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NASH may be trash: causes of NASH
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Gut Feb 2008
David Cassiman1,2, Jaak Jaeken2
1 Department of Hepatology, University Hospital Gasthuisberg, University of Leuven, Belgium
2 Metabolic Center, Department of Paediatrics, University Hospital Gasthuisberg, University of Leuven, Belgium
Correspondence to:
Professor David Cassiman, Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, University of Leuven, Herestraat 49, 3000 Leuven, Belgium; David.cassiman@med.kuleuven.be
"....Mitochondria are the central fuel-burning organelles in the organism and therefore can be expected to play a role in the development of fatty livers. Frank congenital mitochondrial diseases (Alpers syndrome and mtDNA (mitochondrial DNA) depletion syndrome, see table 1) are indeed known to be associated with fatty liver, but there is more. The predisposition to develop insulin resistance and type 2 diabetes is related to decreased numbers and/or function of mitochondria, to deletions and polymorphisms in mtDNA.29 NAFLD and NASH livers show aberrant mitochondria (megamitochondria, paracrystalline inclusions) on electron microscopy.30-32 The progression of NAFLD to NASH is attributed to congenital and/or acquired mitochondrial dysfunction..."
The liver is a stupid organ. It has only limited abilities to express itself. It can necrotise, swell, inflame, clot and scarify. The liver can become leaky, it can sometimes hurt and its plumbing can clog. And then the liver can be fatty. For some time already, we know that, for example, several viruses can cause the inflammation, and that drugs, viruses and autoimmunity cause most of the necrosis, etc. Luckily, for the majority of these causes, we have more or less reliable methods to pin them down. Not so for the fatty sign because, when turning fatty, the liver is at its most stupid. On a communication scale and compared with the eloquent monologue of a viral hepatitis, turning fatty would rate as a grunt. It is never entirely clear what causes a grunt or what is meant by grunting, as it is never clear what provokes fatty infiltration of the liver or what the liver wants to convey by turning fatty. A grunt can be an expression of pain, but also of pleasure. Is it time to expand the liver's vocabulary, or could there also be something wrong with us, the audience?
When turning fatty, the liver is at its most stupid
When fatty liver is not associated with moderate to severe alcohol intake and the most prevalent liver diseases are excluded, it is called "non-alcoholic fatty liver disease" (NAFLD). When the fatty liver is also inflamed, we call it "non-alcoholic steatohepatitis" (NASH). However, there is a very long and ever-expanding list of causes of fatty livers, which cannot simply be named NAFLD/NASH (table 1). Also on a more theoretical level, there is a problem with NAFLD and NASH: they are "non"-diseases, exclusion diagnoses: it's not a bird, it's not a plane, so it must be Superman. Therefore, the diagnosis of NAFLD/NASH can never really be made: there is no Superman. In addition, the first distinction (alcoholic vs non-alcoholic) requires a reliable patient history. The patient history for alcohol intake is notoriously unreliable. The definition of what amount of alcohol is "moderate" is culturally determined. The second distinction (without/with inflammation) requires the taking of a biopsy, but what is needed to distinguish NAFLD from NASH on a biopsy barely reaches the level of consensus, never of proof.1 Finally, what we get to see on the biopsies is highly variable due to sampling error, so the distinction between NAFLD and NASH is never certain.2 That is the refinement we reach, in our understanding and classification of the fatty liver. Study protocols indeed conveniently do not require definitive exclusion of all known causes of fatty liver (table 1), before the diagnosis is made. On the contrary, if the most prevalent liver diseases are excluded and the biopsy shows fat accumulation, we convict the patient and drop him/her in the NAFLD trash bin: start the trial!3-22
Article resumes after table
Table 1 Causes of fatty liver that are not simply NAFLD/NASH
If the most prevalent liver diseases are excluded and the biopsy shows fat accumulation, we convict the patient and drop him/her in the NAFLD trash bin
In our opinion, this approach reflects a profoundly unproductive attitude towards the fatty liver and its pathophysiology, hiding behind a veil of pragmatism. It is the scientist's duty to try to understand, see the detail, reclassify, generate and test hypotheses, and then learn. In the case of fatty livers, we are doing a lousy job. Although the data and insight are out there, we do not succeed in incorporating them in our understanding, classification and treatment of fatty livers. In other words, we refuse to hear the detail in the grunt, its intonation and the gestures associated with it. We just call everything NAFLD.
Because our diagnosis of NAFLD/NASH is questionable, our epidemiological studies yield strange, even worrying results: although insulin resistance is considered the essence of NAFLD/NASH, 10-20% of NAFLD/NASH patients do not have insulin resistance. What is worse, not only insulin-resistant diabetics will develop NAFLD/NASH, but also type 1 diabetics have been known to develop NAFLD/NASH. In addition, NAFLD/NASH is supposedly associated with the metabolic syndrome, but-certainly when the definition of this syndrome is systematically broadened to encompass the majority of the Western population-up to 50% of NAFLD/NASH patients do not fulfil the metabolic syndrome criteria (for a review, see Farrell and Larter23).
We agree that overweight patients with a hyper-reflective liver on ultrasound and raised transaminases which normalise following weight loss probably had something we could call NAFLD/NASH. But these are not the patients that end up in our trials, because their problem is already solved (ie, a selection bias, favouring non-typical fatty liver patients to enter trials). We agree that it might seem reasonable to expect all type 2 diabetics to have the same liver problem, rather than all having various inherited or acquired defects of metabolism or genetic syndromes. What increases the probability of type 2 diabetics having NAFLD is that having an increased fasting plasma glucose level or insulin resistance is a criterion for the metabolic syndrome and having the metabolic syndrome is a criterion for the diagnosis of NAFLD. This makes NAFLD in type 2 diabetics a self-fulfilling prophecy, therefore reaching an unsurprising estimated prevalence of around 62%.23
For the pragmatics, however, there does seem to be some hope. Recent trials with patient inclusion restricted to individuals with fatty livers and proven insulin resistance or type 2 diabetes9 do yield hopeful results. Nevertheless, when many patients have been enrolled in many clinical trials,3-22 and these trials yield surprisingly little clinically useful effect, the patient selection has to be scrutinised.
One of the problems with the patient selection is that gastroenterologists, hepatologists and internists lack familiarity with the "other causes of fatty liver", listed in table 1. Fructose-intolerant patients present with a fatty liver and are urged to eat more fruit. How many "NAFLD" patients have been asked whether they had symptoms suggestive of hypoglycaemia in their younger days (glycogenosis type VI is a mild type of glycogenosis associated with fatty liver and thought to be fairly frequent)? How many "NAFLD" patients have undergone formal isoelectric focusing or genetic testing to exclude homo- or heterozygous -1 antitrypsin deficiency as causal or contributing factor? How many colleagues will notice acanthosis nigricans as a sign of syndromic insulin resistance? How many will do a full family history to document an X-linked, dominant, recessive or mitochondrial inheritance pattern? How many will ask patients if they had supernumerary fingers or toes at birth? Whether they have retinitis pigmentosa or impaired hearing? Anatomically normal kidneys?
How many colleagues will ask patients if they had supernumerary fingers or toes at birth?
Many of the diseases or syndromes in the 'other causes of fatty liver' list (table 1) are inherited metabolic disorders.24 It is becoming clear that mild metabolic disorders can present at any age. The diagnosis of mild metabolic disease, presenting at adult age, will be all the more difficult, however, exactly because it is discrete. In addition, because diagnosis and treatment of metabolic diseases are rapidly improving, more and more metabolic patients are reaching adult age.25 That means they will have time to develop symptoms, signs and complications that have not been described before, and they will increasingly do so at adult age. These are the reasons why the 'adult' doctors will need to learn about these diseases. Not only because they are associated with fatty liver, but also because it is becoming clear that it is wrong to think they are only paediatric diseases.
Another reason why we fail to see the problem might be that we are used to approaching diseases in this way. Although only 10% of heavy drinkers will develop liver disease,26 27 we persist in speaking of, for example, "alcoholic cirrhosis", while "cirrhosis of the metabolically challenged" would be not only more politically, but certainly more scientifically correct. We suspect a similar mechanism might be at play here: the fatty liver patients that move on to develop cirrhosis could be the metabolically challenged subpopulation. Maybe even this is what underlies the magical "two-hit" hypothesis currently invoked to explain the evolution from NAFLD to NASH.28 All we know for now, however, is that some of the patients with fatty liver might develop fibrosis or cirrhosis. As discussed above, there are many kinds of fatty liver (table 1). We do not know if all of these are dangerous. And if not all: which really are.
The up-side is that the (suspected) minority of patients in this category-the patients with rare diseases associated with fatty liver-can instruct us on where to look for the explanation of this "metabolically challenged" status. True metabolic diseases can be considered as "human knockouts", teaching us about normal as well as abnormal metabolism. Therefore, instead of calling everything NAFLD and considering all cryptogenic liver disease as "post-NAFLD/NASH",23 we would indeed better look for mild variants of these strange diseases by means of an exhaustive diagnostic work-up, including a thorough family history, a full metabolic screening, a liver biopsy with electron microscopy (which is very often more instructive than light microscopy in the context of metabolic disease), glycogen quantification and enzymatic testing, genetic advice and karyotyping, ophthalmological exam, audiometry consult, etc. What this testing should exactly comprise can be inspired by the non-exhaustive list of known diseases associated with fatty liver with/without insulin resistance (table 1).
Of particular interest in this respect, but certainly not the easiest to corner diagnostically, are the mitochondrial diseases. Mitochondria are the central fuel-burning organelles in the organism and therefore can be expected to play a role in the development of fatty livers. Frank congenital mitochondrial diseases (Alpers syndrome and mtDNA (mitochondrial DNA) depletion syndrome, see table 1) are indeed known to be associated with fatty liver, but there is more. The predisposition to develop insulin resistance and type 2 diabetes is related to decreased numbers and/or function of mitochondria, to deletions and polymorphisms in mtDNA.29 NAFLD and NASH livers show aberrant mitochondria (megamitochondria, paracrystalline inclusions) on electron microscopy.30-32 The progression of NAFLD to NASH is attributed to congenital and/or acquired mitochondrial dysfunction, resulting in excessive production of reactive oxygen species, cytokine production, increasing damage to mtDNA33-35 and increased apoptosis (for a review, see Begriche et al,36 and Pessayre and Fromenty37). At this point, it is still unclear what part of these mitochondrial abnormalities is cause and what part effect, and in which subpopulations of fatty liver patients these abnormalities are relevant. Therefore, it again seems unwise to pool all these patients and treat them as having one and the same disease.
Mitochondria are the central fuel-burning organelles in the organism and therefore can be expected to play a role in the development of fatty livers
To avoid discussions about cost-effectiveness of the proposed further diagnostics in patients with fatty livers, we suggest a compromise. As discussed above, the overweight patients that normalise their "transaminitis" by losing weight and increasing their physical activity are not the target population for further diagnostics or treatment. Although none of the current fatty liver patients can be excluded on a scientific basis, the patients certainly to be considered for further testing in our opinion would be the non-obese and young patients (especially children), the patients lacking biochemical response to weight loss, the patients showing associated clinical dysmorphic features, the patients having a suggestive family history, the patients with seemingly unrelated organ dysfunction, the patients presenting with moderate to advanced fibrosis or cirrhosis, and the patients without insulin resistance or impaired glucose tolerance.
In conclusion, NASH may be trash and NAFLD appears a pit. Luckily, these are the times of waste recycling: who knows what beautiful or interesting things we can find, by meticulously going through the hepatology waste-bin...
FOOTNOTES
Funding: D.C. is a fundamental-clinical researcher, partly funded by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.
Competing interests: None.
REFERENCES
1. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-21.[CrossRef][Medline]
2. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128: 1898-906.[CrossRef][Medline]
3. Ratziu VCF, Jacqueminet S, Podevin P, et al. A one year randomized, placebo-controlled, double-blind trial of rosiglitazone in non alcoholic steatohepatitis: results of the FLIRT pilot trial. Hepatology 2006; 44: 104A.
4. Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006; 4: 1537-43.[CrossRef][Medline]
5. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004; 39: 770-8.[CrossRef][Medline]
6. Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004; 19: 537-44.[CrossRef][Medline]
7. Abdelmalek MF, Angulo P, Jorgensen RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001; 96: 2711-7.[CrossRef][Medline]
8. Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999; 31: 384.[CrossRef][Medline]
9. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297-307.[Abstract/Free Full Text]
10. Chande N, Laidlaw M, Adams P, et al. Yo Jyo Hen Shi Ko (YHK) improves transaminases in nonalcoholic steatohepatitis (NASH): a randomized pilot study. Dig Dis Sci 2006; 51: 1183-9.[CrossRef][Medline]
11. Daubioul CA, Horsmans Y, Lambert P, et al. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur J Clin Nutr 2005; 59: 723-6.[CrossRef][Medline]
12. Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98: 2485-90.[CrossRef][Medline]
13. Harrison SA, Fincke C, Helinski D, et al. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther 2004; 20: 623-8.[CrossRef][Medline]
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-7.[Medline]
15. Merat S, Malekzadeh R, Sohrabi MR, et al. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatol 2003; 38: 414-8.[CrossRef][Medline]
16. Miglio F, Rovati LC, Santoro A, et al. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung 2000; 50: 722-7.[Medline]
17. Morita Y, Ueno T, Sasaki N, et al. Nateglinide is useful for nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes. Hepatogastroenterology 2005; 52: 1338-43.[Medline]
18. Pamuk GE, Sonsuz A. N-Acetylcysteine in the treatment of non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2003; 18: 1220-1.[CrossRef][Medline]
19. Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004; 2: 1107-15.[CrossRef][Medline]
20. Schwimmer JB, Middleton MS, Deutsch R, et al. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2005; 21: 871-9.[CrossRef][Medline]
21. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004; 39: 188-96.[CrossRef][Medline]
22. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38: 1008-17.[CrossRef][Medline]
23. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43: S99-S112.[CrossRef][Medline]
24. Fernandez J, Saudubray J-M, Van Bergeh G, eds. Inborn metabolic diseases: diagnosis and treatment . 4th edn. New York: Springer-Verlag, 2006.
25. Bhat M, Haase C, Lee PJ. Social outcome in treated individuals with inherited metabolic disorders: UK study. J Inherit Metab Dis 2005; 28: 825-30.[CrossRef][Medline]
26. Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut 1997; 41: 845-50.[Abstract/Free Full Text]
27. Becker U, Gronbaek M, Johansen D, et al. Lower risk for alcohol-induced cirrhosis in wine drinkers. Hepatology 2002; 35: 868-75.[CrossRef][Medline]
28. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114: 842-5.[CrossRef][Medline]
29. Lee HK, Park KS, Cho YM, et al. Mitochondria-based model for fetal origin of adult disease and insulin resistance. Ann NY Acad Sci 2005; 1042: 1-18.[Abstract/Free Full Text]
30. Sobaniec-Lotowska ME, Lebensztejn DM. Ultrastructure of hepatocyte mitochondria in nonalcoholic steatohepatitis in pediatric patients: usefulness of electron microscopy in the diagnosis of the disease. Am J Gastroenterol 2003; 98: 1664-5.[CrossRef][Medline]
31. Le TH, Caldwell SH, Redick JA, et al. The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis. Hepatology 2004; 39: 1423-9.[CrossRef][Medline]
32. Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 1999; 31: 430-4.[CrossRef][Medline]
33. Gao D, Wei C, Chen L, et al. Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2004; 287: G1070-7.[Abstract/Free Full Text]
34. Perez-Carreras M, Del Hoyo P, Martin MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 2003; 38: 999-1007.[CrossRef][Medline]
35. Santamaria E, Avila MA, Latasa MU, et al. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sci USA 2003; 100: 3065-70.[Abstract/Free Full Text]
36. Begriche K, Igoudjil A, Pessayre D, et al. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 2006; 6: 1-28.[Medline]
37. Pessayre D, Fromenty B. NASH: a mitochondrial disease. J Hepatol 2005; 42: 928-40.[CrossRef][Medline]
38. Brunt EM. Non-alcoholic fatty liver disease. In: Alastair D, Burt BCP, Ferrell LD, eds. MacSween's pathology of the liver . Edinburgh: Churchill Livingstone, 2006: 367-97.
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