What You Should Know About Nutritional Deficiency And Diabetic Peripheral Neuropathy

In a thorough review of the relationship between nutrition and diabetic peripheral neuropathy, this author discusses key vitamin deficiencies, the impact of oxidative stress in patients with diabetes, and the need for close postoperative nutrition monitoring in those who have bariatric surgery.

Peripheral neuropathy is a highly prevalent and comorbid condition affecting 2 to 7 percent of the population.¹ An estimated 20 million people in the United States have some form of peripheral neuropathy.²

There are more than 100 types of peripheral neuropathy, each with its own characteristic set of symptoms, pattern of development and prognosis. Peripheral neuropathy may be either inherited or acquired. Neuropathic pain results from primary lesions or dysfunction of the central or peripheral nervous system (see “A Closer Look At The Mechanisms Of Neuropathic Pain” at right).^3,4

The causes of acquired peripheral neuropathy include trauma to a nerve, tumors, toxins, autoimmune responses, nutritional deficiencies, alcoholism, medical procedures, and vascular and metabolic disorders. Distal symmetric polyneuropathy, the most common subtype of peripheral neuropathy, is a major complication of both insulin-dependent and non-insulin-dependent diabetes mellitus, and is the most common form of neuropathy in the developed world.³

There are two main types of neuropathy. The most common is a nerve fiber length-dependent, distal symmetrical sensory polyneuropathy with little motor involvement but frequent and potentially life-threatening autonomic dysfunction.⁵ The second pattern is a focal neuropathy, which more commonly complicates or reveals type 2 diabetes.

Several recent studies have implicated poor glycemic control, the duration of diabetes, hyperlipidemia (particularly hypertriglyceridemia), elevated albumin excretion rates and obesity as risk factors for the development of diabetic peripheral neuropathy.⁶ In their observation research, Yang and colleagues introduce new risk reduction strategies for handling the modifiable cardiovascular risk factors of obesity, dyslipidemia and hypertension as they are associated with diabetic peripheral neuropathy.⁷

Adhering to recommended nutritional guidelines may improve these modifiable risk factors. Recent research from Brown-Riggs emphasizes a balanced diet as key to improving health disparities.⁸ Powers and coworkers outline a position statement for diabetes self-management education and support in patients with type 2 diabetes mellitus.⁹ The authors note proper nutrition and empowerment of patients with educational programs on nutrition and sound nutritional initiatives are key to controlling diabetes and its complications including peripheral neuropathy.

Fundamentally, with our didactic and clinical training, podiatric physicians suspect and expect long-term elevation of plasma glucose as the definitive cause of diabetic peripheral neuropathy.¹⁰ The growing consensus validated by evidence-based medicine is that the microvascular complication of diabetic peripheral neuropathy is multifaceted, including nutritional alterations as its most basic elements.

The central theme of this article is the relationship between nutrition and diabetic peripheral neuropathy. Accordingly, let us take a closer look at nutrition-related neuropathies; the relationship of oxidative stress to the chronic complications of polyneuropathy and diabetes; and bariatric surgery, possible complications and the relationship of the procedure to polyneuropathy.   

The first line of defense to avoid many diseases including peripheral neuropathy is good nutrition. Vitamin deficiency, mineral deficiency, organic substances or inorganic substances that are toxins can be notable causes of nutritional neuropathies. These disorders are usually related to acquired factors, such as deficiency states stemming from lack of nutrient intake and/or malabsorption due to gastrointestinal etiology. Isolated vitamin deficiencies and complex deficiencies can affect all areas of the nervous system.^11-20

Pertinent Insights On Thiamine Deficiency
Thiamine (vitamin B1) is a water-soluble vitamin present in most animal and plant tissues.

Neuropathy due to thiamine deficiency, known as beriberi, was the first clinically described nutritional deficiency in humans.¹¹ Beriberi may manifest with heart failure as “wet beriberi” or without heart failure as “dry beriberi.” Thiamine deficiency is also responsible for Wernicke encephalopathy and Korsakoff syndrome. The small intestine absorbs thiamine by both passive diffusion and active transport, and rapidly converts thiamine to thiamine diphosphate, which serves as an essential co-factor in cellular respiration, adenosine triphosphate production, synthesis of glutamate and g-aminobutyric acid, and myelin sheath maintenance.^11,12

Symptoms of thiamine deficiency usually develop gradually over weeks to months, but sometimes may manifest over a few days mimicking Guillain-Barre syndrome with the patient possibly having fatigue, irritability and muscle cramps within days to weeks of the start of nutritional deficiency.¹¹ Clinically, thiamine deficiency begins with distal sensory loss, burning pain, paraesthesias or muscle weakness in the toes and feet.¹¹ There is often associated aching and cramping in the lower legs. When left untreated, the neuropathy will cause ascending weakness in the legs and eventually evolve to a sensorimotor neuropathy in the hands. Beriberi may include involvement of the recurrent laryngeal nerve, producing hoarseness and cranial nerve involvement manifesting as tongue and facial weakness.

After reaching a definitive diagnosis of thiamine deficiency, one can provide thiamine replacement until proper nutrition has been restored. Thiamine administration is usually intravenous or intramuscular at an initial dose of 100 mg followed by 100 mg per day with a duration up to the clinical judgment of the treating provider.¹¹

How To Recognize And Address Niacin Deficiency
The clinical manifestation of nicotinic acid (niacin or B3) deficiency is pellagra.¹¹ The classic clinical triad of pellagra consists of dermatitis, dementia and diarrhea. Pellagra was once endemic in the United States and Europe, and still arises occasionally. Most modern patients with pellagra have other risk factors for malnutrition such as homelessness, anorexia, certain cancers or malabsorption of niacin.^11,13

The intestine absorbs niacin by simple diffusion. Niacin and its derivatives are important in carbohydrate metabolism. Early neurological symptoms are predominantly neuropsychiatric, and include apathy, inattention, irritability and depression. Without treatment, symptoms can progress to stupor or coma. Isolated niacin is not known to be a cause of neuropathy and most patients deficient in niacin have other nutritional deficiencies as niacin alone will not improve neuropathy.¹⁴

There is no reliable measure of serum niacin. Oral replacement of nicotinic acid of 50 mg two or three times a day is recommended for treatment but dosing may be limited due to flushing. One can use nicotinamide as a substitute in patients who are unable to tolerate nicotinic acid.¹¹ Consider pellagra in any patient deficient in vitamin B12 or thiamine deficiency when a patient’s cognition does not improve with supplementation.¹¹

When There Is A Deficiency Or Excess Of Vitamin B6
Vitamin B6 (or pyridoxine) is unique in that either a deficiency or an excess of vitamin B6 can cause neuropathy.¹¹ Pyridoxine is readily available in the diet and dietary deficiency of B6 is rare.

Humans are not able to synthesize B6 so dietary intake is essential.¹¹ After absorption, pyridoxine converts into pyridoxal phosphate, an important co-factor in numerous metabolic reactions. One should mainly use doses of 50 mg to 100 mg of vitamin B6 for certain conditions such as pyridoxine deficiency seizures and patients taking certain medications to avoid toxicity.¹¹

Vitamin B6 deficiency most commonly occurs in patients treated with certain medications that are vitamin B6 antagonists and there are drug interactions with vitamin B6 (see the table “A Guide To Medications That Can Reduce Vitamin B6 Levels” at left). Vitamin B6 deficiency can also arise in patients receiving chronic hemodialysis. Vitamin B6 deficiency may also result from malnutrition due to chronic alcoholism and in patients with high metabolic needs such as pregnant or lactating women.

In adults, neuropathy due to B6 deficiency starts with numbness, paresthesias or burning pain in the feet, which then ascend to affect the legs and eventually the hands.¹¹ Neurological examination reveals a length dependent polyneuropathy with decreased distal sensation, reduction of deep tendon reflexes, ataxia and mild distal weakness. Vitamin B6 toxicity produces a sensory ataxia, areflexia and impaired cutaneous sensation. Patients often complain of burning or paresthesias.

Electrodiagnostic testing usually shows a sensory neuropathy. However, with severe toxicity, motor nerves can be affected.¹¹ One can detect vitamin B6 deficiency by direct assay of blood or urine. Clinicians can also measure pyridoxal phosphate in the blood. Sural nerve biopsy confirms axonal degeneration of small and large myelinated fibers.

Research suggests vitamin B6 supplementation with 50 mg per day for patients being treated with isoniazid or hydralazine.^11,15 Authors also recommend daily B6 doses of 10 mg to 50 mg for patients undergoing hemodialysis.^11,15

A Guide To The Possible Etiologies Of Vitamin B12 Deficiency
Vitamin B12 (cobalamin) is present in animal and dairy products, and specific microorganisms synthesize it. Humans depend on nutritional intake for their vitamin B12 supply.

Vitamin B12 deficiency occurs in 5 to 20 percent of older adults and up to 40 percent of older adults have low serum vitamin B12 levels.^11,16 Vitamin B12 is an integral component of two biochemical reactions in humans. The first is the formation of methionine by methylation of homocysteine. A byproduct of this reaction is the formation of tetrahydrofolate, an important precursor of purine and pyrimidine synthesis. The second important reaction is the conversion of L-methylmalonyl coenzyme A into succinyl coenzyme A, which is essential for formation of the myelin sheath. The terminal ileum then absorbs the vitamin B12-intrinsic factor complex.

Cases of vitamin B12 deficiency can be due to malabsorption, pernicious anemia, gastrointestinal surgeries or weight reduction surgery.¹¹ As vitamin B12 is only available in animal products, those on strict vegan diets lack vitamin B12 and must take supplements. Certain medications such as proton pump inhibitors and metformin may contribute to vitamin B12 deficiency.^11,17-18

An underappreciated cause of cobalamin deficiency is food-cobalamin malabsorption.¹¹ This typically occurs in older individuals and results from an inability to adequately absorb the cobalamin bound in food protein. Older patients can absorb free cobalamin without difficulty. Therefore, Schilling tests will be normal. No apparent cause of deficiency is evident in a significant number of patients with cobalamin deficiency.

The most common cause of B12 deficiency is pernicious anemia. This autoimmune disorder is characterized by destruction of the gastric mucosa and the presence of parietal cell antibody and intrinsic factor antibody, leading to impaired B12 absorption. The disorder is more common in African-Americans and patients with a Northern European background.¹¹

Chronic exposure to nitrous oxide has been associated with subacute combined degeneration.^11,19 The mechanism by which nitrous oxide induces vitamin B12 deficiency is inactivation of methyl-cobalamin, which inhibits the conversion of homocysteine to methionine and methyltetrahydrofolate and 5,10-methylenetetrahydrofolate, which are required for myelin sheath protein and DNA synthesis.

Keys To Diagnosing And Treating Vitamin B12 Deficiency
Vitamin B12 deficiency is associated with hematologic, neurologic and psychiatric manifestations. Patients may present with neurological symptoms regardless of a normal hematological picture.¹¹ The neuropathy associated with B12 deficiency usually begins with sensory symptoms in the feet. Differentiating vitamin B12 deficiency-related polyneuropathy from cryptogenic sensory polyneuropathy can be difficult on clinical grounds only. Clinical features that are useful to identify vitamin B12 deficiency-related peripheral neuropathy are the onset acuteness of symptoms and concomitant involvement of upper and lower extremities.^11,20

The diagnosis of B12 deficiency usually occurs in the presence of typical neurological symptoms, hematological abnormalities and serum vitamin B12 levels less than 200 pg/mL. However, a significant proportion of patients with vitamin B12 deficiency may have serum levels that are within the low normal range up to 400 pg/mL.^11,20 Historically, clinicians used the Schilling test to diagnose pernicious anemia. Presently, it is difficult to obtain a Schilling test due to the unavailability of the radioisotope. Anti-intrinsic factor and anti-parietal cell antibodies can be helpful in the diagnosis of pernicious anemia with high specificity and low sensitivity for the former and high sensitivity and low specificity for the latter. In typical cases with myelopathic symptoms, increased T2 signal intensity is visible in the posterior column on magnetic resonance imaging studies. Early diagnosis is critical since patients with advanced neuropathy may be left with major residual disability.

The common treatment regimen for vitamin B12 deficiency includes intramuscular administration of 1,000 mcg daily for five to seven days, followed by intramuscular administration of 1,000 mcg monthly. Other approaches are once-a-week injections for four weeks and then monthly injections. Monitor cobalamin levels occasionally to prevent inadequate treatment or non-adherence.¹¹ Initial severity and duration of symptoms, and the initial hemoglobin measurements correlate with the residual neurological damage after cobalamin therapy. Although oral cobalamin may seem preferable to intramuscular injections, parenteral therapy is actually less expensive when patients self-administer it if the provider or pharmacist has properly educated them on how to do so.

Essential Insights On Oxidative Stress And Diabetes Mellitus
Understanding the molecular mechanisms of oxidative stress and damage will provide insight into the role of specific treatment of oxidative stress and assessment of the effects on specific organs and tissues. Oxidative stress and free radicals result from either an increase in production or decrease in clearance.²¹ Excessive free radicals are detrimental to the cell function of beta cells, endothelial cells, fat cells, muscle cells and nerve cells.²¹

Hyperglycemia causes oxidative stress, which increase glycosylation and oxidation of proteins involved in the pathogenesis of the complications of diabetes mellitus.^21,22 Hyperglycemia with over-production of superoxide radicals leads to an increase in polyols, hexosamines, advanced glycation end products, protein kinase C and NF-kB, which all contribute to both vascular complications and neuropathy.^21,23
Further, Vincent and colleagues not only proposed the idea that glucose mediates oxidative stress injuries to the peripheral nervous system, leading to loss of neurons and Schwann cells, they also suggested that dyslipidemia contributes to the development of diabetic neuropathy.²⁴ Research has also shown that the interaction between hyperlipidemia and hyperglycemia causes oxidative stress to dorsal root ganglion neurons in patients with diabetes.²⁴ Large scale trials have revealed that in patients with type 2 diabetes, early dyslipidemia is a major independent risk factor for the development of diabetic neuropathy.²¹

Fenofibrate, a peroxisome proliferator-activated receptor a-agonist, lowers plasma lipids by improving lipid removal by the liver and improves fatty acid metabolism. This drug also dramatically improves hyperglycemia and insulin resistance.^24,25 The Fremantle Type 2 Diabetes observational study suggests that either statin or fibrate therapy protects against diabetic peripheral sensory neuropathy.²⁴

Reducing The Risk Of Neurologic Complications In Patients Who Have Had Bariatric Surgery
Like all surgical interventions, bariatric surgery certainly has some risks, such as the long-term risk of continued diabetes. One should evaluate each patient’s individual risks for surgery in the context of the duration and severity of their diabetes as well as their other obesity-related health problems. With the rapid rise in the number of bariatric surgeries performed for morbid obesity, there are several short- and long-term neurologic complications of this procedure. These complications affect various levels of the neuraxis and most are likely secondary to deficiency of essential minerals and vitamins. Replacement of vitamins results in a slow and variable degree of neurologic recovery.

For patients who have had bariatric surgery, close monitoring of their nutritional status postoperatively is important. Routine supplementation of vitamins and minerals may be a cost-effective strategy for preventing neurologic complications in these patients.

Thaisetthawatkul and colleagues performed a retrospective cohort study of all patients with bariatric surgery at the Mayo Clinic between 1985 and 2002.²⁶ Using univariate analysis, they noted the following risk factors: increased serum glycosylated hemoglobin and triglycerides, prolonged hospitalization, postoperative gastrointestinal symptoms, and nausea and vomiting. Peripheral neuropathy occurred less frequently. The study found that a systematic, multidisciplinary approach of intensive nutritional management before and after surgery with frequent follow-up greatly decreased the development of peripheral neuropathy (especially sensory polyneuropathy) in patients receiving bariatric surgery.

Finally, Miras and coworkers examined the effects of bariatric surgery on microvascular complications in patients with type 2 diabetes using objective measures.²⁷ The authors performed a prospective case-control study of 70 obese surgical patients with type 2 diabetes undergoing gastric bypass surgery matched for age, sex and duration of diabetes to 25 patients treated with medical care using international guidelines. The study authors investigated microvascular complications before and 12 to 18 months after intervention using urine albumin creatinine ratio measurements, two-field digital retinal images and peripheral nerve conduction studies. In their conclusion, the study authors noted that in the short term, bariatric surgery may be superior to medical care in the treatment of diabetic nephropathy, but not retinopathy or neuropathy.

In Conclusion
Good nutrition is often the first line of defense to avoid peripheral neuropathy. Peripheral neuropathy may occur as a result of an unbalanced diet. The podiatric physician may be instrumental in counseling patients with diabetes to adhere to good nutritional guidelines to prevent hyperglycemia and hyperlipidemia that may impact the pathophysiological process that presents with peripheral neuropathy. I hope this information will empower the podiatric physician to provide clinical management skills to assist patients with diabetes in healthy lifestyle choices.

Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla. He is currently deployed in Iraq.

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