[Cholestatic pruritus : new insights into pathophysiology and current treatment]. / Cholestatischer Pruritus : Neues zur Pathophysiologie und aktuelle Therapie.

Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by µ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.

The challenge of cholestatic pruritus.

Pruritus can be the dominant symptom of cholestatic liver disease but is difficult to treat since unraveling its pathophysiology is a great challenge. Serum autotaxin activity correlates with pruritus intensity, but its causal relationship, expression pattern and exact mode of action during cholestasis remain to be established. The anion exchange resin cholestyramine, the PXR agonist rifampicin, the opioid antagonist naltrexone and the serotonine reuptake inhibitor sertraline are recommended by evidence-based guidelines as stepwise therapeutic approaches to treat itch in cholestasis. Rifampicin, the most effective antipruritic agent in cholestatic itch, has been shown to reduce autotaxin transcription in vitro. Experimental approaches include UVB phototherapy, extracorporeal albumin dialysis, nasobiliary drainage and in desperate cases even liver transplantation. Relevant clinical observations along with the different metabolic, neurologic and endocrine targets of available therapies in cholestatic pruritus are reviewed here.

The anion exchanger Ae2 is required for enamel maturation in mouse teeth.

One of the mechanisms by which epithelial cells regulate intracellular pH is exchanging bicarbonate for Cl(-). We tested the hypothesis that in ameloblasts the anion exchanger-2 (Ae2) is involved in pH regulation during maturation stage amelogenesis. Quantitative X-ray microprobe mineral content analysis, scanning electron microscopy, histology, micro-computed tomography and Ae2 immuno-localisation analyses were applied to Ae2-deficient and wild-type mouse mandibles. Immuno-localisation of Ae2 in wild-type mouse incisors showed a very strong expression of Ae2 in the basolateral membranes of the maturation stage ameloblasts. Strikingly, zones of contiguous ameloblasts were found within the maturation stage in which Ae2 expression was extremely low as opposed to neighbouring cells. Maturation stage ameloblasts of the Ae2(a,b)(-/-) mice failed to stain for Ae2 and showed progressive disorganisation as enamel development advanced. Maturation stage enamel of the Ae2(a,b)(-/-) mice contained substantially less mineral and more protein than wild-type enamel as determined by quantitative X-ray microanalysis. Incisor enamel was more severely affected than molar enamel. Scanning electron microscopy revealed that the rod-inter-rod structures of the Ae2(a,b)(-/-) mice incisor enamel were absent. Mineral content of dentine and bone of Ae2(a,b)(-/-) mice was not significantly different from wild-type mice. The enamel from knockout mouse teeth wore down much faster than that from wild-type litter mates. Basolateral bicarbonate secretion via the anionic exchanger Ae2 is essential for mineral growth in the maturation stage enamel. The observed zonal expression of Ae2 in the maturation stage ameloblasts is in line with a model for cyclic proton secretion during maturation stage amelogenesis.

Transporters in the intestine limiting drug and toxin absorption.

The pharmacokinetic behaviour of drugs strongly depends on transporters in intestine and liver. The extent of absorption in the intestine depends on diffusion across the mucosa as well as transporter-mediated uptake across the apical membrane of enterocytes. Efflux pumps in this membrane may strongly reduce the extent of net uptake. These efflux pumps are ATP-binding cassette (ABC) transporters which are also expressed in the apical membrane of the hepatocyte were they mediate excretion into bile. This combined activity strongly determines whether drugs have access to the systemic circulation.

The type 4 subfamily of P-type ATPases, putative aminophospholipid translocases with a role in human disease.

The maintenance of phospholipid asymmetry in membrane bilayers is a paradigm in cell biology. However, the mechanisms and proteins involved in phospholipid translocation are still poorly understood. Members of the type 4 subfamily of P-type ATPases have been implicated in the translocation of phospholipids from the outer to the inner leaflet of membrane bilayers. In humans, several inherited disorders have been identified which are associated with loci harboring type 4 P-type ATPase genes. Up to now, one inherited disorder, Byler disease or progressive familial intrahepatic cholestasis type 1 (PFIC1), has been directly linked to mutations in a type 4 P-type ATPase gene. How the absence of an aminophospholipid translocase activity relates to this severe disease is, however, still unclear. Studies in the yeast Saccharomyces cerevisiae have recently identified important roles for type 4 P-type ATPases in intracellular membrane- and protein-trafficking events. These processes require an (amino)phospholipid translocase activity to initiate budding or fusion of membrane vesicles from or with other membranes. The studies in yeast have greatly contributed to our cell biological insight in membrane dynamics and intracellular-trafficking events; if this knowledge can be translated to mammalian cells and organs, it will help to elucidate the molecular mechanisms which underlie severe inherited human diseases such as Byler disease.

ABC of oral bioavailability: transporters as gatekeepers in the gut.

MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are members of the family of ATP binding cassette (ABC) transporters. These are plasma membrane transporters that are expressed in various organs. The role of MDR1 and MRP2 in the hepatobiliary system is well defined; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane. As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds. The role of ABCG2, which is also expressed in the canalicular membrane of hepatocytes, has not yet been fully characterised. All three proteins are also expressed in the apical membrane of enterocytes where they probably control oral availability of many substances. This important "gatekeeper" function of ABC transporters has been recognised recently and is currently under further investigation. Expression and activity of these transporters in the gut may differ between individuals, due to genetic polymorphisms or pathological conditions. This will lead to individual differences in bioavailability of different drugs, toxins, and (food derived) carcinogens. Recent information on substrates, transport mechanisms, function, and regulation of expression of MDR1, MRP2, and BCRP in different species is summarised in this review.