Tae-Seok Lim

Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study.

Long-term and high-dose treatment with metformin is known to be associated with vitamin B12 deficiency in patients with type 2 diabetes. We investigated whether the prevalence of B12 deficiency was different in patients treated with different combination of hypoglycemic agents with metformin during the same time period. A total of 394 patients with type 2 diabetes treated with metformin and sulfonylurea (S+M group, n = 299) or metformin and insulin (I+M group, n = 95) were consecutively recruited. The vitamin B12 and folate levels were quantified using the chemiluminescent enzyme immunoassay. Vitamin B12 deficiency was defined as vitamin B12≤300 pg/mL without folate deficiency (folate>4 ng/mL). The mean age of and duration of diabetes in the subjects were 59.4±10.5 years and 12.2±6.7 years, respectively. The mean vitamin B12 level of the total population was 638.0±279.6 pg/mL. The mean serum B12 levels were significantly lower in the S+M group compared with the I+M group (600.0±266.5 vs. 757.7±287.6 pg/mL, P<0.001). The prevalence of vitamin B12 deficiency in the metformin-treated patients was significantly higher in the S+M group compared with the I+M group (17.4% vs. 4.2%, P = 0.001). After adjustment for various factors, such as age, sex, diabetic duration, duration or daily dose of metformin, diabetic complications, and presence of anemia, sulfonylurea use was a significant independent risk factor for B12 deficiency (OR = 4.74, 95% CI 1.41–15.99, P = 0.012). In conclusion, our study demonstrated that patients with type 2 diabetes who were treated with metformin combined with sulfonylurea require clinical attention for vitamin B12 deficiency and regular monitoring of their vitamin B12 levels.

Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea

Background We investigated clinical course and risk factors for diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 759 patients with T2DM without DR were included from January 2001 to December 2004. Retinopathy evaluation was performed at least annually by ophthalmologists. The severity of the DR was classified into five categories according to the International Clinical Diabetic Retinopathy Severity Scales. Results Of the 759 patients, 523 patients (68.9%) completed the follow-up evaluation. During the follow-up period, 235 patients (44.9%) developed DR, and 32 patients (13.6%) progressed to severe nonproliferative DR (NPDR) or proliferative DR (PDR). The mean duration of diabetes at the first diagnosis of mild NPDR, moderate NPDR, and severe NPDR or PDR were 14.8, 16.7, and 17.3 years, respectively. After adjusting multiple confounding factors, the significant risk factors for the incidence of DR risk in patients with T2DM were old age, longer duration of diabetes, higher mean glycosylated hemoglobin (HbA1c), and albuminuria. Even in the patients who had been diagnosed with diabetes for longer than 10 years at baseline, a decrease in HbA1c led to a significant reduction in the risk of developing DR (hazard ratio, 0.73 per 1% HbA1c decrement; 95% confidence interval, 0.58 to 0.91; P=0.005). Conclusion This prospective cohort study demonstrates that glycemic control, diabetes duration, age, and albuminuria are important risk factors for the development of DR. More aggressive retinal screening for T2DM patients diagnosed with DR should be required in order to not miss rapid progression of DR.

Cardiovascular Autonomic Dysfunction Predicts Diabetic Foot Ulcers in Patients With Type 2 Diabetes Without Diabetic Polyneuropathy.

AbstractWe investigated the factors that might influence the development of diabetic foot ulcers (DFUs) in type 2 diabetes patients without diabetic polyneuropathy (DPN).From January 2000 to December 2005, a total of 595 patients who had type 2 diabetes without DPN between the ages of 25 and 75 years, and had no prior history of DFUs were consecutively enrolled in the study. A cardiovascular autonomic function test was performed to diagnose cardiovascular autonomic neuropathy (CAN) using heart rate variability parameters.The median follow-up time was 13.3 years. Among the 449 (75.4%) patients who completed the follow-up evaluation, 22 (4.9%) patients developed new ulcers, and 6 (1.3%) patients underwent the procedure for lower extremity amputations. The patients in the DFUs group had a longer duration of diabetes, higher baseline HbA1c levels, higher rates of nephropathy, and CAN. A Cox hazard regression analysis results revealed that the development of DFUs was significantly associated with the presence of CAN (normal vs definite CAN; HR, 4.45; 95% confidence interval, 1.29–15.33) after adjusting for possible confounding factors.The development of DFUs was independently associated with CAN in patients with type 2 diabetes without DPN. We suggested the importance of CAN as a predictor of DFUs even in the patients without DPN, and the need to pay attention to patients with definite CAN and type 2 diabetes.

Severe carbamazepine intoxication unresponsive to albumin-enhanced continuous venovenous hemodiafiltration with low dialysate flow.

Carbamazepine (CBZ) intoxication can be associated with severe toxicity, including neurological and cardio‐respiratory abnormalities. Highly protein‐bound, CBZ is not removed efficiently through conventional hemodialysis. Charcoal hemoperfusion is the most effective extracorporeal elimination therapy for CBZ intoxication. Recent reports have indicated that continuous venovenous hemodiafiltration (CVVHDF), albumin‐enhanced continuous venovenous hemodialysis, high‐flux hemodialysis and plasma exchange can be as effective as charcoal hemoperfusion. In contrast to recent reports, which demonstrated the effectiveness of CVVHDF with high dialysate flow in CBZ intoxication, we observed that serum CBZ level was decreased minimally by albumin‐enhanced CVVHDF with low dialysate flow. Therefore, albumin‐enhanced CVVHDF with high dialysate flow should be considered in severe CBZ intoxication, if hemoperfusion is unavailable because of the lack of facilities or if it cannot be performed.

Diabetic Cardiovascular Autonomic Neuropathy Predicts Recurrent Cardiovascular Diseases in Patients with Type 2 Diabetes

Cardiovascular autonomic neuropathy (CAN) is a risk factor for cardiovascular disease (CVD) and mortality in patients with type 2 diabetes. This study evaluated the relationship between CAN and recurrent CVD in type 2 diabetes. A total of 206 patients with type 2 diabetes who had a history of CVD within 3 years of enrollment were consecutively recruited from January 2001 to December 2009 and followed-up until December 2015. Cardiovascular autonomic function tests were performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to Valsalva maneuver and standing. We estimated the recurrence of CVD events during the follow-up period. A total of 159 (77.2%) of the 206 patients enrolled completed the follow up, and 78 (49.1%) patients had recurrent episodes of CVD, with an incidence rate of 75.6 per 1,000 patient-years. The mean age and diabetes duration were 62.5 ± 8.7 and 9.2 ± 6.9 years, respectively. Patients who developed recurrent CVD also exhibited hypertension (P = 0.004), diabetic nephropathy (P = 0.012), higher mean systolic blood pressure (P = 0.006), urinary albumin excretion (P = 0.015), and mean triglyceride level (P = 0.035) than did patients without recurrent CVD. Multivariable Cox hazard regression analysis revealed that definite CAN was significantly associated with an increased risk of recurrent CVD (hazard ratio [HR] 3.03; 95% confidence interval [CI] 1.39−6.60; P = 0.005). Definite CAN was an independent predictor for recurrent CVD in patients with type 2 diabetes who had a known prior CVD event.

Lipoprotein(a) predicts the development of diabetic retinopathy in people with type 2 diabetes mellitus

BACKGROUND Lipoprotein(a) [Lp(a)] has mainly been considered to be a predictor of the incidence of cardiovascular disease. In addition, previous studies have shown potential linkage between Lp(a) and diabetic microvascular complications. OBJECTIVES We investigated the incidence and risk factors for the development of diabetic retinopathy (DR) in patients with type 2 diabetes. METHODS A total of 787 patients with type 2 diabetes without DR were consecutively enrolled and followed up prospectively. Retinopathy evaluation was annually performed by ophthalmologists. The main outcome was new onset of DR. RESULTS The median follow-up time was 11.1 years. Patients in the DR group had a longer duration of diabetes (P < .001), higher baseline HbA1c (P < .001), higher albuminuria level (P = .033), and higher level of Lp(a) (P = .005). After adjusting for sex, age, diabetes duration, presence of hypertension, renal function, LDL cholesterol, mean HbA1c, and medications, the development of DR was significantly associated with the serum Lp(a) level (HR 1.57, 95% confidence interval [1.11-2.24]; P = .012, comparing the 4th vs 1st quartile of Lp(a)). The patient group with the highest quartile range of Lp(a) and mean HbA1c levels ≥7.0% had an HR of 5.09 (95% confidence interval [2.63-9.84]; P < .001) for developing DR compared with patients with lower levels of both factors. CONCLUSIONS In this prospective cohort study, we demonstrated that the DR was independently associated with the serum Lp(a) level in patients with type 2 diabetes.

Elevated lipoprotein(a) levels predict cardiovascular disease in type 2 diabetes mellitus: a 10-year prospective cohort study

Background/Aims Elevated lipoprotein(a) (Lp[a]) level is known to be a risk factor for cardiovascular disease (CVD). However, the data that has been reported on the association between the Lp(a) level and CVD in type 2 diabetes has been limited and incoherent. The aim of this study was to investigate the relationship between the Lp(a) concentration and new onset CVD in type 2 diabetes. Methods From March 2003 to December 2004, patients with type 2 diabetes without a prior history of CVD were consecutively enrolled. CVD was defined as the occurrence of coronary artery disease or ischemic stroke. Cox proportional hazards models were used to identify the associations between the Lp(a) and CVD after adjusting for confounding variables. Results Of the 1,183 patients who were enrolled, 833 participants were evaluated with a median follow-up time of 11.1 years. A total of 202 participants were diagnosed with CVD (24.2%). The median Lp(a) level for 1st and 4th quartile group was 5.4 (3.5 to 7.1) and 55.7 mg/dL (43.1 to 75.3). Compared with patients without CVD, those with CVD were older, had a longer duration of diabetes and hypertension, and used more insulin and angiotensin converting enzyme inhibitors/angiotensin receptor blockers at baseline. A Cox hazard regression analysis revealed that the development of CVD was significantly associated with serum Lp(a) level (hazard ratio, 1.92; 95% confidence interval [CI], 1.26 to 2.92; p < 0.001, comparing the 4th vs. 1st quartile of Lp[a]). Conclusions Elevated Lp(a) level was an independent predictable risk factor for CVD in type 2 diabetes. Other cardiovascular risk factors should be treated more intensively in type 2 diabetic patients with high Lp(a) levels.

A case report of seronegative cat scratch disease, emphasizing the histopathologic point of view.

Cat scratch disease, necrotizing granulomatous lymphadenitis caused by Bartonella henselae, usually benign and self-limited. However, various clinical manifestations and no pathognomonic histopathologic features can lead to misinterpretations and diagnostic disputes. We report a case of cat scratch disease in a 39-yr-old male patient with fever and left axillary lymphadenitis. He had a history of cat bite on the left hand dorsum. On excision, the lymph node showed follicular hyperplasia, stellate microabscesses with a rim of granulomatous inflammation. Warthin-Starry silver staining showed many clumps of silver-stained bacilli within the necrotic foci. Serological tests were negative. Diagnosis was established by PCR analysis.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1877499238123059

Polymyalgia rheumatica following paraspinal muscle inflammation and sacroiliitis

To the Editor, Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting mainly elderly people. It is characterized by morning stiffness, pain in the shoulder girdle and hip girdle, and elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); it typically shows dramatic responses to low-dose corticosteroid [1]. In addition to myalgia, inflammation frequently develops in the tendon and bursa around the shoulder joint in PMR [2]. However, the cause of PMR is at present unknown. We report a female patient in whom PMR developed following paraspinal muscle inflammation and sacroiliitis. A 68-year-old female presented with pain and stiffness in her low back and left buttock, which had lasted for 4 months. She had been treated with acupuncture and percutaneous nerve block several times but her pain did not improve. On physical examination, she was afebrile and there was tenderness around the left sacroiliac joint and left low paraspinal area. Hand and foot findings were non-specific. On laboratory examination, her white blood cell (WBC) count was 9,980/mm3 (neutrophils 74.6%), hemoglobin (Hb) 10.8 g/dL, platelets 393 × 109/mm3, ESR 120 mm/hr, and CRP 5.43 mg/dL. Serum alkaline phosphatase, creatine phosphokinase, and thyroid function were within normal limits. Rheumatoid factor was negative, antinuclear antibodies were negative, and HLA-B27 was positive. Blood cultures were negative. Magnetic resonance imaging (MRI) showed bone marrow edema of the left transverse process of the fifth lumbar vertebra, left iliac bone, and left sacroiliac joint as well as edema of the left paraspinal muscle (Fig. 1). Figure 1 Initial magnetic resonance imaging (coronal T1-weighted, gadolinium-enhanced fat regression image) shows bone marrow edema of the left transverse process of the fifth lumbar vertebra, left iliac bone, and left sacroiliac joint, as well as edema of the ... She was treated with nonsteroidal anti-inflammatory drugs (NSAID) and antibiotics (vancomycin and ceftriaxone) because we could not exclude the possibility of an infection, given that she had been treated with invasive procedures. Two weeks later, her symptoms had improved and ESR decreased to 85 mm/hr and CRP to 3.01 mg/dL. She was discharged with prescriptions for NSAID and oral antibiotics. Three weeks after discharge, pain and stiffness in her lower back were aggravated and right shoulder pain developed. On laboratory testing, WBC was 10,510/mm3, Hb 11.0g/dL, and platelets 386 × 109/mm3. ESR was elevated to 120 mm/hr and CRP to 5.71 mg/dL. However, MRI showed regression of the bone marrow edema of the left fifth lumbar vertebra, iliac bone, and sacroiliac joint, as well as improvement of the left paraspinal muscle inflammation (Fig. 2). Musculoskeletal ultrasound of the right shoulder revealed subacromial bursitis. Figure 2 Follow-up magnetic resonance imaging (coronal T2-weighted, gadolinium-enhanced fat regression image) shows marked regression of the bone marrow edema and improvement of the left paraspinal muscle inflammation. Elevation of ESR and CRP, the absence of rheumatoid factor, development of subacromial bursitis, aggravation of lower back stiffness and pain despite improvement of the initial inflammation on MRI, and the absence of other joint involvement suggested the possibility of PMR [2] and we added prednisolone 15 mg. Her pain improved markedly the next day; the pain visual analog scale decreased from 7 to 3. On the 6th day of prednisolone treatment, her back pain was almost relieved and CRP decreased to 1.58 mg/day. Based on the rapid and excellent response to the low-dose glucocorticoid, she was diagnosed with PMR. Then, while tapering the dose of prednisolone, she suffered another episode of disease flare, which responded again to an increased dose of prednisolone. Seven months after the last admission, she has been taking prednisolone 7.5 mg/day with methotrexate 10 mg/week and feeling little pain. In the latest laboratory tests, ESR was 54 mm/hr and the CRP level was 0.26 mg/dL, within normal limits. PMR is a clinical diagnosis; no specific diagnostic test or pathological finding is known. Diagnosis is usually made based on the clinical presentation and evidence of systemic inflammation in PMR [1]. In our case, myalgia and stiffness were aggravated and inflammatory markers, such as ESR and CRP, increased despite improvement of the initial inflammatory findings on MRI. Subacromial bursitis occurring in the right shoulder and 15 mg of prednisolone inducing a rapid and dramatic response strongly supported the diagnosis of PMR [2]. Several conditions can present with the inflammatory manifestations seen in our patient and spondyloarthritis (SpA) seemed to be the most important, considering that our patient initially presented with inflammation of the sacroiliac joint, elevation of CRP and HLA-B27 positivity, which are all included in the Assessment in Spondyloarthritis International Society classification criteria [3]. SpA that develops after the age of 50 years is termed late-onset SpA. Patients with late-onset SpA frequently present with PMR-like features, such as pain and stiffness in the shoulders and hip girdles, unexplained constitutional symptoms, and high levels of acute phase reactants at the beginning of the disease. There are several case reports of late-onset SpA mimicking PMR [4]. Thus, it is important to make a differential diagnosis between late-onset SpA and PMR. Late-onset SpA is characterized by the presence of inflammatory swelling with pitting edema over the dorsum of the feet, oligoarthritis involving the lower extremities, such as the ankle and knee joints, and minimal involvement of the axial skeleton [4], which was not compatible with our case. Additionally, while the back pain was aggravated after treatment with antibiotics and NSAIDs in our patient, MRI showed marked improvement of the initial inflammatory findings in the sacroiliac joint. Regarding treatment, it has been reported that a response to corticosteroids is absent or partial in SpA and diagnosis of SpA becomes evident during follow-up when subjects fail to respond to steroid therapy and develop the typical manifestations of SpA. Thus, the possibility of late-onset SpA should be considered in PMR patients with poor responses to corticosteroids and multiple flares [4]. However, our patient showed a marked response to the corticosteroid and stayed in good condition with corticosteroid of < 10 mg per day, making the diagnosis of PMR more likely. In our case, PMR occurred following paraspinal muscle inflammation and sacroiliitis. Considering the sequence of events, we suspect that long-lasting paraspinal muscle inflammation and sacroiliitis might have built up a systemic inflammatory milieu and triggered the PMR. However, it was not clear what caused the initial paraspinal muscle inflammation and sacroiliitis. We first considered the possibility of infection. However, the patient was afebrile, blood cultures were negative, and there was no abscess on MRI, although she had suffered from low back pain and left buttock pain for a prolonged period. These all made it seem less likely that an infection was the initial problem. It was also possible that the initial pain was due to the PMR. However, it is known that typical muscle inflammation is not present on MRI in PMR [1]. In our case, paraspinal muscle inflammation was definite on MRI, suggesting that PMR had not yet developed when the patient was first admitted. Regarding etiology, the cause of PMR is still unknown. There are several reports about a genetic association involving genes for intercellular adhesion molecule 1, interleukin 1 receptor antagonist, and interleukin 6 [1]. There is no direct evidence for an infectious cause of PMR, although the incidence of PMR was reported to coincide with epidemics of Mycoplasma pneumoniae, parvovirus B19, and Chlamydia pneumoniae infections [1]. There is a report of three patients with PMR who were successfully treated with the antibiotic clarithromycin. However, the authors considered that the effectiveness of clarithromycin in PMR was due to its anti-inflammatory effects, not its antibacterial activity [5]. There are reports that patients with PMR may have disturbances in the hypothalamic-pituitary-gonadal axis with some adrenal insufficiency, but this remains to be confirmed [1].