med. J. Reichen
NON-ALCOHOLIC FATTY LIVER DISEASE/STEATOHEPATITIS
(non-alcoholic fatty liver disease) is characterized by accumulation of
fat in the hepatocytes (steatosis); this condition is frequent and
probably completely benign. If steatosis is associated with
inflammation, Mallory bodies and signs of impending cell
death such as ballooning, the entity is termed NASH (non-alcoholic
steatohepatitis). NASH can lead to fibrosis, cirrhosis and even
It is generally agreed now that
insulin resistance is at the center of the problem of NAFLD/NASH (1).
Some of the insulin resistance has a genetic background since NASH
tends to run in families (2). This explains the association with the
- Arterial hypertension
- Dyslipidemia, in particular
important to point out, however, that NAFLD/NASH can occur also in lean
subjects with insulin resistance (3). In the progression of NAFLD to
NASH tumor necrosis factor a
and adipokines, in particular adiponectin (4) play a major role. Iron
overload not due to HFE hemochromatosis leads to the Moirand syndrome,
first described by a French group (5). HFE mutations are found often in
NASH patients, in particular, heterozygosity for C282Y is associated
with advanced fibrosis in Caucasians (6).
and natural history
Up to 20 % of Western subjects suffer
from NAFLD as determined in a representative example of two Italian
towns (7). Only a minority of these will progress to NASH and
eventually cirrhosis. In a
population-based study from Olmsted country only 5 % developed
cirrhosis and 1.7 % died from a hepatic death or needed liver
transplantation (8). In a longitudinal study the same group found that
about 1/3 each progress, regress or remain stable with their fibrosis
grade; diabetes and elevated BMI were major risk factors for
progression (9). Cryptogenic cirrhosis is often due to NASH; in the
stage of cirrhosis, typical NASH features disappear (10). NASH is clearly a risk factor for
hepatocellular carcinoma (11); this can even occur in non-cirrhotic
liver (12). Otherwise, all the usual complications of end-stage liver
disease are seen in NASH cirrhosis.
- Weight loss induced through
life-style change is at the center of treatment (13). A weight loss of
> 5 % is needed to ameliorate liver enzymes (14); when medically
indicated bariatric surgery improves liver histology (15).
- Phlebotomies in patients with
iron overload (16).
- The best drug treatment has yet
to be defined and no general recommendation can be given at present.
Among the drugs being explored, PPAR-g
inhibitors hold promise but they induce weight gain (17). A recent
study from our institute has shown a favourable effect of the
combination of Vitamin E and ursodeoxycholic acid (18). Other
approaches include ursodeoxycholic acid, vitamin E, N-acetylcysteine,
betaine and benzofibrates which are discussed in recent reviews (13;19).
- For end-stage liver disease,
liver transplantation is an option but there is a significant rate of
- Bugianesi E, McCullough AJ,
Marchesini G. Insulin
resistance: A metabolic pathway to chronic liver disease. Hepatology
- Willner IR, Waters B, Patil SR,
Reuben A, Morelli J,
Riely CA. Ninety patients with nonalcoholic steatohepatitis: Insulin
resistance, familial tendency, and severity of disease. Am J
Gastroenterol 2001; 96(10):2957-2961.
- Marchesini G, Brizi M,
Morselli-Labate AM, Bianchi
G, Bugianesi E, McCullough AJ et al. Association of nonalcoholic fatty
liver disease with insulin resistance. Am J Med 1999; 107(5):450-455.Hui JM, Hodge A, Farrell GC, Kench JG,
George J. Beyond insulin resistance in NASH: TNF-a or adiponectin?
Hepatology 2004; 40(1):46-54.
- Moirand R, Mortaji AM,
Loréal O, Paillard F,
Brissot P, Deugnier Y. A new syndrome of liver iron overload with
normal transferrin saturation. Lancet 1997; 349:95-97.
- Moirand R, Jouanolle AM,
Brissot P, Le Gall JY,
David V, Deugnier Y. Phenotypic expression of HFE mutations: A French
study of 1110 unrelated iron-overloaded patients and relatives.
Gastroenterology 1999; 116(2):372-377.
- Nelson JE, Bhattacharya R,
Lindor KD et al. HFE C282Y mutations are associated with advanced
hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis.
Hepatology 2007; 46: 723-729.
- Bellentani S, Tiribelli C. The
spectrum of liver
disease in the general population: lesson from the Dionysos study. J
Hepatol 2001; 35(4):531-537.
- Adams LA, Lymp JF, St Sauver J,
Sanderson SO, Lindor
KD, Feldstein A et al. The natural history of nonalcoholic fatty liver
disease: A population-based cohort study. Gastroenterology 2005;
- Adams LA, Sanderson S, Lindor
KD, Angulo P. The
histological course of nonalcoholic fatty liver disease: a longitudinal
study of 103 patients with sequential liver biopsies. J Hepatol 2005;
- Poonawala A, Nair SP, Thuluvath
PJ. Prevalence of
obesity and diabetes in patients with cryptogenic cirrhosis: A
case-control study. Hepatology 2000; 32(4):689-692.
- Bugianesi E, Leone N, Vanni E,
Brunello F, Carucci P et al. Expanding the natural history from
cryptogenic cirrhosis to of nonalcoholic steatohepatitis:
Hepatocellular carcinoma. Gastroenterology 2002; 123(1):134-140.
- Bullock RE, Zaitoun AM, Aithal
GP, Ryder SD,
Beckingham IJ, Lobo DN. Association of non-alcoholic steatohepatitis
without significant fibrosis with hepatocellular carcinoma. J Hepatol
- Farrell GC, Larter CZ.
Nonalcoholic fatty liver
disease: From steatosis to cirrhosis. Hepatology 2006; 43(2):S99-S112.
- Suzuki A, Lindor K, St Saver J,
Lymp J, Mendes F,
Muto A et al. Effect of changes on body weight and lifestyle in
nonalcoholic fatty liver disease. J Hepatol 2005; 43(6):1060-1066.
- Dixon JB, Bhathal PS, Hughes
NR, O'Brien PE.
Nonalcoholic fatty liver disease: Improvement in liver histological
analysis with weight loss. Hepatology 2004; 39(6):1647-1654.
- Facchini FS, Hua NW, Stoohs RA.
Effect of iron
depletion in carbohydrate-intolerant patients with clinical evidence of
nonalcoholic fatty liver disease. Gastroenterology 2002; 122(4):931-939.
- Neuschwander-Tetri BA, Brunt
EM, Wehmeier KR, Oliver
D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of
treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;
- Dufour JF, Oneta CO, Gonvers JJ et al. Randomized
placebo-controlled trial of ursodeoxycholic acid with vitamin e in
nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 4: 1537-1543.
- Angulo P, Lindor KD. Treatment of
liver: Present and emerging therapies. Semin Liver Dis 2001;
- Angulo P. Nonalcoholic fatty liver
disease and liver
transplantation. Liver Transpl 2006; 12(4):523-534.
June 29th 1998
Last revision October 3rd 2007