| Study summary: |
|
Non-alcoholic fatty liver disease (NAFLD) steatohepatitis represents a spectrum of disease
occurring in the absence of alcohol abuse. It is characterized by the presence of steatosis
and may represent a hepatic manifestation of the metabolic syndrome (including obesity,
diabetes and hypertriglyceridemia). NAFLD is linked to insulin resistance, it causes liver
disease in adults and children and may ultimately lead to cirrhosis (Skelly et al., 2002).
The histologic spectrum of NAFLD ranges from the relatively benign isolated predominantly
macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to steatohepatitis (NASH)
(Angulo, & Lindor, 2002). The latter is characterized by the histologic presence of
steatosis, cytological ballooning, scattered inflammation and pericellular fibrosis(Contos &
Sanyal, 2002). Estimates of prevalence among children can be inferred from pediatric obesity
data and the knowledge that 85% of children with NAFLD are obese. Data from the National
Health and Nutrition Examination Survey has revealed a threefold rise in the prevalence of
childhood and adolescent obesity over the past 35 years; data from 2000 suggests that 14-16%
children between 6-19yrs age are obese with a BMI >95% (Fishbein, Miner, Mogren & Chalekson,
2003), and also the fact that 85% of children with NAFLD are obese.
Treatment of NASH currently revolves around the reduction of the two main pathogenetic
factors, namely, fat accumulation within the liver and excessive accumulation of free
radicals causing oxidative stress. Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is a
major endogenous antioxidant and its depletion is implicated in the development of
hepatocellular injury (Wu, Fang, Yang, Lupton & Turner, 2004). Glutathione itself is does
not enter easily into cells, even when given in large amounts. However, glutathione
precursors do enter into cells and have been shown to be effective in the treatment of
conditions such as acetaminophen toxicity by preventing significant GSH depletion (Prescott
& Critchley, 1983). Examples of GSH precursors include cysteine, N-acetylcysteine,
methionine and other sulphur-containing compounds such as cysteamine (Prescott, Park &
Proudfoot, 1976). Studies have demonstrated that orally and intravenously administered
cysteamine in mice and humans is effective in acetaminophen-induced hepatocellular injury
(Prescott, 1972; Prescott, Stewart & Proudfoot, 1978; Mitchell, Thorgeirsson, Potter, Jollow
& Keiser, 1974). Another study where N-acetylcysteine was used to treat NASH over a period
of 4-12 weeks demonstrated improved amniotransferase levels (Pamuk & Sonsuz, 2003),
suggesting that increasing GSH levels may have a hepato-protective role and may be useful in
the treatment of NASH. A possible mode of action of cysteamine is that it might react with
extracellular cystine to form cysteine which then is readily taken up into the cell and
transformed into GSH.
Recent studies have suggested that the essential amino acid cysteine is a major limiting
factor for GSH synthesis and that factors (e.g., insulin and growth factors) that stimulate
cysteine uptake by cells generally result in increased intracellular GSH levels (Lyons et
al., 2000; Lu, 2000).
Cysteamine, a GSH precursor, is currently available and is used in the treatment of
cystinosis, an intra-lysosomalcystine storage disorder. In cystinosis, cysteamine acts by
converting cystine to cysteine and cysteine-cysteamine mixed disulfide which are the both
able to leave the lysosome through the cysteine and lysine porters respectively (Gahl,
Theone & Shneider, 2002). Within the cytosol the mixed disulfide can be reduced by its
reaction with glutathione and the cysteine released can be used for further GSH synthesis.
The synthesis of GSH from cysteine is catalyzed by two enzymes, gamma-glutamylcysteine
synthetase and GSH synthetase. This pathway occurs in almost all cell types, with the liver
being the major producer and exporter or GSH. The reduced cysteine-cysteamine mixed
disulfide will also release cysteamine, which, in theory is then able to re-enter the
lysosome, bind more cystine and repeat the process (Dohil et al., 2006). In a recent study
in children with cystinosis, enteral administration of cysteamine resulted in increased
plasma cysteamine levels, which subsequently caused prolonged efficacy in the lowering of
leukocyte cystine levels (Dohil et al., 2006). This may have been due to "re-cycling" of
cysteamine when adequate amounts of drug reached the lysosome. If cysteamine does act in
this fashion, then GSH production may also be significantly enhanced. |
| Criteria: |
|
Inclusion Criteria:
- Biopsy confirmed diagnosis of non-alcoholic steatohepatitis (within past 12 months)
- Ages 10 yrs and older
- Must swallow tablets on a regular basis
- ALT level >60 iu/L
Exclusion Criteria:
- Subjects with known hypersensitivity to cysteamine
- History, currently or within the past 3 months, of the following conditions:
- Pancreatitis
- Inflammatory bowel disease
- Malabsorption
- Unstable heart disease, e.g., myocardial infarction, heart failure, arrhythmias.
- Unstable diabetes mellitus
- Any bleeding disorder.
- Zollinger-Ellison syndrome
- Malignant disease
- Subjects whom maybe pregnant or have health issues that make it unsafe for them
participate, or whose concomitant medical problems preclude them from committing to
the study schedule.
- No specific NASH medical therapy for 3 months such as vitamin E, s-adenosyl
methionine or metformin or other NAFLD study drugs. |