**8. How to find a breakthrough for NAFLD/NASH treatment?**

As mentioned before, NAFLD/NASH is in general a heterogeneous group of chronic liver diseases characterised by the accumulation of fat in the liver. The heterogeneity and variation of NAFLD/NASH as well as the sensitivity to many kinds of treatment procedures are reflected in a clinical and histologic spectrum, where some patients develop isolated steatosis of the liver, termed non-alcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation and consequent fibrosis termed as NASH and progress to liver cirrhosis/hepatocellular carcinoma.

Further research is required to determine why progressive scarring develops in only some patients with NASH, define the mechanisms that shift effective regeneration to pathologic scarring [168] and determine how wound-healing responses might be modulated to heal lipotoxicity without scarring [169].

Based on these findings, the risk for NASH is determined by the susceptibility of hepatocytes to toxic lipids and potential for repair of lipotoxic liver damage. Therapies for NASH might, therefore, include those that prevent hepatic lipotoxicity by alleviating systemic metabolic stress [170].

A nascent understanding of this heterogeneity would also suggest that 'combination therapy' might be one of the options for preventing the progression of NASH; however, considering the remarkably wide-ranged heterogeneity of the disease, it may be extremely expensive and sometimes futile. One possible treatment procedure might be the trial with 'bioactive drugs', which have multiple sites of action such as 'antioxidant', 'metabolic regulator' and 'anti-inflammatory effects' at the same time. The sites of action brought about by Laennec on NASH treatment might be so to speak "multicentric" and "covering a wide area" comparing with so called newly developing "monotherapy drugs".

The most important mechanism of Laennec/Porcine might be conducted by the regulation of iron metabolism, which is needed in many kinds of biochemical and biophysical reactions (**Figure 9**). Laennec/Porcine might act on multiple targets, affecting diverse pathological processes and leading to an increased ability to adapt.

### **Figure 9.**

*Possible mechanisms of hepatic iron deposition and pathogenetic roles of iron in NASH/NAFLD. 'Iron reduction therapy' such as phlebotomy or dietary iron restriction may be promising for patients with NASH/NAFLD to reduce insulin resistance as well as serum transaminase activities. Iron is a potent catalyst of oxidative stress and may act synergistically with other promoters of lipid peroxidation by catalysing these reactions. Iron overload can also directly cause lipid peroxidation, and one of the subsequent products, malondialdehyde, has been shown to activate HSCs in vitro, the major source of fibrogenesis in liver injury. Excessive triglyceride accumulation is the most likely first step. The second step may be related to an increase in oxidative stress, which in turn, triggers liver cell necrosis and activation of HSCs, both leading to fibrosis and ultimately to the development of cirrhosis. One of the potential cofactors suspected to enhance this oxidative stress is excessive hepatic iron accumulation (by the courtesy of Ref. [171], partially modified by the author).*

This fits seamlessly in the pathophysiologic model of NAFLD/NASH since diverse pathological processes are involved. This concept is really compatible with the site of action induced by Laennec/Porcine. So that, Laennec/Porcine is capable of covering wide range of pathological abnormalities in NAFLD/NASH (**Figures 10** and **11**). If the drug is safe, has no apparent side effects, is cost beneficial (250–300 USD/m), has multiple mechanisms, which will ameliorate NAFLD/NASH spectrum according to the individual pathogenic background, and its pharmacodynamics are clarified, attempts should be made to use such a drug for treating the patients with NAFLD/ NASH (**Figures 10** and **11**).

In conclusion, considering numerous factors being involved in the pathogenesis of NAFLD/NASH, one of the most preferable and reliable drugs for the control of these diseases might be the "Bioactives" such as Laennec/Porcine, which have multi-ranged sites of action and the potential to modulate iron metabolism appropriately through the action of "hepcidin inducer".

Further studies should confirm the role of iron overload and the meaning of hyperferritinemia in patients with chronic liver diseases, including NAFLD/NASH. 'Hepcidin inducing therapy' using Laennec/Porcine might be one of the preferable treatment options for controlling wide-ranged NAFLD/NASH along with complicating T2DM (**Figures 10** and **11**).

### **Figure 10.**

*Targets of upcoming therapies for NASH are shown in this figure. The supposed sites of action of Laennec seem to be widespread compared with those of other newly developed 'single targeted drugs'. The expected sites of action of Laennec are graded* ★★*—*★★★★ *tentatively judging from formerly obtained data and clinical observations (by the courtesy of Ref. [172], partially modified by the author).*

### **Figure 11.**

*Traditional concept of drugs vs. the mode of actions (Laennec and Porcine), 'traditional' concept of action of drugs versus the contemporary concept of mode of actions such as Laennec and Porcine. Traditional drugs are developed to act on one target, leading to the absence of disease; however, the target diseases are complicated and consist of many kinds of factors. Laennec and Porcine act on multiple targets, affecting diverse pathological processes and leading to increased ability to adapt. This fits seamlessly in the pathophysiologic model of NAFLD since it involves diverse pathological processes. (Dr. Bregje Van De Wier, Ref. [173], partially modified by the author)*

*Regulation of Iron Metabolism in NAFLD/NASH DOI: http://dx.doi.org/10.5772/intechopen.107221*
