatology. 2019; 69: 94-106Crossref PubMed Scopus (10) Google Scholar With the use of a fixed ALT cutoff and disregard of the laboratory reference interval in research studies, it is challenging to interpret, replicate, or apply research findings to diverse clinical and laboratory settings. With fixed ALT cutoffs recommended in multiple US guidelines, Panteghini et al18Panteghini M. Adeli K. Ceriotti F. et al.American liver guidelines and cutoffs for “normal” ALT: a potential for overdiagnosis.Clin Chem. 2017; 63: 1196-1198Crossref PubMed Scopus (19) Google Scholar cautioned “The mentioned guidelines recommend the use of universal cutoffs for ALT without considering any differences between laboratory assays” and “highlight the critical need for laboratory expertise when drafting clinical guidelines involving the use of laboratory tests.” Without the use of laboratory reference intervals despite well-established analytical variation, they concluded “We … are concerned that the implementation of these recommendations may lead to overdiagnosis and unnecessary further testing.”18Panteghini M. Adeli K. Ceriotti F. et al.American liver guidelines and cutoffs for “normal” ALT: a potential for overdiagnosis.Clin Chem. 2017; 63: 1196-1198Crossref PubMed Scopus (19) Google Scholar As highlighted by laboratory professionals, a large national US study reported statistically and clinically meaningful ALT measurement differences between analyzers, particularly within the normal range.5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar This study of 22,950 samples tested in 5 analyzers reported that mean ALT varied 17 U/L between the highest- and lowest-reading analyzers with ALT < 29 U/L, with more than 1 in 3 ALT analyzers exhibiting notably higher ALT values.5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar For example, the same sample within the normal ALT range divided and measured in a low- vs high-reading analyzer could yield an ALT of 28 or 45 U/L, respectively. Beste et al5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar cautioned “With guidelines recommending the evaluation of unexplained ALT elevations, our findings suggest that many patients are at risk for misclassification as having ‘abnormal’ ALT simply as a result of analyzer characteristics.” In this US study,5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar defining ALT 30 U/L as normal would overdiagnose liver disease in approximately 1 in 5 patients nationwide, which can result in needless anxiety for patients and costly additional referrals or testing. With estimated costs of $448–$502 per patient to evaluate elevated liver enzymes,19Tapper E.B. Saini S.D. Sengupta N. Extensive testing or focused testing of patients with elevated liver enzymes.J Hepatol. 2017; 66: 313-319Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar substantive numbers of patients could be tested unnecessarily if clinicians apply the fixed ALT cutoffs in US guidelines (see the case presentation below). Beste et al5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar “highlight the need for provider awareness of the ALT reference range when assessing ALT test results” and concluded that “Universal ALT thresholds should be avoided as a trigger for clinical action until differences between analyzers can be resolved.” To address these issues, ALT reference intervals could be harmonized, as recommended by members of the American Association for Clinical Chemistry and Practice Guidelines Committee of the AASLD20Dufour D.R. Lott J.A. Nolte F.S. et al.Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests.Clin Chem. 2000; 46: 2027-2049Crossref PubMed Scopus (403) Google Scholar as well as by Canadian laboratory professionals.21Parker M.L. Adeli K. CSCC Working Group on Reference Interval HarmonizationPediatric and adult reference interval harmonization in Canada: an update.Clin Chem Lab Med. 2018; 57: 57-60Crossref PubMed Scopus (9) Google Scholar To harmonize ALT reference intervals, ALT measurements must be comparable across laboratories using agreed on standards for quality assurance and consistency. To accomplish this goal, the International Federation of Clinical Chemistry and Laboratory Medicine has made available global standards for ALT and other analytes in more than 100 countries.22The International Federation of Clinical Chemistry and Laboratory Medicine.https://www.ifcc.org/about/Google Scholar The International Federation of Clinical Chemistry and Laboratory Medicine’s standard ALT method defines reaction conditions and specifies the use of coenzyme pyridoxal 5′-phosphate to yield consistent ALT values.3Schumann G. Bonora R. Ceriotti F. et al.IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. International Federation of Clinical Chemistry and Laboratory Medicine. Part 4. Reference procedure for the measurement of catalytic concentration of alanine aminotransferase.Clin Chem Lab Med. 2002; 40: 718-724Crossref PubMed Google Scholar For more than 20 years, the European Union has legally required laboratory result traceability to reference management systems to ensure accuracy.23Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices.OJEC. 1998; L331: 1-37Google Scholar In the United States, because pyridoxal 5′-phosphate is frequently not included in ALT assays, spuriously low ALT values may be observed in some patients.7Diehl A.M. Potter J. Boitnott J. et al.Relationship between pyridoxal 5′-phosphate deficiency and aminotransferase levels in alcoholic hepatitis.Gastroenterology. 1984; 86: 632-636Abstract Full Text PDF PubMed Scopus (101) Google Scholar ALT assays from the same analyzer manufacturer provide reagents with and without pyridoxal 5′-phosphate to US laboratories. In the United States, analyzer manufacturers complete clinical testing to define the assay reference interval, which is not harmonized with other ALT assays. Individual laboratories using an assay mostly use manufacturer’s reference intervals; select well-resourced laboratories may perform clinical studies to refine their own reference interval. However, if US ALT measurements were harmonized to produce closely comparable values across laboratories, specific ALT values could be incorporated in evidence-based guidances for diagnosis and treatment.24American Association for Clinical Chemistry The need to harmonize clinical laboratory test results—a white paper of the American Association for Clinical Chemistry, July 2015.https://www.aacc.org/-/media/Files/Global-Health-Outreach/Harmonization_White_Paper_715.pdf?la=en&hash=7942761541E048BF6C340243A60762775C683BCEGoogle Scholar As an example, harmonizing widely varying prothrombin time coagulation tests to the international normalized ratio (INR) system improved clinical care.25Dorgalaleh A. Favaloro E.J. Bahraini M. et al.Standardization of prothrombin time/international normalized ratio (PT/INR).Int J Lab Hematol. 2021; 43: 21-28Crossref PubMed Scopus (22) Google Scholar In a 2015 white paper, American Association for Clinical Chemistry laboratory professionals supported harmonization of high-priority laboratory tests through broad collaboration with stakeholders and large funded multicenter studies; ALT was not listed as a high priority.24American Association for Clinical Chemistry The need to harmonize clinical laboratory test results—a white paper of the American Association for Clinical Chemistry, July 2015.https://www.aacc.org/-/media/Files/Global-Health-Outreach/Harmonization_White_Paper_715.pdf?la=en&hash=7942761541E048BF6C340243A60762775C683BCEGoogle Scholar With the likely delay of ALT harmonization in the United States, clinician’s concerns can be addressed with a series of actions. US manufacturers can be advised on the selection of subjects for the manufacturer’s ALT reference interval testing. ALT reference intervals are most valid when determined among diverse populations with limited biologic variation (eg, healthy subjects at low risk of liver disease identified by negative hepatitis B and C tests; body mass index ≤ 25 kg/m2; normal glucose, triglycerides, and cholesterol; without illicit drug or regular alcohol use).4Adeli K. Higgins V. Seccombe D. et al.National survey of adult and pediatric reference intervals in clinical laboratories across Canada: a report of the CSCC Working Group on Reference Interval Harmonization.Clin Biochem. 2017; 50: 925-935Crossref PubMed Scopus (25) Google Scholar,10Valenti L. Pelusi S. Bianco C. et al.Definition of healthy ranges for alanine aminotransferase levels: a 2021 update.Hepatol Commun. 2021; 5: 1824-1832Crossref PubMed Scopus (21) Google Scholar,20Dufour D.R. Lott J.A. Nolte F.S. et al.Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests.Clin Chem. 2000; 46: 2027-2049Crossref PubMed Scopus (403) Google Scholar,21Parker M.L. Adeli K. CSCC Working Group on Reference Interval HarmonizationPediatric and adult reference interval harmonization in Canada: an update.Clin Chem Lab Med. 2018; 57: 57-60Crossref PubMed Scopus (9) Google Scholar Regulatory agencies can require the inclusion of pyridoxal-5′-phosphate in ALT assays, whereas laboratory standardization efforts can promote its inclusion to increase ALT consistency. Until US laboratories move toward harmonized ALT methods, interim valid method-specific reference intervals can be advanced to enhance clinicians’ confidence in their laboratory’s reference interval. With similar concerns about reference intervals, the Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization seeks to harmonize ALT reference intervals.21Parker M.L. Adeli K. CSCC Working Group on Reference Interval HarmonizationPediatric and adult reference interval harmonization in Canada: an update.Clin Chem Lab Med. 2018; 57: 57-60Crossref PubMed Scopus (9) Google Scholar These clinical chemists intend to both align methods and develop reference intervals from large healthy populations with the collaboration of clinicians, diagnostics manufacturers, informaticians, and accreditation and quality specialists. Because ALT analyzers are similar throughout North America, Canada’s harmonization of laboratory reference intervals may facilitate US efforts. Laboratory professionals collaborate increasingly with clinicians to identify healthy subjects without liver disease risk factors for ALT reference interval testing. Among 40 such screened healthy US volunteers selected for ALT reference interval testing, nearly half (45%) exhibited ALT values exceeding 30 U/L, yet all were within the manufacturer-recommended reference interval of the Siemens analyzer (Dr John G. Toffaletti, Duke University Professor in Pathology, personal communication). This study and larger datasets5Beste L.A. Icardi M. Hunt C.M. et al.Alanine aminotransferase results differ by analyzer manufacturer in a national integrated health setting, 2012-2017.Arch Pathol Lab Med. 2020; 144: 748-754Crossref PubMed Scopus (5) Google Scholar attest to the clinically significant ALT measurement differences that preclude the use of clinical guidance cutoffs based on unrepresentative assays. In summary, the broad variation in US ALT analyzer and assay measurements suggests the use of a reference interval in clinical care and research rather than a fixed ALT cutoff. Guidelines defining normal ALT as a fixed ALT cutoff, rather than the reference interval, are premature. Because NAFLD and viral hepatitis guidelines suggest evaluation of ALT elevations above a fixed cutoff, up to 1 in 5 patients can be misclassified as “abnormal” and suffer needless anxiety, costly additional testing, and unnecessary referrals or treatment. This unfortunate cascade of events can be addressed by informing clinicians and researchers of ALT analytical differences, including laboratory experts in guideline panels and research, and enhancing ALT measurement with interim US measures as the laboratory community moves toward internationally harmonized ALT methods. A primary care physician referred an asymptomatic, 42-year-old, overweight, nondrinking man with hypertension, an ALT of 42–45 U/L (14–54 U/L reference interval), an aspartate aminotransferase of 31–34 U/L (15–41 IU/L reference interval), and normal bilirubin, alkaline phosphatase, and albumin on repeated measure over 6 months. His recent testing revealed negative hepatitis B surface antigen and core antibody, hepatitis C antibody, antinuclear and anti–smooth muscle antibodies; and normal transferrin saturation, α1-antitrypsin, ceruloplasmin, and liver ultrasound. The physician told the patient he had ongoing liver injury because his liver tests were staying above the so-called true healthy normal ALT level of 33 U/L, and he would benefit from seeing a liver specialist to discuss a liver biopsy. At your clinic, the patient expressed concern about his liver injury; his uncle was told recently that he had serious liver disease. The patient has required time off work and had out-of-pocket testing costs; he expressed concern about the liver biopsy and the costs of any potential treatment. You explain to the patient that you have carefully reviewed his liver tests. You are pleased that his testing does not show liver disease (ie, as his ALT values are within the normal ALT reference interval of the laboratory), and he does not need a liver biopsy or further evaluation at this time. You explain that current medical guidelines have caused confusion about normal liver test values, which you’ll clarify with his doctor. However, as a liver specialist, you are confident that he does not have liver injury and needs no further follow-up with you." @default.
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