L-Carnitine Supplementation to Diet: A New Tool in Treatment of Nonalcoholic Steatohepatitis—A Randomized and Controlled Clinical Trial

Mariano Malaguarnera AP; Maria Pia Gargante MD; Cristina Russo MD; Tijana Antic MD; Marco Vacante MD; Michele Malaguarnera MD; Teresio Avitabile; Giovanni Li Volti AP; Fabio Galvano AP

Disclosures

Am J Gastroenterol

Abstract and Introduction

Abstract

Objectives: Nonalcoholic steatohepatitis (NASH) is a known metabolic disorder of the liver. No treatment has been conclusively shown to improve NASH or prevent disease progression. The function of L-carnitine to modulate lipid profile, glucose metabolism, oxidative stress, and inflammatory responses has been shown. The aim of this study was to evaluate the effects of L-carnitine's supplementation on regression of NASH.
Methods: In patients with NASH and control subjects, we randomly dispensed one 1-g L-carnitine tablet after breakfast plus diet and one 1 g tablet after dinner plus diet for 24 weeks or diet alone at the same dosage and regimen. We evaluated liver enzymes, lipid profile, fasting plasma glucose, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, homeostasis model assessment (HOMA)-IR, body mass index, and histological scores.
Results: At the end of the study, L-carnitine-treated patients showed significant improvements in the following parameters: aspartate aminotransferase (P=0.000), alanine aminotransferase (ALT) (P=0.000), γ-glutamyl-transpeptidase (γ-GT) (P=0.000), total cholesterol (P=0.000), low-density lipoprotein (LDL) (P=0.000), high-density lipoprotein (HDL) (P=0.000), triglycerides (P=0.000), glucose (P=0.000), HOMA-IR (P=0.000), CRP (P=0.000), TNF-α (P=0.000), and histological scores (P=0.000).
Conclusions: L-carnitine supplementation to diet is useful for reducing TNF-α and CRP, and for improving liver function, glucose plasma level, lipid profile, HOMA-IR, and histological manifestations of NASH.

Introduction

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease in the western countries. The prevalence is between 10% and 24% in the general population and reaches 75% in the obese groups.^[1,2] The pathogenesis of NASH is associated with disorders of energy metabolism, including obesity, insulin resistance, and dyslipidemia. The real mechanisms leading to NASH are still unclear, but nutritional, metabolic, genetic, viral, and other factors cause or contribute to fatty liver disease.^[3,4,5] The existing model that explains the pathogenesis of NASH is the "two-hit" hypothesis, first proposed by Day and James.^[6] According to this hypothesis, steatosis represents the "first hit," which increases the vulnerability of the liver to various "second hits" that in turn lead to the inflammation, fibrosis, and cellular death.^[6] Several factors have been suggested to constitute the second hit(s), such as oxidative stress, pro-inflammatory cytokines, and gut-derived bacterial endotoxin.^[6] It was observed that NASH is associated with a more atherogenic lipid profile, including hypertriglyceridemia, a higher plasma concentration of very low-density lipoprotein (VLDL) and LDL that are larger in size, and with lower levels of high-density lipoprotein (HDL).^[7,8] The function of the lipid was highlighted when Unger and Orci^[9] introduced the concept of lipoapoptosis according to which overaccumulation of lipids in nonadipose tissues leads to cell dysfunction and death. Given that, the presence of increased circulating and/or hepatic saturated fatty acids might promote the development and progression of liver damages activating apoptosis.^[10,11] Moreover, in the liver, the increase of fatty acids synthesis associated with the reduction of their delivery from hepatocytes by VLDL because of degradation of apolipoprotein B100 causes the unbalance of hepatic fat turnover resulting in steatosis.^[12] Fatty acids are a source of oxidative stress and damage of mitochondria with increased β-oxidation and raising levels of reactive oxygen species (ROS).^[13] Recently, it has been hypothesized that the L-carnitine, a quaternary amine, could improve the outcome of NASH, because it reduces lipid levels, limits oxidative stress, and modulates inflammatory responses.^[14] It performs a number of essential intracellular and metabolic functions, such as fatty acid transport, detoxification of potentially toxic metabolites, regulation of the mitochondrial acyl-Co A/CoA ratio, and stabilization of cell membranes. It has a pivotal role in the transport of long-chain fatty acids across the inner mitochondrial membrane. L-carnitine facilitates the elimination of short- and medium-chain fatty acids accumulating in mitochondria as a result of normal or abnormal metabolism.^[15] The aim of this study was to evaluate whether L-carnitine treatment could determine histological changes at liver biopsy and modify humoral parameters after a 24-week treatment in patients with NASH.

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Table 1. Baseline characteristics and laboratory parameters at enrollment
Laboratory parameter	Normal values	Diet	L-carnitine+diet	P value
No.		38	36	NS
Age (years)		47.8±5.8	47.9±5.4	NS
Gender (M/F)		20/18	20/16	NS
BMI (kg/m²)		26.5±3.8	26.6±3.7	NS
Heart rate (b.p.m.)		86 ±10	84±11	NS
SBP (mm Hg)		140±11	141±12	NS
DBP (mm Hg)		86±5	84±7	NS
Glucose (mmol/l)	5.0−7.0	6.10±0.67	6.14±0.69	NS
Insulin (mIU/l)	5.0−20.0	17.2±5.6	17.3±5.5	NS
C-peptide (mmol/l)	0.11±0.61	0.98±0.54	0.97±0.61	NS
Albumin (g/l)	34−50	48.2±5.4	47.8±5.6	NS
AST (IU/l)	10−45	135.4±15.1	132.8±14.7	NS
ALT (IU/l)	10−43	120.2±12.8	125.7±12.9	NS
ALP (IU/l)	80−260	196±55	194±60	NS
Prothrombin time (%)	85−100	94±9	95±10	NS
γ-GT (IU/l)	1−36	120.8±37.2	121.1±37.4	NS
Cholesterol (mmol/l)	5.17−6.18	6.24±0.66	6.28±0.64	NS
HDL cholesterol (mmol/l)	1.04−1.29	0.95±0.10	0.92±0.11	NS
LDL cholesterol (mmol/l)	1.55−4.4	4.68±0.82	4.74±0.83	NS
Triglycerides (mmol/l)	0.70−2.1	3.08±0.81	3.10±0.90	NS
CRP (mg/dl)	0.2−1.0	8.8±3.2	9.0±3.4	NS
TNF-α (pg/ml)	0.4−2.5	3.40±0.25	3.51±0.30	NS
HOMA-IR		4.66±0.74	4.72±0.78	NS

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CRP, C-reactive protein; DBP, diastolic blood pressure; γ-GT, γ-glutamyl-transpeptidase; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; SBP, systolic blood pressure; TNF-α, tumor necrosis factor-α; NS, not significant.

Table 2. Laboratory parameters in patients treated with placebo plus diet or L-carnitine plus diet before and after 24 weeks of treatment^a
	Group A (placebo+diet) n=38		Group B (L-carnitine+diet) n=36
	Before treatment	After 24 weeks	Before treatment	After 24 weeks
BMI (kg/m²)	26.5±3.8	25.4±3.9*	26.6±3.7	25.3±3.5*^†††
AST (IU/l)	124.2±12.8	78.1±21.4***^†	128.1±13.9	56.4±18.2***^†
ALT (IU/l)	112.8±13.1	75.4±13.9***^†	110.2±15.6	51.8±16.4***^†
γ-GT (IU/l)	98.2±18.2	77.8±19.4***^††	104.1±17.2	66.5±15.4***^††
Albumin (g/l)	48±5.1	48.7±5.4*^†††	47.8±5.4	48.1±5.6*^†††
Total cholesterol (mmol/l)	6.04±0.91	5.88±0.98*^†	6.09±0.94	4.78±0.82***^†
HDL (mmol/l)	0.98±0.12	1.10±0.14***^†††	0.96±0.14	1.16±0.12***^†††
LDL (mmol/l)	4.45±0.87	4.24±0.88*^†	4.52±0.95	3.15±0.66***^†
Triglycerides (mmol/l)	3.04±0.96	2.68±0.92*^†††	3.07±0.88	2.34±0.66***^†††
Glucose (mmol/l)	6.04±0.66	5.97±0.71*^†	6.12±0.69	5.32±0.55***^†
Insulin (mIU/l)	16.8±5.4	15.2±5.2*^†††	17.1±5.6	13.8±5.0**^†††
C-peptide (mmol/l)	0.96±0.4	0.94±0.41*^†††	0.98±0.41	0.93±0.62*^†††
HOMA-IR	4.5±0.67	4.03±0.71**^†	4.65±0.70	3.26±0.56***^†
CRP (mg/dl)	8.7±3.4	7.4±3.2*^††	9.1±3.2	5.2±3.1***^††
TNF-α (pg/ml)	1.38±0.22	1.30±0.21*^†	1.44±0.28	1.08±0.15***^†

ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CRP, C-reactive protein; γ-GT, γ-glutamyl-transpeptidase; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; TNF-α, tumor necrosis factor-α; NS, not significant.
^a All values are x ± s.d.
Comparison within group A and within group B according to the values before the treatment.
*P = NS; **P < 0.05; ***P < 0.001.
Comparison between groups A and B after 24 weeks of treatment.
^† P < 0.001; ^†† P < 0.05; ^†††NS.

Table 3. Histological data in patients treated with placebo plus diet or L-carnitine plus diet before and after 24 weeks of treatment^a
Parameter (0–4)	Group A (placebo+diet) n=38		Group B (L-carnitine+diet) n=36
Parameter (0–4)	Before treatment	After 24 weeks	Before treatment	After 24 weeks
Steatosis	2.79±0.47	1.68±0.76***^†	3.22±0.63	0.94±0.88***^†
Hepatocellular injury	2.66±0.47	1.47±0.64***^††	3.00±0.33	1.05±0.74***^††
Parenchymal inflammation	2.76±0.43	1.42±0.63***^†	3.22±0.48	1.94±0.7***^†
Portal inflammation	2.89±0.38	1.82±0.68***^††	2.77±0.48	1.28±0.80***^††
Fibrosis	2.74±0.44	1.89±0.72***^††	2.86±0.53	1.55±0.72***^††
Mallory bodies	2.74±0.50	1.53±0.72***^†††	2.94±0.47	1.42±0.68***^†††
NASH activity (0–12)^b	8.21±0.86	4.58±1.31***^†	9.42±0.76	3.19±1.71***^†

NASH, nonalcoholic steatohepatitis.
^aSum of steatosis, hepatocellular injury, and parenchymal inflammation.
^bAll values are x ± s.d.
Comparison within group A and within group B according to the values before the treatment.
*P = NS; **P < 0.05; ***P < 0.001.
Comparison between groups A and B after 24 weeks of treatment.
^† P < 0.001; ^†† P < 0.05; ^†††NS.

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