Edward D. Javor

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy.

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigans partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r‐metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r‐metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206→226 mg/dL, P = .002), glucose (220→144 mg/dL, P = .02), insulin (46.4→24.8 μIU/mL, P = .004), ALT (54→24 U/L, P = .02), AST (47→22 U/L, P = .046), liver volume (3209→2391 cm3, P = .007), and liver fat content (31→11%, P = .006). In conclusion, r‐metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH. (HEPATOLOGY 2005;41:753–760.)

Spectrum of renal diseases associated with extreme forms of insulin resistance.

Diabetic nephropathy is the leading cause of ESRD in the United States. Why the pathogenic mechanisms lead to nephropathy in certain patients with type 1 and 2 diabetes and spare others is unclear, but it is clear that hyperglycemia and glomerular hyperfiltration are important factors. In patients with syndromes of extreme insulin resistance, proteinuric forms of renal disease are common, but it is surprising to find that the renal pathology usually is not diabetic nephropathy. For instance, in the lipodystrophy syndromes, membranoproliferative glomerulonephritis type 1 and type 2, focal segmental glomerulosclerosis, and also diabetic nephropathy are seen. In the syndromes of autoantibodies to the insulin receptor, the various forms of lupus glomerulonephritis are seen. Even in patients with type 2 diabetes, the renal pathology may not be diabetic nephropathy. Therefore, in patients with syndromic forms of insulin resistance and type 2 diabetes, renal biopsy has an important role in defining the pathology that leads to proteinuric nephropathy and in formulating a therapeutic approach. It is the purpose of this article to review these unusual aspects of proteinuric nephropathy in patients with diabetes.

Clinical evidence that hyperinsulinaemia independent of gonadotropins stimulates ovarian growth

Objective  Ovarian enlargement is a constant feature of syndromes of extreme insulin resistance. The objective of this study is to show the role of insulin on ovarian growth in the presence of low gonadotropin levels.

Successful Renal Transplantation in a Patient with Congenital Generalized Lipodystrophy: A Case Report

This report documents what we believe to be the first suc-cessful case of renal transplantation in a patient with totallipodystrophy, a rare disorder of lipid metabolism.EC,a47-year-oldfemale,presentedtoourcenterwithcon-genitalgeneralizedlipodystrophyandrenalfailure.Sheorig-inally presented as a ‘case for diagnosis’ at age 8 months,as previously documented in the literature (1). Associ-ated with her primary diagnosis were insulin-resistant di-abetes mellitus, hypertriglyceridemia, steatohepatitis, andepisodes of pancreatitis. Atypical for persons with congen-ital lipodystrophy, she had five term pregnancies and onemiscarriage. She developed chronic renal failure at age 42,and progressed with nephrotic range proteinuria to end-stage renal disease at age 45. A renal biopsy was not per-formed. She was begun on hemodialysis at age 45, whichwas complicated by uremic pericarditis and GI bleeding.Upon evaluation for renal transplantation she had hema-turia, and 10 g of protein on a 24-h urine collection. ANAwas negative. Serum complements were not obtained.On physical exam, there was a comprehensive absenceof adipose tissue, acromegaloid features, hepatomegalyand a systolic ejection cardiac murmur. Laboratory stud-ies demonstrated a serum creatinine of 11 mg/dL, BUN127 mg/dL, and fasting lipid panel with total cholesterol213 mg/dL, triglycerides 1000 mg/dL, HDL 33 mg/dL, andLDL 178 mg/dL. The c-peptide was markedly elevatedto 30.7 ng/mL, indicative of profound insulin resistancecombined with renal failure. Owing to cholelithiasis anda history of pancreatitis, she underwent a pretransplantcholecystectomy and a liver biopsy, which revealed steato-hepatitis, with mild steatosis, minimal inflammatory infil-trate and perisinusoidal fibrosis.Before transplantation, the patient’s lipids were aggres-sively controlled with an HMG co-A reductase inhibitor,fenofibrateaswellasomega-3fattyacidsupplements(fishoil) and high doses of insulin (