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'''Editor in Chief''': Elliot Tapper, M.D., Beth Israel Deaconess Medical Center
'''Editor in Chief''': Elliot Tapper, M.D., Beth Israel Deaconess Medical Center

Revision as of 17:41, 17 November 2012

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Editor in Chief: Elliot Tapper, M.D., Beth Israel Deaconess Medical Center

Overview

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease in the absence of excessive alcohol use that begins as fatty accumulation in the liver (hepatic steatosis). A fatty liver does not necessarily disturb the function of the liver, but by varying mechanisms and insults, it may progress to inflammation of the liver. When inflammation occurs in this setting, the condition is then called NASH - Non-alcoholic steatohepatitis. NASH, in turn, may progress to fibrosis and, later, cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-15% rate of cirrhosis in less than 6 years. [1][2][3] In 2001, NASH represented 2.9% of the indications of liver transplantation.[4] The impact of NAFLD is manifest at each step along the spectrum of the diease. Studies in the United States and Sweden have revealed that both simple steatosis as well as steatohepatitis significantly reduce life expectancy, even when the diagnosis is made in children.[5][6]

NAFLD/NASH was first described in a 1980 series of obese, non-alcoholic patients of the Mayo Clinic.[7] Since that seminal description, our understanding of NAFLD has progressed minimally. [8] The disease is most closely associated with the increasing obesity, insulin resistance, type two diabetes mellitus and hyperlipedmia endemic to the developed world. Roughly half of all patients with NAFLD, however, do not meet criteria for metabolic syndrome. [9]

Epidemiology

Estimates are that between 30- 90 million Americans have some degree of NAFLD and 5-6% have NASH. [10] A Japanese study estimates the prevalence of NAFLD in that country at 31 per 1000 and found an incidence of approximately 10% - 308 new cases of NAFLD in a group of 3,147 patients followed over 414 days.[11]. In the third National Health and Nutrition Examination Survey (NHANES III), the peak prevalence of NAFLD in men occurred in the fourth decade and in the sixth decade for women.[12][13]

Some have suggested a genetic or sociocultural component to NAFLD spectrum disease.[14] As a part of the Dallas Heart Study,[15] 2,240 patients - 1,105 african-americans, 401 hispanics and 734 caucasians - received abdominal MRI's from which we can infer the presence of steatosis. Hepatic steatosis was found in 45% of hispanics (both men and women), 33% of caucasians (42% of men, 24% of women) and 24% of african-american (23% of men, 24% of women). This pattern may hold true in children as well. In a San Diego study of 742 consecutive autopsies of children victims of trauma over 10 years, fatty liver was found in 9.6% of all children, 38% of the obese, 12% of hispanics, 10% of asians, 8.6% of caucasians and 1.5% of african-americans.[16]

Pathophysiology

Overview

The exact cause is still unknown. However both obesity and insulin resistance likely play a strong role in this disease process. The exact reasons and mechanisms by which this disease progresses from steatosis to steatohepatitis and fibrosis is a subject of much research and debate. The prevailing wisdom comes from the so-called ‘two-hit hypothesis.’ The first hit is steatosis. The second hit is controversial and is likely numerous; likely any injury which causes a change that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation.[17] Oxidative stress, hormonal imbalances, endotoxemia and mitochondrial abnormalities may all be potential causes.

Insulin Resistance

Clinicopathologic studies in patients with NAFLD have confirmed that insulin resistance is a cause and not a result of liver disease. For example, 75% of NAFLD/NASH patients – lean or obese – having insulin resistance while only 7.5% of patients with Hepatitis C are insulin resistant.[18] In another study, a fasting glucose >110 mg/dL was the most predictive feature of NAFLD.[19]

Comorbid Liver Disease

The evidence for oxidative stress as a second-hit comes from many sources. For example, as in hemochromatosis liver disease, any degree of iron overload engenders enhanced free radical production in the liver. As many as 31% of patients with NASH have been discovered to have C282Y mutations of the HFE gene for hemochromatosis(compared to a prevalence of less than 12.5% in the general population).[20] Similarly, while 2-3.6% of the population have the profibrotic MZ alpha-1 antitrypsin deficiency phenotype, it is present in as many as 16.7% of NASH patients requiring liver transplantation.[21]

Endotoxins

One of the original theories of NASH pathogenesis derived from clinical experience involving obese patients who developed cirrhosis after a jejuno-ileal bypass.[22] This sort of intestinal deformity may increase the concentration of bacterial endotoxins in the portal circulation, which in turn may cause an elevation of intrahepatic levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha. One study found the rate of small bowel bacterial overgrowth to be present in twice as many patients with NASH as control. Furthermore, some degree of steatohepatitis can even be reversed after treatment with metronidazole. [23]

Adiponectin

Many groups have implicated variations in different metabolic pathways. One of the principle pathways under investigation is that which is affected by adiponectin. Adiponectin is an anti-atherogenic, insulin sensitizing cytokine whose secretion is decreased in obesity. One study found an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor.[24]. Another implication of the research on adiponectin is that different dietary fats have variable effects on adiponectin levels, with polyunsaturated fatty acids leading to decreased levels and more hepatic inflammation.[25]

Adenosine

Another pathway under investigation is purinergic metabolism. CD39 is the dominant vascular (and immune cell) ectonucleotidase in the liver that hydrolyzes extracellular ATP and ADP to AMP which can then be converted to adenosine via ecto-5’-nucleotidase/CD73. Alterations in purinergic signaling induced by altered CD39 expression have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses.[26] Varying levels of CD39 and adenosine have thus been implicated in the spectrum of NAFLD/NASH phenotypes.

Based on knockout studies, the experimental evidence is mounting in support of a major role for both CD39 and adenosine in the development of steatosis, inflammation and, later, fibrosis. Firstly, the deletion of CD39 and thus the local reduction of adenosine results in hepatic insulin resistance and increased serum levels of several inflammatory cytokines.[27]

Secondly, adenosine appears to be a critical supportive link in the cell’s cascade of responses to inflammation;[28] Adenosine suppresses inflammation and, as inflammation, tissue repair and scarring are closely linked events, it enhances fibrosis by increasing matrix formation in healing insulted tissues and facilitating regeneration.[29][30] CD39 deletion shifts the local population of cytokines toward the pro-inflammatory and non-fibrinogenic (e.g. interferon gamma).[31]

Thirdly, in CD39 knockout models of hepatitis and pancreatitis, there is a marked decrease in fibrogenesis.[32] And adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.[29]

Fibroblast Growth Factor 21

Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. Essentially, FGF21 moderates or induces the hepatic response to a fasting state: gluconeogenesis, fatty acid oxidation, and ketogenesis.[33] Moreover, it is a crucial component of the hepatic lipid oxidation machinery. This probably occurs as a function of proliferator-activated receptor activation. [34].

While the present evidence is contradictory for FGF21's role in the setting of fatty liver, it is evolving. In one study, supplemental, recombinant FGF21 was given to mice and resulted in reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity.[35] At the same time, studies in humans have shown that circulating FGF21 concentrations were increased in subjects who were either overweight or had type 2 diabetes or impaired glucose tolerance.[36] The most recent study has shown that while FGF21 levels are associated with BMI in humans, they are not nutritionally regulated. It may only be a marker of - not causally linked to - NAFLD.[37]

Uric Acid

Another candidate in the pathophysiology of NAFLD is uric acid. While it remains to be seen whether uricemia is causal or a marker of disease, a hypothesis generating paper from China implicates uric acid in NAFLD. A population-based prospective study in China to found that 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. Interestingly, the incidence of NAFLD increased with progressively higher baseline serum uric acid levels (7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively).[38] In animal studies conducted by the same group, they were able to show that hypouricemic medications reduced hepatic steatosis and hyperlipidemia.[39]

Secondary causes

NAFLD can also be caused by the following medications (termed secondary NAFLD):

Signs, Symptoms and Associations

Most patients with NAFLD have no or few symptoms. Infrequently patients may complain of fatigue, malaise and dull right upper quadrant abdominal discomfort. Mild jaundice can rarely be noticed. More commonly it is diagnosed as a result of abnormal liver function tests during routine blood tests. Often following an asymptomatic course, the disease may present first with cirrhosis and/or the complication of portal hypertension. In that respect, NASH is becoming an increasingly common indication for liver transplantation. [40] As awareness of this condition spreads, it has been regarded as a major cause of cryptogenic cirrhosis of the liver.[41] The diagnosis of cryptogenic cirrhosis is usually made in patients with similar clinical characteristics to those with NAFLD spectrum disease. Cryptogenic cirrhotics tend to be women, aged 63 (+/- 11) years who are obese and type 2 diabetics. [14] Moreover, there are case reports of patients with NASH who received serial liver biopsies where there was a progression to cirrhosis with a dissapearance of the histologcal stigmatia of NASH. Without the index biopsy, these patients' cirrhosis would have been classified as cryptogenic.[42][14]

Diagnosis

Disturbed liver enzymes are common. Typically, one finds a 2-4 fold elevation of the ALT above normal limit and an ALT/AST ratio of greater than 1.[43] This ratio is imperfect, as AST tends to rise with the degree of fibrosis.[44] Furthermore,high ALT values within the reference range (less than 40 IU) are still predictive of NAFLD/NASH.[45] Another blood test that can be elevated is the ferritin. Typically, and except in very advanced disease, the liver's synthetic function is intact with normal albumin and INR.

Imaging is often ordered in the workup of suspected NAFLD. Ultrasound and computed tomography have sensitivities between 93-100%, but 62-76% positive predictive values. Problematically, ultrasound of fatty liver reveals a hyperechoic echotexture - a so-called 'bright liver' - that can often be indistinguishable from fibrosis and generally cannot reliably delineate NAFLD from NASH.[46] Computed tomography is less sensitive, rarely detecting steatosis when fatty infiltration is less than 33%, but is potentially more specific.[47] Statistics are similar for MRI, however using advanced MR techniques, some groups have been able to both quantify steatosis and differentiate steatohepatitis from steatosis.[48][49]

A biopsy of the liver is still considered the gold standard in diagnosis. This is especially true for those patients with elevated liver enzymes for whom a non-invasive workup is inconclusive; 34% of these patients, in one series, were found to have NASH.[50] Classically, biopsy reveals macrovesicular steatosis, inflammation, ballooning degeneration, zone 3 perivenular/periportal/perisinusoidal fibrosis and, finally, mallory bodies.[51][52] Unfortunately, however, a standard biopsy is only able to sample a volume that is 1/50,000th of the liver, underscoring substantial room for sampling error.

When considering NAFLD, other tests are generally performed, including those for associated conditions (e.g. glucose, hemoglobin A1C) and those to distinguish this disease from viral hepatitis. Additionally, autoimmune causes are ruled out with serology. TSH is warranted, as hypothyroidism is more prevalent in NASH patients.[53]

Treatment

Trials are presently being conducted to optimize treatment of NASH. No standard treatment has yet emerged as the "gold standard". General recommendations include improving metabolic risk factors - weight loss, treating diabetes, managing lipids - and reducing alcohol intake. One of the largest trials of NAFLD/NASH therapy evaluated rosiglitazone, an insulin-sensitizing thiazolidenedione.[54] This study found, after one year, no significant improvement in markers of liver injury. In May of 2010, Sanyal and colleagues published a randomized, placebo controlled trial of Vitamin E (800 IU daily) and pioglitazone (30 mg daily) with paired-biopsies.[55] They found that Vitamin E was best able to achieve improvement in NAFLD/NASH, vis-a-vis improvements in the histological stigmata of NASH (steatosis, lobular inflammation, ballooning degeneration and fibrosis). Pioglitazone was able to achieve significant improvements in some of the individual markers. Steatohepatitis resolved in 47% of patients taking Vitamin E and 36% taking pioglitazone. Neither medication could achieve significant improvements in fibrosis or portal inflammation.

References

  1. ↑ Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42(1):132–8.
  2. ↑ Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease:a clinical histopathological study. Am J Gastroenterol 2003;98(9):2042–7.
  3. ↑ Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-73.
  4. ↑ Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease. Liver Transpl 2001;7:608-614
  5. ↑ Adams et al. The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study. GASTROENTEROLOGY 2005;129:113–121
  6. ↑ Feldstein AE et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009;58:1538–1544
  7. ↑ Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434-438. PMID 7382552.
  8. ↑ Day, CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut. 2002 May; 50(5): 585–588.
  9. ↑ Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.
  10. ↑ McCullough, AJ. Thiazolidinediones for NASH. NEJM 2006;355(22):2361-2363.
  11. ↑ Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143(10):722–8
  12. ↑ Ong JP et al. Epidemiology and Natural History of NAFLD and NASH. Clin Liver Dis 11 (2007) 1–16
  13. ↑ Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the united states. Gastroenterology 2003;124(1):71–9.
  14. ↑ 14.0 14.1 14.2 Caldwell et al. Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver). J of Gastroenterology and Hepatology 2007;22(S1):S11-S19
  15. ↑ Browning et al. Prevalence of Hepatic Steatosis in an Urban Population in the United States: Impact of Ethnicity. Hepatology 2004;40:1387-1395.
  16. ↑ Schwimmer et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118;1388-93.
  17. ↑ Berson A, De Beco V, Lette´ron P, Robin MA, Moreau C, El KahwajiJ, Verthier N, Feldmann G, Fromenty B, Pessayre D. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 1998;114:764–774.
  18. ↑ Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379
  19. ↑ Marchesini G, Brizi M, Bianchi G, et al.Metformin in nonalcoholic steatohepatitis. Lancet 2001;358:893–894
  20. ↑ George DK, Goldwurm S, Macdonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998;114:311–318.
  21. ↑ Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614
  22. ↑ Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999
  23. ↑ Wigg AJ et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-211
  24. ↑ Anania. Adiponectin and Alcoholic Fatty Liver: Is It, After All, About What You Eat? Hepatology 2005;42(3):530-532
  25. ↑ You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 2005;42:568-577.
  26. ↑ Beldi G, et al. The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism. Frontiers Biosci 2008; 13, 2588-2603
  27. ↑ Enjyoji, K et al. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance. Diabetes. 2008; 57:2311–2320
  28. ↑ Haschemi A, Wagner O, Marculescu R, Wegiel B, Robson SC, Gagliani N, Gallo D, et al. Cross-regulation of carbon monoxide and the adenosine A2A receptor in macrophages. J. Immunol. 2007;178;5921-5929
  29. ↑ 29.0 29.1 Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, et al. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 2006;148:1144-1155.
  30. ↑ Montesinos MC et al. Wound healing is accelerated by agonists of adenosine A2 (G alpha s-linked) receptors. J. Exp. Med.1997;186:1615–162010-11)
  31. ↑ Kunzli BM et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230
  32. ↑ Kunzli BM et al. Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-null mice. Gastroenterology. 2008 January ; 134(1): 292–305.
  33. ↑ Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S
  34. ↑ Badman MK et all. Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARa and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States. Cell Metabolism 2007;5:426–437
  35. ↑ Xu, J et al. Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice. Diabetes 58:250–259, 2009
  36. ↑ Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S
  37. ↑ Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, Badman MK, Martinez-Chantar ML, Maratos-Flier E. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010 Aug;139(2):456-63
  38. ↑ Xu C, Yu C, Xu L, Miao M, Li Y (2010) High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational Study. PLoS ONE 5(7): e11578.
  39. ↑ Xu CF, Yu CH, Xu L, Sa XY, Li YM. Hypouricemic therapy: A novel potential therapeutic option for nonalcoholic fatty liver disease.Hepatology. 2010 Jun 11. [Epub ahead of print]
  40. ↑ Choudhury J, Sanyal A. Clinical Aspects of Fatty Liver Disease. Semin Liver Dis 2004; 24: 349-362.
  41. ↑ Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003;289:3000-4. PMID 12799409.
  42. ↑ Yoshioka Y, Hashimoto E, Yatsuji S. “NASH: cirrhosis, hepatocellular carcinoma and burnt-out NASH.” J Gastroenterol 2004;39;1215-1218
  43. ↑ Powell et al. The Natural History of Nonalcoholic Steatohepatitis: A Follow-up Study of Forty-two Patients for Up to 21 YearsHEPATOLOGY 1990; 11: 74-80
  44. ↑ Sorbi et al. The Ratio of Aspartate Aminotransferase to Alanine Aminotransferase: Potential Value in Differentiating Nonalcoholic Steatohepatitis From Alcoholic Liver DiseaseAm J Gastroenterol 1999;94:1018–1022
  45. ↑ Chang Y et al. Higher Concentrations of Alanine Aminotransferase within the Reference Interval Predict Nonalcoholic Fatty Liver Disease. Clinical Chemistry 2007;53(4):686–692
  46. ↑ MIshra P et al. Abdominal Ultrasound for Diagnosis of Nonalcoholic Fatty Liver Disease (NAFLD). Am J Gastroenterol 2007;102:2716–2717).
  47. ↑ Saadeh et al. The Utility of Radiological Imaging in Nonalcoholic Fatty Liver Disease. GASTROENTEROLOGY 2002;123:745–750
  48. ↑ Taouli B et al. Advanced MRI Methods for Assessment of Chronic Liver Disease. AJR 2009; 193:14–27.
  49. ↑ McPherson S et al. Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered. J Hepatol. 2009;51(2):389-97
  50. ↑ Skelly et al. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol 2001;35:195-9
  51. ↑ Angula P. Nonalcoholic Fatty Liver Disease. NEJM. 2002 346(16):1221-31
  52. ↑ Brunt EM, Janney CG, Di Bisceglie AM et al. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 1999; 94(9):2467-2474
  53. ↑ Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3. PMID 14506393
  54. ↑ Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis:one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.Gastroenterology 2008;135:100-10.
  55. ↑ Sanyal AJ et al.Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med 2010;362:1675-85.

External links

  • NIH page on Nonalcoholic Steatohepatitis


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