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