mecanismos etiopatogenéticos, com destaque para o metabolismo intracelular de ácidos graxos, cascata inflamatória intra-hepática e modificações da flora intestinal. Tem-se demonstrado a potencialização de ação da adiponectina associada a outros agentes farmacológicos, incluindo o ezetimibe, orlistat ou sibutramina, com resultados eficazes na melhora de níveis bioquímicos e enzimáticos, bem como das alterações histológicas do fígado gorduroso em ratos. Similarmente, essa citocina e outras adipocitocinas parecem constituir um alvo promissor no tratamento da doença em humanos. Outra classe de fármacos, como as incretinas, até então de uso exclusivo na terapêutica antidiabética, mostrou-se útil na melhora da sensibilidade à insulina e na perda de peso corporal na DHGNA 303, 337
desenvolvimento de síndrome metabólica em receptores de transplante hepático pode chegar a ser duas vezes mais elevada do que na da população geral 339. Os fatores de maior risco pré-transplante incluem: imunossupressão, idade elevada, sexo masculino, história de tabagismo índice de massa corporal >30 kg/m2, diabetes, índice de massa corporal do doador e a etiologia da doença hepática subjacente que resultou no transplante 340.
10 HISTÓRIA NATURAL E PROGNÓSTICO
A história natural da DHGNA não está bem definida, com base em estudos longitudinais e prospectivos. De uma forma geral, progride lentamente ao longo de muitos anos ou décadas, mas o prognóstico é diferente nos diversos espectros da doença
133. Os pacientes com esteatose parecem ter um prognóstico mais favorável. Estudo de coorte realizado com 109 pacientes obesos mórbidos, acompanhados por quase 17 anos, encontrou incidência de cirrose em <1% da amostra 341. Durante o seguimento, um quarto dos pacientes morreram, mas a curva de sobrevivência da população em geral caiu dentro do intervalo de confiança de 95% da curva de sobrevida dos pacientes com esteatose leve.
Nesse estudo, o paciente que desenvolveu cirrose foi o único que morreu de causas relacionadas com o fígado. Por outro lado, pacientes com cirrose por consequência da esteato-hepatite têm um pior prognóstico,como demonstrado em três estudos, nos quais 9 a 26% dos pacientes morreram dentro de 4 a 10 anos de seguimento, com a maioria das causas de morte relacionadas com a fase final da doença hepática 342-344.
Powelle et al relataram estudo com 13 pacientes com EHNA que foram submetidos a biópsias hepáticas seriadas após acompanhamento de 1 a 9 anos. Em cinco pacientes, foram encontrados sinais de doença histológica progressiva, seis permaneceram inalterados e duas apresentaram melhora histológica 260. Fassio et al 345 descreveram um estudo no qual um terço desses pacientes apresentou progressão da fibrose na segunda biópsia após uma companhamento médio de 4,3 anos. Obesidade e IMC foram os únicos fatores associados à tal progressão, na qual pelo menos metade (45%) da sua população era de pacientes obesos (definida pelo IMC> 30 kg/m2 e caucasianos 345. Telie et al 257
acompanharam 12 pacientes com esteatose pura (sem esteato-hepatite ou fibrose) submetidos à biópsia de repetição após um intervalo de 7,6 a 16 anos. Nesta casuística, um paciente desenvolveu fibrose, e nenhum caso evoluiu para esteato-hepatite. HUI et al 343 estudaram 17 pacientes de origem asiática, que foram acompanhados por um período médio de 6,1 anos (3,8 a 8,0 anos), tendo sido submetidos a uma segunda biópsia hepática.
Nove pacientes (53%) apresentavam doença progressiva, com piora do escore de fibrose.
Nenhuma correlação estatisticamente significativa foi encontrada entre a variação dos escores histológicos e parâmetros metabólicos. Sete pacientes desenvolveram hipertensão ou diabetes mellitus durante o período de seguimento.
A história natural da DHGNA permanece por ser definida. Os pacientes com esteatose pura em biópsia hepática seguem um curso relativamente benigno, enquanto os pacientes com alterações histológicas necro-inflamatórias e / ou fibrose pode progredir para a fase final da doença hepática. Um passo inicial no tratamento é o controle das condições associadas, tais como obesidade, diabetes mellitus e hiperlipidemia. Pacientes com esteato-hepatite e/ ou fibrose na biópsia podem se beneficiar da terapia farmacológica. Já pacientes com cirrose descompensada podem ser candidatos a transplante hepático.
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