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D. ALVARO, Univ. Sapienza, Rome, Italy.
APPROPRIATEZZA IN GASTROENTEROLOGIA
PEDIATRICA, Roma, 4 Marzo 2016.
EPATOPATIE VERE E FALSI MITI SUL FEGATO
Ripercorrere le Linee Guida
Malattie del Fegato
CAUSE DI MALATTIA EPATICA1. Agenti infettivi (virus, batteri, parassiti…)
2. Alcool, Farmaci, Tossici (xenobiotici)
3. Autoimmunità (AIH, PBC, PSC,overlap)
4. M. genetiche/dismetaboliche
Manifestazioni cliniche delle M. Epatiche1. Sintomi (ittero, dolore, febbre, prurito, d. gastrointestinali
astenia, m. dermatologiche)
2. Obiettività clinica (ittero, epato-/splenomegalia, m.
dermatologiche…….)
3. Alterazioni esami di laboratorio
4. Obesita’/sovrappeso/insulino resistenza (?????)
Malattie del Fegato: Alterazioni Biochimiche
2. E’ invece APPROPRIATO classificare gli indici biochimici in:
q Indici di necrosi : Transaminasi: GOT (AST) e GPT (ALT)
q Indici di sintesi epatica: (riduzione in funzione della massa
epatica residua): Albuminemia, Colinesterasi, Attività
protrombinica, Fibrinogeno, Colesterolo, pseudo-colinesterasi
q Indici di colestasi : Bilirubina diretta, Fosfatasi Alcalina,
Gammaglutamiltranspeptidasi (gamma-GT), Sali Biliari
1. L’espressione “indici di funzionalità
epatica” è INAPPROPRIATA !
APPROPRIATO INQUADRAMENTO
DELLE IPERTRANSAMINASEMIE
1. Errore di laboratorio ?
(improbabile se AST+ALT o + altri enzimi epatici)
2. Di origine epatica ? (certo se > 10 volte i v.n., AST+ALT o + altri enzimi epatici ecc.)
3. Entità ?
4. Durata ? ( <6 mesi = acuta; >6 mesi= cronica )
5. Solo necrosi o necrosi+colestasi ?
6. Solo necrosi o + ridotta sintesi epatica e/o
iperbilirubinemi (ALF, m. cronica avanzata…)
• Ipertransaminasemia lieve: < 1.5/2 x ULN
• Ipertransaminasemia moderata: tra 2-10 x ULN
• Ipertransaminasemia severa: >10 x ULN
HBV, HCV, HEV, HGV,
EBV, HHV6, CMV,….
Escludere Alcool e farmaci
Epatite acuta o riacutizzata
Ipetransaminasemia severa: algoritmi per la diagnosi di malattia
epatica in pediatria.
Epatite cronica AUTOIMMUNE
PREVALENZA ADULTI = 1-15 x 100.000 (stimata)
PREVALENZA BAMBINI ?????
About 25% of patients with AIH are asymptomatic at diagnosis
About 40% of cases AIH presents as “acute hepatitis”
Up to 50% of patients may be clinically jaundiced or report previous episodes
About 30% of patients have cirrhosis at presentation
2011
2010
2011
2010
But…..
diagnostic (N=3) and management guidelines (N. 9) are based
on conflicting evidence, divergent opinions, case studies and
uncontrolled observations …..
The AASLD, BSG and EASL guidelines recognize that the
IAIHG score is useful……despite the lack of prospective
validation as diagnostic instruments !
AIH: simplified “scoring system”
≥ 6 points: probable AIH
≥ 7 points: definite AIH
BSG guidelines, Gut 2011
IgG normal and ANA negative in approx. 30% of AIH patients !!!
Diagnosis of AIH: high specificity !
1. High ANA-H titer (> 1:320)
2. High level of serum IgG !
3. HISTOLOGY:
*Lymphoplasmacytic portal, interface hepatitis,
*piecemeal necrosis,
*severe lobular necrosis and inflammation,
*multinucleated hepatocytes,
*broad areas of parenchymal collapse ! !
1. Prompt and timely diagnosis is crucial as untreated
AIH has a high mortality rate !
2. ….about half of children at diagnosis already
advanced disease with the presence of cirrhosis…..
irrespective of the presence of symptoms !
3. All children with a diagnosis of AIH should undergo
(MR-) cholangiography to exclude autoimmune
sclerosing cholangitis (ASC, II-2)
+ CPRM
Pediatric PSC/AIH overlap (or ASC).
•AIH more frequent in PSC of childhood and
adolescents than in adults !
•PSC should be considered in all children with AIH.
•PSC ….toward a hepatitic presentation instead of the
cholestatic profile seen in adults !?.
•Alkaline phosphatase is frequently normal and
therefore especially in the presence of
IBD…………consider PSC/AIH overlap (ASC) !
Ipetransaminasemia lieve asintomatica:
algoritmi per la diagnosi di malattia epatica in pediatria.
NAFLD in pediatria: linee guida !
JPGN Volume 54, Number 5, May 2012
Ipetransaminasemia lieve asintomatica:
algoritmi per la diagnosi di malattia epatica in pediatria.
Tests eziologici: Virus epatotropi, M.
Celiaco, AIH, Wilson, α1-AT, fibrosi
cistica, m. genetico/metaboliche se
sospetto clinico, tiroide, surrene se
sospetto clinico.
Escludere alcol e/o farmaci !
Abdominal US and LTs should be the first diagnostic step in
suspected NAFLD children, followed by exclusion of other
liver diseases !!!!!!!!!!
Children with abnormal liver enzyme levels or ultrasonographic
results should undergo further investigation to rule out other causes
of liver disease, such as viral hepatitis, autoimmune hepatitis, and
metabolic liver disease !.
JAMA Pediatr. 2015
*Retrospective study in 120 obese, asymptomatic children
ALT ≥40 U/L and additional diagnostic testing.
Results: No patients were found to have Wilson’s, hepatitis A, hepatitis
B, hepatitis C, cytomegalovirus, alpha-1 antitrypsin deficiency,
autoimmune hepatitis, celiac disease or Epstein–Barr virus.
•1 pts identified with definite disease other than NAFLD,
which was muscular dystrophy.
• PPV positive predictive value of a screening test was 5%
Conclusion: Extensive testing in asymptomatic,noncholestatic,
obese children with an elevated ALT may be of limited
diagnostic value and false-positive tests are likely.
86 studies included …… 8,515,431 pts. from 22 countries.
- Global prevalence of NAFLD = 25.24%;
- Comorbidities associated with NAFLD:
obesity (51.34% ), T2D (22.51% ), hyperlipidemia (69.16%),
hypertension (39.34% ) and metabolics. (42.5%).
- Fibrosis progression proportion = 40.76%
- Liver-specific mortality among NAFLD and NASH were
0.77 and 11.77/1000 person-years person-years
- Overal mortality 15.44/1000 and 25.56/1000 person-years .
Conclusions: As the global epidemic of obesity fuels metabolic
conditions, the clinical and economic burden of NAFLD will
become enormous.
Nel mondo occidentale, le NAFLD rappresentano la
principale patologia epatica cronica pediatrica
Prevalenza:
3-10% (popolazione generale pediatrica)
70% (popolazione pediatrica sovrappeso o obesa)
Hepatology in press
NAFLD: underdiagnosis and
underscreenig
Undetected hepatomegaly in obese children by primary care
physicians: a pitfall in the diagnosis of pediatric nonalcoholic
fatty liver disease. Fishbein M. et al. Clin Pediatr (Phila).
2005 Mar;44(2):135-41.
A survey among American primary pediatric care ….
in obese children with NAFLD, clinicians detected
hepatomegaly in only 1.4% and requested LTs in 12.5% of
encounters, …likelihood of a delayed or omitted diagnosis.
Australian survey: only 9% of GPs used BMI charts to
correctly diagnose childhood obesity and only 30% assessed for
fatty liver in overweight/obese children !
IPERTRANSAMINASEMIA CRONICA
ASINTOMATICA !
A challenge for physicians !
Hepatology 2008;47(3):880-87
1. For both AST and ALT, abnormal results were
associated with an increased risk of death !
2. Measurement of aminotransferases may allow early
detection and treatment of conditions that could
lead to significant morbidity and mortality in the
future……. !
2008, Volume 371, Number 9628,
VENTO S, and NOBILI V
- N. 4 children with baseline normal fasting glucose developed T2D
-N. 2 children died and two …liver transplantation for
decompensated cirrhosis.
-The observed survival free of liver transplantation was
significantly shorter in the NAFLD cohort as compared to the
expected survival in the general US population !
Malattie del Fegato
CAUSE DI MALATTIA EPATICA1. Agenti infettivi (virus, batteri, parassiti…)
2. Alcool, Farmaci, Tossici (xenobiotici)
3. Autoimmunità (AIH, PBC, PSC,overlap)
4. M. genetiche/dismetaboliche
Manifestazioni cliniche delle M. Epatiche1. Sintomi (ittero, dolore, febbre, prurito, d. gastrointestinali
astenia, m. dermatologiche)
2. Obiettività clinica (ittero, epato-/splenomegalia, m.
dermatologiche…….)
3. Alterazioni esami di laboratorio
4. Obesita’/sovrappeso/insulino resistenza (?????)
-The sensitivity of ALT remains low !
-ALT >35 IU/L sensitivity of 48% and specificity of 94% for
detecting steatosis >5% as measured by (MRI) (Burgert TS );
-In American laboratories conventional ALT cutoff values are set
too high for pediatric chronic liver disease, including NAFLD
(Safety study);
-95th percentile levels for ALT in healthy weight, metabolically
normal, liver disease–free patients were 25.8 U/L (boys) and 22.1
U/L (girls) (NHANES);
-The degree of ALT elevation does not correlate with the presence
or severity of histological findings of NAFLD; a number of
children with normal ALT or minimal serum ALT elevation may
have advanced fibrosis on liver biopsy;
-High serum levels of GGT represent a risk factor for advanced
fibrosis in NAFLD.
-The natural history of the disease is not yet well determined in
children ! (ALT fluctuate and may even normalize).
NAFLD: diagnosis in children
To screen or not to screen ?
Recommendations
1. Due to a paucity of evidence, a formal recommendation
cannot be made with regards to screening for NAFLD !
(Strength –1,Quality – B).
2. Children with fatty liver.. very young or not overweight…
should be tested for monogenic causes of chronic liver disease (FA oxidation lysosomal storage diseases and peroxisomal disorders, in addition to causes
for adults. (Strength 2, Quality – C)
2. Low titers of autoantibodies often present in children with
NAFLD, but higher titers, in association with higher serum
aminotransferases and high globulin should prompt a liver
biopsy (AIH ? ; Strength – 2, Quality – B)
The American Academy of Pediatrics recommends:
ALT and AST measurement to screen for NAFLD in overweight
children (BMI 85-94th percentile) with risk factors in the history
or physical examination in obese children (BMI, 95th percentile)
even in the absence of risk factors !.
It is our practice to screen all obese children (> 3 yrs) with AST, ALT
and ultrasonography, especially if .. family history of NAFLD,
central obesity, evidence of IR (…acanthosis nigricans) according
ESPGHAN !.
JAMA Pediatr. 2015
When Liver Biopsy ?
Both guidelines similar indications for LB:
-to rule out other treatable diseases !
-in cases of clinically suspected advanced liver disease !
-before pharmacological/surgical treatment !
-as part of a structured intervention protocol or clinical
research trial !
The future ?????
-non invasive methods to assess the severity of liver damage
(fibrosis, molecular imaging ?)
-non invasive methods for screening and follow-up
(who progress ? …and how rapid is the progression ?)
q PNPLA3 (Hepatology 2010)
q LPIN – 1 (JPGN 2012)
q KLF – 6 (Gastroenterology
2008)
q SOD – 2 (J of Hepatology 2012
FLTFatty Liver
Test
MARZO 2015
Only the American guideline discuss treatment of pediatric
NAFLD.
1. Intensive lifestyle modification is recommended as the first-
line treatment in pediatric NAFLD !
2. Metformin should be avoided !
3. Vitamin E offers histological benefits to children with NASH,
but confirmatory studies are needed before its use can be
recommended in clinical practice !
NAFLD: the treatment
100
80
60
40
20
0
lost of
follow-up
SDS BMI
reduction
<0.5
SDS BMI
reduction
>0.5
Reinehr T, et al Obesity 2009
time (months)
6 12 24 6 12 24 6 12 24
129 treatment centers
After 24 months, 90% lost and only
5%reduced BMI