A Prospective Open-Label Dose-Response Study to Correct Vitamin D Deficiency in Cirrhosis.

BACKGROUND: Patients with advanced liver disease often have vitamin D deficiency, but the daily dosages of vitamin D3 needed to raise their serum 25-hydrodroxyvitamin D [25(OH)D] concentrations are unknown. OBJECTIVE: We aimed to establish the dose-response relationship between vitamin D3 and 25(OH)D in patients with liver cirrhosis. DESIGN: An open-label study of orally-administered vitamin D3 (gelcaps) was conducted in patients with liver cirrhosis using a tiered-dosing regimen: 4,000 IU/d for baseline 25(OH)D ≤ 15 ng/mL and 2,000 IU/d for baseline 25(OH)D > 15 to ≤ 25 ng/mL (NCT01575717). Supplementation continued for 6 months, or until liver transplantation. Changes in 25(OH)D were measured after ≥ 3 months. Dose-response data on 48 patients (21 receiving 4000 IU/d and 27 receiving 2,000 IU/d) reporting ≥ 80% adherence were analyzed using generalized estimating equations (GEE). RESULTS: Among the 48 patients, 39 (81%) had 25(OH)D > 20 ng/mL while on supplements, and none experienced hypercalcemia. The magnitude of the increase in 25(OH)D was approximately twofold greater in patients receiving the higher dose. The mean incremental increase was 5.1 ng/ml ± 3.9 of 25(OH)D per 1000 IU/d of vitamin D3. Multivariable models demonstrated a significant positive relationship between baseline 25(OH)D and serum albumin (p < 0.01) and hemoglobin (p = 0.01), and a negative relationship with the MELD score (p < 0.01) and total bilirubin (p < 0.01). CONCLUSIONS: A two-tiered dosing regimen of daily oral vitamin D3 supplementation safely raised 25(OH)D concentrations in the majority of adults with liver cirrhosis who were adherent to supplement use.

Index Use of Smoflipid in a Tertiary Intestinal Rehabilitation and Transplantation Program.

Long-term parenteral nutrition (PN) may be complicated by PN-associated liver disease (PNALD), and some studies suggest an association between the use of soy-based fat emulsions and PNALD development. Patients' liver function typically improves and PNALD resolves after reducing or stopping a soy-based fat emulsion, and thus lipid minimization has been the primary strategy for managing PNALD in many intestinal rehabilitation programs. However, fat emulsions often cannot be stopped entirely, leading some patients to develop PNALD even after lipid reduction strategies have been implemented. Smoflipid emulsion (Kabi-Fresenius, Bad Homburg, Germany), a balanced mixture of soybean oil, medium-chain triglycerides (MCTs), olive oil, and fish oil, was recently approved by the Food and Drug Administration for use in the United States as an equivalent alternative to Intralipid (Baxter Healthcare Corporation, Deerfield, IL). In several pediatric studies, patients who received Smoflipid had significantly lower serum bilirubin levels than those who received Intralipid. In this case report, we present a patient who developed severe PNALD with subsequent resolution after 20 weeks on Smoflipid.

The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies.

OBJECTIVE: Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies. METHODS: Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations. RESULTS: Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose. CONCLUSIONS: There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.

Vitamin D status of human immunodeficiency virus-positive patients with advanced liver disease enrolled in the solid organ transplantation in HIV: multi-site study.

An optimal vitamin D status may benefit liver transplantation (LT) patients. Higher levels of 25-hydroxyvitamin D [25(OH)D] mitigate steroid-induced bone loss after LT, correlate with better hepatitis C virus treatment responses, and increase graft survival. This study investigated 25(OH)D levels and assessed strategies for vitamin D deficiency prevention in human immunodeficiency virus (HIV)-positive patients with advanced liver disease who were enrolled in the Solid Organ Transplantation in HIV: Multi-Site Study. 25(OH)D was measured in banked specimens from 154 LT candidates/recipients with the DiaSorin assay; deficiency was defined as a 25(OH)D level < 20 ng/mL. Information about vitamin D supplement use after LT was obtained from medication logs and via surveys. Logistic regression, Cox regression, and linear repeated measures analyses were performed with SAS software. We found that none of the 17 academic medical centers in the United States routinely recommended vitamin D supplements before LT, and only a minority (4/17) recommended vitamin D supplements to all patients after LT. Seventy-one percent of the 139 patients with pre-LT values had vitamin D deficiency, which was significantly associated with cirrhosis (P = 0.01) but no other variable. The vitamin D status improved modestly after LT; however, the status was deficient for 40% of the patients 1 year after LT. In a multivariate linear repeated measures model, a higher pre-LT 25(OH)D level (P < 0.001), specimen collection in the summer (P < 0.001), a routine vitamin D supplementation strategy after LT (P < 0.001), and the time elapsing since LT (P = 0.01) were significantly associated with increases in the post-LT 25(OH)D level; black race was associated with a decreased level (P = 0.02). In conclusion, the majority of patients awaiting LT were vitamin D deficient, and approximately half were vitamin D deficient after LT. More extensive use of vitamin D supplements, more sun exposure, or both are needed to prevent this deficiency in HIV-positive LT candidates and recipients.

Acute liver failure caused by 'fat burners' and dietary supplements: a case report and literature review.

Globally, people are struggling with obesity. Many effective, nonconventional methods of weight reduction, such as herbal and natural dietary supplements, are increasingly being sought. Fat burners are believed to raise metabolism, burn more calories and hasten fat loss. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. The present report describes a young healthy woman who presented with fulminant hepatic failure requiring emergent liver transplantation caused by a dietary supplement and fat burner containing usnic acid, green tea and guggul tree extracts. Thorough investigation, including histopathological examination, revealed no other cause of hepatotoxicity. The present case adds to the increasing number of reports of hepatotoxicity associated with dietary supplements containing usnic acid, and highlights that herbal extracts from green tea or guggul tree may not be free of adverse effects. Until these products are more closely regulated and their advertising better scrutinized, physicians and patients should become more familiar with herbal products that are commonly used as weight loss supplements and recognize those that are potentially harmful.

Hepatotoxicity and complementary and alternative medicines.

Though some herbal medicines have been shown to protect against or treat experimental liver injury in vitro, and many may possess one or a combination of antioxidant, antifibrotic, immunomodulatory, or antiviral activities, they have not been shown effective in human trials. It has been extremely difficult to construct randomized, controlled trials using complementary and alternative medicines because of an incomplete understanding of their modes of action, the lack of standardization in their manufacture, and the complexity of ingredients in any herbal extract. This may become easier once more standardized and broad-based regulatory oversight of marketing and manufacture of these products is achieved. Despite this, the use of complementary and alternative medicines is ever increasing, especially in patients having chronic liver disease. With this growing popularity, it is becoming more apparent that many of these treatments possess the potential for appreciable hepatotoxicity, in some instances resulting in significant morbidity and mortality. Until these products are more closely regulated and their advertising better scrutinized, all physicians and patients should become more familiar with the natural and alternative products that are commonly used, and recognize which can be harmful (Table 4). Better public awareness should be maintained with regard herb and prescription drug interactions.