Niacinamide and Pyruvate for Glaucoma

Forty-two patients (mean age, 65 years) being treated with intraocular pressure-lowering medication for open-angle glaucoma, who had moderate visual field loss in at least one eye, were randomly assigned to receive, in double-blind fashion, in a 2:1 ratio, the combination of niacinamide and pyruvate or placebo. Niacinamide was used because it increases nicotinamide adenine dinucleotide (NAD) levels and pyruvate was used because it can overcome deficits in glycolysis. The dose of niacinamide was 1,000 mg per day for one week, then 2,000 mg per day for one week, then 3,000 mg per day for one week. The dosage of pyruvate was 1,500 mg per day for one week, then 3,000 mg per day for two weeks. Thirty-two patients completed the study (21 in the treatment group and 11 in the placebo group). The primary outcome measure was the number of visual field test locations that improved beyond normal variability in the study eye. The number of test locations that improved was higher in the treatment group than in the placebo group (median, 15 vs. 7; p = 0.005).

Comment: In this study, the combination of niacinamide and pyruvate produced short-term improvement in visual function in patients receiving medical treatment for open-angle glaucoma. Previous research has suggested that an age-related impairment of mitochondrial energy production by retinal ganglion cells plays a role in the pathogenesis of glaucoma by rendering these cells more susceptible to degeneration and more vulnerable to the adverse effects of increased intraocular pressure. This impairment of mitochondrial function appears to be due at least in part to a decline in NAD levels, which may be reversible by supplementing with niacinamide. The importance of pyruvate is less clear. The results of the present study are consistent with a previous 12-week study in which niacinamide supplementation improved visual fields in glaucoma patients.¹ If these findings can be confirmed in studies of longer duration, it would represent a major advance in the treatment of glaucoma.

De Moraes CG, et al. Nicotinamide and pyruvate for neuroenhancement in open-angle glaucoma: a phase 2 randomized clinical trial. JAMA Ophthalmol. 2022;140:11-18.

Interpreting 25-Hydroxyvitamin D Levels in Selected Situations

The median serum 25-hydroxyvitamin D (25[OH]D) level was 4.6 ng/ml in children with steroid-responsive nephrotic syndrome in relapse, 10.6 ng/ml in children with steroid-responsive nephrotic syndrome in remission, and 17.6 ng/ml in healthy controls (p < 0.001 for each group of patients vs. controls). However, values for free 25(OH)D did not differ between groups. The levels of parathyroid hormone (which increase in response to vitamin D deficiency) also did not differ between patients and controls. Total 25(OH)D but not free 25(OH)D correlated significantly and inversely with the degree of proteinuria.

In a second study, the mean 25(OH)D concentration was significantly lower in 38 patients with critical illness than in 68 healthy controls (14.8 vs. 22.8 ng/ml). However, the mean estimated concentration of free 25(OH)D was higher in patients with critical illness than in controls (10.4 vs. 7.6 pg/ml; statistical significance not stated).

Comment: I have argued previously that serum 25(OH)D is often an unreliable indicator of vitamin D status. The two studies discussed above illustrate situations in which 25(OH)D is particularly unreliable. Around 99.9% of 25(OH)D in plasma is bound to protein: 85-90% is bound to vitamin D-binding protein and 10-15% is bound to albumin. It is thought that only free 25(OH)D is biologically active. Patients with nephrotic syndrome lose both vitamin D-binding protein and albumin in their urine, and therefore have less of these proteins available to bind vitamin D. In these patients, it appears that a higher-than-normal proportion of circulating vitamin D is in the free form, as opposed to being protein-bound. While the levels of total 25(OH)D were lower in these patients than in healthy controls, levels of biologically active free vitamin D were similar to those of controls. The fact that parathyroid hormone levels did not differ between groups supports the concept that the vitamin D status of children with nephrotic syndrome was not any worse than that of control children, even though the former had much lower 25(OH)D levels than the latter.

The second study found that total 25(OH)D levels, but not estimated free 25(OH)D levels, were decreased in patients with critical illness. That is because vitamin D-binding protein and albumin are negative acute-phrase reactants (i.e., their levels fall in response to inflammation). Measuring total 25(OH)D in patients with critical illness potentially underestimates vitamin D status and overestimates the number of patients who are deficient in vitamin D.

In patients with nephrotic syndrome or critical illness, free 25(OH)D is probably more reliable than total 25(OH)D as an indicator of vitamin D status. Direct measurement of free 25(OH)D by liquid chromatography-tandem mass spectrometry is not readily available, and immunoassay methods have been reported to be unreliable. However, the concentration of free 25(OH)D can be estimated by measuring total 25(OH)D, vitamin D-binding protein, and albumin levels, and using an equation that includes all of these variables.

Banerjee S, et al. Free vitamin D levels in steroid-sensitive nephrotic syndrome and healthy controls. Pediatr Nephrol. 2020;35:447-454.

Palmer D, et al. Unbound vitamin D concentrations are not decreased in critically ill patients. Intern Med J. 2022;52:89-94.

Kidney Stones Are Becoming More Common

The incidence of kidney stones was assessed using data from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018. Participants were asked, “In the past 12 months, have you passed a kidney stone?” Data were available on 10,521 participants older than 20 years. The 12-month incidence of stones was 2.1%, which was substantially higher than in previous reports. There was a significant positive relation between hypertension and incidence of stones. Being Hispanic, Black, or Asian, as compared with being White, was associated with a significant decrease in incidence.

Comment: Previous studies found that the 12-month incidence of kidney stones was 0.6% in 2005 and 0.9% in 2015. The present study found that the incidence of stones has increased even further. It is not clear why the incidence is rising. Previous studies found that supplementation with 300 to 500 mg per day of magnesium can decrease the recurrence rate of stones by as much as 90%. If calcium supplements are being used, they should be taken with meals, since taking them between meals may promote the development of calcium oxalate kidney stones.

Hill AJ, et al. Incidence of kidney stones in the United States: the continuous National Health and Nutrition Examination Survey. J Urol. 2022;207:851-856.

Can Vitamin D Prevent COVID-19?

Three hundred twenty-one frontline healthcare workers from four hospitals in Mexico City who were caring for patients hospitalized for COVID-19 and who themselves tested negative for were randomly assigned to receive, in double-blind fashion, 4,000 IU per day of vitamin D or placebo for 30 days and were followed for a total of 45 days. The study was conducted from July 15 to December 20, 2020. PCR testing was performed if subjects developed symptoms consistent with COVID-19. Serum IgG antibodies against COVID-19 were measured at baseline and on day 45. One hundred ninety-two subjects completed the trial. Six participants in the vitamin D group (6.4%) and 24 in the placebo group (24.5%) developed a COVID-19 infection (p < 0.001). Of the 30 positive cases, 12 were diagnosed by a positive PCR test and 18 were diagnosed by IgG antibody testing. It was not stated how many in each group were diagnosed by PCR testing vs. antibody testing. The relative risk of COVID-19 infection in those receiving vitamin D was 0.23 (95% confidence interval, 0.09-0.55). The beneficial effect of vitamin D was independent of baseline vitamin D status (as determined by serum 25-hydroxyvitamin D levels).

Comment: In this study, supplementation with 4,000 IU per day of vitamin D prevented COVID-19 infection in highly exposed individuals. Some previous studies found that vitamin D supplementation can decrease the severity of COVID-19 infection, but there had been little prior research on whether vitamin D can prevent people from becoming infected.

A double-blind study conducted in Canada found that long-term use of large doses of vitamin D (i.e., 4,000 IU per day or more for 3 years) accelerated bone loss in men and women between the ages of 55 and 70 years.² This effect was greater in women than in men.³ The risks and benefits of using high-dose vitamin D should be assessed on an individual basis.

Villasis-Keever MA, et al. Efficacy and safety of vitamin D supplementation to prevent COVID-19 in frontline healthcare workers. a randomized clinical trial. Arch Med Res. 2022;53:423-430.

Does Eating Processed Food Cause Inflammatory Bowel Disease?

The association between consumption of ultra-processed foods and risk of developing Crohn’s disease and ulcerative colitis was examined in a prospective study of three cohorts of health professionals in the United States: the Nurses’ Health Study (1986-2014), the Nurses’ Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2012), which included a total of 245,112 participants. During 5,468,444 person-years of follow-up, 369 incident cases of Crohn’s disease and 488 incident cases of ulcerative colitis were documented. The median age at diagnosis was 56 years. Compared with participants in the lowest quartile of ultra-processed food consumption, those in the highest quartile had an increased risk of Crohn’s disease (hazard ratio [HR] = 1.70; p for trend < 0.001). Among different subgroups of ultra-processed foods, the strongest positive associations with Crohn’s disease were seen for ultra-processed breads and breakfast foods; frozen or shelf-stable ready-to-heat and ready-to-eat meals; and sauces, cheeses, spreads, and gravies. There was no consistent association between intake of ultra-processed foods and risk of ulcerative colitis.

Comment: Ultra-processed food has been defined as ingredients produced from a series of industrial processes. Ingredients characteristic of ultra-processed foods include high-fructose corn syrup, hydrogenated oils, flavor enhancers, colors, and emulsifiers. Examples of ultra-processed foods include sweet or savory packaged snacks, sugar-sweetened beverages, candy, industrial bread, industrial breakfast cereal, ready-to-heat-and-eat pasta dishes and pizza, and sausages and other reconstituted meat products.

Consumption of ultra-processed foods has increased in the US in recent years. According to data from National Health and Nutrition Examination Surveys, between 1999 and 2018 the estimated percentage of total energy consumed from ultra-processed foods increased from 61.4% to 67.0%, whereas the percentage of total energy consumed from unprocessed or minimally processed foods decreased from 28.8% to 23.5%.⁴ In other regions around the world that have been undergoing Westernization, an increase in consumption of ultra-processed food has coincided with an increase in incidence of inflammatory bowel disease. Further research is needed to determine whether these associations represent causation and, if so, which types of ultra-processed foods are implicated the most.

Lo CH, et al. Ultra-processed foods and risk of Crohn’s disease and ulcerative colitis: a prospective cohort study. Clin Gastroenterol Hepatol. 2022;20:e1323-e1337.

Examining the Pathophysiology of Non-Celiac Gluten Sensitivity

Duodenal biopsies were performed on 261 patients with celiac disease with milder enteropathy (Marsh score of I-II), 175 patients with non-celiac gluten sensitivity, and 262 control cases with normal gastroscopy and histologic findings. The median villus height was shorter in patients with non-celiac gluten sensitivity than in controls (0.6 vs. 0.9 mm; p<0.001). The median villus height to crypt depth ratio was lower in non-celiac gluten sensitivity patients with a Marsh score of 0 (normal histology) than in controls (p<0.001). The median number of intraepithelial lymphocytes per 100 enterocytes was higher in non-celiac gluten sensitivity patients with a Marsh score of 0 than in controls (p<0.001).

Comment: This study demonstrated that the duodenal mucosa of patients with non-celiac gluten sensitivity showed subtle changes, including reduced villus height, increased crypt depth, and increased lymphocyte infiltration consistent with a mucosal immune response to luminal antigens. Abnormalities were seen even in cases where the mucosa was considered normal by standard criteria (Marsh score of 0). This study confirms that, contrary to the view of skeptics, non-celiac gluten sensitivity is a true clinical entity.

Rostami K, et al. Gluten induces subtle histological changes in duodenal mucosa of patients with non-coeliac gluten sensitivity: a multicentre study. Nutrients. 2022;14:2487

Vitamin C for Septic Shock

One hundred twenty-six adults hospitalized at one of five intensive care units in Minnesota who were within 24 hours of vasopressor initiation for septic shock were randomly assigned to receive, in double-blind fashion, intravenous vitamin C (10 mg/ml in normal saline) or placebo (an equivalent volume of normal saline). The dosage of vitamin C was 10,000 mg as a bolus over 30 minutes, followed by a continuous infusion of 250 mg per hour for 96 hours. The primary outcome of 28-day all-cause mortality was nonsignificantly lower by 34% in the vitamin C group than in the placebo group (26.7% vs. 40.6%; p = 0.10). Initiation of renal replacement therapy was higher in the vitamin C group than in the placebo group (16.7% vs. 3.3%; p = 0.015). In post hoc subgroup analysis, 28-day mortality was lower in the vitamin C group than in the placebo group among patients requiring positive-pressure ventilation at the time of enrollment (36.3% vs. 60.0%; p = 0.05).

Comment: In this study of patients with septic shock, intravenous vitamin C decreased 28-day mortality by 34%, but this decrease was not statistically significant. A larger study would be needed to determine whether this 34% decrease in mortality was real or due to chance. Post hoc analysis suggested that vitamin C may be beneficial for patients who were more seriously ill (those that required positive-pressure ventilation). However, post hoc analyses should be interpreted with caution. The increased need for renal replacement therapy among patients given vitamin C is concerning. Compromised kidney function is common among patients with critical illness. In those with severely compromised kidney function, vitamin C may be converted in part to oxalate, which can be deposited in the kidneys and cause further renal damage.

High-dose vitamin C appears to be useful for many different viral and some bacterial infections. However, there is no clear evidence at this time that high-dose vitamin C should be given to patients with septic shock.

Wacker DA, et al. Evaluating vitamin C in septic shock: a randomized controlled trial of vitamin C monotherapy. Crit Care Med. 2022;50:e458-e467.

L-Carnitine for Cirrhosis

Eighty-three Japanese patients (mean age, 67 years) with hepatic encephalopathy secondary to cirrhosis who were being treated with 1,200 mg per day of rifaximin (an antibiotic used to treat hepatic encephalopathy) were randomly assigned to receive 1,500 mg per day of L-carnitine for 12 weeks or to a control group that did not receive L-carnitine. The proportion of patients who required hospitalization during the study was 68% lower in the L-carnitine group than in the control group (9.8% vs. 30.9%; p < 0.03).

Comment: Patients with cirrhosis appear to have an impaired capacity to synthesize carnitine from lysine and methionine. Since carnitine plays a role in the detoxification of ammonia, carnitine deficiency could exacerbate hyperammonemia in cirrhotic patients, with potentially serious consequences. In the present study, supplementation with L-carnitine markedly decreased the need for hospitalization in patients with cirrhosis and hepatic encephalopathy.

Kubota K, et al. Additional L-carnitine reduced the risk of hospitalization in patients with overt hepatic encephalopathy on rifaximin. Dig Dis. 2022;40:313-321.