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
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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