P1. Liver damage mechanisms/evolution into advanced cirrhosis and transplant

Coordinator: Rafael Bañares

Clinical and scientific relevance of the areas covered in the programme

Clinical, social and economic significance of advanced liver disease: the need for a scientific approach.

Chronic liver diseases are a major cause of morbidity-mortality in Spain which tend to affect individuals from 40 to 60 years of age, the most productive years of life, during which these constitute the fourth cause of death. The natural history of chronic liver disease until this reaches the stage of cirrhosis and decompensated cirrhosis is a lengthy process. The cirrhosis patient’s death takes place when complications from portal hypertension and/or cancer arise. All of this involves a vast social, clinical and economic burden which easily justifies the social relevance of the programme.

It is highly noteworthy that cirrhosis may occur through very different mechanisms and types of disease. Most of the cases in our setting stem from an excessive consumption of alcohol or the existence of chronic viral hepatitis. Liver disease through fatty deposits nevertheless clearly comes forward as a frequent cause of advanced liver disease. Disorders of hepatocellular metabolism may be involved in the physiopathology of both alcoholic (ASH) and non-alcoholic (NASH), steatohepatitis, two of the most common liver diseases worldwide. Although the aetiopathology of ASH and NASH is different, alcohol consumption being the differentiating element in the former, the histological characteristics of both are almost identical. Both display the presence of (macrovesicular>microvesicular) steatosis, lobulillar inflammation with the presence of polymorphonuclear leukocytes and mononuclear cells and hepatocellular death through apoptosis and necrosis. Although fibrosis, generally in zone 3, and the presence of Mallory bodies, are not strictly necessary for the diagnosis of steatohepatitis, their presence reflects the progress of the disease to more advanced stages. In spite of the alarming incidence of steatohepatitis in the population as a whole, the molecular mechanisms involved in its appearance and in the progression from steatosis to steatohepatitis are not however completely known. This has to a large extent limited the availability and development of more effective therapeutic treatments than the currently available ones. Greater knowledge of these processes on both molecular and cell level could therefore facilitate on one hand a better diagnosis of the disease by minimally invasive approaches and on the other the recommendation of  more effective treatments.

Other diseases with different pathogenic mechanisms such as cholestatic and autoimmune diseases converge in a fairly common final expression like cirrhosis. Cholestasis comes about as a result of disorders in the bile flow and entails the retention of substances which are normally eliminated through bile. This may be a result of intrahepatic anomalies: a) in uptake on the level of the sinusoidal pole of the hepatocyte; b) in the synthesis and metabolisation of those substances on the cell level; c) in their elimination in the canalicular pole; d) on the level of the intrahepatic bile ducts which may undergo damage and destruction. Apart from these intrahepatic causes, any mechanical obstruction of the major extrahepatic biliary channels may also give rise to a clinical pattern of cholestasis.

In the paediatric field we should stress a set of diseases connected with disorders on the biliary transporter level. Apart from this chronic cholestatic diseases of the adult tend to be characterised by an inflammation on the level of the small and medium-sized intrahepatic biliary ducts, of unknown cause and frequently in the context of autoimmunity. In Spain these diseases are relatively scarce and basically include primary biliary cholangiopathy (PBC), primary sclerosing cholangitis and the cholestatic forms of autoimmune hepatitis. One should also consider the later forms of genetically-based diseases due to mutations on the biliary transporter level, such as progressive familial cholestasis (Byler disease), in its different variants, including the benign recurrent form, as well as Alagille syndrome, cholestasis associated with hormonal change – for example, intrahepatic cholestasis of pregnancy–, and the iatrogenic situations induced by treatments with steroid hormone preparations, as well as cholestasis induced by hepatotoxins.

One should lastly consider the iatrogenesis of hepatotoxicity through drugs. Its real incidence is difficult to determine accurately due to its poor detection and diagnosis, but it represents the second most frequent cause of acute liver failure after the ones due to viral hepatitis. There are multiple complex mechanisms behind hepatotoxicity through drugs, those of idiosyncratic nature being the most serious and at the same time the least known, also the ones most difficult to predict with non-human models.

Finally, the natural history of advanced liver disease tends to develop manifestations associated with the presence of gradual seriousness of portal hypertension and hepatocellular  failure which can in the final stages only be treated by a liver transplant. At the present time around 15,000 liver transplants a year are carried out worldwide, with satisfactory results in terms of the survival of the patients receiving the transplant: around 90% a year from the transplant, 75% at 5 years and 65% after 10 years. Liver transplants nevertheless continue to involve a number of major clinical problems.

It can easily be deduced from all the above that the basis of the programme’s research activity must be eminently translational, tackling both the study of the mechanisms of the disease and the associated clinical problems.

In short, programme 1 covers a wide range of groups whose research work is clearly complementary and generates potential synergies, and converges in the attempt to produce significant and translational progress in knowledge in the sphere of advanced liver disease. The programme has in general terms an extensive approach to the problem based on the dual view of the laboratory and clinical research, which enables conveying the many questions brought up by these diseases in both directions (from the patient’s bedside to the laboratory and vice versa).

General description of the research work done

A general description of the research work done in the programme should focus on the following aspects:

I)             Portal hypertension and mechanisms producing transition into cirrhosis

a)    Understanding and modifying the inflammation and fibrogenesis programmes which lead to cirrhosis, the pathogeny of distortion of the hepatic vasculature responsible for portal hypertension and the complications stemming from this.

Finding out more about the molecular and cell mechanisms underlying inflammation and fibrogenesis processes is a key matter for designing and developing therapies for slowing down the transition to cirrhosis and proving effective for patients with liver diseases. Although this approach is not incompatible with treatments specifically aimed at the agents responsible for liver diseases, it is also true that most patients can benefit from therapies reducing cell damage and hepatic fibrosis, which tend to have already started when the sick require medical care. These new forms of treatment must be good at mitigating the damage of a wide range of liver diseases since they will affect common lesion mechanisms. Their development will require in-depth knowledge of cascades signalling and recruiting inflammatory cells, of the molecules and cells performing the inflammatory response, of the routes for activation and response of the different liver cells, of the intercellular communication channels and of the mechanisms of hepatocyte death and hepatic repair and fibrogenesis. The aim of clinical research must be to assess drugs preventing hepatocyte death, modulating the inflammatory response, inhibiting fibrosis and promoting orderly liver repair and regeneration. One key aspect not known about is the influence of genetics on the expression of liver disease, on fibrogenesis and on the response to treatment.

b)    Portal hypertension as a key fact in the natural history of cirrhosis

Portal hypertension is essential in the evolution of advanced liver disease; its appearance is a result of the increase of intrahepatic vascular resistance to the portal blood flow which causes the destruction of hepatic architecture by fibrosis and formation of nodules. Different studies have shown that the increase in intrahepatic vascular resistance is also due to an increase in the hepatic vascular tone through the contraction of contractile cell elements and thrombosis phenomena secondary to the activation of endothelial cells of the hepatic sinusoids. Malfunction and endothelial activation are a result of both sinusoidal fibrosis and the recruitment of inflammatory cells, the release of proinflammatory cytokines and angiogenic and proliferative factors. The basic defect responsible for this endothelial malfunction would seem to be damage in the production of nitric oxide by the cells in the sinusoidal endothelium. It has also recently been shown that other molecules are involved, whose excess or deficiency could compensate or exacerbate the shortage in nitric oxide production and whose identification constitutes a fundamental objective of research in this area. If these facts are borne in mind, portal hypertension therapy will in the future include the use of drugs that slow up or reverse fibrosis and/or attenuate the increase of intrahepatic vascular tone.

c)    The complications of cirrhosis are in direct relation with the presence and degree of portal hypertension.

In fact, these only occur when portal pressure, estimated by measuring the gradient of hepatic venous pressure, exceeds a specific threshold value (10 mm Hg). In the natural history of cirrhosis, the increase of portal pressure over this value is one of the most powerful known risk factors of complications and death. Measuring portal pressure is useful for identifying cirrhosis patients at risk of complications and who need urgent treatment; it also establishes what the objective of the treatment has to be. The interest in this point focuses on developing non-invasive methods of measuring portal pressure, identifying the patients whose portal pressure has increased (or reduced) in relation with the threshold value.

d)    Portal hypertension complications cause the death of most patients with cirrhosis.

Portal hypertension is a result of the progress of cirrhosis and its complications are haemorrhage through oesophagogastric varices, ascites and hepatorenal syndrome, hepatic encephalopathy, bacterial infections and the hepatopulmonary syndrome. Portal hypertension is associated with a state of circulatory dysfunction with arterial vasodilation, predominant in the splanchnic area, and which is responsible for the worsening of the portal hypertension itself, for renal hydrosaline retention and kidney failure. Portal hypertension favours bacterial translocation, which along with the damage of the defence mechanisms is the cause of the cirrhosis patient’s greater vulnerability to bacterial infection. In spite of the fact that knowledge of the physiopathology of these complications, in particular the relevance of splanchnic arterial vasodilation, has over the last decades enabled the design of therapeutic strategies effective in reducing associated mortality, the complications of portal hypertension continue to be a predominant cause of death in the cirrhosis patient. This is the case because: i) the individual factors predicting response to known treatments are unknown; ii) there are no methods for estimating individual vulnerability to bacterial infection, which is often associated with these complications and iii) the complications worsen the patients’ liver failure. In this context, a key research area is the development of effective systems for artificial liver support which keep the patient alive while the factor responsible for acute deterioration is solved.

II)            Cholestasis and metabolic disorders

a)    Knowledge of the mechanisms associated with complications proper to cholestasis

The mechanisms involved in the appearance of osteoporosis in chronic cholestasis, a frequent cause of incapacitating morbidity both before and after the transplant, are not known. Similarly, pruritus is another relatively frequent problem in patients with cholestasis, and can become incapacitating and grounds for liver transplant. The pathogeny of pruritus in cholestasis is also unknown. This is what makes the evaluation of the mechanisms associated with these specific complications of chronic cholestasis essential.

b)    Mechanisms for progression of liver disease through fatty deposits and their incorporation to clinical diagnosis

The molecular mechanisms involved in the appearance and progress of the different stages of the disease and its influence in natural history are not fully known, which has to a large extent limited the availability and development of more effective therapeutic treatments than the ones currently available. Better knowledge of these processes on both the molecular and cell level could thus facilitate a more accurate non-invasive approach able to assist in clear phenotypic and non-invasive identification of the patients with this disease with clear prognostic and treatment connotations.

III)           The liver transplant:

a)    Towards optimum immunosuppression:

Immunosuppression is a critical element in the effectiveness of the transplant, in spite of which there are some important questions to be answered: i) its optimisation to adapt this to each patient’s needs in order to reduce the risk of rejection and toxicity; ii) the possibility of the full withdrawal of immunosuppression in patients tolerant with their graft, which could represent a considerable proportion of transplanted patients after several years have elapsed from the transplant; iii) the proper detection and handling of the complications of immunosuppressors; iv) the influence of immunosuppression in the recurrence of hepatocarcinoma, and v) non-invasive markers of rejection. It is not surprising that one of the objectives of the programme should be the identification and clinical validation of a panel of biomarkers predicting the risk of rejection, clinical evolution of the transplant and the personal response to immunosuppressor treatment. Implementation in the clinic of these biomarkers would enable layering the patients by risk of rejection and improving the choice of the immunosuppressor treatment as well as the identification of patients who are candidates for minimisation without this entailing a risk of reactivation of the immune system effecting response (risk of rejection in the maintenance stage).

b)    Relapse of the basic illness

This fact is relevant in many liver diseases, especially hepatitis C; the studies carried out have enabled defining the progress of hepatic fibrosis in transplant patients. After the marketing of powerful new viral agents, liver lesion mechanisms have lost their interest in these patients. The study of the reversibility of fibrosis and associated mechanisms is nevertheless of interest in both transplanted patients (it would be important to treat before irreversible lesions are caused) and in patients on the waiting list for transplants (if the lesion is reversible, the transplant is not necessary).

c)    Complications of immunosuppressive treatment and extrahepatic disorders after the transplant

Diabetes mellitus after a liver transplant is associated with worse results - a greater rate of infections, rejection and mortality having been described. Other complications such as the appearance of neoplasia or the increase of cardiovascular risk are important limiting factors for the survival of patients with liver transplants.

d)     Disparity between the number of organ donors and the number of patients on the waiting list for liver transplants.

This matter of great social and ethical importance generates research work through the implementation and evaluation of a number of measures intended to palliate the problem by investigating strategies to enable increasing the number of liver grafts suitable for transplant and on the other through the implementation of improvements in the management of the waiting list for transplants.

Program Group Members

Main ResearcherConsortium InstitutionRegionsDetails
Agustín Albillos Universidad de Alcalá Madrid View Group
Raúl Andrade Fundación Pública Andaluza para la Investigacion de Málaga en Biomedicina y Salud (FIMABIS) Andalucía View Group
Rafael Bañares (Coordinador de Programa) Servicio Madrileño de Salud Madrid View Group
Marina Berenguer Fundación para la Investigación del Hospital la Fe Valencia View Group
Jaume Bosch Hospital Clínico y Provincial de Barcelona Cataluña View Group
Llorenç Caballeria (grupo vinculado) Instituto de investigación en atención primaria Jordi Gol Cataluña View Group
José V. Castell Fundación para la Investigación del Hospital la Fe Valencia View Group
José Carlos Fernández-Checa Agencia Estatal Consejo Superior De Investigaciones Científicas Cataluña View Group
Rubén Francés Fundación para la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) Valencia View Group
Carmelo García-Monzón (grupo vinculado) Servicio Madrileño de Salud Madrid View Group
Joan Genescà Fundación Hospital Universitario Vall D´hebron - Institut De Recerca (VHIR) Cataluña View Group
Pere Ginés Hospital Clínico y Provincial de Barcelona Barcelona View Group
Javier González-Gallego Universidad de León Cataluña View Group
Carlos Guarner Instituto de Investigacion del Hospital de la Santa Cruz y San Pablo Cataluña View Group
Manuel de la Mata Fundación para la Investigación Biomédica de Córdoba (FIBICO) Andalucía View Group
José Mª Mato CIC Biogune Páis Vasco View Group
Alfredo Minguela (grupo vinculado) Fundación para la Formacion e Investigacion Sanitarias de la Región de Murcia (FFIS) Murcia View Group
Miquel Navasa Hospital Clínico y Provincial de Barcelona Cataluña View Group
Albert Parés Hospital Clínico y Provincial de Barcelona Cataluña View Group
Ramón Planas Fundación Instituto de Investigacion Germans Trias i Pujol Cataluña View Group