To the Editor:

The study by Mofrad1 is a laudable effort to better characterize the clinical spectrum of nonalcoholic fatty liver disease (NAFLD). Previous reports also showed that patients with NAFLD-induced cirrhosis have lower aminotransferase values than those with cirrhosis of other etiologies, 32 suggesting that low aminotransferase levels can coexist with severe histological injury.

In our view there are, however, several methodological limitations relative to the selection of patients and to the definition of “normal” alanine aminotransferase (ALT). Lessons from hepatitis C patients with “normal” ALT levels have taught us that repeated measurements of ALT activity are necessary before concluding that ALT levels are persistently low,4 while half of untreated patients experience rises in ALT.5 Sanyal rightly remarks that in NAFLD, ALT levels can fluctuate6; therefore, a single measurement is insufficient to conclude about the normalcy of ALT. Also, patients included here might have a predisposition toward more severe liver disease. Indeed, most of them (31/51) had various abnormal findings suggestive of liver disease. In this regard, they differ from patients with NAFLD and low ALT levels whom we see in our practice and who are asymptomatic. I

Table 1. Clinical and Laboratory Features of the Two Treatment Groups
Type of TreatmentPenicillamine GroupZinc Group
  1. Abbreviations: ALT, alanine aminotransferase.

Number of patients (males)86 (54)21 (12)
Median age at diagnosis in years (range)7.7 (1–18)5.5 (1–12.3)
Patients with liver disease79 (91%)15 (71%)
Patients with neurological disease4 (5%)2 (10%)
Pre-symptomatic3 (4%)4 (19%)
Basal median ALT values (U/L) (range)274 (54–640)177 (28–452)
Patients with ALT normalization at the end of follow-up56 (65%)12 (57%)
Patients with persistent hyper-ALT at the end of follow-up28 (32.5%)9 (43%)
Median ALT values in patients with persistent hyper-ALT (U/L) (range)76 (46–960)72 (45–268)

The most important problem lies with the definition of “normal” ALT. We believe that a threshold of 75 IU/L is abnormally high for defining normal ALT. The range of normal values was determined long ago in blood donors, on the assumption that absence of risk factors for blood-borne infections, together with low-risk sexual behavior, equates an absence of liver disease. It has been since recognized that ALT activity increases with body mass index7 and that a high body mass index is associated with liver disease.6, 8 The same holds true for the relation between serum triglycerides and ALT activity in patients with metabolic syndrome.9 When both metabolic and viral risk factors for liver disease are taken into account, the range of healthy ALT values is considerably reduced.10. By these standards, 71% (36/51) of the patients reported on here would have had elevated ALT, as do most patients with NAFLD seen in hepatology clinics. The argument that, for analytical reasons, the normal reference value used in the institutional laboratory that performed the tests validates the “normality” of ALT needs also to be challenged. We showed that when ALT activity was measured on the same blood sample in nine different laboratories, interlaboratory variability was high when the result was expressed as upper limit of normal, with some laboratories considering it normal and others high, while this variability was significantly reduced when expressed as IU/L.11 Thus, for both epidemiological and analytical reasons, using a “normal” value of ALT, especially as high as the one proposed here, is questionable. It would be more appropriate, especially in NAFLD patients, to express the results in IU/L rather than as upper limit of normal and to compare the results to updated healthy ranges.10

Unquestionably, there is a group of asymptomatic patients with NAFLD who repeatedly have very low levels of ALT. Whether and in what proportion these patients have significant histological lesions remains to be established.


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  • 1
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    Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. HEPATOLOGY 2000; 32: 689692.
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    Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134140.
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    Bacon BR. Treatment of patients with hepatitis C and normal serum aminotransferase levels. HEPATOLOGY 2002; 36(5 Suppl 1 ): S179184.
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    Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 17051725.
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    Piton A, Poynard T, Imbert-Bismut F, Khalil L, Delattre J, Pelissier E, Sansonetti N, et al. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. MULTIVIRC Group. HEPATOLOGY 1998; 27: 12131219.
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    Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 11171123.
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    Bruckert E, Giral P, Ratziu V, Poynard T, Chapman MJ, Opolon P, Turpin G. A constellation of cardiovascular risk factors is associated with hepatic enzyme elevation in hyperlipidemic patients. Metabolism 2002; 51: 10711076.
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    Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002; 137: 1
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    Halfon P, Imbert-Bismut F, Messous D, Antoniotti G, Benchetrit D, Cart-Lamy P, Delaporte G, et al. A prospective assessment of the inter-laboratory variability of biochemical markers of fibrosis (FibroTest) and activity (ActiTest) in patients with chronic liver disease. Comp Hepatol 2002; 1: 3.

Vlad Ratziu*, Françoise Imbert-Bismut†, Djamila Messous†, Thierry Poynard*, * Service d'hépatogastroentérologie, Hospital Pitié Salpêtrière, Paris, France, † Fédération de Biochimie, Hospital Pitié Salpêtrière, Paris, France.