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Epatopatie autoimmuni

F. Sogari

Epatopatie autoimmuni : 1% dei ricoveri per epatopatia con A I H > PBC

PBCEtà adulta, prevalenza del sesso femminile

AIHSi manifesta in forma acuta, in particolare alla prima diagnosi

PSCPiù frequente nel sesso maschile, in associazione con altre patologie autoimmuni

Almasio, 2013 - modificata

8 – 9 %

6 – 8 %

Confronto tra i casi di PBC, AIH, PSC - 2012

Studio su 562 pazienti

Stroffolini T. 2013

PBC 41,6 %AIH 45,2 %PSC 7,3 %AIH/PBC 5,0 %AIH/PSC 0.9 %Pat . Aut. 37,4%

Rosina 2013

Epatopatie autoimmuni : sierologia

Cirrosi Biliare Primitiva (CBP)

Malattia epatica cronica autoimmune caratterizzata da colestasi intra-epatica progressiva, causata dalla distruzione dei dotti biliari interlobulari.

Interessa donne di mezza età ed è caratterizzata da positività di anticorpi antimitocondrio (AMA) nel 95% pts.

CBP: MANIFESTAZIONI CLINICHE

SPECIFICHE

Astenia Prurito Dolori addominali Ipertensione portale Osteoporosi Xantomi Malassorbimento Infezioni urinarie

ASSOCIATE

M. tiroide (45%) Sindrome sicca (70%) CREST (rara) Raynaud (25%) Artrite Reumatoide (rara) M. Celiaco (6%) IBD (rara)

CBP

PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2);

Characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells.

cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system.

The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ.

Role of Cholangiocytes in Primary Biliary CirrhosisAna Lleo, MD, PhD1 Luca Maroni, MD, PhD2 Shannon Glaser, PhD3,4,5 Gianfranco Alpini, Marco Marzioni, MD2Semin Liver Dis 2014;34:273–284.

The breach of tolerance

active disease involves a disruption in several layers of control

Environmental factors, including infection agents and xenobiotics, also play important roles in breach tolerance.

PBC

Each of these control mechanisms plays a role in preventing an immune response against self, but all of them act in concert to generate effective protection against autoimmunity

genetic susceptibility: human leukocyte antigens (HLA), nonhuman leukocyte antigens, antigen risk loci, epigenetics, and sexassociated factors.

Breach of Tolerance: Primary Biliary CirrhosisLifengWang,MD, PhD1 Fu-ShengWang,MD, PhD1 Christopher Chang,MD, PhD2 M. Eric Gershwin,MD3 - Semin Liver Dis 2014;34:297–317.

CBP:Innate and adaptive immunity

Innate immune cells

Immunosoppressive cells

immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex

PDC-E2

The PDC-E2 present in the apoptotic bodies would be recognized by circulating antimitochondrial autoantibodies (AMAs), and the immune complex would then stimulate the innate immune system in a subject with a susceptible genetic background.

Role of Cholangiocytes in Primary Biliary CirrhosisAna Lleo, MD, PhD1 Luca Maroni, MD, PhD2 Shannon Glaser, PhD3,4,5 Gianfranco Alpini, PhD3,4,5 Marco Marzioni, MD2Semin Liver Dis 2014;34:273–284.

PBC

Epidemiology of Primary Biliary Cirrhosis

Primary biliary cirrhosis is a rare disease that predominantly affects women, with a ratio of 10 females to 1 male.

Primary biliary cirrhosis largely affects middle-aged women (30 to 65 years of age) from all racial groups. The disease may also occur in young women or men.Primary biliary cirrhosis is infrequently diagnosed in patients less than 25 years of age. the youngest described case of PBC was of a 12-year-old girl.

The incidence of PBC in the United States is reported as 2.7 per 100,000 population per year, with a prevalence of 40.2 per 100,000.In the United Kingdom, a higher incidence is reported at 3.1 per 100,000 population per year and a prevalence of 25.1 per 100,000. In Iceland, similar overall incidence is reported at 2.0 to 2.5 cases per 100,000. Age adjusted prevalence per 100,000 persons is reported as 65.4 for women and 12.1 for men.

PBC diagnosi

Hepatology “A Clinical Textbook” edition 2015Mauss, Berg, Rockstroh, Sarrazin, Wedemeyer

Mohamad H. Imam, MBBS1 Keith D. Lindor, MD2 - Semin Liver Dis 2014;34:329–333.

Abnormal serum liver tests (elevation of serum alkaline phosphatase [AP] of liver origin for at least 6 months).

The presence of antimitochondrial antibodies (AMAs) or PBC-specific antinuclear antibodies (titer 1:40) in serum.

Diagnostic or compatible liver biopsy (showing the characteristic florid bile duct lesion). The presence of all three features is interpreted as “definite” PBC.

The presence of two as “probable” PBC.

The diagnosis of PBC is conventionally made using the combination of:

Natural history in patients with primary biliary cirrhosis.

Greater than 25% to 30% of patients with PBC will show a complete response to UDCA

Only one third of PBC patients may show no response to UDCA therapy.

The absence of UDCA response following 1 year of treatment has been linked to increased risk of HCC

Three major forms of PBC

1) the typical or classical form, represented by a slow, progressive loss of small bile ducts and parallel increase in liver fibrosis, leading to biliary cirrhosis over a period of 10 to 20 years

2) fluctuating or persistent presence of AIH features associated with early development of liver fibrosis and liver failure, seen in 10% to 20% of patients;

3) the so-called premature ductopenic variant seen in 5% to 10% of patients, represented by a very rapid onset of ductopenia and severe icteric cholestasis with progression to cirrhosis and liver failure in less than 5 years.

(1) Minimum to very slow progression over time, (2) relatively slow progression to cirrhosis or portal hypertension without the

development of persistent jaundice or hepatic failure (portal hypertension type progression),

(3) relatively rapid progression to jaundice and hepatic failure (jaundice-type progression)

Clinical significance of autoantibodies detected in primary biliary cirrhosis

Three types of primary biliary cirrhosis progression

Antigp210 antibody positivity is a risk factor for hepatic failure-type progression.Anticentromere antibody positivity is a risk factor for portal hypertension.

Clinical Significance of Autoantibodies in Primary Biliary Cirrhosis - Minoru Nakamura, MD, PhD1Semin Liver Dis 2014;34:334–340.

AIH

Forma grave

Presentazione clinica

M. Lenzi 2012

AIH

Tipo 1

Tipo 2

Ipertransaminasemia

Ittero

Ipergammaglobul.

Allungamento PT

AIHCriteri semplificati

diagnosi

istologia

Tipo 1: è la forma più comune di epatite autoimmune con positività agli anticorpi antinucleo (ANA) o antimuscolo liscio (ASMA). Si manifesta a qualsiasi età e in circa la metà dei pazienti si associa ad altre malattie autoimmuni, come colite ulcerosa, tiroiditi, artrite reumatoide.

Tipo 2: si manifesta con maggior frequenza nelle donne di giovane età con altre patologie su base autoimmune. È il tipo positivo per anticorpi microsomiali fegato-rene (LKM1)

Tipo 3:Positivi anti liver citosol tipo 1 (anti-SLA/LP).

AIH Trattamento

End point

End –poin (goal): normalizzazione degli indici di laboratorio (transaminasi – gamma globuline – IgG ).Normalizzazione dei reperti clinici.

Possibile ( 60%) relapse.

Mantenere la dose giornaliera di mantenimento sino alla sicura normalizzazione dei segni infiammatori

Anti-TNF-α antibodies – (Infliximab)There is some emerging evidence that anti-TNF antibodies are capable of inducing remission in AIH patients in whom standard or alternative therapeutic options have been exhausted (Efe 2010, Umekita 2011).


Terapie alternative

CSP: COLANGITE SCLEROSANTE PRIMITIVA

Malattia colestatica cronica del fegato ad eziologia sconosciuta caratterizzata da interessamento dei dotti biliari intra e/o extraepatici con lesioni infiammatorie fibro-obliterative.

•1-6 casi/100.000•M/F= 2:1•50-70% associazione con IBD•HLA B8;DR3 (60%; 56%)

PSC Varianti Biopsia Epatica

PSC/AIH overlapAIH 10% adulti con PSCAIH 25% giovanissimi

PSC dei piccoli dotti!0 % di tutte le PSC

IgG4 colangite.10 % delle PSCMaschi adulti (85%)Coinvolgimento pancreatico

Non necessaria in presenza di colangio RM patologica , PSC a dotti larghi

Necessaria in presenza di PSC dei piccoli dotti e overlap AIH

La fibrosi con fusione periduttale è diagnostica per le CS secondarie

AASLD guidelines 2010

PSC: Caratteristiche cliniche all’esordio

Antoniazzi S. et al. Monotematica AISF 2010

Sospetto di colestasi storia clinica

colangiti ricorrentiALP e gGT

prurito ittero

sintomi in pz con IBD

ANAAMASMA

p-ANCA

Colangio-RM

Diagnosi definitiva

ERCP

CSP

Ecografia : vie biliari non dilatate

PSC Diagnosi


PSC Terapia e follow up

Goal

Trattare la PSCMigliorare la QoL riducendo i sintomiPrevenire la progressionePrevenire il colangiocarcinomaPrevenire il Ca colon nelle PSC/IBD

Eseguire pancolonscopia con biopsie nelle diagnosi recentiTrattare l’IBD secondo le linee guidaNon esistono dati certi per l’uso dell’ UDCAEsistono dati certi contro l’uso di alte dosi di UDCAI Corticosteroidi sono raccomandati nell’ AIH/PSC e nella PSC associata IgG4

PBC - PSC e overlap : diagnostica e terapia

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