**6. Future directions**

Hepatocyte transplantation has been studied predominantly in patients with chronic metabolic disorders. There is evidence, however, that partial liver engraftment is possible and there may be improvement in neurological status, as noted in small groups of patients with ALF who have undergone hepatocyte transplantation (Bilir et al., 2000; Habibullah et al., 1994; Strom et al., 1997). Xenotransplantation is an intriguing concept and porcine livers have been used for ex vivo perfusion but in vivo use has not yet proven effective due to problems with transspecies rejection. Bioartificial livers and extracorporeal liver assist devices (ELAD) have been used to bridge patients to transplantation and have demonstrated improved neurologic outcomes. There are two cell-based devices. One uses porcine hepatocytes and did not show survival advantage in one large multicenter study and another uses hepatoblastoma cells which was noted to decrease severity of encephalopathy without change in survival in one study (Demetriou et al., 2004; Ellis et al., 1996). Non-biological systems also exist such as albumin dialysis (MARS) and plasmapheresis, and no survival advantage was found on meta-analysis (Khuroo et al., 2004).

## **7. Conclusion**

264 Liver Transplantation – Basic Issues

59 years), so age may have influenced results. More ALF patients were employed or were in full-time education (50 vs. 26.5%). The mental health scores were slightly lower for those who had ALF (68 vs. 79; p=0.022), which was attributed to the fact that the ALF recipients did not undergo typical preoperative education and psychological support prior to OLT. There was no significant difference in parasuicide quality of life scores between the two

ALF patients scored slightly lower in the physical function and role emotion areas compared to normal values, but the values were similar to those who were transplanted for chronic liver disease (Sargent et al., 2006). When more carefully interviewed, six ALF recipients described significant physical inactivity and fatigue for the first 3-6 months following OLT due to weight loss and loss of muscle tone. They also noted a health transition lasting between 3-6 months, during which time dependence on others was present. Pretransplant lifestyles were changed in order to regain independence. Support groups or role models were deemed extremely helpful in coping with the ordeal. The majority felt that they had been given a "second chance at life" and were willing to

Following spontaneous recovery, ALF patients with psychiatric illness who had taken a deliberate APAP overdose are at risk of repeated overdoses. Risk of repeated overdose appears to be less common; however, if the patient was transplanted, perhaps due to the intensity of postoperative care. In two series from the United Kingdom, APAP-ALF patients who underwent OLT showed similar long-term survival (median 5 years and 9 years) compared with patients transplanted for chronic liver disease (Cooper et al., 2009; Karvellas et al., 2010). Less than 5% of those transplanted for APAP overdose reattempted overdose. There was worse 30-day mortality for the APAP-ALF patients, and a greater probability of post-OLT medical nonadherence and adverse events in those who had taken APAP for deliberate self-harm compared with both non-APAP-ALF patients and chronic liver disease

Hepatocyte transplantation has been studied predominantly in patients with chronic metabolic disorders. There is evidence, however, that partial liver engraftment is possible and there may be improvement in neurological status, as noted in small groups of patients with ALF who have undergone hepatocyte transplantation (Bilir et al., 2000; Habibullah et al., 1994; Strom et al., 1997). Xenotransplantation is an intriguing concept and porcine livers have been used for ex vivo perfusion but in vivo use has not yet proven effective due to problems with transspecies rejection. Bioartificial livers and extracorporeal liver assist devices (ELAD) have been used to bridge patients to transplantation and have demonstrated improved neurologic outcomes. There are two cell-based devices. One uses porcine hepatocytes and did not show survival advantage in one large multicenter study and another uses hepatoblastoma cells which was noted to decrease severity of encephalopathy without change in survival in one study (Demetriou et al., 2004; Ellis et al., 1996). Non-biological systems also exist such as albumin dialysis (MARS) and plasmapheresis, and no survival advantage was found on meta-analysis (Khuroo et al.,

reciprocate support to other going through the same process (Sargent et al., 2007).

groups (Sargent et al., 2006).

patients (Cooper et al., 2009).

**6. Future directions**

2004).

Many advances have occurred that have significantly improved outcomes following transplantation for ALF. Prognostic models are helpful, but they are not entirely predictive of which individuals need OLT and which will survive without OLT. In the setting of organ shortage, alternatives to conventional OLT are being increasingly used, including living donor split grafts, ABO incompatible grafts, and auxiliary grafts, with variable outcomes. The risks and benefits to both the donor and the recipient must be considered. Long term outcomes and quality of life for both donors and recipients are good but prolonged monitoring may be helpful to identify those in distress. Newer technologies are being developed and enhanced to improve short term and long term survival after acute liver injury.


**Author details**

Juárez‐Cedillo Teresa1,2\*, Hsiung Ging‐Yuek3,4, Sepehry A. Amir3 , Beattie B. Lynn4,5, Jacova Claudia3,4 and Escobedo de la Peña Jorge1

\*Address all correspondence to<EMAIL_ADDRESS>
1 Clinical Epidemiology Research Unit, Hospital General Regional 1, Dr Carlos McGregor, IMSS Mexican Institute of Social Security, Mexico City, Mexico

2 Faculty of High Studies (FES) Zaragoza, National Autonomous University of Mexico, Mexico City, Mexico

3 UBC Division of Neurology, Department of Medicine, Vancouver, B.C., Canada

4 UBC Hospital Clinic for Alzheimer Disease and Related Disorders, Vancouver, B.C., Cana‐ da

5 UBC Division of Geriatric Medicine, Department of Medicine, Vancouver, B.C., Canada


**6. Toxicity**

188 Pesticides in the Modern World - Risks and Benefits

Fig. 6. Blackfoot diseases after chronic arsenic exposure (Better Life Laboratories, USA)

wine (Everall and Dowd 1978).

Endocrine Diabetes

Gastrointestinal Hemorrhage

**System Effect and symptoms**

Skin Skin lesions (melanosis, keratosis)

respiratory Pulmonary insufficiency, emphysem

Cardiovascular Blackfoot disease, atherosclerosis, hypertension

Hematological Bone marrow depression (anemia, leucopenia, thrombocytopenia)

Renal Tubule degeneration, papillary and cortical necrosis Nervous Peripher and central neuropathy, encephalopathy

Table 4. Human effects after chronic arsenic exposure (Singh, Kumar, and Sahu 2007; Schuhmacher-Wolz et al. 2009; Hughes 2002; Balakumar and Kaur 2009; Rahman, Ng, and

Hepatic Hepatomegaly, fibrosis, cirrhosis, altered heme metabolism

following table.

Naidu 2009).

from 20 to 50 years (Haque et al. 2003). It is described that the latent period after exposure can be as long as 60 years, which has been reported in patients treated with Fowler´s solution, in vineyard workers using arsenical pesticides and from drinking contaminated

Many different systems within the body are affected by chronic exposure. Some of these systems and their associated toxic effects from chronic arsenic exposure are listed in the Arsenic compounds or arsenic-containing compounds vary in toxicity to mammalian cells. Arsenic does not directly react with DNA or cause gene mutations, except to a small extent at high dose. As can cause gene amplification and chromosomal damage at lower doses and can enhance mutagenesis by other agents, apparently by inhibiting DNA repair. The following table gives an overview over the modes of carcinogenic action of arsenic.

Table 5. Modes of carcinogenic action of arsenic (Schuhmacher-Wolz, Dieter, Klein, and Schneider 2009; Hughes 2002).

The binding with sulfhydryl groups by arsenite compounds has the potential to influence a wide range of metabolic activities. Arsenic toxicity inactivates up to 200 enzymes. The effects of As occur through indirect alteration of gene expression via disruption of DNA methylation, inhibition of DNA repair, oxidative stress, or altered modulation of signal transduction pathways. Another indirect mechanism is the influence of growth-stimulating chemicals or cytokinesed generated in response to arsenic exposure. Biotranformation is the major metabolic pathway for inorganic arsenic in humans. Toxic inorganic arsenic species can be biomethylated by bacteria, algae, fungi and humans. The high affinity of arsenic for sulphydryl groups makes keratin-rich cells a target for arsenic.

The order of toxicity of arsenicals is:

Monomethylarsonic acid (MMA III) > Arsenite (III) > Arsenate (V) > MMA(V) (Singh, Kumar, and Sahu 2007).

In arsenic biotransformation the intermediate product MMA III is highly toxic than other arsenical, which might be responsible for the arsenic-induced carcinogenesis and other effects (Styblo et al. 2000). As III binds thiol or sulfhydryl groups in tissue proteins of the liver, lungs, kidney, spleen, gastrointestinal mucosa and keratin-rich-issues (skin, hair, nails). By binding a wide range of metabolic activities are influenced including cellular glucose uptake, gluconeogenesis and fatty acid oxidation (Jones 2007). Many other toxic effects of arsenic compounds are detailed by Abernathy et al in 1999 (Abernathy et al. 1999). The acute toxicity is related to its chemical form and oxidation state. In the human adult the lethal range of inorganic arsenic is estimated at a dose of 1-3 mg As / kg (Schoolmeester and

White 1980). The characteristics of acute arsenic toxicity in humans include gastrointestinal discomfort, vomiting, diarrhea, bloody urine, anuria, shock, convulsions, coma and death.


**3.1 Menstrual irregularities**

Menstrual irregularities are a common complaint during menopause transition. Infrequent **ovulation** and anovulation lead to changes in the length of proliferative phase, and in the absence of progesterone, decline of estrogen leads to heavier and irregular menstruation. In some women scanty periods with long cycles may be the main symptom. The changes of bleeding pattern due to hormonal fluctuation usually occurs during perimenopause. The analysuisreported median age at inception of perimenopause is 47.5 years and smokers have not only early but a shorter perimenopause [2]. However, postcoital bleeding, prolonged bleeding, and postmenopausal bleeding require further investigation.