Table 1.
Summary intervention trials that altered growth hormone and studied the impact on nonalcoholic fatty liver/nonalcoholic steatohepatitis endpoints
| Author | Condition | NAFLD/NASH status | Design/intervention | Number of Subjects | Duration | NAFLD-related endpointsa | Glucose-related exclusion criteria | Glucose/insulin-related endpoints and discontinuations |
|---|---|---|---|---|---|---|---|---|
| Hypopituitary studies | ||||||||
| Nishizawa et al (30) | Hypopituitary GHD | Unselected for NAFLD | Open label daily GH | 19 | 6 months | ALT improved | ||
| Nishizawa et al (30) | Hypopituitary GHD | NASH (subset of above) | Open label daily GH | 5 | 6-12 months | Improved histologic steatosis and fibrosis | ||
| Meienberg et al (31) | Hypopituitary GHD | Unselected for NAFLD | Daily GH vs no treatment | 18 (9 GH, 9 untreated) | 6 months | No difference in absolute % ∆IHL | No difference in Δ FPG, fasting insulin, HOMA-IR or HbA1c | |
| Acromegaly studies | ||||||||
| Bredella, et al (32) | Active acromegaly | Unselected for NAFLD | Biochemical control | 16 | mean 8 months (3-22 months) | Increase in IHL by lipid/water ratio | Improved HOMA-IR, fasting insulin & OGTT insulin AUC; no ∆ in FPG or OGTT glucose AUC | |
| Reyes-Vidal et al (33) | Active acromegaly | Unselected for NAFLD | Biochemical control s/p TSS | 23 (12 with 1H-MRS) | 0.5-2 years | Increase in IHL | Improved FPG and HOMA-IR | |
| Winhofer et al (34) | Active acromegaly | Unselected for NAFLD | Biochemical control s/p TSS | 7 | 6 months | No change in absolute % IHL | T2DM | Improved fasting insulin; no change in FPG or mean OGTT glucose |
| Madsen et al (35) | Acromegaly controlled on SSA | Unselected for NAFLD | Randomized: continue SSA vs PEG + reduced dose SSA | 18 (6 SSA, 12 PEG + SSA) | 6 months | Increase in % IHL and ALT in PEG + SSA vs SSA group | No difference in ΔHOMA-IR | |
| Kuker et al (36) | Active acromegaly | Unselected for NAFLD | Initiation of PEG therapy | 21 | mean 5.7 years (1-13.4 years) | Increase in % IHL with PEG: 1.8% to 3.0%, P = 0.04 | Improved HOMA-IR, QUICKI and HbA1c with PEG | |
| Obesity studies | ||||||||
| Pan et al (37) | Young adults (18-29 years) with obesity and NAFLD | NAFLD (≥5% IHL by 1H-MRS) | Randomized, open-label daily GH vs no treatment | 24 (13 GH) | 6 months | No difference in ∆ % IHL or Δ ALT; NAFLD resolution (<5% IHL): 5/9 GH vs 1/9 no treatment | T2DM or any antidiabetic medications | No difference in FPG or OGTT 2hPG. Discontinuations: no subject met drop criteria (FPG > 126 mg/dL or OGTT 2hPG > 200 mg/dL). |
| Bredella et al (38) | Adult men (18-45 years), BMI ≥ 25 kg/m2 and abdominal fat | Unselected for NAFLD | Randomized, double-blind: daily GH vs placebo | 62 (32 GH) | 6 months | Decrease in IHL by ∆ in lipid/water ratio when controlled for ∆ weight | T2DM, FPG ≥ 126 mg/dL, OGTT 2hPG ≥200 mg/dL | Increase in OGTT 2hPG in GH vs pbo; no difference in FPG, HbA1c or HOMA-IR. Discontinuations: 5 subjects met drop criteria, including 2 GH with FPG ≥ 126 mg/dL, 1 GH and 1 placebo with OGTT 2h PG ≥ 200 mg/dL, and 1 GH with HbA1c ≥ 6.5%. |
| HIV and NAFLD studies | ||||||||
| Stanley et al (39) | Adults (18-65 years) with HIV and abdominal fat | Unselected for NAFLD | Randomized, double-blind: daily tesamorelin vs placebo | 54 (28 tesamorelin) | 6 months | Decrease in IHL in tesamorelin group; absolute net treatment effect -2.9%, P = 0.003 | FPG ≥ 126 mg/dL or use of antidiabetic meds | Increased HbA1c; no effect on FPG, OGTT 2hPG, fasting insulin or HOMA-IR; euglycemic hyperinsulinemic clamp (n = 24): IS decreased at 3 months, no longer significant at 6 months. Four subjects met hyperglycemia criteria: n = 1 per group with FPG ≥ 126 mg/dL and n =1 per group with OGTT 2hPG ≥ 200 mg/dL. No subjects met discontinuation criteria of FPG ≥ 150 mg/dL. |
| Stanley et al (40) | Adults (18-70 years) with HIV and NAFLD | NAFLD (≥5% IHL by 1H-MRS) | Randomized, double-blind: daily tesamorelin vs placebo | 61 (31 tesamorelin) | 12 months | Decrease in IHL in tesamorelin vs placebo group: absolute net treatment effect −4.1% (−7.6% to 0.7%), P < 0.02; no treatment effect on ALT | T2DM unless HbA1c ≤ 7% on stable antidiabetic meds (≥6 months) and no insulin or TZDs. Tesamorelin group had 12.9% with T2DM and 9.7% on antidiabetic meds at baseline; similar rates in placebo group. | No treatment effect on FPG or HbA1c. Number meeting hyperglycemia criteria (FPG ≥ 126 mg/dL) were similar in tesamorelin (12/31) vs placebo (11/30) groups. Two subjects in tesamorelin met discontinuation criteria: 1 FPG > 150 mg/dL (non-T2DM drop) and 1 FPG > 180 mg/dL (T2DM drop). |
Abbreviations: 1H-MRS, proton magnetic resonance spectroscopy; 2hPG, 2-hour plasma glucose; ALT, alanine aminotransferase; AUC, area under the curve; BMI, body mass index; FPG, fasting plasma glucose; GHD, growth hormone deficiency; HbA1c, glycated hemoglobin A1c; HIV, human immunodeficiency virus; HOMA-IR, homeostatic model assessment for insulin resistance; IHL, intrahepatic lipid; IS, insulin sensitivity; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OGTT, oral glucose tolerance test; PEG, pegvisomant; QUICKI, Quantitative Insulin Sensitivity Check Index; SSA, somatostatin analog; s/p TSS, status post transsphenoidal surgery; T2DM, type 2 diabetes mellitus; TZD, thiazolidinediones.
aSteatosis endpoints by 1H-MRS unless otherwise noted.