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Keywords:

  • alcoholic liver disease;
  • fatty liver disease;
  • genes;
  • NASH;
  • polymorphisms

Abstract

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Abstract: While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-α, transforming growth factor-β, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.

The risk factors for alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are well established. Patients with ALD consume alcohol excessively while patients with NAFLD are usually obese and insulin resistant and have other conditions associated with the metabolic syndrome. It is clear, however, that while the majority of patients with these risk factors develop hepatic steatosis, only a minority develop more advanced disease – steatohepatitis, fibrosis, and cirrhosis. Biopsy studies in unselected heavy drinkers suggest that only 20–30% of heavy drinkers will develop steatohepatitis and less than 10% cirrhosis (1), while postmortem and liver biopsy studies in obese individuals have demonstrated that only around 10–20% of even morbidly obese patients develop non-alcoholic steatohepatitis (NASH) (2, 3). These observations have led to the obvious question – what factors determine whether a heavy drinker develops advanced ALD and a patient with the metabolic syndrome advanced NAFLD?

Pathogenesis

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Not surprisingly, given their histological similarity, an emerging body of evidence suggests that the pathological mechanisms of advanced ALD and NASH are very similar and involve cytokine and oxidative stress-mediated injury (4–6), with accumulating evidence supporting an immunological component to the progression of ALD (7). In ALD the main stimulus for cytokine release from Kupffer cells in the liver is portal endotoxemia, arising as a result of increased gut permeability due to ethanol and its metabolism to acetaldehyde by the gut mucosa and flora. In NASH, cytokines, notably TNF-α, may also be produced by Kupffer cells in response to gut-derived endotoxin, however, TNF-α may also be produced by hepatocytes in response to an increased supply of free fatty acids (FFA), or by adipose tissue macrophages (reviewed in (6)). In ALD, oxidative stress arises due to ethanol metabolism, Kupffer cell activation and the effect of TNF-α on hepatocyte mitochondria, while in NAFLD it arises principally via the increased oxidation of FFA by mitochondria, peroxisomes, and microsomes. Recent evidence has suggested that low levels of adiponectin, an important antisteatotic and antiinflammatory cytokine produced by adipocytes, may also contribute to steatosis and inflammation in ALD and NAFLD (8, 9). Fibrosis in ALD and NAFLD is thought to arise as part of the normal healing response to inflammation and injury, although recent evidence has suggested that factors related to obesity and insulin resistance per se may be directly fibrogenic (6). These include insulin and glucose [via stimulation of the release of connective tissue growth factor (CTGF) from hepatic stellate cells] and other adipokines synthesised and released by adipocytes, including angiotensinogen, norepinephrine, and leptin. Given these mechanisms, genetic and environmental risk factors for advanced ALD and NAFLD seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis (Fig. 1).

image

Figure 1.  Environmental and genetic factors determining the risk of different stages of nonalcoholic fatty liver disease. SIBO, small intestinal bacterial overgrowth.

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Environmental factors determining disease risk (Table 1)

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References
Table 1.   Non-genetic factors influencing susceptibility to fatty liver diseases
Alcoholic liver diseaseNon-alcoholic liver disease
  • *

    These factors have a genetic component.

Dose and pattern of alcohol intakeAlcohol  Low intake: protective
Dietary factors  Low carbohydrate  High fatDietary factors  Low antioxidant vitamins  High saturated fat
Obesity*  Food intake  ExerciseObesity*  Food intake  Exercise
Hyperglycaemia*Type 2 diabetes mellitus*
SmokingSmall bowel intestinal overgrowth Sleep apnoea syndrome

ALD

The most obvious explanation for susceptibility to ALD is that it depends on the dose and pattern of alcohol consumed. The effect of dose has been best demonstrated by a study that surveyed the dietary and alcohol habits of the entire population of two towns in Northern Italy (1). The study showed a linear correlation between the number of alcohol units consumed per day and the risk of liver disease and cirrhosis. However, only 6% of individuals drinking more than 12 drinks per day had cirrhosis, and several other independent studies have found no difference in cumulative lifetime alcohol intake between drinkers with cirrhosis, fibrosis, and fatty liver alone (10). The Italian study also reported that the risk of ALD depends on the pattern of intake independently of the absolute levels of consumption. Disease risk appears to be increased by drinking alcohol away from meal times, drinking several rather than a single type of alcoholic beverage, and drinking every day versus weekend drinking. Most recently a study from Denmark has shown that wine drinkers may have a lower risk of ALD than consumers of other beverages (11). Whether this is due to an effect of the wine per se or to confounding factors is, however, currently unknown. The environmental factor that has received most attention as a potential determinant of ALD risk is diet, although compared with animal models, data from humans are relatively sparse. One case–control study from France has reported that the risk of cirrhosis is increased by diets high in fat and alcohol and low in carbohydrate (12). A more obvious role for diet in ALD risk has been suggested by two studies showing that obesity and associated hyperglycemia increase the incidence of all stages of ALD in heavy drinkers (13, 14). While these studies have provided evidence that dose, pattern and type of alcohol consumption and dietary (and presumably exercise-related) factors play a role in determining ALD risk, they have also demonstrated that other factors are likely to be equally if not more important.

NAFLD

With respect to environmental factors influencing the risk of NAFLD, diet, exercise, and possibly small bowel bacterial overgrowth are obvious candidates. A recent study has shown a higher intake of saturated fat and a lower intake of the antioxidant vitamins C and E in obese patients with NASH compared with obese controls with no evidence of liver disease (15). In experimental models of obesity, polyunsaturated fatty acids reduce steatosis and improve insulin sensitivity by downregulation of sterol regulatory element-binding protein-1 and activation of peroxisome proliferator-activated receptor (PPAR)α (16), while the effect of antioxidants is compatible with the putative role of oxidative stress in the pathogenesis of NASH. Evidence supporting a role for bacterial overgrowth in the pathogenesis of ‘primary’ rather than postintestinal bypass surgery NASH comes largely from a recent study that reported a higher prevalence of small intestinal bacterial overgrowth in patients with NASH compared with healthy controls (17).

Evidence for genetic factors determining disease risk

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Evidence for genetic susceptibility to ALD comes principally from a twin study showing that the concordance rate for alcoholic cirrhosis was three times higher in monozygotic than in dizygotic twin pairs (18). This difference in concordance rates was not entirely explained by the difference in concordance rates for alcoholism per se. Further indirect evidence of a genetic component to disease risk comes from the observation that the death rate from ALD is subject to wide interethnic variation that is not entirely explained by variations in the prevalence of alcohol abuse (19, 20). Hispanics appear to be at particularly high risk for example. A role for genetic factors in NAFLD is suggested by two recent reports of family clustering. Struben et al. (21) reported the co-existence of NASH and/or cryptogenic cirrhosis in seven of eight kindreds studied, while Willner et al. (22) found that 18% of 90 patients with NASH had an affected first degree relative. Clearly, this clustering could simply be a reflection of the well established heritability of the risk factors for NAFLD – obesity and insulin resistance, however, as with ALD, two studies examining ethnic differences in the prevalence of NAFLD and NAFLD-related ‘cryptogenic’ cirrhosis strongly suggest that susceptibility to NAFLD rather than to its risk factors may have genetic component (23, 24). In the most recent study from Dallas, Texas, the prevalence of cryptogenic cirrhosis in Hispanic and African-Americans was threefold higher and fourfold lower, respectively, compared with European-American patients despite a similar prevalence of type 2 diabetes mellitus (23).

Difficulties in performing family linkage studies in ALD and NAFLD have resulted in almost all of the relevant ‘genetic’ information thus far coming from classical case–control, candidate gene, allele association studies. Accordingly these studies are subject to all the common pitfalls of this type of study design and must be interpreted with caution (25). Many initial reports of positive associations are likely to be subject to type I errors (chance findings), while negative reports may be subject to type II errors (false negatives) attributed to small underpowered studies.

Gender and risk of ALD

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

The most obvious ‘genetic’ factor determining ALD risk is female gender. It has long been appreciated that women develop ALD at a lower intake of alcohol than men. The traditional explanation has been that women develop higher blood alcohol concentrations per unit of alcohol consumed due to their lower volume of distribution for alcohol. This, in turn, is attributed to their lower body mass index and to fat constituting a higher percentage of their body mass than in men. More recent evidence has, however, suggested an explanation based on disease mechanisms. Thurman and colleagues have demonstrated in the rat model that oestrogen increases gut permeability to endotoxin and accordingly upregulates endotoxin receptors on Kupffer cells leading to an increased production of TNF-α in response to endotoxin (26). These exciting data suggest several new directions for research into human gender-specific susceptibility to ALD.

Genes influencing the severity of steatosis

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Recognition of the role played by steatosis in the pathogenesis of progressive liver disease (27) suggests that factors determining its severity may play a role in determining the risk of advanced ALD and NAFLD. Clearly genetic and environmental factors determining the degree of obesity would fall into this category, as would functional polymorphisms of genes encoding enzymes involved in hepatic lipid metabolism. Polymorphisms in genes involved in the synthesis, storage, and export of hepatic triglyceride will clearly influence the magnitude of steatosis, however, thus far, the only gene studied in this respect is the gene encoding microsomal triglyceride transfer protein (MTP). Evidence has recently been presented that patients with NAFLD homozygous for a low activity promoter polymorphism in the MTP gene have increased steatosis compared with heterozygous patients or patients homozygous for the ‘high’ activity allele (28), and the same polymorphism has been associated with advanced ALD in a preliminary study (29). MTP is critical for the synthesis and secretion of VLDL in the liver and intestine and a frame shift mutation in the gene is associated with abetalipoproteinaemia. A G/T polymorphism at position −493 in the promoter appears to influence gene transcription, although the precise effect is controversial. Clearly, more studies are needed, not only of MTP polymorphisms, but also of polymorphisms of other genes encoding proteins involved in hepatic lipid metabolism as susceptibility factors for progressive ALD and NAFLD.

Genes influencing oxidative stress

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

ALD

The principal class of genes that influences the oxidant load in heavy drinkers are those encoding enzymes involved in alcohol metabolism. Polymorphisms have been identified in two of the seven genes encoding alcohol dehydrogenases (ADH2 and ADH3), in the promoter region of the CYP2E1 gene and in the coding region of the gene encoding the mitochondrial form of aldehyde dehydrogenase (ALDH2). The genes encoding ADH2 and ALDH2 undoubtedly play a role in determining the risk of alcoholism and, to a lesser extent, ALD in Oriental populations (30–32). Previously reported associations with ADH3 probably reflect linkage disequlibrium with ADH2 (33). In Caucasians, results from studies reported to date support a role for the ADH2 polymorphism in determining the risk of alcoholism but not ALD (34). Several studies have looked for an association between the c2 promoter (RsaI) polymorphism of the CYP2E1 gene and ALD, with no consistent results emerging in any population, although one study did report that the cumulative lifetime alcohol intake of patients with ALD heterozygous for the c2 (more transcriptionally active) allele was almost half that of patients with ALD homozygous for the c1, wild-type allele (10). The HFE gene is another obvious candidate gene for ALD, as liver iron promotes oxidative stress and iron deposition is common in ALD. Unfortunately, a case–control study of over 400 patients and controls found no evidence of an association between ALD and either of the HFE mutations associated with haemochromatosis (35). This lack of association was explained by the observation that hepatic iron content did not differ between patients with and without the mutations. The lack of any striking associations between polymorphisms in genes encoding proteins involved in the generation of reactive oxygen species and ALD has recently turned attention towards polymorphisms in genes encoding proteins involved in the body's antioxidant defences. Manganese-dependent superoxide dismutase 2 (SOD2) is the most important mitochondrial antioxidant enzyme and a polymorphism altering its mitochondrial targeting sequence has been associated with ALD in a small French study (36) although not confirmed in a larger study from the United Kingdom (37).

NAFLD

The principal class of genes that influences the oxidant load in patients with obesity, insulin resistance, and the metabolic syndrome are those encoding proteins involved in the oxidation of FFA. The role of FFA oxidation in the pathogenesis of NAFLD is complex. On the one hand, appropriate fat oxidation is required to prevent fat accumulation in the liver, while on the other; excessive fatty acid oxidation leads to oxidative stress (5, 38, 39). Children with inherited defects in mitochondrial β-oxidation develop steatosis but they do not get NASH, strongly suggesting that intact mitochondrial oxidation of FFA is required for progression to inflammation and fibrosis. With respect to peroxisomal and microsomal fat oxidation, as both are capable of generating ROS, it might be predicted that ‘gain-of-function’ polymorphisms in genes encoding proteins involved in these processes would predispose to NASH. However, these pathways play a role in limiting mitochondrial overload during times of excessive FFA supply and therefore it may be that ‘loss-of function’ polymorphisms effecting these pathways would predispose to NASH. This latter hypothesis is supported by a study showing that mice lacking the gene encoding fatty acyl-CoA oxidase, the initial enzyme of the peroxisomal β-oxidation system, develop severe microvesicular NASH (40). Similar difficulties apply to interpreting a preliminary report that a mutation (PPARA*3) in the gene encoding PPARα is associated with NASH (41). PPARα regulates the transcription of a variety of genes encoding enzymes involved in mitochondrial, peroxisomal β-oxidation, and microsomal ω-oxidation of fatty acids (42). Functional data on the mutation are somewhat contradictory at present (43), however, studies in PPARα knockout mice (44) and the fact that adiponectin activates PPARα and protects against steatosis (9, 45) suggests that any PPARA mutation associated with NASH should be associated either with loss-of-function or reduced gene expression.

As with ALD, other genes that may influence the magnitude and effect of oxidative stress in NAFLD include the HFE gene and the gene encoding SOD2. With respect to HFE, an initial study from Australia showed that 31% of 51 patients with NASH possessed at least one copy of the C282Y HFE mutation compared with only 13% of controls (46). Most recently, however, an Italian study of 263 consecutive patients with NAFLD has reported a prevalence of the C282Y and H63D mutations identical to the locally matched population (blood donors) (47). Furthermore, among the NAFLD patients, liver iron content was no different in patients with and without the mutations and the severity of fibrosis was unrelated either to liver iron content or to HFE genotype. With respect to the SOD2 polymorphism, there has been one preliminary report of an association with the severity of fibrosis in patients with NAFLD (48).

Genes influencing the response to endotoxin

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Evidence supporting a role for endotoxin-mediated cytokine release in the pathogenesis of ALD and NAFLD, together with the identification of promoter polymorphisms in genes encoding endotoxin receptors, has recently suggested an alternative set of ‘candidates’ to explain genetic susceptibility to advanced fatty liver diseases. CD14, a lipopolysaccharide (LPS) receptor on monocytes, macrophages, and neutrophils, has no intracellular domain but enhances signalling through another LPS receptor, toll-like receptor-4 (TLR4). A C/T polymorphism is present at position −159 in the CD14 promoter, with the TT genotype associated with increased levels of soluble and membrane CD14 (49). A study from Finland has recently reported an association between possession of the TT CD14 genotype and advanced ALD (50), however, this has not been observed in a larger study in north-east England (51). This latter study also showed no association between ALD and possession of the Asp299Gly polymorphism in the TLR4 gene, previously reported to be linked to hyporesponsiveness to LPS (52). A preliminary study in NASH has reported an association with the CD14 polymorphism but not with the TLR4 polymorphism (53).

Genes influencing the release or effect of cytokines

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

The first association between a cytokine gene polymorphism and ALD was reported between alcoholic hepatitis and a polymorphism at position −238 in the TNF-α promoter region (54), and this polymorphism has subsequently been associated with NASH (55). The functional significance of the polymorphism is, however, unclear and the associations may well be either spurious or due to linkage disequilibrium with another true ‘disease-associated polymorphism’ on chromosome 6, although the ALD association has recently been confirmed in a study from Spain (56). An association with ALD has also been reported for a promoter polymorphism in the interleukin-10 (IL-10) gene. IL-10 is the classical antiinflammatory cytokine which inhibits: (i) the activation of CD4+ T-helper cells, (ii) the function of cytotoxic CD8+ T cells and macrophages, (iii) class II HLA/B7 expression on antigen-presenting cells, and (iv) hepatic stellate cell collagen synthesis. A variant C[RIGHTWARDS ARROW]A substitution at position −627 in the IL-10 promoter has been associated with decreased reporter gene transcription, decreased IL-10 secretion by peripheral blood monocytes and an increased response to α-interferon in patients with chronic hepatitis C – all consistent with the polymorphism being associated with lower IL-10 production. A strong association between possession of the A allele and ALD has been reported from a study of over 500 heavy drinkers with and without advanced liver disease (57). This is consistent with low IL-10 favouring inflammatory and immune-mediated mechanisms of disease as well as hepatic stellate cell collagen production.

Immune response genes and risk of ALD

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

In view of the immunoregulatory functions of IL-10, the association between ALD and a low activity promoter polymorphism in IL-10 may be considered as further evidence that immune mechanisms are involved in the pathogenesis of ALD. Further evidence supporting a role for immune mechanisms in determining individual susceptibility to ALD has come from a recent study showing that, compared with drinkers with no evidence of ALD, patients with ALD are more likely to have high titres of autoantibodies against CYP2E1 (58) and to have T cell responses against oxidative stress-derived adducts (7). Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a T cell surface molecule that normally acts to ‘damp down’ the immune response to antigens either directly, by competing with CD28 on the surface of CD4+ Th cells for the antigen-presenting cell co-stimulatory molecule B7, or indirectly, by activating T regulatory cells which act to inhibit CD4+ Th cell function (59). CTLA-4 knockout mice develop lethal autoreactive lymphoproliferative disease and an A[RIGHTWARDS ARROW]G polymorphism in exon 1 leading to a Thr[RIGHTWARDS ARROW]Ala substitution has recently been associated with autoimmune liver diseases, insulin-dependent diabetes and autoimmune thyroid disease. These associations strongly suggest that this polymorphism is associated with impaired CTLA-4 function, although recent data suggest that other tightly linked CTLA-4 polymorphisms may be responsible for the functional effect (60). Although the exon 1 polymorphism has been associated with the titre of anti-CYP2E1 antibodies in one study (58) and with ALD in another (61) this has yet to be confirmed as an ALD susceptibility allele in large studies examining the full CTLA4 gene haplotype.

Genes influencing the severity of fibrosis

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Genes encoding proteins involved in fibrogenesis or fibrinolysis in the liver are clearly candidates for a role in ALD and NAFLD-related fibrosis. Obvious candidates would include the polymorphic genes encoding transforming growth factor (TGF)-β1, CTGF, matrix metalloproteinase 3, PPARγ, and various fibrogenic adipocytokines including angiotensin II. The only study thus far in this regard is a recent report that obese patients inheriting both high TGF-β1 and angiotensinogen producing polymorphisms may be more susceptible to advanced fibrosis (62). Although this relatively small study awaits replication, it does suggest that ‘fibrosis’ genes may be important in determining susceptibility to the more advanced forms of fatty liver disease.

Summary

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

Genetic and environmental risk factors determine why only a minority of heavy drinkers and obese, insulin-resistant individuals progress from simple steatosis to inflammation and fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity and associated hyperglycemia are the most important environmental factors determining disease risk. For NAFLD, single studies have suggested that dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role in disease progression. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining the risk of progressive ALD and NAFLD. For ALD, functional polymorphisms in the ADH and ALDH alcohol metabolising genes play a role in determining susceptibility in Oriental populations. The only replicated association in Caucasians is with the TNF-α−238 polymorphism. No genetic associations with advanced NAFLD have been replicated in large studies in any populations. Preliminary data suggest that polymorphisms in genes encoding MTP, SOD2, the CD14 endotoxin receptor, TNF-α, TGF-β, and angiotensinogen may play a role.

Perspectives and future developments

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References

It is clear that future studies examining susceptibility to ALD and NAFLD need to be considerably larger than those performed thus far if we are to come up with environmental and genetic associations that are robust enough to guide targeted treatment and prevention strategies (Fig. 2). These studies are critically dependent on the collection of large numbers of well phenotyped cases and controls, which almost certainly requires national and multinational collaborations. With respect to genetic studies, in future, the choice of candidate genes (Table 2) is likely to be further extended by: (a) genome and proteome expression studies in tissue from patients with various stages of disease, (b) whole genome single nucleotide polymorphism scans of cases and controls, and (c) mouse mutagenesis studies.

image

Figure 2.  Genetic determinants of fatty liver diseases and tailored therapy.

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Table 2.   Potential candidate genes in fatty liver disease
Category of genesExample (s)
  1. 11 β-HSD-1, 11 β hydroxysteroid dehydrogenase type 1; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CTGF, connective tissue growth factor; CTLA-4, cytotoxic T-cell associated antigen-4; CYP, cytochrome P450; GST, glutathione transferase; GSH-Px, glutathione peroxidase; IL, interleukin; MAT, methionine adenosyltransferase; MMP, matrix metalloproteinase; MTP, microsomal triglyceride transfer protein; PPAR, peroxisomal proliferator receptor; SCD-1, stearoyl CoA desaturase-1; SOD2, superoxide dismutase-2; TIMP, tissue inhibitor of metalloproteinases; TLR, toll-like receptor; TNFR, TNF-α receptor; UCP2, uncoupling protein-2.

Genes determining the magnitude and pattern of fat deposition11β HSD-1, glucocorticoid receptor, β2–adrenoceptor, lipodystrophic genes
Genes determining insulin sensitivityAdiponectin, HFE, resistin, insulin receptor genes, PPAR-γ
Genes involved in hepatic lipid synthesis, storage, and exportLeptin, adiponectin, SREBP-1c, SCD-1, apolipoproteins B, and E, MTP,
Genes involved in hepatic fatty acid oxidationAdiponectin, PPAR-α, acyl-CoA oxidase, CYP2E1, and CYP4A
Genes influencing the generation of oxidant speciesHFE, TNF-α, ADH/ALDH, CYP2E1
Genes encoding proteins involved in the response to oxidant stressSOD2, UCP2, MAT1A, GST, GSH-Px
Cytokine genes and receptorsIL-10, TNF-α, TNFRs
Genes encoding endotoxin receptorsCD14, NOD2, TLR4
Immune response genesCTLA-4, IL-4, IL-10, IL-18
ALD/NAFLD-related fibrosis genesCTGF, leptin, adiponectin, angiotensinogen, norepinephrine
General fibrosis genesTGF-β, MMPs, TIMPs, collagens

References

  1. Top of page
  2. Abstract
  3. Pathogenesis
  4. Environmental factors determining disease risk ()
  5. Evidence for genetic factors determining disease risk
  6. Gender and risk of ALD
  7. Genes influencing the severity of steatosis
  8. Genes influencing oxidative stress
  9. Genes influencing the response to endotoxin
  10. Genes influencing the release or effect of cytokines
  11. Immune response genes and risk of ALD
  12. Genes influencing the severity of fibrosis
  13. Summary
  14. Perspectives and future developments
  15. References
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