Severe vitamin deficiencies in pregnancy complicated by progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) is a rare disease of impaired bile acid excretion which can lead to nutritional deficiencies. Vitamin deficiencies during pregnancy can result in adverse maternal and fetal outcomes. A 20-year-old primiparous woman at 30 4/7 weeks with PFIC type 2 presented with worsening cholestasis, coagulopathy and fat-soluble vitamin deficiency. She developed visual deficits and was found to have severe vitamin A deficiency. Her coagulopathy and visual deficits improved following vitamin K and A supplementation, respectively. She delivered at 32 2/7 weeks following preterm labour. This case highlights several unique aspects in the care of pregnant women with liver disease. These patients are at risk for fat-soluble vitamin deficiencies which can result in significant coagulopathy and rarely, visual deficits due to vitamin A deficiency. Prompt treatment is necessary to prevent permanent sequelae.

Long-term outcomes of six patients after partial internal biliary diversion for progressive familial intrahepatic cholestasis.

BACKGROUND: Partial internal biliary diversion (PIBD) is an alternative approach for the treatment of devastating pruritus in patients with progressive familial intrahepatic cholestasis (PFIC). In these patients quality of life can be improved and progression of liver disease can be delayed while waiting for liver transplantation. The aim of our study was to evaluate six patients with PFIC who have undergone PIBD in long-term follow-up. METHODS: Retrospective review of the records of six patients who underwent PIBD for PFIC between 2008 and 2010 was conducted to evaluate age, growth, clinical and laboratory studies for long-term outcome. RESULTS: Serum postoperative bile acid levels were reduced from a mean 340.1µmol/L (range 851-105) preoperatively to a mean of 96.3µmol/L at postoperative fifth year. The difference between pre- and postoperative bile acid levels was statistically significant (p=0.018). AST decreased from 79.1U/L (range 43-150U/L) to 64.6U/L (range 18-172U/L), ALT decreased from 102.8U/L (range 35-270U/L) to 84.6U/L and total bilirubin decreased from 2.9µmol/L (range 0.35-6.4µmol/L) to 1.53µmol/L (range 0.3-2.4). Again, the decrease in total bilirubin levels was significant (p=0.043). Pruritus was diminished from a mean of +4 (range 4-4) preoperatively to a mean of +2 (4-0). One patient who underwent liver transplantation owing to relapsing pruritus died from postoperative sepsis in the early postoperative period at the fifth year after PBID. Five symptom-free patients have not required liver transplantation at a mean period of 6.1±0.83years (5.1-7.0years) follow-up. CONCLUSION: PBID is an effective surgical procedure in the long-term and can delay the need for liver transplantation in children with PFIC by reducing jaundice and pruritus.

Clinical Variability After Partial External Biliary Diversion in Familial Intrahepatic Cholestasis 1 Deficiency.

OBJECTIVES: Familial intrahepatic cholestasis 1 (FIC1) deficiency is caused by a mutation in the ATP8B1 gene. Partial external biliary diversion (PEBD) is pursued to improve pruritus and arrest disease progression. Our aim is to describe clinical variability after PEBD in FIC1 disease. METHODS: We performed a single-center, retrospective review of genetically confirmed FIC1 deficient patients who received PEBD. Clinical outcomes after PEBD were cholestasis, pruritus, fat-soluble vitamin supplementation, growth, and markers of disease progression that included splenomegaly and aspartate aminotransferase-to-platelet ratio index. RESULTS: Eight patients with FIC1 disease and PEBD were included. Mean follow-up was 32 months (range 15-65 months). After PEBD, total bilirubin was <2 mg/dL in all patients at 8 months after surgery, but 7 of 8 subsequently experienced a total of 15 recurrent cholestatic events. Subjective assessments of pruritus demonstrated improvement, but itching exacerbation occurred during cholestatic episodes. High-dose fat-soluble vitamin supplementation persisted, with increases needed during cholestatic episodes. Weight z scores improved (-3.4 to -1.65, P < 0.01). Splenomegaly did not worsen or develop and 1 patient developed an aminotransferase-to-platelet ratio index score of >0.7 suggesting development of fibrosis 24 months after PEBD. CONCLUSIONS: Clinical variability is evident among genetically defined FIC1 deficient patients after PEBD, even among those with identical mutations. Recurrent, self-limited episodes of cholestasis and pruritus are reminiscent of the benign recurrent intrahepatic cholestasis phenotype. Despite diversion of bile from the intestinal lumen, weight gain improved while fat-soluble vitamin requirements persisted. Significant progression of liver disease was not evident during follow-up.

Trace Element Status (Zinc, Copper, Selenium, Iron, Manganese) in Patients with Long-Term Home Parenteral Nutrition.

BACKGROUND: The objective of the present study was to determine concentrations of zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in blood plasma and manganese (Mn) in the whole blood in patients with long-term home parenteral nutrition (HPN) in comparison to the control group. PATIENTS AND METHODS: We examined 68 patients (16 men and 52 women) aged from 28 to 68 years on a long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily doses of Zn, Cu, Fe, Se and Mn in the last 3 months were determined. RESULTS: No significant differences in blood plasma were found for Zn, Cu and Fe in patients with HPN and in the control group (p > 0.05). The concentration of Mn in whole blood was significantly increased in HPN patients (p < 0.0001), while Se concentration in these patients was significantly decreased (p < 0.005). The concentration of Mn in the whole blood of 16 patients with cholestasis was significantly increased compared to the patients without cholestasis (p < 0.001). The Cu concentration was increased with no statistical significance. CONCLUSION: In long-term HPN, the status of trace elements in the patients has to be continually monitored and the daily substitution doses of these elements have to be flexibly adjusted. Dosing schedule needs to be adjusted especially in cases of cholestatic hepatopathy. A discussion about the optimal daily dose of Mn in patients on HPN is appropriate. For clinical practice, the availability of a substitution mixture of trace elements lacking Mn would be advantageous.

Dermatoses of pregnancy.

The dermatoses of pregnancy represent a distinct heterogenous group of cutaneous disorders that can impact the health of the pregnant woman and potentially the fetus. The current classification of pregnancy-specific cutaneous disorders is reviewed, along with important clinical features. Advances in management of these disorders, along with fetal implications, are discussed. The diagnosis of these disorders is challenging, but important clinical features can aid in diagnosis. There have been important advances in the management of these disorders and better understanding of potential fetal risks. Early recognition is critical for appropriate care.

Extrahepatic complications of chronic cholestasis: current diagnosis and treatment.

Pruritus, fatigue and osteoporosis are the main symptoms of the extra hepatic manifestations of chronic cholestasis that affect patients' quality of life. Pruritus affects more often female patients, varies as intensity during a day and for longer period of time, typically can be localized on the palms of hands and soles of feet or can be generalized. Pruritus can be treated with anions resines exchange--cholestiramine, the pregnanne X receptor agonist Rifampicine, Naltrexone. Liver transplantation can be considered if severe pruritus remains refractory to all medical treatments. Fatigue is the most disabling complain in chronic colestasis. No specific therapies are available for fatigue and liver transplantation doesn't improve it. Osteoporosis and the risk of fractures are more severe with the duration and severity of hepatic disease. For treatment are recommended regular physical exercise, vitamin D and Ca supplimentation and bisphosphonates (Alendronate 70 mg/week) in severe cases. Only patients with atherosclerotic risk and hyperlipemia can be treated with statines. Fat soluble vitamin supplementation can be administrated only in symptomatic and proved vitamin deficiency.

Effects of supplementation on food intake, body weight and hepatic metabolites in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse model of human citrin deficiency.

The C57BL/6:Slc23a13(-/-);Gpd2(-/-) double-knockout (a.k.a., citrin/mitochondrial glycerol 3-phosphate dehydrogenase double knockout or Ctrn/mGPD-KO) mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2), making it a suitable model of human citrin deficiency. In the present study, we show that when mature Ctrn/mGPD-KO mice are switched from a standard chow diet (CE-2) to a purified maintenance diet (AIN-93M), this resulted in a significant loss of body weight as a result of reduced food intake compared to littermate mGPD-KO mice. However, supplementation of the purified maintenance diet with additional protein (from 14% to 22%; and concomitant reduction or corn starch), or with specific supplementation with alanine, sodium glutamate, sodium pyruvate or medium-chain triglycerides (MCT), led to increased food intake and body weight gain near or back to that on chow diet. No such effect was observed when supplementing the diet with other sources of fat that contain long-chain fatty acids. Furthermore, when these supplements were added to a sucrose solution administered enterally to the mice, which has been shown previously to lead to elevated blood ammonia as well as altered hepatic metabolite levels in Ctrn/mGPP-KO mice, this led to metabolic correction. The elevated hepatic glycerol 3-phosphate and citrulline levels after sucrose administration were suppressed by the administration of sodium pyruvate, alanine, sodium glutamate and MCT, although the effect of MCT was relatively small. Low hepatic citrate and increased lysine levels were only found to be corrected by sodium pyruvate, while alanine and sodium glutamate both corrected hepatic glutamate and aspartate levels. Overall, these results suggest that dietary factors including increased protein content, supplementation of specific amino acids like alanine and sodium glutamate, as well as sodium pyruvate and MCT all show beneficial effects on citrin deficiency by increasing the carbohydrate tolerance of Ctrn/mGPD-KO mice, as observed through increased food intake and maintenance of body weight.

Oral absorbable fat-soluble vitamin formulation in pediatric patients with cholestasis.

OBJECTIVE: Fat-soluble vitamin (FSV) deficiencies are common complications in pediatric patients with chronic cholestasis. The aim of the present study was to evaluate the status of FSV deficiencies in patients under present practice and to test the effect of an oral, absorbable, fat-soluble vitamin formulation (OAFSV) in these patients. METHODS: We recruited a total of 23 pediatric patients receiving conventional FSV supplementation in a single medical center, with diagnosis of biliary atresia (10), progressive familial intrahepatic cholestasis (9), Alagille syndrome (2), and other conditions (2). Ten patients switched to OAFSV and continued for 3 months. Plasma levels of vitamins A, D, and E and an international normalized ratio (INR) for prothrombin time (PT), a surrogate marker for vitamin K deficiency, were measured. RESULTS: The proportion of patients with FSV A, D, E, and K deficiencies under conventional supplementation was 73.9%, 81.8%, 91.3%, and 20.0%, respectively. In patients with total bilirubin levels ≥3.0  mg/dL, the proportion of at least 1 FSV deficiency was 100%; and the deficiency rates of vitamin A, D, E, and K were 78.6%, 100.0%, 100.0% and 21.4%, respectively. Of the 10 patients receiving standard daily dose of OAFSV for 3 months, no adverse events or overdose effects were found. The rates of vitamin A, D, and E deficiency in the patients receiving OAFSV decreased from 80.0%, 100%, and 100%, respectively, to 70.0%, 60.0%, and 60.0% after 3 months of oral supplementation. CONCLUSIONS: High rates of FSV deficiency were found in pediatric patients with chronic cholestasis under present follow-up. OAFSV supplementation is safe and potentially effective in pediatric patients with cholestasis.

Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases.

BACKGROUND & AIMS: Methasteron is a nutritional supplement used to increase weight or accelerate the build-up of muscle mass. The aim of this study was to describe 5 cases of hepatotoxicity in patients using methasteron seen at tertiary-care medical centers. METHODS: A case report design was used. RESULTS: Five previously healthy patients who used methasteron developed jaundice 2 weeks after discontinuation; they presented to a tertiary-care medical center 2 weeks later. Within another 2 to 3 weeks, bilirubin levels peaked. About 12 weeks after initial presentation, all cases resolved with no identifiable residual hepatic dysfunction. CONCLUSIONS: Methasteron use can result in severe hepatotoxicity. Liver failure can worsen after initial presentation, especially within 2 weeks. With close observation and supportive care, acute hepatic injury should resolve.

Prolonged intrahepatic cholestasis after exposure to loxoprofen.

OBJECTIVE: The objective of this report was to describe a case of prolonged intrahepatic cholestasis likely associated with the use of loxoprofen, a phenylpropionate NSAID. METHODS: A 36-year-old female patient was transferred to Gunma University Hospital, Maebashi, Japan, with progressive pruritus and jaundice that developed after 5-day treatment with 120 mg/d of loxoprofen (maximum recommended dose, 180 mg/d) for menstrual pain. Liver function tests found the following concentrations: total bilirubin, 27.5 mg/dL (normal [nl] range, 0.3-1.2 mg/dL); aspartate aminotransferase, 151 IU/L (nl, 13-33 IU/L); alkaine aminotransferase, 470 IU/L (nl, 8-42 IU/L); alkaline phosphatase, 1082 IU/L (n1, 115-359 IUAL); and gamma-glutamyl transpeptidase, 795 IU/L (nl, 10-47 IU/L) indicative of intrahepatic cholestasis. No use of alcohol or other drugs or herbal products was reported. The patient had a history of elevated hepatic enzymes of unknown origin following the use of mefenamic acid. The patient was prescribed ursodeoxycholic acid 3 weeks after the onset of symptoms of intrahepatic cholestasis. Thereafter, due to progressive cholestasis, an IV pulse of methylprednisolone (1000 mg/d) and the herbal product Inchin-ko-to (TJ-135) were administered. Plasma bilirubin adsorption (PA) and plasma exchange (PE) were performed. RESULTS: Following treatment with PA and PE for 3 weeks with administration of methylprednisolone and Inchin-ko-to, signs and symptoms of intrahepatic cholestasis began to resolve (3.5 months after the onset); they were completely resolved 8 months after the initial episode. A Naranjo scale score of 6 suggested that loxoprofen was likely the cause of the prolonged cholestasis in this patient. CONCLUSION: Based on the Naranjo score, this case of prolonged intrahepatic cholestasis in a young woman was likely associated with loxoprofen use.

Prevalence of vitamin K deficiency in children with mild to moderate chronic liver disease.

OBJECTIVES: Children with chronic liver disease are at risk for vitamin K deficiency because of fat malabsorption and inadequate dietary intake. The objective of this study was to determine the prevalence of vitamin K deficiency in children with mild to moderate chronic cholestatic and noncholestatic liver disease. METHODS: Vitamin K status was examined in 43 children (0.25-15.9 years) with mild to moderate chronic cholestatic liver disease, 29 children (0.9-16.9 years) with chronic mild to moderate noncholestatic liver disease, and in 44 healthy children (1-18 years). Vitamin K status was assessed by the plasma PIVKA-II (protein induced in vitamin K absence) assay (enzyme-linked immunosorbent assay). Plasma PIVKA-II values greater than 3 ng/mL are indicative of vitamin K deficiency. RESULTS: The mean plasma PIVKA-II (+/-SD) in cholestatic, noncholestatic, and healthy children was 61.9 +/-144, 1.2 +/- 3, and 2.1 +/- ng/mL, respectively (P < 0.002). Fifty-four percent of the children supplemented with vitamin K had plasma PIVKA-II greater than 3 ng/mL. Plasma conjugated bilirubin, total bile acids, and severity of liver disease were positively correlated with plasma PIVKA-II levels (P < 0.05). CONCLUSIONS: Vitamin K deficiency is prevalent in children with mild to moderate chronic cholestatic liver disease, even with vitamin K supplementation. Elevated PIVKA-II levels occurred in children with a normal prothrombin, indicating that more sensitive markers of vitamin K status should be used in children with chronic liver disease. Vitamin K deficiency was related to degree of cholestasis and severity of liver disease in children. Children without cholestasis did not exhibit vitamin K deficiency.

Subacute cholestatic hepatitis likely related to the use of senna for chronic constipation.

We report a case of senna-induced cholestatic hepatitis which was not diagnosed at presentation. A 77 year old male was referred with abdominal pain, jaundice and elevated transaminase levels. A diagnosis of extrahepatic cholestasis was first suspected, due to the observation of a duodenal diverticulum and dilated proximal choledocus. However, the sphincterotomy did not improve cholestasis. At further evaluation, HBsAg was positive but serological work up was compatible with a healthy-carrier status. Further interrogation of the patient revealed a history of chronic senna intake to treat a chronic constipation. Liver biopsy showed bridging hepatocellular necrosis as well as canalicular cholestasis. Drug withdrawal resulted in a slow and progressive reduction in bilirubin levels and liver enzymes. In this case senna was likely the cause of a subacute cholestatic hepatitis exemplifying again the potential role of herbal related liver injury.

Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat.

Oxidative stress, in particular lipid peroxidation, induces collagen synthesis. Thus, we administered various antioxidants to bile duct-ligated rats for 28 days and lipid peroxidation, glutathione content, fibrosis, necrosis and cholestasis were evaluated. Extrahepatic cholestasis was induced by double ligation and section of the common bile duct. The study included eight groups (n=6), four groups were bile duct-ligated and received either vitamin C (50 mg/kg/day, orally), vitamin E (400 IU/rat/day, orally), silymarin (50 mg/kg/12 hr, orally) or vehicles; four groups were sham-operated controls. Collagen content was determined by measuring hydroxyproline in liver samples; malondialdehyde was used to estimate lipid peroxidation levels; reduced and oxidized glutathione were determined fluorometrically; alanine aminotransferase and bilirubins colorimetrically. Bilirubins increased several times, alanine aminotransferase once, reduced/oxidized glutathione ratio decreased three times, lipid peroxidation and collagen increased about three-times by biliary obstruction (p<0.05). Silymarin, vitamin E or C failed to prevent these effects significantly. It is not possible to clarify the role of oxidative stress in the fibrotic process induced by chronic biliary obstruction with the present results. Therefore, it seems reasonable to propose that a wide mixture of antioxidants, administered by the parenteral route (because cholestasis decreased the absorption of lipophilic compounds), is needed to counteract the oxidant stress produced by cholestasis.

Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats.

The anti-fibrotic effects of a hot-water extract form the traditional Chinese medicinal herb Salvia miltiorrhiza (Labiatae) on liver fibrosis induced by biliary obstruction was studied in rats. Liver fibrosis was induced in male Sprague-Dawley rats by bile duct ligation and scission (BDL). After surgery, the hot-water extract of S. miltiorrhiza roots (100 mg kg(-1), p.o.) was administered daily for 28 days. The concentrations of aspartate transaminase, alanine transaminase, alkaline phosphatase, total bilirubin and total cholesterol in serum and hydroxyproline and malondialdehyde contents in liver were significantly increased in BDL rats. Treatment with the extract of S. miltiorrhiza significantly reduced (P < 0.01) the serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and total cholesterol concentrations in BDL rats. The liver hydroxyproline content in BDL rats treated with extract was also reduced to 68% of that in BDL control rats (P < 0.01). The liver malondialdehyde content in BDL rats treated with the extract was also reduced to 47% of that in BDL control rats (P < 0.01). The morphological characteristics of fibrotic livers were improved in BDL rats treated with extract. Immunohistochemical examination of fibrotic liver showed that the extract of S. miltiorrhiza markedly reduced protein expression of alpha-smooth muscle cell-like actin, which indicates that hepatic stellate cell activation was inhibited during liver fibrosis development. The results indicate that the hot-water extract of S. miltiorrhiza roots inhibits fibrosis and lipid peroxidation in rats with liver fibrosis induced by biliary obstruction.

Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity.

Herbal medicines are gaining widespread popularity. Much of the public believes that botanical herbs are both harmless and useful for the treatment of a variety of symptoms. This belief stands in contrast with the fact that many herbal therapies have been shown to be toxic. In the present case report, cascara sagrada (CS) has been associated with the development of cholestatic hepatitis, complicated by portal hypertension. CS is a mixture of ingredients, among which is anthracene glycoside--an herbal agent that previously has been associated with chronic hepatitis. The liver injury in the case herein reported is believed to be related to either anthracene glycoside or one of the other constituents of CS.

Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis.

Neonatal intrahepatic cholestasis is a heterogeneous disease of undetermined cause. There is an unreported subset of idiopathic neonatal intrahepatic cholestasis with an unusual histological combination of hepatic siderosis and macrovesicular steatosis. The patients were a 34-day-old female and a 39-day-old male with normal birth weights. Their mothers had received oral iron supplement 4-6 weeks before delivery. The patients had obstructive jaundice noticed at the well-baby clinic at 1 month of life. They had high levels of serum galactose and tyrosine, hyperferritinemia. Urinary organic acid and bile acid analyses were negative, and galactose-1-phosphate uridyltransferase activity in red cells was normal. Liver biopsies showed diffuse iron deposits and macrovesicular fat. By substituting formula milk with lactose-free milk, the patients responded, and had normal biochemical tests within 5 months of life. Follow-up biopsies, at the age of 12 months, showed mild residual fibrosis without iron or fat deposits. They are both well at 3 and 6 years of age, respectively, without biochemical liver dysfunction and neurologic impairment. Prenatal iron-overload might contribute to the pathogenesis of the disease, but further studies are needed to confirm the assumption.

The role of magnesium in the pathogenesis of bone disease in childhood cholestatic liver disease: a preliminary report.

BACKGROUND: Magnesium deficiency may contribute to the metabolic bone disease that complicates chronic cholestatic liver disease. We hypothesized that magnesium deficiency alters vitamin D metabolism by decreasing parathyroid hormone (PTH) response, resulting in decreased serum osteocalcin and decreased bone accretion. METHODS: Nine subjects, age 3-22 years, with cholestatic liver disease were evaluated with the magnesium retention test. The response of PTH, 1,25(OH)2 vitamin D, and osteocalcin to provocative stimuli and dual x-ray absorptiometry measurement of bone mineral density (BMD) of the lumbar spine were assessed. Thereafter, subjects were treated with oral magnesium supplements. RESULTS: All nine subjects were magnesium depleted. Repletion with magnesium was successful in seven subjects, and required 4 to 31 (median 14) months with doses of 6 to 34 (median 11) mg/kg/day. Baseline serum PTH was significantly reduced in the cholestatic subjects compared to 15 age-matched controls. Comparison of baseline to repleted provocative testing was performed in six Mg-repleted subjects. Osteocalcin response increased significantly (p = 0.048) with repletion, while PTH response increased (p = 0.061). Lumbar spine BMD increased modestly with repletion (p = 0.093). CONCLUSIONS: This preliminary report suggests that magnesium depletion is extremely common in children with chronic cholestasis. We speculate that magnesium supplementation may be warranted to forestall the progression of metabolic bone disease in chronic cholestasis.