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Dr Neil McKinney, ND

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Dr Neil McKinney, ND

Vital Victoria Naturopathic Clinic

Dr Neil McKinney has entrenched himself as a leading authority in integrative cancer treatment. With over 25 years of clinical practice this 1985 graduate of the National College of Naturopathic Medicine retraces training from far earlier in his career as the starting point for his interest in the field. Working as a lab instructor in microbiology at the University of Victoria trained Dr. McKinney to work with cell and tissue culture. He went on to apply this skillset on behalf of the BC Cancer Research Foundation in which his team was requested to generate materials for preclinical cancer research. The team was growing animal and human cell lines, and was creating artificial tissue. An interest to pursue medicine lead to tours of several alternative cancer clinics across North and Central America, culminating in his enrollment at the National College of Naturopathic Medicine.

Neil focused his naturopathic training on expanding his knowledge of cancer. His first patient in private practice was a terminal cancer patient. Neil has coined several interesting expressions to describe the ultimate goals of his practice; first he relates cancers of all types to weeds- resilient to a magnitude that sees them cracking concrete to continue to grow. He highlights that true eradication of an established cancer is extremely difficult to achieve. Instead, he focuses care on reducing cancer burden and teaching patients to become comfortable with living with their cancer. Secondly, he has had tremendous success with “prolonging expiry dates”; helping patients survive, with a greater than expected quality of life, for far longer than the prognosis initially provided by their oncologist. His first patient in private practice survived six months past her expected expiry date.

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Dr McKinney recognizes the importance of the immense task of assimilating and disseminating the knowledge base that is naturopathic medicine, and has been among the most active doctors in the country in moving the profession forward. He has been a professor to naturopathic students throughout his career, still delivering courses to this day at the Boucher Institute of Naturopathic Medicine in New Westminster, BC. He currently teaches naturopathic oncology and naturopathic clinical arts and sciences. Neil has also authored a book that serves as an indispensable tool for any ND seeing cancer patients in practice; Naturopathic Oncology – An Encyclopedia guide for patients and physicians, the third practice guide he has authored to date. The book delivers decades of literature- based research and pearls of wisdom gathered over 25 years of practice.

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Neil has been extremely active in solidifying the profession in his home province of British Columbia. Three pioneering ND’s; Dr McKinney, the late Dr Don Sabourin, and Dr Kerry McGuiness founded the British Columbia Naturopathic Association in the early 1990’s. The recent well- publicized successes of the BCNA and the naturopathic profession as a whole regarding the securing of broad scope of practice privileges are invariably indebted to the pioneering efforts of these visionary ND’s.

Neil also deserves tremendous praise for his role in the creation of the Boucher Institute of Naturopathic Medicine. The West Coast College of Massage Therapy, an institution Neil had direct ties with for several decades, attempted to incorporate a naturopathic curriculum into its program. This program failed, yet had dozens of students enrolled at various stages of completion. Due to Neil’s involvement with the Counsel on Naturopathic Medical Education (CNME), he was able to provide a vital link between the newly formed Boucher Institute and the CNME to work towards creating a program that subsequently allowed Boucher graduates the opportunity to participate in NPLEX examinations. Students enrolled in the naturopathy program at the West Coast College of Massage Therapy were transitioned to and became the first students of Boucher.

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Dr McKinney’s practice has evolved considerably over time. In addition to Dr McKinney, the team of Vital Victoria Naturopathic Clinic includes his wife Lynda, Reiki Master and teacher, and serves as office manager. Melissa St John- Geary is a holistic health practitioner who also supports the team as a clinic assistant. Neil adopts a truly eclectic system of practice, calling upon all of the modalities of naturopathic medicine. Any one patient is likely to receive guidance on clinical nutrition including diet modification and functional food/ nutraceutical/ essential nutrient prescriptions, botanical medicines which include western herbal medicines and a heavy reliance on TCM herbal patents, homeopathic remedies prescribed as single remedies typically at low potency for acute, specific indications, and counseling on mind- body techniques to help guide the healing process.

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There is no IV lounge in the facility, yet Neil remains a strong supporter of IV vitamin C therapy and Meyer’s cocktails for patients with cancer. These are services he frequently refers out for, but is actively seeking an associate to once again bring these services inhouse. Included in the comprehensive eclectic approach described above, Neil considers local subcutaneous injections of mistletoe lectin (Helixor, Iscador) to be a core therapy. Neil also frequently utilizes herbal formulas of Dr Eric Yarnell, ND, and oral artemesia (for prostate, colorectal, breast and lung cancers). He describes frequent use of a select list of pharmaceutical agents including dexamethasone, proton pump inhibitors, and low dose naltrexone. Dr McKinney has also pioneered a strategy in cancer management he has termed “mitochondrial rescue”. In brief, mitochondrial failure causes a cell to lose its ability to generate an apoptotic process. The medication dichloroacetate (DCA) has achieved amazing success in cancer treatment through its ability to resuscitate mitochondrial function, but unfortunately induces severe adverse reactions in many patients. Dr McKinney’s mitochondrial rescue protocol is a selection of natural health product agents demonstrated to exhibit similar mechanisms of action as DCA yet devoid of the extreme adverse reactions. This issue of IHP includes an excellent review of the basis for, and formulation of, this important treatment for individuals with cancer.

Dr McKinney has done an excellent job of integrating with local oncologists in his surrounding community. He rarely runs laboratory tests as a result of his incredibly successful integration; oncologists serving his patient base are pleased to forward all standard testing, and perform additional tests if requested. The clinic also enjoys a steady stream of referrals from local oncologists, and boasts having had oncologists as patients of the facility.

IHP is grateful to the Vital Victoria Naturopathic Clinic team for their willingness to allow us to showcase their facility to you. Dr McKinney has been setting the naturopathic standard of care for management of patients with cancer for decades, continually striving to improve and perfect the approaches he adopts in practice. His generosity and passion for moving the profession forward has seen him expertly assimilate the evidence relating to these techniques, and deliver them to students and practitioners of the profession every opportunity he gets. Naturopathic Oncology – An Encyclopedia guide for patients and physicians is more than the life’s work of an incredibly talented physician; it is an indispensable tool for clinical practice of any integrative healthcare provider wishing the privilege of working with patients with cancer.

Mitochondrial Rescue

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Mitochondrial Rescue

Turning cancer cells off

Professor Otto Warburg of the Max Planck Institute won a Nobel prize for his discoveries of how the human body uses sugars in health and in disease. In his seminal work ‘On the Origin of Cancer Cells” published in 1956 he described the “irreversible” damage to respiration as a metabolic process in malignant cells, resulting in a shift to anaerobic glycolysis. Observing well oxygenated cancer cells with abnormally high glycolysis and lactate production suggested to him that defects in mitochondrial (“grana”) functions are at the heart of the transformation of normal cells to malignant cells (Warburg 1956).

The “Grana” of Warburg are today called mitchondria. Of note is the fact that mitochondrial DNA comes from your mother’s egg, and contains no DNA from your father, whereas the nuclear DNA is a mix from both parents. The most important consequence of mitochondria incurring compromised oxidative capacity is loss of programmed cell death , or the apoptosis “off-switch” for old or mutated cells. This is a process that allows a cell to shut down and be recycled after 50 doublings, or earlier if the nuclear DNA becomes mutated and damaged. It prevents making two bad cells from an old or damaged cell. The cell membranes turn inside out, the cell is recycled, and a local stem cell wakes up out of dormancy to make a fresh new cell with the counter reset to zero. As we lose the ability to weed out bad cells, the potential for mutations that lead to cancer increase.

Cancer cells with mitochondrial failure become very hard to kill, and will continue to accrue mutations which make the cancer more invasive, hypermetabolic, and adaptable to metastatic environments. It is the restoration of this apoptotic switch by the oxidative stress of chemotherapy and radiation which make these the most widely applied and generally successful therapies for most cancers, which otherwise have quite different biology.

Warburg’s hypothesis is often misinterpreted to support the idea that oxygen is cytotoxic to cancer, and cancer cannot arise in a high-oxygen environment. It is also taken to imply that cancers originate only in an acid-environment, and that alkalizing is an effective cytoxic therapy for cancer. These myths have failed to unlock the potential for targeting mitochondria to cure cancer suggested by this seminal work (Wenzel 2004).

Mitochondria of tumour cells lose their ability to perform oxidative phosphorylation. Cellular energy metabolism shifts to anaerobic glycolysis.

Early on in the growth of a tumor, at about 2 mm in diameter, oxygen depletion begins to occur in the center of these cell clusters. Oxygen doesn’t freely diffuse this far into tissues, and the hyper-metabolic nature of cancer cells depletes what is there at an abnormal rate. The hypoxic cells send out distress signals, summoning immune and regulatory cells to reestablish blood inflow by neo-angiogenesis. A chronic inflammation repair process is created, but unable to fix the genetic problems of the transformed cells, it becomes “the wound that will not heal”. Growth factors and other immune cell products support continued tumor growth, and any immune-cell going into attack mode against cancer cells are shut off by cytokines such as transforming growth factor (TGF-B1) (Talmadge 2007). The immune system is now working for the cancer. They can even cannabilize fibroblasts and other cells to give spare parts to the suffering cancer cells (Martinez-Outschoorn 2010.

The new blood vessels in tumors do not remodel into efficient capillary beds, as is expected in normal tissue repair. As cancerous tumors mature, leakiness of the blood vessels creates a build-up of fluid pressure. Oncotic pressure eventually crushes the vessels, creating pockets of severely low oxygen, called hypoxia. If the oxygen tension falls to zero, called anoxia, like any human cell, the cancer cells will die. Sub-lethal hypoxia can cause mitochondria membranes to become hyper- polarized, and oxidative metabolism shuts off (Bonnet 2007). The cancer cell adapts by starting to process sugars into energy without oxygen, through the whole of the cell cytoplasm. This anaerobic glycolysis creates lactic acid as a waste product, and at this point the cancers become highly acidic (Warburg 1956).

This fermentation of sugars, very similar to how yeast generate energy, is not very efficient at creating ATP. This may on the surface appear to create a disadvantage for the cancer cell, but in fact it creates an abundance of building blocks for proteins, fatty acids and nucleic acids desperately needed by the cancer cells to maintain their overly-rapid growth rate (Bui 2006).

Most of the anabolic processes required for accelerated growth rate are accomplished by increased glycolysis. Anaerobic glycolysis is supported by replenishing TCA cycle intermediates, such as acetyl-CoA and citrate, a process called anaplerosis (DeBerardinis 2008, Kroemer 2008, Ramos- Montoya 2006). Anaplerosis sustains TCA cycle function by either converting pyruvate to oxaloacetate or by breaking down glutamine into alphaketoglutarate by glutaminolysis (DeBerardinis 2007).

The critical shift between glycolysis and oxidative phosphorylation is controlled by the relative activities of two enzymes, pyruvate dehydrogenase (PDH) and lactate dehydrogenase (LDH), that determine the catabolic fate of pyruvate. Hypoxia inducible factor (HIF) can induce LDH activity while inhibiting PDH activity by stimulating its inhibitor PDK1 (Kim 2006, Wigfield 2008). Hypoxia results in hydrogen peroxide (H2O2) and nitric oxide (NO) generation, which in turn results in hydroxyl radicals and super oxides. Jurasunas postulated that this scenario results in depletion of the potent antioxidant manganese-super oxide dismutase MnSOD, which destroys the respiratory chain in hypoxic mitochondria (Jurasunas 2006).

As free radicals of oxygen accumulate there is an excessive uptake of lactate and pyruvate in the hypoxic mithochondria. This raises the mitochondrial membrane potential Delta -Psi-m (ΔΨm). Cancer cells thereby have hyperpolarized mitochondrial membranes compared to normal cells, preventing them from throwing the apoptotic off-switch no matter how old or mutated they become. Hexokinase II is highly expressed in cancer cells, induced by alterations to the Ras-P13-Akt signal transduction pathway. Hexokinase binds to mitochondrial porin, suppressing the calcium channels and the potassium channel K+v1.5 (Lemasters 2006, Wallace 2005).

Lactate dehydrogenase is upregulated in tumors, favouring cancer growth via VEGF and HIF-1α, increased angiogenesis, and metastasis via direct enhancement of cellular motility (Gottfried 2006, Koukourakis 2005, Koukourakis 2006, Kulawiec 2009, Ordys 2010, Pelicano 2006, Ralph 2010, Seth 2011, Walenta 2004, Walenta 2000). A build-up of the electron transport molecule NADH inactivates the vital tumor suppressor gene PTEN. This activates Akt protein kinase B survival pathway, resulting in immortalization of the cancer cell (Frezza 2009).

Strategies that successfully allow mitochondria in tumour cells to once again perform oxidative phosphorylation have proven to be potent anti tumour agents.

In 2007 Bonnet, Michelakis and group at the University of Alberta tested an old drug dichloroacetate or DCA on breast cancer infested rats, and made an astonishing discovery. Based on a hypothesis that inhibiting a mitochondrial enzyme pyruvate dehydrogenase kinase or PDK might repolarize mitochondrial membranes and spark up respiration in cancer cells, they found evidence DCA might do the job, and it did indeed reverse what Warburg deemed irreversible (Bonnet 2007).

An important line in the abstract states “DCA induces apoptosis, decreases proliferation and inhibits tumor growth, without apparent toxicity.” This may well apply to the rats in this study, but clear evidence of neurotoxicity and other risks to humans existed before this trial. In fact, human studies on DCA for diabetic acidosis had shown this drug was far from safe. DCA had long been listed as an environmental toxin and carcinogen by the USA Environmental Protection Agency. Release of DCA into the environment was a crime (Backshear 1975, Felitsyn 2007, Kaufmann 2006, Schaefer 2006). This impression of safety was compounded by an article that soon followed in the journal New Scientist claiming this drug was safe, and effective for most cancers (Coghlan 2007).

In the Globe& Mail June 2, 2007, Mikelakis warned of “severe nerve damage. People may lose their ability to walk, or speak” from impurities in DCA bought from sources such as the internet. Others reported nausea, drowsiness and peripheral neuropathy in DCA users (Kaufmann 2006).

There is no question DCA can reduce human tumors. DCA activates private dehydrogenase kinase, triggering an influx of acetyl-CoA into mitochondria. This drives more NADH into complex I. Superoxides that form are converted into hydrogen peroxide by manganese- super oxide dismutase. The H2O2 inhibits proton (H+) efflux, reducing mitochondrial membrane potential Δψm. This opens the mitochondrial transition pore (MTP), inhibiting calcium ion entry via voltage-dependent channels. Reduced intra-mitochondrial calcium (Ca++) suppresses a tonic activation of nuclear factor of activated T lymphocytes (NFAT). NFAT1 is a nuclear transcription activator similar in action to activator protein 1 (AP-1) and nuclear factor kappa B (NFκB). This reduces Kv1.5 expression, increasing potassium ion K+ efflux, reducing inhibition of caspases, and finally triggering cancer cell apoptosis (Bonnet 2007).

An interesting side-note is the fact that DCA converts into glyoxalate, an old remedy once promoted for cancer (Biswas 1997, Herbert 1979, Ray 1997). Victor Herbert quotes the leading DCA researcher Dr. Stacpoole, as saying “ the efficacy and safety of chronic dichloroacetate administration is unknown” (Stacpoole 1998).

I saw the toxicity of DCA on the nervous system for cancer patients who tried this experimental approach. I have seen cases completely disabled by the drug. Because the DCA was offpatent, it took Michelakis many months to fund a human trial. Two of my patients went to Edmonton and were enrolled, but returned to Victoria in about two weeks with severe neuropathy. As a result of this experience, the investigators wisely reduced the dose to 1/3 that level, and restricted its application to CNS tumors. The result was brain tumor responses with “acceptable toxicity” (Michelkakis 2010).

Does there exist a less toxic alternative for activating oxidative phosphorylation in mitochondria of tumour cells?

In 2007 I recognized the potential of this approach, awakening mitochondrial apoptosis switching through inhibition of PDK, but also saw the clinical limitations of the DCA drug. I began a search for a less harmful PDK inhibitor. I was able to find evidence that R+ alpha lipoid acid and thiamine (vitamin B-1) could do this (McKinney 2008). As we have come to expect with all natural and non-toxic approaches to cancer, single agents are rarely very potent. John Boik’s excellent texts have pointed out the need to find synergistic groupings of botanicals and nutraceuticals, if we expect to create significant impact on advanced cancers (Boik 1996, Boik 2001). I can say that the clinical application of my original mitochondrial rescue plan has produced responses in cancers, including rather difficult ones such as sarcoma and lung cancer. It is certainly in need of further refinement. I do not presently see it being useful in lymphomas and leukemias. These are the natural medicines I propose for mitochondrial rescue of cancer cells, to reverse the Warburg Effect:

R+ alpha lipoic acid is a potent natural PDK inhibitor (Hagen 1999, Hagen 2002, Korotchina 2004, Li 2009, Liu 2002, Moungjaroen 2006, Simbula 2007, Wenzel 2005a). It is used intravenously and orally for cancer, and has the added benefit of treating neuropathy.

The only other natural compound which is known to be a direct inhibitor of PDK is thiamin, or vitamin B1. Because it is fat soluble and thought to integrate better into mitochondrial membranes, we favor clinical use of benfotaimine (Babaei-Jadidi 2003, Parkhomenko 1987).

Some believe L-carnitine is key to mitochondrial restoration (Cruciani 2006, Hoang 2007, Wenzel 2005b), but it is not a PDK inhibitor, and will generate enough free radicals of oxygen to damage mitochondria further, unless accompanied by sufficient fat soluble antioxidants such as R+ ALA. In fact, the two supplements have an excellent synergy and should be given together (Hagen 2002, McMackin 2007). My clinical preference is prescription of acetyl-L-carnitine, which is fat soluble.

Co-enzyme Q-10 is widely recognized as a fat-soluble antioxidant that is clinically useful for mitochondrial disorders (Beal 1994, Berbel- Garcia 2004, Matthews 1998, Perumal 2005a, Rodriguez 2007). However, it can inhibit opening of the mitochondrial transition pore, which could counteract the DCA effect (Li 2005). My clinical experience suggests grapeseed extract is a better choice (Hu 2006).

B-vitamins are involved in energy metabolism as co-factors for many important enzymes. A B-complex seems a reasonable support for mitochondria dysfunction (Perumal 2005a, Perumal 2005b).

Indole-3-carbinol has been a most useful cancer therapy as a STAT-3 transcription factor inhibitor, and for its anti-estrogen effects. It has a potent effect on upregulation of bax in mitochondria, causing membrane depolarization and activation of apoptotic caspases (Rahman 2000, Rahman 2003).

Quercitin can increase or decrease mitochondrial membrane potential Delta Psim (Δψm) depending on concentration, inducing apoptosis (Kellner 2004, Kothan 2004, Yang 2006, Zhang 2005). This versatile anti-cancer agent interferes with glycolysis via reduced generation of glycolytic substrates adenosine diphosphate and inorganic phosphate (Suolinna 1975).

Gamma tocopherol is a dietary form of vitamin E that can stabilize mitochondrial membranes. It can be washed out of membranes by intake of excess alpha-tocopherol supplements. Always use the “mixed tocopherols” containing the gamma form, never just the “natural source” d-alpha tocopherol (Mahabir 2008).

Fish oils are an excellent omega 3 oil for mitochondrial membrane health, reducing mitochondria calcium levels (Hansford 1999).

Other adjuncts for mitochondrial regeneration include intense aerobic exercise (Lanza 2010), calorie restricted diets (Spindler 2010), and the diabetic drug Metformin (Suwa 2006)

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NAFLD

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NAFLD

Clinical application of betaine and L-carnitine

Introduction

Alarming trends have emerged for non alcoholic fatty liver disease (NAFLD). The diagnosis of NAFLD is associated with a higher all cause mortality than the general population. The prevalence of NAFLD has been estimated to be as high as 17-33% in certain countries. Furthermore, a subset (approximately 33%) of NAFLD patients develop non alcoholic steatohepatitis (NASH). Increasing concerns have stemmed from the fact that 20-25% of NASH patients could develop severe cirrhosis (Raszeja-Wyszomirska 2008). Once cirrhosis occurs, detrimental effects follow, such as portal hypertension, esophageal varices, ascites, encephalopathy and hepatorenal syndrome (Rahn 2010). The most important factor to consider is the clinically silent nature of disease in its early phases, making effective preventative and therapeutic measures all the more essential.

Clinical Features and Management of Non Alcoholic Fatty Liver Disease

Non alcoholic fatty liver disease (NAFLD) encompasses a comprehensive list of disorders with the hallmark of macrovesicular, hepatic steatosis, and associated pathology ranging from no inflammation to that of fibrosis and cirrhosis (Wedemeyer 2003). The pathogenesis of NAFLD includes insulin resistance, oxidative stress, dysfunctional apoptotic pathways and pro inflammatory cytokine elevations (Younossi 2008). The etiology of NAFLD and contributing factors include obesity, diabetes, hyperlipidemia and hypertension. Specific metabolic risk factors worth noting are waist circumference >90cm for men and 80cm for women, impaired fasting glucose >6.1 mmol/L, triglycerides >1.7 mmol/L, HDL levels <1.3 mmol/L in women and 1.03 mmol/L in men and hypertension >135/80mmHg (Adams 2006).

NAFLD can be asymptomatic or produce non specific early symptoms, such as fatigue and dull upper abdominal pain. Late stage symptoms include but are not limited to nausea, weight loss, lack of libido, gastrointestinal bleeding and itching/swelling of the extremities (Schiff 2007, Wedro 2009). Signs such as jaundice and hepatomegaly may also be present. Laboratory findings for this condition consist of elevated liver function tests (ALT, AST and GGT). Although imaging such as ultrasound (less sensitive) and MRI can be utilized as diagnostics tools, the gold standard for NAFLD is liver biopsy and an exclusion of 20g/day of alcohol consumption (Adams 2006).

Widespread initial treatment for NAFLD consists of diet and exercise alone if NAFLD is mild, however, drug regimens are also utilized. Pharmacological intervention consists of medications, such as lipid regulators (Orlistat-lipase inhibitor that reduces fat absorption, Atorvastatin-statin), insulin regulators (biguanide- Metformin), thiazolidinediones (Pioglitazone, Rosiglitazone), antihypertensives (Telmisartan) and Ursodeoxycholic Acid (Musso 2010).

Natural Health Product Interventions for the Treatment of NAFLD

There are several contenders in addition to conventional treatments of NAFLD, such as betaine, L-carnitine, vitamin B complex, and polyunsaturated fatty acids. Betaine and L-carnitine are very promising (as shown by clinical and laboratory evidence of disease improvement) because of widespread impact (as shown by specific biomolecular mechanisms of action) these supplements have on preventing and reversing multiple dysfunctional pathways in pathogenesis of NAFLD.

Table 1: Betaine and NASH treatment- human trials
Table 1: Betaine and NASH treatment- human trials

Betaine

Betaine is a neutral chemical compound that has both anionic and cationic functional groups. It is obtained through the diet or via choline oxidation, and functions as a methyl donor to increase the efficiency of biochemical processes (Lever 2010). It has been utilized therapeutically in diabetes, metabolic syndrome, hyperlipidemia and liver disease. The value of betaine in liver disease, (NAFLD specifically) is derived from its ability to reverse impaired sulphur related amino acid metabolism, oxidative stress and dysfunctional insulin regulation (Kathirvel 2010).

Animal and in-vitro studies have demonstrated that betaine has a preventative and therapeutic role in NAFLD. In one study mice were fed a high-fat diet (20% of calories from fat) for either 7 or 8 months, with added betaine for the last 6 weeks only or without betaine. Mice with high fat diets had increased weight, fasting glucose, insulin, triglyceride levels and hepatic fat content than controls (controls had chow with 9% calories from fat). Betaine treated mice showed a decrease in fasting glucose, insulin, triglyceride levels and hepatic fat content, as well as improved insulin resistance and hepatic steatosis. In vitro experiments furthered these findings and demonstrated that insulin-resistant HepG2 cells had a restoration of insulin receptor substrate phosphorylation and regulation of associated signalling events, such as gluconeogenesis and glycogenesis (Kathirvel 2010). Table 1 summarizes the therapeutic use of betaine in human studies.

L-carnitine

L-carnitine is a compound synthesized from methionine and lysine, and has been therapeutically utilized for cardiovascular disease, Type II Diabetes, osteoporosis, kidney and liver disease. L-carnitine is promising in the treatment of liver disease because it plays a crucial role in liver carnitine palmitoyltransferase-I sensitization, beta oxidation and peroxisome activity (Bremer 1990). It is part of an effective shuttling mechanism that obtains energy through the Kreb’s Cycle via transport of long chain acyl groups into the mitochondrial matrix to form Acetyl-CoA (Olpin 2005). Several animal studies have revealed how L-carnitine improves mitochondrial enzyme function in the liver. One interesting study in rats showcased the effects of L-carnitine in promoting fat utilization and optimal liver enzyme activity: The rats were administered a diet of hydrogenated fat and were kept with or without exercise defined as swimming for 1 hr a day, 6 days/week, for 24 weeks (4 groups of 8 rats per group) or peanut oil diet (4 groups of 8 rats per group), each given L-carnitine or nothing for 24 weeks. The L-carnitine group with the peanut oil diet, as well as exercise showed increased levels of mitochondrial enzymes: NADH dehydrogenase, NADH oxidase and cytochrome C (Karanth 2010). These findings illustrate that L-carnitine functions to increase the activity of carnitine palmitoyl transferase and the oxidative function of hepatocytes by modulating enzymes in the electron transport chain. Table 2 outlines human trials of L-carnitine in NASH.

Table 2: L- carnitine and NASH treatment- human trials
Table 2: L- carnitine and NASH treatment- human trials

Conclusions

Non alcoholic fatty liver disease and the more critical presentation of NASH require timely and effective prevention and treatment, given the putative endpoint of cirrhosis and the subclinical nature of the disease in its early stages. Although laboratory parameters were greatly improved after treatment with both betaine and L-carnitine, caution should be exercised in equating lab values to improved clinical effects. Future research should be directed at evaluating whether an additive effect exists with supplementation and conventional therapies. It should be noted that safety of this endeavour would be equivocal at this point.

L-carnitine (dose 500-3000mg) has been safely utilized therapeutically, although an effective dosage for NALFD was shown on average at 2g/day with noted side effects of vomiting, nausea, headache, diarrhea, rhinitis, and evening restlessness (Cruciani 2006). Its therapeutic potential can be attributed to its role as an effective shuttle of fatty acids and its ability to modulate mitochondrial enzymes, thus preserving the integrity of liver tissue. Research has demonstrated that betaine exerts mechanisms that involve modulation of oxidative damage and insulin activity, at a dose of 20g/day in NAFLD with side effects of mild gastrointestinal discomfort.

Although initial intervention requires the introduction of dietary change and exercise alongside first line conventional therapies, Betaine and L-carnitine have demonstrated unique mechanisms of action and excellent laboratory/histological outcomes.

References:

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Abdelmalek, MF, Sanderson SO, Angulo P, Soldevila-Pico C, Liu C, Peter J, Keach J, Cave M, Chen T, McClain CJ, Lindor KD. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology (2009): 50(6):1818-26.

Adams, L and P. Angulo. Treatment of non-alcoholic fatty liver disease. Postgrad med (2006): 82:315-322.

Angulo, P. Non alcoholic fatty liver disease. NEJM (2002): 346:1221–31.

Bremer, J. The Role of Carnitine in Intracellular Metabolism. J Clin Chem Clin Biochem (1990): 28(5):297-301.

Cruciani, RA, Dvorkin E, Homel P, Malamud S, Culliney B, Lapin J, Portenoy RK, Esteban-Cruciani N. Safety, tolerability and symptom outcomes associated with L-carnitine supplementation in patients with cancer, fatigue, and carnitine deficiency: a phase I/II study. J Pain Symptom Manage. (2006): 32(6) 551-9.

Giovanni, M, R. Gambino , M Cassader and G. Pagano. A Meta-Analysis of Randomized Trials for the Treatment of NAFLD. Hepatology (2010): 52; 79-104.

Karanth, J and Jeevaratnam, K. Effect of carnitine supplementation on mitochondrial enzymes in liver and skeletal muscle of rat after dietary lipid manipulation and physical activity. Indian J Exp Biol (2010): 48(5):503-10.

Kathirvel, E, Morgan K, Nandgiri G, Sandoval BC, Caudill MA, Bottiglieri T, French SW, Morgan TR. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine. Am J Physiol Gastrointest Liver Physiol (2010): 1068-1077.

Lever, M. and S. Slow. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem (2010): 43(9):732-44.

Lim, CY, Jun DW, Jang SS, Cho WK, Chae JD, Jun JH. Effects of carnitine on peripheral blood mitochondrial DNA copy number and liver function in nonalcoholic fatty liver disease. Korean J Gasteroenterol (2010): 55(6):384-9.

Malaguarnera, M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M, Avitabile T, Li Volti G, Galvano F. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis–a randomized and controlled clinical trial. Am J Gasteroenterol (2010): 1338-45.

Miglio, F, Rovati LC, Santoro A, Setnikar I. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallelgroup, placebo-controlled prospective clinical study. Arzneimittelforschung (2000): 50 (8) 722-7.

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Romano, M, Vacante M, Cristaldi E, Colonna V, Gargante MP, Cammalleri L, Malaguarnera M. L-carnitine treatment reduces steatosis in patients with chronic hepatitis C treated with alpha-interferon and ribavirin. Dig Dis Sci (2008): 53 (4) 1114-21.

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Wedro, Benjamin. www.emedicine.com. 25 Sep 2009. 15 Apr 2011 <http://www. emedicinehealth.com/fatty_liver_disease/page12>. Younossi, ZM. Review article: current management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther (2008): (1):2-12.

Maternal prenatal licorice consumption alters hypothalamicpituitary- adrenocortical axis function in children

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This study investigated whether maternal consumption of glycyrrhizin in licorice was associated with altered HPAA function in children. The children were derived from a random, populationbased birth cohort initially comprising 1049 infants born in 1998 in Helsinki, Finland, and their mothers. Eligible infants were healthy singletons born at 35-42 weeks gestation. Children were categorized into three exposure-level groups according to maternal consumption of glycyrrhizin in licorice: high (>500 mg/week), moderate (250-499 mg/week) and zero-low (0-249 mg/week). Diurnal salivary cortisol and salivary cortisol were measured in 321 children (mean age=8.1, SD=0.3 years) during administration of the Trier Social Stress Test for Children (TSST-C). In comparison to the zero-low exposure group, children in the high exposure group had 19.2% higher salivary cortisol awakening peak, 33.1% higher salivary cortisol awakening slope, 15.4% higher salivary cortisol awakening area under the curve (AUC), 30.8% higher baseline TSST-C salivary cortisol levels, and their salivary cortisol levels remained high throughout the TSST-C protocol (P<0.05 for all). These effects appeared dose-related. These findings lend support to prenatal ‘programming’ of HPAA function by overexposure to glucocorticoids. (Psychoneuroendocrinology. 2010 Nov;35(10):1587-93.) PMID: 20510523.

Hibiscus sabdariffa L. tea lowers blood pressure in prehypertensive and mildly hypertensive adults

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This randomized, double-blind, placebo-controlled clinical trial examined the antihypertensive effects of hibiscus tea consumption in 65 pre- and mildly hypertensive adults, age 30-70 y, not taking blood pressure (BP)-lowering medications. Three daily 240-mL servings of brewed hibiscus tea was compared to a placebo beverage for 6 wk. At 6 wk, hibiscus tea lowered systolic BP (SBP) compared with placebo (-7.2 +/- 11.4 vs. -1.3 +/- 10.0 mm Hg; P = 0.030). Diastolic BP was also lower, although this change did not differ significantly from placebo (-3.1 +/- 7.0 vs. -0.5 +/- 7.5 mm Hg; P = 0.160). The change in mean arterial pressure was of borderline significance compared with placebo (-4.5 +/- 7.7 vs. -0.8 +/- 7.4 mm Hg; P = 0.054). Participants with higher SBP at baseline showed a greater treatment response (r = -0.421 for SBP change; P = 0.010). These results suggest daily consumption of hibiscus tea, in an amount readily incorporated into the diet, lowers BP in pre- and mildly hypertensive adults and may prove an effective component of the dietary changes recommended for people with these conditions. (J Nutr. 2010 Feb;140(2):298-303.) PMID: 20018807

Lactoferrin efficacy versus ferrous sulfate for iron disorders in pregnant and non-pregnant women

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This report demonstrated the safety and efficacy of bovine lactoferrin (bLf) in pregnant women suffering from iron deficiency (ID)/ ID anemia (IDA). Two clinical trials were conducted on pregnant and non-pregnant women of child-bearing age suffering from ID/IDA. In both trials, women received oral administration of bLf 100 mg/twice/day (Arm A), or ferrous sulfate 520 mg/ day (Arm B). Hematological parameters, serum IL-6 and prohepcidin were assayed before and after therapy; IL-6 is a key proinflammatory cytokine and prohepcidin has been shown to play a role in iron absorption and metabolism in the intestine and placenta. Bovine Lf but not ferrous sulfate increased hematological parameters (P <0.0001). In pregnant women, bLf decreased serum IL-6 (P <0.0001), and increased prohepcidin (P=0.0007). In non-pregnant women bLf did not change the low IL-6 levels while it increased prohepcidin (P <0.0001). Ferrous sulfate increased IL-6 (P <0.0001) and decreased prohepcidin (P=0.093). Bovine Lf established iron homeostasis by modulating serum IL-6 and prohepcidin synthesis, whereas ferrous sulfate increased IL-6 and failed to increase hematological parameters and prohepcidin. Authors concluded that bLf is a more effective and safer alternative than ferrous sulfate for treating ID and IDA. (Int J Immunopathol Pharmacol. 2010 Apr-Jun;23(2):577-87.) PMID: 20646353.

Hormonal effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome

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A cross-sectional PCOS cohort (n = 104) was included and plasma fatty acid profiles were analyzed. Effects of LC n-3 PUFA supplementation on fasting and postprandial metabolic and hormonal markers were determined in PCOS subjects (n = 22) by a randomized, crossover, placebo-controlled intervention. Direct effects of n-6 (omega-6) compared with n-3 PUFAs on steroidogenesis were investigated in vitro in primary bovine theca cells. Crosssectional data showed that a greater plasma n-6 PUFA concentration and n-6:n-3 PUFA ratio were associated with higher circulating androgens and that plasma LC n-3 PUFA status was associated with a less atherogenic lipid profile. Supplemenation of LC n-3 PUFA reduced plasma bioavailable testosterone concentrations (P < 0.05), with the greatest reductions among subjects who exhibited greater reductions in plasma n-6:n-3 PUFA ratios. Notably, the treatment of bovine theca cells with n-6 rather than with n-3 PUFAs up-regulated androstenedione secretion (P < 0.05). Arachidonic acid modulates androstenedione secretion, which suggests an inflammatory mechanism in the hormonal perturbment of PCOS and an indirect effect of n-3 PUFAs through the displacement of n-6 PUFAs. (Am J Clin Nutr. 2011 Mar;93(3):652-62.) PMID: 21270384.

Lactoferrin with EPO for anemia in advanced cancer patients undergoing chemotherapy

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Intravenous iron improves the efficacy of recombinant human erythropoietin (rHuEPO) in anemic cancer patients undergoing chemotherapy. Lactoferrin is a naturally occurring iron-binding protein that also possess immunomodulating activity. This open-label, randomized, prospective trial tested the safety and efficacy of treatment with oral lactoferrin versus IV iron, both combined with rHuEPO, for the treatment of anemia in 148 advanced cancer patients undergoing chemotherapy. All patients received subcutanesou rHuEPO-beta 30,000 UI once weekly for 12 weeks, and were randomly assigned to ferric gluconate (125 mg IV weekly) or lactoferrin (200 mg/day). Both arms showed a significant hemoglobin increase. No difference in the mean hemoglobin increase or the hematopoietic response, time to hematopoietic response, or mean change in serum iron, C-reactive protein, or erythrocyte sedimentation rate were observed between arms. Ferritin decreased in the lactoferrin arm (denoting a good response for this type of anemia) whereas it increased in the IV iron arm. These results show similar efficacy for oral lactoferrin and for i.v. iron, combined with rHuEPO, for the treatment of anemia in advanced cancer patients undergoing chemotherapy. (Oncologist. 2010;15(8):894-902.) PMID: 20647390.

Diagnostic Accuracy of Holotranscobalamin and Other Indicators of Tissue Vitamin B12 Status in the Elderly

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This study investigated the ability of serum cobalamin, holotranscobalamin (holoTC), total homocysteine (tHcy), methylmalonic acid (MMA), serum and erythrocyte folate, and other hematologic variables to discriminate cobalamin deficiency, defined as red blood cell cobalamin <33 pmol/L in a large sample of 700 elderly subjects (age range 63-97 years). Serum holoTC was the best predictor, with area under the ROC curve (95% CI) 0.90 (0.86-0.93), and this was significantly better (P ≤0.0002) than the next best predictors; serum cobalamin, 0.80 (0.75-0.85), and MMA, 0.78 (0.72-0.83). For these 3 analytes, a 3-zone partition of positive and negative zones and a deliberate indeterminate zone between was constructed. The boundaries were values of each test that resulted in a posttest probability of deficiency of 60% and a posttest probability of no deficiency of 98%. The proportion of indeterminate observations for holoTC, cobalamin, and MMA was 14%, 45%, and 50%, respectively. Within the holoTC indeterminate zone (defined as 20-30 pmol/L), discriminant analysis selected only erythrocyte folate, which correctly allocated 65% (58/89) of the observations. Renal dysfunction compromised the diagnostic accuracy of MMA but not holoTC or serum cobalamin. (Clin Chem. 2011 Apr 11. [Epub ahead of print]) PMID: 21482749.

Vitamin D insufficiency and prognosis in non-Hodgkin’s lymphoma

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This study investigated the effect of vitamin D insufficiency on NHL prognosis: are circulating 25-hydroxyvitamin D [25(OH) D] levels predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL? Mean patient age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH) D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (HR 1.41, 95% CI 0.98 to 2.04) and OS (HR 1.99, 95% CI 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR 1.94, 95% CI 1.04 to 3.61) and OS (HR 2.38, 95% CI 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)(2)D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity [the enzyme that activates 25(OH)D to 1,25(OH)(2)D] do not explain the 25(OH)D associations. (J Clin Oncol. 2010 Sep 20;28(27):4191-8.) PMID: 20713849.

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