Leptin in the treatment of lipodystrophy-associated nonalcoholic fatty liver disease: are we there already?

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Date: Aug. 2013
Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 2,219 words
Lexile Measure: 1360L

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Author(s): Mariana Verdelho Machado 1 , Helena Cortez-Pinto [*] 2



adipose tissue; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; lipodystrophy; leptin

Summary of methods & results

In the recent paper by Zadeh et al . [1] , the authors increased the cohort of previous studied patients with lipodystrophy (LD), treated with leptin replacement, published in 2005 [2] , further extending the duration of therapy for more than 2 years. This is the largest cohort of patients with congenital or acquired LD, which evaluates the spectrum of liver disease and the effect on liver histology of leptin replacement.

This study comprises a heterogenic population, with patients with acquired and congenital, generalized and partial LD, and with a wide age range, from 7-year-old children to 68-year-old elderly people. That heterogeneity translates a difficulty in recruiting patients with such rare conditions, with less than 1000 cases diagnosed worldwide [3] but brings confounders to the interpretation of the results. Added to this, is the open-label, uncontrolled design of the study.

At baseline, 90% of the patients had steatosis, mimicking what occurs in morbid obesity [4] . However, more than 80% presented nonalcoholic steatohepatitis (NASH), making LD the condition in which the presence of hepatic steatosis precludes the highest risk for NASH, as compared with other high-risk populations, such as obese and Type 2 diabetics. Also, four patients presented with autoimmune hepatitis, at baseline or during follow-up, all of them with acquired generalized LD (Lawrence-Seip Syndrome), which is known to have an autoimmune basis, in a quarter of the patients [5] . Furthermore, four out of 50 patients, 8%, presented with advanced cirrhosis, highlighting the potential for fibrosis progression and life-threatening terminal liver disease. Of note, severity of liver disease varied among different conditions, with the congenital generalized LD type 2, with mutation in BSCL2 gene, having the most extreme fibrosis at an earlier age. In fact, this is the most severe form of congenital generalized LD [6] , representing the only whole-body form of congenital LD, resulting from loss of seipin, involved in adipocyte differentiation and formation of lipid droplets [5] . Apart from these patients, advanced fibrosis only occurred in patients with other concomitant liver disease, autoimmune or viral hepatitis.

As expected, leptin replacement had a beneficial metabolic response, decreasing fasting triglycerides, glucose and hemoglobin A1c. Aminotransferases also decreased significantly.

Only 27 out of the 50 patients included had a second liver biopsy, of which 22 after at least 1 year of treatment. The majority showed improved liver histology, with a decrease in the NASH activity, steatosis and hepatocyte ballooning. At the second biopsy, only 33% of patients continued fulfilling the criteria for NASH; no changes in inflammation (which was mild at baseline) or in fibrosis.


In obesity, adipose tissue cannot deal with excess energy spilling-out fat that accumulate ectopically, leading to nonalcoholic fatty liver disease (NAFLD), in some cases with inflammation associated, NASH. However, in the absence of adipose tissue, the same happens without energy surplus, because we lose the fat reservoir. Adipose tissue is also a major source...

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Gale Document Number: GALE|A341859524