EVALUATION OF ABNORMAL LIVER-ENZYME RESULTS IN ASYMPTOMATIC PATIENTS
C. Verslype Dienst Hepatologie, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven
2 INTRODUCTION End-stage liver failure and hepatocellular carcinoma (HCC) are important causes of morbidity and mortality worldwide, especially in regions with endemically high levels of viral hepatitis B and C infections. In Western countries viral hepatitis C, alcohol abuse and obesity are leading causes of chronic liver disease, making it in the United States among the seven leading causes of death in men and women aged 45-64 yr (1). In Belgium, cirrhosis accounts for 3.5 % of deaths in this age-group (in 1996) and numbers are expected to rise in the next decades (2). Chronic liver diseases are characterized by a long preclinical phase and it may take more than two decades for a liver to gain a cirrhotic architecture. Early detection of significant liver disease allows therapeutic intervention and lifestyle changes, aiming at regression of liver fibrosis. So far, determination of liver-enzymes has emerged as a tool for the detection of liver disease even in asymptomatic patients, which is illustrated by the use of serum aminotransferases (as surrogate markers of viral hepatitis) for the screening of healthy blood-donors. The introduction of automated routine laboratory testing has resulted in a growing asymptomatic population with one or more abnormalities in their liver tests. Some of these persons are unnecessary subjected to a liver biopsy, because of the absence of liver disease or the lack of immediate therapeutical benefit of the biopsy findings. In this review we discuss the battery of liver enzyme tests available in daily clinical practice, their diagnostic accuracy for the detection of liver disease and suggest an approach to abnormal tests in asymptomatic patients. LIVER ENZYME TESTS The battery of liver enzymes includes alanine and aspartate aminotransferases (ALT and AST), alkaline phosphatase (ALP) and gamma-glutumayltransferase (GGT). Normal ranges are based on distributions from “healthy” volunteers. The upper limit of normal (ULN) is defined as the mean + 2 SD, which implies that 2.5% of the liver tests from these healthy persons exceed the ULN. The aminotransferases catalyze the reversible transformation of α-ketoacids into amino acids. Their serum levels reflect the amount of hepatocellular injury and death on a day-by-day basis. Aminotransferases (and predominantly AST) are not only found in hepatocytes but also in other tissues (heart and skeletal muscles, kidney, brain, pancreas, lung, and red blood cells). The liver contains 400 U ALT/g protein (mainly cytoplasmic) and 500 U AST/g protein (> 80
3 % contained in mitochondria and endoplasmic reticulum). Damage to one gram of liver tissue (or the membranes of 171 million hepatocytes) results in a significant increase in the serum ALT activity (3, 4). AST responds in the same fashion, especially following liver cell necrosis and destruction of mitochondria and endoplasmic reticulum. Alkaline phosphatase is found in the biliary pole of the hepatocytes, the bile duct epithelia, osteoblasts, kidney, lung, intestine and placenta (3). The serum activity present in normal individuals is predominantly due to the izoenzymes of the liver, bone and kidney. Thus, an isolated rise in ALP is seen in the third trimester of preganancy, during growth (bone ALP) or may be due to intestinal ALP (following ingestion of a fatty meal). In cholestatic liver disease, the elevated bile acids stimulate the synthesis of ALP. Differentiation between hepatic and non-hepatic causes of ALP elevation can be done by determination of ALP isoenzymes or more easily by testing for GGT, which rises in liver but not in bone disease. GGT is found in hepatocytes, cholangiocytes, kidney, pancreas, epididymis, heart, lung, intestine, bone marrow, salivary glands, thymus, spleen and brain, which is an explanation for the lack of specificity for the diagnosis of hepatobiliary disease. Elevated values of GGT are caused by damage to cellular membranes, cellular regeneration or by enhanced synthesis as a result of induction of the biotransformation enzyme system (3). Known inducers are bile acids (cholestasis), prolonged regular abuse of alcohol and especially antiepileptic drugs (phenytoin, carbamazepine) (5). A decline in GGT can be observed during oestrogen administration or pregnancy (6). Due to the sudden release of intracellular reservoirs of aminotransferases and their short halflife (1 – 2 days), the levels of ALT and AST respond quickly to hepatocellular damage or acute bile duct obstruction. A rise in serum ALP and GGT occurs more slowly in response to cholestasis, and the levels are maintained longer due to a half-life of more than 4 days (3, 7). Knowledge of these enzyme kinetics is important for the correct interpretation of abnormal liver enzymes as predominant hepatocellular or cholestatic patterns. ELEVATED AMINOTRANSFERASE LEVELS Sensitivity and specificity of ALT for the detection of liver disease is around 83 % (3, 4). An isolated rise in ALT is of hepatocellular origin, after exclusion of macroenzyme-I-immune complexes. The diagnostic sensitivity of AST is significantly lower (70%) and less specific The study of the AST:ALT ratio (or DeRits ratio) can yield some additional information but specific etiologic diagnosis cannot usually be based on these routine tests or ratio’s. In
4 alcoholic liver disease the AST:ALT ratio is greater than 2:1, due to a alcohol-related deficiency of pyridoxal 5-phosphate (B6) (8). An isolated rise in AST is not uncommon in patients with end-stage alcoholic cirrhosis. In contrast, patients with non-alcoholic fatty liver disease (NAFLD) the AST:ALT ratio is less than 1 (9). Any confirmed rise in serum aminotransferase activity (especially ALT) warrants additional investigation for the detection of underlying liver disease. A good clinical history is rewarding, especially concerning all the drugs that have been taken over the last 3 months and the help of the pharmacist may speed up the detective work. Additional biochemical and imaging tests should be ordered. In table 1 a work-up is proposed for this patients. Aminotransferases may become abnormal in diseases of the thyroid or muscles (4). A rise in serum transaminases may represent the only finding of silent coeliac disease. In a series of 140 consecutive patients with unexplained chronic elevation of AST and ALT levels, 13 (9.3%) had coeliac disease, which was significantly higer than the expected prevalence of 0.5%. The liver tests normalised after a gluten-free diet. Nine patients had undergone a liver biopsy prior to the diagnosis of coeliac disease, which showed variable degrees of mild steatosis, fibrosis and inflammation (10). The cause of an elevated aminotransferase level varies greatly depending on the population studied and the thoroughness of the examination. Several carefully conducted clinical studies, which included liver biopsy in all patients, have shown that most asymptomatic subjects with persistent liver tests abnormalities in the absence of specific biochemical markers or abnormal imaging, have NAFLD (see table 2) (11, 12). A study of 354 asymptomatic patients with persistently abnormal liver enzymes (> 2 x ULN) showed NAFLD in the majority of cases (66%). The remaining causes are summarized in table 2, but in my opinion these causes should normally have been picked up by a complete pre-biopsy evaluation (13). Similar findings were suggested by a large population-based study, the NHANES III in the United States investigating 15,676 individuals ages 17 yr and older, despite some methodological shortcomings (no liver biopsies, no investigation of autoimmune hepatitis, α-1-antitrypsin deficiency nor occult coeliac disease) (14). The prevalence of disturbed aminotransferase was 7.9% in this large population and only 30% of cases could be explained by alcohol consumption, viral hepatitis (C or B) or hemochromatosis. The remainder were strongly associated with obesity and other features of the metabolic syndrome (body mass index, waist circumference and serum lipids, insulin resistance), suggesting NAFLD (but this could not be proven due to the lack of imaging and histological data) (14).
5 The results of these studies suggest that a liver biopsy is not mandatory in asymptomatic patients with an unexplained rise in AST or ALT, after a thorough non-invasive evaluation (table 1). The probability to diagnose NAFLD is high and lifestyle changes (alcohol abstinention, weight loss, avoidance of hepatotoxic mediactions) or other therapeutic measures for the metabolic syndrome (control of glucose and lipid metabolism) may be implemented without histological proof. Moreover, the finding of minimal changes in the liver biopsy can be due to sampling error and falsely reassure patient and doctor. Important necroinflammation and/or advanced fibrosis will not alter the above mentioned therapeutic measures, but demands a close follow-up of the patient (every 3 months or more frequent depending on liver synthetic function). Liver biopsy findings may sometimes point to a diagnosis which was overlooked at the time of the initial evaluation. Given the possible serious complications of liver biopsy (mortality 0.01%), it should not be performed to make up for a poor initial approach. There is an unmet need for serum markers that can reliably detect the stage of liver fibrosis. Several serum tests are in development, including the Fibrotest (based on a range of clinical chemistry analyses) and GlycoCirrhoTest (based on profiles of serum protein N-glycans). The combination of both tests achieved a sensitivity for cirrhosis of 75% and a specificity of 100%, obviating the need for biopsy in cirrhotic patients. Further and larger studies are necessary to fully validate this promising results (15, 16). There is controversy concerning the need for evaluation of people with slightly increased aminotransferase activity, but still within the normal range. The results of an Italian retrospective cohort study in 6835 first-time blood donors suggested that normal values of ALT were based on a reference population which possibly included patients with subclinical hepatis C infection and NAFLD (17). According to the authors, lowering of the ULN for ALT is advisable in patients with chronic HCV infection or NAFLD. The study and conclusions were criticized by others (18), because lowering the ULN of ALT would create an overwhelming number of false-positive results. However, a recent Korean study showed a positive association between high-normal serum ALT (35-40 IU/L) levels and mortality from liver disease, even after adjustment for alcohol consumption, obesity, plasma glucose en serum lipids (19). It may therefore be justified to lower the ULN for ALT in populations with a high prevalence of liver diseases.
6 ELEVATED ALKALINE PHOSPHATASE & GAMMA-GLUTAMYLTRANSFERASE Isolated elevation of alkaline phospahatase is as a rule not associated with liver disease and suggests either a physiological cause (pregnancy, growth) or bone disease. An associated rise in GGT is suggestive of hepatobiliary disease and in particular cholestatic conditions (e.g. PBC, PSC, “reine cholestase” induced by anabolic steroids, partial obstruction of bile ducts) (4, 7).
This pattern is also associated with infiltrating tumours in the liver. Ultrasound
imaging of the liver is mandatory, and MRI may be appropriate. If no pathology is found on imaging and when there is a persistent (> 3 months) increase of ALP and GGT (> 2 ULN), we consider a liver biopsy or ERCP.
An isolated rise in GGT is not specific for liver disease,
and these patients are unlikely to have liver fibrosis (13, 20). Specifcity increases if there is a steady increase of GGT and if other enzymes become abnormal. SUMMARY Abnormal liver enzymes may be present in the absence of symptoms and signs of liver disease. A good clinical history and physical examination are mandatory. If a systematic approach is adopted, based on additional non-invasive serological tests and imaging procedures covering the most frequent liver diseases, the cause is often apparent.
The
clinician should be aware of non-hepatic diseases that can cause abnormal liver enzymes, such as thyroid disorders and occult celiac disease. In those patients in which no explanation can be found at the time of the initial evaluation for there abnormal liver enzymes, there is a high probability of non-alcoholic fatty liver disease. The risks and benefits of a liver biopsy in this setting should be carefully considered, as it only seldom alters management.
7
TABLE 1: NON-INVASIVE EVALUATION OF ASYMPTOMATIC PATIENTS WITH CHRONICALLY (> 3 MONTHS) ELEVATED AMINOTRANSFERASES 1. Clinical history (medication!) and physical examination 2. Excluding liver disease: - Hepatobiliary imaging: liver ultrasound (or if in doubt CT – MRI) - Liver synthetic and excretory function: prothrombin time, albumin, bilirubin - Specific tests: a. Chronic viral hepatitis B and C: HBsAg, HBcAb, anti-HCV, (HCV-RNA); b. Hemochromatosis: serum iron, iron saturation, ferritin, (genetic testing); c. Autoimmune disease: antinuclear antibody, antimitochondrial antibody, smooth muscle cell antibody; liver-kidney microsomal antibodies ( titers > 1:40); immunoglobulins; d. α-1-antitrypsin deficiency: protein electrophoresis, (phenotyping); e. Wilson’s disease: ceruloplasmin, urinary copper excretion (< 40 yr). 3. Excluding non-hepatic causes of elevated aminotransferases - Thyroid disorders: TSH - Coeliac disease: tissue transglutaminase antibodies (endomysium antibodies) - Muscle pathology: creatine kinase
8
TABLE 2: PROSPECTIVE STUDIES OF ASYMPTOMATIC PATIENTS WITH SUSTAINED ELEVATED LIVER ENZYMES WITHOUT A SPECIFIC LIVER DISEASE AFTER INITIAL NON-INVASIVE EVALUATION. N patients
Cut-off abnormal
Liver biopsy results Pathology
Reference N (%)
liver enzymes 81
ALT or AST
Non-alcoholic fatty liver disease
73 (90.1)
> 1.5 ULN
Normal liver
8 (9.9)
Daniel et al.1999 (11)
(2 x/ 6 months) 36
354
AST or ALT Non-alcoholic fatty liver disease
21(58.3)
or ALP
PSC/PBC
5 (13.8)
> 1.5 ULN
Autoimmune hepatitis
3 (8.3)
Non specific changes
3 (8.3)
Normal liver
3 (8.3)
Porfyria cutanea tarda
1 (2.7)
ALT, GGT or Non-alcoholic fatty liver disease
235 (66)
ALP
Cryptogenic hepatitis
32 (9)
> 2 ULN
Drug related damage
27 (7.6)
Normal liver
21 (5.9)
Alcohol related damage
10 (2.8)
PBC/PSC
9 (2.5)
Autoimmune hepatitis
7 (1.9)
Granuloma
6 (1.7)
Hemochromatosis
3 (0.9)
Secondary biliary cirrhosis
2 (0.6)
Amyloid
1 (0.3)
Glycogen storage disease
1 (0.3)
No fibrosis
261 (73.7)
Bridging fibrosis
30 (8.5)
Cirrhosis
21 (5.9)
Sorbi et al. 2000 (12)
Skelly et al. 2001 (13)
9 REFERENCES 1. Death and death rates in the United States, 1997. National Vital Statistics Reports, 1999. 2. Miermans PJ, Van Oyen H. Gezondheidsrapport: een verkenning van de gezondheidssituatie in België aan de hand van sterftecijfers en gezondheidsverwachtingscijfers. Wetenschappelijk Instituut Volksgezondheid, Afdeling Epidemiologie. Brussel: IPH/EPI Reports 2002 – 031: 10-37. 3. Kuntz E. Laboratory diagnostics. In: Kuntz E, Kuntz HD, eds. Hepatology, principles and practice. Heidelberg: Springer –Verlag. 2001: 78-112. 4. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000; 342: 1266–71. 5. Rosalki SB, Tarlow D, Rau D. Plasma gamma-glutamyl transpeptidase elevation in patients receiving enzyme-inducing drugs. Lancet. 1971; ii: 376–7. 6. Feldmann HU, Pfeiffer R, Hirche H. Hormonal dependency of gamma-glutamyl transpeptidase. Dtsch Med Wochenschr. 1974; 31; 99: 1171-4. 7. Limdi JK, Hyde GM. Evaluation of abnormal liver function tests. Postgrad Med J. 2003; 79: 307-312. 8. Cohen JA, Kaplan MM. The SGOT/SGPT ratio-an indicator of alcoholic liver disease. Dig Dis Sci. 1979; 24: 835–8. 9. Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotransferase to alanine transferase: potential value in differentiating non-alcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999; 94: 1018–22. 10. Bardella MT, Vecchi M, Conte D, et al. Chronic unexplained hypertransaminasemia may be caused by occult coeliac disease. Hepatology. 1999; 29: 654–7. 11. Skelly MM, James PD and Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol. 2001; 35: 195–199. 12. Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol. 1999; 94: 3010–3014. 12. Sorbi D, McGill DB, Thistle JL, Therneau TM, Henry J, Lindor KD. An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities. Am J Gastroenterol. 2000; 95: 3206-10. 14. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003; 98: 960-7. 15. Rossi E, Adams L, Prins A et al. Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients. Clin Chem. 2003; 49: 450-4. 16. Callewaert N, Van Vlierberghe H, Van Hecke A, Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10: 429-34. 17. Prati D, Taioli E, Zanella A et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137: 1-9. 18. Kaplan MM. Alanine aminotransferase levels: what’s normal? Ann Intern Med. 2002; 137: 49-51. 19. Kim HC, Nam CM, Jee SH, Han KH, Oh DY, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver disease: prospective cohort study. BMJ 2004 doi/10.1136/bmj.38050.593634.63. 20. Ireland A, Hartley L, Ryley N, McGee JO, Trowell JM, Chapman RW. Raised gammaglutamyltransferase activity and the need for liver biopsy. BMJ. 1991; 16; 302: 388-9.
Evaluatie van gestoorde levertesten bij asymptomatische patiënten
C. Verslype, MD PhD Hepatologie U.Z. Gasthuisberg Leuven
Gevorderde leverfibrose • Mortaliteit door verwikkelingen van cirrose* – Leeftijdsgroep 25-44 jr: 4.5 % (5de) – Leeftijdsgroep 45-64 yr: 3.5 %
• Lange pre-klinische faze (> 20 jaar) • Vroegtijdige detectie van chronisch leverlijden is mogelijk door routine labo-testen • Toenemende asymptomatische groep met gestoorde levertest(en): evaluatie? * Miermans PJ. IPH/EPI reports 2002
Evaluatie van gestoorde levertesten bij asymptomatische patiënten • Welke levertesten zijn beschikbaar in de dagelijkse klinische praktijk? • De diagnostische waarde van deze levertesten voor de detectie van leverziekten • Benadering van abnormale levertesten bij de asymptomatische patiënt
Aminotransferases • ALT – Lever: 400 U ALT/ g eiwit (cytoplasma) – Schade aan 1 g leverweefsel veroorzaakt een significante stijging in serum ALT activiteit – Sensitiviteit and specificiteit voor de detectie van leverziekte is ~ 83% – Geïsoleerde stijging: uitsluiten van macroenzyme-Iimmuun complexen – Vitamin B6 tekort: minder uitgesproken stijging
• AST – Liver: 500 U AST/ g eiwit (> 80 % mitochondria + ER) – Minder accuraat dan ALT
• AST:ALT ratio’s Pratt et al. N Eng J Med 2000
Alkalische fosfatasen en GGT • Alkalische fosfatasen – Hepatocyten, cholangiocyten, osteoblasten, nier, long, darm en placenta – Geïsoleerde stijging in het 3de trimester van de zwangerschap, groei – Cholestase: galzuren stimuleren synthese
• GGT – Verschillende weefsels – Gestegen waardes: schade aan membranen, celregeneratie, toegenomen synthese – Pover diagnostisch middel voor detectie leverlijden, alleen nuttig in combinatie met ALF – Daling: oestrogenen
Pratt et al. N Eng J Med 2000
Enzyme kinetiek
• ALT en AST: snel antwoord op hepatocellulaire beschadiging of acute galwegobstructie, door een plotse vrijzetting van intracellulaire reservoirs en kort halfleven (1-2 dagen) • ALF en GGT: traag antwoord op cholestase en spiegels blijven langer verhoogd (halfleven > 4 dagen)
NIET-INVASIEVE EVALUATIE VAN ASYMPTOMATISCHE PATIENTEN MET CHRONISCH (> 3 MAANDEN) GESTOORDE AMINOTRANSFERASES 1. Anamnese (medicatie!) en klinisch onderzoek 2. Uitsluiten leverlijden: - Hepatobiliaire beeldvorming: echo (bij twijfel CT – KST) - Liver synthese en excretie-functie: prothrombine tijd, albumine, bilirubine - Specifieke testen: a. Chronische virale hepatitis B en C: HBsAg, HBcAb, anti-HCV, (HCV-RNA); b. Hemochromatose: serum ijzer, ijzer saturatie, ferritine, (genetische tests); c. Autoimmune ziekte: ANA, AMA, AGS; LKM-ab (titers > 1:40); Ig; d. α-1-antitrypsine stapeling: eiwitn electroforese, (fenotypering); e. Ziekte van Wilson: ceruloplasmine, urinaire koper excretie (< 40 jr).
3. Uitsluiten niet-hepatische ooraken van gestoorde levertesten - Schildklierlijden: TSH - Coeliakie: tissue transglutaminase antilichamen (endomysium antilichamen) - Spierpathologie: CK
Verslype C, Acta Clin Belg 2004; 89: 285
Occulte coeliakie •
Onverklaarde ALT/AST stijging > 6 maanden (n=140)
•
AGA/ EmA+ 13/140 (9.3%) – controles: 0.3%
•
Gemiddelde leeftijd 34 + 11.8 jr - M/V ratio 2:1
•
Duodenale biopsie: 12/13 typisch CD
•
Subklinisch in 6/13; geen enkele patiënt presenteerde zich met duidelijk malabsorptie syndroom
•
Lever biopsie (9/13): minimale veranderingen (steatose, fibrose)
•
Gluten-vrij dieet: levertesten beter Bardella et al. Hepatology 1999
PROSPECTIVE STUDIES OF ASYMPTOMATIC PATIENTS WITH SUSTAINED ELEVATED LIVER ENZYMES WITHOUT A SPECIFIC LIVER DISEASE AFTER INITIAL NON-INVASIVE EVALUATION N patients
Cut-off abnormal liver enzymes
Liver biopsy results Pathology
Reference N (%)
81
ALT or AST > 1.5 ULN (2 x/ 6 months)
Non-alcoholic fatty liver disease Normal liver
73 (90.1) 8 (9.9)
Daniel et al.1999
36
AST or ALT or ALP > 1.5 ULN
Non-alcoholic fatty liver disease PSC/PBC Autoimmune hepatitis Non specific changes Normal liver Porfyria cutanea tarda
21(58.3) 5 (13.8) 3 (8.3) 3 (8.3) 3 (8.3) 1 (2.7)
Sorbi et al. 2000
354
ALT, GGT or ALP > 2 ULN
Non-alcoholic fatty liver disease Cryptogenic hepatitis Drug related damage Normal liver Alcohol related damage PBC/PSC Autoimmune hepatitis Granuloma Hemochromatosis Secondary biliary cirrhosis Amyloid Glycogen storage disease
235 (66) 32 (9) 27 (7.6) 21 (5.9) 10 (2.8) 9 (2.5) 7 (1.9) 6 (1.7) 3 (0.9) 2 (0.6) 1 (0.3) 1 (0.3)
Skelly et al. 2001
No fibrosis Bridging fibrosis Cirrhosis
261 (73.7) 30 (8.5) 21 (5.9)
NHANES III • Bevolkingsstudie (USA) van 15.676 personen > 17 jr • Prevalentie van gestoorde ALT: 7.9 % – 30%: alcohol, HCV, HBV en hemochromatose – Rest: associatie met obesitas en andere kenmerken van metabool syndroom (BMI, lendenomtrek, insuline resistentie en serum lipiden) → NAFLD ? Clark JM Am J Gastroenterol 2003
? vetlever (steatose) Steatohepatitis (NASH)
NAFLD NASH
Fibrose
Cirrose Hepatocellulair Carcinoma
Incidentie van NAFLD • Incidentie van vetlever – Gemiddeld 20 % – Autopsie 1 % op 20 jr. 39 % op 60 jr. – 20 % bij 126 levende leverdonoren • Incidentie van steatohepatitis – Magere personen: 3 % – Obese: 20 % (BMI>30) – Morbied obese: 50 % (BMI>35)
Definitie metabool syndroom • Abdominale obesitas (buikomtrek > 94 cm bij mannen en > 80 cm bij vrouwen) • Plus 2 van de volgende 4 elementen: – Triglyceriden (> 150 mg/dl) of onder R/ – Verlaagde HDL-cholesterol (< 40 mg/dl bij mannen en < 50 mg/dl bij vrouwen of onder R/) – AHT: > 130/85 mmHg of onder R/ – Nuchtere glycemie > 100 mg/dl
IDF, 2005
Normale waarden van lever-enzymes •
Normale waarden zijn gebaseerd op verdelingen van gezonde vrijwilligers
•
Bovenste grens van het normale (ULN) = mean + 2 SD → 2.5 % van de gezonde peronsen overschrijden deze ULN
•
Zijn gezonde vrijwilligers werkelijk vrij van leverlijden? – Italiaanse retrospectieve cohort studie* – Koreaanse studie: relatie tussen hoognormale serum ALT (35-40 IU/L) en sterfte door leverziekte, na aanpassing voor alcoholgebruik, obesitas, plasma glucose en serum lipiden**
* Prati D et al. Ann Intern Med 2002 ** Kim HC et al. BMJ 2004
Normal Aminotransferase Levels and Risk of Mortality from Liver Diseases
"Elevated“
"Normal“
ALT (IU/L)
No (men)
RR (95% CI)
< 20
37425
1.0 (0.7-1.4)
20-29
36589
2.9 (2.4-3.5)
30-39
11975
9.5 (7.9-11.5)
40-49
4068
19.2 (15.3-24.2)
50-99
3887
30.0 (25.0-36.1)
≥ 100
589
59.0 (43.4-80.1) Kim HC et al. BMJ 2004; 328:983
Fibrosis in patients with chronic hepatitis C: ‘normal’ vs. elevated aminotransferases Portal 26%
No fibrosis 23%
Bridging 6% Cirrhosis 6%
Mild 39%
‘Normal’ ALT
Bridging 16%
Cirrhosis 22%
Portal 24%
Mild 19%
No fibrosis 19%
Elevated ALT Shiffman et al. J Infect Dis 2000
Serum ALT According to Response Group A (24 weeks) Patients with an SVR Virological nonresponders
36
Serum ALT Activity (IU/L)
Group B (48 weeks)
32
36
Patients with an SVR Virological nonresponders
32
Virological relapsers
Virological relapsers
28
28
24
24
20
20
16
16
12
12
8
8
Treatment
4
Follow-up
Treatment
4
0
Follow-up
0 0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Study Week
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Study Week
The vertical arrows indicate the end of treatment Zeuzem S et al. Gastroenterology 2004;127:1724-1732
Besluit (1) • Abnormale lever-enzymes kunnen aanwezig zijn in de afwezigheid van symptomen en klinische tekenen van leverziekte • Een systematische benadering is noodzakelijk, inclusief aandacht voor niet-hepatische ziekten (occulte coeliakie) • Indien geen verklaring na een initiële evaluatie: – NAFLD is zeer waarschijnlijk de oorzaak – Risico’s en nut van een leverbiopsie moeten zorgvuldig afgewogen worden, aangezien dit zelden het beleid beïnvloedt
Besluit (2) • Normale waarden van leverenzymes zijn gebaseerd op referentie-populaties die patiënten met subklinische leverziekte bevatten • Verlaging van de ULN voor leverenzymes kan nuttig zijn in bepaalde bevolkingsgroepen (v.b. HCVgeïnfecteerde personen) • Alternatieven voor leverenzymes? – Ontwikkeling van niet-invasieve (serum/ beeldvorming) methoden voor de betrouwbare opsporing van de graad van leverfibrose – Screening programma’s voor hemochromatose en virale hepatitis
