Clinical Features and Natural History of Nonalcoholic Steatosis Syndromes

Yngve Falck-Ytter; Zobair M. Younossi; Giulio Marchesini; Arthur J. McCullough

doi:10.1055/s-2001-12926

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2001; 21(1): 017-026
DOI: 10.1055/s-2001-12926

Clinical Features and Natural History of Nonalcoholic Steatosis Syndromes

Yngve Falck-Ytter¹ , Zobair M. Younossi² , Giulio Marchesini³ , Arthur J. McCullough¹

¹The Schwartz Center for Metabolism and Nutrition and the Gastroenterology Division at MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio
²The Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, Virginia
³The University of Bologna, Bologna, Italy

Abstract

ABSTRACT

Nonalcoholic steatohepatitis, along with other forms of nonalcoholic fatty liver disease, is a chronic liver disease that is attracting increasing significance. It is a clinicopathologic syndrome that was originally described in obese, diabetic females who denied alcohol use but in whom the hepatic histology was consistent with alcoholic hepatitis. This typical patient profile has been expanded and is now recognized to occur even in normal weight males without overt abnormalities in carbohydrate metabolism. Although originally believed to be a benign clinical entity, nonalcoholic steatohepatitis is now recognized as a cause of progressive fibrotic liver disease with adverse clinical sequelae. It is important to emphasize that nonalcoholic steatohepatitis is best considered one type of a larger spectrum of nonalcoholic fatty liver disease that is a consequence of insulin resistance and ranges from fat alone to fat plus inflammation, fat plus ballooning degeneration, and nonalcoholic steatohepatitis, the latter being the most serious form. As with any disease, the clinical importance of nonalcoholic steatohepatitis is related to its prevalence and natural history. Recent studies using different methodologies indicate that in the general population the prevalence of fatty liver and nonalcoholic steatohepatitis is approximately 20% and 3%, respectively. These prevalence rates are increased in certain subpopulations such as obesity and type II diabetes. Of greater concern is the recognition that cirrhosis and liver-related deaths occur in approximately 20% and 8% of these patients, respectively, over a 10-year period. Risk factors for these adverse clinical symptoms include patients older than the age of 45, the presence of diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio >1 and hepatic histology. However, a number of important unresolved issues must be clarified before the true natural history of this disease can be fully understood.

KEYWORD

Nonalcoholic fatty-liver liver disease - nonalcoholic steatohepatitis - natural history - cirrhosis - obesity

Full Text

References

REFERENCES

1 Ludwig J, Viggiano T R, McGill D B. Non-alcoholic steatohepatitis. Mayo Clinic experiences with a hither to unnamed disease. Mayo Clin Proc . 1980; 55 434-438
2 Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med . 1979; 67 811-816
3 Thaler H. Relation of steatosis to cirrhosis. Clin Gastroenterol . 1957; 4 273-280
4 Lee R G. Non-alcoholic steatohepatitis: a study of 49 patients. Hum Pathol . 1989; 20 594-598
5 Powell E E, Cooksley W G, Hanson R. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology . 1990; 11 74-80
6 Bacon B R, Farahvash M J, Janney C G. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology . 1994; 107 1103-1109
7 Matteoni C A, Younossi Z M, Gramlich T. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology . 1999; 116 1413-1419
8 Fong D G, Nehra V, Lindor K. Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology . 2000; 32 3-10
9 Burt A D, Mutton A, Day C P. Diagnosis and interpretation of steatosis and steatohepatitis. Semin Diagn Pathol . 1998; 15 246-258
10 Marchesini G, Brizi M, Morselli-Labate A M. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med . 1999; 107 450-455
11 Itoh S, Igarashi M, Tsukada Y. Nonalcoholic fatty liver with alcoholic hyalin after long term glucocorticoid therapy. Acta Hepatogastroenterol . 1977; 24 415-418
12 Seki K, Minami Y, Nishikawa M. ``Nonalcoholic steatohepatitis'' induced by massive doses of synthetic estrogen. Gastroenterol Jpn . 1983; 18 197-203
13 Poucell S, Ireton J, Valencia-Mayoral P. Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies. Gastroenterology . 1984; 86 926-936
14 Pessayre D, Bichara M, Degott C. Perhexiline maleate-induced cirrhosis. Gastroenterology . 1979; 76 170-177
15 Barbany G, Uzzan F, Larrey D. Alcoholic-like liver lesions induced by nifedipine. J Hepatol . 1989; 9 252-255
16 Hamilton D L, Vest T K, Brown B S. Liver injury with alcoholic like hyalin after gastroplasty for morbid obesity. Gastroenterology . 1983; 85 722-726
17 Peters R L. Hepatic morphologic changes after jejunoileal bypass. Prog Liver Dis . 1979; 6 581-594
18 Craig R M, Neumann T, Jeejeebhoy K N. Severe hepatocellular reaction resembling alcoholic hepatitis with cirrhosis after massive small bowel resection and prolonged total parenteral nutrition. Gastroenterology . 1980; 70 131-137
19 Grimm I S, Schindler W, Haluszka O. Steatohepatitis and fatal hepatic failure after biliopancreatic diversion. Am J Gastroenterol . 1992; 87 775-779
20 Partin J S, Partin J C, Schubert W K. Liver ultrastructure in abetalipoproteinemia: evolution of micronodular cirrhosis. Gastroenterology . 1974; 67 107-118
21 Tarugi P, Lonardo A, Ballarini G. Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology . 1996; 111 1125-1133
22 Kimura H, Kako M, Yo K. Alcoholic hyalins (Mallory bodies) in a case of Weber-Christian disease: electron microscopic observations of liver involvement. Gastroenterology . 1980; 78 807-812
23 Fleming C R. Hepatobiliary complications in adults receiving nutrition support. Dig Dis . 1994; 12 191-198
24 Solis-Herruzo J A, Castellano G, Colina F. Hepatic injury in the toxic epidemic syndrome caused by ingestion of adulterated cooking oil. Hepatology . 1984; 4 131-139
25 Nazim M, Stamp G, Hodgson H J. Non-alcoholic steatohepatitis associated with small intestinal diverticulosis and bacterial overgrowth. Hepatogastroenterology . 1989; 36 349-351
26 Hautekeete M L, Degott C, Benhamou J P. Microvesicular steatosis of the liver. Acta Clin Belg . 1990; 45 311-326
27 Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J Hepatol . 1997; 26(suppl 2) 43-53
28 Fromenty B, Berson A, Pessayre D. Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation. J Hepatol . 1997; 26(suppl 2) 13-22
29 Nomura H, Kashiwagi S, Hayashi J. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med . 1988; 27 142-149
30 Nonomura A, Mizukami Y, Unoura M. Clinicopathologic study of alcohol-like liver disease in non-alcoholics; non-alcoholic steatohepatitis and fibrosis. Gastroenterol Jpn . 1992; 27 521-528
31 Araujo L M, DeOliveira D A, Nunes D S. Liver and biliary ultrasonography in diabetic and non-diabetic obese women. Diabetes Metab . 1998; 24 458-462
32 Hultcrantz R, Glaumann H, Lindberg G. Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum aminotransferases. Scand J Gastroenterol . 1986; 21 109-113
33 Lonardo A, Bellini M, Tartoni P. The bright liver syndrome: prevalence and determinants of a ``bright'' liver echo pattern. Ital J Gastroenterol Hepatol . 1997; 29 351-356
34 El-Hassan A Y, Ibrahim E M, Al-Mulhim F A. Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and influence on patient management. Br J Radiol . 1992; 65 774-778
35 Propst A, Propst T, Judmaier G. Prognosis in non-alcoholic steatohepatitis (Letter). Gastroenterology . 1995; 108 1607
36 Hilden M, Christoffersen P, Juhl E. Liver histology in a ``normal'' population-examinations of 503 consecutive fatal traffic casualties. Scand J Gastroenterol . 1977; 12 593-597
37 Ground K E. Liver pathology in aircrew. Aviat Space Environ Med . 1982; 53 14-18
38 Ballentani S, Saccoccio G, Masutti F. Prevalence of and risk factors for hepatic steatosis in northern Italy. Ann Intern Med . 2000; 132 112-117
39 Diehl A M, Goodman Z, Ishak K G. Alcohol-like liver disease in non-alcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology . 1988; 95 1056-1062
40 Itoh S, Yougel T, Kawagoe K. Comparison between non-alcoholic steatohepatitis and alcoholic hepatitis. Am J Gastroenterol . 1987; 82 650-654
41 Angulo P, Keach J C, Batts K P. Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis. Hepatology . 1999; 30 1356-1362
42 Baldridge A D, Perez-Atayde A R, Graeme-Cook F. Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr . 1995; 127 700-704
43 Moran J R, Ghishan F K, Halter S A. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol . 1983; 78 374-377
44 Kinugasa A, Tsunamota K, Furukawa N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr . 1984; 3 408-414
45 Rashid M, Roberts E A. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr . 2000; 30 48-52
46 Sheth S G, Gordon F D, Chopra S. Non-alcoholic steatohepatitis. Ann Intern Med . 1997; 126 137-145
47 Sanyal A J. Non-alcoholic steatohepatitis. Clin Perspect Gastroenterol . 2000; (May/June) 129-139
48 Kumar K S, Malet P F. Nonalcoholic steatohepatitis. Mayo Clin Proc . 2000; 75 733-739
49 VanNess M M, Diehl A M. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes?. Ann Intern Med . 1989; 111 473-478
50 Pinto H C, Baptista A, Camilo M E. Non-alcoholic steatohepatitis: clinicopathological comparison with alcohol hepatitis in ambulatory and hospitalized patients. Dig Dis Sci . 1996; 41 172-179
51 Fletcher L M, Kwoh-Gain I, Powell L W. Markers of chronic alcohol ingestion in patients with non-alcoholic steatohepatitis: an aid to diagnosis. Hepatology . 1991; 13 445-459
52 George D K, Goldwurm S, MacDonald G A. Increased hepatic iron concentration in non-alcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology . 1998; 114 311-318
53 Bonkovsky H L, Jawaid Q, Tortorelli K. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol . 1999; 31 421-429
54 Saleh J, Sniderman A D, Cianflone K. Regulation of plasma fatty acid metabolism. Clin Chem Acta . 1999; 286 163-180
55 Neuschwander-Tetri B A, Bacon B R. Non-alcoholic steatohepatitis. Med Clin North Am . 1996; 80 1147-1166
56 Scheuer P J, Ashrafzadeh P, Sherlock S. The pathology of hepatitis C. Hepatology . 1992; 15 567-571
57 Moriya K, Yotsuyanagi H, Shintani Y. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol . 1997; 78 1527-1531
58 Moriya K, Fujie H, Shintani Y. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med . 1998; 4 1065-1067
59 Rogers D W, Lee C H, Pound D C. Hepatitis C does not cause non-alcoholic steatohepatitis. Dig Dis Sci . 1992; 37 1644-1647
60 McCullough A J, Falck-Ytter Y. Body composition and hepatic steatosis as precursors for fibrotic liver disease. Hepatology . 1999; 29 1328-1330
61 Fiore G, Fera G, Napoli N. Liver steatosis and chronic hepatitis C. A spurious association?. Eur J Gastroenterol Hepatol . 1996; 8 125-129
62 McCullough A J, O'Connor J BF. Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology. Am J Gastroenterol . 1998; 93 2022-2036
63 McCulloough A J. Alcoholic liver disease. In: Schiff ER, Sorrell MF, Maddrey WC (eds). Schiff's Diseases of the Liver, 8th ed. Philadelphia: Lippincott-Raven 1999: 942-971
64 Teli M R, James O F, Burt A D. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology . 1995; 22 1714-1719
65 Coates R A, Halliday M L, Rankin J G. Risk of fatty liver infiltration of cirrhosis of the liver in relation to ethanol consumption: a case-control study. Clin Invest Med . 1986; 9 26-32
66 Bird G L, Williams R. Factors determining cirrhosis in alcoholic liver disease. Mol Aspects Med . 1988; 10 97-105
67 Becker U, Deis A, Sorensen T I. Prediction of risk of liver disease by alcohol intake, sex and age: a prospective population study. Hepatology . 1996; 23 1025-1029
68 Naveau S, Giraud V, Borotto E. Excess weight as a risk factor for alcoholic liver disease. Hepatology . 1997; 25 108-111
69 Bellentani S, Saccoccio G, Costa G. Drinking habits as co-factors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut . 1997; 41 845-850
70 Kitchens J M. Does this patient have an alcohol problem?. JAMA . 1994; 272 1782-1787
71 Lumeng L. New diagnostic markers of alcohol abuse. Hepatology . 1986; 6 742-745
72 Chick J, Erickson C. Conference summary: Consensus Conference on alcohol dependence and the role of pharmacotherapy in its treatment. Alcohol Clin Exp Res . 1996; 20 391-402
73 Storey E L, Anderson G J, Mark U. Desialylated transferrin as a serological marker of chronic excessive alcohol ingestion. Lancet . 1987; 1 1292-1294
74 Stibler H. Carbohydrate deficient transferrin in serum: a new marker of potentially harmful alcohol consumption reviewed. Clin Chem . 1998; 37 2029-2037
75 Rosman A S, Lieber C S. Diagnostic utility of laboratory tests in alcoholic liver disease. Clin Chem . 1994; 40 1641-1651
76 Washington K, Wright K, Shyr Y. Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver. Hum Pathol . 2000; 31 822-828
77 Brolin R E, Bradley L J, Taliwal R V. Unsuspected cirrhosis discovered during obesity operations. Arch Surg . 1998; 133 84-88
78 Abdelmalek M, Ludwig J, Lindor K D. Two cases from the spectrum of non-alcoholic steatohepatitis. J Clin Gastroenterol . 1995; 20 127-130
79 Caldwell S H, Oelsner D H, Iezzoni J C. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology . 1999; 29 664-669
80 Wanless I R, Lentz J S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology . 1990; 12 1106-1110
81 Brunt E M, Janney C G, DiBisceglie A M. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol . 1999; 94 2467-2474
82 Younossi Z M, Gramlich T, Liu Y C. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol . 1998; 11 560-565
83 U.S. Bureau of the Census Statistical Abstract of the United States. 1997, 117th ed. Washington, DC U.S. Bureau of the Census 1997
84 Younossi Z M, Gramlich T, Bacon B R. Hepatic iron and nonalcoholic fatty liver disease. Hepatology . 1999; 30 847-850
85 Ratziu V, Giral P, Charlotte F. Liver fibrosis in overweight patients. Gastroenterology . 2000; 118 1117-1123
86 Day C P, James O F. Steatohepatitis: a tale of two ``hits''?. Gastroenterology . 1998; 114 842-845
87 Sorbi D, Boynton J, Lindor K D. The ratio of aspartate amino transferase to alanine amino transferase: potential value in differentiating non-alcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol . 1999; 94 1018-1022
88 Andersen T, Gluud C. Liver morphology in morbid obesity: a literature study. Int J Obes . 1984; 8 97-106
89 Nasrallah S M, Wills C E, Galambos J T. Hepatic morphology in obesity. Dig Dis Sci . 1981; 26 325-327
90 Kern W H, Heger A H, Payne J H. Fatty metamorphosis of the liver in morbid obesity. Arch Pathol . 1973; 96 342-346
91 Klain J, Fraser D, Goldstein J. Liver histology abnormalities in the morbidly obese. Hepatology . 1989; 10 873-876
92 Wanless I R, Bargman J M, Oreopoulos D G. Subcapsular steatonecrosis in response to peritoneal insulin delivery: a clue to the pathogenesis of steatonecrosis in obesity. Mod Pathol . 1989; 2 69-74
93 Braillon A, Capron J P, Herve M A. Liver in obesity. Gut . 1985; 26 133-139
94 Nomura F, Ohnishi K, Satomura Y. Liver function in moderate obesity-study in 534 moderately obese subjects among 4613 male company employees. Int J Obes . 1986; 10 349-354
95 Day C P, James O F. Hepatic steatosis: innocent bystander or guilty party?. Hepatology . 1998; 27 1463-1466
96 Parola M, Pinzani M, Casini A. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen α1 (I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun . 1993; 194 1044-1050
97 Lee K S, Buck M, Houglum K. Activation of hepatic stellate cells by TGF α and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest . 1995; 96 2461-2468
98 Bedossa P, Houglum K, Trautwein C. Stimulation of collagen alpha 1 (I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis?. Hepatology . 1994; 19 1262-1271
99 Kral J G, Schaffner F, Pierson R N, Wang J. Body fat topography as an independent prediction of fatty liver. Metabolism . 1993; 42 548-551
100 Banerji M A, Buckley M C, Chaiken R L. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin resistant black men with NIDDM. Int J Obes Relat Metab Disord . 1995; 19 846-850
101 Tominaga K, Kurata J H, Chen Y K. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci . 1995; 40 2002-2009
102 Peiris A N, Mueller R A, Smith G A. Splanchnic insulin metabolism in obesity. Influence of body fat distribution. J Clin Invest . 1986; 78 1648-1657
103 Meek S E, Nair K S, Jensen M D. Insulin regulation of regional free fatty acid metabolism. Diabetes . 1999; 48 10-14
104 Barzilai N, Banerjee S, Hawkins M. Calorie restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J Clin Invest . 1998; 101 1353-1361
105 Barzilai N, She L, Liu B Q. Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes . 1999; 48 94-98
106 Jick S S, Stender M, Myers M W. Frequency of liver disease in type 2 diabetic patients treated with oral antidiabetic agents. Diabetes Care . 1999; 22 2067-2071
107 Casselman W GB, Kaplan A, Bockus H L. Studies of hepatic function in diabetes mellitus, portal cirrhosis and other liver diseases. Am J Med . 1955; 18 354-384
108 Leevy C M, Ryan C M, Fineberg J C. Diabetes mellitus and liver dysfunction. Am J Med . 1950; 8 290-299
109 Jaques W E. The incidence of portal cirrhosis and fatty metamorphosis in patients dying with diabetes mellitus. N Engl J Med . 1953; 249 442-445
110 Creutzfeldt W, Frerichs H, Sickinger K. Liver diseases and diabetes mellitus. Prog Liver Dis . 1970; 3 371-407
111 Abraham S, Furth E E. Receiver operating characteristic analysis of glycogenated nuclei in liver biopsy specimens: quantitative evaluation of their relationship with diabetes and obesity. Hum Pathol . 1994; 25 1063-1068
112 Silverman J F, O'Brien K F, Long S. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol . 1990; 85 1349-1355
113 Falchuk K R, Fiske S C, Haggitt R C. Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus. Gastroenterology . 1980; 78 535-541
114 Younossi Z M, Matteoni C A, Gramlich T L. Diabetes and non-alcoholic fatty liver disease: a worrisome combination. Gastroenterology . 1999; 116(Abs) 1292
115 Marceau P, Biron S, Hould F S. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab . 1999; 84 1513-1517
116 Knobler H, Schattner A, Zhornicki T. Fatty liver-an additional and treatable feature of the insulin resistance syndrome. QJM . 1999; 92 73-79