Clinical Briefs with Comments from Russell H. Greenfield, MD
Clinical Briefs
With Comments from Russell H. Greenfield, MD. Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.
"When in China..." Berberine and Diabetes
Source: Zhang Y, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab April 8, 2008 (Epub ahead of print).
Goal: To assess the effectiveness of berberine for people with type II diabetes mellitus (DM) and dyslipidemia.
Study Design: Multicenter randomized, double-blind, placebo-controlled clinical trial.
Subjects: People aged 25-70 years living around Shanghai with recently diagnosed type II DM and dyslipidemia who had not received pharmacotherapy previously (n = 116, evaluable data on n = 110).
Methods: Study participants underwent a screening medical history and physical examination, as well as screening blood and urine testing, including a 75-g oral glucose tolerance test (OGTT). A two-week run-in period followed, during which participants received instruction in diet and exercise. Subjects were then randomly assigned to daily receive either berberine 1.0 g or placebo for three months. Appointments occurred after an overnight fast at baseline, 1, 2, and 3 months. In a subset of participants, a hyperinsulinemic euglycemic clamp was applied to assess insulin sensitivity and glucose disposal rate (GDR, measuring the amount of glucose required to maintain stable blood glucose concentrations during the final 30 minutes of clamping). Primary outcome measures were changes in plasma glucose and serum lipid concentrations. Secondary outcomes of interest were body mass index (BMI) and blood pressure.
Results: A total of 106 subjects completed the trial (data from four who dropped out of the trial were included in the intention-to-treat analysis). Subjects in the berberine group experienced statistically significant improvements in the following parameters: both fasting and two-hour OGTT plasma glucose, HbA1c, triglyceride level, total cholesterol, and LDL-C. Serum fasting and postprandial insulin concentrations were not significantly different between the berberine and placebo arms. No statistically significant differences were noted between active and placebo groups with respect to clamp tests and serum insulin levels. GDR was increased in those who received berberine, but not in a statistically significant manner when compared with the placebo group. A mild reduction in BMI, and moderate decreases in systolic and diastolic blood pressures were also noted in the berberine group. While C-reactive protein levels were similar between the 2 groups, IL-6 concentrations were lower in the berberine bracket. No serious adverse events occurred in either group, including no episodes of hypoglycemia.
Conclusion: Berberine is a safe and effective treatment in the setting of type II DM and dyslipidemia.
Study strengths: Degree of follow-up; use of hyperinsulinemic euglycemic clamp; intention-to-treat analysis.
Study weaknesses: Small sample size; relatively short duration of trial; subjects had relatively mild DM.
Of note: Berberine is isolated from the rhizome of the Chinese medicinal herb Coptis chinensis (Huanglian, or goldthread) and has been used within traditional Chinese medicine as an antibiotic treatment for diarrhea; the mechanism of berberine's glucose lowering action is as yet unknown; the prevalence of DM in adults in China is 4.3% and rising; mild-to-moderate constipation developed in five subjects taking berberine (dose reduction was recommended in such circumstances); liver function tests were also noted to be reduced in the berberine group at trial's end.
We knew that: Animal data suggest that berberine may increase glucose-stimulated insulin secretion, improve glucose tolerance, and reduce body weight; existing human trials of berberine for diabetic patients have employed small sample sizes, and were open, non-controlled studies; research results in humans do, however, likewise support a possible role for berberine as a therapeutic adjunct in the treatment of DM, with results suggesting improvements in fasting as well as postprandial plasma glucose concentrations; additional data show a beneficial impact on triglyceride and total cholesterol levels; because berberine may cross the placenta, it is not recommended for use during pregnancy.
Comments: This nicely done trial brings to light the potential use of an agent rarely considered in Western medical practices. The conclusions suggest that berberine may one day be considered a useful adjunct in the care of people with type II DM. While compelling, the results do not yet lend themselves to rapid institution of berberine therapy for our patients, as the methodological shortcomings of the study are significant. The following statement is overused but appropriate in this instance more study is required. Patients may be using berberine and it is important to be able hold a salient conversation with them about risks and benefits, and the fact that relatively little is known about the agent at present. It is likely that this research will spur further investigation.
What to do with this article: Keep a copy on your computer.
Ouch! Probiotics and Acute Pancreatitis
Source: Besselink MG, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomized, double-blind, placebo-controlled trial. Lancet. 2008;371:651-659.
Goal: To evaluate the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis (the PRObiotics in PAncreatitis TRIAL, or PROPATRIA).
Study Design: Multicenter, randomized, double-blind, placebo-controlled clinical trial.
Subjects: Adult patients (n = 298) admitted with a first episode of acute pancreatitis who were predicted to have severe illness (APACHE II score > 8, Imrie score > 3, or C-reactive protein > 150mg/L) admitted to one of 15 Dutch medical centers.
Methods: Within 72 hours of symptoms, and earlier if possible, subjects were randomized to receive either placebo or a multi-species probiotic preparation containing 1010 CFU of six different strains of freeze-dried, viable bacteria plus cornstarch and maltodextrins (L. acidophilus, L. casei, L. salivarius, L. lactis, B. bifidum, and B. lactis [previously classified as B. infantis]) twice daily, typically via nasojejunal tube. A standard baseline IV contrast-enhanced abdominal CT scan was performed 7 days after admission to detect pancreatic necrosis. Percutaneous or surgical drainage was performed where infected necrosis was suspected, and microbiological assessment performed. Primary end point of interest was a composite of infectious complications during hospital stay and for 90 days thereafter: infected pancreatic necrosis, bacteremia, pneumonia, urosepsis, or infected ascites. Secondary end points included mortality, sequential organ failure assessment (SOFA) scores, (multi) organ failure, and a range of other parameters.
Results: Infectious complications occurred in similar numbers in both active and placebo groups (30% vs 28%, respectively); however, more patients in the probiotic group died compared with placebo (16% vs 6%, relative risk = 2.53), with most deaths due to multi-organ failure. Whereas no patients in the placebo arm developed bowel ischemia, nine patients who received the probiotic mixture did (eight of whom died). There were no differences noted between groups for serial SOFA scores.
Conclusion: In patients with predicted severe acute pancreatitis, prophylaxis with this specific mixture of probiotics is associated with an increased mortality risk, and probiotic therapy should not be offered to this group of patients. Indeed, probiotic mixtures, as employed in this study, cannot be considered harmless additions to enteral nutrition for critically ill patients.
Study strengths: Degree of blinding and compliance with protocol; independent data monitoring; surveillance for contamination or presence of endotoxin in treatment sachets; sample size; intention-to-treat analysis.
Study weaknesses: Minimal five subjects did not start treatment within the standard 72-hour time frame.
Of note: For the purpose of this study, pancreatitis was defined as abdominal pain in combination with abnormally high serum amylase or lipase concentrations; the incidence of acute pancreatitis is increasing by 5% annually in both Europe and the United States (mainly due to an increase in biliary pancreatitis); some have promoted probiotic therapy in the setting of acute pancreatitis in the belief that the local/systemic immune system might be augmented, that small bowel bacterial overgrowth would be lessened, and that mucosal barrier function would be supported; in small studies, probiotic therapy has reduced infections in patients with acute pancreatitis and those undergoing elective abdominal surgeries; antibiotic prophylaxis was permitted but strongly discouraged during this trial; no infections were caused by any of the probiotic strains employed; six of the patients were on vasopressor support at the time of development of bowel ischemia; the probiotics group contained a slightly higher proportion of patients with organ failure prior to randomization, as well as more patients with > 30% pancreatic parenchymal necrosis, and when these data were factored in analyses continued to reveal a higher adjusted mortality rate for the probiotic group.
We knew that: The probiotic strains used in this trial were chosen based on their capacity to inhibit growth of pathogens most often cultured from in vitro studies of infected necrotizing pancreatitis; the same combination of microbes was used in a variety of experimental and animal studies, but only three small clinical trials; about 20% of patients with acute pancreatitis go on to develop necrotizing pancreatitis, which is associated with a mortality rate of 10%-30% ascribed to infectious complications; intestinal blood flow and associated oxygen supply are generally reduced in acute pancreatitis, and direct introduction of enteral feeding, with its associated increased local oxygen demands, might worsen ischemia; results of studies using antibiotic prophylaxis with acute pancreatitis to prevent infectious complications have largely not shown benefit; infections may develop as a result of small bowel bacterial overgrowth, mucosal barrier failure, and a proinflammatory response leading to bacterial translocation.
Comments: The probiotic industry is estimated to be about $4 billion strong based on growing evidence of potential benefit in settings as diverse as eczema, inflammatory bowel disease, and antibiotic-associated diarrhea. Initial studies focused on the use of individual strains, while more recent research has employed multiple strains in light of data suggesting possible synergy. Generally regarded as safe, there have been rare reports of complications with probiotic therapy, most often in immunocompromised hosts.
The trial at hand was very well done, and brings home the fact that the study of probiotic therapy is still in its general infancy. There are as yet no standard recommendations for indication, type of bacterial strain to use, dosage and duration of therapy, nor are contraindications completely defined. The current study used an unusual combination of microbes, at least clinically, and in a population of sick patients. Prior data have suggested that the critically ill may be at risk from probiotic administration, but it has never been shown more clearly.
The results of this study are sobering (even the authors note their surprise). The promise of probiotic therapy is real, yet a vast array of microbes have been promoted as possible probiotics as a practitioner, how to choose, and in which circumstances? There are strong supportive data on but a relatively small number of individual organisms and in select clinical circumstances where the patients are not critically ill. It seems prudent to recommend only those few organisms that have been studied in depth and that have been shown to be safe in the clinical setting studied. Not all probiotic regimens are equal.
The current study clearly warns us against using the specific probiotic combination employed in the setting of severe acute pancreatitis, and helps to serve notice that complications of probiotic therapy are possible (they are usually live organisms, after all). The promise of probiotic therapy remains, and it is important that practitioners not consider them a panacea.
What to do with this article: Make copies to hand out to your peers.
Stress, Childhood Illness and Immunity
Source: Caserta MT, et al. The associations between psychosocial stress and the frequency of illness, and innate and adaptive immune function in children. Brain Behav Immun. 2008, doi:10.1016/j.bbi.2008.01.007
Goal: To examine associations between specific aspects of family stress and frequency of illness in children, measures of immune system function, and human herpesvirus 6 (HHV-6) reactivation.
Study Design: Prospective longitudinal cohort trial performed over three years.
Subjects: Ambulatory children aged 5-10 years (n = 169) and one primary caregiver.
Methods: Parents completed multiple assessments of stress at six-month intervals (n = 7) and maintained weekly illness diaries for the children. Psychosocial stress measures employed included the 51-item Brief Symptom Inventory (BSI), the Stressful Life Events and Conditions Checklist (SLECC), an eight-item family conflict measure, The Parent Isolation and Attachment Problem subscales from the Parenting Stress Inventory (PSI), and the Adult-Adolescent Parenting Inventory (AAPI). Parents also completed the Children's Behavior Questionnaire or Early Adolescent Temperament Questionnaire. A digital thermometer was to be used to detect febrile episodes. Immune function studies were performed at each semi-annual visit and included results on percentages of CD4 and CD8 cells, HHV-6, and natural killer (NK) cell function.
Results: Parents' mean age was 35 years, 93% of whom were female. A total of 120 child-parent sets completed all seven visits. There was a significant association found between parental psychiatric symptoms and increased frequency of childhood illness. For every 1U increase in parental BSI score, children experienced a 40% increase in one-year rate of total illness (rate ratio = 1.40), and a 77% increase in febrile illness (rate ratio = 1.77). Neither SLECC nor family conflict were significantly associated with childhood illness. The mean temperature recorded during febrile illnesses was 38.9° C; HHV-6 reactivation was not detected, but parental BSI scores were also tied to enhanced NK cell function, as well as increased percentages of CD8+CD28-CD57+ cells in seropositive children. Family conflict was associated with lower NK cell function.
Conclusion: Exposure to psychosocial stress is associated with an increased rate of illness and specific immunological changes in normally developing children.
Study strengths: Prospective nature and duration of trial; assessments taking into account missing data; focus on childhood psychosocial stressors widely researched and linked to behavioral adjustments (parental psychiatric symptoms, stressful life events, and family conflict).
Study weaknesses: Relatively small sample size; parental report of illness.
Of note: One child per family was enrolled in the trial, and all children were healthy at time of enrollment; early data suggest that the affects of chronic stress on children are different from those seen in adults, in that whereas chronic stress impairs immune function in adults, children may experience some degree of augmentation (for example, a decreased cortisol response); HHV-6 is acquired by all children by age three years and reactivates in the immunocompromised; changes in immune system parameters due to psychosocial stress are not reliably tied to illness susceptibility; higher scores on the parental BSI were usually due to anxiety and/or depression; higher scores on the BSI, SLECC, PSI and family conflict measure indicate higher levels of stress and dissatisfaction with parenting role; in this trial, if a fever was reported but the temperature not documented, the illness was recorded as a febrile illness.
We knew that: Studies in adults strongly suggest that psychosocial stress has a negative impact on physical health, and is associated with impairment in specific immune system parameters, including measures of anti-viral immunity (specifically reactivation of latent herpes virus infection); family processes have a significant impact on the emotional well-being of children, but little is known about their impact on physical health; family stress is reliably associated with a child's risk for maladaptive development and behaviors in realms cognitive, social and emotional; CD4 and CD8 cells are associated with immune control of cytomegalovirus (CMV) and an increased presence of these cells may be taken as evidence of CMV reactivation.
Comments: Long have practitioners known that psychosocial stress plays a role in physical health and wellbeing amongst adults, but the data in children were largely confined to behavioral issues until recently. This study builds on previously published results showing an increased incidence of illness in children experiencing significant family stress, as well as a defined impact on immune system function, including enhanced NK cell function. It is striking that, while both adults and children may suffer more illness as a result of stress, the immune processes involved may be very different, as evidenced by the varying responses in NK cell function. Indeed, children are not little adults, but they are uniquely at risk from negative family stressors in ways physical and otherwise. Parents may refute the notion that their stress levels and behavior could impact their child's physical health. The data presented in this paper can be used to recommend that each of us as parents examine our ways of being, so that our children might be optimally well.
What to do with this article: Keep a hard copy in your file cabinet.
Greenfield RH. “When in China…” – Berberine and diabetes. 2008;11:57-58. Greenfield RH. Ouch! Priorities and acute pancreatitis. 2008;11:58-59. Greenfield RH. Stress, childhood illness and immunity. 2008;11:59-60.Subscribe Now for Access
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