Jennifer L. Larsen

Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation

Background. Lipoatrophic diabetes is an insulin resistance syndrome characterized by the complete or partial lack of adipose tissue and disturbances in lipid and glucose metabolism. Nonalcoholic steatohepatitis (NASH) is a well-described change in liver pathology consisting of steatosis, hepatitis, and fibrosis that can be associated with lipoatrophic diabetes. Results. This article describes the first reported case of lipoatrophic diabetes with NASH leading to liver failure and liver transplantation. Before transplantation, the patient required 600–700 U of insulin/day. After transplantation, a dramatic decline in her insulin requirements was observed, despite corticosteroids. Eighteen months after transplantation, her glycemic control worsened, and she developed recurrent NASH on serial liver biopsies. Conclusions. NASH associated with lipoatrophic diabetes can recur after liver transplantation, and in this case, was accompanied by increased insulin requirements. These results suggest that the development of NASH itself may contribute to the insulin resistance observed in lipoatrophic diabetes.

Recipient selection and evaluation for vascularized pancreas transplantation

Vascularized pancreas transplantation (PT) is becoming an accepted therapy for selected type I diabetic patients. However, selection and evaluation criteria remain uncertain. In the last 3.5 years, we have interviewed 205 and evaluated 151 diabetic patients for PT. The degree of renal dysfunction (creatinine clearance below 45 ml/min) was used to select patients for combined pancreas-kidney transplantation (PKT) or solitary pancreas transplantation (PTA) (clearance above 70 ml/min). The cardiovascular evaluation (stress thallium study with liberal use of coronary angiography) was used to determine operative risk and provided the other major selection criterion. A total of 104 patients were selected as candidates for PT; 70 have undergone PKT with 98.6% patient survival (1 cardiovascular death), 97.1% kidney graft survival, and 94.2% pancreas graft survival. Thirty-three evaluated patients (24.1%) were not accepted as candidates for PT; 13 have undergone cadaveric kidney transplantation, 5 were placed on the kidney waiting list, and 9 have died. Criteria for PTA include 2 or more diabetic complications or hyperlabile diabetes. Patient (n = 12) and pancreas graft survival after PTA is 83.3 and 50%, respectively. Our conclusion is that a multidisciplinary approach was used for recipient selection for PT based on degree of nephropathy, cardiovascular risk, and presence of diabetic complications. Nearly 75% of diabetic patients evaluated were acceptable candidates for PT. Only 4 (3.8%) of these selected patients died while awaiting or undergoing PT, thus optimizing the use of scarce allograft resources and providing evidence for appropriate patient selection.

Lipid status after combined pancreas-kidney transplantation and kidney transplantation alone in type I diabetes mellitus.

This study was designed to compare changes in lipid status following organ transplantation between type I diabetes mellitus (DM-I) patients receiving combined pancreas-kidney transplantation (PKT) with those receiving kidney transplantation alone (KTA). A retrospective chart review was used to identify pre- and posttransplantation fasting total cholesterol (TC) and triglyceeides (TG) in three groups: DM-I patients receiving KTA (DM:KTA; n=14), DM-I patients receiving PKT (DM:PKT; n=20), and kidney transplant recipients without DM (NDM; n=16). The groups were matched for age, gender, weight, duration of dialysis, smoking history, and duration of diabetes mellitus. Linear regression was used to analyze differences in lipid trends over time (up to 24 months posttransplantation) and the effects of prednisone dose, cyclosporine dose, and serum creatinine. Preoperative TC was significantly lower in the DM:KTA group (P<0.05) compared with DM:PKT or NDM. There were no significant differences in preoperative TG between the three groups. TC and TG decreased over time only in DM:PKT (P=0.0112, P=0.0278, respectively). TC increased and TG was unchanged over time in DM:KTA (P=0.0003, P=0.1103, respectively). Neither TC nor TG changed over time in NDM. Trends of TC and TG for DM:PKT were significantly different from DM:KTA (P<0.01 for both). Trend of TC for NDM was also significantly different from DM:PKT (P=0.0061). Prednisone dose was significantly related to TC in DM:KTA and NDM (P<0.01) while cyclosporine dose was significantly related to TC for DM:KTA only (P=0.0013) in the presence of time. None of the variables tested (prednisone dose, cyclosporine dose, and serum creatinine) significantly affected TG in the presence of time. In summary, TC and TG decreased over time only in DM:PKT. In contrast, TC increased while TG was unchanged in

Solitary Pancreas Transplantation: Experience with 62 consecutive cases

OBJECTIVE To determine the safety and efficacy of solitary pancreas transplantation in the treatment of IDDM. RESEARCH DESIGN AND METHODS A single-center retrospective case series of 62 consecutive solitary pancreas transplants (20 sequential pancreas after kidney, 42 pancreas transplants alone) performed in 57 adult IDDM patients was studied. Indications for solitary pancreas transplantation were 1) the presence of two or more overt diabetic complications and/or 2) glucose hyperlability with hypoglycemic unawareness and impaired quality of life. The recipient group consisted of 31 men and 26 women with a mean age of 38 years (range 25–62) and a mean duration of diabetes of 26 years (range 14–52). Mean pretransplant glycohemoglobin level was 9.9 ± 2.6%. Organ acceptance was restricted to ideal donors and man-dated a minimum of a two-antigen match (mean human leukocyte antigen ABDR match 2.7). The mean cold ischemia time was 16.6 h. Whole-organ pancreas transplantation was performed with bladder drainage by the duodenal segment technique. All patients were managed with either triple or quadruple immunosuppression. Monitoring included prospective urine cytology as well as cystoscopic transduodenal needle biopsies. RESULTS The mean length of initial hospital stay was 18 days, and mean hospital charges were

Comparison of CT and dual-energy DEXA using a modified trunk compartment in the measurement of abdominal fat

106,341. The incidences of rejection, infection, and surgical complications were 70, 55, and 47%, respectively. Overall patient and graft survival rates were 86 and 52%, respectively, with a mean follow-up of 28 months. All patients with functioning grafts had excellent metabolic control (mean glycohemoglobin level 5.1%) and achieved good rehabilitation. CONCLUSIONS Despite morbidity, solitary pancreas transplantation can be performed with improving success, can enhance quality of life, and can offer an opportunity to arrest secondary diabetic complications.

Vitamin D Insufficiency Is Associated With Diabetes Risk in Native American Children

The quantification of abdominal fat is a marker of health risk. While dual-energy x-ray absorptiometry (DEXA) is easily applied, it measures overall fat, although abdominal fat may be a better indicator of health risk from obesity. We have evaluated whether a subcomponent of DEXA measurements correlates better with computed tomography (CT) for body fat than those traditionally used. Forty-seven healthy adults (22 M/25 F), aged 54.5±15.8 yr (mean±SD), with BMI of 27.1±4.6 kg/m2 participated in a cross-sectional study. Body fat was measured using abdominal CT and DEXA for total fat, trunk fat, and a modified trunk measurement that excludes the chest, termed “lower trunk,” and compared. The coefficient of variation for DEXA measurements for trunk, lower trunk, and total body were 1.98, 3.12, and 0.85%, respectively. Mean DEXA for percentage fat ranged from 31.7% to 34.1% for trunk, lower trunk, and total body, compared to 54.2% for abdominal CT (p<0.003 for each pairwise comparison). Lower trunk, whole trunk, and total body DEXA measurements were not different. Measurement of subcomponents of fat content by DEXA is not superior to whole body measurements and remains consistently lower than measurements by CT.

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

Aims/Hypothesis. Vitamin D insufficiency has not been well studied in Native American (NA) children, who are at risk for obesity and diabetes. The authors examined vitamin D insufficiency and its association with body mass index (BMI) and insulin resistance. Methods. In a cross-section of NA children 5 to 18 years old (N = 198), anthropometrics, biomarkers of insulin resistance, and 25-hydroxy-vitamin D concentration [25(OH) vitamin D] were measured. BMI% and homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. Results. Mean age was 10.8 ± 0.3 years (mean ± SEM). Mean serum 25(OH) vitamin D was 17.8 ± 0.4 ng/mL and 97% had vitamin D insufficiency [25(OH) vitamin D <30 ng/mL]. After adjusting for BMI, 25(OH) vitamin D was inversely associated with HOMA-IR (P < .0001) and several other markers of insulin resistance. Conclusions/Interpretation. Vitamin D insufficiency was nearly universal in this cohort of NA children and was associated with diabetes and vascular risk markers. Whether vitamin D supplementation can improve insulin resistance must be studied further.

Body Mass Index Percentile More Sensitive Than Acanthosis Nigricans for Screening Native American Children for Diabetes Risk

Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM.

Pravastatin reduces serum cholesterol and low density lipoprotein concentrations following pancreas transplantation.

BACKGROUND Many Native American tribes use acanthosis nigricans to screen for type 2 diabetes risk. We hypothesized that acanthosis nigricans misses many children at risk for type 2 diabetes. METHODS We evaluated 5- to 18-year-old Native American children and youth to assess the sensitivity and specificity of acanthosis nigricans as a marker for insulin resistance. RESULTS In a cohort of 161 youth (72 males/89 females), mean age was 10.7 years + 3.9. Mean body mass index (BMI) percentile was 76.8 +/- 23.3, and 54% had a BMI at or above the 85th percentile. Acanthosis nigricans was present in 21.7% of the participants and was more common in 12-to 18-year-olds than in 5 to 11-year-olds (p = .02). Of those with acanthosis nigricans, 82.4% had insulin resistance (homeostatic model assessment of insulin resistance >4), but only 48.3% of those with insulin resistance had acanthosis nigricans. In contrast, BMI at or above the 85th percentile had a high sensitivity (74%) for insulin resistance, even though its specificity was lower (58%). CONCLUSIONS The presence of acanthosis nigricans alone was a specific, but not a sensitive, screening tool for identifying youth with insulin resistance. BMI at or above the 85th percentile was a more sensitive screening tool than acanthosis nigricans alone, or acanthosis nigricans and BMI together for identifying children and youth with IR who are at increased risk for type 2 diabetes.

Changing of the Guard

Hyperlipidemia is a significant risk factor for atherosclerotic vascular disease. We have shown previously that pancreas transplantation (PTX) improves but does not normalize lipids in most PTX recipients. We studied whether pravastatin was effective in treating 10 patients with elevated low density lipoprotein (LDL)-cholesterol (LDL-C) following PTX. Seven men and 3 women were studied. Six received combined kidney-pancreas transplantations, while 4 received PTX alone. Age at time of PTX was 37.2±2.2 years (mean ± SEM), and 4 had established coronary artery disease before PTX. Mean cholesterol (C), LDL-C, triglycerides (TG), and high density lipoprotein (HDL)-cholesterol (HDL-C) were 236±12, 142±6, 222±50, and 49±4 mg/dl before PTX. The LDL to HDL ratio was 3.0±0.3. After PTX, excluding the first 45 days, mean C, LDL-C, and HDL-C increased to 278±10, 178±7, and 63±6 mg/dl (all P≤0.05), respectively. TG, LDL to HDL ratio, and weight were unchanged. Pravastatin (11.7±0.8 mg/day, mean ± SEM) was initiated 250±53 days after PTX. During therapy, C and LDL-C decreased on average to 231±10 and 134±8 mg/dl, respectively (both P<0.01), while HDL did not change. The decreases in C and LDL-C were unexplained by a decrease in weight, cyclosporine dose or concentration, or increase in serum creatinine. However, prednisone dose decreased over the same interval, so a contribution from this variable cannot be excluded. No evidence of toxicity was identified during therapy. This is one of the first reports demonstrating that pravastatin is a safe and effective treatment for elevated C and LDL-C in patients following PTX. However, pravastatin did not increase HDL or decrease TG, as observed in the nontransplantation setting. Whether pravastatin or any hypolipidemia therapy can prevent cardiovascular events or mortality following PTX remains to be established.