We thank Dr. Targher, Dr. Manco, and their colleagues for their interest in our work. Both groups of investigators suggest that the existing literature and our observations regarding the correlation between the presence of dorsocervical lipohypertrophy (DCL) and severity of nonalcoholic steatohepatitis (NASH) indicate a dysfunction of the hypothalamic-pituitary axis (HPA). We completely agree with this assessment and had indeed suggested that this possibility should be systematically evaluated.1

Although we agree with Dr. Targher that clinical assessment of DCL is somewhat subjective and thus suspect to variable interpretation, there are also no well-validated and universally accepted quantitative measures of the presence of DCL that perform better than subjective assessment alone. We would also like to point out that the issue is quite complex and requires consideration of several points: (1) Is HPA dysfunction a feature of the metabolic syndrome or a specific feature of nonalcoholic fatty liver disease (NAFLD)? It is well known that several clock genes are affected in the metabolic syndrome and that the hypothalamus plays an important role in circadian rhythms.2 (2) Is HPA dysfunction required for the development of NAFLD, and does it contribute to the development of NASH? (3) What is the relationship of HPA dysfunction with the development of DCL? (4) How does DCL contribute to severity of NASH, for example, via cytokines, or is it simply a surrogate marker for more severe HPA dysfunction that drives NASH development or severity? These are currently the questions of greatest relevance in this area that need to be answered.

We also agree that measurement of free cortisol and its suppression by dexamethasone may provide valuable information about HPA dysfunction in NAFLD. We would, however, caution that such studies must include evaluation of liver histology, which is the only reliable method for assessment of NASH severity.

Finally, with respect to insulin resistance and cardiovascular risk profiles, we have reanalyzed our data as suggested by Dr. Manco. The waist circumference correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) in both females (r = 0.66, P < 0.0001) and males (r = 0.43, P < 0.03), but the hip circumference correlated significantly with HOMA-IR in females only (r = 0.35, P < 0.008).

In summary, we believe that the cumulative published data indicate that there is a subtle dysfunction of the HPA in NAFLD. These data raise several new questions that may provide important new information about the genesis of NAFLD and are thus worthy of investigation.


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Onpan Cheung M.D.*, Arun J. Sanyal M.D.*, * Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA.